2300P - Clonal hematopoiesis of indeterminate potential (CHIP) in patients with advanced NSCLC treated with immune checkpoint blockers (ICB) as monotherapy: Analysis of the PREMIS study

Background

Immunotherapy is one of the mainstays of lung cancer treatment. However, the results presented in pivotal trials do not always reflect those in real life, as patients (pts) are more selected for prognostic factors. Cancer is associated with advanced age, and aging is the main risk factor for developing CHIP, a clonal expansion of mutations affecting genes involved in hematologic malignancies in pts without a hematological disease per se.

Methods

We performed a Next-Generation Sequencing (NGS) panel of 74-genes dedicated to hematological alterations on DNA extracted from whole blood collected before first administration of an ICB for advanced NSCLC, within the PREMIS trial (NCT03984318). CHIP prevalence was assessed according to a variant allele frequency (VAF) threshold of 2%. The main objective is to evaluate CHIP prevalence in a prospective cohort of pts treated with ICB for NSCLC correlating CHIP with clinical outcomes.

Results

We included 104 pts; 68 pts (65%) male, median age of 68 years [range 31-87], and adenocarcinoma represented 68% of cases. ICB setting was 1°L 41%; 2°L 47%; ≥ 3°L 11%, and the most used ICB was Pembrolizumab in 63% of pts. Finally, 98 pts were retained for the analysis. At least 1 CHIP mutation was found in 47 pts (48%).The most frequent mutations were found in DNMT3A (69%), PPM1D (17%), TET2, ASXL1 and CHEK2 genes (7% respectively). Median PFS was 2.6 months (m) for CHIP vs 9.3 m no-CHIP 12 m (p=0.02) and median OS was 9.3 m CHIP vs 15 m no-CHIP (p=0.11), associated to lower percentage of PD-L1 and a higher number of metastatic sites in the multivariate analysis. No pts developed hematological disease during the follow up.

Conclusions

CHIP is commonly found in pts with NSCLC, with a prevalence in our cohort of 48% with statistically significant worse PFS in the CHIP-positive population.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

A. Marabelle: Financial Interests, Personal, Advisory Board: Gritstone, Innate Pharma, Neogene, Deka Biosciences, Hotspot Therapeutics, Johnson & Johnson, Depth Charge, Bioline Rx, Clover Biopharmaceuticals, Grey Wolf Therapeutics, Lytix Biopharma, RedX Pharma, HiFiBiO Therapeutics, ImCheck Therapeutics, Shattuck Labs, Marengo Therapeutics, PegaOne; Financial Interests, Personal, Other, Associate Editor: European Journal of Cancer; Financial Interests, Personal, Stocks/Shares: HiFiBiO Therapeutics, Deka Biosciences, HotSpot Therapeutics, Shattuck Labs; Financial Interests, Institutional, Research Grant: BMS, AstraZeneca, Sanofi; Financial Interests, Institutional, Coordinating PI: IMCheck, SOTIO, Roche/Genentech, MSD, BMS, OSE Immunotherapeutics, Eisai, Pierre Fabre, Adlai Nortye, Molecular Partners; Financial Interests, Steering Committee Member: Roche; Financial Interests, Institutional, Funding: Transgene; Non-Financial Interests, Other, Associate Editor: IOTECH Journal; Non-Financial Interests, Institutional, Product Samples: BMS, Idera, MSD, Transgene; Non-Financial Interests, Leadership Role: Société Française d'Immunothérapie des Cancers; Non-Financial Interests, Member: Society for Immunotherapy of Cancer, American Association for Cancer Research, American Society for Clinical Oncology; Other, Consultant: Third Rock Ventures, Guidepoint; Other, Advisor: Medicxi. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Onxeo, OSE immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals; Financial Interests, Institutional, Research Grant: Genzyme Corporation, Chugai Pharmaceutical, Eisai, Inivata, Ipsen, Turning Point Therapeutics. J. Baptiste Micol: Financial Interests, Advisory Board: AbbVie, Jazz Pharmaceuticals; Financial Interests, Personal, Other: AbbVie, Jazz Pharma, Astellas. S. Ponce Aix: Financial Interests, Advisory Board: Roche, MSD, AstraZeneca, Bristol Myers Squibb, PharmaMar, Boehringer Ingelheim, BMS. Expert testimony: Roche, MSD, AstraZeneca, Bristol Myers Squibb, PharmaMar, Boehringer Ingelheim, BMS. Travel, accommodations, expenses: MSD, Roche, BMS, AstraZeneca, Ph; Financial Interests, Speaker, Consultant, Advisor: Bristol Myers Squibb. C. Marzac: Financial Interests, Advisory Board: Astellas. C. Massard: Other, Consultant/Advisory fees from Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, Orion Principal/sub-Investigator of Clinical Trials for AbbVie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo Pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boehringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 Biomedicine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, MedImmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, PharmaMar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, Xencor: Company. C. Baldini: Other, Institutional, Principal Investigator: AbbVie, Adaptimmune, Adlai Nortye USA Inc., Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd., Bayer Healthcare Ag, Bbb Technologies Bv, Beige; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca, BMS, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Financial Interests, Funding: BMS Fundation; Financial Interests, Speaker, Consultant, Advisor: Bicycle Therapeutics, Rising Tide Fundation, ITEOS. All other authors have declared no conflicts of interest.