Immunotherapy in Advanced Melanoma: Changing the Treatment Paradigm

Immunotherapy in Advanced Melanoma: Changing the Treatment Paradigm

Learning Objectives Explain the importance of immunotherapy to the treatment of advanced melanoma and detail the mechanisms involved in the anti-ctla-4 and anti-pd-1 approaches Review the 2015 NCCN guidelines on the treatment of advanced melanoma, and in particular, recommendations regarding immunotherapy Select appropriate strategies for the management of patients with advanced melanoma based on both patient and therapeutic characteristics and side effect profiles 2 CTLA-4 = cytotoxic T-lymphocyte antigen-4; NCCN = National Comprehensive Cancer Network; PD-1 = programmed cell death-1.

2015 Estimated New Cancer Cases in the United States a Men 848,200 Women 810,170 Prostate 26% Lung and bronchus 14% Colon and rectum 8% Urinary bladder 7% Melanoma of skin 5% Non-Hodgkin lymphoma 5% Kidney 5% Oral cavity 4% Leukemia 4% Liver and bile duct 3% All other sites 19% Invasive melanoma: 73,870 Number of deaths from melanoma: 9940 1.1 patients/hour 29% Breast 13% Lung and bronchus 8% Colon and rectum 7% Uterine corpus 6% Thyroid 4% Non-Hodgkin lymphoma 4% Melanoma 3% Pancreas 3% Leukemia 3% Kidney 20% All other sites 3 a Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. American Cancer Society. www.cancer.org/acs/groups/content/@editorial/documents/document/ acspc-044552.pdf. Accessed June 5, 2015; National Cancer Institute. http://seer.cancer.gov/statfacts/ html/melan.html. Accessed June 8, 2015.

Melanoma: Increasing Incidence, Decreasing Mortality New melanoma cases nearly tripled between 1975 and 2012 (from 7.9/100K to 22.9/100K) Death rate per 100K: no change (2.1/100K in 1975; 2.7/100K in 2012) Historically, average survival for stage IV metastatic melanoma was 6-12 months; 5-year survival was under 10% with standard therapies 4 Deylon J, et al. Semin Oncol. 2015;42:387-401; National Cancer Institute. http://seer.cancer.gov/statfacts/html/melan.html. Accessed June 8, 2015.

Melanoma: An Epidemic Utah Incidence Rates of Melanoma of the Skin by State, 2011 Highest per capita incidence 34.1 / 100,000 73% higher than national average California 27.5 /100,000 40% higher than national average 8560 cases / year 5 Centers for Disease Control. www.cdc.gov/cancer/skin/statistics/state.htm. Accessed June 5, 2015; Centers for Disease Control. http://apps.nccd.cdc.gov/uscs/cancersrankedbystate.aspx. Accessed June 5, 2015; AIM at Melanoma Foundation. https://www.aimatmelanoma.org/ about-melanoma-and-other-lesions/melanoma-stats-facts-and-figures. Accessed June 10, 2015.

Melanoma: 15-Year OS Proportion Surviving 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1 2 3 4 5 6 7 8 Stage I (n = 9175) Stage II (n = 5739) Stage III (n = 1528) Stage IV (n = 1158) 9 10 11 12 13 14 15 Disease status at presentation 84% Localized 8% Regional metastases 4% Distant metastases Presence of lymph node metastasis most important prognostic factor for survival 6 OS = overall survival. Survival (years) Balch CM, et al. J Clin Oncol. 2001;19:3635-3648; Siegel J, et al. CA Cancer J Clin. 2012;61:10-29.

Case 1: Frank 71-year-old married, retired construction worker ~6 months ago, he noticed a dark irregular mole on the sole of his foot that was uncomfortable and ulcerating, but he put off coming in because of fears about what it might be When he showed his wife, she insisted that he see his doctor Symptoms include right abdominal swelling and fatigue Frank has T2DM of 17 years duration, hypertension, and moderate chronic kidney disease Medications include metformin, an angiotensin-converting enzyme inhibitor, and a diuretic 7 T2DM = type 2 diabetes mellitus.

Case 1 (cont d) Physical examination BP: 131/84 mm Hg; heart rate: 86 beats/min, regular; temperature: 97.8ºF (36.5ºC); RR: 14 breaths/min BMI: 29.5 kg/m 2 ; A1C is 7.2%; GFR: 40 ml/min/1.73 m 2 Right plantar foot: irregular, large pigmented lesion Large palpable lymph nodes in the right groin Results of the rest of the examination are within normal limits A punch biopsy of the mole is performed 3.8-mm ulcerated acral lentiginous melanoma: T3b Fine-needle cytology aspiration of right groin lymph nodes Metastatic melanoma Image courtesy of Robert Andtbacka, MD, CM 8 A1C = glycated hemoglobin; BMI = body mass index; BP = blood pressure; GFR = glomerular filtration rate; RR = respiration rate.

Case 1 (cont d) Imaging: chest/abdominal/pelvic CT scan and brain MRI Multiple enlarged metastatic lymph nodes in the right superficial and deep groin Liver lesions with significant peritumoral edema compatible with metastases Multiple lung metastases Final stage pt3b, N3, M1c stage IV with liver and lung metastases Serum LDH: 1838 U/L (normal <264 U/L) Lymph node metastasis: BRAF V600 wild type 9 CT = computed tomography; LDH = lactic dehydrogenase; MRI = magnetic resonance imaging.

History of Melanoma Treatment DTIC IL-2 1975 1998 Dacarbazine FDA approved in 1975 ORRs 5%-10%, poor prognosis High-dose IL-2 approved in 1998 ORR 15% Higher response in patients with disease limited to skin and/or lymph nodes 10 DTIC = dacarbazine; FDA = Food and Drug Administration; IL-2 = interleukin-2; ORR = overall response rate. Buzaid AC, et al. Chin Clin Oncol. 2014;3:32; Buzaid AC, et al. www.cancernetwork.com. Accessed June 5, 2015; Chapman PB, et al. N Engl J Med. 2011;364:2507-2516; Hauschild A, et al. Lancet. 2012;380:358-365.

New Paradigm in the Treatment of Melanoma Immunotherapy Target host Targeted therapy Target tumor 11 Courtesy of Axel Hauschild, MD.

History of Melanoma Treatment (cont d) DTIC IL-2 Ipilimumab 1975 1998 2011 2013 Vemurafenib Dabrafenib alone Trametinib alone Ipilimumab FDA approved in 2011 Improvement in OS in metastatic disease Vemurafenib approved 2011 for BRAF V600E-mutant disease Dabrafenib and trametinib approved in 2013 (monotherapy) Approved in combination (for BRAF V600E-mutant disease) in 2014 12 Buzaid AC, et al. Chin Clin Oncol. 2014;3:32.

Immune System Checkpoint Inhibitors Anti-CTLA-4 agents Ipilimumab Binds to CTLA-4, blocking its ability to downregulate T-cell activation, proliferation, and effector function Anti-PD-1 and PD-L1 agents Pembrolizumab Nivolumab PD-1 pathway is a key immuno-inhibitory mediator of T-cell exhaustion; blockade of pathway leads to T-cell activation, expansion, and enhanced effector functions PD-1 = programmed cell death-1; PD-L1 = programmed death-ligand 1. 13 National Cancer Institute. www.cancer.gov/types/skin/hp/melanoma-treatmentpdq#link/stoc_h2_8. Accessed June 5, 2015; Yervoy [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2015; Keytruda [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc.; 2015; Opdivo [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2015.

Ipilimumab Augments T-Cell Activation and Proliferation T-Cell Activation T-Cell Inhibition T-Cell Activation and Proliferation CTLA-4 T cell T cell T cell TCR MHC APC CD28 CD80/ CD86 TCR MHC APC CD28 CTLA-4 CD80/ CD86 TCR MHC APC CD80/ CD86 CTLA-4 Ipilimumab blocks CTLA-4 APC = antigen-presenting cells; MHC = major histocompatibility complex; TCR = T-cell receptor. 14 O Day S, et al. ASCO 2010 Annual Meeting; June 4-8, 2010; Chicago, IL. Abstract 4.

Clinical Results With Ipilimumab (Second and First Line) Ipilimumab vs Vaccine and Ipilimumab + DTIC vs DTIC HR: 0.66 and 0.68 1 Patients who were pretreated with Ipi 3 mg/kg ± gp100 HR: 0.72 2 First-line Ipi 10 mg/kg + DTIC 15 gp100 = glycoprotein 100; HR = hazard ratio; Ipi = ipilimumab. 1. Hodi FS, et al. N Engl J Med. 2010;363:711-723; 2. Robert C, et al. N Engl J Med. 2011;364:2517-2526.

History of Melanoma Treatment (cont d) DTIC IL-2 Ipilimumab Pembrolizumab Nivolumab 1975 1998 2011 2013 2014 Vemurafenib Dabrafenib combined with trametinib Dabrafenib alone Trametinib alone Pembrolizumab and nivolumab approved in 2014 16 Buzaid AC, et al. Chin Clin Oncol. 2014;3:32.

Role of PD-1 Pathway in Suppressing Anti-Tumor Immunity 17 PD 1 receptor blocking antibody and PD L1/2 receptor blocking antibody CD28 = cluster of differentiation 28; IFN = interferon; NFκB = nuclear factor-kappa B; PI3K = phosphatidylinositol-3 kinase; Shp-2 = Src homology protein tyrosine phosphatase-2. Sznol M. ASCO 2013 Annual Meeting; May 31-June 4, 2013; Chicago, IL. Abstract CRA9006.

Pembrolizumab vs Chemotherapy in Progressive Disease Following Ipilimumab Therapy, Primary End Point: Progression-Free Survival Progression Free Survival, % 100 90 80 70 60 50 40 30 20 10 0 Arm Pembro 2 Q3W Pembro 10 Q3W Chemotherapy Median (95% CI), mo 2.9 (2.8 3.8) 2.9 (2.8 4.7) 2.7 (2.5 2.8) 0 2 4 6 8 10 12 14 16 18 Time, months 180 153 74 53 26 9 4 2 0 0 181 158 82 55 39 15 5 1 1 0 179 128 43 22 15 4 2 1 0 0 Rate at 6 mo Rate at 9 mo Mean, a mo 34% 24% 5.4 38% 29% 5.8 HR (95% CI) 0.57 (0.45 0.73) 0.50 (0.39 0.64) P <.0001 <.0001 16% 8% 3.6 23 Q3W = every 3 weeks. Adapted from Ribas A, et al. Society of Melanoma Research Congress 2014; November 18-21, 2014; San Francisco, CA. Abstract.

Pembrolizumab Dose-Comparison Study in Ipilimumab-Refractory Advanced Melanoma RECIST Criteria; Independent Central Review Pembrolizumab 2 mg/kg (n = 81) Pembrolizumab 10 mg/kg (n = 76) ORR, % (95% CI) 26 (17-37) 26 (17-38) Best Overall Response (%) CR 1 1 PR 25 25 SD 25 24 PD 33 41 Unable to determine 16 9 DCR (95% CI) 51 (39-62) 50 (38-62) 19 CR = complete response; DCR = disease control rate; PD = progressive disease; PR = partial response; RECIST = response evaluation criteria in solid tumors; SD = stable disease. Robert C, et al. Lancet. 2014;384:1109-1117.

Nivolumab vs Standard Chemotherapy With Dacarbazine in Treatment-Naïve Patients With Unresectable Stage III or IV Melanoma: Primary End Point OS Follow-up since randomization: 5.2-16.7 months. 20 Robert C, et al. N Engl J Med. 2015;372:320-330.

Nivolumab vs Standard Chemotherapy With Dacarbazine in Treatment-Naïve Patients With Unresectable Stage III or IV Melanoma Nivolumab (N = 210) Dacarbazine (N = 208) ORR, % (95% CI) 40 (33-47) 14 (10-19) Best Overall Response (%) CR 8 1 PR 32 13 SD 17 22 PD 33 49 Unable to determine 11 15 21 Robert C, et al. N Engl J Med. 2015;372:320-330.

Blocking CTLA-4 and PD-1 22 Wolchok JD, et al. ASCO 2013 Annual Meeting; May 31-June 4, 2013; Chicago, IL. Abstract 9012.

Nivolumab + Ipilimumab Study Best change from baseline in target lesion volume (Median) Nivolumab alone - 34.5% Nivolumab + ipilimumab - 51.9% Ipilimumab alone + 5.9% 23 Larkin J et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1504030

Nivolumab + Ipilimumab Combination Therapy Demonstrates High Response Rate Therapy ORR (%) Response Odds Ratio compared to ipilimumab (95% CI) Ipilimumab 19.0% ----- Nivolumab alone 43.7% 3.40 (2.02 5.72) Nivolumab + ipilimumab 57.6% 6.11 (3.59 10.38) 24 Larkin J, et al. N Engl J Med. 2015 May 31. [Epub ahead of print].

Nivolumab + Ipilimumab Combination Therapy Demonstrates Improvement in Progression-Free Survival 25 Larkin J, et al. N Engl J Med. 2015 May 31. [Epub ahead of print].

Nivolumab Plus Ipilimumab Combination Therapy: Treatment-related Adverse Events Nivolumab alone (N=313) Any Grade % Grade 3/4 % Nivolumab + ipilimumab (N=313) Any Grade % Grade 3/4 % Ipilimumab alone (N=311) Any Grade % Grade 3/4 % All drug-related adverse events 62 8 88 40 74 19 Skin 42 2 59 6 54 3 Gastrointestinal 20 2 46 15 37 12 Hepatic 6 3 30 19 7 2 Endocrine 14 <1 30 5 11 2 Pulmonary 2 < 1 7 1 2 <1 26 Larkin J, et al. N Engl J Med. 2015 May 31. [Epub ahead of print].

Antitumoral Response: Targeted Therapies vs Immunotherapies a Tumor Response a CTLA-4 antibodies, PD-1 antibodies, and combined CTLA-4 and PD-1 antibodies. 27 Hauschild A, et al. ASCO 2014 Annual Meeting; May 30-June 3, 2014; Chicago, IL. Abstract 9013.

According to NCCN guidelines, Frank is not a candidate for IL-2 therapy due to:?decision POINT 1. Elevated LDH 2. Comorbid T2DM 3. Inadequate organ reserve 4. Comorbid hypertension Use your keypad to vote now! 28

Among melanoma metastases, a worse prognosis is associated with:?key QUESTION 1. Nodal metastases 2. Liver metastases 3. Pulmonary metastases 4. Brain metastases Use your keypad to vote now! 29

How would you treat Frank??DECISION POINT 1. Dacarbazine 2. High-dose IL-2 3. BRAF inhibitor 4. Anti-CTLA-4 (ipilimumab) 5. Anti-PD-1 (pembrolizumab or nivolumab) Use your keypad to vote now! 30

Treatment of Advanced Melanoma in a Patient With Liver and Lung Metastases, T2DM, and Moderate Kidney Disease Dacarbazine: not appropriate 1 High-dose IL-2: not appropriate for compromised renal function 2 BRAF inhibitor not appropriate in patients with BRAF wild-type 3 Ipilimumab: FDA-approved for first line, but low response 4 2015 NCCN guidelines recommend anti-pd-1 agents (pembrolizumab and nivolumab) as first-line therapy due to higher response rates and less toxicity than ipilimumab 5 Pembrolizumab and nivolumab are not FDA-approved as first-line treatments 31 1. National Comprehensive Care Network. www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed June 5, 2015; 2. Robert C, et al. N Engl J Med. 2015;372:320-330; 3. Long GV, et al. Society of Melanoma Research Congress 2014; November 13-17; 2014; Zurich, Switzerland; 4. Ribas A, et al. Society of Melanoma Research Congress 2014; November 13-17; 2014; Zurich, Switzerland; 5. Zelboraf [prescribing information]. South San Francisco, CA: Genentech, Inc.; 2014.

Case (cont d) Frank is given pembrolizumab, 200 mg intravenously every 3 weeks After the first treatment, he is assessed by his healthcare provider and is found to be experiencing grade 2 fatigue and constipation He is advised to set priorities, pace himself, establish good sleep hygiene, and join an exercise class at a local cancer center to improve his energy levels He is given bisacodyl 10 mg 3 times daily, with the goal of achieving 1 nonforced bowel movement every 1-2 days 32 1. National Comprehensive Care Network. www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed June 5, 2015; 2. National Comprehensive Care Network. www.nccn.org/professionals/physician_gls/pdf/survivorship.pdf. Accessed June 8, 2015; 3. NCCN 2015 Palliative Care Guidelines. www.nccn.org/professionals/physician_gls/ pdf/palliative.pdf. Accessed June 5, 2015.

AE Profile of Immune Checkpoint Therapies Any Grade AE Ipilimumab (%) Immune Checkpoint Therapy Pembrolizumab (%) Nivolumab (%) Diarrhea 32 20 21 (diarrhea or Colitis 8 1 colitis) Pruritus 31 30 19 Rash 29 29 21 Fatigue 41 47 25 Constipation 2.3 21 2 33 Yervoy [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2015; Keytruda [prescribing information]. Whitehouse Station, NJ: Merck, Inc.; 2015; Opdivo [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2015; Revicki DA, et al. Health Qual Life Outcomes. 2012;10:66; Weber JS, et al. Lancet Oncol. 2015;16:375-384.

Immune-Related AEs: Ipilimumab vs Pembrolizumab Toxicity Ipilimumab (n = 1498) % Pembrolizumab (n = 411) % All Grades Grade 3/4 All Grades Grade 3/4 GI (eg, colitis) 33 9.1 1 <1 Pneumonitis <1 <1 2.9 <1 Hepatitis 1.6 1.1 <1 <1 Dermatologic 45 2.6 11-30 0 Hypophysitis 2.7 2.1 <1 <1 Thyroiditis 1.8 <1 9.5 <1 Nephritis <1 <1 <1 <1 34 Teply BA, Lipson EJ. Oncology. 2014;28(suppl 3):30-38.

Assessment for Treatment AEs Assess the patient for AEs associated with immunotherapy, including: Dermatologic effects GI effects Hepatic effects Endocrine effects Renal effects Uveitis Pneumonitis 35

Management of AEs of Immunotherapy: An Example Ipilimumab: Immune-Mediated Dermatitis Determine Severity of Dermatitis Moderate Severe or life threatening Management Withhold ipilimumab If no improvement within 1 week, administer topical or systemic corticosteroids Permanently discontinue ipilimumab Administer systemic corticosteroids 1-2 mg/kg/d prednisone equivalent Follow-up/Symptoms Resolved Resume ipilimumab if dermatitis resolves or improves to mild and systemic steroid dose is 7.5 mg prednisone equivalent or less When dermatitis is controlled, taper corticosteroid over at least 1 month 36 Yervoy [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2015.

Case 2: Jeanine Jeanine is a 54-year-old married school teacher with 2 college-aged children About a month ago, her husband noticed a dark mole on the outside of her left thigh that appeared to have grown; she made an appointment to come in for a visit Jeanine is healthy, exercises regularly, and maintains a good body weight; she has no comorbidities, and other than having seasonal allergies, is in excellent health BP: 115/70 mm Hg; heart rate: 72 beats/min, regular; temperature: 98.1 F (36.7 C); RR: 15 breaths/min BMI: 23.2 kg/m 2 Medication: vitamins 37

Case 2 (cont d) On examination 2.5-cm-diameter multicolored, irregular border, slightly exophytic pigmented lesion No lymphadenopathy An excisional biopsy of the mole is performed 1.8-mm Breslow thickness Image courtesy of Robert Andtbacka, MD, CM Clarks level IV Ulcerated Superficial spreading melanoma Recommendation for wide local excision and sentinel lymph node biopsy No evidence of residual melanoma in wide local excision No evidence of lymph node metastasis Stage pt2b, N0, M0, stage IIA 38

How would you treat Jeanine??DECISION POINT 1. Observation or clinical trial 2. IFN 3. Anti-CTLA-4 (ipilimumab) 4. Anti-PD-1 (pembrolizumab or nivolumab) Use your keypad to vote now! 39

NCCN Recommendation for Follow-up for Stage IIA Melanoma Adjuvant clinical trial or observation History and physical examination (with emphasis on nodes and skin) every 6-12 months for 5 years, then annual skin exams Routine radiologic imaging to screen for asymptomatic recurrent/metastatic disease is not recommended 40 National Comprehensive Cancer Network. www.nccn.org/professionals/physician_gls/ pdf/melanoma.pdf. Accessed June 8, 2015.

Case 2: Jeanine If, there was a 4 mm micrometastatic disease deposit in 1 of 3 sentinel lymph nodes Recommendation for staging work-up: A chest/abdominal/pelvic CT scan and brain MRI show no evidence of metastatic lesions LDH 156 U/L (normal < 264 U/L) A left groin completion lymph node dissection showed no evidence of metastatic disease in an additional 10 lymph nodes Final stage pt2b, N1a, M0, stage IIIB 41

How would you treat Jeanine, who has stage IIIB disease??decision POINT 1. Observation or clinical trial or IFNα 2. Standard of care anti- CTLA-4 (ipilimumab) 3. Standard of care anti- PD-1 (pembrolizumab or nivolumab) Use your keypad to vote now! 42

NCCN 2015 Guidelines The NCCN 2015 Guideline recommendations for Stage III (sentinel node positive) disease are: o Clinical trial or observation or interferon alfa Stage III (clinically positive node[s]) are: o Clinical trial or observation or interferon alfa and/or RT (radiotherapy) to nodal basin in select patients based on location, size, and number of involved nodes, and or macroscopic extranodal extension 43 NCCN 2015 Melanoma Guidelines.

Interferon alpha Mechanism of action First described in 1957 by Isaacs and Lindenman Interferes with viral replication > IFN IFNα (2a and 2b) Antitumor effects Activates natural killer cells Antiproliferative Antiangiogenic Upregulation of HLA I and II antigen presentation 44 Tarhini AA, et al. J Immunol. 2012;189:3789-3793.

ECOG 1684: Overall Survival Extent of Disease Patients N = 280 pt4, N0 31 (11%) LN micromets 34 (12%) LN macromets 41 (15%) LN recurrence 174 (62%) Over 70% had macrometastatic disease in lymph nodes No. No. Median 5-Year Patients Dead (years) P Value Survival (%) 45 IFN -2b 143 81 3.82 46.047 Observation 137 90 2.78 37 LN = lymph node. Kirkwood JE, et al. J Clin Oncol. 1996;14:7-17.

ECOG 1684 First nonsurgical randomized trial in advanced melanoma to show an OS advantage Led to FDA approval of high-dose IFN Became standard of care in United States in 1995 (entering 19th year) 46 Kirkwood JE, et al. J Clin Oncol. 1996;14:7-17.

Meta-Analyses of All IFN Trials Confirm RFS, OS Impact Meta-Analysis No. of RCTs RFS OS Comment Wheatley Cancer Treat Rev. 2003 Wheatley ASCO. 2007 12 + ± 13 + OR = 0.87; 95% CI, 0.81-0.93; P =.00006 + OR = 0.9; 95% CI = 0.84-0.97; P =.008 Did not include E1694 benefit with IFN dose RFS 13% risk reduction; 10% risk reduction in OS Mocellin JNCI. 2010 14 + HR = 0.82; 95% CI, 0.77-0.87; P <.001 + HR = 0.89; 95% CI, 0.83-0.96; P =.002 RFS 18% risk reduction OS 11% risk reduction 47 OR = odds ratio; RCT = randomized control trial; RFS = relapse-free survival. Tarhini AA, et al. J Immunol. 2012;189:3789-3793.

Adjuvant IFN vs Biochemotherapy: S-0008 Treatment Schema Induction IFN: 20 MIU/m 2 IV; Monday-Friday; week 1-4 Maintenance IFN: 10 MIU/m 2 SC; Monday, Wednesday, and Friday; weeks 5-52 Weeks 0 4 8 12 24 36 48 52 Cisplatin 20 mg/m 2 IV days 1-4 Vinblastine 1.2 mg/m 2 IV days 1-4 DTIC 800 mg/m 2 IV day 1 IL-2 9 MIU/m 2 CIV days 1-4 IFN 5 MIU/m 2 SC days 1-4 IFN 5 MIU SC days 8, 10, 12 G-CSF 5ug/kg SC days 7-16 No treatment 48 CIV = continuous IV; G-CSF = granulocyte-colony stimulating factor; IV = intravenous; SC = subcutaneous.

S-0008: Relapse-Free Survival 5 year RFS BCT 48% HDI 39% Median RFS BCT 4.0 years HDI 1.9 years 49 BCT = biochemotherapy; HDI = high-dose IFN. Flaherty LE, et al. J Clin Oncol. 2014;32:3771-3778.

S-0008: Overall Survival 5 year OS BCT 56% HDI 56% Median OS BCT 9.9 years HDI 6.7 years 50 Flaherty LE, et al. J Clin Oncol. 2014;32:3771-3778.

EORTC 18071 Ipilimumab vs Placebo in Resected Stage III Melanoma Randomization (IIIA, IIIB, IIIC except in-transit) N = 950 Ipilimumab 10 mg/kg Placebo Primary end point: RFS 51 Eggermont AM, et al. ASCO 2014 Annual Meeting; May 30-June 3, 2014; Chicago, IL. Abstract LBA9008.

Primary End Point: RFS Independent Review Committee Ipilimumab Placebo 100 Events/patients 234/475 294/476 100 90 HR (95% CI) a 0.75 (0.64-0.90) 90 Log-rank P value 80.0013 80 2-Year RFS rate (%) 51.5 43.8 70 *Stratified by stage. 70 3-Year RFS rate (%) b 46.5 34.8 60 Median: 26.1 mo **Data are not yet mature. 60 Median: 26.1 months 50 50 Median: 17.1 mo 40 Median: 17.1 months 40 30 30 20 10 Ipilimumab Ipilimumab 10 10 mg/kg mg/kg Placebo Placebo 0 0 12 12 24 24 36 36 48 48 60 60 Patients at Risk Months O O N N Ipilimumab Placebo 234 294 475 476 276 260 205 205 193 193 67 67 62 62 5 4 5 4 0 0 0 0 Patients Alive Without Relapse (%) 52 a Stratified by stage; b Data are not yet mature. Eggermont AM, et al. ASCO 2014 Annual Meeting; May 30-June 3, 2014; Chicago, IL. Abstract LBA9008.

MK-3475 (pembrolizumab) vs IFN for Resected High-Risk Melanoma a A Phase 3 Randomized Study 1:1 53 a SWOG 1404 Intergroup. AJCC = American Joint Committee on Cancer.

Case (cont d) Jeanine choses observation NCCN 2015 guidelines recommend: History and physical examination (with emphasis on nodes and skin) every 3-6 months for 2 years, then every 3-12 months for 3 years, then annually Consider chest x-ray, CT, and/or PET/CT scans every 3-12 months to screen for recurrent/metastatic disease, and an annual brain MRI for stage IIB through IV Routine radiologic imaging to screen for asymptomatic recurrent/metastatic disease is not recommended after 3-5 years 54 PET = positron-emission tomography.

Recap: NCCN 2015 Guidelines on Surveillance Patients with melanoma stages IA-IIA should be assessed by physical examination of skin and lymph nodes every 6-12 months for 5 years Patients with melanoma stages IIB-IV should be assessed every 3-6 months for 2 years by physical examination of skin and lymph nodes and every 3-12 months for 3 years, then annually as clinically indicated Chest x-ray, CT, and/or PET/CT scans every 3-12 months to screen for recurrent/metastatic disease Consider annual brain MRI 55

Assessment for Disease Progression Patients with early-stage melanoma should undergo physical examination of skin and lymph nodes every 6-12 months for 5 years Patients with later-stage disease should receive both regular physical examination of skin and lymph nodes and imaging every 3-12 months; annual brain MRI should be considered 56

Assessment for Disease Progression Patients with more advanced disease should be advised of the existence of ongoing clinical trials for which they may qualify 57

Examples of Clinical Trials in Patients With Advanced Melanoma Oncolytic virus (T-VEC) in combination with ipilimumab Oncolytic virus (T-VEC) in combination with pembrolizumab Pembrolizumab in combination with trametinib and dabrafenib (KEYNOTE-022) T-VEC = talimogene laherparepvec. 58 NIH. www.clinicaltrials.gov/ct2/show/nct01740297?term=ipilimumab+and+talimogene&rank=1. Accessed June 8, 2015; NIH. www.clinicaltrials.gov/ct2/show/nct02263508?term= PEMBROLIZUMAB+AND+TALIMOGENE&rank=1. Accessed June 8, 2015; NIH. www.clinicaltrials.gov/ct2/show/nct02130466?term=pembrolizumab+and+keynote+ AND+MELANOMA&rank=7. Accessed June 8, 2015.

T-VEC + Ipilimumab Phase 1b Trial (20110264) S C R E E N I N G E N R O L L M E N T Screening 28 days prior to enrollment Stage IIIB/C-IV M1c melanoma not suitable for surgical resection, no prior systemic treatment (except adjuvant treatment) T-VEC up to 4 ml 10 6 pfu/ml week 1 day 1, 10 8 pfu/ml week 4, day 1 and then every 2 weeks + Ipilimumab 3 mg/kg every 3 weeks x 4 starting week 6, day 1 N = 19 T-VEC dosing until CR, all injectable tumors disappeared, PD per immune-related response criteria, or intolerance for treatment, whichever comes first E N D O F T R E A T M E N T S A F E T Y F O L L O W - U P 30 (+7) days after last dose of T-VEC or 60 (+7) days after last dose of ipilimumab S U R V I V A L F O L L O W - U P Up to 24 months after end of randomization Primary end point: Incidence of dose-limiting toxicities Secondary end points: ORR, safety: all AEs, grade 3 AEs, serious AEs, events requiring discontinuation of study drug, events with local effects on tumors (pain, inflammation, and ulceration) 59 Puzanov I, et al. ASCO 2014 Annual Meeting. May 30-June 3, 2014; Chicago, IL. Abstract 9029; NIH. https://clinicaltrials.gov/ct2/show/nct01740297. Accessed June 8, 2015.

Maximal Change in Tumor Burden With T-VEC and Ipilimumab Percentage Change From Baseline 550 450 350 250 150 100 50 25 0 Patients (N = 17) a Investigator-Assessed Responses N = 18 b Overall response 10 (56%) (95% CI, 31%-79%) CR 6 (33%) PR 4 (22%) SD 3 (17%) PD 5 (28%) 50 100 Stage IIIb (N = 1) Stage IIIc (N = 3) Stage IV M1a (N = 4) Stage IV M1b (N = 5) Stage IV M1c (N = 4) 60 a One patient assessed to have PD by the investigator was not shown in the plot because tumor burden could not be accurately calculated based on missing post-baseline data. b Efficacy analysis set includes only patients who received both T-VEC and ipilimumab. Puzanov I, et al. ASCO 2014 Annual Meeting; May 30-June 3, 2014; Chicago, IL. Abstract 9029.

PCE ACTION PLAN

PCE Action Plan Counsel patients/caregivers on the importance of anticipating and treating AEs of treatment to avoid interruption of effective therapy Counsel patients/caregivers on the importance of regular follow-ups Counsel patients/caregivers on the possibility of enrolling in a clinical trial PCE Promotes Practice Change 62