Pembrolizumab Makes Inroads in Sarcoma Subtypes

TOP - November 2017, Vol 10, No 4 - Immunotherapy, Online First

Chicago, IL—The tumor types amenable to immunotherapy with the PD-1 inhibitor pembrolizumab (Keytruda) keep expanding and now include sarcoma, which has been difficult to treat.

In the phase 2, multicenter clin­­ical trial SARC028, pembrolizumab achieved encouraging responses in patients with soft-tissue sarcoma, especially in patients with undifferentiated pleomorphic sarcoma and liposarcoma, reported Melissa A. Burgess, MD, Assistant Professor of Medicine, Cancer Therapeutics Program, Hillman Cancer Center, University of Pittsburgh, Pennsylvania, at the 2017 ASCO annual meeting. Dr Burgess presented the final results and biomarker analysis from the clinical trial.

Response in undifferentiated pleomorphic sarcoma correlated with PD-L1 status and baseline infiltrating cytotoxic T-cells, she said.

“Pembrolizumab has clinical activity in undifferentiated pleomorphic sarcoma and liposarcoma, and expansion cohorts in these 2 subtypes are planned. Ongoing biomarker analysis may guide combination strategies,” said Dr Burgess.

SARC028: Phase 2 Clinical Trial

The SARC028 clinical trial evaluated single-agent pembrolizumab in 40 patients with advanced soft-tissue sarcomas (10 patients in each of the 4 different cohorts of undifferentiated pleomorphic sarcoma, dedifferentiated liposarcoma, synovial sarcoma, and leiomyosarcoma) and in 40 patients with bone sarcomas (22 patients with osteosarcoma, 13 with Ewing sarcoma, and 5 with chondrosarcoma). The majority of the patients had received at least 2 previous therapies.

Pembrolizumab was administered at 200 mg intravenously every 3 weeks. Biopsies were obtained at baseline and during treatment. Tumors were tested for PD-L1 expression, and multicolor immunohistochemistry (IHC) was used to assess immune infiltrates.

At a median follow-up of 19 months, the projected overall response rate was 18%. In the soft-tissue sarcoma arm, there was 1 complete response and 6 partial responses: 1 complete response and 3 partial responses in patients with undifferentiated pleomorphic sarcoma, 2 partial responses in patients with liposarcoma, and 1 partial response in patients with synovial sarcoma. The median duration of response was 33 weeks. The median progression-free survival was 18 weeks, and the median overall survival was 49 weeks.

In the bone sarcoma arm, there were 2 partial responses, including 1 patient with osteosarcoma and 1 patient with chondrosarcoma. Overall, 9 patients had stable disease. The median duration of response was 43 weeks. The median progression-free survival was 8 weeks, and the median overall survival was 52 weeks.

“Serious adverse events were infrequent and not unexpected,” said Dr Burgess. Grade 3 or 4 adverse events were reported in 7% of patients in the soft-tissue sarcoma group and in 12% of patients in the bone sarcoma group.

Of the 70 biopsies that were analyzed for PD-L1 expression before treatment, 3 were positive (all in patients with undifferentiated pleomorphic sarcoma). Of these 3 biopsies, 2 were evaluable for response; there was 1 complete response and 1 partial response. None of the posttreatment biopsies were PD-L1–positive.

Multicolor IHC showed that patients who had responded to pembrolizumab had an increased number of infiltrating cytotoxic T-cells at baseline.

Dr Burgess and colleagues plan to conduct further biomarker analysis with IHC and phase 2 expansion cohort clinical trials in patients with undifferentiated pleomorphic sarcoma or liposarcoma.

Expert Commentary

Sarcoma is a complex type of cancer with many different subtypes. “There are multiple levels of complexity in attempting to understand immunotoxicity in sarcoma,” said formal discussant Jean-Yves Blay, MD, PhD, Centre Léon Bérard, Lyon, France.

“The authors are to be commended for looking at biomarkers with a multidimensional approach,” Dr Blay said. “Biomarkers could be a link to guide better therapy in the future,” he added.

“We can say that immunotherapy works in sarcoma, but it works in immune subsets of molecular subsets of histological subgroups. We must do better, and biomarkers are the key question,” concluded Dr Blay.

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Last modified: November 14, 2017