Advances in Metastatic Melanoma

Jeffrey S. Weber, MD, PhD

Although the diagnosis of late-stage melanoma is still associated with a poor prognosis, an encouraging number of new therapies have been developed during the last 3 years. Targeted immunotherapies such as the anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) antibody ipilimumab and the selective BRAF inhibitor vemurafenib have given new hope to patients with advanced disease. In fact, there have been more new and FDA-approved therapies for metastatic melanoma during the last 3 years than during the past several decades combined.¹

In 2002, it was discovered that approximately half of melanomas were associated with a number of activating mutations in the serine/threonine kinase geneBRAF. This led to efforts to develop new therapies to block this kinase. All of these mutations lead to increased activity of the MAPK pathway without the requirement for upstream signaling, resulting in increased proliferation of cells.²

New agents such as vemurafenib and dabrafenib demonstrate increased potency and selectivity compared with sorafenib, the first drug evaluated to targetBRAF-mutated melanoma.²In a phase II trial of vemurafenib (132 patients with stage 4 melanoma who had progressed on other therapies), an objective response rate (ORR) of 53% was observed, and 6% of patients achieved complete remission.³

Dr. Ribas on the Outlook for BRAF Inhibitors in Melanoma

Ribas is a professor of medicine at UCLA.

A subsequent phase III study of vemurafenib versus dacarbazine chemotherapy in 675 previously untreated patients with stage 3 or 4BRAF V600E-mutant melanoma was halted in December 2010 at the first interim analysis, due to a statistically significant benefit in overall survival (OS) in the vemurafenib group.⁴The most common adverse events (AEs) associated with vemurafenib included arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous cell carcinoma, diarrhea, nausea, and photosensitivity. Slightly over one-third of patients required dose modification because of AEs.⁴

Updated data demonstrated a median OS of 13.6 months and 9.7 months in patients receiving vemurafenib and dacarbazine, respectively. This study led to the FDA approval of vemurafenib in late 2011 for unresectable or metastaticBRAF-mutant melanoma.⁵

Another recently approved BRAF inhibitor is dabrafenib. ORRs of 59% and 12.5% were seen during a phase II trial in theV600E- andV600K-mutant cohorts, respectively.⁶These results were confirmed in a phase III trial of treatment-naïve patients with metastatic melanoma; progression-free survival (PFS) was 5.1 months and 2.7 months in the dabrafenib and dacarbazine groups, respectively. The most common AEs associated with dabrafenib were skin-related toxic effects, fever, fatigue, arthralgia, and headache.⁷

It is clear that patients acquire resistance to BRAF inhibitors, as evidenced by the PFS rate of approximately 6 months for these agents. A multitude of mechanisms may lead to drug resistance, and research is continuing to identify them. Combination therapy to block multiple pathways in melanoma may overcome resistance.²A study comparing the combination of dabrafenib and trametinib reported an improved PFS compared with dabrafenib alone (9.4 months and 5.8 months, respectively).⁸Other combination studies are ongoing, including combination therapy with MEK inhibitors and PI3K inhibitors.²

Ipilimumab is a recently approved fully human monoclonal antibody against CTLA-4 for the treatment of metastatic melanoma.²Although an OS benefit is seen with ipilimumab, response rates are still relatively low. However, approximately 20% to 30% of patients exhibit long-term durable disease control (3-4 years following treatment). Ipilimumab is also being studied in combination therapies. In particular, the combination of CTLA-4 antibodies with BRAF inhibitors is of interest.

The most common AEs (≥5%) observed with ipilimumab include fatigue, diarrhea, pruritis, rash, and colitis.⁹A boxed warning in the prescribing information states that ipilimumab may result in severe and fatal immune-mediated reactions involving any organ system, but most commonly include enterocolitis, hepatitis, dermatitis, neuropathy, and endocrinopathy. Most of these immune-mediated reactions initially manifest during treatment; however, a few have occurred weeks to months after discontinuation of ipilimumab.⁹“There is definitely a learning curve to managing adverse events for immunologic agents, but oncologists routinely manage adverse events of complex chemotherapy regimens in the community. It is just a matter of education, experience, and getting through the learning curve,” said Jeffrey S Weber, MD, PhD, H. Lee Moffitt Cancer Center, University of South Florida, Tampa.

Several programmed death-1 (PD-1) antibodies are under evaluation. Nivolumab, a fully human PD-1 antibody, has demonstrated an ORR of approximately 30% in melanoma.¹⁰This agent also exhibits immune toxicities, although at a lesser frequency and severity than CTLA-4 antibodies.

Despite major strides in development of new, targeted therapies for the treatment of metastatic melanoma, long-term survival is still rare. However, new therapies are currently available, and the potential for even more effective therapies is on the horizon. This raises a new set of challenges for evaluation and management of metastatic melanoma. For example, determining the appropriate control arm in clinical trials is difficult in an era where standard therapies for treatment of melanoma are changing. In addition, new guidelines for long-term management and survivorship of patients with metastatic melanoma will be required.¹

References

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5. Chapman PB, Hauschild A, Robert C, et al. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients withBRAF^V600E-mutated melanoma. J Clin Oncol.2012;30(suppl: abstr 8502).
6. Trefzer U. BREAK-2: a phase IIA trial of the selective BRAF kinase inhibitor GSK 2118436 in patients with BRAF (V600E/K) positive metastatic melanoma. Presented at: 8th International Congress for the Society of Melanoma Research; November 9-13, 2011; Tampa, FL. Abstract LBA11.
7. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial.Lancet.2012;380(9839):358-365.
8. 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.
9. Yervoy [package insert]. Princeton, NJ: Bristol-Meyers Squibb; 2013.
10. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med. 2012;366(26):2443-2454.