New Treatment Options in Advanced Melanoma Reinhard Dummer, MD Department of Dermatology, University Hospital Zürich, Switzerland Lifetime Melanoma Risk Rate/100,000 population 16 12 8 4 0 1935 Lifetime risk 1:1,500 1950 1980 1985 1987 2000 1:600 1:250 1:150 1:135 1:75 By permission from American Academy of Dermatology, Rigel DS, et al. J Am Acad Dermatol. 1996;35:1012-1013 GENETICS, UV? http://www.usz.unizh.ch/derma/hautkrebs/ Enhanced UV irradiation Out-door activities Life expectancy UV intensity Melanocyte-Melanoma Functional unit of melanocyte/keratinocytes Mutations Amplifications Translocations Deletions Courtesy of Dept. of Dermatology, University Hospital Zürich Distinct Sets of Genetic Alterations in Melanoma array-based comparative genomic hybridization By permission from N Engl J Med, John A. Curtin et al. N Engl J Med 2005;353:2135-2147 Courtesy of Dept. of Dermatology, University Hospital Zürich High-throughput oncogene mutation profiling in human cancer Melanoma By permission from Macmillan Publishers Ltd: Nature Genetics,. Vol. 39, n3, 347-351, Figure 1, Roman K.Thomas et al. 11 Feb 2007 Targeting signalling pathways RTK Growth factor Farnesylproteintransferase-inhibitors RAF 265, GSK2118436 plasma membrane Shc ras Grb-2 raf mek1/2 AZD6244, GSK1120212 erk1/2 SOS PLX4032 V600E only nuclear membrane erk1/2 DNA Courtesy of Dept. of Dermatology, University Hospital Zürich Tumorthickness (Breslow) Epidermis Corium Subcutis Courtesy of Dept. of Dermatology, University Hospital Zürich 10 Year-Survival of Melanoma patients Survival in % Thin primary tumors Thick primary tumors Lymph node metastases distant metastases Months By permission from Br J Cancer A.C. Häffner et al., Br J Cancer 1992; 66:856-861 Final results of the EORTC 18871/DKG 80-1 randomised phase III trial rIFN-α2b versus rIFN-γ versus ISCADOR M® versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis By permission from European Journal of Cancer U.R. Kleeberg et al. European J Cancer 40 (2004):390-402 Observation Randomization Stratified by: • Microscopic (N1) vs. palpable (N2) • 1 vs. 2-4 vs. 5+ nodes • Breslow • Ulceration • Gender • Site Peg-IFN alfa-2b • Induction (8 weeks) 6 µg/kg/week • Maintenance (5 years or distant metastasis) 3 µg/kg/week • Dose reduction to 3, 2, 1 to maintain performance status Primary Endpoints: • Relapse-free survival (RFS) • Distant metastasis-free survival (DMFS) By permission of A. Eggermont and from Lancet, Eggermont et al. Lancet, 2008; 372:117-26 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 Probability Probability N1 (micro met in SN) +++ +++++++ +++ +++ + 0.5 0.2 0.5 0.4 0.4 0.3 0.6 0.3 RFS HR 0.73 DMFS HR 0.75 0.2 0.1 0.1 0.0 Time 0.0 Time 6 12 18 24 30 36 42 48 54 60 66 72 6 12 18 24 30 36 42 48 54 60 66 72 1.0 0.9 Probability 0.8 Hazard rate over time 0.3 0.7 0.6 0.2 0.5 0.4 0.3 OS HR 0.88 0.2 0.1 0.0 Time 6 12 18 0.1 PEGPEG-IFN OBS Censored OBS PEGPEG-IFN 0.0 0 24 30 36 42 48 54 60 66 72 1 2 3 4 5 Years By permission of Prof. Alexander M.M Eggermont (EORTC Trial 18991) 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 Probability Probability N2 (macro met) 0.6 0.5 0.4 0.1 0.5 0.4 0.3 0.3 0.2 0.6 RFS HR 0.86 0.0 Time 6 12 18 0.1 24 30 36 42 48 54 60 66 72 0.0 Time 6 1.0 PEGPEG-IFN OBS Censored 18 0.7 0.6 0.5 0.4 OS HR 1,01 12 18 36 42 48 54 60 66 42 48 54 60 66 72 0.3 0.2 OBS PEGPEG-IFN 0 30 36 0.4 0.0 24 30 Hazard rate over time 0.1 0.3 0.0 Time 6 24 0.5 Hazard rate Probability 0.8 0.1 12 0.6 0.9 0.2 DMFS HR 0.94 0.2 72 1 2 3 4 5 Years By permission of Prof. Alexander M.M. Eggermont (EORTC Trial 18991) Conclusions IFN-alpha is the only adjuvant therapy with repeatedly proven impact on DFS and DMFS Low dose IFN-alpha is well tolerated in most patients This treatment option should be suggested to young and healthy high risk patients with N1a disease For N1B and higher: clinical trials! ESMO Clinical Practice Guidelines … Since the overall impact of systemic therapy on survival in advanced melanoma patients is questionable, these patients should be treated preferentially in controlled clinical trials evaluating new treatment modalities. By permission from Oxford University press. Annals of Oncology 21 (Supplement 5): v194-197, 2010 – extract v196, Dummer et al. Melanoma: ESMO Clinical Practice Guidelines Inhibition of Mutated, Activated BRAF in Metastatic Melanoma 100 75 %Change From Baseline (Sum of Lesion Size) Phase I Trial: Tumor responses occurred in majority (81%) of patients in V600E+ melanoma extension cohort (960 mg BID) 50 25 0 -25 -50 -75 -100 •Investigator assessments •Includes confirmed & unconfirmed responses By permission from N. Engl J Med, Supplementary Appendix Figure 1A, ”Inhibition of mutated, activated BRAF in metastatic melanoma”. Flaherty K.T. et al N Engl J Med 2010;363:809-19. Courtesy of Dr. Jeff A. Sosman, “Melanoma: What is beyond mutant BRAF?” BRIM-2 Study Design Metastatic Melanoma Prior Treatment V600E+ (n=132) Endpoints: RG7204 (960 mg BID) Primary: BORR (IRC) Secondary: duration of response, PFS, OS, and safety Eligibility Criteria • PD after prior IL-2 or standard chemotherapy (DTIC, TMZ, C/T, fotemustine) • PS=0 or 1 • Brain metastases allowed if treatment with stereotactic RT or surgery, and stable for >3 mo Statistical Considerations • Target BORR is 30% • 10% patients considered unevaluable • Total of 90 patients required to demonstrate the lower boundary of the exact 95% CI is at least 20% By permission of Dr. Jeff A.Sosman, Presented at the 7th International Congress for the Society of Melanoma Research 2010; Abstract 101 Tumor Responses Assessed by IRC • • • BORR 52% by IRC* BORR 55% by investigator assessments (INV) RR, including unconfirmed, 68% (INV) *6 patients were unevaluable By permission of Dr. J. A. Sosman, Vanderbilt-Ingram Cancer Center, “Melanoma: What is beyond mutant BRAF?”, Feb 2011 Progression Free Survival (IRC) n=132 PD or death, n (%) 78 (59.1) Progression-free 54 (40.9) Median PFS, mo (95% CI) 6 mo PFS rate (95% CI) 6.2 (5.6–6.8) 0.51 (0.42–0.60) By permission of Dr. J.A. Sosman, Vanderbilt-Ingram Cancer Center, “ Melanoma: What is beyond mutant BRAF?”, Feb 2011 Most Commonly Reported Drug-Related AEs Adverse Event All Grades, % Grade 3, % Arthralgia 57.6 6.1 Rash 51.5 6.8 Photosensitivity 49.2 3.0 Fatigue 38.6 1.5 Alopecia 33.3 - Cutaneous SCC 24.2 24.2 Pruritis 27.3 2.3 Skin papilloma (verruca) 27.3 0 • 130 patients experienced at least one drug-related AE By permission of Dr. J.A.Sosman, Vanderbilt-Ingram Cancer Center, “Melanoma: What is beyond mutant BRAF?”, Feb 2011 RO5185426 – B-Raf Inhibition: Comparison Day 0 – Day 17 Female, born 1948 Courtesy of Dept. of Dermatology, University Hospital Zürich Courtesy of Dr Paul A. Chapman, Sloan-Kettering Memorial Cancer Clinic Mechanisms of resistance to B-RAF inhibition By permission from Macmillan Publishers Ltd: Nature, Vol. 468, n7326, v902, Figure 1, D. Solit, C. L. Sawyers, Dec 15, 2010 Ipilimumab – Phase 3 study A randomized, double-blind, phase 3 study which enrolled 125 centers in 13 countries in North America, South America, Europe and Africa between September 2004 and August 2008 showed: Improved survival in patients with metastatic melanoma treated with Ipilimumab Hodi S et al. N Engl J Med 2010; 363: 711-723. Modulation of T-cell activation activation inactivation T-regs? APC HLA I L APC L HLA I HLA II HLA II B7 CD28 B7 CTLA4 CD28 Prof. R. Dummer, Dept. of Dermatology, University Hospital Zürich Modulation of T-cell activation by an anti-CTLA4 antibody prevention of the inactivation inactivation APC APC L HLA I HLA II L HLA I HLA II B7 CTLA4 CD28 B7 CD28 CTLA4 MDX-010 Prof. R. Dummer, Dept. of Dermatology, University Hospital Zürich Autoimmunity correlates with tumor regression in: Patients with Metastatic Melanoma treated with Anti-Cytotoxic T-Lymphocyte Antigen-4 By permission from the American Society of Oncology, Attia P. et al. JCO 2006 Sep1;23(25):6043-6053 MDX010-20: Study Design Pre-treated Metastatic Melanoma (N=676) R A N D O M I Z E Ipilimumab + gp100 (N=403) Ipilimumab + placebo (N=137) gp100 + placebo (N=136) By permission of Dr. S.O’Day: “A phase III, randomized, double blind, multicenter study comparing monotherapy with ipilimumab or gp 100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma Study MDX010-20.”, O’Day S et al. Abstract 4, Plenary Session, ASCO 2010 MDX010-20: Study Design Details Accrual: September 2004 – July, 2008 125 Centers in 13 Countries Randomized (3:1:1), Double-Blind Stratified for M-Stage and prior IL-2 Induction Ipilimumab: 3 mg/kg q 3 weeks X 4 doses gp100: 1mg q 3 weeks X 4 doses Re-induction (same regimen) in eligible patients By permission of Dr. S. O’Day: “A phase III, randomized, double blind, multicenter study comparing monotherapy with ipilimumab or gp 100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma Study MDX010-20”, O’Day S et al. Abstract 4, Plenary Session, ASCO 2010 Most Common Immune-Related AEs* (irAEs; All Grades) % of Patients irAE Ipi + gp100 N=380 Ipi + pbo N=131 gp100 + pbo N=132 All grades Any 58.2 61.1 31.8 Dermatologic 40.0 43.5 16.7 GI 32.1 29.0 14.4 Endocrine 3.9 7.6 1.5 Hepatic 2.1 3.8 4.5 *Across entire study duration By permission of Dr. S. O’Day: “A phase III, randomized, double blind, multicenter study comparing monotherapy with ipilimumab or gp 100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma Study MDX010-20.”, O’Day S et al. Abstract 4, Plenary Session, ASCO 2010 Kaplan-Meier Analysis of Survival Ipi + gp100 (A) Ipi alone (B) gp100 alone (C) 1 2 Years 3 4 Ipi + gp100 N=403 Ipi + pbo N=137 gp100 + pbo N=136 1 year 44% 46% 25% 2 year 22% 24% 14% Survival Rate By permission of Dr S. O’Day Summary of MDX010-20 Data First randomized phase III trial to show survival improvement in metastatic melanoma (HR=0.66, 0.68) Superior OS in two independent comparisons of ipilimumab vs gp100 Survival rates in the ipilimumab arms 1 year: 44%, 46% 2 years: 22%, 24% Consistent superiority of ipilimumab for all secondary efficacy endpoints: PFS, BORR, DCR By permission of Dr. S. O’Day: “A phase III, randomized, double blind, multicenter study comparing monotherapy with ipilimumab or gp 100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma Study MDX010-20.”, O’Day S et al. Abstract 4, Plenary Session, ASCO 2010 ESMO Clinical Practice Guidelines …Since the overall impact of systemic therapy on survival in advanced melanoma patients is questionable, these patients should be treated preferentially in controlled clinical trials evaluating new treatment modalities. lesson: 2011 And apply sophisticated translational research to identify predictive biomarkers and investigate resistance mechanism… By permission from Oxford University press. Annals of Oncology 21 (Supplement 5): v194-197, 2010 – extract v196, Dummer et al. Melanoma: ESMO Clinical Practice Guidelines Thank you !