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Old 10-21-2009, 06:22 AM
Dross Dross is offline
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Default Melanoma treatment options 1 step closer

A targeted chemotherapy for the treatment of skin cancer is one step closer, after a team of University of Alberta researchers successfully synthesized a natural substance that shows exceptional potential to specifically treat this often fatal disease.

University chemistry professor Dennis Hall said after three years of work, his research team has successfully produced the substance called Palmerolide A.

"The potency of palmerolide is exceptional and melanoma is a very aggressive cancer for which there is almost no chemotherapeutic recourse," said Hall. "Natural substances like palmerolide offer real hope for such treatments.

"Current chemotherapy as an overall strategy is not very effective in treating melanoma. Less than a quarter of patients respond to chemotherapy and it typically only works for less than a year, and it has little to no effect on survival time. Palmerolide A as a targeted therapy may prove to be more effective [for treatment] with less toxicity," said Hall.

"One of the problems with most cancer drugs is the lack of selectivity for cancer cells versus normal cells. Preliminary data for Palmerolide A looks very promising in terms of solving this issue," he said.

"For commercialization, the structure needs to be made more 'drug-like;' smaller and more water-soluble, while preserving the potency," said Hall, who is optimistic that his U of A team is moving forward in the race to develop a treatment for melanoma.

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Old 08-08-2010, 04:28 PM
gdpawel gdpawel is offline
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Default Ipilimumab significantly improves survival compared to glycoprotein 100 vaccine

Drug significantly improves survival compared to glycoprotein 100 peptide vaccine alone, and is analogous to the way that IL-2 (Interleukin 2) works.

Jun 7, 2010

In patients with previously treated metastatic melanoma, ipilimumab -- either alone or in combination with a glycoprotein 100 (gp100) peptide vaccine -- may significantly improve overall survival, according to a study published online June 5 in the New England Journal of Medicine to coincide with a presentation at the 46th Annual Meeting of the American Society of Clinical Oncology, held from June 4 to 8 in Chicago.

F. Stephen Hodi, M.D., of the Dana-Farber Cancer Institute in Boston, and colleagues conducted a phase 3 study in which 676 patients with unresectable stage III or IV melanoma that had progressed while they were being treated for metastatic disease were randomly assigned to receive either ipilimumab plus gp100, ipilimumab alone, or gp100 alone.

The researchers found that median overall survival was significantly improved in patients receiving ipilimumab plus gp100 or ipilimumab alone (10 and 10.1 months, respectively) compared to those receiving gp100 alone (6.4 months). In patients treated with ipilimumab, they found that the rate of grade 3 or 4 immune-related adverse events was 10 to 15 percent compared to a rate of 3 percent in those treated with gp100 alone, but concluded that most such events are reversible with appropriate treatment. They found that 14 deaths (2.1 percent) were related to the study drugs, including seven which were associated with immune-related adverse events.

"In some patients, side effects can be life-threatening and may be treatment-limiting," the authors conclude. "Reinduction with ipilimumab at the time of disease progression can result in further clinical benefit. Overall, our findings suggest that the T-cell potentiator ipilimumab may be useful as a treatment for patients with metastatic melanoma whose disease progressed while they were receiving one or more previous therapies."

The study was supported by Medarex and Bristol-Myers Squibb; several authors disclosed financial ties to the companies.
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Old 08-08-2010, 04:32 PM
gdpawel gdpawel is offline
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Default Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

F. Stephen Hodi, M.D., Steven J. O'Day, M.D., David F. McDermott, M.D., Robert W. Weber, M.D., Jeffrey A. Sosman, M.D., John B. Haanen, M.D., Rene Gonzalez, M.D., Caroline Robert, M.D., Ph.D., Dirk Schadendorf, M.D., Jessica C. Hassel, M.D., Wallace Akerley, M.D., Alfons J.M. van den Eertwegh, M.D., Ph.D., Jose Lutzky, M.D., Paul Lorigan, M.D., Julia M. Vaubel, M.D., Gerald P. Linette, M.D., Ph.D., David Hogg, M.D., Christian H. Ottensmeier, M.D., Ph.D., Celeste Lebbé, M.D., Christian Peschel, M.D., Ian Quirt, M.D., Joseph I. Clark, M.D., Jedd D. Wolchok, M.D., Ph.D., Jeffrey S. Weber, M.D., Ph.D., Jason Tian, Ph.D., Michael J. Yellin, M.D., Geoffrey M. Nichol, M.B., Ch.B., Axel Hoos, M.D., Ph.D. and Walter J. Urba, M.D., Ph.D. June 5, 2010 (10.1056/NEJMoa1003466)

Background

An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab — which blocks cytotoxic T-lymphocyte–associated antigen 4 to potentiate an antitumor T-cell response — administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma.

Methods

A total of 676 HLA-A*0201–positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival.

Results

The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events.

Conclusions

Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (ClinicalTrials.gov number, NCT00094653.)

Source Information

From the Dana–Farber Cancer Institute (F.S.H.) and Beth Israel Deaconess Medical Center (D.F.M.) — both in Boston; the Angeles Clinic and Research Institute, Los Angeles (S.J.O.); St. Mary's Medical Center, San Francisco (R.W.W.); Vanderbilt University Medical Center, Nashville (J.A.S.); Netherlands Cancer Institute (J.B.H.) and VU University Medical Center (A.J.M.E.) — both in Amsterdam; University of Colorado Cancer Center, Aurora (R.G.); Institut Gustave Roussy, Villejuif, France (C.R.); University Hospital Essen, Essen (D.S., J.M.V.), German Cancer Research Center, University of Mannheim, Mannheim (J.C.H.), and Technical University Munich, Munich (C.P.) — all in Germany; Huntsman Cancer Institute, Salt Lake City (W.A.); Mount Sinai Comprehensive Cancer Center, Miami (J.L.); Christie Hospital NHS Trust, Manchester (P.L.), and Southampton University Hospitals, Southampton (C.H.O.) — both in the United Kingdom; Washington University School of Medicine, St. Louis (G.P.L.); Princess Margaret Hospital, Toronto (D.H., I.Q.); Saint Louis Hospital, Paris (C.L.); Loyola University Medical Center, Maywood, IL (J.I.C.); Memorial Sloan-Kettering Cancer Center, New York (J.D.W.); H. Lee Moffitt Cancer Center, Tampa, FL (J.S.W.); Medarex, Bloomsbury, NJ (J.T., M.J.Y., G.M.N.); Bristol-Myers Squibb, Wallingford, CT (A.H.); and the Earle A. Chiles Research Institute, Portland, OR (W.J.U.). Participating investigators are listed in the Appendix.

Address reprint requests to Dr. Hodi at the Dana–Farber Cancer Institute, 44 Binney St., Boston, MA 02115, or at [email]stephen_hodi@dfci.harvard.edu[/email].
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Old 08-08-2010, 04:42 PM
gdpawel gdpawel is offline
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Default The Beginning of the End of Melanoma?

5-Minute Journal Club – The Beginning of the End of Melanoma?

Dr Steven O'Day must have had his heart in his hand as he ascended the stage at the 2010 ASCO plenary session to present some very provocative and hopeful results in a disease that has until recently been resistant to systemic management.

The focal point of this landmark presentation, which was also published in The New England Journal of Medicine, was a randomized Phase III trial evaluating the potential benefit of ipilimumab, a fully human monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), for patients with previously treated metastatic melanoma.

[url]http://www.researchtopractice.com/Browse-tumor-types/multitumor-programs/5jc/1/1-0/4

The study demonstrated that this innovative immune stimulant — which, as Dr O'Day explained to me during a recent interview, "blocks the brakes" on T cells — when used alone or in combination with a glycoprotein 100 (gp100) peptide vaccine resulted in a four month increase in overall survival compared to a gp100 vaccine alone. Objective responses were uncommon, and PFS was reported but not thought to be relevant with this type of treatment. In terms of toxicity, because for once investigators really were dealing with serious immune modulation, a variety of manageable but potentially serious, even life-threatening, autoimmune complications were reported, particularly in the gut and on the skin.

The highly enthused discussant, Dr Vernon Sondak, a rare surgeon at the head table at ASCO, reminded us all just how groundbreaking these findings are by reviewing the entire list of prior randomized studies in pretreated metastatic melanoma, none of which demonstrated prolonged survival. He then sincerely and empathetically acknowledged the persistence and patience of the many investigators in the audience and beyond who, until now, had little to show for their dedication to finding a solution to this dreadful disease. In a related ASCO presentation, evaluating "Ipi" in patients with melanoma and brain metastases, a series of pretty remarkable MRIs illustrated some of the prolonged responses that were reported.

The other melanoma presentation profiled in this, the second in our series of email/web summaries of key ASCO data sets, is in a sense a follow-up to Keith Flaherty's stunning presentation at ASCO last year on the B-raf kinase inhibitor PLX4032 in patients with V600-mutant melanoma. This year, Dr Richard Kefford showed equally impressive findings from a Phase I-II trial of a similar B-raf kinase inhibitor, GSK2118436, in which 18 of 30 patients with mutant B-raf tumors had tumor responses of greater than 20 percent by RECIST criteria, and the waterfall plots were reminiscent of the ones shown by Dr Flaherty in 2009. Minimal toxicity was observed with this oral agent.

[url]http://www.researchtopractice.com/Browse-tumor-types/multitumor-programs/5jc/1/1-0/6

While the data in melanoma that emerged at this year's ASCO meeting are impressive, this was hardly a home run. But for a disease for which very little has worked, these two novel strategies and others coming along provide hope that we may soon hit one out of the park.

Next up on 5-Minute Journal Club: NHL and CLL at ASCO and the long-awaited and very interesting results of the PRIMA study of rituximab maintenance in follicular lymphoma.

Neil Love, MD
Research To Practice
[url]http://www.researchtopractice.com
Miami, Florida

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Research To Practice is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. This program is supported by educational grants from Bristol-Myers Squibb Company, Celgene Corporation, Genentech BioOncology and
Millennium Pharmaceuticals Inc.

Research To Practice designates each of the three educational activities, comprised of a slide set, for a maximum of 0.25 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

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Old 01-13-2011, 04:50 PM
gdpawel gdpawel is offline
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Default Ipilimumab: A Promising Immunotherapy for Melanoma

By JAYKUMAR R. THUMAR, MD

Oncology Fellow, Yale Cancer Center Yale School of Medicine

HARRIET M. KLUGER, MD

Associate Professor of Medicine, Yale Cancer Center Yale School of Medicine,
New Haven, Connecticut | January 5, 2011

ABSTRACT

Antibody-based targeting of the immune suppressor molecule cytotoxic T-lymphocyte antigen 4 (CTLA-4) with ipilimumab has been studied in metastatic melanoma in a number of clinical trials, including a recent phase III trial. This marks the first randomized clinical trial reporting an overall survival benefit using immune modulation in metastatic melanoma. Along with its therapeutic benefits, ipilimumab presents unique challenges to clinicians; these are related to the monitoring of treatment response and the management of drug-related toxicities. This drug is currently being investigated in various cancers, and its indications are likely to be expanded.

[url]http://www.cancernetwork.com/melanoma-skin-cancer/content/article/10165/1771398?GUID=5A208D79-67C7-4EDD-A587-5D85B4B71AD4&rememberme=1
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Old 01-13-2011, 05:03 PM
gdpawel gdpawel is offline
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Default Immuno-oncology: Framework for a new era of cancer therapy

Ipilimumab has shown survival benefit in Phase III trials. The FDA has recently issued a guidance document for therapeutic cancer vaccines. One challenge for immune-oncology is use of chemotherapy principles for clinical development of immunotherapy. A new clinical development paradigm was developed to address this.

Instead of traditional Phase II trials, proof of principal studies should lead to randomized Phase II trials with appropriate biological endpoints. The clinical kinetics of immunotherapy begins with the start of therapy and immune cell activation and proliferation. With immunotherapy, there may not be a conventional survival benefit seen initially, and survival curves may not begin to separate until 8 months.

The implication of delayed separation of the curves is the necessity to break down the hazard ratio prior to curve separation - and after curve separation to demonstrate the true benefit of the therapy. Otherwise, the HR (hypersensitivity reactions) may not be significant.

Tumor response must be measured differently. Initial tumor infiltration by lymphocytes can suggest there is tumor progression by RECIST criteria (a voluntary, international standard, not an NCI standard), rendering the patient as a failure in a clinical trial. Thus, total tumor burden must be broken down into the index lesion and new lesions. An increase in total tumor burden without an increase in new lesions may not be disease progression in immunotherapy trials.

Using this approach correlates progressive disease with survival. Also discussed is high data variability for immune monitoring in multicenter trials. This is addressed by harmonization of the assays. Different laboratory results of the same assay can impact the determination of response. However, establishing a standard operating procedure to train laboratory personnel to perform standard measures minimizes this.

Another challenge is inconsistent reporting of immune monitoring results in publications. This was addressed by a Minimal Information about T-cell Assays (MIATA) reporting framework. There are 5 core elements to this, and it is being developed in concert with the research community.

Finally, the absence of regulatory guidance for cancer immunotherapy development. The FDA has introduced a guideline for industry immunotherapy trials publication. This effort in conjunction with the immunotherapy clinical trials community defines what needs to be achieved as endpoints.

Presented by Axel Hoos, MD, PhD1 at the Prostate Cancer Foundation (PCF) - Scientific Retreat - September 13 - 18, 2010 - Washington, DC USA
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Old 01-13-2011, 05:12 PM
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Default Ipilimumab for Advanced Melanoma: Let’s Not Throw Caution to the Winds

Ipilimumab for Advanced Melanoma: Let’s Not Throw Caution to the Winds

By MICHAEL LOWE, MD
Resident Surgeon, Department of Surgery, Emory University School of Medicine
KEITH A. DELMAN, MD
Assistant Professor of Surgery, Division of Surgical Oncology Department of Surgery, Emory University School of Medicine Atlanta, Georgia | January 3, 2011

The authors provide a timely and relevant review of the role that the immune system plays in regulating tumor growth and how immune modulation can alter tumor response. This review follows from the recently published phase III trial of ipilimumab,[1] a monoclonal antibody to cytotoxic T-lymphocyte antigen 4 (CTLA-4) and the first therapy in several decades to produce prolonged overall survival (OS) in patients with metastatic melanoma. While this outcome underscores the importance of this therapy in treating metastatic melanoma, its clinical applicability, at least on a widespread level, necessitates further exploration.

Response Rates and Overall Survival

As Thumar and Kluger note, objective response rates (which include complete and partial responses) in patients treated with ipilimumab range from 5% to 20%. Hodi and colleagues showed a comparable objective response rate—11%—in patients who received ipilimumab monotherapy.[1] Median OS improved to 10.1 months compared with control groups who received only glycoprotein 100 (gp100) peptide vaccine (hazard ratio [HR], 0.66; P = .003). While ipilimumab is the first therapeutic agent in decades that has shown prolonged OS in patients with metastatic melanoma, it is important to note that median survival in this patient population with the best-known therapy is generally accepted to be 6 to 9 months.

Adverse Events

The optimism engendered by this observed prolongation in OS must be carefully weighed against the frequent and sometimes life-threatening immune-related adverse events (irAEs) associated with ipilimumab. Since CTLA-4 is important for tolerance to self antigens, blockade of this pathway can result in autoimmune destruction of various organ systems. The resultant irAEs include, but are not limited to, enterocolitis, dermatitis, hypophysitis, hepatitis, pancreatitis, uveitis, nephritis, and arthritis.

The authors provide a thorough discussion of the incidence, diagnosis, and treatment of irAEs. Several important conclusions regarding treatment of irAEs should be emphasized. First, most adverse reactions are treated conservatively with supportive care and high-dose corticosteroids. However, more severe adverse reactions are associated with relatively high mortality rates (5% in one series[2]), necessitate cessation of ipilimumab therapy, and may require further immunosuppresion or surgery.[3] Second, corticosteroid therapy initiated to combat irAEs appears to have no effect on tumor growth or objective clinical responses.[4-6] Corticosteroids thus provide an effective treatment strategy for irAES that does not compromise immune modulation—nonetheless, the side effects of high-dose corticosteroids are well known and threaten the patients’ already fragile health and quality of life. Third, there appears to be a correlation between the development of irAEs and objective response rates and survival.[2,4,7-9] This relationship is strongest when more severe (grade 3 and 4) irAEs occur, although this correlation has not been uniformly present.[10] The association between adverse events and tumor response suggests that a subset of patients produces a more robust response to treatment with CTLA-4 blocking agents. The identification of these patients prior to treatment is of utmost importance, as is the development of strategies to maintain or improve response rates and survival while decreasing the severity of adverse events.

Because severe adverse reactions to ipilimumab occur in a relatively small percentage of patients, and because they are reversible and readily managed in most cases, ipilimumab is certainly an attractive therapy for metastatic melanoma. However, it is important to keep in mind that adverse events can be life-threatening and that managing them with corticosteroids can also be harmful. When weighing the use of this novel agent in patients, clinicians should also recall that this scenario is similar to that seen with other agents used to treat melanoma: a small but significant survival benefit is accompanied by a substantial risk of adverse events. As indications for the use of ipilimumab expand, it is essential that patients be well-selected and have minimal comorbidities. Education regarding the onset and treatment of adverse events is vital for patients and their families, and for medical personnel who will be treating these patients. We strongly recommend that ipilimumab, like interleukin-2, be used only in centers with complete nursing and medical teams familiar with its use.

Mechanism of Action

The most reliable way to maximize efficacy and reduce adverse events with ipilimumab therapy is to determine preemptively which patients will benefit most from this agent. An adequate understanding of its mechanism of action will help in achieving this goal. Several mechanistic theories have been postulated, including reversal of inhibition of memory cell proliferation by regulatory T cells, increased immunogenicity in the presence of melanoma-specific antigens such as NY-ESO-1, and upregulation of intratumoral CD8+ cytotoxic T cells with simultaneous decrease in intratumoral infiltration of regulatory T cells.[11] If these mechanistic speculations are confirmed, therapy with ipilimumab could be targeted to patients with more robust memory T-cell proliferation, higher density of melanoma-specific antigens on tumor cells, or a more favorable intratumoral T-cell microenvironment, respectively. Elucidating the exact mechanism of action would aid in predicting which patients would benefit most while avoiding subjecting other patients to the potential life-threatening adverse events associated with therapy.

Caveats From Experience With Another Anti-CTLA-4 Agent?

As mentioned earlier, ipilimumab is the first agent to demonstrate promise in the treatment of metastatic melanoma in decades. Thumar and Kluger’s review points out some of the limitations of the trial demonstrating the efficacy of this agent; however, it is also important to note that another anti-CTLA-4 agent was previously studied and subsequently abandoned. Tremelimumab underwent phase II investigation in patients with metastatic melanoma and showed early promise.[8,12-14] Despite these early indications, a phase III trial failed to show a greater survival benefit than traditional chemotherapy.[15] It should be noted that the control groups in the phase III trials of ipilimumab and tremelimumab were not comparable and thus do not allow for anything more than reference between them. Additionally, despite these antibodies having identical therapeutic targets, mechanistic differences may exist between them, making anything more than casual comparisons challenging. Nonetheless, the failure of tremelimumab to demonstrate better efficacy than traditional chemotherapeutic agents in its phase III trial should give further pause to those anxiously hoping to embrace ipilimumab as a potentially effective agent in the fight against melanoma.

Conclusions

The recent phase III clinical trial of ipilimumab provides a promising future for immune modulation in the treatment of advanced melanoma. Despite its being the first therapeutic development in decades to show an OS benefit, we caution against its widespread use until more data become available regarding which patients would benefit most. In an era of personalized medicine, it is becoming essential to tailor treatment options to those patients most likely to benefit, especially if the treatments in question are associated with frequent and sometimes life-threatening adverse events. Immunotherapy, particularly blockade of the CTLA-4 pathway, has already proven essential in the battle against advanced melanoma. However, the inherent risks of immunotherapy necessitate judicious use in appropriately selected patient subsets by well-informed clinicians and patients.
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Old 01-13-2011, 05:13 PM
gdpawel gdpawel is offline
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Default References

1. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-23.

2. Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol. 2006;24:2283-9.

3. Phan GQ, Weber JS, Sondak VK, CTLA-4 blockade with monoclonal antibodies in patients with metastatic cancer: surgical issues. Ann Surg Oncol. 2008;15:3014-21.

4. Downey SG, Klapper JA, Smith FO, et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res. 2007;13(22 Pt 1):6681-8.

5. Harmankaya K, Erasim C, Koelblinger C, et al. Continuous systemic corticosteroids do not affect the ongoing regression of metastatic melanoma for more than two years following ipilimumab therapy. Med Oncol. 2010 Jul 1. [Epub ahead of print]

6. Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100:8372-7.

7. Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23:6043-53.

8. Camacho LH, Antonia S, Sosman J, et al. Phase I/II trial of tremelimumab in patients with metastatic melanoma. J Clin Oncol. 2009;27:1075-81.

9. Reuben JM, Lee BN, Gomez-Navarro J, et al. Biologic and immunomodulatory events after CTLA-4 blockade with ticilimumab in patients with advanced malignant melanoma. Cancer. 2006;106:2437-44.

10. Maker AV, Yang JC, Sherry RM, et al. Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother. 2006;29:455-63.

11. Sarnaik AA, Weber JS. Recent advances using anti-CTLA-4 for the treatment of melanoma. Cancer J. 2009;15:169-73.

12. Gomez-Navarro J, et al. Survival of patients (pts) with metastatic melanoma treated with the anti-CTLA4 monoclonal antibody (mAb) CP-675,206 in a phase I/II study. J Clin Oncol (Meeting Abstracts). 2007;25(18 suppl):8524-.

13. Kirkwood JM, Lorigan P, Hersey P, et al. Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma. Clin Cancer Res. 2010;16:1042-8.

14. Ribas A, et al. Results of a phase II clinical trial of 2 doses and schedules of CP-675,206, an anti-CTLA4 monoclonal antibody, in patients (pts) with advanced melanoma. J Clin Oncol (Meeting Abstracts). 2007;25(18 suppl):3000-.

15. Ribas A, et al. Phase III, open-label, randomized, comparative study of tremelimumab (CP-675,206) and chemotherapy (temozolomide [TMZ] or dacarbazine [DTIC]) in patients with advanced melanoma. J Clin Oncol (Meeting Abstracts). 2008;26(15 suppl):LBA9011-.
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Old 03-25-2011, 03:35 PM
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Default FDA approves Ipilimumab (Yervoy)

It was reported today that the FDA has approved the injectable drug ipilimumab (called Yervoy) for late-stage or metastatic melanoma.

Known chemically as ipilimumab, the biotech drug only worked in a small subset of patients studied, and on average they lived just four months longer than patients given older medications. But the drug is an important milestone in treating the deadliest form of skin cancer, which is often unresponsive to therapy.

Yervoy (ipilimumab) is part of a group of targeted cancer medicines that harness the body's immune system to fight cancer, rather than attacking the disease with chemicals like chemotherapy. The drug works by blocking a molecule linked to melanoma called CTLA-4, which interferes with the protective activity of white blood cells. When the molecule is blocked, the cells behave normally and help fight off cancer.

Yervoy carries several side effects related to its effect on the immune system, including: diarrhea, swelling of the colon, rash and fatigue. It can cause fatal immune system reactions. The most frequent severe reactions included inflammations of the colon and small intestine, liver, and skin, as well as nerve damage and endocrine disease. Those side effects usually occurred during treatment, but some occurred after treatment ended.

The FDA said severe to fatal immune reactions occurred in 12.9% of patients during clinical trials. The agency is requiring Bristol-Myers Squibb to create a risk evaluation strategy designed to identify and reduce the severe risks associated with the drug.

Melanoma is the fastest growing form of cancer in terms of new diagnoses. Researchers attribute the acceleration to longer life expectancies among the elderly and increased use of indoor tanning by the young. About 68,000 people in the U.S. were diagnosed last year and 8,700 patients died, according to the American Cancer Society.

The FDA approved the drug based on a Bristol-Myers study of 676 people with advanced, inoperable melanoma who had already failed two other treatments, giving them a very short life expectancy. They were given one of three treatments: Yervoy by itself, Yervoy combined with another immune-stimulating treatment, or the immune-stimulating treatment alone.

Average survival was 10 months with Yervoy vs. just more than six months for the others. But a very small group of patients survived longer than six years, suggesting that with more study the drug could be targeted to those who will respond most.

About 85% of patients had little response to the drug. Hopefully, researchers say the response rate should improve as the drug is used earlier in the disease cycle.

"I think the direction this is headed is toward intervening earlier, when patients' immune systems are still intact, rather than waiting until they are so sick," said Dr. Anna Pavlick, director of the New York University's melanoma program. Pavlick, a spokeswoman for the Skin Cancer Foundation, helped conduct several early-stage trials of Yervoy.

Patients with melanoma are now candidates for the antibody Yervoy (ipilimumab) and/or the B-Raf inhibitor PLX4720. The latter requires identification of a V600E b-RAF mutation. It would seem appropriate for patients to be given insights on those options. The problem in cell function analysis, is that Ipilimumab effects are modest and PLX responses are generally short-lived.
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Old 10-14-2011, 03:33 PM
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Default Yervoy's Unsustainable Cost in the UK

Less than a month after a report determined that the cost of treating cancer is increasingly becoming unaffordable in many developed countries, the UK’s National Institute for Health and Clinical Excellence (NICE) has decided that a new and well-received skin cancer med from Bristol-Myers Squibb is simply not cost effective and will not be recommended for coverage. Called Yervoy (ipilimumab), the drug costs about $125,000 annually, or roughly 80,000 pounds in the UK.

“We need to be sure that new treatments provide sufficient benefits to patients to justify the significant cost the NHS is being asked to pay,” says NICE chief Andrew Dillon in a statement.

Even though Yervoy is the first new skin cancer treatment that has been approved in decades, the rejection was largely expected, given that NICE has regularly drawn a firm line in deciding the extent to which new cancer medicines are able to meet its thresholds for balancing cost with extending or improving lives. But the move serves to underscore the growing rancor that places patients, physicians and investors at loggerheads with regulators and payers.

Patient advocates did not waste any time blasting NICE. “The breakthrough that patients and clinicians throughout the UK have been waiting for has arrived in the form of this drug. Standard treatments that have been available since the 1970s are ineffective and to deny this drug to patients, many of whom are young and with very young families, has undoubtedly handed them down a death sentence,” said SCKIN and Factor 50, two skin cancer groups in a joint statement. “To have come so close to a breakthrough and to be told no at this stage is truly devastating.”

In justifying the decision, Dillon noted that the data submitted by Bristol-Myers mostly came from a trial that did not compare Yervoy with drugs currently used to treat people with advanced or metastatic melanoma, although he acknowledged the med may be very effective for a “small percentage” of patients. But he added that a follow-up failed to determine how long the positive effects would last.

And specialists told an independent appraisal committee that about only 30 percent of those treated with Yervoy would have improved survival, and just 10 percent would get a long-term benefit. What’s more, there are no patient characteristics or biomarkers to identify the patients who are likely to receive this gain. Meanwhile, there are various side effects - such as diarrhea, rash, fatigue and nausea, among other things - that can “significantly affect” quality of life.

The balancing act illustrates a key point made in a report commissioned by The Lancet Oncology journal. The report noted that about 12 million people worldwide get cancer every year, and costs associated with new cases were at least $286 billion in 2009. Meanwhile, as the population ages, about 27 million people can be expected to develop cancer by 2030, leading to questions about the value of treatment and associated benefits. The report found most developed countries spend between 4 percent and 7 percent of healthcare budgets on cancer.

The upshot is that Yervoy signals an escalation in the tension between access to affordable medicines, a need for additional data that demonstrates comparative data and sensitivity to cost. As the Lancet reported noted: “The cancer profession and industry should take responsibility and not accept a substandard evidence base and an ethos of very small benefit at whatever cost; rather, we need delivery of fair prices and real value from new technologies.”

Yervoy costs $125K for a round of treatment. Clinical trials show that Yervoy prolonged survival by an average of 113.4 days. That works out to approximately $1100/day even before QUALY’s are considered.

[url]http://guidance.nice.org.uk/TA/WaveCRS2/48/Consultation/DraftGuidance

[url]http://guidance.nice.org.uk/TA/WaveCRS2/48/Consultation/EvaluationReport

Source: Pharmalot's PharmaLive.com
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Gregory D. Pawelski

Last edited by gdpawel : 03-11-2012 at 01:24 PM. Reason: correct url address
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