EVICTION study: ICT01, an anti-Butyrophilin 3A monoclonal antibody activating γ9δ2 T cells in combination with pembrolizumab in checkpoint inhibitor refractory melanoma.

Stephane Champiat Gustave Roussy, Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Villejuif, France info_outline Stephane Champiat, Martin Wermke, Cecile Vicier, Johann S. De Bono, Emiliano Calvo, Jorge Ramón, Evan Thomas Hall, Elena Garralda, Vladimir Galvao, Emanuela Romano, Antoine Italiano, Esma Saada, Benoit You, Aude De Gassart, Maelle Mairesse, Emmanuel Valentin, Patrick Brune, Daniel Olive, Katrien Lemmens, Paul Frohna

Authors Stephane Champiat Gustave Roussy, Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Villejuif, France info_outline Stephane Champiat, Martin Wermke, Cecile Vicier, Johann S. De Bono, Emiliano Calvo, Jorge Ramón, Evan Thomas Hall, Elena Garralda, Vladimir Galvao, Emanuela Romano, Antoine Italiano, Esma Saada, Benoit You, Aude De Gassart, Maelle Mairesse, Emmanuel Valentin, Patrick Brune, Daniel Olive, Katrien Lemmens, Paul Frohna Organizations Gustave Roussy, Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Villejuif, France, Technical University Dresden, Medical Faculty, NCT/UCC Early Clinical Trial Unit, Dresden, Germany, Institut Paoli-Calmettes, Marseille, France, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom, START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain, University of Washington, Fred Hutchinson Cancer Center, Seattle, WA, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain, Center for Cancer Immunotherapy, Institut Curie, Paris, France, Institut Bergonié - Centre Regional de Lutte Contre Le Cancer de Bordeaux et Sud Ouest, Bordeaux, France, Centre Antoine Lacassagne, Nice, France, Lyon Sud Hospital, Oullins-Pierre-Bénite, France, Imcheck Therapeutics SAS, Marseille, France, Cancer Research of Marseille (CRCM), Institut Paoli-Calmettes, INSERM U1068, CNRS U7258, Aix-Marseille Université, Marseille, France, Imcheck Therapeutics SAS, Marseille, CA, France Abstract Disclosures Research Funding No funding sources reported Background: γ9δ2 T-cell tumor infiltration is associated with a favorable prognosis making these cells a new potential target for immunotherapy. The anti-BTN3A mAb ICT01 selectively activates γ9δ2 T cells and is being studied in the phase1/2a EVICTION Trial (NCT04243499). In preclinical studies, ICT01 induces upregulation of PD-1 on γ9δ2 T-cells and combination with pembrolizumab leads to enhanced cancer cell killing, providing scientific rationale to evaluate this combination. Here we present interim results from EVICTION of ICT01 in combination with pembrolizumab in patients with checkpoint inhibitor (CPI) refractory melanoma. Methods: EVICTION evaluated ICT01 (20 µg to 200 mg, Q3W) plus pembrolizumab (200mg IV Q3W) in a dose escalation solid tumor basket design that resulted in an ongoing expansion cohort of patients with CPI refractory melanoma (2 dose levels, 7 and 200 mg ICT01). Patients are selected based on higher baseline γ9δ2 T cells. Efficacy evaluations by i/RECIST 1.1 are conducted every 8 weeks. Disease Control Rate (DCR) as primary efficacy endpoint is defined as the sum of complete response (CR), partial response (PR) and stable disease (SD, minimum week 16). Baseline and on-treatment blood and biopsy specimens are collected for correlative translational work. Results: ICT01 plus pembrolizumab has a favorable safety profile with first-dose Grade 1/2 infusion related reactions (IRR) and cytokine release syndrome (CRS) as most common adverse events (in 38% and 19% of patients respectively, 5%and 2% Grade 3) among all doses and indications. To date, 35 CPI refractory melanoma patients have been enrolled, of which 65% have received 2+ prior lines of CPI. Currently 21 patients are evaluable at week 16 with a DCR of 42% (including 3 PR) and a 6-month progression free survival of 38%. In the circulation, full BTN3A receptor occupancy on immune cells was achieved at 7 mg dose, with down-modulation of BTN3A observed at doses greater than 20 mg. Clinical response was related to baseline tumoral BTN3A expression, sustained elevation of IFNg levels, and tumor microenvironment remodeling, including increased PD-L1 expression and CD8 T cells proliferation and activation. Conclusions: ICT01 in combination with pembrolizumab has a favorable safety profile and promising efficacy data. Patient selection based on BTN3A tumor expression will be further evaluated as an enrichment strategy. Clinical trial information: NCT04243499.

Clinical