Marc Engelsgjerd; marc.engelsgjerd@wolterskluwer.com / David Yee; david.yee@wolterskluwer.com / Ben Weintraub; ben.weintraub@wolterskluwer.com
Melanoma has been in the spotlight at this year’s ASCO, buoyed by two positive phase III frontline studies and the recent US approval of Yervoy.
Melanoma presentations accounted for two of the five high-profile plenary session abstracts. The separate melanoma oral abstract session was held in a large format auditorium, an upgrade from past venues that seemed to humble and even unnerve some of the speakers. But is the excitement surrounding Yervoy and vemurafenib warranted?
Vemurafenib
For the roughly 50% of melanoma patients whose tumor harbors an activating BRAF V600 mutation, vemurafenib is clearly a very active drug. Updated BRIM-2 data and full BRIM-3 results show a nearly 50% objective response rate and, in the case of BRIM-3, a striking extension of progressionfree survival in the frontline setting when compared to dacarbazine (5.3 vs. 1.6 months; HR 0.26). Early termination of the study will complicate the interpretation of overall survival results, which are not yet mature.
Vemurafenib leads to often dramatic and rapid regression of tumor burden and associated symptomatic relief. The duration of response, however, is limited by the seemingly inevitable development of resistance via a variety of mechanisms that operate downstream of BRAF or via alternate pathways. This will necessitate combination or sequential therapy with other agents, such as MEK inhibitors. Preliminary results from a trial combining GlaxoSmithKline BRAF and MET inhibitors (GSK2118436 and GSK1120212) were reported at ASCO (abstract CRA8503).
A survey of oncogenic BRAF mutation rates in Australia (abstract 8507) points to a declining incidence of V600 mutations with advancing age.
Vemurafenib might therefore be used more by younger melanoma patients. How will such patients react to the prospects of a pronounced but limited duration response? It could be that vemurafenib will be used as a bridging measure to more definitive therapy, but it is unclear what this might be.
Despite the apparent allusion to a cardiac signal in Roche’s pre-ASCO press release (May 18, 2011), there was no mention of cardiotoxicity in the oral ASCO presentations or the concurrent New England Journal of Medicine publication. Antoni Ribbas, MD, a BRIM-3 investigator, commented that extensive EKG testing had shown some mild QTc prolongation but no other abnormalities.
Given the data and discussion at ASCO, we are increasing the inThought approvability index score by 11 points to 86%(B). Nearly all the data support approval, with issues of resistance and toxicity more an issue regarding the ultimate revenue potential of the agent.
Yervoy
The anti-CTLA-4 antibody Yervoy was recently approved in the US for the treatment of advanced melanoma. This approval was based on study 020 in treatment experienced patients. At ASCO, frontline study 024 results have been presented. Like study 020, the frontline 024 trial demonstrated an overall survival benefit for Yervoy, in this case when added to dacarbazine versus dacarbazine alone. The magnitude of the benefit (2.1 months; HR 0.72), however, is somewhat underwhelming. Yervoy is a potentially toxic agent and is also is expensive ($120,000 estimated cost at the approved 3mg/kg dose). Study 020 used a higher 10mg/kg dose, and could therefore be significantly more expensive. Furthermore, unlike vemurafenib, there is no viable biomarker (clinical or immunobiological) that permits identification of patients most likely to respond to Yervoy.
As plans are made to combine Yervoy with a variety of other melanoma agents and the ipilimumab development program is poised to expand into other tumor types, this is starting to sound a bit like Avastin. The net benefit to patients and healthcare systems remains to be seen.
