Belotecan/cisplatin versus etoposide/cisplatin in previously untreated patients with extensive-stage small cell lung carcinoma: a multi-center randomized phase III trial

Abstract

Background: No novel chemotherapeutic combinations have demonstrated superior efficacy to etoposide/cisplatin (EP), a standard treatment regimen for extensive-stage small cell lung carcinoma (ES-SCLC) over the past decade. We aimed to compare the efficacy and safety of belotecan/cisplatin (BP) and EP regimens in chemotherapy- and radiotherapy-naïve patients with previously untreated ES-SCLC.

Methods: We conducted a multi-center, randomized, open-label, parallel-group, phase III clinical study. A total of 157 patients were recruited at 14 centers with 147 patients meeting the inclusion/exclusion criteria and randomized to either BP (n = 71) or EP (n = 76) treatment arms. A non-inferior response rate (RR) in the BP arm, analyzed by intent-to-treat analysis according to Response Evaluation Criteria in Solid Tumors version 1.0 criteria, was used as the primary endpoint. The secondary endpoints were progression-free survival (PFS) and overall survival (OS).

Results: In the BP arm, one patient had a complete response, 41 had a partial response (PR), and 17 had stable disease (SD). In the EP arm, 35 patients had PR and 28 had SD. The RR in the BP arm was non-inferior to the EP regimen in patients with ES-SCLC (BP: 59.2 %, EP: 46.1 %, difference: 13.1 %, 90 % two-sided confidence interval: -0.3-26.5, meeting the predefined non-inferiority criterion of -15.0 %). No significant differences in OS or PFS were observed between the treatment arms. Hematologic toxicities, including grade 3/4 anemia and thrombocytopenia, were significantly more prevalent in the BP arm than the EP arm.

Conclusions: The RR to the BP regimen was non-inferior to the EP regimen in chemotherapy- and radiotherapy-naïve patients with previously untreated ES-SCLC. Hematologic toxicities were significantly more prevalent in the BP group, indicating that BP should be used with care, particularly in patients with a poor performance status. Further studies assessing PFS and OS are required to validate the superiority of the BP regimen.

Trial registration: ClinicalTrials.gov identifier NCT00826644 . Date of Registration: January 21, 2009.

Keywords: Belotecan; Chemotherapy; Extensive stage disease; First-line; Phase III study; Small cell lung carcinoma.

Figures

Fig. 1

Disposition of the study patients. Of the 157 patients we recruited at a total of 14 centers, 147 met inclusion/exclusion criteria and then randomized to either the BP arm (n = 71) or the EP arm (n = 76). In the BP arm, the number of the patients of the mITT set, the PP set and the safety set were 71, 57 and 70, respectively. In the EP arm, these values were 76, 63 and 77 in the corresponding order

Fig. 2

Efficacy endpoints of modified intent-to-treat (mITT) and per protocol (PP) population. The BP group is not inferior to the EP group with regards to the response rate (between group difference 13.1 %, 90 % two-sided confidence interval -0.3 to 26.5, meeting the predefined non-inferiority criterion of -15.0 %) in mITT population. The response of the BP group was superior in PP population

Fig. 3

Overall survival and progression-free survival on Kaplan–Meier analysis. (a) There were no significant differences in the OS and PFS between the two treatment arms. That is, the median OS was 360 days (95 % CI: 285–482) in the BP arm and 305 days (95 % CI: 232–343) in the EP arm (Log-Rank p = 0.210). (b) The median PFS was 190 days (95 % CI: 148-219) in the BP arm and 172 days (95 % CI: 144–195) in the EP arm (Log-Rank p = 0.369)