Neratinib (N) with or Without Temsirolimus (Tem) in Patients (Pts) with Non-Small Cell Lung Cancer (Nsclc) Carrying Her2 Somatic Mutations: an International Randomized Phase Ii Study

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). 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.