732MO - The combination of ICT01, a γ9δ2 T cell-activating mAb, plus pembrolizumab induces a broad antitumor immune response and disease control in patients with CPI-failure melanoma, NSCLC and bladder cancer: EVICTION trial

Background

ICT01, an anti-BTN3A mAb, activates γ9δ2 T cells that orchestrate a robust antitumor immune response of the innate and adaptive immune systems that leads to solid tumor infiltration of γ9δ2 T cells, CD8 T cells, and NK cells. (ESMO 2021, #9580) This immune-remodeling by ICT01 when combined with pembrolizumab unleashes the newly-activated, PD-1 expressing γ9δ2 and CD8 T cells that provide a novel, complementary combination immunotherapy regimen for CPI-failure patients that remain a large unmet medical need.

Methods

In the combination arm of the EVICTION Trial, patients with advanced, metastatic melanoma, bladder cancer, or NSCLC who failed ≥1 prior CPI were treated with ICT01 plus pembrolizumab (200 mg IV Q3W). i/RECIST was conducted every 8 weeks for efficacy (1° Disease Control Rate (DCR) and 2° Overall Response Rate (ORR)) in evaluable patients (recieved 3 cycles and had a Wk 8 i/RECIST). Blood samples were collected for ICT01 target occupancy, immunophenotyping and cytokine analysis (IFNg, TNFa, IL-1b/2/4/6/8/10/12/13). Tumor biopsies (baseline, Day 28) were used for IHC of BTN3A and tumor-infiltrating lymphocytes, and gene expression profiling.

Results

Overall, ICT01 + pembro was considered safe and well-tolerated across a range of ICT01 doses (700 mcg - 200 mg, n=36), without any DLTs. Activation & migration of all circulating γ9δ2 T cells was observed 30 min post dose that returned to baseline only at doses ≤7 mg. NK and CD8 T cell activation and margination was observed 24h post dose at doses of ICT01 ≥ 7 or ≥ 20 mg, respectively. 10- to 100-fold increases in IFNγ, TNFα and CXCL10 were observed for 24h post dose. Intra-tumoral γδ, CD3, CD3+Ki67+, CD8 and CD8+ Ki67+ cell densities increased as did gene signatures for intratumoral inflammation (ImmunoSign21, IFNγ response, T cell activation). Efficacy Evaluable (n=24): 6 Melanoma: 50% DCR, 33% ORR; 11 NSCLC: 36% DCR, 9% ORR; 6 Bladder: 33% DCR, 17% ORR. The 3 melanoma responders were IPI/Nivo refractory, with 2 PRs achieved at 2 & 20 mg in pts with high baseline γ9δ2 T cell counts.

Conclusions

ICT01 plus pembro is a novel immunotherapeutic approach worth further study in CPI failure pts.

Clinical trial identification

EudraCT 2019-003847-31; NCT04243499.

Editorial acknowledgement

Legal entity responsible for the study

ImCheck Therapeutics.

Funding

ImCheck Therapeutics.

Disclosure

S. Champiat: Financial Interests, Personal, Advisory Board: Alderaan Biotechn, Avacta, Ellipses Pharma, Oncovita; Financial Interests, Personal, Invited Speaker: Amgen, Astellas, BMS, Eisai, Genmab, Janssen, Merck, Novartis, Roche, Seagen, UltraHuman8. M. Wermke: Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: BMS, AstraZeneca, Roche, Boehringer Ingelheim, Cellex, Lilly, MSD, Immatics, Pfizer. J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Financial Interests, Institutional, Advisory Board: Harpoon; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, Crescendo Biologics; Non-Financial Interests, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Non-Financial Interests, Institutional, Product Samples: Daiichi, Bayer, Merck Serono, AstraZeneca, Harpoon, Pfizer, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GlaxoSmithKline. N. Vey: Financial Interests, Personal, Invited Speaker: Amgen, BMS, Janssen, Jazz Pharmaceuticals, Novartis, Roche. E. Garralda: Financial Interests, Personal, Advisory Board: Genentech, F.Hoffmann/La Roche, Neomed Therapeutics1 Inc, Boehringer Ingelheim, Janssen Global Services, Alkermes, Thermo Fisher, MabDiscovery, Anaveon, Lilly, Hengrui; Financial Interests, Personal, Invited Speaker: Ellipses Pharma, Seattle Genetics, Bristol Myers Squibb, MSD, F-Star Therapeutics; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho. P. Lorusso: Financial Interests, Personal, Advisory Board: AbbVie, Genmab, Genentech, CytomX, Takeda, Cybrexa, Agenus, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, Glaxo-Smith Kline, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, Silverback, MacroGenics, Kyowa Kirin, Kineta, Zentalis, Molecular Templates, ABL Bio, STCube, Bayer, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanist, Mersana; Financial Interests, Personal, Data Safety Monitoring Board: Agios, Five Prime, Halozyme; Financial Interests, Personal, imCORE Alliance: Roche-Genentech; Financial Interests, Personal, Consultant: Sotio, SK Life; Financial Interests, Personal, Data Safety Monitoring Committee: Tyme; Financial Interests, Personal, Advisory Board, Advisory Board & Consultant: I-Mab; Financial Interests, Institutional, Invited Speaker: AbbVie, ADC Therapeutics, ALX Oncology, Astellas Pharma, Astex Pharmaceuticals, AstraZeneca, Bayer, Black Diamond, Boehringer Ingelheim, Calico Life Sciences, Corvus Pharmaceuticals, CytomX Therapeutics, Eisai Pharmaceuticals, Eli Lilly, EMD Sernono, Five Prime, FLX Bio, F-Star Delta Limited, Genentech, Genmab, Incyte, Linnaeus Therapeutics, MedImmune, Merck Sharp & Dohme, Moderna Therapeutics, NextCure, Pfizer, Ribon Therapeutics, Sotio, Stemline Therapeutics, Takeda, Tesaro; Non-Financial Interests, Other, AACI Clinical Research Innovation Steering Committee - Member: Association of American Cancer Institutes; Non-Financial Interests, Other, AACR Methods in Clinical Cancer Research Workshop - Co-Director: American Association for Cancer Research; Non-Financial Interests, AACR Annual Report Committee - Member: American Association for Cancer Research; Non-Financial Interests, Other, Continuing Medical Education Committee - Member: American Association for Cancer Research; Non-Financial Interests, Molecular Cancer Therapeutics Editorial Board - Member: American Association for Cancer Research; Non-Financial Interests, ASCO Conquer Cancer Young Investigator Award Grand Selection Committee - Member: American Society of Clinical Oncology; Non-Financial Interests, New Drugs in Oncology Seminar Planning Committee - Member: American Society of Clinical Oncology; Non-Financial Interests, New Agents Committee: Translational Research Panel - Chair: Cancer Research Unite Kingdom; Non-Financial Interests, Scientific Advisory Board - Member: Targeted Anti-Cancer Therapies; Non-Financial Interests, Chair - Phase 0 Task Force: American Association of Cancer Research; Non-Financial Interests, Member: American Association for Cancer Research, ASCO; Other, Other, Investigational Drug Steering Committee - Committee Member: National Cancer Institute; Phase I Special Emphasis Panel - Grant Reviewer/Discussion Leader: National Cancer Institute; NeXT Special Emphasis Panel - Grant Reviewer: National Cancer Institute/National Institute of Health; Board of Scientific Counselors, Clinical Sciences & Epidemiology: National Cancer Institute; Young Investigator Meeting, Cancer Therapy Evaluation Program - Professor: National Cancer Institute; Academic Advisory Board SPORE GI Malignancies - Case Western Reserve University: Case Western Reserve University; External Advisory Board - Member: University of Arizona; External Scientific Advisory Board - Member: University of New Mexico; Scientific External Advisory Board - Member: University of California at San Diego. A. de Gassart: Financial Interests, Personal, Full or part-time Employment: ImCheck Therapeutics. E. Valentin: Financial Interests, Personal, Full or part-time Employment: ImCheck Therapeutics. P. Brune: Financial Interests, Personal, Full or part-time Employment: ImCheck Therapeutics. M. Iche: Financial Interests, Personal and Institutional, Sponsor/Funding: ImCheck Therapeutics. C. Leparquier: Financial Interests, Personal, Sponsor/Funding: ImCheck Therapeutics. D. olive: Financial Interests, Personal, Stocks/Shares: ImCheck Therapeutics. A. Marabelle: Financial Interests, Personal, Advisory Board: Merck Serono, Amgen, Sotio, Pfizer, Seattle Genetics, Roche/Genentech, Merck, Centessa Pharmaceuticals, Shattuck Labs, Sanofi; Financial Interests, Personal, Invited Speaker: Novartis, Genmab. P.A. Frohna: Financial Interests, Personal, Full or part-time Employment: ImCheck Therapeutics. All other authors have declared no conflicts of interest.