IASLC: Anti-Bcl 2 Agent Fails to Improve on Docetaxel Survival in NSCLC

September 10, 2007

SEOUL, South Korea -- Adding an antisense agent to chemotherapy failed to improve survival in patients with previously treated non-small-cell lung cancer (NSCLC), according to a study reported here.

SEOUL, South Korea, Sept. 10 -- Adding an antisense agent to chemotherapy failed to improve survival in patients with previously treated non-small cell lung cancer (NSCLC), according to a study reported here.

Patients treated with docetaxel alone had a median survival of 9.4 months versus 9.0 months in the group that received docetaxel plus oblimersen, an antisense oligonucleotide that targets the Bcl-2 oncogene, Roy Herbst, M.D., of the University of Texas M. D. Anderson Cancer Center in Houston reported at the International Association for the Study of Lung Cancer's world conference.

Time to progression and response rate did not differ between treatment groups either, although oblimersen was associated with more durable responses.

"The study was underpowered for its primary endpoint [survival]," said Dr. Herbst. "A phase III expansion of the study was not performed. On the basis of the data I have presented, it is unlikely that a decision would be made to move forward with a phase III study."

Bcl-2, an antiapoptosis gene, is upregulated and induced in lung cancer, said Dr. Herbst. Oblimersen selectively targets Bcl-2 RNA and decreases levels of Bcl-2 protein. Preclinical studies suggested additive or syngeristic activity when oblimersen was combined with docetaxel. The antisense agent has demonstrated activity in other tumor types.

"Increased response rates were seen in trials of chronic lymphoid leukemia and melanoma when oblimersen was combined with chemotherapy," said Dr. Herbst. "Retrospective analysis suggested that responses were more durable [with oblimersen] in both tumor types."

"However, both trials failed to meet their primary objective of improved overall survival, though each had a trend in that direction," he added.

The current study was a phase II trial that involved 298 patients. Depending on the results, the study could be expanded to phase III status and enroll 800 patients.

Patients were randomized to oblimersen 7 mg/kg/d by continuous infusion for seven days plus docetaxel 75 mg/m2 on day 5 or to docetaxel alone. The primary endpoint was survival, and secondary endpoints were response rate, response duration, and time to progression.

Patients who received oblimersen had a median time to progression of 3.1 months versus 2.8 months for chemotherapy alone. The overall response rate was 9.6% with oblimersen and 8.6% without.

The number of durable responses (six months or longer) did favor the oblimersen (10 versus two, P=0.015). The median duration of response was seven months with the antisense agent and three months without it.

Patients in the combination arm had more grade 3 - 4 neutropenia, fatigue, dyspnea, pyrexia, and nausea, but the toxicity was manageable, said Dr. Herbst.

The prolonged duration of response with oblimersen should be considered hypothesis-generating and a possible issue for future trials to address, he added.