Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden

Abstract

Background: Nivolumab plus ipilimumab showed promising efficacy for the treatment of non-small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as a potential biomarker of benefit. In this part of an open-label, multipart, phase 3 trial, we examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (≥10 mutations per megabase).

Methods: We enrolled patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy. Those with a level of tumor programmed death ligand 1 (PD-L1) expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy; those with a tumor PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. Tumor mutational burden was determined by the FoundationOne CDx assay.

Results: Progression-free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free survival was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P<0.001). The objective response rate was 45.3% with nivolumab plus ipilimumab and 26.9% with chemotherapy. The benefit of nivolumab plus ipilimumab over chemotherapy was broadly consistent within subgroups, including patients with a PD-L1 expression level of at least 1% and those with a level of less than 1%. The rate of grade 3 or 4 treatment-related adverse events was 31.2% with nivolumab plus ipilimumab and 36.1% with chemotherapy. ical; CheckMate 227 ClinicalTrials.gov number, NCT02477826 .).

Conclusions: Progression-free survival was significantly longer with first-line nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a high tumor mutational burden, irrespective of PD-L1 expression level. The results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection. (Funded by Bristol-Myers Squibb and Ono Pharmaceut

Figure 1.. Trial Design.

Chemotherapy for patients with nonsquamous non–small-cell lung cancer (NSCLC) consisted of pemetrexed (500 mg per square meter of body-surface area) plus cisplatin (75 mg per square meter) or carboplatin (area under the concentration-time curve [AUC], 5 or 6), every 3 weeks for up to four cycles, with optional maintenance therapy with pemetrexed (500 mg per square meter) after chemotherapy or with nivolumab (360 mg every 3 weeks) plus pemetrexed (500 mg per square meter) after nivolumab plus chemotherapy. Chemotherapy for patients with squamous NSCLC consisted of gemcitabine (1000 or 1250 mg per square meter) plus cisplatin (75 mg per square meter), or gemcitabine (1000 mg per square meter) plus carboplatin (AUC, 5), every 3 weeks for up to four cycles. The tumor mutational burden (TMB) coprimary analysis was conducted in the subgroup of patients assigned to nivolumab plus ipilimumab or chemotherapy who had a TMB of at least 10 mutations per megabase. Given the recommendation of the data and safety monitoring committee to continue the trial for overall survival, analysis of the coprimary end point of overall survival among patients selected on the basis of the programmed death ligand 1 (PD-L1) expression level was not performed for the current database lock. Eastern Cooperative Oncology Group (ECOG) performance-status scores range from 0 to 5, with higher scores indicating greater disability.

Figure 2.. Efficacy of Nivolumab plus Ipilimumab versus Chemotherapy in Patients with a High Tumor Mutational Burden.

A high tumor mutational burden was defined as at least 10 mutations per megabase. In Panel A, the 95% confidence interval for the hazard ratio for disease progression or death was 0.43 to 0.77. In both panels, the circles (for nivolumab plus ipilimumab) and triangles (for chemotherapy) indicate censored data. NR denotes not reached.

Figure 3.. Progression-free Survival among Patients with a High Tumor Mutational Burden According to Tumor PD-L1 Expression and Histologic Type.

A high tumor mutational burden was defined as at least 10 mutations per megabase. The circles (for nivolumab plus ipilimumab) and triangles (for chemotherapy) indicate censored data.

Figure 4.. Subgroup Analyses of Progression-free Survival among Patients with a High Tumor Mutational Burden.

A high tumor mutational burden was defined as at least 10 mutations per megabase. The subgroup of patients who had never smoked could not be evaluated owing to the small sample size.