Immunotherapy Experience in Melanoma Integrating IO into Clinical Practice Sanjiv S. Agarwala, MD

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1 Immunotherapy Experience in Melanoma Integrating IO into Clinical Practice Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Oncology & Hematology St. Luke s Cancer Center, Bethlehem, PA

2 Overview Current Therapy for Melanoma BRAF-WT patient BRAF+ patient Immunotherapy side effects management and practical considerations

3 Transforming the Landscape Immunotherapy Target host Hit a Target Targeted Therapy Target tumor

Immuno-oncology Timeline Clinical Developments William

Steinman Dendritic Cells Laboratory Discoveries BCG

Doherty MHCI Tcell recognition First trial with IL-2

with IFNa Melanoma 1957 1967 1973 1974 1976 1983 1985

st HumanTumour Antigens TNFa Isolated limb perfusion

Burnett Cancer Immunosurveillance Non-myeloablative

Allison CTLA4 blockade enhances cancer immunity Chen &

Regulatory approvals FDA: Brentuximab acd30 HD&AnLC

FDA Nivo Melanoma FDA Blinotumomab (BiTE) ALL FDA

1991 1992 1995 1996 2002 2008 2009 2011-2015 CTLA4

Cancer 2016 FDA Daratumumab Regulatory (acd38)

Bladder FDA Nivo NonSq FDA: NSCLC Nivolumab chl FDA:

Japan: Combination Nivolumab: chl Melanoma Japan:

Japan: Melanoma Pembro NSCLC Japan NSCLC: NSCLC (1 st

4 Immuno-oncology Timeline Clinical Developments William Coley Mixed Toxins 1882 Allogeneic BM transplantation Steinman Dendritic Cells Laboratory Discoveries BCG Bladder Cancer Hepatitis B Vaccine Zinkernagel & Doherty MHCI Tcell recognition First trial with IL-2 First trial Adoptive T cells in cancer First trial with IFNa Melanoma Interferons cloned Boon, Rosenberg Characterisation 1 st HumanTumour Antigens TNFa Isolated limb perfusion melanoma & sarcoma Sakaguchi Rediscovery of Tregs Burnett Cancer Immunosurveillance Non-myeloablative chemorx & adoptive T cell melanoma Discovery of TLRs Allison CTLA4 blockade enhances cancer immunity Chen & Pardoll PD-1 Ligands identified Imiquimod VIN 2011 Regulatory approvals FDA: Brentuximab acd30 HD&AnLC Lymphoma FDA Ipi Melanoma 2014 Regulatory approvals FDA Nivo Melanoma FDA Blinotumomab (BiTE) ALL FDA Pembo Melanoma Japan: Nivo melanoma HPV Vaccine in VIN CTLA4 Identified 2015 Regulatory approvals FDA Nivo Renal Cancer 2016 FDA Daratumumab Regulatory (acd38) approvals Myeloma FDA: Atezolizumab FDA Tvec melanoma Bladder FDA Nivo NonSq FDA: NSCLC Nivolumab chl FDA: pembro Japan: NSCLC Nivolumab RCC : FDA Ipi Nivo Japan: Combination Nivolumab: chl Melanoma Japan: Pembrol: : FDA: Nivo NSCLC Melanoma : Austr: Pembro: Japan: Melanoma Pembro NSCLC Japan NSCLC: NSCLC (1 st & 2 nd line) 2017 Regulatory Approvals FDA: Pembro NSLC 1 st Line Atezolizumab: Lung Avelumab: Merkel Cell CA

5 Immunotherapy for Cancer = Checkpoint Inhibitors

6 What is a Check-Point?

7 T-Cell Activity Is Regulated By Immune Checkpoints to Limit Autoimmunity 1 Dendritic cell TUMOR Inactivated T cell Immune checkpoints, such as CTLA-4, PD-1, LAG-3, and TIM-3 function at different phases in the immune response to regulate the duration and level of the T- cell response. - - Checkpoints CTLA-4 = cytotoxic T-lymphocyte antigen 4; PD-1 = programmed cell death protein 1; LAG-3 = lymphocyte activation gene 3; TIM-3 = T-cell immunoglobulin and mucin protein Pardoll DM. Nat Rev Cancer. 2012;12: Activated T cell Checkpoints LYMPH NODE Inactivated T cell

8 What is a Check-Point Inhibitor?

9 Immunotherapy Immune System Cytokines Antigens Regulatory molecules (CTLA-4, PD-1)

10 Check-Point Inhibitors Approved for Melanoma Anti CTLA4 antibody: Ipilimumab Anti PD-1 inhibitors: pembrolizumab, nivolumab Combination anti CTLA-4 and anti-pd1 (ipilimumab and nivolumab)

shutting down T-cell activity to prevent autoimmunity 1-3 CTLA-4 = cytotoxic T-lymphocyte antigen 4. 1. Pardoll DM.

11 CTLA-4 Primarily Affects The Priming Phase of T-Cell Activation 1 Priming (Early Stage) Phase of Activation Dendritic cell CTLA-4 Inactivated T cell In healthy tissues, CTLA-4 is thought to function as a dominant off switch broadly shutting down T-cell activity to prevent autoimmunity 1-3 CTLA-4 = cytotoxic T-lymphocyte antigen Pardoll DM. Nat Rev Cancer. 2012;12: ; 2. Ribas A. N Engl J Med. 2012;366: ; 3. Topalian SL et al. Curr Opin Immunol. 2012;24:

12 Clinical Results with Ipilimumab (2 nd and 1st line) Ipilimumab vs vaccine and Ipi + DTIC vs DTIC HR: 0.66 and 0.68 Pre-treated pts Ipi 3 mg/kg +/- gp100 HR: 0.72 First line Ipi 10 mg/kg + DTIC Hodi FS, et al. N Engl J Med. 2010;363: Robert C, et al. N Engl J Med. 2011;364:

13 Immune Checkpoint Inhibitors Provide Durable Long-term Survival for Patients with Advanced Melanoma Overall Survival (%) IPI (Pooled analysis) 1 N=1, Years 1. Schadendorf et al. J Clin Oncol 2015;33: ; 2. Current analysis; 3. Poster presentation by Dr. Victoria Atkinson at SMR 2015 International Congress. 13

14 Ipilimumab became the standard of care in USA for advanced melanoma in 2011 But can we do better?

PD-1 Primarily Regulates the Effector Phase of T-Cell Activity Effector Phase Normal cell PD-1 Inactivated T cell The PD-1 immune checkpoint pathway primarily functions during the effector phase of

15 PD-1 Primarily Regulates the Effector Phase of T-Cell Activity Effector Phase Normal cell PD-1 Inactivated T cell The PD-1 immune checkpoint pathway primarily functions during the effector phase of the T-cell response in the peripheral tissue 1 In healthy tissues, PD-1 is thought to limit the activity of antigen-specific T cells to prevent collateral tissue damage during infection 1 In cancer, the PD-1 pathway can be exploited by some tumor cells to inactivate T cells 1 PD-1 = programmed cell death protein Pardoll DM. Nat Rev Cancer. 2012;12:

Keynote-006 Front-line Pembrolizumab vs Ipilimumab Patients

excluding anti CTLA-4, PD-1, or PD-L1 agents Known BRAF status

disease Stratification factors: ECOG PS (0 vs 1) Line of

R 1:1:1 Pembrolizumab 10 mg/kg IV Q2W Pembrolizumab 10 mg/kg IV

and OS Secondary end points: ORR, duration of response, safety

b Prior anti-braf targeted therapy was not required for

tumor-related symptoms or evidence of rapidly progressing

16 Keynote-006 Front-line Pembrolizumab vs Ipilimumab Patients Unresectable, stage III or IV melanoma 1 prior therapy, excluding anti CTLA-4, PD-1, or PD-L1 agents Known BRAF status b ECOG PS 0-1 No active brain metastases No serious autoimmune disease Stratification factors: ECOG PS (0 vs 1) Line of therapy (first vs second) PD-L1 status (positive c vs negative) R 1:1:1 Pembrolizumab 10 mg/kg IV Q2W Pembrolizumab 10 mg/kg IV Q3W Ipilimumab 3 mg/kg IV Q3W x 4 doses Primary end points: PFS and OS Secondary end points: ORR, duration of response, safety a Patients enrolled from 83 sites in 16 countries. b Prior anti-braf targeted therapy was not required for patients with normal LDH levels and no clinically significant tumor-related symptoms or evidence of rapidly progressing disease. c Defined as membranous PD-L1 expression in 1% of tumor cells as assessed by IHC using the 22C3 antibody.

17 Tumor Response (irrc, investigator)

18 Kaplan-Meier Estimates of Survival (Median Follow-Up, 33.9 mo) OS (%) No Risk Pembro Overall Survival Events, n HR (95% CI) Median, mo (95% CI) Pembrolizumab , ( ) 32.3 (24.5-NR) Ipilimumab ( ) Months 55% 42% % 39% Pembro Ipilimumab Ipilimumab PFS (%) PFS per irrc by Investigator Events, n HR (95% CI) Median, mo (95% CI) Pembrolizumab , ( ) 8.3 ( ) Ipilimumab ( ) Months 34% 15% % 14% Adapted from Robert C, et al. ASCO Abstract 9504.

19 Slide 14

20 Slide 15

21 Anti PD-1 is better than ipilimumab frontline and responses are durable even after stopping treatment But what about combining CTLA-4 and PD-1?

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

23 Updated Response To Treatment NIVO+IPI (N=314) NIVO (N=316) IPI (N=315) ORR, % (95% CI)* 58.9 ( ) 44.6 ( ) 19.0 ( ) Best overall response % Complete response Partial response Stable disease Progressive disease Unknown Median duration of response, months (95% CI) NR (NR NR) 31.1 (31.1 NR) 18.2 (8.3 NR) *By RECIST v1.1; NR = not reached. At the 18-month DBL, the CR rate for NIVO+IPI, NIVO and IPI was 12.1%, 9.8% and 2.2%, respectively Database lock: Sept 13, 2016, minimum f/u of 28 months 23

24 Updated Progression-Free Survival Progression-free Percentage Survival of PFS (%) NIVO+IPI NIVO IPI 50% 43% 18% Median PFS, mo (95% CI) HR (95% CI) vs. IPI HR (95% CI) vs. NIVO NIVO+IPI (N=314) NIVO (N=316) IPI (N=315) 11.7 ( ) 0.42 ( ) 0.76 ( ) Months 43% 37% 12% 6.9 ( ) 0.54 ( ) 2.9 ( ) Patients at risk: NIVO+ IPI NIVO IPI Database lock: Sept 13, 2016, minimum f/u of 28 months 7

25 Updated Survival Data in CheckMate-067 Trial of IPI vs. NIVO vs. IPI/NIVO Median OS, months (95% CI) HR (99.5% CI) vs. IPI HR (99.5% CI) vs. NIVO NIVO + IPI (N=314) NIVO (N=316) IPI (N=315) NR 0.55 ( )* 0.88 ( ) NR (29.1-NR) 0.63 ( )* 20 ( ) *P< Larkin J, et al. AACR Abstract CT075. Database lock: September 13, Minimum follow-up of 28 months

26 Decision Point. Immunotherapy PD-1 alone PD-1/CTLA-4 Combination

27 Checkmate 067: Safety Summary With an additional 19 months of follow-up, safety was consistent with the initial report 1 NIVO+IPI (N=313) NIVO (N=313) IPI (N=311) Patients reporting event, % Any Grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade 3-4 Treatment-related adverse event (AE) Treatment-related AE leading to discontinuation Treatment-related death, n (%) 2 (0.6) a 1 (0.3) b 1 (0.3) b Most select AEs were managed and resolved within 3-4 weeks (85 100% across organ categories) ORR was 70.7% for pts who discontinued NIVO+IPI due to AEs, with median OS not reached a Cardiomyopathy (NIVO+IPI, n=1); Liver necrosis (NIVO+IPI, n=1). Both deaths occurred >100 days after the last treatment. b Neutropenia (NIVO, n=1); colon perforation (IPI, n=1) Larkin J, et al. NEJM 2015;373:

28 Checkmate 067: Safety Onset Grade 3 4 Treatment-Related Select AEs Skin (n=18) Skin (n=5) Gastrointestinal (n=46) Gastrointestinal (n=7) Endocrine (n=15) Endocrine (n=2) Hepatic (n=60) 14.1 ( ) Longer Time to Resolution Hepatic (n=8) 3.7 ( ) NIVO+IPI Pulmonary (n=3) 6.7 ( ) NIVO Pulmonary (n=1) 11.3 ( ) Renal (n=6) 5.6 ( ) 7.4 ( ) 19.4 ( ) 26.3 ( ) 12.1 ( ) Toxicity Earlier 28.6 ( ) 7.4 ( ) 50.9 ( ) Renal (n=1) Weeks Circles represent medians; bars signify ranges Larkin J et al ECC 2015

30 Pembro Keynote 001: 4 Year OS

31 Overall Survival at 5 Years of follow-up for Nivolumab (phase I, n=107) All Patients (events: 69/107), median and 95% CI: 17.3 ( ) NIVO 3 mg/kg (events: 11/17), median and 95% CI: 20.3 (7.2 NR) Probability of Survival Months Number of Patients at Risk All Patients NIVO 3 mg/kg Database lock Oct 2015 Hodi et al. AACR 2016

32 Can a biomarker help us decide?

Keynote 001 Pembrolizumab PD-L1 Expression and Response

score. Analysis cut-off date: October 18, 2014.

10-33% Staining APS = 3 PD-L1 Positive 66-100% Staining

33 Keynote 001 Pembrolizumab PD-L1 Expression and Response PD-L1 Negative 0% Staining APS = 0 APS, Allred proportion score. Analysis cut-off date: October 18, PD-L1 Positive 1-10% Staining APS = 2 PD-L1 Positive 10-33% Staining APS = 3 PD-L1 Positive % Staining APS = 5 ORR, % (95% CI) APS 0 n = 28 ORR, RECIST v1.1 APS 1 n = 24 Negative APS 2 n = 72 APS 3 n = 54 Positive APS 4 n = 32 APS 5 n = 34 Daud A et al, ASCO 2015

34 OS by Tumor PDL-1 Expression at a 1% Cutoff PD-L1 Expression Level <1% PD-L1 Expression Level 1% <1% PD-L1 NIVO+IPI NIVO IPI 1% PD-L1 NIVO+IPI NIVO IPI Median OS, mo (95% CI) NR (26.5 NR) 23.5 (13.0 NR) 18.6 ( ) Median OS, mo (95% CI) NR NR 22.1 ( ) 100 HR (95% CI) vs NIVO 0.74 ( ) 100 HR (95% CI) vs NIVO 1.03 ( ) OS (%) % 49% 41% OS (%) % 67% 48% ORR of 54.5% for NIVO+IPI and 35.0% for NIVO 10 ORR of 65.2% for NIVO+IPI and 55.0% for NIVO Months Patients at risk: NIVO+IPI NIVO IPI Months Patients at risk: NIVO+IPI NIVO IPI

35 PFS and OS Subgroup Analyses (All Randomized Patients) Descriptive comparison between NIVO+IPI and NIVO Patients Unstratified Hazard Ratio Unstratified Hazard Ratio (95% CI) Subgroup NIVO+IPI NIVO PFS OS PFS OS Overall <65 years years BRAF Mutant BRAF Wild-type ECOG PS = ECOG PS = M0/M1a/M1b M1c LDH ULN LDH > ULN LDH > 2 x ULN PD-L1 5% PD-L1 <5% NIVO+IPI NIVO NIVO+IPI NIVO 2 35

36 Overview Current Therapy for Melanoma BRAF-WT patient BRAF+ patient Immunotherapy side effects management and practical considerations

37 Melanoma is not one disease (Curtin et al, N Engl J Med 353: , 2005) B-RAF: 50% c-kit: 5-10% c-kit: 10-20% c-kit:15-30%

38 MAPK Pathway Growth Factors RAS BRAF MEK ERK Cell proliferation and survival

39 BRAF Mutation Growth Factors RAS BRAF BRAF mutation is present in ~50% of melanomas MEK ERK Increased cell proliferation and survival

40 MAPK Pathway Targeted Therapy BRAFi (dabrafenib) PFS HR, 0.37 vs DTIC 1 Hyperproliferative skin AEs BRAFi (vemurafenib) PFS HR, 0.38 vs DTIC 2 Hyperproliferative skin AEs PFS HR, 0.45 vs chemotherapy 3 MEKi (trametinib) RAS mutbraf MEK perk Proliferation, Survival, Invasion, Metastasis BRAFi + MEKi ph III studies Dabrafenib + trametinib (D + T) PFS HR, 0.67 vs dabrafenib 4 OS HR, 0.71 vs dabrafenib 4 PFS HR, 0.56 vs vemurafenib 5 OS HR, 0.69 vs vemurafenib 5 Vemurafenib + cobimetinib PFS HR, 0.58 vs vemurafenib 6 OS HR, 0.70 vs vemurafenib 6 Decreased hyperproliferative skin AEs 4,5,6 1. Hauschild A, et al. Lancet. 2012;380(9839): McArthur GA, et al. Lancet Oncol. 2014;15(3): Flaherty KT, et al. N Engl J Med. 2012;367(2): Long GV, et al. Lancet. 2015;386(9992): Robert C, et al. N Engl J Med. 2015;372(1): Atkinson V, et al. Presented at:society for Melanoma Research 2015 Congress.

41 Decision Point. BRAF mutation test BRAF V600 mutation negative Immunotherapy Immunotherapy Or BRAF V600 mutation positive MAP-K Targeted Therapy

42 Slide 34 Presented By Axel Hauschild at 2014 ASCO Annual Meeting

43 Phase III KEYNOTE-006: PFS in Prespecified Subgroups Overall Male Female Age <65 y Age ³65 y White race US Rest of world ECOG PS ECOG PS Favors Pembro Favors IPI 10 Hazard Ratio Pembrolizumab Q2W vs ipilimumab Analysis cut-off date: September 3, First-line therapy Second-line therapy PD-L1 positive PD-L1 negative BRAF wild type BRAF mutant, 95 prior anti-braf 96 BRAF mutant, no prior anti-braf No prior immunotherapy Favors Pembro Favors IPI 10 Pembrolizumab Q3W vs ipilimumab Hazard Ratio

BRAF Inhibitors Second line Vemurafenib 1 Dabrafenib 2 Phase 1 2 3 1 2

ASCO 2012); Sosman JA, et al. N Engl J Med 2012;366:707 714; 2.

44 BRAF Inhibitors Second line Vemurafenib 1 Dabrafenib 2 Phase RR 56% 57% 57% 56% 59% 59% PFS OS Chapman PB, et al. N Engl J Med 2011;364: (updated Chapman et al. ASCO 2012); Sosman JA, et al. N Engl J Med 2012;366: ; 2. Hauschild A, et al. Lancet 2012;380: (updated Hauschild et al. ASCO 2013); Ascierto PA, et al. J Clin Oncol 2013; 31:

45 D+T: Long Term FU LDH < ULN and < 3 metastatic sites (ITT) Progression-Free Survival Overall Survival Progression-Free Survival, % % 40 25% 25% 20 8% 8% 8% Patients at risk, n Time From Randomization, months Patients at risk, n Time From Randomization, months Overall Survival, % % 57% 60 51% 58% 40 42% 31% 20 PRESENTED BY J WEBER AT ASCO 2017

46 Contemplating the Options EA6134 Anti-PD1 therapy BRAF-targeted therapy

47 Combining Immunotherapy and Targeted Therapy for Melanoma? Improved Survival With Ipilimumab in Patients with Metastatic Melanoma 1 Improved Survival With Vemurafenib in Melanoma With BRAF V600E Mutation 2 Percent Alive Immunotherapy Years Percent Alive Targeted therapy Years Percent Alive 0 Combination??? Years Modified from: Ribas A, et al. Clin Cancer Res. 2012;18(2): Hodi FS, et al. N Engl J Med. 2010;363(8): Chapman PB, et al. N Engl J Med. 2011;364(26):

Targeted-Immuno Triplets: BRAF + MEK + PD1/L1 Dabrafenib+Trametinib +Durvalumab Dabrafenib+Trametinib +Pembrolizumab Vemurafenib+Cobimetinib

Trametinib + PDR-001-75 -100 - Vemurafenib + Cobimetinib 0 10 20 30 40+ Atezolizumab 50 60 70 Time, weeks Change From Baseline in Sum of Longest

48 Targeted-Immuno Triplets: BRAF + MEK + PD1/L1 Dabrafenib+Trametinib +Durvalumab Dabrafenib+Trametinib +Pembrolizumab Vemurafenib+Cobimetinib +Atezolizumab 100 Multiple Triplet Combinations Launching Into Phase III: Dabrafenib + Trametinib + Pembrolizumab Dabrafenib + Trametinib + PDR Vemurafenib + Cobimetinib Atezolizumab Time, weeks Change From Baseline in Sum of Longest Diameter of Target Lesion, % Change From Baseline, % Ribas et al. ASCO 2015 Ribas et al. ASCO 2016 Hwu et al. ECCO 2016

49 Overview Current Therapy for Melanoma BRAF-WT patient BRAF+ patient Immunotherapy side effects management and practical considerations

50 Practical Issues in Management Assessing Response Recognizing and managing toxicity

51 Immunotherapy: Heterogeneous Response Patterns Change From Baseline SPD (%) Change From Baseline SPD (%) 4 distinct response patterns associated with favorable OS Response in baseline lesions Relative Day From Randomization Date Response after initial increase in tumor volume Wolchok JD, et al. Clin Cancer Res. 2009;15: N Relative Day From Date of First Dose SPD (mm 2 ) SPD (mm 2 ) Change From Baseline SPD Change (%) From Baseline SPD (%) SD with slow decline in tumor volume Relative Day From Date of First Dose 25 0 Tumor volume reduction after new lesions N N N N N N Relative Day From Date of First Dose SPD (mm 2 ) SPD (mm 2 )

Immune-Related Patterns of Response with

Appearance and Subsequent Disappearance of

3 mg/kg Ipilimumab Q3W X 4 Pseudoprogression

Week 36: Still Regressing Courtesy of J.

52 Immune-Related Patterns of Response with anti-ctla4: Melanoma Response After the Appearance and Subsequent Disappearance of New Lesions Pretreatment Week 20: Regression 3 mg/kg Ipilimumab Q3W X 4 Pseudoprogression Tumor Flare Week 12: Progression New lesions Week 36: Still Regressing Courtesy of J. Wolchok. Source: Wolchok et al, ASCO 2008 (Abstract #3020).

53 Response Assessment: RECIST vs. irrc Category RECIST v1.1 mwho irrc Measurement: tumor burden Complete Response (CR) Unidimensional: Sum Longest Diameter Bidimensional: Sum Product Diameter (SPD) Disappearance of all target and non-target lesions Confirmation required: two consecutive observations no less than 4 weeks apart Partial Response (PR) 30% in tumor burden compared to baseline Confirmation required Progressive Disease (PD) 20% + 5 mm absolute in tumor burden compared to nadir New lesion No confirmation required 50% in tumor burden compared to baseline Confirmation required 25% in tumor burden compared to nadir New lesion No confirmation required Bidimensional: SPD 50% in tumor burden compared to baseline Confirmation required 25% in tumor burden compared to baseline, nadir, or reset baseline New lesions added to tumor burden Confirmation required Stable Disease Neither PR nor PD 1. Agarwala SS. Semin Oncol Miller AB et al. Cancer 1981;47: Wolchok JD et al. Clin Cancer Res 2009;15(23):

54 Immune Checkpoint Blockade Key Points About Response Evaluation Antitumor activity may appear to be delayed compared to response times associated with cytotoxic therapies Patients may experience response after the appearance of progressive disease Development of progressive disease should be confirmed prior to discontinuation of therapy Development of small lesions in the presence of other responsive lesions may be clinically insignificant Responses are durable among CRs but also in PR and SD Agarwala SS. Semin Oncol

55 Practical Issues in Management Assessing Response Recognizing and managing toxicity

iraes Associated With Immuno-Oncology Therapies a Hepatic Autoimmune hepatitis 1,3 ALT/AST increases 1,2 Endocrine Hypophysitis 1 3 Thyroiditis 1,3 Type 1 diabetes 4 Respiratory Renal

represent some but not all iraes that may occur with immune checkpoint inhibitor therapies. 1. Teply BA et al. Oncology (Williston Park). 2014;28 Suppl 3:30 38. 2. Hodi FS et al.

56 iraes Associated With Immuno-Oncology Therapies a Hepatic Autoimmune hepatitis 1,3 ALT/AST increases 1,2 Endocrine Hypophysitis 1 3 Thyroiditis 1,3 Type 1 diabetes 4 Respiratory Renal Pneumonitis 1,3 Nephritis 1 Renal failure 5 Gastrointestinal Skin Colitis/diarrhea 1,2 Macropapular rash 1 Pruritus 1,2 Neuromuscular Peripheral sensory neuropathy 1 a The AEs described here represent some but not all iraes that may occur with immune checkpoint inhibitor therapies. 1. Teply BA et al. Oncology (Williston Park). 2014;28 Suppl 3: Hodi FS et al. N Engl J Med. 2010;363(8): Topalian SL et al. N Engl J Med. 2012;366(26): Mellati M et al. Diabetes Care. 2015;38(9):e137 e Forde PM et al. Anticancer Res. 2012;32(10):

57 CTLA-4 Blockade With Ipilimumab Kinetics of iraes in Melanoma Toxicity Grade Weber JS, et al. J Clin Oncol Time (weeks)

58 PD-1 Blockade: Kinetics of iraes in Melanoma Approximate proportion of patients (%) Time (weeks) Skin Gastrointestinal Endocrine Hepatic Pulmonary Renal Weber JS, et al. ASCO

59 Most Clinically Relevant iraes GI diarrhea Pulmonary pneumonitis Endocrine thyroid, pituitary Dermatologic Hepatic

60 Gastrointestinal Toxicity NCI CTCAE v4.0 Grade 1 Grade 2 Grade 3 Grade 4 Colitis Asymptomatic, pathologic or radiographic findings only Abdominal pain; mucus or blood in stool Abdominal pain, fever, change in bowel habits with ileus; peritoneal signs Life-threatening consequences (eg, perforation, bleeding, ischemia, necrosis, toxic megacolon) Diarrhea Increase of <4 stools per day over CLOSE baseline; mild increase MONITORING in ostomy output compared TREAT to baseline SYMPTOMS Increase of 4-6 stools per day over baseline; ORAL IV fluids CORTICOIDS indicated IF SYMPTOMS <24 hours; moderate increase >5 DAYS in ostomy output compared to baseline; not interfering with ADL Increase IV HIGH of DOSE 7 stools CORTICOIDS Life-threatening per day over baseline; consequences incontinence; CONSIDER ALTERNATIVE fluids (eg, hemodynamic IMMUNOSUPPRESSIVE 24 hours; THERAPY collapse) hospitalization; severe increase CONSULT in ostomy GASTROENTERELOGIST output compared to baseline; interfering with ADL Enteritis Asymptomatic, pathologic or radiographic findings only Abdominal pain; mucus or blood in stool Abdominal pain, fever, change in bowel habits with ileus; peritoneal signs Life-threatening consequences (eg, perforation, bleeding, ischemia, necrosis)

61 Gastrointestinal (colitis, diarrhea), Grade 1 Ø Continue therapy, treat symptomatically with loperamide and/or diphenoxylate/atropine. Ø Follow-up: Monitor closely for worsening symptoms, educate patient to report worsening immediately. Ø If symptoms worsen: treat as grade 2 or 3/4

62 Gastrointestinal (colitis, diarrhea), Grade 2 Ø Hold therapy; treat symptomatically as for grade 1; check C. difficile titres and stool cultures. Ø Follow-up: Resume therapy if symptoms improve to grade 1 Ø If symptoms persist > 5 days or recur: Ø -Initiate mg/kg per day methylprednisolone or oral equivalent -When symptoms improve to grade 1, taper steroids over 1 mo, consider prophylactic antibiotics and resume therapy Ø If symptoms worsen or persist for >3 days with oral steroids: treat as grade 3/4

Gastrointestinal (colitis, diarrhea), Grade 3 Ø -Consider permanent discontinuation of therapy -Consider hospital admission -1.0-2.

63 Gastrointestinal (colitis, diarrhea), Grade 3 Ø -Consider permanent discontinuation of therapy -Consider hospital admission mg/kg/day IV methylprednisolone or equivalent -Add prophylactic antibiotics for opportunistic infections -Consider endoscopy; check C. difficile titres and cultures Ø Follow-up: If symptoms improve, continue steroids until grade 1, then taper over at least 1 month. Ø If symptoms persist > 3 days or recur after improvement: Add infliximab 5 mg/kg/day (if no contraindication, and should not be used in cases of perforation or sepsis)

Gastrointestinal (colitis, diarrhea), Grade 4 Ø -Permanently discontinue therapy -Hospital admission -1.0-2.

64 Gastrointestinal (colitis, diarrhea), Grade 4 Ø -Permanently discontinue therapy -Hospital admission mg/kg/day IV methylprednisolone or equivalent -Consider endoscopy ; check C Difficile titres and cultures -Consult GI consult Ø Follow-up: If symptoms improve, continue steroids until grade 1, then taper over at least 1 month Ø If symptoms persist > 3 days or recur after improvement: Add infliximab 5 mg/kg/day (if no contraindication, and should not be used in cases of perforation or sepsis)

65 Pulmonary (pneumonitis), Grade 1 Ø -Obtain chest x-ray Ø -Consider holding therapy Ø -Monitor for symptoms every 2-3 days Ø -Consider pulmonary and ID consults Ø Follow-up: Re-image at least every 3 weeks Ø If symptoms worsen: Treat as grade 2 or grade 3/4

66 Pulmonary (pneumonitis), Grade 2 Ø -Hold therapy -Consider chest CT -Pulmonary consult -Monitor symptoms daily, strongly consider hospitalization -1.0 mg/kg/day IV methylprednisolone or oral equivalent -Consider bronchoscopy Ø Follow-up: Re-image every 1-3 days Ø If symptoms improve to baseline: Taper steroids over 1 month; resume therapy and consider prophylactic antibiotics Ø If symptoms persist or worsen after 2 wks: Treat as grade 3/4

67 Pulmonary (pneumonitis), Grade 3/4 Ø -Permanently discontinue therapy -Hospitalize? -Pulmonary and ID consults -2-4 mg/kg/day IV methylprednisolone or IV equivalent -Consider bronchoscopy, lung biopsy Ø Follow-up: If symptoms improve to baseline: Taper steroids over 6 weeks Ø If symptoms persist or worsen after 48 hrs: Add additional infliximab, cyclophosphamide, IVIG, or mycophenolate mofetil

68 Ø Continue therapy Endocrine: Thyroid Asymptomatic TSH elevation Ø Follow-up: -If TSH < 0.5 X lower limit of normal, or TSH > 2 x upper limit of normal, or consistently out of range in 2 subsequent measurements: include free T4 at subsequent cycles as indicated Ø -Consider endocrinology consult and start hormone replacement if TSH > 2X ULN

69 Endocrine: Thyroid Symptomatic hypothyroidism Ø -Monitor TFTs every 1 to 3 weeks Ø -Consider pituitary MRI Ø -Endocrinology consult Ø -Initiate hormone replacement therapy Hypothyroidism

Endocrine: hypophysitis, not symptomatic Ø -Hold therapy -Evaluate pituitary function -Consider MRI with pituitary cuts -Initiate hormone replacement with abnormal pituitary scan -Cortisol

70 Endocrine: hypophysitis, not symptomatic Ø -Hold therapy -Evaluate pituitary function -Consider MRI with pituitary cuts -Initiate hormone replacement with abnormal pituitary scan -Cortisol replacement should be initiated 1 week prior to levothyroxine administration Ø Follow-up: -If improved (with or without hormone replacement), can resume treatment -Consider endocrinology consult

Endocrine: hypophysitis, symptomatic Ø -Permanently discontinue therapy -1 mg/kg/day prednisone or equivalent -Evaluate pituitary axis function (morning cortisol, ACTH, TSH, LH, FSH,

71 Endocrine: hypophysitis, symptomatic Ø -Permanently discontinue therapy -1 mg/kg/day prednisone or equivalent -Evaluate pituitary axis function (morning cortisol, ACTH, TSH, LH, FSH, estradiol/testosterone, prolactin) -MRI with pituitary cuts Ø -Taper steroids over 1 month, then initiate hormone replacement if symptomatic with abnormal pituitary scan -IV therapy if hypotensive -Endocrinology consult

Dermatologic, rash, Grade 1/2 Ø Continue therapy, treat symptomatically (antihistamines, hydroxyzine and/or topical steroids) Ø Follow-up: Monitor closely for worsening symptoms Ø If rash persists

72 Dermatologic, rash, Grade 1/2 Ø Continue therapy, treat symptomatically (antihistamines, hydroxyzine and/or topical steroids) Ø Follow-up: Monitor closely for worsening symptoms Ø If rash persists for > 1 wk, recurs and/or worsens: -Hold therapy -Consider a biopsy -Consider mg/kg per day IV methylprednisolone or oral equivalent -When symptoms improve to grade 1, taper steroids over 1 mo, consider prophylactic antibiotics and resume therapy Ø If symptoms worsen: Treat as grade 3/4

Dermatologic, rash, Grade 3 Ø -Hold therapy -1.0-2.

dermatology consultation -Consider skin biopsy Ø Follow-up:

73 Dermatologic, rash, Grade 3 Ø -Hold therapy mg/kg/day IV methylprednisolone or equivalent -Consider dermatology consultation -Consider skin biopsy Ø Follow-up: Continue steroids until grade 2, then taper over at least 1 month before resuming therapy

Dermatologic, rash, Grade 4 Ø -Permanently discontinue therapy -1.0-2.

74 Dermatologic, rash, Grade 4 Ø -Permanently discontinue therapy mg/kg/day IV methylprednisolone or equivalent -Consult dermatology -Consider skin biopsy Ø Follow-up: Continue steroids until grade 2, then taper over at least 1 month

75 Hepatitis: Management LFTs >8x or total bilirubin >5x Intensified monitoring; labs every 1-3 days until begin to resolve High dose steroids, eg, methylprednisolone 1-2 mg/kg/day; if LFTs decrease convert to oral steroids If after 3 days, no improvement or rebound, add mycophenolate 1 g BID PO If no improvement in 5-7 days, add tacrolimus 0.1 to 0.15 mg/kg/day IV (trough level 5-20 ng/ml)

76 Some Pearls We Have Learned Along the Way For grade 3 or 4 toxicity and use of HD steroids, taper SLOWLY over at least 4 weeks Patients receiving > 4-6 weeks of steroids may require Pneumocystis carinii prophylaxis. Numbers don t always match clinical presentation TSH, lipase Delayed side-effects may occur Even in year 2 of treatment with anti-pd1

77 What do I do in my clinic? Separate appointment with nurse for detailed education Preferably on a separate day Verbal and written instructions Refresher course periodically and reminder at each visit Check routine labs including TSH before each dose Regular phone call with nurse depending upon need Education that more drug is not always better

78 Summary Benefit with immunotherapy may occur after initial progression Responses can be durable after stopping therapy Toxicity with anti-pd1 is less than anti-ctla4 Toxicities may be delayed and unpredictable Team Approach!

79 Summary & Conclusions Immunotherapy with CPB is a front-line option for all patients Anti PD1 is better than anti-ctla4 Combination may be better but higher toxicity; Anti-PD1 alone may be enough for most patients BRAF mutated patients may receive MAP-kinase directed therapy or immunotherapy Correct sequence is controversial Combination BRAF/MEK is better than BRAF alone Unique aspects of immunotherapy need to be inegrated into clinical practice Pseudoprogression Immune-related adverse events

Immunotherapy of Melanoma Sanjiv S. Agarwala, MD

Immunotherapy of Melanoma Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Oncology & Hematology St. Luke s Cancer Center, Bethlehem, PA Overview Metastatic Melanoma