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Accreditation/Credit Designation

Physicians' Education Resource® LLC, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Physicians' Education Resource®, LLC, designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Acknowledgment of Commercial Support

This activity is supported by educational grants from Array BioPharma, Inc. and Novartis Pharmaceuticals Corporation.

Medical Crossfire®: Evolving Roles for Targeted Melanoma Therapies: Assessing Rapid Progress in the Field and Looking Toward Future Combinations

Release Date: February 28, 2018
Expiration Date: February 28, 2019
Media: Internet - based

 

Activity Overview

This online activity features an expert panel discussion of the rapidly evolving field of BRAF/MEK inhibitor combination targeted therapy for patients with melanoma. An overview of the cellular pathways that are targeted with BRAF and MEK inhibitors sets the framework for an in-depth discussion pertaining to strategies that inform treatment decisions, including patient characteristics and BRAF testing results. The expert panel will discuss the application of current clinical trial findings to address the use of targeted therapy in the adjuvant and neoadjuvant settings, and management of related toxicities. The panelists will conclude with a discussion of a clinical case and consider the future of melanoma treatment, including the potential role for triplet combinations of targeted therapy plus PD-1/PD-L1‒based immunotherapy.

Acknowledgement of Commercial Support

This activity is supported by educational grants from Array BioPharma, Inc. and Novartis Pharmaceuticals Corporation.

CME Table of Contents

  • Introduction
  • Biology Behind Targeted Therapies
  • Medical Crossfire 1-3: Targeted Therapy vs Immunotherapy, Brain Mets, and Toxicities
  • Medical Crossfire 4-6: Role of Adjuvant vs Neoadjuvant Therapy and BRAF Testing
  • Medical Crossfire 7-8: Triplet Combinations of BRAF + MEK + PD-1/PD-L1‒Based Immunotherapy, and BRAF Wild-Type Melanoma
  • Patient Case
  • Medical Crossfire 9: Future of Melanoma Treatment and Conclusions

Requirements for Successful Completion

  • 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” 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.


Target Audience

This educational activity is directed toward medical oncologists, dermatologists, and fellows who treat patients with melanoma. Nurse practitioners, nurses, physician assistants, pharmacists, researchers, and other healthcare professionals interested in the treatment of melanoma may also participate.

Learning Objectives

At the conclusion of this activity, you should be better prepared to:

  • Apply clinical trial evidence on evolving targeted treatment strategies for melanoma
  • Develop a multidisciplinary approach for the management of melanoma treatment-related toxicities
  • Discuss the use of biomarkers and key testing technologies that can inform clinical decision making
  • in the management of melanoma
  • Evaluate recent clinical trial evidence to optimally sequence targeted therapies in the management of patients with melanoma


Faculty, Staff, and Planners' Disclosures

Moderator

Michael A. Postow, MD
Melanoma and Immunotherapeutics Service
Memorial Sloan Kettering Cancer Center
New York, NY
 
 

Disclosure: Grant/Research Support: BMS, Infinity, Rgenix, Array Biopharma; Consultant: BMS, Merck, Novartis, Incyte, NewLink Genetics, Array Biopharma

Faculty

Omid Hamid, MD 
Chief, Translational Research & Immuno-Oncology
Director, Cutaneous Malignancies, The Angeles Clinic and Research Institute
Director of Experimental Therapeutics, Cedars-Sinai Medical Care Foundation
Los Angeles, CA
 

Disclosure: Consultant: Amgen, Novartis, Roche, BMS, Merck; Speakers Bureau: BMS, Genentech, Novartis, Amgen; Other: Contracted research for institution: AstraZeneca, BMS, Celldex, Genentech, Immunocore, Incyte, Merck, Merck Serono, MedImmune, Novartis, Pfizer, Rinat, Roche

Jason J. Luke, MD, FACP
Assistant Professor of Medicine
The University of Chicago Medicine
Chicago, IL
 
 

Disclosure: Consultant: 7 Hills, Actym, Amgen, Array Biopharma, AstraZeneca, BeneVir, Bristol-Myers Squibb, Castle, Checkmate Pharmaceuticals, EMD Serono, Gilead, Janssen, Merck, NewLink, Nimbus, Novartis, Palleon, RefleXion, Syndax, Tempest, WntRx; Other: Clinical support to institution: AbbVie, Boston Biomedical, Bristol-Myers Squibb, Celldex, Corvus, Delcath, Five Prime, Genentech, Immunocore, Incyte, Intensity, MedImmune, Macrogenics, Novartis, Pharmacyclics, Merck, Tesaro

The staff of Physicians' Education Resource®, LLC 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 education purposes only, and is not meant to substitute for the independent medical judgment of a physician or nurse 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)
 
This first of 3 PER Pulse™ Recaps from the continuing medical education (CME) activity, Medical Crossfire®: Evolving Roles for Targeted Melanoma Therapies: Assessing Rapid Progress in the Field and Looking Toward Future Combinations,
focuses on treatment considerations to individualize care of patients with metastatic melanoma, including patient-level characteristics such as BRAF mutation status and disease burden, including the presence of brain metastases. Assessing the differing toxicity profiles of targeted therapy combinations can help tailor treatment to select the therapy that will deliver the greatest long-term benefit for patients.
 
Patient education is key: Making sure the patient understands the common toxicities associated with targeted therapy, including ways to mitigate the toxicities should they occur, can enhance patient adherence to therapy.
 
Commonly seen toxicities include:



Management of toxicities can include switching to lower dosage, switching to a different combination, or stopping the drug for a short period of time to allow the symptoms to resolve.
 
Given the differences in toxicities between targeted therapy and immunotherapy, patient-level characteristics are important not only for treatment selection, but also for sequencing of therapy.

“Clearly, my experience has been that those patients who tolerate one combination may not tolerate the other combination as well. If I start someone and initially there is no way they are tolerating, I won’t just say, ‘Let’s switch to immunotherapy’; we will switch to the other combinations.”  -- Omid Hamid, MD

Historically, there was a bias that only some therapies were associated with long-term survival, but as more data with longer-term follow-up become available, benefit seems to be similar between PD-1 monotherapy and BRAF/MEK inhibition. Therefore, patient-level considerations become important factors in guiding treatment selection.

Paradoxically to the way we had historically thought about using BRAF inhibition, the subset of patients who appears to have very long-term durable benefit, meaning more than 3-5 years still on drug, looks like the population of patients who are in good performance status, with low numbers of sites of disease and low LDH.”  -- Jason J. Luke, MD, FACP

For a patient with BRAF-mutated melanoma with brain metastases, both BRAF/MEK inhibition and combination checkpoint blockade are highly effective therapies, and treatment selection may depend on other patient-level characteristics, such as concomitant steroid use, which would then favor BRAF/MEK therapy over immunotherapy.
 
For additional commentary about these topics and others, visit www.gotoper.com to access more resources from this and other meetings.


PER Pulse Recap (2 of 3)
 
This second of 3 PER Pulse™ Recaps from the continuing medical education (CME) activity, Medical Crossfire®: Evolving Roles for Targeted Melanoma Therapies: Assessing Rapid Progress in the Field and Looking Toward Future Combinations, focuses on the use of targeted therapy in the adjuvant and neoadjuvant settings, including the benefits of early BRAF testing in patients with high-risk stage II or stage III melanoma and the importance of clinical trial findings in shaping practice.
 
Practice patterns related to BRAF testing are rapidly changing, and testing methodologies and strategies are evolving. Next-generation sequencing is recommended as a methodology because some BRAF mutations can be missed through other assay methods. Dr. Luke noted that early BRAF testing, while more common in the adjuvant space, can even be considered in the neoadjuvant setting in some cases.

“If a patient is going to go for curative surgery, testing ought to be in the mind of the surgeon. I would suggest that any lesion that’s of a reasonable depth on a primary melanoma, in a patient who has a fair chance for a positive node, should be having the test sent.”  -- Jason J. Luke, MD, FACP
-- Jason J. Luke, MD, FACP

The potential for treatment in the neoadjuvant setting is an exciting development in melanoma. Earlier systemic treatment holds the potential to convert unresectable disease into resectable disease, and these treatment options and sequencing are becoming a part of multidisciplinary consultations with surgeons.

“The neoadjuvant, approach now that we have drugs with high response rates and clinical benefit, is the approach we should focus on the most. Why? The whole idea about predictive markers, looking at what is happening in the tumor microenvironment, not just to help one patient, but to clearly delineate which patients should go onto which therapies.”  -- Omid Hamid, MD

Improved outcomes in relapse-free survival in those with melanoma have been demonstrated both for BRAF/MEK inhibitors and anti‒PD-1 monotherapy. Although combination therapies are approved in the metastatic setting, it can be problematic to take findings from the metastatic setting and apply them to the adjuvant setting because the risk of morbidity does not likely outweigh the potential benefit. Benefits need to be proven through clinical trials, and although current clinical trials are investigating ipilimumab/nivolumab at lower dosages in the adjuvant setting, ipilimumab/nivolumab combination therapy should not be used outside of clinical trials at the current time.
 
The importance of evidence-based clinical decision making cannot be overstated. Ongoing clinical trials will help to address many unanswered questions about treatment in the neoadjuvant and adjuvant settings, as well as treatment sequencing in patients with melanoma.
 
For additional commentary about these topics and others, visit www.gotoper.com to access more resources from this and other meetings.


PER Pulse Recap (3 of 3)
 
This third of 3 PER Pulse™ Recaps from the continuing medical education (CME) activity, Medical Crossfire®: Evolving Roles for Targeted Melanoma Therapies: Assessing Rapid Progress in the Field and Looking Toward Future Combinations, focuses on an active area of melanoma research, novel treatment combinations, including the triplet combination therapy of BRAF + MEK + PD-1/PD-L1‒based immunotherapy for stage IV disease.
 
The results of multiple phase III clinical trials are eagerly awaited to more clearly define the potential treatment benefit of triplet therapy for patients with melanoma. The available early data look impressive, with high response rates, although with the caveat of small sample sizes. Emerging preclinical data and patient-level data from biopsies have shown efficacy with triplet therapy, with an early rush of T cells infiltrating the tumor after inhibiting mutated BRAF.



BRAF-mutated or BRAF wild-type distinction may become an important discriminator for patients with melanoma. Approximately 20% of patients have NRAS mutations, and those patients may respond to MEK inhibition.

“With multi-modality therapy, targeted and immunotherapy, there are studies using MEK inhibition in BRAF wild-type patients, with PD-1 or PD-L1 blockade. I really think that’s an area that deserves to be followed very closely, because in other tumor types, there has been a suggestion that this might amplify the benefit as well.”  -- Jason J. Luke, MD, FACP

Noteworthy possible future treatment combinations currently under investigation:
 
  • PD-1 inhibitor (pembrolizumab) and IDO1 inhibitor (epacadostat) – KEYNOTE-252 / ECHO-301 trial has completed accrual, with results expected in 2018.3
  • Potential for triplet targeted therapy—targeting AXL in combination with BRAF/MEK inhibition—may address one of the major mechanisms of resistance to BRAF/MEK inhibition.4
 
Triplet combination regimens can sometimes be associated with increased toxicities, but some of the combination therapies currently under investigation have shown a favorable safety signal, with only slightly greater toxicity compared with single-agent immunotherapy.

“That’s the future; as we’re moving forward, can we give therapies that do not increase toxicities? With the combination of IDO and anti‒PD-1, the grade 3 or 4 toxicity was negligibly greater. That’s it.”
-- Omid Hamid, MD

For additional commentary about these topics and others, visit www.gotoper.com to access more resources from this and other meetings.
 
 
References
  1. Hu-Lieskovan S, Mok S, Homet Moreno B, et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma. Sci Transl Med. 2015;7(279):279ra41.
  2. Ribas A, Hodi FS, Lawrence D, et al. KEYNOTE -022 Update: Phase 1 Study of First of First -Line Pembrolizumab Plus Dabrafenib and Trametinib for BRAF-Mutant Advanced Melanoma. Presented at the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 1216O.
  3. A phase 3 study of pembrolizumab + epacadostat or placebo in subjects with unresectable or metastatic melanoma (Keynote-252 / ECHO-301). https://clinicaltrials.gov/ct2/show/NCT02752074. Updated September 6, 2017. Accessed March 27, 2018.
  4. Boshuizen J, Koopman LA, Krijgsman O, et al. Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors. Nat Med. 2018;24(2):203-212.






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