Background: Recent advances in NSCLC have highlighted the importance of identifying mutations in driver oncogenes (eg EGFR, ALK) and the use of targeted agents to treat genetically-defined pt populations. HER2 (ERBB2) is a member of the ERBB receptor tyrosine kinase (TK) family which, once activated, stimulates several downstream effector pathways including PI3K, MAPK and JAK/STAT. Activating HER2 mutations are documented in approx 2–4% of pts with NSCLC and occur independently of EGFR, KRAS, NRAS and BRAF mutations. The efficacy of single-agent neratinib in HER2-mutated NSCLC is currently unknown; however, in vivo studies suggest that dual inhibition with an irreversible TK inhibitor (TKI) and an mTOR inhibitor is a promising therapeutic approach for HER2-mutated NSCLC [Perera et al. PNAS 2009]. This concept has been supported recently by a phase I study of neratinib, an irreversible pan-ERBB TKI, plus temsirolimus, which showed tumor regression in 5/6 evaluable pts with HER2-mutated NSCLC [Gandhi et al. WCLC, Amsterdam, Netherlands, 2011]. Methods: This international, randomized, open-label phase II study includes pts with previously treated stage IIIB/IV NSCLC and HER2-activating mutations. Pts are randomized 1:1 to oral neratinib 240mg od continuously ± IV temsirolimus 8mg/w (dose escalation to 15mg/w after one 4w cycle if tolerated). The addition of temsirolimus is permitted in pts assigned to neratinib monotherapy after progression. Tumor evaluations will be conducted every 8w. The primary endpoint is overall response rate (RECIST 1.1). Secondary endpoints are: clinical benefit rate; response duration; progression-free and overall survival; safety; health outcomes. Exploratory analyses include: correlative studies between tumor and plasma biomarkers and outcomes; pharmacokinetics. The trial has an optimal 2-stage design. Sample size (13–52 pts/arm) is based on a null response rate of 0.09, an alternative response rate of 0.25, power of 80% and 0.05 type I error rate. Both arms will be compared independently against historical controls. Enrollment is scheduled to open in March 2013. EudraCT identifier: 2012-004743-68. Clinical trial information: 2012-004743-68.