First-in-human first-in-class phase I trial of murlentamab, an anti-Mullerian-hormone receptor II (AMHRII) monoclonal antibody acting through tumor-associated macrophage (TAM) engagement, as single agent and in combination with carboplatin (C) and paclitaxel (P) in AMHRII-expressing advanced/metastatic gynecological cancer patients (pts).

person Alexandra Leary Gustave-Roussy Cancer Campus, Villejuif, and Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens, France info_outline Alexandra Leary, Ahmad Awada, Jean-Pierre Delord, Anne Floquet, Isabelle Laure Ray-Coquard, Cyril Abdeddaim, Michel Fabbro, Elsa Kalbacher, Ignace Vergote, Susana N. Banerjee, François-Xavier Frenois, Grégory Noël, Olivier Lantz, Lydie Cassard, Agnès Coste, Marine Villard, Fanny Lemee, Isabelle Marie Tabah-Fisch, Christophe Le Tourneau

Authors person Alexandra Leary Gustave-Roussy Cancer Campus, Villejuif, and Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens, France info_outline Alexandra Leary, Ahmad Awada, Jean-Pierre Delord, Anne Floquet, Isabelle Laure Ray-Coquard, Cyril Abdeddaim, Michel Fabbro, Elsa Kalbacher, Ignace Vergote, Susana N. Banerjee, François-Xavier Frenois, Grégory Noël, Olivier Lantz, Lydie Cassard, Agnès Coste, Marine Villard, Fanny Lemee, Isabelle Marie Tabah-Fisch, Christophe Le Tourneau Organizations Gustave-Roussy Cancer Campus, Villejuif, and Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens, France, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium, Toulouse University Cancer Institute IUCT-Oncopole, Toulouse, France, Institut Bergonié, Comprehensive Cancer Centre, Bordeaux, and Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens, Bordeaux, France, GINECO Group and Centre Léon Bérard, Lyon, France, Centre Oscar Lambret, Lille, France, GINECO & Institut du Cancer de Montpellier, Montpellier, France, CHU Jean Minjoz, Besançon, France, University Hospital Leuven, Leuven Cancer Institute, Leuven, Belgium, The Royal Marsden Hospital, London, United Kingdom, Institut Universitaire du Cancer Toulouse, CHU Toulouse, Toulouse, France, Institut Jules Bordet - Université Libre de Bruxelles, Brussels, Belgium, Institut Curie, Paris, France, Laboratory of Immunomonitoring in Oncology, Gustave Roussy, Villejuif, France, UMR152 UPS-IRD, Toulouse, France, Hospices Civils de Lyon, Pierre-Bénite, France, GamaMabs Pharma, Toulouse, France Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: Membranous expression of AMHRII is found in ~70% of gynecological tumors. Murlentamab (M) binds with high affinity both AMHRII (at cell membrane) and CD16 (on macrophage, via its low fucose Fc). M reprograms TAMs, restoring their antitumoral functions (phagocytosis) resulting in cytotoxic T cell reactivation. Methods: Pts with advanced/metastatic AMHRII-expressing ovarian, cervical or endometrial cancer with measurable disease and performance status ≤ 1 received M as single agent (SA) in 8 dose escalating and 2 expansion cohorts. Combination with CP was studied in 2 escalating cohorts. Safety, recommended dose determination, antitumor activity, pharmacodynamics (PD) effects (circulating immune cells and tumor microenvironment (TME) from paired biopsies) were assessed. Results: 68 heavily pretreated (median 4 prior lines) pts received M for 0.5 to 11 months (mo) (59 pts M SA and 9 pts M + CP). No dose limiting toxicity was reported. Most common toxicity was G1-2 asthenia (29 %). Eight pts (12%) had G ≥ 3 reversible toxicities (asthenia, nausea/vomiting, anorexia, arthralgia). No antidrug antibody was detected. One partial response (PR) was achieved with M SA in a granulosa pt. In CP combination, 4/9 pts (44%) responded to treatment (1 Complete Response and 3 PRs). Overall, 22/67 (33%) pts were progression-free at 4 mos. Among 17 pts treated ≥ 6 mos, 6/9 (67%) granulosa pts with M SA and 4/5 (80%) endometrium and cervix with CP combination had a longer PFS than under previous regimen. PD blood assessment of 25 pts treated with M SA showed an increase in classical monocytes, and T cells and neutrophils activation. Changes in TME under M will be presented. Conclusions: Murlentamab was very well tolerated, demonstrated immune PD effects and showed hints of antitumor activity. These results together with its innovative immunological mode of action support development of M in AMHRII-expressing cancers, in combination with chemotherapy or other immune oncology drugs. Clinical trial information: NCT02978755