Response to anti-PD1 therapy with nivolumab in metastatic sarcomas

Abstract

BackgroundManipulation of immune checkpoints such as CTLA4 or PD-1 with targeted antibodies has recently emerged as an effective anticancer strategy in multiple malignancies. Sarcomas are a heterogeneous group of diseases in need of more effective treatments. Different subtypes of soft tissue and bone sarcomas have been shown to express PD-1 ligand.MethodsWe retrospectively analyzed a cohort of patients (pts) with relapsed metastatic/unresectable sarcomas, who were treated with nivolumab provided under a patient assistance program from the manufacturer. Pts underwent CT or PET/CT imaging at baseline and after at least four doses of nivolumab; RECIST 1.1 criteria were used for response assessment.ResultsTwenty-eight pts with soft tissue (STS, N = 24) or bone sarcoma (N = 4), received IV nivolumab 3 mg/kg every 2 weeks from July 2015. Median age was 57 (24–78), male:female ratio was 14:14; the median number of nivolumab cycles was eight. Eighteen pts concomitantly received pazopanib at 400–800 mg daily. The most common side effect was grade 1–2 LFT elevations; grade 3–4 toxicity occurred in five patients (colitis, LFT elevations, pneumonitis). Twenty-four pts received at least four cycles. We observed three partial responses: one dedifferentiated chondrosarcoma, one epithelioid sarcoma and one maxillary osteosarcoma (last two patients on pazopanib); nine patients had stable disease including three leiomyosarcomas; 12 patients had progression of disease including 4 leiomyosarcoma. Clinical benefit (response + stability) was observed in 50% of the evaluable patients.ConclusionsThese data provide a rationale for further exploring the efficacy of nivolumab and other checkpoint inhibitors in soft tissue and bone sarcoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s13569-016-0064-0) contains supplementary material, which is available to authorized users.

Rationale and emerging strategies for immune checkpoint blockade in soft tissue sarcoma

“…If regimens that are active against metastatic disease are identified, then they have the potential to be tested as adjuvant therapy in the future. One early, retrospective study of 28 patients who had relapsed, metastatic or unresectable STS or bone sarcoma examined the safety and efficacy of nivolumab . Many patients, including some responders, were concurrently receiving pazopanib, a multikinase inhibitor that was approved for sarcoma in 2012 .…”

“…One early, retrospective study of 28 patients who had relapsed, metastatic or unresectable STS or bone sarcoma examined the safety and efficacy of nivolumab. 55 Many patients, including some responders, were concurrently receiving pazopanib, a multikinase inhibitor that was approved for sarcoma in 2012. 56 Response was assessed using RECIST 1.1 criteria by comparing baseline imaging with positron emission tomography/computed tomography images obtained after at least 4 doses of nivolumab.…”

Advances in the Treatment of Pediatric Bone Sarcomas

“…There are case reports of response to pazopanib monotherapy or in combination with immune checkpoint inhibitor nivolumab. 98,99 Phase II clinical trials of pazopanib, regorafenib, and cabozantinib in patient populations, including osteosarcoma, are ongoing.…”

Development of Checkpoint Inhibitors for Sarcomas

“…Paoluzzi and colleagues reported the results of 28 patients (24 with STS and four with bone sarcomas) with advanced/ unresectable sarcomas treated with nivolumab 3 mg/kg every 2 weeks, through a patient assistance program from the manufacturer. 74 Eighteen patients received concurrent pazopanib at 400-800 mg daily. Objective responses were seen in three cases: on dedifferentiated chondrosarcoma, one maxillary osteosarcoma, and one epithelioid sarcoma-of note, five patients developed grade 3-4 adverse events (colitis, pneumonitis, and elevation of aspartate transaminase [AST] and/or alanine transaminase…”

“…74 The largest experience with PD-1 blockade in sarcomas, however, comes from the SARC-028, a prospective, nonrandomized, phase II trial, recently presented following a preliminary analysis. Pembrolizumab was administered at 200 mg given intravenously every 3 weeks to two concurrent arms: 40 patients were accrued in the STS cohort, with histologies limited to leiomyosarcoma (n=10), dedifferentiated liposarcoma (n=10), UPS (n=10), and synovial sarcoma (n=10), and 40 additional patients were included in the bone sarcoma arm (osteosarcoma, n=21; ES, n=13; dedifferentiated chondrosarcoma, n=6).…”