1. Prior to the start of the program, check your syllabus to ensure you have the participant survey and CME evaluation: In the front of your syllabus Remove from your packet Fill out the demographic information at the top Throughout the program, please take a moment to answer the corresponding Activity Survey questions on this form (slides will be marked as “Polling Questions” throughout the deck) Please Help Us with the Following

2. New and Emerging Therapies for A CME-certified Oncology Exchange Activity Jointly provided by Potomac Center for Medical Education and Rockpointe Oncology This activity is supported by educational grants from Genentech and Novartis Pharmaceuticals Corporation

3. Please note, all pertinent CME information, statements, and disclosures can be found in your program syllabus, including: Faculty/Steering Committee and Non-faculty Planner/Reviewer Disclosures Educational Objectives Accreditation and Credit Designation Statements Faculty/Steering Committee Bios CME Information

4. Polling Question 1 Pre-activity Survey How confident are you in your ability to adopt new and emerging therapies for the management of metastatic melanoma? A.Not at all confident B.Slightly confident C.Confident D.Very confident E.Expert

5. Educational Objectives Evaluate the efficacy and safety of approved and emerging therapies for metastatic melanoma Explain the value of a multidisciplinary approach for the treatment of melanoma to improve patient outcomes Recognize the importance of patients actively participating in their treatment decisions and health management

6. Checkpoint Blockade for Melanoma

7. Case 1: BRAF Wild-type Melanoma A 42-year-old woman is found to have melanoma metastatic to lung and subcutaneous sites Her melanoma does not have a BRAF mutation She has a KPS of 80% She is overweight and has type II diabetes controlled with metformin No other significant medical history

8. Polling Question 2 Case Study 1 Which of the following FDA-approved therapies is associated with the highest response rate for a patient like this? A.Dacarbazine B.Vemurafenib C.High-dose interleukin-2 therapy D.Either nivolumab or pembrolizumab E.Ipilimumab

9. Polling Question 3 Case Study 1 The patient is treated with a PD-1 inhibitor and develops diarrhea up to 8 times per day. She otherwise feels well except for a mild rash and fatigue. The best recommendation for this patient is: A.Imodium and close monitoring B.Intensive oral hydration until diarrhea resolves C.Urgent colonoscopy as an outpatient D.High-dose steroids and close monitoring

10. Blocking CTLA-4 and PD-1 MHC TCR PD-L1PD-1 MHC TCR CD28 B7 CTLA-4 B7 CTLA-4 Blockade PD-1 Blockade anti-CTLA-4 anti-PD-1 Tumor Microenvironment PD-L2PD-1 anti-PD-1

11. FDA-approved Checkpoint Blocking Antibodies AntibodyTrade nameTarget IpilimumabYervoyCTLA4 PembrolizumabKeytrudaPD1 NivolumabOpdivoPD1

12. Ipilimumab vs gp100 Vaccine vs Both: OS and ORR Adapted from Hodi FS et al. N Engl J Med. 2010;363:711. Ipi alone Ipi + vaccine Vaccine alone 11%5.7%1.5% Response rates

13. Dacarbazine ± Ipilimumab: OS and ORR Adapted from Robert C et al. N Engl J Med. 2011;364:2517.

14. Ipilimumab: Pooled OS Data from Multiple Trials Schadendorf D et al. J Clin Oncol. 2015;33:1889-1894.

15. Key Take Away Ipilimumab improves overall survival compared to chemotherapy alone

16. 12/06 5/07 4 blinded doses ipilimumab 4 10 mg/kg doses ipilimumab No drug Delayed Response with Ipilimumab Treatment Pre-treatment 10/06 (Week 12)

17. Ipilimumab Toxicities ToxicitySigns/symptomsTreatment ColitisWatery diarrhea, bowel wall edema on CT Systemic steroids Rash/itching Usually antihistamines or topical steroids HypophysitisHeadache, fatigue, enlarged pituitary on brain MRI Systemic steroids. Usually will need chronic cortisol and thyroid hormone replacement HepatitisUsually asymptomatic; Elevated transaminases Systemic steroids ThyroiditisFatigueSystemic steroids UveitisDecreased visual acuityOphthalmology consult AdrenalitisFatigueSystemic steroids

18. Key Take Away Immunotherapy requires close follow-up for immune-related adverse events

19. FDA-approved Anti-PD1 Antibodies AntibodyTrade nameTarget PembrolizumabKeytrudaPD1 NivolumabOpdivoPD1

20. Antitumor Activity of Pembrolizumab Hamid O et al. N Engl J Med. 2013;369:134.

21. Best Overall Response to Nivolumab Robert C et al. N Engl J Med. 2015;372:320.

22. Nivolumab vs Dacarbazine: OS and PFS Robert C et al. N Engl J Med. 2015;372:320.

23. Pembrolizumab vs Ipilimumab OS and PFS Robert C et al. N Engl J Med 2015;372:2521

24. Ipilimumab vs Ipilimumab + Nivolumab Change in Tumor Burden, Durability of Tumor Regressions, and Progression-free Survival Postow MA et al. N Engl J Med. 2015;372:2006.

25. Ipilimumab vs Nivolumab vs Both: PFS Larkin J et al. N Engl J Med. 2015;373:23. Ipi aloneIpi + NivoNivo alone 2.9 mos11.5 mos6.9 mos

26. Anti-PD1 Antibody Toxicities Same as Ipi Except Less Common, Plus Pneumonitis ToxicitySigns/symptomsTreatment PneumonitisDyspnea, cough, infiltratesSystemic steroids ColitisWatery diarrhea, bowel wall edema on CT Systemic steroids Rash/itching Usually antihistamines or topical steroids HypophysitisHeadache, fatigue, enlarged pituitary on brain MRI Systemic steroids. Usually will need chronic cortisol and thyroid hormone replacement HepatitisUsually asymptomatic. Elevated transaminases Systemic steroids ThyroiditisFatigueSystemic steroids UveitisDecreased acuityOphthalmology consult AdrenalitisFatigueSystemic steroids

27. Key Take Away Anti-PD1 antibodies (pembrolizumab and nivolumab) have higher response rates and lower incidences of immune- related adverse events compared to ipilimumab

28. Response of a Large Chest-wall Melanoma Metastasis to One Dose of Ipilimumab Plus Nivolumab Chapman PB et al. N Engl J Med. 2015;372:2073.

29. Larkin J et al. N Engl J Med 2015;373:23-34 Ipilimumab vs Nivolumab vs Both: Adverse Events

30. FDA-approved Checkpoint Blocking Antibodies: SUMMARY IpilimumabNivolumabPembrolizumab Ipi + Nivo combination ORR (approx.)11-19%40-44%34%58-61% OS11.4 moND Toxicity3+1+ 4+

31. Key Take Away Combination ipilimumab + nivolumab have a higher response rate than either drug alone, but much higher incidence of adverse events

32. Targeted Therapy for Melanoma

33. Case 2: BRAF-Mutated Melanoma A 42-year-old woman is found to have melanoma metastatic to lung and subcutaneous sites Her melanoma is found to have a BRAF V600E mutation She has a KPS of 80% She is overweight and has type II diabetes controlled with metformin No other significant medical history

34. Polling Question 4 Case Study 2 Which of the following FDA-approved therapies is associated with the highest response rate for this patient? A.Dacarbazine B.Either vemurafenib or dabrafenib C.Dabrafenib plus trametinib D.Either nivolumab or pembrolizumab E.Ipilimumab

35. Polling Question 5 Case Study 2 Which of the following FDA-approved therapies has been shown to improve overall survival for a patient with metastatic melanoma harboring BRAF V600E mutation: A.Dabrafenib plus trametinib, nivolumab, IL-2 B.Vemurafenib, dabrafenib plus trametinib, nivolumab C.Dacarbazine, vemurafenib, pembrolizumab D.IL-2, vemurafenib, dabrafenib

36. Blocking BRAF and MEK Modified from Ribas et al. Nat Rev Clin Oncol. 2011;8:426. BRAF Inhibitors Vemurafenib Dabrafenib Encorafenib MEK Inhibitors Trametinib Cobimetinib Binimetinib

37. FDA-approved Molecularly Targeted Therapies DrugTrade nameTarget VemurafenibZelborafBRAF DabrafenibTafinlarBRAF TrametinibMekinistMEK

38. Treating BRAFV600E Mutant Melanoma with a BRAF Inhibitor Leads to Rapid Response McArthur et al. J Clin Oncol. 2012;30:1628. Day 15 Baseline

39. Vemurafenib vs Dacarbazine (DTIC): OS, PFS, and ORR Chapman et al. N Engl J Med. 2011;364:2507. VemuDTIC ORR56.9%8.6% mPFS6.9 months1.6 months mOS13.6 months9.7 months *V600E mutation only

40. 48% confirmed response rate (2 complete responses) 5% confirmed response rate (0 complete responses) Antitumor Activity of Vemurafenib vs DTIC Chapman et al. N Engl J Med. 2011;364:2507.

41. Activity of RAF inhibitor in BRAF-mutated melanoma with brain metastases BaselineWeek 32 Courtesy of Chapman P and Memorial Sloan Kettering Cancer Center.

42. Median time 8 weeks (range 2–36) Each dot represents weeks to development of first lesion BRAF Inhibitor Toxicity: Cutaneous Squamous Carcinomas, Keratoacanthoma Type Ribas et al. Proc ASCO. 2011; abstract 8509. 0510152025353040 Time on vemurafenib (weeks) Median

43. SCC/KAs 9% in monotherapy arm vs 2% in combination arm Response rate 51% in monotherapy arm vs 67% in combination arm, P=0.002 Dabrafenib ± Trametinib: PFS and ORR Long et al. N Engl J Med. 2014;371:1877.

44. Dabrafenib ± Trametinib: PFS – Elevated LDH Patients Long et al. N Engl J Med. 2014;371:1877.

45. Vemurafenib ± Cobimetinib: PFS Larkin et al. N Engl J Med. 2014;371:1867.

46. Dabrafenib ± Trametinib : OS Long et al. N Engl J Med. 2014;371:1877.

47. Dabrafenib ± Trametinib: OS – Elevated LDH Patients Long et al. N Engl J Med. 2014;371:1877.

48. HR 0.69 (95% CI 0.53-0.89) P=0.005 Dabrafenib + Trametinib vs Vemurafenib: OS Robert et al. N Engl J Med. 2015;372:30.

49. Vemurafenib ± Cobimetinib : OS Larkin et al. N Engl J Med. 2014;371:1867.

50. FDA-approved Molecularly Targeted Therapies: SUMMARY VemurafenibDabrafenibTrametinib Dabrafenib + Trametinib combination ORR (approx.)51%53%22%69% OS 17 mos median 65% 1 year 19 mos median 68% 1 year 42% 2 years Not reported 25 mos median 74% 1 year 51% 2 year Toxicity2+ 1+ Based on recent phase III trial data

51. Key Take Away Dabrafenib + trametinib has a higher response rate and better overall survival than dabrafenib alone. The combination regimen also has a higher incidence of fever and fatigue.

52. Questions?

53. Participant Survey and CME Evaluation CME Evaluation –If you’re seeking credit, ensure you’ve filled in your name and demographic information on page 1 and complete the CME Evaluation part of your form (after the In-Activity Survey) –Your answers are important and will help us identify remaining educational gaps and shape future CME activities –Return all forms to on-site CME staff Thank you for joining us today!