MA13.02 Phase II Study of Nivolumab and Ipilimumab Combined With Nintedanib in Recurrent Non-Small Cell Lung Cancer

Abstract

Cancer-associated fibroblasts (CAFs) are a key immunosuppressive component of the tumor microenvironment (TME). Nintedanib is an oral triple kinase inhibitor that suppresses CAFs. Modulating the TME through inhibition of CAFs may represent an important synergistic approach in overcoming resistance to immune checkpoint inhibitors (ICIs). Based on these observations, we initiated a phase IB/II trial to evaluate the combination of nintedanib, nivolumab, and ipilimumab in advanced NSCLC patients. The phase IB dose-escalation results were presented at WCLC 2019 and the combination of nivolumab at 3mg/kg every 2 weeks, ipilimumab 1 mg/kg every 6 weeks, and nintedanib 150 mg once daily was declared as the recommended phase II dose (RP2D). Here we present the 1st interim analysis of phase II of the combination regimen in the ICI pre-treated patients. This is a single institution, investigational, non-randomized, parallel assignment phase I/II clinical trial of patients with locally advanced or metastatic NSCLC. Eligible patients can be immunotherapy naïve (Arm A) or with disease progression following immunotherapy (Arm B). Enrollment into phase II of the trial is being performed by the Bayesian two-stage design method with the primary objective of determining the efficacy of the combination regimen in NSCLC. Key secondary objectives are overall survival (OS) and progression-free survival (PFS). Descriptive statistics were used to summarize demographic and safety data. The Kaplan–Meier method with log-rank test was used for survival analysis. 20 patients received therapy with the combination of nivolumab, ipilimumab, and nintedanib at the RP2D in the ICI pretreated cohort (Arm B). The majority of patients were female (60%) with a current or prior history of tobacco use (84%) and an ECOG performance score of 1 (90%). Adenocarcinoma was the most common histology (75%). The most common treatment-related adverse event of any grade were transaminitis, diarrhea, and pruritis, each observed in 20% (4/20) of patients. Of the 18 patients evaluable for response, 4 (22%) had a partial response (2 confirmed), 7 (39%) had stable disease and 7(39%) developed progressive disease for a disease control rate of 61%. Survival analysis showed a median PFS of 2.7 months (1.4, N.E.) and OS of 7.7 months (5, N.E.). Clinical trial information: NCT03377023. The combination of nivolumab, ipilimumab and nintedanib was well tolerated and demonstrated antitumor activity despite tumor progression on prior ICI therapy. The ICI pretreated cohort has met the predefined response criteria for the 1st interim analysis ( > or = 2 responses) and will continue enrollment (with 20 additional patients) in the second stage.