Release Date: May 31, 2018
Expiration Date: May 31, 2019
Media: Internet - based
This activity, Advances in™ BRAF/MEK Inhibitors for the Treatment of Advanced Melanoma, developed in Physicians’ Education Resource, LLC, (PER®) established Advances in™ legacy format, will highlight best practices in the treatment and management of patients with advanced melanoma, including an extensive update on the biologic rationale, current foundation of evidence, and next steps to integrate the use of BRAF/MEK inhibitors for the treatment of advanced melanoma. Additional focus will be placed on BRAF testing, sequencing strategies, and adverse events related to these targeted combination strategies. You will hear expert perspectives and discussions of recent updates that have the potential to advance the treatment of melanoma in the context of current treatment paradigms to improve outcomes for your patients.
Acknowledgment of Commercial Support
This activity is supported by an educational grant from Array BioPharma Inc.
Instructions for This Activity and Receiving Credit
You will need to login to participate in the activity.
Each presentation may contain an interactive question(s). You may move forward through the presentation; however, you may not go back to change answers or review videos/content until you finish the presentation.
At the end of the activity, “educational content/video files” will be available for your reference.
In order to receive a CME certificate, participants must complete the activity.
Complete the posttest and pass with a score of 70% or higher, complete the evaluation and then click on request for credit. Participants may immediately download a CME certificate upon completion of these steps.
This educational activity is directed toward medical oncologists, researchers, dermatologists, and surgical oncologists who treat patients with melanoma. Nurse practitioners, nurses, physician assistants, pharmacists, and other healthcare professionals interested in the treatment of melanoma are also invited to participate.
At the conclusion of this activity, you should be better prepared to:
Assess recent advances in the understanding of melanoma treatment resistance that provides the mechanistic rationale for BRAF/MEK inhibitor strategies in the context of current management paradigms
Apply knowledge of efficacy profiles on emerging BRAF/MEK combination approaches to inform sequencing decisions that optimize outcomes in patients with melanoma
Apply best practices to proactively identify and manage adverse events associated with combination strategies in the setting of advanced melanoma
Outline key aspects of ongoing clinical trials examining emerging BRAF/MEK combination strategies in melanoma
Faculty, Staff, and Planners' Disclosures
Michael A. Postow, MD
Melanoma and Immunotherapeutics Service
Memorial Sloan Kettering Cancer Center
New York, NY
Disclosure: Grant/Research Support: BMS, Infinity, Rgenix, Novartis, Array BioPharma; Consultant: BMS, NewLink Genetics, Merck, Incyte, Novartis, Array BioPharma
Geoffrey T. Gibney, MD
Co-Leader, Melanoma/Skin Cancer Program
Member, Developmental Therapeutics Program
George Lombardi Comprehensive Cancer Center
Chevy Chase, MD
Disclosure: Consultant: Genentech, Novartis, Incyte, NewLink Genetics; Speakers Bureau: Merck, Genentech
The staff of PER® have no relevant financial relationships with commercial interests to disclose.
Disclosure Policy and Resolution of Conflicts of Interest (COI)
As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME activity to disclose all relevant financial relationships with commercial interests. The ACCME defines “relevant financial relationships” as financial relationships in any amount occurring within the past 12 months that creates a COI.
Additionally, PER® is required by ACCME to resolve all COI. PER® has identified and resolved all COI prior to the start of this activity by using a multistep process.
Off-Label Disclosure and Disclaimer
This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical and nursing education purposes only, and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER® or any of the companies that provided commercial support for this activity..
PER Pulse Recap™
PER Pulse Recap (1 of 3)
Established and Emerging Targeted Therapy in BRAF-Mutated Melanoma
This first of 3 PER Pulse™ Recaps
from the program focuses on the state of BRAF/MEK inhibitors in the treatment of advanced melanoma.
Drs. Postow and Gibney provided details on the multiple clinical trials that have evaluated and are still evaluating BRAF/MEK targeted combination therapies in melanoma:
Dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) were evaluated in 2 phase III trials: COMBI-d and COMBI-v, leading to their approval for patients with advanced melanoma who harbor a BRAF mutation.
In COMBI-d, patients who received the dabrafenib/trametinib combination therapy had an objective response rate (ORR) of 69% compared with 53% for patients who received dabrafenib monotherapy; median progression-free survival (PFS) was 11.0 months and 8.8 months, respectively; median overall survival (OS) was 25.1 months and 18.7 months, respectively.
In COMBI-v, patients who received the dabrafenib/trametinib combination therapy had an ORR of 64% compared with 51% for those who received vemurafenib monotherapy; median PFS was 11.4 months versus 7.3 months, respectively; median OS was 25.6 months versus 18 months, respectively.
In the phase III coBRIM trial evaluating vemurafenib (a BRAF inhibitor) plus cobimetinib (a MEK inhibitor) combination therapy versus vemurafenib alone, patients receiving the combination demonstrated an ORR of 68%, median PFS of 9.9 months, and median OS of 22.3 months. This compared to an ORR of 45%, median PFS of 6.2 months, and median OS of 17.4 months for vemurafenib monotherapy.
A third BRAF/MEK inhibitor combination is undergoing clinical evaluation in the phase III COLUMBUS trial: encorafenib (a BRAF inhibitor) plus binimetinib (a MEK inhibitor). Reported data showed a median PFS of 14.9 months for patients receiving the combination, 9.6 months for patients receiving encorafenib alone, and 7.3 months for patients receiving vemurafenib monotherapy. It was reported that the novel combination had a median OS of 33.6 months compared with 23.5 months for encorafenib alone and 16.9 months for vemurafenib monotherapy.
PER Pulse Recap (2 of 3)
The Role of BRAF/MEK Inhibitors in Adjuvant Therapy, Neoadjuvant Therapy, and Brain Metastases
This second of 3 PER Pulse™ Recaps
from the program focuses on the role of BRAF/MEK inhibitors in the adjuvant treatment of BRAF
Drs. Gibney and Postow commented on the role of dabrafenib plus trametinib in patients with brain metastases, as well as in the pre- or postsurgery setting.
The phase III COMBI-AD trial randomized 870 patients with completely resected phase III melanoma to receive either dabrafenib plus trametinib or placebo. The estimated 3-year relapse-free survival was 58% for patients receiving the combination compared with 39% for patients receiving placebo.
Following the success of this trial, the FDA in April 2018 approved the use of dabrafenib plus trametinib in combination for the adjuvant treatment of patients with BRAF V600E/K mutations with lymph node involvement, following complete surgical resection.
Dr. Gibney said: “We have seen data now in the neoadjuvant use of BRAF-targeted therapy with dabrafenib plus trametinib that did show a very good response rate in that population, and tolerability. A number of patients experienced a complete pathologic response by the time they got to surgery…If you consider this similar to what we’ve done in the adjuvant setting, there will hopefully also be an improvement in relapse-free survival and overall survival.”
The utility of a BRAF/MEK inhibitor combination is also under evaluation for patients with active melanoma brain metastases in the open-label, phase II COMBI-MB trial. Patients across 4 cohorts were evaluated for intracranial response following treatment with dabrafenib plus trametinib.
The main cohort, Cohort A, consisted of patients with BRAF V600E-positive, asymptomatic melanoma brain metastases, who had not previously received local brain therapy and had an ECOG performance status (PS) of 0 or 1. After a median follow-up of 8.5 months, 58% of patients in Cohort A had achieved an intracranial response. Responses were also observed in the other cohorts, which included patients who had previously received local brain therapy, harbored rare BRAF mutations, and/or had a worsened PS.
Dr. Postow said: “We’re very encouraged now that there are data to support BRAF and MEK inhibitors in the brain…I think of it as a treatment that can shrink brain metastases pretty well, but you have to be thinking about another treatment to sequence those patients to.”
PER Pulse Recap (3 of 3)
Targeted Therapies and Immunotherapies in Melanoma
This third and final PER Pulse™ Recap
from the program focuses on the combination and sequencing of immunotherapy with BRAF/MEK inhibitors in the treatment of melanoma.
Drs. Postow and Gibney provided details on the current state of immunotherapy combinations and sequencing investigations under evaluation in BRAF
A retrospective analysis of 114 patients across 4 treatment centers sought to answer whether patients with BRAF-mutated melanoma should first receive anti–PD-1 immunotherapy or BRAF/MEK targeted therapy. While the median overall survival was similar between both the anti–PD-1-first and BRAF/MEK-first groups, investigators reported that patients who progressed while taking anti–PD-1 therapy demonstrated shortened response durations while taking BRAF/MEK inhibitors as opposed to patients who started BRAF/MEK inhibitors in the first line.
Ongoing investigations are looking to answer this question more definitively. The phase III EA6134 trial (NCT02224781) is randomizing patients to receive either dabrafenib plus trametinib, followed by ipilimumab plus nivolumab at time of progression, or ipilimumab plus nivolumab, followed by dabrafenib plus trametinib at time of progression.
Several ongoing and planned investigations are also evaluating BRAF/MEK inhibitors in sequence or in combination with checkpoint inhibitors. Dabrafenib plus trametinib is being evaluated in combination with the PD-1 inhibitor pembrolizumab in the phase I/II KEYNOTE-022 trial (NCT02130466).
Preliminary results presented at the European Society for Medical Oncology (ESMO) 2017 Congress showed that the triplet combination had an objective response rate of 67%; the median duration of response had not yet been reached.
Other selected trials include vemurafenib plus cobimetinib in combination with the PD-L1 inhibitor atezolizumab in both phase I (NCT01656642) and phase III (NCT02908672) investigations, as well as dabrafenib plus trametinib in combination with the PD-L1 inhibitor durvalumab in a phase I/II trial (NCT02027961).
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