Abstract 1325P
Background
The POSEIDON phase 3 trial showed an improvement in overall survival (OS) with T+D+CT vs CT in 1L mNSCLC. A post-hoc analysis showed a trend for sustained OS benefit with T+D+CT vs CT in patients with STK11, KEAP1 or KRAS mutations. These patients may require novel combinations (eg. incl. CTLA4) that might enhance responses to PD(L)-1 inhibitor-based regimens.
Methods
POSEIDON’s clinical and laboratory data in the T+D+CT and D+CT arms were combined with radiomic data from computed tomography scans via a segmentation algorithm to generate the T_full set and with available genomic data for NSq cases, to generate the T_NSq set. ML was used to train models to identify patients predicted to derive higher OS benefit from addition of T to D+CT. Nested cross-validation was used to assess performance.
Results
Comparison of OS for T+D+CT vs D+CT within the T_full set yielded a HR of 0.88 (95% CI: 0.73-1.05). A model based on clinical+radiomics data yielded an improved HR of 0.75 (95% CI: 0.58-0.98) for patients with scores >median. Neutrophil/Lymphocyte ratio, radiomics and albumin contributed most to the predictive power. Within the T_NSq set, a model based on clinical+genomic data yielded a HR of 0.56 (95% CI: 0.33-0.97) for patients with scores >median, as compared to 0.88 (95% CI: 0.68-1.12) in the total T_NSq set. EGFR (non activating), FGFR3, CDKN2A, KRAS, STK11 mutations contributed most to the predictive power. Table: 1325P
| Data set description and baseline characteristics | Dataset | Analysis set | N | Age, median (range) | Sex n (%) | Histology n (%) | PD-L1 status n (%) |
| POSEIDON | P_full | ITT | 676 | 64.0 (27-87) | M: 522 (77.2)F: 54 (22.8) | NSq: 423 (62.6)Sq: 252 (37.3)Other: 1 (0.1) | ConclusionsThe ML multimodal models yielded signatures identifying patients that would benefit from T addition to D+CT in 1L mNSCLC: NSq histology and an EGFRwt, FGFR3wt, CDKN2Awt and KRAS and STK11 mutation signature drive higher benefit. Limitations of this analysis include its post hoc nature and need for external validation (planned). TRITON (NCT06008093) study is further evaluating STK11/KEAP1/KRASm mNSCLC population with T+D+CT vs pembrolizumab+CT. Clinical trial identificationEditorial acknowledgementLegal entity responsible for the studyAstraZeneca. FundingAstraZeneca. DisclosureF. Skoulidis: Financial Interests, Personal, Invited Speaker: ESMO, AACR, IASLC, Japanese Lung Cancer Society, Medscape LLC, Intellisphere LLC, VSPO McGill Université de Montreal, MJH Life Sciences, IDEOlogy Health, MI&T, PER LLC, CURIO LLC, DAVA Oncology, BMS and RV Mais Promocao Eventos LTDS; Financial Interests, Institutional, Research Grant: Amgen, Revolution Medicines, Mirati Therapeutics, Boehringer Ingelheim, Merck & Co, and Novartis; Financial Interests, Institutional, Research Grant, Spouse: Almmune, Genentech; Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen Inc., Revolution Medicines, Novartis, BridgeBio, BeiGene, BergenBio, AstraZeneca, Guardant Health Inc., Calithera Biosciences, Tango Therapeutics, Merck Sharp & Dohme, Roche, Novocure, Hookipa Pharma; Financial Interests, Institutional, Speaker, Consultant, Advisor, Spouse: Genentech, Novartis; Financial Interests, Personal, Stocks or ownership: BioNTech SE, Moderna Inc.; Financial Interests, Institutional, Trial Chair: Pfizer. S. Jabbour: Financial Interests, Personal, Advisory Board: AstraZeneca, Merck; Financial Interests, Personal, Expert Testimony: Dechert LLP; Financial Interests, Institutional, Funding: Merck, Adlai, BeiGene, Guardant; Non-Financial Interests, Institutional, Local PI: Merck; Financial Interests, Personal, Speaker, Consultant, Advisor: Ideology, BeiGene, MJH LifeScience, Binaytara. E.B. Garon: Financial Interests, Institutional, Advisory Role: AbbVie; ABL-Bio; AstraZeneca, Boehringer-Ingelheim; Bristol Myers Squibb; Dracen Pharmaceuticals; EMD Serono; Eisai; Eli Lilly; Gilead, GSK; Merck; Natera; Novartis; Personalis; Regeneron; Sanofi; Shionogi; Xilio; Zymeworks; Financial Interests, Institutional, Research Grant: ABL-Bio; AstraZeneca; Bristol Myers Squibb; Daiichi Sanko; Dynavax Technologies; Eli Lilly; EMD Serono; Genentech; Gilead; Iovance Biotherapeutics, Merck; Mirati Therapeutics; Neon; and Novartis. P. Iyengar: Financial Interests, Personal, Advisory Board: AstraZeneca, Novocure, BioConvergent; Financial Interests, Institutional, Funding: Incyte. G. Scagliotti: Financial Interests, Personal, Speaker, Consultant, Advisor, Independent Consultant: AstraZeneca. L. Ferrer, G. Etchepare, O. Gallinato, T. Colin, P. Menu: Financial Interests, Personal, Full or part-time Employment: Sophia Genetics; Financial Interests, Personal, Stocks/Shares: Sophia Genetics. J. Faure, P. Bernard: Financial Interests, Personal, Full or part-time Employment: Sophia Genetics. Y. Lin: Financial Interests, Personal, Full or part-time Employment: Novartis. L. Cai, J. Faria D. Dellamonica, Y. Zhang: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. A. Remorino, K.P. Miller: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. L. Luciani-Silverman: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca, BMS. 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