The combination of nivolumab plus ipilimumab extended progression-free survival (PFS) versus standard chemotherapy as first-line treatment for patients with advanced non–small cell lung cancer (NSCLC) with a high tumor mutational burden (TMB). This finding was unrelated to levels of PD-L1 expression.
“CheckMate-227 is the first phase 3 study to evaluate TMB, a measurement of the mutations carried by tumor cells, as a predictive biomarker for immunotherapy as a co-primary end point. The identification of a new biomarker for patient selection for this immunotherapy combination is encouraging and allows us to use immunotherapy more efficiently, sparing the use of chemotherapy in the first-line setting,” stated Matthew Hellmann, MD, Memorial Sloan Kettering Cancer Center, New York City. Dr Hellmann presented these findings at the 2018 Annual Meeting of AACR, and the study was published online the same day in The New England Journal of Medicine.
“This study validates the role of TMB to identify those patients with greatest benefit from the immunotherapy combination. TMB is a distinct and definable biomarker that can be determined by next-generation sequencing, which we are already using for treatment selection,” Dr Hellmann said.
A second open-label phase 2 trial reported at AACR also found that high TMB (ie, TMB ≥10 mutations/megabase [mut/Mb]) was a predictive biomarker for response to nivolumab plus ipilimumab (CheckMate-568) as first-line therapy for advanced NSCLC. In that trial, TMB identified subsets of patients most likely to respond irrespective of PD-L1 status.
CheckMate-227 was an open-label, randomized, phase 3 trial comparing nivolumab, or nivolumab plus ipilimumab, or nivolumab plus platinum-doublet chemotherapy versus platinum-doublet chemotherapy alone in 1739 patients with previously untreated stage IV or recurrent NSCLC.
Dr Hellmann’s presentation focused only on part 1 of the study, comparing nivolumab plus ipilimumab versus chemotherapy in patients with previously untreated stage IV or recurrent NSCLC.
Patients were stratified according to PD-L1 expression ≥1% (positive) or <1% (negative). After data suggested that TMB was a potential biomarker for response, it was incorporated as a biomarker using the validated cutoff of TMB ≥10 mut/Mb as “high” and <10 mut/Mb as “low.”
One hundred thirty-nine TMB-high patients were treated with optimized dosing of nivolumab plus ipilimumab (3 mg/kg nivolumab every 3 weeks plus 1 mg/kg ipilimumab every 6 weeks), and 160 TMB-high patients received chemotherapy based on tumor histology.
At 1 year, TMB-high patients receiving nivolumab plus ipilimumab had a PFS rate of 43% versus 13% with chemotherapy, a significant 25% improvement for the immunotherapy combination (P = .0002). Median PFS was 7.2 months versus 5.5 months, respectively, a significant 42% reduction in risk of disease progression or death (P <.001). In TMB-low patients, PFS was similar between nivolumab plus ipilimumab and chemotherapy.
“The immunotherapy combination improved PFS independent of histology type (squamous or nonsquamous) and PD-L1 expression. The breadth, duration, and depth of response were all substantially improved by the immunotherapy combination, with a more than tripling of the 1-year PFS with the immunotherapy combination,” Dr Hellmann said.
Although it is premature to ascertain survival, the trend thus far is encouraging.
“With more than 40% of the data points censored, there is a clear trend toward improved survival with the combination. The control arm performed quite well but is still 7 months less than with the combination,” Dr Hellmann told listeners.
Nivolumab plus ipilimumab was well tolerated, consistent with previous reports of safety with the combination. The rate of grade 3/4 treatment-related adverse events was 31% with the immunotherapy combination versus 36% with chemotherapy.
“TMB should be a standard biomarker for initial evaluation of NSCLC. PD-L1 remains a standard of care and should be used in concert with TMB,” said Naiyer A. Rizvi, MD, Columbia University Medical Center, New York City, who discussed this paper at a plenary session.