Phase I dose-escalation and cohort expansion study of the anti-BTLA antibody, tifcemalimab, in combination with toripalimab (anti-PD-1) in heavily pretreated patients (pts) with advanced malignancies.
Authors: Ma Vincent T , Milhem Mohammed M. , Hidalgo Manuel , Shields Anthony F. , Segar Jennifer Margaret , Khalil Maya , Davis Andrew A. , Verschraegen Claire F. , Wong Deborah J.L. , Schilder Russell J. , Gao Xin , Powderly John D. , Jiang Yixing , Aggarwal Rahul Raj , Awan Farrukh Tauseef , McKean Meredith , Chow Warren Allen , Yao Sheng , Keegan Patricia , Naing Aung 
Published: June 2024

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Background: Tifcemalimab, a humanized IgG4 antibody against BTLA, showed a tolerable safety profile and preliminary single-agent anti-tumor activity in pretreated pts with advanced malignancies. Here we report the dose escalation and cohort expansion study of tifcemalimab in combination with toripalimab (anti-PD-1) in pts with pretreated advanced malignancies. Methods: Eligible pts with advanced malignancies refractory to standard therapies were enrolled in the dose escalation and the cohort expansion phases of this study (NCT04137900). During dose escalation, tifcemalimab was administered at escalating doses of 20, 70, 200 and 500 mg in combination with 240 mg toripalimab given intravenously once every three weeks (Q3W) until disease progression or intolerable toxicity. Dose-limiting toxicity (DLT) was evaluated. Study objectives included safety and efficacy. During cohort expansion, the combination of tifcemalimab (200mg Q3W) and toripalimab (240 mg Q3W) were further evaluated in five indication-specific cohorts (melanoma, non-small cell lung cancer [NSCLC], renal cell carcinoma [RCC], urothelial carcinoma [UC] and lymphoma) for safety and efficacy. Results: By December 16, 2023, a total of 16 pts received study treatment during dose escalation and 69 pts were treated during cohort expansion from 18 participating sites from the US. Pts were heavily pretreated with a median of 4 prior lines of therapy. The median age was 65 (range 32-85) years, 69% of pts were male. As of December 16, 2023, the median follow-up was 11.4 weeks. No DLT was observed during dose escalation. Treatment-emergent adverse event (TEAEs) occurred in 92% pts, 44% experienced grade 3 or higher TEAEs, including 2 (2%) treatment-related Grade 5 events. The most common TEAEs included: fatigue (27%), diarrhea (17%), nausea (17%), anemia (15%), arthralgia (15%), decreased appetite (15%), and dyspnea (15%). TEAE led to discontinuation of study drug in 6% of pts. Nineteen percent of pts experienced immune-related AEs. No new safety signal was identified outside the known risk profiles of tifcemalimab and toripalimab. Among 14 evaluable pts in the dose escalation phase, 8 had stable disease. Among 57 evaluable pts in the cohort expansion phase, 1 complete response (lymphoma), 6 partial responses (2 melanoma, 2 RCC, 1 NSCLC, 1 UC) and 17 stable disease were observed. The ORRs were 5%, 11%, 17%, 18% and 33% in the NSCLC, melanoma, UC, RCC and lymphoma cohorts respectively. All responders were refractory to prior immunotherapy and all responses were still ongoing by the cutoff date. Conclusions: Tifcemalimab in combination with toripalimab showed preliminary efficacy in immunotherapy-refractory pts with a manageable safety profile. Phase II combination studies in various advanced solid tumors are ongoing. Clinical trial information: NCT04137900 .