AVAHO

The oral selective estrogen receptor degrader (SERD) LSZ102 plus either ribociclib or alpelisib shows manageable safety and encouraging clinical activity in heavily pretreated estrogen receptor (ER)–positive breast cancer patients who progressed after prior endocrine therapy, according to interim results of an open-label phase 1/1b study.

The effects seen in the study, which is the first to report on an oral SERD in combination with both CDK4/6 and PI3Ka inhibitors, occurred regardless of ESR1 and PIK3CA mutations, said Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Jhaveri reported the results at the European Society of Medical Oncology: Breast Cancer virtual meeting.

The overall response rate (ORR) among 78 patients enrolled in an LSZ102 monotherapy arm (arm A) was 1.3%, and the progression-free survival (PFS) was 1.8 months. The clinical benefit rate (CBR) was 9.1%.

Among 76 patients enrolled in an LSZ102+ribociclib arm (arm B), the ORR was 15.8%, the PFS was 6.2 months, and the CBR was 35.5%.

Among the 39 patients enrolled in an LSZ102+alpelisib arm (arm C), the ORR was 5.4%, the PFS was 3.5 months, and the CBR was 18.9%.

After the data cutoff, one additional partial response (PR) was reported in arm C, Dr. Jhaveri said, noting that two of three confirmed responses were in known PIKC3A-mutant patients.

Study participants were aged 18 years and older with a confirmed diagnosis of ER-positive breast cancer and good performance status, as well as evidence of progression after endocrine therapy for metastatic disease or evidence of progression while on therapy or within 12 months from the end of adjuvant therapy.

“For all arms, prior fulvestrant, CDK46 inhibitor, or chemotherapy were allowed. For arm C, patients with or without PIK3C were eligible, and no prior treatment with PIK3, mTOR, or AKT inhibitors was allowed,” Dr. Jhaveri said.

Dosing in the LSZ102 monotherapy arm ranged from 200 to 900 mg. Arm B patients received LSZ102 at doses of 200-600 mg and ribociclib at doses of 200-600 mg. Both continuous ribociclib and 3 weeks on/1 week off dosing were evaluated. Arm C patients received LSZ102 at doses of 300-450 mg and alpelisib at 200-300 mg.

The recommended expansion doses were 450 mg daily of LSZ102 for arm A and 450 mg LSZ102 with 400 mg of daily ribociclib for arm B. For arm C, they were 300 mg LSZ102 with 250 mg of alpelisib daily.

Of note, two of three patients with a PR in arm C had received 300 mg LSZ102 and 300 mg alpelisib, Dr. Jhaveri said.

Arm A and arm B results were presented at the San Antonio Breast Cancer Symposium in 2018 and 2019, respectively. The current report updates those findings and presents arm C data for the first time, Dr. Jhaveri said.

LSZ102 was relatively well-tolerated as a single agent and in combination with ribociclib and alpelisib, according to Dr. Jhaveri. The most frequent adverse events were gastrointestinal toxicities, including nausea, vomiting, diarrhea, and decreased appetite, which occurred across all arms.

Neutropenia and aspartate aminotransferase abnormalities, including grade 3 cases, were reported in arm B and were most likely driven by the ribociclib, Dr. Jhaveri said. Grade 3 hypoglycemia and skin rash commonly occurred in arm C, most likely driven by the alpelisib.

Five dose-limiting toxicities occurred in four patients in arm A, three occurred in two patients in arm B, and seven occurred in seven patients in arm C.

Paired biopsies collected at the time of screening and at day 15 of cycle 1 showed consistent down-regulation of ER protein levels across arms.

“No substantial dose-dependent down-regulation of the ER was observed with increasing doses of LSZ,” Dr. Jhaveri said.

Circulating tumor DNA (ctDNA) analysis showed that the dominant mutations across the arms were ESR1, PIK3CA, and TP53. These were not shown to correlate with response and were not enriched upon progression in patients with matched baseline and end-of-treatment samples, she noted.

An exploratory analysis, conducted in “a preliminary attempt to correlate clinical activity with specific mutations,” showed that, in arms B and C, respectively, ORR, CBR, and PFS weren’t correlated with the presence or absence of ESR1 and PIK3CA mutations, respectively, or the absence of detectable ctDNA from baseline samples, Dr. Jhaveri said.

“While numerically higher responses and better CBR were seen in patients with undetectable ctDNA at baseline, no statistically significant difference in any of these outcomes was observed in arms B and C,” she said.

In arm C, the numbers were small at the time of data cutoff, but incoming data suggest relatively enhanced activity of the LSZ102 plus alpelisib combination in PIKC3A-mutant patients, she noted.

“We know that inhibiting ER signaling is the mainstay of treatment for ER-positive breast cancer,” Dr. Jhaveri explained, adding that aromatase inhibitors, estrogen receptor modulators, and SERDs are important classes of antiestrogenic agents, but fulvestrant is the only approved SERD. These are effective, but many patients develop resistance, she said.

“Proposed mechanisms for endocrine resistance include activation of the cell-cycle and cell-survival signaling pathways, or of the PI3K-AKT-mTOR pathway,” Dr. Jhaveri said. “To that end, ribociclib, a CDK46 inhibitor plus fulvestrant improved survival compared to fulvestrant alone in patients with ER-positive metastatic breast cancer.”

More recently, the PI3K inhibitor alpelisib plus fulvestrant also nearly doubled PFS vs. fulvestrant alone in PIKC3A-mutant, ER-positive metastatic breast cancer, which led to the approval of the combination in the United States.

Another mechanism of endocrine resistance includes acquisition of activating mutations in the estrogen receptor gene itself that allow tumors to survive and proliferate without depending on estrogen.

EGFR mutations appear to predict resistance to aromatase inhibitor therapies, but not outcomes in patients treated with fulvestrant. However, fulvestrant, which is delivered by intramuscular injection, has its own limitations, Dr. Jhaveri said.

“LSZ102 is a novel SERD that could achieve higher exposure than fulvestrant, leading to enhanced efficacy,” she said, noting that it was shown in preclinical models to have activity and to be synergistic in combination with ribociclib and alpelisib, forming the basis for the current study.

Invited discussant, Saverio Cinieri, MD, of Ospedale Antonio Perrino, Brindisi, Italy, said the study “elegantly demonstrated that estrogen receptor protein is down-regulated by LSZ102; [that] the genomic landscape of heavily pretreated patients is dominated by mutations in ESR1, PIK3CA, and TP53; [that] common mutations do not correlate with response and are not enriched on progression; [and that] ctDNA analysis at baseline shows similar outcomes with LSZ plus ribociclib or alpelisib, regardless of mutational status.”

LSZ102 is one of four new-generation SERDs in early-phase studies, he said, concluding that “in the COVID-19 era, the use of oral therapies will be even more necessary to limit access to the hospital.”

Dr. Cinieri also said that overcoming the limitations “of a molecule like the intramuscularly administered fulvestrant goes in this direction,” and that “the clinical efficacy and the biomolecular profile of LSZ102 seems to be able to meet these real needs.”

This study was funded by Novartis. Dr. Jhaveri reported advisory and consultancy roles and/or research grants or other funding to her institution from Novartis, ADC Therapeutics, Pfizer, and numerous other pharmaceutical and biotechnology companies. Dr. Cinieri reported relationships with Lily Oncology, Pfizer, Roche, AstraZeneca, Amgen, Novartis, including honoraria, grant and research support to his institution, advisory board participation, and scientific meeting support.

[email protected]

SOURCE: Jhaveri K et al. ESMO Breast Cancer, Abstract LBA1.

The oral selective estrogen receptor degrader (SERD) LSZ102 plus either ribociclib or alpelisib shows manageable safety and encouraging clinical activity in heavily pretreated estrogen receptor (ER)–positive breast cancer patients who progressed after prior endocrine therapy, according to interim results of an open-label phase 1/1b study.

The effects seen in the study, which is the first to report on an oral SERD in combination with both CDK4/6 and PI3Ka inhibitors, occurred regardless of ESR1 and PIK3CA mutations, said Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Jhaveri reported the results at the European Society of Medical Oncology: Breast Cancer virtual meeting.

The overall response rate (ORR) among 78 patients enrolled in an LSZ102 monotherapy arm (arm A) was 1.3%, and the progression-free survival (PFS) was 1.8 months. The clinical benefit rate (CBR) was 9.1%.

Among 76 patients enrolled in an LSZ102+ribociclib arm (arm B), the ORR was 15.8%, the PFS was 6.2 months, and the CBR was 35.5%.

Among the 39 patients enrolled in an LSZ102+alpelisib arm (arm C), the ORR was 5.4%, the PFS was 3.5 months, and the CBR was 18.9%.

After the data cutoff, one additional partial response (PR) was reported in arm C, Dr. Jhaveri said, noting that two of three confirmed responses were in known PIKC3A-mutant patients.

Study participants were aged 18 years and older with a confirmed diagnosis of ER-positive breast cancer and good performance status, as well as evidence of progression after endocrine therapy for metastatic disease or evidence of progression while on therapy or within 12 months from the end of adjuvant therapy.

“For all arms, prior fulvestrant, CDK46 inhibitor, or chemotherapy were allowed. For arm C, patients with or without PIK3C were eligible, and no prior treatment with PIK3, mTOR, or AKT inhibitors was allowed,” Dr. Jhaveri said.

Dosing in the LSZ102 monotherapy arm ranged from 200 to 900 mg. Arm B patients received LSZ102 at doses of 200-600 mg and ribociclib at doses of 200-600 mg. Both continuous ribociclib and 3 weeks on/1 week off dosing were evaluated. Arm C patients received LSZ102 at doses of 300-450 mg and alpelisib at 200-300 mg.

The recommended expansion doses were 450 mg daily of LSZ102 for arm A and 450 mg LSZ102 with 400 mg of daily ribociclib for arm B. For arm C, they were 300 mg LSZ102 with 250 mg of alpelisib daily.

Of note, two of three patients with a PR in arm C had received 300 mg LSZ102 and 300 mg alpelisib, Dr. Jhaveri said.

Arm A and arm B results were presented at the San Antonio Breast Cancer Symposium in 2018 and 2019, respectively. The current report updates those findings and presents arm C data for the first time, Dr. Jhaveri said.

LSZ102 was relatively well-tolerated as a single agent and in combination with ribociclib and alpelisib, according to Dr. Jhaveri. The most frequent adverse events were gastrointestinal toxicities, including nausea, vomiting, diarrhea, and decreased appetite, which occurred across all arms.

Neutropenia and aspartate aminotransferase abnormalities, including grade 3 cases, were reported in arm B and were most likely driven by the ribociclib, Dr. Jhaveri said. Grade 3 hypoglycemia and skin rash commonly occurred in arm C, most likely driven by the alpelisib.

Five dose-limiting toxicities occurred in four patients in arm A, three occurred in two patients in arm B, and seven occurred in seven patients in arm C.

Paired biopsies collected at the time of screening and at day 15 of cycle 1 showed consistent down-regulation of ER protein levels across arms.

“No substantial dose-dependent down-regulation of the ER was observed with increasing doses of LSZ,” Dr. Jhaveri said.

Circulating tumor DNA (ctDNA) analysis showed that the dominant mutations across the arms were ESR1, PIK3CA, and TP53. These were not shown to correlate with response and were not enriched upon progression in patients with matched baseline and end-of-treatment samples, she noted.

An exploratory analysis, conducted in “a preliminary attempt to correlate clinical activity with specific mutations,” showed that, in arms B and C, respectively, ORR, CBR, and PFS weren’t correlated with the presence or absence of ESR1 and PIK3CA mutations, respectively, or the absence of detectable ctDNA from baseline samples, Dr. Jhaveri said.

“While numerically higher responses and better CBR were seen in patients with undetectable ctDNA at baseline, no statistically significant difference in any of these outcomes was observed in arms B and C,” she said.

In arm C, the numbers were small at the time of data cutoff, but incoming data suggest relatively enhanced activity of the LSZ102 plus alpelisib combination in PIKC3A-mutant patients, she noted.

“We know that inhibiting ER signaling is the mainstay of treatment for ER-positive breast cancer,” Dr. Jhaveri explained, adding that aromatase inhibitors, estrogen receptor modulators, and SERDs are important classes of antiestrogenic agents, but fulvestrant is the only approved SERD. These are effective, but many patients develop resistance, she said.

“Proposed mechanisms for endocrine resistance include activation of the cell-cycle and cell-survival signaling pathways, or of the PI3K-AKT-mTOR pathway,” Dr. Jhaveri said. “To that end, ribociclib, a CDK46 inhibitor plus fulvestrant improved survival compared to fulvestrant alone in patients with ER-positive metastatic breast cancer.”

More recently, the PI3K inhibitor alpelisib plus fulvestrant also nearly doubled PFS vs. fulvestrant alone in PIKC3A-mutant, ER-positive metastatic breast cancer, which led to the approval of the combination in the United States.

Another mechanism of endocrine resistance includes acquisition of activating mutations in the estrogen receptor gene itself that allow tumors to survive and proliferate without depending on estrogen.

EGFR mutations appear to predict resistance to aromatase inhibitor therapies, but not outcomes in patients treated with fulvestrant. However, fulvestrant, which is delivered by intramuscular injection, has its own limitations, Dr. Jhaveri said.

“LSZ102 is a novel SERD that could achieve higher exposure than fulvestrant, leading to enhanced efficacy,” she said, noting that it was shown in preclinical models to have activity and to be synergistic in combination with ribociclib and alpelisib, forming the basis for the current study.

Invited discussant, Saverio Cinieri, MD, of Ospedale Antonio Perrino, Brindisi, Italy, said the study “elegantly demonstrated that estrogen receptor protein is down-regulated by LSZ102; [that] the genomic landscape of heavily pretreated patients is dominated by mutations in ESR1, PIK3CA, and TP53; [that] common mutations do not correlate with response and are not enriched on progression; [and that] ctDNA analysis at baseline shows similar outcomes with LSZ plus ribociclib or alpelisib, regardless of mutational status.”

LSZ102 is one of four new-generation SERDs in early-phase studies, he said, concluding that “in the COVID-19 era, the use of oral therapies will be even more necessary to limit access to the hospital.”

Dr. Cinieri also said that overcoming the limitations “of a molecule like the intramuscularly administered fulvestrant goes in this direction,” and that “the clinical efficacy and the biomolecular profile of LSZ102 seems to be able to meet these real needs.”

This study was funded by Novartis. Dr. Jhaveri reported advisory and consultancy roles and/or research grants or other funding to her institution from Novartis, ADC Therapeutics, Pfizer, and numerous other pharmaceutical and biotechnology companies. Dr. Cinieri reported relationships with Lily Oncology, Pfizer, Roche, AstraZeneca, Amgen, Novartis, including honoraria, grant and research support to his institution, advisory board participation, and scientific meeting support.

[email protected]

SOURCE: Jhaveri K et al. ESMO Breast Cancer, Abstract LBA1.

The oral selective estrogen receptor degrader (SERD) LSZ102 plus either ribociclib or alpelisib shows manageable safety and encouraging clinical activity in heavily pretreated estrogen receptor (ER)–positive breast cancer patients who progressed after prior endocrine therapy, according to interim results of an open-label phase 1/1b study.

The effects seen in the study, which is the first to report on an oral SERD in combination with both CDK4/6 and PI3Ka inhibitors, occurred regardless of ESR1 and PIK3CA mutations, said Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Jhaveri reported the results at the European Society of Medical Oncology: Breast Cancer virtual meeting.

The overall response rate (ORR) among 78 patients enrolled in an LSZ102 monotherapy arm (arm A) was 1.3%, and the progression-free survival (PFS) was 1.8 months. The clinical benefit rate (CBR) was 9.1%.

Among 76 patients enrolled in an LSZ102+ribociclib arm (arm B), the ORR was 15.8%, the PFS was 6.2 months, and the CBR was 35.5%.

Among the 39 patients enrolled in an LSZ102+alpelisib arm (arm C), the ORR was 5.4%, the PFS was 3.5 months, and the CBR was 18.9%.

After the data cutoff, one additional partial response (PR) was reported in arm C, Dr. Jhaveri said, noting that two of three confirmed responses were in known PIKC3A-mutant patients.

Study participants were aged 18 years and older with a confirmed diagnosis of ER-positive breast cancer and good performance status, as well as evidence of progression after endocrine therapy for metastatic disease or evidence of progression while on therapy or within 12 months from the end of adjuvant therapy.

“For all arms, prior fulvestrant, CDK46 inhibitor, or chemotherapy were allowed. For arm C, patients with or without PIK3C were eligible, and no prior treatment with PIK3, mTOR, or AKT inhibitors was allowed,” Dr. Jhaveri said.

Dosing in the LSZ102 monotherapy arm ranged from 200 to 900 mg. Arm B patients received LSZ102 at doses of 200-600 mg and ribociclib at doses of 200-600 mg. Both continuous ribociclib and 3 weeks on/1 week off dosing were evaluated. Arm C patients received LSZ102 at doses of 300-450 mg and alpelisib at 200-300 mg.

The recommended expansion doses were 450 mg daily of LSZ102 for arm A and 450 mg LSZ102 with 400 mg of daily ribociclib for arm B. For arm C, they were 300 mg LSZ102 with 250 mg of alpelisib daily.

Of note, two of three patients with a PR in arm C had received 300 mg LSZ102 and 300 mg alpelisib, Dr. Jhaveri said.

Arm A and arm B results were presented at the San Antonio Breast Cancer Symposium in 2018 and 2019, respectively. The current report updates those findings and presents arm C data for the first time, Dr. Jhaveri said.

LSZ102 was relatively well-tolerated as a single agent and in combination with ribociclib and alpelisib, according to Dr. Jhaveri. The most frequent adverse events were gastrointestinal toxicities, including nausea, vomiting, diarrhea, and decreased appetite, which occurred across all arms.

Neutropenia and aspartate aminotransferase abnormalities, including grade 3 cases, were reported in arm B and were most likely driven by the ribociclib, Dr. Jhaveri said. Grade 3 hypoglycemia and skin rash commonly occurred in arm C, most likely driven by the alpelisib.

Five dose-limiting toxicities occurred in four patients in arm A, three occurred in two patients in arm B, and seven occurred in seven patients in arm C.

Paired biopsies collected at the time of screening and at day 15 of cycle 1 showed consistent down-regulation of ER protein levels across arms.

“No substantial dose-dependent down-regulation of the ER was observed with increasing doses of LSZ,” Dr. Jhaveri said.

Circulating tumor DNA (ctDNA) analysis showed that the dominant mutations across the arms were ESR1, PIK3CA, and TP53. These were not shown to correlate with response and were not enriched upon progression in patients with matched baseline and end-of-treatment samples, she noted.

An exploratory analysis, conducted in “a preliminary attempt to correlate clinical activity with specific mutations,” showed that, in arms B and C, respectively, ORR, CBR, and PFS weren’t correlated with the presence or absence of ESR1 and PIK3CA mutations, respectively, or the absence of detectable ctDNA from baseline samples, Dr. Jhaveri said.

“While numerically higher responses and better CBR were seen in patients with undetectable ctDNA at baseline, no statistically significant difference in any of these outcomes was observed in arms B and C,” she said.

In arm C, the numbers were small at the time of data cutoff, but incoming data suggest relatively enhanced activity of the LSZ102 plus alpelisib combination in PIKC3A-mutant patients, she noted.

“We know that inhibiting ER signaling is the mainstay of treatment for ER-positive breast cancer,” Dr. Jhaveri explained, adding that aromatase inhibitors, estrogen receptor modulators, and SERDs are important classes of antiestrogenic agents, but fulvestrant is the only approved SERD. These are effective, but many patients develop resistance, she said.

“Proposed mechanisms for endocrine resistance include activation of the cell-cycle and cell-survival signaling pathways, or of the PI3K-AKT-mTOR pathway,” Dr. Jhaveri said. “To that end, ribociclib, a CDK46 inhibitor plus fulvestrant improved survival compared to fulvestrant alone in patients with ER-positive metastatic breast cancer.”

More recently, the PI3K inhibitor alpelisib plus fulvestrant also nearly doubled PFS vs. fulvestrant alone in PIKC3A-mutant, ER-positive metastatic breast cancer, which led to the approval of the combination in the United States.

Another mechanism of endocrine resistance includes acquisition of activating mutations in the estrogen receptor gene itself that allow tumors to survive and proliferate without depending on estrogen.

EGFR mutations appear to predict resistance to aromatase inhibitor therapies, but not outcomes in patients treated with fulvestrant. However, fulvestrant, which is delivered by intramuscular injection, has its own limitations, Dr. Jhaveri said.

“LSZ102 is a novel SERD that could achieve higher exposure than fulvestrant, leading to enhanced efficacy,” she said, noting that it was shown in preclinical models to have activity and to be synergistic in combination with ribociclib and alpelisib, forming the basis for the current study.

Invited discussant, Saverio Cinieri, MD, of Ospedale Antonio Perrino, Brindisi, Italy, said the study “elegantly demonstrated that estrogen receptor protein is down-regulated by LSZ102; [that] the genomic landscape of heavily pretreated patients is dominated by mutations in ESR1, PIK3CA, and TP53; [that] common mutations do not correlate with response and are not enriched on progression; [and that] ctDNA analysis at baseline shows similar outcomes with LSZ plus ribociclib or alpelisib, regardless of mutational status.”

LSZ102 is one of four new-generation SERDs in early-phase studies, he said, concluding that “in the COVID-19 era, the use of oral therapies will be even more necessary to limit access to the hospital.”

Dr. Cinieri also said that overcoming the limitations “of a molecule like the intramuscularly administered fulvestrant goes in this direction,” and that “the clinical efficacy and the biomolecular profile of LSZ102 seems to be able to meet these real needs.”

This study was funded by Novartis. Dr. Jhaveri reported advisory and consultancy roles and/or research grants or other funding to her institution from Novartis, ADC Therapeutics, Pfizer, and numerous other pharmaceutical and biotechnology companies. Dr. Cinieri reported relationships with Lily Oncology, Pfizer, Roche, AstraZeneca, Amgen, Novartis, including honoraria, grant and research support to his institution, advisory board participation, and scientific meeting support.

[email protected]

SOURCE: Jhaveri K et al. ESMO Breast Cancer, Abstract LBA1.

The Food and Drug Administration approved a combination of pertuzumab (Perjeta, Genentech/Roche), trastuzumab (Herceptin, Genentech/Roche) and hyaluronidase (Phesgo, Genentech/Roche) that is administered subcutaneously – rather than intravenously – for the treatment of early and metastatic HER2-positive breast cancers.

Phesgo is initially used in combination with chemotherapy at an infusion center but could continue to be administered in a patient’s home by a qualified health care professional once chemotherapy is complete, according to the FDA.

Administration takes approximately 8 minutes for the initial loading dose and approximately 5 minutes for maintenance doses, according to a Genentech press statement. This compares favorably with the 150 minutes needed for the combined loading dose of intravenous pertuzumab and trastuzumab, and the 60-150 minutes for intravenous maintenance infusions, the company said.

“Currently, most patients with HER2-positive breast cancer receive trastuzumab and pertuzumab at infusion centers. With a new administration route, Phesgo offers an outpatient option for patients to receive trastuzumab and pertuzumab,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, in an agency press release.

“The fixed-dose combination of trastuzumab and pertuzumab offers a simpler, faster, and easier treatment experience for patients with HER2-positive breast cancer,” said Antoinette Tan, MD, MHSc, chief of breast medical oncology at Levine Cancer Institute, Charlotte, N.C., in the company statement.

Dr. Tan also said that home administration “can be advantageous for patients and infusion centers.”

However, in April, the Community Oncology Alliance strenuously objected to this type of treatment in a patient’s home, as reported by Medscape Medical News.

The group, which represents U.S. community-based practices, said it “fundamentally opposes home infusion of chemotherapy, cancer immunotherapy, and cancer treatment supportive drugs because of serious patient safety concerns.”

The FDA’s approval was based on the results of the pivotal phase 3 FeDeriCa trial, a noninferiority study in patients with HER2-positive early breast cancer, which demonstrated that the new product had comparable efficacy and safety as intravenous pertuzumab and intravenous trastuzumab.

In terms of efficacy, the subcutaneous product demonstrated noninferior plasma levels of pertuzumab, which was the primary endpoint, when compared with IV administration of pertuzumab.

Safety was comparable between the two approaches, with no new safety signals using the subcutaneous delivery method, including no “meaningful difference” in cardiac toxicity, according to Genentech. However, there were more administration-related reactions with the new product. The most common adverse events in both groups were alopecia, nausea, diarrhea, and anemia.

The new product uses a drug delivery technology (Enhanze, Halozyme Therapeutics) that employs a proprietary enzyme that temporarily degrades hyaluronan, a glycosaminoglycan or chain of natural sugars in the body, to facilitate the dispersion and absorption of injected therapeutic drugs, according to Genentech.

In May, at the European Society for Medical Oncology Breast Cancer Virtual Meeting 2020, investigators of the phase 2 PHranceSCa study reported that “more than 80%” of patients preferred subcutaneous to intravenous administration of pertuzumab and trastuzumab.

This article first appeared on Medscape.com.

The Food and Drug Administration approved a combination of pertuzumab (Perjeta, Genentech/Roche), trastuzumab (Herceptin, Genentech/Roche) and hyaluronidase (Phesgo, Genentech/Roche) that is administered subcutaneously – rather than intravenously – for the treatment of early and metastatic HER2-positive breast cancers.

Phesgo is initially used in combination with chemotherapy at an infusion center but could continue to be administered in a patient’s home by a qualified health care professional once chemotherapy is complete, according to the FDA.

Administration takes approximately 8 minutes for the initial loading dose and approximately 5 minutes for maintenance doses, according to a Genentech press statement. This compares favorably with the 150 minutes needed for the combined loading dose of intravenous pertuzumab and trastuzumab, and the 60-150 minutes for intravenous maintenance infusions, the company said.

“Currently, most patients with HER2-positive breast cancer receive trastuzumab and pertuzumab at infusion centers. With a new administration route, Phesgo offers an outpatient option for patients to receive trastuzumab and pertuzumab,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, in an agency press release.

“The fixed-dose combination of trastuzumab and pertuzumab offers a simpler, faster, and easier treatment experience for patients with HER2-positive breast cancer,” said Antoinette Tan, MD, MHSc, chief of breast medical oncology at Levine Cancer Institute, Charlotte, N.C., in the company statement.

Dr. Tan also said that home administration “can be advantageous for patients and infusion centers.”

However, in April, the Community Oncology Alliance strenuously objected to this type of treatment in a patient’s home, as reported by Medscape Medical News.

The group, which represents U.S. community-based practices, said it “fundamentally opposes home infusion of chemotherapy, cancer immunotherapy, and cancer treatment supportive drugs because of serious patient safety concerns.”

The FDA’s approval was based on the results of the pivotal phase 3 FeDeriCa trial, a noninferiority study in patients with HER2-positive early breast cancer, which demonstrated that the new product had comparable efficacy and safety as intravenous pertuzumab and intravenous trastuzumab.

In terms of efficacy, the subcutaneous product demonstrated noninferior plasma levels of pertuzumab, which was the primary endpoint, when compared with IV administration of pertuzumab.

Safety was comparable between the two approaches, with no new safety signals using the subcutaneous delivery method, including no “meaningful difference” in cardiac toxicity, according to Genentech. However, there were more administration-related reactions with the new product. The most common adverse events in both groups were alopecia, nausea, diarrhea, and anemia.

The new product uses a drug delivery technology (Enhanze, Halozyme Therapeutics) that employs a proprietary enzyme that temporarily degrades hyaluronan, a glycosaminoglycan or chain of natural sugars in the body, to facilitate the dispersion and absorption of injected therapeutic drugs, according to Genentech.

In May, at the European Society for Medical Oncology Breast Cancer Virtual Meeting 2020, investigators of the phase 2 PHranceSCa study reported that “more than 80%” of patients preferred subcutaneous to intravenous administration of pertuzumab and trastuzumab.

This article first appeared on Medscape.com.

The Food and Drug Administration approved a combination of pertuzumab (Perjeta, Genentech/Roche), trastuzumab (Herceptin, Genentech/Roche) and hyaluronidase (Phesgo, Genentech/Roche) that is administered subcutaneously – rather than intravenously – for the treatment of early and metastatic HER2-positive breast cancers.

Phesgo is initially used in combination with chemotherapy at an infusion center but could continue to be administered in a patient’s home by a qualified health care professional once chemotherapy is complete, according to the FDA.

Administration takes approximately 8 minutes for the initial loading dose and approximately 5 minutes for maintenance doses, according to a Genentech press statement. This compares favorably with the 150 minutes needed for the combined loading dose of intravenous pertuzumab and trastuzumab, and the 60-150 minutes for intravenous maintenance infusions, the company said.

“Currently, most patients with HER2-positive breast cancer receive trastuzumab and pertuzumab at infusion centers. With a new administration route, Phesgo offers an outpatient option for patients to receive trastuzumab and pertuzumab,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, in an agency press release.

“The fixed-dose combination of trastuzumab and pertuzumab offers a simpler, faster, and easier treatment experience for patients with HER2-positive breast cancer,” said Antoinette Tan, MD, MHSc, chief of breast medical oncology at Levine Cancer Institute, Charlotte, N.C., in the company statement.

Dr. Tan also said that home administration “can be advantageous for patients and infusion centers.”

However, in April, the Community Oncology Alliance strenuously objected to this type of treatment in a patient’s home, as reported by Medscape Medical News.

The group, which represents U.S. community-based practices, said it “fundamentally opposes home infusion of chemotherapy, cancer immunotherapy, and cancer treatment supportive drugs because of serious patient safety concerns.”

The FDA’s approval was based on the results of the pivotal phase 3 FeDeriCa trial, a noninferiority study in patients with HER2-positive early breast cancer, which demonstrated that the new product had comparable efficacy and safety as intravenous pertuzumab and intravenous trastuzumab.

In terms of efficacy, the subcutaneous product demonstrated noninferior plasma levels of pertuzumab, which was the primary endpoint, when compared with IV administration of pertuzumab.

Safety was comparable between the two approaches, with no new safety signals using the subcutaneous delivery method, including no “meaningful difference” in cardiac toxicity, according to Genentech. However, there were more administration-related reactions with the new product. The most common adverse events in both groups were alopecia, nausea, diarrhea, and anemia.

The new product uses a drug delivery technology (Enhanze, Halozyme Therapeutics) that employs a proprietary enzyme that temporarily degrades hyaluronan, a glycosaminoglycan or chain of natural sugars in the body, to facilitate the dispersion and absorption of injected therapeutic drugs, according to Genentech.

In May, at the European Society for Medical Oncology Breast Cancer Virtual Meeting 2020, investigators of the phase 2 PHranceSCa study reported that “more than 80%” of patients preferred subcutaneous to intravenous administration of pertuzumab and trastuzumab.

This article first appeared on Medscape.com.

Despite a lack of financial penalties, the U.S. Veterans Affairs Health Care System has seen a steady 15% reduction in 30-day all-cause readmissions for patients admitted for heart failure, with no concurrent increase in 30-day mortality, a large cohort study suggests.

Unlike the Center for Medicare & Medicaid’s Hospital Readmissions Reduction Program (HRRP), whose primary objective is reducing payments to hospitals with excess readmissions, the VA’s efforts to reduce readmissions across their system did not include any financial penalties.

“The intervention focused on encouraging participation in transitions of care programs, such as the American College of Cardiology’s Hospital to Home Initiative and the creation of a heart failure provider network that included more than 900 heart failure providers throughout the VA system,” said the study’s lead author Justin T. Parizo, MD, of Stanford (Calif.) University.

The only measuring sticks the VA used were the public reporting of 30-day readmission rates (starting in 2012) and inclusion of those rates into hospitals’ overall star ratings (starting in 2014).  

“The readmissions reductions we saw were similar in magnitude to those seen in patients in CMS fee-for-service categories in the HRRP,” said Dr. Parizo. “And while we had no ability to evaluate causality here, our best guess from what we can see is that there’s been no impact of the readmissions program on mortality,” he added.

Their results were published online June 17 in JAMA Cardiology.

Dr. Parizo and colleagues conducted a cohort study of 304,374 heart failure hospital admissions in 164,566 patients from January 2007 to September 2017. Importantly, he stressed, the researchers were able to do sophisticated risk adjustment for illness trends, something that has been a sticking point in some of the HRRP studies to date.

“We leveraged the robust dataset that the VA provides to adjust for illness severity. Accounting for clinical factors, like blood pressure, weight, creatinine, BNP [B-type natriuretic peptide], and other markers of heart failure severity, but also for changes in coding,” said Dr. Parizo.

Stratification according to left ventricular ejection fraction (LVEF) showed similar results both in terms of 30-day readmission and 30-day mortality for those with LVEF of 40% or greater and those with LVEF less than 40%.

In an interview, Dr. Parizo noted that they actually saw a small but significant uptick in mortality in the 2011-2012 period (compared with 2007-2008) that remains unexplained. “By the 2015-2017 period, 30-day death had returned to baseline levels,” he said.

In contrast, the HRRP, which was rolled out in 2012, has also been shown to reduce readmissions but, in most studies, 30-day mortality had gone up.

“The VA has a very robust quality infrastructure and a robust mechanism for prioritizing certain quality-improvement goals and getting them accomplished that I think they are underrecognized for,” said Leora Horwitz, MD, MHS, the director of the Center for Healthcare Innovation and Delivery Science at NYU Langone Medical Center, New York.

In an interview, she also noted some concern with the uptick seen in the 2011-2012 period, noting that the increase might be the same signal seen with the HRRP intervention.

“This is around the same time period where other people were writing the HRRP papers that showed an increase in mortality, so that’s something to consider,” she said.

Dr. Horwitz coauthored a study published in 2017 indicating that, on a hospital level (compared with a patient level, the approach most other studies took), reductions in readmissions were only weakly correlated with 30-day mortality rates after discharge.

“So, if you think that a hospital that’s behaving badly and keeping people out of the hospital inappropriately to cut down their readmissions, you’d expect to see increased mortality in that hospital, and in our study there was no correlation whatsoever. So there is still debate as to what is behind the increase in mortality on a patient level with heart failure that we’ve seen in some studies,” she said.

Dr. Horwitz doubts an intervention such as the one undertaken in the VA system – even with its fairly soft-touch “name and shame” component – would work in the non-VA hospital world.

“Those who have been in favor of financial penalties have pointed to the fact that, in general, it’s hard to get health systems to respond without financial alignment, even if it’s not an overt financial incentive,” she said.

“The VA is a unique environment,” she noted. “They have a very strong top-down command control focus where people are kind of used to being told, ‘OK, here are the measures we have to address this year.’ It’s good to see that the system that has worked for them for other outcomes also worked for them for heart failure readmissions too.”

Dr. Parizo has disclosed no relevant financial relationships. Dr. Horwitz has worked under contract to Medicare to develop readmission measures. 

A version of this article originally appeared on Medscape.com.

Despite a lack of financial penalties, the U.S. Veterans Affairs Health Care System has seen a steady 15% reduction in 30-day all-cause readmissions for patients admitted for heart failure, with no concurrent increase in 30-day mortality, a large cohort study suggests.

Unlike the Center for Medicare & Medicaid’s Hospital Readmissions Reduction Program (HRRP), whose primary objective is reducing payments to hospitals with excess readmissions, the VA’s efforts to reduce readmissions across their system did not include any financial penalties.

“The intervention focused on encouraging participation in transitions of care programs, such as the American College of Cardiology’s Hospital to Home Initiative and the creation of a heart failure provider network that included more than 900 heart failure providers throughout the VA system,” said the study’s lead author Justin T. Parizo, MD, of Stanford (Calif.) University.

The only measuring sticks the VA used were the public reporting of 30-day readmission rates (starting in 2012) and inclusion of those rates into hospitals’ overall star ratings (starting in 2014).  

“The readmissions reductions we saw were similar in magnitude to those seen in patients in CMS fee-for-service categories in the HRRP,” said Dr. Parizo. “And while we had no ability to evaluate causality here, our best guess from what we can see is that there’s been no impact of the readmissions program on mortality,” he added.

Their results were published online June 17 in JAMA Cardiology.

Dr. Parizo and colleagues conducted a cohort study of 304,374 heart failure hospital admissions in 164,566 patients from January 2007 to September 2017. Importantly, he stressed, the researchers were able to do sophisticated risk adjustment for illness trends, something that has been a sticking point in some of the HRRP studies to date.

“We leveraged the robust dataset that the VA provides to adjust for illness severity. Accounting for clinical factors, like blood pressure, weight, creatinine, BNP [B-type natriuretic peptide], and other markers of heart failure severity, but also for changes in coding,” said Dr. Parizo.

Stratification according to left ventricular ejection fraction (LVEF) showed similar results both in terms of 30-day readmission and 30-day mortality for those with LVEF of 40% or greater and those with LVEF less than 40%.

In an interview, Dr. Parizo noted that they actually saw a small but significant uptick in mortality in the 2011-2012 period (compared with 2007-2008) that remains unexplained. “By the 2015-2017 period, 30-day death had returned to baseline levels,” he said.

In contrast, the HRRP, which was rolled out in 2012, has also been shown to reduce readmissions but, in most studies, 30-day mortality had gone up.

“The VA has a very robust quality infrastructure and a robust mechanism for prioritizing certain quality-improvement goals and getting them accomplished that I think they are underrecognized for,” said Leora Horwitz, MD, MHS, the director of the Center for Healthcare Innovation and Delivery Science at NYU Langone Medical Center, New York.

In an interview, she also noted some concern with the uptick seen in the 2011-2012 period, noting that the increase might be the same signal seen with the HRRP intervention.

“This is around the same time period where other people were writing the HRRP papers that showed an increase in mortality, so that’s something to consider,” she said.

Dr. Horwitz coauthored a study published in 2017 indicating that, on a hospital level (compared with a patient level, the approach most other studies took), reductions in readmissions were only weakly correlated with 30-day mortality rates after discharge.

“So, if you think that a hospital that’s behaving badly and keeping people out of the hospital inappropriately to cut down their readmissions, you’d expect to see increased mortality in that hospital, and in our study there was no correlation whatsoever. So there is still debate as to what is behind the increase in mortality on a patient level with heart failure that we’ve seen in some studies,” she said.

Dr. Horwitz doubts an intervention such as the one undertaken in the VA system – even with its fairly soft-touch “name and shame” component – would work in the non-VA hospital world.

“Those who have been in favor of financial penalties have pointed to the fact that, in general, it’s hard to get health systems to respond without financial alignment, even if it’s not an overt financial incentive,” she said.

“The VA is a unique environment,” she noted. “They have a very strong top-down command control focus where people are kind of used to being told, ‘OK, here are the measures we have to address this year.’ It’s good to see that the system that has worked for them for other outcomes also worked for them for heart failure readmissions too.”

Dr. Parizo has disclosed no relevant financial relationships. Dr. Horwitz has worked under contract to Medicare to develop readmission measures. 

A version of this article originally appeared on Medscape.com.

Despite a lack of financial penalties, the U.S. Veterans Affairs Health Care System has seen a steady 15% reduction in 30-day all-cause readmissions for patients admitted for heart failure, with no concurrent increase in 30-day mortality, a large cohort study suggests.

Unlike the Center for Medicare & Medicaid’s Hospital Readmissions Reduction Program (HRRP), whose primary objective is reducing payments to hospitals with excess readmissions, the VA’s efforts to reduce readmissions across their system did not include any financial penalties.

“The intervention focused on encouraging participation in transitions of care programs, such as the American College of Cardiology’s Hospital to Home Initiative and the creation of a heart failure provider network that included more than 900 heart failure providers throughout the VA system,” said the study’s lead author Justin T. Parizo, MD, of Stanford (Calif.) University.

The only measuring sticks the VA used were the public reporting of 30-day readmission rates (starting in 2012) and inclusion of those rates into hospitals’ overall star ratings (starting in 2014).  

“The readmissions reductions we saw were similar in magnitude to those seen in patients in CMS fee-for-service categories in the HRRP,” said Dr. Parizo. “And while we had no ability to evaluate causality here, our best guess from what we can see is that there’s been no impact of the readmissions program on mortality,” he added.

Their results were published online June 17 in JAMA Cardiology.

Dr. Parizo and colleagues conducted a cohort study of 304,374 heart failure hospital admissions in 164,566 patients from January 2007 to September 2017. Importantly, he stressed, the researchers were able to do sophisticated risk adjustment for illness trends, something that has been a sticking point in some of the HRRP studies to date.

“We leveraged the robust dataset that the VA provides to adjust for illness severity. Accounting for clinical factors, like blood pressure, weight, creatinine, BNP [B-type natriuretic peptide], and other markers of heart failure severity, but also for changes in coding,” said Dr. Parizo.

Stratification according to left ventricular ejection fraction (LVEF) showed similar results both in terms of 30-day readmission and 30-day mortality for those with LVEF of 40% or greater and those with LVEF less than 40%.

In an interview, Dr. Parizo noted that they actually saw a small but significant uptick in mortality in the 2011-2012 period (compared with 2007-2008) that remains unexplained. “By the 2015-2017 period, 30-day death had returned to baseline levels,” he said.

In contrast, the HRRP, which was rolled out in 2012, has also been shown to reduce readmissions but, in most studies, 30-day mortality had gone up.

“The VA has a very robust quality infrastructure and a robust mechanism for prioritizing certain quality-improvement goals and getting them accomplished that I think they are underrecognized for,” said Leora Horwitz, MD, MHS, the director of the Center for Healthcare Innovation and Delivery Science at NYU Langone Medical Center, New York.

In an interview, she also noted some concern with the uptick seen in the 2011-2012 period, noting that the increase might be the same signal seen with the HRRP intervention.

“This is around the same time period where other people were writing the HRRP papers that showed an increase in mortality, so that’s something to consider,” she said.

Dr. Horwitz coauthored a study published in 2017 indicating that, on a hospital level (compared with a patient level, the approach most other studies took), reductions in readmissions were only weakly correlated with 30-day mortality rates after discharge.

“So, if you think that a hospital that’s behaving badly and keeping people out of the hospital inappropriately to cut down their readmissions, you’d expect to see increased mortality in that hospital, and in our study there was no correlation whatsoever. So there is still debate as to what is behind the increase in mortality on a patient level with heart failure that we’ve seen in some studies,” she said.

Dr. Horwitz doubts an intervention such as the one undertaken in the VA system – even with its fairly soft-touch “name and shame” component – would work in the non-VA hospital world.

“Those who have been in favor of financial penalties have pointed to the fact that, in general, it’s hard to get health systems to respond without financial alignment, even if it’s not an overt financial incentive,” she said.

“The VA is a unique environment,” she noted. “They have a very strong top-down command control focus where people are kind of used to being told, ‘OK, here are the measures we have to address this year.’ It’s good to see that the system that has worked for them for other outcomes also worked for them for heart failure readmissions too.”

Dr. Parizo has disclosed no relevant financial relationships. Dr. Horwitz has worked under contract to Medicare to develop readmission measures. 

A version of this article originally appeared on Medscape.com.

Combining a personalized cancer vaccine with an immune checkpoint inhibitor induced neoantigen-specific immune responses in most patients with advanced solid tumors in a phase 1b study.

Only two clinical responses were seen in this early investigation of the vaccine, RO7198457, combined with the PD-L1 inhibitor atezolizumab. However, T-cell responses were observed in about three-quarters of the patients evaluated, according to study investigator Juanita Lopez, MB BChir, PhD.

Those immune responses, coupled with preliminary evidence of infiltration of RO7198457-stimulated T cells into tumors, suggest the viability of this individualized anticancer strategy, according to Dr. Lopez, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London.

“Failure of T-cell priming is a major cause of lack of response to immune checkpoint inhibitors,” Dr. Lopez said in an interview. “We hoped that, by eliciting a tumor-specific T-cell response, we would be able to overcome this.”

Preclinical data suggested the combination of vaccine and immune checkpoint inhibitors improved outcomes, which prompted the current study, added Dr. Lopez, who presented results from this study at the American Association for Cancer Research virtual meeting II.

Dr. Lopez noted that mutated neoantigens are recognized as foreign and have been shown to induce stronger T-cell responses, compared with shared antigens, likely because of a lack of central tolerance.

“Most of these mutated neoantigens are not shared between the patients, and therefore, targeted neoantigen-specific therapy requires an individualized approach,” she explained.

RO7198457 is manufactured on a per-patient basis and includes as many as 20 tumor-specific neoepitopes.
 

Study details

Dr. Lopez presented results from dose-escalation and expansion cohorts of the study, which included 142 patients with advanced solid tumors. The patients had colorectal, skin, kidney, lung, urothelial, breast, gynecologic, and head and neck cancers.

Most patients had low or no PD-L1 expression, and nearly 40% had received prior treatment with a checkpoint inhibitor.

Patients received nine doses of RO7198457 at 25-50 mcg during the 12-week induction stage. They then received RO7198457 every eight cycles until disease progression. Patients received atezolizumab at 1,200 mg on day 1 of each 21-day cycle.

Induction of proinflammatory cytokines was observed at each dose tested, and ex vivo T-cell responses were noted in 46 of 63 patients evaluated, or 73%.

T-cell receptors specific to RO7198457 were present posttreatment in a patient with rectal cancer, providing some preliminary evidence suggesting infiltration of RO7198457-stimulated T cells in the tumor, Dr. Lopez said.

There were two clinical responses. A patient with rectal cancer had a complete response, and a patient with triple-negative breast cancer had a partial response.

The combination of RO7198457 with atezolizumab was generally well tolerated, and the maximum tolerated dose was not reached, Dr. Lopez said. Most adverse events were grade 1/2, and immune-mediated adverse events were rare.
 

Implications and next steps

This study furthers earlier observations from neoantigen vaccine studies by linking dosing of the vaccine to dosing with immune checkpoint inhibitor, rather than giving the vaccine in the period leading up to immune checkpoint inhibitor administration, according to former AACR President Elaine R. Mardis, PhD, of Nationwide Children’s Hospital and The Ohio State University College of Medicine, both in Columbus.

That said, the implications for clinical practice remain unclear, according to Dr. Mardis.

“This combination did elicit an immune response that was highly specific for the neoantigen vaccine, but most patients did not receive a clinical benefit of disease response,” Dr. Mardis said in an interview. “This tells us the combination approach used was, overall, not quite right, and we need to continue to innovate in this area.”

The low clinical response rate in the study was likely caused in part by the fact that patients had very advanced disease and were heavily pretreated, according to Dr. Lopez

Randomized phase 2 studies of RO7198457 are now underway, Dr. Lopez said. One is a study of RO7198457 plus atezolizumab as adjuvant treatment for non–small cell lung cancer (NCT04267237). Another is testing RO7198457 in combination with pembrolizumab as first-line treatment for melanoma (NCT03815058).

The current study was funded by Genentech and BioNTech. Dr. Lopez reported disclosures related to Roche/Genentech, Basilea Pharmaceutica, and Genmab. Dr. Mardis reported disclosures related to Quiagen NV, PACT Pharma, Kiadis Pharma NV, and Interpreta.

SOURCE: Lopez J et al. AACR 2020, Abstract CT301.

Combining a personalized cancer vaccine with an immune checkpoint inhibitor induced neoantigen-specific immune responses in most patients with advanced solid tumors in a phase 1b study.

Only two clinical responses were seen in this early investigation of the vaccine, RO7198457, combined with the PD-L1 inhibitor atezolizumab. However, T-cell responses were observed in about three-quarters of the patients evaluated, according to study investigator Juanita Lopez, MB BChir, PhD.

Those immune responses, coupled with preliminary evidence of infiltration of RO7198457-stimulated T cells into tumors, suggest the viability of this individualized anticancer strategy, according to Dr. Lopez, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London.

“Failure of T-cell priming is a major cause of lack of response to immune checkpoint inhibitors,” Dr. Lopez said in an interview. “We hoped that, by eliciting a tumor-specific T-cell response, we would be able to overcome this.”

Preclinical data suggested the combination of vaccine and immune checkpoint inhibitors improved outcomes, which prompted the current study, added Dr. Lopez, who presented results from this study at the American Association for Cancer Research virtual meeting II.

Dr. Lopez noted that mutated neoantigens are recognized as foreign and have been shown to induce stronger T-cell responses, compared with shared antigens, likely because of a lack of central tolerance.

“Most of these mutated neoantigens are not shared between the patients, and therefore, targeted neoantigen-specific therapy requires an individualized approach,” she explained.

RO7198457 is manufactured on a per-patient basis and includes as many as 20 tumor-specific neoepitopes.
 

Study details

Dr. Lopez presented results from dose-escalation and expansion cohorts of the study, which included 142 patients with advanced solid tumors. The patients had colorectal, skin, kidney, lung, urothelial, breast, gynecologic, and head and neck cancers.

Most patients had low or no PD-L1 expression, and nearly 40% had received prior treatment with a checkpoint inhibitor.

Patients received nine doses of RO7198457 at 25-50 mcg during the 12-week induction stage. They then received RO7198457 every eight cycles until disease progression. Patients received atezolizumab at 1,200 mg on day 1 of each 21-day cycle.

Induction of proinflammatory cytokines was observed at each dose tested, and ex vivo T-cell responses were noted in 46 of 63 patients evaluated, or 73%.

T-cell receptors specific to RO7198457 were present posttreatment in a patient with rectal cancer, providing some preliminary evidence suggesting infiltration of RO7198457-stimulated T cells in the tumor, Dr. Lopez said.

There were two clinical responses. A patient with rectal cancer had a complete response, and a patient with triple-negative breast cancer had a partial response.

The combination of RO7198457 with atezolizumab was generally well tolerated, and the maximum tolerated dose was not reached, Dr. Lopez said. Most adverse events were grade 1/2, and immune-mediated adverse events were rare.
 

Implications and next steps

This study furthers earlier observations from neoantigen vaccine studies by linking dosing of the vaccine to dosing with immune checkpoint inhibitor, rather than giving the vaccine in the period leading up to immune checkpoint inhibitor administration, according to former AACR President Elaine R. Mardis, PhD, of Nationwide Children’s Hospital and The Ohio State University College of Medicine, both in Columbus.

That said, the implications for clinical practice remain unclear, according to Dr. Mardis.

“This combination did elicit an immune response that was highly specific for the neoantigen vaccine, but most patients did not receive a clinical benefit of disease response,” Dr. Mardis said in an interview. “This tells us the combination approach used was, overall, not quite right, and we need to continue to innovate in this area.”

The low clinical response rate in the study was likely caused in part by the fact that patients had very advanced disease and were heavily pretreated, according to Dr. Lopez

Randomized phase 2 studies of RO7198457 are now underway, Dr. Lopez said. One is a study of RO7198457 plus atezolizumab as adjuvant treatment for non–small cell lung cancer (NCT04267237). Another is testing RO7198457 in combination with pembrolizumab as first-line treatment for melanoma (NCT03815058).

The current study was funded by Genentech and BioNTech. Dr. Lopez reported disclosures related to Roche/Genentech, Basilea Pharmaceutica, and Genmab. Dr. Mardis reported disclosures related to Quiagen NV, PACT Pharma, Kiadis Pharma NV, and Interpreta.

SOURCE: Lopez J et al. AACR 2020, Abstract CT301.

Combining a personalized cancer vaccine with an immune checkpoint inhibitor induced neoantigen-specific immune responses in most patients with advanced solid tumors in a phase 1b study.

Only two clinical responses were seen in this early investigation of the vaccine, RO7198457, combined with the PD-L1 inhibitor atezolizumab. However, T-cell responses were observed in about three-quarters of the patients evaluated, according to study investigator Juanita Lopez, MB BChir, PhD.

Those immune responses, coupled with preliminary evidence of infiltration of RO7198457-stimulated T cells into tumors, suggest the viability of this individualized anticancer strategy, according to Dr. Lopez, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London.

“Failure of T-cell priming is a major cause of lack of response to immune checkpoint inhibitors,” Dr. Lopez said in an interview. “We hoped that, by eliciting a tumor-specific T-cell response, we would be able to overcome this.”

Preclinical data suggested the combination of vaccine and immune checkpoint inhibitors improved outcomes, which prompted the current study, added Dr. Lopez, who presented results from this study at the American Association for Cancer Research virtual meeting II.

Dr. Lopez noted that mutated neoantigens are recognized as foreign and have been shown to induce stronger T-cell responses, compared with shared antigens, likely because of a lack of central tolerance.

“Most of these mutated neoantigens are not shared between the patients, and therefore, targeted neoantigen-specific therapy requires an individualized approach,” she explained.

RO7198457 is manufactured on a per-patient basis and includes as many as 20 tumor-specific neoepitopes.
 

Study details

Dr. Lopez presented results from dose-escalation and expansion cohorts of the study, which included 142 patients with advanced solid tumors. The patients had colorectal, skin, kidney, lung, urothelial, breast, gynecologic, and head and neck cancers.

Most patients had low or no PD-L1 expression, and nearly 40% had received prior treatment with a checkpoint inhibitor.

Patients received nine doses of RO7198457 at 25-50 mcg during the 12-week induction stage. They then received RO7198457 every eight cycles until disease progression. Patients received atezolizumab at 1,200 mg on day 1 of each 21-day cycle.

Induction of proinflammatory cytokines was observed at each dose tested, and ex vivo T-cell responses were noted in 46 of 63 patients evaluated, or 73%.

T-cell receptors specific to RO7198457 were present posttreatment in a patient with rectal cancer, providing some preliminary evidence suggesting infiltration of RO7198457-stimulated T cells in the tumor, Dr. Lopez said.

There were two clinical responses. A patient with rectal cancer had a complete response, and a patient with triple-negative breast cancer had a partial response.

The combination of RO7198457 with atezolizumab was generally well tolerated, and the maximum tolerated dose was not reached, Dr. Lopez said. Most adverse events were grade 1/2, and immune-mediated adverse events were rare.
 

Implications and next steps

This study furthers earlier observations from neoantigen vaccine studies by linking dosing of the vaccine to dosing with immune checkpoint inhibitor, rather than giving the vaccine in the period leading up to immune checkpoint inhibitor administration, according to former AACR President Elaine R. Mardis, PhD, of Nationwide Children’s Hospital and The Ohio State University College of Medicine, both in Columbus.

That said, the implications for clinical practice remain unclear, according to Dr. Mardis.

“This combination did elicit an immune response that was highly specific for the neoantigen vaccine, but most patients did not receive a clinical benefit of disease response,” Dr. Mardis said in an interview. “This tells us the combination approach used was, overall, not quite right, and we need to continue to innovate in this area.”

The low clinical response rate in the study was likely caused in part by the fact that patients had very advanced disease and were heavily pretreated, according to Dr. Lopez

Randomized phase 2 studies of RO7198457 are now underway, Dr. Lopez said. One is a study of RO7198457 plus atezolizumab as adjuvant treatment for non–small cell lung cancer (NCT04267237). Another is testing RO7198457 in combination with pembrolizumab as first-line treatment for melanoma (NCT03815058).

The current study was funded by Genentech and BioNTech. Dr. Lopez reported disclosures related to Roche/Genentech, Basilea Pharmaceutica, and Genmab. Dr. Mardis reported disclosures related to Quiagen NV, PACT Pharma, Kiadis Pharma NV, and Interpreta.

SOURCE: Lopez J et al. AACR 2020, Abstract CT301.

A model created by the National Cancer Institute predicts that tens of thousands of excess cancer deaths will occur over the next decade as a result of missed screenings, delays in diagnosis, and reductions in oncology care caused by the COVID-19 pandemic.

“As director of NCI, I am deeply concerned about the potential impacts of delayed diagnoses and deferred or modified treatment plans on cancer incidence and mortality,” said Norman “Ned” Sharpless, MD.

“In the past 3 decades, we have seen steady and strong progress against death and suffering from cancer, thanks to improvements in prevention, screening, diagnosis, and treatment. I worry that the SARS-CoV-2 pandemic has put those decades of steady progress at risk and may precipitate reversals of these trends.”

In an editorial published June 19 in Science, Dr. Sharpless highlighted modeling performed by the NCI that predicts an excess of 10,000 deaths from breast and colorectal cancer over the next 10 years.

The number of excess deaths per year would peak in the next year or 2, likely sooner for colorectal than for breast cancer, but “for both cancer types, we believe the pandemic will influence cancer deaths for at least a decade.”

In an interview, Dr. Sharpless pointed out that this analysis is conservative because the researchers only evaluated two types of cancer. They chose breast and colorectal cancer because these are common cancers (accounting for about one-sixth of all cancers) with relatively high screening rates.

“We didn’t model other cancer types, but we have no reason to think that we’re not going to see the same thing with other types of malignancies,” he said. “That is a significant amount of excess mortality.”
 

Delayed diagnosis, modified therapy

One of the effects of the pandemic has been to cause delays in cancer diagnosis. “Routine screening has plummeted and is running at less than 90% in some systems,” Dr. Sharpless said.

“Most cancers are diagnosed when people experience symptoms and go see their doctors, and those symptomatic screening events are also not happening,” he continued. “Fear of contracting the coronavirus in health care settings has dissuaded people from visits.”

In some cases, a delay in diagnosis will allow the cancer to progress to a more advanced stage. “The earlier the diagnosis, the better, and if the stages are more advanced, patients will not do as well for virtually every kind of cancer,” he said.

In addition to delays in diagnosis, treatments are being postponed or modified for patients recently diagnosed with cancer. Because of delays and reductions in curative therapies, patients may be receiving less than optimal care.

“We are seeing a lot of nonstandard care,” said Dr. Sharpless. “All of these things add up to increased cancer morbidity and mortality.”

He also pointed out that the term “elective” is confusing and problematic. “It doesn’t mean that it’s not needed, just that it’s not an emergency and doesn’t need to be done today,” said Dr. Sharpless. “But if we’re talking about chemotherapy and surgery, we don’t think they can be delayed for too long – maybe a week, but not for several months.”

Dr. Sharpless feels that overall it is time for cancer care to resume as much as possible, because “ignoring cancer for too long is an untenable choice and may turn one public health crisis into another.”

“If we act now, we can make up for lost time,” he wrote in the editorial. “Clearly, postponing procedures and deferring care due to the pandemic was prudent at one time, but now that we have made it through the initial shock of the pandemic, I believe it is time to resume robust cancer care.”

Through their network of cancer centers, researchers with the NCI can develop innovative solutions that allow screening and treatment to move forward while maintaining safety. “We need to make patients feel safe, and we have to answer important questions quickly,” he said.
 

Impact of COVID-19 on cancer care

The COVID-19 pandemic has overwhelmed health care systems worldwide and has created major challenges for clinicians who are caring for patients with cancer.

As previously reported, hospitals reprioritized resources for an impending onslaught of COVID-19 patients. Services and procedures deemed to be nonessential were canceled or delayed, including surgeries and imaging.

In a survey conducted by the American Cancer Society Cancer Action Network, half of the 1219 respondents reported changes, delays, or disruptions to the care they were receiving. The services most frequently affected included in-person provider visits (50%), supportive services (20%), and imaging procedures to monitor tumor growth (20%).

In addition, 8% reported that their treatment, including chemotherapy and immunotherapy, had been affected by the COVID-19 pandemic.

In the United Kingdom, Cancer Research UK estimated that because of the disruption to cancer services, 2.4 million people did not undergo cancer screening or further testing or did not receive cancer treatment and that tens of thousands of cases have gone undiagnosed.

Similarly, a survey by Macmillan Cancer Support showed that almost half (45%) of cancer patients have experienced delays or cancellations of cancer treatments, or their treatments have been altered as a result of coronavirus, leaving many living in fear. Calling cancer “the forgotten C” of the pandemic, it warned of a potential cancer “time bomb” when, as the number of deaths from COVID-19 falls, cancer returns as the leading cause of death in the United Kingdom.

Last month, a report also predicted that there will be an excess of cancer deaths in both the United States and United Kingdom because of patients not accessing health care services.

The authors calculated that there will be 6270 excess deaths among cancer patients 1 year from now in England and 33,890 excess deaths among cancer patients older than 40 years in the United States.

This article first appeared on Medscape.com.

A model created by the National Cancer Institute predicts that tens of thousands of excess cancer deaths will occur over the next decade as a result of missed screenings, delays in diagnosis, and reductions in oncology care caused by the COVID-19 pandemic.

“As director of NCI, I am deeply concerned about the potential impacts of delayed diagnoses and deferred or modified treatment plans on cancer incidence and mortality,” said Norman “Ned” Sharpless, MD.

“In the past 3 decades, we have seen steady and strong progress against death and suffering from cancer, thanks to improvements in prevention, screening, diagnosis, and treatment. I worry that the SARS-CoV-2 pandemic has put those decades of steady progress at risk and may precipitate reversals of these trends.”

In an editorial published June 19 in Science, Dr. Sharpless highlighted modeling performed by the NCI that predicts an excess of 10,000 deaths from breast and colorectal cancer over the next 10 years.

The number of excess deaths per year would peak in the next year or 2, likely sooner for colorectal than for breast cancer, but “for both cancer types, we believe the pandemic will influence cancer deaths for at least a decade.”

In an interview, Dr. Sharpless pointed out that this analysis is conservative because the researchers only evaluated two types of cancer. They chose breast and colorectal cancer because these are common cancers (accounting for about one-sixth of all cancers) with relatively high screening rates.

“We didn’t model other cancer types, but we have no reason to think that we’re not going to see the same thing with other types of malignancies,” he said. “That is a significant amount of excess mortality.”
 

Delayed diagnosis, modified therapy

One of the effects of the pandemic has been to cause delays in cancer diagnosis. “Routine screening has plummeted and is running at less than 90% in some systems,” Dr. Sharpless said.

“Most cancers are diagnosed when people experience symptoms and go see their doctors, and those symptomatic screening events are also not happening,” he continued. “Fear of contracting the coronavirus in health care settings has dissuaded people from visits.”

In some cases, a delay in diagnosis will allow the cancer to progress to a more advanced stage. “The earlier the diagnosis, the better, and if the stages are more advanced, patients will not do as well for virtually every kind of cancer,” he said.

In addition to delays in diagnosis, treatments are being postponed or modified for patients recently diagnosed with cancer. Because of delays and reductions in curative therapies, patients may be receiving less than optimal care.

“We are seeing a lot of nonstandard care,” said Dr. Sharpless. “All of these things add up to increased cancer morbidity and mortality.”

He also pointed out that the term “elective” is confusing and problematic. “It doesn’t mean that it’s not needed, just that it’s not an emergency and doesn’t need to be done today,” said Dr. Sharpless. “But if we’re talking about chemotherapy and surgery, we don’t think they can be delayed for too long – maybe a week, but not for several months.”

Dr. Sharpless feels that overall it is time for cancer care to resume as much as possible, because “ignoring cancer for too long is an untenable choice and may turn one public health crisis into another.”

“If we act now, we can make up for lost time,” he wrote in the editorial. “Clearly, postponing procedures and deferring care due to the pandemic was prudent at one time, but now that we have made it through the initial shock of the pandemic, I believe it is time to resume robust cancer care.”

Through their network of cancer centers, researchers with the NCI can develop innovative solutions that allow screening and treatment to move forward while maintaining safety. “We need to make patients feel safe, and we have to answer important questions quickly,” he said.
 

Impact of COVID-19 on cancer care

The COVID-19 pandemic has overwhelmed health care systems worldwide and has created major challenges for clinicians who are caring for patients with cancer.

As previously reported, hospitals reprioritized resources for an impending onslaught of COVID-19 patients. Services and procedures deemed to be nonessential were canceled or delayed, including surgeries and imaging.

In a survey conducted by the American Cancer Society Cancer Action Network, half of the 1219 respondents reported changes, delays, or disruptions to the care they were receiving. The services most frequently affected included in-person provider visits (50%), supportive services (20%), and imaging procedures to monitor tumor growth (20%).

In addition, 8% reported that their treatment, including chemotherapy and immunotherapy, had been affected by the COVID-19 pandemic.

In the United Kingdom, Cancer Research UK estimated that because of the disruption to cancer services, 2.4 million people did not undergo cancer screening or further testing or did not receive cancer treatment and that tens of thousands of cases have gone undiagnosed.

Similarly, a survey by Macmillan Cancer Support showed that almost half (45%) of cancer patients have experienced delays or cancellations of cancer treatments, or their treatments have been altered as a result of coronavirus, leaving many living in fear. Calling cancer “the forgotten C” of the pandemic, it warned of a potential cancer “time bomb” when, as the number of deaths from COVID-19 falls, cancer returns as the leading cause of death in the United Kingdom.

Last month, a report also predicted that there will be an excess of cancer deaths in both the United States and United Kingdom because of patients not accessing health care services.

The authors calculated that there will be 6270 excess deaths among cancer patients 1 year from now in England and 33,890 excess deaths among cancer patients older than 40 years in the United States.

This article first appeared on Medscape.com.

A model created by the National Cancer Institute predicts that tens of thousands of excess cancer deaths will occur over the next decade as a result of missed screenings, delays in diagnosis, and reductions in oncology care caused by the COVID-19 pandemic.

“As director of NCI, I am deeply concerned about the potential impacts of delayed diagnoses and deferred or modified treatment plans on cancer incidence and mortality,” said Norman “Ned” Sharpless, MD.

“In the past 3 decades, we have seen steady and strong progress against death and suffering from cancer, thanks to improvements in prevention, screening, diagnosis, and treatment. I worry that the SARS-CoV-2 pandemic has put those decades of steady progress at risk and may precipitate reversals of these trends.”

In an editorial published June 19 in Science, Dr. Sharpless highlighted modeling performed by the NCI that predicts an excess of 10,000 deaths from breast and colorectal cancer over the next 10 years.

The number of excess deaths per year would peak in the next year or 2, likely sooner for colorectal than for breast cancer, but “for both cancer types, we believe the pandemic will influence cancer deaths for at least a decade.”

In an interview, Dr. Sharpless pointed out that this analysis is conservative because the researchers only evaluated two types of cancer. They chose breast and colorectal cancer because these are common cancers (accounting for about one-sixth of all cancers) with relatively high screening rates.

“We didn’t model other cancer types, but we have no reason to think that we’re not going to see the same thing with other types of malignancies,” he said. “That is a significant amount of excess mortality.”
 

Delayed diagnosis, modified therapy

One of the effects of the pandemic has been to cause delays in cancer diagnosis. “Routine screening has plummeted and is running at less than 90% in some systems,” Dr. Sharpless said.

“Most cancers are diagnosed when people experience symptoms and go see their doctors, and those symptomatic screening events are also not happening,” he continued. “Fear of contracting the coronavirus in health care settings has dissuaded people from visits.”

In some cases, a delay in diagnosis will allow the cancer to progress to a more advanced stage. “The earlier the diagnosis, the better, and if the stages are more advanced, patients will not do as well for virtually every kind of cancer,” he said.

In addition to delays in diagnosis, treatments are being postponed or modified for patients recently diagnosed with cancer. Because of delays and reductions in curative therapies, patients may be receiving less than optimal care.

“We are seeing a lot of nonstandard care,” said Dr. Sharpless. “All of these things add up to increased cancer morbidity and mortality.”

He also pointed out that the term “elective” is confusing and problematic. “It doesn’t mean that it’s not needed, just that it’s not an emergency and doesn’t need to be done today,” said Dr. Sharpless. “But if we’re talking about chemotherapy and surgery, we don’t think they can be delayed for too long – maybe a week, but not for several months.”

Dr. Sharpless feels that overall it is time for cancer care to resume as much as possible, because “ignoring cancer for too long is an untenable choice and may turn one public health crisis into another.”

“If we act now, we can make up for lost time,” he wrote in the editorial. “Clearly, postponing procedures and deferring care due to the pandemic was prudent at one time, but now that we have made it through the initial shock of the pandemic, I believe it is time to resume robust cancer care.”

Through their network of cancer centers, researchers with the NCI can develop innovative solutions that allow screening and treatment to move forward while maintaining safety. “We need to make patients feel safe, and we have to answer important questions quickly,” he said.
 

Impact of COVID-19 on cancer care

The COVID-19 pandemic has overwhelmed health care systems worldwide and has created major challenges for clinicians who are caring for patients with cancer.

As previously reported, hospitals reprioritized resources for an impending onslaught of COVID-19 patients. Services and procedures deemed to be nonessential were canceled or delayed, including surgeries and imaging.

In a survey conducted by the American Cancer Society Cancer Action Network, half of the 1219 respondents reported changes, delays, or disruptions to the care they were receiving. The services most frequently affected included in-person provider visits (50%), supportive services (20%), and imaging procedures to monitor tumor growth (20%).

In addition, 8% reported that their treatment, including chemotherapy and immunotherapy, had been affected by the COVID-19 pandemic.

In the United Kingdom, Cancer Research UK estimated that because of the disruption to cancer services, 2.4 million people did not undergo cancer screening or further testing or did not receive cancer treatment and that tens of thousands of cases have gone undiagnosed.

Similarly, a survey by Macmillan Cancer Support showed that almost half (45%) of cancer patients have experienced delays or cancellations of cancer treatments, or their treatments have been altered as a result of coronavirus, leaving many living in fear. Calling cancer “the forgotten C” of the pandemic, it warned of a potential cancer “time bomb” when, as the number of deaths from COVID-19 falls, cancer returns as the leading cause of death in the United Kingdom.

Last month, a report also predicted that there will be an excess of cancer deaths in both the United States and United Kingdom because of patients not accessing health care services.

The authors calculated that there will be 6270 excess deaths among cancer patients 1 year from now in England and 33,890 excess deaths among cancer patients older than 40 years in the United States.

This article first appeared on Medscape.com.

The number of suspicious lesions needed to refer to diagnose melanoma was 31.5, while the number needed to biopsy was 7.5. At the same time, the number needed to refer to diagnose non-melanoma skin cancer was 4 and the number needed to biopsy was 1.5.

The findings come from a retrospective review of 707 patients referred to a tertiary medical center dermatology practice for suspicious lesions, presented in a poster session at the virtual annual meeting of the American Academy of Dermatology

“Multiple studies in the dermatology literature have looked at the number needed to treat (NNT) as a quality metric for dermatology clinics, where a lower number is ‘better,’” the study’s first author, Nikolai Klebanov, MD, said in an interview following the virtual meeting. “Our particular study is unique in that we estimated both the number needed to refer and number needed to biopsy to closely examine the process of referrals for suspicious lesions from primary care settings to specialists. We also looked closely at the underlying patient-centered characteristics, which could be used by all clinicians to streamline the referral process by reducing the volume of low-risk referrals.”

Dr. Klebanov, of the department of dermatology at Massachusetts General Hospital, Boston, and his associates reviewed 707 unique patient visits to the department during July 2015–February 2016. They calculated the number needed to refer and biopsy for melanoma as the ratio of biopsy-proven melanoma diagnoses among benign and dysplastic nevi and seborrheic keratoses. For nonmelanoma skin cancer, they used the ratio of basal and squamous cell carcinoma among actinic keratoses and seborrheic keratoses.

Of the 707 patients, 54% were female, and males were slightly older than females (a mean of 58 vs. 54 years, respectively). The researchers found that lesions were more commonly benign among all age groups, while the frequency of premalignant and malignant lesions such as actinic keratoses, nonmelanoma skin cancer, and melanoma was highest for males and increased with age. Nevi were the most common benign diagnosis among patients 39 years of age and younger, while seborrheic keratoses were more common among patients aged 40 years and older.

The researchers found that the number needed to treat for melanoma was 31.5 and the number needed to biopsy was 7.5, which represents a 4.2-fold difference. Meanwhile, the number needed to refer for nonmelanoma skin cancer was 4, and the number needed to biopsy was 1.5, which represents a 2.7-fold difference. Despite variable rates of skin cancer between demographics, the biopsy rate ranged between 18% and 30%, for a mean of 23.4%.

“We found that most young patients referred for a ‘suspicious lesion’ on clinical prebiopsy assessment by the dermatologist were determined to actually have a benign nevus, and that older patients were most likely to have a seborrheic keratosis as the underlying lesion,” Dr. Klebanov said. “Among the minority of patients in each demographic group who were selected for biopsy, those lesions which were found to be benign were also largely nevi and keratoses. Even by being mindful of just the patient’s age, primary care providers can follow patients clinically with a tailored differential diagnosis in mind before referral, and dermatologists can reduce the number of biopsies they perform on patients who are being referred.”

He added that he and his colleagues were surprised that despite very low rates of skin cancer in young patients, and thus different pretest probabilities of cancer, biopsy rates across demographics were consistently around 20%. “We also found a disproportionate number of female patients younger than age 40 who were referred for suspicious lesions, while in the older age groups, the ratio of males to females was approximately equal.”

Dr. Klebanov acknowledged certain limitations of the study, including its single-center, retrospective design, and that information was not collected on patients’ family history of skin cancer, Fitzpatrick skin type, nor the clinical course of the lesion while it was followed by the primary care office. “The nuanced differences in these factors may certainly play a role in decisions for individual patients,” he said.

The study’s principal investigator was Hensin Tsao MD, PhD, clinical director of the MGH Melanoma & Pigmented Lesion Center The work was supported by the Alpha Omega Alpha Carolyn Kuckein Research Fellowship. The researchers reported having no financial disclosures.

[email protected]

SOURCE: Klebanov N et al. AAD 20. Abstract 15881.

The number of suspicious lesions needed to refer to diagnose melanoma was 31.5, while the number needed to biopsy was 7.5. At the same time, the number needed to refer to diagnose non-melanoma skin cancer was 4 and the number needed to biopsy was 1.5.

The findings come from a retrospective review of 707 patients referred to a tertiary medical center dermatology practice for suspicious lesions, presented in a poster session at the virtual annual meeting of the American Academy of Dermatology

“Multiple studies in the dermatology literature have looked at the number needed to treat (NNT) as a quality metric for dermatology clinics, where a lower number is ‘better,’” the study’s first author, Nikolai Klebanov, MD, said in an interview following the virtual meeting. “Our particular study is unique in that we estimated both the number needed to refer and number needed to biopsy to closely examine the process of referrals for suspicious lesions from primary care settings to specialists. We also looked closely at the underlying patient-centered characteristics, which could be used by all clinicians to streamline the referral process by reducing the volume of low-risk referrals.”

Dr. Klebanov, of the department of dermatology at Massachusetts General Hospital, Boston, and his associates reviewed 707 unique patient visits to the department during July 2015–February 2016. They calculated the number needed to refer and biopsy for melanoma as the ratio of biopsy-proven melanoma diagnoses among benign and dysplastic nevi and seborrheic keratoses. For nonmelanoma skin cancer, they used the ratio of basal and squamous cell carcinoma among actinic keratoses and seborrheic keratoses.

Of the 707 patients, 54% were female, and males were slightly older than females (a mean of 58 vs. 54 years, respectively). The researchers found that lesions were more commonly benign among all age groups, while the frequency of premalignant and malignant lesions such as actinic keratoses, nonmelanoma skin cancer, and melanoma was highest for males and increased with age. Nevi were the most common benign diagnosis among patients 39 years of age and younger, while seborrheic keratoses were more common among patients aged 40 years and older.

The researchers found that the number needed to treat for melanoma was 31.5 and the number needed to biopsy was 7.5, which represents a 4.2-fold difference. Meanwhile, the number needed to refer for nonmelanoma skin cancer was 4, and the number needed to biopsy was 1.5, which represents a 2.7-fold difference. Despite variable rates of skin cancer between demographics, the biopsy rate ranged between 18% and 30%, for a mean of 23.4%.

“We found that most young patients referred for a ‘suspicious lesion’ on clinical prebiopsy assessment by the dermatologist were determined to actually have a benign nevus, and that older patients were most likely to have a seborrheic keratosis as the underlying lesion,” Dr. Klebanov said. “Among the minority of patients in each demographic group who were selected for biopsy, those lesions which were found to be benign were also largely nevi and keratoses. Even by being mindful of just the patient’s age, primary care providers can follow patients clinically with a tailored differential diagnosis in mind before referral, and dermatologists can reduce the number of biopsies they perform on patients who are being referred.”

He added that he and his colleagues were surprised that despite very low rates of skin cancer in young patients, and thus different pretest probabilities of cancer, biopsy rates across demographics were consistently around 20%. “We also found a disproportionate number of female patients younger than age 40 who were referred for suspicious lesions, while in the older age groups, the ratio of males to females was approximately equal.”

Dr. Klebanov acknowledged certain limitations of the study, including its single-center, retrospective design, and that information was not collected on patients’ family history of skin cancer, Fitzpatrick skin type, nor the clinical course of the lesion while it was followed by the primary care office. “The nuanced differences in these factors may certainly play a role in decisions for individual patients,” he said.

The study’s principal investigator was Hensin Tsao MD, PhD, clinical director of the MGH Melanoma & Pigmented Lesion Center The work was supported by the Alpha Omega Alpha Carolyn Kuckein Research Fellowship. The researchers reported having no financial disclosures.

[email protected]

SOURCE: Klebanov N et al. AAD 20. Abstract 15881.

The number of suspicious lesions needed to refer to diagnose melanoma was 31.5, while the number needed to biopsy was 7.5. At the same time, the number needed to refer to diagnose non-melanoma skin cancer was 4 and the number needed to biopsy was 1.5.

The findings come from a retrospective review of 707 patients referred to a tertiary medical center dermatology practice for suspicious lesions, presented in a poster session at the virtual annual meeting of the American Academy of Dermatology

“Multiple studies in the dermatology literature have looked at the number needed to treat (NNT) as a quality metric for dermatology clinics, where a lower number is ‘better,’” the study’s first author, Nikolai Klebanov, MD, said in an interview following the virtual meeting. “Our particular study is unique in that we estimated both the number needed to refer and number needed to biopsy to closely examine the process of referrals for suspicious lesions from primary care settings to specialists. We also looked closely at the underlying patient-centered characteristics, which could be used by all clinicians to streamline the referral process by reducing the volume of low-risk referrals.”

Dr. Klebanov, of the department of dermatology at Massachusetts General Hospital, Boston, and his associates reviewed 707 unique patient visits to the department during July 2015–February 2016. They calculated the number needed to refer and biopsy for melanoma as the ratio of biopsy-proven melanoma diagnoses among benign and dysplastic nevi and seborrheic keratoses. For nonmelanoma skin cancer, they used the ratio of basal and squamous cell carcinoma among actinic keratoses and seborrheic keratoses.

Of the 707 patients, 54% were female, and males were slightly older than females (a mean of 58 vs. 54 years, respectively). The researchers found that lesions were more commonly benign among all age groups, while the frequency of premalignant and malignant lesions such as actinic keratoses, nonmelanoma skin cancer, and melanoma was highest for males and increased with age. Nevi were the most common benign diagnosis among patients 39 years of age and younger, while seborrheic keratoses were more common among patients aged 40 years and older.

The researchers found that the number needed to treat for melanoma was 31.5 and the number needed to biopsy was 7.5, which represents a 4.2-fold difference. Meanwhile, the number needed to refer for nonmelanoma skin cancer was 4, and the number needed to biopsy was 1.5, which represents a 2.7-fold difference. Despite variable rates of skin cancer between demographics, the biopsy rate ranged between 18% and 30%, for a mean of 23.4%.

“We found that most young patients referred for a ‘suspicious lesion’ on clinical prebiopsy assessment by the dermatologist were determined to actually have a benign nevus, and that older patients were most likely to have a seborrheic keratosis as the underlying lesion,” Dr. Klebanov said. “Among the minority of patients in each demographic group who were selected for biopsy, those lesions which were found to be benign were also largely nevi and keratoses. Even by being mindful of just the patient’s age, primary care providers can follow patients clinically with a tailored differential diagnosis in mind before referral, and dermatologists can reduce the number of biopsies they perform on patients who are being referred.”

He added that he and his colleagues were surprised that despite very low rates of skin cancer in young patients, and thus different pretest probabilities of cancer, biopsy rates across demographics were consistently around 20%. “We also found a disproportionate number of female patients younger than age 40 who were referred for suspicious lesions, while in the older age groups, the ratio of males to females was approximately equal.”

Dr. Klebanov acknowledged certain limitations of the study, including its single-center, retrospective design, and that information was not collected on patients’ family history of skin cancer, Fitzpatrick skin type, nor the clinical course of the lesion while it was followed by the primary care office. “The nuanced differences in these factors may certainly play a role in decisions for individual patients,” he said.

The study’s principal investigator was Hensin Tsao MD, PhD, clinical director of the MGH Melanoma & Pigmented Lesion Center The work was supported by the Alpha Omega Alpha Carolyn Kuckein Research Fellowship. The researchers reported having no financial disclosures.

[email protected]

SOURCE: Klebanov N et al. AAD 20. Abstract 15881.

Left atrial appendage closure was noninferior to use of direct oral anticoagulants for the prevention of atrial fibrillation (AFib)–related events in high-risk patients, based on data from 402 adults.

Given the limitations of vitamin K antagonists for preventing stroke in AFib, “a novel site-specific therapeutic alternative, mechanical left atrial appendage occlusion [LAAO], entered clinical practice,” but has not been compared with current safe and effective oral anticoagulants, wrote Pavel Osmancik, MD, of University Hospital Kralovske Vinohrady, Prague, and colleagues.

In a study published in the Journal of the American College of Cardiology, the researchers randomized 201 moderate- or high-risk adults with nonvalvular AFib to LAAO and another 201 to direct oral anticoagulants (DOAC).

Patients in the LAAO group underwent transesophageal echocardiography to exclude left atrial thrombi and underwent implantation with Boston Scientific’s Watchman, Watchman-FLX, or Abbott’s Amulet devices. Patients in the DOAC group received rivaroxaban, apixaban, or dabigatran at the manufacturer-recommended dose.

The primary outcome was a composite of complications related to procedures or devices, thromboembolic events (including stroke), and clinically significant bleeding. After an average of 20 months follow-up, 35 patients in the LAAO group and 41 in the DOAC group met the primary outcome (11% per 100 patient-years vs. 13% per 100 patient-years).

In addition, no differences appeared between the groups for the endpoint components of all-stroke/transient ischemic attack event (subdistribution hazard ratio, 1.00), clinically significantly bleeding (sHR, 0.81), or cardiovascular death (sHR, 0.75).

Nine patients experienced major complications related to LAAO, including clinically significant bleeding (sHR, 0.81; 95% CI, 0.44-1.52) and cardiovascular death (sHR, 0.75; 95% CI, 0.34-1.62). Major LAAO-related complications occurred in nine (4.5%) patients, with a short-term (up to 7 days or hospital discharge) complication rate of 2.1% and a 2.7% late complication rate. The late complications included three pericardial effusions, one of which resulted in death, the researchers wrote.

The study findings were limited by several factors, including the inability to assess the differences among the components of the composite primary endpoint. For example, “Regarding the primary endpoint, stroke reduction may be more important than bleeding reduction,” the investigators wrote.

The results were strengthened, however, by the enrollment of a high-risk AF population and is the first known randomized trial to compare percutaneous LAAO and DOACs for stroke prevention in this group. But the late complication rate of 2.7% is “suboptimal” and safety issues reinforce the need for refinement of operator technique and device technology with LAAO, they concluded.

‘Important step forward,’ with caveats

“How LAAO might stack up against DOAC therapy has remained an open question: Compared with warfarin, DOACs are easier to use and are associated with a reduction in mortality, driven by a substantially lower risk of intracranial hemorrhage and fatal bleeding,” wrote Matthew J. Price, MD, of the Scripps Clinic in La Jolla, Calif., and Jacqueline Saw, MD, of Vancouver General Hospital, in an accompanying editorial.

Bruce Jancin/Frontline Medical News

SOURCES: Osmancik P et al. J Am Coll Cardiol. 2020;75:3122-35; Price MJ, Saw J. J Am Coll Cardiol. 2020;75:3136-9.

Left atrial appendage closure was noninferior to use of direct oral anticoagulants for the prevention of atrial fibrillation (AFib)–related events in high-risk patients, based on data from 402 adults.

Given the limitations of vitamin K antagonists for preventing stroke in AFib, “a novel site-specific therapeutic alternative, mechanical left atrial appendage occlusion [LAAO], entered clinical practice,” but has not been compared with current safe and effective oral anticoagulants, wrote Pavel Osmancik, MD, of University Hospital Kralovske Vinohrady, Prague, and colleagues.

In a study published in the Journal of the American College of Cardiology, the researchers randomized 201 moderate- or high-risk adults with nonvalvular AFib to LAAO and another 201 to direct oral anticoagulants (DOAC).

Patients in the LAAO group underwent transesophageal echocardiography to exclude left atrial thrombi and underwent implantation with Boston Scientific’s Watchman, Watchman-FLX, or Abbott’s Amulet devices. Patients in the DOAC group received rivaroxaban, apixaban, or dabigatran at the manufacturer-recommended dose.

The primary outcome was a composite of complications related to procedures or devices, thromboembolic events (including stroke), and clinically significant bleeding. After an average of 20 months follow-up, 35 patients in the LAAO group and 41 in the DOAC group met the primary outcome (11% per 100 patient-years vs. 13% per 100 patient-years).

In addition, no differences appeared between the groups for the endpoint components of all-stroke/transient ischemic attack event (subdistribution hazard ratio, 1.00), clinically significantly bleeding (sHR, 0.81), or cardiovascular death (sHR, 0.75).

Nine patients experienced major complications related to LAAO, including clinically significant bleeding (sHR, 0.81; 95% CI, 0.44-1.52) and cardiovascular death (sHR, 0.75; 95% CI, 0.34-1.62). Major LAAO-related complications occurred in nine (4.5%) patients, with a short-term (up to 7 days or hospital discharge) complication rate of 2.1% and a 2.7% late complication rate. The late complications included three pericardial effusions, one of which resulted in death, the researchers wrote.

The study findings were limited by several factors, including the inability to assess the differences among the components of the composite primary endpoint. For example, “Regarding the primary endpoint, stroke reduction may be more important than bleeding reduction,” the investigators wrote.

The results were strengthened, however, by the enrollment of a high-risk AF population and is the first known randomized trial to compare percutaneous LAAO and DOACs for stroke prevention in this group. But the late complication rate of 2.7% is “suboptimal” and safety issues reinforce the need for refinement of operator technique and device technology with LAAO, they concluded.

‘Important step forward,’ with caveats

“How LAAO might stack up against DOAC therapy has remained an open question: Compared with warfarin, DOACs are easier to use and are associated with a reduction in mortality, driven by a substantially lower risk of intracranial hemorrhage and fatal bleeding,” wrote Matthew J. Price, MD, of the Scripps Clinic in La Jolla, Calif., and Jacqueline Saw, MD, of Vancouver General Hospital, in an accompanying editorial.

Bruce Jancin/Frontline Medical News

SOURCES: Osmancik P et al. J Am Coll Cardiol. 2020;75:3122-35; Price MJ, Saw J. J Am Coll Cardiol. 2020;75:3136-9.

Left atrial appendage closure was noninferior to use of direct oral anticoagulants for the prevention of atrial fibrillation (AFib)–related events in high-risk patients, based on data from 402 adults.

Given the limitations of vitamin K antagonists for preventing stroke in AFib, “a novel site-specific therapeutic alternative, mechanical left atrial appendage occlusion [LAAO], entered clinical practice,” but has not been compared with current safe and effective oral anticoagulants, wrote Pavel Osmancik, MD, of University Hospital Kralovske Vinohrady, Prague, and colleagues.

In a study published in the Journal of the American College of Cardiology, the researchers randomized 201 moderate- or high-risk adults with nonvalvular AFib to LAAO and another 201 to direct oral anticoagulants (DOAC).

Patients in the LAAO group underwent transesophageal echocardiography to exclude left atrial thrombi and underwent implantation with Boston Scientific’s Watchman, Watchman-FLX, or Abbott’s Amulet devices. Patients in the DOAC group received rivaroxaban, apixaban, or dabigatran at the manufacturer-recommended dose.

The primary outcome was a composite of complications related to procedures or devices, thromboembolic events (including stroke), and clinically significant bleeding. After an average of 20 months follow-up, 35 patients in the LAAO group and 41 in the DOAC group met the primary outcome (11% per 100 patient-years vs. 13% per 100 patient-years).

In addition, no differences appeared between the groups for the endpoint components of all-stroke/transient ischemic attack event (subdistribution hazard ratio, 1.00), clinically significantly bleeding (sHR, 0.81), or cardiovascular death (sHR, 0.75).

Nine patients experienced major complications related to LAAO, including clinically significant bleeding (sHR, 0.81; 95% CI, 0.44-1.52) and cardiovascular death (sHR, 0.75; 95% CI, 0.34-1.62). Major LAAO-related complications occurred in nine (4.5%) patients, with a short-term (up to 7 days or hospital discharge) complication rate of 2.1% and a 2.7% late complication rate. The late complications included three pericardial effusions, one of which resulted in death, the researchers wrote.

The study findings were limited by several factors, including the inability to assess the differences among the components of the composite primary endpoint. For example, “Regarding the primary endpoint, stroke reduction may be more important than bleeding reduction,” the investigators wrote.

The results were strengthened, however, by the enrollment of a high-risk AF population and is the first known randomized trial to compare percutaneous LAAO and DOACs for stroke prevention in this group. But the late complication rate of 2.7% is “suboptimal” and safety issues reinforce the need for refinement of operator technique and device technology with LAAO, they concluded.

‘Important step forward,’ with caveats

“How LAAO might stack up against DOAC therapy has remained an open question: Compared with warfarin, DOACs are easier to use and are associated with a reduction in mortality, driven by a substantially lower risk of intracranial hemorrhage and fatal bleeding,” wrote Matthew J. Price, MD, of the Scripps Clinic in La Jolla, Calif., and Jacqueline Saw, MD, of Vancouver General Hospital, in an accompanying editorial.

Bruce Jancin/Frontline Medical News

SOURCES: Osmancik P et al. J Am Coll Cardiol. 2020;75:3122-35; Price MJ, Saw J. J Am Coll Cardiol. 2020;75:3136-9.

Presented during the ASCO 2020 plenary session, the results of the phase 3 ADAURA trial will prove practice-changing, according to Dr. Mark Kris of Memorial Sloan Kettering Cancer Center. Over 600 patients whose resected tumors were found to have EGFR mutations were treated with osimertinib. The results more than doubled disease-free survival rates, from 44% to 90% at 2 years.

Among other adjuvant trials, the phase 2 VISION study looked at tepotinib, a once-daily, highly selective oral MET inhibitor. The study showed durable responses coupled with acceptable side effects. The drug has been given fast-track status by the US Food and Drug Administration.

Dr. Kris notes that the DESTINY study introduces trastuzumab deruxtecan, an antibody-drug conjugate, as a promising new class of drugs for lung cancer patients. Interim results presented at ASCO further support the HER2 mutation as another potential target for patients with lung cancer.

Finally, the phase 2 CITYSCAPE study provides preliminary evidence for a new checkpoint inhibitor. The monoclonal antibody tiragolumab was developed to block TIGIT. The study showed that the combination of tiragolumab and atezolizumab can improve both rates of response and time to disease recurrence — results Dr. Kris considers encouraging for patients with advanced lung cancer.

Mark G. Kris, MD

Mark G. Kris, MD, Professor, Department of Medicine, Weill Cornell Medical College; Attending Physician, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Presented during the ASCO 2020 plenary session, the results of the phase 3 ADAURA trial will prove practice-changing, according to Dr. Mark Kris of Memorial Sloan Kettering Cancer Center. Over 600 patients whose resected tumors were found to have EGFR mutations were treated with osimertinib. The results more than doubled disease-free survival rates, from 44% to 90% at 2 years.

Among other adjuvant trials, the phase 2 VISION study looked at tepotinib, a once-daily, highly selective oral MET inhibitor. The study showed durable responses coupled with acceptable side effects. The drug has been given fast-track status by the US Food and Drug Administration.

Dr. Kris notes that the DESTINY study introduces trastuzumab deruxtecan, an antibody-drug conjugate, as a promising new class of drugs for lung cancer patients. Interim results presented at ASCO further support the HER2 mutation as another potential target for patients with lung cancer.

Finally, the phase 2 CITYSCAPE study provides preliminary evidence for a new checkpoint inhibitor. The monoclonal antibody tiragolumab was developed to block TIGIT. The study showed that the combination of tiragolumab and atezolizumab can improve both rates of response and time to disease recurrence — results Dr. Kris considers encouraging for patients with advanced lung cancer.

Mark G. Kris, MD

Mark G. Kris, MD, Professor, Department of Medicine, Weill Cornell Medical College; Attending Physician, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Presented during the ASCO 2020 plenary session, the results of the phase 3 ADAURA trial will prove practice-changing, according to Dr. Mark Kris of Memorial Sloan Kettering Cancer Center. Over 600 patients whose resected tumors were found to have EGFR mutations were treated with osimertinib. The results more than doubled disease-free survival rates, from 44% to 90% at 2 years.

Among other adjuvant trials, the phase 2 VISION study looked at tepotinib, a once-daily, highly selective oral MET inhibitor. The study showed durable responses coupled with acceptable side effects. The drug has been given fast-track status by the US Food and Drug Administration.

Dr. Kris notes that the DESTINY study introduces trastuzumab deruxtecan, an antibody-drug conjugate, as a promising new class of drugs for lung cancer patients. Interim results presented at ASCO further support the HER2 mutation as another potential target for patients with lung cancer.

Finally, the phase 2 CITYSCAPE study provides preliminary evidence for a new checkpoint inhibitor. The monoclonal antibody tiragolumab was developed to block TIGIT. The study showed that the combination of tiragolumab and atezolizumab can improve both rates of response and time to disease recurrence — results Dr. Kris considers encouraging for patients with advanced lung cancer.

Mark G. Kris, MD

Mark G. Kris, MD, Professor, Department of Medicine, Weill Cornell Medical College; Attending Physician, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Adding tiragolumab to first-line treatment with atezolizumab improves outcomes in patients with PD-L1–positive non–small cell lung cancer (NSCLC), according to updated results from the phase 2 CITYSCAPE study.

Patients who received tiragolumab, an anti-TIGIT antibody, in combination with atezolizumab, a PD-L1 inhibitor, had superior overall response rates (ORR) and progression-free survival (PFS), when compared with results of patients who received placebo with atezolizumab.

Melissa L. Johnson, MD, of the Sarah Cannon Research Institute in Nashville, Tenn., presented these results as part of the American Society of Clinical Oncology virtual scientific program.

Dr. Johnson explained that TIGIT is an immunomodulatory receptor present on activated T cells and natural killer cells in multiple cancers, including NSCLC.

“TIGIT inhibits T cells and natural killer cells by binding to its ligand PVR on tumor cells and antigen-presenting cells,” she said. “TIGIT expression strongly correlates with PD-1 expression, sometimes on the same tumor-infiltrating T cells in lung cancer. So the hypothesis of this trial was that anti-TIGIT antibodies, which prevent TIGIT from binding to its ligand, could restore the antitumor response and could complement the activity of anti–PD-L1/PD-1 antibodies.”

Dr. Johnson noted that combination anti–TIGIT/PD-L1 antibody treatment synergistically improved tumor control and prolonged survival over either antibody alone in preclinical models (Cancer Cell. 2014 Dec 8;26[6]:923-937). In addition, tiragolumab has been evaluated in a phase 1 study, both as monotherapy and in combination with atezolizumab, in multiple solid tumors (NCT02794571).

The phase 2 CITYSCAPE study (NCT03563716) was initiated to confirm the efficacy and safety of tiragolumab plus atezolizumab versus placebo plus atezolizumab for the first-line treatment of NSCLC, Dr. Johnson said.

CITYSCAPE enrolled 135 patients with chemotherapy-naive, PD-L1–positive, locally advanced or metastatic NSCLC. Patients did not have EGFR or ALK alterations.

Half of patients (n = 68) were randomized to receive tiragolumab at 600 mg plus atezolizumab at 1,200 mg, both given on day 1 of every 3-week cycle. The other half of patients (n = 67) were randomized to receive atezolizumab at the same dose and schedule plus placebo.
 

ORR and PFS

The study’s primary analysis was conducted in June 2019 at a median follow-up of 5.9 months. At that time, the ORR and PFS data showed an early benefit with tiragolumab. The ORR was 31% in the tiragolumab arm and 16% in the placebo arm. The median PFS was 5.42 months and 3.58 months, respectively (hazard ratio, 0.57).

With an additional 6 months of follow-up, the tiragolumab benefit persisted, Dr. Johnson said. The updated ORR in the intent-to-treat population was 37% in the tiragolumab arm and 21% in the placebo arm. The median PFS was 5.6 months and 3.9 months, respectively (HR, 0.58).

The tiragolumab combination showed “clinically meaningful” improvements in ORR and PFS, Dr. Johnson said. She also noted “a greater magnitude of improvement” was seen in patients with a PD-L1 tumor proportion score of 50% or greater.

There were 29 patients in each treatment arm with a PD-L1 tumor proportion score of 50% or greater. Among these patients, the ORR was 66% in the tiragolumab arm and 24% in the placebo arm. The median PFS was not reached and 4.1 months, respectively (HR, 0.30).

There were no significant differences in ORR or PFS among patients with PD-L1 tumor proportion scores below 50%, Dr. Johnson noted.

She added that duration of response and overall survival data are not yet mature and will be presented at a future conference.
 

Adverse events

As reported in the primary analysis, tiragolumab plus atezolizumab had a tolerable safety profile, Dr. Johnson said.

“Despite a near doubling of the median treatment duration [at the updated analysis], there were similar numbers of any-cause adverse events, grade 3-5 adverse events, and serious adverse events,” she said.

Overall, adverse events occurred in 99% of patients in the tiragolumab arm and 96% of those in the placebo arm. Rates of grade 3-5 adverse events were 48% and 44%, respectively. Rates of serious adverse events were 37% and 35%, respectively.

A higher frequency of adverse events in the tiragolumab arm was related to an increase in immune-related events, including infusion reactions, pruritus, rash, arthralgia, and nephritis. This makes sense because the patients in that group were receiving two active immunotherapies, Dr. Johnson said.
 

Data inspire cautious optimism

The safety and activity of tiragolumab plus atezolizumab are “to be confirmed in an ongoing phase 3 study called SKYSCRAPER-01 [NCT04294810],” Dr. Johnson said.

Invited discussant Grace K. Dy, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., said the ORRs in CITYSCAPE have “generated a lot of buzz,” but she urged caution pending phase 3 results.

“While we are all excited by the data and want to see a winner, we should be careful, as speed can also crash and burn,” she said. “We have plenty of examples of promising studies that collapsed in later phase trials.”

There is room, however, for cautious optimism that the combination is a promising advance “as long as no prognostic or confounding variable is determined later on to be nonrandomly distributed between the groups to account for the difference seen,” Dr. Dy said.

She also noted that “the distribution of favorable or unfavorable mutations between the groups is unknown, and understanding this will be relevant.”

Preclinical data suggest the presence of DNM1 expression is crucial for maximizing the effect of TIGIT blockade, and tumor MHC class 1 expression appears to be reduced alongside reductions in DNM1 expression in the intratumoral natural kill cells in lung cancer specimens, Dr. Dy explained.

“Assessment of these biomarkers will be instructive,” she said. “More recent data also appear to implicate a paradoxical role of soluble CD155 or PVR ligand in actually inhibiting DNM1, so the effect of systemic TIGIT blockade may be mitigated if there is rebound increase of counterbalancing signals by increased secretion of soluble CD155, and we look forward to more data in the future regarding this.”

CITYSCAPE was sponsored by Genentech. Dr. Johnson disclosed relationships with Genentech and numerous other companies. Dr. Dy disclosed relationships with AstraZeneca, GlaxoSmithKline, Takeda, Amgen, Bristol-Myers Squibb, Regeneron, and Tesaro.

[email protected]

SOURCE: Rodriguez-Abreu D et al. ASCO 2020, Abstract 9503.

Adding tiragolumab to first-line treatment with atezolizumab improves outcomes in patients with PD-L1–positive non–small cell lung cancer (NSCLC), according to updated results from the phase 2 CITYSCAPE study.

Patients who received tiragolumab, an anti-TIGIT antibody, in combination with atezolizumab, a PD-L1 inhibitor, had superior overall response rates (ORR) and progression-free survival (PFS), when compared with results of patients who received placebo with atezolizumab.

Melissa L. Johnson, MD, of the Sarah Cannon Research Institute in Nashville, Tenn., presented these results as part of the American Society of Clinical Oncology virtual scientific program.

Dr. Johnson explained that TIGIT is an immunomodulatory receptor present on activated T cells and natural killer cells in multiple cancers, including NSCLC.

“TIGIT inhibits T cells and natural killer cells by binding to its ligand PVR on tumor cells and antigen-presenting cells,” she said. “TIGIT expression strongly correlates with PD-1 expression, sometimes on the same tumor-infiltrating T cells in lung cancer. So the hypothesis of this trial was that anti-TIGIT antibodies, which prevent TIGIT from binding to its ligand, could restore the antitumor response and could complement the activity of anti–PD-L1/PD-1 antibodies.”

Dr. Johnson noted that combination anti–TIGIT/PD-L1 antibody treatment synergistically improved tumor control and prolonged survival over either antibody alone in preclinical models (Cancer Cell. 2014 Dec 8;26[6]:923-937). In addition, tiragolumab has been evaluated in a phase 1 study, both as monotherapy and in combination with atezolizumab, in multiple solid tumors (NCT02794571).

The phase 2 CITYSCAPE study (NCT03563716) was initiated to confirm the efficacy and safety of tiragolumab plus atezolizumab versus placebo plus atezolizumab for the first-line treatment of NSCLC, Dr. Johnson said.

CITYSCAPE enrolled 135 patients with chemotherapy-naive, PD-L1–positive, locally advanced or metastatic NSCLC. Patients did not have EGFR or ALK alterations.

Half of patients (n = 68) were randomized to receive tiragolumab at 600 mg plus atezolizumab at 1,200 mg, both given on day 1 of every 3-week cycle. The other half of patients (n = 67) were randomized to receive atezolizumab at the same dose and schedule plus placebo.
 

ORR and PFS

The study’s primary analysis was conducted in June 2019 at a median follow-up of 5.9 months. At that time, the ORR and PFS data showed an early benefit with tiragolumab. The ORR was 31% in the tiragolumab arm and 16% in the placebo arm. The median PFS was 5.42 months and 3.58 months, respectively (hazard ratio, 0.57).

With an additional 6 months of follow-up, the tiragolumab benefit persisted, Dr. Johnson said. The updated ORR in the intent-to-treat population was 37% in the tiragolumab arm and 21% in the placebo arm. The median PFS was 5.6 months and 3.9 months, respectively (HR, 0.58).

The tiragolumab combination showed “clinically meaningful” improvements in ORR and PFS, Dr. Johnson said. She also noted “a greater magnitude of improvement” was seen in patients with a PD-L1 tumor proportion score of 50% or greater.

There were 29 patients in each treatment arm with a PD-L1 tumor proportion score of 50% or greater. Among these patients, the ORR was 66% in the tiragolumab arm and 24% in the placebo arm. The median PFS was not reached and 4.1 months, respectively (HR, 0.30).

There were no significant differences in ORR or PFS among patients with PD-L1 tumor proportion scores below 50%, Dr. Johnson noted.

She added that duration of response and overall survival data are not yet mature and will be presented at a future conference.
 

Adverse events

As reported in the primary analysis, tiragolumab plus atezolizumab had a tolerable safety profile, Dr. Johnson said.

“Despite a near doubling of the median treatment duration [at the updated analysis], there were similar numbers of any-cause adverse events, grade 3-5 adverse events, and serious adverse events,” she said.

Overall, adverse events occurred in 99% of patients in the tiragolumab arm and 96% of those in the placebo arm. Rates of grade 3-5 adverse events were 48% and 44%, respectively. Rates of serious adverse events were 37% and 35%, respectively.

A higher frequency of adverse events in the tiragolumab arm was related to an increase in immune-related events, including infusion reactions, pruritus, rash, arthralgia, and nephritis. This makes sense because the patients in that group were receiving two active immunotherapies, Dr. Johnson said.
 

Data inspire cautious optimism

The safety and activity of tiragolumab plus atezolizumab are “to be confirmed in an ongoing phase 3 study called SKYSCRAPER-01 [NCT04294810],” Dr. Johnson said.

Invited discussant Grace K. Dy, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., said the ORRs in CITYSCAPE have “generated a lot of buzz,” but she urged caution pending phase 3 results.

“While we are all excited by the data and want to see a winner, we should be careful, as speed can also crash and burn,” she said. “We have plenty of examples of promising studies that collapsed in later phase trials.”

There is room, however, for cautious optimism that the combination is a promising advance “as long as no prognostic or confounding variable is determined later on to be nonrandomly distributed between the groups to account for the difference seen,” Dr. Dy said.

She also noted that “the distribution of favorable or unfavorable mutations between the groups is unknown, and understanding this will be relevant.”

Preclinical data suggest the presence of DNM1 expression is crucial for maximizing the effect of TIGIT blockade, and tumor MHC class 1 expression appears to be reduced alongside reductions in DNM1 expression in the intratumoral natural kill cells in lung cancer specimens, Dr. Dy explained.

“Assessment of these biomarkers will be instructive,” she said. “More recent data also appear to implicate a paradoxical role of soluble CD155 or PVR ligand in actually inhibiting DNM1, so the effect of systemic TIGIT blockade may be mitigated if there is rebound increase of counterbalancing signals by increased secretion of soluble CD155, and we look forward to more data in the future regarding this.”

CITYSCAPE was sponsored by Genentech. Dr. Johnson disclosed relationships with Genentech and numerous other companies. Dr. Dy disclosed relationships with AstraZeneca, GlaxoSmithKline, Takeda, Amgen, Bristol-Myers Squibb, Regeneron, and Tesaro.

[email protected]

SOURCE: Rodriguez-Abreu D et al. ASCO 2020, Abstract 9503.

Adding tiragolumab to first-line treatment with atezolizumab improves outcomes in patients with PD-L1–positive non–small cell lung cancer (NSCLC), according to updated results from the phase 2 CITYSCAPE study.

Patients who received tiragolumab, an anti-TIGIT antibody, in combination with atezolizumab, a PD-L1 inhibitor, had superior overall response rates (ORR) and progression-free survival (PFS), when compared with results of patients who received placebo with atezolizumab.

Melissa L. Johnson, MD, of the Sarah Cannon Research Institute in Nashville, Tenn., presented these results as part of the American Society of Clinical Oncology virtual scientific program.

Dr. Johnson explained that TIGIT is an immunomodulatory receptor present on activated T cells and natural killer cells in multiple cancers, including NSCLC.

“TIGIT inhibits T cells and natural killer cells by binding to its ligand PVR on tumor cells and antigen-presenting cells,” she said. “TIGIT expression strongly correlates with PD-1 expression, sometimes on the same tumor-infiltrating T cells in lung cancer. So the hypothesis of this trial was that anti-TIGIT antibodies, which prevent TIGIT from binding to its ligand, could restore the antitumor response and could complement the activity of anti–PD-L1/PD-1 antibodies.”

Dr. Johnson noted that combination anti–TIGIT/PD-L1 antibody treatment synergistically improved tumor control and prolonged survival over either antibody alone in preclinical models (Cancer Cell. 2014 Dec 8;26[6]:923-937). In addition, tiragolumab has been evaluated in a phase 1 study, both as monotherapy and in combination with atezolizumab, in multiple solid tumors (NCT02794571).

The phase 2 CITYSCAPE study (NCT03563716) was initiated to confirm the efficacy and safety of tiragolumab plus atezolizumab versus placebo plus atezolizumab for the first-line treatment of NSCLC, Dr. Johnson said.

CITYSCAPE enrolled 135 patients with chemotherapy-naive, PD-L1–positive, locally advanced or metastatic NSCLC. Patients did not have EGFR or ALK alterations.

Half of patients (n = 68) were randomized to receive tiragolumab at 600 mg plus atezolizumab at 1,200 mg, both given on day 1 of every 3-week cycle. The other half of patients (n = 67) were randomized to receive atezolizumab at the same dose and schedule plus placebo.
 

ORR and PFS

The study’s primary analysis was conducted in June 2019 at a median follow-up of 5.9 months. At that time, the ORR and PFS data showed an early benefit with tiragolumab. The ORR was 31% in the tiragolumab arm and 16% in the placebo arm. The median PFS was 5.42 months and 3.58 months, respectively (hazard ratio, 0.57).

With an additional 6 months of follow-up, the tiragolumab benefit persisted, Dr. Johnson said. The updated ORR in the intent-to-treat population was 37% in the tiragolumab arm and 21% in the placebo arm. The median PFS was 5.6 months and 3.9 months, respectively (HR, 0.58).

The tiragolumab combination showed “clinically meaningful” improvements in ORR and PFS, Dr. Johnson said. She also noted “a greater magnitude of improvement” was seen in patients with a PD-L1 tumor proportion score of 50% or greater.

There were 29 patients in each treatment arm with a PD-L1 tumor proportion score of 50% or greater. Among these patients, the ORR was 66% in the tiragolumab arm and 24% in the placebo arm. The median PFS was not reached and 4.1 months, respectively (HR, 0.30).

There were no significant differences in ORR or PFS among patients with PD-L1 tumor proportion scores below 50%, Dr. Johnson noted.

She added that duration of response and overall survival data are not yet mature and will be presented at a future conference.
 

Adverse events

As reported in the primary analysis, tiragolumab plus atezolizumab had a tolerable safety profile, Dr. Johnson said.

“Despite a near doubling of the median treatment duration [at the updated analysis], there were similar numbers of any-cause adverse events, grade 3-5 adverse events, and serious adverse events,” she said.

Overall, adverse events occurred in 99% of patients in the tiragolumab arm and 96% of those in the placebo arm. Rates of grade 3-5 adverse events were 48% and 44%, respectively. Rates of serious adverse events were 37% and 35%, respectively.

A higher frequency of adverse events in the tiragolumab arm was related to an increase in immune-related events, including infusion reactions, pruritus, rash, arthralgia, and nephritis. This makes sense because the patients in that group were receiving two active immunotherapies, Dr. Johnson said.
 

Data inspire cautious optimism

The safety and activity of tiragolumab plus atezolizumab are “to be confirmed in an ongoing phase 3 study called SKYSCRAPER-01 [NCT04294810],” Dr. Johnson said.

Invited discussant Grace K. Dy, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., said the ORRs in CITYSCAPE have “generated a lot of buzz,” but she urged caution pending phase 3 results.

“While we are all excited by the data and want to see a winner, we should be careful, as speed can also crash and burn,” she said. “We have plenty of examples of promising studies that collapsed in later phase trials.”

There is room, however, for cautious optimism that the combination is a promising advance “as long as no prognostic or confounding variable is determined later on to be nonrandomly distributed between the groups to account for the difference seen,” Dr. Dy said.

She also noted that “the distribution of favorable or unfavorable mutations between the groups is unknown, and understanding this will be relevant.”

Preclinical data suggest the presence of DNM1 expression is crucial for maximizing the effect of TIGIT blockade, and tumor MHC class 1 expression appears to be reduced alongside reductions in DNM1 expression in the intratumoral natural kill cells in lung cancer specimens, Dr. Dy explained.

“Assessment of these biomarkers will be instructive,” she said. “More recent data also appear to implicate a paradoxical role of soluble CD155 or PVR ligand in actually inhibiting DNM1, so the effect of systemic TIGIT blockade may be mitigated if there is rebound increase of counterbalancing signals by increased secretion of soluble CD155, and we look forward to more data in the future regarding this.”

CITYSCAPE was sponsored by Genentech. Dr. Johnson disclosed relationships with Genentech and numerous other companies. Dr. Dy disclosed relationships with AstraZeneca, GlaxoSmithKline, Takeda, Amgen, Bristol-Myers Squibb, Regeneron, and Tesaro.

[email protected]

SOURCE: Rodriguez-Abreu D et al. ASCO 2020, Abstract 9503.

Magrolimab plus azacitidine (AZA) improved outcomes in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients according to the results of a phase 1b study (NCT03248479) presented at the virtual ASCO meeting. The combo especially was promising for the underserved patient population that have the TP53 (p53) mutation.

Magrolimab is a first-in-kind IgG anti-CD47 monoclonal antibody that promotes the elimination of tumor cells through macrophage phagocytosis. CD47 is a “do not eat me” signal on cancer cells that allows the cells to evade macrophages. Its increased expression is predictive of a worse outcome in AML patients, according to David A. Sallman, MD, of the Moffitt Cancer Center, Tampa, Fla., and colleagues.

Dr. Sallman presented the results of a study examining whether magrolimab would provide a synergistic benefit when combined with AZA (which induces other prophagocytic “eat me” signals such as calreticulin on cancer cells). The primary objectives of the study were to examine the safety of magrolimab alone or with AZA, and to assess the efficacy of the magrolimab/AZA combo in 29 untreated AML patients and 39 untreated MDS patients. The majority of both the MDS and AML patients were poor cytogenetic risk at 64% and 72%, respectively. Mutant p53 was present in 13% of the MDS patients and 45% of the AML patients.

No deaths occurred in the first 60 days of the study among either the MDS or AML patients and discontinuation of treatment because of drug-related adverse events was seen in only one of the patients (1.5%) treated with magrolimab/AZA. There was no significant neutropenia or thrombocytopenia caused by the therapy seen, and the majority of the patients improved their neutrophil and platelet counts while on therapy.

Anemia from CD47 blockade was mitigated by the use of a priming dose of magrolimab coupled to a maintenance-dose regimen, resulting in a mild hemoglobin drop on the first dose, which returned to baseline with a majority of patients experiencing significant hemoglobin improvement and a decrease in transfusion frequency over time, according to Dr. Sallman and his colleagues.

The results showed that magrolimab/AZA induced a 91% overall response rate (ORR), with a 42% complete remission (CR) that increased to 56% at 6 months, in the MDS patients. AML patients experienced a 64% ORR (56% CR/CRi [CR with incomplete hematological remission]). These results compare favorably with the CR rate of 6%-17% rate seen for AZA monotherapy, according to Dr. Sallman.

Red blood cell transfusion independence was achieved in 58% of the MDS patients and 64% of the AML patients, and a complete cytogenetic response was seen in 35% and 50% of the MDS and AML patients, respectively.

The combined treatment was especially effective in the patients with p53 mutations, with an overall response rate of 75% for both MDS and AML, and a complete response of 42% and 50%, respectively. During the reported time of the study, the median survival was not reached, which compares favorably with current therapies, according to Dr. Sallman.

“Specifically looking at a very-high-risk p53-mutant subset, complete remissions have been observed in the majority of patients. And again, these have been durable. Based on all of these data, expansion cohorts both in MDS and p53 and AML continue to accrue with registrational studies in progress for MDS and planned for p53-mutant AML,” Dr. Sallman concluded.

The trial was sponsored by Gilead Sciences, and funding was obtained from the California Institute for Regenerative Medicine. Dr. Sallman disclosed that he received research funding from Celgene and has acted in a consulting or advisory role for Agios, argenx, and Celyad. He was also on the speaker’s bureau for a variety of pharmaceutical/biotech companies.

[email protected]

SOURCE: Sallman DA et al. ASCO 2020, Abstract 7507.

Magrolimab plus azacitidine (AZA) improved outcomes in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients according to the results of a phase 1b study (NCT03248479) presented at the virtual ASCO meeting. The combo especially was promising for the underserved patient population that have the TP53 (p53) mutation.

Magrolimab is a first-in-kind IgG anti-CD47 monoclonal antibody that promotes the elimination of tumor cells through macrophage phagocytosis. CD47 is a “do not eat me” signal on cancer cells that allows the cells to evade macrophages. Its increased expression is predictive of a worse outcome in AML patients, according to David A. Sallman, MD, of the Moffitt Cancer Center, Tampa, Fla., and colleagues.

Dr. Sallman presented the results of a study examining whether magrolimab would provide a synergistic benefit when combined with AZA (which induces other prophagocytic “eat me” signals such as calreticulin on cancer cells). The primary objectives of the study were to examine the safety of magrolimab alone or with AZA, and to assess the efficacy of the magrolimab/AZA combo in 29 untreated AML patients and 39 untreated MDS patients. The majority of both the MDS and AML patients were poor cytogenetic risk at 64% and 72%, respectively. Mutant p53 was present in 13% of the MDS patients and 45% of the AML patients.

No deaths occurred in the first 60 days of the study among either the MDS or AML patients and discontinuation of treatment because of drug-related adverse events was seen in only one of the patients (1.5%) treated with magrolimab/AZA. There was no significant neutropenia or thrombocytopenia caused by the therapy seen, and the majority of the patients improved their neutrophil and platelet counts while on therapy.

Anemia from CD47 blockade was mitigated by the use of a priming dose of magrolimab coupled to a maintenance-dose regimen, resulting in a mild hemoglobin drop on the first dose, which returned to baseline with a majority of patients experiencing significant hemoglobin improvement and a decrease in transfusion frequency over time, according to Dr. Sallman and his colleagues.

The results showed that magrolimab/AZA induced a 91% overall response rate (ORR), with a 42% complete remission (CR) that increased to 56% at 6 months, in the MDS patients. AML patients experienced a 64% ORR (56% CR/CRi [CR with incomplete hematological remission]). These results compare favorably with the CR rate of 6%-17% rate seen for AZA monotherapy, according to Dr. Sallman.

Red blood cell transfusion independence was achieved in 58% of the MDS patients and 64% of the AML patients, and a complete cytogenetic response was seen in 35% and 50% of the MDS and AML patients, respectively.

The combined treatment was especially effective in the patients with p53 mutations, with an overall response rate of 75% for both MDS and AML, and a complete response of 42% and 50%, respectively. During the reported time of the study, the median survival was not reached, which compares favorably with current therapies, according to Dr. Sallman.

“Specifically looking at a very-high-risk p53-mutant subset, complete remissions have been observed in the majority of patients. And again, these have been durable. Based on all of these data, expansion cohorts both in MDS and p53 and AML continue to accrue with registrational studies in progress for MDS and planned for p53-mutant AML,” Dr. Sallman concluded.

The trial was sponsored by Gilead Sciences, and funding was obtained from the California Institute for Regenerative Medicine. Dr. Sallman disclosed that he received research funding from Celgene and has acted in a consulting or advisory role for Agios, argenx, and Celyad. He was also on the speaker’s bureau for a variety of pharmaceutical/biotech companies.

[email protected]

SOURCE: Sallman DA et al. ASCO 2020, Abstract 7507.

Magrolimab plus azacitidine (AZA) improved outcomes in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients according to the results of a phase 1b study (NCT03248479) presented at the virtual ASCO meeting. The combo especially was promising for the underserved patient population that have the TP53 (p53) mutation.

Magrolimab is a first-in-kind IgG anti-CD47 monoclonal antibody that promotes the elimination of tumor cells through macrophage phagocytosis. CD47 is a “do not eat me” signal on cancer cells that allows the cells to evade macrophages. Its increased expression is predictive of a worse outcome in AML patients, according to David A. Sallman, MD, of the Moffitt Cancer Center, Tampa, Fla., and colleagues.

Dr. Sallman presented the results of a study examining whether magrolimab would provide a synergistic benefit when combined with AZA (which induces other prophagocytic “eat me” signals such as calreticulin on cancer cells). The primary objectives of the study were to examine the safety of magrolimab alone or with AZA, and to assess the efficacy of the magrolimab/AZA combo in 29 untreated AML patients and 39 untreated MDS patients. The majority of both the MDS and AML patients were poor cytogenetic risk at 64% and 72%, respectively. Mutant p53 was present in 13% of the MDS patients and 45% of the AML patients.

No deaths occurred in the first 60 days of the study among either the MDS or AML patients and discontinuation of treatment because of drug-related adverse events was seen in only one of the patients (1.5%) treated with magrolimab/AZA. There was no significant neutropenia or thrombocytopenia caused by the therapy seen, and the majority of the patients improved their neutrophil and platelet counts while on therapy.

Anemia from CD47 blockade was mitigated by the use of a priming dose of magrolimab coupled to a maintenance-dose regimen, resulting in a mild hemoglobin drop on the first dose, which returned to baseline with a majority of patients experiencing significant hemoglobin improvement and a decrease in transfusion frequency over time, according to Dr. Sallman and his colleagues.

The results showed that magrolimab/AZA induced a 91% overall response rate (ORR), with a 42% complete remission (CR) that increased to 56% at 6 months, in the MDS patients. AML patients experienced a 64% ORR (56% CR/CRi [CR with incomplete hematological remission]). These results compare favorably with the CR rate of 6%-17% rate seen for AZA monotherapy, according to Dr. Sallman.

Red blood cell transfusion independence was achieved in 58% of the MDS patients and 64% of the AML patients, and a complete cytogenetic response was seen in 35% and 50% of the MDS and AML patients, respectively.

The combined treatment was especially effective in the patients with p53 mutations, with an overall response rate of 75% for both MDS and AML, and a complete response of 42% and 50%, respectively. During the reported time of the study, the median survival was not reached, which compares favorably with current therapies, according to Dr. Sallman.

“Specifically looking at a very-high-risk p53-mutant subset, complete remissions have been observed in the majority of patients. And again, these have been durable. Based on all of these data, expansion cohorts both in MDS and p53 and AML continue to accrue with registrational studies in progress for MDS and planned for p53-mutant AML,” Dr. Sallman concluded.

The trial was sponsored by Gilead Sciences, and funding was obtained from the California Institute for Regenerative Medicine. Dr. Sallman disclosed that he received research funding from Celgene and has acted in a consulting or advisory role for Agios, argenx, and Celyad. He was also on the speaker’s bureau for a variety of pharmaceutical/biotech companies.

[email protected]

SOURCE: Sallman DA et al. ASCO 2020, Abstract 7507.