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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.

SUBMITTER: Martin-Broto J

PROVIDER: S-EPMC7674086 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Martin-Broto Javier J Hindi Nadia N Grignani Giovanni G Martinez-Trufero Javier J Redondo Andres A Valverde Claudia C Stacchiotti Silvia S Lopez-Pousa Antonio A D'Ambrosio Lorenzo L Gutierrez Antonio A Perez-Vega Herminia H Encinas-Tobajas Victor V de Alava Enrique E Collini Paola P Peña-Chilet Maria M Dopazo Joaquin J Carrasco-Garcia Irene I Lopez-Alvarez Maria M Moura David S DS Lopez-Martin Jose A JA

Journal for immunotherapy of cancer 20201101 2

<h4>Background</h4>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).<h4>Methods</h4>This single-arm, phase Ib/II trial enrolled adult patients ...[more]

PMID: 33203665

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Project description:Lessons learnedOur results highlight some of the challenges in the management of soft tissue sarcomas, which requires close cooperation between surgeons and medical oncologists and a careful selection of patients. The incidence of hepatotoxicity was a concerning finding and had been previously reported in patients treated with pazopanib.Although pharmacokinetic analysis was not part of this study, concomitant treatment with pazopanib has been recently reported to increase docetaxel exposure, which may explain the increased toxicity of combination regimens. It remains possible that lower doses of combined gemcitabine, docetaxel, and pazopanib may be tolerable. However, caution should be exercised in future trials investigating similar combinations.BackgroundFor extremity soft tissue sarcomas (STS), surgical resection remains the standard of care, and the addition of chemotherapy is controversial. This was a phase Ib/II trial of neoadjuvant therapy for patients with STS.MethodsPatients with high grade, extremity STS of >8 cm and amenable to definitive resection were treated with up to four 21-day cycles of 900 mg/m(2) gemcitabine on days 1 and 8, 75 mg/m(2) docetaxel on day 8, and 400 mg of pazopanib daily (GDP), followed by surgery and, if indicated, radiation therapy. Primary and secondary endpoints (phase Ib portion) were the safety and rate of pathologic response.ResultsThe trial was discontinued because of slow accrual after inclusion of five patients (leiomyosarcoma: two; undifferentiated pleomorphic sarcoma: three). Two patients completed four treatment cycles: one underwent surgery and one had insufficient response and received additional therapies. Three patients discontinued treatment because of toxicity. Grade 3 adverse events included hypertension, fatigue, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation, hoarseness, and myelotoxicity. There were no complete or partial responses. One patient had ≥ 90% pathologic response. Among four patients who underwent resection, three remain free of disease, and one patient eventually relapsed.ConclusionGDP combination used in the neoadjuvant setting resulted in significant toxicity; despite pathologic responses, no objective responses occurred.

Dataset Information

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

Publications

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

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