The first data from the phase III CheckMate-227 trial of ipilimumab plus nivolumab for the treatment of non–small cell lung cancer suggests that the two drugs boost progression-free survival in patients with a high tumor mutation burden. After 1 year, progression-free survival was 43% for patients treated with the checkpoint inhibitor combination, compared with 13% for patients treated with chemotherapy.

The combination of ipilimumab (Yervoy; Bristol-Myers Squibb) and nivolumab (Opdivo; Bristol-Myers Squibb) increases progression-free survival (PFS) in some patients with advanced non–small cell lung cancer (NSCLC), according to a recent study (N Engl J Med 2018 Apr 16 [Epub ahead of print]). The findings, reported concurrently at the American Association for Cancer Research Annual Meeting 2018 in Chicago, IL, reveal that the two drugs were more effective than chemotherapy in patients with a high tumor mutation burden (TMB), suggesting that this biomarker could predict which patients could benefit from the drug combination.

The phase III CheckMate-227 trial is evaluating various combinations of the PD-1 inhibitor nivolumab, the CTLA4 inhibitor ipilimumab, and chemotherapy as first-line treatments in 1,739 patients with newly diagnosed stage IV or recurrent NSCLC. The original trial design stratifies patients by PD-L1 levels. The investigators later added TMB as a primary endpoint because other studies suggested that it could be an independent indicator of response.

TMB measurements were available for about 60% of the trial participants. In the subgroup of 299 patients with high TMB, defined as more than 10 mutations per Mb, 139 received ipilimumab and nivolumab, and 160 received platinum chemotherapy. For the patients treated with the checkpoint inhibitor combination, the 1-year PFS was 43%, compared with 13% for the patients treated with chemotherapy. The overall response rate after a minimum of 11.5 months of follow-up was also higher among patients who received ipilimumab and nivolumab than among those who received chemotherapy, 45.3% versus 26.9%.

Grade 3 and 4 side effects were less frequent among patients who received ipilimumab and nivolumab than among patients treated with chemotherapy, 31.3% versus 36.1%.

Although it was successful in patients with a high TMB, the checkpoint inhibitor combination was no better at extending PFS than chemotherapy in patients with a low or moderate TMB, suggesting that “mutation burden is an effective biomarker” in NSCLC, said co-author Matthew Hellmann, MD, of Memorial Sloan Kettering Cancer Center in New York, NY. The study “validates the clinical value of ipilimumab and nivolumab” and may help some patients avoid chemotherapy as an initial treatment.

“It's an important study,” said Patrick Forde, MB, BCh, of Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy in Baltimore, MD, who wasn't connected to the research. “The study is the first large lung cancer trial to evaluate TMB in detail—and to show that the 40% to 50% of patients with higher mutation levels may respond well to the two drugs.”

However, Daniel Morgensztern, MD, of Washington University School of Medicine in St. Louis, MO, cautioned that “although the results are interesting and promising, there are still some caveats.” The patients were not randomized by TMB, he noted. “Therefore, it remains unclear whether CheckMate-227 established a role for nivolumab plus ipilimumab in the first-line therapy of stage IV NSCLC.”

Whether the immunotherapy duo will become a standard treatment depends onhow the results of CheckMate-227 compare with those for other checkpoint blockers being tested in NSCLC, said Justin Gainor, MD, of Massachusetts General Hospital in Boston. “To get a firm grasp on how widely this [combination] will be used, we need to see the results of KEYNOTE-189,” a phase III trial of pembrolizumab (Keytruda; Merck) and chemotherapy whose data haven't been presented. –Mitch Leslie

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