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Pembrolizumab Demonstrates Anti-Tumor Activity in Sarcoma Subtypes

Virginia Powers, PhD
Published Online: 12:21 PM, Fri November 11, 2016
Treatment with pembrolizumab, an immunotherapeutic agent approved in melanoma, lung, and head and neck cancer, and which is undergoing investigation in several other cancer types, reduced the size of tumors in patients with a specific soft tissue sarcoma, according to interim results from the phase II SARC028, multicenter clinical trial reported at the Sarcoma Meeting at the Connective Tissue Oncology Society (CTOS) conference in Lisbon, Portugal.
 
Although the response rate was approximately 20% in the overall cohort of patients with soft tissue and bone sarcomas, a higher response of 44% was demonstrated in a subgroup of patients with undifferentiated pleomorphic sarcoma (UPS) who also experienced a reduction in tumor size.
 
Sarcoma is a relatively rare cancer that accounts for approximetly 1% of adult cancers. There are few available treatments making the need for new therapies a priority, explained lead author Melissa Burgess MD, assistant professor of Medicine at the University of Pittsburgh Cancer Institute. Burgess and colleagues evaluated the safety and efficacy of pembrolizumab at 200 mg IV every 21 days in 4 types of soft tissue, and 3 types of bone sarcomas. The primary endpoint was objective response rate (ORR) by RECIST 1.1, with a target endpoint of 25%. The secondary endpoints were safety, progression-free survival (PFS), overall survival (OS), and correlative studies. For enrollment, patients were required to have biopsies at 0 weeks and 8 weeks and a biopsy upon progression was optional.
 
“Unfortunately, these early results suggest that there is limited efficacy of pembrolizumab in the patient population as a whole. However, it’s promising that the drug seems to be beneficial in specific sarcoma subtypes. Our ongoing immune monitoring studies will allow us to better characterize the patients who will most benefit from this therapy for future clinical trials,” said Burgess.
 
SARC028 enrolled 86 patients with measurable disease, of which 2 were ineligible and 4 withdrew consent. Pembrolizumab was administered to 40 patients in the soft tissue sarcoma arm, which included 10 patients each with leiomyosarcoma, liposarcoma, synovial sarcoma, and undifferentiated pleomorphic sarcoma (UPS), plus 40 patients in the bone sarcoma arm, including 13 with Ewing sarcoma, 5 with chondrosarcoma and 22 patients with osteosarcoma. The patients had received from one to 3 prior treatment regimens; 35% of patients in each arm had received 2 or more prior treatments. The mean patient age was 33 years and 53 years in the soft tissue and bone sarcoma study arm, respectively, and 61% of patients overall were male.
 
After 8 weeks on pembrolizumab, no complete responses were observed in 37 patients evaluated for response.
 
In the soft tissue arm, 6 (60%) patients with leiomyosarcoma achieved stable disease (SD), and 4 patients experienced disease progression (PD). Two (22%) patients with liposarcoma (differentiated poorly diffuse) achieved partial response (PR), 4 (44%) had SD, and 3 (33%) had PD. Of the 9 patients with synovial sarcoma, 1 (11%) patient achieved PR, 2 (22%) had SD, and 6 (66%) patients had PD. The most promising response was seen in 9 patients with UPS where 4 (44%) patients achieved PR, 3 (33%) showed SD, and just 2 (22%) patients experienced PD.
 
The 12-week PFS was 55% in patients with soft tissue sarcoma.
 
In arm B, no patients with Ewing sarcoma showed PR, 2 (15%) showed stable disease, and 11 (65%) PD. Of 6 patients with chondrosarcoma, one (17%) PR was reported, 2 (33%) SD, and 3 (50%) patients had PD. One (5%) patient with osteosarcoma showed PR, 5 (26%) patients had SD, and 13 (69%) had PD.
 
Overall, 7 (19%) of patients in arm A showed PR, 15 (40%) had SD, and 15 (40%) patients showed PD. In arm B overall, 2 (5%) patients had PR, 9 (24%) patients had SD, and 27 (71%) patients had PD.
 
The median duration of response was 24 (range, 7.4 – 65.3) weeks in the responding patients with soft tissue sarcoma, and 43.1 weeks (range, 25.1 – 61.1) weeks in patients with bone sarcoma.
 
Burgess underscored the importance of the sample collection for correlative studies: “Sample collection and handling were great; 78 (>90%) baseline, and 62 (72%) post-treatment tumor biopsies were collected. In addition, there are peripheral blood samples for all patients from at least 3 timepoints.” Of these samples, there are 24 paired samples for lymphocyte analysis and 86 samples for the evaluation of circulating cytokines and checkpoint analysis.
 
“This is a pivotal trial for sarcoma, the first and largest trial to be conducted using immunotherapy. What makes this trial special is that we collected biopsies and blood samples to really study how the treatment is working or not working in these patients. These immune monitoring studies will offer unique insights into the biology of immunotherapy in sarcoma,” Burgess said.
 
Pembrolizumab was well tolerated and toxicities were consistent with published data.
 
“Pembrolizumab has demonstrated limited activity in unselected sarcoma patients. Although early responses were infrequent, partial responses and stable disease were observed that warrant further investigation,” Burgess remarked. She also noted that that the correlative studies were underway: “Of 94 baseline samples taken, only 7 were not usable! These samples are being evaluated by multi-color immunohistochemistry and whole exome/RNA sequencing to correlate response to PD-L1 expression.”

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