학술논문
The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1 trial
Document Type
Original Paper
Author
Luke, Jason J.; Patel, Manish R.; Blumenschein, George R.; Hamilton, Erika; Chmielowski, Bartosz; 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, Nada; Kindler, Hedy L.; Sumrow, Bradley J.; Kaminker, Patrick; Chen, Francine Z.; Zhang, Xiaoyu; Shah, Kalpana; Smith, Douglas H.; De Costa, Anushka; Li, Jonathan; Li, Hua; Sun, Jichao; Moore, Paul A.
Source
Nature Medicine. 29(11):2814-2824
Subject
Language
English
ISSN
1078-8956
1546-170X
1546-170X
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.
The bispecific molecule tebotelimab, which blocks both PD-1 and LAG-3, is well tolerated as a monotherapy and in combination with the anti-HER-2 antibody margetuximab and elicits encouraging clinical activity in solid tumors with high LAG-3 levels and/or expression of IFN-γ-regulated genes.
The bispecific molecule tebotelimab, which blocks both PD-1 and LAG-3, is well tolerated as a monotherapy and in combination with the anti-HER-2 antibody margetuximab and elicits encouraging clinical activity in solid tumors with high LAG-3 levels and/or expression of IFN-γ-regulated genes.