ES-SCLC: New pembrolizumab KEYNOTE-604 trial data

The phase 3 KEYNOTE-604 trial showed that patients with extensive-stage small-cell lung cancer who received pembrolizumab with etoposide/platinum, compared with patients who received EP and placebo, did not benefit from improved overall survival.

Data from the phase 3 KEYNOTE-604 trial showed that patients with extensive-stage small-cell lung cancer (ES-SCLC) who received pembrolizumab with backbone chemotherapy etoposide/platinum (EP) compared with patients who received EP and placebo did not benefit from improved overall survival (OS). However, progression-free survival (PFS) rates did reach the threshold for significance.

Dr. Charles M. Rudin (Memorial Sloan Kettering Cancer Center, USA) presented the findings [1]. The KEYNOTE-604 study aimed to improve upon the efficacy of immunotherapy in newly diagnosed ES-SCLC with the combination of pembrolizumab and EP.

The study randomized 453 patients; and were provided with pembrolizumab 220 mg on day 1 plus EP 100 mg/m2 on days 1 and 2 and carboplatin AUC 5 on day 1 or cisplatin 75 mg/m2 on day 1 (n=228) or placebo, matching EP, and carboplatin or cisplatin (n=225) for up to 31 cycles. The co-primary endpoints were PFS per RECIST v1.1 by blinded independent central review and OS. Secondary endpoints were overall response rate (ORR) and duration of response (DOR) per RECIST v1.1 by an independent review as well as safety.

The final PFS analysis was significant (4.8 vs 4.3 months; HR 0.73; 95% CI 0.60-0.88). The 12-month PFS rate observed with the pembrolizumab combination was 15.9% versus 5.0% with the placebo combination. Even at 18 months, the PFS rate in the pembrolizumab arm was higher than the placebo arm at 10.8% versus 2.1%. In terms of OS, pembrolizumab/EP prolonged OS compared with the control combination (10.8 v 9.7 months; HR 0.80; 95% CI, 0.64-0.98; P=0.0164), but it did not reach the superiority threshold, which was P≤0.0128. The 12-month OS rate was 45.1% in the pembrolizumab arm compared with 39.6% in the placebo arm. At 24 months, the OS rate was 22.5% in the pembrolizumab arm compared with 11.2% in the placebo arm.

The safety analysis showed that adverse events (AEs) of any grade occurred in 100% of patients in the pembrolizumab arm and 99.6% of patients in the placebo arm, in the as-treated population. AEs were grade 3/4 in 76.7% of subjects who received pembrolizumab/EP compared with 74.9% of those who received the placebo combination. Grade 5 AEs/death occurred in 6.3% of patients in the pembrolizumab arm versus 5.4% in the control arm.

Placing these results in context, other trials looking at immunotherapy in this setting like the phase 3 IMpower 133 study, as well as the CASPIAN trial significantly improved OS compared with EP alone. However, both of these other trials provided stronger responses, raising the question of whether there may be a distinction in targeting PD-L1 as opposed to PD-1.

1. Rudin CM, et al. KEYNOTE-604: Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer. ASCO Virtual Meeting, 29-31 May 2020, Abstract 9001.

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