Research Into Newer Agents Under Way for NRAS Melanoma

Caroline Robert, MD, PhD

More than 50% of melanoma involves mutation in the BRAF protein, which is part of the mitogen-activated protein kinase (MAPK) signal transduction pathway. An additional 15% to 25% of melanomas display mutations in the NRAS signaling molecule, which acts upstream of BRAF in the MAPK pathway. Although less prevalent,NRAS-mutant melanoma is associated with a worse prognosis than eitherBRAF-mutant melanoma or melanoma that is wild-type for bothNRASandBRAF. In addition,NRAS-mutated tumors are thicker and grow more aggressively.¹

Another concern regarding theNRAS-mutant melanoma variant is the paucity of therapies available for its treatment compared with theBRAFmutant. The American Cancer Society estimates that approximately 75,000 people in the United States will be diagnosed with melanoma in 2014; consequently, mutations inNRASwill affect some 10,000 patients this year.

MEK Inhibitors forNRAS-Mutant Melanoma

BRAF inhibitors have shown promising results addressing the mutation in the more commonBRAF-mutated form of melanoma, with two compounds already having received US Food and Drug Administration (FDA) approval. Unfortunately, data indicate that the application of BRAF inhibitors toNRASmelanoma can lead to increased proliferation of tumor cells, highlighting the importance of accurate genotyping before using these agents.²Some of the advances in targeted therapy forBRAF-mutant melanoma may also be relevant toNRAS-mutated melanomas, however. Treatment ofBRAF-mutant melanoma with BRAF inhibitors yields initially positive results, but resistance often occurs later, as the tumor evolves to evade inhibition and to resume proliferation, often mutating in other elements of the MAPK signaling pathway.³To address this issue, researchers have devised a combination therapy forBRAF-mutant melanoma by adding an inhibitor to MEK, a protein downstream ofBRAF. MEK inhibitors are now also being tested inNRAS-mutant melanoma.

In 2013, Paolo Ascierto, MD, from the National Tumor Institute Fondazione G. Pascale in Naples, Italy, and his colleagues published the results from a phase II study (NCT01320085) of the MEK1/2 inhibitor, MEK162, in treatment ofNRAS-mutant andBRAF-mutant melanoma. The report included the preliminary finding that 6 of 30 patients (20%) withNRAS-mutated melanoma had a partial response (three confirmed). Researchers reported that, unlike the application of BRAF inhibitors toNRAS-mutant melanoma, MEK162 was well tolerated and adverse effects were manageable with standard treatments.⁴

Oncolytic Viral Therapy for Malignant Melanoma

Immunomodulatory Therapy

A recent development inBRAF-mutant melanoma treatment involves combining either BRAF or MEK inhibitors with inhibitors for cyclin-dependent kinases (CDK) 4/6. One such CDK4/6 inhibitor that has shown promise for treatingBRAF-mutant melanoma is LEE011 from Novartis. In a recent discussion of the potential of LEE011 in combination therapy, William Sellers, MD, vice president and global head of oncology at the Novartis Institutes for Biomedical Research in Cambridge, Massachusetts, noted, “One of the most notable findings is that, when paired with other targeted agents, LEE011 is often able to prevent the emergence of resistance to the partner compound that would otherwise arise when the partner compound is dosed alone.”⁵LEE011 is now being paired with MEK162 in a phase Ib/2 study ofNRAS-mutant melanoma (NCT01781572).Another approach to the treatment of late-stage melanoma is the oncolytic virus T-VEC (talimogene laherparepvec), which is currently in a phase III trial that is scheduled to be completed in September 2014. Oncolytic viral therapy operates on the principle that tumor cells have typically dismantled the cellular defenses that healthy cells maintain to prevent viral infection, such as undergoing apoptosis or slowing cellular metabolism. For this reason, tumor cells are particularly susceptible to viral infection, while healthy cells are spared. T-VEC, an attenuated herpes simplex virus (HSV), has an additional feature, in that the virus has been engineered to release granulocyte-macrophage colony-stimulating factor (GM-CSF) after infection of the melanoma, priming the host’s immune system to also attack the tumor.⁶The study compares T-VEC to GM-CSF alone. In 2013, at the Society for Melanoma Research Congress, Amgen cited a median overall survival (OS) of 23.3 months in the T-VEC arm compared with 19.0 months in the GM-CSF arm (hazard ratio [HR] = 0.79; 95% confidence interval [CI], 0.61-1.02; P = .075).⁷March 2014, Amgen announced results of a prespecified retrospective analysis,⁸which showed a 50% or greater reduction in tumor size in 64% of injected tumors. In addition, one-third of uninjected non-visceral tumors, and 15% of visceral tumors were also reduced by at least 50 percent. April 2014, the company reported that, while the primary end point of durable response was met in the study, the secondary endpoint of OS was not, although there was a strong trend in favor of T-VEC (P = .051).⁹Ipilimumab, a monoclonal antibody to cytotoxic T-lymphocyte antigen-4 (CTLA-4), is approved for use in unresectable or metastatic melanoma.¹⁰Immunomodulators such as ipilimumab stimulate the immune system to persistently recognize and attack tumor cells, providing a long-lasting response that may avoid the acquired resistance often observed with targeted therapies. Some of the most promising therapies forBRAF-mutant melanoma involve combining FDA-approved targeted therapies such as the BRAF inhibitors vemurafenib or dabrafenib with immunotherapy agents.¹¹

Additional immunomodulating antibodies are under investigation. Programmed cell death protein-1 (PD-1), or its ligand, PD-L1, may be more even more effective targets for activating the patient’s own immune system to provide a durable antitumor response. Merck recently announced several new collaborations that will involve phase I/II studies of its PD-1 antibody, MK3475 (formerly lambrolizumab). A collaboration with Amgen will explore the use of MK3475 in combination with T-VEC in previously untreated advanced melanoma.

“Merck clinical scientists intend to explore the potential of our PD-1 inhibitor across a wide range of cancers, both as monotherapy and in combination,” said Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories.¹²

MK3475 received Breakthrough Therapy designation from the FDA in April 2013 for the treatment of patients with advanced melanoma. Results from the melanoma portion of a monotherapy trial of MK3475 were presented in November 2013, at the 10th International Congress of the Society for Melanoma Research. An OS rate of 81% at one year was observed for 135 patients with advanced melanoma, with an objective response rate (ORR) of 41%, with complete responses in 9% of patients.

References

Commenting on the results, Caroline Robert, MD, head of dermatology at Gustave Roussy, Cancer Campus, Grand Paris, said, “New agents are needed for patients with advanced melanoma, I am excited by the results seen for MK-3475 to date as a single agent and believe these findings support further study both as a monotherapy and in combination.”¹³

1. Kelleher FC, McArthur GA. Targeting NRAS in melanoma.Cancer J. 2012;18(2):132-136.
2. Poulikakos PI, Zhang C, Bollag G, et al. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF.Nature. 2010;464:427-430.
3. Wagle N, Emery C, Berger MF, et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling.J Clin Oncol. 2011;29(22):3085-3096.
4. Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study.Lancet Oncol. 2013;14(3):249-256.
5. American Association of Cancer Research. News release. October 10, 2013. http://www.aacr.org/home/public--media/aacr-in-the-news.aspx?d=3184. Accessed March 23, 2014.
6. Patel MR, Kratzke RA. Oncolytic virus therapy for cancer: the first wave of translational clinical trials.Transl Res. 2013;161(4):355-364.
7. Harrington KJ, Vile RG, Melcher A, Chester J, Pandha HS. Clinical trials with oncolytic reovirus: Moving beyond phase I into combinations with standard therapeutics.Cytokine Growth Factor Rev. 2010;21(0):91-98.
8. Amgen. Press release. March 2014. http://www.amgen.com/media/media_pr_detail.jsp?year=2014&releaseID=1909116. Accessed April 15, 2014.
9. Amgen. Press release. April 4, 2014. http://www.amgen.com/media/media_pr_detail.jsp?year=2014&releaseID=1915897. Accessed April 15, 2014.
10. Lipson EJ, Drake CG. Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma.Clin Cancer Res. 2011;17(22):6958-6962.
11. Koya RC, Mok S, Otte N, et al. BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy.Cancer Res. 2012;72(16):3928-3937.
12. Merck. Press release. February 5, 2014. http://www.mercknewsroom.com/news-release/oncology-newsroom/merck-enters-strategic-collaborations-amgen-incyte-and-pfizer-evaluat. Accessed March 23, 2014.
13. Merck. Press release. November 18, 2013 http://www.mercknewsroom.com/news-release/research-and-development-news/additional-interim-data-mercks-investigational-anti-pd-1-. Accessed March 23, 2014.