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Efficacy and safety of oral MEK162 in patients with locally advanced and unresectable or metastatic cutaneous melanoma harboring BRAFV600 or NRAS mutations Paolo A. Ascierto,* Carola Berking, Sanjiv S. Agarwala, Dirk Schadendorf, Carla van Herpen, Paola Queirolo, Christian U. Blank, Axel Hauschild, J. Thaddeaus Beck, Angela Zubel, Faiz Niazi, Simon Wandel, Reinhard Dummer *National Cancer Institute, Naples Italy Disclosures • Employment or Leadership Position: None • Advisory Role: Bristol-Meyers Squibb, Merck Sharp & Dohme, Roche-Genentech, Glaxo Smith-Kline, Amgen, Celgene, Medimmune, Novartis • Consultant: Merck Sharp & Dohme • Stock Ownership: None • Honoraria: Bristol-Meyers Squibb, Merck Sharp & Dohme, Roche-Genentech • Research Funding: None • Expert Testimony: None • Other Remuneration: None Advanced melanoma: different approaches according to mutational status BRAFV600E/K c-KIT Q61NRAS NRAS wt BRAF wt Ascierto P, et al. J Transl Med. 2012 May 2;10(1):83 Survival of patients with BRAF- or NRAS-mutant melanoma (n = 313) N Median OS (y) P WT 94 1.3 ------ BRAF with inhibitor 41 NR .02 BRAF without inhibitor 112 0.9 .10 NRAS 66 0.7 .003 Inhibitors: PLX-4032;GSK-2118436;GSK-1120212;AZD-6244 OS for NRAS vs WT NRAS: Candidate as a new prognostic marker for stage IV? Jakob JA , et al., Cancer 2011: epub MEK inhibitors: targeting RAS and BRAF mutations in cancer 70-90% pancreatic cancer RAS 30-40% colon cancer ~30% lung cancer ~20% melanoma MEK162 50-60% melanoma BRAF 36% thyroid cancer 12% ovarian cancer 8- 12% colorectal cancer Frémin C, Meloche S. J Hematol Oncol. 2010;3:8; Pratilis CA, Solit DB. Clin Cancer Research, 2010;16:3329 MEK162 is active against BRAFV600E mutant melanoma cell lines in vitro/in vivo 8 cell lines Mean Tumor Volume Log(10) EC50 (μM) 18 cell lines Effect of MEK162 on the Growth of the A-375 B-RAFV600E Melanoma Model In Vivo SEM (mm3) EC50 of MEK162 in 26 B-RAFV600E Melanoma Cell Lines Time on Treatment (days) MEK162 SEM, standard error of the mean; T/C tumor growth inhibition ratio. MEK162 is active against NRAS mutant melanoma cell lines in vitro/in vivo EC50 of MEK162 in 6 N-RAS Mutant Melanoma Cell Lines Mean Tumor Volume Log(10) EC50 (μM) 4 cell lines SEM (mm3) 2 cell lines Effect of MEK162 on the Growth of the Q61K N-RAS Mutant Melanoma Model In Vivo Time on Treatment (days) MEK162 SEM, standard error of the mean. Open-label phase II study • Primary objective of the study was to estimate the ORRs of MEK162 in patients with BRAFV600 and NRAS-mutant advanced cutaneous melanoma at a dose of 45mg BID • Secondary objectives included PFS, duration of response, safety and tolerability BID, twice daily. Single-agent MEK162 in advanced BRAFor NRAS-mutant melanoma patients Patients with advanced cutaneous melanoma BRAFV600 - mutant n = 41 pts MEK162 45 mg BID AJCC stage IIIB-IV NRAS or BRAF mutation WHO PS 0-2 No prior MEKi therapy Prior BRAF inhibitor permitted Prior therapy permitted *as of 29 Feb 2012. NRAS-mutant n = 30 pts MEK162 45 mg BID Study centers Germany N=19 Essen Kiel Munich The Netherlands N=15 Amsterdam Nijmegen USA N=10 Bethlehem, PA Fayetteville, AR Portland, OR Switzerland N=5 Zurich Italy N=22 Genoa Naples Patient characteristics NRAS* n = 30 BRAF* n = 41 56.0 [15.0] 53.7 [14.6] 66.7/33.3 53.7/46.3 0-1 27 (90.0) 41 (100.0) 2 3 (10.0) 0 (0.0) Stage IV, n (%) 30 (100.0) 39 (95.1) No. pts with prior anticancer therapy, n (%) 23 (76.6) 27 (65.9) BRAF inhibitor 0 (0.0) 7 (17.1) Chemotherapy 16 (53.3) 16 (39.0) Immunotherapy 14 (46.7) 19 (46.3) 2(6.6) 2 (4.9) 9 (30.0) 10 (24.4) Age Mean [SD] Gender Male/Female, % WHO performance status, n (%) Other Radiotherapy (yes) *as of 29 Feb 2012; SD, standard deviation. Note: patients with more than one prior line of therapy are counted more than once. Number of prior antineoplastic therapies NRAS* n =30 BRAF* n =41 Median 1.0 1.0 Min 0.0 0.0 Max 6.0 4.0 0 7 (23.3) 14 (34.1) 1 12 (40.0) 10 (24.4) 2 6 (20.0) 11 (26.8) 3 3 (10.0) 4 (9.8) 4 0 (0.0) 2 (4.9) 5 1 (3.3) 0 (0.0) 6 1 (3.3) 0 (0.0) Number of prior medications n, (%) *as of 29 Feb 2012. Note: patients with more than one prior line of therapy are counted more than once. Best percentage change from baseline and best overall response (NRAS) N=28* 45 mg NRAS Progressive Disease (PD) Stable Disease (SD) Partial Response (PR) Unconfirmed PR *Patients with missing best % change from baseline and unknown overall response are not included. Ongoing pts Best percentage change from baseline and best overall response (BRAF) 45 mg BRAFV600E N=35* Progressive Disease (PD) Stable Disease (SD) Partial Response (PR) Unconfirmed PR Unknown (UNK) SD PD SD UNK PD SD UNK *Patients with missing best % change from baseline and unknown overall response are not included. denotes a missing best % change from baseline. UNK indicates patients not qualifying for confirmed CR or PR and without SD after more than 6 weeks or early progression within the first 12 weeks. Denotes pre-treated with BRAF inhibitor. Clinical activity NRAS* 45 mg BRAF* 45 mg Patients enrolled 30 41 Patients without efficacy assessment (only baseline available) - too early in the study - patient death - discontinuation due to AEs - discontinuation due to withdrawn consent 2 6 2 0 0 0 0 2 35 1 Patients with at least 2 scans (BL and at least one evaluation on treatment) 28 35 Best overall response, n (%)* 28 35 Complete response (CR) 0 0 6 (3 + 31) (21%) 8 (2 + 62) (23%) Stable disease (SD) 13 (46) 13 (37) Progressive disease 9 (32) 12 (34) Unknown3,4 0 (0) 2 (6) Overall respone rate (CR+PR) 6 (21) 8 (23) Disease control rate (CR+PR+SD) 19 (68) 21(60) Total partial responses (PR) (confirmed + unconfirmed) *as of 29 Feb 2012 patient PD, 1 AE and 1 too early; 2 3 patients PD, 3 AE; 3 Unknown resposponse in non-target lesion; 4 Unknown due to target lesions not measured; 5 Femur fracture Gr 3, Gr 3 bilateral pain in hands, Gr3 reduction in performance status. 11 Time to response and duration of response in patients with NRAS- and BRAF-mutant melanoma who achieved confirmed PRs* Mutation Time to response** (weeks) Duration of Response*** (weeks) NRAS 7.6 16.3 NRAS 7.0 7.1 NRAS 8.0 17.3 BRAF 10.7 15.6 BRAF 8.0 16.1 *as of 29.02. 2012. **Time to response was calculated as the time between the first day of treatment until the date of first documented response. ***Duration of response was calculated as the time from the date of first documented response to the date of event/censoring for PFS. PFS – NRAS- /BRAF-mutant 100 NRAS mt PFS (%) 80 Median (months) [95% CI]: 3.65 [2.53, 5.39] Median (days) [95% CI]: 111 [77, 164] BRAF mt Median (months) [95% CI]: 3.55 [2.00, 3.81] Median (days) [95% CI]: 108 [61, 116] 60 40 20 0 0 61 122 Number of patients at risk All 71 43 14 183 Time (days) 2 274 365 0 0 Most frequent adverse events suspected to be MEK162-related BRAFV600* 45 mg n = 41 NRAS* 45mg n = 30 Preferred term All grades n (%) 29 (96.7) Grade 3/4 n (%) 14 (46.7) All grades n (%) 39 (95.1) Grade 3/4 n (%) 18 (43.9) 6 ( 20.0) 18 ( 60.0) 7 (23.3) 5 (16.7) 1 ( 3.3) 1 ( 3.3) 0 (0.0) 0 (0.0) 16 (39.0) 15 (36.6) 2 (4.9) 1 (2.4) 0 (0.0) 3 (7.3) 0 (0.0) 0 (0.0) 10( 33.3) 6 (20.0) 4 (13.3) 1 (3.3) 0 (0.0) 1 (3.3) 14( 34.1) 3 (7.3) 5 (12.2) 1 (2.4) 0 (0.0) 0 (0.0) 8 (26.7) 7 (23.3) 6 (20.0) 2 (6.7) 0 (0.0) 0 (0.0) 15 (36.6) 7 (17.1) 3 ( 7.3) 1 (2.4) 0 (0.0) 0 (0.0) Blood creatine phosphokinase increased 11( 36.7) 7 ( 23.3) 9 ( 22.0) 7 (17.1) Fatigue 4 (13.3) 0 ( 0.0) 10 (24.4) 2 (4.9) Dysgeusia 0 (0.0) 0 ( 0.0) 8 (19.5) 0 (0.0) Total Skin-related Rash Dermatitis acneiform Pruritis Dry skin Fluid retention Edema, peripheral Edema, periorbital Edema, facial Gastrointestinal-related Diarrhea Nausea Vomiting *as of 29 Feb 2012.. There were no treatment related deaths Central serous retinopathy-like events* MEK 162 45 mg BID, n=71 Retinal Events** Grade 1 Grade 2 Grade 3/4 Total Patients, n (%) 7 (10%) 6 (8%) 0 (0%) 13 (18%) ** as of 29 Feb 2012. • Retinal events were reversible without interruption of treatment in the majority of patients *Central serous retinopathy-like retinal events included: retinal detachment, retinal pigment epitheliopathy, retinoschisis, retinal oedema, chorioretinopathy, retinopathy and retinal exudates. Conclusions • MEK162 showed clinical activity in patients with either BRAF- or NRAS-mutant advanced melanoma • Acceptable safety profile at 45 mg BID with manageable side effects • MEK162 is the first targeted therapy to show activity in patients with NRAS-mutant melanoma Acknowledgements • The author would like to thank: – Patients and their families – Investigators, co-investigators and the study teams at each participating center – Unit of Medical Oncology and Innovative Therapies, National Cancer Institute, Naples, Italy • The study was sponsored by Novartis Pharma AG, Basel, Switzerland