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Systemic Therapy of Melanoma: The Dawn of A New Era

Systemic Therapy of Melanoma: The Dawn of A New Era. Shailender Bhatia, MD University Of Washington. Melanoma Incidence And Mortality (United States 2008). [Jemal et al. CA Cancer J Clin . 2008]. Historically, outcomes of patients with advanced melanoma have been dismal.

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Systemic Therapy of Melanoma: The Dawn of A New Era

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

  2. Melanoma Incidence And Mortality (United States 2008) [Jemal et al. CA Cancer J Clin. 2008]

  3. Historically, outcomes of patients with advanced melanoma have been dismal 10-year survival rate less than 10% [Balch CM et al. J Clin Oncol2001]

  4. 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; 488-500 E-mail: sbhatia@u.washington.edu

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

  6. Immunotherapy Works(Albeit only in a small subset of melanoma patients) n=17 (6%) n=26 (10%) Pooled analysis of 270 Melanoma patients treated with High-dose Interleukin-2 [Atkins MB et al. JCO1999 113:293]

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

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

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

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

  11. ALT-801 Targeting Cytokine Delivery To Tumors: ALT-801 [Belmont et al. 2006 Clin. Immunol. 121:29 Wen et al. 2008 Cancer Immunol Immunother. 57:1781]

  12. [Courtesy: Hing Wong. Altor Biosciences] 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.

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

  14. 20% 60% V600E Mutations in BRAF and NRAS are frequent in cutaneous melanomas and contribute to tumorigenesis [Curtin JA et al. NEJM 2005]

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

  16. Effective inhibition of target Structure-based discovery Anti-tumor activity in mice Selectivity for B-rafV600E Selective inhibitor of BRAFV600E had potent anti-melanoma activity in preclinical models [Tsai J et al. PNAS 2008]

  17. Expansion Cohort patients at MTD (960 mg BID) RO5185624 (PLX4032) led to tumor regressions in majority of melanoma patients with V600E mutation in BRAF [Chapman P et al. ECCO/ESMO. 2009]

  18. 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]

  19. Pre-treatment Post-treatment Pre-treatment Day 15 Cycle 2 Pre-treatment Several patients had significant reductions in tumor size and metabolism . Cycle 4

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

  21. [Shepherd C et al. Curr Oncol Rep. 2010] RAF inhibitors in clinical trials in Melanoma RO5185426 vs Dacarbazine for Untreated Metastatic Melanoma (RO5185426)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 RO5185426 or DacarbazineStatus: Open and enrolling at SCCA

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

  23. 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. 2009 ASCO Abstract 9001]

  24. Until CURE happens, participation in well-designed clinical trials should be considered Standard of Care

  25. Personalized therapy of melanoma is finally picking up speed. 25

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