Phase II Study of Pembrolizumab in Combination with Doxorubicin in Metastatic and Unresectable Soft-Tissue Sarcoma

Abstract

Purpose: Doxorubicin is standard therapy for advanced soft-tissue sarcoma (STS) with minimal improvement in efficacy and increased toxicity with addition of other cytotoxic agents. Pembrolizumab monotherapy has demonstrated modest activity and tolerability in previous advanced STS studies. This study combined pembrolizumab with doxorubicin to assess safety and efficacy in frontline and relapsed settings of advanced STS. Patients and Methods: This single-center, single-arm, phase II trial enrolled patients with unresectable or metastatic STS with no prior anthracycline therapy. Patients received pembrolizumab 200 mg i.v. and doxorubicin (60 mg/m2 cycle 1 with subsequent escalation to 75 mg/m2 as tolerated). The primary endpoint was safety. Secondary endpoints included overall survival (OS), objective response rate (ORR), and progression-free survival (PFS) based on RECIST v1.1 guidelines. Results: Thirty patients were enrolled (53.3% female; median age 61.5 years; 87% previously untreated) with 4 (13.3%) patients continuing treatment. The study met its primary safety endpoint by prespecified Bayesian stopping rules. The majority of grade 3+ treatment-emergent adverse events were hematologic (36.7% 3+ neutropenia). ORR was 36.7% [95% confidence interval (CI), 19.9–56.1%], with documented disease control in 80.0% (95% CI, 61.4–92.3%) of patients. Ten (33.3%) patients achieved partial response, 1 (3.3%) patient achieved complete response, and 13 (43.3%) patients had stable disease. Median PFS and OS were 5.7 months (6-month PFS rate: 44%) and 17 months (12-month OS rate: 62%), respectively. Programmed cell death ligand-1 (PD-L1) expression was associated with improved ORR, but not OS or PFS. Conclusions: Combination pembrolizumab and doxorubicin has manageable toxicity and preliminary promising activity in treatment of patients with anthracycline-naive advanced STS.

Nanoparticle albumin-bound paclitaxel and PD-1 inhibitor (sintilimab) combination therapy for soft tissue sarcoma: a retrospective study

“…Patients with a complete or partial response are indicated in green, those with progressive disease in red, and those with stable disease in yellow Chemotherapy combined with a PD-1 inhibitor has been shown to have a beneficial effect against various other malignancies [20,25,29]. Recent clinical trials have demonstrated the efficacy and safety of the combination of the PD-1 inhibitor, pembrolizumab, and the chemotherapy drug, doxorubicin, for treating patients with advanced STS [22,30]. These results suggest that it is feasible to improve the sensitivity of PD-1 inhibitors by combining them with chemotherapeutic agents.…”

“…Although recent evidence shows that the response rate of PD-1 inhibitor monotherapy is low in patients with STS [17,18], there have been encouraging reports of efficacy in some sarcoma subtypes [19]. The combination of PD-1 inhibitors with cytotoxic chemotherapy agents is a promising way to improve the efficacy of PD-1 inhibitors in the treatment of patients with malignant tumors, including STS [18,[20][21][22].…”

The Role of Immunotherapy in the Management of Soft Tissue Sarcomas: Current Landscape and Future Outlook

“…Two clinical trials evaluating the efficacy of doxorubicin with pembrolizumab had promising results, one with an ORR of 36.7%. 34,35 ICI in combination with trabectedin has also demonstrated clinical activity, with an ORR of 19.5%, including 3 complete responses. 36 Combining ICI with tyrosine kinase inhibitors was evaluated in ImmunoSarc, which evaluated the safety and efficacy of sunitinib and nivolumab in advanced STS.…”

Emerging mechanisms of immunotherapy resistance in sarcomas

“…Other commonly used cytotoxic therapies in sarcomas, including gemcitabine, trabectedin, and eribulin, also have pro-immunogenic effects. Gemcitabine suppresses MDSCs within other cancer subtypes [84] , trabectedin has been shown to diminish the production of immunosuppressive cytokines in myxoid liposarcomas [85] , and eribulin helps to remodel aberrant tumor blood vessels in murine mouse models [86] . In hopes of providing a source of immunogenic neoantigens and pro-inflammatory mediators for poorly immunogenic sarcomas, multiple studies exploring chemotherapy with checkpoint inhibitors have been recently reported or are ongoing.…”

“…No additional phenotyping was reported to explain this surprising finding. More recently, Livingston et al [ 87 ] reported an overall response rate of 36.7%, median PFS of 5.7 months, and a 6 month PFS rate of 44%, in 30 patients with advanced soft tissue sarcomas. Interestingly, analysis of PD-L1 expression in 29 of the 30 patients revealed an association of high PD-L1 expression with objective response rate, however, did not correlate with PFS or overall survival.…”