ABSTRACT Aim: Somatic HER2 (ERBB2) mutations occur in approx. 2-4% of pts with NSCLC. In vivo data suggest that combined HER2/mTOR inhibition has synergistic effects in HER2-driven lung tumors [Perera PNAS 2009]. In a phase I study, 5/7 HER2-mutated NSCLC pts showed tumor regression (PR/SD) after treatment with N, an irreversible pan-HER tyrosine kinase inhibitor, and TEM [Gandhi JCO 2014]. The effects of N alone are unknown. This randomized 2-stage phase II study compares N +/- TEM in pts with stage IIIB/IV NSCLC with HER2 somatic mutations. Methods: Pts whose tumors had a documented HER2 mutation were randomized 1:1 to receive oral N 240 mg once daily continuously +/- IV TEM 8 mg/wk (escalated to 15 mg/wk after one 3-wk cycle if tolerated). Addition of TEM was permitted in pts assigned to N alone after progression. High-dose loperamide prophylaxis for diarrhea was mandatory throughout cycle 1. Primary endpoint: overall response rate. Secondary endpoints included: clinical benefit rate, progression-free survival, safety. If > = 2 of 13 pts in each arm have a response at 12 wks in stage 1, a further 26 pts per arm will be enrolled in stage 2. EudraCT ID: 2012-004743-68. Results: 27 pts were enrolled (N, n = 13; N + TEM, n = 14) in stage 1 with approx. 12 wks between randomization of last pt and data cut-off. Baseline characteristics (n = 27): male/female 52%/48%; median age 65 yr; never smokers 63%. Two pts, both in N + TEM arm, had not received prior anticancer medications. Stage 1 results are shown in table. In all pts (n = 27), most common all-grade adverse events (AEs): diarrhea (n = 24), constipation (13), nausea (13), dyspnea (11), asthenia (11), vomiting (11); most common grade 3/4 AEs: dyspnea (4), diarrhea (3; grade 3 only), vomiting (3), nausea (2). Stage 1 Neratinib (N = 13) Neratinib + Temsirolimus (N = 14) Efficacy Overall response rate,* n (%) [90% CI] 0 (0) [0-21] 3** (21) [6-47] Partial response, n 0 3 Stable disease ( > = 12 weeks), n 4 6 Median PFS, months (95% CI) 2.9 (1.4-NE) 4.0 (2.9-9.8) Treatment-emergent diarrhea, n (%) All-grade diarrhea 10 (77) 14 (100) Grade 3 diarrhea 1 (8) 2 (14) * RECIST, version 1.1. ** Two confirmed responses; both pts had not received any prior anticancer medications. Abbreviations: CI, confidence interval; NE, not estimable; PFS, progression-free survival. Conclusions: N + TEM met the efficacy criteria for stage 1 and has been expanded into stage 2. Diarrhea was not a limiting toxicity with aggressive upfront management. Disclosure: B. Besse: Research grants from Puma; B. Yao, A. Lalani, L. McCulloch and R. Bryce: Employed by Puma Biotechnology Inc (study sponsor). All other authors have declared no conflicts of interest.