Marc Engelsgjerd; marc.engelsgjerd@wolterskluwer.com / David Yee; david.yee@wolterskluwer.com / Ben Weintraub; ben.weintraub@wolterskluwer.com
The incidence of melanoma is rising, with over 68,000 cases diagnosed each year in the US. If detected early, melanoma can be cured by surgical resection. However, advanced melanoma is notoriously difficult to control and systemic therapy options — principally dacarbazine (DTIC) or highdose interleukin-6 — are inadequate for many patients.
The long dry spell in melanoma drug development appears to be over, with the immunotherapeutic Yervoy approved by FDA in March 2011 and the BRAF V600E inhibitor vemurafenib now undergoing regulatory review in the US and in Europe.
Plans for a collaborative phase I/II trial combining Yervoy with vemurafenib were announced by Bristol and Roche. The potential for synergy between an immunomodulatory agent and an oncogenic kinase inhibitor is intriguing, but the toxicity of this regimen, not to mention the cost, must be considered.
Yervoy
Yervoy was approved based on study 020 in patients with previously treated advanced melanoma. A frontline trial, known as study 024, produced positive topline results just four days before the FDA approval. Although not formally in the current label, the official indication (“the treatment of unresectable or metastatic melanoma”) does not specifically limit use to previously treated patients.
Nevertheless, study 024 is important because it could solidify Yervoy’s standing as a viable frontline option. This will be important commercially given possible competition from vemurafenib later this year.
The study 020 results seem to indicate that Yervoy has a profound impact on a small subset of melanoma patients, leading to very durable responses. It will be interesting to see if the same phenomenon holds true in the frontline setting in study 024. A full appraisal of safety and tolerability will also be important, given the higher dose (10 mg/kg) and combination with chemotherapy.
Vemurafenib
The BRAF V600E inhibitor vemurafenib has emerged as the latest example of the clinical development efficiency that is possible by combining a well-defined molecular target with a companion diagnostic assay.
Vemurafenib has considerable potential as a treatment for the ~50% of melanomas with the BRAF V600E mutation. Full details of the frontline BRIM-3 study will give a better sense of vemurafenib’s potential and its ability to challenge Yervoy.
A recent Roche press release noted that vemurafenib’s adversity profile includes “changes in heartbeat or very fast or abnormal heartbeats.”
This is the first mention, to our knowledge, of a cardiac signal, and bears careful monitoring.
Despite the impressive results seen to date with vemurafenib, resistance seems to develop in most patients. Plexxikon is working on second-generation BRAF inhibitors, including those that do not stimulate RAF signaling in the setting of wild-type BRAF (the “Raf inhibitor paradox”). This phenomenon is incompletely understood. It is thought to explain some of the skin toxicities seen with vemurafenib, such as the rapid and extensive development of squamous cell carcinomas, and may also facilitate resistance.
Other BRAF inhibitors in the clinic include GlaxoSmithKline’s GSK2218436, in phase III for melanoma, and ArQule’s ARQ 736, currently in phase I testing.
