Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) versus intercalated TKI with chemotherapy for EGFR-mutated nonsmall cell lung cancer.

Introduction: Previous studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC). Materials and methods: Treatment-naïve patients with an activating EGFR mutation, ECOG performance score of 0-3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2-16 out of 21 days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival, objective response rate (ORR) and toxicity. Results: Between April 2014 and September 2016, 22 patients were randomised equally into both arms; the study was stopped due to slow accrual. Median follow-up was 64 months. Median PFS was 13.7 months (95% CI 5.2-18.8) for CPE and 10.3 months (95% CI 7.1-15.5; hazard ratio (HR) 0.62, 95% CI 0.25-1.57) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.24, 95% CI 0.07-0.83; p=0.02). ORR was 64% for CPE versus 55% for erlotinib monotherapy. Median overall survival was 31.7 months (95% CI 21.8-61.9 months) for CPE compared to 17.2 months (95% CI 11.5-45.5 months) for erlotinib monotherapy (HR 0.58, 95% CI 0.22-1.41 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity. Conclusion: Intercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in EGFR-mutated NSCLC at the expense of more toxicity.

Population-Based Patterns of Surgical Care for Stage IIIA NSCLC in the Netherlands between 2010 and 2013.

INTRODUCTION: Current guidelines include both induction therapy plus an operation and chemoradiotherapy (CRT) as options for clinical stage IIIA (cIIIA) non-small cell lung cancer (NSCLC) after multidisciplinary evaluation. We explored the use of operations for cIIIA NSCLC in the Netherlands. METHODS: Data about the primary treatment of patients with cIIIA NSCLC (according to the seventh edition of the Tumour, Node, and Metastasis Classification of Malignant Tumours) between 2010 and 2013 were extracted from the Netherlands Cancer Registry. Mortality information was obtained from the automated civil registry. RESULTS: A total of 4816 patients with cIIIA NSCLC (stage cN2, 3240 [67%]; stage T4, 1252 [26%]) were identified. CRT was used in 45% of patients and an operation was a component of treatment in 15%, with 28% of the latter having induction therapy. The 4-year survival rate was highest with induction therapy plus an operation (51%), followed by an operation plus adjuvant therapy (39%) and CRT (27%). Patients receiving induction therapy plus an operation were younger than those receiving CRT (median age 60 versus 66 years). The 30- and 90-day postoperative mortality rates after induction therapy plus lobectomy were 0.6% and 3.7% compared with 4.2% and 12.5% after induction therapy plus bilobectomy or pneumonectomy. Factors associated with poorer survival after induction therapy plus an operation were age older than 69 years, histological findings of nonsquamous cell carcinoma, and bilobectomy or pneumonectomy. Pathological stage IIIA NSCLC was present in only 51% of patients with cIIIA NSCLC who underwent an operation with or without adjuvant therapy, and the disease was of a lower stage in most of the remaining patients. CONCLUSIONS: In the Netherlands between 2010 and 2013, 15% of patients with cIIIA NSCLC received an operation, with the minority of these patients receiving induction therapy. In those receiving induction therapy, 90-day mortality after bilobectomy or pneumonectomy was more than three times higher than that for lobectomy. The discrepancy between clinical and pathological stage in patients receiving an upfront operation merits further investigation.