Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group

Abstract

Purpose: Phase II trials with biochemotherapy (BCT) have shown encouraging response rates in metastatic melanoma, and meta-analyses and one phase III trial have suggested a survival benefit. In an effort to determine the relative efficacy of BCT compared with chemotherapy alone, a phase III trial was performed within the United States Intergroup.

Patients and methods: Patients were randomly assigned to receive cisplatin, vinblastine, and dacarbazine (CVD) either alone or concurrent with interleukin-2 and interferon alfa-2b (BCT). Treatment cycles were repeated at 21-day intervals for a maximum of four cycles. Tumor response was assessed after cycles 2 and 4, then every 3 months.

Results: Four hundred fifteen patients were enrolled, and 395 patients (CVD, n = 195; BCT, n = 200) were deemed eligible and assessable. The two study arms were well balanced for stratification factors and other prognostic factors. Response rate was 19.5% for BCT and 13.8% for CVD (P = .140). Median progression-free survival was significantly longer for BCT than for CVD (4.8 v 2.9 months; P = .015), although this did not translate into an advantage in either median overall survival (9.0 v 8.7 months) or the percentage of patients alive at 1 year (41% v 36.9%). More patients experienced grade 3 or worse toxic events with BCT than CVD (95% v 73%; P = .001).

Conclusion: Although BCT produced slightly higher response rates and longer median progression-free survival than CVD alone, this was not associated with either improved overall survival or durable responses. Considering the extra toxicity and complexity, this concurrent BCT regimen cannot be recommended for patients with metastatic melanoma.

Fig 1.

CONSORT flow diagram and study schema displays the study design and treatment regimens as well as the proportion of eligible and assessable patients on each treatment arm. IFNC, interferon alfa chemotherapy; CVD, cisplatin, vinblastine, and dacarbazine; BCT, biochemotherapy; IV, intravenously; CIV, continuous intravenous infusion; GCSF, granulocyte colony-stimulating factor. (*,**) Refer to Appendix.

Fig 2.

Kaplan-Meier plots for (A) overall survival and (B) progression-free survival by treatment arm. The (A) 1-year overall survival and (B) 6-month progression-free survival points (with 95% CIs) are overlaid for each treatment arm. CVD, cisplatin, vinblastine, and dacarbazine; BCT, biochemotherapy.