Background: Combination immunotherapy with nivolumab and ipilimumab has proven clinical activity in NSCLC. There is growing evidence to suggest that the tumor microenvironment (TME) may interfere with effective immune recognition, even in the presence of checkpoint inhibitors. Unpublished preclinical data from our group demonstrates that human lung cancer derived cancer-associated fibroblasts (CAFs) inhibit tumor infiltrating lymphocyte activation and are potentially immunosuppressive. Targeting the TME may represent an important synergistic approach in immunotherapy. Nintedanib is an orally available triple kinase inhibitor that is active against NSCLC, inhibits CAFs, and targets VEGFR, FGFR and PDGFR. Based on these observations a phase IB/II trial of the combination of nintedanib, nivolumab and ipilimumab was initiated in NSCLC patients. Methods: 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 or with disease progression following immunotherapy. Primary objective of phase I is to determine the tolerability of concurrent administration of the proposed regimen. Three dose levels of nintedanib (100mg, 150 mg and 200 mg twice daily) are given with fixed doses of nivolumab (3mg/kg every 2 weeks) and ipilimumab (1mg/kg every 6 weeks). Dose escalation will be done by the modified continuous re assessment method (O, Quigley et al, 1990). Phase II is divided into two single arm cohorts (Arm A: Treatment or immunotherapy naïve; Arm B: Immunotherapy pretreated). Enrollment to phase II will be done by the Bayesian two-stage design method. The primary objective of phase II is to determine the efficacy of the combination regimen in NSCLC. Key secondary objectives are overall survival and progression free survival. The sample size calculation of 18 patients in phase I and 80 patients in phase II assumes 18 months for accrual and 2-3 years for follow up. Enrollment to phase I was started on 29^th January 2018 and to date 1 patient has been enrolled. Serial blood and tumor biopsies are obtained to evaluate potential predictive and resistance mechanisms. Clinical trial information: NCT03377023