Enhanced Benefit of First-Line Nivolumab + Ipilimumab Combination in NSCLC With High Tumor Mutational Burden

Treatment with immune checkpoint inhibitors has become a standard in non-small cell lung cancer (NSCLC) across multiple lines of therapy. In the first-line setting, pembrolizumab monotherapy is approved for patients with high PD-L1 expression (≥50%) and in combination with chemotherapy for nonsquamous NSCLC, regardless PD-L1 expression. There is an unmet need for more effective frontline therapies for majority of NSCLC and for improved biomarkers that can accurately predict which patients are most likely to benefit from these agents. Tumor mutational burden (TMB) is a potential independent biomarker of outcomes with immune checkpoint inhibitors in multiple tumor types, including lung cancer. In an analysis of the first part of the ongoing multipart CheckMate-227 trial that was recently presented at the American Association for Cancer Research (AACR) meeting and simultaneously published in The New England Journal of Medicine, the combination of nivolumab and ipilimumab was compared to chemotherapy in patients with stage IV NSCLC with high TMB (defined as ≥10 mutations/megabase) who had not previously received chemotherapy.

A total of 299 patients with high TMB were included in this analysis. The combination of nivolumab and ipilimumab significantly improved progression-free survival (PFS), compared to chemotherapy (7.2 months vs 5.5 months; HR 0.58, P<.001). The 1-year PFS rate was 42.6% in patients receiving nivolumab plus ipilimumab, compared to 13.2% in patients receiving chemotherapy. The objective response rate (ORR) was also improved in patients receiving nivolumab and ipilimumab (45.3% vs 26.9%). A multivariate analysis found that the PFS benefit associated with nivolumab and ipilimumab was consistent for all patients with high TMB, regardless of PD-L1 expression status (≥1% vs <1%) and histologic subtype (squamous vs non-squamous).

In patients with low TMB, outcomes favored chemotherapy over nivolumab plus ipilimumab. PFS was 3.2 months with nivolumab/ipilimumab, compared to 5.5 months for patients receiving chemotherapy (HR 1.07).

The safety profile of nivolumab plus ipilimumab in this study was consistent with previous trials of combination nivolumab and ipilimumab. Grade 3/4 treatment-related adverse events (AEs) occurred in 31.2% of patients receiving nivolumab and ipilimumab and 36.1% of patients receiving chemotherapy. Treatment related AEs leading to discontinuation were more common with nivolumab plus ipilimumab than with chemotherapy (17.4% vs 8.9%), though patients continued immunotherapy combination longer than chemotherapy. The most common all grade immune-related AEs (irAEs) associated with the immunotherapy combination were skin reactions (33.9%), and the most common grade 3/4 irAEs were hepatic events (8%).

The investigators concluded that these results support the role of nivolumab plus ipilimumab as an effective first-line treatment and validate TMB as an independent predictive biomarker independent of PD-L1 expression level.

N Engl J Med. 2018 April 16 [Epub ahead of print].

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