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Updates in Community Oncology 2011: A Focus on Melanoma

Updates in Community Oncology 2011: A Focus on Melanoma. This program is supported by educational grants from Bristol-Myers Squibb, Genentech BioOncology, and Merck. About These Slides. Our thanks to the presenters who gave permission to include their original data

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Updates in Community Oncology 2011: A Focus on Melanoma

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  1. Updates in Community Oncology 2011:A Focus on Melanoma This program is supported by educational grants fromBristol-Myers Squibb, Genentech BioOncology, and Merck.

  2. About These Slides • Our thanks to the presenters who gave permission to include their original data • Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent • These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

  3. Faculty • Keith T. Flaherty, MDDirector of Developmental TherapeuticsMassachusetts General Hospital Cancer CenterBoston, Massachusetts • John M. Kirkwood, MDProfessor, Medicine, Dermatology, and Translational ScienceDirector, Melanoma and Skin Cancer ProgramUniversity of Pittsburgh Cancer InstitutePittsburgh, Pennsylvania • Jedd D. Wolchok, MD, PhDDirector, Immunotherapy Clinical Trials Department of Medicine Associate Attending Physician Department of Medicine, Melanoma/Sacroma Services Memorial Sloan-Kettering Cancer Center New York, New York

  4. Disclosures • Keith T. Flaherty, MD, has disclosed that he has received consulting fees from GlaxoSmithKline and Roche-Genentech BioOncology. • John M. Kirkwood, MD, has disclosed that he has received consulting fees from GlaxoSmithKline, Merck, and Roche-Genentech BioOncology. • Jedd D. Wolchok, MD, PhD, has disclosed that he has received consulting fees from Bristol-Myers Squibb.

  5. Adjuvant Therapy for Melanoma

  6. E1684, E1690, and E1694: Durable Impact on RFS and OS • All trials of IFNα with durable benefit in terms of RFS and OS used IV induction at 20 MU/m2(Cmax > 10,000 µ/mL) 1. Kirkwood JM, et al. J Clin Oncol. 1996;14:7-17. 2. Kirkwood JM, et al. J Clin Oncol. 2000;18:2444-2458. 3. Kirkwood JM, et al. J Clin Oncol. 2001;19:1430-1436.

  7. 3 Meta-analyses of All Trials of IFN-alfa Confirm RFS, OS Impact 1. Ives NJ, et al. J Clin Oncol. 2007;25:5426-5434. 2. Wheatley K, et al. ASCO 2007. Abstract 8526. 3. Mocellin S, et al. J Natl Cancer Inst. 2010;102:493-501.

  8. E1697: 4 Wks of High-Dose IFN alfa-2b in Stage T3-T4 or N1 Melanoma Hypothesis: 1-month induction IV IFN is necessary and sufficient to achieve durable adjuvant benefit in intermediate-risk melanoma patients STRATIFICATION Pathologic Lymph Node StatusKnownUnknown Lymph Node Staging ProcedureSentinel lymph node procedure; elective lymph node dissection; no lymphadenectomy Breslow Depth1.5-3.0 mm3.1-4.0 mm > 4 mm Ulceration of Primary LesionYesNo Disease StageLymph node positiveLymph node negative R ANDOM IZE Arm A: Observation Arm B: 4-wk high-dose IFN alfa-2b 20 MU/m2/day QD IV for 5 consecutive days out of 7 (M-F) every wk x 4 wks Agarwala SS, et al. ASCO 2011. Abstract 8505.

  9. E1697: 3rd Interim Analysis—RFS (N = 838) 1.0 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 0 0 1 2 3 4 5 6 7 8 9 10 11 Yrs TreatmentObservationHDI Total413425 Failed111123 Censored302302 Median7.36.8 Agarwala SS, et al. ASCO 2011. Abstract 8505.

  10. E1697: Current Assessment • No benefit from 1 mo of IFN in stage IIB/IIIA disease • Patients with IIB/IIIA melanoma require 1 year of standard therapy (E1684, E1690, E1694) • Analysis of mortality and role of salvage therapy indicate that • Crossover has confounded both adjuvant and advanced disease therapy • IFN from observation in E1690[1] • Anti-CTLA4 abstract: tremelimumab phase III trial[2] • BRAF inhibitor trials? • Potential predictive biomarkers of immunotherapy? • Autoimmunity[3] • Cytokine profile pretreatment[4] 1. Kirkwood JM, et al. J Clin Oncol. 2000;18:2444-2458. 2. Ribas A, et al. ASCO 2008. Abstract LBA9011. 3. Gogas H, et al. N Engl J Med. 2006;354:708-718. 4. Yurkovetsky ZR, et al. Clin Cancer Res. 2007;13:2422-2428.

  11. Multivariate Analysis of High-Risk Melanoma Patients Receiving HDI Time to Progression OS 1.0 1.0 Patients with autoimmunity (n = 52) Patients with autoimmunity (n = 52) 0.5 0.5 Probability Probability Patients without autoimmunity (n = 148) Patients without autoimmunity (n = 148) 0 0 0 20 40 60 80 100 0 20 40 60 80 100 Mos Mos Gogas H, et al. N Engl J Med. 2006;354:709-718.

  12. EORTC 18991: Peg-IFN alfa-2b vsObservation Patients (N = 1256): Resected TxN1-2M0 melanoma, within 7 wks of lymphadenectomy Observation Randomization Stratified by: • Microscopic (N1) vs palpable (N2) • 1 vs 2-4 vs 5+ nodes • Breslow • Ulceration • Gender and site Peg-IFN alfa-2b • Induction (8 wks) 6 µg/kg/wk • Maintenance (5 years or distant metastasis) 3 µg/kg/wk • Dose reduction to 3, 2, 1 to maintain performance status Primary Endpoints: • Relapse-free survival • Distant metastasis-free survival Eggermont AM, et al. Lancet. 2008;372:117-126.

  13. EORTC 18991 (2011 Update): Outcome at 7.6 Yrs of Follow-up • RFS benefit with pegIFN alfa-2b still significant at 7.6 yrs, but eroded 2007  2009 • No change in DMFS or OS Eggermont AM, et al. ASCO 2011. Abstract 8506b.

  14. EORTC 18991 (2011 Update): RFS by Subgroup *Statistically significant vs observation in 2007, but not in 2011 Eggermont AM, et al. ASCO 2011. Abstract 8506b.

  15. EORTC 18991 (2011 Update): Stage III N1, Ulcerated Disease • Stage III N1 and ulcerated primary tumors showed significant benefit for multiple endpoints, including OS • Median OS pegIFN vs observation: > 9.0 vs 3.7 yrs • EORTC 18081 plans comparison of pegIFN x 2 yrs vs observation in ulcerated primary tumors > 1 mm Eggermont AM, et al. ASCO 2011. Abstract 8506b.

  16. Adverse Event Summary and Treatment Compliance Treatment compliance • Median induction duration: 8 wks • Median maintenance duration: 14.9 mos • 31% of patients discontinued treatment due to AEs; 23% remain on treatment in Yrs 4-5 Eggermont AM, et al. ASCO 2011. Abstract 8506b.

  17. Summary: Adjuvant Modalities Evaluated to Date

  18. Molecularly Targeted Therapies for Metastatic Melanoma

  19. Oncogenes in Melanoma *80% to 90% of uveal.

  20. Distribution of Genetic Alterations in BRAF, NRAS, and KIT by Primary Site KITKIT and NRASKIT and BRAFNRASBRAF 100 50 Percent Aberrant 0 Non-CSD CSD Acral Mucosal Curtin J, et al. J Clin Oncol. 2006;24:4340-4346.

  21. Relative Frequency of BRAF Mutations Submitted to COSMIC Database Flaherty KT, et al. Cancer. 2010;116:4902-4913.

  22. BRAF Mutation Testing • BRAF mutations are present throughout melanoma disease progression • If metastasis biopsy not available, most recent melanoma surgery sample adequate (eg, lymph node) • BRAF mutation testing is commercially available • FDA-approved method used in vemurafenib clinical trials • cobas 4800 BRAF V600 Mutation Test

  23. Change in Tumor Size with Vemurafenib in 132 V600EBRAF-Mutant Patients 60 Disease stage M1a M1b M1c 40 20 0 Percent Change From Baseline in Diameter of Target Lesion -20 -40 -60 -80 -100 ******* Individual Patients Treated With Vemurafenib *7 confirmed CRs. Ribas A, et al. ASCO 2011. Abstract 8509.

  24. Phase III BRIM-3 Study Design Screening Vemurafenib • V600EBRAF mutation • Stratification • Stage • ECOG PS (0 vs 1) • LDH level (↑ vs nl) • Geographic region 960 mg PO BID (n = 337) Randomization (N = 675) Dacarbazine 1000 mg/m2 IV q3w (n = 338) Chapman PB, et al. N Engl J Med. 2011;364:2507-2516.

  25. 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Vemurafenib vs Dacarbazine in BRAF V600E–Positive Melanoma: OS Vemurafenib (n = 336) Est 6-mo survival: 84% Dacarbazine (n = 336) Est 6-mo survival: 64% OS (%) HR: 0.37 (95% CI: 0.26-0.55; log-rank P < .0001) Mos Patients in follow-up, n Dacarbazine Vemurafenib 336 336 283 320 192 266 137 210 98 162 64 111 39 80 20 35 9 14 1 6 1 1 Chapman PB, et al. N Engl J Med. 2011;364:2507-2516.

  26. Change in Tumor Size in 26 V600EBRAF Mutant Melanoma Patients (GSK2118436) B-RAF V600E 0.6 Isolated kinase IC50 (nM): 20 C-RAF WT 5 20 10 B-RAF WT 12 10 0 0 -10 -10 -20 -20 -30 -30 -40 -40 Maximum % Reduction From Baseline -50 -50 -60 -60 -70 -70 -80 -80 CR SD -90 -90 PR PD -100 -100

  27. Response to GSK2118436 in Patients WithV600EBRAF-Positive Brain Lesions (N = 10) 40 40 30 30 20 20 10 10 0 0 -10 -10 * -20 -20 Maximum % Change From Baseline -30 -30 -40 -40 -50 -50 -60 -60 -70 -70 -80 -80 -90 -90 -100 -100 Patients *V600K. Long G, et al. ESMO 2010. Abstract 5016.

  28. Most Common Toxicities With Vemurafenib and GSK2118436 1. Flaherty KT, et al. N Engl J Med. 2010;363:809-819. 2. Kefford R, et al. Society for Melanoma Research Congress 2010. Abstract 100.

  29. Timing of Keratoacanthoma/SCC 0 12 24 36 48 60 72 Wks on PLX4032 Lacouture ME, et al. ASCO 2010. Abstract 8592.

  30. Tumor Response With MEK Inhibitor (GSK1120212) in BRAF-Mutant Melanoma • N = 29; 2 CRs and 10 PRs • ~ 90% M1c; 48% history of brain metastases • No previous treatment with a BRAF inhibitor CR PR SD PD 100 100 Preliminary RR is 41% (95% CI: 23% to 61%) 80 80 60 60 40 40 20 20 Maximum % Reduction From Baseline 0 0 -20 -20 -40 -40 -60 -60 -80 -80 -100 -100 Subjects Falchook G, et al. ESMO 2010. Abstract 4950.

  31. Most Common AEs (≥ 20%) for GSK1120212 (N = 68) Falchook G, et al. ESMO 2010. Abstract 4950.

  32. Phase II Trial of Imatinib in Patients With c-KIT Genetic Aberrations • N = 43 patients with metastatic melanoma and c-KIT aberrations • Treatment: imatinib 400 mg/day continuously unless intolerant toxicities or disease progression occurred • 15 patients with progression escalated to 800 mg/day • Endpoints: PFS, 6-month PFS, ORR, OS, 1-year OS Guo J, et al. J Clin Oncol. 2011;29:2904-2909.

  33. Phase II Trial of Imatinib in Patients With c-KIT Aberrations: Patient Characteristics Guo J, et al. J Clin Oncol. 2011;29:2904-2909.

  34. Phase II Trial of Imatinib in Patients With c-KIT Aberrations: Change in Tumor Size 120 100 M1a M1b M1c 80 60 40 Change in tumor size, % 30 0 -20 -40 -60 -80 Guo J, et al. ASCO 2010. Abstract 8527.

  35. Phase II Trial of Imatinib: Correlation of Response and c-KIT Aberrations 68.6% *5 patients harbored multiple c-KIT aberrations, one each as follows: K642E (exon 13) + amplification; I653T (exon 13) + T1940C (exon 13); F848L (exon 18) + T2576C (exon 18); L576P (exon 11) + amplification; P577H (exon 13) + N486D (exon 9). Guo J, et al. J Clin Oncol. 2011;29:2904-2909.

  36. Conclusions • BRAF inhibitors associated with high response rate and improved survival • Duration of response highly variable • MEK inhibition is active in BRAF-mutant melanoma • c-KIT mutations present in 10% of mucosal and acral melanomas • c-KIT inhibitors active in a subset of melanoma patients

  37. Advances in Immunotherapy for Metastatic Melanoma

  38. High-Dose IL-2 Therapy • RR: 16% (43/270) • Durable responses • Median: 8.9 mos • CR: not reached 1.0 CR (n = 17) PR (n = 26) CR + PR (n = 43) 0.8 0.6 Probability of Continuing Response 0.4 0.2 0 0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 Duration of Response (Mos) Atkins MB, et al. J Clin Oncol. 1999;17:2105-2116.

  39. IL-2 ± gp100 Peptide Vaccine in Patients With Advanced Melanoma • Based on previous phase II studies demonstrating efficacy • NCI phase II study: OR in 13/31 (42%)[1] • CWG phase II trials: OR in 20/121 (16%)[2] • Multicenter phase III trial of IL-2 ± gp100, accruing 185 patients from 21 centers over 7 yrs[3] 1. Rosenberg SA, et al. Nat Med. 1998;4:321-327. 2. Sosman JA, et al. J Clin Oncol. 2008;26:2292-2298. 3. Schwartzentruber DJ, et al. N Engl J Med. 2011;364:2119-2127.

  40. CTLA-4 T cell T cell resting T cell CTLA-4 TCR CD28 CTLA-4 Ipilimumab HLA B7 APC APC APC Ipilimumab, CTLA-4 Blocking mAb, Augments T-Cell Activation T-Cell Activation T-CellInactivation T-Cell Remains Active Korman AJ, et al. Adv Immunol. 2006;90:297-339 .

  41. Ipilimumab Pattern of Response July 2006 Wk 12: Progression Pretreatment • Responses after appearance and subsequent disappearance of new lesions 3 mg/kg ipilimumab q3w x 4 New lesions Wk 20: Regression Wk 36: Still Regressing Wolchok JD, et al. ASCO 2008. Abstract 3020.

  42. Ipilimumab Therapy: 4 Patterns of Response • 2 conventional • Response in baseline lesions • “Stable disease” with slow, steady decline in total tumor volume • 2 novel • Response after initial increase in total tumor volume • Response in index plus new lesions at or after the appearance of new lesions

  43. Patient Education Tips • Educate patients that a response to ipilimumab is different from a response to chemotherapy • Symptoms that could indicate disease progression may indicate a positive response to ipilimumab • Assure patients that these response patterns are normal

  44. MDX010-20 Study Schema Screening Induction ≥ 1 Reinduction (eligible patients) 3:1:1 PD Ipilimumab+ gp100 (n = 403) Ipilimumab + gp100 Previously treated, HLA-A*0201+ patients with advanced melanoma (N = 676) Follow- up PD Ipilimumab alone (n = 137) Ipilimumab alone R A N D O M I Z E gp100 alone (n = 136) gp100 alone PD Induction: Ipilimumab at 3 mg/kg, with or without gp100, q3w for 4 treatments. Reinduction: Patients with SD for 3 months’ duration from Wk 12, or a confirmed CR or PR, could receive additional therapy with their assigned treatment regimen upon PD. Hodi FS, et al. N Engl J Med. 2010;363:711-723.

  45. MDX010-20: Kaplan-Meier Analysis of OS Comparison HR P Value Arm A vs C 0.68 < .001 Arm B vs C 0.66 .003 Arm A vs B 1.04 .76 1.0 0.9 0.8 0.7 0.6 Ipilimumab + gp100 (A) Ipilimumab alone (B) gp100 alone (C) Proportion Alive 0.5 0.4 0.3 0.2 0.1 0 0 1 2 3 4 Yrs Hodi FS, et al. N Engl J Med. 2010;363:711-723.

  46. Most Common Immune-Related Adverse Events* (Grades 3, 4, and 5) *Across entire study duration. Hodi FS, et al. N Engl J Med. 2010;363:711-723. O’Day S, et al. ASCO 2010. Abstract 4.

  47. Study 024: Design Screening Induction Maintenance* Ipilimumab 10 mg/kg q3w x 4 Ipilimumab 10 mg/kg q12w Previously untreated metastatic Melanoma (N = 502) Dacarbazine 850 mg/m2 q3w x 8 R Placebo q3w x 4 Placebo q12w = blinded randomization (1:1) R Dacarbazine 850 mg/m2 q3w x 8 Wk 1 Wk 12 Wk 24 *In absence of progression or dose-limiting toxicity. Baseline Tumor Assessment First Scheduled Tumor Assessment Robert C, et al. N Engl J Med. 2011;364:2517-2526.

  48. Study 024: Overall Survival 100 CensoredCensored 90 80 70 60 Patients Surviving (%) 50 40 Ipilimumab + dacarbazine 30 20 Placebo + dacarbazine 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 Months Patients at Risk, n Ipilimumab + dacarbazinePlacebo + dacarbazine 250252 230229 199190 181160 157136 131116 11489 10478 9172 8564 7956 7447 6844 6142 5942 5637 5634 5231 4126 3119 1711 107 45 23 00 *3-yr survival was a post hoc analysis. Robert C, et al. N Engl J Med. 2011;364:2517-2526.

  49. Study 024: Tumor Response *HR: 0.76; 95% CI: 0.63-0.93; P = .006 Robert C, et al. N Engl J Med. 2011;364:2517-2526.

  50. Study 024: Duration of Response 100 CensoredCensored 90 80 70 Ipilimumab + dacarbazine 60 50 Patients With CR or PR (%) 40 Placebo + dacarbazine 30 20 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Duration of Response (Mos) Patients at Risk, n Ipilimumab + dacarbazinePlacebo + dacarbazine 3826 3825 3320 3014 2712 2310 229 208 177 86 42 11 11 10 00 Robert C, et al. N Engl J Med. 2011;364:2517-2526.

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