Immuno-oncology

Tumor microenvironment (TME) profiles could help tailor treatment for triple-negative breast cancer (TNBC), with the TME profile of the immunomodulatory subtype of TNBC making it the most susceptible to the effects of the immune checkpoint inhibitors.

“This study allowed us to gain more insight into the complex interactions between tumor cells and their microenvironment, in particular immune cells,” wrote a team of Belgian and Canadian researchers. Their report is in the Journal of the National Cancer Institute.

At least five molecular subtypes of TNBC have been identified but little was previously known about the heterogeneity of their surroundings, noted Yacine Bareche, MSc, of Institut Jules Bordet, Université Libre de Bruxelles, Brussels, and associates. They looked at a series of 1,512 TNBC samples from four large and publicly available transcriptomic and genomic datasets and their TME, which is made up of many cell types – fibroblasts, adipose, and immune-inflammatory cells – and blood and lymphatic vascular networks.

The researchers explained that each of the four TNBC subtypes identified so far have “distinct mutational profiles, genomic alterations, and biological processes” which were matched by differences in their surrounding environments.

For instance, the immunomodulatory subtype of TNBC was associated with high expression of “adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check-point inhibitors.” By contrast, Mr. Bareche and coauthors said that “most mesenchymal stem-like and luminal androgen receptor TNBC tumors had an immunosuppressive phenotype with high expression levels of stromal gene signatures.”

The findings include “novel evidence” of how TNBC tumors may become resistant to the effects of immune checkpoint inhibitors.

The results demonstrate that each TNBC subtype is associated with specific TME profiles, “setting the ground for a rationale tailoring of immunotherapy in TNBC patients,” the researchers noted. Mr. Bareche and associates cautioned, however, that “prospective validation of our findings is warranted before their clinical implementation.”

The study was supported by a grant from the Breast Cancer Research Foundation. The researchers had no conflicts of interest.
 

SOURCE: Bareche Y et al. J Natl Cancer Inst. 2019 Oct 29. doi: 10.1093/jnci/djz208.

Tumor microenvironment (TME) profiles could help tailor treatment for triple-negative breast cancer (TNBC), with the TME profile of the immunomodulatory subtype of TNBC making it the most susceptible to the effects of the immune checkpoint inhibitors.

“This study allowed us to gain more insight into the complex interactions between tumor cells and their microenvironment, in particular immune cells,” wrote a team of Belgian and Canadian researchers. Their report is in the Journal of the National Cancer Institute.

At least five molecular subtypes of TNBC have been identified but little was previously known about the heterogeneity of their surroundings, noted Yacine Bareche, MSc, of Institut Jules Bordet, Université Libre de Bruxelles, Brussels, and associates. They looked at a series of 1,512 TNBC samples from four large and publicly available transcriptomic and genomic datasets and their TME, which is made up of many cell types – fibroblasts, adipose, and immune-inflammatory cells – and blood and lymphatic vascular networks.

The researchers explained that each of the four TNBC subtypes identified so far have “distinct mutational profiles, genomic alterations, and biological processes” which were matched by differences in their surrounding environments.

For instance, the immunomodulatory subtype of TNBC was associated with high expression of “adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check-point inhibitors.” By contrast, Mr. Bareche and coauthors said that “most mesenchymal stem-like and luminal androgen receptor TNBC tumors had an immunosuppressive phenotype with high expression levels of stromal gene signatures.”

The findings include “novel evidence” of how TNBC tumors may become resistant to the effects of immune checkpoint inhibitors.

The results demonstrate that each TNBC subtype is associated with specific TME profiles, “setting the ground for a rationale tailoring of immunotherapy in TNBC patients,” the researchers noted. Mr. Bareche and associates cautioned, however, that “prospective validation of our findings is warranted before their clinical implementation.”

The study was supported by a grant from the Breast Cancer Research Foundation. The researchers had no conflicts of interest.
 

SOURCE: Bareche Y et al. J Natl Cancer Inst. 2019 Oct 29. doi: 10.1093/jnci/djz208.

Tumor microenvironment (TME) profiles could help tailor treatment for triple-negative breast cancer (TNBC), with the TME profile of the immunomodulatory subtype of TNBC making it the most susceptible to the effects of the immune checkpoint inhibitors.

“This study allowed us to gain more insight into the complex interactions between tumor cells and their microenvironment, in particular immune cells,” wrote a team of Belgian and Canadian researchers. Their report is in the Journal of the National Cancer Institute.

At least five molecular subtypes of TNBC have been identified but little was previously known about the heterogeneity of their surroundings, noted Yacine Bareche, MSc, of Institut Jules Bordet, Université Libre de Bruxelles, Brussels, and associates. They looked at a series of 1,512 TNBC samples from four large and publicly available transcriptomic and genomic datasets and their TME, which is made up of many cell types – fibroblasts, adipose, and immune-inflammatory cells – and blood and lymphatic vascular networks.

The researchers explained that each of the four TNBC subtypes identified so far have “distinct mutational profiles, genomic alterations, and biological processes” which were matched by differences in their surrounding environments.

For instance, the immunomodulatory subtype of TNBC was associated with high expression of “adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check-point inhibitors.” By contrast, Mr. Bareche and coauthors said that “most mesenchymal stem-like and luminal androgen receptor TNBC tumors had an immunosuppressive phenotype with high expression levels of stromal gene signatures.”

The findings include “novel evidence” of how TNBC tumors may become resistant to the effects of immune checkpoint inhibitors.

The results demonstrate that each TNBC subtype is associated with specific TME profiles, “setting the ground for a rationale tailoring of immunotherapy in TNBC patients,” the researchers noted. Mr. Bareche and associates cautioned, however, that “prospective validation of our findings is warranted before their clinical implementation.”

The study was supported by a grant from the Breast Cancer Research Foundation. The researchers had no conflicts of interest.
 

SOURCE: Bareche Y et al. J Natl Cancer Inst. 2019 Oct 29. doi: 10.1093/jnci/djz208.

BARCELONA – Nivolumab was associated with improved overall survival and a favorable safety profile, compared with chemotherapy, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) in the open-label phase 3 ATTRACTION-3 study.

The overall survival (OS) benefit was observed regardless of tumor programmed death-ligand 1 (PD-L1) expression, Byoung Chul Cho, MD, reported at the European Society for Medical Oncology Congress.

The findings were reported online simultaneously in The Lancet Oncology.

Median OS at a minimum follow-up of 17.6 months was 10.9 vs. 8.4 months in 210 patients randomized to receive treatment with the PD-1 inhibitor nivolumab and 209 who received chemotherapy, respectively (hazard ratio, 0.77), said Dr. Cho of Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

“Notably, there was a 13% and 10% improvement in overall survival rates at 12 months (47% vs. 34%) and 18 months (31% vs. 21%), respectively,” he said, also noting that the HRs for death favored nivolumab vs. chemotherapy across multiple prespecified subgroups, including those based on tumor PD-L1 expression (HRs, 0.69 and 0.84 for PD-L1 of 1% or greater and less than 1%, respectively).

No meaningful difference was seen in progression-free survival between the nivolumab and chemotherapy groups (12% vs. 7%; HR, 1.08), or in objective response rates (19% vs. 22%), he said.

“However, responses were substantially more durable with nivolumab, compared to chemotherapy; duration of response was 6.9 months with nivolumab vs. 3.9 months in the chemotherapy arm,” he said. “Notably, 21% of patients in the nivolumab arm were still in response, compared to only 6% in the chemotherapy arm.”

Patients enrolled in the open label study had unresectable advanced or recurrent ESCC refractory or intolerant to one prior fluoropyrimidine/platinum-based therapy. They were randomized 1:1 to receive 240 mg of nivolumab every 2 weeks or investigators’ choice of paclitaxel or docetaxel.

Fewer treatment-related adverse events (TRAEs) were reported with nivolumab, Dr. Cho said.

Any grade TRAEs occurred in 66% vs. 95% of patients in the groups, respectively, and grade 3-4 TRAEs occurred in 18% vs. 63%. The majority of select TRAEs – defined as those with potential immunologic etiology, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin effects – were grade 1 or 2, and the only difference between the nivolumab and chemotherapy groups with respect to those was in endocrine effects, which affected 11% vs. less than 1% of patients, respectively.

Grade 3/4 select TRAEs occurred in less than 2% of patients, Dr. Cho noted.

An exploratory analysis further showed significant overall improvement in health-related quality of life with nivolumab through week 42 on treatment, he added.

The findings are of note, because metastatic esophageal cancer has a 5-year relative survival rate of less than 8%, and ESCC accounts for about 90% of cases worldwide, he said, adding that current second-line chemotherapy options for ESCC offer poor long-term survival and are associated with toxicity.

Nivolumab, which showed promising antitumor activity and manageable toxicity for advanced ESCC in patients who were refractory to or intolerant of standard chemotherapies in the phase 2 ATTRACTION-1 study, is the first immune checkpoint inhibitor to demonstrate a statistically significant, clinically meaningful improvement in OS vs. chemotherapy in this setting, he said.

The findings of this final analysis of ATTRACTION-3, which shows a 23% reduction in the risk of death, a 2.5-month improvement in median OS, benefit across PD-L1 subgroups, and a favorable safety profile, suggest that nivolumab represents a new standard second-line treatment option for patients with advanced ESCC, he concluded.

ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He also reported stock ownership and/or patents with TheraCanVac and Champions Oncology.

SOURCE: Cho B et al. ESMO 2019, Abstract LBA11.

BARCELONA – Nivolumab was associated with improved overall survival and a favorable safety profile, compared with chemotherapy, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) in the open-label phase 3 ATTRACTION-3 study.

The overall survival (OS) benefit was observed regardless of tumor programmed death-ligand 1 (PD-L1) expression, Byoung Chul Cho, MD, reported at the European Society for Medical Oncology Congress.

The findings were reported online simultaneously in The Lancet Oncology.

Median OS at a minimum follow-up of 17.6 months was 10.9 vs. 8.4 months in 210 patients randomized to receive treatment with the PD-1 inhibitor nivolumab and 209 who received chemotherapy, respectively (hazard ratio, 0.77), said Dr. Cho of Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

“Notably, there was a 13% and 10% improvement in overall survival rates at 12 months (47% vs. 34%) and 18 months (31% vs. 21%), respectively,” he said, also noting that the HRs for death favored nivolumab vs. chemotherapy across multiple prespecified subgroups, including those based on tumor PD-L1 expression (HRs, 0.69 and 0.84 for PD-L1 of 1% or greater and less than 1%, respectively).

No meaningful difference was seen in progression-free survival between the nivolumab and chemotherapy groups (12% vs. 7%; HR, 1.08), or in objective response rates (19% vs. 22%), he said.

“However, responses were substantially more durable with nivolumab, compared to chemotherapy; duration of response was 6.9 months with nivolumab vs. 3.9 months in the chemotherapy arm,” he said. “Notably, 21% of patients in the nivolumab arm were still in response, compared to only 6% in the chemotherapy arm.”

Patients enrolled in the open label study had unresectable advanced or recurrent ESCC refractory or intolerant to one prior fluoropyrimidine/platinum-based therapy. They were randomized 1:1 to receive 240 mg of nivolumab every 2 weeks or investigators’ choice of paclitaxel or docetaxel.

Fewer treatment-related adverse events (TRAEs) were reported with nivolumab, Dr. Cho said.

Any grade TRAEs occurred in 66% vs. 95% of patients in the groups, respectively, and grade 3-4 TRAEs occurred in 18% vs. 63%. The majority of select TRAEs – defined as those with potential immunologic etiology, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin effects – were grade 1 or 2, and the only difference between the nivolumab and chemotherapy groups with respect to those was in endocrine effects, which affected 11% vs. less than 1% of patients, respectively.

Grade 3/4 select TRAEs occurred in less than 2% of patients, Dr. Cho noted.

An exploratory analysis further showed significant overall improvement in health-related quality of life with nivolumab through week 42 on treatment, he added.

The findings are of note, because metastatic esophageal cancer has a 5-year relative survival rate of less than 8%, and ESCC accounts for about 90% of cases worldwide, he said, adding that current second-line chemotherapy options for ESCC offer poor long-term survival and are associated with toxicity.

Nivolumab, which showed promising antitumor activity and manageable toxicity for advanced ESCC in patients who were refractory to or intolerant of standard chemotherapies in the phase 2 ATTRACTION-1 study, is the first immune checkpoint inhibitor to demonstrate a statistically significant, clinically meaningful improvement in OS vs. chemotherapy in this setting, he said.

The findings of this final analysis of ATTRACTION-3, which shows a 23% reduction in the risk of death, a 2.5-month improvement in median OS, benefit across PD-L1 subgroups, and a favorable safety profile, suggest that nivolumab represents a new standard second-line treatment option for patients with advanced ESCC, he concluded.

ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He also reported stock ownership and/or patents with TheraCanVac and Champions Oncology.

SOURCE: Cho B et al. ESMO 2019, Abstract LBA11.

BARCELONA – Nivolumab was associated with improved overall survival and a favorable safety profile, compared with chemotherapy, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) in the open-label phase 3 ATTRACTION-3 study.

The overall survival (OS) benefit was observed regardless of tumor programmed death-ligand 1 (PD-L1) expression, Byoung Chul Cho, MD, reported at the European Society for Medical Oncology Congress.

The findings were reported online simultaneously in The Lancet Oncology.

Median OS at a minimum follow-up of 17.6 months was 10.9 vs. 8.4 months in 210 patients randomized to receive treatment with the PD-1 inhibitor nivolumab and 209 who received chemotherapy, respectively (hazard ratio, 0.77), said Dr. Cho of Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

“Notably, there was a 13% and 10% improvement in overall survival rates at 12 months (47% vs. 34%) and 18 months (31% vs. 21%), respectively,” he said, also noting that the HRs for death favored nivolumab vs. chemotherapy across multiple prespecified subgroups, including those based on tumor PD-L1 expression (HRs, 0.69 and 0.84 for PD-L1 of 1% or greater and less than 1%, respectively).

No meaningful difference was seen in progression-free survival between the nivolumab and chemotherapy groups (12% vs. 7%; HR, 1.08), or in objective response rates (19% vs. 22%), he said.

“However, responses were substantially more durable with nivolumab, compared to chemotherapy; duration of response was 6.9 months with nivolumab vs. 3.9 months in the chemotherapy arm,” he said. “Notably, 21% of patients in the nivolumab arm were still in response, compared to only 6% in the chemotherapy arm.”

Patients enrolled in the open label study had unresectable advanced or recurrent ESCC refractory or intolerant to one prior fluoropyrimidine/platinum-based therapy. They were randomized 1:1 to receive 240 mg of nivolumab every 2 weeks or investigators’ choice of paclitaxel or docetaxel.

Fewer treatment-related adverse events (TRAEs) were reported with nivolumab, Dr. Cho said.

Any grade TRAEs occurred in 66% vs. 95% of patients in the groups, respectively, and grade 3-4 TRAEs occurred in 18% vs. 63%. The majority of select TRAEs – defined as those with potential immunologic etiology, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin effects – were grade 1 or 2, and the only difference between the nivolumab and chemotherapy groups with respect to those was in endocrine effects, which affected 11% vs. less than 1% of patients, respectively.

Grade 3/4 select TRAEs occurred in less than 2% of patients, Dr. Cho noted.

An exploratory analysis further showed significant overall improvement in health-related quality of life with nivolumab through week 42 on treatment, he added.

The findings are of note, because metastatic esophageal cancer has a 5-year relative survival rate of less than 8%, and ESCC accounts for about 90% of cases worldwide, he said, adding that current second-line chemotherapy options for ESCC offer poor long-term survival and are associated with toxicity.

Nivolumab, which showed promising antitumor activity and manageable toxicity for advanced ESCC in patients who were refractory to or intolerant of standard chemotherapies in the phase 2 ATTRACTION-1 study, is the first immune checkpoint inhibitor to demonstrate a statistically significant, clinically meaningful improvement in OS vs. chemotherapy in this setting, he said.

The findings of this final analysis of ATTRACTION-3, which shows a 23% reduction in the risk of death, a 2.5-month improvement in median OS, benefit across PD-L1 subgroups, and a favorable safety profile, suggest that nivolumab represents a new standard second-line treatment option for patients with advanced ESCC, he concluded.

ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He also reported stock ownership and/or patents with TheraCanVac and Champions Oncology.

SOURCE: Cho B et al. ESMO 2019, Abstract LBA11.

BARCELONA – Nivolumab, compared with docetaxel chemotherapy, led to a fivefold improvement in 5-year overall survival among previously treated patients with non–small cell lung cancer (NSCLC), according to a pooled analysis of data from the phase 3 CheckMate 017 and 057 trials.

Sharon Worcester/MDedge News

The 5-year overall survival (OS) rates from the two randomized registrational trials, which established the programmed death-1 (PD-1) inhibitor nivolumab as the standard salvage therapy for NSCLC, were 13.4% vs. 2.6% (median, 11.1 vs. 8.1 months) with nivolumab and docetaxel, respectively, Scott Gettinger, MD, reported at the World Conference on Lung Cancer.

“These are the first randomized trials to report 5-year outcomes for a PD-1 axis inhibitor in patients with previously treated advanced non–small lung cancer,” said Dr. Gettinger, a professor at the Yale Comprehensive Cancer Center, New Haven, Conn. “This is really unprecedented; we wouldn’t expect many patients to be out 5 years in this scenario.”

Notably, the 5-year OS benefit was seen in both trials, he said, explaining that each compared nivolumab and docetaxel, but CheckMate 017 included patients with only squamous NSCLC, and CheckMate 057 included only non–squamous NSCLC patients.

The trials randomized 272 and 582 patients, respectively, and both demonstrated significantly improved 12-month OS with nivolumab – regardless of programmed death-ligand 1 (PD-L1) expression levels. Common eligibility criteria included stage IIIb/IV disease, good performance status (ECOG performance score of 0-1), and 1 prior platinum-based chemotherapy; CheckMate 057 further allowed prior tyrosine kinase inhibitor treatment for known anaplastic lymphoma kinase (ALK) translocation or epidermal growth factor receptor (EGFR) mutation, and allowed prior maintenance therapy. Doses in both trials were 3 mg/kg of nivolumab every 2 weeks or 75 mg/m² of intravenous docetaxel every 3 weeks until disease progression or unacceptable toxicity.

The pooled data also showed an improvement in progression-free survival (PFS) at 5 years (8% vs. 0%) with nivolumab vs. docetaxel groups.

“Again, we don’t see this in trials – more commonly we see zero patients without progression, and that’s what we saw with the docetaxel arm,” said Dr. Gettinger, who also is the Disease Aligned Research Team Leader, Thoracic Oncology Program, at the cancer center.

The median duration of responses with nivolumab was 19.9 months vs. 5.6 months with docetaxel, and 32.2% of nivolumab responders were still without progression at 5 years, he noted.

A common question in the clinic relates to the prognosis in patients who do well with PD-1 axis inhibitors, which prompted an additional analysis across the two trials, he said, noting that 60%, 78%, and 88% of patients who had not progressed at 2, 3, or 4 years, respectively, also had not progressed at 5 years, and 80%, 93%, and 100%, of patients in those groups were alive at 5 years. In the docetaxel arm, only 4, 1, and 0 patients had PFS at 2, 3, and 4, years, respectively, and none of those patients survived to 5 years, he said.

No new safety signals were seen with long-term follow-up, he added.

“In fact there was only one grade 3 or higher toxicity that was related to treatment in the nivolumab arm, and this was a grade 3 lipase elevation. There was one patient who discontinued nivolumab after 3 years, and this was for a grade 2 rash and eczema that had waxed and waned since starting nivolumab,” he said.

Also of note, 10% of nivolumab-treated patients who were off treatment at 5 years – for variable periods of time – had not progressed and had not received subsequent therapy.

“So we clearly see benefit in our patients long after they finish a course or stop for some reason,” he said.

CheckMate 017 and 057 were funded by Bristol-Myers Squibb. Dr. Gettinger reported advisory board and/or consulting work for, and/or research funding from Bristol-Myers Squibb, Nektar Therapeutics, Genentech/Roche, Iovance, and Takeda/Ariad.

SOURCE: Gettinger S et al. WCLC 2019, Abstract PR04.03.

BARCELONA – Nivolumab, compared with docetaxel chemotherapy, led to a fivefold improvement in 5-year overall survival among previously treated patients with non–small cell lung cancer (NSCLC), according to a pooled analysis of data from the phase 3 CheckMate 017 and 057 trials.

Sharon Worcester/MDedge News

The 5-year overall survival (OS) rates from the two randomized registrational trials, which established the programmed death-1 (PD-1) inhibitor nivolumab as the standard salvage therapy for NSCLC, were 13.4% vs. 2.6% (median, 11.1 vs. 8.1 months) with nivolumab and docetaxel, respectively, Scott Gettinger, MD, reported at the World Conference on Lung Cancer.

“These are the first randomized trials to report 5-year outcomes for a PD-1 axis inhibitor in patients with previously treated advanced non–small lung cancer,” said Dr. Gettinger, a professor at the Yale Comprehensive Cancer Center, New Haven, Conn. “This is really unprecedented; we wouldn’t expect many patients to be out 5 years in this scenario.”

Notably, the 5-year OS benefit was seen in both trials, he said, explaining that each compared nivolumab and docetaxel, but CheckMate 017 included patients with only squamous NSCLC, and CheckMate 057 included only non–squamous NSCLC patients.

The trials randomized 272 and 582 patients, respectively, and both demonstrated significantly improved 12-month OS with nivolumab – regardless of programmed death-ligand 1 (PD-L1) expression levels. Common eligibility criteria included stage IIIb/IV disease, good performance status (ECOG performance score of 0-1), and 1 prior platinum-based chemotherapy; CheckMate 057 further allowed prior tyrosine kinase inhibitor treatment for known anaplastic lymphoma kinase (ALK) translocation or epidermal growth factor receptor (EGFR) mutation, and allowed prior maintenance therapy. Doses in both trials were 3 mg/kg of nivolumab every 2 weeks or 75 mg/m² of intravenous docetaxel every 3 weeks until disease progression or unacceptable toxicity.

The pooled data also showed an improvement in progression-free survival (PFS) at 5 years (8% vs. 0%) with nivolumab vs. docetaxel groups.

“Again, we don’t see this in trials – more commonly we see zero patients without progression, and that’s what we saw with the docetaxel arm,” said Dr. Gettinger, who also is the Disease Aligned Research Team Leader, Thoracic Oncology Program, at the cancer center.

The median duration of responses with nivolumab was 19.9 months vs. 5.6 months with docetaxel, and 32.2% of nivolumab responders were still without progression at 5 years, he noted.

A common question in the clinic relates to the prognosis in patients who do well with PD-1 axis inhibitors, which prompted an additional analysis across the two trials, he said, noting that 60%, 78%, and 88% of patients who had not progressed at 2, 3, or 4 years, respectively, also had not progressed at 5 years, and 80%, 93%, and 100%, of patients in those groups were alive at 5 years. In the docetaxel arm, only 4, 1, and 0 patients had PFS at 2, 3, and 4, years, respectively, and none of those patients survived to 5 years, he said.

No new safety signals were seen with long-term follow-up, he added.

“In fact there was only one grade 3 or higher toxicity that was related to treatment in the nivolumab arm, and this was a grade 3 lipase elevation. There was one patient who discontinued nivolumab after 3 years, and this was for a grade 2 rash and eczema that had waxed and waned since starting nivolumab,” he said.

Also of note, 10% of nivolumab-treated patients who were off treatment at 5 years – for variable periods of time – had not progressed and had not received subsequent therapy.

“So we clearly see benefit in our patients long after they finish a course or stop for some reason,” he said.

CheckMate 017 and 057 were funded by Bristol-Myers Squibb. Dr. Gettinger reported advisory board and/or consulting work for, and/or research funding from Bristol-Myers Squibb, Nektar Therapeutics, Genentech/Roche, Iovance, and Takeda/Ariad.

SOURCE: Gettinger S et al. WCLC 2019, Abstract PR04.03.

BARCELONA – Nivolumab, compared with docetaxel chemotherapy, led to a fivefold improvement in 5-year overall survival among previously treated patients with non–small cell lung cancer (NSCLC), according to a pooled analysis of data from the phase 3 CheckMate 017 and 057 trials.

Sharon Worcester/MDedge News

The 5-year overall survival (OS) rates from the two randomized registrational trials, which established the programmed death-1 (PD-1) inhibitor nivolumab as the standard salvage therapy for NSCLC, were 13.4% vs. 2.6% (median, 11.1 vs. 8.1 months) with nivolumab and docetaxel, respectively, Scott Gettinger, MD, reported at the World Conference on Lung Cancer.

“These are the first randomized trials to report 5-year outcomes for a PD-1 axis inhibitor in patients with previously treated advanced non–small lung cancer,” said Dr. Gettinger, a professor at the Yale Comprehensive Cancer Center, New Haven, Conn. “This is really unprecedented; we wouldn’t expect many patients to be out 5 years in this scenario.”

Notably, the 5-year OS benefit was seen in both trials, he said, explaining that each compared nivolumab and docetaxel, but CheckMate 017 included patients with only squamous NSCLC, and CheckMate 057 included only non–squamous NSCLC patients.

The trials randomized 272 and 582 patients, respectively, and both demonstrated significantly improved 12-month OS with nivolumab – regardless of programmed death-ligand 1 (PD-L1) expression levels. Common eligibility criteria included stage IIIb/IV disease, good performance status (ECOG performance score of 0-1), and 1 prior platinum-based chemotherapy; CheckMate 057 further allowed prior tyrosine kinase inhibitor treatment for known anaplastic lymphoma kinase (ALK) translocation or epidermal growth factor receptor (EGFR) mutation, and allowed prior maintenance therapy. Doses in both trials were 3 mg/kg of nivolumab every 2 weeks or 75 mg/m² of intravenous docetaxel every 3 weeks until disease progression or unacceptable toxicity.

The pooled data also showed an improvement in progression-free survival (PFS) at 5 years (8% vs. 0%) with nivolumab vs. docetaxel groups.

“Again, we don’t see this in trials – more commonly we see zero patients without progression, and that’s what we saw with the docetaxel arm,” said Dr. Gettinger, who also is the Disease Aligned Research Team Leader, Thoracic Oncology Program, at the cancer center.

The median duration of responses with nivolumab was 19.9 months vs. 5.6 months with docetaxel, and 32.2% of nivolumab responders were still without progression at 5 years, he noted.

A common question in the clinic relates to the prognosis in patients who do well with PD-1 axis inhibitors, which prompted an additional analysis across the two trials, he said, noting that 60%, 78%, and 88% of patients who had not progressed at 2, 3, or 4 years, respectively, also had not progressed at 5 years, and 80%, 93%, and 100%, of patients in those groups were alive at 5 years. In the docetaxel arm, only 4, 1, and 0 patients had PFS at 2, 3, and 4, years, respectively, and none of those patients survived to 5 years, he said.

No new safety signals were seen with long-term follow-up, he added.

“In fact there was only one grade 3 or higher toxicity that was related to treatment in the nivolumab arm, and this was a grade 3 lipase elevation. There was one patient who discontinued nivolumab after 3 years, and this was for a grade 2 rash and eczema that had waxed and waned since starting nivolumab,” he said.

Also of note, 10% of nivolumab-treated patients who were off treatment at 5 years – for variable periods of time – had not progressed and had not received subsequent therapy.

“So we clearly see benefit in our patients long after they finish a course or stop for some reason,” he said.

CheckMate 017 and 057 were funded by Bristol-Myers Squibb. Dr. Gettinger reported advisory board and/or consulting work for, and/or research funding from Bristol-Myers Squibb, Nektar Therapeutics, Genentech/Roche, Iovance, and Takeda/Ariad.

SOURCE: Gettinger S et al. WCLC 2019, Abstract PR04.03.

BARCELONA – Immune checkpoint inhibitors demonstrate activity in small cell lung cancer (SCLC), but achieving more durable disease control and better survival requires improved understanding of biomarkers and the immune microenvironment.

That was the overarching message from experts speaking at a minisymposium on immunotherapy in SCLC at the World Conference on Lung Cancer.

“None of us are disputing that immunotherapy is clearly active in this space, but I think that we can all agree that the outcomes have been somewhat modest in an unselected population, and there is certainly room to grow,” said Dr. Stephen V. Liu, MD. “Moving forward, while we will look for any advances we can, we also feel strongly that these incremental gains are probably not enough.”
 

The state of the art

Hints that immunotherapy could be clinically efficacious in SCLC emerged in 2016 when interim findings from the CheckMate 032 study showed that the programmed cell death-1 (PD-1) inhibitor nivolumab, either alone or in combination with the anti-CTLA4 antibody ipilimumab, had efficacy in recurrent SCLC. Efficacy was seen regardless of programmed death-ligand 1 (PD-L1) status, which is “a good thing since PD-L1 is expressed much less frequently in SCLC than in non-SCLC,” Scott J. Antonia, MD, of Duke Cancer Institute, Durham, N.C., who was the first author on that study, said during the symposium.

A particularly encouraging finding was that responders included patients with platinum-refractory SCLC for whom treatments in the relapse setting are lacking, Dr Antonia said.

An exploratory analysis of CheckMate 032 also showed better responses among patients in the highest tumor mutation burden (TMB) tertile, especially in the combination therapy group, leading to the hypothesis-generating finding that TMB may predict response, he said.

Another suggestion of nivolumab’s potential came from the randomized CheckMate 331 study comparing the checkpoint inhibitor with chemotherapy in relapsed SCLC patients. As reported in 2018 at the European Society for Medical Oncology (ESMO), no overall survival (OS) benefit was apparent at 12 months (37% vs. 34%), but a separation of the curves at 36 months suggested a possible OS benefit with nivolumab, Dr. Antonia noted, adding that the difference was “obviously small” and requires “a lot more work related to that.”

Subgroup analyses in that study also were “perhaps revealing” in that patients without liver metastases derived benefit (hazard ratio, 0.75), as did those who were platinum resistant (HR, 0.71), he said.

The phase 1b KEYNOTE-028 study showed that the anti–PD-1 monoclonal antibody pembrolizumab also has activity in PD-L1–positive SCLC patients in the relapsed setting, and pooled data from that study and KEYNOTE-158, which included both PD-L1–positive and –negative patients, showed promising antitumor activity and durable responses with pembrolizumab. The pooled data, as presented at the 2019 annual meeting of the American Association for Cancer Research, showed an objective response rate (ORR) of 19%, including complete and partial response rates of 2% and 17%, respectively.

“And there appears to be, at least preliminarily, some durability to the responses,” he said, noting that 9 of 16 patients experienced at least an 18-month response. “Progression-free survival was 2 months, and overall survival was 7.7 months.”

The IMpower133 study showed significantly longer OS and progression-free survival (PFS) with the addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage SCLC (HR, 0.70). Some late merging of the survival curves was apparent, but the data haven’t matured.

“Hopefully there will be some evidence of a lifting of the tail of the survival curve with some durability of responsiveness like we see in non–small cell lung cancer,” he said.

When it comes to “making the next leap” toward improved clinical efficacy with immunotherapy for SCLC, “we need to think about three general categories of how it is that tumors evade rejection by the immune system,” he said.

One category involves SCLC patients with an insufficient numbers of T cells generated within the lymphoid compartment; in those patients, an immunotherapeutic approach directed at the tumor microenvironment won’t lead to a response. Another category includes patients who generate enough T cells within the lymphoid compartment but in whom those cells aren’t driven into the tumor parenchyma. The third involves those whose T cells may make it into the tumor parenchyma, but are inhibited in the tumor microenvironment, he explained.

Strategies to increase the number of T cells generated in the lymphoid compartment – such as vaccines, radiation, adoptive cell therapy with chimeric antigen receptors, to name a few – were a focus of research efforts more than a decade ago, but the pendulum swung more toward addressing the tumor microenvironment.

“I think that the pendulum needs to swing back to the middle, and we do need to develop combination immunotherapies paying attention to the lymphoid compartment as well as the tumor microenvironment,” Dr. Antonia said, listing these “guiding principles” for the development of effective SCLC immunotherapy:

• Combination immunotherapy is necessary.
• Mechanisms exploited by SCLC to evade immune-mediated rejection need to be identified.
• Inclusion of strategies for driving tumor-reactive T cells into the tumor microenvironment should be considered.
• PD-1 blockade should continue.
• Biomarkers should be identified for selecting patients for tumor microenvironment–targeted agents.

Clinical and molecular biomarkers

Indeed, there is much work to do with respect to biomarkers, but their use in the selection of SCLC patients for immunotherapy is “finally starting to evolve and evolve more rapidly,” according to Lauren Averett Byers, MD, of the University of Texas MD Anderson Cancer Center, Houston.

Numerous groups are identifying biomarkers for both targeted therapy and immunotherapy, Dr. Byers said, noting that “this has been a really incredible time for those of us who take care of small cell lung cancer patients.”

“It’s been many decades since we’ve had a new option for our patients ... and so I think with the landmark clinical trials ... we really do have a new option in terms of a new standard of care,” she said of immunotherapy. “But I think we also recognize that there is significant room for further improvement.”

Many patients don’t respond or don’t respond as well as hoped, and therefore an “incredible need” exists for personalized biomarker-driven therapy for SCLC and its distinct molecular subsets, she said.

Emerging and potential biomarkers and other factors to guide treatment decisions include TMB, PD-L1, clinical history/duration of response in immunotherapy-naive relapsed patients, gene expression profile–driven SCLC subgroup identification, and DNA damage response (DDR) inhibitors such as Chk1, PARP, and Wee1 inhibitors.

TMB, as described by Dr. Antonia with respect to the CheckMate 032 findings of improved outcomes in those in the highest TMB tertile, is one potentially helpful biomarker for response.

“In thinking about how we apply this, though, we have to think about what we’re deciding between,” Dr. Byers said, explaining that the responses in patients with medium or low TMB – between 0% and 10% in most studies in the relapsed SCLC setting – aren’t that different from those seen with other treatment options.

“Currently we’re not routinely ordering TMB to decide on immunotherapy because there are still patients that can be as likely to benefit from immunotherapy as they are from chemotherapy, and potentially with more durable responses,” she said. “But certainly, it is a way to potentially identify patients where immunotherapy alone may have very high rates of response.”

IMPower133 showed no difference in hazard ratios for death based on TMB detected in the blood in SCLC patients treated with first-line atezolizumab plus chemotherapy, but “this still supports using the immunotherapy/chemotherapy combination broadly, and also emphasizes the need for an improved – and probably expanded – look at other biomarkers that may help predict response,” she said.

PD-L1 appears to have a role as a biomarker in this setting as well, she said, citing the KEYNOTE-028 findings of numerically improved responses in PD-L1–positive SCLC patients treated with pembrolizumab.

“We should be looking at PD-L1 levels, but we need further information to know how we might use this,” she said.

In immunotherapy-naive patients who relapse after front-line chemotherapy, the most important biomarker is clinical history and duration of response to platinum, which helps guide second-line treatment, Dr. Byers said.

“I think there’s consensus among most of us that patients who have platinum-refractory disease and are unlikely to respond to further platinum therapy or other chemotherapy agents are patients who really should get immunotherapy,” she added, explaining that the available data suggest there is no cross-resistance and that there may actually be enhanced benefit with immunotherapy in such patients.

Using molecular data to identify SCLC subtypes based on gene expression profiles is another area of interest, she said.

In fact, new data presented at the WCLC conference by Carl Gay, MD, PhD, a former fellow in her lab and now a junior faculty member at MD Anderson, identified four specific SCLC subgroups; three were driven by activation of the known transcription factors ASCL1, NEUROD1, and POU2F3, but an additional “inflamed” group without expression of those three transcription factors was also identified.

That “triple-negative” group had significantly higher expression of human leukocyte antigen and very high T-cell activation with expression of multiple immune checkpoints representing candidate targets, she said, adding: “We hypothesize that this group may be the group in SCLC that gets relatively greater benefit from immune checkpoint blockade.”

DDR is also garnering attention.

“Since there was this signal that [patients with] DNA damage ... tend to be more sensitive to immunotherapy ... we looked at whether or not targeted agents that prevented repair of DNA damage and induced increased levels of DNA damage ... might activate the innate immune system through the STING pathway and if that could be a potential approach to enhance immunotherapy response,” she said.

The approach showed promise in cell lines in a mouse model and also in an immunocompetent SCLC mouse model.

“It was really interesting to see how these drugs might potentially enhance response to immunotherapy,” Dr. Byers said, noting that the same phenomenon has been seen with PARP inhibitors in breast and colon cancer models and in other solid tumors.

“So I think that there is something there, and fortunately we’re now at a point now where we can start looking at some of these combinations in the clinic across many different cancer types,” she said. “I think we’ll be learning a lot more about what’s happening with these patients.”

At present, however, “there is more that we don’t know about the immune landscape of small cell lung cancer than what we do know, and that’s a real opportunity where, over the next several years, we will gain a deeper understanding ... that will direct where we’re going in terms of translating that back into the clinic.”
 

The SCLC immune microenvironment

The immune microenvironment will be an integral part of that journey, according to Dr. Liu.

“We consider small cell lung cancer – a carcinogen-associated cancer – to be one that has a high somatic mutation rate, but what we’ve learned over the past few years is that tumor neoantigens are certainly necessary – but not sufficient,” he said, noting that mutational burden represents the potential for immune-mediated antitumor responses, but is not a guarantee.

“As a group, we need to develop strategies to overcome the powerful immunosuppressive microenvironment in small cell lung cancer,” he added.

Lessons learned from studying PD-L1 provided the first insight into the importance of the immune microenvironment: PD-L1 expression, as measured by tumor proportion score (TPS) holds predictive value in non–small cell lung cancer patients treated with PD-1 inhibitors, but the SCLC story is much more complex, he said.

Only 18% of SCLC patients in CheckMate 032 were PD-L1–positive, and “paradoxically, we see responses were better in the PD-L1–negative group,” he explained. The response rates for nivolumab/ipilimumab were 32% in the PD-L1–negative group and 10% in the PD-L1–positive group.

Recent findings regarding the use of the combined positive score (CPS), which unlike the TPS for determining PD-L1 status, includes PD-L1 expression on stromal cells, are also notable. In a phase 2 study of maintenance pembrolizumab in SCLC, for example, 3 of 30 patients were PD-L1 positive by TPS, and 8 of 20 were positive by CPS.

“And that did predict outcomes: We see a higher response rate [38% vs. 8%], better PFS [6.5 vs. 1.3 months], and better overall survival [13 months vs. 8 months] in pretreated small cell lung cancer,” he said.

Similarly, in KEYNOTE-158 when looking at pembrolizumab in previously treated SCLC, the overall response was modest at 18.7%, and median PFS was 2.0 months.

“Again, breaking it down by CPS, we see a different story,” Dr. Liu said. “We see better outcomes in the PD-L1–positive [group] if you’re factoring in expression in the microenvironment.” When assessed by CPS, 39% of patients were PD-L1 positive; those patients, when compared with PD-L1–negative patients, had improved 12-month PFS (28.5% vs. 8.2%, respectively), 12-month OS (53.3% vs. 30.7%), and median OS (14.9 vs. 5.9 months).

Checkpoint expression in tumor-infiltrating lymphocytes (TILs) also has been shown to vary when compared with tumor expression. SCLC tissue microarrays in a study presented at ASCO 2017 (Rivalland et al. Abstract 8569), for example, showed that tumor expression versus TIL expression of PD-L1, TIMS3, and LAG3 was 18% vs. 67%, 0% vs. 59%, and 0% vs. 45%, respectively, and the TIL expression correlated with survival, Dr. Liu said.

“So when we consider things like PD-L1 expression, looking at a narrow scope of just the tumor is not enough. We need to consider the stromal cells, the microenvironment,” he said. “And even larger than that, PD-1/PD-L1 interaction is but a fraction of powerful, dynamic, immunosuppressive factors in small cell lung cancer.

“All of these will need to be accounted for in various patients.”

These findings and others, like those from a recent study showing differentially expressed genes and pathways in the stromal cells of longer- versus shorter-term survivors, raise questions about whether the lymphoid compartment can be manipulated in SCLC to improve immune responses using the strategies discussed by Dr. Antonia and Dr. Byers, he said.

In “cold” tumor phenotypes, one hypothesis has tumor-associated macrophages (TAMs) preventing infiltration of the cytotoxic T lymphocytes, which raises the possibility that TAMs are a therapeutic target, he said.

“At this meeting and others we’ve heard of lurbinectedin as a possible active drug in SCLC,” he said, noting that preclinical data also demonstrate that lurbinectedin targets TAMs. Perhaps the agent’s future role will be that of an immune modulator rather than a cytotoxic agent, he suggested.

Regulatory T cells (Tregs) are another potential immunomodulatory target, but the problem is their redundancy and the lack of good models to identify which ones are active, he said.

“Myeloid-derived suppressor cells [MDSC] are another important part of the microenvironment and could be potential targets to restore immune responses,” he added.

But many questions remain, he said.

For example: How can we overcome an immunosuppressive tumor microenvironment? Can we inhibit arginine or adenosine? Can we restore interleukin-2? Can we target things like LAG3? Can we eliminate the Treg and MDSC population? Which strategies are appropriate? Are they the same in immunotherapy-naive vs. immunotherapy-experienced patients – is intrinsic resistance the same as acquired resistance? Are they the same in each patient, or even throughout each tumor?

And importantly, “how will we choose between these various molecules we have?” he asked.

“At this point we’ve learned that empiric strategies are unlikely to yield meaningful results. We’ve been through empiric strategies in SCLC for years, and it doesn’t work because of that heterogeneity – unless there’s a universal underlying mechanism,” he said. “I think more than likely the studies have to be enriched for the right patients; we need to apply everything we’ve learned from non–small cell lung cancer and apply the principles of targeted therapy to immunotherapy – and that requires the identification of predictive biomarkers.”

It’s a challenging task in SCLC, but “it still needs to be done,” he said, noting that the lack of “perfect models” means relying on cell lines in surgical specimens.

However, while surgical tissue banks are an important resource, there is doubt about whether the specimens are representative of patients in the clinic, he noted.

“At best need to confirm what we know; at worst we may need to rework a lot of the underlying maps,” he said.

Therefore, future SCLC studies “are simply going to need more biopsies,” and that is yet another challenge, he added, explaining that the largely central tumors and fairly aggressive, rapid course of disease in SCLC make it difficult to obtain meaningful biopsies.

“But it’s the only way to move forward,” he said. “As a community we have to stand up and obtain more biopsies and tissue for in-depth analysis.”

As much as that will advance the field, the greatest impact for SCLC will be through prevention, including by smoking cessation, he added.

“Our overarching goal for small cell lung cancer remains achieving durable disease control and long-term survival for our patients,” Dr. Liu said. “That certainly is a lofty goal, but those are probably the only goals worth having.”

Dr. Liu, Dr. Byers, and Dr. Antonia reported relationships with numerous pharmaceutical companies.




 

BARCELONA – Immune checkpoint inhibitors demonstrate activity in small cell lung cancer (SCLC), but achieving more durable disease control and better survival requires improved understanding of biomarkers and the immune microenvironment.

That was the overarching message from experts speaking at a minisymposium on immunotherapy in SCLC at the World Conference on Lung Cancer.

“None of us are disputing that immunotherapy is clearly active in this space, but I think that we can all agree that the outcomes have been somewhat modest in an unselected population, and there is certainly room to grow,” said Dr. Stephen V. Liu, MD. “Moving forward, while we will look for any advances we can, we also feel strongly that these incremental gains are probably not enough.”
 

The state of the art

Hints that immunotherapy could be clinically efficacious in SCLC emerged in 2016 when interim findings from the CheckMate 032 study showed that the programmed cell death-1 (PD-1) inhibitor nivolumab, either alone or in combination with the anti-CTLA4 antibody ipilimumab, had efficacy in recurrent SCLC. Efficacy was seen regardless of programmed death-ligand 1 (PD-L1) status, which is “a good thing since PD-L1 is expressed much less frequently in SCLC than in non-SCLC,” Scott J. Antonia, MD, of Duke Cancer Institute, Durham, N.C., who was the first author on that study, said during the symposium.

A particularly encouraging finding was that responders included patients with platinum-refractory SCLC for whom treatments in the relapse setting are lacking, Dr Antonia said.

An exploratory analysis of CheckMate 032 also showed better responses among patients in the highest tumor mutation burden (TMB) tertile, especially in the combination therapy group, leading to the hypothesis-generating finding that TMB may predict response, he said.

Another suggestion of nivolumab’s potential came from the randomized CheckMate 331 study comparing the checkpoint inhibitor with chemotherapy in relapsed SCLC patients. As reported in 2018 at the European Society for Medical Oncology (ESMO), no overall survival (OS) benefit was apparent at 12 months (37% vs. 34%), but a separation of the curves at 36 months suggested a possible OS benefit with nivolumab, Dr. Antonia noted, adding that the difference was “obviously small” and requires “a lot more work related to that.”

Subgroup analyses in that study also were “perhaps revealing” in that patients without liver metastases derived benefit (hazard ratio, 0.75), as did those who were platinum resistant (HR, 0.71), he said.

The phase 1b KEYNOTE-028 study showed that the anti–PD-1 monoclonal antibody pembrolizumab also has activity in PD-L1–positive SCLC patients in the relapsed setting, and pooled data from that study and KEYNOTE-158, which included both PD-L1–positive and –negative patients, showed promising antitumor activity and durable responses with pembrolizumab. The pooled data, as presented at the 2019 annual meeting of the American Association for Cancer Research, showed an objective response rate (ORR) of 19%, including complete and partial response rates of 2% and 17%, respectively.

“And there appears to be, at least preliminarily, some durability to the responses,” he said, noting that 9 of 16 patients experienced at least an 18-month response. “Progression-free survival was 2 months, and overall survival was 7.7 months.”

The IMpower133 study showed significantly longer OS and progression-free survival (PFS) with the addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage SCLC (HR, 0.70). Some late merging of the survival curves was apparent, but the data haven’t matured.

“Hopefully there will be some evidence of a lifting of the tail of the survival curve with some durability of responsiveness like we see in non–small cell lung cancer,” he said.

When it comes to “making the next leap” toward improved clinical efficacy with immunotherapy for SCLC, “we need to think about three general categories of how it is that tumors evade rejection by the immune system,” he said.

One category involves SCLC patients with an insufficient numbers of T cells generated within the lymphoid compartment; in those patients, an immunotherapeutic approach directed at the tumor microenvironment won’t lead to a response. Another category includes patients who generate enough T cells within the lymphoid compartment but in whom those cells aren’t driven into the tumor parenchyma. The third involves those whose T cells may make it into the tumor parenchyma, but are inhibited in the tumor microenvironment, he explained.

Strategies to increase the number of T cells generated in the lymphoid compartment – such as vaccines, radiation, adoptive cell therapy with chimeric antigen receptors, to name a few – were a focus of research efforts more than a decade ago, but the pendulum swung more toward addressing the tumor microenvironment.

“I think that the pendulum needs to swing back to the middle, and we do need to develop combination immunotherapies paying attention to the lymphoid compartment as well as the tumor microenvironment,” Dr. Antonia said, listing these “guiding principles” for the development of effective SCLC immunotherapy:

• Combination immunotherapy is necessary.
• Mechanisms exploited by SCLC to evade immune-mediated rejection need to be identified.
• Inclusion of strategies for driving tumor-reactive T cells into the tumor microenvironment should be considered.
• PD-1 blockade should continue.
• Biomarkers should be identified for selecting patients for tumor microenvironment–targeted agents.

Clinical and molecular biomarkers

Indeed, there is much work to do with respect to biomarkers, but their use in the selection of SCLC patients for immunotherapy is “finally starting to evolve and evolve more rapidly,” according to Lauren Averett Byers, MD, of the University of Texas MD Anderson Cancer Center, Houston.

Numerous groups are identifying biomarkers for both targeted therapy and immunotherapy, Dr. Byers said, noting that “this has been a really incredible time for those of us who take care of small cell lung cancer patients.”

“It’s been many decades since we’ve had a new option for our patients ... and so I think with the landmark clinical trials ... we really do have a new option in terms of a new standard of care,” she said of immunotherapy. “But I think we also recognize that there is significant room for further improvement.”

Many patients don’t respond or don’t respond as well as hoped, and therefore an “incredible need” exists for personalized biomarker-driven therapy for SCLC and its distinct molecular subsets, she said.

Emerging and potential biomarkers and other factors to guide treatment decisions include TMB, PD-L1, clinical history/duration of response in immunotherapy-naive relapsed patients, gene expression profile–driven SCLC subgroup identification, and DNA damage response (DDR) inhibitors such as Chk1, PARP, and Wee1 inhibitors.

TMB, as described by Dr. Antonia with respect to the CheckMate 032 findings of improved outcomes in those in the highest TMB tertile, is one potentially helpful biomarker for response.

“In thinking about how we apply this, though, we have to think about what we’re deciding between,” Dr. Byers said, explaining that the responses in patients with medium or low TMB – between 0% and 10% in most studies in the relapsed SCLC setting – aren’t that different from those seen with other treatment options.

“Currently we’re not routinely ordering TMB to decide on immunotherapy because there are still patients that can be as likely to benefit from immunotherapy as they are from chemotherapy, and potentially with more durable responses,” she said. “But certainly, it is a way to potentially identify patients where immunotherapy alone may have very high rates of response.”

IMPower133 showed no difference in hazard ratios for death based on TMB detected in the blood in SCLC patients treated with first-line atezolizumab plus chemotherapy, but “this still supports using the immunotherapy/chemotherapy combination broadly, and also emphasizes the need for an improved – and probably expanded – look at other biomarkers that may help predict response,” she said.

PD-L1 appears to have a role as a biomarker in this setting as well, she said, citing the KEYNOTE-028 findings of numerically improved responses in PD-L1–positive SCLC patients treated with pembrolizumab.

“We should be looking at PD-L1 levels, but we need further information to know how we might use this,” she said.

In immunotherapy-naive patients who relapse after front-line chemotherapy, the most important biomarker is clinical history and duration of response to platinum, which helps guide second-line treatment, Dr. Byers said.

“I think there’s consensus among most of us that patients who have platinum-refractory disease and are unlikely to respond to further platinum therapy or other chemotherapy agents are patients who really should get immunotherapy,” she added, explaining that the available data suggest there is no cross-resistance and that there may actually be enhanced benefit with immunotherapy in such patients.

Using molecular data to identify SCLC subtypes based on gene expression profiles is another area of interest, she said.

In fact, new data presented at the WCLC conference by Carl Gay, MD, PhD, a former fellow in her lab and now a junior faculty member at MD Anderson, identified four specific SCLC subgroups; three were driven by activation of the known transcription factors ASCL1, NEUROD1, and POU2F3, but an additional “inflamed” group without expression of those three transcription factors was also identified.

That “triple-negative” group had significantly higher expression of human leukocyte antigen and very high T-cell activation with expression of multiple immune checkpoints representing candidate targets, she said, adding: “We hypothesize that this group may be the group in SCLC that gets relatively greater benefit from immune checkpoint blockade.”

DDR is also garnering attention.

“Since there was this signal that [patients with] DNA damage ... tend to be more sensitive to immunotherapy ... we looked at whether or not targeted agents that prevented repair of DNA damage and induced increased levels of DNA damage ... might activate the innate immune system through the STING pathway and if that could be a potential approach to enhance immunotherapy response,” she said.

The approach showed promise in cell lines in a mouse model and also in an immunocompetent SCLC mouse model.

“It was really interesting to see how these drugs might potentially enhance response to immunotherapy,” Dr. Byers said, noting that the same phenomenon has been seen with PARP inhibitors in breast and colon cancer models and in other solid tumors.

“So I think that there is something there, and fortunately we’re now at a point now where we can start looking at some of these combinations in the clinic across many different cancer types,” she said. “I think we’ll be learning a lot more about what’s happening with these patients.”

At present, however, “there is more that we don’t know about the immune landscape of small cell lung cancer than what we do know, and that’s a real opportunity where, over the next several years, we will gain a deeper understanding ... that will direct where we’re going in terms of translating that back into the clinic.”
 

The SCLC immune microenvironment

The immune microenvironment will be an integral part of that journey, according to Dr. Liu.

“We consider small cell lung cancer – a carcinogen-associated cancer – to be one that has a high somatic mutation rate, but what we’ve learned over the past few years is that tumor neoantigens are certainly necessary – but not sufficient,” he said, noting that mutational burden represents the potential for immune-mediated antitumor responses, but is not a guarantee.

“As a group, we need to develop strategies to overcome the powerful immunosuppressive microenvironment in small cell lung cancer,” he added.

Lessons learned from studying PD-L1 provided the first insight into the importance of the immune microenvironment: PD-L1 expression, as measured by tumor proportion score (TPS) holds predictive value in non–small cell lung cancer patients treated with PD-1 inhibitors, but the SCLC story is much more complex, he said.

Only 18% of SCLC patients in CheckMate 032 were PD-L1–positive, and “paradoxically, we see responses were better in the PD-L1–negative group,” he explained. The response rates for nivolumab/ipilimumab were 32% in the PD-L1–negative group and 10% in the PD-L1–positive group.

Recent findings regarding the use of the combined positive score (CPS), which unlike the TPS for determining PD-L1 status, includes PD-L1 expression on stromal cells, are also notable. In a phase 2 study of maintenance pembrolizumab in SCLC, for example, 3 of 30 patients were PD-L1 positive by TPS, and 8 of 20 were positive by CPS.

“And that did predict outcomes: We see a higher response rate [38% vs. 8%], better PFS [6.5 vs. 1.3 months], and better overall survival [13 months vs. 8 months] in pretreated small cell lung cancer,” he said.

Similarly, in KEYNOTE-158 when looking at pembrolizumab in previously treated SCLC, the overall response was modest at 18.7%, and median PFS was 2.0 months.

“Again, breaking it down by CPS, we see a different story,” Dr. Liu said. “We see better outcomes in the PD-L1–positive [group] if you’re factoring in expression in the microenvironment.” When assessed by CPS, 39% of patients were PD-L1 positive; those patients, when compared with PD-L1–negative patients, had improved 12-month PFS (28.5% vs. 8.2%, respectively), 12-month OS (53.3% vs. 30.7%), and median OS (14.9 vs. 5.9 months).

Checkpoint expression in tumor-infiltrating lymphocytes (TILs) also has been shown to vary when compared with tumor expression. SCLC tissue microarrays in a study presented at ASCO 2017 (Rivalland et al. Abstract 8569), for example, showed that tumor expression versus TIL expression of PD-L1, TIMS3, and LAG3 was 18% vs. 67%, 0% vs. 59%, and 0% vs. 45%, respectively, and the TIL expression correlated with survival, Dr. Liu said.

“So when we consider things like PD-L1 expression, looking at a narrow scope of just the tumor is not enough. We need to consider the stromal cells, the microenvironment,” he said. “And even larger than that, PD-1/PD-L1 interaction is but a fraction of powerful, dynamic, immunosuppressive factors in small cell lung cancer.

“All of these will need to be accounted for in various patients.”

These findings and others, like those from a recent study showing differentially expressed genes and pathways in the stromal cells of longer- versus shorter-term survivors, raise questions about whether the lymphoid compartment can be manipulated in SCLC to improve immune responses using the strategies discussed by Dr. Antonia and Dr. Byers, he said.

In “cold” tumor phenotypes, one hypothesis has tumor-associated macrophages (TAMs) preventing infiltration of the cytotoxic T lymphocytes, which raises the possibility that TAMs are a therapeutic target, he said.

“At this meeting and others we’ve heard of lurbinectedin as a possible active drug in SCLC,” he said, noting that preclinical data also demonstrate that lurbinectedin targets TAMs. Perhaps the agent’s future role will be that of an immune modulator rather than a cytotoxic agent, he suggested.

Regulatory T cells (Tregs) are another potential immunomodulatory target, but the problem is their redundancy and the lack of good models to identify which ones are active, he said.

“Myeloid-derived suppressor cells [MDSC] are another important part of the microenvironment and could be potential targets to restore immune responses,” he added.

But many questions remain, he said.

For example: How can we overcome an immunosuppressive tumor microenvironment? Can we inhibit arginine or adenosine? Can we restore interleukin-2? Can we target things like LAG3? Can we eliminate the Treg and MDSC population? Which strategies are appropriate? Are they the same in immunotherapy-naive vs. immunotherapy-experienced patients – is intrinsic resistance the same as acquired resistance? Are they the same in each patient, or even throughout each tumor?

And importantly, “how will we choose between these various molecules we have?” he asked.

“At this point we’ve learned that empiric strategies are unlikely to yield meaningful results. We’ve been through empiric strategies in SCLC for years, and it doesn’t work because of that heterogeneity – unless there’s a universal underlying mechanism,” he said. “I think more than likely the studies have to be enriched for the right patients; we need to apply everything we’ve learned from non–small cell lung cancer and apply the principles of targeted therapy to immunotherapy – and that requires the identification of predictive biomarkers.”

It’s a challenging task in SCLC, but “it still needs to be done,” he said, noting that the lack of “perfect models” means relying on cell lines in surgical specimens.

However, while surgical tissue banks are an important resource, there is doubt about whether the specimens are representative of patients in the clinic, he noted.

“At best need to confirm what we know; at worst we may need to rework a lot of the underlying maps,” he said.

Therefore, future SCLC studies “are simply going to need more biopsies,” and that is yet another challenge, he added, explaining that the largely central tumors and fairly aggressive, rapid course of disease in SCLC make it difficult to obtain meaningful biopsies.

“But it’s the only way to move forward,” he said. “As a community we have to stand up and obtain more biopsies and tissue for in-depth analysis.”

As much as that will advance the field, the greatest impact for SCLC will be through prevention, including by smoking cessation, he added.

“Our overarching goal for small cell lung cancer remains achieving durable disease control and long-term survival for our patients,” Dr. Liu said. “That certainly is a lofty goal, but those are probably the only goals worth having.”

Dr. Liu, Dr. Byers, and Dr. Antonia reported relationships with numerous pharmaceutical companies.




 

BARCELONA – Immune checkpoint inhibitors demonstrate activity in small cell lung cancer (SCLC), but achieving more durable disease control and better survival requires improved understanding of biomarkers and the immune microenvironment.

That was the overarching message from experts speaking at a minisymposium on immunotherapy in SCLC at the World Conference on Lung Cancer.

“None of us are disputing that immunotherapy is clearly active in this space, but I think that we can all agree that the outcomes have been somewhat modest in an unselected population, and there is certainly room to grow,” said Dr. Stephen V. Liu, MD. “Moving forward, while we will look for any advances we can, we also feel strongly that these incremental gains are probably not enough.”
 

The state of the art

Hints that immunotherapy could be clinically efficacious in SCLC emerged in 2016 when interim findings from the CheckMate 032 study showed that the programmed cell death-1 (PD-1) inhibitor nivolumab, either alone or in combination with the anti-CTLA4 antibody ipilimumab, had efficacy in recurrent SCLC. Efficacy was seen regardless of programmed death-ligand 1 (PD-L1) status, which is “a good thing since PD-L1 is expressed much less frequently in SCLC than in non-SCLC,” Scott J. Antonia, MD, of Duke Cancer Institute, Durham, N.C., who was the first author on that study, said during the symposium.

A particularly encouraging finding was that responders included patients with platinum-refractory SCLC for whom treatments in the relapse setting are lacking, Dr Antonia said.

An exploratory analysis of CheckMate 032 also showed better responses among patients in the highest tumor mutation burden (TMB) tertile, especially in the combination therapy group, leading to the hypothesis-generating finding that TMB may predict response, he said.

Another suggestion of nivolumab’s potential came from the randomized CheckMate 331 study comparing the checkpoint inhibitor with chemotherapy in relapsed SCLC patients. As reported in 2018 at the European Society for Medical Oncology (ESMO), no overall survival (OS) benefit was apparent at 12 months (37% vs. 34%), but a separation of the curves at 36 months suggested a possible OS benefit with nivolumab, Dr. Antonia noted, adding that the difference was “obviously small” and requires “a lot more work related to that.”

Subgroup analyses in that study also were “perhaps revealing” in that patients without liver metastases derived benefit (hazard ratio, 0.75), as did those who were platinum resistant (HR, 0.71), he said.

The phase 1b KEYNOTE-028 study showed that the anti–PD-1 monoclonal antibody pembrolizumab also has activity in PD-L1–positive SCLC patients in the relapsed setting, and pooled data from that study and KEYNOTE-158, which included both PD-L1–positive and –negative patients, showed promising antitumor activity and durable responses with pembrolizumab. The pooled data, as presented at the 2019 annual meeting of the American Association for Cancer Research, showed an objective response rate (ORR) of 19%, including complete and partial response rates of 2% and 17%, respectively.

“And there appears to be, at least preliminarily, some durability to the responses,” he said, noting that 9 of 16 patients experienced at least an 18-month response. “Progression-free survival was 2 months, and overall survival was 7.7 months.”

The IMpower133 study showed significantly longer OS and progression-free survival (PFS) with the addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage SCLC (HR, 0.70). Some late merging of the survival curves was apparent, but the data haven’t matured.

“Hopefully there will be some evidence of a lifting of the tail of the survival curve with some durability of responsiveness like we see in non–small cell lung cancer,” he said.

When it comes to “making the next leap” toward improved clinical efficacy with immunotherapy for SCLC, “we need to think about three general categories of how it is that tumors evade rejection by the immune system,” he said.

One category involves SCLC patients with an insufficient numbers of T cells generated within the lymphoid compartment; in those patients, an immunotherapeutic approach directed at the tumor microenvironment won’t lead to a response. Another category includes patients who generate enough T cells within the lymphoid compartment but in whom those cells aren’t driven into the tumor parenchyma. The third involves those whose T cells may make it into the tumor parenchyma, but are inhibited in the tumor microenvironment, he explained.

Strategies to increase the number of T cells generated in the lymphoid compartment – such as vaccines, radiation, adoptive cell therapy with chimeric antigen receptors, to name a few – were a focus of research efforts more than a decade ago, but the pendulum swung more toward addressing the tumor microenvironment.

“I think that the pendulum needs to swing back to the middle, and we do need to develop combination immunotherapies paying attention to the lymphoid compartment as well as the tumor microenvironment,” Dr. Antonia said, listing these “guiding principles” for the development of effective SCLC immunotherapy:

• Combination immunotherapy is necessary.
• Mechanisms exploited by SCLC to evade immune-mediated rejection need to be identified.
• Inclusion of strategies for driving tumor-reactive T cells into the tumor microenvironment should be considered.
• PD-1 blockade should continue.
• Biomarkers should be identified for selecting patients for tumor microenvironment–targeted agents.

Clinical and molecular biomarkers

Indeed, there is much work to do with respect to biomarkers, but their use in the selection of SCLC patients for immunotherapy is “finally starting to evolve and evolve more rapidly,” according to Lauren Averett Byers, MD, of the University of Texas MD Anderson Cancer Center, Houston.

Numerous groups are identifying biomarkers for both targeted therapy and immunotherapy, Dr. Byers said, noting that “this has been a really incredible time for those of us who take care of small cell lung cancer patients.”

“It’s been many decades since we’ve had a new option for our patients ... and so I think with the landmark clinical trials ... we really do have a new option in terms of a new standard of care,” she said of immunotherapy. “But I think we also recognize that there is significant room for further improvement.”

Many patients don’t respond or don’t respond as well as hoped, and therefore an “incredible need” exists for personalized biomarker-driven therapy for SCLC and its distinct molecular subsets, she said.

Emerging and potential biomarkers and other factors to guide treatment decisions include TMB, PD-L1, clinical history/duration of response in immunotherapy-naive relapsed patients, gene expression profile–driven SCLC subgroup identification, and DNA damage response (DDR) inhibitors such as Chk1, PARP, and Wee1 inhibitors.

TMB, as described by Dr. Antonia with respect to the CheckMate 032 findings of improved outcomes in those in the highest TMB tertile, is one potentially helpful biomarker for response.

“In thinking about how we apply this, though, we have to think about what we’re deciding between,” Dr. Byers said, explaining that the responses in patients with medium or low TMB – between 0% and 10% in most studies in the relapsed SCLC setting – aren’t that different from those seen with other treatment options.

“Currently we’re not routinely ordering TMB to decide on immunotherapy because there are still patients that can be as likely to benefit from immunotherapy as they are from chemotherapy, and potentially with more durable responses,” she said. “But certainly, it is a way to potentially identify patients where immunotherapy alone may have very high rates of response.”

IMPower133 showed no difference in hazard ratios for death based on TMB detected in the blood in SCLC patients treated with first-line atezolizumab plus chemotherapy, but “this still supports using the immunotherapy/chemotherapy combination broadly, and also emphasizes the need for an improved – and probably expanded – look at other biomarkers that may help predict response,” she said.

PD-L1 appears to have a role as a biomarker in this setting as well, she said, citing the KEYNOTE-028 findings of numerically improved responses in PD-L1–positive SCLC patients treated with pembrolizumab.

“We should be looking at PD-L1 levels, but we need further information to know how we might use this,” she said.

In immunotherapy-naive patients who relapse after front-line chemotherapy, the most important biomarker is clinical history and duration of response to platinum, which helps guide second-line treatment, Dr. Byers said.

“I think there’s consensus among most of us that patients who have platinum-refractory disease and are unlikely to respond to further platinum therapy or other chemotherapy agents are patients who really should get immunotherapy,” she added, explaining that the available data suggest there is no cross-resistance and that there may actually be enhanced benefit with immunotherapy in such patients.

Using molecular data to identify SCLC subtypes based on gene expression profiles is another area of interest, she said.

In fact, new data presented at the WCLC conference by Carl Gay, MD, PhD, a former fellow in her lab and now a junior faculty member at MD Anderson, identified four specific SCLC subgroups; three were driven by activation of the known transcription factors ASCL1, NEUROD1, and POU2F3, but an additional “inflamed” group without expression of those three transcription factors was also identified.

That “triple-negative” group had significantly higher expression of human leukocyte antigen and very high T-cell activation with expression of multiple immune checkpoints representing candidate targets, she said, adding: “We hypothesize that this group may be the group in SCLC that gets relatively greater benefit from immune checkpoint blockade.”

DDR is also garnering attention.

“Since there was this signal that [patients with] DNA damage ... tend to be more sensitive to immunotherapy ... we looked at whether or not targeted agents that prevented repair of DNA damage and induced increased levels of DNA damage ... might activate the innate immune system through the STING pathway and if that could be a potential approach to enhance immunotherapy response,” she said.

The approach showed promise in cell lines in a mouse model and also in an immunocompetent SCLC mouse model.

“It was really interesting to see how these drugs might potentially enhance response to immunotherapy,” Dr. Byers said, noting that the same phenomenon has been seen with PARP inhibitors in breast and colon cancer models and in other solid tumors.

“So I think that there is something there, and fortunately we’re now at a point now where we can start looking at some of these combinations in the clinic across many different cancer types,” she said. “I think we’ll be learning a lot more about what’s happening with these patients.”

At present, however, “there is more that we don’t know about the immune landscape of small cell lung cancer than what we do know, and that’s a real opportunity where, over the next several years, we will gain a deeper understanding ... that will direct where we’re going in terms of translating that back into the clinic.”
 

The SCLC immune microenvironment

The immune microenvironment will be an integral part of that journey, according to Dr. Liu.

“We consider small cell lung cancer – a carcinogen-associated cancer – to be one that has a high somatic mutation rate, but what we’ve learned over the past few years is that tumor neoantigens are certainly necessary – but not sufficient,” he said, noting that mutational burden represents the potential for immune-mediated antitumor responses, but is not a guarantee.

“As a group, we need to develop strategies to overcome the powerful immunosuppressive microenvironment in small cell lung cancer,” he added.

Lessons learned from studying PD-L1 provided the first insight into the importance of the immune microenvironment: PD-L1 expression, as measured by tumor proportion score (TPS) holds predictive value in non–small cell lung cancer patients treated with PD-1 inhibitors, but the SCLC story is much more complex, he said.

Only 18% of SCLC patients in CheckMate 032 were PD-L1–positive, and “paradoxically, we see responses were better in the PD-L1–negative group,” he explained. The response rates for nivolumab/ipilimumab were 32% in the PD-L1–negative group and 10% in the PD-L1–positive group.

Recent findings regarding the use of the combined positive score (CPS), which unlike the TPS for determining PD-L1 status, includes PD-L1 expression on stromal cells, are also notable. In a phase 2 study of maintenance pembrolizumab in SCLC, for example, 3 of 30 patients were PD-L1 positive by TPS, and 8 of 20 were positive by CPS.

“And that did predict outcomes: We see a higher response rate [38% vs. 8%], better PFS [6.5 vs. 1.3 months], and better overall survival [13 months vs. 8 months] in pretreated small cell lung cancer,” he said.

Similarly, in KEYNOTE-158 when looking at pembrolizumab in previously treated SCLC, the overall response was modest at 18.7%, and median PFS was 2.0 months.

“Again, breaking it down by CPS, we see a different story,” Dr. Liu said. “We see better outcomes in the PD-L1–positive [group] if you’re factoring in expression in the microenvironment.” When assessed by CPS, 39% of patients were PD-L1 positive; those patients, when compared with PD-L1–negative patients, had improved 12-month PFS (28.5% vs. 8.2%, respectively), 12-month OS (53.3% vs. 30.7%), and median OS (14.9 vs. 5.9 months).

Checkpoint expression in tumor-infiltrating lymphocytes (TILs) also has been shown to vary when compared with tumor expression. SCLC tissue microarrays in a study presented at ASCO 2017 (Rivalland et al. Abstract 8569), for example, showed that tumor expression versus TIL expression of PD-L1, TIMS3, and LAG3 was 18% vs. 67%, 0% vs. 59%, and 0% vs. 45%, respectively, and the TIL expression correlated with survival, Dr. Liu said.

“So when we consider things like PD-L1 expression, looking at a narrow scope of just the tumor is not enough. We need to consider the stromal cells, the microenvironment,” he said. “And even larger than that, PD-1/PD-L1 interaction is but a fraction of powerful, dynamic, immunosuppressive factors in small cell lung cancer.

“All of these will need to be accounted for in various patients.”

These findings and others, like those from a recent study showing differentially expressed genes and pathways in the stromal cells of longer- versus shorter-term survivors, raise questions about whether the lymphoid compartment can be manipulated in SCLC to improve immune responses using the strategies discussed by Dr. Antonia and Dr. Byers, he said.

In “cold” tumor phenotypes, one hypothesis has tumor-associated macrophages (TAMs) preventing infiltration of the cytotoxic T lymphocytes, which raises the possibility that TAMs are a therapeutic target, he said.

“At this meeting and others we’ve heard of lurbinectedin as a possible active drug in SCLC,” he said, noting that preclinical data also demonstrate that lurbinectedin targets TAMs. Perhaps the agent’s future role will be that of an immune modulator rather than a cytotoxic agent, he suggested.

Regulatory T cells (Tregs) are another potential immunomodulatory target, but the problem is their redundancy and the lack of good models to identify which ones are active, he said.

“Myeloid-derived suppressor cells [MDSC] are another important part of the microenvironment and could be potential targets to restore immune responses,” he added.

But many questions remain, he said.

For example: How can we overcome an immunosuppressive tumor microenvironment? Can we inhibit arginine or adenosine? Can we restore interleukin-2? Can we target things like LAG3? Can we eliminate the Treg and MDSC population? Which strategies are appropriate? Are they the same in immunotherapy-naive vs. immunotherapy-experienced patients – is intrinsic resistance the same as acquired resistance? Are they the same in each patient, or even throughout each tumor?

And importantly, “how will we choose between these various molecules we have?” he asked.

“At this point we’ve learned that empiric strategies are unlikely to yield meaningful results. We’ve been through empiric strategies in SCLC for years, and it doesn’t work because of that heterogeneity – unless there’s a universal underlying mechanism,” he said. “I think more than likely the studies have to be enriched for the right patients; we need to apply everything we’ve learned from non–small cell lung cancer and apply the principles of targeted therapy to immunotherapy – and that requires the identification of predictive biomarkers.”

It’s a challenging task in SCLC, but “it still needs to be done,” he said, noting that the lack of “perfect models” means relying on cell lines in surgical specimens.

However, while surgical tissue banks are an important resource, there is doubt about whether the specimens are representative of patients in the clinic, he noted.

“At best need to confirm what we know; at worst we may need to rework a lot of the underlying maps,” he said.

Therefore, future SCLC studies “are simply going to need more biopsies,” and that is yet another challenge, he added, explaining that the largely central tumors and fairly aggressive, rapid course of disease in SCLC make it difficult to obtain meaningful biopsies.

“But it’s the only way to move forward,” he said. “As a community we have to stand up and obtain more biopsies and tissue for in-depth analysis.”

As much as that will advance the field, the greatest impact for SCLC will be through prevention, including by smoking cessation, he added.

“Our overarching goal for small cell lung cancer remains achieving durable disease control and long-term survival for our patients,” Dr. Liu said. “That certainly is a lofty goal, but those are probably the only goals worth having.”

Dr. Liu, Dr. Byers, and Dr. Antonia reported relationships with numerous pharmaceutical companies.




 

BARCELONA – Programmed death-ligand 1 (PD-L1) status in patients with advanced triple negative or HER2-positive breast cancer appears to identify distinct disease entities with varying likelihood of benefit from immune checkpoint inhibition, according to Giampaolo Bianchini, MD.

This observation, which contrasts with findings in other solid tumors and expands the road map to improved outcomes with immunotherapy for metastatic breast cancer, is based in part on new findings presented at the European Society for Medical Oncology Congress.

Among additional lessons from those findings: PD-L1 assays are not easily interchangeable, and studies with a “one size fits all” approach should be avoided, Dr. Bianchini, head of the Breast Cancer Group – Medical Oncology and clinical translational and immunotherapy research at Ospedale San Raffaele, Milan, said at the congress.
 

IMPassion130 and PD-L1 assays

In the phase 3 IMpassion130 trial assessing nanoparticle, albumin-bound (nab)-paclitaxel chemotherapy + either the anti-PD-L1 monoclonal antibody atezolizumab or placebo for the first-line treatment of metastatic triple-negative breast cancer (mTNBC), investigators used, and validated, the VENTANA PD-L1 SP142 assay to evaluate PD-L1 expression in immune cells (IC). PD-L1 positivity was defined using a 1% cutoff, meaning that PD-L1-stained IC encompassed at least 1% of the tumor area.

The trial demonstrated significantly improved progression-free survival (PFS) in the atezolizumab arm, both in the intention-to-treat (ITT) analysis (7.2 vs. 5.5 months in the placebo arm; hazard ratio, 0.80), and the PD-L1-positive subgroup (7.5 vs. 5.0 months; HR, 0.62), and the results were published in November 2018 (N Engl J Med. 2018; 379:2108-21).

“IMpassion130 is the first phase 3 trial demonstrating clinical benefit of cancer immunotherapy in patients with PD-L1-positive, metastatic triple-negative breast cancer,” Hope S. Rugo, MD, said at the congress. “The combination of atezolizumab and nab-paclitaxel is now approved in the United States and Europe for this indication.”

Subgroup analyses indicated that PFS and OS benefit with atezolizumab + nab-paclitaxel vs. nab-paclitaxel alone was greater in double-positive patients (those with SP142 positivity and either SP263 or 22C3 positivity) than in patients who were SP263-positive/SP142-negative or 22C3-positive/SP142-negative.

Dr. Rugo and her colleagues also found that the benefits with atezolizumab + nab-paclitaxel in PD-L1-positive patients were apparent regardless of the source of tissue for testing (breast or distant metastases).

They concluded that the findings of the assays are not equivalent; 22C3 and SP263 identified more patients as PD-L1 positive, and SP142-positivity was encompassed in positive tests for both.

“The clinical benefit in the 22C3-positive and the SP263-positive subgroups appear to be driven by the SP142-positive subgroup, and [SP142] identifies patients with the longest median progression-free and overall survival from the addition of atezolizumab to nab-paclitaxel,” she said “The SP142 assay with an IC cutoff of 1% or greater is the approved diagnostic test used to identify patients with metastatic triple-negative breast cancer who are most likely to benefit from the addition of the checkpoint inhibitor atezolizumab to nab-paclitaxel.”

As for whether the SP142 should be the assay of choice in other settings in which it hasn’t been validated, Dr. Rugo said it is advisable to use the assay that has been validated in a positive trial.

“That’s what we would generally do ... however, recognizing that some countries are not using SP142, and some sites may not have access, certainly you encompass that population in the patients whose tumors are positive by both other assays,” she said. “The risk is that you might overtreat, and the cost of treatment is greater.”

Excess toxicity is also a concern in that situation, she said, adding that “hopefully in the future we’ll be able to figure out ways to have even more patients benefit from the addition of immunotherapy so that won’t be an issue.”

“What this data shows is that you can feel secure that you are encompassing the patient population identified by the parent trial to benefit from the addition of atezolizumab by using either of the other two assays; you’re only missing 1% – so that’s very reasonable,” she said. “The risk is that you’re overtreating; it’s quite likely that there’s a population there that isn’t benefiting as much, but that’s a balance.”

The findings from IMPassion130 with regard to OS in the unselected population that included PD-L1-negative patients (18.7 vs. 21.0 months with vs. without atezolizumab; HR, 0.86) underscore the fact that “one size does not fit all” when it comes to immunotherapy benefit, Dr. Bianchini said.

This is further demonstrated by the post hoc analysis comparing IHC assays, he said, explaining that 63% of IMPassion130 patients who were considered PD-L1-negative based on the SP142 “actually scored as PD-L1-positive by the other tests.

“So the very clinically important question is if there is any evidence from the data that [the PD-L1-negative group] benefits in a significant way from the addition of atezolizumab,” he said. “I don’t see evidence for a clinical benefit, I see evidence to look for new biomarkers to identify a potential population who will benefit.”

The “absence of evidence is not evidence of absence,” he stressed, noting that it may be possible – with the right biomarkers – to identify PD-L1-negative patients who would benefit.

What the findings do show, however, is support for the FDA decision to approve the SP142 assay with an IC cutoff of 1% as a companion diagnostic tool, and that PD-L1 is ideally assessed using samples from both the primary and metastatic site, as the IMPassion130 data “do not inform whether PD-L1 assessment in primary and metastatic sites is equally informative,” he said.

In addition, Dr. Bianchini said the findings suggest that more information is needed about using different cutoffs for SP263 and 22C3, and he cautioned against “directly translating these finding to other disease settings or immune combinations.

“Defining new biomarkers to identify who within the PD-L1-negative group might benefit from this combination remains an unmet need,” he said. “For sure, I don’t see a space for the other tests to define this population,” he added.

KEYNOTE-119, KATE2, and future directions

Both the randomized, open-label, phase 3 KEYNOTE-119 study of the checkpoint inhibitor pembrolizumab vs. single-agent chemotherapy for mTNBC, and the phase 2 KATE2 trial of the antibody-drug conjugate trastuzumab emtansine (T-DM1) + either atezolizumab or placebo in previously treated HER2-positive breast cancer patients, failed to meet their respective primary study endpoints.

But the news isn’t all bad, Dr. Bianchini said.

For example, in KEYNOTE-119, second- or third-line pembrolizumab monotherapy did not significantly improve OS vs. chemotherapy for mTNBC, but the pembrolizumab treatment effect increased as PD-L1 enrichment increased, he explained.

Pembrolizumab showed promising antitumor activity and manageable safety in mTNBC in prior trials, and was therefore further assessed in the KEYNOTE-119 study of 601 patients with centrally confirmed TNBC, 1-2 prior systemic treatments for mTNBC, progression on the latest therapy, and a prior anthracycline or taxane, Javier Cortés, MD, PhD, of Instituto Oncológico, Madrid, reported at the congress.

Sharon Worcester/MDedge News

Pembrolizumab was given at a dose of 200 mg every 3 weeks, and chemotherapy was physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.

At a median follow-up of 9.9 months in the pembrolizumab group and 10.9 months in the chemotherapy group, OS did not differ significantly between the groups; this was true overall, in patients with a CPS of 10 or greater, and in those with a CPS of 1 or greater.

In all-comers, the HR for OS was 0.97, compared with 0.78 in patients with CPS of 10 or greater, and 0.86 in those with CPS of 1 or greater, Dr. Cortés said.

“One of the most interesting exploratory analyses was OS in those patients with CPS of 20 or higher,” he said, noting that median OS in that group was 14.9 vs.12.5 months with pembrolizumab vs. with chemotherapy (HR, 0.58).

Pembrolizumab did not improve overall PFS, but again, the rates improved with higher CPS. Duration of response, however, was longer with pembrolizumab vs. chemotherapy (12.2 vs. 8.3 months overall; 12.2 vs. 6.5 months for CPS of 1 or greater; and not reached vs. 7.1 months for CPS of 10 or greater).

Grade 3-5 AEs occurred in 35% vs. 49% of patients in the pembrolizumab vs. chemotherapy groups, with nine deaths occurring in each, Dr. Cortés said, adding that treatment-related AEs occurred in 14% (with one death) and 36% (with two deaths), respectively, and grade 3-4 immune-mediated AEs and infusion reactions occurred in 3.2% vs. 1.0% (no deaths), respectively.

In the double-blind, signal-seeking KATE2 trial, as reported in 2018 at the San Antonio Breast Cancer Symposium, no overall PFS improvement was seen with atezolizumab + T-DM1 (median of 8.2 vs. 6.8 months; HR, 0.82; 12-month PFS 38% vs. 34%), but again, a possible benefit was seen in PD-L1-positive patients (8.5 vs. 4.1 months; HR, 0.60).

KATE2 included 202 patients with advanced HER2-positive breast cancer that progressed after treatment with T-DM1 and a taxane. They were randomized 2:1 to receive intravenous T-DM1 at a dose of 3.6 mg/kg plus atezolizumab (1,200 mg) or placebo every 3 weeks until loss of clinical benefit or intolerable toxicity.

The “overall survival and final safety results” show that at a median follow-up of 19.0 months in the atezolizumab arm and 18.2 months in the placebo arm, with 52 OS events reported, median OS was not reached in either arm and 1-year survival was similar in the two groups (89.1% and 89.0%), Leisha A. Emens, MD, PhD, professor of medicine in hematology/oncology and co-leader of the Hillman Cancer Immunology and Immunotherapy Program at Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC) reported at the congress.

“And when you look at duration of response, you see an increase not just in the number ... but the quality of the response,” he said, noting that for PFS, as well, a trend toward superiority is seen “that is consistent with all the other endpoints.”

“So overall, the application of incrementally restrictive cut-off of CPS lends weight to the exploratory analysis showing better survival from pembrolizumab in tumors with CPS more than 20,” Dr. Bianchini said, noting that the “real question,” however, is whether the finding “is worth clinical implementation.

“We know a lot about the primary tumor and immune infiltration. We’ve learned ... that if you wait and look ahead at immune infiltration in the advanced stage, you find that the tumor becomes smart,” he said, explaining that tumor/immune co-evolution leads to increased immuno-editing and immune subversion and it becomes “much harder to just hit the tumor with PD-L1, because this is not the only mechanism of immune escape.”

A review of several studies shows that in similar populations defined by biomarkers, response rates in patients treated with checkpoint inhibitors decrease in the second- and third-line setting vs. the first-line setting, he said.

For example, pembrolizumab response rates in the first-line and second-line or greater setting in cohort B of the KEYNOTE-086 study were 21.4% and 5.7%, respectively, compared with 12.3% in the second- to third-line setting in KEYNOTE-119, he said.

Another consideration is whether monotherapy or combination therapy is preferable, and the data suggest that regardless of how PD-L1-positivity is defined (by CPS cutoff of 1 vs. 20, for example), most patients treated with monotherapy progress within the first 3 months, he said.

“I don’t see that this is a safe approach for the majority of these patients. So without better biomarkers, combinations should always be preferred, at least to avoid early progression,” Dr. Bianchini said, adding that the open question, then, is: “If we set the new standard in the first-line as the combination of nab-paclitaxel and atezolizumab for PD-L1-positive patients defined by the VENTANA [SP142 assay], should we continue with immune checkpoint [inhibition] using different combinations?”

“Of course, at the time the trial was designed, the results of IMpassion were not available, but it’s very important, because [the findings] add to the evidence that immunotherapy is extremely relevant for some patients,” he said.

KATE2 further demonstrated the importance of PD-L1 status, he said, adding that due to its limitations, including small sample size and short follow-up, longer follow-up is needed to better evaluate duration of response and PFS.

“Despite the trial limitations, the qualitative effect seen in all clinical endpoints – overall response rate, progression-free survival, overall survival – in PD-L1-positive tumors defined by SP142 ... provided strong and robust signals supporting the investigation of immune checkpoint inhibitors in HER-positive breast cancer,” he said, noting that “many trials are ongoing in the early setting and the advanced setting.”

In addition to the lessons of these trials with respect to the interchangeability of PD-L1 IHC assays and the value of PD-L1 assessment for identifying the likelihood of benefit from immune checkpoint inhibitors, the findings highlight the possibility that PD-L1-negative tumors require different immunotherapy approaches or alternative therapeutic strategies, and underscore that the benefit of immunotherapy in PD-L1-positive patients is still restricted to a minority.

“So new studies and approaches with immuno-oncology are needed, and we need more effective biomarkers, because we need to have precision oncology applied – we need to go in that direction,” he concluded.

Dr. Bianchini reported consultancy/honorarium and or advisory board activity associated with Roche, MSD, AstraZeneca, Pfizer, Chugai, EISAI, Lilly, Novartis, Amgen, Sanofi, Neopharm, and Genomic Health. The IMPassion30 trial was funded by F. Hoffmann-La Roche Ltd.; Dr. Rugo reported research grants, other funding, and or travel/accommodation/expenses from Pfizer, Novartis, Eli Lilly, Merck, OBI, EISAI, Plexxikon, Genentech/Roche, MacroGenics, PUMA, Mylan, Immunomedics, Daiichi Sankyo, and Celltrion. KEYNOTE-119 was funded by Merck Sharp & Dohme Corp.; Dr. Cortés and Dr. Emens reported numerous funding relationships but none with F. Hoffman-La Roche. KATE2 was funded by F. Hoffmann-La Roche.
 

Sources: IMPassion130; ESMO Abstract LBA20; KEYNOTE-119: ESMO Abstract LBA21; KATE2: ESMO Abstract 305O.

BARCELONA – Programmed death-ligand 1 (PD-L1) status in patients with advanced triple negative or HER2-positive breast cancer appears to identify distinct disease entities with varying likelihood of benefit from immune checkpoint inhibition, according to Giampaolo Bianchini, MD.

This observation, which contrasts with findings in other solid tumors and expands the road map to improved outcomes with immunotherapy for metastatic breast cancer, is based in part on new findings presented at the European Society for Medical Oncology Congress.

Among additional lessons from those findings: PD-L1 assays are not easily interchangeable, and studies with a “one size fits all” approach should be avoided, Dr. Bianchini, head of the Breast Cancer Group – Medical Oncology and clinical translational and immunotherapy research at Ospedale San Raffaele, Milan, said at the congress.
 

IMPassion130 and PD-L1 assays

In the phase 3 IMpassion130 trial assessing nanoparticle, albumin-bound (nab)-paclitaxel chemotherapy + either the anti-PD-L1 monoclonal antibody atezolizumab or placebo for the first-line treatment of metastatic triple-negative breast cancer (mTNBC), investigators used, and validated, the VENTANA PD-L1 SP142 assay to evaluate PD-L1 expression in immune cells (IC). PD-L1 positivity was defined using a 1% cutoff, meaning that PD-L1-stained IC encompassed at least 1% of the tumor area.

The trial demonstrated significantly improved progression-free survival (PFS) in the atezolizumab arm, both in the intention-to-treat (ITT) analysis (7.2 vs. 5.5 months in the placebo arm; hazard ratio, 0.80), and the PD-L1-positive subgroup (7.5 vs. 5.0 months; HR, 0.62), and the results were published in November 2018 (N Engl J Med. 2018; 379:2108-21).

“IMpassion130 is the first phase 3 trial demonstrating clinical benefit of cancer immunotherapy in patients with PD-L1-positive, metastatic triple-negative breast cancer,” Hope S. Rugo, MD, said at the congress. “The combination of atezolizumab and nab-paclitaxel is now approved in the United States and Europe for this indication.”

Subgroup analyses indicated that PFS and OS benefit with atezolizumab + nab-paclitaxel vs. nab-paclitaxel alone was greater in double-positive patients (those with SP142 positivity and either SP263 or 22C3 positivity) than in patients who were SP263-positive/SP142-negative or 22C3-positive/SP142-negative.

Dr. Rugo and her colleagues also found that the benefits with atezolizumab + nab-paclitaxel in PD-L1-positive patients were apparent regardless of the source of tissue for testing (breast or distant metastases).

They concluded that the findings of the assays are not equivalent; 22C3 and SP263 identified more patients as PD-L1 positive, and SP142-positivity was encompassed in positive tests for both.

“The clinical benefit in the 22C3-positive and the SP263-positive subgroups appear to be driven by the SP142-positive subgroup, and [SP142] identifies patients with the longest median progression-free and overall survival from the addition of atezolizumab to nab-paclitaxel,” she said “The SP142 assay with an IC cutoff of 1% or greater is the approved diagnostic test used to identify patients with metastatic triple-negative breast cancer who are most likely to benefit from the addition of the checkpoint inhibitor atezolizumab to nab-paclitaxel.”

As for whether the SP142 should be the assay of choice in other settings in which it hasn’t been validated, Dr. Rugo said it is advisable to use the assay that has been validated in a positive trial.

“That’s what we would generally do ... however, recognizing that some countries are not using SP142, and some sites may not have access, certainly you encompass that population in the patients whose tumors are positive by both other assays,” she said. “The risk is that you might overtreat, and the cost of treatment is greater.”

Excess toxicity is also a concern in that situation, she said, adding that “hopefully in the future we’ll be able to figure out ways to have even more patients benefit from the addition of immunotherapy so that won’t be an issue.”

“What this data shows is that you can feel secure that you are encompassing the patient population identified by the parent trial to benefit from the addition of atezolizumab by using either of the other two assays; you’re only missing 1% – so that’s very reasonable,” she said. “The risk is that you’re overtreating; it’s quite likely that there’s a population there that isn’t benefiting as much, but that’s a balance.”

The findings from IMPassion130 with regard to OS in the unselected population that included PD-L1-negative patients (18.7 vs. 21.0 months with vs. without atezolizumab; HR, 0.86) underscore the fact that “one size does not fit all” when it comes to immunotherapy benefit, Dr. Bianchini said.

This is further demonstrated by the post hoc analysis comparing IHC assays, he said, explaining that 63% of IMPassion130 patients who were considered PD-L1-negative based on the SP142 “actually scored as PD-L1-positive by the other tests.

“So the very clinically important question is if there is any evidence from the data that [the PD-L1-negative group] benefits in a significant way from the addition of atezolizumab,” he said. “I don’t see evidence for a clinical benefit, I see evidence to look for new biomarkers to identify a potential population who will benefit.”

The “absence of evidence is not evidence of absence,” he stressed, noting that it may be possible – with the right biomarkers – to identify PD-L1-negative patients who would benefit.

What the findings do show, however, is support for the FDA decision to approve the SP142 assay with an IC cutoff of 1% as a companion diagnostic tool, and that PD-L1 is ideally assessed using samples from both the primary and metastatic site, as the IMPassion130 data “do not inform whether PD-L1 assessment in primary and metastatic sites is equally informative,” he said.

In addition, Dr. Bianchini said the findings suggest that more information is needed about using different cutoffs for SP263 and 22C3, and he cautioned against “directly translating these finding to other disease settings or immune combinations.

“Defining new biomarkers to identify who within the PD-L1-negative group might benefit from this combination remains an unmet need,” he said. “For sure, I don’t see a space for the other tests to define this population,” he added.

KEYNOTE-119, KATE2, and future directions

Both the randomized, open-label, phase 3 KEYNOTE-119 study of the checkpoint inhibitor pembrolizumab vs. single-agent chemotherapy for mTNBC, and the phase 2 KATE2 trial of the antibody-drug conjugate trastuzumab emtansine (T-DM1) + either atezolizumab or placebo in previously treated HER2-positive breast cancer patients, failed to meet their respective primary study endpoints.

But the news isn’t all bad, Dr. Bianchini said.

For example, in KEYNOTE-119, second- or third-line pembrolizumab monotherapy did not significantly improve OS vs. chemotherapy for mTNBC, but the pembrolizumab treatment effect increased as PD-L1 enrichment increased, he explained.

Pembrolizumab showed promising antitumor activity and manageable safety in mTNBC in prior trials, and was therefore further assessed in the KEYNOTE-119 study of 601 patients with centrally confirmed TNBC, 1-2 prior systemic treatments for mTNBC, progression on the latest therapy, and a prior anthracycline or taxane, Javier Cortés, MD, PhD, of Instituto Oncológico, Madrid, reported at the congress.

Sharon Worcester/MDedge News

Pembrolizumab was given at a dose of 200 mg every 3 weeks, and chemotherapy was physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.

At a median follow-up of 9.9 months in the pembrolizumab group and 10.9 months in the chemotherapy group, OS did not differ significantly between the groups; this was true overall, in patients with a CPS of 10 or greater, and in those with a CPS of 1 or greater.

In all-comers, the HR for OS was 0.97, compared with 0.78 in patients with CPS of 10 or greater, and 0.86 in those with CPS of 1 or greater, Dr. Cortés said.

“One of the most interesting exploratory analyses was OS in those patients with CPS of 20 or higher,” he said, noting that median OS in that group was 14.9 vs.12.5 months with pembrolizumab vs. with chemotherapy (HR, 0.58).

Pembrolizumab did not improve overall PFS, but again, the rates improved with higher CPS. Duration of response, however, was longer with pembrolizumab vs. chemotherapy (12.2 vs. 8.3 months overall; 12.2 vs. 6.5 months for CPS of 1 or greater; and not reached vs. 7.1 months for CPS of 10 or greater).

Grade 3-5 AEs occurred in 35% vs. 49% of patients in the pembrolizumab vs. chemotherapy groups, with nine deaths occurring in each, Dr. Cortés said, adding that treatment-related AEs occurred in 14% (with one death) and 36% (with two deaths), respectively, and grade 3-4 immune-mediated AEs and infusion reactions occurred in 3.2% vs. 1.0% (no deaths), respectively.

In the double-blind, signal-seeking KATE2 trial, as reported in 2018 at the San Antonio Breast Cancer Symposium, no overall PFS improvement was seen with atezolizumab + T-DM1 (median of 8.2 vs. 6.8 months; HR, 0.82; 12-month PFS 38% vs. 34%), but again, a possible benefit was seen in PD-L1-positive patients (8.5 vs. 4.1 months; HR, 0.60).

KATE2 included 202 patients with advanced HER2-positive breast cancer that progressed after treatment with T-DM1 and a taxane. They were randomized 2:1 to receive intravenous T-DM1 at a dose of 3.6 mg/kg plus atezolizumab (1,200 mg) or placebo every 3 weeks until loss of clinical benefit or intolerable toxicity.

The “overall survival and final safety results” show that at a median follow-up of 19.0 months in the atezolizumab arm and 18.2 months in the placebo arm, with 52 OS events reported, median OS was not reached in either arm and 1-year survival was similar in the two groups (89.1% and 89.0%), Leisha A. Emens, MD, PhD, professor of medicine in hematology/oncology and co-leader of the Hillman Cancer Immunology and Immunotherapy Program at Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC) reported at the congress.

“And when you look at duration of response, you see an increase not just in the number ... but the quality of the response,” he said, noting that for PFS, as well, a trend toward superiority is seen “that is consistent with all the other endpoints.”

“So overall, the application of incrementally restrictive cut-off of CPS lends weight to the exploratory analysis showing better survival from pembrolizumab in tumors with CPS more than 20,” Dr. Bianchini said, noting that the “real question,” however, is whether the finding “is worth clinical implementation.

“We know a lot about the primary tumor and immune infiltration. We’ve learned ... that if you wait and look ahead at immune infiltration in the advanced stage, you find that the tumor becomes smart,” he said, explaining that tumor/immune co-evolution leads to increased immuno-editing and immune subversion and it becomes “much harder to just hit the tumor with PD-L1, because this is not the only mechanism of immune escape.”

A review of several studies shows that in similar populations defined by biomarkers, response rates in patients treated with checkpoint inhibitors decrease in the second- and third-line setting vs. the first-line setting, he said.

For example, pembrolizumab response rates in the first-line and second-line or greater setting in cohort B of the KEYNOTE-086 study were 21.4% and 5.7%, respectively, compared with 12.3% in the second- to third-line setting in KEYNOTE-119, he said.

Another consideration is whether monotherapy or combination therapy is preferable, and the data suggest that regardless of how PD-L1-positivity is defined (by CPS cutoff of 1 vs. 20, for example), most patients treated with monotherapy progress within the first 3 months, he said.

“I don’t see that this is a safe approach for the majority of these patients. So without better biomarkers, combinations should always be preferred, at least to avoid early progression,” Dr. Bianchini said, adding that the open question, then, is: “If we set the new standard in the first-line as the combination of nab-paclitaxel and atezolizumab for PD-L1-positive patients defined by the VENTANA [SP142 assay], should we continue with immune checkpoint [inhibition] using different combinations?”

“Of course, at the time the trial was designed, the results of IMpassion were not available, but it’s very important, because [the findings] add to the evidence that immunotherapy is extremely relevant for some patients,” he said.

KATE2 further demonstrated the importance of PD-L1 status, he said, adding that due to its limitations, including small sample size and short follow-up, longer follow-up is needed to better evaluate duration of response and PFS.

“Despite the trial limitations, the qualitative effect seen in all clinical endpoints – overall response rate, progression-free survival, overall survival – in PD-L1-positive tumors defined by SP142 ... provided strong and robust signals supporting the investigation of immune checkpoint inhibitors in HER-positive breast cancer,” he said, noting that “many trials are ongoing in the early setting and the advanced setting.”

In addition to the lessons of these trials with respect to the interchangeability of PD-L1 IHC assays and the value of PD-L1 assessment for identifying the likelihood of benefit from immune checkpoint inhibitors, the findings highlight the possibility that PD-L1-negative tumors require different immunotherapy approaches or alternative therapeutic strategies, and underscore that the benefit of immunotherapy in PD-L1-positive patients is still restricted to a minority.

“So new studies and approaches with immuno-oncology are needed, and we need more effective biomarkers, because we need to have precision oncology applied – we need to go in that direction,” he concluded.

Dr. Bianchini reported consultancy/honorarium and or advisory board activity associated with Roche, MSD, AstraZeneca, Pfizer, Chugai, EISAI, Lilly, Novartis, Amgen, Sanofi, Neopharm, and Genomic Health. The IMPassion30 trial was funded by F. Hoffmann-La Roche Ltd.; Dr. Rugo reported research grants, other funding, and or travel/accommodation/expenses from Pfizer, Novartis, Eli Lilly, Merck, OBI, EISAI, Plexxikon, Genentech/Roche, MacroGenics, PUMA, Mylan, Immunomedics, Daiichi Sankyo, and Celltrion. KEYNOTE-119 was funded by Merck Sharp & Dohme Corp.; Dr. Cortés and Dr. Emens reported numerous funding relationships but none with F. Hoffman-La Roche. KATE2 was funded by F. Hoffmann-La Roche.
 

Sources: IMPassion130; ESMO Abstract LBA20; KEYNOTE-119: ESMO Abstract LBA21; KATE2: ESMO Abstract 305O.

BARCELONA – Programmed death-ligand 1 (PD-L1) status in patients with advanced triple negative or HER2-positive breast cancer appears to identify distinct disease entities with varying likelihood of benefit from immune checkpoint inhibition, according to Giampaolo Bianchini, MD.

This observation, which contrasts with findings in other solid tumors and expands the road map to improved outcomes with immunotherapy for metastatic breast cancer, is based in part on new findings presented at the European Society for Medical Oncology Congress.

Among additional lessons from those findings: PD-L1 assays are not easily interchangeable, and studies with a “one size fits all” approach should be avoided, Dr. Bianchini, head of the Breast Cancer Group – Medical Oncology and clinical translational and immunotherapy research at Ospedale San Raffaele, Milan, said at the congress.
 

IMPassion130 and PD-L1 assays

In the phase 3 IMpassion130 trial assessing nanoparticle, albumin-bound (nab)-paclitaxel chemotherapy + either the anti-PD-L1 monoclonal antibody atezolizumab or placebo for the first-line treatment of metastatic triple-negative breast cancer (mTNBC), investigators used, and validated, the VENTANA PD-L1 SP142 assay to evaluate PD-L1 expression in immune cells (IC). PD-L1 positivity was defined using a 1% cutoff, meaning that PD-L1-stained IC encompassed at least 1% of the tumor area.

The trial demonstrated significantly improved progression-free survival (PFS) in the atezolizumab arm, both in the intention-to-treat (ITT) analysis (7.2 vs. 5.5 months in the placebo arm; hazard ratio, 0.80), and the PD-L1-positive subgroup (7.5 vs. 5.0 months; HR, 0.62), and the results were published in November 2018 (N Engl J Med. 2018; 379:2108-21).

“IMpassion130 is the first phase 3 trial demonstrating clinical benefit of cancer immunotherapy in patients with PD-L1-positive, metastatic triple-negative breast cancer,” Hope S. Rugo, MD, said at the congress. “The combination of atezolizumab and nab-paclitaxel is now approved in the United States and Europe for this indication.”

Subgroup analyses indicated that PFS and OS benefit with atezolizumab + nab-paclitaxel vs. nab-paclitaxel alone was greater in double-positive patients (those with SP142 positivity and either SP263 or 22C3 positivity) than in patients who were SP263-positive/SP142-negative or 22C3-positive/SP142-negative.

Dr. Rugo and her colleagues also found that the benefits with atezolizumab + nab-paclitaxel in PD-L1-positive patients were apparent regardless of the source of tissue for testing (breast or distant metastases).

They concluded that the findings of the assays are not equivalent; 22C3 and SP263 identified more patients as PD-L1 positive, and SP142-positivity was encompassed in positive tests for both.

“The clinical benefit in the 22C3-positive and the SP263-positive subgroups appear to be driven by the SP142-positive subgroup, and [SP142] identifies patients with the longest median progression-free and overall survival from the addition of atezolizumab to nab-paclitaxel,” she said “The SP142 assay with an IC cutoff of 1% or greater is the approved diagnostic test used to identify patients with metastatic triple-negative breast cancer who are most likely to benefit from the addition of the checkpoint inhibitor atezolizumab to nab-paclitaxel.”

As for whether the SP142 should be the assay of choice in other settings in which it hasn’t been validated, Dr. Rugo said it is advisable to use the assay that has been validated in a positive trial.

“That’s what we would generally do ... however, recognizing that some countries are not using SP142, and some sites may not have access, certainly you encompass that population in the patients whose tumors are positive by both other assays,” she said. “The risk is that you might overtreat, and the cost of treatment is greater.”

Excess toxicity is also a concern in that situation, she said, adding that “hopefully in the future we’ll be able to figure out ways to have even more patients benefit from the addition of immunotherapy so that won’t be an issue.”

“What this data shows is that you can feel secure that you are encompassing the patient population identified by the parent trial to benefit from the addition of atezolizumab by using either of the other two assays; you’re only missing 1% – so that’s very reasonable,” she said. “The risk is that you’re overtreating; it’s quite likely that there’s a population there that isn’t benefiting as much, but that’s a balance.”

The findings from IMPassion130 with regard to OS in the unselected population that included PD-L1-negative patients (18.7 vs. 21.0 months with vs. without atezolizumab; HR, 0.86) underscore the fact that “one size does not fit all” when it comes to immunotherapy benefit, Dr. Bianchini said.

This is further demonstrated by the post hoc analysis comparing IHC assays, he said, explaining that 63% of IMPassion130 patients who were considered PD-L1-negative based on the SP142 “actually scored as PD-L1-positive by the other tests.

“So the very clinically important question is if there is any evidence from the data that [the PD-L1-negative group] benefits in a significant way from the addition of atezolizumab,” he said. “I don’t see evidence for a clinical benefit, I see evidence to look for new biomarkers to identify a potential population who will benefit.”

The “absence of evidence is not evidence of absence,” he stressed, noting that it may be possible – with the right biomarkers – to identify PD-L1-negative patients who would benefit.

What the findings do show, however, is support for the FDA decision to approve the SP142 assay with an IC cutoff of 1% as a companion diagnostic tool, and that PD-L1 is ideally assessed using samples from both the primary and metastatic site, as the IMPassion130 data “do not inform whether PD-L1 assessment in primary and metastatic sites is equally informative,” he said.

In addition, Dr. Bianchini said the findings suggest that more information is needed about using different cutoffs for SP263 and 22C3, and he cautioned against “directly translating these finding to other disease settings or immune combinations.

“Defining new biomarkers to identify who within the PD-L1-negative group might benefit from this combination remains an unmet need,” he said. “For sure, I don’t see a space for the other tests to define this population,” he added.

KEYNOTE-119, KATE2, and future directions

Both the randomized, open-label, phase 3 KEYNOTE-119 study of the checkpoint inhibitor pembrolizumab vs. single-agent chemotherapy for mTNBC, and the phase 2 KATE2 trial of the antibody-drug conjugate trastuzumab emtansine (T-DM1) + either atezolizumab or placebo in previously treated HER2-positive breast cancer patients, failed to meet their respective primary study endpoints.

But the news isn’t all bad, Dr. Bianchini said.

For example, in KEYNOTE-119, second- or third-line pembrolizumab monotherapy did not significantly improve OS vs. chemotherapy for mTNBC, but the pembrolizumab treatment effect increased as PD-L1 enrichment increased, he explained.

Pembrolizumab showed promising antitumor activity and manageable safety in mTNBC in prior trials, and was therefore further assessed in the KEYNOTE-119 study of 601 patients with centrally confirmed TNBC, 1-2 prior systemic treatments for mTNBC, progression on the latest therapy, and a prior anthracycline or taxane, Javier Cortés, MD, PhD, of Instituto Oncológico, Madrid, reported at the congress.

Sharon Worcester/MDedge News

Pembrolizumab was given at a dose of 200 mg every 3 weeks, and chemotherapy was physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.

At a median follow-up of 9.9 months in the pembrolizumab group and 10.9 months in the chemotherapy group, OS did not differ significantly between the groups; this was true overall, in patients with a CPS of 10 or greater, and in those with a CPS of 1 or greater.

In all-comers, the HR for OS was 0.97, compared with 0.78 in patients with CPS of 10 or greater, and 0.86 in those with CPS of 1 or greater, Dr. Cortés said.

“One of the most interesting exploratory analyses was OS in those patients with CPS of 20 or higher,” he said, noting that median OS in that group was 14.9 vs.12.5 months with pembrolizumab vs. with chemotherapy (HR, 0.58).

Pembrolizumab did not improve overall PFS, but again, the rates improved with higher CPS. Duration of response, however, was longer with pembrolizumab vs. chemotherapy (12.2 vs. 8.3 months overall; 12.2 vs. 6.5 months for CPS of 1 or greater; and not reached vs. 7.1 months for CPS of 10 or greater).

Grade 3-5 AEs occurred in 35% vs. 49% of patients in the pembrolizumab vs. chemotherapy groups, with nine deaths occurring in each, Dr. Cortés said, adding that treatment-related AEs occurred in 14% (with one death) and 36% (with two deaths), respectively, and grade 3-4 immune-mediated AEs and infusion reactions occurred in 3.2% vs. 1.0% (no deaths), respectively.

In the double-blind, signal-seeking KATE2 trial, as reported in 2018 at the San Antonio Breast Cancer Symposium, no overall PFS improvement was seen with atezolizumab + T-DM1 (median of 8.2 vs. 6.8 months; HR, 0.82; 12-month PFS 38% vs. 34%), but again, a possible benefit was seen in PD-L1-positive patients (8.5 vs. 4.1 months; HR, 0.60).

KATE2 included 202 patients with advanced HER2-positive breast cancer that progressed after treatment with T-DM1 and a taxane. They were randomized 2:1 to receive intravenous T-DM1 at a dose of 3.6 mg/kg plus atezolizumab (1,200 mg) or placebo every 3 weeks until loss of clinical benefit or intolerable toxicity.

The “overall survival and final safety results” show that at a median follow-up of 19.0 months in the atezolizumab arm and 18.2 months in the placebo arm, with 52 OS events reported, median OS was not reached in either arm and 1-year survival was similar in the two groups (89.1% and 89.0%), Leisha A. Emens, MD, PhD, professor of medicine in hematology/oncology and co-leader of the Hillman Cancer Immunology and Immunotherapy Program at Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC) reported at the congress.

“And when you look at duration of response, you see an increase not just in the number ... but the quality of the response,” he said, noting that for PFS, as well, a trend toward superiority is seen “that is consistent with all the other endpoints.”

“So overall, the application of incrementally restrictive cut-off of CPS lends weight to the exploratory analysis showing better survival from pembrolizumab in tumors with CPS more than 20,” Dr. Bianchini said, noting that the “real question,” however, is whether the finding “is worth clinical implementation.

“We know a lot about the primary tumor and immune infiltration. We’ve learned ... that if you wait and look ahead at immune infiltration in the advanced stage, you find that the tumor becomes smart,” he said, explaining that tumor/immune co-evolution leads to increased immuno-editing and immune subversion and it becomes “much harder to just hit the tumor with PD-L1, because this is not the only mechanism of immune escape.”

A review of several studies shows that in similar populations defined by biomarkers, response rates in patients treated with checkpoint inhibitors decrease in the second- and third-line setting vs. the first-line setting, he said.

For example, pembrolizumab response rates in the first-line and second-line or greater setting in cohort B of the KEYNOTE-086 study were 21.4% and 5.7%, respectively, compared with 12.3% in the second- to third-line setting in KEYNOTE-119, he said.

Another consideration is whether monotherapy or combination therapy is preferable, and the data suggest that regardless of how PD-L1-positivity is defined (by CPS cutoff of 1 vs. 20, for example), most patients treated with monotherapy progress within the first 3 months, he said.

“I don’t see that this is a safe approach for the majority of these patients. So without better biomarkers, combinations should always be preferred, at least to avoid early progression,” Dr. Bianchini said, adding that the open question, then, is: “If we set the new standard in the first-line as the combination of nab-paclitaxel and atezolizumab for PD-L1-positive patients defined by the VENTANA [SP142 assay], should we continue with immune checkpoint [inhibition] using different combinations?”

“Of course, at the time the trial was designed, the results of IMpassion were not available, but it’s very important, because [the findings] add to the evidence that immunotherapy is extremely relevant for some patients,” he said.

KATE2 further demonstrated the importance of PD-L1 status, he said, adding that due to its limitations, including small sample size and short follow-up, longer follow-up is needed to better evaluate duration of response and PFS.

“Despite the trial limitations, the qualitative effect seen in all clinical endpoints – overall response rate, progression-free survival, overall survival – in PD-L1-positive tumors defined by SP142 ... provided strong and robust signals supporting the investigation of immune checkpoint inhibitors in HER-positive breast cancer,” he said, noting that “many trials are ongoing in the early setting and the advanced setting.”

In addition to the lessons of these trials with respect to the interchangeability of PD-L1 IHC assays and the value of PD-L1 assessment for identifying the likelihood of benefit from immune checkpoint inhibitors, the findings highlight the possibility that PD-L1-negative tumors require different immunotherapy approaches or alternative therapeutic strategies, and underscore that the benefit of immunotherapy in PD-L1-positive patients is still restricted to a minority.

“So new studies and approaches with immuno-oncology are needed, and we need more effective biomarkers, because we need to have precision oncology applied – we need to go in that direction,” he concluded.

Dr. Bianchini reported consultancy/honorarium and or advisory board activity associated with Roche, MSD, AstraZeneca, Pfizer, Chugai, EISAI, Lilly, Novartis, Amgen, Sanofi, Neopharm, and Genomic Health. The IMPassion30 trial was funded by F. Hoffmann-La Roche Ltd.; Dr. Rugo reported research grants, other funding, and or travel/accommodation/expenses from Pfizer, Novartis, Eli Lilly, Merck, OBI, EISAI, Plexxikon, Genentech/Roche, MacroGenics, PUMA, Mylan, Immunomedics, Daiichi Sankyo, and Celltrion. KEYNOTE-119 was funded by Merck Sharp & Dohme Corp.; Dr. Cortés and Dr. Emens reported numerous funding relationships but none with F. Hoffman-La Roche. KATE2 was funded by F. Hoffmann-La Roche.
 

Sources: IMPassion130; ESMO Abstract LBA20; KEYNOTE-119: ESMO Abstract LBA21; KATE2: ESMO Abstract 305O.

The programmed death-ligand 1 (PD-L1) inhibitor pembrolizumab showed manageable safety and promising clinical activity in patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL), according to results from two early-phase studies.

The phase 1b KEYNOTE-013 study included an expansion cohort that evaluated pembrolizumab monotherapy in patients with relapsed/refractory PMBCL. Based on preliminary findings from KEYNOTE-013, the phase 2 KEYNOTE-170 study was initiated to validate these results.

Philippe Armand, MD, PhD, of Dana-Farber Cancer Institute, Boston, and colleagues reported results from 53 patients in KEYNOTE-170 and extended follow-up of 21 patients in KEYNOTE-013. Data from these two trials formed the basis of an accelerated approval by the Food and Drug Administration of pembrolizumab in patients with relapsed/refractory PMBCL in June 2018.

“Frequent amplification and translocation events occur at 9p24.1 in PMBCL, resulting in tumor expression of the programmed cell death-1 (PD-1) ligands PD-L1 and PD-L2. This suggests susceptibility of PMBCL to PD-1 blockade,” the researchers wrote in the Journal of Clinical Oncology.

KEYNOTE-170 included patients with relapsed or refractory disease who were transplant-ineligible and had failed a minimum of two prior lines of treatment. KEYNOTE-013 enrolled patients who relapsed following autologous stem cell transplantation or were ineligible for transplant.

Among patients in KEYNOTE-013 and KEYNOTE-170, the objective response rates were 48% and 45%, respectively. In total, 33% of patients in KEYNOTE-013 and 13% of patients in KEYNOTE-170 achieved a complete response. Among these patients, no disease progression was observed.

The median progression-free survival in KEYNOTE-170 was 5.5 months and 10.4 months in KEYNOTE-013. In KEYNOTE-170, median overall survival was not reached, while in KEYNOTE-013, the median overall survival was 31.4 months.

After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either trial, the researchers reported.

With respect to safety, pembrolizumab-related grade 3 or 4 adverse events were observed in 23% and 24% of patients in KEYNOTE-170 and KEYNOTE-013, respectively. The most common adverse event in both trials was neutropenia. No deaths related to pembrolizumab were observed.

Response rates were lower in KEYNOTE-170, compared with KEYNOTE-013, but the researchers noted that longer follow-up could change these results.

“Although the small numbers allow only a tentative hypothesis, they raise the question of whether PD-1 blockade in this setting might resensitize tumors to chemotherapy, as recently suggested. If this can be further validated, it could have profound implication for the management of patients with [relapsed/refractory] PMBCL,” the researchers wrote.

The study was supported by Merck Sharp & Dohme, the Harold and Virginia Lash Foundation, the Leukemia and Lymphoma Society, and the Center for Immuno-Oncology of the Dana-Farber Cancer Institute. The authors reported financial affiliations with Merck Sharp & Dohme and several other companies.

SOURCE: Armand P et al. J Clin Oncol. 2019 Sep 10. doi: 10.1200/JCO.19.01389.

The programmed death-ligand 1 (PD-L1) inhibitor pembrolizumab showed manageable safety and promising clinical activity in patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL), according to results from two early-phase studies.

The phase 1b KEYNOTE-013 study included an expansion cohort that evaluated pembrolizumab monotherapy in patients with relapsed/refractory PMBCL. Based on preliminary findings from KEYNOTE-013, the phase 2 KEYNOTE-170 study was initiated to validate these results.

Philippe Armand, MD, PhD, of Dana-Farber Cancer Institute, Boston, and colleagues reported results from 53 patients in KEYNOTE-170 and extended follow-up of 21 patients in KEYNOTE-013. Data from these two trials formed the basis of an accelerated approval by the Food and Drug Administration of pembrolizumab in patients with relapsed/refractory PMBCL in June 2018.

“Frequent amplification and translocation events occur at 9p24.1 in PMBCL, resulting in tumor expression of the programmed cell death-1 (PD-1) ligands PD-L1 and PD-L2. This suggests susceptibility of PMBCL to PD-1 blockade,” the researchers wrote in the Journal of Clinical Oncology.

KEYNOTE-170 included patients with relapsed or refractory disease who were transplant-ineligible and had failed a minimum of two prior lines of treatment. KEYNOTE-013 enrolled patients who relapsed following autologous stem cell transplantation or were ineligible for transplant.

Among patients in KEYNOTE-013 and KEYNOTE-170, the objective response rates were 48% and 45%, respectively. In total, 33% of patients in KEYNOTE-013 and 13% of patients in KEYNOTE-170 achieved a complete response. Among these patients, no disease progression was observed.

The median progression-free survival in KEYNOTE-170 was 5.5 months and 10.4 months in KEYNOTE-013. In KEYNOTE-170, median overall survival was not reached, while in KEYNOTE-013, the median overall survival was 31.4 months.

After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either trial, the researchers reported.

With respect to safety, pembrolizumab-related grade 3 or 4 adverse events were observed in 23% and 24% of patients in KEYNOTE-170 and KEYNOTE-013, respectively. The most common adverse event in both trials was neutropenia. No deaths related to pembrolizumab were observed.

Response rates were lower in KEYNOTE-170, compared with KEYNOTE-013, but the researchers noted that longer follow-up could change these results.

“Although the small numbers allow only a tentative hypothesis, they raise the question of whether PD-1 blockade in this setting might resensitize tumors to chemotherapy, as recently suggested. If this can be further validated, it could have profound implication for the management of patients with [relapsed/refractory] PMBCL,” the researchers wrote.

The study was supported by Merck Sharp & Dohme, the Harold and Virginia Lash Foundation, the Leukemia and Lymphoma Society, and the Center for Immuno-Oncology of the Dana-Farber Cancer Institute. The authors reported financial affiliations with Merck Sharp & Dohme and several other companies.

SOURCE: Armand P et al. J Clin Oncol. 2019 Sep 10. doi: 10.1200/JCO.19.01389.

The programmed death-ligand 1 (PD-L1) inhibitor pembrolizumab showed manageable safety and promising clinical activity in patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL), according to results from two early-phase studies.

The phase 1b KEYNOTE-013 study included an expansion cohort that evaluated pembrolizumab monotherapy in patients with relapsed/refractory PMBCL. Based on preliminary findings from KEYNOTE-013, the phase 2 KEYNOTE-170 study was initiated to validate these results.

Philippe Armand, MD, PhD, of Dana-Farber Cancer Institute, Boston, and colleagues reported results from 53 patients in KEYNOTE-170 and extended follow-up of 21 patients in KEYNOTE-013. Data from these two trials formed the basis of an accelerated approval by the Food and Drug Administration of pembrolizumab in patients with relapsed/refractory PMBCL in June 2018.

“Frequent amplification and translocation events occur at 9p24.1 in PMBCL, resulting in tumor expression of the programmed cell death-1 (PD-1) ligands PD-L1 and PD-L2. This suggests susceptibility of PMBCL to PD-1 blockade,” the researchers wrote in the Journal of Clinical Oncology.

KEYNOTE-170 included patients with relapsed or refractory disease who were transplant-ineligible and had failed a minimum of two prior lines of treatment. KEYNOTE-013 enrolled patients who relapsed following autologous stem cell transplantation or were ineligible for transplant.

Among patients in KEYNOTE-013 and KEYNOTE-170, the objective response rates were 48% and 45%, respectively. In total, 33% of patients in KEYNOTE-013 and 13% of patients in KEYNOTE-170 achieved a complete response. Among these patients, no disease progression was observed.

The median progression-free survival in KEYNOTE-170 was 5.5 months and 10.4 months in KEYNOTE-013. In KEYNOTE-170, median overall survival was not reached, while in KEYNOTE-013, the median overall survival was 31.4 months.

After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either trial, the researchers reported.

With respect to safety, pembrolizumab-related grade 3 or 4 adverse events were observed in 23% and 24% of patients in KEYNOTE-170 and KEYNOTE-013, respectively. The most common adverse event in both trials was neutropenia. No deaths related to pembrolizumab were observed.

Response rates were lower in KEYNOTE-170, compared with KEYNOTE-013, but the researchers noted that longer follow-up could change these results.

“Although the small numbers allow only a tentative hypothesis, they raise the question of whether PD-1 blockade in this setting might resensitize tumors to chemotherapy, as recently suggested. If this can be further validated, it could have profound implication for the management of patients with [relapsed/refractory] PMBCL,” the researchers wrote.

The study was supported by Merck Sharp & Dohme, the Harold and Virginia Lash Foundation, the Leukemia and Lymphoma Society, and the Center for Immuno-Oncology of the Dana-Farber Cancer Institute. The authors reported financial affiliations with Merck Sharp & Dohme and several other companies.

SOURCE: Armand P et al. J Clin Oncol. 2019 Sep 10. doi: 10.1200/JCO.19.01389.

Some patients with advanced renal cell carcinoma (RCC) treated with immune checkpoint inhibitors (ICIs) can safely undergo nephrectomy and experience favorable surgical outcomes and pathologic responses, a cohort study suggests.

“The introduction of several novel classes of systemic therapies, including targeted therapies and most recently ICI, has revolutionized the management of metastatic RCC over the last decade,” noted the investigators, who were led by Nirmish Singla, MD, from the department of urology at the University of Texas Southwestern Medical Center, Dallas. “With these new therapies, the role of nephrectomy in the treatment paradigm for advanced RCC has continued to evolve.”

The investigators undertook a single-center retrospective cohort study, assessing outcomes of 11 nephrectomies (10 radical, 1 partial) in 10 patients with advanced RCC who had received ICIs. Half had received nivolumab (Opdivo) alone, while the other half had received nivolumab in combination with ipilimumab (Yervoy); in six patients, these therapies were given first line.

Study results reported in Urologic Oncology showed that, at the time of nephrectomy, the patients had a median age of 64 years, with a range from 41 years to 83 years. Surgery was performed laparoscopically in five cases, and four patients had a concomitant thrombectomy.

The median operative time was 180 minutes, and the median estimated blood loss was 100 mL. None of the patients experienced major intraoperative complications. Four experienced postoperative complications; in three, they were addressed with interventional radiology procedures. The median length of stay was 4 days.

Pathology findings showed that one patient achieved a response to immunotherapy in the primary tumor (pT0), and three of four patients who underwent resection of hepatic, pulmonary, or adrenal metastases had no detectable cancer (pM0). All surgical margins were negative.

During a median postoperative follow-up of 180 days, one patient died of progressive disease more than 3 months after surgery, and another died of pulmonary embolism complicated by sepsis. Six patients did not have any complications or readmissions.

“In our experience, nephrectomy following ICI for RCC is both safe and technically feasible. Surgical and postoperative outcomes are encouraging, and pathologic response to ICI is strikingly favorable in both the primary tumor and metastatic sites,” Dr. Singla and coinvestigators wrote. “Biopsies of lesions responding radiographically to ICIs should be considered prior to surgical excision.”

“As multimodal management in the immunotherapy era continues to evolve, the utility and timing of nephrectomy combined with ICI in selected patients warrants further study,” they conclude.

Dr. Singla disclosed that he had no relevant conflicts of interest. The study did not receive any specific funding.

SOURCE: Singla N et al. Urol Oncol. 2019 Sep 12. doi: 10.1016/j.urolonc.2019.08.012.

Some patients with advanced renal cell carcinoma (RCC) treated with immune checkpoint inhibitors (ICIs) can safely undergo nephrectomy and experience favorable surgical outcomes and pathologic responses, a cohort study suggests.

“The introduction of several novel classes of systemic therapies, including targeted therapies and most recently ICI, has revolutionized the management of metastatic RCC over the last decade,” noted the investigators, who were led by Nirmish Singla, MD, from the department of urology at the University of Texas Southwestern Medical Center, Dallas. “With these new therapies, the role of nephrectomy in the treatment paradigm for advanced RCC has continued to evolve.”

The investigators undertook a single-center retrospective cohort study, assessing outcomes of 11 nephrectomies (10 radical, 1 partial) in 10 patients with advanced RCC who had received ICIs. Half had received nivolumab (Opdivo) alone, while the other half had received nivolumab in combination with ipilimumab (Yervoy); in six patients, these therapies were given first line.

Study results reported in Urologic Oncology showed that, at the time of nephrectomy, the patients had a median age of 64 years, with a range from 41 years to 83 years. Surgery was performed laparoscopically in five cases, and four patients had a concomitant thrombectomy.

The median operative time was 180 minutes, and the median estimated blood loss was 100 mL. None of the patients experienced major intraoperative complications. Four experienced postoperative complications; in three, they were addressed with interventional radiology procedures. The median length of stay was 4 days.

Pathology findings showed that one patient achieved a response to immunotherapy in the primary tumor (pT0), and three of four patients who underwent resection of hepatic, pulmonary, or adrenal metastases had no detectable cancer (pM0). All surgical margins were negative.

During a median postoperative follow-up of 180 days, one patient died of progressive disease more than 3 months after surgery, and another died of pulmonary embolism complicated by sepsis. Six patients did not have any complications or readmissions.

“In our experience, nephrectomy following ICI for RCC is both safe and technically feasible. Surgical and postoperative outcomes are encouraging, and pathologic response to ICI is strikingly favorable in both the primary tumor and metastatic sites,” Dr. Singla and coinvestigators wrote. “Biopsies of lesions responding radiographically to ICIs should be considered prior to surgical excision.”

“As multimodal management in the immunotherapy era continues to evolve, the utility and timing of nephrectomy combined with ICI in selected patients warrants further study,” they conclude.

Dr. Singla disclosed that he had no relevant conflicts of interest. The study did not receive any specific funding.

SOURCE: Singla N et al. Urol Oncol. 2019 Sep 12. doi: 10.1016/j.urolonc.2019.08.012.

Some patients with advanced renal cell carcinoma (RCC) treated with immune checkpoint inhibitors (ICIs) can safely undergo nephrectomy and experience favorable surgical outcomes and pathologic responses, a cohort study suggests.

“The introduction of several novel classes of systemic therapies, including targeted therapies and most recently ICI, has revolutionized the management of metastatic RCC over the last decade,” noted the investigators, who were led by Nirmish Singla, MD, from the department of urology at the University of Texas Southwestern Medical Center, Dallas. “With these new therapies, the role of nephrectomy in the treatment paradigm for advanced RCC has continued to evolve.”

The investigators undertook a single-center retrospective cohort study, assessing outcomes of 11 nephrectomies (10 radical, 1 partial) in 10 patients with advanced RCC who had received ICIs. Half had received nivolumab (Opdivo) alone, while the other half had received nivolumab in combination with ipilimumab (Yervoy); in six patients, these therapies were given first line.

Study results reported in Urologic Oncology showed that, at the time of nephrectomy, the patients had a median age of 64 years, with a range from 41 years to 83 years. Surgery was performed laparoscopically in five cases, and four patients had a concomitant thrombectomy.

The median operative time was 180 minutes, and the median estimated blood loss was 100 mL. None of the patients experienced major intraoperative complications. Four experienced postoperative complications; in three, they were addressed with interventional radiology procedures. The median length of stay was 4 days.

Pathology findings showed that one patient achieved a response to immunotherapy in the primary tumor (pT0), and three of four patients who underwent resection of hepatic, pulmonary, or adrenal metastases had no detectable cancer (pM0). All surgical margins were negative.

During a median postoperative follow-up of 180 days, one patient died of progressive disease more than 3 months after surgery, and another died of pulmonary embolism complicated by sepsis. Six patients did not have any complications or readmissions.

“In our experience, nephrectomy following ICI for RCC is both safe and technically feasible. Surgical and postoperative outcomes are encouraging, and pathologic response to ICI is strikingly favorable in both the primary tumor and metastatic sites,” Dr. Singla and coinvestigators wrote. “Biopsies of lesions responding radiographically to ICIs should be considered prior to surgical excision.”

“As multimodal management in the immunotherapy era continues to evolve, the utility and timing of nephrectomy combined with ICI in selected patients warrants further study,” they conclude.

Dr. Singla disclosed that he had no relevant conflicts of interest. The study did not receive any specific funding.

SOURCE: Singla N et al. Urol Oncol. 2019 Sep 12. doi: 10.1016/j.urolonc.2019.08.012.

BARCELONA – Checkpoint inhibition with nivolumab led to a clinically meaningful, but not statistically significant, improvement in overall survival, compared with sorafenib for the first-line treatment of advanced hepatocellular carcinoma (HCC) in the phase 3 CheckMate 459 study.

Median overall survival (OS), the primary study endpoint, was 16.4 months in 371 patients randomized to receive the programmed death-1 (PD-1) inhibitor nivolumab, and 14.7 months in 372 patients who received the tyrosine kinase inhibitor sorafenib – the current standard for advanced HCC therapy (hazard ratio, 0.85; P = .0752), Thomas Yau, MD, reported at the European Society for Medical Oncology Congress.

The median OS seen with nivolumab is the longest ever reported in a first-line phase 3 HCC trial, but the difference between the arms did not meet the predefined threshold for statistical significance (HR, 0.84 and P = .419). However, clinical benefit was observed across predefined subgroups of patients, including those with hepatitis infection and those with vascular invasion and/or extrahepatic spread, said Dr. Yau of the University of Hong Kong.

The overall response rates (ORR) were 15% and 7% in the nivolumab and sorafenib arms, with 14 and 5 patients in each group experiencing a complete response (CR), respectively, he said.

At 12 and 24 months, the OS rates in the groups were 59.7% vs. 55.1%, and 36.5% vs. 33.1%, respectively. Median progression-free survival (PFS) was similar in the groups, at 3.7 and 3.8 months, respectively, and analysis by baseline tumor programmed death-ligand 1 (PD-L1) expression showed that ORR was 28% vs. 9% with PD-L1 expression of 1% or greater in the groups, respectively, and 12% vs. 7% among those with PD-L1 expression less than 1%.

Additionally, nivolumab had a more tolerable safety profile; grade 3/4 treatment-related adverse events were reported in 22% and 49% of patients in the groups, respectively, and led to discontinuation in 4% and 8%, respectively. No new safety signals were observed, Dr. Yau said.

Participants in the multicenter study were systemic therapy–naive adults with advanced disease. They were randomized 1:1 to receive intravenous nivolumab at a dose of 240 mg every 2 weeks or oral sorafenib at a dose of 400 mg twice daily, and were followed for at least 22.8 months.

“These results are important in the treatment of hepatocellular carcinoma, as there have been no significant advances over sorafenib in the first-line setting in more than a decade,” Dr. Yau said in an ESMO press release. “HCC is often diagnosed in the advanced stage, where effective treatment options are limited. The encouraging efficacy and favorable safety profile seen with nivolumab demonstrates the potential benefit of immunotherapy as a first-line treatment for patients with this aggressive cancer.”

He further noted that the OS benefit seen in this study is “particularly impactful considering the high frequency of subsequent use of systemic therapy, including immunotherapy, in the sorafenib arm,” and that the OS impact is bolstered by patient-reported outcomes suggesting improved quality of life in the nivolumab arm.

Nevertheless, the fact that CheckMate 459 did not meet its primary OS endpoint means the findings are unlikely to change the current standard of care, according to Angela Lamarca, MD, PhD, consultant medical oncologist and honorary senior lecturer at the Christie NHS Foundation Trust, University of Manchester (England).

She added, however, that the findings do underscore a potential role for immunotherapy in the first-line treatment of advanced HCC and noted that the clinically meaningful improvement in response rates with nivolumab, along with the checkpoint inhibitor’s favorable safety profile in this study, raise the possibility of its selection in this setting.

“In a hypothetical scenario in which both options ... were available and reimbursed, and if quality of life was shown to be better with nivolumab ... clinicians and patients may favor the option with a more tolerable safety profile,” she said in the press release.

She added, however, that at this point conclusions should be made cautiously and the high cost of immunotherapy should be considered.

Dr. Lamarca also highlighted the finding that patients with high PD-L1 expression had an increased response rate only in the nivolumab arm. This suggests a potential role for PD-L1 expression as a predictive biomarker in advanced HCC, but more research is needed to better understand how to select patients for immunotherapy, she said, adding that the lack of a reliable biomarker may have contributed to the study’s failure to show improved OS with nivolumab.

“In addition, the study design with a ‘high’ predefined threshold of statistical significance is generating confusion in the community, with potentially beneficial therapies generating statistically negative studies,” she noted.

CheckMate 459 was funded by Bristol-Myers Squibb. Dr. Yau is an advisor and/or consultant to Bristol-Myers Squibb, and reported honoraria from the company to his institution. Dr. Lamarca reported honoraria, consultation fees, travel funding, and/or education funding from Eisai, Nutricia, Ipsen, Pfizer, Bayer, AAA, Sirtex, Delcath, Novartis, and Mylan, as well as participation in company-sponsored speaker bureaus for Pfizer, Ipsen, Merck, and Incyte.

SOURCE: Yau T et al. ESMO 2019, Abstract LBA38-PR
 

BARCELONA – Checkpoint inhibition with nivolumab led to a clinically meaningful, but not statistically significant, improvement in overall survival, compared with sorafenib for the first-line treatment of advanced hepatocellular carcinoma (HCC) in the phase 3 CheckMate 459 study.

Median overall survival (OS), the primary study endpoint, was 16.4 months in 371 patients randomized to receive the programmed death-1 (PD-1) inhibitor nivolumab, and 14.7 months in 372 patients who received the tyrosine kinase inhibitor sorafenib – the current standard for advanced HCC therapy (hazard ratio, 0.85; P = .0752), Thomas Yau, MD, reported at the European Society for Medical Oncology Congress.

The median OS seen with nivolumab is the longest ever reported in a first-line phase 3 HCC trial, but the difference between the arms did not meet the predefined threshold for statistical significance (HR, 0.84 and P = .419). However, clinical benefit was observed across predefined subgroups of patients, including those with hepatitis infection and those with vascular invasion and/or extrahepatic spread, said Dr. Yau of the University of Hong Kong.

The overall response rates (ORR) were 15% and 7% in the nivolumab and sorafenib arms, with 14 and 5 patients in each group experiencing a complete response (CR), respectively, he said.

At 12 and 24 months, the OS rates in the groups were 59.7% vs. 55.1%, and 36.5% vs. 33.1%, respectively. Median progression-free survival (PFS) was similar in the groups, at 3.7 and 3.8 months, respectively, and analysis by baseline tumor programmed death-ligand 1 (PD-L1) expression showed that ORR was 28% vs. 9% with PD-L1 expression of 1% or greater in the groups, respectively, and 12% vs. 7% among those with PD-L1 expression less than 1%.

Additionally, nivolumab had a more tolerable safety profile; grade 3/4 treatment-related adverse events were reported in 22% and 49% of patients in the groups, respectively, and led to discontinuation in 4% and 8%, respectively. No new safety signals were observed, Dr. Yau said.

Participants in the multicenter study were systemic therapy–naive adults with advanced disease. They were randomized 1:1 to receive intravenous nivolumab at a dose of 240 mg every 2 weeks or oral sorafenib at a dose of 400 mg twice daily, and were followed for at least 22.8 months.

“These results are important in the treatment of hepatocellular carcinoma, as there have been no significant advances over sorafenib in the first-line setting in more than a decade,” Dr. Yau said in an ESMO press release. “HCC is often diagnosed in the advanced stage, where effective treatment options are limited. The encouraging efficacy and favorable safety profile seen with nivolumab demonstrates the potential benefit of immunotherapy as a first-line treatment for patients with this aggressive cancer.”

He further noted that the OS benefit seen in this study is “particularly impactful considering the high frequency of subsequent use of systemic therapy, including immunotherapy, in the sorafenib arm,” and that the OS impact is bolstered by patient-reported outcomes suggesting improved quality of life in the nivolumab arm.

Nevertheless, the fact that CheckMate 459 did not meet its primary OS endpoint means the findings are unlikely to change the current standard of care, according to Angela Lamarca, MD, PhD, consultant medical oncologist and honorary senior lecturer at the Christie NHS Foundation Trust, University of Manchester (England).

She added, however, that the findings do underscore a potential role for immunotherapy in the first-line treatment of advanced HCC and noted that the clinically meaningful improvement in response rates with nivolumab, along with the checkpoint inhibitor’s favorable safety profile in this study, raise the possibility of its selection in this setting.

“In a hypothetical scenario in which both options ... were available and reimbursed, and if quality of life was shown to be better with nivolumab ... clinicians and patients may favor the option with a more tolerable safety profile,” she said in the press release.

She added, however, that at this point conclusions should be made cautiously and the high cost of immunotherapy should be considered.

Dr. Lamarca also highlighted the finding that patients with high PD-L1 expression had an increased response rate only in the nivolumab arm. This suggests a potential role for PD-L1 expression as a predictive biomarker in advanced HCC, but more research is needed to better understand how to select patients for immunotherapy, she said, adding that the lack of a reliable biomarker may have contributed to the study’s failure to show improved OS with nivolumab.

“In addition, the study design with a ‘high’ predefined threshold of statistical significance is generating confusion in the community, with potentially beneficial therapies generating statistically negative studies,” she noted.

CheckMate 459 was funded by Bristol-Myers Squibb. Dr. Yau is an advisor and/or consultant to Bristol-Myers Squibb, and reported honoraria from the company to his institution. Dr. Lamarca reported honoraria, consultation fees, travel funding, and/or education funding from Eisai, Nutricia, Ipsen, Pfizer, Bayer, AAA, Sirtex, Delcath, Novartis, and Mylan, as well as participation in company-sponsored speaker bureaus for Pfizer, Ipsen, Merck, and Incyte.

SOURCE: Yau T et al. ESMO 2019, Abstract LBA38-PR
 

BARCELONA – Checkpoint inhibition with nivolumab led to a clinically meaningful, but not statistically significant, improvement in overall survival, compared with sorafenib for the first-line treatment of advanced hepatocellular carcinoma (HCC) in the phase 3 CheckMate 459 study.

Median overall survival (OS), the primary study endpoint, was 16.4 months in 371 patients randomized to receive the programmed death-1 (PD-1) inhibitor nivolumab, and 14.7 months in 372 patients who received the tyrosine kinase inhibitor sorafenib – the current standard for advanced HCC therapy (hazard ratio, 0.85; P = .0752), Thomas Yau, MD, reported at the European Society for Medical Oncology Congress.

The median OS seen with nivolumab is the longest ever reported in a first-line phase 3 HCC trial, but the difference between the arms did not meet the predefined threshold for statistical significance (HR, 0.84 and P = .419). However, clinical benefit was observed across predefined subgroups of patients, including those with hepatitis infection and those with vascular invasion and/or extrahepatic spread, said Dr. Yau of the University of Hong Kong.

The overall response rates (ORR) were 15% and 7% in the nivolumab and sorafenib arms, with 14 and 5 patients in each group experiencing a complete response (CR), respectively, he said.

At 12 and 24 months, the OS rates in the groups were 59.7% vs. 55.1%, and 36.5% vs. 33.1%, respectively. Median progression-free survival (PFS) was similar in the groups, at 3.7 and 3.8 months, respectively, and analysis by baseline tumor programmed death-ligand 1 (PD-L1) expression showed that ORR was 28% vs. 9% with PD-L1 expression of 1% or greater in the groups, respectively, and 12% vs. 7% among those with PD-L1 expression less than 1%.

Additionally, nivolumab had a more tolerable safety profile; grade 3/4 treatment-related adverse events were reported in 22% and 49% of patients in the groups, respectively, and led to discontinuation in 4% and 8%, respectively. No new safety signals were observed, Dr. Yau said.

Participants in the multicenter study were systemic therapy–naive adults with advanced disease. They were randomized 1:1 to receive intravenous nivolumab at a dose of 240 mg every 2 weeks or oral sorafenib at a dose of 400 mg twice daily, and were followed for at least 22.8 months.

“These results are important in the treatment of hepatocellular carcinoma, as there have been no significant advances over sorafenib in the first-line setting in more than a decade,” Dr. Yau said in an ESMO press release. “HCC is often diagnosed in the advanced stage, where effective treatment options are limited. The encouraging efficacy and favorable safety profile seen with nivolumab demonstrates the potential benefit of immunotherapy as a first-line treatment for patients with this aggressive cancer.”

He further noted that the OS benefit seen in this study is “particularly impactful considering the high frequency of subsequent use of systemic therapy, including immunotherapy, in the sorafenib arm,” and that the OS impact is bolstered by patient-reported outcomes suggesting improved quality of life in the nivolumab arm.

Nevertheless, the fact that CheckMate 459 did not meet its primary OS endpoint means the findings are unlikely to change the current standard of care, according to Angela Lamarca, MD, PhD, consultant medical oncologist and honorary senior lecturer at the Christie NHS Foundation Trust, University of Manchester (England).

She added, however, that the findings do underscore a potential role for immunotherapy in the first-line treatment of advanced HCC and noted that the clinically meaningful improvement in response rates with nivolumab, along with the checkpoint inhibitor’s favorable safety profile in this study, raise the possibility of its selection in this setting.

“In a hypothetical scenario in which both options ... were available and reimbursed, and if quality of life was shown to be better with nivolumab ... clinicians and patients may favor the option with a more tolerable safety profile,” she said in the press release.

She added, however, that at this point conclusions should be made cautiously and the high cost of immunotherapy should be considered.

Dr. Lamarca also highlighted the finding that patients with high PD-L1 expression had an increased response rate only in the nivolumab arm. This suggests a potential role for PD-L1 expression as a predictive biomarker in advanced HCC, but more research is needed to better understand how to select patients for immunotherapy, she said, adding that the lack of a reliable biomarker may have contributed to the study’s failure to show improved OS with nivolumab.

“In addition, the study design with a ‘high’ predefined threshold of statistical significance is generating confusion in the community, with potentially beneficial therapies generating statistically negative studies,” she noted.

CheckMate 459 was funded by Bristol-Myers Squibb. Dr. Yau is an advisor and/or consultant to Bristol-Myers Squibb, and reported honoraria from the company to his institution. Dr. Lamarca reported honoraria, consultation fees, travel funding, and/or education funding from Eisai, Nutricia, Ipsen, Pfizer, Bayer, AAA, Sirtex, Delcath, Novartis, and Mylan, as well as participation in company-sponsored speaker bureaus for Pfizer, Ipsen, Merck, and Incyte.

SOURCE: Yau T et al. ESMO 2019, Abstract LBA38-PR
 

BARCELONA – Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to standard platinum-based chemotherapy was associated with a small but statistically significant progression-free survival benefit for patients with previously untreated metastatic urothelial carcinoma, investigators in the IMvigor130 trial found.

Neil Osterweil/MDedge News

Among 1,213 patients with newly diagnosed metastatic urothelial carcinoma assigned to receive either atezolizumab monotherapy or chemotherapy with a platinum compound and gemcitabine plus either atezolizumab or placebo, the median progression-free survival (PFS) at a median follow-up of 11.8 months was 8.2 months with atezolizumab/chemotherapy, compared with 6.3 months with chemotherapy plus placebo, reported Enrique Grande, MD, of MD Anderson Cancer Center Madrid.

“IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in progression-free survival over the standard of care in first-line metastatic urothelial carcinoma. At this interim analysis, we observed a clinically meaningful improvement in the overall survival for the combination of atezolizumab plus chemotherapy that did not meet the prespecified interim boundary for significance,” he said at the European Society for Medical Oncology Congress.

Median overall survival (OS) at the interim analysis was 16.0 months in the atezolizumab arm, vs. 13.4 months in the placebo arm, translating into a hazard ratio (HR) of 0.83 trending in favor of the combination. But as noted by Dr. Grande, the P value was .027, which did not reach the interim efficacy boundary of .007.

IMvigor130 investigators enrolled patients with locally advanced metastatic urothelial carcinoma with no prior systemic therapy in the metastatic setting who had good performance status (ECOG 2 or less) and were eligible for chemotherapy with either cisplatin or carboplatin plus gemcitabine.

The patients were stratified by programmed death ligand-1 (PD-L1) status, prognostic (Bajorin) risk factor scores, and investigator choice of cisplatin or carboplatin, and then randomized to either atezolizumab plus chemotherapy, atezolizumab monotherapy, or placebo plus chemotherapy.

As noted, the co-primary endpoint of PFS in the chemotherapy arms in the intention-to-treat population was statistically significant at the preplanned interim analysis, but the other primary endpoint of OS had not reached significance.

At the time of the data cutoff in May 2019, the stratified HR for progression with atezolizumab was 0.82 (P = .007).

An analysis by subgroup showed either significant benefit or a trend favoring atezolizumab across all stratification factors, Dr. Grande said.

A hierarchical analysis of atezolizumab monotherapy vs. chemotherapy in the placebo-control arm showed a median OS of 15.7 vs. 13.1 months, respectively, with a hazard ratio of 1.02 (nonsignificant).

The benefit of atezolizumab appeared to be almost entirely among patients whose tumors had higher levels of PD-L1 expression according to immunohistochemistry (IC). The interim OS among patients with PD-L1 IC0/1 was a median of 13.5 months with atezolizumab vs. 12.9 months with chemotherapy alone, with an unstratified HR of 1.07 (nonsignificant). In contrast, among patients with PD-L1 IC2/3 status, the median OS was not reached for patients in the atezolizumab arm, vs. 17.8 months in the chemotherapy alone arm, for a stratified HR of 0.68, although this too did not reach statistical significance.

Responses were similar between the two chemotherapy arms, with an overall response rate (ORR) of 47% with atezolizumab added, vs. 44% with placebo added. The complete response (CR) rates were 13% and 7%, respectively. The ORR in the monotherapy arm was 23%, consisting of 6% complete and 17% partial responses.

Grade 3 or 4 treatment-related adverse events occurred in 81% of patients in each chemotherapy arm, compared with 15% in the atezolizumab monotherapy arm. Nine patients in the atezolizumab/chemotherapy arm died from a treatment-related cause, compared with four in the chemotherapy alone arm, and three in the atezolizumab monotherapy arm.

Adverse events leading to treatment discontinuation occurred in one-fourth of patients in each chemotherapy-containing arm, vs. less than 1% of patients in the monotherapy arm.

“The results from the IMvigor130 trial support the use of atezolizumab in combination with chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma,” Dr. Grande concluded.

But invited discussant Thomas Powles, MD, of Barts Cancer Institute in London, cautioned that more data are needed to conclude that the addition of atezolizumab should become a standard of care.

Neil Osterweil/MDedge News

“Does this change practice? Well, the for and against: significant delay in PFS, but how meaningful is that? OS trending the right way, but not significant yet. CR rates, yes with 13% CRs, but response rates weren’t very different from one another, and as response rates are similar, it’s hard to argue that the two are synergistic together, for example,” he said.

He added that the adverse event profiles “actually are very acceptable to me, and I’m really looking forward to the quality-of-life data.”

The IMvigor130 study is sponsored by F. Hoffman-La Roche. Dr. Grande disclosed honoraria and research grants from Roche and others. Dr. Powles disclosed research funding, honoraria, and travel costs from Roche and others.
 

SOURCE: Grande E et al. ESMO 2019. Abstract LBA14_PR.

BARCELONA – Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to standard platinum-based chemotherapy was associated with a small but statistically significant progression-free survival benefit for patients with previously untreated metastatic urothelial carcinoma, investigators in the IMvigor130 trial found.

Neil Osterweil/MDedge News

Among 1,213 patients with newly diagnosed metastatic urothelial carcinoma assigned to receive either atezolizumab monotherapy or chemotherapy with a platinum compound and gemcitabine plus either atezolizumab or placebo, the median progression-free survival (PFS) at a median follow-up of 11.8 months was 8.2 months with atezolizumab/chemotherapy, compared with 6.3 months with chemotherapy plus placebo, reported Enrique Grande, MD, of MD Anderson Cancer Center Madrid.

“IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in progression-free survival over the standard of care in first-line metastatic urothelial carcinoma. At this interim analysis, we observed a clinically meaningful improvement in the overall survival for the combination of atezolizumab plus chemotherapy that did not meet the prespecified interim boundary for significance,” he said at the European Society for Medical Oncology Congress.

Median overall survival (OS) at the interim analysis was 16.0 months in the atezolizumab arm, vs. 13.4 months in the placebo arm, translating into a hazard ratio (HR) of 0.83 trending in favor of the combination. But as noted by Dr. Grande, the P value was .027, which did not reach the interim efficacy boundary of .007.

IMvigor130 investigators enrolled patients with locally advanced metastatic urothelial carcinoma with no prior systemic therapy in the metastatic setting who had good performance status (ECOG 2 or less) and were eligible for chemotherapy with either cisplatin or carboplatin plus gemcitabine.

The patients were stratified by programmed death ligand-1 (PD-L1) status, prognostic (Bajorin) risk factor scores, and investigator choice of cisplatin or carboplatin, and then randomized to either atezolizumab plus chemotherapy, atezolizumab monotherapy, or placebo plus chemotherapy.

As noted, the co-primary endpoint of PFS in the chemotherapy arms in the intention-to-treat population was statistically significant at the preplanned interim analysis, but the other primary endpoint of OS had not reached significance.

At the time of the data cutoff in May 2019, the stratified HR for progression with atezolizumab was 0.82 (P = .007).

An analysis by subgroup showed either significant benefit or a trend favoring atezolizumab across all stratification factors, Dr. Grande said.

A hierarchical analysis of atezolizumab monotherapy vs. chemotherapy in the placebo-control arm showed a median OS of 15.7 vs. 13.1 months, respectively, with a hazard ratio of 1.02 (nonsignificant).

The benefit of atezolizumab appeared to be almost entirely among patients whose tumors had higher levels of PD-L1 expression according to immunohistochemistry (IC). The interim OS among patients with PD-L1 IC0/1 was a median of 13.5 months with atezolizumab vs. 12.9 months with chemotherapy alone, with an unstratified HR of 1.07 (nonsignificant). In contrast, among patients with PD-L1 IC2/3 status, the median OS was not reached for patients in the atezolizumab arm, vs. 17.8 months in the chemotherapy alone arm, for a stratified HR of 0.68, although this too did not reach statistical significance.

Responses were similar between the two chemotherapy arms, with an overall response rate (ORR) of 47% with atezolizumab added, vs. 44% with placebo added. The complete response (CR) rates were 13% and 7%, respectively. The ORR in the monotherapy arm was 23%, consisting of 6% complete and 17% partial responses.

Grade 3 or 4 treatment-related adverse events occurred in 81% of patients in each chemotherapy arm, compared with 15% in the atezolizumab monotherapy arm. Nine patients in the atezolizumab/chemotherapy arm died from a treatment-related cause, compared with four in the chemotherapy alone arm, and three in the atezolizumab monotherapy arm.

Adverse events leading to treatment discontinuation occurred in one-fourth of patients in each chemotherapy-containing arm, vs. less than 1% of patients in the monotherapy arm.

“The results from the IMvigor130 trial support the use of atezolizumab in combination with chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma,” Dr. Grande concluded.

But invited discussant Thomas Powles, MD, of Barts Cancer Institute in London, cautioned that more data are needed to conclude that the addition of atezolizumab should become a standard of care.

Neil Osterweil/MDedge News

“Does this change practice? Well, the for and against: significant delay in PFS, but how meaningful is that? OS trending the right way, but not significant yet. CR rates, yes with 13% CRs, but response rates weren’t very different from one another, and as response rates are similar, it’s hard to argue that the two are synergistic together, for example,” he said.

He added that the adverse event profiles “actually are very acceptable to me, and I’m really looking forward to the quality-of-life data.”

The IMvigor130 study is sponsored by F. Hoffman-La Roche. Dr. Grande disclosed honoraria and research grants from Roche and others. Dr. Powles disclosed research funding, honoraria, and travel costs from Roche and others.
 

SOURCE: Grande E et al. ESMO 2019. Abstract LBA14_PR.

BARCELONA – Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to standard platinum-based chemotherapy was associated with a small but statistically significant progression-free survival benefit for patients with previously untreated metastatic urothelial carcinoma, investigators in the IMvigor130 trial found.

Neil Osterweil/MDedge News

Among 1,213 patients with newly diagnosed metastatic urothelial carcinoma assigned to receive either atezolizumab monotherapy or chemotherapy with a platinum compound and gemcitabine plus either atezolizumab or placebo, the median progression-free survival (PFS) at a median follow-up of 11.8 months was 8.2 months with atezolizumab/chemotherapy, compared with 6.3 months with chemotherapy plus placebo, reported Enrique Grande, MD, of MD Anderson Cancer Center Madrid.

“IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in progression-free survival over the standard of care in first-line metastatic urothelial carcinoma. At this interim analysis, we observed a clinically meaningful improvement in the overall survival for the combination of atezolizumab plus chemotherapy that did not meet the prespecified interim boundary for significance,” he said at the European Society for Medical Oncology Congress.

Median overall survival (OS) at the interim analysis was 16.0 months in the atezolizumab arm, vs. 13.4 months in the placebo arm, translating into a hazard ratio (HR) of 0.83 trending in favor of the combination. But as noted by Dr. Grande, the P value was .027, which did not reach the interim efficacy boundary of .007.

IMvigor130 investigators enrolled patients with locally advanced metastatic urothelial carcinoma with no prior systemic therapy in the metastatic setting who had good performance status (ECOG 2 or less) and were eligible for chemotherapy with either cisplatin or carboplatin plus gemcitabine.

The patients were stratified by programmed death ligand-1 (PD-L1) status, prognostic (Bajorin) risk factor scores, and investigator choice of cisplatin or carboplatin, and then randomized to either atezolizumab plus chemotherapy, atezolizumab monotherapy, or placebo plus chemotherapy.

As noted, the co-primary endpoint of PFS in the chemotherapy arms in the intention-to-treat population was statistically significant at the preplanned interim analysis, but the other primary endpoint of OS had not reached significance.

At the time of the data cutoff in May 2019, the stratified HR for progression with atezolizumab was 0.82 (P = .007).

An analysis by subgroup showed either significant benefit or a trend favoring atezolizumab across all stratification factors, Dr. Grande said.

A hierarchical analysis of atezolizumab monotherapy vs. chemotherapy in the placebo-control arm showed a median OS of 15.7 vs. 13.1 months, respectively, with a hazard ratio of 1.02 (nonsignificant).

The benefit of atezolizumab appeared to be almost entirely among patients whose tumors had higher levels of PD-L1 expression according to immunohistochemistry (IC). The interim OS among patients with PD-L1 IC0/1 was a median of 13.5 months with atezolizumab vs. 12.9 months with chemotherapy alone, with an unstratified HR of 1.07 (nonsignificant). In contrast, among patients with PD-L1 IC2/3 status, the median OS was not reached for patients in the atezolizumab arm, vs. 17.8 months in the chemotherapy alone arm, for a stratified HR of 0.68, although this too did not reach statistical significance.

Responses were similar between the two chemotherapy arms, with an overall response rate (ORR) of 47% with atezolizumab added, vs. 44% with placebo added. The complete response (CR) rates were 13% and 7%, respectively. The ORR in the monotherapy arm was 23%, consisting of 6% complete and 17% partial responses.

Grade 3 or 4 treatment-related adverse events occurred in 81% of patients in each chemotherapy arm, compared with 15% in the atezolizumab monotherapy arm. Nine patients in the atezolizumab/chemotherapy arm died from a treatment-related cause, compared with four in the chemotherapy alone arm, and three in the atezolizumab monotherapy arm.

Adverse events leading to treatment discontinuation occurred in one-fourth of patients in each chemotherapy-containing arm, vs. less than 1% of patients in the monotherapy arm.

“The results from the IMvigor130 trial support the use of atezolizumab in combination with chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma,” Dr. Grande concluded.

But invited discussant Thomas Powles, MD, of Barts Cancer Institute in London, cautioned that more data are needed to conclude that the addition of atezolizumab should become a standard of care.

Neil Osterweil/MDedge News

“Does this change practice? Well, the for and against: significant delay in PFS, but how meaningful is that? OS trending the right way, but not significant yet. CR rates, yes with 13% CRs, but response rates weren’t very different from one another, and as response rates are similar, it’s hard to argue that the two are synergistic together, for example,” he said.

He added that the adverse event profiles “actually are very acceptable to me, and I’m really looking forward to the quality-of-life data.”

The IMvigor130 study is sponsored by F. Hoffman-La Roche. Dr. Grande disclosed honoraria and research grants from Roche and others. Dr. Powles disclosed research funding, honoraria, and travel costs from Roche and others.
 

SOURCE: Grande E et al. ESMO 2019. Abstract LBA14_PR.

Combination therapy with the immune checkpoint inhibitors nivolumab and ipilimumab has durable efficacy in patients with untreated advanced melanoma, with more than half still alive at 5 years and almost three-fourths of them no longer on any treatment, found an update of the CheckMate 067 trial. The combination also had a manageable safety profile and generally maintained health-related quality of life in the long term.

“The apparent plateau with nivolumab plus ipilimumab has continued with longer follow-up … nivolumab plus ipilimumab is … currently the only treatment for metastatic melanoma for which median overall survival has not been reached at 5 years,” noted the investigators, led by James Larkin, FRCP, PhD, a consultant medical oncologist at the Royal Marsden National Health Service Foundation Trust, London. “The current results of the CheckMate 067 trial set a new foundation on which to make improvements in long-term efficacy outcomes with the combination of nivolumab plus ipilimumab.”

The phase 3, randomized, controlled trial pitted nivolumab (Opdivo) plus ipilimumab (Yervoy) combination therapy and nivolumab monotherapy against ipilimumab monotherapy among 945 adults with previously untreated or unresectable metastatic melanoma. Initial results at a median follow-up of about 1 year showed a progression-free survival benefit of the nivolumab regimens (N Engl J Med. 2015;373:23-34), a pattern that has persisted in updates and has been augmented by an overall survival benefit, as seen most recently at a median follow-up of about 4 years (Lancet Oncol. 2018;19:1480-92).

Dr. Larkin and colleagues performed another update, now at a minimum follow-up of 5 years in all patients. This update additionally looked at subsequent therapies and health-related quality of life.

Results reported in the New England Journal of Medicine showed that median overall survival was now 19.9 months with ipilimumab. In comparison, it was not reached with nivolumab-ipilimumab (hazard ratio for death, 0.52) and was 36.9 months with nivolumab alone (HR, 0.63). The 5-year overall survival rate was 26%, compared with 52% and 44%, respectively.

In all groups, complete response rates continued an increase seen since the trial’s initial results were reported. “[T]his indicates that the best response can improve over time with immune checkpoint inhibitors,” Dr. Larkin and coinvestigators maintained.

“The treatment-free interval continued to lengthen in the nivolumab-plus-ipilimumab group, and the percentage of patients who were alive and not receiving treatment continued to increase across the groups,” they further noted. As of the update, the median treatment-free interval was 18.1 months with nivolumab-ipilimumab, 1.8 months with nivolumab, and 1.9 months with ipilimumab. The percentage of those alive who were not receiving any trial treatment or subsequent systemic therapy was 74%, 58%, and 45%, respectively.

Meanwhile, the data did not show any new safety signals. And health-related quality of life, measured with European Quality of Life 5-Dimensions 3-Level questionnaire, was generally sustained during and after treatment, with limited fluctuations outside a 0.08-point clinically meaningful boundary, in the combination-therapy group and the nivolumab group, whereas it deteriorated more often in the ipilimumab group.

Dr. Larkin disclosed grants and personal fees from numerous pharmaceutical companies. The trial was supported by Bristol-Myers Squibb, a grant from the National Cancer Institute, and a grant (to Dr. Larkin) from the National Institute for Health Research Royal Marsden–Institute of Cancer Research Biomedical Research Centre.

SOURCE: Larkin J et al. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910836.

Combination therapy with the immune checkpoint inhibitors nivolumab and ipilimumab has durable efficacy in patients with untreated advanced melanoma, with more than half still alive at 5 years and almost three-fourths of them no longer on any treatment, found an update of the CheckMate 067 trial. The combination also had a manageable safety profile and generally maintained health-related quality of life in the long term.

“The apparent plateau with nivolumab plus ipilimumab has continued with longer follow-up … nivolumab plus ipilimumab is … currently the only treatment for metastatic melanoma for which median overall survival has not been reached at 5 years,” noted the investigators, led by James Larkin, FRCP, PhD, a consultant medical oncologist at the Royal Marsden National Health Service Foundation Trust, London. “The current results of the CheckMate 067 trial set a new foundation on which to make improvements in long-term efficacy outcomes with the combination of nivolumab plus ipilimumab.”

The phase 3, randomized, controlled trial pitted nivolumab (Opdivo) plus ipilimumab (Yervoy) combination therapy and nivolumab monotherapy against ipilimumab monotherapy among 945 adults with previously untreated or unresectable metastatic melanoma. Initial results at a median follow-up of about 1 year showed a progression-free survival benefit of the nivolumab regimens (N Engl J Med. 2015;373:23-34), a pattern that has persisted in updates and has been augmented by an overall survival benefit, as seen most recently at a median follow-up of about 4 years (Lancet Oncol. 2018;19:1480-92).

Dr. Larkin and colleagues performed another update, now at a minimum follow-up of 5 years in all patients. This update additionally looked at subsequent therapies and health-related quality of life.

Results reported in the New England Journal of Medicine showed that median overall survival was now 19.9 months with ipilimumab. In comparison, it was not reached with nivolumab-ipilimumab (hazard ratio for death, 0.52) and was 36.9 months with nivolumab alone (HR, 0.63). The 5-year overall survival rate was 26%, compared with 52% and 44%, respectively.

In all groups, complete response rates continued an increase seen since the trial’s initial results were reported. “[T]his indicates that the best response can improve over time with immune checkpoint inhibitors,” Dr. Larkin and coinvestigators maintained.

“The treatment-free interval continued to lengthen in the nivolumab-plus-ipilimumab group, and the percentage of patients who were alive and not receiving treatment continued to increase across the groups,” they further noted. As of the update, the median treatment-free interval was 18.1 months with nivolumab-ipilimumab, 1.8 months with nivolumab, and 1.9 months with ipilimumab. The percentage of those alive who were not receiving any trial treatment or subsequent systemic therapy was 74%, 58%, and 45%, respectively.

Meanwhile, the data did not show any new safety signals. And health-related quality of life, measured with European Quality of Life 5-Dimensions 3-Level questionnaire, was generally sustained during and after treatment, with limited fluctuations outside a 0.08-point clinically meaningful boundary, in the combination-therapy group and the nivolumab group, whereas it deteriorated more often in the ipilimumab group.

Dr. Larkin disclosed grants and personal fees from numerous pharmaceutical companies. The trial was supported by Bristol-Myers Squibb, a grant from the National Cancer Institute, and a grant (to Dr. Larkin) from the National Institute for Health Research Royal Marsden–Institute of Cancer Research Biomedical Research Centre.

SOURCE: Larkin J et al. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910836.

Combination therapy with the immune checkpoint inhibitors nivolumab and ipilimumab has durable efficacy in patients with untreated advanced melanoma, with more than half still alive at 5 years and almost three-fourths of them no longer on any treatment, found an update of the CheckMate 067 trial. The combination also had a manageable safety profile and generally maintained health-related quality of life in the long term.

“The apparent plateau with nivolumab plus ipilimumab has continued with longer follow-up … nivolumab plus ipilimumab is … currently the only treatment for metastatic melanoma for which median overall survival has not been reached at 5 years,” noted the investigators, led by James Larkin, FRCP, PhD, a consultant medical oncologist at the Royal Marsden National Health Service Foundation Trust, London. “The current results of the CheckMate 067 trial set a new foundation on which to make improvements in long-term efficacy outcomes with the combination of nivolumab plus ipilimumab.”

The phase 3, randomized, controlled trial pitted nivolumab (Opdivo) plus ipilimumab (Yervoy) combination therapy and nivolumab monotherapy against ipilimumab monotherapy among 945 adults with previously untreated or unresectable metastatic melanoma. Initial results at a median follow-up of about 1 year showed a progression-free survival benefit of the nivolumab regimens (N Engl J Med. 2015;373:23-34), a pattern that has persisted in updates and has been augmented by an overall survival benefit, as seen most recently at a median follow-up of about 4 years (Lancet Oncol. 2018;19:1480-92).

Dr. Larkin and colleagues performed another update, now at a minimum follow-up of 5 years in all patients. This update additionally looked at subsequent therapies and health-related quality of life.

Results reported in the New England Journal of Medicine showed that median overall survival was now 19.9 months with ipilimumab. In comparison, it was not reached with nivolumab-ipilimumab (hazard ratio for death, 0.52) and was 36.9 months with nivolumab alone (HR, 0.63). The 5-year overall survival rate was 26%, compared with 52% and 44%, respectively.

In all groups, complete response rates continued an increase seen since the trial’s initial results were reported. “[T]his indicates that the best response can improve over time with immune checkpoint inhibitors,” Dr. Larkin and coinvestigators maintained.

“The treatment-free interval continued to lengthen in the nivolumab-plus-ipilimumab group, and the percentage of patients who were alive and not receiving treatment continued to increase across the groups,” they further noted. As of the update, the median treatment-free interval was 18.1 months with nivolumab-ipilimumab, 1.8 months with nivolumab, and 1.9 months with ipilimumab. The percentage of those alive who were not receiving any trial treatment or subsequent systemic therapy was 74%, 58%, and 45%, respectively.

Meanwhile, the data did not show any new safety signals. And health-related quality of life, measured with European Quality of Life 5-Dimensions 3-Level questionnaire, was generally sustained during and after treatment, with limited fluctuations outside a 0.08-point clinically meaningful boundary, in the combination-therapy group and the nivolumab group, whereas it deteriorated more often in the ipilimumab group.

Dr. Larkin disclosed grants and personal fees from numerous pharmaceutical companies. The trial was supported by Bristol-Myers Squibb, a grant from the National Cancer Institute, and a grant (to Dr. Larkin) from the National Institute for Health Research Royal Marsden–Institute of Cancer Research Biomedical Research Centre.

SOURCE: Larkin J et al. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910836.