Melanoma- Fighting the Dark Side Anna C. Pavlick, BSN, MSc, DO, MBA Professor of Medicine and Dermatology Director, NYU Melanoma Program Director, NYU Clinical Trials Office NYU Perlmutter Cancer Center
Disclosures American Osteopathic College of Dermatology Anna C. Pavlick, BSN, MSc, DO, MBA I have the following financial relationships to disclose: Consultant for: BMS, Merck, Novartis Research Support (funds go to NYU); BMS, Merck, Novartis, Celldex, Millineum, Genentech, Roche I will investigational in clinical trials in my presentation. I will not discuss off label use.
Overview Overview of Cutaneous Metastatic Melanoma Targeted Therapies BRAF inhibitors MEK inhibitors Checkpoint Inhibitors CTLA4 inhibition PD1 inhibition Combination therapy Conjugated Monoclonal Antibodies
Melanoma Most deadly of all skin cancers If caught early, it is 95% curable One person dies from melanoma every hour Only cancer in the US that is rising 1 in 50 Americans will be diagnosed with melanoma Once you have one melanoma you are 10 times more likely to develop another melanoma Risk for melanoma doubles if you have had more than 5 sunburns One or more blistering sunburn as a child doubles melanoma risk Use of tanning beds dramatically increases melanoma risk
Metastatic Disease Less than 5% of all patients survived for 5 years with metastatic disease prior to 2011 With new therapies, approximately 25% of patients will survive metastatic disease. Disease response to therapy is approximately 75% 50% with metastatic disease develop brain metastases. 2 FDA approved therapies prior to 2011: Dacarbazine and Il-2-both with response rates between 6 and 15% and NO impact on overall survival. 2011-ipilimumab and BRAF inhibitors FDA approved and changed overall survival.
Unprecedented Progress : Two Different Approaches Targeting MAP Kinase Pathway Immune Checkpoint Inhibitors
Targeted Therapies
Mutations in Melanoma BRAF NRAS MEK KIT GNAQ GNA11
BRAF Mutated in approximately 50% of melanoma Most common mutation is V600E Other mutations- V600 K (20%), V 600D, 601 Sensitivity to BRAF inhibitors to be defined Younger age, fewer markers of chronic sun damage, trunk primary, superficial spreading melanoma or nodular subtype. Perhaps worse overall survival
MAPK and PI3K Pathways RTK KIT mut 20% ~10-20% mucosal ~10-20% acral ~20-25% ~10% cutaneous ~9% mucosal ~9% acral ~50% Primarily cutaneous melanomas NRAS RAS mut P BRAF RAF mut P MEK PI3K P Akt P ERK P mtor Cell Responses
The Target: B-RAF Kinase RTK RAS ATP MEKi ATP Trametinib BRAF V600E Raf MEK ERK BRAFi Vemurafenib Dabrafenib Cellular Proliferation
2 nd Generation V600-Selective BRAF Inhibitors Vemurafenib Dabrafanib/GSK2118436 Day 1 Day 15 Pre Week 10 Flaherty NEJM, 2010 Long, ESMO, 2010 ORR Median PFS (Mos) OS at 6 Mos Vemurafenib 48.6% 5.3 84% DTIC 5.5% 1.6 64% Chapman, NEJM, 2011
Possible Adverse Effects of BRAFi Arthralgias Myalgias Rash Hepatotoxicity Hand/Foot Syndrome Pyrexia Photosensitivity New cutaneous skin cancers (SCC, Melanoma)
Skin Toxicities-BRAFi Plantar-palmar Hyperkeratoses Squamous Cell Carcinoma Verrucal Lesion
Diffuse Macular Rash From BRAF Inhibitor
Photosensitivity Secondary to BRAF Inhibitors
BRAF/MEK Inhibition
Progression Progression-Free Survival Survival Mono = Dabrafenib monotherapy 150/1 = Dabrafenib (150 mg) plus trametinib (1 mg) 150/2 = Dabrafenib (150 mg) plus trametinib (2 mg) Flaherty KT et al. N Engl J Med 2012 Sept 29;[Epub ahead of print]
Maximum percent reduction from baseline measurement MEK, BRAF & BRAF/MEK combination (1 st line) 100 60 20 Trametinib 2 mg QD Disease stage IIIC M1a M1b M1c Unknown 20 60 100 100 Dabrafenib 150 mg BID Flaherty KT et al. NEJM 2012 0-100 100 50 Best confirmed response Progressive disease Stable disease Partial response Complete response Dabrafenib 150 mg BID/Trametinib 2 mg QD 0-50 -100 Long G et al. ESMO 2012
Rash on MEK Inhibitor
Erythematous Acneiform Rash Typical of MEK Inhibitors
Erythema Surrounding All Tattoos
Checkpoint Inhibitors
Anti-CTLA4 Monoclonal Antibodies for Melanoma Stimulate T cells to recognize cancer antigens and develop mechanisms for cell death- taking the brakes off the immune system Break tolerance of T cells to self antigens in order to permit anti-tumor response Potential side effects are autoimmune diseases
Ipilimumab Augments T-Cell Activation and Proliferation T-cell activation T-cell inhibition T-cell remains active T-cell T-cell T-cell CD28 CTLA-4 TCR CD28 TCR CTLA-4 TCR APC HLA CD80/ CD86 APC HLA CD80/ CD86 APC HLA CD80/ CD86 Ipilimumab blocks CTLA-4 Adapted from O Day et al. Plenary session presentation, abstract #4, ASCO 2010.
Antigen recognition by T cells activation T cell ab T cell antigen receptor (TCR) cytokines MHC Antigen presenting cell Antigen Processing
Pivotal Phase 3 Study of Ipilimumab a Due to the inclusion of the gp100 peptide vaccine comparator, the study was restricted to patients with HLA-A2*0201 genotype. b All patients had been previously treated with one or more of the following: aldesleukin (IL-2), dacarbazine, temozolomide, fotemustine, or carboplatin. Primary Endpoint: Overall survival in ipilimumab + gp100 arm vs gp100 arm 14
Ipilimumab Overall Survival 1 Year OS = 46% 2 Year OS =24% ipilimumab + gp100 (A) ipilimumab alone (B) gp100 alone (C) Survival Rate 1 2 Years 3 4 ipilimumab + gp100 N=403 ipilimumab + placebo N=137 gp100 + placebo N=136 1 year 44% 46% 25% 2 year 22% 24% 14% Hodi et al NEJM 2010
Ipilimumab Toxicities Management: 1) Early Detection 2) Early Consult 3) Early Treatment (Steroids) Thyroiditis (1.5-2.5%) Dermatitis (43.5%) Panhypopituitary Hypophysitis (4%) Adrenal failure (1.5-3%) ALT/AST rise( 30%*) Hepatitis (4%) Colitis Diarrhea( 30%)
Immune-Mediated Side Effects: Time to Onset Time-to-onset data are not available for hepatitis, neuropathy, and other immune-mediated side effects 1. YERVOY package insert. Princeton, NJ: Bristol-Myers Squibb; 2011. 2. Data on file. YERV009. 29
Nonconventional Kinetics Are Most Apparent With Pseudo-Progression Pseudo-progression may occur when T-cell infiltration causes tumors to flare or new lesions to appear upon imaging 1 Considerations when evaluating true progression vs pseudo-progression May indicate progression May indicate pseudo-progression Performance status Deterioration of performance Remains stable or improves Systemic symptoms Worsen May or may not improve Symptoms of tumor enlargement Tumor burden Baseline New lesions Present Increase Appear and increase in size May or may not be present Increase followed by response Appear then remain stable and/or subsequently respond Biopsy may reveal Evidence of tumor growth Evidence of T-cell infiltration 1. Wolchok JD, et al. Clin Cancer Res. 2009;15:7412-7420; 2. Topalian SL, et al. N Engl J Med. 2012;366:2443-2354; 3. Eisenhauer EA, et al. Eur J Cancer. 2009;45:228-247; 4. Chow LQ. Am Soc Clin Oncol Educ Book. 2013:280-285; 5. American Cancer Society. Lung Cancer. http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lungcancer-diagnosis. Accessed September 30, 2013.
Ipilimumab: Response After Tumor Volume Increase Screening Week 72 Durable & ongoing response without signs of IRAEs Week 12 Initial increase in total tumor burden (mwho PD) Week 16 Responding Courtesy of K. Harmankaya and S. Hodi
11/28/06 1/9/14
Tumorous nodule with melanin pigment (macrophages and lymphocytes; no melanocytes) Macrophages and lymphocytes are present, but no tumor cells
Skin Toxicity Ribas, A. et al. J Clin Oncol; 23:8968-8977 2005
Hair Depigmentation
Anti-PD1 Antibodies for Melanoma Immunotherapy for melanoma only available through clinical trials targets anti-programmed cell death 1 receptor. Targets PDL-1and 2 receptors on tumor cells. As a single agent approximately 30% of patients with metastatic melanoma respond. Less of a chance of side effects when compared to ipilimumab. Side effects include rash, itching, diarrhea and pneumonitis. Given by vein every 2-3 weeks depending on PD1 compound. May be even better if combined with ipilimumab, but toxicity is also increased.
Role of PD-1 Pathway in Tumor Immunity Recognition of tumor by T cell through MHC/antigen interaction mediates IFNγ release and PD-L1/2 up-regulation on tumor Priming and activation of T cells through MHC/antigen & CD28/B7 interactions with antigen-presenting cells IFNγ IFNγR MHC T-cell receptor T-cell receptor MHC Tumor cell PD-L1 PD-L2 PD-1 Shp-2 PI3K NFκB Other T cell Shp-2 CD28 PD-1 B7 PD-L1 Dendritic cell PD-1 PD-1 PD-L2 Sznol et al., ASCO, 2013 Nivolumab PD-1 Receptor Blocking Ab 45
Change in target lesions from baseline (%) Best Responses in All Evaluable Patients in Sequenced Cohorts -80 Patients Patients who had stable disease with prior ipilimumab treatment. Patients who had radiographic D. Wolchok, progression PhD with prior ipilimumab treatment.
Pembrolizumab (anti-pd1) Skin Rash
Dual Checkpoint Blockade
Blocking CTLA-4 and PD-1 Tumor Microenvironment Activation (cytokines, lysis, proliferation, migration to tumor) Dendritic cell MHC B7 TCR CD28 +++ +++ B7 CTLA-4 - - - anti-ctla-4 T cell CTLA-4 Blockade (ipilimumab) T cell ++ + - - - - - - TCR MHC PD-1 PD-L1 anti-pd-1 PD-1 PD-L2 anti-pd-1 PD-1 Blockade (nivolumab) Tumor cell
Phase II CA209-069: Study Design Eligible patients with unresectable stage III or IV melanoma Treatment-naïve BRAF WT (N = 100) or MT (N = 50) Stratified by BRAF status R 2:1 NIVO 1 mg/kg + IPI 3 mg/kg Double-blind Placebo + IPI 3 mg/kg Q3Wx4 Q3Wx4 NIVO 3 mg/kg Placebo Q2W Q2W Treat until: disease progression a or unacceptable toxicity a Treatment beyond initial investigator-assessed RECIST v1.1- defined progression is permitted in patients experiencing clinical benefit and tolerating study therapy. Arm B patients have option to receive nivolumab monotherapy after progression. Upon confirmed progression and change of treatment, all patients are unblinded. MT = mutation; PFS = progression-free survival; Q3W = every 3 weeks; WT = wild type Primary endpoint: ORR in BRAF WT patients Secondary endpoints: PFS in BRAF WT patients ORR and PFS in BRAF MT patients Safety
Objective Response, Investigator-Assessed All Randomized Patients NIVO + IPI (N = 95) IPI (N = 47) ORR, % (95% CI) a 59 (48, 69) 11 (4, 23) P value for comparison <0.0001 Best overall response, % b Complete response 22 0 Partial response 37 11 Stable disease 13 30 Progressive disease 16 47 Unable to determine 13 13 a (Complete response + partial response)/(all randomized patients); 95% CI based on Clopper and Pearson method b RECIST v1.1 CI = confidence interval
PD-1 Inhibition after Ipilimumab Progression 7/1/13 3/20/14
Probability of Progression-Free Survival PFS in All Randomized Patients 1.0 0.9 0.8 0.7 0.6 0.5 Death or disease progression, n/n Median PFS, months (95% CI) HR (95% CI) NIVO + IPI (N=95) IPI (N=47) 42/95 32/47 NR 0.39 (0.25, 0.63) 3.0 (2.8-5.1) -- 0.4 0.3 0.2 0.1 NIVO + IPI (all randomized) IPI (all randomized) 0.0 0 3 6 9 12 15 18 Number of Patients at Risk NIVO + IPI 95 69 58 Progression-Free Survival (months) 47 26 1 0 IPI monotherapy 47 22 10 7 2 0 0
Probability of Progression Free Survival PFS in Patient Subgroups: M1c Stage 100 90 80 70 60 M1c stage subgroup Death or disease progression, n/n Median PFS, mo (95% CI) NIVO + IPI 22/44 10.2 (4.1, NA) IPI monotherapy 14/21 3.9 (2.7, 6.8) 50 40 30 20 10 Nivolumab + Ipilimumab Ipilimumab 0 0 3 6 9 12 15 18 Number of Patients at Risk Nivolumab + Ipilimumab Progression-Free Survival per Investigator (months) 44 33 27 22 10 0 0 Ipilimumab 21 11 6 5 1 0 0
Patients Alive and Progression-Free (%) PFS in Patient Subgroups: BRAF V600 Mutation-positive 100 90 80 70 BRAF V600 mutant subgroup Death or disease progression, n/n Median PFS, mo (95% CI) NIVO + IPI 12/23 8.5 (2.8 NR) IPI monotherapy 7/10 2.7 (1.0 5.4) 60 50 40 30 20 10 Nivolumab + Ipilimumab (N = 23) Ipilimumab (N = 10) 0 0 3 6 9 12 15 Number of Patients at Risk Nivolumab + Ipilimumab Progression-Free Survival (months) 23 15 13 9 6 0 Ipilimumab 10 2 1 1 0 0
Safety Summary Patients Reporting Event, % NIVO + IPI (N = 94) a IPI (N = 46) a Any Grade Grade 3 4 Any Grade Grade 3 4 Treatment-related AEs 91 54 93 24 Age <65 years 46 28 41 11 Age 65 years 46 26 52 9 M1c disease 42 28 39 9 Treatment-related AEs leading to discontinuation 47 38 17 13 Treatment-related death 3 b 0 a Safety was evaluated in all patients who received at least one dose of study treatment b Associated with ventricular arrhythmia, pneumonitis, and pneumonia/hypercalcemia AEs = adverse events
Most Common Treatment-Related Select AEs Patients Reporting, % NIVO + IPI (N = 94) a IPI (N =46) a Any Grade Grade 3 4 Any Grade Grade 3 4 Gastrointestinal AEs 51 21 37 11 Diarrhea 45 11 37 11 Colitis 23 17 13 7 Hepatic AEs 28 15 4 0 ALT increased 22 11 4 0 AST increased 21 7 4 0 Pulmonary AEs 12 2 4 2 Pneumonitis 11 2 4 2 Renal AEs 3 1 2 0 Creatinine increased 2 1 0 0 Endocrine AEs 34 5 17 4 Thyroid disorder 23 1 15 0 Hypothyroidism 16 0 15 0 Hypophysitis 12 2 7 4 Skin AEs 71 10 59 0 Rash 42 5 26 0 Pruritus 35 1 28 0 Apart from endocrinopathies, the majority (~80%) of treatment-related select AEs resolved when immune-modulating medications were utilized
Time to Onset of Grade 3/4 Treatment-related Select AEs in Patients Treated with Immune-modulating Medication Skin (n=8) 2.2 (0.1 3.1) NIVO + IPI IPI Gastrointestinal (n=18) 6.9 (0.9 23.0) Gastrointestinal (n=5) 5.7 (4.1 11.3) Endocrine (n=5) Endocrine (n=2) Hepatic (n=12) Pulmonary (n=2) 9.4 (6.7 19.0) 8.0 (7.7 8.3) 12.1 (3.1 26.6) 14.6 (9.4 19.9) 29.0 (29.0 29.0) Renal (n=1) 0 5 10 15 20 25 30 Weeks Most grade 3/4 treatment-related select AEs occurred during the combination phase Circles represent median; bars signify ranges.
Conjugated Monoclonal Antibody Glembatumumab
CR011-vcMMAE-Glembatumumab Fully human monoclonal IgG 2 antibody (CR011) conjugated to cytotoxic monomethyl auristatin-e (MMAE) MMAE is related to dolastatin, a marine-peptide derived tubulin inhibitor Enzyme-cleavable valine-citrulline linker Stable in the circulation Antibody targets glycoprotein NMB (GPNMB) Originally identified by high throughput genomic screening technologies Overexpressed in melanoma and other cancers
CR011-vcMMAE CR011-vcMMAE: Mechanism of Action MMAE vc Linker Cell membrane GPNMB Binding Cleavage Tubulin inhibition 1. CR011-vcMMAE binds to GPNMB on the surface of cancer cells 2. After internalization, the valine-citrulline linker is cleaved by endosomal enzymes 3. Free MMAE inhibits tubulin polymerization, leading to cell death
Presented at ASCO 2008 Immunohistochemical Staining of Patient Tumor Tissue for GPNMB Pt 001-105 Pt 002-114 CR011 antibody Control IgG 2 CR011 antibody Control IgG 2 Specific expression of GPNMB in patient tumor biopsies
CR011-vcMMAE: Phase I/II Study in Patients with Melanoma Patient Population: Unresectable Stage III or Stage IV melanoma Progressive disease at study entry Any prior cytokines or immunotherapy 1 prior cytotoxic regimen Stable brain metastases allowed Study Design: Phase I enrolls sequential cohorts of patients at increasing doses IV infusion once every 3 weeks (IV Q3W) Starting dose 0.03 mg/kg IV Q3W Phase II Simon 2-stage design Primary endpoint is response rate, n=32 Phase I Dose Escalation Establish MTD Phase II Study at MTD Simon Two Stage Design Primary Endpoint: Response Rate
Skin Rash from Glembatumumab
Conclusions: Metastatic melanoma is no longer an incurable, universally fatal disease. Immunotherapy has provided patients with long term, durable responses. Targeted therapy has provided a rapid mechanism for disease control in BRAF mutated patients. We have made dramatic strides in the treatment and long term control of melanoma, however, more work needs to be done to cure everyone. Participation in a clinical research trial remains the gold standard for patients with metastatic melanoma.
Acknowledgements: Thank you to all the patients who participated in our melanoma research trials and changed the outcome of this disease. Thank you to all the patient who agreed to having photos taken of their responses or toxicity, so that we could learn from them. Thank you to all of my referring physicians who trust their patients to my care Finally, thank you to my dedicated staff for their dedication to our patients and most importantly for putting up with me.