Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133)

Abstract

Purpose: IMpower133 (ClinicalTrials.gov identifier: NCT02763579), a randomized, double-blind, phase I/III study, demonstrated that adding atezolizumab (anti-programmed death-ligand 1 [PD-L1]) to carboplatin plus etoposide (CP/ET) for first-line (1L) treatment of extensive-stage small-cell lung cancer (ES-SCLC) resulted in significant improvement in overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET. Updated OS, disease progression patterns, safety, and exploratory biomarkers (PD-L1, blood-based tumor mutational burden [bTMB]) are reported.

Patients and methods: Patients with untreated ES-SCLC were randomly assigned 1:1 to receive four 21-day cycles of CP (area under the curve 5 mg per mL/min intravenously [IV], day 1) plus ET (100 mg/m² IV, days 1-3) with atezolizumab (1,200 mg IV, day 1) or placebo, and then maintenance atezolizumab or placebo until unacceptable toxicity, disease progression, or loss of clinical benefit. Tumor specimens were collected; PD-L1 testing was not required for enrollment. The two primary end points, investigator-assessed PFS and OS, were statistically significant at the interim analysis. Updated OS and PFS and exploratory biomarker analyses were conducted.

Results: Patients received atezolizumab plus CP/ET (n = 201) or placebo plus CP/ET (n = 202). At the updated analysis, median follow-up for OS was 22.9 months; 302 deaths had occurred. Median OS was 12.3 and 10.3 months with atezolizumab plus CP/ET and placebo plus CP/ET, respectively (hazard ratio, 0.76; 95% CI, 0.60 to 0.95; descriptive P = .0154). At 18 months, 34.0% and 21.0% of patients were alive in atezolizumab plus CP/ET and placebo plus CP/ET arms, respectively. Patients derived benefit from the addition of atezolizumab, regardless of PD-L1 immunohistochemistry or bTMB status.

Conclusion: Adding atezolizumab to CP/ET as 1L treatment for ES-SCLC continued to demonstrate improved OS and a tolerable safety profile at the updated analysis, confirming the regimen as a new standard of care. Exploratory analyses demonstrated treatment benefit independent of biomarker status.

FIG 1.

Patient flow diagram in IMpower133. All patients who underwent random assignment were included in the intention-to-treat analysis. Patients were assigned to receive either atezolizumab plus carboplatin plus etoposide or placebo plus carboplatin plus etoposide. One patient assigned to the placebo group received a dose of atezolizumab and was included in the atezolizumab group in the safety analyses. Clinical cutoff date: January 24, 2019.

FIG 2.

(A) Kaplan-Meier analysis of overall survival (OS) at the updated analysis of the intention-to-treat (ITT) population and (B) OS by baseline characteristics. A total of 57 patients had unknown bTMB score. These patients comprised the nonbiomarker evaluable population, which included 28 patients who had a bTMB result with a maximum somatic allele frequency < 1%, 15 patients who had a sample that either failed quality control at the testing vendor or had median exon coverage < 800, and 14 patients who did not submit a plasma sample at baseline. *P value used for descriptive purposes only. ^aHazard ratios (HRs) are unstratified for patient subgroups and are stratified for the ITT population. Clinical cutoff date: January 24, 2019. bTMB, blood-based tumor mutational burden; CP/ET, carboplatin plus etoposide; ECOG PS, Eastern Cooperative Oncology Group performance status.

FIG 3.

Kaplan-Meier analysis of (A) overall survival (OS) and (B) progression-free survival (PFS) and (C) subgroup analysis of PFS (clinical cutoff date: April 4, 2018) and OS (clinical cutoff date: January 24, 2019) by programmed death-ligand 1 (PD-L1) expression in the biomarker-evaluable population (BEP). *P values used for descriptive purposes only. ^aHazard ratios (HRs) are unstratified for patient subgroups and stratified for the intention-to-treat (ITT) population. CP/ET, carboplatin plus etoposide; NE, not evaluable.