Pembrolizumab in Advanced Soft Tissue and Bone Sarcomas: Results of SARC028, A Multicentre, Single arm, Phase 2 Trial

By H. Tawbi, M. Burgess, V. Bolejack, B. Van Tine, S. Schuetze, James Hu, S. D’Angelo, S. Attia, R. Riedel, D. Priebat and 14 more. The Lancet Oncology, 2017

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Background: Patients with advanced sarcomas have a poor prognosis and few treatment options improve overall survival. Chemotherapy and targeted therapies offer short-lived disease control. We assessed pembrolizumab (P), an anti-PD-1 antibody, for safety and activity in patients with advanced soft tissue (STS) and bone (BS) sarcomas. Methods: In this non-randomized, open-label, phase 2 study, we enrolled patients 18 years or older (12 years or older if they had BS), who had received at least one prior systemic therapy, had at least one measurable lesion by RECIST 1.1, and had at least one lesion accessible for biopsy. The primary endpoint was objective response rate (ORR) by RECIST 1.1. Secondary endpoints included safety, ORR by immune-related response criteria (irRC), progression-free survival (PFS), overall survival (OS), and correlation of PD-L1 expression with clinical benefit. The STS arm had 10 pts in each of 4 cohorts: undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (DDLPS), synovial sarcoma (SS) and leiomyosarcoma (LMS). The BS arm included 40 pts with osteosarcoma (OGS), Ewing sarcoma (ES) or dedifferentiated chondrosarcoma (CS). All patients were treated with pembrolizumab at 200 mg intravenously every 3 weeks. Imaging was performed at week 8 and every 12 weeks thereafter. Pre- and on-treatment biopsies and blood were required and collected for correlative studies. Patients who received at least one dose of pembrolizumab were included in the safety analysis and patients who progressed or reached at least one scan assessment were included in the efficacy analysis. The study has completed accrual to all BS cohorts, as well as to LMS and SS cohorts, however the UPS and DDLPS cohorts have resumed accrual to a planned 30 patient expansion in each cohort. This trial is registered on ClinicalTrials.gov, NCT02301039. Findings: 86 pts were enrolled, 80 were evaluable for response. For STS, median follow-up was 19.1 months. The ORR in the STS cohort was 18% and clinical activity was variable by histologic subtype: 40% ORR in UPS (1 CR+3PR/10), 2 PR/10 in LPS, 1PR/10 in SS and 0/10 in LMS. For BS, median follow-up was 17.8 months, ORR 5%, with 1PR/22 in OGS, 1PR/5 in CS and 0/13 in ES. The most common grade 3–4 adverse events included fatigue in 11 patients, anemia in 9 patients, and lymphopenia in 8 patients. Nine patients experienced serious adverse events including 2 with adrenal insufficiency, 2 with pneumonitis, and 1 with interstitial nephritis, all considered immune-related. Interpretation: Pembrolizumab has meaningful clinical activity in UPS and LPS, and expansion cohorts in those subtypes are ongoing to confirm and better characterize its efficacy. The study was partially funded by Merck, Inc., SARC, the Sarcoma Foundation of America, QuadW, and other philanthropic sources.

Subfields: Oncology, Pulmonary and Respiratory Medicine

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