Cancer research communications · 2026
Phase 1 Study of INBRX-105, a TNFRSF9 (4-1BB) and PD-L1 Bispecific Antibody, in Patients with Select Solid Tumors.
СтатьяКлиническое исследование I фазыМногоцентровое исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Park Jong Chul, Berz David, Sharma Manish R, Malhotra Jyoti, Tolcher Anthony W, Hauke Ralph J, Call Justin A, Hamm John T, Sanborn Rachel E, Haas Naomi B, Tsai Frank, Adkins Doug R, Camidge D Ross, Spira Alexander I, Senne Lane, Kalabus James, O'Neill Brianne, Kinkead Heather, Garcia Josep, Massarelli Erminia
Аннотация
PURPOSE: INBRX-105, a tetravalent, PD-L1-targeted TNFRSF9 (4-1BB) agonist, demonstrated preclinical antitumor activity. This first-in-human study evaluated INBRX-105 in solid tumors.
PATIENTS AND METHODS: This open-label, 4-part, phase 1 study evaluated INBRX-105 alone or with pembrolizumab in adults with locally advanced/metastatic, unresectable solid tumors (NCT03809624). INBRX-105 was administered intravenously once every 2 weeks or 4 weeks in parts 1 (single-agent dose escalation; 0.001-3 mg/kg) and 2 (single-agent expansion) or once every 3 weeks in parts 3 (combination dose escalation; INBRX-105 0.03-1.0 mg/kg) and 4 (combination expansion). Part 2 enrolled patients with checkpoint inhibitor-relapsed/refractory (CPI-R/R) tumors. Part 4 enrolled patients with CPI-R/R or CPI-naïve disease. The primary endpoint was safety and tolerability of INBRX-105. Preliminary clinical response was a secondary endpoint.
RESULTS: Of 160 patients assessed, 81 received monotherapy (median age, 65 years; female, 50.6%), and 79 combination therapy (median age, 64 years; female, 38%). The INBRX-105 maximum tolerated dose was 0.3 mg/kg once every 3 weeks. Head and neck squamous cell carcinoma (n = 61) and non-small cell lung cancer (n = 25) were the most common tumor types. The most common any-grade INBRX-105-related adverse events (AE) were fatigue (monotherapy, 35.8%; combination, 17.7%), increased aspartate aminotransferase (25.9%; 15.2%), and nausea (19.8%; 17.7%). INBRX-105-related hepatic AEs occurred in 41 patients [monotherapy, n = 25 (grade ≥3, n = 11); combination, n = 16 (grade ≥3, n = 6)]. In all patients, the objective response rate was 8.8% [monotherapy, 3.7%; combination, 13.9% (CPI-naïve, 30%; CPI-R/R, 8.6%)]; the disease control rate was 43.1%.
CONCLUSIONS: The low response rates and hepatic safety signals observed do not support further clinical development of INBRX-105.
SIGNIFICANCE: Tumor resistance to CPIs often develops, underscoring an unmet need. This first-in-human phase 1 trial evaluated INBRX-105-a tetravalent, PD-L1-targeted 4-1BB agonist-alone or with pembrolizumab. Unfortunately, clinical development of INBRX-105 was ended because of hepatotoxicity and limited efficacy. Novel treatment combinations with nonredundant, complementary immunotherapies are needed.
PATIENTS AND METHODS: This open-label, 4-part, phase 1 study evaluated INBRX-105 alone or with pembrolizumab in adults with locally advanced/metastatic, unresectable solid tumors (NCT03809624). INBRX-105 was administered intravenously once every 2 weeks or 4 weeks in parts 1 (single-agent dose escalation; 0.001-3 mg/kg) and 2 (single-agent expansion) or once every 3 weeks in parts 3 (combination dose escalation; INBRX-105 0.03-1.0 mg/kg) and 4 (combination expansion). Part 2 enrolled patients with checkpoint inhibitor-relapsed/refractory (CPI-R/R) tumors. Part 4 enrolled patients with CPI-R/R or CPI-naïve disease. The primary endpoint was safety and tolerability of INBRX-105. Preliminary clinical response was a secondary endpoint.
RESULTS: Of 160 patients assessed, 81 received monotherapy (median age, 65 years; female, 50.6%), and 79 combination therapy (median age, 64 years; female, 38%). The INBRX-105 maximum tolerated dose was 0.3 mg/kg once every 3 weeks. Head and neck squamous cell carcinoma (n = 61) and non-small cell lung cancer (n = 25) were the most common tumor types. The most common any-grade INBRX-105-related adverse events (AE) were fatigue (monotherapy, 35.8%; combination, 17.7%), increased aspartate aminotransferase (25.9%; 15.2%), and nausea (19.8%; 17.7%). INBRX-105-related hepatic AEs occurred in 41 patients [monotherapy, n = 25 (grade ≥3, n = 11); combination, n = 16 (grade ≥3, n = 6)]. In all patients, the objective response rate was 8.8% [monotherapy, 3.7%; combination, 13.9% (CPI-naïve, 30%; CPI-R/R, 8.6%)]; the disease control rate was 43.1%.
CONCLUSIONS: The low response rates and hepatic safety signals observed do not support further clinical development of INBRX-105.
SIGNIFICANCE: Tumor resistance to CPIs often develops, underscoring an unmet need. This first-in-human phase 1 trial evaluated INBRX-105-a tetravalent, PD-L1-targeted 4-1BB agonist-alone or with pembrolizumab. Unfortunately, clinical development of INBRX-105 was ended because of hepatotoxicity and limited efficacy. Novel treatment combinations with nonredundant, complementary immunotherapies are needed.