9121 Amrubicin monotherapy in patients with extensive disease small cell lung cancer (ED-SCLC) refractory to first-line platinum-based chemotherapy: final results of a phase 2 trial

Abstract

Background: Amrubicin (AMR) is a 3rd-generation synthetic anthracycline and potent topoisomerase II inhibitor. It is approved in Japan for treatment of NSCLC and SCLC. Literature indicates that SCLC patients (pts) who are refractory to 1 st-line chemotherapy are unlikely to respond to additional chemotherapy and their expected median survival is 3-5 mos. This phase 2 open-label trial (NCT 00375193) evaluated the efficacy and safety of AMR monotherapy for treatment of pts with refractory ED-SCLC. Methods: Pts with ED-SCLC refractory to 1st-line platinum-based chemotherapy (progression [PD] during therapy or relapse ≤90 days of treatment end) and ECOG performance status (PS) ≤2 were eligible. Pts received IV AMR 40 mg/m2/day ×3 days every 21 days until PD, unacceptable toxicity, or withdrawal. The primary endpoint was overall response rate (ORR, CR+PR; by RECIST), with a goal of demonstrating an ORR ≥18%. Secondary endpoints included time to progression (TTP) duration of response (DR), progression-free survival (PFS) and overall survival (OS). Left ventricular ejection fraction (LVEF) was measured by ECHO or by MUGA at baseline, cycles 3, 6, then every 2 cycles, and end of treatment. Results: 75 patients enrolled; median age was 63 years (range 43-88) and 17% were PS 2. Median time from end of 1st-line therapy to PD was 1.3 mos. Six pts died or discontinued before receiving AMR; the remaining 69 pts (92%) received a median of 4 AMR cycles (range 1-12). The primary endpoint was met: ORR was 21% (16/75, 95%Clopper-Pearson lower bound 13.9%), including 1 CR (1%) and 15 PR (20%). Stable disease (SD) was achieved by 30 (40%) pts. Of note, 7 pts with SD or PD as best response to 1st-line therapy achieved a PR with AMR treatment. Median DR was 4.3 months (95% CI 3.1, 5.8 mos), TTP was 3.8 mos (95% CI 2.7, 4.2 mos), PFS was 3.3 mos (95% CI 2.5, 4.0 mos), and OS was 6.1 mos (95% CI 4.9, 7.2 mos). Changes from baseline LVEF were similar across cumulative dosing groups, including in 4 pts who received cumulative AMR doses >1000 mg/m2. The most common grade 3 or 4 adverse events were neutropenia (67%), thrombocytopenia (41%), and leukopenia (35%). Eight pts (12%) experienced febrile neutropenia. Twenty-six pts (38%) required dose reductions. Conclusions: AMR shows promising activity in pts with refractory ED-SCLC, with an ORR of 21% and an acceptable safety profile.