Abstract CT024: Durvalumab (D) + platinum-etoposide (EP) in 1L extensive-stage small-cell lung cancer (ES-SCLC): Exploratory analysis of SCLC molecular subtypes in CASPIAN
Authors: Xie Mingchao , Chugh Priti , Broadhurst Helen , Lai Zhongwu , Whitston David , Paz-Ares Luis , Gay Carl , Byers Lauren , Rudin Charles M. , Stewart Ross , Barrett J. Carl , Shrestha Yashaswi 
Published: June 2022

Background: In the Phase 3 CASPIAN study, 1L D+EP significantly improved OS vs EP in pts with ES-SCLC with benefit sustained after &gt;3 years of median follow-up (HR 0.71; 95% CI 0.60-0.86; nominal p=0.0003; median OS [mOS] 12.9 mos vs 10.5 mos). 4 SCLC subtypes with distinct therapeutic vulnerabilities were recently identified using 2 different methods (Rudin et al, 2019; Gay et al, 2021) based on differential gene expression. In this exploratory analysis using RNA sequencing (RNAseq) data from CASPIAN, we explored the concordance between the 2 methods and the association of subtypes with OS.

Methods: Pts with ES-SCLC received 4 cycles of D+EP followed by maintenance D; or up to 6 cycles of EP. RNAseq data were generated from FFPE tumor samples collected at screening. Data cutoff: Mar 22, 2021.

Results: 57/268 (21.3%) pts in the D+EP arm and 47/269 (17.5%) pts in the EP arm had RNAseq data (biomarker-evaluable population; BEP). In the BEP, the % of pts with WHO PS 1 was slightly higher and the % with brain metastases slightly lower at baseline vs the ITT population. In the BEP, mOS was 11.8 mos in the D+EP arm vs 9.1 mos in the EP arm (HR 0.61; 95% CI 0.40-0.92). Prevalence of neuroendocrine (ASCL1 and NEUROD1) and non-neuroendocrine subtypes (POU2F3 and YAP1 [Rudin] or Inflamed [Gay]) was similar using both methods (Table). However, ASCL1 was more prevalent and NEUROD1 less prevalent with the Rudin method. Inflamed and YAP1 subtypes (11% and 8% prevalence) showed high concordance between methods. Using either method, the mOS in the D+EP arm was higher in the Inflamed or YAP1 subtype vs the other 3 subtypes (Table). Analysis of OS by gene signature will be presented.

Conclusions: Among the 4 subtypes, the Inflamed or YAP1 subtype showed the longest OS in the D+EP arm, suggesting this may represent a subgroup primed to respond to immunotherapy. Despite the limited sample size, this finding is consistent with other studies.

mOS (95% CI) Rudin et al, 2019 ASCL1 NEUROD1 POU2F3 YAP1* D+EP (n=50) (n=1) (n=2) (n=4) 11.5 (8.4-14.9) 9.5 (NE-NE) 4.8 (2.9-NE) 17.3 (12.8-NE) EP (n=38) (n=2) (n=3) (n=4) 10.7 (8.1-12.4) 7.1 (4.8-NE) 6.1 (1.3-NE) 6.9 (4.5-NE) Gay et al, 2021 ASCL1 NEUROD1 POU2F3 Inflamed D+EP (n=21) (n=25) (n=5) (n=6) 9.5 (6.1-14.9) 14.6 (8.6-16.6) 6.8 (2.9-NE) 17.6 (11.4-NE) EP (n=16) (n=19) (n=7) (n=5) 8.3 (3.0-15.1) 10.5 (7.9-13.6) 7.5 (1.3-10.2) 11.3 (6.3-NE) *A sample is assigned as YAP1 subtype per Rudin et al, 2019, when expression of YAP1 is higher than that of ASCL1, NEUROD1 and POU2F3; NE, not estimable

Citation Format: Mingchao Xie, Priti Chugh, Helen Broadhurst, Zhongwu Lai, David Whitston, Luis Paz-Ares, Carl Gay, Lauren Byers, Charles M. Rudin, Ross Stewart, J. Carl Barrett, Yashaswi Shrestha. Durvalumab (D) + platinum-etoposide (EP) in 1L extensive-stage small-cell lung cancer (ES-SCLC): Exploratory analysis of SCLC molecular subtypes in CASPIAN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT024.