September 2011 ASCO 2011

New Treatment Strategies and Ongoing Clinical Research for Metastatic Melanoma

Metastatic melanoma is a devastating disease with a very poor prognosis and historically, therapeutic options have been limited. However, new agents and treatment strategies are changing the landscape of the management of melanoma. Research is ongoing to explore these novel agents, identify therapeutic combinations, as well as uncover biomarkers that may further cause a paradigm shift toward personalized medicine. Personalized medicine is an emerging approach that may dramatically impact patient outcomes in the future.

When making treatment decisions for metastatic melanoma patients, a number of factors are considered that include, but are not limited to, molecular markers, tumour burden, rapidly versus slowly progressing disease, presence of brain metastases, performance status, and the ability to tolerate treatment.

For several decades, little progress has been made in the treatment of metastatic melanoma and standard therapies have had little impact on overall survival (OS). Vemurafenib and ipilimumab are promising new agents that have recently emerged. Both are regarded as major advances in this field offering patients superior outcomes when compared with standard therapy. Vemurafenib and ipilimumab are currently available in Canada through Early Access Programs pending approval by Health Canada.

The discovery of targeted therapies and tests for these targets has changed the landscape of cancer therapy and paved the way for personalized medicine. Vemurafenib is an example of a targeted therapy that inhibits the V600E-activating mutation in the BRAF gene and has demonstrated activity in metastatic melanoma patients harbouring this mutation. It is an oral agent which simplifies administration. It is also fast acting which makes it particularly useful in patients with extensive and rapidly progressing disease. Results are often observed within one to two weeks of treatment initiation. In addition, vemurafenib has a manageable toxicity profile. Squamous cell carcinoma is observed in approximately 23% of patients but if it is monitored well, caught early, and treated, it does not impact treatment or outcomes.

Both vemurafenib and ipilimumab have demonstrated an advantage with respect to OS—something that has never been seen with any other drug before in this therapeutic area. Ipilimumab has demonstrated durable responses of up to three years in the most recent trial and is also well tolerated. However 10% to 15% of patients can develop serious immune-related adverse effects (IRAEs) which require immunosuppressive therapy with steroids. These “serious potentially life-threatening complications” with ipilimumab require a committed multidisciplinary team to manage them. Currently, the challenge is how to better identify patients who are likely to respond as not to impose unnecessary toxicity.

Several studies assessing vemurafenib in the treatment of BRAF positive metastatic melanoma patients were presented at ASCO 2011. The study by Dummer, et al. demonstrated early efficacy signals for vemurafenib in an open-label pilot study of the agent in previously treated metastatic melanoma patients with brain metastases. These patients have a very poor prognosis usually measured in weeks and currently available therapy is inadequate. Brain metastases are commonly treated with either surgery followed by radiation or either whole-brain radiation or stereotactic radiation. The potential impact of these findings, once verified in larger studies with longer follow-up times, may revolutionize how these patients are treated. Vemurafenib has the potential to become the new standard of care for BRAF-positive patients with brain metastases.

Ribas, et al. presented the phase II BRIM-2 trial of vemurafenib in previously treated patients with BRAF-positive metastatic melanoma and Chapman, et al. reported on BRIM-3, a phase III randomized, open-label, multicentre trial comparing vemurafenib with dacarbazine (DTIC) in patients with BRAFpositive melanoma. Both trials allowed the enrollment of patients with high lactate dehydrogenase (LDH) and M1c disease—subgroups that have a poorer prognosis. Vemurafenib is the first drug to demonstrate improvement in response rates, progression-free survival (PFS), and OS over standard chemotherapy. The results are very impressive with rapidly observed responses and improvements in quality of life. In both of these studies, vemurafenib was well tolerated with photosensitivity, rash and arthralgias being common adverse events (AEs) that were manageable. Squamous cell carcinoma was not as prominent a problem as expected and the BRIM-3 trial showed its incidence to be only 12%, compared with 23% as seen in previous trials. Vemurafenib fills an unmet need for metastatic melanoma patients with BRAF mutations. It is very gratifying for physicians who, until recently have been unable to offer much hope to their patients. However despite these advances, unfortunately the majority of patients will die from their metastatic melanoma. Clinical trials, whenever appropriate should remain the mainstay of treatment in these patients.

Bloom, et al. evaluated the clinical utility and the reliability of the cobas 4800 BRAF V600 Mutation Test. Accurate molecular testing can be achieved with this test, which is a critical component of personalized medicine and this test will undergo approval simultaneously to vemurafenib. In Canada, funding and availability of the test will be governed provincially. It is likely that testing will be centralized as not all treatment centres have a molecular or melanoma pathologist. Strategies will need to be implemented to allow for efficient testing in order to avoid treatment delays. Ideally, it would be best if patients were tested for an array of molecular markers including BRAF, c-kit, NRAS, etc. before they became metastatic. However when the cobas test is approved it will likely be used for metastatic patients and hopefully also for high risk stage 3 patients. Given that the incidence of BRAF mutations can be 40–50%, fast and accurate testing for the mutation is necessary in order to initiate vemurafenib in a timely fashion, particularly in rapidly progressing disease.

The pharmacoeconomic analysis of the burden of metastatic melanoma by Reyes, et al. is an interesting study that is highly relevant in the current era of escalating drug costs. Studies such as this allow us to identify better ways to allocate available resources. It is difficult to tell how applicable the findings of this study would be to Canadian metastatic melanoma patients as some factors would likely be very different. In Ontario, the drug approval process includes the conduction of an economic analysis for each drug that is reviewed. In depth pharmacoeconomic analyses are becoming more important as cancer therapy costs escalate in Canada with the advent of targeted therapies.

Wolchok, et al. presented the results of a phase III randomized study of ipilimumab plus DTIC versus DTIC alone as firstline treatment in patients with unresectable advanced stage melanoma. This was a well-designed study with demonstrated OS improvement. The key finding of this study was the long duration of response. The three-year survival was 20.8% versus 12.2% in favour of ipilimumab plus DTIC and this is one of the few studies in metastatic melanoma to follow patients for this long. The risk for AEs is high with this treatment combination, which may be attributed to the agent that ipilimumab is paired with. Studies to identify safe and effective combinations with ipilimumab are ongoing as demonstrated by the phase I study of ipilimumab plus bevacizumab in patients with unresectable advanced stage melanoma by Hodi, et al. This is a novel approach that targets different mechanisms in melanoma. The first impression of this study is that ipilimumab plus bevacizumab is too toxic to be delivered safely, as 14 of 22 patients studied had inflammatory AEs. Despite this, studies like these are necessary to move science forward and phase I studies are the first step in identifying combinations that may be worthwhile and feasible to pursue. Multi-targeting is likely the way of the future; however, efforts need to focus on identifying agents that have scientific rationale and can be combined with the least amount of toxicity.

The study by Sharfman, et al. was a dose escalation study of a novel small molecule multi-kinase inhibitor, RAF265, in patients with advanced cutaneous melanoma. There were eight dose levels included in this study and 48 mg was selected as the maximum tolerate dose (MTD). Clinical activity was seen at multiple dose levels, though response rates were low. At present it is too early to predict the potential of this agent; however this is an interesting drug due to its multiple target potential.

Both vemurafenib and ipilimumab may revolutionize how metastatic melanoma patients are treated, with an agent such as vemurafenib having the potential to become the standard of care for BRAF-positive patients. As both of these agents may be approved in Canada in the near future, it will be important for oncologists, to understand and manage their AEs early. With the targeting of multiple pathways, a solid foundation is being laid for further research and treatment combinations that will optimize therapy, while taking into account the different onsets of efficacy or resistance mechanisms. Agents such as vemurafenib and ipilimumab are leading a new era for melanoma research with numerous opportunities that did not exist 10 years ago.