An anti-PMEL antibody-drug conjugate with a Gq/11 inhibitor payload in GNAQ/GNA11-mutant melanomas: a phase 1 trial.
СтатьяКлиническое исследование I фазыНазвание и аннотация: Перевод в очереди
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Carlino Matteo S, Kapiteijn Ellen, Piperno-Neumann Sophie, Sullivan Ryan J, Carvajal Richard, Dummer Reinhard, Gromke Tanja, Hassel Jessica C, Kee Damien, Ramelyte Egle, Shoushtari Alexander N, Wei Alexander Z, Enk Alexander, Handel Eleanor E, Montazeri Kamaneh, Ramon-Patino Jorge, Richly Heike, Rodrigues Manuel, Sandhu Shahneen, Smithy James, Speetjens Frank M, Milanez-Almeida Pedro, Chaudhury Anwesha, Hoffmaster Keith, Ising Mary, Otero Javier A, RamKumar Thiruvamoor, Reynolds Aimee, Sharaby Sherif, Werner Lillian, Yerramilli-Rao Padmaja, Calvo Emiliano
Аннотация
Metastatic uveal melanoma (mUM) is an aggressive cancer with limited treatment options; 85-90% of tumors harbor activating GNAQ and GNA11 mutations. Uveal melanoma cells also express PMEL (also known as PMEL17 or gp100), a melanocyte lineage antigen. DYP688, a novel biology-matched antibody-drug conjugate, binds surface PMEL and delivers the potent Gαq/Gα11 (Gq/11) inhibitor SDZ475 as payload by internalization. This dose-escalating first-in-human phase 1 study of DYP688 in patients with metastatic uveal melanoma and other GNAQ/GNA11-mutant melanomas assessed safety as the primary endpoint and pharmacokinetics and preliminary antitumor activity as secondary endpoints. Sixty-six patients received varying DYP688 doses and schedules. Grade 3 treatment-related adverse events occurred in five patients (7.6%), including one dose-limiting toxicity of grade 3 hypotension. Objective responses were seen in 13 out of 66 patients (19.7%) and tumor reduction in 47 out of 66 patients (71.2%). Median progression-free survival was 7.2 (95% CI: 5.3-7.8) months. In summary, DYP688 was well tolerated and showed preliminary efficacy, supporting this novel therapeutic approach. ClinicalTrials.gov identifier: NCT05415072 .