High Tumor Mutational Burden Predicts Response to Nivolumab plus Ipilimumab Combination in Lung Cancer

The combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) extended progression-free survival (PFS) versus standard chemotherapy as first-line treatment for patients with advanced non–small-cell lung cancer (NSCLC) and a high tumor mutational burden (TMB). This finding was unrelated to levels of PD-L1 expression, said Matthew D. Hellmann, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York City.

“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,” Dr Hellmann stated. He presented these findings at the 2018 American Association for Cancer Research (AACR) meeting, and the study was published the same day (Hellmann MD, et al. N Engl J Med. 2018;378:2093-2104).

“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 clinical trial reported at AACR, CheckMate-568, also showed that high TMB (ie, TMB ≥10 mutations/megabase [mut/mb]) was a predictive biomarker for response to nivolumab plus ipilimumab combination as first-line therapy for advanced NSCLC. In that trial, TMB identified subsets of patients most likely to respond to the combination, regardless of PD-L1 status.


CheckMate-227 was an open-label, randomized phase 3 clinical trial comparing nivolumab, nivolumab plus ipilimumab, or nivolumab plus platinum-doublet chemotherapy versus platinum-doublet chemotherapy alone in 1739 patients with untreated stage IV or recurrent NSCLC.

Dr Hellmann focused only on part 1 of the study, comparing nivolumab plus ipilimumab versus chemotherapy in this patient population.

Patients were stratified according to PD-L1 expression, ≥1% (positive) or <1% (negative). After data suggested that TMB was a potential biomarker for response, TMB was incorporated as a biomarker, using the validated cutoff of TMB ≥10 mut/mb as “high” and <10 mut/mb as “low.”

Of patients with a high TMB, 139 received optimized dosing of the combination (3 mg/kg of nivolumab every 3 weeks plus 1 mg/kg of ipilimumab every 6 weeks), and 160 received chemotherapy based on tumor histology.

At 1 year, the PFS was 43% in patients with high TMB in the immunotherapy combination arm versus 13% in the chemotherapy arm, a 25% improvement with the combination (P = .0002). The median PFS was 7.2 months versus 5.5 months, respectively, a 42% reduction (P <.001) in risk for disease progression or death. In patients with low TMB, PFS was similar between the combination and chemotherapy arms.

“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.

The combination of nivolumab plus ipilimumab was well-tolerated, which is consistent with previous reports. The rate of grade 3 or 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, Co-Director, Cancer Immunotherapy, Columbia University Medical Center, New York City, who discussed this paper at a plenary session.

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