Background: Major pathologic response (mPR) in resected NSCLC following neoadjuvant chemotherapy correlates with long-term survival. This phase 1 study assessed the safety and efficacy of N added to neoadjuvant C and D, using mPR as primary surrogate of efficacy endpoint. Methods: Eligible patients (pts) had stage IB (≥4 cm) to IIIA (single station N2) resectable NSCLC (AJCC 7^th). The study included an expansion phase of N 200 mg p.o. bid priming monotherapy for 28 days, followed by 3 cycles of C 75 mg/m², D 75 mg/m² every 21 days, and N 200 mg p.o. bid, and surgery (after a run-in phase in 6 pts determined safety of escalating N doses). With 33 pts, the study had 90% power to detect an increase in mPR from 15% (historical controls) to 35%, with a 10% type I error rate. Based on the Simon’s two-stage design, the protocol called for discontinuation of the trial if there were < 4 responders in the first 19 pts treated at N 200 dose level (NCT02225405). Results: From July 2015 to May 2017, 21 pts (15 female, 1/8/12 stages I/II/III) were treated (6 with N 150 mg bid, 15 with N 200 mg bid). Only 1/15 pts treated with N 200 mg bid achieved a mPR (6.7%, 95% CI 0.2% - 32.0%). An interim analysis demonstrated that the probability of observing ≥4 mPRs if accrual were to continue to 19 pts was only 5.4%, assuming the prior of p beta(0.35, 0.65). Hence, the study was discontinued for futility. The best objective response rate by RECIST 1.1 in all 21 pts was 33.3%. No patients responded to N priming monotherapy. With a median follow up time of 11 months, the 12-month RFS in the whole cohort was 71% (95% CI 49%, 100%). The most frequent treatment-related grade 3-4 toxicities in all pts were: transaminitis (14.3%); nausea (9.5%) and electrolyte abnormalities (14.3%). No unexpected perioperative complications were observed. Conclusions: Although tolerable, neoadjuvant N, C, and D did not increase the mPR rate compared to historical controls of induction chemotherapy alone. Additional studies of the combination in this setting are not recommended. Our trial design, utilizing mPR as an intermediary endpoint, may serve as a framework to rapidly screen novel compounds that should be investigated further as neoadjuvant therapies for resectable NSCLC. Clinical trial information: NCT02225405