TY - JOUR
T1 - The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers
T2 - a phase 1 trial
AU - Luke, Jason J.
AU - Patel, Manish R.
AU - Blumenschein, George R.
AU - Hamilton, Erika
AU - Chmielowski, Bartosz
AU - Ulahannan, Susanna V.
AU - Connolly, Roisin M.
AU - Santa-Maria, Cesar A.
AU - Wang, Jie
AU - Bahadur, Shakeela W.
AU - Weickhardt, Andrew
AU - Asch, Adam S.
AU - Mallesara, Girish
AU - Clingan, Philip
AU - Dlugosz-Danecka, Monika
AU - Tomaszewska-Kiecana, Monika
AU - Pylypenko, Halyna
AU - Hamad, Nada
AU - Kindler, Hedy L.
AU - Sumrow, Bradley J.
AU - Kaminker, Patrick
AU - Chen, Francine Z.
AU - Zhang, Xiaoyu
AU - Shah, Kalpana
AU - Smith, Douglas H.
AU - De Costa, Anushka
AU - Li, Jonathan
AU - Li, Hua
AU - Sun, Jichao
AU - Moore, Paul A.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/11
Y1 - 2023/11
N2 - 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 .
AB - 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 .
UR - http://www.scopus.com/inward/record.url?scp=85174542599&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85174542599&partnerID=8YFLogxK
U2 - 10.1038/s41591-023-02593-0
DO - 10.1038/s41591-023-02593-0
M3 - Article
C2 - 37857711
AN - SCOPUS:85174542599
SN - 1078-8956
VL - 29
SP - 2814
EP - 2824
JO - Nature medicine
JF - Nature medicine
IS - 11
ER -