New Frontiers in Metastatic Melanoma: A Closer Look at the Role of Immunotherapy Philip Friedlander MD PhD Director of Melanoma Medical Oncology Program Assistant Professor Division of Hematology Oncology Assistant Professor Department of Dermatology Mount Sinai School of Medicine The Tisch Cancer Institute April 27, 2017 Melanoma Estimated that 76,380 people will be diagnosed with melanoma in the US in 2016 and approximately 10,130 people died from the disease Detection when early stage has greater than 90% cure rate. Lifetime risk is 1 in 34 for women, 1 in 53 for men Median age at diagnosis is 59 years old Incidence increasing rapidly 1
Staging Stage 5 yr survival 10 yr survival IA T1a N0 M0 T1 < 1 mm a ulc, b no IB T1b or T2a N0 M0 T2 1.01 2mm IIA T2b or T3a N0 M0 T3 2.01 4 mm IIB T3b or T4a N0 M0 T4 >4mm IIC T4b N0 M0 53% 40% N1 1LN IIIA T1 4a N1 2a 78% 68% N2 2 3LN IIIB b a 59% 43% N2c satellite/intransit a b N3 >4LN N2c IIIC T1 4b N1 2b or N3 40% 24% Stage IV M1 15% 10% Lymph node Primary lesion a macroscopic a no ulceration b macroscopic b ulcerated Survival curves of 7,635 patients with metastatic melanomas at distant sites (stage IV) subgrouped by (A) the site of metastatic disease and (B) serum lactose dehydrogenase (LDH) levels. Charles M. Balch et al. JCO 2009;27:6199-6206 2009 by American Society of Clinical Oncology 2
FDA Approved Therapies for Stage IV Melanoma (prior to 2011) 1975 1998 2011 2013 2014 Dacarbazine Interleukin 2 Targeted Immunotherapy Chemotherapy What About Immunotherapy? Rare spontaneous regressions Tumor infiltrating lymphocytes Activity HD IL2 in stage IV melanoma Activity Interferon Alpha in deep Stage II b/c and Stage III melanoma 3
Key Factors to Assess Immunotherapy EFFICACY TOXICITY HEALTH CARE EXPENDITURE The Balanced Immune system Activator Suppressor Activator Suppressor Activator Suppressor 4
Clinically Relevant Immune Checkpoints CTLA 4 PD 1 B7 CD28 Dendritic Cell MHC Ag TCR T cell T cell Tumor MHC Ag TCR B7 CTLA4 PD 1 PD L1 Ipilimumab Nivolumab Pembroluzimab Improved Survival with Ipilumimab in Patients with Metastatic Melanoma Ipilimumab N=137 Stage IV melanoma Not first Line Ipilimumab + gp100 N= 403 gp100 alone N= 136 Hodi et al. NEJM(2010): 363, pg 711 723 5
Kaplan Meier Curves for Overall Survival and Progression-free Survival in the Intention-to-Treat Population. Hodi et al., NEJM (2010) 363:711 723 Long Term Efficacy Ipilimumab Pooled Analysis OS Data 1861 patients 10 prospective and 2 retrospective ipilimumab melanoma studies Median OS 9.5 months Survival curve plateau at 21% beginning around year 3 with up to approximately 10 year f/u data IMPROVING THE TAIL END OF THE SURIVAL CURVE Schadendorf et al. (2015) JCO(33) 1889 95 6
Clinically Relevant Immune Checkpoints CTLA 4 PD 1 B7 CD28 Dendritic Cell MHC Ag TCR T cell T cell Tumor MHC Ag TCR B7 CTLA4 PD 1 PD L1 Ipilimumab Nivolumab Pembroluzimab PD 1 Targeted Therapy Two Large Phase I Studies Study Phase Agent Dose Freq RR DR Med PFS Robert et al. Lancet (2014) 1 Topalian et al. JCO (2014) 2 I Pembrolizumab 2 mg/kg q 3wk 26% NR (12 42 week) 1yr OS 7.5 m 58% Prior ipi ibraf if mt I Nivolumab 3 mg/kg q 2 wk 41% 76 wk 9.7 m 62% 1 5 prior therapies 1. Robert et al. Lancet (2014) 384: 1109 17 2. Topalian et al. JCO (2014) 32: 1020 30 7
Nivolumab versus DTIC Phase III Stage IV melanoma No BRAF mutation First line therapy OS primary endpoint 418 pts Placebo controlled 61% pts M1C disease Nivolumab 3mg/kg q 2 wk Or DTIC 1000 mg/m 2 q 3 weeks Robert et al. (2015) NEJM, vol 372, pg. 320 Nivolumab versus DTIC Phase III: RESULTS Nivolumab DTIC HR / p value 1 yr OS 72.9% 42.1% 0.42 / <0.001 Median PFS 5.1 m 2.2 m 0.43 / <0.001 RR 40% 13.9% <0.001 >gd3 toxicity 11.7% 17.6% Robert et al. (2015) NEJM, vol 372, pg. 320 8
Pembrolizumab versus Ipilimumab Phase III Comparison 834 pts Stage IV melanoma No prior anti CTLA4 or anti PD 1 therapy Primary endpoints: PFS, OS Pembro 10 mg/kg q2wk Pembro 10 mg/kg q3wk Ipilimumab 3mg/kg q3wk x 4 doses Pembro q2wk Pembro q3wk Ipi P values 6m PFS 47% 46% 26.5% <0.001 12 m OS 74% 68% 58% 0.0036 RR 33.7% 32.9% 11.9% <0.001 >gd3 toxicity 13.3% 10.1% 19.9% Robert et al. (2015) NEJM, vol 372; pg. 2521 Immune Checkpoint Modulation PD 1 inhibitors more efficacious than ipilimumab as initial immunotherapy Immune cell infiltration can lead to difficult assessing response purely by size of metastasis on imaging Durability of benefit 5 year survival nivolumab 34% While PD 1 inhibitor monotherapy a significant treatment advance still only effective in subset of patients 9
Clinically Relevant Immune Checkpoints CTLA 4 PD 1 B7 CD28 Dendritic Cell MHC Ag TCR T cell T cell Tumor MHC Ag TCR B7 CTLA4 PD 1 PD L1 Ipilimumab Nivolumab Pembroluzimab Combined Checkpoint Modulation Pembroluzimab Nivolumab Nivolumab plus Ipilimumab Hamid O et al. N Engl J Med 2013;369:134 144. Hamid et al. NEJM (2013) 369:134 44 Topalian et al. NEJM (2012) 366: 2443 54 Wolchok et al. NEJM (2013) 369:122 33 10
CHECKMATE 067 Ipilimumab alone 3mg/kg q3wk x 4 doses +placebo Stage IV melanoma, 945 pts No prior systemic therapy for advanced disease Stratify: PD L1 expression BRAF mt vs wild type AJCC M stage Nivolumab 3 mg/kg q 2 wk +placebo Ipilimumab + Nivolumab ( 1mg/kg nivo q 3 wk + 3 mg/kg ipi q 3wk x 4 doses followed by 3mg/kg nivo q2 wk) Co primary endpoints: PFS and OS Only PFS data presented Larkin et al. (2015) NEJM, vol 373, pg. 23 Wolchock et al, 2016 ASCO Annual Meeting Abstract #9505 21 Results N+I N alone I alone P value Median PFS 11.5 m 6.9 m 2.9 m <0.001 12m PFS 49% 42% 18% 18m PFS 46% 39% 14% ORR 57.6% 43.7% 19% AE > gd 3 56% 19.8% 27% Median PFS PD L1 + PD L1 N+I NR 11.1 m N alone 22 m 5.3 m I alone 3.9 m 2.8 m Response Rate PD L1 + PD L1 N+I 72% 54% N alone 57% 41% I alone 21% 18% Larkin et al. (2015) NEJM, vol 373, pg. 23 Wolchock et al, 2016 ASCO Annual Meeting Abstract #9505 11
Key Factors to Assess Immunotherapy EFFICACY RR 12m PFS Survival Ipi 12% 18% 58% 12m 21% 3yr Nivo 40% 42% 73% 12m 34% 5 yr Pembro 33% 46% 6m 68% 12m Ipi + Nivo 58% 49% TOXICITY HEALTH CARE EXPENDITURE Toxicity Immune Mediated Toxicity Type Rash Colitis Hepatitis Nephritis Uveitis Endocrine Pneumonitis Neurologic Other organs TOXICITY MANAGEMENT DEPENDS ON TYPE AND SEVERITY OF TOXICITY 12
AE I Gd any Toxicity Risk % I Gd 3/4 N+I Gd any N+I Gd 3/4 N Gd any N Gd 3/4 P Gd any P Gd 3/4 Rash 35 2 40 5 26 0.6 13 0 Colitis 12 9 12 8 1 0.6 3 1 Diarrhea 33 6 44 9 19 2.2 14 2 Hepatic (inc AST/ALT) Pneumonitis Hypothyroidism Hypophysitis 7 2 33 14 7 2 4 0.4 2 0.3 6.4 1 1 0.3 2 0.4 4.2 0 15 0.3 9 0 8 0 0 0 0.3 0 0 0 0.4 0.4 Abbreviation I N P Name ipilimumab nivolumab pemrolizumab Adapted from Weber et al.(2016), The Oncologist, vol 21:1230 40 Diarrhea/Colitis Grade Management Follow up I <4 stool/d above baseline Continue therapy Monitor closely II 4 6 BM/d above baseline or abd pain/blood stool III/IV >7 BM/d above baseline Severe colitis Hold Therapy Discontinue therapy, consider endoscopy, rule out infection, high dose steroids If persist >5 7 d then high dose steroids slow taper High dose steorids, slow taper Hepatitis Grade Management Follow up I AST/ALT >ULN to 3xULN T.Bili >ULN to 1.5xULN II AST/ALT > 3x to < 5xULN T.Bili >1.5x to <3xULN Continue therapy Hold treatment Recheck approx q3d Monitor closely Slow taper when gd 1 III/IV AST/ALT > 5xULN and/or T.Bili > 3xULN Discontinue therapy High dose steorids Consider GI consult Slow taper whe n gd 1 If not improve in 3 5 days mycophenolatemofetil 13
Endocrine Grade Management 1 Management 2 Asymptomatic TSH elevation Symptomatic Endocrinopathy Continue therapy If TSH <0.5xLLN or > 2xULN check FT4 and consider endocrinology consult Evaluate Endocrine function Delay therapy High dose steroids Initiate appropriate hormone therapy Endocrinology consult Adrenal Crisis Discontinue or delay therapy Rule out sepsis Stress dose steroids Hydration intravenously Consult endocrinology Monitor closely If improves then taper steroids over at least a month. Resume therapy For adrenal insufficiency continue steroids with mineralocorticoid component High dose steroids slow taper once improved. Usually need continue steroids lifelong. Adapted from Weber et al.(2016), The Oncologist, vol 21:1230 40 Any Rx related AE Grade 3/4 Ipi 86% 27% Nivo 82% 16% Pembro 73% 10% Ipi + Nivo 96% 55% Key Factors to Assess Immunotherapy EFFICACY RR 12m PFS Survival Ipi 12% 18% 58% 12m 21% 3yr Nivo 40% 42% 73% 12m 34% 5 yr Pembro 33% 46% 6m 68% 12m Ipi + Nivo 58% 49% TOXICITY HEALTH CARE EXPENDITURE Robert et al. (2015) NEJM 372, 2521 32; Larkin et al. (2015) NEJM 373, 2331 14
Cost Effectiveness of Treatment Benefits in terms of efficacy Through efficacy prevent morbidity of cancer and therefore reduce admission to hospital risk, procedures, interventions that have financial cost. Cost Effectiveness of Treatment Benefits Efficacy Through significant efficacy decrease need to manage morbidity related to progressing cancer (hospitalizations, procedures, subsequent systemic therapy or localized therapy such as surgery or RT) Costs Cost of managing treatment related toxicity Depending on degree efficacy are costs in patients who progress or do not tolerate treatment (other systemic therapy, localized approaches like surgery or RT, other procedures or hospitalizations) Financial costs of the treatment 15
The Financial cost of Immunotherapy Prices from the first quarter of 2015 show the average per milligram wholesale prices to be: Average per mg wholesale costs first quarter 2015 Immunotherapy Average Wholesale Price Per Milligram ($) FDA approved dose (# milligrams) Wholesale cost per dose ($) (100 kg person) Nivolumab 28.78 3 mg/kg $8634 Pembrolizumab 51.79 2 mg/kg $10,358 Ipilimumab 157.46 3 mg/kg $47,238 Nivolumab Plus Ipilimumab 186.24 N= 1 mg/kg I= 3mg/kg $50,116 Health Economic (2015), vol 8, pg 9 Estimated Cost Typical Patient Treated on CHECKMATE 067 $158,252 $103,220 $295,566 Approximate cost of 20% copay for I +N = $60,000 Ipilimumab alone 3mg/kg q3wk x 4 doses +placebo Nivolumab 3 mg/kg q 2 wk +placebo Ipilimumab + Nivolumab ( 1mg/kg nivo q 3 wk + 3 mg/kg ipi q 3wk x 4 doses followed by 3mg/kg nivo q2 wk) Health Economic (2015), vol 8, pg 9 Larkin et al. (2015) NEJM, vol 373, pg. 23 Wolchock et al, 2016 ASCO Annual Meeting Abstract #9505 32 16
Any Rx related AE TOXICITY Grade 3/4 Ipi 86% 27% Nivo 82% 16% Pembro 73% 10% Ipi + Nivo 96% 55% Key Factors to Assess Immunotherapy EFFICACY RR 12m PFS Survival Ipi 12% 18% 58% 12m 21% 3yr Nivo 40% 42% 73% 12m 34% 5 yr Pembro 33% 46% 6m 68% 12m Ipi + Nivo 58% 49% Estimated Cost Typical Patient ($) Ipi $158,252 Nivo $103,220 Ipi+ Nivo $295,566 HEALTH CARE EXPENDITURE Health Economic (2015), vol 8, pg 9; Robert et al. (2015) NEJM 372, 2521 32; Larkin et al. (2015) NEJM 373, 2331 Strategies to Decrease cost and Improve Efficacy Develop effective adjuvant treatment for earlier stage melanoma to prevent recurrence and the development of stage IV disease Identify biomarkers predictive of response 17
Melanoma Adjuvant High Dose Interferon Trials Trial name E1684(Kirkwood, Strawderman et al. 1996) E1690(Kirkwood, Ibrahim et al. 2000) E1694(Kirkwood, Ibrahim et al. 2001) Year 1996 2000 2001 Regimen HD IFN -2b 1 vs. obs HD IFN -2b vs. LD INF -2b 2 vs. obs HD IFN -2b vs. GMK vaccine 3 # patients enrolled 287 642 880 Median follow up at initial reporting (yrs) 6.9 4.3 1.3 Clinical Pathologic stage (% pts) T 4 cn 0 T 1-4 pn 1 cn 0 T 1-4 pn 0 cn 1 T 1-4 pn 0 cn 1 recurrent 11 12 15 62 RFS benefit + p 5 = (.0023) OS benefit + p= (.0237) Median RFS (obs vs. HD IFN ) yrs Median OS (obs vs. HD IFN ) yrs 25 11 13 51 + (only HD INF ) HR 6 =1.28 p=(.05) 23 35 6 36 + HR=1.47 p=(.0007) - + HR=1.28 p=(.035) 1 vs. 1.7 2.8 vs. 3.8 1.9 vs. NR 7 2.8 vs. 3.8 6 vs. 5.1 NR Melanoma Adjuvant High Dose Interferon Trials Trial name Median follow up at latest reporting (yrs) RFS benefit OS benefit E1684(Kirkwood, Strawderman et al. 1996) E1690(Kirkwood, Ibrahim et al. 2000) E1694(Kirkwood, Ibrahim et al. 2001) 12.6 6.6 2.1 + HR=1.38 p=(.02) - HR=1.22 p=(.18) - HR=1.24 p=(.09) + HR=1.33 p=(.006) - + HR=1.32 p=(.04) 1) HD IFN -2b 20MIU IV 5 days per week x 4 weeks followed by 10 MIU SQ TIW x 48 weeks 2) LD INF -2b 3 MIU TIW SQ x 2 years 3) GMK vaccine 1mL SQ on days 1, 8, 15, 22 then every 12 weeks 4) T 4c N 0 Primary >4 mm depth No LN involvement detected T 1-4 pn 1 cn 0 LN involvement determined on pathology T 1-4 pn 0 cn 1 LN determined on clinical evaluation at time of primary diagnosis T 1-4 pn 0 cn 1 recurrent LN determined on clinical evaluation after primary diagnosis 5) P value one sided 6) Hazard ratio 7) Not reached 18
Ipilimumab adjuvant therapy Resected stage III melanoma (to regional lymph nodes) N=475 Ipilimumab 10 mg/kg q3k x4 doses followed by q3month for up to 3 years N=476 Placebo Characteristic Ipilimumab Placebo Median Age 51 yr 52 yr IIIa 20.6% 20.6% IIIb 38.3% 38.2% IIIc 41.1% 41.2% LN macroscopic 55.8% 59.5% Eggermont et al. (2016) NEJM vol 375 p1845 55 Results Median f/u 5.3yr Ipilimumab Placebo Median RFS 27.6m 17.1m HR 0.76, p<0.001 5 yr RFS 40.8% 30.3% Overall survival 5 yr 65.4% 54.4% HR 0.72 p=0.001 Median Distant Metastasis Free Survival Distant Metastasis Free Survival 5 yr 48.3 m 27.5 m HR 0.76 p=0.002 48.3% 38.9% Post protocol treatment if recurred anti PD1 Distant Metastasis Free Survival BRAF inhibitor 24/264 (9.1%) 30/323 (9.3%) 63/264 (23.9%) 88/323 (27.2%) Pt recruitment 2008 11 19
Toxicity Event Ipilimumab % Placebo % Any immune related 90.4% 39.7% AE Any immune related AE gd3 35.9% 2.5% Any immune related AE gd4 5.7% 0.2% Gd5 immune related AE >gd3 diarrhea/colitis >gd3 hepatic >gd3 endocrine 1.1% (5/471) 0% 16.6% 0.6% 8.1% 7.2% 0.2% 0.2% >gd3 dermatologic 4.2% 0% Financial cost Ipilimumab $ 157.46 average per mg wholesale cost (1 st quarter 2015) Dose = 10 mg/kg Cost $1574.60/kg/dose For 100 kg person = $157,460/dose Dose every 3 weeks x 4 = $629,840 20
Talimogene Laherparepvec (TVEC) Intratumorally delivered Oncolytic immunotherapy Herpes virus that selectively replicates in solid tumors Deletion of HSV 1 viral genes encoding ICP34.5, providing for tumor selective replication, and ICP47 which increases US11 expression enhancing virus growth and tumor cell replication. Gene for GM CSF has been inserted into the viral genome Duel Mechanism of Action: 1. Direct oncolytic effect by viral replication in tumor leading to tumor cell lysis 2. Anti tumor response in setting GM CSF expression in tumor microenvirnoment leading to systemic immune response Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, secondgeneration oncolytic herpesvirus in patients with unresectable metastatic melanoma. 50 pts IIIc 10 M1a 16 M1b 4 M1c 20 Senzer N et al. JCO 2009;27:5763-5771 21
Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, secondgeneration oncolytic herpesvirus in patients with unresectable metastatic melanoma. 50 pts IIIc 10 M1a 16 M1b 4 M1c 20 Senzer N et al. JCO 2009;27:5763-5771 Combination Therapy Optimize Efficacy while minimize toxicity Combinations of checkpoint inhibitors Combination checkpoint inhibitors with TVEC Combination checkpoint inhibitors with tumor microenvironment modulators (anti vascular agents, IDO inhibitors) Combination checkpoint inhibitors and targeted therapy 22
Biomarkers of Immunotherapy Efficacy Blood Neutrophil/lymphocyte ratio Effector to Suppressor T cells CTLA 4 polymorphisms Tumor PD L1 expression TILs Mutation burden Easily obtained with minimal risk to patient Ideally Pretreatment Optimize treatment planning Limit toxicity risk Improve healthcare expenditure Patient Population Kirkwood JM, Lorigan P, Hersey P, Hauschild A, Robert C, McDermott D, Marshall MA, Gomez Navarro J, Liang JQ, Bulanhagui CA: Phase II trial of tremelimumab (CP 675,206) in patients with advanced refractory or relapsed melanoma. Clin Cancer Res 2010, 16(3):1042 1048. Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G et al: Phase III randomized clinical trial comparing tremelimumab with standard of care chemotherapy in patients with advanced melanoma. J Clin Oncol 2013, 31(5):616 622. 23
16 Gene Pre treatment Gene Signature From Blood Sample Predicts For Response and Survival The sensitivity, specificity, negative predictive value, and area under the curve of the pre treatment 16 gene signature predicting response in the training data set and both response and survival in the test dataset. 16 Gene Pre Treatment Response Predictive Model Training Data. X Axis is the correlated component score and Y axis is the composite response prediction score. Red squares (responders) and blue circles (non responders). Friedlander P, et al, (2016) SITC abstract #158, Poster presentation titled: Consistent blood based gene expression correlates with change in CTLA4 in two large independent clinical studies of advanced melanoma patients treated with tremelimumab FDA Approved Therapies for Stage IV Melanoma 1975 1998 2011 2013 2014 Dacarbazine Interleukin 2 Ipilimumab Targeted Vemurafenib Dabrafenib Trametinib Dabrafenib + Trametinib Pembroluzimab Nivolumab Immunotherapy Chemotherapy 24
Conclusions Dramatic advances in managing stage IV melanoma through immunomodulation Need biomarkers for efficacy and toxicity Overcome molecular and immune resistance mechanisms Goal to optimize efficacy and quality of life while minimizing toxicity and health care expenditure 25