特別演講1:2018台灣醫學週台灣聯合醫學會學術演講會
       開幕典禮及大會特別演講節目程序表

程 序 表

P-2
Melanoma Therapeutic Designs Based on Resistance Mechanisms
Professor Roger Lo, MD, Ph.D.
Medicine/Dermatology & Molecular and Medical Pharmacology
Associate Chief, Division of Dermatology
Director, Dermatology STAR Residency Program
Director, Melanoma Clinic in Dermatology
Member, Jonsson Comprehensive Cancer Center
David Geffen School of Medicine at UCLA

  The fervent pace of therapeutic development, especially in the area of combination therapies, for melanoma has the potential to inform drug development for other cancer histologies. Melanoma is an aggressive skin cancer that has gained notoriety as one of the most mutated and metastatic human malignancies. An understanding of its evolutionary biology should reveal fundamental insights into tumor heterogeneity and its microenvironment and suggest novel therapeutic strategies. Because the recent breakthrough therapies based on blocking the MAPK and PD-1/L1 pathways were first developed for patients with advanced melanoma, we have focused our work on understanding drug resistance mechanisms in melanoma patients as a rational basis to build next-generation therapeutic regiments.
  About half of advanced melanoma harbor activating mutations in BRAF and another twenty-thirty percent harbor activating mutations in NRAS. BRAF inhibitor (BRAFi) was approved for the treatment of BRAF mutant melanoma but was soon supplanted by the combo of BRAFi and MEK inhibitors (BRAFi+MEKi), which extends progression-free and overall survival by suppressing a common tumor cell-intrinsic route of resistance (we called this MAPK pathway reactivation). Among patients with BRAF mutant melanoma, up to three quarters on BRAFi+MEKi therapy still succumb to drug-resistant melanoma three years after initiating therapy. Today, there is no available targeted therapy for NRAS mutant melanoma, but early clinical data suggest the potential utility of MEKi, although tumor control was transient due to a rapid acquisition of resistance. BRAF and RAS mutations are commonly detected in other cancers. The successful development of the first BRAFi (vemurafenib) against melanoma led to the concept of “basket trials”, which test oncology drugs against cancers not based on the specific cancer histology but based on a common driver mutation. As of early 2018, there are nearly 40 basket trials.
  Blocking immune checkpoints such as the PD-1/L1 pathway is active in about 40% of melanoma patients, but, across other cancers, the efficacy is usually much lower. Blocking both PD-1 and MAPK pathways has been predicted to be highly active, but early clinical data seem to disappoint. Three categories of therapeutic designs based on resistance mechanisms are promising. First are combinatorial therapies that suppress convergent tumor cell-intrinsic resistance mechanisms. Second are combinatorial therapies that harness the combined mechanisms of MAPK and PD-1/L1 blockade by identifying and addressing areas of incompatibility. Third, I will discuss the importance of sequencing for combination therapies in order for them to have their maximal anti-tumor impacts. Some of the therapeutic designs I will discuss have been or are being tested in clinical trials; others are in advanced stages of clinical trial design/approval.