Phase I dose-escalation study of oral vinflunine in combination with erlotinib in pre-treated and unselected EGFR patients with locally advanced or metastatic non-small-cell lung cancer

BACKGROUND: Erlotinib, the epidermal growth factor receptor tyrosine kinase inhibitor, and the intra-venous vinflunine vinca alkaloid microtubule inhibitor have been shown to be effective in the setting of non-small-cell lung cancer (NSCLC) palliative patients with acceptable toxicities. This phase I study was conducted to determine the maximal tolerated dose (MTD) and the safety of an all-oral combination. A potential pharmacokinetic drug–drug interaction was also investigated. PATIENTS AND METHODS: Patients with unresectable stage IIIB or stage IV NSCLC who failed one or two previous chemotherapy regimens were treated with flat doses of oral vinflunine from day 1 to day 5 and from day 8 to day 12 every 3 weeks and erlotinib daily on a continuous basis. The dose levels of vinflunine/erlotinib were 95/100, 115/100, 115/150 and 135/100 mg. RESULTS: Thirty patients were enroled. The recommended dose was 115/150 mg and the MTD 135/100 mg. Dose-limiting toxicities included grade 3 febrile neutropenia (1 patient) and related death (1 patient). Non-haematologic grade 3/4 toxicities included fatigue, condition aggravated, hypokalaemia, tumour pain, acneiform dermatitis, diarrhoea, hyperbilirubinaemia and pulmonary haemorrhage, in one patient each. Of 25 patients evaluable for tumour response, 2 patients had partial response and 20 patients had stable disease. CONCLUSION: The recommended doses for oral vinflunine and erlotinib combination were, respectively, 115 mg/day from day 1 to day 5 and from day 8 to day 12 every 3 weeks and 150 mg/day. There was no mutual impact on pharmacokinetics. The combination was safe but evaluation in phase II is needed to further refine the activity and toxicity that can be expected with prolonged administration of this dose schedule.