Reaching First Base in the Treatment of Metastatic Melanoma

Melanoma and renal cell cancer have long been considered twin tumors because little if any progress was made in treatment for decades. In renal cell cancer recent developments have been spectacular, and the highlights of the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, demonstrated that a number of teams have been hitting home runs lately. This is in sharp contrast to the situation in melanoma, where we continue to have problems even reaching first base. It is sobering to see how little, if any, progress has been made over the last three decades in the systemic treatment of metastatic melanoma. The alkylating agent dacarbazine (DTIC-Dome; Bayer, West Haven, CT) is considered to be the reference single agent for the management of advanced melanoma, with objective tumor responses in some 15% to 20% of patients according to old studies, but with below 10% response rates in recent multicenter trials. Most responses are partial, although complete responses have been observed and can be durable. Interleukin 2 (IL-2) was approved in the US based on a 6% complete response rate in a 270-patient phase II study data set. The absence of any phase III data demonstrating a benefit of any dose of IL-2 in metastatic melanoma prevented approval in Europe, and it is unlikely that IL-2 would be approved at present as we still do not know which patients will respond. All in all no agent has been shown to have an impact on survival in metastatic melanoma and thus no single agent can be considered as a standard of care. A myriad of about 30 randomized phase III trials have been conducted over the last two decades to investigate the impact of polychemotherapy, the addition of tamoxifen, low and high-dose interferon-alfa, low and high-dose IL-2, granulocyte-macrophage colony-stimulating factor, and any combination of the above. Overall there is plenty of evidence that these combinations increase toxicity significantly, but there is no evidence that any combination improves survival. Moreover vaccine therapy trials have yielded very low response rates and no indication of any impact on survival. So new agents should be offered in first line to stage IV melanoma patients to identify active new agents. Times may be changing as there are a number of interesting drugs around. Sorafenib, a vascular endothelial growth factor receptor 2 and Braf-inhibitor, and the anti-CTLA-4 antibodies are, at present, agents that evoke substantial attention in the melanoma world. So is the antisense agent oblimersen. In this issue of the Journal of Clinical Oncology, Bedikian et al, report on the largest phase III trial ever conducted in advanced melanoma. Treatment with either DTIC alone or DTIC in combination with the antisense agent oblimersen was allocated in a randomized fashion to 771 patients with irresectable stage III or stage IV melanoma. Oblimersen is an antisense oligonucleotide that binds to the bcl-2 mRNA open reading frame and thus downregulates Bcl-2 protein expression and thereby increases or restores chemotherapyinduced apoptosis in a number of tumor cell lines and in vivo tumor models including melanoma. Patient characteristics, as can be expected in such a large trial, were well balanced between the treatment arms. Stratification involved the following: lactate dehydrogenase (LDH), site of metastases, and Eastern Cooperative Oncology Group performance status. The primary end point of the trial was overall survival (OS); secondary end points included progression-free survival (PFS), response rate and durability, and toxicity. The prospective analysis plan provided for analysis after 508 deaths had occurred. After that analysis (with a minimum follow-up of 6 months of all patients), patients continued to be observed as specified by protocol to further assess OS. A final analysis at a minimum follow-up time of 24 months of all patients was specified and is presented herein. The results are quite interesting. OS in the intent-to-treat population at 24 months is 9 months in the combination group months compared with 7.8 months in the dacarbazine group (hazard ratio [HR], .87; 95% CI, 75 to 1.01; P .077). This trend of superiority for the combination arm is consistent with significant differences for secondary end points: PFS (HR, .75; P .001), response rate (13.5% v 7.5%; P .007), and response durability longer than 6 months (7.3% v 3.6%; P .03). An interesting and important observation was made regarding LDH. There were 508 patients with a normal LDH at random assignment, and in almost all of these patients the normal LDH had been the main stratification factor. Multivariate analysis demonstrated a significant impact of treatment with the combination regimen in this patient population for all end points. OS was significantly improved in these patients: OS (11.4 v 9.7 months; P .02), PFS (3.1 v 1.6 months; P .001), overall response (17.2% v 9.3%; P .009), complete response (3.4% v 0.8%), and durable response (9.6% v 4.0%; P .01). Multivariate analyses demonstrated that this treatment effect was maintained after adjusting for baseline prognostic factors. What should we conclude from these data? First, one may say that the consistency in this overall data set demonstrates that JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 29 OCTOBER 1