Clinical and molecular characterization of long-term survivors with extensive-stage small cell lung cancer treated with first-line atezolizumab plus carboplatin and etoposide.

Abstract

OBJECTIVES:

In the Phase I/III IMpower133 study, first-line atezolizumab plus carboplatin and etoposide (CP/ET) treatment for extensive-stage small cell lung cancer (ES-SCLC) significantly improved overall survival (OS) and progression-free survival versus placebo plus CP/ET. We explored patient and disease characteristics associated with long-term survival in IMpower133, and associations of differential gene expression and SCLC-A (ASCL1-driven), SCLC-N (NEUROD1-driven), SCLC-P (POU2F3-driven), and SCLC-inflamed (SCLC-I) transcriptional subtypes with long-term survival.

MATERIALS AND METHODS:

Patients with previously untreated ES-SCLC were randomized 1:1 to four 21-day cycles of CP/ET with atezolizumab or placebo. Long-term survivors (LTS) were defined as patients who lived ≥ 18 months post randomization. A generalized linear model was used to evaluate the odds of living ≥ 18 months. Differential gene expression was analyzed using RNA-sequencing data in LTS and non-LTS. OS was assessed by T-effector and B-cell gene signature expression. Distribution of SCLC transcriptional subtypes was assessed in LTS and non-LTS.

RESULTS:

More LTS were in the atezolizumab arm (34%) than in the placebo arm (20%). The odds ratio for living ≥ 18 months in the atezolizumab arm versus the placebo arm was 2.1 (P < 0.03). Enhanced immune-related signaling was seen in LTS in both arms. Exploratory OS analyses showed atezolizumab treatment benefit versus placebo across T-effector and B-cell gene signature expression subgroups. A higher proportion of LTS than non-LTS in both arms had the SCLC-I subtype; this difference was particularly pronounced in the atezolizumab arm.

CONCLUSION:

These exploratory analyses suggest that long-term survival is more likely with atezolizumab than placebo in ES-SCLC, confirming the treatment benefit of the IMpower133 regimen.

CLINICALTRIAL:

gov Identifier: NCT02763579.

• Authors: Stephen V Liu, Tony S K Mok, Barzin Y Nabet, Aaron S Mansfield, Richard De Boer, György Losonczy, Shunichi Sugawara, Rafal Dziadziuszko, Maciej Krzakowski, Alexey Smolin, Maximilian J Hochmair, Marina C Garassino, Carl M Gay, John V Heymach, Lauren A Byers, Sivuonthanh Lam, Andrés Cardona, Stefanie Morris, Leah Adler, David S Shames, Martin Reck
• Journal: Lung cancer (Amsterdam, Netherlands) (Lung Cancer) Vol. 186 Pg. 107418 (12 2023) ISSN: 1872-8332 [Electronic] Ireland
• PMID: 37931445 (Publication Type: Randomized Controlled Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023. Published by Elsevier B.V.

Chemical References

• Carboplatin
• Etoposide
• atezolizumab

Topics

• Humans
• Small Cell Lung Carcinoma (drug therapy, genetics)
• Carboplatin
• Etoposide
• Lung Neoplasms (drug therapy, genetics)
• Survivors
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)