Among the more interesting discoveries in recent years have been two breakthroughs in the management of malignant melanoma. One drug, vemurafenib, a tyrosine kinase inhibitor, acts specifically in patients who carry the BRAF (V600E) mutation. The second drug ipilimumab, offered commercially from Bristol-Meyers Squibb as Yervoy, is a monoclonal antibody that acts by blocking CTLA-4, thereby enhancing T-cell response to tumor antigens. While vemurafenib has a somewhat narrow target population, ipilimumab targets may extend to a broader range of melanoma patients and will likely find a role in other cancers.
The data supporting ipilimumab’s use in advanced melanoma was reported in a 2010 Phase III trial, which provided a superior median survival for those treated with the drug over those who received a placebo. Superior one and two-year survivals were also reported. Unfortunately, this did not rise to the level that met the standards of the English watchdog organization, National Institute for Health and Clinical Excellence (NICE). The chief executive of NICE did admit that the drug could “potentially be very effective for a small percentage of patients.” Unfortunately, under current NICE guidelines, that small percentage of patients will not have access to the drug.
This is not the first time that a drug, found effective for the treatment of a subpopulation of patients has been denied approval based upon cost efficacy and the comparatively limited population of patients who stand to gain.
The role of Avastin in breast cancer represents a similar dilemma for those patients who might benefit but cannot afford the out-of-pocket expenses. Indeed, NICE originally denied approval to bortezomib, a highly active drug for the treatment of multiple myeloma, based upon similar cost considerations.
What ipilimumab, Avastin and bortezomib have in common is that they are harbingers of the coming conflict between patients-in-need and society’s capacity to cover the increasing costs of cancer therapy. Cost efficacy questions will only be resolved when we have the capacity to identify likely responders prior to therapy, enabling us to use drugs only in those patients with the highest expectations of response. Marginal overall benefits that come at high price will continue to fail until we redouble our efforts to refine the process of drug selection for individual patients. Janet Woodcock, MD, from the FDA once said, that we need “a critical path” from bench to bedside to guide clinical decisions. The human tumor primary culture functional analyses that we employ can provide that critical path and we would hope limit the need for the broad-brush policy decisions that are being handed down by NICE and similar entities both here in the U.S. and abroad.