Best Practices in the Treatment and Management of Metastatic Melanoma. Melanoma

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1 Best Practices in the Treatment and Management of Metastatic Melanoma 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 23, 2015 Melanoma It is estimated that 76,100 people will be diagnosed with melanoma in the US in 2014 and that 9,710 people died from the disease Approximately 82% of melanoma patients present with localized disease, 13% with regional disease and 5% with distant disease Detection and intervention of early stage melanomas has greater than 90% cure rate. Average age at diagnosis: 59 years old Incidence is increasing rapidly: 4 8% annually for decades. 1

2 Histological Subtypes Superficial Spreading Lentigo Maligna Nodular % of all melanomas 70 75% 5 10% 10 15% Mean age presentation Common locations back, head, neck, Any site lower legs of females back hands Duration radial GP 1 7 yr (up to 14 yr) 5 30 yr (to 50yr) None Border of lesion Raised Flat Raised Stage Staging IA T1a N0 M0 T1 <1 mm IB T1b or T2a N0 M0 T mm IIA T2b or T3a N0 M0 T mm IIB T3b or T4a N0 M0 T4 >4mm IIC T4b N0 M0 N1 1LN IIIA T1 4a N1 2a N2 2 3LN IIIB b a N2c sat/intransit a b N3 >4LN N2c IIIC T1 4b N1 2b or N3 Stage IV M1 a,b,c LN+sat/intrans A: no ulc, <1 mit/mm 2 B: Ulc or mit > 1 mit/mm2 A: Micrometastasis B: Macrometastasis Breslow thickness, LN involvement with number and micro vs macro, ulceration, mitoses, location of metastases. 2

3 Overall Survival Balch C M et al. JCO 2001;19: by American Society of Clinical Oncology FDA Approved Therapies for Stage IV Melanoma (prior to 2011) Dacarbazine Interleukin 2 Targeted Immunotherapy Chemotherapy 3

4 The MAPK Signal Transduction Pathway RTK NRAS BRAF CRAF MEK PI3K AKT PTEN KIT ERK CDK4/6 + cyclin D1 Proliferation mtor Survival BRAF Mutations Detected in Human Cancer Direct sequence of PCR products of BRAF gene 530 cancer cell lines Melanoma 20/34 59% CRC 7/40 18% Glioma 4/38 11% Lung 4/35 3% Sarcoma 5/59 9% Ovarian 1/26 4% Breast 1/45 2% Liver 1/7 14% Neuroblastoma 0/29 Bladder 0/10 Leukemia.Lympohoma 0/53 Cervical 0/11 Testicular 0/7 Prostate 0/3 Davies et al Nature (2002)417: pp949 4

5 BRAF Mutations Over 90% are V600E (valine to glutamic acid) Adjacent to activating phosphorylation site Distinct from CC TT or C T changes associated with pyrimidine dimer formation following exposure to UV light Mutually exclusive from NRAS mutations Early event found in benign nevi Diverse sites of origin Cutaneous 90% chronic sun exposed skin intermittent sun exposed skin acral Mucosal 5% Uveal 5% Does site of origin predict for MAPK pathway activating mutation? 5

6 KIT Detection of a sub centromeric amplification in a region encompassing KIT on chromosome 4q in acral melanoma specimens Led to speculation that activating abnormalities of KIT may play role in development of these melanomas The boundary of the amplification refined using comparative genomic hybridization Confirmed presence of KIT within the amplified region The amplification limited to melanomas lacking mutant BRAF or NRAS KIT mutations detected by direct sequencing 17% CSD, 11% acral, 21% mucosal, <1% noncsd Bastian et al (1998) Cancer Research 58: Curtin et al (2005) NEJM 353: Genetic Subtypes Example: chest, abdomen face palm, sole vagina, sinus (Curtin et al, JCO (2006) 24: ) 6

7 Inhibition of V600 Mutated BRAF RAS BRAF INHIBIT BRAF Vemurafenib Dabrafenib CRAF MEK ERK Proliferation BRIM3 STUDY DESIGN Vemurafenib 337 pts Stage IV Melanoma V600E Mutation Randomization Dacarbazine 338 pts Primary endpoints: Progression free survival and Overall survival Treatment Complete Partial Overall Vemurafenib 0.9% 47.5% 48.4% Dacarbazine 0% 5.5% 5.5% Chapman et al. NEJM (2011) 364:

8 FDG-PET Baseline Day 15 Flaherty et al. NEJM (2010), 363: pp Survival Benefit with BRAF Inhibitor Treatment Chapman PB et al. N Engl J Med 2011;364: Median PFS increased from 1.6m to 5.3m Chapman et al. NEJM (2011) 364:

9 Updated Survival Results BRIM3 Study Vemurafenib DTIC Median length f/u 10.5m ( ) 8.4m( ) Median OS 13.3m (95%CI 12 15) 9.6m(95%CI ) 12month OS 55% 43% HR death 0.62 (95%CI ) Chapman et al. ASCO 2012, abstract 8502 BREAK 3 STUDY Dabrafenib 150 mg po bid V600 mutant BRAF melanoma N=250 pt 93 centers Primary endpoint: PFS Crossover allowed N= 127 3:1randomization N=63 DTIC 1000 mg/m2 q3wk Patient Characteristics Median age 52 yrs ECOG>1 = 31% 12/19/11 data cutoff: 141 pt on study 127 dabrafenib 14 DTIC 21/28 who crossed over to dabrafenib Stage M1C = 66% Elevated LDH= 33% Hauschild et al. Lancet 2012;380:

10 BREAK 3 Study Results DABRAFENIB DACARBAZINE # events 77/187 41/63 Median PFS 5.1 month 2.7 month Response Rate 50% 19% Hazard Ratio PFS 0.3 (95% CI , p<.0001) Overall survival data not mature Hauschild et al. Lancet 2012;380: Inhibit MEK RAS BRAF MEK INHIBIT MEK Trametinib ERK??? Proliferation 10

11 METRIC Study: MEK Inhibition Trametinib Chemotherapy HR Median PFS 4.8 m 1.5 m 0.45 (95% CI.33.63) p< month OS 81% 67% 0.54 (95% CI.32.92) p=0.01 Response Rate 22% 8% p=0.01 CR 2% 0% PR 20% 8% SD 56% 31% Flaherty et al., NEJM (2012) 367: Combination BRAF and MEK inhibition RAS Key Cutaneous Toxicity BRAF INHIBIT BRAF SCC MEK INHIBIT MEK RASH Rationale for Combining the therapies: 1. Synergy 2. Prevent or overcome resistance 3. Decrease incidence cutaneous toxicity 11

12 Dabrafenib + Trametinib 150mg/0mg N=54 150mg/1mg N= mg/2mg N= 54 Median PFS 5.8 m 9.2 m 9.4 m HR yr PFS 9 % 26% 41 % RR 54 % 50 % 76 % Median DR 5.6 m 9.5 m 10.5 m 12 month OS 70 % 68 % 79 % Cut SCC 19 % 2% 7 % Despite 80% crossover Pyrexia 26 % 63 % 71% Flaherty et al. NEJM (2012) 367: 1694 Efficacy of MAPK Targeted Approaches in Stage IV V600 Mutated BRAF Melanoma Study Phase Agent Prior BRAF Inhibitor N # Response Rate (%) Median PFS (months) Sosman et al. II vemurafenib No McArthur et al. III vemurafenib No Ascierto et al. II dabrafenib No Hauschild et al. III dabrafenib No Kim et al. II trametinib Yes Kim et al. II trametinib No Flaherty et al. III trametinib No Flaherty et al. (part C) II Dabrafenib Dabrafenib plus trametinib No No Friedlander P. New Drug Approvals in Oncology: Combination BRAF MEK inhibition with dabrafenib and trametinib for BRAF mutant melanoma. Journal of Contemporary Oncology 2014 Aug; 6(3):

13 Combination Therapy Phase III Investigation [Larkin et al, NEJM (2014) 371: ] Vemurafenib + combimetinib Vemurafenib P value RR 68% 45% <0.001 Median PFS 9.9m 6.2m < month OS 81% 73% (not cross prespecified HR boundary for significance) [Robert et al, NEJM (2014) 373:30 39] Dabrafenib + trametinib vemurafenib P value RR 64% 51% <0.001 Median PFS 11.4 m 7.3 m < month OS 72% 65% MAPK Targeted Therapy High RRs Development of resistance a major concern No benefit in wild type BRAF melanoma 13

14 Targeting KIT: KIT Mutated Mucosal Melanoma Exon 11 amplicon HPLC Seven codon duplication exon 11 Direct sequence: 7 codon duplication Hodi, F. S. et al. J Clin Oncol; 26: KIT Inhibition with Imatinib PET 4 weeks after imatinib CT imaging Day 42 Hodi, F. S. et al. J Clin Oncol; 26:

15 Immunotherapy High Dose Interleukin 2 Cytokine therapy able to induce durable benefit in small subset of patients with Stage IV melanoma RR 16%, Durable CR rate 5% 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 15

16 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 Kaplan Meier Curves for Overall Survival and Progression-free Survival in the Intention-to-Treat Population. Hodi FS et al. N Engl J Med 2010;363: Hodi et al., NEJM (2010) 363:

17 PD 1 Targeted Therapy Study Robert et al. Lancet (2014) 1 Topalian et al. JCO (2014) 2 Robert et al. NEJM (2015) 3 Robert et al. NEJM (2015) 3 Phas e Agent Dose Freq RR DR Med PFS 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 III Nivolumab 3 mg/kg q 2 wk 40% NR 5.1 m 73% wt BRAF 1 st line III Dacarbazine 1000 mg/m 2 q 3 wk 14% 24 wk 2.2 m 42% wtbraf 1 st line 1. Robert et al. Lancet (2014) 384: Topalian et al. JCO (2014) 32: Robert et al. NEJM (2015) 372: Immune Checkpoint Modulation Durability of benefit RRs higher with PD 1 targeted therapy Difficult to capture full degree benefit with standard RECIST measurement criteria 17

18 Can we Improve Upon the Efficacy of Single Agent Ipilimumab? Ipilimumab + Avastin: Rationale VEGF suppresses dendritic cell maturation and modulates lymphocyte trafficking across endothelia 46 pts. RR 11%, 6month PFS = 63%, median PFS = 9 m 1 yr OS = 79% median OS = 25.1 m Ipilimumab + G CSF verses ipilimumab alone (10 mg/kg) 245 pts, 1 yr OS = 68.9% vs 52.9% median OS = 17.5 m vs 12.7 m Ipilimumab Plus Nivolumab. Pembroluzimab Nivolumab Nivolumab plus Ipilimumab Hamid O et al. N Engl J Med 2013;369: Hamid et al. NEJM (2013) 369: Topalian et al. NEJM (2012) 366: Wolchok et al. NEJM (2013) 369:

19 Ipilumimab Related Toxicity Immune related events 60 80% pts with ipi Gd3/ % Most common GI and skin Most common of any grade diarrhea 30% For >gd2 diarrhea median time to resolution 2 weeks with steroids Nephritis, pneumonitis, hepatitis, uveitis, neurologic, endocrine: AUTOIMMUNE Benefits and Limitations PRO CON TARGETED THERAPY: RESPONSE RATE DURABILITY IMMUNOTHERAPY: DURABILITY RESPONSE RATE 19

20 FDA Approved Therapies for Stage IV Melanoma Dacarbazine Interleukin 2 Ipilimumab Targeted Vemurafenib Dabrafenib Trametinib Dabrafenib + Trametinib Pembroluzimab Nivolumab Immunotherapy Chemotherapy NCCN Guidelines Limited resect and then observation or clinical trial Disseminated: First Line Therapy Anticipate >12 week clinical stable BRAF wild type Anticipate <12 week clinical stable BRAF wild type Anticipate >12 week clinical stable BRAF V600 Anticipate <12 week clinical stable BRAF V600 pembroluzimab pembroluzimab pembroluzimab Dabrafenib+ trametinib nivolumab nivolumab nivolumab vemurafenib Ipilimumab imatinib if mt KIT ipilimumab dabrafenib HD IL2 Biochemotherapy (2b) dabrafenib+ trametinib HD IL2 pembroluzimab nivolumab 20

21 Conclusions There have been dramatic advances in management of stage IV melanoma Need determine optimal treatment sequence using immunotherapy and targeted therapy Biomarkers for efficacy and toxicity needed Need to overcome molecular and immune resistance mechanisms Goal to prevent stage IV melanoma from developing For deep stage II and for stage III only FDA approved therapy is INF alpha with benefits limited relative to toxicity. 21