Combination Use of Doxorubicin, Pembrolizumab Well-Tolerated in Advanced Anthracycline-Naïve Sarcoma

A phase 1/2 nonrandomized clinical trial in patients with advanced anthracycline-naïve sarcoma indicated that the treatment combination was well tolerated in this patient population.

A phase 1/2 nonrandomized clinical trial of doxorubicin (Adriamycin) and pembrolizumab (Keytruda) in patients with advanced anthracycline-naïve sarcoma indicated that the treatment combination was well tolerated in this patient population.

The study, published in JAMA Oncology, did not meet its primary end point of objective response rate (ORR), however the progression-free survival (PFS) and overall survival (OS) results observed compared favorably with previously published studies. Given these results, the researchers indicated that further studies are warranted.

“This nonrandomized phase 1/2 trial demonstrated that doxorubicin plus pembrolizumab can be given safely and may be associated with clinical benefit for patients with advanced sarcoma,” the authors wrote.

The trial used a 2-stage phase 2 design and was performed at a single, academic sarcoma specialty center. Patients with all sarcoma subtypes were allowed to enroll in the study, with the exception of osteosarcoma, Ewing sarcoma, and alveolar and embryonal rhabdomyosarcoma.

Researchers evaluated 2 dose levels of doxorubicin, including 45 mg/m2 and 75 mg/m2, in combination with pembrolizumab. The primary end point was ORR and key secondary end points were OS and PFS.

Overall, 37 patients were treated in the combined phase 1/2 trial, including 22 men and 15 women. The most common histologic subtype of advanced anthracycline-naïve sarcoma observed was leiomyosarcoma in 11 patients.

The ORR was 13% for patients included in the phase 2 portion of the study, and 19% overall. Median PFS was 8.1 (95% CI, 7.6-10.8) months and median OS was 27.6 (95% CI, 18.7-not reached) months at the time of this analysis. Specifically, 2 of 3 patients with undifferentiated pleomorphic sarcoma and 2 of 4 patients with dedifferentiated liposarcoma had durable partial responses.

Notably, tumor-infiltrating lymphocytes were present in 21% of evaluable tumors and associated with inferior PFS (log-rank P = .03).

“In correlative studies, we found that tumor-infiltrating lymphocytes were associated with inferior PFS. This may reflect more aggressive tumor biology rather than as association with the PD-1 inhibitor,” the authors explained.

Importantly though, the combination use of doxorubicin and pembrolizumab was found to be well tolerated and no dose-limiting toxic effects were observed. In both of the study cohorts, the most common toxic effects were nausea (n = 32) and fatigue (n = 21). Moreover, no grade 5 toxic effects were seen, and the only attributable grade 4 toxic effects were neutropenia (n = 6), leukopenia (n = 1), and febrile neutropenia (n = 1), all of which eventually resolved.

“Our trial, like others, demonstrated a higher response rate and clinical benefit of pembrolizumab in [undifferentiated pleomorphic sarcomas] compared with other sarcoma subtypes, despite their generally worse prognosis,” the authors noted. “Durable PRs were also seen in 2 of 4 patients with dedifferentiated liposarcoma. Chondrosarcomas are generally resistant to doxorubicin; inclusion of these patients in the study likely lowered the ORR.”

“Still, 2 patients with chondrosarcoma had durable disease regression, suggesting that doxorubicin/pembrolizumab may benefit these patients,” the authors concluded. “For patients with these selected subtypes, follow-up studies are warranted.”


Pollack SM, Redman MW, Baker KK, et al. Assessment of Doxorubicin and Pembrolizumab in Patients With Advanced Anthracycline-Naive Sarcoma. JAMA Oncology. doi: 10.1001/jamaoncol.2020.3689

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