Assessment of Doxorubicin and Pembrolizumab in Patients With Advanced Anthracycline-Naive Sarcoma: A Phase 1/2 Nonrandomized Clinical Trial

Abstract

Importance: 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.

Objective: To evaluate the safety and efficacy of doxorubicin in combination with pembrolizumab in patients with advanced, anthracycline-naive sarcomas.

Design, setting, and participants: This nonrandomized clinical trial used a 2-stage phase 2 design and was performed at a single, academic sarcoma specialty center. Patients were adults with good performance status and end-organ function. Patients with all sarcoma subtypes were allowed to enroll with the exception of osteosarcoma, Ewing sarcoma, and alveolar and embryonal rhabdomyosarcoma.

Interventions: Two dose levels of doxorubicin (45 and 75 mg/m2) were tested for safety in combination with pembrolizumab.

Main outcomes and measures: Objective response rate (ORR) was the primary end point. Overall survival (OS) and progression-free survival (PFS) were secondary end points. Correlative studies included immunohistochemistry, gene expression, and serum cytokines.

Results: A total of 37 patients (22 men; 15 women) were treated in the combined phase 1/2 trial. The median (range) patient age was 58.4 (25-80) years. The most common histologic subtype was leiomyosarcoma (11 patients). Doxorubicin plus pembrolizumab was well tolerated without significant unexpected toxic effects. The ORR was 13% for phase 2 patients and 19% overall. Median PFS was 8.1 (95% CI, 7.6-10.8) months. Median OS was 27.6 (95% CI, 18.7-not reached) months at the time of this analysis. Two of 3 patients with undifferentiated pleomorphic sarcoma and 2 of 4 patients with dedifferentiated liposarcoma had durable partial responses. Tumor-infiltrating lymphocytes were present in 21% of evaluable tumors and associated with inferior PFS (log-rank P = .03). No dose-limiting toxic effects were observed.

Conclusions and relevance: In this nonrandomized clinical trial, doxorubicin plus pembrolizumab was well tolerated. Although the primary end point for ORR was not reached, the PFS and OS observed compared favorably with prior published studies. Further studies are warranted, especially those focusing on undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma.

Trial registration: ClinicalTrials.gov Identifier: NCT02888665.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Pollack reported research funding from Merck during the conduct of the study; research funding from EMD Serono, Incyte, Presage, Janssen, OncoSec, and Juno and consulting, honoraria, and advisory activity with GlaxoSmithKline, Eli Lilly and Company, Seattle Genetics, Bayer, Tempus, Daiichi Sankyo, and Blueprint Medicine outside the submitted work. Dr Redman reported grants and other from Merck outside the submitted work. Dr Wagner reported research funding from Athenex, Deciphera, Incyte, Tempus, Adaptimmune, and GlaxoSmithKline and consulting, honoraria, and advisory activity with Tempus, Deciphera, and Adaptimmune outside the submitted work. Mr Black reported grants from Merck during the conduct of the study. Mr Gregory and Mss McDonnell, Johnson, and Moore reported grants and nonfinancial support from Merck & Co during the conduct of the study. Dr Jones reported grants from Merck during the conduct of the study; research support from Merck Sharp & Dohme and GlaxoSmithKline and consultation fees from Adaptimmune, Athenex, Blueprint Medicine, Clinigen, Eisai, Epizyme, Daiichi Sankyo, Deciphera, Immune Design, Eli Lilly and Company, Merck, Pharma Mar, and UpToDate outside the submitted work; in addition, Dr Jones had a patent to biomarker, issued. Dr Cranmer reported grants from Merck during the conduct of the study; research funding from Eli Lilly and Company, AADi, Blueprint Medicine, Iterion, Gradalis, Philogen, Advenchen Laboratories, and CBA Pharma; research funding to his institution from Eli Lilly and Company; and honoraria or advisory board membership for Blueprint Medicines, Daiichi Sankyo, and Regeneron outside the submitted work. No other disclosures were reported.

Figures

Figure.. Patient Responses

A, Waterfall plot demonstrating the percentage change in tumor size from baseline constituting the best response for each patient. B, Spider plots showing responses for all patients.