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  1. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

  2. Melanoma … the lymphatic system.

  3. Melanin is a natural pigment formed in the body by specialized cells called melanocytes. Melanin provides pigmentation for the iris, skin, hair – as well as other parts of the body. Melanoma is a cancer whose primary cells are melanocytes. Source:

  4. Melanoma is a cancer of the melanocytes. Melanocytes become increasing deranged, becoming dysfunctional, atypical and eventually malignant. Malignant cells are characterized in terms of excessive reproduction, invasion and spread.

  5. Cancer is typically staged from 0 to 4, depending on the locality of the cancer and degree of malignancy of the cancer cells. Stage 0 – Locally contained in the upper layers of the skin.

  6. Stage I – The cancer penetrates more deeply into the upper layers of the skin and is poised to spread more deeply.

  7. Stage II: The cancer penetrates into the middle layers of the skin, the dermis, and is poised to spread further.

  8. Stage III: The cancer has spread beyond the skin to the lymph nodes. The lymphatic system gives access to other parts of the body.

  9. Stage IV: The cancer has spread to other organ systems.

  10. gp100: melanoma antigen Glyco-protein gp100 is a protein expressed by melanoma cells – gp100 is an antigen – it can provoke an immune response. In particular, there is interest in training the immune system to aggressively react to gp100 via gp100-based vaccines. gp100:209-217(210M) peptide vaccine A synthetic peptide cancer vaccine consisting of amino acid residues 209 through 217 of the glycoprotein 100 (gp100) melanoma antigen, with a methionine substitution at position 210 designed to improve immunogenicity. Vaccination with gp100:209-217(210M) peptide may stimulate the host immune system to mount a cytotoxic T lymphocyte (CTL) response against tumor cells expressing gp100. The purpose of this type of vaccine is to train the patient’s immune system to recognize cancer cells as a threat, and to stimulate an immune response to the cancer.

  11. ipilimumab (ih-pih-LIH-myoo-mab) A monoclonal antibody being studied in the treatment of certain types of cancer. Ipilimumab is made in the laboratory and binds to the molecule CTLA-4 on T cells (a type of white blood cell). Ipilimumab may block CTLA-4 and help the immune system kill cancer cells. Also called MDX-010. Source: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) limits the therapeutic potency of cancer vaccines by decreasing T-cell function, which is critical in melanoma immunity. Source: The idea is that ipilimumab enhances the function of vaccines by blocking the ability of CTLA-4 to interfere with T-cell function.

  12. The study focused on people with stage III/IV melanoma, whose cancer was inoperable. “Patients were randomly assigned, in a 3:1:1 ratio, to treatmentwith an induction course of ipilimumab, at a dose of 3 mg perkilogram of body weight, plus a gp100 peptide vaccine; ipilimumabplus gp100 placebo; or gp100 plus ipilimumab placebo —all administered once every 3 weeks for four treatments. ” Under a double-blinded design, the treatment groups involved three treatments: Vaccine (gp100) plus CTLA-4 Blocker(ipilimumab) Vaccine (gp100) plus PlaceboCTLA-4 Blocker(ipilimumab) PlaceboVaccine (gp100)plus CTLA-4 Blocker(ipilimumab) Enrolled subjects, having given informed consent, are randomly assigned to a single treatment group. In a double-blinded study, neither the subjects nor the clinical personnel know the individual treatment assignments.

  13. Primary Endpoint: Overall Survival Time The basic standard of benefit considered was overall survival – there are two measures of overall survival. Survival Rate: By the end of the study, what proportion of each treatment group survived? Survival Time: Among the subjects who died during the study, what was the distribution of time-to-death? An alternative to Overall Survival is Progression Free Survival, which considers time in stage rather than survival time. Some treatments may give patients more time at less severe stages of disease without extending overall survival time. “Survival was defined as the time from randomization to deathfrom any cause, and progression-free survival as the time fromrandomization to documented disease progression or death. ” Other endpoints include safety and toxicity. The treatments themselves may have side effects and toxicity, up to and including severe/fatal risks.

  14. hazard ratio A measure of how often a particular event happens in one group compared to how often it happens in another group, over time. In cancer research, hazard ratios are often used in clinical trials to measure survival at any point in time in a group of patients who have been given a specific treatment compared to a control group given another treatment or a placebo. A hazard ratio of one means that there is no difference in survival between the two groups. A hazard ratio of greater than one or less than one means that survival was better in one of the groups. Source:

  15. Safety Considerations: Adverse Events “Adverse events were graded according to the National CancerInstitute's Common Terminology Criteria for Adverse Events,version 3.0. An immune-related adverse event was defined asan adverse event that was associated with exposure to the studydrug and that was consistent with an immune phenomenon. Protocolguidelines for the management of immune-related adverse eventsincluded the administration of corticosteroids (orally or intravenously),a delay in a scheduled dose, or discontinuation of therapy.Assigned doses were delayed in the case of nondermatologicimmune-related adverse events of grade 2 or higher until theevent improved to grade 1 or lower; if the event did not improveto grade 1 or lower, treatment was discontinued permanently.Monitoring of adverse events continued for at least 70 daysafter the last dose of study drugs had been administered oruntil any ongoing event resolved or stabilized. All patients,including those with low-grade changes in bowel frequency orstool consistency, were followed closely. A data and safetymonitoring committee provided independent oversight of safetyand the risk–benefit ratio.”

  16. Safety Considerations: Stopping Rules “During the study enrollment, the following stopping rule wasin place: if 10% or more of the patients in any study treatmentgroup, evaluated cumulatively every 3 months, had a nondermatologic-relatedtoxic adverse event of grade 3 or higher that was attributableto the investigational agents and that could not be alleviatedor controlled by appropriate care or corticosteroid therapywithin 14 days after the initiation of supportive care or corticosteroidtherapy, assignment of patients to that study group would besuspended until the sponsor and the data and safety monitoringcommittee had reviewed the events and determined the appropriatecourse of action. “

  17. Figure 1. Kaplan-Meier Curves for Overall Survival and Progression-free Survival in the Intention-to-Treat Population. The median follow-up for overall survival (Panel A) in the ipilimumab (Ipi)-plus-glycoprotein 100 (gp100) group was 21.0 months, and the median overall survival was 10.0 months (95% CI, 8.5 to 11.5); in the ipilimumab-alone group, the median follow-up was 27.8 months, and the median overall survival, 10.1 months (95% CI, 8.0 to 13.8); and in the gp100-alone group, the median follow-up was 17.2 months, and the median overall survival, 6.4 months (95% CI, 5.5 to 8.7). The median progression-free survival (Panel B) was 2.76 months (95% CI, 2.73 to 2.79) in the ipilimumab-plus-gp100 group, 2.86 months (95% CI, 2.76 to 3.02) in the ipilimumab-alone group, and 2.76 months (95% CI, 2.73 to 2.83) in the gp100-alone group. The rates of progression-free survival at week 12 were 49.1% (95% CI, 44.1 to 53.9) in the ipilimumab-plus-gp100 group, 57.7% (95% CI, 48.9 to 65.5) in the ipilimumab-alone group, and 48.5% (95% CI, 39.6 to 56.7) in the gp100-alone group.

  18. Kaplan-Meier Curves for Overall Survival and Progression-free Survival in the Intention-to-Treat Population Hodi F et al. N Engl J Med 2010;10.1056/NEJMoa1003466

  19. Figure 2. Subgroup Analyses of Overall Survival. The pre-specified analyses of overall survival among subgroups of patients, as defined by baseline demographic characteristics and stratification factors (metastasis [M] stage, classified according to the tumor-node-metastasis [TNM] categorization for melanoma of the American Joint Committee on Cancer; and receipt or nonreceipt of interleukin-2 therapy), showed that hazard ratios were lower than 1 (indicating a lower risk of death) for each subgroup in the ipilimumab (Ipi)-plus-glycoprotein 100 (gp100) group as compared with the gp100-alone group (Panel A) and for each subgroup in the ipilimumab-alone group as compared with the gp100-alone group (Panel B). Hazard ratios were estimated with the use of unstratified Cox proportional-hazards models. Horizontal lines represent 95% confidence intervals. LDH denotes lactate dehydrogenase, and ULN the upper limit of the normal range.

  20. Subgroup Analyses of Overall Survival Hodi F et al. N Engl J Med 2010;10.1056/NEJMoa1003466

  21. 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.D., Axel Hoos, M.D., Ph.D., and Walter J. Urba, M.D., Ph.D.

  22. ABSTRACT Background An improvement in overall survival among patientswith metastatic melanoma has been an elusive goal. In this phase3 study, ipilimumab — which blocks cytotoxic T-lymphocyte–associatedantigen 4 to potentiate an antitumor T-cell response —administered with or without a glycoprotein 100 (gp100) peptidevaccine was compared with gp100 alone in patients with previouslytreated metastatic melanoma. Methods A total of 676 HLA-A*0201–positive patients withunresectable stage III or IV melanoma, whose disease had progressedwhile they were receiving therapy for metastatic disease, wererandomly assigned, in a 3:1:1 ratio, to receive ipilimumab plusgp100 (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 upto four treatments (induction). Eligible patients could receivereinduction therapy. The primary end point was overall survival.

  23. Results The median overall survival was 10.0 months among patientsreceiving ipilimumab plus gp100, as compared with 6.4 monthsamong patients receiving gp100 alone (hazard ratio for death,0.68; P<0.001). The median overall survival with ipilimumabalone was 10.1 months (hazard ratio for death in the comparisonwith gp100 alone, 0.66; P=0.003). No difference in overall survivalwas detected between the ipilimumab groups (hazard ratio withipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-relatedadverse events occurred in 10 to 15% of patients treated withipilimumab and in 3% treated with gp100 alone. There were 14deaths related to the study drugs (2.1%), and 7 were associatedwith immune-related adverse events. Conclusions Ipilimumab, with or without a gp100 peptide vaccine,as compared with gp100 alone, improved overall survival in patientswith previously treated metastatic melanoma. Adverse eventscan be severe, long-lasting, or both, but most are reversiblewith appropriate treatment. ( number, NCT00094653 [] .)