Nivolumab plus ipilimumab boosts PFS in advanced NSCLC with high tumor mutational burden

CHICAGO – The combination of nivolumab plus ipilimumab prolonged progression-free survival (PFS), in comparison with platinum based chemotherapy, as initial treatment for advanced non–small cell lung cancer (NSCLC) patients with a high tumor mutation burden (TMB), regardless of PDL-1 status, according to the first analysis of Checkmate 227.

Median PFS was 7.2 months for patients receiving the immunotherapy combination (95% confidence interval, 5.5-13.2) versus 5.5 months (95% CI, 4.4-5.8) for those receiving platinum-based chemotherapy (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41-0.81; P less than .001).

The trial results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection, Matthew D. Hellmann, MD, said at the annual meeting of the American Association for Cancer Research.

“Checkmate 227 is the pivotal phase 3 study to validate TMB as an important and independent biomarker to be routinely tested in treatment-naive advanced NSCLC,” he said.

Overall survival data with the combination versus chemotherapy was “encouraging” but not yet complete in patients with high TMB, Dr. Hellmann said.

Results from this first analysis (part 1) of Checkmate 227, a multipart trial, were simultaneously published in the New England Journal of Medicine.

The trial was designed prior to emerging data about TMB. The study was later amended prior to initial analysis to include a second coprimary endpoint evaluating PFS with nivolumab plus ipilimumab versus chemotherapy among patients with a tumor mutational burden of at least 10 mutations per megabase (mut/Mb), irrespective of PD-L1 expression level.

For part 1 of the trial, patients were randomized 1:1:1 to nivolumab 3 mg/kg every 2 weeks plus low-dose ipilimumab 1 mg/kg every 6 weeks; histology-based platinum-doublet chemotherapy every 3 weeks for up to four cycles; and nivolumab 240 mg every 2 weeks or nivolumab 360 mg plus histology-based platinum-doublet chemotherapy every 3 weeks for up to four cycles, followed by nivolumab monotherapy.

Of all randomized patients in part 1 (n=1,739), 1,004 (58%) were evaluable for TMB analyses. Of all TMB-evaluable patients, 444 (44%) had TMB greater than or equal to 10 mut/Mb, including 139 patients randomized to nivolumab plus ipilimumab and 160 patients randomized to chemotherapy. TMB was assessed using the validated assay, FoundationOne CDx.

One-year PFS was higher with nivolumab plus ipilimumab than with chemotherapy among all randomized patients in part 1 (30.9% vs. 17.0%; HR for disease progression or death, 0.83; 95% CI, 0.72-0.96).

The PFS was significantly prolonged with the combination, compared with chemotherapy among patients with a high TMB; the 1-year PFS rate was 42.6% versus 13.2%, respectively, and the median PFS was 7.2 months (95% CI, 5.5-13.2) versus 5.5 months (95% CI, 4.4-5.8) respectively (HR for disease progression or death, 0.58; 97.5% CI, 0.41-0.81; P less than .001). In a subgroup analysis, PFS was longer with nivolumab plus ipilimumab versus chemotherapy for patients with a programmed death ligand 1 expression level of at least 1% and those with a level of less than 1%, reported Dr. Hellmann of Memorial Sloan Kettering Cancer Center, New York.

Safety was manageable and consistent with previous reports of nivolumab plus low-dose ipilimumab in NSCLC. Grade 3-4 treatment-related adverse events with the combination were skin reactions (34%), endocrine (23%), gastrointestinal (18%), hepatic (15%), pulmonary (8%), hypersensitivity (4%), and renal (4%) events. Overall, treatment-related deaths occurred in 1% of patients treated in both the combination and chemotherapy arms.

Results from Checkmate 227 may introduce two new standards of care for the first-line treatment of NSCLC, Dr. Hellmann said. The immunotherapy combination is introduced as a new option for the first-line treatment of NSCLC with a high TMB, sparing first-line chemotherapy, and it validates TMB as an “important and independent biomarker to be routinely tested in treatment-naive, advanced NSCLC,” he concluded.

Dr. Hellmann disclosed relationships with Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, Novartis, Janssen, Mirati, and Shattuck Labs.

SOURCE: Hellmann MD et al. AACR Annual Meeting, Abstract CT077.

CHICAGO – The combination of nivolumab plus ipilimumab prolonged progression-free survival (PFS), in comparison with platinum based chemotherapy, as initial treatment for advanced non–small cell lung cancer (NSCLC) patients with a high tumor mutation burden (TMB), regardless of PDL-1 status, according to the first analysis of Checkmate 227.

Median PFS was 7.2 months for patients receiving the immunotherapy combination (95% confidence interval, 5.5-13.2) versus 5.5 months (95% CI, 4.4-5.8) for those receiving platinum-based chemotherapy (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41-0.81; P less than .001).

The trial results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection, Matthew D. Hellmann, MD, said at the annual meeting of the American Association for Cancer Research.

“Checkmate 227 is the pivotal phase 3 study to validate TMB as an important and independent biomarker to be routinely tested in treatment-naive advanced NSCLC,” he said.

Overall survival data with the combination versus chemotherapy was “encouraging” but not yet complete in patients with high TMB, Dr. Hellmann said.

Results from this first analysis (part 1) of Checkmate 227, a multipart trial, were simultaneously published in the New England Journal of Medicine.

The trial was designed prior to emerging data about TMB. The study was later amended prior to initial analysis to include a second coprimary endpoint evaluating PFS with nivolumab plus ipilimumab versus chemotherapy among patients with a tumor mutational burden of at least 10 mutations per megabase (mut/Mb), irrespective of PD-L1 expression level.

For part 1 of the trial, patients were randomized 1:1:1 to nivolumab 3 mg/kg every 2 weeks plus low-dose ipilimumab 1 mg/kg every 6 weeks; histology-based platinum-doublet chemotherapy every 3 weeks for up to four cycles; and nivolumab 240 mg every 2 weeks or nivolumab 360 mg plus histology-based platinum-doublet chemotherapy every 3 weeks for up to four cycles, followed by nivolumab monotherapy.

Of all randomized patients in part 1 (n=1,739), 1,004 (58%) were evaluable for TMB analyses. Of all TMB-evaluable patients, 444 (44%) had TMB greater than or equal to 10 mut/Mb, including 139 patients randomized to nivolumab plus ipilimumab and 160 patients randomized to chemotherapy. TMB was assessed using the validated assay, FoundationOne CDx.

One-year PFS was higher with nivolumab plus ipilimumab than with chemotherapy among all randomized patients in part 1 (30.9% vs. 17.0%; HR for disease progression or death, 0.83; 95% CI, 0.72-0.96).

The PFS was significantly prolonged with the combination, compared with chemotherapy among patients with a high TMB; the 1-year PFS rate was 42.6% versus 13.2%, respectively, and the median PFS was 7.2 months (95% CI, 5.5-13.2) versus 5.5 months (95% CI, 4.4-5.8) respectively (HR for disease progression or death, 0.58; 97.5% CI, 0.41-0.81; P less than .001). In a subgroup analysis, PFS was longer with nivolumab plus ipilimumab versus chemotherapy for patients with a programmed death ligand 1 expression level of at least 1% and those with a level of less than 1%, reported Dr. Hellmann of Memorial Sloan Kettering Cancer Center, New York.

Safety was manageable and consistent with previous reports of nivolumab plus low-dose ipilimumab in NSCLC. Grade 3-4 treatment-related adverse events with the combination were skin reactions (34%), endocrine (23%), gastrointestinal (18%), hepatic (15%), pulmonary (8%), hypersensitivity (4%), and renal (4%) events. Overall, treatment-related deaths occurred in 1% of patients treated in both the combination and chemotherapy arms.

Results from Checkmate 227 may introduce two new standards of care for the first-line treatment of NSCLC, Dr. Hellmann said. The immunotherapy combination is introduced as a new option for the first-line treatment of NSCLC with a high TMB, sparing first-line chemotherapy, and it validates TMB as an “important and independent biomarker to be routinely tested in treatment-naive, advanced NSCLC,” he concluded.

Dr. Hellmann disclosed relationships with Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, Novartis, Janssen, Mirati, and Shattuck Labs.

SOURCE: Hellmann MD et al. AACR Annual Meeting, Abstract CT077.

CHICAGO – The combination of nivolumab plus ipilimumab prolonged progression-free survival (PFS), in comparison with platinum based chemotherapy, as initial treatment for advanced non–small cell lung cancer (NSCLC) patients with a high tumor mutation burden (TMB), regardless of PDL-1 status, according to the first analysis of Checkmate 227.

Median PFS was 7.2 months for patients receiving the immunotherapy combination (95% confidence interval, 5.5-13.2) versus 5.5 months (95% CI, 4.4-5.8) for those receiving platinum-based chemotherapy (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41-0.81; P less than .001).

The trial results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection, Matthew D. Hellmann, MD, said at the annual meeting of the American Association for Cancer Research.

“Checkmate 227 is the pivotal phase 3 study to validate TMB as an important and independent biomarker to be routinely tested in treatment-naive advanced NSCLC,” he said.

Overall survival data with the combination versus chemotherapy was “encouraging” but not yet complete in patients with high TMB, Dr. Hellmann said.

Results from this first analysis (part 1) of Checkmate 227, a multipart trial, were simultaneously published in the New England Journal of Medicine.

The trial was designed prior to emerging data about TMB. The study was later amended prior to initial analysis to include a second coprimary endpoint evaluating PFS with nivolumab plus ipilimumab versus chemotherapy among patients with a tumor mutational burden of at least 10 mutations per megabase (mut/Mb), irrespective of PD-L1 expression level.

For part 1 of the trial, patients were randomized 1:1:1 to nivolumab 3 mg/kg every 2 weeks plus low-dose ipilimumab 1 mg/kg every 6 weeks; histology-based platinum-doublet chemotherapy every 3 weeks for up to four cycles; and nivolumab 240 mg every 2 weeks or nivolumab 360 mg plus histology-based platinum-doublet chemotherapy every 3 weeks for up to four cycles, followed by nivolumab monotherapy.

Of all randomized patients in part 1 (n=1,739), 1,004 (58%) were evaluable for TMB analyses. Of all TMB-evaluable patients, 444 (44%) had TMB greater than or equal to 10 mut/Mb, including 139 patients randomized to nivolumab plus ipilimumab and 160 patients randomized to chemotherapy. TMB was assessed using the validated assay, FoundationOne CDx.

One-year PFS was higher with nivolumab plus ipilimumab than with chemotherapy among all randomized patients in part 1 (30.9% vs. 17.0%; HR for disease progression or death, 0.83; 95% CI, 0.72-0.96).

The PFS was significantly prolonged with the combination, compared with chemotherapy among patients with a high TMB; the 1-year PFS rate was 42.6% versus 13.2%, respectively, and the median PFS was 7.2 months (95% CI, 5.5-13.2) versus 5.5 months (95% CI, 4.4-5.8) respectively (HR for disease progression or death, 0.58; 97.5% CI, 0.41-0.81; P less than .001). In a subgroup analysis, PFS was longer with nivolumab plus ipilimumab versus chemotherapy for patients with a programmed death ligand 1 expression level of at least 1% and those with a level of less than 1%, reported Dr. Hellmann of Memorial Sloan Kettering Cancer Center, New York.

Safety was manageable and consistent with previous reports of nivolumab plus low-dose ipilimumab in NSCLC. Grade 3-4 treatment-related adverse events with the combination were skin reactions (34%), endocrine (23%), gastrointestinal (18%), hepatic (15%), pulmonary (8%), hypersensitivity (4%), and renal (4%) events. Overall, treatment-related deaths occurred in 1% of patients treated in both the combination and chemotherapy arms.

Results from Checkmate 227 may introduce two new standards of care for the first-line treatment of NSCLC, Dr. Hellmann said. The immunotherapy combination is introduced as a new option for the first-line treatment of NSCLC with a high TMB, sparing first-line chemotherapy, and it validates TMB as an “important and independent biomarker to be routinely tested in treatment-naive, advanced NSCLC,” he concluded.

Dr. Hellmann disclosed relationships with Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, Novartis, Janssen, Mirati, and Shattuck Labs.

SOURCE: Hellmann MD et al. AACR Annual Meeting, Abstract CT077.