Immunotherapy for the Treatment of Melanoma

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1 University of Wisconsin School of Medicine & Public Health Department of Medicine Immunotherapy for the Treatment of Melanoma Mark R. Albertini, M.D. Advances in Cancer Immunotherapy April 7, 2016 William S. Middleton Veterans Memorial Hospital

2 Disclosure Information Prior Research Funding: EMD Serono and EMD Pharmaceuticals Eisai MedImmune LLC Merck Serono Genentech Bristol-Myers Squibb Pfizer Agalimmune, Inc Conflict of Interest: None Non-FDA indications will not be discussed

3 Learning Objective Appreciate the potential of the immune system to improve survival of melanoma patients

4 Lecture Outline Background New insights that have changed clinical practice Key clinical trial findings Identify immunotherapy drugs and review dosing guidelines Recognize adverse events and review adverse event management guidelines Putting it all together with case reviews

5 Background Lecture Outline

6 Melanoma 2016: Extent of the Problem (2016 Statistics from the ACS) USA Incidence: 76,380 cases (46,870 male; 29,510 female) 10,130 deaths (6,750 male; 3,380 female)

7 Historical Data from Balch et al.; JCO, Vol 19, No 16 (August 15), 2001: pp

8 Outline for Today s presentation New insights that have changed clinical practice

9 Exciting and Impressive Data Molecular Driver Mutations in Melanoma Immune System Recognition of Melanoma Immune Checkpoint Blockade in Melanoma

10 Requirements for Melanoma-Specific T- Cell Immunity Melanoma expresses markers on the melanoma cell surface (antigens) that can elicit immune responses The immune response against a melanoma antigen can destroy the melanoma

11 Immunologic Responses to Melanoma Melanoma-specific cytolytic T cells Identify genes encoding antigens on human melanoma recognized by T cells The curative potential of T cell immunotherapy Association of autoimmunity and antimelanoma immunity

12 Melanoma & Vitiligo Melanoma pts responding to immunotherapies can develop vitiligo in vivo to MAA. Yeh, S, et al Opthalmology. 116:

13 Ipilimumab, a CTLA-4 Blocking Monoclonal Antibody, Augments T-Cell Activation T-cell Activation resting T-cell CTLA-4 T-cell Inactivation T-cell T-cell Remains Active T-cell TCR CD28 CTLA-4 CTLA-4 HLA B7 Ipilimumab APC APC APC Korman, Peggs and Allison: Adv. In Immunol. 2006;90: Wolchek, J ASCO Meeting 4

14 Slide 8 Presented By Suzanne Topalian at 2015 ASCO Annual Meeting

15 Slide 9 Presented By Suzanne Topalian at 2015 ASCO Annual Meeting

16 Slide 10 Presented By Suzanne Topalian at 2015 ASCO Annual Meeting

17 Key clinical trial findings Lecture Outline

Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D,

18 Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved Survival with Ipilimumab in patients with metastatic melanoma. N Engl J Med. 363(8):711-23, 2010.

19 Figure 1. Kaplan Meier Curves for Overall Survival and Progression-free Survival in the Intention-to-Treat Population. N Engl J Med. 363(8):711-23, 2010

Pembrolizumab versus Ipilimumab in Advanced Melanoma Caroline Robert, M.D., Ph.D., Jacob Schachter, M.D., Georgina V. Long, M.D., Ph.D., Ana Arance, M.D., Ph.D., Jean Jacques Grob, M.D., Ph.D., Laurent Mortier, M.

20 Pembrolizumab versus Ipilimumab in Advanced Melanoma Caroline Robert, M.D., Ph.D., Jacob Schachter, M.D., Georgina V. Long, M.D., Ph.D., Ana Arance, M.D., Ph.D., Jean Jacques Grob, M.D., Ph.D., Laurent Mortier, M.D., Ph.D., Adil Daud, M.D., Matteo S. Carlino, M.B., B.S., Catriona McNeil, M.D., Ph.D., Michal Lotem, M.D., James Larkin, M.D., Ph.D., Paul Lorigan, M.D., Bart Neyns, M.D., Ph.D., Christian U. Blank, M.D., Ph.D., Omid Hamid, M.D., Christine Mateus, M.D., Ronnie Shapira-Frommer, M.D., Michele Kosh, R.N., B.S.N., Honghong Zhou, Ph.D., Nageatte Ibrahim, M.D., Scot Ebbinghaus, M.D., and Antoni Ribas, M.D., Ph.D., for the KEYNOTE-006 investigators* Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med, 372(26): , 2015.

21 OS at the Second Interim Analysis Presented By Lynn Schuchter at 2015 ASCO Annual Meeting

22 OS at the Second Interim Analysis Presented By Lynn Schuchter at 2015 ASCO Annual Meeting

23 Clinical activity and safety of nivolumab (anti-pd-1, BMS , ONO-4538) in combination with ipilimumab in patients with advanced melanoma Jedd D. Wolchok, 1 Harriet Kluger, 2 Margaret K. Callahan, 1 Michael A. Postow, 1 RuthAnn Gordon, 1 Neil H. Segal, 1 Naiyer A. Rizvi, 1 Alexander M. Lesokhin, 1 Kathleen Reed, 2 Matthew M. Burke, 2 Anne Caldwell, 2 Stephanie A. Kronenberg, 1 Blessing U. Agunwamba, 1 William Feely, 3 Quan Hong, 3 Christine E. Horak, 3 Alan J. Korman, 4 Jon M. Wigginton, 3 Ashok Gupta, 3 and Mario Sznol 2 1 Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, NY; 2 Yale University School of Medicine and Yale Cancer Center, New Haven, CT; Bristol-Myers Squibb, 3 Princeton, NJ and 4 Redwood City, CA Wolchok et al, abstract 9012, ASCO 2013

24 Clinical Activity: Concurrent Regimen Dose (mg/kg) Nivolumab Ipilimumab Response Evaluable Patients n CR n PR n Objective Response Rate % [95% CI] Aggregate Clinical Activity Rate % [95% CI] 80% Tumor Reduction at 12 wk n (%) [5-51] 50 [23-77] 4 (29) [28-77] 65 [38-86] 7 (41) [16-68] 73 [45-92] 5 (33) [12-88] 83 [36-100] 0 Concurrent [27-55] 65 [51-78] 16 (31) With 1 mg/kg nivolumab + 3 mg/kb ipilimumab, 53% of patients had confirmed objective responses (3 CRs and 6 PRs) All 9 of these had 80% tumor reduction, 7 at 12 weeks and 2 at their first assessment, which was after week 12 80% tumor reductions appear infrequently (<10%) in the nivolumab and ipilimumab monotherapy experiences Wolchok et al, abstract 9012, ASCO 2013

25 Change in target lesions from baseline (%) -80 Best Responses in All Evaluable Patients in Concurrent Cohorts Patients After ~13 months of follow-up, for all concurrent cohorts, 90% of all responding patients continue to respond as of Feb Wolchok et al, abstract 9012, ASCO 2013

extensive nodal and visceral disease Baseline LDH was elevated (2.

26 Rapid and Durable Changes in Target Lesions 1 mg/kg nivolumab + 3 mg/kg ipilimumab Change in target lesions from baseline (%) First occurrence of new lesion Weeks since treatment initiation Pretreatment 12 weeks A 52-year-old patient presented with extensive nodal and visceral disease Baseline LDH was elevated (2.3 x ULN); symptoms included nausea and vomiting Within 4 wk, LDH normalized and symptoms resolved At 12 wk, there was marked reduction in all areas of disease as shown Wolchok et al, abstract 9012, ASCO 2013

27 ESTABLISHED IN 1812 July 11, 2013 VOL. 369 NO. 2 Nivolumab plus Ipilimumab in Advanced Melanoma Jedd D. Wolchok, M.D., Ph.D., Harriet Kluger, M.D., Margaret K. Callahan, M.D., Ph.D., Michael A. Postow, M.D., Naiyer A. Rizvi, M.D., Alexander M. Lesokhin, M.D., Neil H. Segal, M.D., Ph.D., Charlotte E. Ariyan, M.D., Ph.D., Ruth-Ann Gordon, B.S.N., Kathleen Reed, M.S., Matthew M. Burke, M.B.A., M.S.N., Anne Caldwell, B.S.N., Stephanie A. Kronenberg, B.A., Blessing U. Agunwamba, B.A., Xiaoling Zhang, Ph.D., Israel Lowy, M.D., Ph.D., Hector David Inzunza, M.D., William Feely, M.S., Christine E. Horak, Ph.D., Quan Hong, Ph.D., Alan J. Korman, Ph.D., Jon M. Wigginton, M.D., Ashok Gupta, M.D., Ph.D., and Mario Sznol, M.D. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon R-A, Reed K, Burke MM, Caldwell A, Kronenberg SA, Blessing U. Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus Ipilimumab in Advanced Melanoma. New England Journal of Medicine, 369(2): , 2013.

28 Slide 6 Presented By Jedd Wolchok at 2015 ASCO Annual Meeting

29 Slide 10 Presented By Jedd Wolchok at 2015 ASCO Annual Meeting

30 Slide 13 Presented By Jedd Wolchok at 2015 ASCO Annual Meeting

31 Slide 15 Presented By Jedd Wolchok at 2015 ASCO Annual Meeting

ESTABLISHED IN 1812 July 2, 2015 VOL. 373 NO. 1 Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. J. Larkin, V. Chiarion-Sileni, R. Gonzalez, J.J. Grob, C.L. Cowey, C.D. Lao, D.

32 ESTABLISHED IN 1812 July 2, 2015 VOL. 373 NO. 1 Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. J. Larkin, V. Chiarion-Sileni, R. Gonzalez, J.J. Grob, C.L. Cowey, C.D. Lao, D. Schadendorf, R. Dummer, M. Smylie, P. Rutkowski, P.F. Ferrucci, A. Hill, J. Wagstaff, M.S. Carlino, J.B. Haanen, M. Maio, I. Marquez-Rodas, G.A. McArthur, P.A. Ascierto, G.V. Long, M.K. Callahan, M.A. Postow, K. Grossmann, M. Sznol, B. Dreno, L. Bastholt, A. Yang, L.M. Rollin, C. Horak, F.S. Hodi, and J.D. Wolchok Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, and Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. New England Journal of Medicine, 373(1):23-34, 2015

33 Identify immunotherapy drugs Lecture Outline

34 Immunotherapy of Advanced Melanoma Agent Interleukin-2 Dose 600,000 units/kg every 8 hours for a maximum of 14 doses Repeat after 9 days for a total of 28 doses/course Re-treat if tumor shrinkage observed and no contraindications at least 7 days after hospital discharge date Source: Drug Information from Up To Date

35 Immunotherapy of Advanced Melanoma with Immune Checkpoint Inhibition Agent Dose Ipilimumab 3mg/kg every 3 weeks for a maximum of 4 doses Doses may be delayed due to toxicity, but all doses must be administered within 16 weeks of the initial dose Pembrolizumab 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity Nivolumab 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity Source: Drug Information from Up To Date

36 Immunotherapy of Advanced Melanoma with Immune Checkpoint Inhibition Agent Ipilimumab (combination therapy) + Nivolumab (combination therapy) Dose 3 mg/kg every 3 weeks for 4 doses (in combination with Nivolumab) 1 mg/kg every 3 weeks for 4 doses (in combination with Ipilimumab), followed by 3 mg/kg every 2 weeks (Nivolumab monotherapy) until disease progression or unacceptable toxicity Source: Drug Information from Up To Date

37 Immunotherapy of Advanced Melanoma with Intralesional injections into cutaneous, subcutaneous and /or nodal lesions Agent Talimogene Laherparepvec (T-VEC) Dose Initial treatment with injection up to 4 ml at a concentration of 10 6 (1 million) PFU/ml Second treatment (3 weeks after initial treatment) with injection up to 4 ml at a concentration of 10 8 (100 million) PFU/ml All subsequent treatment (2 weeks after previous treatment) with up to 4 ml at a concentration of 10 8 (100 million) PFU/ml Inject largest lesion first and then remaining lesions based on lesion size until maximal injection volume is reached. Source: Drug Information from Up To Date

38 Adjuvant Immunotherapy for Melanoma Agent Dose Interferon Alfa-2b Induction with 20 million units/m 2 IV for 5 consecutive days/week for 4 weeks, followed by Maintenance with 10 million units/m 2 subcutaneous injection 3 times weekly for 48 weeks Peginterferon Alfa- 2b Initial treatment with 6 mcg/kg/week for 8 doses, followed by Maintenance with 3 mcg/kg/week for up to 5 years Ipilimumab 10 mg/kg every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years If toxicity occurs, doses are omitted (not delayed) Source: Drug Information from Up To Date

39 FDA-Approved Immunotherapy Drugs Available in 4/2016 for Melanoma A. Antineoplastic Agent, Biological Response Modifier Interleukin-2 (IL-2): advanced disease Recombinant Interferon Alfa-2b: adjuvant therapy Peginterferon Alfa-2b: adjuvant therapy B. Antineoplastic Agent, anti-ctla-4 Monoclonal Antibody Ipilimumab: advanced disease and adjuvant therapy C. Antineoplastic Agent, anti-pd-1 Monoclonal Antibody Pembrolizumab: advanced disease Nivolumab: advanced disease D. Antineoplastic Agent, anti-ctla-4 + anti-pd-1 Monoclonal Antibody Ipilimumab + Nivolumab: advanced disease E. Antineoplastic Agent, Oncolytic Virus Talimogene Laherparepvec (T-VEC); advanced disease

40 FDA-Approved Non-Immunotherapy Drugs Available in 4/2016 for Advanced Melanoma A. Antineoplastic Agent, BRAF Kinase Inhibitor Vemurafenib Dabrafenib B. Antineoplastic Agent, MEK-Inhibitor Trametinib C. Antineoplastic Agent, BRAF Kinase + MEK-Inhibitor Dabrafenib + Trametinib Vemurafenib + Cobimetinib D. Antineoplastic Agent, Alkylating Agent Dacarbazine

41 Lecture Outline Recognize adverse events and review adverse event management guidelines

42 Immune-Related Adverse Events Colitis Hepatitis Dermatitis Hypophysitis Thyroiditis Adrenalitis Pneumonitis

43 Slide 16 Presented By Jedd Wolchok at 2015 ASCO Annual Meeting

44 Treatment-Related Select AEs Reported in <br /> 10% of Patients Presented By Jedd Wolchok at 2015 ASCO Annual Meeting

45 Representative management considerations for iraes (specific plans may vary depending on system involved) S. Champiat et al. Annals of Oncology 00: 1 16, doi: /ann

46 Lecture Outline Putting it all together with case reviews

47 Case #1 42 year old woman with metastatic melanoma with an antitumor response following ipilimumab treatment.

48 7 months before treatment 4 weeks before treatment 3 months after induction treatment Courtesy of Dr. Meghan Lubner

49 Case #2 52 year old man with metastatic melanoma and a delayed antitumor response after receiving 4 cycles of ipilimumab.

50 Courtesy of Dr. Meghan Lubner Pre-treatment Rx completed 3 months after Rx 8 months after Rx

51 Case #3 49 year old man with metastatic melanoma with systemic response in mediastinal lymph nodes after development of hypophysitis following 3 cycles of combined immunotherapy with ipilimumab and nivolumab.

52 2 weeks after treatment 6 weeks after treatment Courtesy of Dr. Meghan Lubner

53 Pre-treatment 6 weeks after treatment Courtesy of Dr. Meghan Lubner

54 Take Home Points about Melanoma Immunotherapy Laboratory insights have changed the standard of care for metastatic melanoma patients. Immunotherapy can achieve durable responses and improve survival in metastatic melanoma. Awareness of possible immune-related adverse events is essential following immunotherapy. Improved biomarkers of response to immune checkpoint blockade are needed. Enthusiasm is present to study treatment combinations with immune checkpoint blockade.

55 Concepts at the UWCCC to Improve Melanoma Immunotherapy Induce an immune response to melanoma that could be amplified with immune checkpoint blockade alpha gal glycolipids (study completed) intratumoral hu14.18-il2 (study planned) DNA microseeding (canine model) Identify predictive biomarkers of response to immune checkpoint blockade HPRT mutant T cells Molecular imaging

56 Acknowledgments (1) Albertini Lab Cindy Zuleger, PhD Daniel Roque Chulhi Kang Collaborators Paul Sondel, M.D., PhD Jacquelyn Hank, PhD Erik Ranheim, M.D. David Vail, D.V.M. Ilene Kurzman, PhD Elof Eriksson, M.D. Robert Jeraj, PhD Michael Newton, PhD Clinical Research Team Renae Quale Tamara Koehn Erin Clements Kate Kernien Molly Maher Jen Collins Tom McFarland, M.D. Heather Neuman, M.D. Sharon Weber, M.D. Mary Beth Henry, N.P. Melanoma Clinic Anne Wolvin, R.N. Nancy Kerl, M.A.

57 Acknowledgments (2) NIH Grants: R35CA (Sondel) and CA (Galili) UW ICTR and UW Skin Disease Research Center Pilot Award (Albertini) Ann s Hope Foundation Kennedy/Harris Golf Tournament Steve Leuthold Family Foundation Tim Eagle Memorial Gretchen and Andrew Dawes Charitable Trust

58 Special Thanks and Appreciation Melanoma Patients for whom this work is dedicated While meaningful progress is being made, much more work needs to be done for patients with melanoma

Evolving Treatment Strategies in the Management of Metastatic Melanoma: Novel Therapies for Improved Patient Outcomes. Disclosures

Evolving Treatment Strategies in the Management of Metastatic Melanoma: Novel Therapies for Improved Patient Outcomes Fall Managed Care Forum November 11, 2016 Matthew Taylor, M.D. Disclosures Consulting/Advisory