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First-in-class ADC has benefit across mTNBC subgroups
But both an observer and the lead study author cautioned that the results were hypothesis generating.
Nonetheless, the data suggest the drug yields good survival outcomes in comparison with placebo in both BRCA1/2-positive and -negative patients and is effective even for those with low expression of the target protein, trophoblast cell surface antigen 2 (Trop-2).
The research was presented at the San Antonio Breast Cancer Symposium (SABCS) 2020.
Study presenter Sara Hurvitz, MD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, urged caution in interpreting the data, given the small sample sizes in the Trop-2–low subgroup and germline BRCA1/2-positive subgroup.
Jennifer K. Litton, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, who was not involved in the research, echoed those comments.
She told Medscape Medical News that the numbers, particularly for the BRCA1/2 analysis, were “very small.”
She added: “This was not a prespecified group, so it represents an interesting analysis to be hypothesis generating for future studies but not anything applicable to current clinical practice.”
Nevertheless, Litton said the data from the primary analysis of ASCENT remain “practice changing” for women with mTNBC who have received at least two previous lines of therapy.
As to whether SG will eventually move beyond this advanced setting, she emphasized that “more trials would need to be done and reported evaluating its role in other settings, and hopefully expanding its usefulness for patients.”
SG is a first-in-class drug comprising an antibody directed at Trop-2, which is highly expressed in breast cancer, and linked to SN-38, the active metabolite of irinotecan.
On the basis of positive phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with mTNBC who experience disease progression after at least two prior therapies.
As reported by Medscape Medical News, primary results from ASCENT that were presented at ESMO 2020 showed that SG improved progression-free survival (PFS) by nearly 4 months and overall survival by more than 5 months for women with pretreated mTNBC compared to chemotherapy.
Study details
At SABCS, Hurvitz presented an exploratory biomarker evaluation of data from the trial regarding the association between SG efficacy and Trop-2 expression, as well as germline BRCA1/2 mutation status.
She reminded the audience that, in ASCENT, 529 patients with mTNBC who had experienced disease progression after undergoing at least two chemotherapy regimens for advanced disease were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or physician’s choice of treatment.
Treatment was continued until disease progression or unacceptable toxicity occurred.
For the current analysis, which focused on patients who did not have brain metastases, the team studied primary or metastatic archival biopsy or surgical specimens collected at study entry.
These were analyzed using a validated immunohistochemistry assay. Tumors were categorized as Trop-2–low, –medium, or –-high expressers on the basis of H-score, which is a weighted summation of percent staining. In addition, germline BRCA1/2 mutation status was determined at baseline.
Mutation status was known for 149 SG patients and 143 control patients. Of those, the majority (57% and 54%, respectively) were BRCA1/2 negative.
Among 151 SG patients for whom Trop-2 expression status was available, 56% had tumors of high expression; 26%, medium expression; and 18%, low expression. In the control group, Trop-2 expression was known in 139 patients, of whom 52% had tumors of high expression; 25%, medium expression; and 23%, low expression.
Hurvitz reported that, although median PFS among patients given SG decreased with decreasing Trop-2 expression, it remained longer than that seen with control treatment. In patients with tumors of Trop-2–high status, median PFS was 6.9 months with SG, vs. 2.5 for patients who underwent control treatment. This fell to 5.6 months vs. 2.2 months in the Trop-2–medium group and 2.7 months vs 1.6 months in Trop-2–low group.
A similar pattern was seen for overall survival. In the Trop-2–high group, median overall survival was 14.2 months with SG, vs. 6.9 months with control therapy; 14.9 months vs. 6.9 months in the Trop-2–medium group; and 9.3 months vs. 7.6 months in the Trop-2–low group.
Again, the objective response rate fell from 44% to 38% and then to 22% with SG in the Trop-2–high, –medium, and –low groups, compared with 1%, 11%, and 6%, respectively, with control treatment.
There did not seem to be any interaction between Trop-2 expression and treatment-related adverse events of special interest. Rates of neutropenia, diarrhea, and anemia were consistently higher in SG-treated patients than in those given placebo.
Hurvitz said the objective response rate was markedly higher with SG vs. control treatment in both BRCA1/2-positive and -negative patients, at 19% vs. 6% in the positive group and 33% vs. 6% in the negative group.
This was reflected in improved median PFS with SG in both subgroups, at 4.6 months vs. 2.5 months with control therapy in BRCA1/2-positive patients and 4.9 months vs. 1.6 months in BRCA1/2-negative patients.
Overall survival was 15.6 months with SG, vs. 4.4 months with control treatment in BRCA1/2-positive patients. In BRCA1/2-negative patients, the respective figures were 10.9 months and 7.0 months.
The study was sponsored by Immunomedics. Hurvitz has financial ties to Immunomedics and multiple other pharmaceutical companies. Litton has financial ties to multiple companies, including Medscape and companies developing and marketing breast cancer therapies.
This article first appeared on Medscape.com.
But both an observer and the lead study author cautioned that the results were hypothesis generating.
Nonetheless, the data suggest the drug yields good survival outcomes in comparison with placebo in both BRCA1/2-positive and -negative patients and is effective even for those with low expression of the target protein, trophoblast cell surface antigen 2 (Trop-2).
The research was presented at the San Antonio Breast Cancer Symposium (SABCS) 2020.
Study presenter Sara Hurvitz, MD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, urged caution in interpreting the data, given the small sample sizes in the Trop-2–low subgroup and germline BRCA1/2-positive subgroup.
Jennifer K. Litton, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, who was not involved in the research, echoed those comments.
She told Medscape Medical News that the numbers, particularly for the BRCA1/2 analysis, were “very small.”
She added: “This was not a prespecified group, so it represents an interesting analysis to be hypothesis generating for future studies but not anything applicable to current clinical practice.”
Nevertheless, Litton said the data from the primary analysis of ASCENT remain “practice changing” for women with mTNBC who have received at least two previous lines of therapy.
As to whether SG will eventually move beyond this advanced setting, she emphasized that “more trials would need to be done and reported evaluating its role in other settings, and hopefully expanding its usefulness for patients.”
SG is a first-in-class drug comprising an antibody directed at Trop-2, which is highly expressed in breast cancer, and linked to SN-38, the active metabolite of irinotecan.
On the basis of positive phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with mTNBC who experience disease progression after at least two prior therapies.
As reported by Medscape Medical News, primary results from ASCENT that were presented at ESMO 2020 showed that SG improved progression-free survival (PFS) by nearly 4 months and overall survival by more than 5 months for women with pretreated mTNBC compared to chemotherapy.
Study details
At SABCS, Hurvitz presented an exploratory biomarker evaluation of data from the trial regarding the association between SG efficacy and Trop-2 expression, as well as germline BRCA1/2 mutation status.
She reminded the audience that, in ASCENT, 529 patients with mTNBC who had experienced disease progression after undergoing at least two chemotherapy regimens for advanced disease were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or physician’s choice of treatment.
Treatment was continued until disease progression or unacceptable toxicity occurred.
For the current analysis, which focused on patients who did not have brain metastases, the team studied primary or metastatic archival biopsy or surgical specimens collected at study entry.
These were analyzed using a validated immunohistochemistry assay. Tumors were categorized as Trop-2–low, –medium, or –-high expressers on the basis of H-score, which is a weighted summation of percent staining. In addition, germline BRCA1/2 mutation status was determined at baseline.
Mutation status was known for 149 SG patients and 143 control patients. Of those, the majority (57% and 54%, respectively) were BRCA1/2 negative.
Among 151 SG patients for whom Trop-2 expression status was available, 56% had tumors of high expression; 26%, medium expression; and 18%, low expression. In the control group, Trop-2 expression was known in 139 patients, of whom 52% had tumors of high expression; 25%, medium expression; and 23%, low expression.
Hurvitz reported that, although median PFS among patients given SG decreased with decreasing Trop-2 expression, it remained longer than that seen with control treatment. In patients with tumors of Trop-2–high status, median PFS was 6.9 months with SG, vs. 2.5 for patients who underwent control treatment. This fell to 5.6 months vs. 2.2 months in the Trop-2–medium group and 2.7 months vs 1.6 months in Trop-2–low group.
A similar pattern was seen for overall survival. In the Trop-2–high group, median overall survival was 14.2 months with SG, vs. 6.9 months with control therapy; 14.9 months vs. 6.9 months in the Trop-2–medium group; and 9.3 months vs. 7.6 months in the Trop-2–low group.
Again, the objective response rate fell from 44% to 38% and then to 22% with SG in the Trop-2–high, –medium, and –low groups, compared with 1%, 11%, and 6%, respectively, with control treatment.
There did not seem to be any interaction between Trop-2 expression and treatment-related adverse events of special interest. Rates of neutropenia, diarrhea, and anemia were consistently higher in SG-treated patients than in those given placebo.
Hurvitz said the objective response rate was markedly higher with SG vs. control treatment in both BRCA1/2-positive and -negative patients, at 19% vs. 6% in the positive group and 33% vs. 6% in the negative group.
This was reflected in improved median PFS with SG in both subgroups, at 4.6 months vs. 2.5 months with control therapy in BRCA1/2-positive patients and 4.9 months vs. 1.6 months in BRCA1/2-negative patients.
Overall survival was 15.6 months with SG, vs. 4.4 months with control treatment in BRCA1/2-positive patients. In BRCA1/2-negative patients, the respective figures were 10.9 months and 7.0 months.
The study was sponsored by Immunomedics. Hurvitz has financial ties to Immunomedics and multiple other pharmaceutical companies. Litton has financial ties to multiple companies, including Medscape and companies developing and marketing breast cancer therapies.
This article first appeared on Medscape.com.
But both an observer and the lead study author cautioned that the results were hypothesis generating.
Nonetheless, the data suggest the drug yields good survival outcomes in comparison with placebo in both BRCA1/2-positive and -negative patients and is effective even for those with low expression of the target protein, trophoblast cell surface antigen 2 (Trop-2).
The research was presented at the San Antonio Breast Cancer Symposium (SABCS) 2020.
Study presenter Sara Hurvitz, MD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, urged caution in interpreting the data, given the small sample sizes in the Trop-2–low subgroup and germline BRCA1/2-positive subgroup.
Jennifer K. Litton, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, who was not involved in the research, echoed those comments.
She told Medscape Medical News that the numbers, particularly for the BRCA1/2 analysis, were “very small.”
She added: “This was not a prespecified group, so it represents an interesting analysis to be hypothesis generating for future studies but not anything applicable to current clinical practice.”
Nevertheless, Litton said the data from the primary analysis of ASCENT remain “practice changing” for women with mTNBC who have received at least two previous lines of therapy.
As to whether SG will eventually move beyond this advanced setting, she emphasized that “more trials would need to be done and reported evaluating its role in other settings, and hopefully expanding its usefulness for patients.”
SG is a first-in-class drug comprising an antibody directed at Trop-2, which is highly expressed in breast cancer, and linked to SN-38, the active metabolite of irinotecan.
On the basis of positive phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with mTNBC who experience disease progression after at least two prior therapies.
As reported by Medscape Medical News, primary results from ASCENT that were presented at ESMO 2020 showed that SG improved progression-free survival (PFS) by nearly 4 months and overall survival by more than 5 months for women with pretreated mTNBC compared to chemotherapy.
Study details
At SABCS, Hurvitz presented an exploratory biomarker evaluation of data from the trial regarding the association between SG efficacy and Trop-2 expression, as well as germline BRCA1/2 mutation status.
She reminded the audience that, in ASCENT, 529 patients with mTNBC who had experienced disease progression after undergoing at least two chemotherapy regimens for advanced disease were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or physician’s choice of treatment.
Treatment was continued until disease progression or unacceptable toxicity occurred.
For the current analysis, which focused on patients who did not have brain metastases, the team studied primary or metastatic archival biopsy or surgical specimens collected at study entry.
These were analyzed using a validated immunohistochemistry assay. Tumors were categorized as Trop-2–low, –medium, or –-high expressers on the basis of H-score, which is a weighted summation of percent staining. In addition, germline BRCA1/2 mutation status was determined at baseline.
Mutation status was known for 149 SG patients and 143 control patients. Of those, the majority (57% and 54%, respectively) were BRCA1/2 negative.
Among 151 SG patients for whom Trop-2 expression status was available, 56% had tumors of high expression; 26%, medium expression; and 18%, low expression. In the control group, Trop-2 expression was known in 139 patients, of whom 52% had tumors of high expression; 25%, medium expression; and 23%, low expression.
Hurvitz reported that, although median PFS among patients given SG decreased with decreasing Trop-2 expression, it remained longer than that seen with control treatment. In patients with tumors of Trop-2–high status, median PFS was 6.9 months with SG, vs. 2.5 for patients who underwent control treatment. This fell to 5.6 months vs. 2.2 months in the Trop-2–medium group and 2.7 months vs 1.6 months in Trop-2–low group.
A similar pattern was seen for overall survival. In the Trop-2–high group, median overall survival was 14.2 months with SG, vs. 6.9 months with control therapy; 14.9 months vs. 6.9 months in the Trop-2–medium group; and 9.3 months vs. 7.6 months in the Trop-2–low group.
Again, the objective response rate fell from 44% to 38% and then to 22% with SG in the Trop-2–high, –medium, and –low groups, compared with 1%, 11%, and 6%, respectively, with control treatment.
There did not seem to be any interaction between Trop-2 expression and treatment-related adverse events of special interest. Rates of neutropenia, diarrhea, and anemia were consistently higher in SG-treated patients than in those given placebo.
Hurvitz said the objective response rate was markedly higher with SG vs. control treatment in both BRCA1/2-positive and -negative patients, at 19% vs. 6% in the positive group and 33% vs. 6% in the negative group.
This was reflected in improved median PFS with SG in both subgroups, at 4.6 months vs. 2.5 months with control therapy in BRCA1/2-positive patients and 4.9 months vs. 1.6 months in BRCA1/2-negative patients.
Overall survival was 15.6 months with SG, vs. 4.4 months with control treatment in BRCA1/2-positive patients. In BRCA1/2-negative patients, the respective figures were 10.9 months and 7.0 months.
The study was sponsored by Immunomedics. Hurvitz has financial ties to Immunomedics and multiple other pharmaceutical companies. Litton has financial ties to multiple companies, including Medscape and companies developing and marketing breast cancer therapies.
This article first appeared on Medscape.com.
FROM SABCS 2020
RxPONDER: Even more women may forgo chemo for breast cancer
More women with early-stage breast cancer may safely forgo chemotherapy, suggests an interim analysis of the large-scale phase 3 RxPONDER trial, presented at the San Antonio Breast Cancer Symposium 2020.
The investigators reported that adding chemotherapy to endocrine therapy did not improve outcomes for postmenopausal women with low-risk, node-positive, hormone receptor–positive (HR+), HER2-negative (HER2–) breast cancer in comparison with endocrine therapy alone.
These results are akin to those from the TAILORx trial. The results of that trial were first presented in 2018 and have changed practice for women with early-stage disease who have no lymph node involvement.
Clinicians celebrated the new results for women with lymph node–positive disease.
“RxPonder: practice changing!!!” tweeted meeting attendee Sarah Sammons, MD, Duke Cancer Center, Durham, N.C.
“Data from RxPonder are the most clinically important this year at @SABCSSanAntonio,” tweeted Hal Burstein, MD, Dana Farber Cancer Institute, Boston, who was not involved in the study.
“This will save tens of thousands of women the time, expense, and potentially harmful side effects that can be associated with chemotherapy infusions,” asserted study lead author Kevin Kalinsky, MD, Winship Cancer Institute of Emory University, Atlanta, during a meeting press conference.
But the trial, run by the SWOG Cancer Research Network, was not without controversy.
That’s because the trial also included premenopausal women whose disease characteristics were the same and who were found to have benefited from chemotherapy.
It was not clear whether the benefit was from chemotherapy’s cytotoxicity or its endocrine effects/ovarian suppression (which limits the production of estrogen, a breast cell stimulant) in these young women. But multiple experts asserted that the effect was very likely from ovarian suppression.
“There are less toxic ways than chemo to suppress ovarian function,” tweeted Tatiana Prowell, MD, Johns Hopkins University, Baltimore, who is not a study investigator.
Some experts strongly doubted the findings in premenopausal women.
“I hate to come away with the message that all [low-risk, node-positive] premenopausal patients should get chemotherapy,” summarized C. Kent Osborne, MD, Baylor College of Medicine, Houston, who is codirector of SABCS and was not involved in the study.
RxPONDER will follow patients for 15 years, so additional data and insights will follow, observed SWOG in a press statement.
Women had limited positive nodes
RxPONDER, or SWOG S1007, involved more than 5000 women who had HR+, HER2– breast cancer with involvement of one to three lymph nodes. The patients’ recurrence score was ≤25 on a 21-tumor gene expression assay (Oncotype Dx), which is characterized as low risk.
Approximately 20% of U.S. women with nonmetastatic HR+, HER2– breast cancer present with involvement of one to three lymph nodes, Dr. Kalinsky noted.
Study participants were randomly assigned to receive either standard chemotherapy plus endocrine therapy or endocrine therapy alone. Follow-up was for a median of 5 years before the current preplanned analysis.
Over a median follow-up of 5.1 years, there were 447 observed invasive disease-free survival (IDFS) events, the primary endpoint, which is 54% of the expected number at final analysis.
Across the whole cohort, adding chemotherapy to endocrine therapy was associated with a significant improvement in IDFS, with a 5-year rate of 92.4% vs 91.0% for endocrine therapy (P = .026).
Among the postmenopausal women, no such improvement was seen. The 5-year IDFS rate was 91.6% with chemotherapy plus endocrine therapy and 91.9% with endocrine therapy alone (P = .82).
Among premenopausal women, there was improvement in IDFS. The 5-year rate was 94.2% with chemotherapy plus endocrine therapy and 89.0% for endocrine therapy alone (P = .0004).
These differences were reflected in the results for overall survival. For postmenopausal women, there was a nonsignificant difference in 5-year overall survival rates (96.2% vs. 96.1%).
On the other hand, for premenopausal women, there was a significant difference in 5-year overall survival rates (98.6% vs. 97.3%; P = .032).
Stratifying patients by recurrence score, 0-13 versus 14-25, and by involvement of one versus two to three nodes did not have a major impact on the results, said Dr. Kalinsky, who also noted that future analyses will include quality of life and other outcomes.
More about endocrine therapy in RxPONDER
Dr. Osborne said that premenopausal women in RxPONDER were “nearly always” prescribed tamoxifen.
However, he observed that the current standard approach to treatment in this age group would be ovarian suppression plus either an aromatase inhibitor or tamoxifen, “both of which have been shown to be superior to tamoxifen alone in this subgroup.
“Since the adjuvant chemotherapy causes ovarian suppression in many premenopausal patients,” he said, “these patients then, in fact, received ovarian suppression plus tamoxifen,” rather than tamoxifen alone for the group that did not receive chemotherapy.
Dr. Osborne asked a question that came up again and again during the postpresentation discussion: “Is the difference in outcome in this subset due to the endocrine effects of chemotherapy? Unfortunately, we may never know the answer to this question,” he said.
Dr. Kalinsky replied that whether the difference in benefit of chemotherapy in premenopausal women “was a direct benefit, meaning that there’s something about the biology difference” between tumors in premenopausal versus postmenopausal women, “or whether this was an indirect effect, meaning impacting rates of amenorrhea... is not specifically how this study was designed.”
However, an exploratory landmark analysis at 6 months suggested that the use of ovarian suppression with endocrine therapy did not have an effect on outcomes.
Dr. Osborne said he is nevertheless “still skeptical that chemotherapy works differently in premenopausal women. Until we show that it’s not an endocrine effect ... I just can’t imagine why that group of patients, even the ones with very low Oncotype [score], would have a different response to chemotherapy.”
He added: “If I can think of a rationale ... I would believe it, but right now, I’m a little bit skeptical.”
Virginia Kaklamani, MD, of the University of Texas Health San Antonio Cancer Center, San Antonio, who is a meeting codirector, said she wanted to “second that.
“I honestly think that this is an OFS [ovarian function suppression effect] that we are seeing. We have several clinical trials that have been done looking at ovarian function suppression versus not ... showing that [it] can help as much as chemotherapy.”
Dr. Kaklamani continued: “Unfortunately, the arms to those trials were not perfect for now, and this is going to be an unanswered question until we have a large trial comparing OFS to chemotherapy.”
The study was sponsored by the National Cancer Institute, the Susan G. Komen for the Cure Research Program, the Hope Foundation for Cancer Research, the Breast Cancer Research Foundation, and Exact Sciences. Dr. Kalinsky, Dr. Osborne, and Dr. Kaklamani report financial ties to multiple pharmaceutical companies.
This article first appeared on Medscape.com.
More women with early-stage breast cancer may safely forgo chemotherapy, suggests an interim analysis of the large-scale phase 3 RxPONDER trial, presented at the San Antonio Breast Cancer Symposium 2020.
The investigators reported that adding chemotherapy to endocrine therapy did not improve outcomes for postmenopausal women with low-risk, node-positive, hormone receptor–positive (HR+), HER2-negative (HER2–) breast cancer in comparison with endocrine therapy alone.
These results are akin to those from the TAILORx trial. The results of that trial were first presented in 2018 and have changed practice for women with early-stage disease who have no lymph node involvement.
Clinicians celebrated the new results for women with lymph node–positive disease.
“RxPonder: practice changing!!!” tweeted meeting attendee Sarah Sammons, MD, Duke Cancer Center, Durham, N.C.
“Data from RxPonder are the most clinically important this year at @SABCSSanAntonio,” tweeted Hal Burstein, MD, Dana Farber Cancer Institute, Boston, who was not involved in the study.
“This will save tens of thousands of women the time, expense, and potentially harmful side effects that can be associated with chemotherapy infusions,” asserted study lead author Kevin Kalinsky, MD, Winship Cancer Institute of Emory University, Atlanta, during a meeting press conference.
But the trial, run by the SWOG Cancer Research Network, was not without controversy.
That’s because the trial also included premenopausal women whose disease characteristics were the same and who were found to have benefited from chemotherapy.
It was not clear whether the benefit was from chemotherapy’s cytotoxicity or its endocrine effects/ovarian suppression (which limits the production of estrogen, a breast cell stimulant) in these young women. But multiple experts asserted that the effect was very likely from ovarian suppression.
“There are less toxic ways than chemo to suppress ovarian function,” tweeted Tatiana Prowell, MD, Johns Hopkins University, Baltimore, who is not a study investigator.
Some experts strongly doubted the findings in premenopausal women.
“I hate to come away with the message that all [low-risk, node-positive] premenopausal patients should get chemotherapy,” summarized C. Kent Osborne, MD, Baylor College of Medicine, Houston, who is codirector of SABCS and was not involved in the study.
RxPONDER will follow patients for 15 years, so additional data and insights will follow, observed SWOG in a press statement.
Women had limited positive nodes
RxPONDER, or SWOG S1007, involved more than 5000 women who had HR+, HER2– breast cancer with involvement of one to three lymph nodes. The patients’ recurrence score was ≤25 on a 21-tumor gene expression assay (Oncotype Dx), which is characterized as low risk.
Approximately 20% of U.S. women with nonmetastatic HR+, HER2– breast cancer present with involvement of one to three lymph nodes, Dr. Kalinsky noted.
Study participants were randomly assigned to receive either standard chemotherapy plus endocrine therapy or endocrine therapy alone. Follow-up was for a median of 5 years before the current preplanned analysis.
Over a median follow-up of 5.1 years, there were 447 observed invasive disease-free survival (IDFS) events, the primary endpoint, which is 54% of the expected number at final analysis.
Across the whole cohort, adding chemotherapy to endocrine therapy was associated with a significant improvement in IDFS, with a 5-year rate of 92.4% vs 91.0% for endocrine therapy (P = .026).
Among the postmenopausal women, no such improvement was seen. The 5-year IDFS rate was 91.6% with chemotherapy plus endocrine therapy and 91.9% with endocrine therapy alone (P = .82).
Among premenopausal women, there was improvement in IDFS. The 5-year rate was 94.2% with chemotherapy plus endocrine therapy and 89.0% for endocrine therapy alone (P = .0004).
These differences were reflected in the results for overall survival. For postmenopausal women, there was a nonsignificant difference in 5-year overall survival rates (96.2% vs. 96.1%).
On the other hand, for premenopausal women, there was a significant difference in 5-year overall survival rates (98.6% vs. 97.3%; P = .032).
Stratifying patients by recurrence score, 0-13 versus 14-25, and by involvement of one versus two to three nodes did not have a major impact on the results, said Dr. Kalinsky, who also noted that future analyses will include quality of life and other outcomes.
More about endocrine therapy in RxPONDER
Dr. Osborne said that premenopausal women in RxPONDER were “nearly always” prescribed tamoxifen.
However, he observed that the current standard approach to treatment in this age group would be ovarian suppression plus either an aromatase inhibitor or tamoxifen, “both of which have been shown to be superior to tamoxifen alone in this subgroup.
“Since the adjuvant chemotherapy causes ovarian suppression in many premenopausal patients,” he said, “these patients then, in fact, received ovarian suppression plus tamoxifen,” rather than tamoxifen alone for the group that did not receive chemotherapy.
Dr. Osborne asked a question that came up again and again during the postpresentation discussion: “Is the difference in outcome in this subset due to the endocrine effects of chemotherapy? Unfortunately, we may never know the answer to this question,” he said.
Dr. Kalinsky replied that whether the difference in benefit of chemotherapy in premenopausal women “was a direct benefit, meaning that there’s something about the biology difference” between tumors in premenopausal versus postmenopausal women, “or whether this was an indirect effect, meaning impacting rates of amenorrhea... is not specifically how this study was designed.”
However, an exploratory landmark analysis at 6 months suggested that the use of ovarian suppression with endocrine therapy did not have an effect on outcomes.
Dr. Osborne said he is nevertheless “still skeptical that chemotherapy works differently in premenopausal women. Until we show that it’s not an endocrine effect ... I just can’t imagine why that group of patients, even the ones with very low Oncotype [score], would have a different response to chemotherapy.”
He added: “If I can think of a rationale ... I would believe it, but right now, I’m a little bit skeptical.”
Virginia Kaklamani, MD, of the University of Texas Health San Antonio Cancer Center, San Antonio, who is a meeting codirector, said she wanted to “second that.
“I honestly think that this is an OFS [ovarian function suppression effect] that we are seeing. We have several clinical trials that have been done looking at ovarian function suppression versus not ... showing that [it] can help as much as chemotherapy.”
Dr. Kaklamani continued: “Unfortunately, the arms to those trials were not perfect for now, and this is going to be an unanswered question until we have a large trial comparing OFS to chemotherapy.”
The study was sponsored by the National Cancer Institute, the Susan G. Komen for the Cure Research Program, the Hope Foundation for Cancer Research, the Breast Cancer Research Foundation, and Exact Sciences. Dr. Kalinsky, Dr. Osborne, and Dr. Kaklamani report financial ties to multiple pharmaceutical companies.
This article first appeared on Medscape.com.
More women with early-stage breast cancer may safely forgo chemotherapy, suggests an interim analysis of the large-scale phase 3 RxPONDER trial, presented at the San Antonio Breast Cancer Symposium 2020.
The investigators reported that adding chemotherapy to endocrine therapy did not improve outcomes for postmenopausal women with low-risk, node-positive, hormone receptor–positive (HR+), HER2-negative (HER2–) breast cancer in comparison with endocrine therapy alone.
These results are akin to those from the TAILORx trial. The results of that trial were first presented in 2018 and have changed practice for women with early-stage disease who have no lymph node involvement.
Clinicians celebrated the new results for women with lymph node–positive disease.
“RxPonder: practice changing!!!” tweeted meeting attendee Sarah Sammons, MD, Duke Cancer Center, Durham, N.C.
“Data from RxPonder are the most clinically important this year at @SABCSSanAntonio,” tweeted Hal Burstein, MD, Dana Farber Cancer Institute, Boston, who was not involved in the study.
“This will save tens of thousands of women the time, expense, and potentially harmful side effects that can be associated with chemotherapy infusions,” asserted study lead author Kevin Kalinsky, MD, Winship Cancer Institute of Emory University, Atlanta, during a meeting press conference.
But the trial, run by the SWOG Cancer Research Network, was not without controversy.
That’s because the trial also included premenopausal women whose disease characteristics were the same and who were found to have benefited from chemotherapy.
It was not clear whether the benefit was from chemotherapy’s cytotoxicity or its endocrine effects/ovarian suppression (which limits the production of estrogen, a breast cell stimulant) in these young women. But multiple experts asserted that the effect was very likely from ovarian suppression.
“There are less toxic ways than chemo to suppress ovarian function,” tweeted Tatiana Prowell, MD, Johns Hopkins University, Baltimore, who is not a study investigator.
Some experts strongly doubted the findings in premenopausal women.
“I hate to come away with the message that all [low-risk, node-positive] premenopausal patients should get chemotherapy,” summarized C. Kent Osborne, MD, Baylor College of Medicine, Houston, who is codirector of SABCS and was not involved in the study.
RxPONDER will follow patients for 15 years, so additional data and insights will follow, observed SWOG in a press statement.
Women had limited positive nodes
RxPONDER, or SWOG S1007, involved more than 5000 women who had HR+, HER2– breast cancer with involvement of one to three lymph nodes. The patients’ recurrence score was ≤25 on a 21-tumor gene expression assay (Oncotype Dx), which is characterized as low risk.
Approximately 20% of U.S. women with nonmetastatic HR+, HER2– breast cancer present with involvement of one to three lymph nodes, Dr. Kalinsky noted.
Study participants were randomly assigned to receive either standard chemotherapy plus endocrine therapy or endocrine therapy alone. Follow-up was for a median of 5 years before the current preplanned analysis.
Over a median follow-up of 5.1 years, there were 447 observed invasive disease-free survival (IDFS) events, the primary endpoint, which is 54% of the expected number at final analysis.
Across the whole cohort, adding chemotherapy to endocrine therapy was associated with a significant improvement in IDFS, with a 5-year rate of 92.4% vs 91.0% for endocrine therapy (P = .026).
Among the postmenopausal women, no such improvement was seen. The 5-year IDFS rate was 91.6% with chemotherapy plus endocrine therapy and 91.9% with endocrine therapy alone (P = .82).
Among premenopausal women, there was improvement in IDFS. The 5-year rate was 94.2% with chemotherapy plus endocrine therapy and 89.0% for endocrine therapy alone (P = .0004).
These differences were reflected in the results for overall survival. For postmenopausal women, there was a nonsignificant difference in 5-year overall survival rates (96.2% vs. 96.1%).
On the other hand, for premenopausal women, there was a significant difference in 5-year overall survival rates (98.6% vs. 97.3%; P = .032).
Stratifying patients by recurrence score, 0-13 versus 14-25, and by involvement of one versus two to three nodes did not have a major impact on the results, said Dr. Kalinsky, who also noted that future analyses will include quality of life and other outcomes.
More about endocrine therapy in RxPONDER
Dr. Osborne said that premenopausal women in RxPONDER were “nearly always” prescribed tamoxifen.
However, he observed that the current standard approach to treatment in this age group would be ovarian suppression plus either an aromatase inhibitor or tamoxifen, “both of which have been shown to be superior to tamoxifen alone in this subgroup.
“Since the adjuvant chemotherapy causes ovarian suppression in many premenopausal patients,” he said, “these patients then, in fact, received ovarian suppression plus tamoxifen,” rather than tamoxifen alone for the group that did not receive chemotherapy.
Dr. Osborne asked a question that came up again and again during the postpresentation discussion: “Is the difference in outcome in this subset due to the endocrine effects of chemotherapy? Unfortunately, we may never know the answer to this question,” he said.
Dr. Kalinsky replied that whether the difference in benefit of chemotherapy in premenopausal women “was a direct benefit, meaning that there’s something about the biology difference” between tumors in premenopausal versus postmenopausal women, “or whether this was an indirect effect, meaning impacting rates of amenorrhea... is not specifically how this study was designed.”
However, an exploratory landmark analysis at 6 months suggested that the use of ovarian suppression with endocrine therapy did not have an effect on outcomes.
Dr. Osborne said he is nevertheless “still skeptical that chemotherapy works differently in premenopausal women. Until we show that it’s not an endocrine effect ... I just can’t imagine why that group of patients, even the ones with very low Oncotype [score], would have a different response to chemotherapy.”
He added: “If I can think of a rationale ... I would believe it, but right now, I’m a little bit skeptical.”
Virginia Kaklamani, MD, of the University of Texas Health San Antonio Cancer Center, San Antonio, who is a meeting codirector, said she wanted to “second that.
“I honestly think that this is an OFS [ovarian function suppression effect] that we are seeing. We have several clinical trials that have been done looking at ovarian function suppression versus not ... showing that [it] can help as much as chemotherapy.”
Dr. Kaklamani continued: “Unfortunately, the arms to those trials were not perfect for now, and this is going to be an unanswered question until we have a large trial comparing OFS to chemotherapy.”
The study was sponsored by the National Cancer Institute, the Susan G. Komen for the Cure Research Program, the Hope Foundation for Cancer Research, the Breast Cancer Research Foundation, and Exact Sciences. Dr. Kalinsky, Dr. Osborne, and Dr. Kaklamani report financial ties to multiple pharmaceutical companies.
This article first appeared on Medscape.com.
FROM SABCS 2020
monarchE: Abemaciclib reigns on in high-risk breast cancer
The addition of the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy continues to offer improved event-free survival in women with high-risk hormone receptor-positive (HR+), HER2-negative breast cancer, indicate updated results, which now extend to about a year and a half, from the landmark monarchE trial.
However, experts warned that longer follow-up – at least to 5 years – will be required to understand the impact of the combination treatment on survival, particularly as HR+ breast cancer is associated with a high rate of late recurrences.
The research was presented Dec. 9 at the 2020 San Antonio Breast Cancer Symposium, being held online this year because of the pandemic.
An earlier preplanned interim analysis the phase 3 trial of over 5600 patients was presented at the ESMO Virtual Congress 2020, and simultaneously published in the Journal of Clinical Oncology.
As previously reported by Medscape Medical News, this showed that, after a median follow-up of 15.5 months, abemaciclib plus endocrine therapy was associated with a 25% relative risk reduction in the primary endpoint of invasive disease-free survival (IDFS) vs endocrine therapy alone.
At the time, the findings were hailed as practice changing and, once approved for high-risk HR+ HER2-negative early breast cancer, as the “new standard of care” by one expert.
Now, with median follow-up extended to 19.1 months, Priya Rastogi, MD, associate professor at the University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania, presented new study data, including additional results on patients with a Ki-67 index ≥20%, which is indicative of fast tumor growth.
Abemaciclib plus endocrine therapy was associated with a significant 28.7% reduction in the relative risk of developing an IDFS event vs endocrine therapy alone across the whole patient population, and with a 30.9% risk reduction in those with a Ki-67 index ≥20%.
Moreover, patients taking the drug combination had a significant 31.3% reduction in the relative risk of a distant relapse-free survival (DRFS) event.
Crucially, these improvements, which were deemed clinically meaningful, were not gained at the expense of additional safety concerns, although high rates of any grade diarrhea, fatigue, and neutropenia were noted.
Rastogi said the findings underline that abemaciclib combined with standard endocrine therapy “is the first CDK4/6 inhibitor to demonstrate efficacy and tolerability for patients with HR+ HER2-negative, node-positive, high-risk early breast cancer.”
Longer follow-up is ‘reassuring’ but still ‘quite short’
George W. Sledge Jr, MD, professor of medicine at Stanford University Medical Center, Palo Alto, California, was the study discussant for the earlier interim analysis presented at ESMO 2020.
At the time, he said that the study had “very, very short follow-up,” and it was consequently unclear whether the improvements will “lead to what we really care about: improved overall survival.”
Approached to comment on the current analysis, Sledge told Medscape Medical News the data “appear quite consistent” with those presented earlier this year, “which is certainly reassuring.”
Referring to the analysis in patients with a Ki-67 index ≥20%, he added the results “show a higher absolute benefit in patients with more rapidly proliferating tumors, as might be expected for a drug affecting cell-cycle division.”
However, Sledge underlined that the median follow-up time “is still quite short for a study of ER-positive adjuvant therapy, where the majority of recurrences and deaths occur after 5 years in many studies”.
Consequently, “we still have a long way to go to understand the ultimate effects of CDK4/6 inhibition on early-stage, ER-positive breast cancer, particularly on late recurrences.”
Agreed, said C. Kent Osborne, MD, codirector of SABCS and founding director of the Duncan Cancer Center at Baylor College of Medicine, Houston, Texas.
Commenting in a press conference, he said the results are “very encouraging, especially in the subgroup of tumors with high proliferation.”
However, Osborne also urged “caution” in the interpretation of the results “given the still rather short follow-up [and] given that ER+ disease is known for its persistent recurrence rate, even past 10 years.”
He also noted “this class of inhibitors is likely cytostatic, rather than cytocidal, meaning that it blocks cell proliferation rather than killing the cells.” Questions therefore remain over whether the survival curves for combination therapy will come together with those for endocrine therapy alone once the drug is stopped.
Osborne nevertheless said that, “with these caveats in mind, this is still an extremely important trial that could be practice changing in this very high-risk patient population…if the results continue to be positive and show improved overall survival with longer follow-up.”
During the press conference, Rastogi confirmed that the study will indeed to continue out to 10 years until the final assessment of overall survival.
More study details
The 5637 women who were enrolled in monarchE were divided into two cohorts:
Cohort 1, which included patients with four or more positive nodes, or those with up to three positive nodes and a tumor size ≥5 cm or grade 3 disease
Cohort 2, which included women with up to three positive nodes and a Ki-67 index ≥20% based on a standard assay
“Cohort 2 opened one year after Cohort 1 and enrolled 517 patients,” Rastogi said.
Regardless of cohort, the patients were randomly assigned in a 1:1 fashion to abemaciclib for 2 years plus endocrine therapy for 5 to 10 years, as clinically indicated, or endocrine therapy alone.
At the primary efficacy outcome analysis, 395 IDFS events had occurred in the intention-to-treat analysis. The median follow-up was 19.1 months, and 25.5% of patients had completed the 2-year treatment period. A further 58.2% were still on treatment.
The results showed 163 IDFS events had occurred with abemaciclib plus endocrine therapy vs 232 with endocrine therapy alone, to give a 2-year IDFS rate of 92.3% vs 89.3%, at a hazard ratio of 0.713 (P = .0009).
Moving on to the subgroup analysis, Rastogi added that there were “no statistically significant interactions observed, indicating a consistent treatment benefit across all groups.”
The researchers also looked at IDFS rates in patients from both cohorts with Ki-67 index ≥20%, again finding that abemaciclib plus endocrine therapy was associated with significantly fewer events than endocrine therapy alone.
There were 82 events with the combination treatment vs 115 with endocrine therapy, at a 2-year IDFS rate of 91.6% vs 87.1% and a hazard ratio of 0.691 (P = .0111).
DRFS also significantly improved with abemaciclib plus endocrine therapy vs endocrine therapy alone, at a 2-year DRFS rate of 93.8% vs 90% or a hazard ratio of 0.687 (P = .0009).
“Safety remained consistent with the known profile of abemaciclib,” Rastogi said, “and what was observed at the second interim analysis, [with] minimal increases in any grade and grade ≥3 treatment-related adverse events.”
The most common adverse events were diarrhea, fatigue, and neutropenia, which were largely grades 1 and 2.
Notably, 2.4% of combination therapy patients experienced a venous thromboembolic event of any grade vs 0.6% of endocrine therapy patients, while 2.9% and 1.2%, respectively, had any grade interstitial lung disease.
At least one dose hold because of an adverse event was reported by 59.5% of patients on abemaciclib plus endocrine therapy, while 42.5% had at least one dose reduction because of an adverse event. In both cases, the primary reason was diarrhea.
Finally, Rastogi said that “over half of the discontinuations of abemaciclib due to adverse events occurred during the first 5 months of treatment, with the highest number…in the first month.”
Ki-67 issues
During the press conference, Virginia Kaklamani, MD, codirector of SABCS and leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center, Texas, asked about the practicalities of the Ki-67 index.
She said that testing is “great when it’s centrally done, but what do we expect physicians to do when some institutions do it, some don’t, and obviously it’s not really validated in most institutions around the world?”
Rastogi replied that is a “great question,” adding “this is something that is going to have to be sorted as we continue to have discussions and get more granularity of what to do when abemaciclib is administered in that patient population.”
Carlos L. Arteaga, MD, codirector of SABCS and director of the Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, Dallas, Texas, added that “most of us think of 10% as a cutoff between high and low” for the Ki-67 index, rather than ≥20%.
He said that he knows it is “arbitrary” but he thinks of 20% as “extremely high” and asked whether the researchers would be able to conduct a retrospective analysis to look at Ki-67 as a gradient to determine “at what point it stops predicting.”
Rastogi replied that, at the time monarchE was developed, some of the international guidelines used a Ki-67 index ≥20% as the cutoff.
She also noted that, although Ki-67 index ≥20% was an entry criterion for cohort 2, cohort 1 patients also provided tissue after randomization, “and so we’ll be able to look at these types of questions with our translational research committee.”
This study was sponsored by Eli Lilly. Rastogi has financial ties to AstraZeneca, Genentech/Roche, and the study sponsor, Eli Lilly. Regan has ties to Lilly and multiple other pharmaceutical companies. Sledge has ties to Lilly and other companies. Osborne has ties to Lilly and other companies.
This article first appeared on Medscape.com.
The addition of the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy continues to offer improved event-free survival in women with high-risk hormone receptor-positive (HR+), HER2-negative breast cancer, indicate updated results, which now extend to about a year and a half, from the landmark monarchE trial.
However, experts warned that longer follow-up – at least to 5 years – will be required to understand the impact of the combination treatment on survival, particularly as HR+ breast cancer is associated with a high rate of late recurrences.
The research was presented Dec. 9 at the 2020 San Antonio Breast Cancer Symposium, being held online this year because of the pandemic.
An earlier preplanned interim analysis the phase 3 trial of over 5600 patients was presented at the ESMO Virtual Congress 2020, and simultaneously published in the Journal of Clinical Oncology.
As previously reported by Medscape Medical News, this showed that, after a median follow-up of 15.5 months, abemaciclib plus endocrine therapy was associated with a 25% relative risk reduction in the primary endpoint of invasive disease-free survival (IDFS) vs endocrine therapy alone.
At the time, the findings were hailed as practice changing and, once approved for high-risk HR+ HER2-negative early breast cancer, as the “new standard of care” by one expert.
Now, with median follow-up extended to 19.1 months, Priya Rastogi, MD, associate professor at the University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania, presented new study data, including additional results on patients with a Ki-67 index ≥20%, which is indicative of fast tumor growth.
Abemaciclib plus endocrine therapy was associated with a significant 28.7% reduction in the relative risk of developing an IDFS event vs endocrine therapy alone across the whole patient population, and with a 30.9% risk reduction in those with a Ki-67 index ≥20%.
Moreover, patients taking the drug combination had a significant 31.3% reduction in the relative risk of a distant relapse-free survival (DRFS) event.
Crucially, these improvements, which were deemed clinically meaningful, were not gained at the expense of additional safety concerns, although high rates of any grade diarrhea, fatigue, and neutropenia were noted.
Rastogi said the findings underline that abemaciclib combined with standard endocrine therapy “is the first CDK4/6 inhibitor to demonstrate efficacy and tolerability for patients with HR+ HER2-negative, node-positive, high-risk early breast cancer.”
Longer follow-up is ‘reassuring’ but still ‘quite short’
George W. Sledge Jr, MD, professor of medicine at Stanford University Medical Center, Palo Alto, California, was the study discussant for the earlier interim analysis presented at ESMO 2020.
At the time, he said that the study had “very, very short follow-up,” and it was consequently unclear whether the improvements will “lead to what we really care about: improved overall survival.”
Approached to comment on the current analysis, Sledge told Medscape Medical News the data “appear quite consistent” with those presented earlier this year, “which is certainly reassuring.”
Referring to the analysis in patients with a Ki-67 index ≥20%, he added the results “show a higher absolute benefit in patients with more rapidly proliferating tumors, as might be expected for a drug affecting cell-cycle division.”
However, Sledge underlined that the median follow-up time “is still quite short for a study of ER-positive adjuvant therapy, where the majority of recurrences and deaths occur after 5 years in many studies”.
Consequently, “we still have a long way to go to understand the ultimate effects of CDK4/6 inhibition on early-stage, ER-positive breast cancer, particularly on late recurrences.”
Agreed, said C. Kent Osborne, MD, codirector of SABCS and founding director of the Duncan Cancer Center at Baylor College of Medicine, Houston, Texas.
Commenting in a press conference, he said the results are “very encouraging, especially in the subgroup of tumors with high proliferation.”
However, Osborne also urged “caution” in the interpretation of the results “given the still rather short follow-up [and] given that ER+ disease is known for its persistent recurrence rate, even past 10 years.”
He also noted “this class of inhibitors is likely cytostatic, rather than cytocidal, meaning that it blocks cell proliferation rather than killing the cells.” Questions therefore remain over whether the survival curves for combination therapy will come together with those for endocrine therapy alone once the drug is stopped.
Osborne nevertheless said that, “with these caveats in mind, this is still an extremely important trial that could be practice changing in this very high-risk patient population…if the results continue to be positive and show improved overall survival with longer follow-up.”
During the press conference, Rastogi confirmed that the study will indeed to continue out to 10 years until the final assessment of overall survival.
More study details
The 5637 women who were enrolled in monarchE were divided into two cohorts:
Cohort 1, which included patients with four or more positive nodes, or those with up to three positive nodes and a tumor size ≥5 cm or grade 3 disease
Cohort 2, which included women with up to three positive nodes and a Ki-67 index ≥20% based on a standard assay
“Cohort 2 opened one year after Cohort 1 and enrolled 517 patients,” Rastogi said.
Regardless of cohort, the patients were randomly assigned in a 1:1 fashion to abemaciclib for 2 years plus endocrine therapy for 5 to 10 years, as clinically indicated, or endocrine therapy alone.
At the primary efficacy outcome analysis, 395 IDFS events had occurred in the intention-to-treat analysis. The median follow-up was 19.1 months, and 25.5% of patients had completed the 2-year treatment period. A further 58.2% were still on treatment.
The results showed 163 IDFS events had occurred with abemaciclib plus endocrine therapy vs 232 with endocrine therapy alone, to give a 2-year IDFS rate of 92.3% vs 89.3%, at a hazard ratio of 0.713 (P = .0009).
Moving on to the subgroup analysis, Rastogi added that there were “no statistically significant interactions observed, indicating a consistent treatment benefit across all groups.”
The researchers also looked at IDFS rates in patients from both cohorts with Ki-67 index ≥20%, again finding that abemaciclib plus endocrine therapy was associated with significantly fewer events than endocrine therapy alone.
There were 82 events with the combination treatment vs 115 with endocrine therapy, at a 2-year IDFS rate of 91.6% vs 87.1% and a hazard ratio of 0.691 (P = .0111).
DRFS also significantly improved with abemaciclib plus endocrine therapy vs endocrine therapy alone, at a 2-year DRFS rate of 93.8% vs 90% or a hazard ratio of 0.687 (P = .0009).
“Safety remained consistent with the known profile of abemaciclib,” Rastogi said, “and what was observed at the second interim analysis, [with] minimal increases in any grade and grade ≥3 treatment-related adverse events.”
The most common adverse events were diarrhea, fatigue, and neutropenia, which were largely grades 1 and 2.
Notably, 2.4% of combination therapy patients experienced a venous thromboembolic event of any grade vs 0.6% of endocrine therapy patients, while 2.9% and 1.2%, respectively, had any grade interstitial lung disease.
At least one dose hold because of an adverse event was reported by 59.5% of patients on abemaciclib plus endocrine therapy, while 42.5% had at least one dose reduction because of an adverse event. In both cases, the primary reason was diarrhea.
Finally, Rastogi said that “over half of the discontinuations of abemaciclib due to adverse events occurred during the first 5 months of treatment, with the highest number…in the first month.”
Ki-67 issues
During the press conference, Virginia Kaklamani, MD, codirector of SABCS and leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center, Texas, asked about the practicalities of the Ki-67 index.
She said that testing is “great when it’s centrally done, but what do we expect physicians to do when some institutions do it, some don’t, and obviously it’s not really validated in most institutions around the world?”
Rastogi replied that is a “great question,” adding “this is something that is going to have to be sorted as we continue to have discussions and get more granularity of what to do when abemaciclib is administered in that patient population.”
Carlos L. Arteaga, MD, codirector of SABCS and director of the Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, Dallas, Texas, added that “most of us think of 10% as a cutoff between high and low” for the Ki-67 index, rather than ≥20%.
He said that he knows it is “arbitrary” but he thinks of 20% as “extremely high” and asked whether the researchers would be able to conduct a retrospective analysis to look at Ki-67 as a gradient to determine “at what point it stops predicting.”
Rastogi replied that, at the time monarchE was developed, some of the international guidelines used a Ki-67 index ≥20% as the cutoff.
She also noted that, although Ki-67 index ≥20% was an entry criterion for cohort 2, cohort 1 patients also provided tissue after randomization, “and so we’ll be able to look at these types of questions with our translational research committee.”
This study was sponsored by Eli Lilly. Rastogi has financial ties to AstraZeneca, Genentech/Roche, and the study sponsor, Eli Lilly. Regan has ties to Lilly and multiple other pharmaceutical companies. Sledge has ties to Lilly and other companies. Osborne has ties to Lilly and other companies.
This article first appeared on Medscape.com.
The addition of the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy continues to offer improved event-free survival in women with high-risk hormone receptor-positive (HR+), HER2-negative breast cancer, indicate updated results, which now extend to about a year and a half, from the landmark monarchE trial.
However, experts warned that longer follow-up – at least to 5 years – will be required to understand the impact of the combination treatment on survival, particularly as HR+ breast cancer is associated with a high rate of late recurrences.
The research was presented Dec. 9 at the 2020 San Antonio Breast Cancer Symposium, being held online this year because of the pandemic.
An earlier preplanned interim analysis the phase 3 trial of over 5600 patients was presented at the ESMO Virtual Congress 2020, and simultaneously published in the Journal of Clinical Oncology.
As previously reported by Medscape Medical News, this showed that, after a median follow-up of 15.5 months, abemaciclib plus endocrine therapy was associated with a 25% relative risk reduction in the primary endpoint of invasive disease-free survival (IDFS) vs endocrine therapy alone.
At the time, the findings were hailed as practice changing and, once approved for high-risk HR+ HER2-negative early breast cancer, as the “new standard of care” by one expert.
Now, with median follow-up extended to 19.1 months, Priya Rastogi, MD, associate professor at the University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania, presented new study data, including additional results on patients with a Ki-67 index ≥20%, which is indicative of fast tumor growth.
Abemaciclib plus endocrine therapy was associated with a significant 28.7% reduction in the relative risk of developing an IDFS event vs endocrine therapy alone across the whole patient population, and with a 30.9% risk reduction in those with a Ki-67 index ≥20%.
Moreover, patients taking the drug combination had a significant 31.3% reduction in the relative risk of a distant relapse-free survival (DRFS) event.
Crucially, these improvements, which were deemed clinically meaningful, were not gained at the expense of additional safety concerns, although high rates of any grade diarrhea, fatigue, and neutropenia were noted.
Rastogi said the findings underline that abemaciclib combined with standard endocrine therapy “is the first CDK4/6 inhibitor to demonstrate efficacy and tolerability for patients with HR+ HER2-negative, node-positive, high-risk early breast cancer.”
Longer follow-up is ‘reassuring’ but still ‘quite short’
George W. Sledge Jr, MD, professor of medicine at Stanford University Medical Center, Palo Alto, California, was the study discussant for the earlier interim analysis presented at ESMO 2020.
At the time, he said that the study had “very, very short follow-up,” and it was consequently unclear whether the improvements will “lead to what we really care about: improved overall survival.”
Approached to comment on the current analysis, Sledge told Medscape Medical News the data “appear quite consistent” with those presented earlier this year, “which is certainly reassuring.”
Referring to the analysis in patients with a Ki-67 index ≥20%, he added the results “show a higher absolute benefit in patients with more rapidly proliferating tumors, as might be expected for a drug affecting cell-cycle division.”
However, Sledge underlined that the median follow-up time “is still quite short for a study of ER-positive adjuvant therapy, where the majority of recurrences and deaths occur after 5 years in many studies”.
Consequently, “we still have a long way to go to understand the ultimate effects of CDK4/6 inhibition on early-stage, ER-positive breast cancer, particularly on late recurrences.”
Agreed, said C. Kent Osborne, MD, codirector of SABCS and founding director of the Duncan Cancer Center at Baylor College of Medicine, Houston, Texas.
Commenting in a press conference, he said the results are “very encouraging, especially in the subgroup of tumors with high proliferation.”
However, Osborne also urged “caution” in the interpretation of the results “given the still rather short follow-up [and] given that ER+ disease is known for its persistent recurrence rate, even past 10 years.”
He also noted “this class of inhibitors is likely cytostatic, rather than cytocidal, meaning that it blocks cell proliferation rather than killing the cells.” Questions therefore remain over whether the survival curves for combination therapy will come together with those for endocrine therapy alone once the drug is stopped.
Osborne nevertheless said that, “with these caveats in mind, this is still an extremely important trial that could be practice changing in this very high-risk patient population…if the results continue to be positive and show improved overall survival with longer follow-up.”
During the press conference, Rastogi confirmed that the study will indeed to continue out to 10 years until the final assessment of overall survival.
More study details
The 5637 women who were enrolled in monarchE were divided into two cohorts:
Cohort 1, which included patients with four or more positive nodes, or those with up to three positive nodes and a tumor size ≥5 cm or grade 3 disease
Cohort 2, which included women with up to three positive nodes and a Ki-67 index ≥20% based on a standard assay
“Cohort 2 opened one year after Cohort 1 and enrolled 517 patients,” Rastogi said.
Regardless of cohort, the patients were randomly assigned in a 1:1 fashion to abemaciclib for 2 years plus endocrine therapy for 5 to 10 years, as clinically indicated, or endocrine therapy alone.
At the primary efficacy outcome analysis, 395 IDFS events had occurred in the intention-to-treat analysis. The median follow-up was 19.1 months, and 25.5% of patients had completed the 2-year treatment period. A further 58.2% were still on treatment.
The results showed 163 IDFS events had occurred with abemaciclib plus endocrine therapy vs 232 with endocrine therapy alone, to give a 2-year IDFS rate of 92.3% vs 89.3%, at a hazard ratio of 0.713 (P = .0009).
Moving on to the subgroup analysis, Rastogi added that there were “no statistically significant interactions observed, indicating a consistent treatment benefit across all groups.”
The researchers also looked at IDFS rates in patients from both cohorts with Ki-67 index ≥20%, again finding that abemaciclib plus endocrine therapy was associated with significantly fewer events than endocrine therapy alone.
There were 82 events with the combination treatment vs 115 with endocrine therapy, at a 2-year IDFS rate of 91.6% vs 87.1% and a hazard ratio of 0.691 (P = .0111).
DRFS also significantly improved with abemaciclib plus endocrine therapy vs endocrine therapy alone, at a 2-year DRFS rate of 93.8% vs 90% or a hazard ratio of 0.687 (P = .0009).
“Safety remained consistent with the known profile of abemaciclib,” Rastogi said, “and what was observed at the second interim analysis, [with] minimal increases in any grade and grade ≥3 treatment-related adverse events.”
The most common adverse events were diarrhea, fatigue, and neutropenia, which were largely grades 1 and 2.
Notably, 2.4% of combination therapy patients experienced a venous thromboembolic event of any grade vs 0.6% of endocrine therapy patients, while 2.9% and 1.2%, respectively, had any grade interstitial lung disease.
At least one dose hold because of an adverse event was reported by 59.5% of patients on abemaciclib plus endocrine therapy, while 42.5% had at least one dose reduction because of an adverse event. In both cases, the primary reason was diarrhea.
Finally, Rastogi said that “over half of the discontinuations of abemaciclib due to adverse events occurred during the first 5 months of treatment, with the highest number…in the first month.”
Ki-67 issues
During the press conference, Virginia Kaklamani, MD, codirector of SABCS and leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center, Texas, asked about the practicalities of the Ki-67 index.
She said that testing is “great when it’s centrally done, but what do we expect physicians to do when some institutions do it, some don’t, and obviously it’s not really validated in most institutions around the world?”
Rastogi replied that is a “great question,” adding “this is something that is going to have to be sorted as we continue to have discussions and get more granularity of what to do when abemaciclib is administered in that patient population.”
Carlos L. Arteaga, MD, codirector of SABCS and director of the Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, Dallas, Texas, added that “most of us think of 10% as a cutoff between high and low” for the Ki-67 index, rather than ≥20%.
He said that he knows it is “arbitrary” but he thinks of 20% as “extremely high” and asked whether the researchers would be able to conduct a retrospective analysis to look at Ki-67 as a gradient to determine “at what point it stops predicting.”
Rastogi replied that, at the time monarchE was developed, some of the international guidelines used a Ki-67 index ≥20% as the cutoff.
She also noted that, although Ki-67 index ≥20% was an entry criterion for cohort 2, cohort 1 patients also provided tissue after randomization, “and so we’ll be able to look at these types of questions with our translational research committee.”
This study was sponsored by Eli Lilly. Rastogi has financial ties to AstraZeneca, Genentech/Roche, and the study sponsor, Eli Lilly. Regan has ties to Lilly and multiple other pharmaceutical companies. Sledge has ties to Lilly and other companies. Osborne has ties to Lilly and other companies.
This article first appeared on Medscape.com.
FROM SABCS 2020
NHS England starts pilot trial of blood test for many cancers
“Early detection, particularly for hard-to-treat conditions like ovarian and pancreatic cancer, has the potential to save many lives,” said NHS Chief Executive Sir Simon Stevens in a statement.
The pilot trial will use the Galleri blood test, developed by Grail. Sir Stevens described the blood test as “promising” and said it could “be a game changer in cancer care, helping thousands more people to get successful treatment.”
However, some clinicians have expressed concerns over the potential for false-positive results with the test.
Results of a study of the Galleri blood test, published earlier this year, showed that the test detected 50 types of cancer with a specificity of 99.3% and a false positive rate of 0.7%.
It also correctly identified the originating tissue in 90% of cases. However, the sensitivity was lower, at 67%, for the 12 most common cancers, as reported at the time.
The senior author of that study, Michael Seiden, MD, PhD, president of the U.S. Oncology Network, The Woodlands, Tex., noted that it was not a screening study: the test had been used in patients with cancer and in healthy volunteers. He said the test “is intended to be complementary to, and not replace, existing guideline-recommended screening tests and might provide new avenues of investigation for cancers that don’t currently have screening tests.”
The Galleri test uses next-generation sequencing to analyze the arrangement of methyl groups on circulating cell-free DNA in a blood sample.
Several other blood tests for cancer are under development, including the CancerSEEK test, which has been reported to be able to identify eight common cancers. It measures circulating tumor DNA from 16 genes and eight protein biomarkers and then uses machine learning to analyze the data.
Improving early detection rates
The pilot trial of the blood test is due to start in mid-2021 and will involve 165,000 people.
The trial will include 140,000 individuals aged 50-79 years who were identified through their health records and who have no cancer symptoms. They will undergo blood tests annually for 3 years and will be referred for investigation if a test result is positive.
A second group will include 25,000 people with potential cancer symptoms. These patients will be offered the blood test to speed up their diagnosis after referral to a hospital via the normal channels.
The results of the pilot are expected in 2023. If successful, the test will be rolled out to 1 million individuals from 2024 to 2025.
The pilot trial is part of the NHS Long Term Plan, which aims to increase early detection of cancer. At present, around half of cancers in England are diagnosed in stage I or II; the NHS aims to increase this to 75% by 2028.
“The NHS has set itself an ambitious target,” commented Peter Johnson, MD, PhD, national clinical director for cancer at NHS England and Improvement.
“Tests like this may help us get there far faster, and I am excited to see how this cutting-edge technology will work out as we test it in clinics across the NHS,” he added.
Lord David Prior, chair of NHS England, noted that almost 200,000 people die from cancer in the United Kingdom every year and that “many of these people are diagnosed too late for treatment to be effective.
“This collaboration between the NHS and Grail offers the chance for a wide range of cancers to be diagnosed much earlier and could fundamentally change the outlook for people with cancer,” he said.
However, some clinicians raised potential concerns.
Stephen Duffy, PhD, Center for Cancer Prevention, Queen Mary University of London, described the pilot as “very exciting,” but cautioned: “We will need to find out just how early the test detects cancers and whether it can it be used in a way which minimizes anxiety from false positives.”
Yong-Jie Lu, MD, PhD, also at Queen Mary University of London, said: “It is not clear how early it aims to catch cancer. For a cancer screen test, it needs very high specificity (>99%), otherwise it may end up in a similar situation as the PSA [prostate-specific antigen] test for prostate cancer, or even worse.”
Mangesh Thorat, MD, Cancer Prevention Trials Unit, King’s College London, warned: “It is likely that for every testing round ... there will be about 1,000 false-positive results, and the test may not be able to pinpoint the location of cancer in 3%-4% of those with a true positive result, necessitating a range of imaging and other investigations in these participants.”
No funding for the study has been declared. The investigators have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
“Early detection, particularly for hard-to-treat conditions like ovarian and pancreatic cancer, has the potential to save many lives,” said NHS Chief Executive Sir Simon Stevens in a statement.
The pilot trial will use the Galleri blood test, developed by Grail. Sir Stevens described the blood test as “promising” and said it could “be a game changer in cancer care, helping thousands more people to get successful treatment.”
However, some clinicians have expressed concerns over the potential for false-positive results with the test.
Results of a study of the Galleri blood test, published earlier this year, showed that the test detected 50 types of cancer with a specificity of 99.3% and a false positive rate of 0.7%.
It also correctly identified the originating tissue in 90% of cases. However, the sensitivity was lower, at 67%, for the 12 most common cancers, as reported at the time.
The senior author of that study, Michael Seiden, MD, PhD, president of the U.S. Oncology Network, The Woodlands, Tex., noted that it was not a screening study: the test had been used in patients with cancer and in healthy volunteers. He said the test “is intended to be complementary to, and not replace, existing guideline-recommended screening tests and might provide new avenues of investigation for cancers that don’t currently have screening tests.”
The Galleri test uses next-generation sequencing to analyze the arrangement of methyl groups on circulating cell-free DNA in a blood sample.
Several other blood tests for cancer are under development, including the CancerSEEK test, which has been reported to be able to identify eight common cancers. It measures circulating tumor DNA from 16 genes and eight protein biomarkers and then uses machine learning to analyze the data.
Improving early detection rates
The pilot trial of the blood test is due to start in mid-2021 and will involve 165,000 people.
The trial will include 140,000 individuals aged 50-79 years who were identified through their health records and who have no cancer symptoms. They will undergo blood tests annually for 3 years and will be referred for investigation if a test result is positive.
A second group will include 25,000 people with potential cancer symptoms. These patients will be offered the blood test to speed up their diagnosis after referral to a hospital via the normal channels.
The results of the pilot are expected in 2023. If successful, the test will be rolled out to 1 million individuals from 2024 to 2025.
The pilot trial is part of the NHS Long Term Plan, which aims to increase early detection of cancer. At present, around half of cancers in England are diagnosed in stage I or II; the NHS aims to increase this to 75% by 2028.
“The NHS has set itself an ambitious target,” commented Peter Johnson, MD, PhD, national clinical director for cancer at NHS England and Improvement.
“Tests like this may help us get there far faster, and I am excited to see how this cutting-edge technology will work out as we test it in clinics across the NHS,” he added.
Lord David Prior, chair of NHS England, noted that almost 200,000 people die from cancer in the United Kingdom every year and that “many of these people are diagnosed too late for treatment to be effective.
“This collaboration between the NHS and Grail offers the chance for a wide range of cancers to be diagnosed much earlier and could fundamentally change the outlook for people with cancer,” he said.
However, some clinicians raised potential concerns.
Stephen Duffy, PhD, Center for Cancer Prevention, Queen Mary University of London, described the pilot as “very exciting,” but cautioned: “We will need to find out just how early the test detects cancers and whether it can it be used in a way which minimizes anxiety from false positives.”
Yong-Jie Lu, MD, PhD, also at Queen Mary University of London, said: “It is not clear how early it aims to catch cancer. For a cancer screen test, it needs very high specificity (>99%), otherwise it may end up in a similar situation as the PSA [prostate-specific antigen] test for prostate cancer, or even worse.”
Mangesh Thorat, MD, Cancer Prevention Trials Unit, King’s College London, warned: “It is likely that for every testing round ... there will be about 1,000 false-positive results, and the test may not be able to pinpoint the location of cancer in 3%-4% of those with a true positive result, necessitating a range of imaging and other investigations in these participants.”
No funding for the study has been declared. The investigators have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
“Early detection, particularly for hard-to-treat conditions like ovarian and pancreatic cancer, has the potential to save many lives,” said NHS Chief Executive Sir Simon Stevens in a statement.
The pilot trial will use the Galleri blood test, developed by Grail. Sir Stevens described the blood test as “promising” and said it could “be a game changer in cancer care, helping thousands more people to get successful treatment.”
However, some clinicians have expressed concerns over the potential for false-positive results with the test.
Results of a study of the Galleri blood test, published earlier this year, showed that the test detected 50 types of cancer with a specificity of 99.3% and a false positive rate of 0.7%.
It also correctly identified the originating tissue in 90% of cases. However, the sensitivity was lower, at 67%, for the 12 most common cancers, as reported at the time.
The senior author of that study, Michael Seiden, MD, PhD, president of the U.S. Oncology Network, The Woodlands, Tex., noted that it was not a screening study: the test had been used in patients with cancer and in healthy volunteers. He said the test “is intended to be complementary to, and not replace, existing guideline-recommended screening tests and might provide new avenues of investigation for cancers that don’t currently have screening tests.”
The Galleri test uses next-generation sequencing to analyze the arrangement of methyl groups on circulating cell-free DNA in a blood sample.
Several other blood tests for cancer are under development, including the CancerSEEK test, which has been reported to be able to identify eight common cancers. It measures circulating tumor DNA from 16 genes and eight protein biomarkers and then uses machine learning to analyze the data.
Improving early detection rates
The pilot trial of the blood test is due to start in mid-2021 and will involve 165,000 people.
The trial will include 140,000 individuals aged 50-79 years who were identified through their health records and who have no cancer symptoms. They will undergo blood tests annually for 3 years and will be referred for investigation if a test result is positive.
A second group will include 25,000 people with potential cancer symptoms. These patients will be offered the blood test to speed up their diagnosis after referral to a hospital via the normal channels.
The results of the pilot are expected in 2023. If successful, the test will be rolled out to 1 million individuals from 2024 to 2025.
The pilot trial is part of the NHS Long Term Plan, which aims to increase early detection of cancer. At present, around half of cancers in England are diagnosed in stage I or II; the NHS aims to increase this to 75% by 2028.
“The NHS has set itself an ambitious target,” commented Peter Johnson, MD, PhD, national clinical director for cancer at NHS England and Improvement.
“Tests like this may help us get there far faster, and I am excited to see how this cutting-edge technology will work out as we test it in clinics across the NHS,” he added.
Lord David Prior, chair of NHS England, noted that almost 200,000 people die from cancer in the United Kingdom every year and that “many of these people are diagnosed too late for treatment to be effective.
“This collaboration between the NHS and Grail offers the chance for a wide range of cancers to be diagnosed much earlier and could fundamentally change the outlook for people with cancer,” he said.
However, some clinicians raised potential concerns.
Stephen Duffy, PhD, Center for Cancer Prevention, Queen Mary University of London, described the pilot as “very exciting,” but cautioned: “We will need to find out just how early the test detects cancers and whether it can it be used in a way which minimizes anxiety from false positives.”
Yong-Jie Lu, MD, PhD, also at Queen Mary University of London, said: “It is not clear how early it aims to catch cancer. For a cancer screen test, it needs very high specificity (>99%), otherwise it may end up in a similar situation as the PSA [prostate-specific antigen] test for prostate cancer, or even worse.”
Mangesh Thorat, MD, Cancer Prevention Trials Unit, King’s College London, warned: “It is likely that for every testing round ... there will be about 1,000 false-positive results, and the test may not be able to pinpoint the location of cancer in 3%-4% of those with a true positive result, necessitating a range of imaging and other investigations in these participants.”
No funding for the study has been declared. The investigators have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Age no barrier to weight loss in those with morbid obesity
Older adults should be recommended for hospital-based lifestyle interventions to reduce weight, say U.K. investigators after finding there was no difference in weight loss between older and younger individuals in their program for those with morbid obesity.
Thomas M. Barber, PhD, and colleagues looked back at nearly 250 randomly selected adults who attended their obesity service over an 11-year period.
Older individuals, defined as aged 60 years and over, had higher rates of type 2 diabetes but experienced a similar percentage weight loss and reduction in body mass index (BMI) as younger patients over the course of around 40 months.
“Age should be no barrier to lifestyle management of obesity,” said Dr. Barber, of University Hospitals Coventry (England) and Warwickshire, in a news release from his institution. “Rather than putting up barriers to older people accessing weight-loss programs, we should be proactively facilitating that process. To do otherwise would risk further and unnecessary neglect of older people through societal ageist misconceptions.”
He urged service providers and policy makers to “appreciate the importance of weight loss in older people with obesity for the maintenance of health and well-being and the facilitation of healthy aging. Furthermore, age per se should not contribute toward clinical decisions regarding the implementation of lifestyle management of older people.”
The research was published online Nov. 22 in Clinical Endocrinology.
Real-world data will inform clinical practice
Jason Halford, PhD, a professor of biological psychology and health behavior, said in an interview: “The fear is that older patients are perceived not to respond” to lifestyle interventions to control obesity, “and that’s clearly a fallacy, according to this study.”
The findings are strengthened by the fact that these are real-world data, “and so it will inform clinical practice,” he added.
And one of the “more interesting” findings was that [type 2] diabetes was “more prevalent” in the older group “but they’re still losing weight,” he noted.
“Traditionally it’s been thought that people with type 2 diabetes find it more difficult to lose weight because you’re trying to manage two conditions,” said Dr. Halford, of the University of Leeds (England), who is also president-elect of the European Association for the Study of Obesity.
Don’t discount older patients
The researchers note that many of the comorbidities associated with obesity “develop over time” and that “no one is immune to obesity,” regardless of their age, sex, ethnicity, and socioeconomic status.
Barber said there are “a number of reasons” why health care professionals “may discount weight loss in older people,” including “an ‘ageist’ perspective that weight-loss is not relevant to older people and misconceptions of reduced ability of older people to lose weight through dietary modification and increased exercise.”
And “older people may feel that hospital-based obesity services are not for them,” he noted.
To determine the effect of age on the ability to lose weight through lifestyle interventions, Dr. Barber and colleagues randomly selected 242 patients with morbid obesity who attended their hospital-based service between 2005 and 2016.
Of these, 167 were aged 18-60 years and 75 were aged 60 years and older. Most participants were women (75.4% of the younger patients and 60.0% of the older patients).
The proportion of patients with confirmed diabetes was markedly higher in the older group, compared with the younger group, at 62.7% versus 35.3%, although older patients had a significantly lower baseline BMI, at 46.9 versus 49.7 kg/m2 (P < .05).
The average duration of the lifestyle intervention was over 3 years (41.5 months) in the younger patients and 33.6 months in the older patients.
There was no significant difference in percentage weight loss between younger and older patients, at 6.9% and 7.3%, respectively, and no difference in percentage reduction in BMI, at 8.1% versus 7.8%.
Further analysis demonstrated that there was no significant correlation between age at referral to the hospital-based service and percentage weight loss (correlation coefficient, –0.13).
Dr. Halford said it would have been “useful” to know the proportion of patients achieving 5% and 10% weight loss because, if a third of patients lost more than 10% of their weight, “even in an elderly population, that would suggest there’d be real benefits in terms of things like type 2 diabetes,” he noted.
And he would like to have seen more data around how long participants had been struggling with obesity, as it’s “just an assumption that the second group is further down the path because they’re older, but we can’t be 100% sure.”
The team noted the study is limited by being retrospective and including a random selection of patients attending the service rather than the entire cohort.
Dr. Halford agreed but said the analysis is a “starting point” and could be used as a platform to conduct “much more systematic research on this area.”
No funding or relevant financial relationships were declared.
A version of this article originally appeared on Medscape.com.
Older adults should be recommended for hospital-based lifestyle interventions to reduce weight, say U.K. investigators after finding there was no difference in weight loss between older and younger individuals in their program for those with morbid obesity.
Thomas M. Barber, PhD, and colleagues looked back at nearly 250 randomly selected adults who attended their obesity service over an 11-year period.
Older individuals, defined as aged 60 years and over, had higher rates of type 2 diabetes but experienced a similar percentage weight loss and reduction in body mass index (BMI) as younger patients over the course of around 40 months.
“Age should be no barrier to lifestyle management of obesity,” said Dr. Barber, of University Hospitals Coventry (England) and Warwickshire, in a news release from his institution. “Rather than putting up barriers to older people accessing weight-loss programs, we should be proactively facilitating that process. To do otherwise would risk further and unnecessary neglect of older people through societal ageist misconceptions.”
He urged service providers and policy makers to “appreciate the importance of weight loss in older people with obesity for the maintenance of health and well-being and the facilitation of healthy aging. Furthermore, age per se should not contribute toward clinical decisions regarding the implementation of lifestyle management of older people.”
The research was published online Nov. 22 in Clinical Endocrinology.
Real-world data will inform clinical practice
Jason Halford, PhD, a professor of biological psychology and health behavior, said in an interview: “The fear is that older patients are perceived not to respond” to lifestyle interventions to control obesity, “and that’s clearly a fallacy, according to this study.”
The findings are strengthened by the fact that these are real-world data, “and so it will inform clinical practice,” he added.
And one of the “more interesting” findings was that [type 2] diabetes was “more prevalent” in the older group “but they’re still losing weight,” he noted.
“Traditionally it’s been thought that people with type 2 diabetes find it more difficult to lose weight because you’re trying to manage two conditions,” said Dr. Halford, of the University of Leeds (England), who is also president-elect of the European Association for the Study of Obesity.
Don’t discount older patients
The researchers note that many of the comorbidities associated with obesity “develop over time” and that “no one is immune to obesity,” regardless of their age, sex, ethnicity, and socioeconomic status.
Barber said there are “a number of reasons” why health care professionals “may discount weight loss in older people,” including “an ‘ageist’ perspective that weight-loss is not relevant to older people and misconceptions of reduced ability of older people to lose weight through dietary modification and increased exercise.”
And “older people may feel that hospital-based obesity services are not for them,” he noted.
To determine the effect of age on the ability to lose weight through lifestyle interventions, Dr. Barber and colleagues randomly selected 242 patients with morbid obesity who attended their hospital-based service between 2005 and 2016.
Of these, 167 were aged 18-60 years and 75 were aged 60 years and older. Most participants were women (75.4% of the younger patients and 60.0% of the older patients).
The proportion of patients with confirmed diabetes was markedly higher in the older group, compared with the younger group, at 62.7% versus 35.3%, although older patients had a significantly lower baseline BMI, at 46.9 versus 49.7 kg/m2 (P < .05).
The average duration of the lifestyle intervention was over 3 years (41.5 months) in the younger patients and 33.6 months in the older patients.
There was no significant difference in percentage weight loss between younger and older patients, at 6.9% and 7.3%, respectively, and no difference in percentage reduction in BMI, at 8.1% versus 7.8%.
Further analysis demonstrated that there was no significant correlation between age at referral to the hospital-based service and percentage weight loss (correlation coefficient, –0.13).
Dr. Halford said it would have been “useful” to know the proportion of patients achieving 5% and 10% weight loss because, if a third of patients lost more than 10% of their weight, “even in an elderly population, that would suggest there’d be real benefits in terms of things like type 2 diabetes,” he noted.
And he would like to have seen more data around how long participants had been struggling with obesity, as it’s “just an assumption that the second group is further down the path because they’re older, but we can’t be 100% sure.”
The team noted the study is limited by being retrospective and including a random selection of patients attending the service rather than the entire cohort.
Dr. Halford agreed but said the analysis is a “starting point” and could be used as a platform to conduct “much more systematic research on this area.”
No funding or relevant financial relationships were declared.
A version of this article originally appeared on Medscape.com.
Older adults should be recommended for hospital-based lifestyle interventions to reduce weight, say U.K. investigators after finding there was no difference in weight loss between older and younger individuals in their program for those with morbid obesity.
Thomas M. Barber, PhD, and colleagues looked back at nearly 250 randomly selected adults who attended their obesity service over an 11-year period.
Older individuals, defined as aged 60 years and over, had higher rates of type 2 diabetes but experienced a similar percentage weight loss and reduction in body mass index (BMI) as younger patients over the course of around 40 months.
“Age should be no barrier to lifestyle management of obesity,” said Dr. Barber, of University Hospitals Coventry (England) and Warwickshire, in a news release from his institution. “Rather than putting up barriers to older people accessing weight-loss programs, we should be proactively facilitating that process. To do otherwise would risk further and unnecessary neglect of older people through societal ageist misconceptions.”
He urged service providers and policy makers to “appreciate the importance of weight loss in older people with obesity for the maintenance of health and well-being and the facilitation of healthy aging. Furthermore, age per se should not contribute toward clinical decisions regarding the implementation of lifestyle management of older people.”
The research was published online Nov. 22 in Clinical Endocrinology.
Real-world data will inform clinical practice
Jason Halford, PhD, a professor of biological psychology and health behavior, said in an interview: “The fear is that older patients are perceived not to respond” to lifestyle interventions to control obesity, “and that’s clearly a fallacy, according to this study.”
The findings are strengthened by the fact that these are real-world data, “and so it will inform clinical practice,” he added.
And one of the “more interesting” findings was that [type 2] diabetes was “more prevalent” in the older group “but they’re still losing weight,” he noted.
“Traditionally it’s been thought that people with type 2 diabetes find it more difficult to lose weight because you’re trying to manage two conditions,” said Dr. Halford, of the University of Leeds (England), who is also president-elect of the European Association for the Study of Obesity.
Don’t discount older patients
The researchers note that many of the comorbidities associated with obesity “develop over time” and that “no one is immune to obesity,” regardless of their age, sex, ethnicity, and socioeconomic status.
Barber said there are “a number of reasons” why health care professionals “may discount weight loss in older people,” including “an ‘ageist’ perspective that weight-loss is not relevant to older people and misconceptions of reduced ability of older people to lose weight through dietary modification and increased exercise.”
And “older people may feel that hospital-based obesity services are not for them,” he noted.
To determine the effect of age on the ability to lose weight through lifestyle interventions, Dr. Barber and colleagues randomly selected 242 patients with morbid obesity who attended their hospital-based service between 2005 and 2016.
Of these, 167 were aged 18-60 years and 75 were aged 60 years and older. Most participants were women (75.4% of the younger patients and 60.0% of the older patients).
The proportion of patients with confirmed diabetes was markedly higher in the older group, compared with the younger group, at 62.7% versus 35.3%, although older patients had a significantly lower baseline BMI, at 46.9 versus 49.7 kg/m2 (P < .05).
The average duration of the lifestyle intervention was over 3 years (41.5 months) in the younger patients and 33.6 months in the older patients.
There was no significant difference in percentage weight loss between younger and older patients, at 6.9% and 7.3%, respectively, and no difference in percentage reduction in BMI, at 8.1% versus 7.8%.
Further analysis demonstrated that there was no significant correlation between age at referral to the hospital-based service and percentage weight loss (correlation coefficient, –0.13).
Dr. Halford said it would have been “useful” to know the proportion of patients achieving 5% and 10% weight loss because, if a third of patients lost more than 10% of their weight, “even in an elderly population, that would suggest there’d be real benefits in terms of things like type 2 diabetes,” he noted.
And he would like to have seen more data around how long participants had been struggling with obesity, as it’s “just an assumption that the second group is further down the path because they’re older, but we can’t be 100% sure.”
The team noted the study is limited by being retrospective and including a random selection of patients attending the service rather than the entire cohort.
Dr. Halford agreed but said the analysis is a “starting point” and could be used as a platform to conduct “much more systematic research on this area.”
No funding or relevant financial relationships were declared.
A version of this article originally appeared on Medscape.com.
Metformin improves most outcomes for T2D during pregnancy
including reduced weight gain, reduced insulin doses, and fewer large-for-gestational-age babies, suggest the results of a randomized controlled trial.
However, the drug was associated with an increased risk of small-for-gestational-age babies, which poses the question as to risk versus benefit of metformin on the health of offspring.
“Better understanding of the short- and long-term implications of these effects on infants will be important to properly advise patients with type 2 diabetes contemplating use of metformin during pregnancy,” said lead author Denice S. Feig, MD, Mount Sinai Hospital, Toronto.
The research was presented at the Diabetes UK Professional Conference: Online Series on Nov. 17 and recently published in The Lancet Diabetes & Endocrinology.
Summing up, Dr. Feig said that, on balance, she would be inclined to give metformin to most pregnant women with type 2 diabetes, perhaps with the exception of those who may have risk factors for small-for-gestational-age babies; for example, women who’ve had intrauterine growth restriction, who are smokers, and have significant renal disease, or have a lower body mass index.
Increased prevalence of type 2 diabetes in pregnancy
Dr. Feig said that across the developed world there have been huge increases in the prevalence of type 2 diabetes in pregnancy in recent years.
Insulin is the standard treatment for the management of type 2 diabetes in pregnancy, but these women have marked insulin resistance that worsens in pregnancy, which means their insulin requirements increase, leading to weight gain, painful injections, high cost, and noncompliance.
So despite treatment with insulin, these women continue to face increased rates of adverse maternal and fetal outcomes.
And although metformin is increasingly being used in women with type 2 diabetes during pregnancy, there is a scarcity of data on the benefits and harms of metformin use on pregnancy outcomes in these women.
The MiTy trial was therefore undertaken to determine whether metformin could improve outcomes.
The team recruited 502 women from 29 sites in Canada and Australia who had type 2 diabetes prior to pregnancy or were diagnosed during pregnancy, before 20 weeks’ gestation. The women were randomized to metformin 1 g twice daily or placebo, in addition to their usual insulin regimen, at between 6 and 28 weeks’ gestation.
Type 2 diabetes was diagnosed prior to pregnancy in 83% of women in the metformin group and in 90% of those assigned to placebo. The mean hemoglobin A1c level at randomization was 47 mmol/mol (6.5%) in both groups.
The average maternal age at baseline was approximately 35 years and mean gestational age at randomization was 16 weeks. Mean prepregnancy BMI was approximately 34 kg/m2.
Of note, only 30% were of European ethnicity.
Less weight gain, lower A1c, less insulin needed with metformin
Dr. Feig reported that there was no significant difference between the treatment groups in terms of the proportion of women with the composite primary outcome of pregnancy loss, preterm birth, birth injury, respiratory distress, neonatal hypoglycemia, or admission to neonatal intensive care lasting more than 24 hours (P = 0.86).
However, women in the metformin group had significantly less overall weight gain during pregnancy than did those in the placebo group, at –1.8 kg (P < .0001).
They also had a significantly lower last A1c level in pregnancy, at 41 mmol/mol (5.9%) versus 43.2 mmol/mol (6.1%) in those given placebo (P = .015), and required fewer insulin doses, at 1.1 versus 1.5 units/kg/day (P < .0001), which translated to a reduction of almost 44 units/day.
Women given metformin were also less likely to require Cesarean section delivery, at 53.4% versus 62.7% in the placebo group (P = .03), although there was no difference between groups in terms of gestational hypertension or preeclampsia.
The most common adverse events were gastrointestinal complications, which occurred in 27.3% of women in the metformin group and 22.3% of those given placebo.
There were no significant differences between the metformin and placebo groups in rates of pregnancy loss (P = .81), preterm birth (P = .16), birth injury (P = .37), respiratory distress (P = .49), and congenital anomalies (P = .16).
Average birth weight lower with metformin
However, Dr. Feig showed that the average birth weight was lower for offspring of women given metformin than those assigned to placebo, at 3.2 kg (7.05 lb) versus 3.4 kg (7.4 lb) (P = .002).
Women given metformin were also less likely to have a baby with a birth weight of 4 kg (8.8 lb) or more, at 12.1% versus 19.2%, or a relative risk of 0.65 (P = .046), and a baby that was extremely large for gestational age, at 8.6% versus 14.8%, or a relative risk of 0.58 (P = .046).
But of concern, metformin was associated with an increased risk of small-for-gestational-age babies, at 12.9% versus 6.6% with placebo, or a relative risk of 1.96 (P = .03).
Dr. Feig suggested that this may be due to a direct effect of metformin “because as we know metformin inhibits the mTOR pathway,” which is a “primary nutrient sensor in the placenta” and could “attenuate nutrient flux and fetal growth.”
She said it is not clear whether the small-for-gestational-age babies were “healthy or unhealthy.”
To investigate further, the team has launched the MiTy Kids study, which will follow the offspring in the MiTy trial to determine whether metformin during pregnancy is associated with a reduction in adiposity and improvement in insulin resistance in the babies at 2 years of age.
Who should be given metformin?
During the discussion, Helen R. Murphy, MD, PhD, Norwich Medical School, University of East Anglia, England, asked whether Dr. Feig would recommend continuing metformin in pregnancy if it was started preconception for fertility issues rather than diabetes.
She replied: “If they don’t have diabetes and it’s simply for PCOS [polycystic ovary syndrome], then I have either stopped it as soon as they got pregnant or sometimes continued it through the first trimester, and then stopped.
“If the person has diabetes, however, I think given this work, for most people I would continue it,” she said.
The study was funded by the Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, and the University of Toronto. The authors have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
including reduced weight gain, reduced insulin doses, and fewer large-for-gestational-age babies, suggest the results of a randomized controlled trial.
However, the drug was associated with an increased risk of small-for-gestational-age babies, which poses the question as to risk versus benefit of metformin on the health of offspring.
“Better understanding of the short- and long-term implications of these effects on infants will be important to properly advise patients with type 2 diabetes contemplating use of metformin during pregnancy,” said lead author Denice S. Feig, MD, Mount Sinai Hospital, Toronto.
The research was presented at the Diabetes UK Professional Conference: Online Series on Nov. 17 and recently published in The Lancet Diabetes & Endocrinology.
Summing up, Dr. Feig said that, on balance, she would be inclined to give metformin to most pregnant women with type 2 diabetes, perhaps with the exception of those who may have risk factors for small-for-gestational-age babies; for example, women who’ve had intrauterine growth restriction, who are smokers, and have significant renal disease, or have a lower body mass index.
Increased prevalence of type 2 diabetes in pregnancy
Dr. Feig said that across the developed world there have been huge increases in the prevalence of type 2 diabetes in pregnancy in recent years.
Insulin is the standard treatment for the management of type 2 diabetes in pregnancy, but these women have marked insulin resistance that worsens in pregnancy, which means their insulin requirements increase, leading to weight gain, painful injections, high cost, and noncompliance.
So despite treatment with insulin, these women continue to face increased rates of adverse maternal and fetal outcomes.
And although metformin is increasingly being used in women with type 2 diabetes during pregnancy, there is a scarcity of data on the benefits and harms of metformin use on pregnancy outcomes in these women.
The MiTy trial was therefore undertaken to determine whether metformin could improve outcomes.
The team recruited 502 women from 29 sites in Canada and Australia who had type 2 diabetes prior to pregnancy or were diagnosed during pregnancy, before 20 weeks’ gestation. The women were randomized to metformin 1 g twice daily or placebo, in addition to their usual insulin regimen, at between 6 and 28 weeks’ gestation.
Type 2 diabetes was diagnosed prior to pregnancy in 83% of women in the metformin group and in 90% of those assigned to placebo. The mean hemoglobin A1c level at randomization was 47 mmol/mol (6.5%) in both groups.
The average maternal age at baseline was approximately 35 years and mean gestational age at randomization was 16 weeks. Mean prepregnancy BMI was approximately 34 kg/m2.
Of note, only 30% were of European ethnicity.
Less weight gain, lower A1c, less insulin needed with metformin
Dr. Feig reported that there was no significant difference between the treatment groups in terms of the proportion of women with the composite primary outcome of pregnancy loss, preterm birth, birth injury, respiratory distress, neonatal hypoglycemia, or admission to neonatal intensive care lasting more than 24 hours (P = 0.86).
However, women in the metformin group had significantly less overall weight gain during pregnancy than did those in the placebo group, at –1.8 kg (P < .0001).
They also had a significantly lower last A1c level in pregnancy, at 41 mmol/mol (5.9%) versus 43.2 mmol/mol (6.1%) in those given placebo (P = .015), and required fewer insulin doses, at 1.1 versus 1.5 units/kg/day (P < .0001), which translated to a reduction of almost 44 units/day.
Women given metformin were also less likely to require Cesarean section delivery, at 53.4% versus 62.7% in the placebo group (P = .03), although there was no difference between groups in terms of gestational hypertension or preeclampsia.
The most common adverse events were gastrointestinal complications, which occurred in 27.3% of women in the metformin group and 22.3% of those given placebo.
There were no significant differences between the metformin and placebo groups in rates of pregnancy loss (P = .81), preterm birth (P = .16), birth injury (P = .37), respiratory distress (P = .49), and congenital anomalies (P = .16).
Average birth weight lower with metformin
However, Dr. Feig showed that the average birth weight was lower for offspring of women given metformin than those assigned to placebo, at 3.2 kg (7.05 lb) versus 3.4 kg (7.4 lb) (P = .002).
Women given metformin were also less likely to have a baby with a birth weight of 4 kg (8.8 lb) or more, at 12.1% versus 19.2%, or a relative risk of 0.65 (P = .046), and a baby that was extremely large for gestational age, at 8.6% versus 14.8%, or a relative risk of 0.58 (P = .046).
But of concern, metformin was associated with an increased risk of small-for-gestational-age babies, at 12.9% versus 6.6% with placebo, or a relative risk of 1.96 (P = .03).
Dr. Feig suggested that this may be due to a direct effect of metformin “because as we know metformin inhibits the mTOR pathway,” which is a “primary nutrient sensor in the placenta” and could “attenuate nutrient flux and fetal growth.”
She said it is not clear whether the small-for-gestational-age babies were “healthy or unhealthy.”
To investigate further, the team has launched the MiTy Kids study, which will follow the offspring in the MiTy trial to determine whether metformin during pregnancy is associated with a reduction in adiposity and improvement in insulin resistance in the babies at 2 years of age.
Who should be given metformin?
During the discussion, Helen R. Murphy, MD, PhD, Norwich Medical School, University of East Anglia, England, asked whether Dr. Feig would recommend continuing metformin in pregnancy if it was started preconception for fertility issues rather than diabetes.
She replied: “If they don’t have diabetes and it’s simply for PCOS [polycystic ovary syndrome], then I have either stopped it as soon as they got pregnant or sometimes continued it through the first trimester, and then stopped.
“If the person has diabetes, however, I think given this work, for most people I would continue it,” she said.
The study was funded by the Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, and the University of Toronto. The authors have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
including reduced weight gain, reduced insulin doses, and fewer large-for-gestational-age babies, suggest the results of a randomized controlled trial.
However, the drug was associated with an increased risk of small-for-gestational-age babies, which poses the question as to risk versus benefit of metformin on the health of offspring.
“Better understanding of the short- and long-term implications of these effects on infants will be important to properly advise patients with type 2 diabetes contemplating use of metformin during pregnancy,” said lead author Denice S. Feig, MD, Mount Sinai Hospital, Toronto.
The research was presented at the Diabetes UK Professional Conference: Online Series on Nov. 17 and recently published in The Lancet Diabetes & Endocrinology.
Summing up, Dr. Feig said that, on balance, she would be inclined to give metformin to most pregnant women with type 2 diabetes, perhaps with the exception of those who may have risk factors for small-for-gestational-age babies; for example, women who’ve had intrauterine growth restriction, who are smokers, and have significant renal disease, or have a lower body mass index.
Increased prevalence of type 2 diabetes in pregnancy
Dr. Feig said that across the developed world there have been huge increases in the prevalence of type 2 diabetes in pregnancy in recent years.
Insulin is the standard treatment for the management of type 2 diabetes in pregnancy, but these women have marked insulin resistance that worsens in pregnancy, which means their insulin requirements increase, leading to weight gain, painful injections, high cost, and noncompliance.
So despite treatment with insulin, these women continue to face increased rates of adverse maternal and fetal outcomes.
And although metformin is increasingly being used in women with type 2 diabetes during pregnancy, there is a scarcity of data on the benefits and harms of metformin use on pregnancy outcomes in these women.
The MiTy trial was therefore undertaken to determine whether metformin could improve outcomes.
The team recruited 502 women from 29 sites in Canada and Australia who had type 2 diabetes prior to pregnancy or were diagnosed during pregnancy, before 20 weeks’ gestation. The women were randomized to metformin 1 g twice daily or placebo, in addition to their usual insulin regimen, at between 6 and 28 weeks’ gestation.
Type 2 diabetes was diagnosed prior to pregnancy in 83% of women in the metformin group and in 90% of those assigned to placebo. The mean hemoglobin A1c level at randomization was 47 mmol/mol (6.5%) in both groups.
The average maternal age at baseline was approximately 35 years and mean gestational age at randomization was 16 weeks. Mean prepregnancy BMI was approximately 34 kg/m2.
Of note, only 30% were of European ethnicity.
Less weight gain, lower A1c, less insulin needed with metformin
Dr. Feig reported that there was no significant difference between the treatment groups in terms of the proportion of women with the composite primary outcome of pregnancy loss, preterm birth, birth injury, respiratory distress, neonatal hypoglycemia, or admission to neonatal intensive care lasting more than 24 hours (P = 0.86).
However, women in the metformin group had significantly less overall weight gain during pregnancy than did those in the placebo group, at –1.8 kg (P < .0001).
They also had a significantly lower last A1c level in pregnancy, at 41 mmol/mol (5.9%) versus 43.2 mmol/mol (6.1%) in those given placebo (P = .015), and required fewer insulin doses, at 1.1 versus 1.5 units/kg/day (P < .0001), which translated to a reduction of almost 44 units/day.
Women given metformin were also less likely to require Cesarean section delivery, at 53.4% versus 62.7% in the placebo group (P = .03), although there was no difference between groups in terms of gestational hypertension or preeclampsia.
The most common adverse events were gastrointestinal complications, which occurred in 27.3% of women in the metformin group and 22.3% of those given placebo.
There were no significant differences between the metformin and placebo groups in rates of pregnancy loss (P = .81), preterm birth (P = .16), birth injury (P = .37), respiratory distress (P = .49), and congenital anomalies (P = .16).
Average birth weight lower with metformin
However, Dr. Feig showed that the average birth weight was lower for offspring of women given metformin than those assigned to placebo, at 3.2 kg (7.05 lb) versus 3.4 kg (7.4 lb) (P = .002).
Women given metformin were also less likely to have a baby with a birth weight of 4 kg (8.8 lb) or more, at 12.1% versus 19.2%, or a relative risk of 0.65 (P = .046), and a baby that was extremely large for gestational age, at 8.6% versus 14.8%, or a relative risk of 0.58 (P = .046).
But of concern, metformin was associated with an increased risk of small-for-gestational-age babies, at 12.9% versus 6.6% with placebo, or a relative risk of 1.96 (P = .03).
Dr. Feig suggested that this may be due to a direct effect of metformin “because as we know metformin inhibits the mTOR pathway,” which is a “primary nutrient sensor in the placenta” and could “attenuate nutrient flux and fetal growth.”
She said it is not clear whether the small-for-gestational-age babies were “healthy or unhealthy.”
To investigate further, the team has launched the MiTy Kids study, which will follow the offspring in the MiTy trial to determine whether metformin during pregnancy is associated with a reduction in adiposity and improvement in insulin resistance in the babies at 2 years of age.
Who should be given metformin?
During the discussion, Helen R. Murphy, MD, PhD, Norwich Medical School, University of East Anglia, England, asked whether Dr. Feig would recommend continuing metformin in pregnancy if it was started preconception for fertility issues rather than diabetes.
She replied: “If they don’t have diabetes and it’s simply for PCOS [polycystic ovary syndrome], then I have either stopped it as soon as they got pregnant or sometimes continued it through the first trimester, and then stopped.
“If the person has diabetes, however, I think given this work, for most people I would continue it,” she said.
The study was funded by the Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, and the University of Toronto. The authors have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
LSD microdosing to boost attention: Too soon to tell?
Microdosing with lysergic acid diethylamide (LSD) is associated with improved mood and increased attention, early research suggests. However, at least one expert believes it’s far too soon to tell and warns against endorsing patient microdosing.
In a dose-finding exploratory study, three low doses of LSD were compared with placebo in healthy volunteers who were all recreational drug users. Adjusted results showed that the highest dose boosted attention and mood, although participants were aware of psychedelic effects, prompting researchers to conclude the results demonstrated “selective, beneficial effects.”
“The majority of participants have improved attention,” study investigator Nadia Hutten, PhD, Department of Neuropsychology and Psychopharmacology, Maastricht University, the Netherlands, told Medscape Medical News.
“So we think that patients with attention deficits might have more beneficial effects,” she added, noting her team plans to study LSD microdosing in patients with attention deficit hyperactivity disorder.
The study was presented at the 33rd European College of Neuropsychopharmacology (ECNP) Congress, which was held online this year because of the COVID-19 pandemic.
Growing interest
Over the past 10 years there has been growing interest in psychedelic microdosing, which is defined as a dose that aims to enhance mood and/or performance but does not affect perception.
However, there has been considerable debate over what constitutes a “microdose.” One tenth of a “full” psychedelic dose is typically suggested, but users report a much wider dose range in practice, suggesting potential “individual variation in response to low doses,” the researchers note.
In the current dose-finding study, the researchers explored whether the effects of LSD on cognition and subjective measures differed between individuals.
The study included 24 healthy recreational drug users and compared the acute effects of 5 mcg, 20 mcg, and 20 mcg LSD with placebo on a computer-based psychomotor vigilance task (PVT) that measured attention and on a Digit Symbol Substitution Test (DSST).
Participants also completed the 72-item Profile of Mood States (POMS) questionnaire, a visual analog scale (VAS) on mood, and the 94-item 5-Dimensional Altered States of Consciousness Rating scales (5D-ASC).
Unadjusted results showed that the 20-mcg LSD dose significantly reduced correct substitutions on the DSST vs placebo (P < .05), but had no effect on attentional lapses on the PCT or on positive mood on the POMS.
Correcting the DSST score for the number of total responses revealed no dose effect of LSD. This suggested that participants were no less accurate when under the influence of LSD, even though they encoded fewer digits, the researchers note.
Participants also reported that both the 10-mcg and 20-mcg dose of LSD increased subjective experiences on the VAS and alternated states of consciousness on the 5D-ASC compared with placebo.
After stratifying the results by dose and participant, the effect of LSD differed between individuals. For example, both the 5-mcg and 20-mcg doses were associated with improvement in attention on the PVT (P < .05), but not the 10-mcg dose.
These results also indicated that the 20-mcg dose was associated with a significant increase in the correct number of substitutions on the DSST and with a significant increase in positive mood on the POMS (P < .05 for both outcomes).
The findings suggest that future studies in patient populations with impaired attention are needed, “including biological parameters involved in LSD receptor-binding and metabolism, in order to understand the inter-individual variation in response to LSD,” the investigators note.
In an educational session at the meeting, the study’s lead researcher, Kim Kuypers, PhD, associate professor at Maastricht University, said research shows individuals are already self-medicating with psychedelic microdosing to treat a wide range of mental health problems, and rated it as significantly more effective than conventional therapy at alleviating symptoms and improving quality of life.
Nevertheless, Kuypers noted there have been fewer than 20 published placebo-controlled studies examining psychedelic microdosing in humans – and much of the current evidence is anecdotal.
However, there is some clinical research suggesting that low-dose LSD is associated with improved mood and cognitive performance and that it also has an effect on resting-state amygdala functional connectivity and acutely increases brain-derived neurotrophic factor plasma levels.
Furthermore, said Kuypers, the evidence in healthy volunteers thus far suggests microdosing is “safe.”
Jumping ahead of the science?
Commenting on the study for Medscape Medical News, Jeffrey A. Lieberman, MD, professor and chair of psychiatry at Columbia University, New York City, said he “gives the investigators credit for doing such a study” but does not believe anything can be gleaned from the findings.
He said he is also concerned that the resurgence of psychedelic research is not congruent with “the methodologic rigor and scientific thinking that accompanies treatment development in other disease areas.”
Lieberman, who is also psychiatrist-in-chief at the NewYork–Presbyterian Hospital Columbia Medical Center and was not involved with the study, added that some of the research is also being conducted in individuals who are “true believers and not sufficiently dispassionate and objective.”
“ But because these are such notorious and interesting compounds, they have attracted a lot of peripheral interest to promote and to disseminate; and the risk is that it will be done in the wrong way and there may be consequences,” he said.
Moreover, Lieberman noted that the psychedelic drugs may be used in practice ahead of strong evidence of safety and efficacy. As an example, he pointed to ketamine, a drug that was identified as a treatment for people with depression who had not responded to standard treatments, he noted.
“But before you knew it, there were clinics being opened up all over the place by anesthesiologists or other people that were trying to make a quick buck,” he said.
“That was alarming because they were stretching the criteria for whom the treatment was appropriate; there were no protocols for dosing, for frequency of administration, and there was inadequate psychiatric follow-up,” Lieberman added.
Preliminary but promising
He agreed with Kuypers that cases of microdosing with psychedelics are largely anecdotal.
“So in that context, when these investigators tried to put it to a test, which is commendable, the results in no way tell you whether it’s good, bad, or indifferent,” Lieberman said. In fact, the results are “disappointing in terms of suggesting any beneficial effect.”
Lieberman said more and larger studies are needed in order to determine whether LSD microdosing is beneficial.
In response to Lieberman’s comments, Kuypers told Medscape Medical News that the investigators tried to base their placebo-controlled research on previous anecdotal research.
She emphasized that the “whole field is still in its infancy,” including research on the use of “full” doses of psychedelics.
“I sometimes think that the message is too positive. We should never forget to communicate that not a lot of research has been done.” In addition, she agreed that researchers should “keep a balanced message.”
“All the data to date is preliminary, in my view, but promising,” she stressed, “and the evidence is growing.”
The study received financial support from the Beckley Foundation. The study authors and Lieberman have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Microdosing with lysergic acid diethylamide (LSD) is associated with improved mood and increased attention, early research suggests. However, at least one expert believes it’s far too soon to tell and warns against endorsing patient microdosing.
In a dose-finding exploratory study, three low doses of LSD were compared with placebo in healthy volunteers who were all recreational drug users. Adjusted results showed that the highest dose boosted attention and mood, although participants were aware of psychedelic effects, prompting researchers to conclude the results demonstrated “selective, beneficial effects.”
“The majority of participants have improved attention,” study investigator Nadia Hutten, PhD, Department of Neuropsychology and Psychopharmacology, Maastricht University, the Netherlands, told Medscape Medical News.
“So we think that patients with attention deficits might have more beneficial effects,” she added, noting her team plans to study LSD microdosing in patients with attention deficit hyperactivity disorder.
The study was presented at the 33rd European College of Neuropsychopharmacology (ECNP) Congress, which was held online this year because of the COVID-19 pandemic.
Growing interest
Over the past 10 years there has been growing interest in psychedelic microdosing, which is defined as a dose that aims to enhance mood and/or performance but does not affect perception.
However, there has been considerable debate over what constitutes a “microdose.” One tenth of a “full” psychedelic dose is typically suggested, but users report a much wider dose range in practice, suggesting potential “individual variation in response to low doses,” the researchers note.
In the current dose-finding study, the researchers explored whether the effects of LSD on cognition and subjective measures differed between individuals.
The study included 24 healthy recreational drug users and compared the acute effects of 5 mcg, 20 mcg, and 20 mcg LSD with placebo on a computer-based psychomotor vigilance task (PVT) that measured attention and on a Digit Symbol Substitution Test (DSST).
Participants also completed the 72-item Profile of Mood States (POMS) questionnaire, a visual analog scale (VAS) on mood, and the 94-item 5-Dimensional Altered States of Consciousness Rating scales (5D-ASC).
Unadjusted results showed that the 20-mcg LSD dose significantly reduced correct substitutions on the DSST vs placebo (P < .05), but had no effect on attentional lapses on the PCT or on positive mood on the POMS.
Correcting the DSST score for the number of total responses revealed no dose effect of LSD. This suggested that participants were no less accurate when under the influence of LSD, even though they encoded fewer digits, the researchers note.
Participants also reported that both the 10-mcg and 20-mcg dose of LSD increased subjective experiences on the VAS and alternated states of consciousness on the 5D-ASC compared with placebo.
After stratifying the results by dose and participant, the effect of LSD differed between individuals. For example, both the 5-mcg and 20-mcg doses were associated with improvement in attention on the PVT (P < .05), but not the 10-mcg dose.
These results also indicated that the 20-mcg dose was associated with a significant increase in the correct number of substitutions on the DSST and with a significant increase in positive mood on the POMS (P < .05 for both outcomes).
The findings suggest that future studies in patient populations with impaired attention are needed, “including biological parameters involved in LSD receptor-binding and metabolism, in order to understand the inter-individual variation in response to LSD,” the investigators note.
In an educational session at the meeting, the study’s lead researcher, Kim Kuypers, PhD, associate professor at Maastricht University, said research shows individuals are already self-medicating with psychedelic microdosing to treat a wide range of mental health problems, and rated it as significantly more effective than conventional therapy at alleviating symptoms and improving quality of life.
Nevertheless, Kuypers noted there have been fewer than 20 published placebo-controlled studies examining psychedelic microdosing in humans – and much of the current evidence is anecdotal.
However, there is some clinical research suggesting that low-dose LSD is associated with improved mood and cognitive performance and that it also has an effect on resting-state amygdala functional connectivity and acutely increases brain-derived neurotrophic factor plasma levels.
Furthermore, said Kuypers, the evidence in healthy volunteers thus far suggests microdosing is “safe.”
Jumping ahead of the science?
Commenting on the study for Medscape Medical News, Jeffrey A. Lieberman, MD, professor and chair of psychiatry at Columbia University, New York City, said he “gives the investigators credit for doing such a study” but does not believe anything can be gleaned from the findings.
He said he is also concerned that the resurgence of psychedelic research is not congruent with “the methodologic rigor and scientific thinking that accompanies treatment development in other disease areas.”
Lieberman, who is also psychiatrist-in-chief at the NewYork–Presbyterian Hospital Columbia Medical Center and was not involved with the study, added that some of the research is also being conducted in individuals who are “true believers and not sufficiently dispassionate and objective.”
“ But because these are such notorious and interesting compounds, they have attracted a lot of peripheral interest to promote and to disseminate; and the risk is that it will be done in the wrong way and there may be consequences,” he said.
Moreover, Lieberman noted that the psychedelic drugs may be used in practice ahead of strong evidence of safety and efficacy. As an example, he pointed to ketamine, a drug that was identified as a treatment for people with depression who had not responded to standard treatments, he noted.
“But before you knew it, there were clinics being opened up all over the place by anesthesiologists or other people that were trying to make a quick buck,” he said.
“That was alarming because they were stretching the criteria for whom the treatment was appropriate; there were no protocols for dosing, for frequency of administration, and there was inadequate psychiatric follow-up,” Lieberman added.
Preliminary but promising
He agreed with Kuypers that cases of microdosing with psychedelics are largely anecdotal.
“So in that context, when these investigators tried to put it to a test, which is commendable, the results in no way tell you whether it’s good, bad, or indifferent,” Lieberman said. In fact, the results are “disappointing in terms of suggesting any beneficial effect.”
Lieberman said more and larger studies are needed in order to determine whether LSD microdosing is beneficial.
In response to Lieberman’s comments, Kuypers told Medscape Medical News that the investigators tried to base their placebo-controlled research on previous anecdotal research.
She emphasized that the “whole field is still in its infancy,” including research on the use of “full” doses of psychedelics.
“I sometimes think that the message is too positive. We should never forget to communicate that not a lot of research has been done.” In addition, she agreed that researchers should “keep a balanced message.”
“All the data to date is preliminary, in my view, but promising,” she stressed, “and the evidence is growing.”
The study received financial support from the Beckley Foundation. The study authors and Lieberman have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Microdosing with lysergic acid diethylamide (LSD) is associated with improved mood and increased attention, early research suggests. However, at least one expert believes it’s far too soon to tell and warns against endorsing patient microdosing.
In a dose-finding exploratory study, three low doses of LSD were compared with placebo in healthy volunteers who were all recreational drug users. Adjusted results showed that the highest dose boosted attention and mood, although participants were aware of psychedelic effects, prompting researchers to conclude the results demonstrated “selective, beneficial effects.”
“The majority of participants have improved attention,” study investigator Nadia Hutten, PhD, Department of Neuropsychology and Psychopharmacology, Maastricht University, the Netherlands, told Medscape Medical News.
“So we think that patients with attention deficits might have more beneficial effects,” she added, noting her team plans to study LSD microdosing in patients with attention deficit hyperactivity disorder.
The study was presented at the 33rd European College of Neuropsychopharmacology (ECNP) Congress, which was held online this year because of the COVID-19 pandemic.
Growing interest
Over the past 10 years there has been growing interest in psychedelic microdosing, which is defined as a dose that aims to enhance mood and/or performance but does not affect perception.
However, there has been considerable debate over what constitutes a “microdose.” One tenth of a “full” psychedelic dose is typically suggested, but users report a much wider dose range in practice, suggesting potential “individual variation in response to low doses,” the researchers note.
In the current dose-finding study, the researchers explored whether the effects of LSD on cognition and subjective measures differed between individuals.
The study included 24 healthy recreational drug users and compared the acute effects of 5 mcg, 20 mcg, and 20 mcg LSD with placebo on a computer-based psychomotor vigilance task (PVT) that measured attention and on a Digit Symbol Substitution Test (DSST).
Participants also completed the 72-item Profile of Mood States (POMS) questionnaire, a visual analog scale (VAS) on mood, and the 94-item 5-Dimensional Altered States of Consciousness Rating scales (5D-ASC).
Unadjusted results showed that the 20-mcg LSD dose significantly reduced correct substitutions on the DSST vs placebo (P < .05), but had no effect on attentional lapses on the PCT or on positive mood on the POMS.
Correcting the DSST score for the number of total responses revealed no dose effect of LSD. This suggested that participants were no less accurate when under the influence of LSD, even though they encoded fewer digits, the researchers note.
Participants also reported that both the 10-mcg and 20-mcg dose of LSD increased subjective experiences on the VAS and alternated states of consciousness on the 5D-ASC compared with placebo.
After stratifying the results by dose and participant, the effect of LSD differed between individuals. For example, both the 5-mcg and 20-mcg doses were associated with improvement in attention on the PVT (P < .05), but not the 10-mcg dose.
These results also indicated that the 20-mcg dose was associated with a significant increase in the correct number of substitutions on the DSST and with a significant increase in positive mood on the POMS (P < .05 for both outcomes).
The findings suggest that future studies in patient populations with impaired attention are needed, “including biological parameters involved in LSD receptor-binding and metabolism, in order to understand the inter-individual variation in response to LSD,” the investigators note.
In an educational session at the meeting, the study’s lead researcher, Kim Kuypers, PhD, associate professor at Maastricht University, said research shows individuals are already self-medicating with psychedelic microdosing to treat a wide range of mental health problems, and rated it as significantly more effective than conventional therapy at alleviating symptoms and improving quality of life.
Nevertheless, Kuypers noted there have been fewer than 20 published placebo-controlled studies examining psychedelic microdosing in humans – and much of the current evidence is anecdotal.
However, there is some clinical research suggesting that low-dose LSD is associated with improved mood and cognitive performance and that it also has an effect on resting-state amygdala functional connectivity and acutely increases brain-derived neurotrophic factor plasma levels.
Furthermore, said Kuypers, the evidence in healthy volunteers thus far suggests microdosing is “safe.”
Jumping ahead of the science?
Commenting on the study for Medscape Medical News, Jeffrey A. Lieberman, MD, professor and chair of psychiatry at Columbia University, New York City, said he “gives the investigators credit for doing such a study” but does not believe anything can be gleaned from the findings.
He said he is also concerned that the resurgence of psychedelic research is not congruent with “the methodologic rigor and scientific thinking that accompanies treatment development in other disease areas.”
Lieberman, who is also psychiatrist-in-chief at the NewYork–Presbyterian Hospital Columbia Medical Center and was not involved with the study, added that some of the research is also being conducted in individuals who are “true believers and not sufficiently dispassionate and objective.”
“ But because these are such notorious and interesting compounds, they have attracted a lot of peripheral interest to promote and to disseminate; and the risk is that it will be done in the wrong way and there may be consequences,” he said.
Moreover, Lieberman noted that the psychedelic drugs may be used in practice ahead of strong evidence of safety and efficacy. As an example, he pointed to ketamine, a drug that was identified as a treatment for people with depression who had not responded to standard treatments, he noted.
“But before you knew it, there were clinics being opened up all over the place by anesthesiologists or other people that were trying to make a quick buck,” he said.
“That was alarming because they were stretching the criteria for whom the treatment was appropriate; there were no protocols for dosing, for frequency of administration, and there was inadequate psychiatric follow-up,” Lieberman added.
Preliminary but promising
He agreed with Kuypers that cases of microdosing with psychedelics are largely anecdotal.
“So in that context, when these investigators tried to put it to a test, which is commendable, the results in no way tell you whether it’s good, bad, or indifferent,” Lieberman said. In fact, the results are “disappointing in terms of suggesting any beneficial effect.”
Lieberman said more and larger studies are needed in order to determine whether LSD microdosing is beneficial.
In response to Lieberman’s comments, Kuypers told Medscape Medical News that the investigators tried to base their placebo-controlled research on previous anecdotal research.
She emphasized that the “whole field is still in its infancy,” including research on the use of “full” doses of psychedelics.
“I sometimes think that the message is too positive. We should never forget to communicate that not a lot of research has been done.” In addition, she agreed that researchers should “keep a balanced message.”
“All the data to date is preliminary, in my view, but promising,” she stressed, “and the evidence is growing.”
The study received financial support from the Beckley Foundation. The study authors and Lieberman have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Deep brain stimulation ‘promising’ in severe schizophrenia
Deep brain stimulation (DBS) may be an effective option for patients with treatment-resistant schizophrenia (TRS), new research suggests. However, until further studies are conducted, the treatment should only be considered for the most severe cases.
The first clinical trial to assess DBS in this challenging patient population included eight patients initially randomly assigned to receive electrode placement in one of two locations in the brain. Once a clinical response was achieved and participants were stabilized, they were randomly assigned to a second crossover phase.
Preliminary findings from the first phase of the DBS-SCHIZO pilot study, which were reported in 2017, showed promising efficacy.
The newly released final results revealed an association between DBS and significant improvements in Positive and Negative Symptoms Scale (PANSS) scores, as well as reductions in doses of antipsychotic medication. Moreover, the effect reversed when the electrode was switched off.
“DBS may be a potential option for severe treatment-resistant schizophrenia patients,” lead investigator Iluminada Corripio, MD, PhD, department of psychiatry, Hospital de la Santa Creu i Sant Pau, Barcelona, said during her presentation at the virtual congress of the European College of Neuropsychopharmacology. The new data were updated results of a study published in EBioMedicine earlier this year.
Dr. Corripio underlined that it is important to balance the risks and benefits of the intervention. DBS is “not useful for all phenotypes,” and benefits have been seen in patients with hallucinations but not in those with a disorganized phenotype, she added.
High economic burden
Managing TRS is challenging and is associated with a high clinical and economic burden, Corripio noted. Relapse rates can reach 80%, increasing resource use by between 200% and 900%.
There is a strong rationale for studying the use of DBS in schizophrenia, because schizophrenia shares a neurologic basis with other neurologic and psychiatric disorders centered around the cortical-striatal-thalamic-cortical circuit, said Dr. Corripio.
The study included eight patients with a DSM-IV-TR diagnosis of schizophrenia whose conditions were resistant to at least two different atypical antipsychotics and who had not responded to clozapine monotherapy, combination therapy, or electroconvulsive therapy.
All were randomly assigned in a 1:1 ratio to DBS electrode implantation in one of two locations. Investigators chose the nucleus accumbens (NAcc), because recent studies have shown that DBS can increase dopamine levels there, and the subgenual anterior cingulate cortex (ACC). Deactivation failure in the ACC region has been observed in patients with schizophrenia and other mental illnesses.
Stimulation began 48-72 hours postoperatively with unilateral left stimulation at 2.5 volts. It was increased in 0.5 volt increments to a maximum of 7.5 volts. Patients who did not respond were switched to bilateral stimulation.
Follow-up was conducted every 2 weeks for up to 20 months. The study’s primary outcome was a symptomatic response, defined as an improvement of at least 25% on the PANSS.
Once that was achieved, patients could enter a second randomization phase in which they were assigned, in a 24-week, double-blind crossover design, to on- or off-treatment DBS arms such that patients received stimulation for 12 weeks before the device was turned off for 12 weeks, or vice versa.
Those who experienced relapse while off treatment were crossed over to the on-treatment arm; those who experienced relapsed while on treatment were withdrawn from the study. The patients’ average age was 42.5 years, and 50% were women. All were taking clozapine in combination with another antipsychotic.
Adverse events
Five patients experienced adverse events during the first phase, four of which were associated with rechargeable battery replacement. One experienced akathisia, another experienced behavioral changes, and a third experienced electrical disturbances.
A fourth patient experienced postsurgical hemorrhage of the right internal capsule on day 4, followed by encephalitis at week 8. He had a clinical improvement but experienced relapsed during follow-up.
The fifth patient accidentally switched off the device and withdrew from the study.
During the first randomization phase, DBS was associated with significant improvements on total, positive, and negative PANSS scores in comparison with the postoperative baseline measure in the seven remaining patients (P < .001).
When the team compared the baseline measure with the last observation, the improvement in PANSS scores remained significant for total scores (P = .007) and positive scores (P = .002), but not for negative scores (P = .18).
Three patients entered the second crossover phase of the study. Two began in the off-treatment arm and experienced relapsed within 1 and 2 weeks, respectively. Total PANSS scores increased from 79 to 98 for the first patient and from 47 to 93 for the second patient.
Neuroimaging showed that, among patients who responded to DBS, brain metabolism increased in some brain areas and decreased in others. Dr. Corripio said this suggests a “rebalancing” of neural circuits.
As of July 2020, one of three patients with an electrode placed in the NAcc had experienced remission of positive symptoms and now has predominant negative symptoms. Another experienced significant improvements in negative symptoms. Two patients currently require psychosocial rehabilitation.
Patients for whom an electrode was placed in the ACC required higher voltages and more time to achieve an effect in comparison with those for whom an electrode was placed in the NAcc. Two patients required bilateral stimulation.
However, for all three patients who remained in the study, their clozapine dose was reduced.
Dr. Corripio reported that the team has observed negative thoughts and obsessive symptoms in patients with electrodes in the ACC, and all have needed either psychosocial rehabilitation or cognitive-behavioral therapy.
The investigators are now planning another DBS study involving patients with TRS, although this one will include a clinical recovery program focusing on family interventions and cognitive-behavioral therapy.
“Last-resort” treatment
In the postpresentation debate, Damiaan Denys, PhD, professor and chair of the department of psychiatry at the Academic Medical Canter, University of Amsterdam, said that DBS remains a treatment of “last resort” in TRS.
This is because it is both costly and invasive, and although the associated risk of bleeding and infection is low, he noted that the consequences are significant.
Dr. Denys added that patients need to have the potential for improvement; electrodes can be easily implanted, and the approach may tempt clinicians who sometimes “struggle with a huge amount of treatment-refractory cases.”
He also pointed to results achieved in studies of obsessive-compulsive disorder and depression, in which around 50% of patients responded to DBS.
“I think that’s the reason why we should be reluctant and not treat anyone at any stage, but first look for the more severe cases,” Dr. Denys said.
Unmet need
Judith M. Gault, PhD, associate research professor of neurosurgery at the University of Colorado at Denver, Aurora, also took part in the debate.
She said in an interview that patients with TRS have a lot of unmet needs and that DBS is worth trying in this patient population, with the goal being to “conduct a really good clinical trial” similar to the current study.
Antipsychotic drugs work well in responsive patients, but “in some cases the person is treatment refractory ... and in other cases the patient relapses,” Dr. Gault said.
She believes that DBS has the “potential to be more potent than antipsychotics in modulating the circuit of interest” and so fulfills the unmet needs of these patients while alleviating their symptoms.
Dr. Gault added that some patients experience “breakthrough symptoms” even while they are medication adherent. “That is a call for an intervention that is more potent” and suggests another potential role for DBS.
Overall, there are “a lot of really compelling reasons to pursue” DBS. However, there are also questions about how motivated patients with TRS are to participate in a clinical trial, Dr. Gault noted.
Patients with schizophrenia “tend not to be very motivated, especially if they have negative symptoms.” However, “if you were able to consider more of the population and not just the most severely affected, eventually you would find more people who are interested,” she said.
Still, it will take a better understanding of the efficacy and safety of the intervention for more people to be interested in trying it, said Dr. Gault.
“I think it’s hard early on, when you don’t actually know what the outcomes would be, if it’s even effective at all. But as you get more and more data in the population and at the different targets, people would be more open to it,” she said.
Another issue in generating interest among patients with schizophrenia is that many have not considered DBS as an option.
“It takes a while to think about it,” she noted. “You don’t want to rush into something that you just heard about, and so part of it is just education.”
The study was funded by Instituto Carlos III. Dr. Corripio reported having received research grants and conducting consultancy for Otsuka, Ferrer, Janssen, and Lilly. No other relevant financial relationships were reported.
A version of this article originally appeared on Medscape.com.
Deep brain stimulation (DBS) may be an effective option for patients with treatment-resistant schizophrenia (TRS), new research suggests. However, until further studies are conducted, the treatment should only be considered for the most severe cases.
The first clinical trial to assess DBS in this challenging patient population included eight patients initially randomly assigned to receive electrode placement in one of two locations in the brain. Once a clinical response was achieved and participants were stabilized, they were randomly assigned to a second crossover phase.
Preliminary findings from the first phase of the DBS-SCHIZO pilot study, which were reported in 2017, showed promising efficacy.
The newly released final results revealed an association between DBS and significant improvements in Positive and Negative Symptoms Scale (PANSS) scores, as well as reductions in doses of antipsychotic medication. Moreover, the effect reversed when the electrode was switched off.
“DBS may be a potential option for severe treatment-resistant schizophrenia patients,” lead investigator Iluminada Corripio, MD, PhD, department of psychiatry, Hospital de la Santa Creu i Sant Pau, Barcelona, said during her presentation at the virtual congress of the European College of Neuropsychopharmacology. The new data were updated results of a study published in EBioMedicine earlier this year.
Dr. Corripio underlined that it is important to balance the risks and benefits of the intervention. DBS is “not useful for all phenotypes,” and benefits have been seen in patients with hallucinations but not in those with a disorganized phenotype, she added.
High economic burden
Managing TRS is challenging and is associated with a high clinical and economic burden, Corripio noted. Relapse rates can reach 80%, increasing resource use by between 200% and 900%.
There is a strong rationale for studying the use of DBS in schizophrenia, because schizophrenia shares a neurologic basis with other neurologic and psychiatric disorders centered around the cortical-striatal-thalamic-cortical circuit, said Dr. Corripio.
The study included eight patients with a DSM-IV-TR diagnosis of schizophrenia whose conditions were resistant to at least two different atypical antipsychotics and who had not responded to clozapine monotherapy, combination therapy, or electroconvulsive therapy.
All were randomly assigned in a 1:1 ratio to DBS electrode implantation in one of two locations. Investigators chose the nucleus accumbens (NAcc), because recent studies have shown that DBS can increase dopamine levels there, and the subgenual anterior cingulate cortex (ACC). Deactivation failure in the ACC region has been observed in patients with schizophrenia and other mental illnesses.
Stimulation began 48-72 hours postoperatively with unilateral left stimulation at 2.5 volts. It was increased in 0.5 volt increments to a maximum of 7.5 volts. Patients who did not respond were switched to bilateral stimulation.
Follow-up was conducted every 2 weeks for up to 20 months. The study’s primary outcome was a symptomatic response, defined as an improvement of at least 25% on the PANSS.
Once that was achieved, patients could enter a second randomization phase in which they were assigned, in a 24-week, double-blind crossover design, to on- or off-treatment DBS arms such that patients received stimulation for 12 weeks before the device was turned off for 12 weeks, or vice versa.
Those who experienced relapse while off treatment were crossed over to the on-treatment arm; those who experienced relapsed while on treatment were withdrawn from the study. The patients’ average age was 42.5 years, and 50% were women. All were taking clozapine in combination with another antipsychotic.
Adverse events
Five patients experienced adverse events during the first phase, four of which were associated with rechargeable battery replacement. One experienced akathisia, another experienced behavioral changes, and a third experienced electrical disturbances.
A fourth patient experienced postsurgical hemorrhage of the right internal capsule on day 4, followed by encephalitis at week 8. He had a clinical improvement but experienced relapsed during follow-up.
The fifth patient accidentally switched off the device and withdrew from the study.
During the first randomization phase, DBS was associated with significant improvements on total, positive, and negative PANSS scores in comparison with the postoperative baseline measure in the seven remaining patients (P < .001).
When the team compared the baseline measure with the last observation, the improvement in PANSS scores remained significant for total scores (P = .007) and positive scores (P = .002), but not for negative scores (P = .18).
Three patients entered the second crossover phase of the study. Two began in the off-treatment arm and experienced relapsed within 1 and 2 weeks, respectively. Total PANSS scores increased from 79 to 98 for the first patient and from 47 to 93 for the second patient.
Neuroimaging showed that, among patients who responded to DBS, brain metabolism increased in some brain areas and decreased in others. Dr. Corripio said this suggests a “rebalancing” of neural circuits.
As of July 2020, one of three patients with an electrode placed in the NAcc had experienced remission of positive symptoms and now has predominant negative symptoms. Another experienced significant improvements in negative symptoms. Two patients currently require psychosocial rehabilitation.
Patients for whom an electrode was placed in the ACC required higher voltages and more time to achieve an effect in comparison with those for whom an electrode was placed in the NAcc. Two patients required bilateral stimulation.
However, for all three patients who remained in the study, their clozapine dose was reduced.
Dr. Corripio reported that the team has observed negative thoughts and obsessive symptoms in patients with electrodes in the ACC, and all have needed either psychosocial rehabilitation or cognitive-behavioral therapy.
The investigators are now planning another DBS study involving patients with TRS, although this one will include a clinical recovery program focusing on family interventions and cognitive-behavioral therapy.
“Last-resort” treatment
In the postpresentation debate, Damiaan Denys, PhD, professor and chair of the department of psychiatry at the Academic Medical Canter, University of Amsterdam, said that DBS remains a treatment of “last resort” in TRS.
This is because it is both costly and invasive, and although the associated risk of bleeding and infection is low, he noted that the consequences are significant.
Dr. Denys added that patients need to have the potential for improvement; electrodes can be easily implanted, and the approach may tempt clinicians who sometimes “struggle with a huge amount of treatment-refractory cases.”
He also pointed to results achieved in studies of obsessive-compulsive disorder and depression, in which around 50% of patients responded to DBS.
“I think that’s the reason why we should be reluctant and not treat anyone at any stage, but first look for the more severe cases,” Dr. Denys said.
Unmet need
Judith M. Gault, PhD, associate research professor of neurosurgery at the University of Colorado at Denver, Aurora, also took part in the debate.
She said in an interview that patients with TRS have a lot of unmet needs and that DBS is worth trying in this patient population, with the goal being to “conduct a really good clinical trial” similar to the current study.
Antipsychotic drugs work well in responsive patients, but “in some cases the person is treatment refractory ... and in other cases the patient relapses,” Dr. Gault said.
She believes that DBS has the “potential to be more potent than antipsychotics in modulating the circuit of interest” and so fulfills the unmet needs of these patients while alleviating their symptoms.
Dr. Gault added that some patients experience “breakthrough symptoms” even while they are medication adherent. “That is a call for an intervention that is more potent” and suggests another potential role for DBS.
Overall, there are “a lot of really compelling reasons to pursue” DBS. However, there are also questions about how motivated patients with TRS are to participate in a clinical trial, Dr. Gault noted.
Patients with schizophrenia “tend not to be very motivated, especially if they have negative symptoms.” However, “if you were able to consider more of the population and not just the most severely affected, eventually you would find more people who are interested,” she said.
Still, it will take a better understanding of the efficacy and safety of the intervention for more people to be interested in trying it, said Dr. Gault.
“I think it’s hard early on, when you don’t actually know what the outcomes would be, if it’s even effective at all. But as you get more and more data in the population and at the different targets, people would be more open to it,” she said.
Another issue in generating interest among patients with schizophrenia is that many have not considered DBS as an option.
“It takes a while to think about it,” she noted. “You don’t want to rush into something that you just heard about, and so part of it is just education.”
The study was funded by Instituto Carlos III. Dr. Corripio reported having received research grants and conducting consultancy for Otsuka, Ferrer, Janssen, and Lilly. No other relevant financial relationships were reported.
A version of this article originally appeared on Medscape.com.
Deep brain stimulation (DBS) may be an effective option for patients with treatment-resistant schizophrenia (TRS), new research suggests. However, until further studies are conducted, the treatment should only be considered for the most severe cases.
The first clinical trial to assess DBS in this challenging patient population included eight patients initially randomly assigned to receive electrode placement in one of two locations in the brain. Once a clinical response was achieved and participants were stabilized, they were randomly assigned to a second crossover phase.
Preliminary findings from the first phase of the DBS-SCHIZO pilot study, which were reported in 2017, showed promising efficacy.
The newly released final results revealed an association between DBS and significant improvements in Positive and Negative Symptoms Scale (PANSS) scores, as well as reductions in doses of antipsychotic medication. Moreover, the effect reversed when the electrode was switched off.
“DBS may be a potential option for severe treatment-resistant schizophrenia patients,” lead investigator Iluminada Corripio, MD, PhD, department of psychiatry, Hospital de la Santa Creu i Sant Pau, Barcelona, said during her presentation at the virtual congress of the European College of Neuropsychopharmacology. The new data were updated results of a study published in EBioMedicine earlier this year.
Dr. Corripio underlined that it is important to balance the risks and benefits of the intervention. DBS is “not useful for all phenotypes,” and benefits have been seen in patients with hallucinations but not in those with a disorganized phenotype, she added.
High economic burden
Managing TRS is challenging and is associated with a high clinical and economic burden, Corripio noted. Relapse rates can reach 80%, increasing resource use by between 200% and 900%.
There is a strong rationale for studying the use of DBS in schizophrenia, because schizophrenia shares a neurologic basis with other neurologic and psychiatric disorders centered around the cortical-striatal-thalamic-cortical circuit, said Dr. Corripio.
The study included eight patients with a DSM-IV-TR diagnosis of schizophrenia whose conditions were resistant to at least two different atypical antipsychotics and who had not responded to clozapine monotherapy, combination therapy, or electroconvulsive therapy.
All were randomly assigned in a 1:1 ratio to DBS electrode implantation in one of two locations. Investigators chose the nucleus accumbens (NAcc), because recent studies have shown that DBS can increase dopamine levels there, and the subgenual anterior cingulate cortex (ACC). Deactivation failure in the ACC region has been observed in patients with schizophrenia and other mental illnesses.
Stimulation began 48-72 hours postoperatively with unilateral left stimulation at 2.5 volts. It was increased in 0.5 volt increments to a maximum of 7.5 volts. Patients who did not respond were switched to bilateral stimulation.
Follow-up was conducted every 2 weeks for up to 20 months. The study’s primary outcome was a symptomatic response, defined as an improvement of at least 25% on the PANSS.
Once that was achieved, patients could enter a second randomization phase in which they were assigned, in a 24-week, double-blind crossover design, to on- or off-treatment DBS arms such that patients received stimulation for 12 weeks before the device was turned off for 12 weeks, or vice versa.
Those who experienced relapse while off treatment were crossed over to the on-treatment arm; those who experienced relapsed while on treatment were withdrawn from the study. The patients’ average age was 42.5 years, and 50% were women. All were taking clozapine in combination with another antipsychotic.
Adverse events
Five patients experienced adverse events during the first phase, four of which were associated with rechargeable battery replacement. One experienced akathisia, another experienced behavioral changes, and a third experienced electrical disturbances.
A fourth patient experienced postsurgical hemorrhage of the right internal capsule on day 4, followed by encephalitis at week 8. He had a clinical improvement but experienced relapsed during follow-up.
The fifth patient accidentally switched off the device and withdrew from the study.
During the first randomization phase, DBS was associated with significant improvements on total, positive, and negative PANSS scores in comparison with the postoperative baseline measure in the seven remaining patients (P < .001).
When the team compared the baseline measure with the last observation, the improvement in PANSS scores remained significant for total scores (P = .007) and positive scores (P = .002), but not for negative scores (P = .18).
Three patients entered the second crossover phase of the study. Two began in the off-treatment arm and experienced relapsed within 1 and 2 weeks, respectively. Total PANSS scores increased from 79 to 98 for the first patient and from 47 to 93 for the second patient.
Neuroimaging showed that, among patients who responded to DBS, brain metabolism increased in some brain areas and decreased in others. Dr. Corripio said this suggests a “rebalancing” of neural circuits.
As of July 2020, one of three patients with an electrode placed in the NAcc had experienced remission of positive symptoms and now has predominant negative symptoms. Another experienced significant improvements in negative symptoms. Two patients currently require psychosocial rehabilitation.
Patients for whom an electrode was placed in the ACC required higher voltages and more time to achieve an effect in comparison with those for whom an electrode was placed in the NAcc. Two patients required bilateral stimulation.
However, for all three patients who remained in the study, their clozapine dose was reduced.
Dr. Corripio reported that the team has observed negative thoughts and obsessive symptoms in patients with electrodes in the ACC, and all have needed either psychosocial rehabilitation or cognitive-behavioral therapy.
The investigators are now planning another DBS study involving patients with TRS, although this one will include a clinical recovery program focusing on family interventions and cognitive-behavioral therapy.
“Last-resort” treatment
In the postpresentation debate, Damiaan Denys, PhD, professor and chair of the department of psychiatry at the Academic Medical Canter, University of Amsterdam, said that DBS remains a treatment of “last resort” in TRS.
This is because it is both costly and invasive, and although the associated risk of bleeding and infection is low, he noted that the consequences are significant.
Dr. Denys added that patients need to have the potential for improvement; electrodes can be easily implanted, and the approach may tempt clinicians who sometimes “struggle with a huge amount of treatment-refractory cases.”
He also pointed to results achieved in studies of obsessive-compulsive disorder and depression, in which around 50% of patients responded to DBS.
“I think that’s the reason why we should be reluctant and not treat anyone at any stage, but first look for the more severe cases,” Dr. Denys said.
Unmet need
Judith M. Gault, PhD, associate research professor of neurosurgery at the University of Colorado at Denver, Aurora, also took part in the debate.
She said in an interview that patients with TRS have a lot of unmet needs and that DBS is worth trying in this patient population, with the goal being to “conduct a really good clinical trial” similar to the current study.
Antipsychotic drugs work well in responsive patients, but “in some cases the person is treatment refractory ... and in other cases the patient relapses,” Dr. Gault said.
She believes that DBS has the “potential to be more potent than antipsychotics in modulating the circuit of interest” and so fulfills the unmet needs of these patients while alleviating their symptoms.
Dr. Gault added that some patients experience “breakthrough symptoms” even while they are medication adherent. “That is a call for an intervention that is more potent” and suggests another potential role for DBS.
Overall, there are “a lot of really compelling reasons to pursue” DBS. However, there are also questions about how motivated patients with TRS are to participate in a clinical trial, Dr. Gault noted.
Patients with schizophrenia “tend not to be very motivated, especially if they have negative symptoms.” However, “if you were able to consider more of the population and not just the most severely affected, eventually you would find more people who are interested,” she said.
Still, it will take a better understanding of the efficacy and safety of the intervention for more people to be interested in trying it, said Dr. Gault.
“I think it’s hard early on, when you don’t actually know what the outcomes would be, if it’s even effective at all. But as you get more and more data in the population and at the different targets, people would be more open to it,” she said.
Another issue in generating interest among patients with schizophrenia is that many have not considered DBS as an option.
“It takes a while to think about it,” she noted. “You don’t want to rush into something that you just heard about, and so part of it is just education.”
The study was funded by Instituto Carlos III. Dr. Corripio reported having received research grants and conducting consultancy for Otsuka, Ferrer, Janssen, and Lilly. No other relevant financial relationships were reported.
A version of this article originally appeared on Medscape.com.
‘Paradigm shift’ in gastric junction cancers with nivolumab
Patients with gastric cancer or gastroesophageal junction cancer (GEJ) could experience significantly improved progression-free survival (PFS), and maybe overall survival (OS), with nivolumab (Opdivo) in the first-line and neoadjuvant settings, suggest data from three phase 3 trials.
However, contrasting results between the trials and question marks over the effect of the drug in all-comers leave some questions yet to be answered, despite the “practice-changing” findings, said experts discussing the new data.
The research was presented Sept. 21 at the European Society for Medical Oncology Virtual Congress 2020.
Gastric cancer and GEJ have been an area of interest for immunotherapy in recent years, as standard first-line chemotherapy is associated with poor OS at a median of less than 1 year.
Previous smaller studies have suggested that nivolumab has promising activity in the first-line setting, improving survival particularly in individuals with a combined positive score (CPS) for programmed death–ligand 1 (PD-L1) expression ≥5.
The new results come from the largest phase 3 trial of its kind to date, CheckMate 649, which involved 1,581 previously untreated patients with unresectable HER2-negative gastric cancer, GEJ, or esophageal adenocarcinoma.
Among these patients, 60% had a PD-L1 CPS ≥5.
Patients were randomly assigned to one of three treatment groups: Nivolumab plus ipilimumab (Yervoy), nivolumab plus oxaliplatin-based chemotherapy, or chemotherapy alone.
Results, after a minimum follow-up of 12 months, show that nivolumab plus chemotherapy was associated with significantly better OS than chemotherapy alone, reported Markus Moehler, MD, PhD, Johannes-Gutenberg University Clinic, Mainz, Germany.
In patients with PD-L1 CPS ≥5, median OS was 14.4 months with nivolumab-chemotherapy versus 11.1 months for chemotherapy alone (hazard ratio 0.71, P < .0001).
The figures were similar for patients with a PD-L1 CPS ≥1, at 14.0 months and 11.3 months (HR, 0.77; P = .0001), and also across the whole study population (13.8 months vs. 11.6 months; HR, 0.80, P = .0002).
PFS, however, was significantly improved with the nivolumab-chemotherapy combination only in patients with a PD-L1 CPS ≥5, at a median of 7.7 months vs 6.0 months (HR, 0.68, P < .0001).
The proportion of patients with treatment-related adverse events leading to discontinuation were 36% with nivolumab plus chemotherapy and 24% for chemotherapy alone.
At a press conference, Dr. Moehler said the benefits seen with nivolumab plus chemotherapy are “highly clinically meaningful,” and the combination “represents a new potential standard first-line treatment” for these patients.
These results are “practice changing” and are “clearly significant,” commented Salah-Eddin Al-Batran, MD, Krankenhaus Nordwest-University Cancer Center, Frankfurt, Germany, who was not involved with the study.
“However, as a physician,” he continued, “I am treating an individual patient and, for me, it’s important to know the efficacy in the patients with a CPS of 1-4, or of 0.”
“We have to be sure that we do not inflate the results for the all-comers by the very responsive group of high-expressers,” he said, adding that other factors to consider will be microsatellite instability and tumor mutational burden. “I think these questions have to be addressed to give us a clear picture of how to treat the patient sitting in front of us.”
Surprisingly, the results from ATTRACTION-4, a very similar phase 3 trial conducted in Japan, Korea, and Taiwan, did not follow the same pattern.
This trial involved 724 previously untreated patients with HER2-negative gastric cancer or GEJ randomly assigned to receive nivolumab plus chemotherapy or chemotherapy alone.
Lead author Narikazu Boku, MD, PhD, National Cancer Center Hospital, Tokyo, Japan, said that, after a median follow-up of 11.6 months, the combination treatment was associated with a significant improvement in PFS, at a median 10.5 months versus 8.3 months with chemotherapy alone (HR, 0.68, P = .0007).
In contrast, there was no significant difference in OS between the nivolumab and placebo arms, at a median of 17.5 months and 17.2 months, respectively (HR, 0.90; P = .257).
Invited discussant Elizabeth Smyth, MD, from Addenbrooke’s Hospital in Cambridge, England, suggested the lack of OS benefit seen in ATTRACTION-4 could be the result of a number of factors, including that PD-L1 status was assessed on tumor cells only and there were no key endpoints based around PD-L1 status.
Moreover, the posttrial therapy could have affected the overall results, as Asian patients typically receive more subsequent therapies than those elsewhere.
Dr. Smyth also commented that both CheckMate 649 and ATTRACTION-4 represent a “paradigm shift” in the first-line treatment of gastroesophageal adenocarcinoma.
Nivolumab in adjuvant setting
The results of a third trial presented at the ESMO meeting suggest a role for nivolumab in the adjuvant setting, following neoadjuvant chemoradiation therapy in patients with resected esophageal or GEJ cancer.
This was the CheckMate 577 trial, which compared adjuvant nivolumab with placebo in 794 patients from across the globe.
Nivolumab significantly increased median disease-free survival to 22.4 months versus 11.0 months with placebo (HR, 0.69, P = .0003).
Treatment-related adverse events leading to discontinuation were reported in 9% of nivolumab patients versus 3% on placebo, reported Ronan J. Kelly, MD, chief of oncology at Baylor Scott & White Health in Dallas.
Interestingly, patient-reported health status on the EQ-5D-3L visual analogue scale (VAS) and utility index were similar between nivolumab- and placebo-treated patients, with both groups experiencing clinically meaningful improvements.
Dr. Kelly said this is “the first adjuvant therapy to provide a statistically significant and clinically meaningful improvement” in patients with esophageal cancer or GEJ cancer following neoadjuvant chemoradiation.
Consequently, the results “represent the first advance in years for this group of patients, potentially establishing adjuvant nivolumab as a new standard of care.”
However, the invited discussant raised several issues with the trial design. Preoperative chemoradiation is not “universally accepted” as the standard of care in this setting, disease-free survival is not currently validated as a major endpoint in gastroesophageal cancers, and the median follow-up was short, commented Andrés Cervantes, MD, PhD, University of Valencia (Spain), and president-elect of ESMO.
In addition, there was no differentiation between esophageal squamous cell and adenocarcinoma histologies.
Nevertheless, CheckMate 577 is the first positive adjuvant study for checkpoint inhibitors in gastrointestinal tumors and, crucially, the results “are independent of PD-L1 status,” Dr. Cervantes said.
CheckMate 649 was funded by Bristol-Myers Squibb. ATTRACTION-4 was funded by Ono Pharmaceutical and Bristol-Myers Squibb. CheckMate 577 was funded by Bristol-Myers Squibb. Many of the presenters reported relationships with pharmaceutical companies.
This article first appeared on Medscape.com.
Patients with gastric cancer or gastroesophageal junction cancer (GEJ) could experience significantly improved progression-free survival (PFS), and maybe overall survival (OS), with nivolumab (Opdivo) in the first-line and neoadjuvant settings, suggest data from three phase 3 trials.
However, contrasting results between the trials and question marks over the effect of the drug in all-comers leave some questions yet to be answered, despite the “practice-changing” findings, said experts discussing the new data.
The research was presented Sept. 21 at the European Society for Medical Oncology Virtual Congress 2020.
Gastric cancer and GEJ have been an area of interest for immunotherapy in recent years, as standard first-line chemotherapy is associated with poor OS at a median of less than 1 year.
Previous smaller studies have suggested that nivolumab has promising activity in the first-line setting, improving survival particularly in individuals with a combined positive score (CPS) for programmed death–ligand 1 (PD-L1) expression ≥5.
The new results come from the largest phase 3 trial of its kind to date, CheckMate 649, which involved 1,581 previously untreated patients with unresectable HER2-negative gastric cancer, GEJ, or esophageal adenocarcinoma.
Among these patients, 60% had a PD-L1 CPS ≥5.
Patients were randomly assigned to one of three treatment groups: Nivolumab plus ipilimumab (Yervoy), nivolumab plus oxaliplatin-based chemotherapy, or chemotherapy alone.
Results, after a minimum follow-up of 12 months, show that nivolumab plus chemotherapy was associated with significantly better OS than chemotherapy alone, reported Markus Moehler, MD, PhD, Johannes-Gutenberg University Clinic, Mainz, Germany.
In patients with PD-L1 CPS ≥5, median OS was 14.4 months with nivolumab-chemotherapy versus 11.1 months for chemotherapy alone (hazard ratio 0.71, P < .0001).
The figures were similar for patients with a PD-L1 CPS ≥1, at 14.0 months and 11.3 months (HR, 0.77; P = .0001), and also across the whole study population (13.8 months vs. 11.6 months; HR, 0.80, P = .0002).
PFS, however, was significantly improved with the nivolumab-chemotherapy combination only in patients with a PD-L1 CPS ≥5, at a median of 7.7 months vs 6.0 months (HR, 0.68, P < .0001).
The proportion of patients with treatment-related adverse events leading to discontinuation were 36% with nivolumab plus chemotherapy and 24% for chemotherapy alone.
At a press conference, Dr. Moehler said the benefits seen with nivolumab plus chemotherapy are “highly clinically meaningful,” and the combination “represents a new potential standard first-line treatment” for these patients.
These results are “practice changing” and are “clearly significant,” commented Salah-Eddin Al-Batran, MD, Krankenhaus Nordwest-University Cancer Center, Frankfurt, Germany, who was not involved with the study.
“However, as a physician,” he continued, “I am treating an individual patient and, for me, it’s important to know the efficacy in the patients with a CPS of 1-4, or of 0.”
“We have to be sure that we do not inflate the results for the all-comers by the very responsive group of high-expressers,” he said, adding that other factors to consider will be microsatellite instability and tumor mutational burden. “I think these questions have to be addressed to give us a clear picture of how to treat the patient sitting in front of us.”
Surprisingly, the results from ATTRACTION-4, a very similar phase 3 trial conducted in Japan, Korea, and Taiwan, did not follow the same pattern.
This trial involved 724 previously untreated patients with HER2-negative gastric cancer or GEJ randomly assigned to receive nivolumab plus chemotherapy or chemotherapy alone.
Lead author Narikazu Boku, MD, PhD, National Cancer Center Hospital, Tokyo, Japan, said that, after a median follow-up of 11.6 months, the combination treatment was associated with a significant improvement in PFS, at a median 10.5 months versus 8.3 months with chemotherapy alone (HR, 0.68, P = .0007).
In contrast, there was no significant difference in OS between the nivolumab and placebo arms, at a median of 17.5 months and 17.2 months, respectively (HR, 0.90; P = .257).
Invited discussant Elizabeth Smyth, MD, from Addenbrooke’s Hospital in Cambridge, England, suggested the lack of OS benefit seen in ATTRACTION-4 could be the result of a number of factors, including that PD-L1 status was assessed on tumor cells only and there were no key endpoints based around PD-L1 status.
Moreover, the posttrial therapy could have affected the overall results, as Asian patients typically receive more subsequent therapies than those elsewhere.
Dr. Smyth also commented that both CheckMate 649 and ATTRACTION-4 represent a “paradigm shift” in the first-line treatment of gastroesophageal adenocarcinoma.
Nivolumab in adjuvant setting
The results of a third trial presented at the ESMO meeting suggest a role for nivolumab in the adjuvant setting, following neoadjuvant chemoradiation therapy in patients with resected esophageal or GEJ cancer.
This was the CheckMate 577 trial, which compared adjuvant nivolumab with placebo in 794 patients from across the globe.
Nivolumab significantly increased median disease-free survival to 22.4 months versus 11.0 months with placebo (HR, 0.69, P = .0003).
Treatment-related adverse events leading to discontinuation were reported in 9% of nivolumab patients versus 3% on placebo, reported Ronan J. Kelly, MD, chief of oncology at Baylor Scott & White Health in Dallas.
Interestingly, patient-reported health status on the EQ-5D-3L visual analogue scale (VAS) and utility index were similar between nivolumab- and placebo-treated patients, with both groups experiencing clinically meaningful improvements.
Dr. Kelly said this is “the first adjuvant therapy to provide a statistically significant and clinically meaningful improvement” in patients with esophageal cancer or GEJ cancer following neoadjuvant chemoradiation.
Consequently, the results “represent the first advance in years for this group of patients, potentially establishing adjuvant nivolumab as a new standard of care.”
However, the invited discussant raised several issues with the trial design. Preoperative chemoradiation is not “universally accepted” as the standard of care in this setting, disease-free survival is not currently validated as a major endpoint in gastroesophageal cancers, and the median follow-up was short, commented Andrés Cervantes, MD, PhD, University of Valencia (Spain), and president-elect of ESMO.
In addition, there was no differentiation between esophageal squamous cell and adenocarcinoma histologies.
Nevertheless, CheckMate 577 is the first positive adjuvant study for checkpoint inhibitors in gastrointestinal tumors and, crucially, the results “are independent of PD-L1 status,” Dr. Cervantes said.
CheckMate 649 was funded by Bristol-Myers Squibb. ATTRACTION-4 was funded by Ono Pharmaceutical and Bristol-Myers Squibb. CheckMate 577 was funded by Bristol-Myers Squibb. Many of the presenters reported relationships with pharmaceutical companies.
This article first appeared on Medscape.com.
Patients with gastric cancer or gastroesophageal junction cancer (GEJ) could experience significantly improved progression-free survival (PFS), and maybe overall survival (OS), with nivolumab (Opdivo) in the first-line and neoadjuvant settings, suggest data from three phase 3 trials.
However, contrasting results between the trials and question marks over the effect of the drug in all-comers leave some questions yet to be answered, despite the “practice-changing” findings, said experts discussing the new data.
The research was presented Sept. 21 at the European Society for Medical Oncology Virtual Congress 2020.
Gastric cancer and GEJ have been an area of interest for immunotherapy in recent years, as standard first-line chemotherapy is associated with poor OS at a median of less than 1 year.
Previous smaller studies have suggested that nivolumab has promising activity in the first-line setting, improving survival particularly in individuals with a combined positive score (CPS) for programmed death–ligand 1 (PD-L1) expression ≥5.
The new results come from the largest phase 3 trial of its kind to date, CheckMate 649, which involved 1,581 previously untreated patients with unresectable HER2-negative gastric cancer, GEJ, or esophageal adenocarcinoma.
Among these patients, 60% had a PD-L1 CPS ≥5.
Patients were randomly assigned to one of three treatment groups: Nivolumab plus ipilimumab (Yervoy), nivolumab plus oxaliplatin-based chemotherapy, or chemotherapy alone.
Results, after a minimum follow-up of 12 months, show that nivolumab plus chemotherapy was associated with significantly better OS than chemotherapy alone, reported Markus Moehler, MD, PhD, Johannes-Gutenberg University Clinic, Mainz, Germany.
In patients with PD-L1 CPS ≥5, median OS was 14.4 months with nivolumab-chemotherapy versus 11.1 months for chemotherapy alone (hazard ratio 0.71, P < .0001).
The figures were similar for patients with a PD-L1 CPS ≥1, at 14.0 months and 11.3 months (HR, 0.77; P = .0001), and also across the whole study population (13.8 months vs. 11.6 months; HR, 0.80, P = .0002).
PFS, however, was significantly improved with the nivolumab-chemotherapy combination only in patients with a PD-L1 CPS ≥5, at a median of 7.7 months vs 6.0 months (HR, 0.68, P < .0001).
The proportion of patients with treatment-related adverse events leading to discontinuation were 36% with nivolumab plus chemotherapy and 24% for chemotherapy alone.
At a press conference, Dr. Moehler said the benefits seen with nivolumab plus chemotherapy are “highly clinically meaningful,” and the combination “represents a new potential standard first-line treatment” for these patients.
These results are “practice changing” and are “clearly significant,” commented Salah-Eddin Al-Batran, MD, Krankenhaus Nordwest-University Cancer Center, Frankfurt, Germany, who was not involved with the study.
“However, as a physician,” he continued, “I am treating an individual patient and, for me, it’s important to know the efficacy in the patients with a CPS of 1-4, or of 0.”
“We have to be sure that we do not inflate the results for the all-comers by the very responsive group of high-expressers,” he said, adding that other factors to consider will be microsatellite instability and tumor mutational burden. “I think these questions have to be addressed to give us a clear picture of how to treat the patient sitting in front of us.”
Surprisingly, the results from ATTRACTION-4, a very similar phase 3 trial conducted in Japan, Korea, and Taiwan, did not follow the same pattern.
This trial involved 724 previously untreated patients with HER2-negative gastric cancer or GEJ randomly assigned to receive nivolumab plus chemotherapy or chemotherapy alone.
Lead author Narikazu Boku, MD, PhD, National Cancer Center Hospital, Tokyo, Japan, said that, after a median follow-up of 11.6 months, the combination treatment was associated with a significant improvement in PFS, at a median 10.5 months versus 8.3 months with chemotherapy alone (HR, 0.68, P = .0007).
In contrast, there was no significant difference in OS between the nivolumab and placebo arms, at a median of 17.5 months and 17.2 months, respectively (HR, 0.90; P = .257).
Invited discussant Elizabeth Smyth, MD, from Addenbrooke’s Hospital in Cambridge, England, suggested the lack of OS benefit seen in ATTRACTION-4 could be the result of a number of factors, including that PD-L1 status was assessed on tumor cells only and there were no key endpoints based around PD-L1 status.
Moreover, the posttrial therapy could have affected the overall results, as Asian patients typically receive more subsequent therapies than those elsewhere.
Dr. Smyth also commented that both CheckMate 649 and ATTRACTION-4 represent a “paradigm shift” in the first-line treatment of gastroesophageal adenocarcinoma.
Nivolumab in adjuvant setting
The results of a third trial presented at the ESMO meeting suggest a role for nivolumab in the adjuvant setting, following neoadjuvant chemoradiation therapy in patients with resected esophageal or GEJ cancer.
This was the CheckMate 577 trial, which compared adjuvant nivolumab with placebo in 794 patients from across the globe.
Nivolumab significantly increased median disease-free survival to 22.4 months versus 11.0 months with placebo (HR, 0.69, P = .0003).
Treatment-related adverse events leading to discontinuation were reported in 9% of nivolumab patients versus 3% on placebo, reported Ronan J. Kelly, MD, chief of oncology at Baylor Scott & White Health in Dallas.
Interestingly, patient-reported health status on the EQ-5D-3L visual analogue scale (VAS) and utility index were similar between nivolumab- and placebo-treated patients, with both groups experiencing clinically meaningful improvements.
Dr. Kelly said this is “the first adjuvant therapy to provide a statistically significant and clinically meaningful improvement” in patients with esophageal cancer or GEJ cancer following neoadjuvant chemoradiation.
Consequently, the results “represent the first advance in years for this group of patients, potentially establishing adjuvant nivolumab as a new standard of care.”
However, the invited discussant raised several issues with the trial design. Preoperative chemoradiation is not “universally accepted” as the standard of care in this setting, disease-free survival is not currently validated as a major endpoint in gastroesophageal cancers, and the median follow-up was short, commented Andrés Cervantes, MD, PhD, University of Valencia (Spain), and president-elect of ESMO.
In addition, there was no differentiation between esophageal squamous cell and adenocarcinoma histologies.
Nevertheless, CheckMate 577 is the first positive adjuvant study for checkpoint inhibitors in gastrointestinal tumors and, crucially, the results “are independent of PD-L1 status,” Dr. Cervantes said.
CheckMate 649 was funded by Bristol-Myers Squibb. ATTRACTION-4 was funded by Ono Pharmaceutical and Bristol-Myers Squibb. CheckMate 577 was funded by Bristol-Myers Squibb. Many of the presenters reported relationships with pharmaceutical companies.
This article first appeared on Medscape.com.
FROM ESMO 2020
Lenvatinib combo may offer hope after immunotherapy in melanoma
Patients with advanced melanoma who have progressed on anti–programmed death 1/PD-ligand 1 (PD-L1) immunotherapy could substantially extend their overall survival (OS) with a combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and pembrolizumab (Keytruda), suggests an open-label, single arm study.
The research was presented Sept. 19 at the European Society for Medical Oncology Virtual Congress 2020.
In LEAP-004 trial, over 100 patients with stage 3 or 4 melanoma who had progressed after immunotherapy were given lenvatinib plus pembrolizumab, which yielded a median progression-free survival (PFS) of more than 4 months and a median OS of more than a year. Median follow-up was 12 months.
Presenting the findings, Ana Maria Arance Fernandez, MD, PhD, Hospital Clínic de Barcelona, Spain, said lenvatinib plus pembrolizumab has “promising” antitumor activity in patients with advanced melanoma with confirmed progression on a PD-1 inhibitor given alone or in combination. “These results are encouraging given the stringent definition of progression on prior anti-PD-1 therapy and the enrollment of poor-risk patients.”
Dr. Arance Fernandez added that “these data support lenvatinib plus pembrolizumab as a potential treatment regimen for this population of high unmet medical need.”
Bartosz Chmielowski, MD, PhD, Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, who was not involved in the study, discussed the findings.
He highlighted that the patients were not randomly assigned in LEAP-004, with all of them receiving the same therapy.
Nevertheless, the response rate was “quite impressive for this patient population.”
He also drew comparison with previous data with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) in a similar population, noting that the overall survival was less than half that seen in the current trial, “which makes these results even more important.”
“It tells us that this combination might be an option with disease progression on anti-PD-1,” Dr. Chmielowski noted.
Dr. Arance Fernandez pointed out that patients with advanced melanoma who progress on standard-of-care treatment with anti-PD-1 therapy or a cytotoxic T-lymphocyte–associated protein 4 (CTLA4) inhibitor plus anti-PD-1 “have very limited therapeutic options available and there is no approved regimen in this indication.”
Response rate, PFS, and OS
Previous studies have indicated that adding an anti-PD-1 drug to lenvatinib achieves superior antitumor activity than either treatment alone, with promising results in phase 1/2b data in pretreated metastatic melanoma.
LEAP-004 therefore enrolled patients with unresectable stage 3 or 4 melanoma, who had disease progression within 12 weeks of their last dose of anti-PD-(L)1 therapy either alone or with a CTLA4 inhibitor. There was no limit on the number of prior treatments.
The patients received pembrolizumab 200 mg IV for up to 35 cycles plus lenvatinib 20 mg daily until progression, unacceptable toxicity, or patient or physician decision.
They were imaged at baseline and every 9 weeks through to week 54, then every 12 weeks until week 102, and then every 24 weeks.
From February to September 2019, 103 patients were enrolled, all of whom received at least one dose of lenvatinib plus pembrolizumab. The median age of the patients was 63 years, and 53.4% were male.
Dr. Arance Fernandez pointed out that this was a high-risk population, with 20.4% having a lactate dehydrogenase level twice the upper limit of normal and 14.6% having brain metastasis, while the median sum of target lesions was 100 mm.
A BRAFv600 mutation was identified in 36.9% of patients, and 64.1% were PD-L1 positive.
Nearly one third (28.2%) had received a prior anti-CTLA4 plus anti-PD-(L)1 combination, and 19.5% had undergone four or more prior lines of therapy.
The overall response rate to lenvatinib plus pembrolizumab was 21.4%, with 1.9% having a complete response and 19.4% a partial response. This was seen across subgroups, including by age and disease stage.
Dr. Arance Fernandez said the overall response rate was even higher in patients who had previously been treated with an anti-CTLA4 plus anti-PD-(L)1 combination, at 31%.
However, Dr. Chmielowski warned that “we must interpret this result with caution since only 29 patients were in this subpopulation.”
The median duration of response (per blinded independent committee review) across the study population was 6.3 months, with 72.6% still responding at 6 months.
The median PFS was 4.2 months with the combination therapy, with 41.7% of patients progression free at 6 months, and 26.2% at 9 months.
Median overall survival was 13.9 months, with 77.3% of patients still alive at 6 months and 65.4% alive at 9 months.
Although 96.1% of patients experienced at least one treatment-related adverse event of any grade, only 44.7% had grade 3 or higher events, and only in 7.8% of cases did that lead to treatment discontinuation.
The most common adverse events were hypertension (56.3%), diarrhea (35.9%), nausea (34%), and hypothyroidism (33%), although, in the vast majority of cases, these events were grade 1 or 2.
LEAP presents challenges
Dr. Chmielowski would like to see treatment in this setting individualized somehow.
“It will be also important to come up with personalized immunotherapy so that, based on the mechanism of resistance in patient populations, we would be able to choose the subsequent treatments,” he commented.
Dr. Arance Fernandez explained that lenvatinib inhibits multiple tyrosine kinases involved in angiogenesis, cell proliferation, and immune modulation, and has demonstrated immunomodulatory activity in the tumor microenvironment.
However, Dr. Arance Fernandez noted that, as resistance to immunotherapy is “multifactorial,” it may be that a combination treatment will be more effective in these patients.
The study was funded by Merck. Dr. Arance Fernandez has financial ties to Merck and multiple other drug companies. Dr. Chmielowski has financial ties to Merck Serono and multiple other companies.
This article first appeared on Medscape.com.
Patients with advanced melanoma who have progressed on anti–programmed death 1/PD-ligand 1 (PD-L1) immunotherapy could substantially extend their overall survival (OS) with a combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and pembrolizumab (Keytruda), suggests an open-label, single arm study.
The research was presented Sept. 19 at the European Society for Medical Oncology Virtual Congress 2020.
In LEAP-004 trial, over 100 patients with stage 3 or 4 melanoma who had progressed after immunotherapy were given lenvatinib plus pembrolizumab, which yielded a median progression-free survival (PFS) of more than 4 months and a median OS of more than a year. Median follow-up was 12 months.
Presenting the findings, Ana Maria Arance Fernandez, MD, PhD, Hospital Clínic de Barcelona, Spain, said lenvatinib plus pembrolizumab has “promising” antitumor activity in patients with advanced melanoma with confirmed progression on a PD-1 inhibitor given alone or in combination. “These results are encouraging given the stringent definition of progression on prior anti-PD-1 therapy and the enrollment of poor-risk patients.”
Dr. Arance Fernandez added that “these data support lenvatinib plus pembrolizumab as a potential treatment regimen for this population of high unmet medical need.”
Bartosz Chmielowski, MD, PhD, Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, who was not involved in the study, discussed the findings.
He highlighted that the patients were not randomly assigned in LEAP-004, with all of them receiving the same therapy.
Nevertheless, the response rate was “quite impressive for this patient population.”
He also drew comparison with previous data with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) in a similar population, noting that the overall survival was less than half that seen in the current trial, “which makes these results even more important.”
“It tells us that this combination might be an option with disease progression on anti-PD-1,” Dr. Chmielowski noted.
Dr. Arance Fernandez pointed out that patients with advanced melanoma who progress on standard-of-care treatment with anti-PD-1 therapy or a cytotoxic T-lymphocyte–associated protein 4 (CTLA4) inhibitor plus anti-PD-1 “have very limited therapeutic options available and there is no approved regimen in this indication.”
Response rate, PFS, and OS
Previous studies have indicated that adding an anti-PD-1 drug to lenvatinib achieves superior antitumor activity than either treatment alone, with promising results in phase 1/2b data in pretreated metastatic melanoma.
LEAP-004 therefore enrolled patients with unresectable stage 3 or 4 melanoma, who had disease progression within 12 weeks of their last dose of anti-PD-(L)1 therapy either alone or with a CTLA4 inhibitor. There was no limit on the number of prior treatments.
The patients received pembrolizumab 200 mg IV for up to 35 cycles plus lenvatinib 20 mg daily until progression, unacceptable toxicity, or patient or physician decision.
They were imaged at baseline and every 9 weeks through to week 54, then every 12 weeks until week 102, and then every 24 weeks.
From February to September 2019, 103 patients were enrolled, all of whom received at least one dose of lenvatinib plus pembrolizumab. The median age of the patients was 63 years, and 53.4% were male.
Dr. Arance Fernandez pointed out that this was a high-risk population, with 20.4% having a lactate dehydrogenase level twice the upper limit of normal and 14.6% having brain metastasis, while the median sum of target lesions was 100 mm.
A BRAFv600 mutation was identified in 36.9% of patients, and 64.1% were PD-L1 positive.
Nearly one third (28.2%) had received a prior anti-CTLA4 plus anti-PD-(L)1 combination, and 19.5% had undergone four or more prior lines of therapy.
The overall response rate to lenvatinib plus pembrolizumab was 21.4%, with 1.9% having a complete response and 19.4% a partial response. This was seen across subgroups, including by age and disease stage.
Dr. Arance Fernandez said the overall response rate was even higher in patients who had previously been treated with an anti-CTLA4 plus anti-PD-(L)1 combination, at 31%.
However, Dr. Chmielowski warned that “we must interpret this result with caution since only 29 patients were in this subpopulation.”
The median duration of response (per blinded independent committee review) across the study population was 6.3 months, with 72.6% still responding at 6 months.
The median PFS was 4.2 months with the combination therapy, with 41.7% of patients progression free at 6 months, and 26.2% at 9 months.
Median overall survival was 13.9 months, with 77.3% of patients still alive at 6 months and 65.4% alive at 9 months.
Although 96.1% of patients experienced at least one treatment-related adverse event of any grade, only 44.7% had grade 3 or higher events, and only in 7.8% of cases did that lead to treatment discontinuation.
The most common adverse events were hypertension (56.3%), diarrhea (35.9%), nausea (34%), and hypothyroidism (33%), although, in the vast majority of cases, these events were grade 1 or 2.
LEAP presents challenges
Dr. Chmielowski would like to see treatment in this setting individualized somehow.
“It will be also important to come up with personalized immunotherapy so that, based on the mechanism of resistance in patient populations, we would be able to choose the subsequent treatments,” he commented.
Dr. Arance Fernandez explained that lenvatinib inhibits multiple tyrosine kinases involved in angiogenesis, cell proliferation, and immune modulation, and has demonstrated immunomodulatory activity in the tumor microenvironment.
However, Dr. Arance Fernandez noted that, as resistance to immunotherapy is “multifactorial,” it may be that a combination treatment will be more effective in these patients.
The study was funded by Merck. Dr. Arance Fernandez has financial ties to Merck and multiple other drug companies. Dr. Chmielowski has financial ties to Merck Serono and multiple other companies.
This article first appeared on Medscape.com.
Patients with advanced melanoma who have progressed on anti–programmed death 1/PD-ligand 1 (PD-L1) immunotherapy could substantially extend their overall survival (OS) with a combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and pembrolizumab (Keytruda), suggests an open-label, single arm study.
The research was presented Sept. 19 at the European Society for Medical Oncology Virtual Congress 2020.
In LEAP-004 trial, over 100 patients with stage 3 or 4 melanoma who had progressed after immunotherapy were given lenvatinib plus pembrolizumab, which yielded a median progression-free survival (PFS) of more than 4 months and a median OS of more than a year. Median follow-up was 12 months.
Presenting the findings, Ana Maria Arance Fernandez, MD, PhD, Hospital Clínic de Barcelona, Spain, said lenvatinib plus pembrolizumab has “promising” antitumor activity in patients with advanced melanoma with confirmed progression on a PD-1 inhibitor given alone or in combination. “These results are encouraging given the stringent definition of progression on prior anti-PD-1 therapy and the enrollment of poor-risk patients.”
Dr. Arance Fernandez added that “these data support lenvatinib plus pembrolizumab as a potential treatment regimen for this population of high unmet medical need.”
Bartosz Chmielowski, MD, PhD, Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, who was not involved in the study, discussed the findings.
He highlighted that the patients were not randomly assigned in LEAP-004, with all of them receiving the same therapy.
Nevertheless, the response rate was “quite impressive for this patient population.”
He also drew comparison with previous data with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) in a similar population, noting that the overall survival was less than half that seen in the current trial, “which makes these results even more important.”
“It tells us that this combination might be an option with disease progression on anti-PD-1,” Dr. Chmielowski noted.
Dr. Arance Fernandez pointed out that patients with advanced melanoma who progress on standard-of-care treatment with anti-PD-1 therapy or a cytotoxic T-lymphocyte–associated protein 4 (CTLA4) inhibitor plus anti-PD-1 “have very limited therapeutic options available and there is no approved regimen in this indication.”
Response rate, PFS, and OS
Previous studies have indicated that adding an anti-PD-1 drug to lenvatinib achieves superior antitumor activity than either treatment alone, with promising results in phase 1/2b data in pretreated metastatic melanoma.
LEAP-004 therefore enrolled patients with unresectable stage 3 or 4 melanoma, who had disease progression within 12 weeks of their last dose of anti-PD-(L)1 therapy either alone or with a CTLA4 inhibitor. There was no limit on the number of prior treatments.
The patients received pembrolizumab 200 mg IV for up to 35 cycles plus lenvatinib 20 mg daily until progression, unacceptable toxicity, or patient or physician decision.
They were imaged at baseline and every 9 weeks through to week 54, then every 12 weeks until week 102, and then every 24 weeks.
From February to September 2019, 103 patients were enrolled, all of whom received at least one dose of lenvatinib plus pembrolizumab. The median age of the patients was 63 years, and 53.4% were male.
Dr. Arance Fernandez pointed out that this was a high-risk population, with 20.4% having a lactate dehydrogenase level twice the upper limit of normal and 14.6% having brain metastasis, while the median sum of target lesions was 100 mm.
A BRAFv600 mutation was identified in 36.9% of patients, and 64.1% were PD-L1 positive.
Nearly one third (28.2%) had received a prior anti-CTLA4 plus anti-PD-(L)1 combination, and 19.5% had undergone four or more prior lines of therapy.
The overall response rate to lenvatinib plus pembrolizumab was 21.4%, with 1.9% having a complete response and 19.4% a partial response. This was seen across subgroups, including by age and disease stage.
Dr. Arance Fernandez said the overall response rate was even higher in patients who had previously been treated with an anti-CTLA4 plus anti-PD-(L)1 combination, at 31%.
However, Dr. Chmielowski warned that “we must interpret this result with caution since only 29 patients were in this subpopulation.”
The median duration of response (per blinded independent committee review) across the study population was 6.3 months, with 72.6% still responding at 6 months.
The median PFS was 4.2 months with the combination therapy, with 41.7% of patients progression free at 6 months, and 26.2% at 9 months.
Median overall survival was 13.9 months, with 77.3% of patients still alive at 6 months and 65.4% alive at 9 months.
Although 96.1% of patients experienced at least one treatment-related adverse event of any grade, only 44.7% had grade 3 or higher events, and only in 7.8% of cases did that lead to treatment discontinuation.
The most common adverse events were hypertension (56.3%), diarrhea (35.9%), nausea (34%), and hypothyroidism (33%), although, in the vast majority of cases, these events were grade 1 or 2.
LEAP presents challenges
Dr. Chmielowski would like to see treatment in this setting individualized somehow.
“It will be also important to come up with personalized immunotherapy so that, based on the mechanism of resistance in patient populations, we would be able to choose the subsequent treatments,” he commented.
Dr. Arance Fernandez explained that lenvatinib inhibits multiple tyrosine kinases involved in angiogenesis, cell proliferation, and immune modulation, and has demonstrated immunomodulatory activity in the tumor microenvironment.
However, Dr. Arance Fernandez noted that, as resistance to immunotherapy is “multifactorial,” it may be that a combination treatment will be more effective in these patients.
The study was funded by Merck. Dr. Arance Fernandez has financial ties to Merck and multiple other drug companies. Dr. Chmielowski has financial ties to Merck Serono and multiple other companies.
This article first appeared on Medscape.com.
FROM ESMO 2020