English Patients Denied Access to Ipilimumab

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.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

3 Responses to English Patients Denied Access to Ipilimumab

  1. Elaine L. says:

    My oncologist told me that he fronted the money for one of the new Melanoma medications and he has two patients, whose insurance companies won’t pay for the high cost of the medication. This is their last hope.

  2. You might bring to your readers’ attention my recent co-authored publication on Yervoy. Our point is that the side effects of Yervoy are more significant than are generally mentioned and the number of response (especially complete responses) are uncommon. We also point to the similarity of this drug with a catastrophic drug (TGN 1412) that had to be withdrawn from clinical trials when some patients almost died of the effects. This is a case that is crying for our the type of personalized pretesting that Dr. Nagourney specializes in!

    Here is the abstract (from Immunobiology, via PubMed):

    Immunobiology. 2011 Jul 7. [Epub ahead of print]
    Ipilimumab (Yervoy) and the TGN1412 catastrophe.
    Bakacs T, Mehrishi JN, Moss RW.

    Department of Probability, Alfred Renyi Institute of Mathematics, Hungarian Academy of Sciences, Realtanoda utca 13-15, H-1053 Budapest, Hungary.

    The development of the anti-CTLA-4 antibody (ipilimumab; marketed as Yervoy(1)) immune regulatory therapy was based on the premise that “Abrogation of the function of CTLA-4 would permit CD28 to function unopposed and might swing the balance in favor of immune stimulation, tolerance breakdown and tumor eradication…” (Weber, 2009). By now, the vast majority of data collected from more than 4000 patients proves that this prediction was entirely correct. Paradoxically, the successful blockade of immune checkpoints raises the question whether an anti-CTLA-4 antibody could ever become an important therapy against cancer. T cells lost their ability to discriminate between self and non-self. Thus, tolerance to self tissues was broken in ∼70% of the patients. In the recent industry-sponsored phase III clinical trial of ipilimumab, 147 (38.7%) of the patients experienced severe adverse events and 6.8% suffered dose-limiting events (8.4%, in the ipilimumab-alone group). There were 14 deaths related to the study drugs and 7 of these were associated with immune-related adverse events. In contrast, the complete response rate was only 0.2%, in one patient out of 403 who received ipilimumab plus a peptide vaccine. Promoters of ipilimumab appear to be unmindful of the clinical trial catastrophe in London. Then, a humanized “superagonist” anti-CD28 monoclonal antibody, TGN1412, which “preferentially” activated regulatory T cells, at a higher dose, also activated all CD28 positive T cells. This precipitated a “cytokine storm” leading to life-threatening multiple organ failure in the six healthy human volunteers. Neither anti-CD28 nor anti-CTLA-4 therapies rely on antigen-specificity. Both release free antibody into the body against common molecular targets that are expressed on the targeted as well as on the non-targeted T cells. At lower antibody doses specific T cells are preferentially activated. With increasing antibody dose, however, the kinetics of the interaction is pushed in favor of widespread non-specific T cell expansion. Using the law of mass action we calculated that the vast majority of the CTLA-4 receptors on all activated T cells (including melanoma specific T cells) in the phase III clinical trial of ipilimumab will have been saturated. This would explain the runaway immune response observed. The conclusions drawn by the authors of the ipilimumab trial paper could bear an independent inspection and reassessment concerning the validation of the blockade of immune checkpoints as an important therapeutic strategy against cancer.

    Copyright © 2011 Elsevier GmbH. All rights reserved.

    [PubMed – as supplied by publisher]

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