The information in this activity is intended for healthcare professionals based outside of the United States. This activity may contain information

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1 The information in this activity is intended for healthcare professionals based outside of the United States. This activity may contain information on products outside the approved indications where you practice.

2 Expert Review: Navigating the Expanding Treatment Landscape for Advanced Melanoma Complete Reference Slide Deck

3 2016 Approach to Melanoma Immunotherapy Checkpoint inhibitors Anti CTLA-4 (ipilimumab) Anti PD-1 (nivolumab, pembrolizumab) Anti PD-1 + anti CTLA-4 (nivolumab + ipilimumab) Intralesional oncolytic immunotherapy T-VEC (talimogene laherparepvec) Targeted Therapy Targeting MAPK Pathway BRAF-mutant melanoma BRAF/MEK combination therapy Dabrafenib/trametinib Vemurafenib/cobimetinib

4 MAPK Pathway As Oncogenic Driver for Melanoma <5% melanomas (mucosal, acral) 20% melanomas (>age) ckit NRAS NF1 Kit inhibitors: Imatinib, nilotinib, dasatinib 40% to 50% melanomas (<age) BRAF BRAF inhibitors: Vemurafenib, dabrafenib, encorafenib MEK MEK inhibitors: Trametinib, cobimetinib, binimetinib ERK ERK inhibitors Oncogenic cell proliferation and survival Xing Y, et al. Cancer. 2010;116(9): Curtin JA, et al. N Engl J Med. 2005;353(20): Curtin JA, et al. J Clin Oncol. 2006;24(26): Van Raamsdonk CD, et al. N Engl J Med. 2010;363(23): Ribas A, et al. J Clin Oncol. 2011;29(suppl): Abstract 8509.

5 New BRAF Inhibitor + MEK Inhibitor Combination

6 COLUMBUS: Study Design and Objectives PART 1 Locally advanced unresectable or metastatic melanoma with BRAF V600 mutation Randomized 1:1:1 N = 577 ENCO 450 mg qd + BINI 45 mg bid (COMBO450) n = 192 ENCO 300 mg qd (ENCO300) n = 194 VEM 960 mg bid n = 191 Untreated or progressed on/after prior first-line immunotherapy BRAF V600E and/or V600K ECOG PS 0-1 Stratified by: AJCC stage ECOG status BRAF mutation status/prior first-line immunotherapy* Primary endpoint: PFS for COMBO450 vs VEM Key secondary endpoint (tested sequentially): PFS for COMBO450 vs ENCO300 Patient-reported outcomes: FACT-M, EORTC QLQ-C30 Key secondary endpoint of overall survival for COMBO450 vs VEM not yet sufficiently mature PART 2 (ongoing): Primary objective is to further evaluate the contribution of BINI to combination therapy by comparing a lower dose of ENCO (300 mg qd) + BINI to single-agent ENCO (300 mg qd) *Prior first-line immunotherapy replaced BRAF mutation status as a stratification factor after protocol amendment; PFS determined based on blinded independent radiology assessment AJCC, American Joint Committee on Cancer; bid, twice daily; COMBO450, ENCO 450 mg qd + BINI 45 mg bid; ECOG PS, Eastern Cooperative Oncology Group performance status; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer s core quality of life questionnaire; FACT-M, Functional Assessment of Cancer Therapy-Melanoma; PFS, progression free survival; qd, once daily; VEM, vemurafenib Dummer R, et al. Presented at: The 13 th International Congress for the Society for Melanoma Research; November 6-9, 2016: Boston, Massachusetts.

7 COLUMBUS Trial: Encorafenib + Binimetinib (COMBO450) Encorafenib (ENCO): ATP-competitive BRAF kinase inhibitor Unique pharmacologic profile 1 Potent inhibition of proliferation in cells with BRAF V600 mutations Highly selective with no significant activity observed against a panel of 100 kinases (IC 50 >900 nm) Dissociation half-life >24 hours leading to sustained target inhibition Binimetinib (BINI): Potent, selective allosteric, ATP-uncompetitive inhibitor of MEK1/2 2 Shorter half-life than other MEK1/2 inhibitors; may provide more rapid resolution of toxicity upon interruption 3 ATP, adenosine triphosphate; IC 50, half-maximal inhibitory concentration 1. Stuart DD, et al. Cancer Res. 2012;72(8 suppl): Ascierto PA, et al. Lancet Oncol. 2013;14(3): Data on File. Array BioPharma Inc. Dummer R, et al. Presented at: The 13 th International Congress for the Society for Melanoma Research; November 6-9, 2016: Boston, Massachusetts.

8 PFS, % PFS, % COLUMBUS: Progression-Free Survival COMBO450 vs VEM (Primary Endpoint) Central Review Median PFS in months (95% CI) COMBO450 VEM 14.9 ( ) 7.3 ( ) HR (95% CI), 0.54 ( ) P< COMBO450 VEM Patients at risk Time, Months COMBO VEM CI, confidence internal; HR, hazard ratio Median PFS in months (95% CI) COMBO450 VEM 14.8 ( ) 7.3 ( ) *Nominal P value HR (95% CI), 0.49 ( ) P<.001* Patients at risk COMBO VEM 191 COMBO450 VEM Local Review Time, Months Dummer R, et al. Presented at: The 13 th International Congress for the Society for Melanoma Research; November 6-9, 2016: Boston, Massachusetts

9 PFS, % PFS, % COLUMBUS: Progression-Free Survival COMBO450 vs ENCO300 Central Review Median PFS in months (95% CI) COMBO450 ENCO ( ) 9.6 ( ) HR (95% CI), 0.75 ( ) P = COMBO450 ENCO Patients at risk Time, Months COMBO ENCO Median PFS in months (95% CI) COMBO450 ENCO Local Review 14.8 ( ) 9.2 ( ) *Nominal P value HR (95% CI), 0.68 ( ) P =.006* 20 COMBO450 0 ENCO Time, Months Patients at risk COMBO ENCO Dummer R, et al. Presented at: The 13 th International Congress for the Society for Melanoma Research; November 6-9, 2016: Boston, Massachusetts.

10 COLUMBUS: Progression-Free Survival in Patient Subgroups Central Review Subgroup Event/n HR (95% CI) <ULN 126/ ( ) LDH ULN 78/ ( ) COMBO450 vs VEM AJCC stage IIIB, IIIC, IVM1a,b IVM1c 79/ / ( ) 0.48 ( ) Prior ipilimumab, anti-pd-1 or anti-pd-l1 Yes No 9/15 195/ ( ) 0.59 ( ) LDH <ULN ULN 114/284 80/ ( ) 0.94 ( ) COMBO450 vs ENCO300 AJCC stage IIIB, IIIC, IVM1a,b IVM1c 73/ / ( ) 0.68 ( ) Prior ipilimumab, anti-pd-1 or anti-pd-l1 Yes No 10/19 184/ ( ) 0.81 ( ) LDH, lactate dehydrogenase; ULN, upper limit of normal HR Favors Favors COMBO450 monotherapy Dummer R, et al. Presented at: The 13 th International Congress for the Society for Melanoma Research; November 6-9, 2016: Boston, Massachusetts.

11 PFS, % PFS, % ENCO300 VEM COLUMBUS: Progression-Free Survival ENCO300 vs VEM Central Review Patients at risk Time, Months ENCO VEM Median PFS in months (95% CI) ENCO300 Median PFS in months (95% CI) ENCO300 VEM 9.6 ( ) 7.3 ( ) HR (95% CI), 0.68 ( ) P =.007* *Nominal P value VEM 9.2 ( ) 7.3 ( ) HR (95% CI), 0.70 ( ) P =.008* 100 Local Review ENCO300 0 VEM Patients at risk Time, Months ENCO VEM Dummer R, et al. Presented at: The 13 th International Congress for the Society for Melanoma Research; November 6-9, 2016: Boston, Massachusetts.

12 COLUMBUS: Confirmed Response Rates Confirmed Response Central Review COMBO450 n = 192 Local Review Central Review ENCO300 n = 194 Local Review Central Review VEM n = 191 Local Review ORR (95% CI),* % 63 (56-70) 75 (68-81) 51 (43-58) 58 (50-65) 40 (33-48) 49 (42-57) CR, % PR, % Median DOR (95% CI), months 16.6 ( ) 16.2 ( ) 14.9 (11.0-NE) 14.8 (11.0-NE) 12.5 ( ) 8.4 ( ) SD, % PD, % DCR (95% CI), % 92 (87-96) 93 (89-96) 84 (78-89) 87 (81-91) 82 (75-87) 84 (78-89) *ORR = CR + PR. Includes patients with only nontarget lesions with best response of noncr/nonpd. Includes patients with best response of unknown or no assessment. DCR = CR + PR + SD CR, complete response; DCR, disease control rate; DOR, duration of response; NE, not evaluable; ORR, overall response rate; PR, partial response; SD, stable disease Dummer R, et al. Presented at: The 13 th International Congress for the Society for Melanoma Research; November 6-9, 2016: Boston, Massachusetts.

13 COLUMBUS: Overall Summary of Safety Event, % COMBO450 n = 192 Median DoE: 51 weeks ENCO300 n=192 Median DoE: 31 weeks VEM n = 186 Median DoE: 27 weeks Adverse events (AEs) 98 >99 >99 Grade 3/4 AEs AEs leading to discontinuation AEs requiring dose modification* On-treatment deaths *Dose interruption and/or change. Includes on-treatment deaths and deaths within 30 days of stopping study treatment COMBO450 most common AEs (occurring in at least 5 [3%] patients) Adverse events leading to discontinuation: ALT increased (3%), AST increased (3%) Adverse events requiring dose modification: Nausea (8%), vomiting (7%), ejection fraction decreased (5%), GGT increased (5%), pyrexia (4%), ALT increased (4%), diarrhea (4%), AST increased (3%), blood creatine phosphokinase increased (3%), abdominal pain (3%) On-treatment death: Malignant melanoma (5%) ALT, alanine aminotransferase; AST, aspartate aminotransferase; DoE, duration of exposure; GGT, gamma-glutamyltransferase Dummer R, et al. Presented at: The 13 th International Congress for the Society for Melanoma Research; November 6-9, 2016: Boston, Massachusetts.

14 COLUMBUS: Selected AEs of Interest COMBO450 n = 192 Median DoE: 51 weeks ENCO300 n = 192 Median DoE: 31 weeks VEM n = 186 Median DoE: 27 weeks Event, % Any Grade Grade 3/4 Any Grade Grade 3/4 Any Grade Grade 3/4 Rash Dermatitis acneiform Photosensitivity Secondary non-melanoma skin neoplasms Skin papilloma Retinal pigment epithelial detachment Left ventricular dysfunction* Transaminases increased** Blood bilirubin increased Pyrexia *Includes ejection fraction decreased, cardiac failure, left ventricular dysfunction, and left ventricular failure. **Includes alanine aminotransferase increased, aspartate aminotransferase increased, and transaminases increased. Includes rash, rash generalized, rash erythematous, rash maculo-papular, dermatitis, rash follicular, rash macular, rash papular, rash pruritic, generalized erythema, rash vesicular, dermatitis psoriasiform, and rash pustular. Includes photosensitivity reaction and solar dermatitis. Includes chorioretinopathy, detachment of macular retinal pigment epithelium, detachment of retinal pigment epithelium, retinal detachment, and subretinal fluid. Includes basal cell carcinoma, Bowen's disease, keratoacanthoma, lip squamous cell carcinoma, neoplasm skin, squamous cell carcinoma, and squamous cell carcinoma of skin. Adapted from Dummer R, et al. Presented at: The 13 th International Congress for the Society for Melanoma Research; November 6-9, 2016: Boston, Massachusetts.

15 Probability, % Probability, % COLUMBUS: Maintenance of Quality of Life (QoL)* 100 FACT-Melanoma Scale Score COMBO450 ENCO300 VEM EORTC QLQ-C30 Global Health Status/QoL Scale Score 100 COMBO450 ENCO300 VEM HR (95% CI) COMBO450 vs VEM: 0.46 ( ) COMBO450 vs ENCO300: 0.48 ( ) 20 0 HR (95% CI) COMBO450 vs VEM: 0.55 ( ) COMBO450 vs ENCO300: 0.45 ( ) Time, Months Time, Months EORTC QLQ-C30 subscale scores showed a similar pattern *As measured by time to definitive 10% deterioration in score, defined as the time from the date of randomization to the date of at least 10% (relative to baseline) worsening of the corresponding scale score with no later improvement above this threshold observed while on treatment or death due to any cause. Dummer R, et al. Presented at: The 13 th International Congress for the Society for Melanoma Research; November 6-9, 2016: Boston, Massachusetts.

16 Efficacy of Targeted Combination Therapy in Phase III Clinical Trials a BRAF/MEK combination vs BRAF monotherapy Patients, n CR + PR, % Median PFS, Months Median OS, Months Median DOR, Months Approval Status Vemurafenib + cobimetinib vs vemurafenib 1 Treatment-naïve BRAF + (n = 495) 70 vs 50 P< vs 7.2 HR 0.58 P< vs 17.4 HR 0.70 P = vs 9.2 A Dabrafenib + trametinib vs dabrafenib 2 Dabrafenib + trametinib vs vemurafenib 3 Treatment-naïve BRAF + (n = 423) Treatment-naïve BRAF + (n = 704) 69 vs 53 P = vs 51 P< vs 8.8 HR 0.67 P = vs 7.3 HR 0.56 P< vs 18.7 HR 0.71 P =.0107 NR vs 17.2 HR 0.69 P = vs vs 7.5 A Encorafenib + binimetinib vs encorafenib vs vemurafenib 4c Treatment-naïve or previously treated b BRAF + 63 vs 51 vs vs 9.6 vs 7.3 HR 0.75 and 0.54 P =.051 and <.001 Not yet Reported 16.2 vs 14.8 vs 8.4 a Trials are not meant to be compared they may have had different entry criteria/patient selection, outcome statistical analyses, locations, and potentially SOC/alternative options at the time of trial and after progression. b Patients with untreated or progressed on/after prior first-line immunotherapy. c Results reported according to central review NA Encorafenib + binimetinib combination represents a potential new treatment option for patients with BRAF-mutant melanoma with a favorable efficacy and safety profile 4 OS, overall survival 1. Ascierto PA, et al. Lancet Oncol. 2016;17: Long GV, et al. Lancet. 2015;386(9992): Robert C, et al. N Engl J Med. 2015;372(1):30-39; 4. Dummer R, et al. Presented at: The 13 th International Congress for the Society for Melanoma Research; November 6-9, 2016: Boston, Massachusetts.

17 Treatment Selection in Metastatic BRAF-Mutant Melanoma

18 Which is the Best First Approach in BRAF-Mutant Melanoma? We have no head-to-head comparative trial data available which treatment select first Currently treatment decision is based on patient s / disease characteristics BRAF+ melanoma Normal LDH, low tumor burden asymptomatic Elevated LDH, brain metastases, high tumor burden symptomatic disease Immunotherapy or targeted therapy Targeted therapy first is preferred Modified from: Jang S, et al. Lancet Oncol. 2013;14:60-69.

19 Five Baseline Factors Influenced Overall Survival Long G, at al. Presented at: The 12 th International Congress for the Society for Melanoma Research; November 18-21, 2015: San Francisco, California.

20 Ongoing Clinical Trials Are Evaluating Best Sequential Approach With Combination Immunotherapy and Combination Targeted Therapy SECOMBIT Trial SECOMBIT Trial. Available at: Accessed: November 10, ECOG-ACRIN EA Available at: Accessed November 10, 2016.

21 Molecular Testing is Essential for Treatment Decision Making Driver Oncogenes in Melanoma Standard of care today: BRAF mutation testing from the first available metastases (typically stage III with lymph node metastases) If BRAF is negative, NRAS testing is recommended Multiple genetic alterations tests are also available Melanoma array under development Garbe C, et al. Eur J Canc. 2016;63:

22 Genomic Classification of Cutaneous Melanoma The Cancer Genome Atlas Network. Cell. 2015;161(7):

23 Future: Biomarkers From Plasma DNA Testing Cell-free DNA (cfdna) is released from healthy, inflamed, or cancerous tissue undergoing apoptosis or necrosis Circulating tumor (ctdna) is only a small fraction of cfdna in blood The amount of ctdna is related to the tumor burden and varies between patients with different clinical presentations Evidence for blood-based mutation testing in EGFR-mutant lung adenocarcinoma Studies in melanoma ongoing Crowley E, et al. Nat Rev Clin Oncol. 2013;10(8):

24 Combination of Targeted Therapy + Immunotherapy

25 Percent Alive Percent Alive Percent Alive Combining Targeted Therapy With Immunotherapy Current treatment options for BRAF V600 -mutated melanoma include: BRAF alone or BRAF/MEK inhibitors rapid clinically significant responses usually with limited durability Immunotherapy less frequent objective responses but clinically significant durability Immunotherapy Targeted Therapy Combination? + = Years Years Years Hypothesis: Combining anti PD-L1 with BRAF and MEK inhibitors may result in higher frequency of long-lasting responses in patients with advanced BRAF V600 -mutated melanoma Ribas A, et al. J Clin Oncol. 2015;33(suppl): Abstract 3003.

26 BRAF/MEK Inhibition Modulates the Immune Microenvironment CD8+ TILs 1,2 Melanoma antigen expression 1 Antitumor activity of combined BRAFi+MEKi plus anti-pd-1 3 MHC and melanoma antigen expression 3 1. Frederick DT, et al. Clin Cancer Res. 2013;19(5): Wilmott JS, et al. Clin Cancer Res. 2011;18(5): Hu-Lieskovan S, et al. Sci Transl Med. 2015;7(279):279ra41. Ribas A, et al. J Clin Oncol. 2015;33(suppl): Abstract 3003.

27 Phase Ib: Atezolizumab + Cobimetinib + Vemurafenib (NCT ) Study of atezolizumab + vemurafenib or atezolizumab + cobimetinib + vemurafenib in previously untreated patients with BRAF V600 -mutant metastatic melanoma During the dose escalation phase, atezo + vem regimen demonstrated good tolerability and promising efficacy 1,2 Expansion cohort with atezo + cobi + vem regimen was initiated and is ongoing Additional expansion cohort in anti PD-1 antibody treatment failure Key Eligibility Criteria BRAF V600 mutation-positive stage IIIC unresectable or metastatic melanoma Histologic or cytologic assessment of melanoma Confirmation of BRAF V600 mutation ECOG PS 0 or 1 Measurable disease per RECIST v1.1 Previously untreated with BRAF inhibitor or immunotherapy Study Objectives Primary: Safety and tolerability of atezo + cobi + vem combination treatment Secondary: Efficacy - Best overall response (BoR), objective response (CR/PR), DOR, PFS, OS Exploratory - PD-L1 as a predictive biomarker of antitumor activity of triple combination treatment Atezo, atezolizumab; cobi, cobimetinib; RECIST, Response Evaluation Criteria in Solid Tumors 1. Hamid O, et al. Presented at: The 12 th International Congress for the Society for Melanoma Research; November 18-21, 2015: San Francisco, California. 2. Sullivan R, et al. Presented at: Society for Immunotherapy of Cancer Melanoma Bridge 2015; December 1-5, 2015: Naples, Italy. Sullivan R, et al. Presented at: The 13 th International Congress for the Society for Melanoma Research; November 6-9, 2016: Boston, Massachusetts.

28 Phase Ib: Atezolizumab + Cobimetinib + Vemurafenib: Expansion Cohort Study Design Screening Vem + Cobi Days 1-21: Cobi 60 mg, Vem 960 mg Days 22-28: Vem 720 mg Atezo + Vem + Cobi Atezo 800 mg, Cobi 60 mg, Vem 720 mg Up to 28 days Cobi (PO qd, 21/7) 28 days C1 C2+ Vem (PO bid) Atezo (IV q 2 w) During the dose-escalation phase, a run-in period with vem before administration of atezo provided an ameliorative effect for safety while showing promising activity 1,2 A 28-day run-in provided good tolerability and was short enough to harness the immune modulatory effect of BRAF + MEK inhibitors 1-4 Therefore, a 28-day cobi + vem doublet treatment phase was completed prior to administration of atezo to the expansion cohort 1. Hamid O, et al. Presented at: The 12 th International Congress for the Society for Melanoma Research; November 18-21, 2015: San Francisco, California. 2. Sullivan R, et al. Melanoma Bridge Frederick DT, et al. Clin Cancer Res. 2013;19(5): Zhu Z, et al. Crit Rev Oncol Hematol. 2016;99: Sullivan R, et al. Presented at: The 13 th International Congress for the Society for Melanoma Research; November 6-9, 2016: Boston, Massachusetts.

29 Atezolizumab + Cobimetinib + Vemurafenib: Response to Triple Combination Best Objective Response (RECIST v1.1) N = 29 n (%) 95% CI ORR a 24 (83) 64.2, 94.2 CR 3 (10) 2.2, 27.4 PR 21 (72) 52.8, 87.3 SD 3 (10) 2.2, 27.4 PD 1 (3) 0.1, 17.8 NE b 1 (3) -- a Unconfirmed ORR. 15 responses were confirmed as of data cutoff on June 15, 2016 b Patients were classified as not evaluable (NE) due to unavailability of any postbaseline response assessments or nonevaluability of all postbaseline assessments Patients who received 1 dose of atezolizumab and received the first dose before May 4, 2016 to allow for 1 on-treatment, postbaseline assessment were evaluated for efficacy Sullivan R, et al. Presented at: The 13 th International Congress for the Society for Melanoma Research; November 6-9, 2016: Boston, Massachusetts.

30 Safety of Triple Combination N = 30 Median safety follow-up, months (range) 3.9 months ( ) Treatment-emergent AEs during combination period, N (%) All grade atezo- and/or cobi- and/or vem-related AEs 30 (100) Grade 3-4 atezo- and/or cobi- and/or vem-related AEs 12 (40) Grade 3-4 atezo-related AEs 8(27) Treatment-related SAEs 3(10) All treatment discontinuations* 2(7) The triple combination treatment was generally well tolerated; no unexpected AEs occurred No grade 5 AEs occurred All AEs were manageable and reversible with dose interruption and/or reduction Treatment-related SAEs: Grade 3 blood creatinine phosphokinase levels increased (cobi-related) Grade 4 sepsis (cobi- and/or vem-related) Grade 3 diarrhea and ALT/AST levels increased (atezo- and/or cobi- and/or vem-related) All 3 patients continued on study treatments after interruption SAE, serious adverse event; Patients who received 1 dose of atezolizumab were evaluated for safety. Data cutoff June 15, *Due to elevated ALT/AST. Sullivan R, et al. Presented at: The 13 th International Congress for the Society for Melanoma Research; November 6-9, 2016: Boston, Massachusetts.

31 TRILOGY: A Phase III Study of Atezo + Cobi + Vem in BRAF V600 -Mutant Melanoma A phase III study evaluating atezo + cobi + vem vs placebo + cobi + vem in patients with BRAF V600 -mutant advanced melanoma is planned Previously Untreated Advanced Melanoma Vem 960 mg bid a Cobi 60 mg qd b Atezo 840 mg q 2 w Vem 720 mg bid + Vem placebo 240 mg bid Cobi 60 mg qd b BRAF V600 mutation ECOG PS 0-1 Measurable disease No significant history of liver disease N = 500 R 28 Days Treatment until PD or toxicity Vem 960 mg bid a Cobi 60 mg qd b Placebo q 2 w Vem 960 mg bid Cobi 60 mg qd b Key study objectives Primary: Investigator-assessed PFS Secondary: PFS (IRF-assessed), OS, ORR, DOR, safety, and PK a Vemurafenib dose will decrease to 720 mg bid + placebo 240 mg bid beginning day 22 of vem + cobi doublet treatment phase. b Cobimetinib administered on 21 days on/7 days off schedule. IRF, independent review facility; PK, pharmacokinetics Sullivan R, et al. Presented at: The 13 th International Congress for the Society for Melanoma Research; November 6-9, 2016: Boston, Massachusetts.

32 Change From Baseline, % KEYNOTE-022 Phase 1 Study: Pembrolizumab + Dabrafenib/Trametinib in BRAF-Mutant Advanced Melanoma Dabrafenib 150 mg bid Trametinib 2 mg qd Pembrolizumab 2 mg/kg q 3 w 9 objective responses, 5 of which were confirmed Median (range) time to response: 84 (82-92) days Manageable toxicity profile Week // 105 Longitudinal Change From Baseline in Tumor Size a Maximum Percentage Change From Baseline in Tumor Size b Time, weeks a Assessed in all patients who received 1 dose of study treatment (n = 13). Data cutoff date: January 8, Ribas A, et al. J Clin Oncol. 2016;34(suppl): Abstract 3014.

33 Phase 1 Study Durvalumab (MEDI3746) + Dabrafenib ± Trametinib: Study Design and Population Cohort A Cohort B Cohort C BRAF mutation positive BRAF wildtype BRAF wildtype 12-month treatment period MEDI or 10 mg/kg q 2 w Dabrafenib 180 mg bid Trametinib 2 mg qd 12-month treatment period MEDI or 10 mg/kg q 2 w Trametinib 2 mg qd Until PD* Until PD* 12-month treatment period MEDI mg/kg q 2 w 6-week Trametinib 2 mg qd *MEDI4736 can be reintroduced upon PD for up to 12 months Follow-up Follow-up Follow-up Key inclusion criteria Stage IIIC/IV melanoma BRAF mutation status Cohort A confirmed BRAF V600E/K mutation positive Cohort B and C confirmed BRAF V600E/K mutation negative ECOG PS 0-1 Adequate organ and marrow function Prior immunotherapy permitted anti CTLA-4 anti PD-L1/anti PD-L1 Measurable disease required Key exclusion criteria Active or prior autoimmune disease Prior BRAF or MEK inhibitor therapy Prior severe or persistent irae irae, immune-related adverse event Ribas A, et al. J Clin Oncol. 2015;33(suppl): Abstract 3003.

34 Durvalumab + Dabrafenib ± Trametinib: Clinical Activity Cohort A (n = 26) Cohort B (n = 19) Cohort C* (n = 15) Clinical Activity D + T + M T + M T M (Sequential) ORR, n (%) 18 (69) 4 (21) 2 a (13) DCR (CR + PR + SD), n (%) 26 (100) 15 (79) 12 (80) SD 12 weeks, n (%) b 4 (15) 10 (53) 6 (40) Ongoing responders, n/n (%) 16/18 (89%) 4/4 (100%) 1/2 (50%) Range of duration of ongoing response, weeks c 7.7+ to to Median duration of response has not yet been reached for cohorts A and B *Shorter follow up in cohort C, with 5 additional patients ongoing with best response of unconfirmed PR D, dabrafenib; M, durvalumab/medi4736; T, trametinib a Responses based on the principles of immune-related RECIST; the two patients in Cohort C had unconventional confirmed PRs; b Includes subjects with unconfirmed PR or SD as the best overall response. c Duration of response is calculated for subjects with confirmed responses Data cut-off: May 8, 2015 Ribas A, et al. J Clin Oncol. 2015;33(suppl): Abstract 3003.

35 AE Preferred Term, n (%) Durvalumab + Dabrafenib ± Trametinib Selected Drug-Related AEs of Interest Cohort A (n = 26) Cohort B (n =20) Cohort C (n = 19) D + T + M T + M T M (Sequential) All Grades Grade 3 All Grades Grade 3 All Grades Grade 3 Pneumonitis 0 (0) 0 (0) 0 (0) 0 (0) 1 (5) 0 (0) Colitis 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Hypothyroidism 1 (4) 0 (0) 2 (10) 0 (0) 0 (0) 0 (0) Hyperthyroidism 1 (4) 0 (0) 0 (0) 0 (0) 1 (5) 0 (0) Hepatic events AST increased 5 (19) 2 (8) 1 (5) 0 (0) 2 (11) 0 (0) ALT increased 5 (19) 1 (4) 1 (5) 0 (0) 1 (5) 0 (0) Blood bilirubin increased 1 (4) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Liver function test abnormal 0 (0) 0 (0) 1 (5) 1 (5) 0 (0) 0 (0) Tubulointerstitial nephritis 1 (4) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Cardiac events Ejection fraction decreased 1 (4) 1 (4) 1 (5) 1 (5) 0 (0) 0 (0) Hypertension 0 (0) 0 (0) 2 (10) 2 (10) 1 (5) 1 (5) Ocular toxicities Retinal vein occlusion 0 (0) 0 (0) 1 (5) 0 (0) 0 (0) 0 (0) Detachment of retinal pigment epithelium 1 (4) 0 (0) 1 (5) 0 (0) 0 (0) 0 (0) Vision blurred 2 (8) 0 (0) 2 (10) 0 (0) 0 (0) 0 (0) Cutaneous squamous cell carcinoma 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Hyperkeratosis 1 (4) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) As-treated population. Data cut-off: May 7, 2015 Ribas A, et al. J Clin Oncol. 2015;33(suppl): Abstract 3003.

36 Immune Activation Posttreatment Evidence of immune activation is observed post-treatment in all cohorts Frequency of tumor-infiltrating CD8 T cells increases post-treatment Levels of interferon gamma and other Th1- associated factors in plasma are increased post-treatment More dramatic and consistent changes are observed in Cohort A versus Cohorts B and C Ribas A, et al. J Clin Oncol. 2015;33(suppl): Abstract 3003.

37 Treatment-Related Adverse Events: Immunotherapy-Related AEs and Class-Dependent AEs of Targeted Therapy

38 Immunotherapy: Unique Immune-Related Adverse Effects Early recognition and early treatment (steroids!) is essential Education of patients and nurses is important Chapimat S, et al. Ann Oncol. 2016;27(4):

39 Class-dependent Targeted Therapy Side Effects Toxicity of BRAF inhibitors: Dermatologic complications (rash, photosensitivity reactions, hyperkeratosis), keratoacanthomas/squamous cell carcinoma, arthralgia, fatigue, alopecia, nausea, diarrhea, ocular toxicity (including uveitis, conjunctivitis, dry eyes), and pyrexia Toxicity of MEK inhibitors: Cutaneous toxicity, diarrhea, edema, CK elevation, less common decreased cardiac ejection fraction, and ocular toxicity The combined BRAF and MEK inhibition minimized the dermatologic toxicity associated with BRAF inhibitors (eg, keratoacanthomas) Dabrafenib+trametinib (more pyrexia); vemurafenib+cobimetinib (more photosensitivity) CK, creatine kinase Chapman PB, et al. N Engl J Med. 2011;364(26): Hauschiled A, et al. Lancet. 2012;380(9839): Larkin J, et al. N Engl J Med. 2014;371(20): Long GV, et al. Lancet. 2015;386(9992): Robert C, et al. N Engl J Med. 2015;372(1):30-39.

40 Any Grade, Grade 3/4, % cobrim 1 Combi-d 2 Combi-v 3 BRAF Inhibitor: Vemurafenib Vemurafenib Dabrafenib Dabrafenib Dabrafenib Vemurafenib MEK Inhibitor: Cobimetinib Placebo Trametinib Placebo Trametinib Placebo Alopecia 14, <1 29, <1 5, 0 26, 0 6, 0 39, <1 Arthralgia 33, 2 40, 5 16, <1 23, 0 24, 1 51, 4 Cutaneous squamous cell carcinoma 3, 2 11, 11 3, 3 9, 9 1, 1 18, 17 Diarrhea 57, 6 28, 0 18, <1 9, 1 32, 1 38, <1 Ejection fraction decrease Most Common Targeted Therapy Adverse Events 8, 1 3, 1 4, 1 3, 2 8, 4 0, 0 Fatigue 32, 4 31, 3 27, 2 28, <1 29, NR 33, NR Increased alanine aminotransferase 24, 11 18, 6 10, 2 3, 0 NRep NRep Photosensitivity 28, 2 15, 0 NR NR 4, 0 22, <1 Pruritus NR NR 7, 0 11, 0 NR NR Pyrexia 26, 2 22, 0 52, 7 25, 2 53, 4 21, 1 Rash 39, 6 36, 5 24, 0 20, <1 22, 1 43, 9 Patient education is important! 1. Larkin J, et al. N Engl J Med. 2014;371(20): Long GV, et al. Lancet. 2015;386(9992): Robert C, et al. N Engl J Med. 2015;372(1):30-39.

41 Feasibility of Combining Immunotherapy With Targeted Therapy Concurrent administration of vemurafenib and ipilimumab may not be feasible 1 Increased incidence of hepatotoxicity observed in a phase I safety study Toxicity may preclude adequate dosing Concurrent administration of dabrafenib/trametinib and ipilimumab is not feasible Phase I data show that combinations of dabrafenib + ipilimumab with or without trametinib are not associated with hepatotoxicity 2 The triple combination of ipilimumab/dabrafenib/trametinib is not feasible due to the increase of gastrointestinal toxicity (bowel perforation) 3 Combination of anti PD-1/anti PD-L1 with targeted therapy is feasible with no reported unexpected toxicity 4,5,6 1.Ribas A, et al. N Engl J Med 2013;368: ; 2. Puzanov I, et al. J Clin Oncol 2014;32(suppl 5s): abstract 2511; 3. Minor DR, et al. Pigment Cell Melanoma Res ; ; 4.Sullivan R, et al. Presented at: The 13 th International Congress for the Society for Melanoma Research; November 6-9, 2016: Boston, Massachusetts; 5. Ribas A, et al. J Clin Oncol. 2016;34(suppl): Abstract 3014; 6. Ribas A, et al. J Clin Oncol. 2015;33(suppl): Abstract 3003.

42 NRAS- and NF1-Mutated Metastatic Melanoma

43 NRAS Mutations in Melanoma NRAS mutations present in ~20% of patients with metastatic melanoma 1,2 May constitutively activate the MAPK pathway, driving cell proliferation and inhibiting apoptosis 2-4 Preclinical studies: NRAS-mutant melanoma is sensitive to MEK inhibition 5,6 NRAS-mutant melanoma more aggressive subtype, less favorable prognosis 1 Substantial unmet clinical need, particularly after failure of immunotherapy 1. Jakob JA, et al. Cancer. 2012;118(16): Krauthammer M, et al. Nat Genet. 2015;47(9): Johnson, et al. Curr Treat Options Oncol. 2015;16(4): Richman J, et al. Expert Opin Pharmacother. 2015;16(9): Solit DB, et al. Nature. 2006;439(7074): Lee PA, et al. Cancer Res. 2010;70(8 Suppl): Abstract Dummer R, et al. J Clin Oncol. 2016; 34(suppl): Abstract 9500.

44 Survival of Patients With BRAF- or NRAS-Mutant Melanoma N mos, months P WT NRAS P =.004 BRAF with inhibitor 41 NR P =.0145 BRAF without inhibitor P =.10 WT, wildtype Jakob JA, et al., Cancer. 2012;118(6):

45 Efficacy of First-Line Immune-Based Therapy for NRAS-Mutant and Non NRAS-Mutant Melanoma PFS (BRAF-mutant and WT) OS (BRAF-mutant and WT) Best response to any line of therapy NRAS- Mutant BRAF- Mutant WT P Value a n = 60 n = 53 n = 116 CR/PR 19 (32%) 12 (23%) 22 (19%) SD/PD 41 (68%) 41 (77%) 94 (81%) CR/PR/SD 30 (50%) 16 (30%) 34 (29%) PD 30 (50%) 16 (30%) 34 (29%) Response to first-line immune therapy Response to Immunotherapy n = 60 n = 53 n = 116 CR/PR 17 (28%) 8 (15%) 19 (16%) SD/PD 43 (72%) 45 (85%) 97 (84%) CR/PR/SD 27 (45%) 13 (25%) 31 (27%) PD 33 (55)% 40 (75%) 85 (73%) Johnson D, et al. Cancer Immunol Res. 2015;3:

46 MEK Inhibitor Binimetinib Oral, selective, ATPuncompetitive inhibitor of MEK1 and MEK2 1 Inhibits in vitro growth of tumors with driver mutations in NRAS genes 1 Phase II study demonstrated clinical activity of binimetinib in NRAS-mutant metastatic melanoma 2 15% confirmed response rate 3 Growth factor receptor Growth factor RAS Binimetinib RAF Activating NRAS mutations (~20%) MEK ERK Growth, proliferation, and survival 1. Lee PA, et al. Cancer Res. 2010;70(8 Suppl): Abstract Ascierto PA, et al. Lancet Oncol. 2013;14(3): van Herpen CM, et al. Ann Oncol. 2014;25(Suppl 4): Abstract LBA35. Dummer R, et al. J Clin Oncol. 2016; 34(suppl): Abstract 9500.

47 Phase III NEMO Trial: Study Design Patients with unresectable or metastatic cutaneous or unknown primary NRAS-mutant melanoma Randomized 2:1 (N = 402) Binimetinib 45 mg PO bid (n = 269) Dacarbazine 1000 mg/m 2 IV every 3 weeks (n = 133)* Previously untreated or who had progressed on/after immunotherapy ECOG PS 0-1 NRAS Q61 mutation Stable brain metastases allowed Stratified by AJCC stage ECOG status Prior immunotherapy Endpoints Primary: PFS per blinded independent central review Key secondary: OS Other secondary: ORR, DCR ClinicalTrials.gov, NCT ; EudraCT, *19 patients not treated; Prior immunotherapy for unresectable/metastatic disease IV, intravenous; PO, by mouth Dummer R, et al. J Clin Oncol. 2016; 34(suppl): Abstract 9500.

48 Progression-Free Survival, % NEMO: Progression-Free Survival Binimetinib significantly improves progression-free survival Time, Months Censoring times Binimetinib (n/n = 179/269) Dacarbazine (n/n = 88/133) Hazard ratio: 0.62 (95% CI, ; P<.001) PFS Binimetinib Dacarbazine Median (95% CI), mo 2.8 ( ) 1.5 ( ) Number still at risk Months Binimetinib Dacarbazine Stratified log-rank test and stratified Cox model using strata defined by AJCC stage, prior line immunotherapy, and ECOG performance status Dummer R, et al. J Clin Oncol. 2016; 34(suppl): Abstract 9500.

49 Progression-Free Survival, % NEMO: Progression-Free Survival By Prior Immunotherapy Stratum Stratum: Prior Immunotherapy Stratum: No Prior Immunotherapy Kaplan-Meier medians, months Binimetinib: 5.5 (95% CI, ) Dacarbazine: 1.6 (95% CI, ) Censoring times Binimetinib (n/n = 32/57) Dacarbazine (n/n = 20/28) Progression-Free Survival, % 100 Kaplan-Meier medians, months Binimetinib: 2.8 (95% CI, ) Dacarbazine: 1.5 (95% CI, ) Censoring times Binimetinib (n/n = 147/212) Dacarbazine (n/n = 68/105) Number still at risk Months BINI DTIC DTIC, dacarbazine Time, Months Hazard ratio: 0.5 (95% CI, ) Dummer R, et al. J Clin Oncol. 2016; 34(suppl): Abstract Number still at risk Time, Months Hazard ratio: 0.7 (95% CI, ) The safety profile was consistent with other currently marketed MEK inhibitors. 0 0

50 Safety: All-Cause AEs and Grade 3/4 AEs Preferred Term, % Binimetinib (n = 269) Dacarbazine (n = 114) All Grades* Grade 3/4 All Grades* Grade 3/4 Total Skin-related Rash Dermatitis acneiform Gastrointestinal Diarrhea Nausea Vomiting Muscle-related Blood CPK increased Other Peripheral edema 36 <1 3 0 Fatigue Asthenia *>15% of patients in any treatment group; >2.0% of patients in any treatment group CPK, creatine phosphokinase Dummer R, et al. J Clin Oncol. 2016; 34(suppl): Abstract 9500.

51 Safety: All-Cause AEs and Grade 3/4 AEs (Cont d.) Preferred Term, % Binimetinib (n = 269) Dacarbazine (n = 114) All Grades* Grade 3/4 All Grades* Grade 3/4 Other (cont d) Hypertension AST increased Decreased appetite Ejection fraction decreased ALT increased General physical health deterioration Anemia GGT increased Lymphopenia Neutropenia Thrombocytopenia 1 < Neutrophil count decreased < Leukopenia *>15% of patients in any treatment group; >2.0% of patients in any treatment group Dummer R, et al. J Clin Oncol. 2016; 34(suppl): Abstract 9500.

52 Mean # of Mutations Mean Age of Onset NF1-Mutated Melanoma NF1 gene is the third most frequently mutated driver gene in melanoma (12%); occurred in older patients Inactivating NF1 mutations do not necessarily lead to full RAS activation NF1 melanomas have increased mutation burden and concurrent MAPK pathway mutations (RASopathy genes) NF1 mutations are insufficient for full MAPK activation and need concurrent mutations in the MAPK pathway Treatment: Immunotherapy first-line, MEK inhibitor BRAF NF1 50 Combination of immunotherapy plus MEK inhibitor promising: Response of 45% in patients with nonocular BRAF-mutant and wildtype metastatic melanoma Krauthammer M, et al. Nat Gen. 2015;47(9): Infante J, et al. Presented at: The 13 th International Congress for the Society for Melanoma Research; November 6-9, 2016: Boston, Massachusetts.

53 MAPK-targeted therapy and immunotherapy with immune checkpoint inhibitors are both important treatment strategies for advanced BRAF-mutant melanoma Combination of BRAF/MEK inhibitors is better than BRAF inhibitor alone Anti PD-1 beats anti CTLA-4 therapy; combinations are better than single agent Deciding which treatment approach to use first is currently based on patient s/disease characteristics For patients with aggressive disease (eg, high LDH, large tumor burden, brain metastases, or symptomatic disease), combination BRAF/MEK targeted therapy is preferred first BRAF/MEK combination of encorafenib + binimetinib (COMBO450) represents a potential new targeted treatment option for patients with BRAF-mutant melanoma with a favorable efficacy and safety profile BRAF mutation testing is essential for treatment decision making; if BRAF is negative, NRAS mutation testing is recommended. Use of liquid biopsy is promising, but not ready for use in routine practice in melanoma Early recognition and early treatment of adverse events is key Immunotherapy adverse events are immune-related (use steroids) Patient education is important Trials evaluating the sequencing of combination immunotherapy and combination targeted therapy are ongoing Combinations of BRAF inhibitor + MEK inhibitor + anti PD-1/PD-L1 antibodies are feasible with promising activity and without unexpected toxicity in early clinical trials MEK inhibition (binimetinib) is effective in patients with NRAS-mutant melanoma who progressed on immunotherapy