Emerging Therapies for the Treatment of Advanced Melanoma: Focus on Immunotherapy

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1 Emerging Therapies for the Treatment of Advanced Melanoma: Focus on Immunotherapy Presented as a Midday Symposium and Live Webinar at the 50 th ASHP Midyear Clinical Meeting and Exhibition Monday, December 7, 2015 New Orleans, Louisiana Sponsored by the American Society of Health-System Pharmacists (ASHP) and planned by ASHP Advantage, a division of ASHP. Supported by an educational grant from Merck

2 Please be advised that this activity is being audio and/or video recorded for archival purposes and, in some cases, for repurposing of the content for enduring materials. 2

3 Emerging Therapies for the Treatment of Advanced Melanoma: Focus on Immunotherapy Agenda 11:30 a.m. 11:40 a.m. Welcome and Introductions Christine M. Walko, Pharm.D., BCOP, FCCP 11:40 a.m. 11:50 a.m. Overview of Melanoma Epidemiology and Pathogenesis Morganna Freeman, D.O., FACP 11:50 a.m. 12:20 p.m. The Evolution of Melanoma Immunotherapy: Past and Present Morganna Freeman, D.O., FACP 12:20 p.m. 12:40 p.m. Recognizing and Managing Immune-related Adverse Events Christine M. Walko, Pharm.D., BCOP, FCCP 12:40 p.m. 12:50 p.m. Future Directions: Oncolytic Viruses and Potential Biomarkers Christine M. Walko, Pharm.D., BCOP, FCCP 12:50 p.m. 1:00 p.m. Faculty Discussion and Audience Questions All Faculty Faculty Christine M. Walko, Pharm.D., BCOP, FCCP, Activity Chair Personalized Medicine Specialist DeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center Associate Professor University of South Florida Morsani School of Medicine Tampa, Florida Morganna Freeman, D.O., FACP Chief Medical Oncology Fellow H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida 3

4 Emerging Therapies for the Treatment of Advanced Melanoma: Focus on Immunotherapy Disclosure Statement In accordance with the Accreditation Council for Continuing Medical Education s Standards for Commercial Support and the Accreditation Council for Pharmacy Education s Standards for Commercial Support, ASHP Advantage requires that all individuals involved in the development of activity content disclose their relevant financial relationships. A person has a relevant financial relationship if the individual or his or her spouse/partner has a financial relationship (e.g., employee, consultant, research grant recipient, speakers bureau, or stockholder) in any amount occurring in the last 12 months with a commercial interest whose products or series may be discussed in the educational activity content over which the individual has control. The existence of these relationships is provided for the information of participants and should not be assumed to have an adverse impact on the content. All faculty and planners for ASHP Advantage education activities are qualified and selected by ASHP Advantage and required to disclose any relevant financial relationships with commercial interests. ASHP Advantage identifies and resolves conflicts of interest prior to an individual s participation in development of content for an educational activity. All faculty and planners report no financial relationships relevant to this activity. 4

5 Emerging Therapies for the Treatment of Advanced Melanoma: Focus on Immunotherapy Activity Overview This activity will describe the use of, and outcomes with, agents that stimulate immune function in the treatment of advanced melanoma. The focus will center upon the evolution of immunotherapy from interferon and interleukin-2 to newly-approved immune checkpoint inhibitors, including the CTLA-4 inhibitor ipilimumab and the PD-1 inhibitors pembrolizumab and nivolumab. Discussion will include recent information on disease response outcomes, practical recommendations for immune-related adverse event management, and future directions of immunotherapy including identification of biomarkers to guide treatment selection and emerging strategies utilizing oncolytic vaccines. Learning Objectives At the conclusion of this application-based educational activity, participants should be able to Review the epidemiology, patient presentation, diagnosis, staging, and prognosis of advanced melanoma. Describe the pathogenesis of melanoma, including the role of genetic mutations and the inherent immunogenicity of this cancer. Compare the mechanisms of action for immunotherapy agents (including interleukin 2, ipilimumab, pembrolizumab, and nivolumab). Recommend best practices for the management of the unique toxicity profiles associated with immunotherapy. Adapt the use of immunotherapy to special populations, including elderly patients and those with concomitant autoimmune disease. Discuss the future landscape of melanoma immunotherapy, including oncolytic vaccines and the potential use of biomarkers to guide therapy selection. Additional Educational Opportunities about Melanoma Coming in 2016 Ask the Experts webinar February 16, 2016 Faculty will explore issues raised by participant questions in today s symposium (1 hour CE) Web-based activity - Based on today s live symposium (1.5 hours of CE, please note that individuals who claim CE credit for the live symposium or webinar are ineligible to claim credit for the webbased activity) For more information and to sign up to receive updates about this educational series, visit 5

6 Emerging Therapies for the Treatment of Advanced Melanoma: Focus on Immunotherapy Continuing Education Accreditation The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity provides 1.5 hours (0.15 CEUs no partial credit) of continuing pharmacy education credit. Live Activity ACPE #: L01-P On-Demand Activity ACPE #: H01-P The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The American Society of Health-System Pharmacists designates this live activity for a maximum of 1.5 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Complete instructions for processing continuing education credit online are listed on the last page. Webinar Information Visit to find: Webinar registration link Group viewing information and technical requirements 6

7 Emerging Therapies for the Treatment of Advanced Melanoma: Focus on Immunotherapy Christine M. Walko, Pharm.D., BCOP, FCCP, Activity Chair Personalized Medicine Specialist DeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center Associate Professor USF School of Medicine Tampa, Florida Christine M. Walko, Pharm.D., BCOP, FCCP, is Clinical Pharmacogenetics Scientist at the DeBartolo Family Personalized Medicine Institute and Clinical Scientist in the division of population science at the H. Lee Moffitt Cancer Center and is also Associate Professor at the University of South Florida Morsani College of Medicine in Tampa, Florida. She is also Co-Chair of the Clinical Genomics Action Committee (CGAC) at H. Lee Moffitt Cancer Center. Dr. Walko received her Doctor of Pharmacy degree from Duquesne University in Pittsburgh. She completed a pharmacy practice residency at Virginia Commonwealth University Health System/Medical College of Virginia Hospitals in Richmond, Virginia. She also completed a hematology/oncology specialty residency at the University of North Carolina (UNC) Hospitals and Clinics and a hematology/oncology fellowship at the University of North Carolina School of Pharmacy in Chapel Hill, North Carolina. She is a board-certified oncology pharmacist. Prior to her current position, Dr. Walko was Clinical Assistant Professor, Division of Pharmacotherapy and Experimental Therapeutics in the Institute of Pharmacogenomics and Individualized Therapy at the University of North Carolina Eshelman School of Pharmacy and Director of the Clinical Trial Unit Clinical Pharmacology Lab at the North Carolina Cancer Hospital at University of North Carolina Hospitals and Clinics Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina. Dr. Walko is a member of ASHP and is a fellow of the American College of Clinical Pharmacy (ACCP) and has served as Oncology PRN president elect and secretary/treasurer for ACCP. She is also a member of the Hematology and Oncology Pharmacists Association (HOPA), the American Society of Clinical Oncology (ASCO) and the North Carolina Oncology Pharmacists Association. Dr. Walko has also served as president and secretary/treasurer at the Triangle College of Clinical Pharmacy. She serves on the International Society of Geriatric Oncology (SIOG) Task Force on Oral Cytotoxic Chemotherapy Dosing in the Elderly and is faculty for the Global Resource for Advancing Cancer Education (GRACE). Dr. Walko has received the teacher of the year award at the UNC Eshelman School of Pharmacy multiple times. She has conducted research and published extensively in oncology therapy and presented nationally and internationally on oncology, pharmacogenomics, and other topics related to treating patients with cancer. 7

8 Emerging Therapies for the Treatment of Advanced Melanoma: Focus on Immunotherapy Morganna Freeman, D.O., FACP Chief Medical Oncology Fellow H Lee Moffitt Cancer Center & Research Institute Tampa, Florida Morganna Freeman, D.O., FACP, is Chief Medical Oncology Fellow at H. Lee Moffitt Cancer Institute, a National Cancer Institute and National Comprehensive Cancer Network member institution. Dr. Freeman obtained her undergraduate degree in biology from St. Mary's University in San Antonio, Texas. After graduation, she worked as a certified clinical research coordinator before entering medical school at Lake Erie College of Osteopathic Medicine. She completed her internship and residency in internal medicine at the University of Florida in Gainesville, Florida. As Chief Resident, her interests in education and health policy flourished. Dr. Freeman received her medical oncology fellowship training at H. Lee Moffitt Cancer Institute where she has spent the majority of her fellowship under the mentorship of Dr. Jeffrey Weber M.D., Ph.D., an internationally-recognized expert in melanoma and immunotherapy. Dr. Freeman has frequently collaborated with Dr. Weber on melanoma immunotherapy research, and recently presented the results of their work at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting. In addition to her academic accomplishments, Dr. Freeman has participated in the ASCO/American Association for Cancer Research Methods in Clinical Cancer Research workshop, holds National Institute of Health and Collaborative Institutional Training Initiative (CITI) certifications in clinical research, and has served numerous physician organizations in positions of leadership. 8

9 CE IN THE MIDDAY Emerging Therapies for the Treatment of Advanced Melanoma: Focus on Immunotherapy Christine M. Walko, Pharm.D., BCOP, FCCP, Activity Chair Personalized Medicine Specialist DeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center Associate Professor, USF School of Medicine Tampa, Florida Morganna Freeman, D.O., FACP Chief Medical Oncology Fellow H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida This activity is sponsored by the American Society of Health System Pharmacists (ASHP) and planned by ASHP Advantage, a division of ASHP. Supported by an educational grant from Merck Disclosures All faculty and planners report no financial relationships relevant to this activity. Learning Objectives Review the epidemiology, patient presentation, diagnosis staging, and prognosis of advanced melanoma. Describe the pathogenesis of melanoma, including the role of genetic mutations and the inherent immunogenicity of this cancer. Compare the mechanisms of action for immunotherapy agents including interleukin 2, ipilimumab, pembrolizumab, and nivolumab. Recommend best practices for the management of the unique toxicity profiles associated with immunotherapy. Adapt the use of immunotherapy to special populations, including elderly patients and those with concomitant autoimmune disease. Understand the future landscape of melanoma immunotherapy, including oncolytic vaccines and the potential use of biomarkers to guide therapy selection. 9

10 Overview of Melanoma Epidemiology and Pathogenesis Morganna Freeman, D.O., FACP Chief Medical Oncology Fellow H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida Melanoma Epidemiology 4.5% of all new cancers (6 th most common in U.S.) Steady rate of increase: 1.4% annually for last 10 years Less than 2% of skin cancer cases, but the vast majority of skin cancer deaths 74,000 new U.S. cases each year & rising High cure rates if treated early Dismal 16% five year survival rate in metastatic disease Data from SEER ( ) and American Cancer Society Cancer Facts & Figures, 2015 Risk Factors UV Radiation Indoor tanning Prior sunburns 5+ sunburns in youth increases lifetime melanoma risk by 80 percent Age >65 years Male sex Fair skin Dysplastic nevi Others: Familial melanoma, immunosuppression, xeroderma pigmentosum National Cancer Institute: A snapshot of melanoma Wu S et al. Cancer Epidemiol Biomar Prev. 2014; 23:

11 Patient Presentation Most frequently diagnosed among people aged Diagnosis at presentation: 84% local disease 9% regional lymph node spread 4% distant metastases Data from SEER ( ) A B C D E ABCDEs of Melanoma Evolution of existing mole (accessed 2015 Sep 30). Biopsy Indicated for a suspicious lesion Full thickness excisional biopsy with 1 3 mm margins into normal skin Not always feasible (i.e., face, acral/large lesions) 11

12 Further Work Up History and complete physical exam (including retina) Full dermatologic examination for other lesions Suspected lymph node involvement confirmation (intraoperative mapping, PET) PET=positron emission tomography NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) Melanoma V Prognostic Factors Breslow thickness / Clark level Ulceration Dermal mitotic rate Deep/peripheral margin status Microsatellitosis NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) Melanoma V Breslow s Depth Tumor thickness one of the 3 most important prognostic factors in melanoma (the others being T stage and ulceration) Depth Thickness 5 Year DFS I <0.75mm % II mm 80 96% III mm IV mm 60 75% V >3 mm 50% DFS=disease free survival NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) Melanoma V

13 Clark Level How deep tumor has penetrated base histology Level I V Level I restricted to epidermis (in situ) Level V invasive to subcutaneous fat Lower predictive value, less reproducible, more operator dependent than Breslow's depth, thus reserved for thickness <1 mm Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, eds. AJCC Cancer Staging Manual. 7th ed. New York: Springer; Lymph Node Involvement Important prognostic factor Sentinel LN = First node melanoma spreads to Tumor follows an orderly nodal distribution Complete lymph node dissection if SLN + Labor intensive, may be anatomically challenging Important for final TNM staging, recommendations for adjuvant therapy LN=lymph node SLN=sentinel lymph node Morton DL et al. Ann Surg. 2005; 242: Staging and 5 Year Survival Rates Stage I Stage II Stage III Stage IV A: < 1 mm thick, no ulceration, Clark II III B: < 1 mm thick with ulceration, Clark IV V 5yr OS: 90 95% 1 2 mm thick with any characteristic 5yr OS: 45 78% Lymph node involvement (at least N1) 5yr OS: 28 70% (depends on # of nodes) Metastatic Disease 5yr OS: 16% (though may be increasing) OS=overall survival 13

14 Melanoma Molecular Subsets Sosman, J: 2011 Education Book American Society of Clinical Oncology 2011: Used with permission. Treatment Overview Stage I or II Surgical removal and observation Diagnosis Stage III Lymph Node Positive Stage IV Metastatic Surgical removal and observation Surgical removal and IFN or ipilimumab If BRAF positive, vemurafenib, dabrafenib +/ trametinib or immunotherapy or trial If BRAF negative, immunotherapy NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) Melanoma V Case 1: TC TC is a 38 year old male presenting with increasing shortness of breath and right upper quadrant pain. He was found to have a 1 cm newly diagnosed lesion on his left arm. Further imaging also revealed 2 liver lesions and numerous lung lesions. Biopsy confirmed metastatic melanoma. Genetic testing revealed BRAF V600E positivity. 14

15 BRAF Mutant Melanoma Found in 40 50% of cutaneous melanoma Nearly 60% of melanoma in skin without chronic suninduced damage 80 90% are the V600E and 5 12% are V600K Generally non overlapping with other mutations Results in enhanced BRAF kinase activity and subsequent MAPK activation Current FDA approved therapies: BRAF inhibitors: vemurafenib, dabrafenib MEK inhibitor: trametinib BRAF + MEK vs. BRAF alone n = 704 Previously untreated, unresectable Stage IIIC or IV melanoma with BRAF V600E or V600K mutations R A N D O M I Z A T I O N Dabrafenib 150 mg PO BID + trametinib 2 mg PO daily Vemurafenib 960 mg PO BID Primary endpoint: Overall survival Secondary endpoint: Progression free survival Preplanned interim survival analysis performed after 77% of the total number of expected events Robert C et al. N Eng J Med. 2015; 372:30 9. BRAF + MEK vs. BRAF alone Median overall survival at 12 months Dabrafenib + trametinib: 72% Vemurafenib: 65% HR 0.69 (95% CI ), p = Median progression free survival Dabrafenib + trametinib: 11.4 months Vemurafenib: 7.3 months HR 0.56 (95% CI ), p < HR=hazard ratio Robert C, et al. N Eng J Med. 2015; 372:

16 BRAF Targeted Selected Toxicities Toxicity Vemurafenib Dabrafenib + Trametinib All grade Grade 3 and 4 All grade Grade 3 and 4 Pyrexia 21% 1% 53% 4% Rash 43% 9% 22% 1% Diarrhea 38% < 1% 32% 1% Hand foot syndrome 25% < 1% 4% 0% Hyperkeratosis 25% 1% 4% 0% Cutaneous SqCC 18% 17% 1% 1% Decreased ejection fraction 0% 0% 8% 4% SqCC=squamous cell carcinoma Robert C, et al. N Eng J Med. 2015; 372: BRAF Inhibitor Dermatologic Effects Maculopapular rash with keratoacanthomas Pustular white head reactions treated like traditional acne Photo courtesy of Dr. Walko. Used with patient permission. Vemurafenib Relapse Baseline before therapy 15 weeks of therapy with vemurafenib 23 weeks of therapy with vemurafenib Wagle N et al. J Clin Oncol. 2011; 29: Used with permission. 16

17 BRAF Mutated Melanoma: Summary Resistance to BRAF inhibitors typically occurs after 6 7 months in most BRAF mutant metastatic melanoma patients Combination of a BRAF and MEK inhibitors may suppress downstream resistance mechanisms Combination therapy had longer mpfs compared with monotherapy Median overall survival not yet reached Combination therapy resulted in higher occurrence of pyrexia, chills, nausea and vomiting but less skin toxicities Potential place in therapy: First line for BRAF positive metastatic melanoma mpfs=median progression free survival Flaherty KT et al. N Eng J Med. 2012; 367: Case 1: TC TC is a 38 year old male presenting with increasing shortness of breath and right upper quadrant pain. He was found to have a 1 cm newly diagnosed lesion on his left arm. Further imaging also revealed 2 liver lesions and numerous lung lesions. Biopsy confirmed metastatic melanoma. Genetic testing revealed BRAF V600E positivity. Case 1: TC Which of the following first line treatments is the preferred option for this patient? a. Vemurafenib alone b. Dabrafenib alone c. Dabrafenib + trametinib d. Vemurafenib + dabrafenib 17

18 Case 1: TC Which of the following first line treatments is the preferred option for this patient? Vemurafenib alone Dabrafenib alone Dabrafenib + trametinib Vemurafenib + dabrafenib The Evolution of Melanoma Immunotherapy: Past and Present Morganna Freeman, D.O., FACP Cancer and Immune Evasion Evasion of immune surveillance critical to early tumor survival Immunosuppressive cytokines (e.g., TGF β, IL 4, IL 6, IL 10) Increase number and function of immune suppressor cells (MDSCs, macrophages, regulatory T cells [Tregs]) Altered cell signaling to avoid tumor death (e.g., increased IDO, reduced MHC receptors) Inhibitory checkpoints (PD 1, PD L1, CTLA 4) MDSC=myeloid derived stem cells, IDO=indoleamine 2,3 dioxygenase 18

19 General Immunotherapy Approaches Active Vaccination Autologous Allogenic Cytokines Interferon, interleukin 2, GM CSF, denileukin diftitox Passive Conventional naked (e.g., rituximab) and loaded (e.g., ado trastuzumab emtansine) monoclonal antibodies Passive leading to active Ipilimumab, pembrolizumab GM CSF=granulocyte macrophage colony stimulating factor Current Immunotherapies in Melanoma Direct immune stimulation Interleukin 2 (IL 2) used for metastatic disease Interferon alfa 2B (IFN) for adjuvant therapy Inhibition of immune checkpoints Cytotoxic T lymphocyte antigen 4 (CTLA 4) Ipilimumab approved for metastatic melanoma in 2011 Approved for adjuvant therapy in 2015 Programmed cell death protein 1 (PD 1) receptor Pembrolizumab approved for patients who failed ipilimumab in 9/4/2014 Nivolumab approved for same indication 12/22/2014 Probability of Continuing Response High Dose IL 2 Therapy: Durable Responses High dose (HD) IL 2 produces durable responses in 6% to 10% of patients with advanced melanoma or renal cell carcinoma (RCC) Few relapses in patients responding for over 2.5 years (therefore, can be considered cured) FDA approval in 1992 (RCC) and 1997 (melanoma) Metastatic Melanoma (n = 270) Metastatic RCC (n = 255) CR (n = 17) 1.0 CR PR (n = 26) PR CR + PR (n = 43) 0.8 All Duration of Response (Months) CR=complete response, PR=partial response Probability of Continuing Response Duration of Response (Months) Atkins MB, et al. J Clin Oncol. 1999; 17: McDermott DF, et al. Expert Opin Biol Ther. 2004; 4:

20 HD IL 2 Therapy in Melanoma and RCC High dose IL 2 benefits patients, but: Toxic Impractical: must be delivered as an inpatient Use remains limited to selected patients treated at experienced centers Efforts to develop more tolerable IL 2 based regimens unsuccessful Efforts to better select patients who might benefit from HD IL 2 therapy have produced modest advances Proof of principle that immunotherapy can produce durable benefit in patients with solid tumor malignancies Case 2: LC LC is a 58 year old female who was initially diagnosed with local melanoma of the scalp in This was a Stage IIA, treated with resection and no further chemotherapy. In September 2015, she presented with increasing confusion and was found to have a right parietal lesion in her brain. This was resected and found to be melanoma. Further work up showed BRAF negativity. Comparison of CTLA 4 vs. PD 1 CTLA 4 pathway Exclusively on T cells Ligands: CD80 and CD86 Ligands only expressed on APCs CTLA 4 deficient mice suffer early, fatal autoimmune syndrome Blockade enhances proliferation of CD4+ and CD8+ T cells with increase in ratio to regulatory T cells PD 1 pathway On T, B, and NK cells Ligands: PD L1 and PD L2 Ligand expressed on APCs and tumor cells PD 1 deficient mice develop strainspecific autoimmunity late in life APC=antigen presenting cells, PD L1=programmed death ligand 1 Blockade enhances CD8+ T cells greater than CD4+ with increase of CD8+ to Tregs and cytotoxicity of CD8+ Greenwald RJ et al. Ann Rev Immunol. 2005; 23: Chambers CA et al. Ann Rev Immunol. 2001; 19: Dong H et al. Nat Med. 2002; 8: Curran MA et al. Proc Natl Acad Sci U S A. 2010; 107: Pilon Thomas S et al. J Immunol. 2010; 184:

21 Ipilimumab in Metastatic Melanoma: Durable Survival Previously Treated Patients Previously Untreated Patients 100 Median OS, Mos Ipi + gp Ipi 10.1 gp HR P Value 0.68 < Median OS, Mos Ipi + D 11.2 Placebo + D 9.1 Est 1, 2, 3 Yr Survival, % 47.3, 28.5, , 17.9, 12.2 P HR Value 0.72 < Patients Survival (%) Ipilimumab + dacarbazine Placebo + dacarbazine Mos OS=overall survival, gp100=gp100 vaccine Mos Ipilimumab vs Placebo [2] Adapted from Hodi FS et al. N Engl J Med. 2010; 363: Robert C et al. N Engl J Med. 2011; 364: Phase III Ipilimumab vs. gp100 n = 676 HLA A*0201 positive patients with unresectable stage III or IV previously treated melanoma R A N D O M I Z A T I O N 3:1:1 Ipilimumab 3 mg/kg q 3 weeks x 4 treatments + gp100 Ipilimumab 3 mg/kg q 3 weeks x 4 treatments gp100 vaccine alone Primary endpoint: Overall survival The gp100 vaccine comprised HLA A*0201 restricted peptides derived from melanosomal protein and was used as comparison since there was no accepted standard of care. Hodi FS et al. N Eng J Med. 2010; 363: Phase III Ipilimumab vs. gp100 Median overall survival Ipilimumab + gp100: 10.0 months HR 1.04, p=0.76 Ipilimumab alone: 10.1 months gp100 alone: 6.4 months HR 0.68, p<0.001 Disease control rate of 28.5% in ipilimumab alone arm, 60% of patients with an objective response maintained it for >2 years Grade 3 or 4 Toxicity 10 15% of patients treated with ipilimumab Hodi FS et al. N Eng J Med. 2010; 363:

22 Adjuvant Ipilimumab Phase III randomized, double blind study of ipilimumab (10 mg/kg) [n=475] vs. placebo [n=476] in Stage III melanoma at high risk of recurrence following complete surgical resection Primary endpoint: recurrence free survival (RFS) Secondary endpoint: OS EORTC trial data, released 10/28/15. Adjuvant Ipilimumab Interim analysis: 25% reduction in risk of recurrence or death (95% CI = ; p = ) Median RFS 26.1 months (ipilimumab) vs months (placebo) At three years: 46.5% (ipilimumab) vs. 34.8% (placebo) free of disease Survival data to be announced at ASCO 2016 EORTC trial data, released 10/28/15. Adjuvant Ipilimumab Grade 3 adverse events (AE) Gastrointestinal (GI)(15.9%) Hepatotoxicity (10.6%) Endocrine (8.5%) Dermatologic (4.5%) Incidence of drug related death 1.1% (n=5) Ipilimumab: 48.8% discontinued (n=230) due to drug related AEs vs. 1.7% (n=8) in the placebo arm EORTC trial data, released 10/28/15. 22

23 CTLA 4 and PD 1 Pathways Ipilimumab Nivolumab Pembrolizumab Brahmer JR. J Clin Oncol. 2013; 31: Clinical Development of Inhibitors of the PD 1 Immune Checkpoint Target Antibody Molecule Development Stage PD 1 PD L1 Nivolumab (BMS ) Pembrolizumab (MK 3475) Pidilizumab (CT 011) Fully human IgG4 Humanized IgG4 Humanized IgG1 Approved Approved Phase II multiple tumors BMS Fully human IgG4 Phase I MedI 4736 Engineered human IgG1 Phase I MPDL 3280A Engineered human IgG1 Phase I II IgG=immunoglobulin G Checkmate 037: Nivolumab vs. Investigator s Choice in Advanced Melanoma Weber JS et al. Lancet Oncol. 2015; 16:

24 Activity of Anti PD 1/PD L1 in Patients With Advanced Melanoma Agent Pts, n ORR (at Optimal Dose), % Grades 3/4 Tx Related AEs, % 6 Mo PFS, % 12 Mo PFS, % Median PFS, Mos 1 Yr OS, % 2 Yr OS, % Nivolumab (anti PD 1) [1 3] (41) Pembrolizumab 13 NA NA > 7 81 NA (anti PD 1) [4,5] (52) BMS NA NA NA NA NA (anti PD L1) [6] MPDL3280A 44 29* NA NA NA NA (anti PD L1) [7] *Includes 4 patients with uveal melanoma (UM) without a response. ORR=overall response rate, PFS=progression free survival 1. Topalian SL et al. J Clin Oncol. 2014; 32: Sznol M et al. Abstract 9006 presented at ASCO Topalian SL et al. N Engl J Med. 2012; 366: Ribas A et al. Abstract 9009 presented at ASCO Hamid O et al. N Engl J Med. 2013; 369: Brahmer JR et al. N Eng J Med. 2012; 366: Hamid O et al. Abstract 9010 presented at ASCO Phase III Pembrolizumab vs. Ipilimumab n = 834 Unresectable stage III or IV melanoma with no more than 1 prior treatment 1:1:1 R A N D O M I Z A T I O N Pembrolizumab 10 mg/kg every 2 weeks over 30 min Pembrolizumab 10 mg/kg every 3 weeks over 30 min Ipilimumab 3 mg/kg every 3 weeks x 4 doses Co primary endpoints: Overall survival and progression free survival Tumor response assessed by RECIST v1.1 criteria Robert C et al. N Eng J Med. 2015; 372: Phase III Pembrolizumab vs. Ipilimumab Toxicity (%) Pembrolizumab q2 weeks All grade Grade 3 and 4 Pembrolizumab q3 weeks All grade Grade 3 and 4 Ipilimumab All grade Grade 3 and 4 Diarrhea Fatigue Rash Vitiligo Hypothyroidism Hyperthyroidism Colitis Arthralgia Hepatitis Robert C et al. N Eng J Med. 2015; 372:

25 Phase III Pembrolizumab vs. Ipilimumab 6 month progression free survival: Pembrolizumab q 2 weeks: 47.3% Pembrolizumab q 3 weeks: 46.4% Ipilimumab x 4 doses: 26.5% Estimated 12 month overall survival: Pembrolizumab q 2 weeks: 74.1% Pembrolizumab q 3 weeks: 68.4% Ipilimumab x 4 doses: 58.2% HR = 0.58, p<0.001 HR = 0.63, p= HR = 0.69, p= Robert C et al. N Eng J Med. 2015; 372: Phase III Nivolumab +/ Ipilimumab n = 945 Previously untreated patients with unresectable stage III or IV melanoma 1:1:1 R A N D O M I Z A T I O N Nivolumab 3 mg/kg every 2 weeks with placebo Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks x 4 followed by nivolumab 3 mg/kg every 2 weeks (cycle 3 and beyond) Ipilimumab 3 mg/kg every 3 weeks x 4 doses with placebo Co primary endpoints: Overall survival and progression free survival Tumor response assessed by RECIST v1.1 criteria Larkin J et al. N Eng J Med. 2015; 373: Phase III Nivolumab +/ Ipilimumab Efficacy Median progression free survival (mpfs): Nivolumab alone: 6.9 months Ipilimumab alone: 2.9 months Nivolumab and Ipilimumab: 11.5 months PD L1 positive tumors (mpfs) HR = 0.57; ; p<0.001 HR = 0.42; ; p<0.001 PD L1 negative tumors (mpfs) Nivolumab 14 months 5.3 months Nivolumab and Ipilimumab 14 months 11 months Larkin J et al. N Eng J Med. 2015; 373:

26 Phase III Nivolumab +/ Ipilimumab Toxicity Toxicity Nivolumab Ipilimumab All grade Grade 3 and 4 All grade Grade 3 and 4 Nivolumab and Ipilimumab All grade Grade 3 and 4 Diarrhea Fatigue Rash Increased ALT Increased AST Hypothyroidism Colitis Arthralgia Dyspnea Larkin J et al. N Eng J Med. 2015; 373: Comparison of Anti PD 1 Agents Initial FDA Approval Date Type of Antibody Approved Dosing (single agent) Dose forms Approved indication in unresectable or metastatic melanoma Pembrolizumab Nivolumab September 4, 2014 December 22, 2014 Humanized, IgG4 kappa immunoglobulin 2 mg/kg over 30 minutes every 3 weeks 50 mg lyophilized powder in single use vial and 100 mg/4 ml solution in single use vial Single agent in patients with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor Human, IgG4 kappa immunoglobulin 3mg/kg IV over 60 minutes every 2 weeks 40 mg/4 ml and 100 mg/10 ml solution in single use vial Single agent or in combination with ipilimumab in patients with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor Nivolumab: Current Approvals Unresectable or metastatic melanoma Single agent in patients with disease progression following ipilimumab and, if BRAF V600 positive, a BRAF inhibitor Nivolumab 3 mg/kg every 2 weeks until progression or toxicity In combination with ipilimumab in patients with BRAF V600 wild type melanoma Nivolumab 1 mg/kg immediately followed by ipilimumab 3 mg/kg every 3 weeks x 4 doses Nivolumab 3 mg/kg every 2 weeks until progression or toxicity Metastatic non small cell lung cancer Single agent in patients with progression on or after platinumbased chemotherapy. In patients who are EGFR or ALK positive, they should have progressed on agents targeting these mutations Opdivo (nivolumab) prescribing information. Bristol Myers Squibb Company Oct. 26

27 Pembrolizumab: Current Approvals Unresectable or metastatic melanoma Single agent in patients with disease progression following ipilimumab and, if BRAF V600 positive, a BRAF inhibitor Pembrolizumab 2 mg/kg every 3 weeks until progression or toxicity Metastatic non small cell lung cancer Single agent in patients with progression on or after platinum based chemotherapy. In patients who are EGFR or ALK positive, they should have progressed on agents targeting these mutations Keytruda (pembrolizumab) prescribing information. Merck & Co., Inc Oct. Case 2: LC LC is a 58 year old female who was initially diagnosed with local melanoma of the scalp in This was a Stage IIA, treated with resection and no further chemotherapy. In September 2015, she presented with increasing confusion and was found to have a right parietal lesion in her brain. This was resected and found to be melanoma. Further work up showed BRAF negativity and PD L1 negativity. Case 2: LC Which of the following first line treatments is the best option for this patient? a. Ipilimumab alone b. Nivolumab alone c. Nivolumab + ipilimumab d. Pembrolizumab + nivolumab 27

28 Recognizing and Managing Immune related Adverse Events Christine M. Walko, Pharm.D., BCOP, FCCP Personalized Medicine Specialist DeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center Associate Professor, USF School of Medicine Tampa, Florida Ipilimumab: Immune related Adverse Events System Symptoms Management GI tract Skin Liver CNS Endocrine Eyes Diarrhea Abdominal pain Dark, bloody stools Rash (± itching) Blistering/peeling Oral sores Jaundice Nausea/vomiting Weakness in extremities Numbness/tingling Sensory changes Headaches Fatigue Behavior/mood changes Menstruation changes Dizziness/light-headedness Vision problems Irritation Moderate enterocolitis: hold ipilimumab, administer antidiarrheal. Persistent diarrhea (> 1 wk): systemic corticosteroids. 7+ stools/day: start methylprednisone, permanently discontinue ipilimumab. Consider infliximab for corticosteroid-refractory patients Moderate/nonlocalized rash: hold ipilimumab, start topical or systemic corticosteroids. Severe dermatitis: permanently discontinue ipilimumab, start corticosteroids Assess ALT/AST, bilirubin, and thyroid function before each dose and as necessary. Hold ipilimumab if ALT/AST > 2.5 x but 5 x ULN; permanently discontinue if AST/ALT > 5 x ULN or bilirubin > 3 x ULN. The immunosuppressant mycophenolate can be used for hepatotoxicity in corticosteroid-refractory patients Moderate neuropathy: hold ipilimumab. New or worsening neuropathy: permanently discontinue ipilimumab. Consider corticosteroids Moderate endocrinopathy: hold ipilimumab, start corticosteroids. Endocrine abnormalities can be difficult to detect, due to nonspecific symptoms. Consider having an endocrinologist follow the patient Monitor for redness suggesting uveitis, treat with topical steroidal eye drops Weber JS et al. J Clin Oncol. 2012; 30: Ipilimumab Adverse Effects #2 #3 #4 Weber JS et al. J Clin Oncol. 2012; 30: Used with permission. 28

29 Immune-related Adverse Event (irae) Toxicity Skin Gastrointestinal Liver Endocrine Clinical Effects Rash, vitiligo, pruritus Diarrhea, colitis Elevated enzymes, bilirubin, hepatitis Hypophysitis, hypothyroidism All grade (grade 3/4) 47-68% (0-4%) 31-46% (8-23%) 3-9% (3-7%) 4-6% (1-5%) Time Frame 2-3 weeks 6-7 weeks 6-7 weeks After 9 weeks Importance of close monitoring and patient education Weber JS et al. J Clin Oncol. 2012; 30: Management Algorithm: Diarrhea Grade 1 * Grade 2 * Grade 3 4* Symptom control NO STEROID Resolved to Grade 1 Symptom control NO STEROID No resolution Stool WBC Stool Calprotectin Endoscopy Likely colitis Grade 2 Grade 3 4 Continue Anti CTLA 4 Budesonide or moderate dose steroid High dose steroid No response in 1 week No response in 1 week * NCI Common Toxicity Criteria NCI=National Cancer Institute, WBC=white blood cells Infliximab O Day et al. Cancer. 2007; 110: Phase III Nivolumab +/ Ipilimumab Toxicity Toxicity Nivolumab Ipilimumab All grade Grade 3 and 4 All grade Grade 3 and 4 Nivolumab and Ipilimumab All grade Grade 3 and 4 Diarrhea Fatigue Rash Increased ALT Increased AST Hypothyroidism Colitis Arthralgia Dyspnea Larkin J et al. N Eng J Med. 2015; 373:

30 Case 2 Continued: LC LC is a 58 year old female who was recently diagnosed with metastatic melanoma to the brain. She has undergone craniotomy with resection and now is about to start treatment with nivolumab and ipilimumab concurrently. Case 2 Continued: LC LC should be counseled on all of the following toxicities except: a. Any changes to bowel habits should be reported b. Appearance of skin rash may occur after 1 2 doses c. Inflammation of the pituitary gland known as hypophysitis may occur d. QTc prolongation may occur and so regular EKGs are required Future Directions: Oncolytic Viruses and Potential Biomarkers Christine M. Walko, Pharm.D., BCOP, FCCP 30

31 Talimogene Laherparepvec (T VEC) Herpes simplex virus (HSV) type 1 derived oncolytic virus Selectively replicates in tumor cells Cell lysis Modifications: Deletion of ICP34.5: decreases viral pathogenicity and increases tumor selective replication Deletion of ICP47: decreases virally mediated antigen presentation suppression and increases expression of the HSV US11 gene Engineered to express granulocyte macrophage colonystimulating factor (GM CSF) to increase cancer immunity FDA Approval: October 27, 2015 local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery Andtbacka RH et al. J Clin Oncol. 2015; 33: Phase III T VEC vs. GM CSF n = 436 Patients with Stage IIIB to IV injectable melanoma sites not amendable to surgical resection 2:1 R A N D O M I Z A T I O N Intralesional T VEC 10 6 pfu/ml x 1 to seroconvert HSVnegative patients, then 3 weeks later, 10 8 pfu/ml started every 2 weeks Subcutaneous GM CSF 125 ug/m 2 once daily x 14 days, repeated every 28 days Primary endpoint: Durable response rate (DRR) defined as objective response lasting continuously >6 months per independent review. Exclusions included: patients with more than 3 visceral metastatic sites (except lung or nodal) and those requiring intermittent or chronic antivirals (eg. Acyclovir) or high dose steroids. Patients with autoimmune disease NOT requiring high dose steroids WERE eligible. pfu=plaque forming unit Andtbacka RH et al. J Clin Oncol. 2015; 33: Phase III T VEC vs. GM CSF T VEC GM CSF P value Durable Response Rate 16.3% 2.1% <0.001 Overall Response Rate 26.4% 5.7% Not available Complete Response Rate 10.8% <1% <0.001 Overall survival 23.3 months 18.9 months Responses were seen in both injected and uninjected lesions Of the 78 patients responding to T VEC, 54% initially met criteria for disease progression before experiencing a response Adverse effects were manageable with the most common being chills, pyrexia, injection site pain, nausea, flu like illness and fatigue Andtbacka RH et al. J Clin Oncol. 2015; 33:

32 T VEC Summary T VEC is the first oncolytic immunotherapy vaccine to show therapeutic benefits in melanoma Responses were higher in previously untreated patients or those with skin, subcutaneous or nodal only disease Treatment was well tolerated Neoantigens and Ipilimumab Response 64 patients with melanoma treated with ipilimumab or tremelimumab Whole exome sequencing performed on tumors with matched whole blood samples Characterized somatic mutations and candidate neoantigens Neoantigens were tested for their ability to activate lymphocytes from ipilimumab treated patients Neoantigens are newly acquired antigens expressed in tumor cells that can activate T cells Neoantigen signature was then validated in a separate set of 39 patients with melanoma treated with the same agents Synder A et al. N Eng J Med. 2014; 371: Neoantigens and Ipilimumab Response Clinical benefit was associated with number of mutations but was not the only predictor of benefit Patients with >100 mutations had improved survival over those patients with <100 mutations (p = 0.04) A neoantigen landscape was discovered and validated in patients who had a strong response to CTLA 4 inhibitors These antigens resembled those produced by other infectious organisms Were associated with activation of T cells Synder A et al. N Eng J Med. 2014; 371:

33 Key Takeaways Novel immunotherapy treatments have revolutionized the treatment for metastatic melanoma with increased number and duration of response rates along with tolerable toxicity Ipilimumab, nivolumab, and pembrolizumab have unique immune related toxicities that require awareness and knowledge regarding proper treatment in a timely manner Novel biomarker trials will help to further predict patients who may respond to novel immunotherapies 33

34 ABCDEs of Melanoma A B C D E Evolution of existing mole (accessed 2015 Sep 30). 34

35 Probability of Continuing Response High Dose IL 2 Therapy: Durable Responses High dose (HD) IL 2 produces durable responses in 6% to 10% of patients with advanced melanoma or renal cell carcinoma (RCC) Few relapses in patients responding for over 2.5 years (therefore, can be considered cured) FDA approval in 1992 (RCC) and 1997 (melanoma) Metastatic Melanoma (n = 270) Metastatic RCC (n = 255) CR (n = 17) PR (n = 26) CR + PR (n = 43) Probability of Continuing Response CR PR All Duration of Response (Months) Duration of Response (Months) CR=complete response, PR=partial response Atkins MB, et al. J Clin Oncol. 1999; 17: McDermott DF, et al. Expert Opin Biol Ther. 2004; 4:

36 Ipilimumab in Metastatic Melanoma: Durable Survival Previously Treated Patients Previously Untreated Patients 100 Ipi + gp100 Ipi gp100 Median OS, Mos HR P Value < Ipi + D Placebo + D Median OS, Mos Est 1, 2, 3 Yr Survival, % 47.3, 28.5, , 17.9, 12.2 HR 0.72 P Value < Patients Survival (%) Ipilimumab + dacarbazine Placebo + dacarbazine Mos OS=overall survival, gp100=gp100 vaccine Mos Ipilimumab vs Placebo [2] Adapted from Hodi FS et al. N Engl J Med. 2010; 363: Robert C et al. N Engl J Med. 2011; 364:

37 Checkmate 037: Nivolumab vs. Investigator s Choice in Advanced Melanoma Weber JS et al. Lancet Oncol. 2015; 16:

38 Ipilimumab: Immune related Adverse Events System Symptoms Management GI tract Skin Liver CNS Endocrine Eyes Diarrhea Abdominal pain Dark, bloody stools Rash (± itching) Blistering/peeling Oral sores Jaundice Nausea/vomiting Weakness in extremities Numbness/tingling Sensory changes Headaches Fatigue Behavior/mood changes Menstruation changes Dizziness/light-headedness Vision problems Irritation Moderate enterocolitis: hold ipilimumab, administer antidiarrheal. Persistent diarrhea (> 1 wk): systemic corticosteroids. 7+ stools/day: start methylprednisone, permanently discontinue ipilimumab. Consider infliximab for corticosteroid-refractory patients Moderate/nonlocalized rash: hold ipilimumab, start topical or systemic corticosteroids. Severe dermatitis: permanently discontinue ipilimumab, start corticosteroids Assess ALT/AST, bilirubin, and thyroid function before each dose and as necessary. Hold ipilimumab if ALT/AST > 2.5 x but 5 x ULN; permanently discontinue if AST/ALT > 5 x ULN or bilirubin > 3 x ULN. The immunosuppressant mycophenolate can be used for hepatotoxicity in corticosteroid-refractory patients Moderate neuropathy: hold ipilimumab. New or worsening neuropathy: permanently discontinue ipilimumab. Consider corticosteroids Moderate endocrinopathy: hold ipilimumab, start corticosteroids. Endocrine abnormalities can be difficult to detect, due to nonspecific symptoms. Consider having an endocrinologist follow the patient Monitor for redness suggesting uveitis, treat with topical steroidal eye drops Weber JS et al. J Clin Oncol. 2012; 30:

39 Emerging Therapies for the Treatment of Advanced Melanoma: Focus on Immunotherapy Self-assessment Questions 1. MM is a 52 yo female with newly diagnosed metastatic melanoma that is positive for the BRAF V600E mutation. She has extensive disease in her liver and her lactate dehydrogenase (LDH) is elevated above 800 u/l. Which of the following is the most appropriate therapy for this patient? a. Single-agent trametinib. b. Single-agent dabrafenib. c. Combination therapy with trametinib and dabrafenib. d. Ipilimumab since the patient is unlikely to response to BRAF-directed therapy. 2. Compared to single agent ipilimumab, the PD-1 inhibitors pembrolizumab and nivolumab resulted in which of the following outcomes? a. Higher response rates and lower toxicity. b. Higher response rates and higher toxicity. c. Lower response rates and lower toxicity. d. Lower response rates and higher toxicity. 3. PT is a 55-year-old male with newly diagnosed stage III melanoma who has just undergone resection. He is about to start adjuvant therapy with ipilimumab. Which of the following toxicities would you counsel him to expect to see first? a. Diarrhea. b. Increased liver enzymes. c. Skin rash. d. Hypothyroidism. 4. Which of the following is TRUE regarding the oncolytic virus vaccine, talimogene laherparepvec (T-VEC)? a. T-VEC is approved for patients with metastatic melanoma who have progressed on at least one prior line of immunotherapy. b. T-VEC is administered directly into the melanoma lesions. c. T-VEC is derived from the human papillomavirus (HPV). d. T-VEC must be administered with granulocyte-macrophage colony-stimulating factor (GM-CSF). Answers 1. c 2. a 3. c 4. b 39

40 Emerging Therapies for the Treatment of Advanced Melanoma: Focus on Immunotherapy CE Instructions Participants must claim CE no later than 60 days from the date of the live activity or completion of a home-study activity. All ACPE-accredited activities processed on the elearning portal are reported directly to CPE Monitor. To claim credit, you must have your NABP e-profile ID, birth month, and birth day. If you do not have an NABP e-profile ID, go to for information and application. For Midyear Attendees in New Orleans 1. Log in to the ASHP elearning Portal at elearning.ashp.org with the address and password used to register for the Midyear. The system validates your meeting registration to grant you access to claim credit. 2. Click on Process CE for the Midyear Clinical Meeting and Exhibition. 3. Enter the attendance code announced during the session and click submit. 4. Click Claim for any session. 5. Complete the evaluation. 6. Once all requirements are complete (indicated with a green check mark), click Claim Credit. 7. Review the information for the credit you are claiming. If all information is correct, check the box at the bottom and click Claim. You will see a message if there are any problems claiming your credit. For Offsite Webinar Attendees 1. Log in to the ASHP elearning Portal at elearning.ashp.org/my-activities. If you have never registered with ASHP, use the Register link to set up a free account. 2. Enter the enrollment code announced during the webinar in the Enrollment Code box and click Redeem. The title of this activity will appear in a pop-up box on your screen. Click on Go or the activity title. 3. Complete all required elements. Go to step six above. Activity Date: Monday, December 7, 2015 Code: _ CE Hours: 1.5 NEED HELP? Contact elearning@ashp.org 40