As reviewed in this issue of The ASCO Post, Long et al1 have reported the final overall survival analysis of the COMBI-d phase III trial comparing combination therapy with the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) to monotherapy with dabrafenib alone, confirming the superiority of combination therapy in patients with advanced melanoma harboring the BRAF V600 mutation. As witnessed before, such combination therapy not only improves survival, but also reduces many of the complications associated with paradoxical activation of the MAPK pathway.
Further Insight
While the COMBI-d study findings serve primarily to support the idea that combination therapy should be the standard targeted therapy for patients with BRAF V600 mutation–positive melanoma, the more mature survival analysis provides further insight into the rapidly changing management of advanced melanoma. It has been stated before, but cannot be overemphasized, that this is a unique and challenging period for clinicians treating patients with melanoma. After years of limited options, the rapid introduction and development of two distinct classes of systemic agents for melanoma have been extremely exciting but uniquely perplexing, as each new clinical trial raises additional questions regarding both clinical application and basic science.
In their discussion, the authors compare the progression-free and overall survival data with those from trials of single-agent immunotherapies and find that they compare favorably. This shines a light on one of the challenges facing clinicians—the most appropriate choice of therapy in patients with a BRAF V600 mutation. And, while it may be tempting to compare 1-year survival data between trials, the patient populations being treated are not the same, as immunotherapy trials are often restricted to, or dominated by, patients with BRAF wild-type melanoma.
In addition, these are moving targets. At the same time Long et al are providing additional support for combination targeted therapy, new data are emerging supporting combination immunotherapy. These classes of drugs are also substantially different in terms of ease of delivery, cost, expected toxicities, and the time course of response, all of which must be considered when translating clinical trial results to individual patients.
Persistent Holes in Our Knowledge
These questions highlight many of the issues we have to address moving forward, particularly as ongoing trials begin to explore the combination of these two classes. With new agents being developed, many of the clinical trials are designed with a focus on comparing efficacy and establishing position. We must be diligent in assuring that ongoing research continues to address persistent holes in our knowledge—not only the most appropriate clinical use of current drugs, but also gaining additional insight into the basic science that dictates their successes (and failures).
The triumphs of the checkpoint inhibitors ipilimumab (Yervoy), pembrolizumab (Keytruda), and nivolumab (Opdivo) have been a tremendous boon to patients and have altered the landscape of melanoma management, but have also challenged our understanding of the interactions between the immune system and cancer. Likewise, data such as those presented by Long et al regarding dabrafenib and trametinib highlight ongoing questions regarding the molecular basis of melanoma.
These questions will only become more apparent as we continue to explore future combinations and shift to the adjuvant setting, where the goals of therapy and the biology of the disease can be considerably different. Our clinical research must strive not only to document moderate improvements in outcome, but to identify predictive factors that optimize patient selection and address gaps in our basic science knowledge. These might then allow us to optimize the timing and sequence of combination therapies in concordance with how these agents function and interact and identify new potential targets for intervention. The “bench to bedside” model should more appropriately be visualized as a continuous “back and forth” between the bench and bedside.
Curbing Overenthusiasm
With each newly reported success of both targeted therapies and immunotherapies, it is sometimes hard to prevent our enthusiasm and excitement from overshadowing some of the gaps in knowledge we still have. We must also be aware that this same phenomenon is present in our patients, who are also witness to the trumpeted successes of the new systemic agents in the media.
In surgical oncology, we have seen an increasing, and concerning, trend for patients refusing surgery or seeking to greatly limit surgery, secondary to their enthusiasm for “new drugs” they read about. This includes patients declining completion node dissections as well as those refusing surgery for clinically evident stage III disease or isolated, resectable M1a disease.
While it is important that our research efforts moving forward address these clinical questions regarding the multidisciplinary management of melanoma, we also must spend time educating patients, in both the office and the media, about the limitations of these therapies and the many questions that still exist regarding their optimal use. ■
Disclosure: Dr. Sabel reported no potential conflicts of interest.
Reference
1. Long GV, Stroyakovskiy D, Gogas H, et al: Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: A multicentre, double-blind, phase 3 randomised controlled trial. Lancet. May 29, 2015 (early release online).
Dr. Sabel is Chief, Division of Surgical Oncology, University of Michigan Health Systems, Ann Arbor.
