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1 "NRAS mutation status in advanced melanoma: how much does this really matter to prognosis and therapy?" John Jakob, MD, PhD Department of Melanoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Current Affiliation: Summa Health Systems/NEOMED, Akron, Ohio. Conflict of Interest Disclosure John Jakob: None Clinical Characteristics and Outcomes Associated with and NRAS Mutations in Metastatic Melanoma Patients (ASCO 2011 Abstract #8500) Michael Davies: -Research Support: AstraZeneca, GlaxoSmithKline, Merck, Roche -Consultant: GlaxoSmithKline Jeffrey Gershenwald -Advisory Board: GlaxoSmithKline Kevin Kim -Advisory board(s): Genetech, Roche -Research Support: AstraZeneca, Genetech, GlaxoSmithKline, Roche 1

2 Metastatic Melanoma: Background Prognostic Markers - LDH - Sites of Metastasis Activating mutations in MAPK signaling pathway genes - (~ 45 %) - NRAS (~ 20 %) Prognostic value of and NRAS status poorly defined - Limited data in stage IV melanoma Central Hypothesis: and NRAS mutation status is associated with clinical characteristics and outcomes in stage IV melanoma. 2

3 Study Design Retrospective analysis of patients tested for mutations at the MD Anderson Cancer Center, 2/07-09/10. CLIA-certified pyrosequencing : Exon 15 NRAS: Codons and Data Collection: At Initial and Stage IV diagnosis Outcomes / Follow up Mutation Analysis Mt % V600E 72 % V600K 23 % V600R/L 4 % Non-V600 2 % Mt % NRAS Q61R 39 % Q61K 24 % Q61L 15 % Q61H/60E 4 % G12/13 18 % 3

4 Associations with Mutations: Initial Diagnosis Associations with Mutations: Stage IV Diagnosis 4

5 Mutation Status: Survival from Stage IV Stage IV, all patients (n = 519) Median N OS (Mos) WT NRAS NRAS vs WT, p = 0.02 OS analysis: Limitations All Stage IV (n = 519) Long-term survivors, bias? OS analysis: Modifications (n = 313) /NRAS w/in 6 mos, Stage IV dx by i / MEKi i / MEKi in? b i / MEKi Uveal excluded 5

6 Mutation Status: Survival from Stage IV /NRAS testing within 6 mos stage IV (n = 313) N Median OS (Mos) WT w/inhibitor 41 NR w/o inhibitor NRAS (Inhibitors: vemurafenib; GSK ; GSK ; selumetinib) NRAS vs WT, p = Median OS N (Mos) HR 95 % CI p value Age (per year) Gender Female Male M1 Category 1 M1a M1b M1c LDH Not Elevated Unknown Elevated Mutation WT w/ inhibitor w/o inhibitor NRAS Elevated < NR

7 Review: Associations with /NRAS (MDACC) Mutation Pattern : Cutaneous > Mucosal (Curtin, NEJM, 2005) /NRAS: Unknown 1 ~ Cutaneous Diagnosis : Younger age (Viros, PLOS, 2008) /NRAS: Brain involvement Stage IV: Survival NRAS OS (vs WT) (Devitt et al., 2011; Si et al. 2011) /NRAS mutation status and modern therapies in clinical practice Unresectable/ metastatic melanoma NRAS +/- c KIT testing : vemurafenib 1,2 (V600E) or ipilimumab 3,4 WT: ipilimumab 3,4 NRAS: ipilimumab 3,4 1. Vemurafenib FDA approval; 2. Chapman NEJM 2011; 3. Ipilimumab, FDA approval; 4. Hodi, NEJM

8 NRAS testing: recommendations 1. testing is the priority. ($$$) 2. NRAS testing (probably) unnecessary if testing reveals mutation. 3. Consider NRAS testing if patient desires additional prognostic information. 4. Current MDACC data only applies to Stage IV disease. Conclusions NRAS mutation status Candidate prognostic marker for stage IV melanoma. No current utility re: ipilimumab decision. 8

9 Acknowledgements Department of Melanoma Medical Oncology Michael Davies, MD PhD Michelle Rohlfs, APN Jessie Richard, APN Gladys Alvarado, MD Patrick Hwu, MD Kevin Kim, MD Agop Bedikian, MD Jade Homsi, MD Wen-Jen Hwu, MD PhD Nicholas Papadopoulos, MD Sapna Patel, MD Scott Woodman, MD PhD Rahat Noor, MD Richard Joseph, MD Department of Statistics Roland Bassett Department of Pathology Alexander Lazar, MD PhD Department of Surgical Oncology Jeffrey Gershenwald, MD Chris Schacherer, PhD Department of Diagnostic Radiology Chaan Ng, MD M.A.D. supported by an ASCO Career Development Award and MD Anderson Physician-Scientist Award MD Anderson Cancer Center Melanoma SPORE References Chapman PB, Hauschild A, Robert C, et. al. N Engl J Med Jun 30;364(26): Curtin JA, Fridlyand J, Kageshita T, et. al. N Engl J Med Nov 17;353(20): Devitt B, Liu W, Salemi R, et. al. Pigment Cell Melanoma Res Aug;24(4): Hocker T, Tsao H. Hum Mutat Jun;28(6): Hodi FS, O'Day SJ, McDermott DF, et al. N Engl J Med Aug 19;363(8): Ipilimumab FDA approval 03/25/2011; Lee JH, Choi JW, Kim YS. Br J Dermatol Apr;164(4): Si L, Kong Y, Xu X Flaherty KT, et. al. Eur J Cancer Jul 23. Viros A, Fridlyand J, Bauer J, et. al. PLoS Med Jun 3;5(6):e120. Vemurafenib FDA approval 08/17/2011; 9

10 Contact Information John Jakob (cell) Does Brain involvement (vs WT) explain NRAS OS (vs WT)? /NRAS testing within 6 mos stage IV, no brain Stage IV (n = 240) Median OS N (Mos) WT w/inhibitor 36 NR w/o inhibitor NRAS NRAS vs WT, p =