Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials

Autor: Elise Horvath, William D. Tap, Cristina R. Antonescu, Sandra P. D'Angelo, Howard Streicher, Mohammed M. Milhem, Brian A. Van Tine, James N. Atkins, Balkrishna N. Jahagirdar, Michelle R. Mahoney, Gary K. Schwartz
Rok vydání: 2017
Předmět:
Zdroj: The Lancet. Oncology. 19(3)
ISSN: 1474-5488
Popis: BACKGROUND: Metastatic sarcoma patients have limited options. Nivolumab and ipilimumab are monoclonal antibodies targeting PD-1 and CTLA-4, respectively. We evaluated the efficacy and safety of nivolumab and nivolumab plus ipilimumab separately in sarcoma patients. METHODS: We did an open-label, unblinded, non-comparative multi-center randomized phase II study that enrolled patients from 15 centers in the USA that were members of the Alliance Clinical Trials in Oncology Group (Alliance) and National Clinical Trials Network (NCTN.) Initial study design was a simon stage 2; however due to rapid accrual the study design was changed to Simon single stage design. Patients with central pathology confirmation of sarcoma had to be at least 18 years old to enroll and have evidence of metastatic or unresectable disease and adequate performance status. Patients must have received at least one previous line of systemic therapy and have at least one measurable lesion as per the Response Evaluation Criteria In Solid Tumors version 1.1. Disease progression was not a requirement for enrollment. Patients were assigned to treatment in an unblinded manner, as this trial was conducted as two independent, non-comparative phase II trials. Following registration, the patient was assigned one of the two treatments in a 1:1 ratio utilizing a dynamic allocation algorithm based on the methods by Pocock and Simon. Patients received either nivolumab 3 mg/kg every two weeks or nivolumab 3mg/kg and ipilimumab 1mg/kg every three weeks x four doses followed by nivolumab (3mg/kg) every two weeks thereafter. The primary endpoint was confirmed objective response rate, using a per-protocol analysis for evaluability. Secondary endpoints included safety, duration of response, clinical benefit rate, progression-free and overall survival (PFS, OS). Enrollment is closed and 3 patients remain on treatment as of the data lock on April 24, 2017. ClinicalTrials.gov Identifier: NCT02500797. FINDINGS: A total of 96 patients from 13 Alliance sites and 2 NCTN sites underwent central pathology review for eligibility between the following dates: August 13 to December 24, 2016 (81 patients); March 16, 2016, to March 17, 2016 (14 patients). Eighty-five patients proceeded to be allocated to one of the two treatment arms. Efficacy was determined in the first 76 evaluable patients, per protocol. Among the 38 patients that received nivolumab monotherapy, the confirmed ORR was 5% [92% CI (1–15%)]. Responses occurred in UPS and sarcoma, NOS. For the 38 patients that received combination therapy, the confirmed ORR was 16%, [92% CI (7–29%)]. Responses occurred in UPS, LMS, myxofibrosarcoma and angiosarcoma. In the monotherapy arm, the most common grade 3 or worse adverse events included anemia (four [10%]), decreased lymphocyte count (three [7%] each) and dehydration, increased lipase, pain, pleural effusion, respiratory failure, secondary benign neoplasm and urinary tract obstruction (two [5%] each.) In the combination arm, the most common grade 3 or worse adverse events included: anemia (seven [17%]), hypotension (four [10%]), pain and urinary tract infection (three [7%.]). Treatment related serious adverse events on the monotherapy arm occurred in eight patients and included anemia, anorexia, dehydration, decreased platelet count, diarrhea, fever, increased creatinine, and pleural effusion (one [2%] each). On the combination arm, treatment related serious adverse events occurred in11 patients. Three [7%] patients had adrenal insufficiency, two [5%] had increased alanine aminotransferase, two [5%] with hyponatremia, one [2%] each experienced anemia, increased aspartate aminotransferase, fatigue, pain and pruritus. INTERPRETATION: Nivolumab alone does not warrant further study in an unselected sarcoma population given the limited efficacy. Nivolumab combined with ipilimumab demonstrated promising efficacy in certain sarcoma subtypes (UPS, LMS, myxofibrosarcoma and angiosarcoma) with a manageable safety profile comparable to current available treatment options. The combination therapy arm met its pre-defined primary study endpoint; further evaluation of nivolumab plus ipilimumab in a randomized study is warranted. FUNDING: Alliance Clinical Trials in Oncology, NCI-CTEP, Bristol-Myers Squibb, Cycle for Survival
Databáze: OpenAIRE
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