Doxorubicin–Pembrolizumab Combo Shows Promise in Advanced Anthracycline-Naïve Sarcoma

Findings from a phase 1/2 clinical trial suggest that doxorubicin combined with pembrolizumab is a promising therapy for patients with certain sarcoma subtypes, including advanced anthracycline-naïve sarcoma (JAMA Oncol. 2020 Sep 10. Epub ahead of print).

“Anthracycline-based therapy is standard first-line treatment for most patients with advanced and metastatic sarcomas. Although multiple trials have attempted to show improved outcomes in patients with soft-tissue sarcoma over doxorubicin monotherapy, each has fallen short of demonstrating improved outcomes,” wrote Seth M. Pollack, MD, Associate Professor, Division of Oncology University of Washington School of Medicine, Seattle, and colleagues.

Researchers used a 2-stage design for this trial, which took place at an academic sarcoma specialty center. A total of 37 patients (median age, 54.8 years) with sarcoma subtypes aside from osteosarcoma, Ewing sarcoma, and alveolar and embryonal rhabdomyosarcoma were included in the trial. Leiomyosarcoma was the most common histologic subtype, reported in 11 patients.

Two dose levels of doxorubicin (45 mg/m2 and 75 mg/m2) were tested for safety in combination with pembrolizumab. The primary end point was objective response rate (ORR), while overall survival (OS) and progression-free survival (PFS) were secondary end points. Correlative studies included immunohistochemistry, gene expression, and serum cytokines.

The combination regimen was found to be well-tolerated and without significant unexpected toxicities. The ORR was 13% for patients in the phase 2 portion of the study and and 19% overall, and the median PFS was 8.1 (95% CI, 7.6-10.8) months. As of this analysis, the median OS was 27.6 months (95% CI, 18.7 to not reached).

“Two of 3 patients with undifferentiated pleomorphic sarcoma and 2 of 4 patients with dedifferentiated liposarcoma had durable partial responses,” Dr Pollack et al reported.

Furthermore, tumor-infiltrating lymphocytes were present in 21% of evaluable tumors and tied to inferior PFS (log-rank P = .03). There were no dose-limiting toxicities reported.

“In this nonrandomized clinical trial, doxorubicin plus pembrolizumab was well tolerated. Although the primary endpoint for ORR was not reached, the PFS and OS observed compared favorably with prior published studies,”Dr Pollack and co-investigators concluded.

“Further studies are warranted, especially those focusing on undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma,” they added.—Alexandra Graziano