Winship Cancer Institute of Emory University Combination therapy in melanoma: ready for primetime? Ragini Kudchadkar, MD Disclosures • Fees from non ‐ CME services such as speaker’s bureaus: – Bristol ‐ Myers Squibb, Genentech 1
Winship Cancer Institute of Emory University Medical Oncology Rule # 1: If one drug works, then two will work better. Winship Cancer Institute of Emory University Growth Factors: TKR VEGF, PDGF, FBGF, FLT-3 CKIT Pro-Growth CRAF RAS PIP2 Pro-apoptosis BRAF PTEN PI3K ARAF PIP3 MEK 1/2 PDK1 AKT FOXO ERK 1/2 MTOR Cyclin D CDK2 CDK4 P16 MITF 2
BRAF V600E melanoma patient PET scan at baseline and day 15 after vemurafenib treatment MISSION ACCOMPLISHED! Baseline Day 15 Flaherty K et al. N Engl J Med 2010;363:809 Vemurafenib Single Agent Activity • BRIM ‐ 3 Vem vs DTIC in treatment naïve ‐ McArthur et al Lancet Oncology 2014 – 675 patients randomized, though cross over was allowed once benefit was established – Median OS 13.6 months vs 9.7 – Median PFS 6.9 months vs 1.6 3
Dabrafenib Single Agent Activity • BREAK ‐ 3 Dabrafenib vs DTIC in treatment naïve ‐ Hauschild et al Lancet 2012 • 250 patients randomized, 187 to dabrafenib vs 63 to dacarbazine – Median PFS 5.1 vs 2.7 months Rationale for Combination Therapy RAS Dabrafenib BRAF RR 63% 1 Goals of Combination 1. Synergy in combination Trametinib MEK RR 40% 1 2. Prevent/overcome potential monotherapy resistance 3. Potentially decrease incidence of BRAFi-induced hyper-proliferative skin lesions pERK Proliferation, Survival, Invasion, Metastasis 1 Data presented at ASCO 2010 4
Dabrafenib vs Dabrafenib + Trametinib • D + T (2mg) – PFS 9.4 mo – RR (CR +PR) 76% – SD 24% • D + T (1mg) – PFS 9.2 – RR 50% – SD 44% • D – 5.8 mo – RR 54% – SD 41% • Combination therapy had more pyrexia (71% vs 26%) but less cutaneous squamous cell carcinomas (7% vs 19%) Flaherty KT et al. N Engl J Med 2012;367:1694-1703. 5
Is combination better? • Statistically, yes. • PFS 9.3 vs 8.8 months, HR 0.75 • Clinically, unknown. – Most experts say yes – We were convinced with phase II data but did we drink the kool ‐ aid? – Lots of statically jargon to say yes. Early censoring in the dabrafenib arm lead to “better” single agent activity than expected • By side effects, toss up. – Much less skin toxicity – Higher rate of fevers • Fiscally, no. – Single agent costs 8 ‐ 10K a month, Combination approximately 18K per month 6
My opinion… • Combination is better – PFS is better statistically, though not as dramatic as expected – Fevers easier to control and tolerate than the skin toxicity – In the end we are all influenced by our practice and I have many more longer term survivors on combination therapy than on single agent – Awaiting results of other combination studies from other BRAF/MEK inhibitors to finalize my opinion Winship Cancer Institute of Emory University Combination Immunotherapy 7
Single Agent IPI (3mg/kg) Ipi + gp100 (A) Hodi et al. N Engl J Med 2010;363:711 Ipi alone (B) gp100 alone (C) 1 2 3 4 Years Ipi + gp100 Ipi + pbo gp100 + pbo Survival Rate N=403 N=137 N=136 1 year 44% 46% 25% 2 year 22% 24% 14% Phase I Study of Nivolumab • Melanoma Responses – 26 of 94 patients – At 3mg/kg 7/17 41% RR • PDL ‐ 1 staining – All tumor types – Positive 9/25 – Negative 0/17 – Results have not held true in other studies • PDL1 positive respond at a higher rate, but PDL1 negative can respond In nivolumab-treated pts: 1-yr OS 62% 2-year OS 43% Topalian et al JCO 2014 Topalian SL et al. N Engl J Med 2012;366:2443-2454 8
Pembrolizumab in IPI refractory http://dx.doi.org/10.1016/S0140-6736(14)60958-2 Robert C et al Lancet 2014 Context: Nivolumab compared to Pembrolizumab? Presented By Jeffrey Weber at 2014 ASCO Annual Meeting 9
Ipi + Nivolumab: Do we need Phase III data? • Tolerable dose: IPI 3mg/kg + Nivo 1mg/kg • 21/52 (40%) ORR • “Rapid and Deep Responses” Toxicity • – 93% ALL grades, treatment related – Grade 3/4 Toxicity 53% • Elevated lipase, AST, ALT • 21% Dose ‐ limiting • PDL ‐ 1 Staining – 6/13 PDL ‐ 1 positive – 9/22 PDL ‐ 1 negative Wolchok JD et al. N Engl J Med 2013;369:122-133 Combination Immunotherapy 10
Is combination better? • Unknown – await phase III data – We’ve been fooled before, but early data is very promising • Toxicity may be the limiting factor – Will the combination need to be used in specific centers like HD ‐ IL2? • Will sequencing of therapies be just as good with less toxicity? – Sequencing trial data is pending Conclusion • Combination therapy is the way of the future. • The next frontier will better define how to combine both immunotherapy with targeted tyrosine kinase inhibitors. • A word of caution, more is not always better. 11
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