The combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) improved progression-free survival compared with chemotherapy as first-line treatment for patients with advanced non–small cell lung cancer (NSCLC) and a high tumor mutational burden irrespective of programmed cell death ligand 1 (PD-L1) levels of expression, according to data from the CheckMate 227 trial.¹ A noteworthy aspect of the trial is the confirmation of tumor mutational burden as a predictive biomarker for immunotherapy that is independent and distinct from PD-L1.

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.

— Matthew Hellmann, MD

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“The study demonstrates the efficacy of nivolumab plus ipilimumab immunotherapy as a first-line treatment for people with high–tumor mutational burden NSCLC,” explained lead author Matthew Hellmann, MD, of Memorial Sloan Kettering Cancer Center, New York. “This is the first phase III study to evaluate tumor mutational burden as a predictive biomarker for immunotherapy as a coprimary endpoint. 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 told listeners at the 2018 Annual Meeting of the American Association for Cancer Research (AACR). The study was published online in TheNew England Journal of Medicine to coincide with the presentation at the AACR meeting.²

“This study validates the role of tumor mutational burden to identify those patients with greatest benefit from the immunotherapy combination. Tumor mutational burden is a distinct and definable biomarker that can be determined by next-generation sequencing, which we are already using for treatment selection,” he added.

The standard of care for first-line treatment of advanced NSCLC is a platinum-doublet chemotherapy combination or pembrolizumab (Keytruda) in patients with ≥ 50% PD-L1 expression. About 20% to 25% of patients benefit from immunotherapy, and biomarkers are needed to select patients for this expensive treatment. In addition to PD-L1, tumor mutational burden has recently emerged as a potential biomarker for immunotherapy.

Study Design

CheckMate 227 is a three-part, open-label, randomized, phase III trial comparing nivolumab, nivolumab plus ipilimumab, or nivolumab plus platinum-doublet chemotherapy vs platinum-doublet chemotherapy alone in 1,739 patients with previously untreated stage IV or recurrent NSCLC. At the AACR meeting, Dr. Hellmann reported data from part 1 of the study: the comparison between 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). The study was emended to incorporate tumor mutational burden as a biomarker, using the validated cutoff of tumor mutational burden ≥ 10 mutations/megabase as “high” and < 10 mutations/megabase as “low.”

In the comparison Dr. Hellmann reported, 139 tumor mutational burden–high patients were treated with optimized dosing of nivolumab plus ipilimumab (3 mg/kg of nivolumab every 3 weeks plus 1 mg/kg of ipilimumab every 6 weeks) and 160 tumor mutational burden–high patients received chemotherapy based on tumor histology. 

Improved Outcomes With Immunotherapy Combination

For the coprimary endpoint of progression-free survival, at 1 year in tumor mutational burden–high patients, nivolumab plus ipilimumab was more than tripled compared with chemotherapy. Median progression-free survival was 7.2 months vs 5.5 months, respectively, representing a 42% reduction in the risk of disease progression or death (P = .0002). In tumor mutational burden–low patients, progression-free survival was similar between nivolu-mab plus ipilimumab and chemotherapy, highlighting the effectiveness of the tumor mutational burden biomarker and cutpoint in predicting the group of patients who are most likely to benefit from nivolumab plus ipilimumab.

“The breadth, duration, and depth of response were all substantially improved by the immunotherapy combination, with a more than tripling of the 1-year progression-free survival with the immunotherapy combination,” Dr. Hellmann said. 

The immunotherapy combination improved progression-free survival independent of histology (squamous or nonsquamous) and PD-L1 expression. One-year progression-free survival was 45% with immunotherapy vs 8% with chemotherapy for PD-L1 < 1%; 42% vs 16%, respectively, for PD-L1 ≥ 1%; 35% vs 7%, respectively, for squamous NSCLC; and 46% vs 17%, respectively, for nonsquamous NSCLC.

The objective response rate was 45.3% with the immunotherapy combination vs 26.9% with chemotherapy. At 1 year, 68% of the tumor mutational burden–high patients maintained their response to immunotherapy vs 25% of those randomized to receive chemotherapy. The median time to response was 2.7 months with nivolumab plus ipilimumab and 1.5 months with chemotherapy.

The depth of response was significantly improved in tumor mutational burden–high patients treated with the immunotherapy combination. More than 50% of tumor shrinkage was observed in 35% of the immunotherapy combination group and 12% of the chemotherapy group; more than 80% of tumor shrinkage was observed in 9% vs 1%, respectively.

It is still too early to establish survival, but preliminary data are encouraging. “These are descriptive data, 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 was well tolerated, and safety data were consistent with previous reports of this therapy. The rate of grade 3/4 treatment-related adverse events was 31% with the immunotherapy combination vs 36% with chemotherapy. The rates of specific grade 3/4 treatment-related adverse events with the immunotherapy combination were skin reactions (34%), endocrine (23%), gastrointestinal (18%), hepatic (15%), pulmonary (8%), hypersensitivity (4%), and renal events. Treatment-related deaths were reported in 1% of patients in both study arms. 

Evaluation of Tumor Mutational Burden

The investigators had sufficient tissue samples to evaluate tumor mutational burden in 58% of all randomized patients. A total of 44% were tumor mutational burden–high, including the 139 patients randomized to receive the immunotherapy combination and the 160 randomized to receive chemotherapy. 

“These results highlight that tumor mutational burden and PD-L1 are independent biomarkers, that tumor mutational burden is predictive of benefit of nivolumab plus ipilimumab irrespective of PD-L1, and that tumor mutational burden–high represents a distinct subgroup of NSCLC,” Dr. Hellmann said.

The assay used to assess tumor mutational burden status is one of three U.S. Food and Drug Administration–approved tests for molecular profiling, Dr. Hellmann noted. “This is a readout of information we already get from next-generation sequencing, which we do to identify epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS1 alterations. The data from that readout allow us to quantify tumor mutational burden,” Dr. Hellmann explained.

“This trial is a sizable piece of the pie [of the distinct biology of lung cancer.] Think of tumor mutational burden as yet another reason to do next-generation sequencing. The turnaround time is 2 to 3 weeks, and we hope to shorten it,” he told listeners. ■

DISCLOSURE: Dr. Hellmann is a paid consultant for Bristol-Myers Squibb, Merck, Genentech, AstraZeneca/Medimmune, Janssen, Mirati Therapeutics, Syndax, and Shattuck Labs; has received research funding from Bristol-Myers Squibb; and has a patent filed by MSK related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208).

REFERENCES

1. Hellmann MD, Ciuleanu T, Pluzanski A, et al: Nivolumab + ipilimumab vs platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: Initial results from CheckMate 227. 2018 AACR Annual Meeting. Abstract CT077. Presented April 16, 2018.

2. Hellmann MD, Ciuleanu TE, Pluzanski A, et al: Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 378:2093-2104, 2018.