Advances in Melanoma The Blue, the Black and the Ugly 1
Outline History of Melanoma Why be concerned? Skin cancer updates What s old? What s new (and why are Skin Tumor Group med oncs excited again)? What might be coming? 2
History of Melanoma Not a new disease ( evidence found in Peruvian mummies dated for 550 BC ) 1787 John Hunter first operated on a condition subsequently identified (1968) as melanoma 1804 condition first described in a lecture by Laennec 1820 first English language description (report by English GP, William Norris) 1840 Samuel Cooper stated the only chance for benefit depends upon early removal of disease 3
Ml Melanoma: A Brief Bi fintroduction ti Malignancy whose cell of origin is the melanocyte Typically found in the epidermis Various host and environmental factors contribute to risk Host: nevi / light skin / genetic / first degree relative Environmental: sun exposure / geography / tanning beds >90% of cases are sporadic; germ line mutations in CDKN2A gene are typical in inherited melanoma Four main subtypes SSM is most common (70%) ; nodular, LMM and ALM (10% in Caucasians, but 50% in black / Asian) make up the rest Molecular subtypes? 4
Why should we be concerned Epidemiology 6000 diagnosed d in 2013 (3300 men, 2700 women) 1050 will die from disease in 2013 (640 men, 390 women) In 2007, 1 in 63 chance of developing melanoma for men (1 in 287 of death) In 2007, 1 in 79 chance of developing melanoma for women (1 in 420 of death) BCCA stats 7 th most common cancer in men and women during 2001 2010 in BC Est # of cases for 2011 919 (7 th ) Deaths 141 (14 th ) Est # of cases for 2026 1653 (6 th ) Deaths 268 (12 th ) 5
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Skin cancer Updates Tanning and Tanorexia Sunscreen and protection Proper sunscreen use and prevention of MM (JAMA Dermatol, May 2013) (treated nevi with screen or blocker over 50% of area then exposed to single UVB dose. Found a reduction or prevention of most biological effects of UVB, including no activated melanocytes in treated area) Daily Sunscreen use and regular reapplication significantly retarded dd photoaging of the skin (Ann. Intern. Med. June 2013) No effect for beta carotene; daily use better than discretionary but both showed effects. 10
UV Awareness (Myths) Darker skin makes one immune to harmful effects of the sun (melanoma rarer in people of colour but greater risk of late presentation and lower survival) There is no risk of exposure on cloudy days (up to 80% UVB penetrates cloud) One needs to get Vitamin D via sun exposure 11
TANNING Now linked with Melanoma, BCC and SCC Study in US (2008). In 40 major US cities there are more tanning salons than Starbucks coffee shops Up to 1 in 7 tanning bed users return to tanning after a skin cancer diagnosis (JAMA Dermatology, June 2013), suggesting an addictive aspect to tanning Tanorexia 12
Stage 4 Treatment What s old? Dacarbazine approved 1975 Interleukin approved 1998 Interferon Review of metastatic melanoma by Bhatia et al, Oncology, May 2009 10 year survival < 10% Systemic Rx is mainstay but single agent response 5 20% Combination chemotherapy may improve response but not survival and associated with increased toxicity Immunotherapy associated with durable response in a small subset attempts to improve upon the survival of the patient with metastatic disease have met with failure and the need for successful new therapies cannot be overemphasized 13
Gloomy!! 14
What s new in treatment Advances in cell and molecular biology 15
l u Ipilumumab m i m a b FDA approved 2011 for first and second line Rx of advanced melanoma Targets CTLA-4 (ligand) a negative regulator of T cells, therefore T cell activation and proliferation is augmented by Ipi. 16
CTLA 4 inhibition and Ipilumumab A key element in immune tolerance and the main negative regulator of T cell mediated d antitumor immune responses Serves as a natural braking mechanism for T cell activation, allowing a return to homeostasis after an immune response Homolog of CD28 that functions as an inhibitory receptor for B7 co stimulatory molecules expressed on mature APCs After T cell activation, CTLA4 cell surface receptors are upregulated and successfully compete with CD28 for binding to B7, resulting in an inhibitory signal that downregulates T cell activation Kirkwood et al., JCO 2008;26:3445 55 17
CTLA4 Kirkwood et al., JCO 2008;26:3445 55 18
CTLA4 Blockade Kirkwood et al., JCO 2008;26:3445 55 19
Ipilimumab Blocks signalling gfromctla 4 delays engagement of natural braking system and continues acceleration system Resulting blockade of CTLA 4 prolongs T cell activation restores T cell proliferation Amplifies T cell mediated immunity enhances patients capacity to mount an anti tumour response 20
Does it work? Ipilumumab Phase 2 - > 50% OS (2 years ) in 1 st line - > 30% OS in 2 nd line Phase 3 (2010) - Compared Ipi, Ipi + gp100 vaccine to vaccine alone Med survival: 10.1 months (Ipi) 10.0 months (Ipi + vaccine) 6.4 months (vaccine alone) 21
Ipi vs Dacarbazine Ipilumimab survival (est): 1 year 47.3% vs. 36.3% 2 year 28.5% vs. 17.9% 3 year 20.8% vs. 12.2% Combinations Ipi + high dose IL-2 Ipi + Bevacizumab 22
Ipilumumab Adjuvant (?) - encouraging phase 1 and 2 studies Phase 3 underway reporting soon - EORTC 18071 (Ipi vs. observation in high risk (3a-c) lymph node positive patients 23
Ipilimumab: Patterns of Response Screening Week 12: Initial increase in total tumour burden (mwho PD) Week 96: Durable & ongoing response without signs of iraes Week 16: Responding Harmankaya K, et al: EADO 5th Congress / 7th World Congress of Melanoma 2009/BMS 24
Ipilimumab Caveats No predictivebiomarkers foripi as yet Potential for significant (particularly immune related) toxicity Greatest benefit seen in a subset of patients 25
Vemurafenib Mutation Driven Drug Development MD Anderson series 47% BRAF, 20% NRAS, 33% wild type Increasing number of inhibitors targeting mutated signal transduction molecules 26
Mutated targets c-kit BRAF c-kit MEK NRAS P13K Akt mtor GNAC Combinations in development 27
BRAF Found in 40 55% caucasian melanomas - ~75% V600E - ~19% V600K Serine-threonine kinase 28
BRAF Selective Inhibitors - Vemurafenib (approved 2012) BRIM 3 compared VF to Dacarbazine (ASCO 2011) -median PFS 5.3 vs. 1.6 months -OS 84% vs. 64% at 6 months -Response rate 48% vs. 5% 29
BRAF Non-Selective inhibitors - Sorafenib (30% response in phase 2, but failed phase 3) - RAF 265 (response disappointing in phase 1 30
Growth factors RTK RAS RAF in Melanoma: A Cell Proliferation and Survival Pathway RAS GTP Normal activation of RAS by extracellular factors Normal RAS RAF pathway signaling (adapted from Garnett MJ, et al) P Activated RAS BRAF MEK Oncogenic BRAF signaling (adapted from Wan PTC, et al) P Mutated BRAF MEK Constitutive activation is independent of extracellular factors Not responsive to normal regulatory signals P ERK P ERK Normal cell proliferation and survival Excessive cell proliferation and survival 49 Garnett MJ, et al. Cancer Cell 2004;6:313 9. Wan PTC, et al. Cell 2004;116:855 67. 31
rogression free survival (%) Pr Dr. A. Hauschild / Roche Progression free survival (December 30, 2010 final pre planned analysis at IA) 100 Hazard ratio 0.26 90 (95% CI 0.20 0.33) 80 Vemurafenib (n=275) Log rank p<0.0001 70 60 Dacarbazine 50 (n=274) 40 30 Median 1.6 mos Median 5.3 mos 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 No. of patients in follow up Time (months) Dacarbazine Vemurafenib 274 275 213 268 85 211 48 122 28 105 16 50 10 35 6 16 3 4 0 3 32
BRAF Vemurafenib Problems and Side effects 1) 18-24% SCC (keratoacanthoma) 2) Photosensitivity Arthralgia, Rash, fatigue, alopecia, pruritus and skin papilloma Combination with a MEK inhibitor may be preferred option GSK2118436 33
c-kit - 39 % mucosal 39 % mucosal - 36 % acral - 28 % arising in sun damaged skin China phase 2 study - 20-30% response with Imatinib - Phase 3 comparing Nilotinib to Dacarbazine ongoing 34
A New Treatment Algorithm for Advanced Melanoma? BRAF mutation positive? 1 st line yes BRAFi *BRAFi+MEKi? no DTIC or TMZ *Ipilimumab? 2 nd line Ipilimumab DTIC or TMZ Ipilimumab 35
New Dawn or False Start? 36
IFN sensitivity Ulceration (in melanoma) and microscopic nodal involvement may indicate a biological variant which is sensitive to pegylated interferon-alpha2b 40-50% improvement in - RFS -DMFS - OS 37
Future Combination therapies Combination therapies improve outcomes reduce side effects New and better targets 38
Take home messages Incidence of melanoma is rising ABCDE ( ) still the cornerstone of diagnosis i Sunscreen application reduces melanoma incidence (and photoaging) Tanning bed use increases melanoma incidence ~45% of patients with primary melanoma have a BRAF mutation (all with stage 4 should be tested for it) Ipilumimab and Vemurafenib are recently approved treatments Vaccine trials il continue (poor results in past) Ongoing trials of emerging immunomodulators and targeted mutation inhibitors 39
References www.bccancer.bc.ca www.cancer.ca (Canadian cancer society) The Emperor of all Maladies Save Your Skin Foundation 40