Challenges Apparent With Current Targeted Therapies for BRAF Metastatic Melanoma

Several landmark advances in the treatment of metastatic melanoma have occurred in the last 5 years, one of which has been the approval by the US Food and Drug Administration (FDA) of targeted treatments for patients with melanomas harboring a mutation in theBRAFgene.¹

Between 40% and 60% of melanomas contain activating mutations in this gene, which encodes a serine/threonine protein kinase, BRAF.^1,2The most common of theseBRAFmutations is the valine for glutamate substitution at position 600, orV600E, and the first therapy designed to specifically target this mutation, vemurafenib, was FDA approved for use in advanced melanoma in 2011.¹Vemurafenib, and more recently, dabrafenib and trametinib, have therefore been important additions to the treatment choices for advanced melanoma, which, until fairly recently, had no life-prolonging options for therapy.

Igor Puzanov, MD, Discusses Partnering a Targeted Agent with T-VEC

Puzanov is a medical oncologist from Vanderbilt-Ingram Cancer Center.

In view of the 3 approved therapies for advanced melanoma withBRAFmutations, Michael A. Postow, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, considers testing forBRAFmutations an important step to guide treatment decisions.

“I would call [BRAF testing] a mandatory part of standard of care” he said, adding, “I think clinical oncologists need to be aware of all 3 medications.”

The benefits of vemurafenib therapy are limited by its toxicities, its limited median duration of response (MDR), and its selective benefit for patients with theV600Emutation, while its efficacy in patients without theV600Emutation is not yet known.¹Similarly, toxicity profiles of dabrafenib and trametinib must be considered when deciding on treatment for patients withBRAFmutation-positive melanomas.

“I do think side effects are an issue, because it results in patients discontinuing drugs for a while,” Postow noted, adding that, “each drug has some different patterns of side effects as monotherapy.” The principal adverse reactions associated with vemurafenib therapy include problems with the liver, photosensitivity reactions, joint aches, and general malaise, Postow summarized.

Some of these symptoms can also be observed with dabrafenib, but Postow noted that febrile reactions with fevers typically on the order of 103ºF to 104ºF may also be observed with this agent; these reactions are also associated with rigors, chills, sweats, and constitutional symptoms.

Common to both vemurafenib and dabrafenib are skin changes, such as thickening of the skin on the hands and feet, a scaly rash, and warty skin growths; in some cases, Postow explained, squamous cell carcinomas (SCC) may occur, so patients on these agents need to be monitored by a dermatologist. Trametinib, by comparison, has a different mechanism of action, and Postow cited the primary adverse events (AEs) associated with it as a distinct acneiform rash, diarrhea, and varying liver enzyme elevations. He also noted that trametinib should not be used in patients with poor cardiac function because it may reduce the contractile ability of the heart; accordingly, its use needs to be very carefully considered in any patient with an extensive cardiac history.

Vemurafenib

Management of these AEs, Postow explained, is typically done via monitoring and proactive steps, such as advising patients to stay “sun-safe” because of the potential for phototoxicity. Routine monitoring of blood work, particularly liver function, is important, he explained, and because some of these agents may prolong the QTc interval, periodic electrocardiograms are also indicated. As to how frequently monitoring should be performed, Postow indicates that since most events occur within the first few weeks of therapy “every 2 weeks is sufficient, until we know that everything is going well.” A notable exception, however, is the febrile reactions with dabrafenib, which he noted can happen in a largely idiosyncratic manner, at many different times. Some of the key clinical data on efficacy and safety for the different therapies forBRAFmutation-positive melanoma are summarized in this article.Vemurafenib is an orally available inhibitor of several mutant BRAF kinases, includingV600E, and is approved for use in unresectable or metastatic melanoma with theV600Emutation, as detected by an FDA approved test; it is not indicated in patients with wild-typeBRAFstatus melanomas.³In a phase II study of patients withBRAFV600mutant metastatic melanoma (n = 132), an overall response rate (ORR) of 53% has been observed for patients treated with vemurafenib.⁴The most commonly reported AEs in the study were arthralgia, rash, photosensitivity, fatigue, alopecia, and asymptomatic, transient increases in liver enzyme levels. Notably, 34 patients (26%) in the study developed cutaneous SCC or keratocanthomas (KC).⁴

Clinical Pearls

• Vemurafenib, and more recently, dabrafenib and trametinib, have been important additions to treatment for advanced melanoma.
• Toxicity profiles of targeted agents must be considered when deciding on treatment for patients withBRAFmutation-positive melanomas.
• Adverse reactions associated with vemurafenib therapy include problems with the liver, photosensitivity reactions, joint aches, and general malaise.
• Some of these symptoms can also be observed with dabrafenib, as well as febrile reactions with fevers typically on the order of 103ºF to 104ºF; these reactions are also associated with rigors, chills, sweats, and constitutional symptoms.
• Rash/acneiform dermatitis and diarrhea were the most commonly observed AEs with trametinib.
• Ongoing phase III studies may help to resolve some of these issues.

Dabrafenib

Trametinib

Dabrafenib/Trametinib Combination

Phase III results with vemurafenib reported in 2011 showed a significant improvement in overall survival (OS) in patients withV600Emelanoma (N = 672) with vemurafenib therapy compared with dacarbazine, the previous standard of care for patients with advanced melanoma (P< .001).⁵Cutaneous SCC, KC, or both occurred in 18% of the patients in the study, and in all cases were removed with simple excision.Dabrafenib is an inhibitor of several mutant BRAF kinases, includingV600E,V600K, andV600D, and is approved for use as a single agent in unresectable or metastatic melanoma with theV600Emutation, as detected by an FDA approved test, or in combination with trametinib; like vemurafenib, it is not indicated in patients with wildtypeBRAFstatus melanomas.6 In a single-arm, phase II study, dabrafenib was found to have activity in patients withV600E- orV600K-mutant metastatic melanoma, with a median PFS of 6.3 and 4.5 months, respectively, and a corresponding OS of 13.1 and 12.9 months in the respective groups; arthralgia, hyperkeratosis, and pyrexia were the most common AEs.⁷Trametinib differs from vemurafenib and dabrafenib by virtue of its inhibition of mitogen-activated extracellular signal regulated kinases 1 and 2 (MEK1 and MEK2), which are constitutively activated by mutations in the BRAF pathway such asV600E.⁸In phase I, dose-escalation studies, trametinib has demonstrated clinical activity (40% response rate) in patients withBRAFmutant or BRAF-inhibitor na&iuml;ve melanoma.⁹Rash/acneiform dermatitis (82%) and diarrhea (45%) were the most commonly observed AEs, and in most cases could be easily controlled.In 2014, a fast-track approval was granted by the FDA for the combination of trametinib with dabrafenib in patients with unresectable advanced melanoma with theV600EorV600Kmutations, as detected by an FDA approved test.^8,10The rationale for this therapy is to simultaneously inhibit both the BRAF and MEK pathways and allow for more durable responses to BRAF targeted therapy.²Use of dabrafenib and trametinib in combination targets 2 different kinases in the BRAF signaling pathway in melanoma, and may be useful for patients who eventually progress on a BRAF-targeted treatment.^6,8In an open-label study of patients with metastatic melanoma andV600mutations, the combination of dabrafenib with trametinib was found to significantly improve both PFS (9.4 vs 5.8 months;P<.001) and ORR (76% vs 54%,P= .03) over dabrafenib monotherapy.¹¹Commenting on the use of these 2 agents in advanced melanoma, Postow noted that the spectrum of AEs observed with the combination therapy is different from that observed in the monotherapies; whereas skin side effects appear to be less common, other AEs, such as fevers and fatigue, are more common. Postow added, &ldquo;I&rsquo;m not yet sure that dabrafenib and trametinib need to always be given together in all patients,&rdquo; and he expects that ongoing phase III studies (one of which is examining dabrafenib versus the dabrafenib/trametinib combination) may help to resolve some of these questions.

References

1. Menaa F. Latest approved therapies for metastatic melanoma: what comes next?J Skin Cancer. 2013;2013:735282. doi: 10.1155/2013/735282.
2. Luke JJ, Ott PA. New developments in the treatment of metastatic melanoma -role of dabrafenib-trametinib combination therapy.Drug Healthc Patient Saf. 2014;6:77-88.
3. Vemurafenib Prescribing Information. Revised March 2014. Genentech USA, Inc.
4. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib.N Engl J Med. 2012;366(8):707-714.
5. Chapman PB, Hauschild A, Robert C, et al; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation.N Engl J Med. 2011;364(26):2507-2516.
6. Dabrafenib Prescribing Information. Revised January 2014. GlaxoSmithKline, Research Triangle Park, NC.
7. Ascierto PA, Minor D, Ribas A, et al. Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma.J Clin Oncol. 2013;31(26):3205-3211.
8. Trametinib Prescribing Information. Revised January 2014. GlaxoSmithKline, Research Triangle Park, NC.
9. Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial.Lancet Oncol. 2012;13(8):782-789.
10. Goldenberg MM. Pharmaceutical approval update.P T. 2014;39(3):153-154.
11. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.N Engl J Med. 2012;367(18):1694-1703.