No Overall Survival Difference for Amrubicin vs Topotecan in Second-Line Treatment of Small Cell Lung Cancer
In a phase III trial reported in the Journal of Clinical Oncology, Pawel et al found no difference in overall survival with amrubicin vs topotecan as second-line therapy in patients with first-line sensitive or refractory small cell lung cancer. An overall survival benefit of amrubicin was observed in the subgroup of patients with refractory disease.
Study Details
In this open-label trial, 637 patients from 116 centers in Europe, Canada, Australia, and the United States were randomly assigned 2:1 between December 2007 and January 2010 to receive 21-day cycles of amrubicin at 40 mg/m2 intravenously on days 1 to 3 (n = 424) or topotecan at 1.5 mg/m2 intravenously on days 1 to 5 (n = 213). Patients were stratified according to sensitivity to first-line therapy: sensitivity was defined as complete response, partial response, or stable disease after first-line therapy and recurrence- or progression-free interval ≥ 90 days after completion of first-line therapy; refractoriness was defined as progressive disease as best response to first-line therapy or progression-free interval < 90 days.
Treatment was continued for six cycles or until progression; patients with at least stable disease at cycle six could receive an additional six treatment cycles. The protocol was amended to require use of prophylactic hematopoietic growth factors in all cycles in all patients. The primary endpoint was overall survival in the intent-to-treat population.
Patients in the amrubicin and topotecan groups were generally balanced for age (median = 62 and 61 years, 40% and 35% ≥65 years), sex (58% and 60% male), Eastern Cooperative Oncology Group performance status (0 in 30% and 34%, 1 in 68% and 64%), extensive disease (88% in both), median time from small cell lung cancer diagnosis (8.4 months in both), smoking status (30% and 23% current, 60% and 66% former, 11% never in both), prior radiotherapy (47% and 50%), time from end of first-line treatment to progression (median ≥ 90 days in 54% and 56%), and response to first-line treatment (complete response in 13% and 16%, partial response in 57% and 49%, stable disease in 20% and 23%, progressive disease in 11% and 12%). Response to first-line therapy was categorized as sensitive in 53% and 55% and refractory in 47% and 45%.
Survival and Response Rates
A total of 605 patients received treatment (16 in each group did not). Median overall survival was 7.5 months in the amrubicin group vs 7.8 months in the topotecan group (hazard ratio [HR] = 0.880, P = .170), including 9.2 vs 9.9 months in sensitive patients (HR = 0.936, P = .615) and 6.2 vs 5.7 months in refractory patients (HR = 0.77, P = .047).
Median progression-free survival was 4.1 vs 3.5 months (HR = 0.802, P = .018), including 5.5 vs 4.3 months in sensitive patients (HR = 0.671, P = .0023) and 2.8 vs 2.6 months in refractory patients (HR = 0.934, P = .6110).
Objective response rates were 31.1% vs 16.9% (odds ratio [OR] = 2.22, P < .001), including 40.9% vs 23.1% in sensitive patients (OR = 2.31, P = .001) and 20.1% vs 9.4% in refractory patients (OR = 2.43, P = .024).
Adverse Events
Grade ≥ 3 adverse events in the amrubicin and topotecan groups included neutropenia (41% vs54%, P = .004), thrombocytopenia (21% vs54%, P < .001), anemia (16% vs31%, P < .001), infections (16% vs10%, P = .043), febrile neutropenia (10% vs3%, P = .003), and cardiac disorders (5% vs5%, P = .759). Transfusion rates were 32% vs 53% (P < .001). One dose reduction was required in 22.3% vs 44.7% of patients, and two were required in 4.9% vs 18.8%. Analysis in a subgroup of patients showed that NQO1 polymorphisms did not affect safety outcomes.
The investigators concluded: “Amrubicin did not improve survival when compared with topotecan in the second-line treatment of patients with [small cell lung cancer]. [Overall survival] did not differ significantly between treatment groups, although an improvement in [overall survival] was noted in patients with refractory disease treated with amrubicin.” The authors noted that the findings in patients with refractory disease warrant further confirmation, with additional studies being considered in this setting.
Joachim von Pawel, MD, of Asklepios Fachkliniken, München-Gauting, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by the National Institute for Health Research Royal Marsden/Institute of Cancer Research Biomedical Research Center and by Celgene. For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
