Phase I /II S tudy o f G emcitabine P lus V inorelbine a s F irst- Line C hemotherapy o f N on-Small-Cell L ung C ancer

Purpose: To determine the maximum-tolerated dose of gemcitabine when combined with a fixed dose of vinorelbine in the treatment of non‐small-cell lung cancer (NSCLC) and to evaluate in a phase II trial the activity of this combination. Patients and Methods: Sixty-eight patients with stage IIIB/IV NSCLC were treated with vinorelbine at fixed dose of 30 mg/m 2 intravenously and gemcitabine at increasing dose levels from 800 to 1,500 mg/m 2 intravenously on days 1 and 8 every 3 weeks. Results: In phase I, dose-limiting toxicity occurred at the dosage of 1,500 mg/m 2 gemcitabine, with three of five patients developing grade 4 thrombocytopenia. In phase II, with gemcitabine at 1,200 mg/m 2 , 19 (36%) of 52 assessable patients responded. Objective response was observed in 11 (39%) of 28 patients with stage IIIB disease and in eight (33%) of 24 patients with stage IV. The median time to progression was 29 weeks (range, 2 to 41 weeks; 35 weeks and 16 weeks for stages IIIB and IV, respectively), and median survival was 54 weeks (range, 2 to 841 weeks; 63 weeks and 42 weeks for stages IIIB and IV, respectively). One-year survival was 64% for patients with stage IIIB disease and 29% for those with stage IV. Clinical benefit response was observed in 29 (59%) of 49 assessable patients. Grade 4 leukopenia and thrombocytopenia were uncommon (6% and 8% of cases, respectively); however, grade 3/4 leukothrombocytopenia occurred more frequently in patients aged more than 70 years (52% and 24%, respectively). Conclusion: The combination of vinorelbine and gemcitabine is effective and tolerable in the treatment of NSCLC, thus deserving randomized trials with cisplatin combination regimens. J Clin Oncol 18:405-411. © 2000 by American Society of Clinical Oncology. R ECENT META-ANALYSIS of randomized clinical studies in patients with advanced non‐small-cell lung cancer (NSCLC) that compared chemotherapy to best supportive care demonstrated some degree of benefit of treatment with cisplatin-based regimens with regard to survival 1,2 and quality of life. 3 However, this benefit of improved survival is limited, and a real impact on quality of life is debatable. 4 In fact, approximately one third to one half of patients treated in randomized trials experience some form of severe side effects, particularly with the platinum-based regimens. 5 In particular, in one phase II trial, although there was a high objective response rate (48%) with a platinum combination, the patients’ general deterioration negated any potential advantage achieved by the majority of patients, even in those with objective responses. 6 A number of new antineoplastic agents active in NSCLC were recently introduced in clinical practice; therefore, a combination of these new agents may achieve results comparable to cisplatin regimens with better patient compliance. Vinorelbine is a new semisynthetic vinca alkaloid with excellent activity against NSCLC. In phase II studies, this drug was administered on a weekly schedule with doses from 25 mg/m 2 to 30 mg/m 2 , and a 29% to 44% response rate was reported in chemotherapy-naive patients, with mild hematologic toxicity and moderate neurotoxicity. 7,8 The single-agent activity of vinorelbine, as well as its activity in combination with cisplatin, has been extensively confirmed in randomized phase III trials. 9,10 Gemcitabine is an analog of the pirimidine antimetabolite cytarabine with a wider spectrum of activity in solid tumors compared with its parent compound. In phase I trials, gemcitabine has been shown to exhibit schedule-dependent cytotoxicity, and weekly administration seemed to be the most efficacious and tolerable schedule. 11 In phase II trials of NSCLC that used gemcitabine in a weekly-times-three regimen repeated every 28 days with a dose range of 800 mg/m 2 to 2,100 mg/m 2 , the response rates in previously untreated patients ranged from 20% to 28%. 11-14 Gemcitabine also showed good tolerability. In fact, the major side effects of gemcitabine were mild myelotoxicity, flu-like syndrome, fever, rash, and occasionally liver toxicity. 11 The aim of the present study was to determine the maximum-tolerated dose (MTD) of gemcitabine when combined with a fixed dose of vinorelbine in the treatment of non‐small-cell lung cancer and subsequently to evaluate in a large phase II trial the activity of this combination.