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August 2017 VOL 8, NO 8
Pembrolizumab Makes Inroads in Sarcoma Subtypes
The number of tumor types amenable to pembrolizumab immunotherapy keeps expanding and now includes sarcoma, which has been difficult to treat. In the SARC028 phase 2 multicenter trial, reported at the 2017 ASCO Annual Meeting, pembrolizumab achieved encouraging responses in soft tissue sarcoma, especially undifferentiated pleomorphic sarcoma (UPS) and liposarcoma.
Final results and biomarker analysis of the trial were presented by Melissa A. Burgess, MD, of the University of Pittsburgh, PA. Response in UPS 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,” Dr Burgess said.
SARC028 evaluated single-agent pembrolizumab in patients with advanced soft tissue sarcomas and bone sarcomas. Two groups of patients were treated in the trial: patients with soft tissue sarcomas (10 patients in each of 4 different cohorts of UPS, dedifferentiated liposarcoma, synovial sarcoma, and leiomyosarcoma) and those with bone sarcoma (40 patients—22 with osteosarcoma, 13 with Ewing sarcoma, and 5 with chondrosarcoma). Most patients in the trial had received at least 2 previous treatments.
Pembrolizumab was given at a dose of 200 mg intravenously every 3 weeks. Biopsies were obtained at baseline and then during treatment. Tumors were tested for PD-L1 expression and immune infiltrates by multicolor immunohistochemistry (IHC).
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 (CR) and 6 partial responses (PRs). Breaking responses down by soft tissue sarcoma type, 1 CR and 3 PRs occurred in UPS; PR was reported in 2 patients with liposarcoma and 1 with synovial sarcoma. Median duration of response in the soft tissue sarcoma arm was 33 weeks, median progression-free survival was 18 weeks, and median overall survival was 49 weeks.
In the bone sarcoma arm, there were 2 PRs, 1 with osteosarcoma and 1 with chondrosarcoma. Nine patients had stable disease. Median duration of response was 43 weeks, median progression-free survival was 8 weeks, and median overall survival was 52 weeks.
“Serious adverse events were infrequent and not unexpected,” Dr Burgess said. Grade 3/4 adverse events were reported in 7% of the soft tissue sarcoma group and 12% of the bone sarcoma group.
Three of 70 biopsies analyzed for pretreatment PD-L1 expression were positive (all in UPS patients). Two of the 3 patients were evaluable: 1 achieved a CR and 1 a PR. None of the posttreatment biopsies were PD-L1–positive.
Multicolor IHC showed that responders had an increased number of infiltrating cytotoxic T cells at baseline.
Dr Burgess and colleagues plan to do further biomarker analysis with IHC and phase 2 expansion cohort trials in UPS and liposarcoma.
Sarcoma is an incredibly 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. Biomarkers could be a link to guide better therapy in the future,” Dr Blay said.
“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,” he stated.
The novel combination of the investigational IDO pathway inhibitor indoximod plus pembrolizumab led to higher response rates in patients with advanced melanoma than what is seen with pembrolizumab alone, according [ Read More ]