A Phase 1/2 Trial Combining Avelumab and Trabectedin for Advanced Liposarcoma and Leiomyosarcoma
Mené sur 33 patients atteints d'un liposarcome ou d'un léiomyosarcome de stade avancé, cet essai de phase I/II évalue la dose maximale tolérée de la trabectédine en combinaison avec l'avélumab, et l'efficacité, du point de vue du taux de réponse objective, de cette combinaison
Purpose: Leiomyosarcoma (LMS) and liposarcoma (LPS) frequently express PD-L1 but are generally resistant to PD-1/PD-L1 inhibition (ICI). Trabectedin is FDA-approved for LMS and LPS. This study aimed to evaluate the safety and efficacy of trabectedin with anti-PD-L1 antibody avelumab in patients with advanced LMS and LPS. Patients and Methods: A single-arm, open-label, Phase 1/2 study tested avelumab with trabectedin for advanced LMS and LPS. The phase I portion evaluated safety and feasibility of trabectedin (1, 1.2 and 1.5 mg/m2) with avelumab at standard dosing. Primary endpoint of the phase II portion was objective response rate (ORR) by RECIST 1.1. Correlative studies included T-cell receptor sequencing (TCRseq), multiplex immunohistochemistry, and tumor gene expression. Results: 33 patients were evaluable; 24 with LMS (6 uterine and 18 non-uterine) and 11 with LPS. In Phase 1, dose limiting toxicities (DLTs) were observed in 2 of 6 patients at both trabectedin 1.2 and 1.5 mg/m2. The recommended Phase 2 dose (RP2D) was 1.0 mg/m2 trabectedin and 800 mg avelumab. Of 23 patients evaluable at RP2D, three (13%) had partial response (PR), ten (43%) had stable disease (SD) as best response. 6-month PFS was 52%; median PFS was 8.3 months. Patients with PR had higher Simpson Clonality score on TCRseq from peripheral blood mononuclear cells (PBMC) versus those with SD (0.182 vs 0.067, p = 0.02) or PD (0.182 vs 0.064, p = 0.01). Conclusions: Although the trial did not meet the primary ORR endpoint, PFS compared favorably to prior studies of trabectedin warranting further investigation.