KEYNOTE-604: Pembrolizumab (pembro) or placebo plus etoposide and platinum (EP) as first-line therapy for extensive-stage (ES) small-cell lung cancer (SCLC).

Abstract

9001 Background: Pembro monotherapy showed durable antitumor activity as third-line or later therapy for metastatic SCLC, leading to FDA approval in that setting. KEYNOTE-604 was a double-blind, phase 3 study of pembro + EP vs placebo + EP as first-line therapy for ES-SCLC (NCT03066778). Methods: Eligible patients (pts) with previously untreated ES-SCLC and no untreated CNS metastases were randomized 1:1 to pembro 200 mg Q3W or saline placebo for up to 35 cycles plus 4 cycles of standard-dose EP. Pts with CR or PR after cycle 4 could receive PCI at investigator discretion. Randomization was stratified by platinum choice (carboplatin vs cisplatin), ECOG PS (0 vs 1), and LDH (≤ULN vs > ULN). Primary endpoints were OS and PFS (RECIST v1.1, blinded central review) in the ITT population. ORR, DOR, and safety were secondary endpoints. OS and PFS treatment differences were assessed by the stratified log-rank test. The protocol specified 2 interim analyses (IAs) and a final analysis (FA). Prespecified efficacy boundaries were one-sided P = 0.0048 for PFS at IA2 (prespecified final PFS analysis) and 0.0128 for OS at FA. Results: 453 pts were randomized. 223/228 pts assigned to pembro + EP and 222/225 assigned to placebo + EP received ≥1 dose of assigned treatment; 1 pt assigned to pembro + EP received placebo + EP in error. Median age was 65 y, 74% had ECOG PS 1, and 57% had LDH > ULN; more pts in the pembro + EP arm had baseline brain metastases (14% vs 10%). At FA (median follow-up, 21.6 mo), 9% of pts in the pembro + EP arm and 1% in the placebo + EP arm remained on study treatment; 12% and 14% received PCI. At IA2 (median follow-up, 13.5 mo), pembro + EP significantly improved PFS in the ITT population (HR 0.75 [95% CI 0.61-0.91], P = 0.0023; median 4.5 vs 4.3 mo). At FA, pembro + EP prolonged OS in the ITT population, but the significance threshold was not met (HR 0.80 [95% CI 0.64-0.98], P = 0.0164; median 10.8 vs 9.7 mo). In a post hoc analysis of OS in the as-treated population, the nominal P value was smaller than the significance threshold (HR 0.78 [95% CI 0.63-0.97], P = 0.0124). ORR at FA was 71% for pembro + EP vs 62% for placebo + EP; median DOR was 4.2 vs 3.7 mo. Observed AEs were as expected; any-cause AEs were grade 3-4 in 77% vs 75%, grade 5 in 6% vs 5%, and led to discontinuation in 15% vs 6%. Conclusions: Pembro + EP significantly improved PFS and prolonged OS compared with placebo + EP as first-line therapy for pts with ES-SCLC. No unexpected toxicities were seen with pembro + EP. These data support the benefit of pembro-containing regimens for ES-SCLC. Clinical trial information: NCT03066778.

Report from the ASCO Virtual Congress, May 29th – 31st 2020

“…Patients with asymptomatic brain metastases were allowed to enroll. Le et al reported the primary efficacy, safety, and biomarker results of the VISION trial [9].…”

“…The co-inhibitory receptor TIGIT is expressed on multiple immune cells and inhibits T cells as well as NK cells by binding to its ligand on tumor and antigenpresenting cells [8][9][10]. It was hypothesized that anti-TIGIT antibodies preventing this binding reaction might restore the anti-tumor response and complement the activity of anti-PD-(L)1 antibodies.…”

“…The randomized, phase III CTONG 1104 trial has established a significant DFS benefit of adjuvant treatment with the first-generation EGFR TKI gefitinib 250 mg daily compared to standard doublet chemotherapy consisting of vinorelbine plus cisplatin in EGFR-mutant, completely resected stage II/IIIA NSCLC [8]. Wu et al presented the final OS results after a median follow-up of 80.0 months at the ASCO Congress [9]. The intent-totreat (ITT) population included 111 patients in each treatment arm, while the per-protocol (PP) population included 106 and 87 patients in the gefitinib and chemotherapy arms, respectively.…”

“…Preclinical and clinical studies have demonstrated activity of dual inhibition of the VEGF and EGFR pathways in EGFR-mutant NSCLC [8][9][10][11]. In the phase III RELAY study, the anti-VEGFR2 antibody ramucirumab in combination with the EGFR TKI erlotinib gave rise to prolonged PFS compared to erlotinib alone (19.4 vs. 12.4 months; HR, 0.59) [12].…”

“…The open-label, randomized, multicenter, phase III ALTA-1L study evaluated brigatinib in patients with ALK-TKI-naïve, ALK-positive advanced NSCLC, demonstrating superior efficacy compared to crizotinib with acceptable tolerability at the second interim analysis [9]. Camidge et al evaluated the impact of EML4-ALK fusion variants and other baseline variables on the activity of brigatinib vs. crizotinib in the ALTA-1L trial [10].…”