FDA Gets New Analysis of Oblimersen CLL Study

NEW YORK—Back in September, the FDA's Oncologic Drugs Advisory Committee (ODAC) failed to recommend that the agency grant accelerated approval to Genta's oblimersen (Genasense) plus chemotherapy (fludarabine/cyclophosphamide) for treatment of relapsed/refractory chronic lymphocytic leukemia (CLL).

Oblimersen inhibits production of Bcl-2, a protein made by cancer cells that is thought to block chemotherapy-induced apoptosis. By reducing the amount of Bcl-2 in cancer cells, oblimersen may enhance the effectiveness of anticancer treatment.

The ODAC panel had concerns that the pivotal study did not identify potentially responsive patients, despite the fact that it met its primary intent-to-treat endpoint, a significant increase in patients who achieved a complete or nodular partial response (CR/nPR)—17% vs 7% for chemotherapy alone, with responses confirmed by CT scan. Further, CRs with oblimersen lasted significantly longer than those with chemotherapy alone (median not reached but exceeding 36 months vs 22 months). Overall survival with 3 years of follow-up did not differ significantly between arms, but did correlate with best response.

Speaking at the Chemotherapy Foundation Symposium XXIV, Kanti R. Rai, MD, professor of medicine, Albert Einstein College of Medicine, and chief of hematology and oncology, Long Island Jewish Medical Center, presented a new analysis of the phase III trial (n = 241) according to stratification by tumor responsiveness to prior chemotherapy: fludarabine refractory vs nonrefractory (relapsed), one to two prior regimens vs three or more, and response to last therapy more than 6 months vs 6 months or less.

The new analysis showed that in patients nonrefractory to fludarabine (n = 101), CR/nPR was four times greater with oblimersen/chemotherapy than with chemotherapy alone (25% vs 6%, P = .016), and that overall survival in this group was significantly superior (median not reached but exceeding 39 months vs 33 months, HR 0.53, P = .05). "This is the first randomized study of patients with relapsed CLL to demonstrate a statistically significant improvement in overall survival," Dr. Rai emphasized. Time to progression was also increased (median, 12 months vs 10 months) but not significantly.

Genta submitted the new data analysis to FDA, which has extended the review period for the New Drug Application for oblimersen in CLL to January 29, 2007.

"The achievement of complete remission with its inherent clinical benefit remains the primary goal of leukemia therapy," Dr. Rai said. "Patients who remain sensitive to fludarabine are the most likely to achieve benefit. In light of these important efficacy results and excellent safety profile, Genasense is appropriate for use in CLL."