Frontline ipilimumab/nivolumab improves OS in advanced NCLSC

The first-line combination of ipilimumab plus nivolumab provided clinically meaningful improvement in overall survival (OS) compared with chemotherapy in patients with advanced non–small cell lung cancer (NSCLC), regardless of PD-L1 expression, according to a final analysis of part 1 of the phase 3 CheckMate-227 trial [1].

The open-label CheckMate-227 trial is a multi-cohort study in treatment-naïve patients with stage IV or recurrent NSCLC. In part 1 of the trial, presented by Prof. Solange Peters (Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland), there were 2 cohorts: patients whose tumours expressed ≥1% PD-L1 (part 1a) and those whose PD-L1 expression was <1% (part 1b). In part 1a, 1,189 patients were randomised 1:1:1 to receive either chemotherapy, nivolumab monotherapy, or nivolumab plus low-dose ipilimumab. In part 1b, 550 patients were randomised 1:1:1 to nivolumab/low-dose ipilimumab, chemotherapy, or nivolumab/chemotherapy.

The independent co-primary endpoints of the study were progression-free survival (PFS) in a high tumour mutational burden (TMB) population and OS in the PD-L1 ≥1% population. Secondary endpoints included PFS and OS with nivolumab/chemotherapy vs chemotherapy in the PD-L1 <1% subgroup, and OS with nivolumab vs chemotherapy in patients with PD-L1 expression ≥50%. The minimum follow-up for the primary endpoint was 29 months.

In patients with tumours expressing PD-L1 ≥1% the median OS with nivolumab plus ipilimumab compared with chemotherapy was 17.1 months vs 14.9 months, respectively (HR 0.79; 97.72% CI 0.65-0.96; P=0.007). Moreover, the median OS was 17.1 months with the combination and 13.9 months with chemotherapy in patients regardless of PD-L1 expression (HR 0.73; 95% CI 0.64-0.84). The 1- and 2-year OS rates were 63% and 40% with nivolumab/ipilimumab and 56% and 33% with chemotherapy, respectively. The median duration of response by blinded independent central review was 23.2 months, 15.5 months, and 6.2 months for nivolumab/ipilimumab, nivolumab, and chemotherapy, respectively. Objective response rates (ORR) at 1 year were 64%, 63%, and 28%, respectively; the rates of those in response at 2 years were 49%, 40%, and 11%, respectively. Notably, patients with tumours expressing PD-L1 ≥50% benefitted the most from nivolumab/ipilimumab combination therapy.

In part 1b, patients whose tumours had <1% PD-L1 expression had a median OS of 17.2 months, 15.2 months, and 12.2 months with nivolumab/ipilimumab, nivolumab/chemotherapy, and chemotherapy, respectively (HR for nivolumab/ipilimumab vs chemotherapy 0.62; 95% CI 0.48-0.78; HR for nivolumab/chemotherapy vs chemotherapy 0.78; 95% CI 0.60-1.02) The 1-year OS rates with nivolumab/ipilimumab, nivolumab/chemotherapy, and chemotherapy were 60%, 59%, and 51%, respectively; the 2-year OS rates were 40%, 35%, and 23%, respectively.

For all randomised patients, regardless of PD-L1 expression, the 1-year OS rates with nivolumab/ipilimumab and chemotherapy were 62% and 54%, respectively; the 2-year OS rates were 40% and 30%, respectively.

Additionally, no new safety findings of the combination were reported with longer follow-up. Grade 3/4 treatment-related adverse events were reported in 33%, 19%, and 36% of patients in the nivolumab/ipilimumab, single-agent nivolumab, and chemotherapy arms, respectively.

One limitation of this study was that it compared nivolumab/ipilimumab with nivolumab monotherapy as a second immunotherapy option (which has not shown benefit in the first-line setting in PD-L1 expressing patients). In the treatment group expressing PD-L1, the main response seems to have been driven by the high PD-L1 expressing tumours, with an overall response similar to other checkpoint inhibitor monotherapy in other studies, but higher toxicity. In tumours not expressing PD-L1, the response rate was significantly higher as compared with platinum doublet chemotherapy. This did however not translate in a survival benefit and came with notable toxicity.

1. Peters S, et al. ESMO Congress 2019. Abstract LBA4.
2. Hellmann MD et al. N Eng J Med. doi: 10.1056/NEJMoa1910231.

Posted on 26 November 201918 March 2021