Is programmed cell death protein 1 (PD-1) targeting a relevant strategy for patients with soft-tissue sarcomas (STS)?
This phase 2 clinical trial assessed the combination of the selective PD-1 inhibitor pembrolizumab in combination with low-dose cyclophosphamide in 4 cohorts of patients with soft-tissue sarcoma (STS). Only 3 of 50 patients assessable for efficacy experienced tumor shrinkage, and analyses of tumor samples showed strong infiltration by M2 macrophages expressing the immunosuppressive enzyme inhibitory enzyme indoleamine 2,3-dioxygenase (IDO).
Given the importance of macrophage infiltration and the IDO1/kynurenine pathway in patients with STS, further strategies are warranted to assess the combination of anti–PD-1/programmed cell death 1 ligand 1 with colony-stimulating factor 1 receptor inhibitors and/or IDO inhibitors in patients with selected sarcoma subtypes.
There is a strong rationale for treating sarcomas with immunotherapy.
To assess the efficacy and safety of programmed cell death protein 1 (PD-1) targeting in combination with metronomic chemotherapy in sarcomas.
Design, Setting, and Participants
This was an open-label, multicenter, phase 2 study of 4 cohorts of patients with advanced soft-tissue sarcoma (STS), including leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), other sarcomas (others), and gastrointestinal stromal tumor (GIST). All patients received 50 mg twice daily cyclophosphamide 1 week on and 1 week off and 200 mg of intravenous pembrolizumab every 3 weeks.
Intervention or Exposure
Pembrolizumab in combination with metronomic cyclophosphamide.
Main Outcomes and Measures
There was a dual primary end point, encompassing both the nonprogression and objective responses at 6 months per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 for LMS, UPS, and others and 6-month nonprogression for GIST. An objective response rate of 20% and/or a 6-month nonprogression rate of 60% were determined as reasonable objectives for treatment with meaningful effect. Correlative studies of immune biomarkers were planned from patient tumor and plasma samples.
Between June 2015 and July 2016, 57 patients were included (median [range] age, 59.5 [18.5-84.0] years; 24 women [42%]); 50 patients were assessable for the efficacy end point. Three patients experienced tumor shrinkage, resulting in a partial response in a single solitary fibrous tumor. The 6-month nonprogression rates were 0%, 0%, 14.3% (95% CI, 1.8%-42.8%) for LMS, UPS, and others, respectively, and 11.1% (95% CI, 2.8%-48.3%) for GIST. The most frequent adverse events were grade 1 or 2 fatigue, diarrhea, and anemia. The only patient who experienced partial response was the only one with strong programmed cell death 1 ligand 1–positive staining in immune cell. Strong infiltration by macrophage expressing the inhibitory enzyme indoleamine 2,3-dioxygenase 1 (IDO1) was observed in the majority of cases. Moreover, a significant increase in the kynurenine to tryptophan ratio was observed in patient plasma samples during the study treatment.
Conclusions and Relevance
We found that PD-1 inhibition has limited activity in selected STS and GIST. This may be explained by an immunosuppressive tumor microenvironment resulting from macrophage infiltration and IDO1 pathway activation.
clinicaltrials.gov Identifier: NCT02406781
Toulmonde M, Penel N, Adam J, Chevreau C, Blay J, Le Cesne A, Bompas E, Piperno-Neumann S, Cousin S, Grellety T, Ryckewaert T, Bessede A, Ghiringhelli F, Pulido M, Italiano A. Use of PD-1 Targeting, Macrophage Infiltration, and IDO Pathway Activation in SarcomasA Phase 2 Clinical Trial. JAMA Oncol. Published online June 29, 2017. doi:10.1001/jamaoncol.2017.1617