The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1 trial
Jason J. Luke, Manish R. Patel, George R. Blumenschein, Erika Hamilton, Bartosz Chmielowski, Susanna V. Ulahannan, Roisín M. Connolly, Cesar A. Santa‐Maria, Jie Wang, Shakeela Bahadur, Andrew Weickhardt, Adam S. Asch, Girish Mallesara, Philip R. Clingan, Monika Długosz‐Danecka, Monika Tomaszewska‐Kiecana, Halyna Pylypenko, Nada Hamad, Hedy L. Kindler, Bradley Sumrow, Patrick Kaminker, Francine Z. Chen, Xiaoyu Zhang, Kalpana Shah, Douglas H. Smith, Anushka De Costa, Jonathan Li, Hua Li, Jichao Sun, Paul A. Moore
Abstract
Abstract Tebotelimab, a bispecific PD-1×LAG-3 DART molecule that blocks both PD-1 and LAG-3, was investigated for clinical safety and activity in a phase 1 dose-escalation and cohort-expansion clinical trial in patients with solid tumors or hematologic malignancies and disease progression on previous treatment. Primary endpoints were safety and maximum tolerated dose of tebotelimab when administered as a single agent ( n = 269) or in combination with the anti-HER2 antibody margetuximab ( n = 84). Secondary endpoints included anti-tumor activity. In patients with advanced cancer treated with tebotelimab monotherapy, 68% (184/269) experienced treatment-related adverse events (TRAEs; 22% were grade ≥3). No maximum tolerated dose was defined; the recommended phase 2 dose (RP2D) was 600 mg once every 2 weeks. There were tumor decreases in 34% (59/172) of response-evaluable patients in the dose-escalation cohorts, with objective responses in multiple solid tumor types, including PD-1-refractory disease, and in LAG-3 + non-Hodgkin lymphomas, including CAR-T refractory disease. To enhance potential anti-tumor responses, we tested margetuximab plus tebotelimab. In patients with HER2 + tumors treated with tebotelimab plus margetuximab, 74% (62/84) had TRAEs (17% were grade ≥3). The RP2D was 600 mg once every 3 weeks. The confirmed objective response rate in these patients was 19% (14/72), including responses in patients typically not responsive to anti-HER2/anti-PD-1 combination therapy. ClinicalTrials.gov identifier: NCT03219268 .