Maud Toulmonde 1 , Mehdi Brahmi 2 , Antoine Giraud 3 , Camille Chakiba 1 , Alban Bessede 4 , Michèle Kind 5 , Emilie Toulza 6 , Marina Pulido 3 , Sabrina Albert 3 , Jean-Philippe Guégan 4 , Sophie Cousin 1 , Simone Mathoulin-Pelissier 3 , Raul Perret 7 , Sabrina Croce 7 , Jean-Yves Blay 2 , Isabelle Ray-Coquard 2 , Anne Floquet 1 , Antoine Italiano 1,8 Show Affiliations »
Abstract
PURPOSE: Trabectedin has shown preclinical synergy with immune checkpoint inhibitors in preclinical models. PATIENTS AND METHODS: TRAMUNE is a phase Ib study investigating the combination of trabectedin with durvalumab through a dose escalation phase and two expansion cohorts, soft tissue sarcoma (STS) and ovarian carcinoma. Trabectedin was given at three dose levels (1 mg/m2, 1.2 mg/m2, and 1.5 mg/m2) on day 1, in combination with durvalumab, 1,120 mg on day 2, every 3 weeks. The primary endpoints were the recommended phase II dose (RP2D) of trabectedin combined with durvalumab and the objective response rate (ORR) as per RECIST 1.1. The secondary endpoints included safety, 6-month progression-free rate (PFR), progression-free survival (PFS), overall survival, and biomarker analyses. RESULTS: A total of 40 patients were included (dose escalation, n = 9; STS cohort, n = 16; ovarian carcinoma cohort, n = 15, 80% platinum resistant/refractory). The most frequent toxicities were grade 1-2 fatigue, nausea, neutropenia, and alanine/aspartate aminotransferase increase. One patient experienced a dose-limiting toxicity at dose level 2. Trabectedin at 1.2 mg/m2 was selected as the RP2D. In the STS cohort, 43% of patients experienced tumor shrinkage, the ORR was 7% [95% confidence interval (CI), 0.2-33.9], and the 6-month PFR was 28.6% (95% CI, 8.4-58.1). In the ovarian carcinoma cohort, 43% of patients experienced tumor shrinkage, the ORR was 21.4% (95% CI, 4.7-50.8), and the 6-month PFR was 42.9% (95% CI, 17.7-71.1). Baseline levels of programmed death-ligand 1 expression and CD8-positive T-cell infiltrates were associated with PFS in patients with ovarian carcinoma. CONCLUSIONS: Combining trabectedin and durvalumab is manageable. Promising activity is observed in patients with platinum-refractory ovarian carcinoma. See related commentary by Digklia et al., p. 1745. ©2021 American Association for Cancer Research.
PURPOSE: Trabectedin has shown preclinical synergy with immune checkpoint inhibitors in preclinical models. PATIENTS AND METHODS: TRAMUNE is a phase Ib study investigating the combination of trabectedin with durvalumab through a dose escalation phase and two expansion cohorts, soft tissue sarcoma (STS) and ovarian carcinoma. Trabectedin was given at three dose levels (1 mg/m2, 1.2 mg/m2, and 1.5 mg/m2) on day 1, in combination with durvalumab, 1,120 mg on day 2, every 3 weeks. The primary endpoints were the recommended phase II dose (RP2D) of trabectedin combined with durvalumab and the objective response rate (ORR) as per RECIST 1.1. The secondary endpoints included safety, 6-month progression-free rate (PFR), progression-free survival (PFS), overall survival, and biomarker analyses. RESULTS: A total of 40 patients were included (dose escalation, n = 9; STS cohort, n = 16; ovarian carcinoma cohort, n = 15, 80% platinum resistant/refractory). The most frequent toxicities were grade 1-2 fatigue, nausea, neutropenia, and alanine/aspartate aminotransferase increase. One patient experienced a dose-limiting toxicity at dose level 2. Trabectedin at 1.2 mg/m2 was selected as the RP2D. In the STS cohort, 43% of patients experienced tumor shrinkage, the ORR was 7% [95% confidence interval (CI), 0.2-33.9], and the 6-month PFR was 28.6% (95% CI, 8.4-58.1). In the ovarian carcinoma cohort, 43% of patients experienced tumor shrinkage, the ORR was 21.4% (95% CI, 4.7-50.8), and the 6-month PFR was 42.9% (95% CI, 17.7-71.1). Baseline levels of programmed death-ligand 1 expression and CD8-positive T-cell infiltrates were associated with PFS in patients with ovarian carcinoma. CONCLUSIONS: Combining trabectedin and durvalumab is manageable. Promising activity is observed in patients with platinum-refractory ovarian carcinoma. See related commentary by Digklia et al., p. 1745. ©2021 American Association for Cancer Research.
Entities: Chemical
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Year: 2022
PMID： 34965951 DOI： 10.1158/1078-0432.CCR-21-2258
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531