The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: A phase 1 trial
Publication Details
Luke, J. J.,
Patel, M. R.,
Blumenschein, G. R.,
Hamilton, E.,
Chmielowski, B.,
Ulhannan, S. V.,
Connolly, R. M.,
Santa-Maria, C. A.,
Wang, J.,
Bahadur, S. W.,
Weickhardt, A.,
Asch, A. S.,
Mallesara, G.,
Clinigan, P.,
Dlugosz-Danecka, M.,
Tomaszewska-Kiecana, M.,
Pylypenko, H.,
Hamad, N.,
Kindler, H. L.,
Sumrow, B. J.,
Kaminker, P.,
Chen, F. Z.,
Zhang, X.,
Shah, K.,
Smith, D. H.,
De Costa, A.,
Li, J.,
Li, H.,
Sun, J.,
&
Moore, P. A.
(2023).
The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: A phase 1 trial.
Nature Medicine,.
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.
Keywords
B-cell lymphoma, breast cancer, cancer immunotherapy, drug development, ovarian cancer
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