2MO - First-line (1L) nivolumab (NIVO) + ipilimumab (IPI) in metastatic non-small cell lung cancer (mNSCLC): clinical outcomes and biomarker analyses from CheckMate 592

Background

A high unmet need remains for predictive biomarkers for efficacy in patients (pts) treated with immunotherapy. Here we report primary results from Parts 1 and 2 of CheckMate 592 (NCT03001882), an open-label, phase 2 trial exploring the association of biomarkers with efficacy of 1L NIVO + IPI in pts with mNSCLC.

Methods

Pts with previously untreated mNSCLC were enrolled to either Part 1 (stratified by tumor PD-L1 ≥1% and <1%) or Part 2 and received NIVO (240 mg Q2W) + IPI (1 mg/kg Q6W) until disease progression, unacceptable toxicity, or for ≤ 2 y of treatment (tx). Primary endpoints (EPs): ORR (per investigator) by baseline (BL) and on-tx biomarkers including PD-L1 expression in Part 1; ORR by BL tumor mutational burden in tissue and blood (tTMB and bTMB) in both Parts 1 and 2. Other EPs included safety and exploratory biomarker analyses. Four-gene inflammatory gene signature (CD8A, CD274, STAT-1, LAG-3) was assessed in biopsy samples at BL and on-tx by RNA sequencing.

Results

BL characteristics were generally similar between Part 1 (n = 60) and Part 2 (n = 170), and across tTMB and bTMB subgroups. At 12.5-mo minimum follow up, ORR in Part 1 was 30% and 39% in PD-L1 ≥1% (n = 30) and <1% (n = 28) subgroups, respectively. ORR by TMB (Parts 1 and 2 combined) is shown in the table. Four-gene inflammatory gene signature score showed a trend of increase on-tx (n = 17) compared to BL (n = 40) and was numerically higher in responders (complete or partial response; n = 13) vs non-responders (stable or progressive disease; n = 27); supporting data and additional efficacy results will be presented. Grade 3/4 tx-related adverse events occurred in 33% of treated pts. Table: 2MO

ORR by TMB

^atTMB was measured by the Illumina TruSight Oncology 500 assay or the FoundationOne CDx assay; bTMB by Guardant OMNI. TMB cutoffs were determined by the Youden Index, which enables the selection of an optimal threshold value for the diagnostic marker.

Conclusions

In CheckMate 592, high tTMB and bTMB were associated with better responses to 1L NIVO + IPI in pts with mNSCLC. Exploratory analyses suggest that tumor inflammation, measured by 4-gene inflammatory gene signature score, may increase with NIVO + IPI treatment.

Clinical trial identification

NCT03001882.

Editorial acknowledgement

Medical writing and editorial assistance was provided by Meenakshi Subramanian at Evidence Scientific Solutions Inc.

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

S. Gettinger: Other, Personal and Institutional, Member, Member of safety committee for another BMS trial evaluating immunotherapy: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Thoracic Medical Oncology, Yale Comprehensive Cancer Center. M. Schenker: Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, MSD, Roche, Merck Serono, AstraZeneca, Sanofi, Regeneron, GSK, BeiGene, Astellas, Amgen, Bayer, Clovis, Gilead, Ipsen, Novartis, Pfizer, PharmaMar, Eisai, Tesaro. J. De Langen: Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, MSD, Boehringer, AstraZeneca; Non-Financial Interests, Institutional, Other: Merck Serono, Roche. J.R. Fischer: Financial Interests, Institutional, Research Grant: Bristol Meyers Squibb, MSD, Roche, Novartis, AstraZeneca, Sanofi, Pfizer, GSK, BeiGene, Pharma Mar, Amgen, Bayer, Gilead; Financial Interests, Institutional, Advisory Role: Bristol Meyers Squibb, MSD, Roche, Novartis, AstraZeneca, Sanofi, Pfizer, GSK, BeiGene, Pharma Mar, Amgen, Bayer, Gilead. D. Morgensztern: Financial Interests, Personal, Advisory Role: AbbVie, G1 Therapeutics, Lilly, Arcus; Financial Interests, Institutional, Research Grant: Heat Biologics, Merck, Celgene, AstraZeneca, Baxter, Incyte, Bristol Myers-Squibb, Epicentrx, Pfizer, Roche, Lilly, Altum, Array, Surface, Boehringer Ingelheim, Y-mabs. T. Ciuleanu: Financial Interests, Personal and Institutional, Other, Fee for clinical trial activities: Astelas Pharma, Janssen, Merck Sharp & Dohme, Amgen, Roche, Pfizer, Sanofi Genzyme, Servier, Ipsen, AstraZeneca, Lilly, Novartis, Boerigher Ingelheim, Bristol Meyers Squibb; Financial Interests, Institutional, Research Grant, PN-II-P4-ID-PCE-2020-2: University of Medicine and Pharmacy Iuliu Hatieganu Cluj-Napoca. T. Beck: Financial Interests, Institutional, Writing Engagements: Bristol Myers Squibb. J. De Castro Carpeno: Financial Interests, Institutional, Research Grant: AstraZeneca, Bristol Myers Squibb, Merck Sharp and Dohme; Financial Interests, Personal, Advisory Role, Consulting fees: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, GSK, Jansen-Cilag, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, F. Hoffmann-La Roche, Takeda, Sanofi; Financial Interests, Personal, Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, Pfizer, F. Hoffmann-la Roche, Takeda, Sanofi, Bayer. C. Schumann: Non-Financial Interests, Personal, Writing Engagements: Bristol Myers Squibb; Financial Interests, Institutional, Other, Clinical trial: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Advisory Board, Presentation and medical writing: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Advisory Board: Bristol Myers Squibb. K. Deschepper: Financial Interests, Institutional, Advisory Board: Amgen Belgium, Bristol Myers Squibb, AstraZeneca, MSD Belgium. E. Nadal: Financial Interests, Institutional, Writing Engagements: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Merck Serono, Roche; Financial Interests, Personal and Institutional, Advisory Role: Bristol Myers Squibb, MSD, Merck Serono, AstraZeneca, Lilly, Sanofi, Boehringer Ingelheim, Amgen, Roche, Bayer; Financial Interests, Institutional, Advisory Board: Roche, Apollomica. K. Schalper: Financial Interests, Institutional, Funding: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Navigate Biopharma, Tesaro/GSK, Moderna Inc., Takeda, Surface Oncology, Pierre-Fabre, Merck, Bristol Myers Squibb, AstraZeneca, Ribon Therapeutics, Eli Lilly, Boehringer Ingelheim, Akoya Biosciences; Financial Interests, Personal and Institutional, Advisory Role: Clinica Alemana Santiago, Shattuck Labs, EMD Serono, Torque/Repertoire Therapeutics, Agenus, Genmab, OnCusp, Parthenon Therapeutics, Molecular Templates, Genmab; Financial Interests, Institutional, Invited Speaker: PeerView, Roche, Genmab, BMS, Takeda, Merck; Financial Interests, Institutional, Advisory Board: Agenus, Shattuck Labs. T. Spires: Financial Interests, Personal, Full or part-time Employment, Stock or stock options: Bristol Myers Squibb. D. Balli: Financial Interests, Personal, Full or part-time Employment, Stock or stock options: Bristol Myers Squibb. S. Karam: Financial Interests, Personal, Full or part-time Employment, Stock Options: Bristol Myers Squibb. D.R. Spigel: Financial Interests, Institutional, Research Grant: Aeglea Biotherapeutics, Agios, Amgen, AnHeart Therapeutics, Apollomics, Arcus, Arrys Therapeutics, Ascendis Pharma, Astellas, AstraZeneca, Bayer, BeiGene, BIND Therapeutics, BioNTech RNA Pharmaceuticals, Blueprint Medicine, Boehringer Ingelheim, Bristol Meyers Squibb, Calithera, Celgene, Celldex, Clovis, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, Endeavor, Erasca, Faeth Therapeutics, FujiFilm Pharmaceuticals, G1 Therapeutics, Roche/Genentech, Gilead Sciences, GlaxoSmithKline, GRAIL, Hutchison MediPharma, ImClone Systems, Incyte, Ipsen, Janssen, Jazz Pharmaceuticals, Kronos Bio, Lilly, Loxo Oncology, Lyell Immunopharma, MacroGenics, MedImmune, Merck, Molecular Template, Nektar, Neon Therapeutics, Novartis, Novocure, PureTech Health, Razor Genomics, Repare Therapeutics, Rgenix, SeaGen, Shenzhen Chipscreen Biosciences, Synthekine, Taiho, Tango Therapeutics, Tarveda, Tesaro, Tizona Therapeutics, Transgene, UT Southwestern, Verastem, Zai Laboratory; Financial Interests, Institutional, Advisory Role: AstraZeneca, BeiGene, Bristol Myers Squibb, Curio Science, EMD Serono, Evidera, GlaxoSmithKline, Ipsen Biopharmaceuticals, Janssen, Jazz Pharmaceuticals, Lilly, Molecular Templates, Monte Rosa Therapeutics, Novartis, Novocure, Pfizer, Pyxis Oncology, Regeneron Pharmaceuticals, Roche/Genentech, Sanofi-Aventis. All other authors have declared no conflicts of interest.