Melanoma International Congress: Clinicians and Researchers Make Sense of Resistance Mechanisms

The theme of the Society for Melanoma Research (SMR) meeting in Tampa this year was “Advancement through Collaboration,” and this theme was clearly reflected. With melanoma therapies stealing the plenary session limelight two years in a row at the annual meeting of the American Society of Clinical Oncology (ASCO), with the presentation of ipilimumab in previously treated metastatic melanoma patients, and two abstract presentations: ipilimumab as a first-line treatment for metastatic melanoma, and the targeted BRAF inhibitor, vemurafenib, for first-line treatment of metastatic melanoma in patients with BRAF-mutated tumors.

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Ipilimumab, approved in March of this year, was the first agent approved for metastatic melanoma in 13 years, with vemurafenib not far behind. These two drugs appear to be just the tip of the iceberg for melanoma treatment. Already, there are trials testing a combined BRAF and MEK inhibitor that will move into a phase III trial next year and, based on the partial phase I and II results, the combo is more efficacious and has lower adverse events than a single BRAF inhibitor.

Patients from clinical trials of targeted agents (and especially from the BRAF inhibitor trials) are providing important data in the form of tumor and blood samples and response rates. A major hot topic of the meeting is also the study of the mechanisms of resistance to vemurafenib.

Vemurafenib has an approximately 80% response rate within a two-month treatment cycle, with a two- to eighteen-month period of regression. However, all patients eventually develop resistance to the drug and relapse. The mechanisms of relapse are sometimes through a secondary BRAF mutation; another mutation in the same, MAPK pathway; or activation or up-regulation of an alternative survival pathway. Several papers have already been published documenting the types of novel mutations seen in patients’ resistant tumors. These analyses are ongoing along with pre-clinical research on mechanisms of resistance.

The rationale is that knowing what other genes and pathways become important upon resistance to BRAF inhibitor exposure will direct the development of unique combinations to block these pathways and prevent both resistance and disease recurrence. Researchers at the Melanoma Congress highlighted the importance of identifying the “universe” of resistance mechanisms and integrating these with clinical characterization of the disease.

The laboratory of Gavin Robertson, PhD of the Department of Pharmacology at Penn State is looking at the epigenetic changes that occur in melanoma upon BRAF inhibitor exposure using a melanoma cell model. Robertson and colleagues have found that an invasive suppressor, CD82, is both methylated and silenced upon BRAF inhibitor exposure, suggesting that a combination of BRAF and DNA demethylation targets is a potential clinical approach to overcome resistant, invasive melanoma.

Keiran Smalley, PhD of the H. Lee Moffitt Cancer Center and Research Institute and colleagues are studying a unified approach to overcome resistance based on the observation that the majority of genes implicated in vemurafenib resistance are targeted by the heatshock protein HSP90. Treating melanoma cell lines with either intrinsic or acquired resistance to vemurafenib with XL188 (veliparib), a targeted HSP90 inhibitor, resulted in inhibition of growth and survival.

The negative results of a phase II clinical trial of veliparib combined with temozolomide in late-stage metastatic melanoma patients was also reported at the meeting. These new data reinforce the common sentiment of researchers in the field that the complexity of melanoma requires combination and, potentially, sequential combination treatments. A phase I clinical trial combining a BRAF inhibitor and XL188 is currently being planned.

Rather than going on a “fishing expedition,” researchers now have the tools to create hypothesis-driven models of melanoma resistance in the laboratory. With the large number of available targeted agents, many of which have already been tested in human trials, clinical trials with the most promising combination treatments can be taken to the clinic. “The biology of late, compared to early, resistance may be different,” said Dr. Jeffrey Sosman, director of the melanoma and tumor immunotherapy program at the Vanderbilt Cancer Center in Nashville, highlighting another key area of research that needs to be pursued. The key will be the continued collaboration of laboratory researchers and clinicians.