A Phase 1/2 Trial Combining Avelumab and Trabectedin for Advanced Liposarcoma and Leiomyosarcoma

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Purpose: Leiomyosarcoma and liposarcoma frequently express PD-L1 but are generally resistant to PD-1/PD-L1 inhibition (immune checkpoint inhibitor). Trabectedin is FDA approved for leiomyosarcoma and liposarcoma. This study aimed to evaluate the safety and efficacy of trabectedin with anti-PD-L1 antibody avelumab in patients with advanced leiomyosarcoma and liposarcoma. Patients and Methods:A single-arm, open-label, Phase 1/2 study tested avelumab with trabectedin for advanced leiomyosarcoma and liposarcoma. 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 Tcell receptor sequencing (TCRseq), multiplex IHC, and tumor gene expression. Results: 33 patients were evaluable: 24 with leiomyosarcoma (6 uterine and 18 non-uterine) and 11 with liposarcoma. In Phase 1, dose-limiting toxicities (DLT) 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, 3 (13%) had partial response (PR) and 10 (43%) had stable disease (SD) as best response. Six-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 versus those with SD (0.182 vs. 0.067, P = 0.02) or progressive disease (0.182 vs. 0.064, P = 0.01). Conclusions: Although the trial did not meet the primary objective response rate endpoint, PFS compared favorably with prior studies of trabectedin warranting further investigation.




Wagner, M. J., Zhang, Y., Cranmer, L. D., Loggers, E. T., Black, G., McDonnell, S., … Pollack, S. M. (2022). A Phase 1/2 Trial Combining Avelumab and Trabectedin for Advanced Liposarcoma and Leiomyosarcoma. Clinical Cancer Research, 28(11), 2306–2312. https://doi.org/10.1158/1078-0432.CCR-22-0240

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