Sharon Worcester

CHICAGO – Tumor protein 53 (TP53) mutation, fibroblast growth factor receptor 1 (FGFR1) amplification, and tumor purity in plasma each predict early progression on palbociclib and/or fulvestrant in patients with advanced estrogen receptor–positive (ER+) breast cancer, according to genomic analyses of PALOMA-3 trial data.

Sharon Worcester/MDedge News

Overall, the presence of one or more of these genomic changes identified 131 out of 310 patients from the phase 3 trial who had baseline samples available, Ben O’Leary, MBBS, said at the annual meeting of the American Society of Clinical Oncology.

“So, a significant minority of patients – 42.3% – potentially who fall into a more poor-prognosis group,” said Dr. O’Leary of the Institute of Cancer Research at the Royal Marsden Hospital in London.

The findings suggest that a “liquid biopsy” at the start of treatment could identify patients at risk for progression.

The PALOMA-3 trial randomized 521 patients with ER+, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer who had previously progressed on endocrine therapy 2:1 to CDK4/CDK6 inhibition with palbociclib plus fulvestrant (P+F) or placebo plus fulvestrant (F), and it showed that adding palbociclib significantly improved progression-free survival (PFS) (N Engl J Med. Jul 16 2015;373:209-19).

For the current analysis, the investigators assessed circulating tumor DNA (ctDNA) in baseline plasma samples from 459 study participants in an effort to identify genomic biomarkers for progression, to examine the association between baseline tumor fraction and clinical outcome, and to explore differences in predictive markers by treatment arm. A custom amplicon-sequencing analysis was performed to look for mutations in 17 different relevant genes, and another was used to estimate tumor fraction by looking at about 800 common germline single-nucleotide polymorphisms and to assess copy-number gain in the amplification status in 11 different genes, Dr. O’Leary said.


Results for mutations and circulating nucleic acids were available in 203 and 107 patients from the P+F and F groups, respectively, and on multivariable analysis of all 310 patients (including palbociclib as a variable in the model and with ctDNA fraction as a continuous variable), higher baseline tumor purity in plasma was associated with highly significantly worse PFS (HR 1.2 per 10% increase in purity), and baseline TP53 mutation and FGFR1 amplification each were associated with significantly shorter PFS (HRs, 1.8 and 2.9, respectively).

“[It is] very important to note ... that we did look specifically for interaction between our genomic changes and treatment, and we didn’t find any evidence of a significant interaction, so these genomic markers [are] prognostic rather than predictive in terms of the two treatment arms of the trial,” he said.

A survival analysis showed a median PFS of 3.7 vs. 12.7 months in patients with vs. without TP53 mutation in the P+F arm, and 1.8 vs. 5.4 months, respectively, in the F arm, with similar HRs of 2.0 and 2.3 in the arms, respectively.

“Even in the [P+F] arm, you see almost half of the patients with a TP53 mutation ... have relapsed by 2 months, the earliest clinical assessment in the trial,” he noted.

For FGFR1, the PFS was 3.9 vs. 12 months with vs. without amplification in the P+F arms, and 1.8 vs. 5.8 months, respectively in th F arm, with HRs of 3.4 and 3.6, respectively.

These findings are notable because markers of early progression on endocrine therapy in combination with CDK4/6 inhibitors remain limited – despite the key role of these combinations in treating ER+ advanced breast cancer, Dr. O’Leary explained.

“Although many patients derive a great deal of benefit from these combinations, there are a subset of patients who will relapse relatively early, and ... we don’t have an established means of identifying those patients at the present,” he said. “From the technical perspective, liquid biopsies have emerged in recent years as a promising means of genotyping patients’ cancers from circulating tumor DNA, and in addition, the overall level of circulating tumor DNA – the fractional purity – has been associated with poor prognosis, specifically in the triple-negative breast cancer setting.”

The results, which require independent validation, could potentially inform future clinical trials of CDK4/6 inhibitor combinations in advanced ER+ breast cancer to identify a high-risk group of patients who require escalation of therapy, he concluded.

Dr. O’Leary reported receiving research funding from Pfizer to his institution.

SOURCE: O’Leary B et al. ASCO 2019, Abstract 1010.

CHICAGO – Tumor protein 53 (TP53) mutation, fibroblast growth factor receptor 1 (FGFR1) amplification, and tumor purity in plasma each predict early progression on palbociclib and/or fulvestrant in patients with advanced estrogen receptor–positive (ER+) breast cancer, according to genomic analyses of PALOMA-3 trial data.

Sharon Worcester/MDedge News

Overall, the presence of one or more of these genomic changes identified 131 out of 310 patients from the phase 3 trial who had baseline samples available, Ben O’Leary, MBBS, said at the annual meeting of the American Society of Clinical Oncology.

“So, a significant minority of patients – 42.3% – potentially who fall into a more poor-prognosis group,” said Dr. O’Leary of the Institute of Cancer Research at the Royal Marsden Hospital in London.

The findings suggest that a “liquid biopsy” at the start of treatment could identify patients at risk for progression.

The PALOMA-3 trial randomized 521 patients with ER+, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer who had previously progressed on endocrine therapy 2:1 to CDK4/CDK6 inhibition with palbociclib plus fulvestrant (P+F) or placebo plus fulvestrant (F), and it showed that adding palbociclib significantly improved progression-free survival (PFS) (N Engl J Med. Jul 16 2015;373:209-19).

For the current analysis, the investigators assessed circulating tumor DNA (ctDNA) in baseline plasma samples from 459 study participants in an effort to identify genomic biomarkers for progression, to examine the association between baseline tumor fraction and clinical outcome, and to explore differences in predictive markers by treatment arm. A custom amplicon-sequencing analysis was performed to look for mutations in 17 different relevant genes, and another was used to estimate tumor fraction by looking at about 800 common germline single-nucleotide polymorphisms and to assess copy-number gain in the amplification status in 11 different genes, Dr. O’Leary said.


Results for mutations and circulating nucleic acids were available in 203 and 107 patients from the P+F and F groups, respectively, and on multivariable analysis of all 310 patients (including palbociclib as a variable in the model and with ctDNA fraction as a continuous variable), higher baseline tumor purity in plasma was associated with highly significantly worse PFS (HR 1.2 per 10% increase in purity), and baseline TP53 mutation and FGFR1 amplification each were associated with significantly shorter PFS (HRs, 1.8 and 2.9, respectively).

“[It is] very important to note ... that we did look specifically for interaction between our genomic changes and treatment, and we didn’t find any evidence of a significant interaction, so these genomic markers [are] prognostic rather than predictive in terms of the two treatment arms of the trial,” he said.

A survival analysis showed a median PFS of 3.7 vs. 12.7 months in patients with vs. without TP53 mutation in the P+F arm, and 1.8 vs. 5.4 months, respectively, in the F arm, with similar HRs of 2.0 and 2.3 in the arms, respectively.

“Even in the [P+F] arm, you see almost half of the patients with a TP53 mutation ... have relapsed by 2 months, the earliest clinical assessment in the trial,” he noted.

For FGFR1, the PFS was 3.9 vs. 12 months with vs. without amplification in the P+F arms, and 1.8 vs. 5.8 months, respectively in th F arm, with HRs of 3.4 and 3.6, respectively.

These findings are notable because markers of early progression on endocrine therapy in combination with CDK4/6 inhibitors remain limited – despite the key role of these combinations in treating ER+ advanced breast cancer, Dr. O’Leary explained.

“Although many patients derive a great deal of benefit from these combinations, there are a subset of patients who will relapse relatively early, and ... we don’t have an established means of identifying those patients at the present,” he said. “From the technical perspective, liquid biopsies have emerged in recent years as a promising means of genotyping patients’ cancers from circulating tumor DNA, and in addition, the overall level of circulating tumor DNA – the fractional purity – has been associated with poor prognosis, specifically in the triple-negative breast cancer setting.”

The results, which require independent validation, could potentially inform future clinical trials of CDK4/6 inhibitor combinations in advanced ER+ breast cancer to identify a high-risk group of patients who require escalation of therapy, he concluded.

Dr. O’Leary reported receiving research funding from Pfizer to his institution.

SOURCE: O’Leary B et al. ASCO 2019, Abstract 1010.

CHICAGO – Tumor protein 53 (TP53) mutation, fibroblast growth factor receptor 1 (FGFR1) amplification, and tumor purity in plasma each predict early progression on palbociclib and/or fulvestrant in patients with advanced estrogen receptor–positive (ER+) breast cancer, according to genomic analyses of PALOMA-3 trial data.

Sharon Worcester/MDedge News

Overall, the presence of one or more of these genomic changes identified 131 out of 310 patients from the phase 3 trial who had baseline samples available, Ben O’Leary, MBBS, said at the annual meeting of the American Society of Clinical Oncology.

“So, a significant minority of patients – 42.3% – potentially who fall into a more poor-prognosis group,” said Dr. O’Leary of the Institute of Cancer Research at the Royal Marsden Hospital in London.

The findings suggest that a “liquid biopsy” at the start of treatment could identify patients at risk for progression.

The PALOMA-3 trial randomized 521 patients with ER+, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer who had previously progressed on endocrine therapy 2:1 to CDK4/CDK6 inhibition with palbociclib plus fulvestrant (P+F) or placebo plus fulvestrant (F), and it showed that adding palbociclib significantly improved progression-free survival (PFS) (N Engl J Med. Jul 16 2015;373:209-19).

For the current analysis, the investigators assessed circulating tumor DNA (ctDNA) in baseline plasma samples from 459 study participants in an effort to identify genomic biomarkers for progression, to examine the association between baseline tumor fraction and clinical outcome, and to explore differences in predictive markers by treatment arm. A custom amplicon-sequencing analysis was performed to look for mutations in 17 different relevant genes, and another was used to estimate tumor fraction by looking at about 800 common germline single-nucleotide polymorphisms and to assess copy-number gain in the amplification status in 11 different genes, Dr. O’Leary said.


Results for mutations and circulating nucleic acids were available in 203 and 107 patients from the P+F and F groups, respectively, and on multivariable analysis of all 310 patients (including palbociclib as a variable in the model and with ctDNA fraction as a continuous variable), higher baseline tumor purity in plasma was associated with highly significantly worse PFS (HR 1.2 per 10% increase in purity), and baseline TP53 mutation and FGFR1 amplification each were associated with significantly shorter PFS (HRs, 1.8 and 2.9, respectively).

“[It is] very important to note ... that we did look specifically for interaction between our genomic changes and treatment, and we didn’t find any evidence of a significant interaction, so these genomic markers [are] prognostic rather than predictive in terms of the two treatment arms of the trial,” he said.

A survival analysis showed a median PFS of 3.7 vs. 12.7 months in patients with vs. without TP53 mutation in the P+F arm, and 1.8 vs. 5.4 months, respectively, in the F arm, with similar HRs of 2.0 and 2.3 in the arms, respectively.

“Even in the [P+F] arm, you see almost half of the patients with a TP53 mutation ... have relapsed by 2 months, the earliest clinical assessment in the trial,” he noted.

For FGFR1, the PFS was 3.9 vs. 12 months with vs. without amplification in the P+F arms, and 1.8 vs. 5.8 months, respectively in th F arm, with HRs of 3.4 and 3.6, respectively.

These findings are notable because markers of early progression on endocrine therapy in combination with CDK4/6 inhibitors remain limited – despite the key role of these combinations in treating ER+ advanced breast cancer, Dr. O’Leary explained.

“Although many patients derive a great deal of benefit from these combinations, there are a subset of patients who will relapse relatively early, and ... we don’t have an established means of identifying those patients at the present,” he said. “From the technical perspective, liquid biopsies have emerged in recent years as a promising means of genotyping patients’ cancers from circulating tumor DNA, and in addition, the overall level of circulating tumor DNA – the fractional purity – has been associated with poor prognosis, specifically in the triple-negative breast cancer setting.”

The results, which require independent validation, could potentially inform future clinical trials of CDK4/6 inhibitor combinations in advanced ER+ breast cancer to identify a high-risk group of patients who require escalation of therapy, he concluded.

Dr. O’Leary reported receiving research funding from Pfizer to his institution.

SOURCE: O’Leary B et al. ASCO 2019, Abstract 1010.

CHICAGO – Clinical risk stratification adds prognostic value to the 21-gene recurrence score for guiding treatment selection in patients with early breast cancer, according to a secondary analysis of data from the practice-changing TAILORx study.

Sharon Worcester/MDedge News

Specifically, tumor size and histology-based risk stratification improves the prediction of disease-free survival and distant recurrence, and – for some patient groups – chemotherapy benefit, Joseph A. Sparano, MD, reported at the annual meeting of the American Society of Clinical Oncology.

Combining these tools could help determine whether endocrine therapy (ET) alone or ET with adjuvant chemotherapy is the best treatment approach for a given patient, said Dr. Sparano, professor of medicine and obstetrics, gynecology, and women’s health at Albert Einstein College of Medicine, New York.

The phase 3 TAILORx study established that ET alone is noninferior to adjuvant chemotherapy (CT) plus ET in patients with early breast cancer and RS of 11-25, and that ET alone has some benefit over ET+CT in women aged 50 years and younger with RS of 16-25, he explained.

Those findings were presented at the 2018 ASCO annual meeting and subsequently published in the New England Journal of Medicine.

The current analysis focused on the integration of clinical and genomic features for prognosis, and the results were published online June 3 in a corresponding article in the New England Journal of Medicine.

“The totality of the data, including TAILORx and the prior prospective validation studies, indicate that assessment of genomic risk with the 21-gene recurrence score provides complementary prognostic information to pathologic features, and is also predictive of a large chemotherapy benefit if the recurrence score is greater than 25, or lack thereof if 25 or lower,” he said.

However, there is a three-way interaction between age, RS, and CT use, which results in an absolute CT benefit in women aged 50 or younger of about 2% for RS of 16-20, and about 7% for RS of 21-25, he added.

“Assessment of clinical risk using pathological features also provides prognostic information that doesn’t correlate well with the recurrence score, therefore it stands to reason that integration of clinical and genomic risk offers the potential for greater precision in prognosis and, ultimately, guiding the use of adjuvant therapy,” he said.

Clinical risk for this analysis was assessed using a binary clinical risk categorization employed in the MINDACT trial and calibrated to greater than 92% 10-year breast cancer-specific survival for ET alone based on Adjuvant! version 8.0. Low-grade tumors up to 3 cm, intermediate-grade tumors up to 2 cm, and high-grade tumors up to 1 cm were categorized as low clinical risk (LCR), and all others not meeting these criteria were categorized as high clinical risk (HCR), he explained.

Of 9,427 patients included in the analysis, 70% had LCR and 30% had HCR.

“For distant recurrence, high clinical risk was associated with a 2.5- to 3-fold higher recurrence rate for those with a recurrence score of 11 or higher, and in a multivariate model for distant recurrence in the [group with a] recurrence score of 11-25, high clinical risk was independently associated with a 2.4-fold higher recurrence risk,” he said. “Continuous recurrence score also provided significant prognostic information, with each 1-unit increase associated with an 8% higher distant recurrence risk.”

For the overall population, clinical risk added significant prognostic information to the RS for both distant recurrence and disease-free survival, and stratification by age showed that among women over age 50 years, the hazard ratios for distant recurrence ranged from 2.20 to 2.36, and did not substantially vary by age or RS, he said.

However, for the overall population, adding clinical risk to the RS did not improve prediction of chemotherapy benefit.

“This was also true for the two-thirds of women who were over 50 years of age. For the remaining women 50 or younger, there was a trend favoring chemo, irrespective of clinical risk, though not significant – a finding consistent with the treatment interaction previously described,” he said.

Finally, the absolute differences in 9-year distant recurrence rates by clinical risk stratified by age, RS, and CT use showed an absolute 4%-6% higher distant recurrence risk for HCR vs. LCR among those over age 50 with RS of 0-25 irrespective of CT use, and a 13% difference for those with RS of 26-100 who were treated with CT.

“For those 50 or younger, clinical risk had no impact on recurrence if the RS was 0-10. For RS of 11-25, the difference was about 9% with endocrine therapy alone, and 2% with chemo plus ET, reflecting absolute chemo benefit in younger women who had high clinical risk,” he said, adding that for those with RS of 26-100, there was a 9% higher absolute recurrence rate in the HCR vs. LCR population.

“We therefore further evaluated absolute differences in distance recurrence rates associated with chemotherapy use in women 50 and younger with RS of 16-25, further stratified by RS and clinical risk,” he said, noting that when not stratified by clinical risk, as reported in the primary analysis, the absolute CT benefit was 1.6% for RS of 16-20, and 6.5% for RS of 21-25.

When stratified by clinical risk, the absolute CT benefit ranged from 6% to 9% in those with RS of 21-25, irrespective of clinical risk, and in those with RS of 16-20 and HCR.

“This accounted for 51% of patients with RS of 16-25,” he said. “However, there was no demonstrable chemo benefit for those with LCR and RS of 16-20, who accounted for the remaining 49%.”

Additional analysis looking at age at diagnosis and CT benefit showed a benefit in premenopausal women aged 46-50 years (but not postmenopausal women), a trend toward benefit in those aged 41-45 years, and no benefit in those aged 40 years and younger, who are less likely to develop premature menopause as a consequence of cytotoxic CT.

“In addition, we saw no consistent effect favoring chemotherapy in older women. Taken together, these findings suggest the chemo benefit observed for the RS 16-25 group may, in fact, be due to a castration effect associated with cytotoxic therapy rather than an effect in eradicating micrometastatic disease,” Dr. Sparano said.

Applying this framework to the TAILORx study population categorized 68% of those aged 50 years and younger into a low integrated risk group with less than 5% risk of distant recurrence. This included all patients with RS of 0-10 irrespective of clinical risk (14% of the patient population; distant recurrence rate 1.8% or less), and all with RS of 11-25 and LCR (54% of the patient population, 4.7% distant recurrence rate).

In contrast, 25% fell into the high integrated risk group (greater than 10% distant recurrence risk), including those with RS of 11-25 and HCR (17% of the patient population; distant recurrence rate 12.3%), and RS of 26-100 and HCR (8% of the patient population; distant recurrence rate 15.2%).

“This framework encompasses 93% of all TAILORx subjects, with the remaining 7% having a distant recurrence risk of between 5% and 10%,” he said.


Overall, the primary results of TAILORx remain unchanged based on this secondary analysis as the addition of clinical risk did not predict CT benefit in the RS 11-25 group, he noted.

“However, for women 50 and under and RS 16-25, integrated risk distinguished 50% who derived no chemo benefit from the 50% who derived an absolute benefit of approximately 6%-9% – a level that is higher than an unselected population,” he said, reiterating that the absolute CT benefit was greater in premenopausal women aged 45-50 with RS 16-25, suggesting that the absolute CR benefit seen in younger women in TAILORx may be due to an endocrine effect.

“Integrated risk clearly provides greater prognostic precision and may have clinical utility; the prognostic precision afforded by the integrated risk model is superior to that by the use of clinical or genomic features alone, and in addition, the genomic assay also provides predictive information for chemo benefit that is not captured by clinical features alone,” he concluded.

As an example of the potential clinical utility of this integrated approach for guiding treatment in women aged 50 years or younger, he presented “a highly stratified integrated risk assessment model” separating TAILORx patients into low integrated risk (58% of the study population) and high integrated risk (31% of the study population).

In the low integrated risk patients with RS of 0-10 and any clinical risk level, or with RS of 11-25 and LCR, tamoxifen alone appears adequate, he said.

In those with high integrated risk and RS of 16-25 with HCR, ovarian function suppression plus an aromatase inhibitor (OFS/AI) could be considered as an alternative to chemo, and in those with high integrated risk, RS of 26-100, and HCR who have not developed chemotherapy-induced menopause, ovarian function suppression and an AI could be added to chemotherapy.

“Indeed, data from the SOFT and TEXT trials indicate that patients with a high RS risk experienced an absolute improvement of up to 10%-15% in 5-year breast cancer–free interval with an OFS/AI, compared with tamoxifen, whereas improvement was minimal in those at lowest risk, supporting the strategy of using integrated clinical and genomic risk to select for ovarian function suppression plus an AI,” he said.

During a discussion of the findings and how they might impact practice, Vered Stearns, MD, an oncology professor and codirector of the Breast Cancer Program at Johns Hopkins University, Baltimore, noted that in her practice she will “carefully select women for whom genomic assay [use] is appropriate.

“I will also assess clinical risk and RS to inform recommendations for chemotherapy use, and possibly appropriate endocrine agents in select populations,” she said.

Sharon Worcester/MDedge News

Dr. Stearns further noted that the interaction between RS and age as reported by Dr. Sparano is exploratory and should be interpreted with caution as the majority of those aged 50 and younger received tamoxifen alone and the question remains as to whether they would have received similar benefits from ovarian suppression and tamoxifen/AI instead of chemo-endocrine therapy.

“Indeed, indirect hypotheses from other studies suggest that may be the case,” she said, adding that these women may be offered ovarian suppression and tamoxifen or AI based on the SOFT and TEXT results.

“TAILORx remains a rich resource for new explorations, new biomarkers, new models, and new machine learning opportunities,” she said.

TAILORx was funded by the National Institutes of Health. Dr. Sparano reported stock ownership, a consulting role, and research funding from several pharmaceutical companies. Dr. Stearns reported consulting or advisory roles with Iridium Therapeutics; research funding from Abbvie, Biocept, MedImmune, Novartis, Pfizer, and Puma Biotechnology; and an “other relationship” with Immunomedics.

SOURCE: Sparano JA et al. ASCO 2019. Abstract 503.

CHICAGO – Clinical risk stratification adds prognostic value to the 21-gene recurrence score for guiding treatment selection in patients with early breast cancer, according to a secondary analysis of data from the practice-changing TAILORx study.

Sharon Worcester/MDedge News

Specifically, tumor size and histology-based risk stratification improves the prediction of disease-free survival and distant recurrence, and – for some patient groups – chemotherapy benefit, Joseph A. Sparano, MD, reported at the annual meeting of the American Society of Clinical Oncology.

Combining these tools could help determine whether endocrine therapy (ET) alone or ET with adjuvant chemotherapy is the best treatment approach for a given patient, said Dr. Sparano, professor of medicine and obstetrics, gynecology, and women’s health at Albert Einstein College of Medicine, New York.

The phase 3 TAILORx study established that ET alone is noninferior to adjuvant chemotherapy (CT) plus ET in patients with early breast cancer and RS of 11-25, and that ET alone has some benefit over ET+CT in women aged 50 years and younger with RS of 16-25, he explained.

Those findings were presented at the 2018 ASCO annual meeting and subsequently published in the New England Journal of Medicine.

The current analysis focused on the integration of clinical and genomic features for prognosis, and the results were published online June 3 in a corresponding article in the New England Journal of Medicine.

“The totality of the data, including TAILORx and the prior prospective validation studies, indicate that assessment of genomic risk with the 21-gene recurrence score provides complementary prognostic information to pathologic features, and is also predictive of a large chemotherapy benefit if the recurrence score is greater than 25, or lack thereof if 25 or lower,” he said.

However, there is a three-way interaction between age, RS, and CT use, which results in an absolute CT benefit in women aged 50 or younger of about 2% for RS of 16-20, and about 7% for RS of 21-25, he added.

“Assessment of clinical risk using pathological features also provides prognostic information that doesn’t correlate well with the recurrence score, therefore it stands to reason that integration of clinical and genomic risk offers the potential for greater precision in prognosis and, ultimately, guiding the use of adjuvant therapy,” he said.

Clinical risk for this analysis was assessed using a binary clinical risk categorization employed in the MINDACT trial and calibrated to greater than 92% 10-year breast cancer-specific survival for ET alone based on Adjuvant! version 8.0. Low-grade tumors up to 3 cm, intermediate-grade tumors up to 2 cm, and high-grade tumors up to 1 cm were categorized as low clinical risk (LCR), and all others not meeting these criteria were categorized as high clinical risk (HCR), he explained.

Of 9,427 patients included in the analysis, 70% had LCR and 30% had HCR.

“For distant recurrence, high clinical risk was associated with a 2.5- to 3-fold higher recurrence rate for those with a recurrence score of 11 or higher, and in a multivariate model for distant recurrence in the [group with a] recurrence score of 11-25, high clinical risk was independently associated with a 2.4-fold higher recurrence risk,” he said. “Continuous recurrence score also provided significant prognostic information, with each 1-unit increase associated with an 8% higher distant recurrence risk.”

For the overall population, clinical risk added significant prognostic information to the RS for both distant recurrence and disease-free survival, and stratification by age showed that among women over age 50 years, the hazard ratios for distant recurrence ranged from 2.20 to 2.36, and did not substantially vary by age or RS, he said.

However, for the overall population, adding clinical risk to the RS did not improve prediction of chemotherapy benefit.

“This was also true for the two-thirds of women who were over 50 years of age. For the remaining women 50 or younger, there was a trend favoring chemo, irrespective of clinical risk, though not significant – a finding consistent with the treatment interaction previously described,” he said.

Finally, the absolute differences in 9-year distant recurrence rates by clinical risk stratified by age, RS, and CT use showed an absolute 4%-6% higher distant recurrence risk for HCR vs. LCR among those over age 50 with RS of 0-25 irrespective of CT use, and a 13% difference for those with RS of 26-100 who were treated with CT.

“For those 50 or younger, clinical risk had no impact on recurrence if the RS was 0-10. For RS of 11-25, the difference was about 9% with endocrine therapy alone, and 2% with chemo plus ET, reflecting absolute chemo benefit in younger women who had high clinical risk,” he said, adding that for those with RS of 26-100, there was a 9% higher absolute recurrence rate in the HCR vs. LCR population.

“We therefore further evaluated absolute differences in distance recurrence rates associated with chemotherapy use in women 50 and younger with RS of 16-25, further stratified by RS and clinical risk,” he said, noting that when not stratified by clinical risk, as reported in the primary analysis, the absolute CT benefit was 1.6% for RS of 16-20, and 6.5% for RS of 21-25.

When stratified by clinical risk, the absolute CT benefit ranged from 6% to 9% in those with RS of 21-25, irrespective of clinical risk, and in those with RS of 16-20 and HCR.

“This accounted for 51% of patients with RS of 16-25,” he said. “However, there was no demonstrable chemo benefit for those with LCR and RS of 16-20, who accounted for the remaining 49%.”

Additional analysis looking at age at diagnosis and CT benefit showed a benefit in premenopausal women aged 46-50 years (but not postmenopausal women), a trend toward benefit in those aged 41-45 years, and no benefit in those aged 40 years and younger, who are less likely to develop premature menopause as a consequence of cytotoxic CT.

“In addition, we saw no consistent effect favoring chemotherapy in older women. Taken together, these findings suggest the chemo benefit observed for the RS 16-25 group may, in fact, be due to a castration effect associated with cytotoxic therapy rather than an effect in eradicating micrometastatic disease,” Dr. Sparano said.

Applying this framework to the TAILORx study population categorized 68% of those aged 50 years and younger into a low integrated risk group with less than 5% risk of distant recurrence. This included all patients with RS of 0-10 irrespective of clinical risk (14% of the patient population; distant recurrence rate 1.8% or less), and all with RS of 11-25 and LCR (54% of the patient population, 4.7% distant recurrence rate).

In contrast, 25% fell into the high integrated risk group (greater than 10% distant recurrence risk), including those with RS of 11-25 and HCR (17% of the patient population; distant recurrence rate 12.3%), and RS of 26-100 and HCR (8% of the patient population; distant recurrence rate 15.2%).

“This framework encompasses 93% of all TAILORx subjects, with the remaining 7% having a distant recurrence risk of between 5% and 10%,” he said.


Overall, the primary results of TAILORx remain unchanged based on this secondary analysis as the addition of clinical risk did not predict CT benefit in the RS 11-25 group, he noted.

“However, for women 50 and under and RS 16-25, integrated risk distinguished 50% who derived no chemo benefit from the 50% who derived an absolute benefit of approximately 6%-9% – a level that is higher than an unselected population,” he said, reiterating that the absolute CT benefit was greater in premenopausal women aged 45-50 with RS 16-25, suggesting that the absolute CR benefit seen in younger women in TAILORx may be due to an endocrine effect.

“Integrated risk clearly provides greater prognostic precision and may have clinical utility; the prognostic precision afforded by the integrated risk model is superior to that by the use of clinical or genomic features alone, and in addition, the genomic assay also provides predictive information for chemo benefit that is not captured by clinical features alone,” he concluded.

As an example of the potential clinical utility of this integrated approach for guiding treatment in women aged 50 years or younger, he presented “a highly stratified integrated risk assessment model” separating TAILORx patients into low integrated risk (58% of the study population) and high integrated risk (31% of the study population).

In the low integrated risk patients with RS of 0-10 and any clinical risk level, or with RS of 11-25 and LCR, tamoxifen alone appears adequate, he said.

In those with high integrated risk and RS of 16-25 with HCR, ovarian function suppression plus an aromatase inhibitor (OFS/AI) could be considered as an alternative to chemo, and in those with high integrated risk, RS of 26-100, and HCR who have not developed chemotherapy-induced menopause, ovarian function suppression and an AI could be added to chemotherapy.

“Indeed, data from the SOFT and TEXT trials indicate that patients with a high RS risk experienced an absolute improvement of up to 10%-15% in 5-year breast cancer–free interval with an OFS/AI, compared with tamoxifen, whereas improvement was minimal in those at lowest risk, supporting the strategy of using integrated clinical and genomic risk to select for ovarian function suppression plus an AI,” he said.

During a discussion of the findings and how they might impact practice, Vered Stearns, MD, an oncology professor and codirector of the Breast Cancer Program at Johns Hopkins University, Baltimore, noted that in her practice she will “carefully select women for whom genomic assay [use] is appropriate.

“I will also assess clinical risk and RS to inform recommendations for chemotherapy use, and possibly appropriate endocrine agents in select populations,” she said.

Sharon Worcester/MDedge News

Dr. Stearns further noted that the interaction between RS and age as reported by Dr. Sparano is exploratory and should be interpreted with caution as the majority of those aged 50 and younger received tamoxifen alone and the question remains as to whether they would have received similar benefits from ovarian suppression and tamoxifen/AI instead of chemo-endocrine therapy.

“Indeed, indirect hypotheses from other studies suggest that may be the case,” she said, adding that these women may be offered ovarian suppression and tamoxifen or AI based on the SOFT and TEXT results.

“TAILORx remains a rich resource for new explorations, new biomarkers, new models, and new machine learning opportunities,” she said.

TAILORx was funded by the National Institutes of Health. Dr. Sparano reported stock ownership, a consulting role, and research funding from several pharmaceutical companies. Dr. Stearns reported consulting or advisory roles with Iridium Therapeutics; research funding from Abbvie, Biocept, MedImmune, Novartis, Pfizer, and Puma Biotechnology; and an “other relationship” with Immunomedics.

SOURCE: Sparano JA et al. ASCO 2019. Abstract 503.

CHICAGO – Clinical risk stratification adds prognostic value to the 21-gene recurrence score for guiding treatment selection in patients with early breast cancer, according to a secondary analysis of data from the practice-changing TAILORx study.

Sharon Worcester/MDedge News

Specifically, tumor size and histology-based risk stratification improves the prediction of disease-free survival and distant recurrence, and – for some patient groups – chemotherapy benefit, Joseph A. Sparano, MD, reported at the annual meeting of the American Society of Clinical Oncology.

Combining these tools could help determine whether endocrine therapy (ET) alone or ET with adjuvant chemotherapy is the best treatment approach for a given patient, said Dr. Sparano, professor of medicine and obstetrics, gynecology, and women’s health at Albert Einstein College of Medicine, New York.

The phase 3 TAILORx study established that ET alone is noninferior to adjuvant chemotherapy (CT) plus ET in patients with early breast cancer and RS of 11-25, and that ET alone has some benefit over ET+CT in women aged 50 years and younger with RS of 16-25, he explained.

Those findings were presented at the 2018 ASCO annual meeting and subsequently published in the New England Journal of Medicine.

The current analysis focused on the integration of clinical and genomic features for prognosis, and the results were published online June 3 in a corresponding article in the New England Journal of Medicine.

“The totality of the data, including TAILORx and the prior prospective validation studies, indicate that assessment of genomic risk with the 21-gene recurrence score provides complementary prognostic information to pathologic features, and is also predictive of a large chemotherapy benefit if the recurrence score is greater than 25, or lack thereof if 25 or lower,” he said.

However, there is a three-way interaction between age, RS, and CT use, which results in an absolute CT benefit in women aged 50 or younger of about 2% for RS of 16-20, and about 7% for RS of 21-25, he added.

“Assessment of clinical risk using pathological features also provides prognostic information that doesn’t correlate well with the recurrence score, therefore it stands to reason that integration of clinical and genomic risk offers the potential for greater precision in prognosis and, ultimately, guiding the use of adjuvant therapy,” he said.

Clinical risk for this analysis was assessed using a binary clinical risk categorization employed in the MINDACT trial and calibrated to greater than 92% 10-year breast cancer-specific survival for ET alone based on Adjuvant! version 8.0. Low-grade tumors up to 3 cm, intermediate-grade tumors up to 2 cm, and high-grade tumors up to 1 cm were categorized as low clinical risk (LCR), and all others not meeting these criteria were categorized as high clinical risk (HCR), he explained.

Of 9,427 patients included in the analysis, 70% had LCR and 30% had HCR.

“For distant recurrence, high clinical risk was associated with a 2.5- to 3-fold higher recurrence rate for those with a recurrence score of 11 or higher, and in a multivariate model for distant recurrence in the [group with a] recurrence score of 11-25, high clinical risk was independently associated with a 2.4-fold higher recurrence risk,” he said. “Continuous recurrence score also provided significant prognostic information, with each 1-unit increase associated with an 8% higher distant recurrence risk.”

For the overall population, clinical risk added significant prognostic information to the RS for both distant recurrence and disease-free survival, and stratification by age showed that among women over age 50 years, the hazard ratios for distant recurrence ranged from 2.20 to 2.36, and did not substantially vary by age or RS, he said.

However, for the overall population, adding clinical risk to the RS did not improve prediction of chemotherapy benefit.

“This was also true for the two-thirds of women who were over 50 years of age. For the remaining women 50 or younger, there was a trend favoring chemo, irrespective of clinical risk, though not significant – a finding consistent with the treatment interaction previously described,” he said.

Finally, the absolute differences in 9-year distant recurrence rates by clinical risk stratified by age, RS, and CT use showed an absolute 4%-6% higher distant recurrence risk for HCR vs. LCR among those over age 50 with RS of 0-25 irrespective of CT use, and a 13% difference for those with RS of 26-100 who were treated with CT.

“For those 50 or younger, clinical risk had no impact on recurrence if the RS was 0-10. For RS of 11-25, the difference was about 9% with endocrine therapy alone, and 2% with chemo plus ET, reflecting absolute chemo benefit in younger women who had high clinical risk,” he said, adding that for those with RS of 26-100, there was a 9% higher absolute recurrence rate in the HCR vs. LCR population.

“We therefore further evaluated absolute differences in distance recurrence rates associated with chemotherapy use in women 50 and younger with RS of 16-25, further stratified by RS and clinical risk,” he said, noting that when not stratified by clinical risk, as reported in the primary analysis, the absolute CT benefit was 1.6% for RS of 16-20, and 6.5% for RS of 21-25.

When stratified by clinical risk, the absolute CT benefit ranged from 6% to 9% in those with RS of 21-25, irrespective of clinical risk, and in those with RS of 16-20 and HCR.

“This accounted for 51% of patients with RS of 16-25,” he said. “However, there was no demonstrable chemo benefit for those with LCR and RS of 16-20, who accounted for the remaining 49%.”

Additional analysis looking at age at diagnosis and CT benefit showed a benefit in premenopausal women aged 46-50 years (but not postmenopausal women), a trend toward benefit in those aged 41-45 years, and no benefit in those aged 40 years and younger, who are less likely to develop premature menopause as a consequence of cytotoxic CT.

“In addition, we saw no consistent effect favoring chemotherapy in older women. Taken together, these findings suggest the chemo benefit observed for the RS 16-25 group may, in fact, be due to a castration effect associated with cytotoxic therapy rather than an effect in eradicating micrometastatic disease,” Dr. Sparano said.

Applying this framework to the TAILORx study population categorized 68% of those aged 50 years and younger into a low integrated risk group with less than 5% risk of distant recurrence. This included all patients with RS of 0-10 irrespective of clinical risk (14% of the patient population; distant recurrence rate 1.8% or less), and all with RS of 11-25 and LCR (54% of the patient population, 4.7% distant recurrence rate).

In contrast, 25% fell into the high integrated risk group (greater than 10% distant recurrence risk), including those with RS of 11-25 and HCR (17% of the patient population; distant recurrence rate 12.3%), and RS of 26-100 and HCR (8% of the patient population; distant recurrence rate 15.2%).

“This framework encompasses 93% of all TAILORx subjects, with the remaining 7% having a distant recurrence risk of between 5% and 10%,” he said.


Overall, the primary results of TAILORx remain unchanged based on this secondary analysis as the addition of clinical risk did not predict CT benefit in the RS 11-25 group, he noted.

“However, for women 50 and under and RS 16-25, integrated risk distinguished 50% who derived no chemo benefit from the 50% who derived an absolute benefit of approximately 6%-9% – a level that is higher than an unselected population,” he said, reiterating that the absolute CT benefit was greater in premenopausal women aged 45-50 with RS 16-25, suggesting that the absolute CR benefit seen in younger women in TAILORx may be due to an endocrine effect.

“Integrated risk clearly provides greater prognostic precision and may have clinical utility; the prognostic precision afforded by the integrated risk model is superior to that by the use of clinical or genomic features alone, and in addition, the genomic assay also provides predictive information for chemo benefit that is not captured by clinical features alone,” he concluded.

As an example of the potential clinical utility of this integrated approach for guiding treatment in women aged 50 years or younger, he presented “a highly stratified integrated risk assessment model” separating TAILORx patients into low integrated risk (58% of the study population) and high integrated risk (31% of the study population).

In the low integrated risk patients with RS of 0-10 and any clinical risk level, or with RS of 11-25 and LCR, tamoxifen alone appears adequate, he said.

In those with high integrated risk and RS of 16-25 with HCR, ovarian function suppression plus an aromatase inhibitor (OFS/AI) could be considered as an alternative to chemo, and in those with high integrated risk, RS of 26-100, and HCR who have not developed chemotherapy-induced menopause, ovarian function suppression and an AI could be added to chemotherapy.

“Indeed, data from the SOFT and TEXT trials indicate that patients with a high RS risk experienced an absolute improvement of up to 10%-15% in 5-year breast cancer–free interval with an OFS/AI, compared with tamoxifen, whereas improvement was minimal in those at lowest risk, supporting the strategy of using integrated clinical and genomic risk to select for ovarian function suppression plus an AI,” he said.

During a discussion of the findings and how they might impact practice, Vered Stearns, MD, an oncology professor and codirector of the Breast Cancer Program at Johns Hopkins University, Baltimore, noted that in her practice she will “carefully select women for whom genomic assay [use] is appropriate.

“I will also assess clinical risk and RS to inform recommendations for chemotherapy use, and possibly appropriate endocrine agents in select populations,” she said.

Sharon Worcester/MDedge News

Dr. Stearns further noted that the interaction between RS and age as reported by Dr. Sparano is exploratory and should be interpreted with caution as the majority of those aged 50 and younger received tamoxifen alone and the question remains as to whether they would have received similar benefits from ovarian suppression and tamoxifen/AI instead of chemo-endocrine therapy.

“Indeed, indirect hypotheses from other studies suggest that may be the case,” she said, adding that these women may be offered ovarian suppression and tamoxifen or AI based on the SOFT and TEXT results.

“TAILORx remains a rich resource for new explorations, new biomarkers, new models, and new machine learning opportunities,” she said.

TAILORx was funded by the National Institutes of Health. Dr. Sparano reported stock ownership, a consulting role, and research funding from several pharmaceutical companies. Dr. Stearns reported consulting or advisory roles with Iridium Therapeutics; research funding from Abbvie, Biocept, MedImmune, Novartis, Pfizer, and Puma Biotechnology; and an “other relationship” with Immunomedics.

SOURCE: Sparano JA et al. ASCO 2019. Abstract 503.

CHICAGO – Targeted neoadjuvant therapy with trastuzumab emtansine (T-DM1) had similar efficacy with less toxicity, compared with a standard chemotherapy–based regimen for patients with HER2- and hormone receptor–positive breast cancers in the phase 2 Swedish PREDIX HER2 trial.

Sharon Worcester/MDedge News

The pathologic complete response (pCR) rate was 45% among 98 participants who were randomized to received T-DM1, and 47% in those randomized to receive docetaxel, trastuzumab, and pertuzumab (DTP), Jonas C.S. Bergh, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

The pCR rate in hormone receptor(HR) –positive tumors was 36% in both groups, and the rates in HR-negative tumors were 59% and 67% in the T-DM1 and DTP arms, respectively; any differences in pCR rates between the groups were not statistically significant, said Dr. Bergh of the Karolinska Institute and University Hospital, Stockholm.

Patients were adults with HER2-positive breast cancer and tumor size greater than 20 mm or verified lymph node metastases at enrollment, and 62.6% of tumors were HR positive. Both treatment arms received their assigned therapy every 3 weeks for a planned total of six courses, but the protocol allowed a switch to the competing treatment upon progression, lack of response, or drug-related severe toxicity. All received postoperative epirubicin+cyclophosphamide every 3 weeks, with the T-DM1 arm receiving 4 courses and the DTP arm receiving 2 courses, and both arms also received adjuvant trastuzumab for 11 courses.

Age (median of 52 years), menopausal status, and histological type and grade were well balanced between the treatment groups.


Grade 3/4 adverse events occurred on 63 occasions in the DTP arm, compared with 10 in the T-DM1 arm; febrile neutropenia accounted for 26 and 3 of the events in the groups, respectively. All events, with the exception of liver toxicity, occurred more frequently in the DTP arm, Dr. Bergh said.

Ultimately, 9 patients switched from T-DM1 to DTP – 7 for progression or lack of response and 2 because of toxicity, and 18 switched from DTP to T-DM1 because of either progression or lack of response, and 14 because of toxicity. One patient in each group achieved pCR after switching, he noted.

“There was clearly better quality of life [during the study] for the T-DM1 group,” he added, noting that the quality of life data were reported separately at the meeting.

Additionally, an exploratory analysis demonstrated an early steep decrease of F-FDG uptake, suggesting that PET/CT may be a useful tool for predicting pCR.

Although neoadjuvant therapy produces high pCR rates and is the standard of care in HER2 positive breast cancer, the optimal treatment regimen remains to be established; but the current findings, along with prior data showing efficacy with T-DM1 in patients who fail to respond to two or more lines of anti-HER2 therapies, suggest it is a potential new standard for neoadjuvant therapy, particularly for patients with HER2- and HR-positive disease, he concluded.

Dr. Bergh reported a financial relationship with UpToDate, and research funding to his institution from Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche, and Sanofi.

SOURCE: Bergh J et al. ASCO 2019, Abstract 501.

CHICAGO – Targeted neoadjuvant therapy with trastuzumab emtansine (T-DM1) had similar efficacy with less toxicity, compared with a standard chemotherapy–based regimen for patients with HER2- and hormone receptor–positive breast cancers in the phase 2 Swedish PREDIX HER2 trial.

Sharon Worcester/MDedge News

The pathologic complete response (pCR) rate was 45% among 98 participants who were randomized to received T-DM1, and 47% in those randomized to receive docetaxel, trastuzumab, and pertuzumab (DTP), Jonas C.S. Bergh, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

The pCR rate in hormone receptor(HR) –positive tumors was 36% in both groups, and the rates in HR-negative tumors were 59% and 67% in the T-DM1 and DTP arms, respectively; any differences in pCR rates between the groups were not statistically significant, said Dr. Bergh of the Karolinska Institute and University Hospital, Stockholm.

Patients were adults with HER2-positive breast cancer and tumor size greater than 20 mm or verified lymph node metastases at enrollment, and 62.6% of tumors were HR positive. Both treatment arms received their assigned therapy every 3 weeks for a planned total of six courses, but the protocol allowed a switch to the competing treatment upon progression, lack of response, or drug-related severe toxicity. All received postoperative epirubicin+cyclophosphamide every 3 weeks, with the T-DM1 arm receiving 4 courses and the DTP arm receiving 2 courses, and both arms also received adjuvant trastuzumab for 11 courses.

Age (median of 52 years), menopausal status, and histological type and grade were well balanced between the treatment groups.


Grade 3/4 adverse events occurred on 63 occasions in the DTP arm, compared with 10 in the T-DM1 arm; febrile neutropenia accounted for 26 and 3 of the events in the groups, respectively. All events, with the exception of liver toxicity, occurred more frequently in the DTP arm, Dr. Bergh said.

Ultimately, 9 patients switched from T-DM1 to DTP – 7 for progression or lack of response and 2 because of toxicity, and 18 switched from DTP to T-DM1 because of either progression or lack of response, and 14 because of toxicity. One patient in each group achieved pCR after switching, he noted.

“There was clearly better quality of life [during the study] for the T-DM1 group,” he added, noting that the quality of life data were reported separately at the meeting.

Additionally, an exploratory analysis demonstrated an early steep decrease of F-FDG uptake, suggesting that PET/CT may be a useful tool for predicting pCR.

Although neoadjuvant therapy produces high pCR rates and is the standard of care in HER2 positive breast cancer, the optimal treatment regimen remains to be established; but the current findings, along with prior data showing efficacy with T-DM1 in patients who fail to respond to two or more lines of anti-HER2 therapies, suggest it is a potential new standard for neoadjuvant therapy, particularly for patients with HER2- and HR-positive disease, he concluded.

Dr. Bergh reported a financial relationship with UpToDate, and research funding to his institution from Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche, and Sanofi.

SOURCE: Bergh J et al. ASCO 2019, Abstract 501.

CHICAGO – Targeted neoadjuvant therapy with trastuzumab emtansine (T-DM1) had similar efficacy with less toxicity, compared with a standard chemotherapy–based regimen for patients with HER2- and hormone receptor–positive breast cancers in the phase 2 Swedish PREDIX HER2 trial.

Sharon Worcester/MDedge News

The pathologic complete response (pCR) rate was 45% among 98 participants who were randomized to received T-DM1, and 47% in those randomized to receive docetaxel, trastuzumab, and pertuzumab (DTP), Jonas C.S. Bergh, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

The pCR rate in hormone receptor(HR) –positive tumors was 36% in both groups, and the rates in HR-negative tumors were 59% and 67% in the T-DM1 and DTP arms, respectively; any differences in pCR rates between the groups were not statistically significant, said Dr. Bergh of the Karolinska Institute and University Hospital, Stockholm.

Patients were adults with HER2-positive breast cancer and tumor size greater than 20 mm or verified lymph node metastases at enrollment, and 62.6% of tumors were HR positive. Both treatment arms received their assigned therapy every 3 weeks for a planned total of six courses, but the protocol allowed a switch to the competing treatment upon progression, lack of response, or drug-related severe toxicity. All received postoperative epirubicin+cyclophosphamide every 3 weeks, with the T-DM1 arm receiving 4 courses and the DTP arm receiving 2 courses, and both arms also received adjuvant trastuzumab for 11 courses.

Age (median of 52 years), menopausal status, and histological type and grade were well balanced between the treatment groups.


Grade 3/4 adverse events occurred on 63 occasions in the DTP arm, compared with 10 in the T-DM1 arm; febrile neutropenia accounted for 26 and 3 of the events in the groups, respectively. All events, with the exception of liver toxicity, occurred more frequently in the DTP arm, Dr. Bergh said.

Ultimately, 9 patients switched from T-DM1 to DTP – 7 for progression or lack of response and 2 because of toxicity, and 18 switched from DTP to T-DM1 because of either progression or lack of response, and 14 because of toxicity. One patient in each group achieved pCR after switching, he noted.

“There was clearly better quality of life [during the study] for the T-DM1 group,” he added, noting that the quality of life data were reported separately at the meeting.

Additionally, an exploratory analysis demonstrated an early steep decrease of F-FDG uptake, suggesting that PET/CT may be a useful tool for predicting pCR.

Although neoadjuvant therapy produces high pCR rates and is the standard of care in HER2 positive breast cancer, the optimal treatment regimen remains to be established; but the current findings, along with prior data showing efficacy with T-DM1 in patients who fail to respond to two or more lines of anti-HER2 therapies, suggest it is a potential new standard for neoadjuvant therapy, particularly for patients with HER2- and HR-positive disease, he concluded.

Dr. Bergh reported a financial relationship with UpToDate, and research funding to his institution from Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche, and Sanofi.

SOURCE: Bergh J et al. ASCO 2019, Abstract 501.

CHICAGO – Combining trastuzumab emtansine (T-DM1) and pertuzumab (P) reduced grade 3+ toxicity in patients with HER2-positive stage I-III breast cancer in the KRISTINE trial, but led to lower event-free survival (EFS) and pathological complete response (pCR) rates vs. standard chemotherapy plus dual HER2 blockade, according to the preplanned 3-year final data analysis.

Sharon Worcester/MDedge News

The EFS rate among participants in the randomized, phase 3 study who completed follow-up was 94.2% in 189 patients who received neoadjuvant T-DM1+P treatment and 85.3% in 196 patients who received docetaxel, carboplatin, and trastuzumab (TCH) plus pertuzumab (hazard ratio, 2.61). The difference was due to more locoregional progression events before surgery (15 [6.7%] vs. 0 in the groups, respectively), Dr. Sara A. Hurvitz, MD, reported at the annual meeting of the American Association of Clinical Oncology.

The curves separated early, prior to surgery, without much change after surgery, noted Dr. Hurvitz, a medical oncologist at the University of California, Los Angeles, where she also serves as director of the Breast Cancer Clinical Trials Program.

Additional analysis showed that low HER2 expression by mRNA or immunohistochemistry (IHC), and HER2 heterogeneity “tended to correlate with locoregional progression.”

Invasive disease-free survival (IDFS) risk, however, was similar with the two treatments (93% and 92%, respectively; HR, 1.11), and, as has been shown “many times over,” experiencing a pCR was associated with reduced risk of an IDFS event (HR, 0.24), regardless of treatment arm, Dr. Hurvitz said.


The previously reported primary results of the study, which failed to reach its primary endpoint, showed a pCR of 44% vs. 56% in 223 women who received TDM-1+P and 221 who received TCH+P, respectively. (Lancet Oncol. 2018 Jan;19[1]:115-126. doi: 10.1016/S1470-2045[17]30716-7).

Of note, additional data reported in a poster at the 2016 San Antonio Breast Cancer Symposium showed that pCR rates “were higher with TCH+P in those tumors with IHC2+ HER2 staining (20% vs. 7% in the T-DM1 arm), or IHC3+ HER2 staining (61% vs. 50%),” she said (SABCS 2016 P6-07-09).

“During neoadjuvant treatment, however, it’s not surprising that the T-DM1+P arm had a more favorable safety profile with a lower incidence of grade 3-4 events, lower incidence of [serious adverse events], and lower incidence of AEs leading to treatment discontinuation,” she said.

The overall rate of grade 3 or greater AEs was 31.8% vs. 67.6% with T-DM1+P vs. TCH+P, but the T-DM1 regimen was associated with more grade 3+ AEs during adjuvant treatment (24.5% vs. 9.9%), and with more adverse events leading to treatment discontinuation – both overall (20.2% vs. 11.0%) and during adjuvant therapy (18.4% vs. 3.8%), said Dr. Hurvitz, noting, however, that 50 patients in the T-DM1+P arm received cytotoxic chemotherapy in the adjuvant phase as allowed by study protocol.

Patient-reported outcomes favored T-DM1+P during the neoadjuvant phase, but were similar in the two groups during the adjuvant phase.

Adverse events occurring substantially more often with TCH+P (2% or greater difference in incidence between the groups) mainly included neutropenia, diarrhea, febrile neutropenia, and anemia, but peripheral neuropathy was a bit higher in the T-DM1 arm, she said.

“Standard-of-care neoadjuvant therapy for HER2-positive breast cancer is chemotherapy plus dual HER2 blockade with trastuzumab and pertuzumab, followed by continued HER2 blockade in the adjuvant setting,” Dr. Hurvitz said, noting that rates of pCR, which is associated with prolonged survival, range from 46% to 62%. “Despite the good outcomes ... 15% of patients will relapse or die; moreover, our standard cytotoxic approaches are associated with systemic toxicity, so there still is a need for effective, less toxic therapies.”

The antibody drug conjugate (ADC) T-DM1 is associated with a lower incidence of AEs typically associated with cytotoxic chemotherapy due to its targeted nature, and in the German ADAPT study it has shown some evidence of efficacy as monotherapy or with endocrine therapy in the neoadjuvant setting in HER2-positive, hormone receptor-positive breast cancer.

“So when we designed this clinical trial we thought that combining T-DM1 with pertuzumab might be an efficacious therapy that would provide patients with a less toxic regimen,” she said.

Participants had centrally-confirmed HER2-positive breast cancer over 2 cm and were randomly assigned 1:1 to T-DM1+P or TCH+P every 3 weeks for six cycles prior to surgery. Those who received T-DM1+P continued adjuvant T-DM1+P for 12 cycles, and those who received TCH+P received adjuvant trastuzumab plus pertuzumab for 12 cycles.

Those in the T-DM1 arm were allowed to receive standard adjuvant chemotherapy at physician discretion – and were encouraged to do so if they had residual disease in the breast greater than 1 cm or lymph node-positive disease. They then went on to receive T-DM1+P for 12 cycles, she said.

“We know that patients who achieve a pathologic complete response have a very good 3-year [IDFS], and for our study, for either arm, it was around 97%. Patients with residual disease have a lower 3-year IDFS in the mid [80% range] representing an unmet need,” she said.

In addition, the similar overall risk of an IDFS event with T-DM1+P and TCH+P in this study suggests that systemic chemotherapy might be unnecessary for some patients.

“But, of course, identification of these patients is going to be critical in determining who can have a deescalation approach, and the clinical utility of chemotherapy-sparing regimens must be confirmed in prospective studies, hopefully using biomarkers,” she concluded.

In a companion article published June 3 in the Journal of Clinical Oncology, Dr. Hurvitz and her colleagues further noted that “the role of T-DM1 in early HER2-positive breast cancer is evolving, with two trials evaluating this agent in the adjuvant setting.”


These include the KATHERINE trial, which showed a lower risk of invasive breast cancer recurrence or death with adjuvant T-DM1 vs. adjuvant trastuzumab in patients with residual disease after neoadjuvant systemic chemotherapy plus single or dual HER-directed therapy (HR, 0.50), and the ongoing KAITLIN trial, which is comparing T-DM1+P with taxane plus trastuzumab after anthracyclines as adjuvant therapy in patients who have not received prior neoadjuvant therapy.

“Data from KAITLIN will further define the clinical utility of adjuvant T-DM1+P in patients with HER2-positive early breast cancer,” they wrote.

During a discussion of the KRISTINE study findings and other related data presented at ASCO 2019, Mark D. Pegram, MD, a medical oncologist and professor at Stanford (Calif.) University, said that T-DM1-based neoadjuvant regimens appear, based on peer-reviewed published data from KRISTINE and other studies (such as the Swedish PREDIX HER2 trial, which was also discussed during the session), to be clinically active and well tolerated in HER2-positive early breast cancer.

Sharon Worcester/MDedge News

“Early adopters may consider neoadjuvant T-DM1 in patients who are perhaps not candidates for chemotherapy due to comorbidities, age, et cetera, or those patients who frankly refuse chemotherapy, of which we all have a few,” said Dr. Pegram, who also is the first director of the Breast Cancer Oncology Program at Stanford Women’s Cancer Center. “The burden is on us to identify molecular, genetic, or perhaps imaging markers to identify patients who are most suitable for consideration of deescalation strategies with T-DM1 or newer HER2 antibody drug conjugates [in development].”

Dr. Pegram also highlighted the KRISTINE EFS finding on locoregional progression prior to surgery.

“Sara showed you that the ... event-free survival outcomes that are deleterious happen prior to surgery, which is, I think, fascinating, and if we could identify those patients prospectively, it could be very powerful in maximally exploiting the potential of deescalation with T-DM1 or T-DM1-based regimens,” he said. “But we’re not there yet, obviously.”

The KRISTINE study was funded by F. Hoffmann-La Roche and Genentech. Dr. Hurvitz reported research funding to her institution from Ambryx, Amgen, Bayer, Biomarin, Boehringer Ingelheim, Cascadian Therapeutics, Daiichi Sankyo, Dignitana, Genentech/Roche, GlaxoSmithKline, Lilly, Macrogenics, Medivation, Merrimack, Novartis, OBI Pharma, Pfizer, Puma Biotechnology, Sanofi, and Seattle Genetics, and travel/accommodations/expenses from Lilly, Novartis, and OBI Pharma. Dr. Pegram reported relationships (honoraria; consulting/advisory roles) with Daiichi Sankyo, Genentech/Roche, Macrogenics, and Seattle Genetics.

SOURCE: Hurvitz S et al. ASCO 2019: Abstract 500.

CHICAGO – Combining trastuzumab emtansine (T-DM1) and pertuzumab (P) reduced grade 3+ toxicity in patients with HER2-positive stage I-III breast cancer in the KRISTINE trial, but led to lower event-free survival (EFS) and pathological complete response (pCR) rates vs. standard chemotherapy plus dual HER2 blockade, according to the preplanned 3-year final data analysis.

Sharon Worcester/MDedge News

The EFS rate among participants in the randomized, phase 3 study who completed follow-up was 94.2% in 189 patients who received neoadjuvant T-DM1+P treatment and 85.3% in 196 patients who received docetaxel, carboplatin, and trastuzumab (TCH) plus pertuzumab (hazard ratio, 2.61). The difference was due to more locoregional progression events before surgery (15 [6.7%] vs. 0 in the groups, respectively), Dr. Sara A. Hurvitz, MD, reported at the annual meeting of the American Association of Clinical Oncology.

The curves separated early, prior to surgery, without much change after surgery, noted Dr. Hurvitz, a medical oncologist at the University of California, Los Angeles, where she also serves as director of the Breast Cancer Clinical Trials Program.

Additional analysis showed that low HER2 expression by mRNA or immunohistochemistry (IHC), and HER2 heterogeneity “tended to correlate with locoregional progression.”

Invasive disease-free survival (IDFS) risk, however, was similar with the two treatments (93% and 92%, respectively; HR, 1.11), and, as has been shown “many times over,” experiencing a pCR was associated with reduced risk of an IDFS event (HR, 0.24), regardless of treatment arm, Dr. Hurvitz said.


The previously reported primary results of the study, which failed to reach its primary endpoint, showed a pCR of 44% vs. 56% in 223 women who received TDM-1+P and 221 who received TCH+P, respectively. (Lancet Oncol. 2018 Jan;19[1]:115-126. doi: 10.1016/S1470-2045[17]30716-7).

Of note, additional data reported in a poster at the 2016 San Antonio Breast Cancer Symposium showed that pCR rates “were higher with TCH+P in those tumors with IHC2+ HER2 staining (20% vs. 7% in the T-DM1 arm), or IHC3+ HER2 staining (61% vs. 50%),” she said (SABCS 2016 P6-07-09).

“During neoadjuvant treatment, however, it’s not surprising that the T-DM1+P arm had a more favorable safety profile with a lower incidence of grade 3-4 events, lower incidence of [serious adverse events], and lower incidence of AEs leading to treatment discontinuation,” she said.

The overall rate of grade 3 or greater AEs was 31.8% vs. 67.6% with T-DM1+P vs. TCH+P, but the T-DM1 regimen was associated with more grade 3+ AEs during adjuvant treatment (24.5% vs. 9.9%), and with more adverse events leading to treatment discontinuation – both overall (20.2% vs. 11.0%) and during adjuvant therapy (18.4% vs. 3.8%), said Dr. Hurvitz, noting, however, that 50 patients in the T-DM1+P arm received cytotoxic chemotherapy in the adjuvant phase as allowed by study protocol.

Patient-reported outcomes favored T-DM1+P during the neoadjuvant phase, but were similar in the two groups during the adjuvant phase.

Adverse events occurring substantially more often with TCH+P (2% or greater difference in incidence between the groups) mainly included neutropenia, diarrhea, febrile neutropenia, and anemia, but peripheral neuropathy was a bit higher in the T-DM1 arm, she said.

“Standard-of-care neoadjuvant therapy for HER2-positive breast cancer is chemotherapy plus dual HER2 blockade with trastuzumab and pertuzumab, followed by continued HER2 blockade in the adjuvant setting,” Dr. Hurvitz said, noting that rates of pCR, which is associated with prolonged survival, range from 46% to 62%. “Despite the good outcomes ... 15% of patients will relapse or die; moreover, our standard cytotoxic approaches are associated with systemic toxicity, so there still is a need for effective, less toxic therapies.”

The antibody drug conjugate (ADC) T-DM1 is associated with a lower incidence of AEs typically associated with cytotoxic chemotherapy due to its targeted nature, and in the German ADAPT study it has shown some evidence of efficacy as monotherapy or with endocrine therapy in the neoadjuvant setting in HER2-positive, hormone receptor-positive breast cancer.

“So when we designed this clinical trial we thought that combining T-DM1 with pertuzumab might be an efficacious therapy that would provide patients with a less toxic regimen,” she said.

Participants had centrally-confirmed HER2-positive breast cancer over 2 cm and were randomly assigned 1:1 to T-DM1+P or TCH+P every 3 weeks for six cycles prior to surgery. Those who received T-DM1+P continued adjuvant T-DM1+P for 12 cycles, and those who received TCH+P received adjuvant trastuzumab plus pertuzumab for 12 cycles.

Those in the T-DM1 arm were allowed to receive standard adjuvant chemotherapy at physician discretion – and were encouraged to do so if they had residual disease in the breast greater than 1 cm or lymph node-positive disease. They then went on to receive T-DM1+P for 12 cycles, she said.

“We know that patients who achieve a pathologic complete response have a very good 3-year [IDFS], and for our study, for either arm, it was around 97%. Patients with residual disease have a lower 3-year IDFS in the mid [80% range] representing an unmet need,” she said.

In addition, the similar overall risk of an IDFS event with T-DM1+P and TCH+P in this study suggests that systemic chemotherapy might be unnecessary for some patients.

“But, of course, identification of these patients is going to be critical in determining who can have a deescalation approach, and the clinical utility of chemotherapy-sparing regimens must be confirmed in prospective studies, hopefully using biomarkers,” she concluded.

In a companion article published June 3 in the Journal of Clinical Oncology, Dr. Hurvitz and her colleagues further noted that “the role of T-DM1 in early HER2-positive breast cancer is evolving, with two trials evaluating this agent in the adjuvant setting.”


These include the KATHERINE trial, which showed a lower risk of invasive breast cancer recurrence or death with adjuvant T-DM1 vs. adjuvant trastuzumab in patients with residual disease after neoadjuvant systemic chemotherapy plus single or dual HER-directed therapy (HR, 0.50), and the ongoing KAITLIN trial, which is comparing T-DM1+P with taxane plus trastuzumab after anthracyclines as adjuvant therapy in patients who have not received prior neoadjuvant therapy.

“Data from KAITLIN will further define the clinical utility of adjuvant T-DM1+P in patients with HER2-positive early breast cancer,” they wrote.

During a discussion of the KRISTINE study findings and other related data presented at ASCO 2019, Mark D. Pegram, MD, a medical oncologist and professor at Stanford (Calif.) University, said that T-DM1-based neoadjuvant regimens appear, based on peer-reviewed published data from KRISTINE and other studies (such as the Swedish PREDIX HER2 trial, which was also discussed during the session), to be clinically active and well tolerated in HER2-positive early breast cancer.

Sharon Worcester/MDedge News

“Early adopters may consider neoadjuvant T-DM1 in patients who are perhaps not candidates for chemotherapy due to comorbidities, age, et cetera, or those patients who frankly refuse chemotherapy, of which we all have a few,” said Dr. Pegram, who also is the first director of the Breast Cancer Oncology Program at Stanford Women’s Cancer Center. “The burden is on us to identify molecular, genetic, or perhaps imaging markers to identify patients who are most suitable for consideration of deescalation strategies with T-DM1 or newer HER2 antibody drug conjugates [in development].”

Dr. Pegram also highlighted the KRISTINE EFS finding on locoregional progression prior to surgery.

“Sara showed you that the ... event-free survival outcomes that are deleterious happen prior to surgery, which is, I think, fascinating, and if we could identify those patients prospectively, it could be very powerful in maximally exploiting the potential of deescalation with T-DM1 or T-DM1-based regimens,” he said. “But we’re not there yet, obviously.”

The KRISTINE study was funded by F. Hoffmann-La Roche and Genentech. Dr. Hurvitz reported research funding to her institution from Ambryx, Amgen, Bayer, Biomarin, Boehringer Ingelheim, Cascadian Therapeutics, Daiichi Sankyo, Dignitana, Genentech/Roche, GlaxoSmithKline, Lilly, Macrogenics, Medivation, Merrimack, Novartis, OBI Pharma, Pfizer, Puma Biotechnology, Sanofi, and Seattle Genetics, and travel/accommodations/expenses from Lilly, Novartis, and OBI Pharma. Dr. Pegram reported relationships (honoraria; consulting/advisory roles) with Daiichi Sankyo, Genentech/Roche, Macrogenics, and Seattle Genetics.

SOURCE: Hurvitz S et al. ASCO 2019: Abstract 500.

CHICAGO – Combining trastuzumab emtansine (T-DM1) and pertuzumab (P) reduced grade 3+ toxicity in patients with HER2-positive stage I-III breast cancer in the KRISTINE trial, but led to lower event-free survival (EFS) and pathological complete response (pCR) rates vs. standard chemotherapy plus dual HER2 blockade, according to the preplanned 3-year final data analysis.

Sharon Worcester/MDedge News

The EFS rate among participants in the randomized, phase 3 study who completed follow-up was 94.2% in 189 patients who received neoadjuvant T-DM1+P treatment and 85.3% in 196 patients who received docetaxel, carboplatin, and trastuzumab (TCH) plus pertuzumab (hazard ratio, 2.61). The difference was due to more locoregional progression events before surgery (15 [6.7%] vs. 0 in the groups, respectively), Dr. Sara A. Hurvitz, MD, reported at the annual meeting of the American Association of Clinical Oncology.

The curves separated early, prior to surgery, without much change after surgery, noted Dr. Hurvitz, a medical oncologist at the University of California, Los Angeles, where she also serves as director of the Breast Cancer Clinical Trials Program.

Additional analysis showed that low HER2 expression by mRNA or immunohistochemistry (IHC), and HER2 heterogeneity “tended to correlate with locoregional progression.”

Invasive disease-free survival (IDFS) risk, however, was similar with the two treatments (93% and 92%, respectively; HR, 1.11), and, as has been shown “many times over,” experiencing a pCR was associated with reduced risk of an IDFS event (HR, 0.24), regardless of treatment arm, Dr. Hurvitz said.


The previously reported primary results of the study, which failed to reach its primary endpoint, showed a pCR of 44% vs. 56% in 223 women who received TDM-1+P and 221 who received TCH+P, respectively. (Lancet Oncol. 2018 Jan;19[1]:115-126. doi: 10.1016/S1470-2045[17]30716-7).

Of note, additional data reported in a poster at the 2016 San Antonio Breast Cancer Symposium showed that pCR rates “were higher with TCH+P in those tumors with IHC2+ HER2 staining (20% vs. 7% in the T-DM1 arm), or IHC3+ HER2 staining (61% vs. 50%),” she said (SABCS 2016 P6-07-09).

“During neoadjuvant treatment, however, it’s not surprising that the T-DM1+P arm had a more favorable safety profile with a lower incidence of grade 3-4 events, lower incidence of [serious adverse events], and lower incidence of AEs leading to treatment discontinuation,” she said.

The overall rate of grade 3 or greater AEs was 31.8% vs. 67.6% with T-DM1+P vs. TCH+P, but the T-DM1 regimen was associated with more grade 3+ AEs during adjuvant treatment (24.5% vs. 9.9%), and with more adverse events leading to treatment discontinuation – both overall (20.2% vs. 11.0%) and during adjuvant therapy (18.4% vs. 3.8%), said Dr. Hurvitz, noting, however, that 50 patients in the T-DM1+P arm received cytotoxic chemotherapy in the adjuvant phase as allowed by study protocol.

Patient-reported outcomes favored T-DM1+P during the neoadjuvant phase, but were similar in the two groups during the adjuvant phase.

Adverse events occurring substantially more often with TCH+P (2% or greater difference in incidence between the groups) mainly included neutropenia, diarrhea, febrile neutropenia, and anemia, but peripheral neuropathy was a bit higher in the T-DM1 arm, she said.

“Standard-of-care neoadjuvant therapy for HER2-positive breast cancer is chemotherapy plus dual HER2 blockade with trastuzumab and pertuzumab, followed by continued HER2 blockade in the adjuvant setting,” Dr. Hurvitz said, noting that rates of pCR, which is associated with prolonged survival, range from 46% to 62%. “Despite the good outcomes ... 15% of patients will relapse or die; moreover, our standard cytotoxic approaches are associated with systemic toxicity, so there still is a need for effective, less toxic therapies.”

The antibody drug conjugate (ADC) T-DM1 is associated with a lower incidence of AEs typically associated with cytotoxic chemotherapy due to its targeted nature, and in the German ADAPT study it has shown some evidence of efficacy as monotherapy or with endocrine therapy in the neoadjuvant setting in HER2-positive, hormone receptor-positive breast cancer.

“So when we designed this clinical trial we thought that combining T-DM1 with pertuzumab might be an efficacious therapy that would provide patients with a less toxic regimen,” she said.

Participants had centrally-confirmed HER2-positive breast cancer over 2 cm and were randomly assigned 1:1 to T-DM1+P or TCH+P every 3 weeks for six cycles prior to surgery. Those who received T-DM1+P continued adjuvant T-DM1+P for 12 cycles, and those who received TCH+P received adjuvant trastuzumab plus pertuzumab for 12 cycles.

Those in the T-DM1 arm were allowed to receive standard adjuvant chemotherapy at physician discretion – and were encouraged to do so if they had residual disease in the breast greater than 1 cm or lymph node-positive disease. They then went on to receive T-DM1+P for 12 cycles, she said.

“We know that patients who achieve a pathologic complete response have a very good 3-year [IDFS], and for our study, for either arm, it was around 97%. Patients with residual disease have a lower 3-year IDFS in the mid [80% range] representing an unmet need,” she said.

In addition, the similar overall risk of an IDFS event with T-DM1+P and TCH+P in this study suggests that systemic chemotherapy might be unnecessary for some patients.

“But, of course, identification of these patients is going to be critical in determining who can have a deescalation approach, and the clinical utility of chemotherapy-sparing regimens must be confirmed in prospective studies, hopefully using biomarkers,” she concluded.

In a companion article published June 3 in the Journal of Clinical Oncology, Dr. Hurvitz and her colleagues further noted that “the role of T-DM1 in early HER2-positive breast cancer is evolving, with two trials evaluating this agent in the adjuvant setting.”


These include the KATHERINE trial, which showed a lower risk of invasive breast cancer recurrence or death with adjuvant T-DM1 vs. adjuvant trastuzumab in patients with residual disease after neoadjuvant systemic chemotherapy plus single or dual HER-directed therapy (HR, 0.50), and the ongoing KAITLIN trial, which is comparing T-DM1+P with taxane plus trastuzumab after anthracyclines as adjuvant therapy in patients who have not received prior neoadjuvant therapy.

“Data from KAITLIN will further define the clinical utility of adjuvant T-DM1+P in patients with HER2-positive early breast cancer,” they wrote.

During a discussion of the KRISTINE study findings and other related data presented at ASCO 2019, Mark D. Pegram, MD, a medical oncologist and professor at Stanford (Calif.) University, said that T-DM1-based neoadjuvant regimens appear, based on peer-reviewed published data from KRISTINE and other studies (such as the Swedish PREDIX HER2 trial, which was also discussed during the session), to be clinically active and well tolerated in HER2-positive early breast cancer.

Sharon Worcester/MDedge News

“Early adopters may consider neoadjuvant T-DM1 in patients who are perhaps not candidates for chemotherapy due to comorbidities, age, et cetera, or those patients who frankly refuse chemotherapy, of which we all have a few,” said Dr. Pegram, who also is the first director of the Breast Cancer Oncology Program at Stanford Women’s Cancer Center. “The burden is on us to identify molecular, genetic, or perhaps imaging markers to identify patients who are most suitable for consideration of deescalation strategies with T-DM1 or newer HER2 antibody drug conjugates [in development].”

Dr. Pegram also highlighted the KRISTINE EFS finding on locoregional progression prior to surgery.

“Sara showed you that the ... event-free survival outcomes that are deleterious happen prior to surgery, which is, I think, fascinating, and if we could identify those patients prospectively, it could be very powerful in maximally exploiting the potential of deescalation with T-DM1 or T-DM1-based regimens,” he said. “But we’re not there yet, obviously.”

The KRISTINE study was funded by F. Hoffmann-La Roche and Genentech. Dr. Hurvitz reported research funding to her institution from Ambryx, Amgen, Bayer, Biomarin, Boehringer Ingelheim, Cascadian Therapeutics, Daiichi Sankyo, Dignitana, Genentech/Roche, GlaxoSmithKline, Lilly, Macrogenics, Medivation, Merrimack, Novartis, OBI Pharma, Pfizer, Puma Biotechnology, Sanofi, and Seattle Genetics, and travel/accommodations/expenses from Lilly, Novartis, and OBI Pharma. Dr. Pegram reported relationships (honoraria; consulting/advisory roles) with Daiichi Sankyo, Genentech/Roche, Macrogenics, and Seattle Genetics.

SOURCE: Hurvitz S et al. ASCO 2019: Abstract 500.

CHICAGO – Nearly two-thirds of more than 400 U.S.-based physician members of the Society of Gynecologic Oncology who participated in a recent survey reported experiencing sexual harassment in training or practice.

Notably, of the 255 women and 147 men who responded, 71% and 51%, respectively, reported such sexual harassment – and only 15% overall reported it to officials, Marina Stasenko, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The survey also addressed gender-based discrimination and disparities, including respondents’ views on pay disparities. In this video interview, Dr. Stasenko, a gynecologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York, discusses the findings, their implications and context in this age of #MeToo and #TimesUp, and potential approaches to addressing the ongoing problem and the concerns victims have about reporting harassment.

“We need to start by setting an example, saying these things are not tolerated [and] put that into policy – really show folks how it can be reported and what is being done once that report is filed,” she said.

Dr. Stasenko reported having no disclosures.

[email protected]

SOURCE: Stasenko M et al. ASCO 2019, Abstract LBA10502.

CHICAGO – Nearly two-thirds of more than 400 U.S.-based physician members of the Society of Gynecologic Oncology who participated in a recent survey reported experiencing sexual harassment in training or practice.

Notably, of the 255 women and 147 men who responded, 71% and 51%, respectively, reported such sexual harassment – and only 15% overall reported it to officials, Marina Stasenko, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The survey also addressed gender-based discrimination and disparities, including respondents’ views on pay disparities. In this video interview, Dr. Stasenko, a gynecologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York, discusses the findings, their implications and context in this age of #MeToo and #TimesUp, and potential approaches to addressing the ongoing problem and the concerns victims have about reporting harassment.

“We need to start by setting an example, saying these things are not tolerated [and] put that into policy – really show folks how it can be reported and what is being done once that report is filed,” she said.

Dr. Stasenko reported having no disclosures.

[email protected]

SOURCE: Stasenko M et al. ASCO 2019, Abstract LBA10502.

CHICAGO – Nearly two-thirds of more than 400 U.S.-based physician members of the Society of Gynecologic Oncology who participated in a recent survey reported experiencing sexual harassment in training or practice.

Notably, of the 255 women and 147 men who responded, 71% and 51%, respectively, reported such sexual harassment – and only 15% overall reported it to officials, Marina Stasenko, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The survey also addressed gender-based discrimination and disparities, including respondents’ views on pay disparities. In this video interview, Dr. Stasenko, a gynecologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York, discusses the findings, their implications and context in this age of #MeToo and #TimesUp, and potential approaches to addressing the ongoing problem and the concerns victims have about reporting harassment.

“We need to start by setting an example, saying these things are not tolerated [and] put that into policy – really show folks how it can be reported and what is being done once that report is filed,” she said.

Dr. Stasenko reported having no disclosures.

[email protected]

SOURCE: Stasenko M et al. ASCO 2019, Abstract LBA10502.

CHICAGO – The Food and Drug Administration launched a new call center project to assist physicians seeking to help cancer patients access unapproved therapies.

MDedge/Neil Osterweil

Entitled “Project Facilitate,” the program aims to create a single point of contact with FDA oncology staff who can guide physicians through the process of submitting Expanded Access (EA) requests on behalf of individual patients.

“This is a pilot program to provide continuous support to health care professionals throughout the entire Expanded Access process,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products said during the unveiling of the project during a press briefing at the annual meeting of the American Society of Clinical Oncology.

Physicians utilizing Project Facilitate can expect a “concierge service” experience including advice on the information needed to complete requests, assistance completing forms, pharma/biotech contact information, independent review board resource options, and follow-up on patient outcomes.

The project will work in synergy with the Reagan-Udall EA Navigator website, an “online road map” for physicians and patients that was launched 2 years ago “to facilitate and coordinate and collaborate with the FDA to advance the science mission of FDA,” and which has been expanded in conjunction with Project Facilitate, Ellen V. Sigal, PhD, chair of the board of the Reagan-Udall Foundation for the FDA, said at the press briefing.

“EA Navigator delivers transparent, concise, and searchable information provided by companies about their Expanded Access policies,” Dr. Sigal said. “Today I’m pleased to announce that the Navigator now features Expanded Access opportunities listed in ClinicalTrials.gov for companies in the directory.

“For the first time, those who need quick access to drug availability and Expanded Access options will find it in one place without having to visit site by site by site, or sift through thousands of studies that don’t merit their needs,” she added, noting that EA Navigator will often be the first step for physicians before they engage with Project Facilitate.

Project Facilitate can be reached Monday-Friday, 9 a.m.-5 p.m. ET at 240-402-0004, or by email at [email protected].

CHICAGO – The Food and Drug Administration launched a new call center project to assist physicians seeking to help cancer patients access unapproved therapies.

MDedge/Neil Osterweil

Entitled “Project Facilitate,” the program aims to create a single point of contact with FDA oncology staff who can guide physicians through the process of submitting Expanded Access (EA) requests on behalf of individual patients.

“This is a pilot program to provide continuous support to health care professionals throughout the entire Expanded Access process,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products said during the unveiling of the project during a press briefing at the annual meeting of the American Society of Clinical Oncology.

Physicians utilizing Project Facilitate can expect a “concierge service” experience including advice on the information needed to complete requests, assistance completing forms, pharma/biotech contact information, independent review board resource options, and follow-up on patient outcomes.

The project will work in synergy with the Reagan-Udall EA Navigator website, an “online road map” for physicians and patients that was launched 2 years ago “to facilitate and coordinate and collaborate with the FDA to advance the science mission of FDA,” and which has been expanded in conjunction with Project Facilitate, Ellen V. Sigal, PhD, chair of the board of the Reagan-Udall Foundation for the FDA, said at the press briefing.

“EA Navigator delivers transparent, concise, and searchable information provided by companies about their Expanded Access policies,” Dr. Sigal said. “Today I’m pleased to announce that the Navigator now features Expanded Access opportunities listed in ClinicalTrials.gov for companies in the directory.

“For the first time, those who need quick access to drug availability and Expanded Access options will find it in one place without having to visit site by site by site, or sift through thousands of studies that don’t merit their needs,” she added, noting that EA Navigator will often be the first step for physicians before they engage with Project Facilitate.

Project Facilitate can be reached Monday-Friday, 9 a.m.-5 p.m. ET at 240-402-0004, or by email at [email protected].

CHICAGO – The Food and Drug Administration launched a new call center project to assist physicians seeking to help cancer patients access unapproved therapies.

MDedge/Neil Osterweil

Entitled “Project Facilitate,” the program aims to create a single point of contact with FDA oncology staff who can guide physicians through the process of submitting Expanded Access (EA) requests on behalf of individual patients.

“This is a pilot program to provide continuous support to health care professionals throughout the entire Expanded Access process,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products said during the unveiling of the project during a press briefing at the annual meeting of the American Society of Clinical Oncology.

Physicians utilizing Project Facilitate can expect a “concierge service” experience including advice on the information needed to complete requests, assistance completing forms, pharma/biotech contact information, independent review board resource options, and follow-up on patient outcomes.

The project will work in synergy with the Reagan-Udall EA Navigator website, an “online road map” for physicians and patients that was launched 2 years ago “to facilitate and coordinate and collaborate with the FDA to advance the science mission of FDA,” and which has been expanded in conjunction with Project Facilitate, Ellen V. Sigal, PhD, chair of the board of the Reagan-Udall Foundation for the FDA, said at the press briefing.

“EA Navigator delivers transparent, concise, and searchable information provided by companies about their Expanded Access policies,” Dr. Sigal said. “Today I’m pleased to announce that the Navigator now features Expanded Access opportunities listed in ClinicalTrials.gov for companies in the directory.

“For the first time, those who need quick access to drug availability and Expanded Access options will find it in one place without having to visit site by site by site, or sift through thousands of studies that don’t merit their needs,” she added, noting that EA Navigator will often be the first step for physicians before they engage with Project Facilitate.

Project Facilitate can be reached Monday-Friday, 9 a.m.-5 p.m. ET at 240-402-0004, or by email at [email protected].

CHICAGO – Adding the oral androgen receptor inhibitor enzalutamide to standard first-line testosterone suppression delays progression and improves survival in men with metastatic hormone-sensitive prostate cancer (mHSPC), according to “practice-informing” interim results from the randomized phase 3 ENZAMET trial.

The survival rate at 3 years in 563 men with mHSPC who were enrolled in the international trial and who received early testosterone suppression and enzalutamide was 80%, compared with 72% among 562 men who received testosterone suppression and standard nonsteroidal antiandrogen therapy with or without docetaxel, study cochair Christopher Sweeney, MBBS, reported at the annual meeting of the American Society of Clinical Oncology (Abstract LBA2).

The findings of the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group study (ANZUP 1304/ENZAMET) were published simultaneously in the New England Journal of Medicine.

“So ... we’re moving forward by going backwards in the disease setting where the disease is more sensitive and responds better to therapy,” Dr. Sweeney, of Dana-Farber Cancer Institute’s Lank Center for Genitourinary Oncology and professor of medicine at Harvard Medical School, Boston, explained in this video interview.

He also described the future directions for the research – in particular the need for longer follow-up to clarify the effects of docetaxel in this setting – and how the current findings will be reflected in his own management of patients with prostate cancer.

The findings have immediate implications for practice, ASCO expert Neeraj Agarwal, MD, professor of medicine and investigator at the Huntsman Cancer Institute, University of Utah, Salt Lake City, said during a press briefing at the meeting.

“In my view, using enzalutamide early on will allow our patients to avoid chemotherapy and steroids for many years, and thus, hopefully, improve their quality of life,” he said, noting that the findings are particularly exciting when considered in the context of the “equally impressive margin of benefit” seen with the similar drug apalutamide in the TITAN trial, which was presented separately during the ASCO meeting.

“One study is encouraging, but two large studies ... demonstrating similar findings, is even better,” he said. “This increases my confidence that targeting [the androgen receptor] is the optimal approach for newly diagnosed patients with advanced prostate cancer.”

Dr. Sweeney reported relationships (stock and other ownership interests, consulting or advisory roles, research funding to his institution, and/or patents/royalties/other intellectual property) with Leuchemix, Amgen, Astellas Pharma, AstraZeneca, Bayer, Genentech/Roche, Janssen Biotech, Pfizer, Sanofi, Dendreon, Sotio, and Exelixis. Dr. Agarwal reported consultancy or research for Pfizer, Novartis, Exelixis, Eisai, Genentech, Medivation, Clovis, Merck, Bayer, GlaxoSmithKline, AstraZeneca, EMD Serono, and Bristol-Myers Squibb.

CHICAGO – Adding the oral androgen receptor inhibitor enzalutamide to standard first-line testosterone suppression delays progression and improves survival in men with metastatic hormone-sensitive prostate cancer (mHSPC), according to “practice-informing” interim results from the randomized phase 3 ENZAMET trial.

The survival rate at 3 years in 563 men with mHSPC who were enrolled in the international trial and who received early testosterone suppression and enzalutamide was 80%, compared with 72% among 562 men who received testosterone suppression and standard nonsteroidal antiandrogen therapy with or without docetaxel, study cochair Christopher Sweeney, MBBS, reported at the annual meeting of the American Society of Clinical Oncology (Abstract LBA2).

The findings of the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group study (ANZUP 1304/ENZAMET) were published simultaneously in the New England Journal of Medicine.

“So ... we’re moving forward by going backwards in the disease setting where the disease is more sensitive and responds better to therapy,” Dr. Sweeney, of Dana-Farber Cancer Institute’s Lank Center for Genitourinary Oncology and professor of medicine at Harvard Medical School, Boston, explained in this video interview.

He also described the future directions for the research – in particular the need for longer follow-up to clarify the effects of docetaxel in this setting – and how the current findings will be reflected in his own management of patients with prostate cancer.

The findings have immediate implications for practice, ASCO expert Neeraj Agarwal, MD, professor of medicine and investigator at the Huntsman Cancer Institute, University of Utah, Salt Lake City, said during a press briefing at the meeting.

“In my view, using enzalutamide early on will allow our patients to avoid chemotherapy and steroids for many years, and thus, hopefully, improve their quality of life,” he said, noting that the findings are particularly exciting when considered in the context of the “equally impressive margin of benefit” seen with the similar drug apalutamide in the TITAN trial, which was presented separately during the ASCO meeting.

“One study is encouraging, but two large studies ... demonstrating similar findings, is even better,” he said. “This increases my confidence that targeting [the androgen receptor] is the optimal approach for newly diagnosed patients with advanced prostate cancer.”

Dr. Sweeney reported relationships (stock and other ownership interests, consulting or advisory roles, research funding to his institution, and/or patents/royalties/other intellectual property) with Leuchemix, Amgen, Astellas Pharma, AstraZeneca, Bayer, Genentech/Roche, Janssen Biotech, Pfizer, Sanofi, Dendreon, Sotio, and Exelixis. Dr. Agarwal reported consultancy or research for Pfizer, Novartis, Exelixis, Eisai, Genentech, Medivation, Clovis, Merck, Bayer, GlaxoSmithKline, AstraZeneca, EMD Serono, and Bristol-Myers Squibb.

CHICAGO – Adding the oral androgen receptor inhibitor enzalutamide to standard first-line testosterone suppression delays progression and improves survival in men with metastatic hormone-sensitive prostate cancer (mHSPC), according to “practice-informing” interim results from the randomized phase 3 ENZAMET trial.

The survival rate at 3 years in 563 men with mHSPC who were enrolled in the international trial and who received early testosterone suppression and enzalutamide was 80%, compared with 72% among 562 men who received testosterone suppression and standard nonsteroidal antiandrogen therapy with or without docetaxel, study cochair Christopher Sweeney, MBBS, reported at the annual meeting of the American Society of Clinical Oncology (Abstract LBA2).

The findings of the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group study (ANZUP 1304/ENZAMET) were published simultaneously in the New England Journal of Medicine.

“So ... we’re moving forward by going backwards in the disease setting where the disease is more sensitive and responds better to therapy,” Dr. Sweeney, of Dana-Farber Cancer Institute’s Lank Center for Genitourinary Oncology and professor of medicine at Harvard Medical School, Boston, explained in this video interview.

He also described the future directions for the research – in particular the need for longer follow-up to clarify the effects of docetaxel in this setting – and how the current findings will be reflected in his own management of patients with prostate cancer.

The findings have immediate implications for practice, ASCO expert Neeraj Agarwal, MD, professor of medicine and investigator at the Huntsman Cancer Institute, University of Utah, Salt Lake City, said during a press briefing at the meeting.

“In my view, using enzalutamide early on will allow our patients to avoid chemotherapy and steroids for many years, and thus, hopefully, improve their quality of life,” he said, noting that the findings are particularly exciting when considered in the context of the “equally impressive margin of benefit” seen with the similar drug apalutamide in the TITAN trial, which was presented separately during the ASCO meeting.

“One study is encouraging, but two large studies ... demonstrating similar findings, is even better,” he said. “This increases my confidence that targeting [the androgen receptor] is the optimal approach for newly diagnosed patients with advanced prostate cancer.”

Dr. Sweeney reported relationships (stock and other ownership interests, consulting or advisory roles, research funding to his institution, and/or patents/royalties/other intellectual property) with Leuchemix, Amgen, Astellas Pharma, AstraZeneca, Bayer, Genentech/Roche, Janssen Biotech, Pfizer, Sanofi, Dendreon, Sotio, and Exelixis. Dr. Agarwal reported consultancy or research for Pfizer, Novartis, Exelixis, Eisai, Genentech, Medivation, Clovis, Merck, Bayer, GlaxoSmithKline, AstraZeneca, EMD Serono, and Bristol-Myers Squibb.

CHICAGO – Ado-trastuzumab emtansine, previously known as T-DM1, is highly efficacious in patients with HER2-amplified salivary gland cancers, according to findings from an ongoing phase 2 multi-histology basket trial.

Sharon Worcester/MDedge News

In fact, nine of 10 patients with this rare tumor responded to treatment with the HER2-targeted antibody drug conjugate after prior trastuzumab, pertuzumab, and anti-androgen therapy, and 5 of those had a complete response, Bob T. Li, MD, said at the annual meeting of the American Society of Clinical Oncology.

“We are reporting this study early because it has already met its primary endpoint,” said Dr. Li of Memorial Sloan Kettering Cancer Center, N.Y.

The 90% response rate was based on either Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) criteria; the latter was used because many patients with HER-amplified salivary gland cancer aren’t “RECIST measurable” due to presentation with only lymph node- and bone-only metastasis, he explained, adding that “many of the responses were quite durable, with some lasting 2 years.”

Even at a median of 12 months, neither duration of response nor median progression-free survival have been reached, he said.

Study subjects included nine men and one woman with salivary gland cancers (SGCs) and HER2 amplification identified by next-generation sequencing (NGS). They had a median age of 65 years and a median of 2 prior lines of systemic therapy.

Dr. Li described one patient who had bone and vertebral metastases.

“After just two doses, he had a complete metabolic response,” he said. “His symptoms improved, his pain went away, he feels well, and just recently he celebrated his 92nd birthday.”

Treatment, which included 3.6 mg/kg delivered intravenously every 3 weeks until disease progression or unacceptable toxicity, was well tolerated; toxicities included grade 1 or 2 infusion reactions, thrombocytopenia, and transaminitis. Two dose reductions were required, but no treatment-related deaths occurred, Dr. Li said.


SGCs are rare tumors accounting for only about 0.8% of malignancies. There is no approved therapy for metastatic disease, and due to the rarity of the disease there is no established standard of care, he said, noting, however, that chemotherapy and anti-androgen therapy are considered treatment options based on some retrospective case series.

“Now, coming in from a molecular angle, HER2 amplification turns out to be very common in this rare tumor,” he said.

In fact, NGS of more than 40,000 tumors using the MSK-IMPACT 468-gene oncopanel showed that HER2 amplification occurs in 8% of all SGC histologies, and additional published data show that it occurs in about 30% of those with “the very aggressive salivary duct carcinoma histologic subtype,” he said, adding that case reports and a phase 2 study reported at ASCO 2018 showed encouraging response rates with chemotherapy plus trastuzumab.

Ado-trastuzumab emtansine is a Food and Drug Administration-approved agent for the treatment HER2-positive breast cancer.

“It’s got the trastuzumab antibody, it has a linker which attaches the highly toxic DM1 chemotherapy to it, and ... it binds to the over-expressed HER2 receptor and uses that receptor to internalize the drug into the cancer cell and by lysosome deregulation release the highly toxic DM1 into the cell to cause cancer cell kill,” he explained. “We hypothesized that this drug, as a single agent, would be efficacious in HER2-amplified SGC tumors, and it turns out [that] recently there was a nice case series published from the University of Pennsylvania supporting this hypothesis in a group of patients.”

Indeed, the findings are encouraging and warrant cohort expansion to confirm the results, he said.

Of note, HER2 amplification by NGS (fold change 2.8 to 22.8) correlated with findings on fluorescence in situ hybridization (FISH) in 8 of 8 patients tested, and with immunohistochemistry (IHC) 3+ in 10 of 10 patients tested, thereby confirming the validity of this testing method for the biomarker and as a study entry criterion, he said, adding that ongoing correlative analyses are focusing on cell-free DNA NGS to look for acquired resistance, quantitative HER2 protein analysis by mass spectrometry, and also a dimerization assay looking at the degree of HER2-HER3 dimerization, which leads to receptor internalization that may predict response to HER2 antibody drug conjugates.


“We wanted to see why [HER2-amplified SGC patients] respond so well in contrast to the other diseases in the basket trial,” Dr. Li said, explaining that the trial also includes lung, bladder and urinary tract, endometrial, and colorectal cancer cohorts.

Sharon Worcester/MDedge News

“However, to me as an oncologist, the most pressing thing is that with these kind of results and with this kind of response rate and progression-free survival ... there are patients in need of this treatment, so that is certainly the priority–to further accrue patients, complete the trial, publish the data, and hopefully have this new treatment approved to benefit all patients,” he concluded.

Discussant Vanita Noronha, MD, noted that the survival data are immature but “very clinically relevant and clinically significant,” and that they fulfill an unmet need.

“As much as we would like to have randomized trial, this is really a challenge in these kind of rare tumors,” said Dr. Noronha, a professor in the Department of Medical Oncology at Tata Memorial Hospital in Mumbai, India. “So my take-home message ... is that HER2neu is an important molecule driver in salivary gland tumors [and] all patients with salivary gland cancers should be tested for HER2neu amplification.”

Ado trastuzumab emtansine appears to be a good treatment option in those with HER2 amplified SGC, she added.

“Is this a practice changing study? Yes, potentially it is,” she said, noting that in patients with recurrent/metastatic SGC not amenable to radical therapy who are found to have HER2neu amplification, treatment options include either ado trastuzumab emtansine or the combination of trastuzumab and chemotherapy.

Dr. Li reported consulting or advisory roles with Biosceptre International, Guardant Health, Hengrui Therapeutics, Mersana, Roche, and Thermo Fisher Scientific. He reported research funding to his institution from AstraZeneca, BioMed Valley Discoveries, Daiichi Sankyo, GRAIL, Guardant Health, Hengrui Therapeutics, Illumina, and Roche/Genentech. Dr. Noronha has received research funding (to her institution) from Amgen,and Sanofi Aventis.

SOURCE: Li B et al., ASCO 2019: Abstract 6001.

CHICAGO – Ado-trastuzumab emtansine, previously known as T-DM1, is highly efficacious in patients with HER2-amplified salivary gland cancers, according to findings from an ongoing phase 2 multi-histology basket trial.

Sharon Worcester/MDedge News

In fact, nine of 10 patients with this rare tumor responded to treatment with the HER2-targeted antibody drug conjugate after prior trastuzumab, pertuzumab, and anti-androgen therapy, and 5 of those had a complete response, Bob T. Li, MD, said at the annual meeting of the American Society of Clinical Oncology.

“We are reporting this study early because it has already met its primary endpoint,” said Dr. Li of Memorial Sloan Kettering Cancer Center, N.Y.

The 90% response rate was based on either Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) criteria; the latter was used because many patients with HER-amplified salivary gland cancer aren’t “RECIST measurable” due to presentation with only lymph node- and bone-only metastasis, he explained, adding that “many of the responses were quite durable, with some lasting 2 years.”

Even at a median of 12 months, neither duration of response nor median progression-free survival have been reached, he said.

Study subjects included nine men and one woman with salivary gland cancers (SGCs) and HER2 amplification identified by next-generation sequencing (NGS). They had a median age of 65 years and a median of 2 prior lines of systemic therapy.

Dr. Li described one patient who had bone and vertebral metastases.

“After just two doses, he had a complete metabolic response,” he said. “His symptoms improved, his pain went away, he feels well, and just recently he celebrated his 92nd birthday.”

Treatment, which included 3.6 mg/kg delivered intravenously every 3 weeks until disease progression or unacceptable toxicity, was well tolerated; toxicities included grade 1 or 2 infusion reactions, thrombocytopenia, and transaminitis. Two dose reductions were required, but no treatment-related deaths occurred, Dr. Li said.


SGCs are rare tumors accounting for only about 0.8% of malignancies. There is no approved therapy for metastatic disease, and due to the rarity of the disease there is no established standard of care, he said, noting, however, that chemotherapy and anti-androgen therapy are considered treatment options based on some retrospective case series.

“Now, coming in from a molecular angle, HER2 amplification turns out to be very common in this rare tumor,” he said.

In fact, NGS of more than 40,000 tumors using the MSK-IMPACT 468-gene oncopanel showed that HER2 amplification occurs in 8% of all SGC histologies, and additional published data show that it occurs in about 30% of those with “the very aggressive salivary duct carcinoma histologic subtype,” he said, adding that case reports and a phase 2 study reported at ASCO 2018 showed encouraging response rates with chemotherapy plus trastuzumab.

Ado-trastuzumab emtansine is a Food and Drug Administration-approved agent for the treatment HER2-positive breast cancer.

“It’s got the trastuzumab antibody, it has a linker which attaches the highly toxic DM1 chemotherapy to it, and ... it binds to the over-expressed HER2 receptor and uses that receptor to internalize the drug into the cancer cell and by lysosome deregulation release the highly toxic DM1 into the cell to cause cancer cell kill,” he explained. “We hypothesized that this drug, as a single agent, would be efficacious in HER2-amplified SGC tumors, and it turns out [that] recently there was a nice case series published from the University of Pennsylvania supporting this hypothesis in a group of patients.”

Indeed, the findings are encouraging and warrant cohort expansion to confirm the results, he said.

Of note, HER2 amplification by NGS (fold change 2.8 to 22.8) correlated with findings on fluorescence in situ hybridization (FISH) in 8 of 8 patients tested, and with immunohistochemistry (IHC) 3+ in 10 of 10 patients tested, thereby confirming the validity of this testing method for the biomarker and as a study entry criterion, he said, adding that ongoing correlative analyses are focusing on cell-free DNA NGS to look for acquired resistance, quantitative HER2 protein analysis by mass spectrometry, and also a dimerization assay looking at the degree of HER2-HER3 dimerization, which leads to receptor internalization that may predict response to HER2 antibody drug conjugates.


“We wanted to see why [HER2-amplified SGC patients] respond so well in contrast to the other diseases in the basket trial,” Dr. Li said, explaining that the trial also includes lung, bladder and urinary tract, endometrial, and colorectal cancer cohorts.

Sharon Worcester/MDedge News

“However, to me as an oncologist, the most pressing thing is that with these kind of results and with this kind of response rate and progression-free survival ... there are patients in need of this treatment, so that is certainly the priority–to further accrue patients, complete the trial, publish the data, and hopefully have this new treatment approved to benefit all patients,” he concluded.

Discussant Vanita Noronha, MD, noted that the survival data are immature but “very clinically relevant and clinically significant,” and that they fulfill an unmet need.

“As much as we would like to have randomized trial, this is really a challenge in these kind of rare tumors,” said Dr. Noronha, a professor in the Department of Medical Oncology at Tata Memorial Hospital in Mumbai, India. “So my take-home message ... is that HER2neu is an important molecule driver in salivary gland tumors [and] all patients with salivary gland cancers should be tested for HER2neu amplification.”

Ado trastuzumab emtansine appears to be a good treatment option in those with HER2 amplified SGC, she added.

“Is this a practice changing study? Yes, potentially it is,” she said, noting that in patients with recurrent/metastatic SGC not amenable to radical therapy who are found to have HER2neu amplification, treatment options include either ado trastuzumab emtansine or the combination of trastuzumab and chemotherapy.

Dr. Li reported consulting or advisory roles with Biosceptre International, Guardant Health, Hengrui Therapeutics, Mersana, Roche, and Thermo Fisher Scientific. He reported research funding to his institution from AstraZeneca, BioMed Valley Discoveries, Daiichi Sankyo, GRAIL, Guardant Health, Hengrui Therapeutics, Illumina, and Roche/Genentech. Dr. Noronha has received research funding (to her institution) from Amgen,and Sanofi Aventis.

SOURCE: Li B et al., ASCO 2019: Abstract 6001.

CHICAGO – Ado-trastuzumab emtansine, previously known as T-DM1, is highly efficacious in patients with HER2-amplified salivary gland cancers, according to findings from an ongoing phase 2 multi-histology basket trial.

Sharon Worcester/MDedge News

In fact, nine of 10 patients with this rare tumor responded to treatment with the HER2-targeted antibody drug conjugate after prior trastuzumab, pertuzumab, and anti-androgen therapy, and 5 of those had a complete response, Bob T. Li, MD, said at the annual meeting of the American Society of Clinical Oncology.

“We are reporting this study early because it has already met its primary endpoint,” said Dr. Li of Memorial Sloan Kettering Cancer Center, N.Y.

The 90% response rate was based on either Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) criteria; the latter was used because many patients with HER-amplified salivary gland cancer aren’t “RECIST measurable” due to presentation with only lymph node- and bone-only metastasis, he explained, adding that “many of the responses were quite durable, with some lasting 2 years.”

Even at a median of 12 months, neither duration of response nor median progression-free survival have been reached, he said.

Study subjects included nine men and one woman with salivary gland cancers (SGCs) and HER2 amplification identified by next-generation sequencing (NGS). They had a median age of 65 years and a median of 2 prior lines of systemic therapy.

Dr. Li described one patient who had bone and vertebral metastases.

“After just two doses, he had a complete metabolic response,” he said. “His symptoms improved, his pain went away, he feels well, and just recently he celebrated his 92nd birthday.”

Treatment, which included 3.6 mg/kg delivered intravenously every 3 weeks until disease progression or unacceptable toxicity, was well tolerated; toxicities included grade 1 or 2 infusion reactions, thrombocytopenia, and transaminitis. Two dose reductions were required, but no treatment-related deaths occurred, Dr. Li said.


SGCs are rare tumors accounting for only about 0.8% of malignancies. There is no approved therapy for metastatic disease, and due to the rarity of the disease there is no established standard of care, he said, noting, however, that chemotherapy and anti-androgen therapy are considered treatment options based on some retrospective case series.

“Now, coming in from a molecular angle, HER2 amplification turns out to be very common in this rare tumor,” he said.

In fact, NGS of more than 40,000 tumors using the MSK-IMPACT 468-gene oncopanel showed that HER2 amplification occurs in 8% of all SGC histologies, and additional published data show that it occurs in about 30% of those with “the very aggressive salivary duct carcinoma histologic subtype,” he said, adding that case reports and a phase 2 study reported at ASCO 2018 showed encouraging response rates with chemotherapy plus trastuzumab.

Ado-trastuzumab emtansine is a Food and Drug Administration-approved agent for the treatment HER2-positive breast cancer.

“It’s got the trastuzumab antibody, it has a linker which attaches the highly toxic DM1 chemotherapy to it, and ... it binds to the over-expressed HER2 receptor and uses that receptor to internalize the drug into the cancer cell and by lysosome deregulation release the highly toxic DM1 into the cell to cause cancer cell kill,” he explained. “We hypothesized that this drug, as a single agent, would be efficacious in HER2-amplified SGC tumors, and it turns out [that] recently there was a nice case series published from the University of Pennsylvania supporting this hypothesis in a group of patients.”

Indeed, the findings are encouraging and warrant cohort expansion to confirm the results, he said.

Of note, HER2 amplification by NGS (fold change 2.8 to 22.8) correlated with findings on fluorescence in situ hybridization (FISH) in 8 of 8 patients tested, and with immunohistochemistry (IHC) 3+ in 10 of 10 patients tested, thereby confirming the validity of this testing method for the biomarker and as a study entry criterion, he said, adding that ongoing correlative analyses are focusing on cell-free DNA NGS to look for acquired resistance, quantitative HER2 protein analysis by mass spectrometry, and also a dimerization assay looking at the degree of HER2-HER3 dimerization, which leads to receptor internalization that may predict response to HER2 antibody drug conjugates.


“We wanted to see why [HER2-amplified SGC patients] respond so well in contrast to the other diseases in the basket trial,” Dr. Li said, explaining that the trial also includes lung, bladder and urinary tract, endometrial, and colorectal cancer cohorts.

Sharon Worcester/MDedge News

“However, to me as an oncologist, the most pressing thing is that with these kind of results and with this kind of response rate and progression-free survival ... there are patients in need of this treatment, so that is certainly the priority–to further accrue patients, complete the trial, publish the data, and hopefully have this new treatment approved to benefit all patients,” he concluded.

Discussant Vanita Noronha, MD, noted that the survival data are immature but “very clinically relevant and clinically significant,” and that they fulfill an unmet need.

“As much as we would like to have randomized trial, this is really a challenge in these kind of rare tumors,” said Dr. Noronha, a professor in the Department of Medical Oncology at Tata Memorial Hospital in Mumbai, India. “So my take-home message ... is that HER2neu is an important molecule driver in salivary gland tumors [and] all patients with salivary gland cancers should be tested for HER2neu amplification.”

Ado trastuzumab emtansine appears to be a good treatment option in those with HER2 amplified SGC, she added.

“Is this a practice changing study? Yes, potentially it is,” she said, noting that in patients with recurrent/metastatic SGC not amenable to radical therapy who are found to have HER2neu amplification, treatment options include either ado trastuzumab emtansine or the combination of trastuzumab and chemotherapy.

Dr. Li reported consulting or advisory roles with Biosceptre International, Guardant Health, Hengrui Therapeutics, Mersana, Roche, and Thermo Fisher Scientific. He reported research funding to his institution from AstraZeneca, BioMed Valley Discoveries, Daiichi Sankyo, GRAIL, Guardant Health, Hengrui Therapeutics, Illumina, and Roche/Genentech. Dr. Noronha has received research funding (to her institution) from Amgen,and Sanofi Aventis.

SOURCE: Li B et al., ASCO 2019: Abstract 6001.

CHICAGO – Pembrolizumab with and without chemotherapy proved superior for overall survival compared with the EXTREME regimen when used first line in certain subgroups of patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), according to “practice-changing” final results from the randomized phase 3 KEYNOTE-048 study.

Sharon Worcester/MDedge News

Compared with 300 patients randomized to receive the EXTREME regimen (a certuximab loading dose followed by carboplatin or cisplatin and 5-fluorouracil), 281 who received pembrolizumab plus chemotherapy (P+C) had superior overall survival (OS) with comparable safety–including both those with programmed death-Ligand 1 (PD-L1) combined positive score (CPS) of 20 or greater (median 14.7 vs 11.0 months; hazard ratio, 0.60) and with CPS of 1 or greater (median, 13.6 vs. 10.4 months; HR, 0.65), Danny Rischin, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The differences were highly statistically significant, said Dr. Rischin, a professor and director of the Division of Cancer Medicine and head of the Department of Medical Oncology at Peter MacCallum Cancer Centre, Melbourne, Australia.

“And this benefit in overall survival in CPS greater than or equal to 20 and greater than or equal to 1 appeared to be present across all the subgroups that we looked at,” he added.

The response rates did not differ between P+C and EXTREME groups, but the median duration of response was significantly greater with P+C vs. EXTREME in both the CPS of 20 or greater and 1 or greater (7.1 vs. 4.2 months and 6.7 vs. 4.3 months, respectively).

Additionally, the final results of the study showed an OS benefit with P+C vs. EXTREME in the total population (13.0 vs. 10.7 months; HR, 0.72), Dr. Rischin said.

The difference between the groups with respect to progression-free survival (PFS), however, was not statistically significant and did not reach the superiority threshold, he noted.

In the 301 patients who received pembrolizumab alone, OS was superior in the CPS 20 or greater and 1 or greater populations (median, 14.8 vs. 10.7 months; HR, 0.58 and 12.4 vs. 10.3 months; HR, 0.74, respectively), compared with EXTREME, but was noninferior in the total population (median 11.5 vs. 10.7 months; HR, 0.83), and safety was favorable .

Again, PFS did not differ between the groups (median, 2.3 vs. 5.2 months; HR, 1.34), and while the overall response rates did not differ significantly, the median duration of response was substantially longer with pembrolizumab at 22.6 vs. 4.5 months with EXTREME, he said.

Study participants had locally incurable R/M HNSCC and no prior systemic therapy in the R/M setting. Those in he P+C arm received pembrolizumab at 200 mg plus 6 cycles of cisplatin at 100 mg/m2 or carboplatin AUC 5, and 5-fluorouracil at a dose of 1000 mg/m2/day for 4 days every 3 weeks; those in the pembrolizumab alone arm received 200 mg every 3 weeks for up to 35 cycles, and those in the EXTREME arm received certuximab at a 400 mg/m2 loading dose followed by 250 mg/m2 weekly with carboplatin AUC 5 or cisplatin at 100 mg/m2, and 5-FU at 1000 mg/m2/day for 4 days for 6 cycles.

“The data from KEYNOTE-048 support pembrolizumab plus platinum-based chemotherapy and pembrolizumab monotherapy as new standard of care monotherapies for recurrent/metastatic head and neck squamous cell carcinoma,” he concluded.

Sharon Worcester/MDedge News

Discussant Vanita Noronha, MD, a professor in the Department of Medical Oncology at Tata Memorial Hospital in Mumbai, India, said that while the findings are practice changing, they also raise a number of questions, such as which patients should get pembrolizumab and which should get P+C, why there is a differential effect of pembrolizumab based on PD-L1 by CPS–and what about those with CPS of 0 or 1-20, and why the response rates and PFS rates were not improved in the pembrolizumab groups.

Other important questions include whether there are predictive biomarkers for response, and whether sequential therapy would be of benefit, she added.

While these and other questions remain to be addressed, the KEYNOTE-048 findings have implications for practice going forward; based on the current data, her approach to treating patients with R/M HNSCC not amenable to radical therapy is to treat with pembrolizumab alone in those with disease-free interval of 6 months or less, she said.

For those with disease-free interval greater than 6 months and good performance status who have controlled comorbidities, are platinum eligible, and for whom the treatment is reimbursable/affordable, treatment depends on symptom severity; she would treat those with mild/moderate symptoms and CPS of 20 or greater with pembrolizumab alone, those with CPS of 1 or greater with P+C or pembrolizumab alone, and those with CPS of 0 or unknown CPS with EXTREME or a similar regimen or with P+C, and she would treat those with severe symptoms with P+C.

“If the patient were a bit borderline, had multiple comorbidities, could not receive platinum, or had financial constraints, I would treat the patient with singe-agent intravenous chemotherapy or with oral metronomic chemotherapy, single-agent targeted therapy or with best supportive care,” she said.

Dr. Rischin has received research funding from Amgen, Bristol-Myers Squibb, Genentech/Roche, GSK, Merck, and Regeneron. Dr. Noronha has received research funding (to her institution) from Amgen,and Sanofi Aventis.

SOURCE: D Rischin et al., ASCO 2019: Abstract 6000.

CHICAGO – Pembrolizumab with and without chemotherapy proved superior for overall survival compared with the EXTREME regimen when used first line in certain subgroups of patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), according to “practice-changing” final results from the randomized phase 3 KEYNOTE-048 study.

Sharon Worcester/MDedge News

Compared with 300 patients randomized to receive the EXTREME regimen (a certuximab loading dose followed by carboplatin or cisplatin and 5-fluorouracil), 281 who received pembrolizumab plus chemotherapy (P+C) had superior overall survival (OS) with comparable safety–including both those with programmed death-Ligand 1 (PD-L1) combined positive score (CPS) of 20 or greater (median 14.7 vs 11.0 months; hazard ratio, 0.60) and with CPS of 1 or greater (median, 13.6 vs. 10.4 months; HR, 0.65), Danny Rischin, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The differences were highly statistically significant, said Dr. Rischin, a professor and director of the Division of Cancer Medicine and head of the Department of Medical Oncology at Peter MacCallum Cancer Centre, Melbourne, Australia.

“And this benefit in overall survival in CPS greater than or equal to 20 and greater than or equal to 1 appeared to be present across all the subgroups that we looked at,” he added.

The response rates did not differ between P+C and EXTREME groups, but the median duration of response was significantly greater with P+C vs. EXTREME in both the CPS of 20 or greater and 1 or greater (7.1 vs. 4.2 months and 6.7 vs. 4.3 months, respectively).

Additionally, the final results of the study showed an OS benefit with P+C vs. EXTREME in the total population (13.0 vs. 10.7 months; HR, 0.72), Dr. Rischin said.

The difference between the groups with respect to progression-free survival (PFS), however, was not statistically significant and did not reach the superiority threshold, he noted.

In the 301 patients who received pembrolizumab alone, OS was superior in the CPS 20 or greater and 1 or greater populations (median, 14.8 vs. 10.7 months; HR, 0.58 and 12.4 vs. 10.3 months; HR, 0.74, respectively), compared with EXTREME, but was noninferior in the total population (median 11.5 vs. 10.7 months; HR, 0.83), and safety was favorable .

Again, PFS did not differ between the groups (median, 2.3 vs. 5.2 months; HR, 1.34), and while the overall response rates did not differ significantly, the median duration of response was substantially longer with pembrolizumab at 22.6 vs. 4.5 months with EXTREME, he said.

Study participants had locally incurable R/M HNSCC and no prior systemic therapy in the R/M setting. Those in he P+C arm received pembrolizumab at 200 mg plus 6 cycles of cisplatin at 100 mg/m2 or carboplatin AUC 5, and 5-fluorouracil at a dose of 1000 mg/m2/day for 4 days every 3 weeks; those in the pembrolizumab alone arm received 200 mg every 3 weeks for up to 35 cycles, and those in the EXTREME arm received certuximab at a 400 mg/m2 loading dose followed by 250 mg/m2 weekly with carboplatin AUC 5 or cisplatin at 100 mg/m2, and 5-FU at 1000 mg/m2/day for 4 days for 6 cycles.

“The data from KEYNOTE-048 support pembrolizumab plus platinum-based chemotherapy and pembrolizumab monotherapy as new standard of care monotherapies for recurrent/metastatic head and neck squamous cell carcinoma,” he concluded.

Sharon Worcester/MDedge News

Discussant Vanita Noronha, MD, a professor in the Department of Medical Oncology at Tata Memorial Hospital in Mumbai, India, said that while the findings are practice changing, they also raise a number of questions, such as which patients should get pembrolizumab and which should get P+C, why there is a differential effect of pembrolizumab based on PD-L1 by CPS–and what about those with CPS of 0 or 1-20, and why the response rates and PFS rates were not improved in the pembrolizumab groups.

Other important questions include whether there are predictive biomarkers for response, and whether sequential therapy would be of benefit, she added.

While these and other questions remain to be addressed, the KEYNOTE-048 findings have implications for practice going forward; based on the current data, her approach to treating patients with R/M HNSCC not amenable to radical therapy is to treat with pembrolizumab alone in those with disease-free interval of 6 months or less, she said.

For those with disease-free interval greater than 6 months and good performance status who have controlled comorbidities, are platinum eligible, and for whom the treatment is reimbursable/affordable, treatment depends on symptom severity; she would treat those with mild/moderate symptoms and CPS of 20 or greater with pembrolizumab alone, those with CPS of 1 or greater with P+C or pembrolizumab alone, and those with CPS of 0 or unknown CPS with EXTREME or a similar regimen or with P+C, and she would treat those with severe symptoms with P+C.

“If the patient were a bit borderline, had multiple comorbidities, could not receive platinum, or had financial constraints, I would treat the patient with singe-agent intravenous chemotherapy or with oral metronomic chemotherapy, single-agent targeted therapy or with best supportive care,” she said.

Dr. Rischin has received research funding from Amgen, Bristol-Myers Squibb, Genentech/Roche, GSK, Merck, and Regeneron. Dr. Noronha has received research funding (to her institution) from Amgen,and Sanofi Aventis.

SOURCE: D Rischin et al., ASCO 2019: Abstract 6000.

CHICAGO – Pembrolizumab with and without chemotherapy proved superior for overall survival compared with the EXTREME regimen when used first line in certain subgroups of patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), according to “practice-changing” final results from the randomized phase 3 KEYNOTE-048 study.

Sharon Worcester/MDedge News

Compared with 300 patients randomized to receive the EXTREME regimen (a certuximab loading dose followed by carboplatin or cisplatin and 5-fluorouracil), 281 who received pembrolizumab plus chemotherapy (P+C) had superior overall survival (OS) with comparable safety–including both those with programmed death-Ligand 1 (PD-L1) combined positive score (CPS) of 20 or greater (median 14.7 vs 11.0 months; hazard ratio, 0.60) and with CPS of 1 or greater (median, 13.6 vs. 10.4 months; HR, 0.65), Danny Rischin, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The differences were highly statistically significant, said Dr. Rischin, a professor and director of the Division of Cancer Medicine and head of the Department of Medical Oncology at Peter MacCallum Cancer Centre, Melbourne, Australia.

“And this benefit in overall survival in CPS greater than or equal to 20 and greater than or equal to 1 appeared to be present across all the subgroups that we looked at,” he added.

The response rates did not differ between P+C and EXTREME groups, but the median duration of response was significantly greater with P+C vs. EXTREME in both the CPS of 20 or greater and 1 or greater (7.1 vs. 4.2 months and 6.7 vs. 4.3 months, respectively).

Additionally, the final results of the study showed an OS benefit with P+C vs. EXTREME in the total population (13.0 vs. 10.7 months; HR, 0.72), Dr. Rischin said.

The difference between the groups with respect to progression-free survival (PFS), however, was not statistically significant and did not reach the superiority threshold, he noted.

In the 301 patients who received pembrolizumab alone, OS was superior in the CPS 20 or greater and 1 or greater populations (median, 14.8 vs. 10.7 months; HR, 0.58 and 12.4 vs. 10.3 months; HR, 0.74, respectively), compared with EXTREME, but was noninferior in the total population (median 11.5 vs. 10.7 months; HR, 0.83), and safety was favorable .

Again, PFS did not differ between the groups (median, 2.3 vs. 5.2 months; HR, 1.34), and while the overall response rates did not differ significantly, the median duration of response was substantially longer with pembrolizumab at 22.6 vs. 4.5 months with EXTREME, he said.

Study participants had locally incurable R/M HNSCC and no prior systemic therapy in the R/M setting. Those in he P+C arm received pembrolizumab at 200 mg plus 6 cycles of cisplatin at 100 mg/m2 or carboplatin AUC 5, and 5-fluorouracil at a dose of 1000 mg/m2/day for 4 days every 3 weeks; those in the pembrolizumab alone arm received 200 mg every 3 weeks for up to 35 cycles, and those in the EXTREME arm received certuximab at a 400 mg/m2 loading dose followed by 250 mg/m2 weekly with carboplatin AUC 5 or cisplatin at 100 mg/m2, and 5-FU at 1000 mg/m2/day for 4 days for 6 cycles.

“The data from KEYNOTE-048 support pembrolizumab plus platinum-based chemotherapy and pembrolizumab monotherapy as new standard of care monotherapies for recurrent/metastatic head and neck squamous cell carcinoma,” he concluded.

Sharon Worcester/MDedge News

Discussant Vanita Noronha, MD, a professor in the Department of Medical Oncology at Tata Memorial Hospital in Mumbai, India, said that while the findings are practice changing, they also raise a number of questions, such as which patients should get pembrolizumab and which should get P+C, why there is a differential effect of pembrolizumab based on PD-L1 by CPS–and what about those with CPS of 0 or 1-20, and why the response rates and PFS rates were not improved in the pembrolizumab groups.

Other important questions include whether there are predictive biomarkers for response, and whether sequential therapy would be of benefit, she added.

While these and other questions remain to be addressed, the KEYNOTE-048 findings have implications for practice going forward; based on the current data, her approach to treating patients with R/M HNSCC not amenable to radical therapy is to treat with pembrolizumab alone in those with disease-free interval of 6 months or less, she said.

For those with disease-free interval greater than 6 months and good performance status who have controlled comorbidities, are platinum eligible, and for whom the treatment is reimbursable/affordable, treatment depends on symptom severity; she would treat those with mild/moderate symptoms and CPS of 20 or greater with pembrolizumab alone, those with CPS of 1 or greater with P+C or pembrolizumab alone, and those with CPS of 0 or unknown CPS with EXTREME or a similar regimen or with P+C, and she would treat those with severe symptoms with P+C.

“If the patient were a bit borderline, had multiple comorbidities, could not receive platinum, or had financial constraints, I would treat the patient with singe-agent intravenous chemotherapy or with oral metronomic chemotherapy, single-agent targeted therapy or with best supportive care,” she said.

Dr. Rischin has received research funding from Amgen, Bristol-Myers Squibb, Genentech/Roche, GSK, Merck, and Regeneron. Dr. Noronha has received research funding (to her institution) from Amgen,and Sanofi Aventis.

SOURCE: D Rischin et al., ASCO 2019: Abstract 6000.

All pregnant women should be screened for preterm preeclampsia (PE) in the first trimester using a combined test with maternal risk factors and biomarkers as a one-step procedure, according to new recommendations from The International Federation of Gynecology and Obstetrics (FIGO).

FIGO “encourages all countries and its member associations to adopt and promote strategies to ensure [universal screening],” Liona C. Poon, MD, of Prince of Wales Hospital, the Chinese University of Hong Kong, Shatin, and colleagues wrote in a guide published in the International Journal of Gynecology & Obstetrics.

“The best combined test is one that includes maternal risk factors, measurements of mean arterial pressure (MAP), serum placental growth factor (PLGF), and uterine artery pulsatility index (UTPI),” the authors said, noting that the baseline screening test plus a combination of maternal risk factors with MAP is an alternative when PLGF and/or UTPI can’t be measured.

The FIGO recommendations are the culmination of an initiative on PE, which involved a group of international experts convened to discuss and evaluate current knowledge on PE and to “develop a document to frame the issues and suggest key actions to address the health burden posed by PE.” Among the group’s objectives are raising awareness of the links between PE and poor outcomes, and demanding a “clearly defined global health agenda” to address the issue because preeclampsia affects 2%-5% of all pregnant women and is a leading cause of maternal and perinatal morbidity and mortality.

The recommendations represent a consensus document that provides guidance for the first trimester screening and prevention of preterm PE.

“Based on high‐quality evidence, the document outlines current global standards for the first‐trimester screening and prevention of preterm PE, which is in line with FIGO good clinical practice advice on first trimester screening and prevention of preeclampsia in singleton pregnancy,” the authors said, explaining that “[it] provides both the best and the most pragmatic recommendations according to the level of acceptability, feasibility, and ease of implementation that have the potential to produce the most significant impact in different resource settings” (Int J Gynecol Obstet. 2019;145[Suppl. 1]:1-33).


Specific suggestions are made based on region and resources, and research priorities are outlined to “bridge the current knowledge and evidence gap.”

In addition to universal first trimester screening for PE, the guide stresses a need for improved public health focus, and contingent screening approaches in areas with limited resources (including routine screening for preterm PE by maternal factors and MAP in most cases, with PLGF and UTPI measurement reserved for higher-risk women). It also recommends that women at high risk should receive prophylactic measures such as aspirin therapy beginning at 11–14⁺⁶ weeks of gestation at a dose of about 150 mg to be taken every night until 36 weeks of gestation, when delivery occurs, or when PE is diagnosed.

Mary E. D’Alton, MD, a maternal-fetal medicine specialist who is chair of the department of obstetrics and gynecology and the Willard C. Rappleye Professor of Obstetrics & Gynecology at Columbia University, New York, was asked to comment on Dr. Sibai’s concerns about the guidelines. “I would simply say that ACOG and SMFM are the organizations in the United States [that] provide educational guidelines about practice in the United States.” Dr. D’Alton assisted Dr. Poon and her associates on the guidelines as an expert on preeclampsia.

Dr. Poon, given a chance to comment on the concern that the FIGO guidelines diverged from those of ACOG and SMFM, responded in an interview, “FIGO, being the global voice for women’s health, likes to ensure that our recommendations are resource appropriate. The objective of these guidelines is to provide a best practice approach, and also offers other pragmatic options for lower resource settings to ensure that preeclampsia testing can be implemented globally. We urge the broader membership of FIGO to adapt these guidelines to their local contexts.”*

She also emphasized that “PerkinElmer’s sponsorship was an unrestricted grant. The company had no involvement in writing the guideline.”*


This work was funded by an unrestricted grant from PerkinElmer, which markets an assay used for first trimester preeclampsia screening. Dr. Poon and her associates reported having no conflicts of interest.

[email protected]

*This article was updated 5/31/2019.

All pregnant women should be screened for preterm preeclampsia (PE) in the first trimester using a combined test with maternal risk factors and biomarkers as a one-step procedure, according to new recommendations from The International Federation of Gynecology and Obstetrics (FIGO).

FIGO “encourages all countries and its member associations to adopt and promote strategies to ensure [universal screening],” Liona C. Poon, MD, of Prince of Wales Hospital, the Chinese University of Hong Kong, Shatin, and colleagues wrote in a guide published in the International Journal of Gynecology & Obstetrics.

“The best combined test is one that includes maternal risk factors, measurements of mean arterial pressure (MAP), serum placental growth factor (PLGF), and uterine artery pulsatility index (UTPI),” the authors said, noting that the baseline screening test plus a combination of maternal risk factors with MAP is an alternative when PLGF and/or UTPI can’t be measured.

The FIGO recommendations are the culmination of an initiative on PE, which involved a group of international experts convened to discuss and evaluate current knowledge on PE and to “develop a document to frame the issues and suggest key actions to address the health burden posed by PE.” Among the group’s objectives are raising awareness of the links between PE and poor outcomes, and demanding a “clearly defined global health agenda” to address the issue because preeclampsia affects 2%-5% of all pregnant women and is a leading cause of maternal and perinatal morbidity and mortality.

The recommendations represent a consensus document that provides guidance for the first trimester screening and prevention of preterm PE.

“Based on high‐quality evidence, the document outlines current global standards for the first‐trimester screening and prevention of preterm PE, which is in line with FIGO good clinical practice advice on first trimester screening and prevention of preeclampsia in singleton pregnancy,” the authors said, explaining that “[it] provides both the best and the most pragmatic recommendations according to the level of acceptability, feasibility, and ease of implementation that have the potential to produce the most significant impact in different resource settings” (Int J Gynecol Obstet. 2019;145[Suppl. 1]:1-33).


Specific suggestions are made based on region and resources, and research priorities are outlined to “bridge the current knowledge and evidence gap.”

In addition to universal first trimester screening for PE, the guide stresses a need for improved public health focus, and contingent screening approaches in areas with limited resources (including routine screening for preterm PE by maternal factors and MAP in most cases, with PLGF and UTPI measurement reserved for higher-risk women). It also recommends that women at high risk should receive prophylactic measures such as aspirin therapy beginning at 11–14⁺⁶ weeks of gestation at a dose of about 150 mg to be taken every night until 36 weeks of gestation, when delivery occurs, or when PE is diagnosed.

Mary E. D’Alton, MD, a maternal-fetal medicine specialist who is chair of the department of obstetrics and gynecology and the Willard C. Rappleye Professor of Obstetrics & Gynecology at Columbia University, New York, was asked to comment on Dr. Sibai’s concerns about the guidelines. “I would simply say that ACOG and SMFM are the organizations in the United States [that] provide educational guidelines about practice in the United States.” Dr. D’Alton assisted Dr. Poon and her associates on the guidelines as an expert on preeclampsia.

Dr. Poon, given a chance to comment on the concern that the FIGO guidelines diverged from those of ACOG and SMFM, responded in an interview, “FIGO, being the global voice for women’s health, likes to ensure that our recommendations are resource appropriate. The objective of these guidelines is to provide a best practice approach, and also offers other pragmatic options for lower resource settings to ensure that preeclampsia testing can be implemented globally. We urge the broader membership of FIGO to adapt these guidelines to their local contexts.”*

She also emphasized that “PerkinElmer’s sponsorship was an unrestricted grant. The company had no involvement in writing the guideline.”*


This work was funded by an unrestricted grant from PerkinElmer, which markets an assay used for first trimester preeclampsia screening. Dr. Poon and her associates reported having no conflicts of interest.

[email protected]

*This article was updated 5/31/2019.

All pregnant women should be screened for preterm preeclampsia (PE) in the first trimester using a combined test with maternal risk factors and biomarkers as a one-step procedure, according to new recommendations from The International Federation of Gynecology and Obstetrics (FIGO).

FIGO “encourages all countries and its member associations to adopt and promote strategies to ensure [universal screening],” Liona C. Poon, MD, of Prince of Wales Hospital, the Chinese University of Hong Kong, Shatin, and colleagues wrote in a guide published in the International Journal of Gynecology & Obstetrics.

“The best combined test is one that includes maternal risk factors, measurements of mean arterial pressure (MAP), serum placental growth factor (PLGF), and uterine artery pulsatility index (UTPI),” the authors said, noting that the baseline screening test plus a combination of maternal risk factors with MAP is an alternative when PLGF and/or UTPI can’t be measured.

The FIGO recommendations are the culmination of an initiative on PE, which involved a group of international experts convened to discuss and evaluate current knowledge on PE and to “develop a document to frame the issues and suggest key actions to address the health burden posed by PE.” Among the group’s objectives are raising awareness of the links between PE and poor outcomes, and demanding a “clearly defined global health agenda” to address the issue because preeclampsia affects 2%-5% of all pregnant women and is a leading cause of maternal and perinatal morbidity and mortality.

The recommendations represent a consensus document that provides guidance for the first trimester screening and prevention of preterm PE.

“Based on high‐quality evidence, the document outlines current global standards for the first‐trimester screening and prevention of preterm PE, which is in line with FIGO good clinical practice advice on first trimester screening and prevention of preeclampsia in singleton pregnancy,” the authors said, explaining that “[it] provides both the best and the most pragmatic recommendations according to the level of acceptability, feasibility, and ease of implementation that have the potential to produce the most significant impact in different resource settings” (Int J Gynecol Obstet. 2019;145[Suppl. 1]:1-33).


Specific suggestions are made based on region and resources, and research priorities are outlined to “bridge the current knowledge and evidence gap.”

In addition to universal first trimester screening for PE, the guide stresses a need for improved public health focus, and contingent screening approaches in areas with limited resources (including routine screening for preterm PE by maternal factors and MAP in most cases, with PLGF and UTPI measurement reserved for higher-risk women). It also recommends that women at high risk should receive prophylactic measures such as aspirin therapy beginning at 11–14⁺⁶ weeks of gestation at a dose of about 150 mg to be taken every night until 36 weeks of gestation, when delivery occurs, or when PE is diagnosed.

Mary E. D’Alton, MD, a maternal-fetal medicine specialist who is chair of the department of obstetrics and gynecology and the Willard C. Rappleye Professor of Obstetrics & Gynecology at Columbia University, New York, was asked to comment on Dr. Sibai’s concerns about the guidelines. “I would simply say that ACOG and SMFM are the organizations in the United States [that] provide educational guidelines about practice in the United States.” Dr. D’Alton assisted Dr. Poon and her associates on the guidelines as an expert on preeclampsia.

Dr. Poon, given a chance to comment on the concern that the FIGO guidelines diverged from those of ACOG and SMFM, responded in an interview, “FIGO, being the global voice for women’s health, likes to ensure that our recommendations are resource appropriate. The objective of these guidelines is to provide a best practice approach, and also offers other pragmatic options for lower resource settings to ensure that preeclampsia testing can be implemented globally. We urge the broader membership of FIGO to adapt these guidelines to their local contexts.”*

She also emphasized that “PerkinElmer’s sponsorship was an unrestricted grant. The company had no involvement in writing the guideline.”*


This work was funded by an unrestricted grant from PerkinElmer, which markets an assay used for first trimester preeclampsia screening. Dr. Poon and her associates reported having no conflicts of interest.

[email protected]

*This article was updated 5/31/2019.