Oblimersen Added to DTIC Ups Survival in Melanoma

NEW YORK—At follow-up of more than 2 years, the largest study ever conducted in patients with advanced melanoma has continued to show a trend toward improved survival and a near-doubling of both progression-free survival (PFS) and durable response rates when the targeted antisense drug oblimersen sodium (G3139, Genasense) was added to standard therapy with the alkylating agent dacarbazine (DTIC).

A highly significant survival benefit was seen among patients with normal-range levels of lactate dehydrogenase (LDH) who received the oblimersen/DTIC combination vs DTIC alone, and a continuous relationship emerged between LDH levels and survival outcome. The survival benefit persisted at 3 years or longer follow-up among patients with normal-range LDH.

In an update on use of oblimersen in melanoma, at the Chemotherapy Foundation Symposium XXIV, Sanjiv S. Agarwala, MD, commented on the clinical value of the LDH findings in identifying patients most likely to benefit from an oblimersen/DTIC regimen.

Dr. Agarwala, chief, Medical Oncology Division, St. Luke's Medical Center, Bethlehem, Pennsylvania, presented results of a randomized multinational phase III trial, GM301, by the Oblimersen Study Group. Two-year follow-up results of the study were published recently in the Journal of Clinical Oncology (24:4738-4745, 2006).

The investigators randomly assigned 771 chemotherapy-naive patients with stage IV or unresectable stage III melanoma to treatment with DTIC alone (at 1,000 mg/m

²

) or DTIC preceded by a 5-day continuous infusion of oblimersen (at 7 mg/kg daily intravenously) every 21 days for up to eight cycles. No cross-over was permitted.

Overall Survival

Addition of oblimersen to DTIC yielded a trend toward improved overall survival (OS) at 24-month minimum follow-up (median, 9.0 months vs 7.8 months with DTIC alone, P = .077) as well as significant increases in PFS (median, 2.6 months vs 1.6 months, respectively, P < .001); overall response (13.5% vs 7.5%, P = .007); complete response (2.8% vs 0.8%, P = .031); and durable response (partial response or better lasting at least 6 months; 7.3% vs 3.6%, P = .027).

The incidences of neutropenia and thrombocytopenia were increased in the oblimersen/DTIC group, but there was no increase in the incidences of serious infections or bleeding events. The majority of adverse events in both groups consisted of flulike symptoms.

Impact of LDH

Of the three major stratification factors in the study (metastatic disease site, performance status, and baseline LDH levels), only baseline LDH levels showed a significant interaction with treatment. The interaction was also observed after adjusting for other known prognostic factors. At 24-month minimum follow-up, oblimersen significantly increased

survival time in the 508 patients with normal baseline serum LDH (median OS, 11.4 months vs 9.7 months, P = .018). In contrast, no survival benefit was seen with addition of oblimersen to DTIC in the 252 patients with elevated baseline LDH levels, defined as more than 1.1 times the upper limit of normal.

In the GM301 study, elevated LDH was found to be "important not only as a number but as a continuous variable," Dr. Agarwala said. "At LDH cutoff points ranging from 0.8 through 1.4 times the upper limit of normal, the addition of oblimersen to DTIC significantly improved survival; the lowest LDH levels were associated with the best outcome, even within the normal range."

As a result of the GM301 data, the European Association of Dermato-Oncology is planning a large randomized study of neoadjuvant therapy with oblimersen/DTIC in patients with stage IIIB and stage IIIC melanoma, "a population that should mimic the low-LDH group in the GM301 study," Dr. Agarwala said. Negative response and survival outcomes seen in major metastatic melanoma trials of the last 5 years, he emphasized, underscore that "this is a disease of major unmet need, and the search for new agents has to continue."