ORLANDO-Adding the investigational antisense agent oblimersen sodium (Genasense, G3139) to dacarbazine (DTIC) significantly improved response and survival in patients with advanced malignant melanoma in a phase III trial. John M. Kirkwood, MD, of the University of Pittsburgh Cancer Institute, reported 2-year results at the 41st Annual Meeting of the American Society of Clinical Oncology (abstract 7506) (see Table).
ORLANDOAdding the investigational antisense agent oblimersen sodium (Genasense, G3139) to dacarbazine (DTIC) significantly improved response and survival in patients with advanced malignant melanoma in a phase III trial. John M. Kirkwood, MD, of the University of Pittsburgh Cancer Institute, reported 2-year results at the 41st Annual Meeting of the American Society of Clinical Oncology (abstract 7506) (see Table).
The chemotherapy resistance of malignant melanoma has been linked to antiapoptotic proteins, including bcl-2, which is overexpressed in more than 80% of patients with malignant melanoma, Dr. Kirkwood said. While "no drug or combination has proved to be superior to single-agent dacarbazine in the past 30 years," he said, oblimersen was considered a promising prospect because it targets bcl-2 mRNA and increases cell apoptosis when added to chemotherapy. "Reduction of bcl-2 coincident with the administration of chemotherapy may amplify the benefit of chemotherapy in this disease," he said.
The randomized, open-label trial involved 771 patients. "This study is the largest randomized trial ever conducted in patients with advanced melanoma and involved 139 sites in 9 countries," Dr. Kirkwood said.
Patients in the trial had stage III or IV unresectable melanoma and were stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1-2); whether or not they had liver metastasis; and whether they had no visceral metastasis and normal lactase dehydrogenase (LDH) vs any visceral metastasis or elevated LDH. "Stratification achieved very good balance," Dr. Kirkwood said.
The population that was accrued to this trial was generally older than reported for other advanced melanoma trials, Dr. Kirkwood noted. The median age was 60 (range, 16 to 93). Almost 40% of patients were over age 65, and more than 10% were over 75. Males were predominant in both treatment groups.
Patients received oblimersen at a dosage of 7 mg/kg/d by continuous IV infusion for 5 days plus the standard DTIC dose of 1,000 mg/m2 or DTIC alone. Treatment cycles were repeated every 21 days, for a maximum of eight cycles, with restaging after every two cycles. No crossover was allowed. Adding oblimersen did not decrease the amount of DTIC given, he said.
In the intent-to-treat analysis, objective response was "highly significant," Dr. Kirkwood said, occurring in 48 patients (12.4%) in the oblimersen/DTIC group and 26 patients (6.8%) in the DTIC-only group (P = .007). Complete responses were seen in 11 patients (3%) treated with combination therapy and 2 patients (0.5%) treated with DTIC alone (P = .02). Durable response (6 months or longer) occurred in 28 patients (7%) with the combination therapy and 13 (3%) with DTIC only (P = .02). Dr. Kirkwood noted that the study protocol has been amended to extend follow-up for 5 years.
As an example of the high quality of responses seen in this trial, Dr. Kirkwood described a patient with extensive liver disease at the outset of the trial that completely resolved during treatment with oblimersen/DTIC. The patient was still alive and in complete remission 3 years later.
Results for progression-free survival were significant (median 2.4 months for combination therapy vs 1.6 for DTIC only; P = .0003). Median overall survival was 9 months in the combination therapy arm and 7.8 months in the DTIC-only group (P = .077), consistent with results reported at 12 and 18 months, Dr. Kirkwood said.
Normal LDH "recognized as one of the major prognostic factors in melanoma," Dr. Kirkwood said, was associated with significant increases in overall survival. The significance of the survival benefit was also seen in patients with "up to double" of the upper limit of normal LDH, he reported.
No Unexpected Toxicity
"No new or unexpected adverse events were observed in this study that had not been reported with DTIC alone," Dr. Kirkwood commented. "Nor were there any side effects of G3139 that had not previously been reported."
In the oblimersen group, there was a significant increased incidence of fever, neutropenia, thrombocytopenia, and catheter-related complications. Adverse events leading to discontinuation of therapy were more likely to occur among patients taking combination therapy (69 patients or 19%) than those taking DTIC alone (39 patients or 11%). However, Dr. Kirkwood said, the majority of adverse events in both arms were related to disease progression, which in this study could be designated an adverse event. For 9% of patients in both groups, the outcome of adverse events was death.
Grade 3-4 thrombocytopenia was more likely to occur among those in the combination therapy group (58 patients or 16%) than those in the DTIC group (23 patients or 6%). Dr. Kirkwood noted, however, that the incidence of bleeding and the number of platelet transfusions required were similar in both groups.
Grade 3-4 neutropenia occurred in 79 patients (21%) taking combination therapy vs 45 patients (13%) taking DTIC alone. The incidence of neutropenic infection, however, was low in both study groups. "In part, the slightly higher incidence in the oblimersen group was related to the requirement of an indwelling catheter for the delivery of the drug," Dr. Kirkwood said.
A key limitation of this study, Dr. Kirkwood pointed out, is the low response rate to dacarbazine. Coupling oblimersen with a more active chemotherapy agent, he said, would allow greater effects. He also noted that a new formulation of oblimersen has been developed to allow for subcutaneous dosing, which will avoid the problems related to catheter delivery.