Molecular characterization from IMfirst: Atezolizumab plus chemotherapy in extensive-stage small cell lung cancer (ES-SCLC) in Spain

BackgroundSmall cell lung cancer (SCLC) is a highly aggressive disease, mostly diagnosed at a metastatic stage. Its tumorigenesis is linked to heavy tobacco exposure, which causes genomic instability. An in-depth understanding of the genomic alterations is key to advance in the management of the disease. Here, we characterized the mutational landscape at baseline and progression of SCLC patients (pts) from IMfirst (EudraCT: 2019-002784-10), a phase IIIb study that evaluates the safety of atezolizumab + carboplatin/cisplatin + etoposide in ES-SCLC in Spain.MethodsTissue and liquid biopsies were analyzed by FoundationONE®CDx and FoundationOne®Liquid, respectively. The association of mutations (with an absolute frequency ≥5) or TMB with overall survival (OS) was assessed by univariate Cox regression. TMB was classified as high or low based on a 10 mutations/megabase cut-off. A p <0.05 was considered statistically significant.ResultsIn total, 155 pts were included. Median follow-up was 28.4 months (data cut off: 14 Dec 2022). Tissue baseline, liquid baseline and liquid progression biopsies were reported for 64, 131 and 63 pts, respectively. Most pts harbored at least one genomic alteration, with a median (range) of mutations/pt of 3 (1-19), 4 (1-34) and 4 (1-29) in the aforementioned types of biopsies, respectively. The most common altered genes (>10% of pts) in tissue or liquid baseline biopsies were TP53, RB1, PTEN, DNMT3A, and KMT2D, while in liquid biopsies at progression were TP53, RB1, PTEN, DNMT3A, and CHEK2. Baseline mutations in DNMT3A (HR [95% CI] = 0.52 [0.28, 0.97]), NOTCH1 (HR [95% CI] = 3.52 [1.74, 7.12]), NOTCH3 (HR [95% CI] = 4.69 ([1.87, 11.76]), and MYCN (HR [95% CI] = 3.31 [1.42, 7.71]) were significantly associated with OS. Of the 60 pts with a TMB report in tissue baseline biopsy, 21 (35%) had a TMB-high status and showed a tendency towards a favorable OS compared to TMB-low pts [13.1 vs. 9.9 months, HR 0.60 (95% CI: 0.32–1.12)].ConclusionsThis exploratory analysis provides a detailed profiling of the molecular alterations found in ES-SCLC pts from IMfirst, assessed by solid and liquid biopsies at baseline and progression. The potential prognostic value of the identified genes should be further validated.Clinical trial identificationEudraCT: 2019-002784-10.Legal entity responsible for the studyRoche Farma, S.A.FundingRoche Farma, S.A.DisclosureM. Cobo Dols: Financial Interests, Personal, Advisory Role: Roche, BMS, AstraZeneca, Pfizer, Boehringer; Financial Interests, Personal, Other, travel/accommodation/congress: Roche, BMS, AstraZeneca. M. Dómine Gómez: Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, MSD, BMS, AstraZeneca, Pfizer; Financial Interests, Personal, Other, travel/accommodation/congress: MSD, AstraZeneca, Pfizer, Takeda, Sanofi; Financial Interests, Personal, Advisory Role: PharmaMar, Amgen, Janssen, Takeda, Sanofi. J. de Castro Carpeño: Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, Merck, AstraZeneca, Pfizer, Amgen, Janssen, Takeda, Sanofi; Financial Interests, Personal, Advisory Role: BMS, GSK, Boehringer; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Personal, Other, travel/accommodation/congress: Roche, Merck, BMS, AstraZeneca. A.L. Moreno Vega: Financial Interests, Personal, Other, honoraria: Roche, AstraZeneca, PharmaMar; Financial Interests, Personal, Other, travel/accommodation/congress: Roche, Pfizer. S. Ponce Aix: Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, Merck, BMS, AstraZeneca, Lilly; Financial Interests, Personal, Invited Speaker: Pfizer, PharmaMar, Bayer, Amgen, Boehringer Ingelheim Takeda. E. Arriola Aperribay: Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, Merck, BMS, AstraZeneca, Lilly, Pfizer, Boehringer Ingelheim Takeda; Financial Interests, Personal, Other, honoraria: Roche, Merck, BMS, AstraZeneca, Lilly, Pfizer, Boehringer Ingelheim Takeda; Financial Interests, Institutional, Research Grant: Roche, BMS, Pfizer, Boehringer; Financial Interests, Personal, Other, travel/accommodation/congress: Roche, Merck, BMS, AstraZeneca, Lilly, Pfizer, Boehringer. E. Carcereny: Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, Merck, BMS, Takeda; Financial Interests, Personal, Other, travel/accommodation/congress: Roche, AstraZeneca, Pfizer; Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK; Financial Interests, Personal, Advisory Role: Pfizer, Boehringer. M. Majem: Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, Merck, BMS, AstraZeneca, Amgen, Boehringer; Financial Interests, Institutional, Research Grant: Roche, BMS, AstraZeneca; Financial Interests, Personal, Other, travel/accommodation/congress: Roche, Merck, AstraZeneca, Pfizer; Financial Interests, Personal, Advisory Role: Lilly, Janssen, Takeda, Sanofi; Financial Interests, Personal, Ownership Interest, travel/accommodation/congress: Lilly; Financial Interests, Personal, Invited Speaker: Pfizer. E. Esteban González: Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, Merck, BMS, AstraZeneca, Pfizer, Janssen, Ipsen, Takeda; Financial Interests, Institutional, Research Grant: Roche, Merck, BMS, AstraZeneca, Lilly, Pfizer, Bayer, Janssen, Ipsen, Takeda; Financial Interests, Personal, Invited Speaker: Lilly, Bayer; Financial Interests, Personal, Advisory Role: Boehringer. J. Fuentes Pradera: Financial Interests, Personal, Advisory Role: Roche, BMS, Pfizer, GSK. A.L.O. Ortega Granados: Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, Merck, BMS, Boehringer; Financial Interests, Personal, Other, travel/accommodation/congress: Roche, Merck, BMS. M. Guillot Morales: Financial Interests, Personal, Speaker, Consultant, Advisor: Roche; Financial Interests, Personal, Invited Speaker: Merck, Servier, Amgen; Financial Interests, Personal, Other, travel/accommodation/congress: Merck, Servier, Amgen. B. Massuti Sureda: Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, Merck, Boehringer; Financial Interests, Personal, Invited Speaker: BMS, Pfizer; Financial Interests, Personal, Advisory Role: AstraZeneca, Takeda. N. González Mancha: Financial Interests, Personal, Full or part-time Employment: Roche. C.A. Fajardo: Financial Interests, Personal, Full or part-time Employment: Roche. L. García Palacios: Financial Interests, Personal, Full or part-time Employment: Roche. N. Lerones Laborda: Financial Interests, Personal, Full or part-time Employment: Roche. M.R. García Campelo: Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Roche, Janssen, MSD, Pfizer, Takeda; Financial Interests, Personal, Advisory Role: Lilly, Sanofi; Financial Interests, Personal, Invited Speaker: Merck, Novartis; Financial Interests, Institutional, Research Grant: BMS, Merck, Pfizer; Financial Interests, Institutional, Other, clinical trial: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Roche, GSK, Janssen, Lilly, Merck, Mirati Therapeutics, MSD, Novartis, Amgen, Pfizer. All other authors have declared no conflicts of interest.