Amrubicin combination fails in phase III trial

The combination of amrubicin plus cisplatin proved inferior to irinotecan plus cisplatin for the treatment of extensive-disease small-cell lung cancer in a phase III trial of 284 patients.

Patients in the amrubicin/cisplatin group survived a median of 15 months, significantly shorter than the median overall survival of 17.7 months in the irinotecan/cisplatin group.

The hazard ratio for the amrubicin/cisplatin group compared with the irinotecan/cisplatin group was 1.43, exceeding the predetermined noninferiority margin of 1.31, which triggered early publication of results in Journal of Clinical Oncology, Dr. Miyako Satouchi and associates reported (2014 March 17 [doi:10.1200/JCO.2013.53.5153]).

Enrollment ended in December 2010, and updated interim analyses included results as of May 2012.

Amrubicin is a synthetic anthracycline derivative that had shown some promise in phase I/II clinical trials. The investigators had hoped it might be as effective as irinotecan and cause less grade 3-4 diarrhea. Compared with the irinotecan/cisplatin group, patients in the amrubicin/cisplatin group in the current study were less likely to develop grade 3-4 diarrhea (1% vs. 8%) but were more likely to develop grade 4 neutropenia (79% vs. 22%) or grade 3-4 febrile neutropenia (32% vs. 11%), reported Dr. Satouchi of Hyogo Cancer Center, Akashi, Japan, and associates.

Initially, patients in the amrubicin/cisplatin group underwent four cycles of IV amrubicin 40 mg/m² on days 1, 2, and 3 and IV cisplatin 60 mg/m² on day 1 every 3 weeks. In an effort to reduce severe hematologic toxicities, the investigators revised the protocol during the study to reduce the initial dose of amrubicin to 35 mg/m². Patients in the irinotecan/cisplatin group underwent four cycles of IV irinotecan 60 mg/m² on days 1, 8, and 15 and IV cisplatin 60 mg/m² on day 1.

Among secondary outcomes, in the amrubicin/cisplatin group, the response rate was 78%, and the median progression-free survival was 5.1 months, compared with a response rate of 72% and a median progression-free survival of 5.6 months on irinotecan/cisplatin.

An analysis of treatment after the study found that two-thirds of patients from the irinotecan/cisplatin group subsequently received amrubicin as a single agent, which may have contributed to the group’s better overall survival, the investigators said. It may be that amrubicin is less synergistic than irinotecan with cisplatin and thus is inferior as a first-line combination, but amrubicin may still be a valuable second- or third-line therapy for extensive-disease small-cell lung cancer, the investigators said.

Dr. Satouchi reported receiving honoraria from Nippon Kayaku, and some of the other investigators in the study reported financial relationships with Nippon Kayaku, Daiichi Sankyo, and/or Bristol-Myers Squibb.

[email protected]

On Twitter @sherryboschert

The combination of amrubicin plus cisplatin proved inferior to irinotecan plus cisplatin for the treatment of extensive-disease small-cell lung cancer in a phase III trial of 284 patients.

Patients in the amrubicin/cisplatin group survived a median of 15 months, significantly shorter than the median overall survival of 17.7 months in the irinotecan/cisplatin group.

The hazard ratio for the amrubicin/cisplatin group compared with the irinotecan/cisplatin group was 1.43, exceeding the predetermined noninferiority margin of 1.31, which triggered early publication of results in Journal of Clinical Oncology, Dr. Miyako Satouchi and associates reported (2014 March 17 [doi:10.1200/JCO.2013.53.5153]).

Enrollment ended in December 2010, and updated interim analyses included results as of May 2012.

Amrubicin is a synthetic anthracycline derivative that had shown some promise in phase I/II clinical trials. The investigators had hoped it might be as effective as irinotecan and cause less grade 3-4 diarrhea. Compared with the irinotecan/cisplatin group, patients in the amrubicin/cisplatin group in the current study were less likely to develop grade 3-4 diarrhea (1% vs. 8%) but were more likely to develop grade 4 neutropenia (79% vs. 22%) or grade 3-4 febrile neutropenia (32% vs. 11%), reported Dr. Satouchi of Hyogo Cancer Center, Akashi, Japan, and associates.

Initially, patients in the amrubicin/cisplatin group underwent four cycles of IV amrubicin 40 mg/m² on days 1, 2, and 3 and IV cisplatin 60 mg/m² on day 1 every 3 weeks. In an effort to reduce severe hematologic toxicities, the investigators revised the protocol during the study to reduce the initial dose of amrubicin to 35 mg/m². Patients in the irinotecan/cisplatin group underwent four cycles of IV irinotecan 60 mg/m² on days 1, 8, and 15 and IV cisplatin 60 mg/m² on day 1.

Among secondary outcomes, in the amrubicin/cisplatin group, the response rate was 78%, and the median progression-free survival was 5.1 months, compared with a response rate of 72% and a median progression-free survival of 5.6 months on irinotecan/cisplatin.

An analysis of treatment after the study found that two-thirds of patients from the irinotecan/cisplatin group subsequently received amrubicin as a single agent, which may have contributed to the group’s better overall survival, the investigators said. It may be that amrubicin is less synergistic than irinotecan with cisplatin and thus is inferior as a first-line combination, but amrubicin may still be a valuable second- or third-line therapy for extensive-disease small-cell lung cancer, the investigators said.

Dr. Satouchi reported receiving honoraria from Nippon Kayaku, and some of the other investigators in the study reported financial relationships with Nippon Kayaku, Daiichi Sankyo, and/or Bristol-Myers Squibb.

[email protected]

On Twitter @sherryboschert

The combination of amrubicin plus cisplatin proved inferior to irinotecan plus cisplatin for the treatment of extensive-disease small-cell lung cancer in a phase III trial of 284 patients.

Patients in the amrubicin/cisplatin group survived a median of 15 months, significantly shorter than the median overall survival of 17.7 months in the irinotecan/cisplatin group.

The hazard ratio for the amrubicin/cisplatin group compared with the irinotecan/cisplatin group was 1.43, exceeding the predetermined noninferiority margin of 1.31, which triggered early publication of results in Journal of Clinical Oncology, Dr. Miyako Satouchi and associates reported (2014 March 17 [doi:10.1200/JCO.2013.53.5153]).

Enrollment ended in December 2010, and updated interim analyses included results as of May 2012.

Amrubicin is a synthetic anthracycline derivative that had shown some promise in phase I/II clinical trials. The investigators had hoped it might be as effective as irinotecan and cause less grade 3-4 diarrhea. Compared with the irinotecan/cisplatin group, patients in the amrubicin/cisplatin group in the current study were less likely to develop grade 3-4 diarrhea (1% vs. 8%) but were more likely to develop grade 4 neutropenia (79% vs. 22%) or grade 3-4 febrile neutropenia (32% vs. 11%), reported Dr. Satouchi of Hyogo Cancer Center, Akashi, Japan, and associates.

Initially, patients in the amrubicin/cisplatin group underwent four cycles of IV amrubicin 40 mg/m² on days 1, 2, and 3 and IV cisplatin 60 mg/m² on day 1 every 3 weeks. In an effort to reduce severe hematologic toxicities, the investigators revised the protocol during the study to reduce the initial dose of amrubicin to 35 mg/m². Patients in the irinotecan/cisplatin group underwent four cycles of IV irinotecan 60 mg/m² on days 1, 8, and 15 and IV cisplatin 60 mg/m² on day 1.

Among secondary outcomes, in the amrubicin/cisplatin group, the response rate was 78%, and the median progression-free survival was 5.1 months, compared with a response rate of 72% and a median progression-free survival of 5.6 months on irinotecan/cisplatin.

An analysis of treatment after the study found that two-thirds of patients from the irinotecan/cisplatin group subsequently received amrubicin as a single agent, which may have contributed to the group’s better overall survival, the investigators said. It may be that amrubicin is less synergistic than irinotecan with cisplatin and thus is inferior as a first-line combination, but amrubicin may still be a valuable second- or third-line therapy for extensive-disease small-cell lung cancer, the investigators said.

Dr. Satouchi reported receiving honoraria from Nippon Kayaku, and some of the other investigators in the study reported financial relationships with Nippon Kayaku, Daiichi Sankyo, and/or Bristol-Myers Squibb.

[email protected]

On Twitter @sherryboschert