The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1 trial
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Published:2023-10-19
Issue:11
Volume:29
Page:2814-2824
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ISSN:1078-8956
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Container-title:Nature Medicine
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language:en
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Short-container-title:Nat Med
Author:
Luke Jason J.ORCID, Patel Manish R., Blumenschein George R., Hamilton ErikaORCID, Chmielowski BartoszORCID, Ulahannan Susanna V., Connolly Roisin M., Santa-Maria Cesar A., Wang Jie, Bahadur Shakeela W., Weickhardt Andrew, Asch Adam S., Mallesara Girish, Clingan Philip, Dlugosz-Danecka Monika, Tomaszewska-Kiecana Monika, Pylypenko Halyna, Hamad NadaORCID, Kindler Hedy L., Sumrow Bradley J.ORCID, Kaminker Patrick, Chen Francine Z., Zhang Xiaoyu, Shah Kalpana, Smith Douglas H., De Costa Anushka, Li Jonathan, Li Hua, Sun Jichao, Moore Paul A.ORCID
Abstract
AbstractTebotelimab, 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.
Publisher
Springer Science and Business Media LLC
Subject
General Biochemistry, Genetics and Molecular Biology,General Medicine
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