Determining the Optimal Treatment Approach in Advanced Melanoma: Practical Considerations

Course Director

Antoni Ribas, MD, PhD

Antoni Ribas, MD, PhD
Jonsson Comprehensive Cancer Center
University of California Los Angeles
Los Angeles, California


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Part 1 of a 2-part series

Dr. Ribas provides expert feedback to the questions submitted by your peers during a recent survey on this topic.

Overview

The management of advanced skin cancers, particularly melanoma, is a challenging problem. However, a better understanding of the mechanisms and molecular pathways underlying the development of these tumors has led to the identification of a number of new drug targets. This, in turn, has resulted in the development of important therapeutic approaches for the treatment of advanced skin cancers in various patient subsets. It is important for clinicians to remain current on these advances and understand how to optimally integrate the new therapies into practice.


Disclosures

This activity is supported by an educational grant from Genentech.
Additional support provided by Penn State College of Medicine and Answers in CME.

Course Director
Antoni Ribas, MD, PhD,, has a financial interest/relationship or affiliation in the form of:
Consultant for Amgen Inc.; Genentech, Inc.; GlaxoSmithKline; Merck & Co., Inc.; and Novartis Corporation.
Other Financial or Material Support from Kite Pharma, Inc. in the form of stock ownership.
Medical Director
Kadrin Wilfong, MD
Answers in CME, Inc.
Kadrin Wilfong, MD, has no financial interests/relationships or affiliations in relation to this activity.

Answers in CME staff who may potentially review content for this activity have disclosed no relevant financial relationships.

Penn State College of Medicine staff and faculty involved in the development and review of this activity have disclosed no relevant financial relationships.

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Which mutations should we be testing to help guide treatment selection for patients with melanoma?

Dr. Ribas: The decision-making to treat a patient with advanced melanoma starts by understanding the mutation that drives that cancer. The incidence of mutations relates to the pathogenesis of that cancer. Melanomas that appear in [intermittently] sun-exposed areas are more likely to have a BRAF mutation or a NRAS mutation. These are mutually exclusive mutations; BRAF is in around 50% of all melanomas, and NRAS is in around 20%.1-3 BRAF V600E mutations, which are the ones that are more common in BRAF, are more frequent in younger populations and decrease in incidence with age, as opposed to NRAS mutations or BRAF V600K, another variant of the BRAF mutation. [On the other hand,] c-kit mutations are more common in melanomas that are in mucosas or acral lentiginous melanoma.4,5

And that's important, because two of those mutations, BRAF and c-kit, can lead to specific treatments with BRAF and c-kit inhibitors in addition to other treatments. Patients who have a BRAF mutation should be considered for approved BRAF inhibitors vemurafenib, dabrafenib, or the MEK inhibitor trametinib. Patients who have c-kit–mutant melanoma should be considered for [c-]kit inhibitors, even though there's no specific approval for melanoma.

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If a patient with melanoma has BRAF V600E or V600K mutation, should treatment be initiated with a targeted agent or an immunotherapeutic agent? What would be the optimal approach?

Dr. Ribas: In the last three years, there have been approvals of several agents that have improved overall survival in patients with metastatic melanoma. Those have included ipilimumab, which is a CTLA-4–blocking antibody; it's an immunotherapeutic approach that is not restricted by the driver mutation of the cancer.6,7

And then the targeted agents vemurafenib and dabrafenib, which are two BRAF inhibitors, and trametinib, which is a MEK inhibitor, all of which are approved only in patients who have a BRAF-mutant melanoma.8-14 So the good thing is that in a short period of time, we have a series of agents that have been demonstrated to be active and improve survival in the majority of patients with BRAF-mutant melanoma.

The decision on which is the optimal first therapy may depend on several variables, but I think one of the main variables is the discussion between the physician and the patient about the pros and cons of each mode of therapy. The immunotherapeutic ipilimumab and also high-dose interleukin-2, which is also approved in the US for metastatic melanoma, are agents that give low frequency of responses, but those tend to be very durable responses and can last years. The problem is that this durable response rate is [observed in] between 5% and 10% of the patients, and the overall response rate is [observed in] between 10% and 15% of the patients.

That's very different from the benefit that's given by the targeted therapies that block oncogenic BRAF, which have a very high response rate. Between 50% and 60% of patients have an objective response by RECIST criteria; but those responses tend to have a limited duration, with a median of six to seven months—although some patients can have durable responses, and some are going on for four years from the phase 1 trial of vemurafenib.

We have to talk about the potential toxicities, with ipilimumab having the risk of occasional life-threatening autoimmune conditions like colitis with bowel perforation or hypophysitis or hepatitis. These are infrequent, but can really affect particular patients, as opposed to the BRAF inhibitors, which have less serious—but more common—toxicities that can alter the life of patients, like proliferative skin processes, joint pains, and the development of secondary squamous cell carcinomas.

The approvals of all of these agents were not based on a particular subset of BRAF-mutant melanoma, even though many melanoma oncologists consider that patients with a slow-growing melanoma with normal LDH and good characteristic features are better off starting with ipilimumab. Those patients are also the ones who derive the best and longest benefit with the BRAF inhibitors. And the other way around, if we have a patient with a fast-growing melanoma that can respond transiently to a BRAF inhibitor, if that patient was one of the few who responds to ipilimumab, then that patient could go from having a life-threatening disease to being alive long term.15

So my decision-making is not particularly based on growth kinetics or presentation features, but more of [a] discussion of the pros and cons of each mode of therapy to the patients. In practice, the majority of patients will get both ipilimumab and a BRAF inhibitor.

Should [the] BRAF inhibitor be given with a MEK inhibitor? The data so far in the clinic suggest that it's a very promising strategy,16 where we have higher, more durable response rates, because this combination addresses some main mechanisms of resistance to single-agent BRAF inhibitors. But also, it decreases the side effects, because BRAF inhibitors have a pharmacological property called paradoxical mitogen-activated protein [MAP] kinase pathway activation, which transactivates this pathway in cells that are wild-type for BRAF, and that leads to some of the toxicities of BRAF inhibitors. If we give a MEK inhibitor, it will block this phenomenon of paradoxical MAP kinase activation, and then there are less skin proliferative conditions and less joint pains and other side effects from BRAF inhibitors.

These combinations are in clinical trials,17,18 and we eagerly await the results, because I'm pretty sure that those clinical trials will demonstrate that there is a benefit for doing the combined therapy, and I would assume that's going to be what we'll be doing not too long from now as the standard of care.

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What treatment could be considered for a patient with melanoma who is showing progression while receiving a BRAF inhibitor?

Dr. Ribas: When we have a patient who is progressing on a BRAF inhibitor [as a] single agent, we can add a MEK inhibitor, and we can have the secondary response. [As mentioned,] the data so far in the clinic suggest that it's a very promising strategy.16

When we treat with a single-agent BRAF inhibitor, we're blocking the most important driver for that cancer; these inhibitors, vemurafenib and dabrafenib, are quite specific for blocking the protein that's mutated, and then blocking the pathway. But with time, as with many other targeted therapies, the melanoma finds a way around it, and we're understanding that most of this resistance goes through a reactivation of the MAP kinase pathway. This pathway goes from RAS, RAF, MEK and ERK, and ERK goes into the nucleus and tells the cell to be proliferating. If we're blocking BRAF and the pathway reactivates, then it makes sense to have an inhibitor that blocks immediately downstream, which is a MEK inhibitor. When we have a patient who is progressing on a BRAF inhibitor [as a] single agent and has genetic features in the progressive lesion that demonstrate a reactivation of this pathway, we can add a MEK inhibitor. A MEK inhibitor does not work as [a] single agent, so stopping the BRAF inhibitor and giving the MEK inhibitor does not work, and that has been tested in two clinical trials. But it works whenever the MEK inhibitor is added to the BRAF inhibitor.

Narrator: This combination strategy is promising, but currently considered investigational. Other strategies have also been investigated for patients progressing on a BRAF inhibitor, such as the use of chemotherapy, which has demonstrated limited benefit.

Dr. Ribas: Occasionally some patients can respond to chemotherapy, because now the cell is back on cell cycle, and even though many people claim that there's no role of giving an immunotherapy after progressing on a BRAF inhibitor, I have certainly seen responses to ipilimumab and to the new PD-1/PD-L1 antibodies. So I think all of the options should be on the table for treating these patients.

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References

  1. Wellbrock C, Hurlstone A. Biochem Pharmacol. 2010;80:561-567.
  2. Smalley KS, Sondak VK. N Engl J Med. 2010;363:876-878.
  3. Long GV et al. J Clin Oncol. 2011;29:1239-1246.
  4. Carvajal RD et al. JAMA. 2011;305:2327-2334.
  5. Curtin JA et al. J Clin Oncol. 2006;24:4340-4346.
  6. Hodi FS et al. N Engl J Med. 2010;363:711-723.
  7. Robert C et al. N Engl J Med. 2011;364:2517-2526.
  8. Chapman PB et al. N Engl J Med. 2011;364:2507-2516.
  9. Sosman JA et al. J Clin Oncol. 2012;30(suppl):8503.
  10. Chapman PB et al. J Clin Oncol. 2012;30(suppl):8502.
  11. TAFINLAR (dabrafenib) Prescribing Information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202806s000lbl.pdf. Accessed October 25, 2013.
  12. Hauschild A et al. Lancet. 2012;380:358-365.
  13. Hauschild A et al. J Clin Oncol. 2013;31(suppl):9013.
  14. MEKINIST (trametinib) Prescribing Information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204114s000lbl.pdf. Accessed October 25, 2013.
  15. Ascierto PA et al. J Transl Med. 2012;10:107.
  16. Flaherty KT et al. N Engl J Med. 2012;367:1694-1703.
  17. A Study Comparing Trametinib and Dabrafenib Combination Therapy to Dabrafenib Monotherapy in Subjects With BRAF-mutant Melanoma.
    http://clinicaltrials.gov/ct2/show/NCT01584648. Accessed October 25, 2013.
  18. Dabrafenib Plus Trametinib vs Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma (COMBI-v).
    http://clinicaltrials.gov/ct2/show/NCT01597908. Accessed October 25, 2013.

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This activity is supported by an educational grant from Genentech.
Additional support provided by Penn State College of Medicine and Answers in CME.

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Q&A: Current Status and New Directions in the Treatment of Advanced Skin Cancers

  1. Translating an Improved Understanding of Disease Biology Into New Targets and Combinations for the Treatment of Advanced Skin Cancers