A Personalized Approach: Molecular Testing and Targeted Therapy – Hussein Tawbi, MD, PhD
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This document summarizes a presentation by Dr. Hussein Tawbi on targeted therapy approaches for melanoma. It discusses the history of chemotherapy and development of targeted therapies. It explains key signaling pathways and genetic mutations involved in melanoma, and how targeted therapies like BRAF inhibitors work to block oncogenic signaling. The presentation reviews clinical results of BRAF inhibitors including response rates and toxicities. It also discusses challenges of resistance and approaches to overcome resistance through combination targeted therapies or targeted therapy plus immunotherapy.
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A Personalized Approach: Molecular Testing and Targeted Therapy – Hussein Tawbi, MD, PhD
- 2. Disclosures • Research support from – Bristol Myers Squibb – Novartis – Roche/Genentech – Merck – GlaxoSmithKline • Advisory Board – Bristol Myers Squibb – Roche/Genentech – Novartis – EMD Serono
- 3. Targeted Therapy: A Personalized Approach • What is targeted therapy? • Why do we use targeted therapy for melanoma? • What have we learned & what are we working on
- 4. A Brief History of Chemotherapy • WW I: Nitrogen mustards gas • → 1946 1st successful systemic treatment of cancer with chemotherapy • 1950s‐1980s most standard chemotherapies • 1977 First report of an oncogene • 1980s‐2000s Oncogenes in most cancers Dr. Sidney Farber And Patient ‘Targeted Therapy’: Treat cancer by targeting the genes activated in cancer cells
- 6. Melanocytes in the Basal Layer of the Skin Rigel DS, et al.
- 7. The Main Ingredient of Melanoma Rigel DS, et al. • Overall melanomas have more mutations than any other type of cancer
- 10. Accumulation of Genetic “Hits” and Melanoma Progression Miller et al. NEJM, 2006
- 12. Imatinib Mechanism BCR-ABL or KIT or PDGFR Adapted from Imatinib / CML Prescribing Guidelines, Novartis Signals for growth, survival BCR-ABL or KIT or PDGFR
- 16. Ras GTP Baseline pERK cyclin D Ki67 Day 15 Cyclin D BRAFV600 MEK ERK P P Cell cycle (Ki67) PLX4032 RTK Y‐PY‐P GF Inhibition of MAPK Signaling in Biopsies of BRAFV600 Melanoma From Patients Treated With Vemurafenib Smalley et al, 2010; Flaherty et al, 2010b.
- 19. Clinical Activity of BRAF Inhibitors Tumor Grew Tumor Shrank • 50% of patient achieve a “clinical response” • 90% achieve disease control, usually very quickly (<1 month) • KEY: Only work in patients that have a BRAFV600 mutation • If don’t have a mutation they will make the tumors grow faster FDA‐Approved BRAF Inhibitors • Vemurafenib, 2011 • Dabrafenib, 2013 Champman et al, NEJM, 2011
- 20. All grades n (%) Grade 3 n (%) Grade 4 n (%) Overall 130 (99) 79 (60) 5 (4)† Arthralgia 78 (59) 8 (6) – Rash 69 (52) 9 (7) – Photosensitivity reaction 69 (52) 4 (3) – Fatigue 56 (42) 2 (2) – Alopecia 48 (36) – – Pruritus 38 (29) 3 (2) – Skin papilloma 38 (29) – – cuSCC / KA‡ 34 (26) 34 (26) – Nausea 30 (23) 2 (2) – Elevated liver enzymes 23 (17) 8 (6) § 4 (3)¶ Toxicity of BRAF InhibitorsToxicity of BRAF Inhibitors
- 23. Mechanisms of Resistance to BRAF Inhibitors Survival BRAFV600E MEK ERK P P BRAF inh PDGFRb or IGF1R PI3K AKT MEK-independent progression NRASQ61 COT CRAF MEK-dependent progression Adapted from Poulikakos et al, 2011; Shi et al, 2012; Nazarian et al, 2010; Villanueva et al, 2010; Johannessen et al, 2010; Wagle et al, 2011. MEKi PI3Ki or AKTi
- 24. Combinations to Overcome Resistance: Targeted Therapy + Targeted Therapy ‐100 ‐80 ‐60 ‐40 ‐20 0 20 40 60 80 100 Tumor Shrank BRAFi + MEKi • ~100% disease control rate • Average response duration 11 months (~2X BRAFi) • Less skin toxicity than BRAFi alone Flaherty et al, NEJM, 2012
- 25. A New Hypothesis: Combining BRAF Inhibitors & Immunotherapy BRAF Inhibitors • Almost all patients respond • Responses but not cures Immunotherapies • Some patients respond • Responses can → cures Can BRAF Inhibitors + Immunotherapy → High rate of cures?
- 26. Combinations to Overcome Resistance: Targeted Therapy + Immune Therapy Liu, …Hwu, CCR, 2013 Frederick,…Wargo, CCR, 2013 BRAF Inhibitor: In Mice BRAF Inhibitor: In Patients → Clinical trials of targeted therapy + immune therapy ongoing & planned
- 28. Targeted Therapy: What We Have Learned • Virtually all patients with cutaneous melanomas have many DNA mutations • BRAF‐Mutant Melanoma (~ 50%) – Inhibi ng driver oncogenes can → benefit – Right patient, right drug, right dose – Combinations can be even better! • Have to identify ways to understand, prevent & overcome resistance
- 29. THANK YOU