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CHICAGO -- A first-line immunotherapy combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) significantly delayed disease progression among patients with advanced but untreated non-small cell lung cancer (NSCLC) and highly mutated tumors, according to phase III trial results presented here.

The rate of progression-free survival (PFS) at 12 months in NSCLC patients with high tumor mutational burden (TMB) was 42.6% with the combination versus 13.2% with chemotherapy, reported Matthew D. Hellmann, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues.

"The breadth, duration, and depth of response were all substantially improved with a more than tripling of the 1-year PFS with the immunotherapy combination," said Hellmann during a press briefing at the American Association for Cancer Research (AACR) annual meeting. The results were simultaneously published in the .

Median PFS was 7.2 months (95% CI 5.5 to 13.2) with the combination versus 5.5 months (95% CI 4.4 to 5.8) with chemotherapy (HR 0.58, 97.5% CI 0.41 to 0.81, P<0.001).

Rate of objective response was also better with nivolumab/ipilimumab, with 45.3% of patients responding (95% CI 36.9 to 54.0) versus 26.9% among those on chemotherapy (95% CI 20.2 to 34.4).

The final analysis for this portion of the CheckMate 227 trial included 139 high-TMB patients who received nivolumab/ipilimumab and 160 high-TMB patients who received chemotherapy based on their tumor histology. High TMB was defined >10 mutations per megabase.

This study "establishes TMB as a distinct, definable subgroup of lung cancer, and broadens the clinical actionability of data we can derive from routine next-generation sequencing," said Hellmann, adding that "a readout of data that we're already routinely getting" is all that's required to evaluate a patient's TMB status.

Subgroup analyses revealed that the benefit of the immunotherapy combination among high-TMB patients was broadly consistent and independent of either PD-L1 levels or histology, with 1-year PFS estimates all favoring nivolumab plus ipilimumab over chemotherapy:

• PD-L1 levels <1%: 45% versus 8%
• PD-L1 ≥1%: 42% versus 16%
• Squamous NSCLC: 35% versus 7%
• Non-squamous NSCLC: 46% versus 17%

Overall survival data are still maturing but preliminary results were encouraging, Hellmann said.

Five patients (3.6%) in the nivolumab plus ipilimumab arm had complete responses versus one (0.6%) in the chemotherapy arm. Median duration of response was not available among those in the immunotherapy arm compared with 5.4 months in the chemotherapy arm. Among those who did respond, 68% in the nivolumab/ipilimumab arm continued to have a response compared with 25% of those in the chemotherapy arm.

The multipart CheckMate 227 trial randomized 1,739 patients 1:1:1 to either nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone if they had PD-L1 levels <1%; or to either nivolumab plus ipilimumab, nivolumab alone, or chemotherapy alone if they had PD-L1 levels ≥1%. Of those, the 299 patients with high TMB were included in this analysis.

Patients eligible for therapies targeting EGFR mutations or ALK translocations were excluded from the trial.

Dosing for the immunotherapy combination -- which was previously optimized for first-line NSCLC in CheckMate 012 -- was 3 mg/kg nivolumab every 2 weeks and 1 mg/kg ipilimumab every 6 weeks. While patients receiving the immunotherapy combination had more treatment-related adverse events (TRAEs) that led to treatment discontinuation (17.4% versus 8.9%), more patients were able to stay on therapy for a longer duration than with chemotherapy.

Overall the rate of grade 3/4 TRAEs was 31.2% with the immunotherapy combination versus 36.1% with chemotherapy.