Pembrolizumab plus chemotherapy shows limited activity in sarcoma

PD-1 targeted therapy plus metronomic chemotherapy induced limited responses in patients with soft tissue sarcoma or gastrointestinal stromal tumors, according to data from a phase 2 clinical trial published in JAMA Oncology.

PD-L1 therapy induced activity in patients with osteosarcoma during preclinical trials.

“Historically, sarcomas were the first tumor model for which immunotherapy was suggested as a relevant therapeutic strategy,” Maud Toulmonde, MD, from the department of medical oncology at the Institut Bergonié, in Bordeaux, France, and colleagues wrote.

Pembrolizumab (Keytruda, Merck) — a potent and highly selective humanized monoclonal antibody that directly blocks the interaction between PD-1 and PD-L1 — has demonstrated positive outcomes in various malignancies. Metronomic cyclophosphamide has previously showed a synergistic effect on immuno-stimulation when combined with immunotherapies.

Toulmonde and colleagues conducted an open-label, multicenter study to evaluate outcomes following treatment with pembrolizumab plus metronomic cyclophosphamide in 57 patients (median age, 59.5; 42% women), with leiomyosarcoma (cohort 1, n = 15), undifferentiated pleomorphic sarcoma (cohort 2, n = 16), other sarcomas (cohort 3, n = 16) and gastrointestinal stromal tumors (cohort 4, n = 10).

All patients received 50 mg cyclophosphamide twice daily for 1 week followed by 1 week off and 200 mg IV pembrolizumab on day 8 of every 3-week cycle (median cycles, 2).

PFS of 60% and objective response rates of 20% at 6 months served as dual primary endpoints.

Researchers assessed 50 patients for the efficacy endpoint.

Three patients appeared progression free at 6 months, which indicated that the first-stage objective was not satisfied for any cohort.

Sixteen patients achieved stable disease, including three patients each in cohorts 1 and 4 and five patients each in cohorts 2 and 3.

Researchers reported 6-month nonprogression rates of 0% in cohorts 1 and 2, 14.3% (95% CI, 1.8-42.8) in cohort 3 and 11.1% (95% CI, 2.8-48.3) in cohort 4.

Each cohort achieved a median PFS of 1.4 months (95% CI, 0.9-5.3).

Median OS range from 9.2 months (95% CI, 2.4-15.9) in patients with leiomyosarcoma, 5.6 months (95% CI, 3.2-16.1) in undifferentiated pleomorphic sarcoma and 7.1 months (95% CI, 2.0-16.3) in other sarcomas. Patients with gastrointestinal stromal tumors did not reach median OS at the time of analysis.

The only responding patient showed greater than 10% PD-L1 expression in immune cells.

After a median follow-up of 6.8 months, three patients continued treatment whereas 54 patients discontinued treatment due to disease progression (n = 45), toxic effects (n = 4), death (n = 4) or investigator’s decision (n = 1).

The most common serious adverse events included fatigue, oral mucositis and anemia.

Researchers observed expression of inhibitory enzyme indoleamine 2,3-dioxygenase 1 (IDO1), largely by macrophages, in immune cells in 69% of patients in cohort 1, 73% in cohort 2, 29% in cohort 3 and 63% in cohort 4.

In addition, they observed a statistically significant increase in the kynurenine-to-tryptophan ratio between plasma samples collected before the first infusion of pembrolizumab at day 8 of cycles 1, 2 and 3 (median increase, 34.6; Wilcoxon, 162; P < .001). Increases in the same ratio between cycle 1, day 8 and cycle 3, day 8 correlated with a higher density of IDO1 expression in pretreated tumor samples (Wilcoxon, 18.5; P = .04).

“This study indicates that the activity of PD-1 targeting in advanced soft tissue sarcoma and gastrointestinal stromal tumors is limited,” Toulmonde and colleagues wrote. “Given the importance of macrophage infiltration and the IDO1/kynurenine pathway in soft tissue sarcoma as suggested by our data, further strategies are warranted to assess the combination of anti-D-1/PD-L1 with therapies targeting these immunological features, such as colony stimulating factor 1 receptor inhibitors and/or IDO inhibitors in selected sarcoma subtypes.” – by Kristie L. Kahl

Disclosure: The researchers report they have no relevant financial disclosures.