Systemic Therapy of Melanoma: The Dawn of A New Era Shailender Bhatia, MD University Of Washington

Melanoma Incidence And Mortality (United States 2008) Estimated New Cases of Melanoma 62,480 MalesFemales Prostate186,32025%Breast182,46026% Lung & bronchus114,69015%Lung & bronchus100,33014% Colon & rectum77,25010%Colon & rectum71,56010% Urinary bladder51,2307%Uterine corpus40,1006% Non-Hodgkin lymphoma 35,4505%Non-Hodgkin lymphoma30,6704% Melanoma of the skin34,9505%Thyroid28,4104% Kidney & renal pelvis33,1304%Melanoma of the skin27,5304% Oral cavity & pharynx25,3103%Ovary21,6503% Leukemia25,1803%Kidney & renal pelvis21,2603% Pancreas18,7703%Leukemia19,0903% All sites745,180100%All sites690,000100% Mortality of Melanoma 8,420 [Jemal et al. CA Cancer J Clin. 2008]

Historically, outcomes of patients with advanced melanoma have been dismal [Balch CM et al. J Clin Oncol 2001] 10-year survival rate less than 10%

Systemic therapy is the mainstay of metastatic melanoma. US-FDA approved therapies for metastatic melanoma Dacarbazine (1975) High-dose IL-2 (1998) Treatment of Metastatic Melanoma: An Overview Bhatia S et al. ONCOLOGY. 2009; 23:6;

How can we cure patients with advanced melanoma? Immunotherapy versus Chemotherapy / Targeted therapy COMBINATION THERAPIES

Immunotherapy Works (Albeit only in a small subset of melanoma patients) [Atkins MB et al. JCO :293] n=17 (6%) n=26 (10%) Pooled analysis of 270 Melanoma patients treated with High-dose Interleukin-2

High-dose Interleukin-2 is very toxic and requires administration in the ICU [Google images]

CTLA-4 blockade leads to immune stimulation [Halama N et al Journal of Oncology 2010]

Ipilimumab is active in melanoma; although responses are infrequent. [Wolchok JD et al Lancet Oncology 2010]

Stay Tuned for Major Ipi Update!! Ipilimumab is available, through an expanded-access trial, for SCCA patients with metastatic melanoma.

ALT-801 Targeting Cytokine Delivery To Tumors: ALT-801 [Belmont et al Clin. Immunol. 121:29 Wen et al Cancer Immunol Immunother. 57:1781]

ALT-801 phase I/IIa trial: Tumor shrinkage seen in several patients Phase Ib/II Study of ALT-801 With Cisplatin in Patients With Metastatic Melanoma is open and enrolling at SCCA. [Courtesy: Hing Wong. Altor Biosciences]

Melanomas arising in different locations have unique biologic features [Curtin JA et al. J Clin Oncol. 2006] CSD= Chronic Sun Damaged-skin V600E mutant BRAF present in 60% of Non- CSD cutaneous melanoma patients; Mutant NRAS in another 20%

Mutations in BRAF and NRAS are frequent in cutaneous melanomas and contribute to tumorigenesis 60% V600E 20% [Curtin JA et al. NEJM 2005]

Early attempts at BRAF inhibition with Sorafenib were disappointing. Non-selective BRAF inhibitor. BRAF wild-type 22 nmol/L BRAF V600E 38 nmol/L CRAF, VEGFR-2, PDGFR-β, Flt-3, c-KIT [Hauschild A. et al. J Clin Oncol; 2009]

Selective inhibitor of BRAF V600E had potent anti-melanoma activity in preclinical models [Tsai J et al. PNAS 2008] Structure-based discovery Selectivity for B-raf V600E Effective inhibition of target Anti-tumor activity in mice

RO (PLX4032) led to tumor regressions in majority of melanoma patients with V600E mutation in BRAF [Chapman P et al. ECCO/ESMO. 2009] Expansion Cohort patients at MTD (960 mg BID)

Progression-free survival data looks promising as well. Median PFS not yet reached in patients treated at 960 mg PO BID (as of 08/2009) [Chapman P et al. ECCO/ESMO. 2009]

Several patients had significant reductions in tumor size and metabolism. Pre-treatmentPost-treatment Pre-treatmentDay 15 Pre-treatment Cycle 2 Cycle 4

A Roller Coaster Chase for a Cure After Long Fight, Drug Gives Sudden Reprieve A Drug Trial Cycle: Recovery, Relapse, Reinvention By AMY HARMONAMY HARMON Published: February, 2010

RAF inhibitors in clinical trials in Melanoma [Shepherd C et al. Curr Oncol Rep. 2010] RO vs Dacarbazine for Untreated Metastatic Melanoma (RO ) RO vs Dacarbazine for Untreated Metastatic Melanoma (RO ) BRIM 3: A Randomized, Open-label, Controlled, Multicenter, Global Study on Progression-free and Overall Survival in Previously Untreated Patients With Unresectable Stage IIIC or Stage IV Melanoma With V600E BRAF Mutation Receiving RO or Dacarbazine Status: Open and enrolling at SCCA

Aberrations in Kit are relatively more frequent in uncommon melanoma subtypes [Curtin JA et al. J Clin Oncol. 2006] 28% 36% 39% CSD= Chronic Sun Damaged-skin

31 out of 145 melanoma patients (21%) had KIT aberrations. CSD 12% (4/34) Mucosal 24% (14/59) Acral 30% (13/43) Unknown 0% (0/9) Objective response rate - 33% (4/12) Complete remission - 17% (2/12) Stable Disease - 50% (6/12) Imatinib, an oral inhibitor of KIT, works in melanoma patients harboring somatic alterations of KIT. [Carvajal RD et al ASCO Abstract 9001]

Until CURE happens, participation in well-designed clinical trials should be considered Standard of Care Therapeutic Trials at SCCA (not including the T-cell Therapy trials) Disease StatusImmunotherapyTargeted therapyChemotherapy Adjuvant MAGE-A3 Vaccine vs Placebo Ipilimumab vs Placebo 1 st Line Metastatic Cisplatin + ALT-801 MAGE-A3 Vaccine RO (BRAF inhibitor) vs Dacarbazine Abraxane vs Dacarbazine 2 nd Line or beyond Ipilimumab (expanded access) BRAF inhibitor (coming soon) MLN4924 (Nedd-8 enzyme inhibitor) Tasisulam vs Paclitaxel

25 Personalized therapy of melanoma is finally picking up speed.