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

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

doi:10.1016/j.lungcan.2023.107418

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

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. ShamesMartin Reck

Medical Oncology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	107418
Journal	Lung Cancer
Volume	186
DOIs	https://doi.org/10.1016/j.lungcan.2023.107418
State	Published - Dec 2023

Keywords

(maximum 6): Small cell lung carcinoma
Atezolizumab
Carboplatin
Clinical trial IMpower133
Etoposide
Gene expression profiling
Immune checkpoint inhibitors
RNA Sequence analysis

ASJC Scopus subject areas

Oncology
Pulmonary and Respiratory Medicine
Cancer Research

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10.1016/j.lungcan.2023.107418

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Liu, S. V., Mok, T. S. K., Nabet, B. Y., Mansfield, A. S., De Boer, R., Losonczy, G., Sugawara, S., Dziadziuszko, R., Krzakowski, M., Smolin, A., Hochmair, M. J., Garassino, M. C., Gay, C. M., Heymach, J. V., Byers, L. A., Lam, S., Cardona, A., Morris, S., Adler, L., ... Reck, M. (2023). Clinical and molecular characterization of long-term survivors with extensive-stage small cell lung cancer treated with first-line atezolizumab plus carboplatin and etoposide. Lung Cancer, 186, Article 107418. https://doi.org/10.1016/j.lungcan.2023.107418

Liu, SV, Mok, TSK, Nabet, BY, Mansfield, AS, De Boer, R, Losonczy, G, Sugawara, S, Dziadziuszko, R, Krzakowski, M, Smolin, A, Hochmair, MJ, Garassino, MC, Gay, CM, Heymach, JV, Byers, LA, Lam, S, Cardona, A, Morris, S, Adler, L, Shames, DS & Reck, M 2023, 'Clinical and molecular characterization of long-term survivors with extensive-stage small cell lung cancer treated with first-line atezolizumab plus carboplatin and etoposide', Lung Cancer, vol. 186, 107418. https://doi.org/10.1016/j.lungcan.2023.107418

@article{da6f755f728148f6942fa4e1a662b8aa,

title = "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.",

keywords = "(maximum 6): Small cell lung carcinoma, Atezolizumab, Carboplatin, Clinical trial IMpower133, Etoposide, Gene expression profiling, Immune checkpoint inhibitors, RNA Sequence analysis",

author = "Liu, {Stephen V.} and Mok, {Tony S.K.} and Nabet, {Barzin Y.} and Mansfield, {Aaron S.} and {De Boer}, Richard and Gy{\"o}rgy Losonczy and Shunichi Sugawara and Rafal Dziadziuszko and Maciej Krzakowski and Alexey Smolin and Hochmair, {Maximilian J.} and Garassino, {Marina C.} and Gay, {Carl M.} and Heymach, {John V.} and Byers, {Lauren A.} and Sivuonthanh Lam and Andr{\'e}s Cardona and Stefanie Morris and Leah Adler and Shames, {David S.} and Martin Reck",

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = dec,

doi = "10.1016/j.lungcan.2023.107418",

language = "English (US)",

volume = "186",

journal = "Lung Cancer",

issn = "0169-5002",

publisher = "Elsevier Ireland Ltd",

}

TY - JOUR

T1 - Clinical and molecular characterization of long-term survivors with extensive-stage small cell lung cancer treated with first-line atezolizumab plus carboplatin and etoposide

AU - Liu, Stephen V.

AU - Mok, Tony S.K.

AU - Nabet, Barzin Y.

AU - Mansfield, Aaron S.

AU - De Boer, Richard

AU - Losonczy, György

AU - Sugawara, Shunichi

AU - Dziadziuszko, Rafal

AU - Krzakowski, Maciej

AU - Smolin, Alexey

AU - Hochmair, Maximilian J.

AU - Garassino, Marina C.

AU - Gay, Carl M.

AU - Heymach, John V.

AU - Byers, Lauren A.

AU - Lam, Sivuonthanh

AU - Cardona, Andrés

AU - Morris, Stefanie

AU - Adler, Leah

AU - Shames, David S.

AU - Reck, Martin

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

KW - (maximum 6): Small cell lung carcinoma

KW - Atezolizumab

KW - Carboplatin

KW - Clinical trial IMpower133

KW - Etoposide

KW - Gene expression profiling

KW - Immune checkpoint inhibitors

KW - RNA Sequence analysis

UR - http://www.scopus.com/inward/record.url?scp=85175797330&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85175797330&partnerID=8YFLogxK

U2 - 10.1016/j.lungcan.2023.107418

DO - 10.1016/j.lungcan.2023.107418

M3 - Article

C2 - 37931445

AN - SCOPUS:85175797330

SN - 0169-5002

VL - 186

JO - Lung Cancer

JF - Lung Cancer

M1 - 107418

ER -

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

Keywords

ASJC Scopus subject areas

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