Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial

Abstract

Background: Sarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab).

Methods: This single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5 mg daily from day 1, plus nivolumab 3 mg/kg intravenously on day 15, and then every 2 weeks; and level -1 with sunitinib 37.5 mg on the first 14 days (induction) and then 25 mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression-free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II).

Results: From May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5 mg as induction and then 25 mg in combination with nivolumab. After a median follow-up of 17 months (4-26), the 6-month progression-free survival rate was 48% (95% CI 41% to 55%). The most common grade 3-4 adverse events included transaminitis (17.3%) and neutropenia (11.5%).

Conclusions: Sunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6 months.Trial registration number NCT03277924.

Keywords: clinical trials as topic; immunotherapy; sarcoma; translational medical research.

Conflict of interest statement

Competing interests: JM-B reports research grants from PharmaMar, Eisai, Immix BioPharma and Novartis, outside the submitted work; honoraria for advisory board participation and expert testimony from PharmaMar, Eli Lilly and Company, Bayer and Eisai; and research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint, Nektar, Forma, Amgen and Daiichi Sankyo. NH reports grants, personal fees and non-financial support from PharmaMar, personal fees from Lilly, and grants from Eisai and Novartis, outside the submitted work, and research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint, Nektar, Forma, Amgen and Daiichi Sankyo. GG reports grants and personal fees from PharmaMar, grants from Novartis, and personal fees from Lilly, Pfizer, Bayer and Eisai, outside the submitted work. AR reports grants and personal fees from PharmaMar, personal fees from Lilly, Novartis, Amgen, AstraZeneca and Tesaro, grants and personal fees from Roche, and grants from Eisai, outside the submitted work. SS reports grants and personal fees from Bayer, Lilly and PharmaMar, and grants from GlaxoSmithKline, Novartis and Pfizer, outside the submitted work. EdA reports personal fees and non-financial support from Roche, BMS and PharmaMar, and personal fees from Bayer, outside the submitted work. ML-A declares institutional research grants from PharmaMar, Eisai, Immix BioPharma and Novartis, outside the submitted work. DSM reports institutional research grants from PharmaMar, Eisai, Immix BioPharma and Novartis, outside the submitted work, and travel support from PharmaMar, Eisai, Celgene, Bayer and Pfizer. JAL-M reports honoraria for advisory board participation and travel support from PharmaMar, Eli Lilly and Company, Bayer, Eisai, Novartis, BMS, MSD, Roche, Celgene, Pierre Fabre, Pfizer, GSK, Daiichi Sankyo, Amgen, and Chobani. All other authors declare no relevant relationship to disclose.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

CONSORT diagram. CONSORT, Consolidated Standards of Reporting Trials; ECOG, Eastern Cooperative Oncology Group; RECIST, Response Evaluation Criteria in Solid Tumors.

Figure 2

Response to treatment by patient according to RECIST. All evaluable patients (N=60) from phase Ib (n=14) and phase II (n=46) are shown. Tumor diameter was measured in millimeters. The dashed lines represent 20% increase in diameter and 30% decrease in diameter (RECIST progression and response cut-offs, respectively). *No size variation. RECIST, Response Evaluation Criteria in Solid Tumors.

Figure 3

Progression-free survival to treatment by patient, based on RECIST central radiological assessment. Each patient in the efficacy population in phase II is represented as bars (n=49). The vertical dashed line represents the median progression-free survival (5.6 months). The stars represent patients achieving RECIST objective responses. The arrows represent patients non-progressing in the last central radiological assessment. RECIST, Response Evaluation Criteria in Solid Tumors.