Randomized phase III study of docetaxel versus docetaxel plus intercalated erlotinib in patients with relapsed non-squamous non-small cell lung carcinoma

•Patients with relapsed NSQ-NSCLC were included in this phase III trial.•We compared docetaxel plus intercalated erlotinib to docetaxel monotherapy.•Docetaxel plus intercalated erlotinib showed detrimental results.•Combination of docetaxel and intercalated erlotinib should not be explored further. Earlier preclinical and phase II research showed enhanced effect of docetaxel plus intercalated erlotinib. The NVALT-18 phase III study was designed to compare docetaxel with docetaxel plus intercalated erlotinib in relapsed metastasized non-squamous (NSQ) non-small cell lung cancer (NSCLC). Patients with relapsed Epidermal Growth Factor Receptor (EGFR) wild type (WT) NSQ-NSCLC were randomized 1:1 to docetaxel 75 mg/m2 intravenously on day 1 every 21 days (control), or docetaxel 75 mg/m2 intravenously on day 1 plus erlotinib 150 mg/day orally on day 2–16 every 21 days (experimental arm). Progression free survival (PFS) was the primary endpoint, secondary objectives were duration of response, overall survival (OS) and toxicity. Between October 2016 and April 2018 a total of 45 patients were randomized and received treatment in the control (N = 23) or experimental arm (N = 22), the study was stopped due to slow accrual. Median PFS was 4.0 months (95% CI: 1.5–7.1) versus 1.9 months (95% CI 1.4–3.5), p = 0.01 respectively; adjusted hazard ratio (HR) 2.51 (95% CI: 1.16–5.43). Corresponding median OS was 10.6 months (95% CI: 7.0–8.6) versus 4.7 months (95% CI: 3.2–8.6), p = 0.004, with an adjusted HR of 3.67 (95% CI: 1.46–9.27). Toxicity was higher with combination therapy, with toxicity ≥ CTCAE grade 3 in N = 6 (26%) in the control arm and N = 17 (77%) in the experimental arm (p