A pilot study evaluating the safety, tolerability, and efficacy of doxorubicin and pembrolizumab in patients with metastatic or unresectable soft tissue sarcoma.

Abstract

11519 Background: Doxorubicin has been the traditional standard therapy for treatment of advanced soft tissue sarcoma (STS). The addition of cytotoxic agents leads to increased toxicity with minimal improvement in efficacy. Pembrolizumab monotherapy has demonstrated activity and tolerability in previous study of advanced STS. This study combined pembrolizumab with doxorubicin to determine safety and efficacy in the frontline setting. Methods: This single-center, single-arm, phase 2 trial enrolled subjects with unresectable or metastatic STS and no prior anthracycline therapy. Subjects were treated with pembrolizumab 200 mg IV and doxorubicin 60 mg/m2 (75 mg/m2 dose escalation per investigator discretion) IV every 3 weeks. The primary endpoint of safety, based on Bayesian stopping rules, evaluated if the severe or life-threatening treatment emergent adverse event (TEAE) rate exceeded 0.55. Secondary endpoints included overall survival (OS), objective response rate (ORR), and progression free survival (PFS). Efficacy and safety were based on RECIST 1.1 and CTCAE v 4.0, respectively. Kaplan-Meier methods evaluated time to event outcomes. Results: From 4/2017 to 12/2019, 30 subjects (53% female, median age 61.5 years, 10 patients > 70 years (33%)) were enrolled in the study with 6 (20%) patients still on treatment and 27 evaluable for response. The most common histologic subtypes were leiomyosarcoma (33%) and liposarcoma (23%), and a majority of patients demonstrated high grade disease (60%). Current analysis shows a median follow-up of 9.9 months. One subject experienced a stopping rule event (grade 3 autoimmune disorder). ORR was 33% (95% CI 17-54%), with documented disease control in 78% (95% CI 57.7-91.4%) of patients. Eight (30%) patients achieved a partial response, one (4%) patient achieved a complete response and 12 (44%) patients had stable disease. Preliminary results demonstrate median PFS of 6.9 months (PFS-6 mo: 52%) and median OS of 15 months (OS-6 mo: 81%) compared to historical PFS-6mo of 4.6 months and OS of 12.8 months with doxorubicin alone.1 Most common grade 3+ TEAEs included neutropenia (11 [37%]), febrile neutropenia (6 [20%]), anemia (5 [17%]), and nausea (4 [13%]). Molecular and biomarker analysis is currently in progress. Conclusions: The combination of pembrolizumab with doxorubicin has manageable toxicity and preliminary promising activity in the treatment of anthracycline-naive advanced soft tissue sarcomas. Ref: 1. Lancet Oncol. 2014 Apr; 15(4):415-23. Clinical trial information: NCT03056001 .

Immune checkpoint inhibitors in treatment of soft-tissue sarcoma: A systematic review and meta-analysis

“…The combination of a checkpoint inhibitor þ chemotherapy as first-line treatment resulted in an ORR of 0.23. Two regimens have been evaluated: doxorubicin þ pembrolizumab (dox þ pem) [20,35] and nivolumab þ ipilimumab þ trabectedin (the SAINT regimen) [18,31]. Although one trial with dox þ pem was considered negative because of insufficient ORR (0.22), survival rates were higher than expected with a mean OS (mOS) of 27.6 months [20].…”

“…The second trial with dox þ pem had an ORR of 0.37 and DCR of 0.80. Further updates are awaited [35]. The safety profile of dox þ pem was manageable, as the addition of pembrolizumab did not result in unexpected toxicity [20,35].…”

“…Further updates are awaited [35]. The safety profile of dox þ pem was manageable, as the addition of pembrolizumab did not result in unexpected toxicity [20,35]. Responses of dox þ pem are encouraging, compared with historical data from the EORTC62012 trial, with ORR of 0.14 for doxorubicin monotherapy and 0.26 for doxorubicin þ ifosfamide, but the latter failed to improve survival [8].…”

Improving Immunotherapy Efficacy in Soft-Tissue Sarcomas: A Biomarker Driven and Histotype Tailored Review

“…DDLPS and WDLPS seem to have some degree of response to ICIs, but monotherapy is insufficient. Interesting results have been reported in combination with chemotherapy, as displayed in Figure 1 (136,137). Another perspective could be combinations with molecularly targeted therapies, namely MDM2 antagonists and anti-CDK4/6.…”

Efficacy and safety of toripalimab combined with doxorubicin as first-line treatment for metastatic soft tissue sarcomas: an observational study

“…There are one ongoing trial of PD-1 inhibitor and doxorubicin in advanced STS. It is an open-label phase II study that recruited 30 patients with advanced sarcomas to assess the safety, tolerability, and efficacy of doxorubicin in combination with pembrolizumab in metastatic or unresectable soft tissue sarcoma (NCT03056001) [ 24 ]. The primary end point was the serious or life-threatening treatment emergent adverse event rate.…”