No long-term benefit of adding ipilimumab to pembrolizumab in metastatic NSCLC

Although the addition of ipilimumab to first-line nivolumab improved overall survival (OS) of patients with metastatic non-small cell lung cancer (NSCLC), long-term results from KEYNOTE-598 demonstrated that adding ipilimumab to first-line pembrolizumab does not improve survival of patients with metastatic NSCLC and PD-L1 TPS ≥50%.

Previously, results of the phase 3 CheckMate 227 trial (NCT02477826) showed that first-line dual immune blockade with nivolumab plus ipilimumab provides a durable, long-term OS benefit versus chemotherapy in patients with advanced NSCLC, regardless of PD-L1 expression or histology [1].

The phase 3 KEYNOTE-598 trial (NCT03302234) evaluated the efficacy and toxicity of first-line pembrolizumab plus ipilimumab versus pembrolizumab monotherapy in patients with metastatic NSCLC with PD-L1 tumour proportion score (TPS) ≥50%. In the protocol-specified interim analysis, it was concluded that the addition of ipilimumab to pembrolizumab did not improve OS or progression-free survival (PFS) [2]. As a consequence, ipilimumab was discontinued and all patients continued with pembrolizumab monotherapy. Dr Delvys Rodriguez-Abreu (Universidad de Las Palmas de Gran Canaria, Spain) presented the 3-year follow-up results [3].

In KEYNOTE-598, a total of 568 patients with previously untreated, stage IV NSCLC and PD-L1 TPS ≥50% were randomised 1:1 to pembrolizumab plus ipilimumab or pembrolizumab plus placebo. Ipilimumab and placebo were given up to 18 doses; pembrolizumab up to 35 doses. Dual primary endpoints were OS and PFS. The median time from randomisation to data cut-off was 33.6 months.

After discontinuing ipilimumab or placebo for all patients, median OS and PFS remained similar between groups. Median OS was 22.1 and 22.7 months, and median PFS was 8.2 and 8.4 months, respectively, in the pembrolizumab plus ipilimumab and pembrolizumab plus placebo arms. Two-year OS rate was 48.0% and 48.5%, respectively; 2-year PFS rate was 27.2% and 25.1%, respectively. Objective response rate (ORR) was 46.5% and 46.1%, respectively.

Among participants initially treated with pembrolizumab plus ipilimumab (n=52) versus pembrolizumab plus placebo (n=71) who completed 35 cycles of pembrolizumab, ORR was 88.5% versus 87.3%, respectively; OS and PFS rates 1 year from completing pembrolizumab were 86.3% versus 87.6% and 72.8% versus 83.5%, respectively.

Grade 3–5 treatment-related adverse events occurred in 35.1% and 20.3% of participants in the pembrolizumab plus ipilimumab and pembrolizumab plus placebo arm, respectively.

Overall, with continued follow-up, results did not show a survival benefit with pembrolizumab plus ipilimumab versus pembrolizumab monotherapy. Two-year OS rates were similar between groups and safety favoured pembrolizumab monotherapy. “Therefore, pembrolizumab monotherapy remains a standard of care therapy for metastatic NSCLC with PD-L1 TPS ≥50%,” concluded Dr Rodriguez-Abreu.

1. Paz-Ares LG, et al. Abstract 9016, ASCO Annual Meeting 2021, 04–08 June.
2. Boyer M, et al. J Clin Oncol. 2021;39:2327–2338.
3. Rodriguez-Abreu D, et al. Pembrolizumab plus ipilimumab or placebo in previously untreated metastatic NSCLC with PD-L1 tumor proportion score ≥50%: KEYNOTE-598 3-year follow-up. Abstract 6MO. ELCC 2022 Virtual Meeting, 30 March–02 April.

 

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Posted on 25 May 202215 February 2024