Abstract 631P
Background
The combination of Atezolizumab, Bevacizumab, and chemotherapy (ABCP) in EGFR-mutated NSCLCpatients has demonstrated enhanced clinical efficacy after tyrosine kinase inhibitor failure. This study investigates exploratory biomarkers using circulating tumor DNA (ctDNA) and tissue-based genomic and immune phenotyping (IP).
Methods
Among the 228 patients who participated in the ATTLAS study, Guardant 360 was conducted using plasma collected at the study's initiation (n=143) for patients treated with the ABCP regimen. Whole genome sequencing (WGS, n=66) and IP analysis (LunitSCOPE, n=148) were performed for both the ABCP and the pemetrexed/carboplatin (PC) arms.
Results
WGS analysis showed high mutant allele tumor heterogeneity (MATH-high) predicted favorable progression-free survival (PFS) with ABCP compared to PC (P=0.02), while no difference in PFS was observed in MATH-low patients. The Guardant 360 conducted within ABCP arm showed no difference in both PFS and overall survival (OS) by tumor mutation burden. Analysis by individual sSNVs subgroups revealed that co-alterations in ASXL1 were associated with significantly longer PFS (P=0.043) within the ABCP arm. Conversely, co-alterations in ERBB2 and STAG2 were associated with shorter OS (P=0.037, P=0.027, respectively). In patients with CNAs, shorter PFS (P=0.011) and OS (P=0.030) were observed within the ABCP arm. Specifically, CNAs in MET, BRAF, EZH2, and CDK6 were linked to both shorter PFS and OS. The analysis exploring the impact of CNAs on survival according to IP revealed that the inflamed phenotype without CNAs (CNA-hot) exhibited significantly longer PFS compared to the immune-desert and excluded phenotype with CNAs (CNA+ cold) (P=0.016) within ABCP arm.
Conclusions
This study explores the predictive value of tumor heterogeneity analyzed by WGS, which showed a favorable outcome with the ABCP regimen compared to chemotherapy alone. The predictive significance of CNAs, analyzed by ctDNA, combined with IP in EGFR-mutated NSCLC patients was observed in patients treated with the ABCP regimen. These results underscore the importance of integrating both genomic and immune profiling to optimize therapeutic strategies.
Clinical trial identification
NCT03991403.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Yuhan.
Disclosure
T.M. Kim: Financial Interests, Personal, Other, Consultancy: AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Janssen, Novartis, Takeda, Samsung Bioepis, REGENERON, Boryng; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca/MedImmune, Boryung, Hanmi, Janssen, Boehringer-Ingelheim, Novartis, Takeda, Sanofi, Roche/Genentech, Merck Sharp & Dohme Corp, Merck Serono, Regeneron, Genmab, Bayer, RAPT Therapeutics, Blueprint Medicines Corporation, Black Diamond Therapeutics, AbbVie, Amgen, Beyondbio Inc, Fore Biotherapeutics, Dizal Pharmaceutical, Incyte Corporation, BeiGene. J. Han: Financial Interests, Personal, Advisory Board: Norvatis, Lantern, Takeda, Janssen, Merck, Pfizer, Amgen, AstraZeneca, Oncobix, AbbVie; Financial Interests, Personal, Invited Speaker: AstraZeneca, Janssen, Merck, Roche, Yuhan, Pfizer, Norvatis. Y. Lee: Non-Financial Interests, Institutional, Advisory Role: Guardant Health. S. Lee: Financial Interests, Personal, Advisory Board: AstraZeneca/MedImmune, Roche, Merck Sharp & Dohme, Pfizer, Eli Lilly, BMS/Ono, Takeda, Janssen, IMBdx, Merck (German), Novartis, Abion, Abion, Beigene, ImmuneOncia, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca/MedImmune, Roche, Merck Sharp & Dohme, Eli Lilly, Amgen, Yuhan; Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme, AstraZeneca, Lunit. M. Ahn: Financial Interests, Personal, Advisory Board: AstraZeneca, Takeda, MSD, Yuhan, Amgen, Alpha Pharmaceutical, Janssen, Bristol Myers Squibb, Roche, Daiichi Sankyo, Merck, Boronoi. All other authors have declared no conflicts of interest.