Resistance in Melanoma May Be Addressed With MAPK Inhibitors and Immunotherapies

Keith T. Flaherty, MD

BRAFMutations

Of the many signaling cascades being targeted for therapeutic intervention in cancer, one of the most important and best understood is the mitogen-activated protein kinase (MAPK) pathway, particularly the RAS/RAF/MEK/ERK cascade.¹Most melanomas harbor mutations in the upstream components of this pathway, specificallyNRASandBRAF, and they are therefore key targets of current therapeutic development.In 2002 a sequencing study revealed missense mutations in theBRAFgene in two-thirds of malignant melanomas. A single substitution,V600E, comprised 80% of the mutations discovered, and all of the mutations were gain-of-function changes in the kinase domain of the protein.²

Lawrence Fong, MD, on Inducing an Immune Response With a Patient’s Tumor

Fong is an associate professor at UCSF.

The second-generation RAF inhibitor vemurafenib is selective for the common mutant forms of BRAF,V600EandV600K. Clinical trials in patients with metastatic melanoma harboring theV600Esubstitution demonstrated greater survival and response rates with vemurafenib than with chemotherapy,^3,4and in 2011 it became the first targeted therapy approved by the US Food and Drug Administration (FDA) for melanoma. A second mutant BRAF inhibitor, dabrafenib, gained FDA approval in 2013.

Despite these successes, the median duration of responses recorded in trials is less than 7 months for both vemurafenib and dabrafenib. Acquired drug resistance develops in most patients treated with BRAF inhibitors and is frequently the result of mutations in other components of the MAPK pathway, including RAS and MEK mutations and CRAF overexpression.⁵

NRASMutations

One strategy to prevent or overcome acquired resistance is vertical cotargeting of the MAPK cascade by inhibiting the pathway at multiple points simultaneously. Data from a phase I/II trial showed that combining dabrafenib with the MEK inhibitor trametinib improved the progression-free survival (PFS) and rate of response of patients over dabrafenib monotherapy.⁶This combination was approved by the FDA in 2014 for the treatment of patients with melanoma harboringV600 BRAFmutations.RAS proteins are GTPase enzymes that activate downstream RAF kinases. Activating mutations ofNRAShave been identified in 15% to 20% of melanomas⁷; but there are currently no selective targeted agents for mutantNRAS. Several MEK inhibitors are therefore being tested for efficacy in this population.

Binimetinib (MEK162) is a MEK 1/2 inhibitor that is the first targeted therapy to demonstrate activity in patients withNRAS-mutated melanoma; results from a phase II trial showed a 20% response rate in this population.⁸Building on these results, the NRAS mElanoma and MEK inhibitOr (NEMO) trial has been launched to determine the efficacy of binimetinib monotherapy in a larger population.⁹

“The NEMO trial represents the first instance of a MEK inhibitor being evaluated in a definitive phase III trial as a monotherapy in a cancer population harboring RAS mutations,” said Keith T. Flaherty, MD, director of developmental therapeutics at the Massachusetts General Hospital Cancer Center, Boston, who is an investigator in the study.

Checkpoint Inhibitors

“Given that nearly 30% of all cancers have eitherKRAS,NRAS, orHRASmutations, we hope that this trial has ramifications not only forNRAS-mutant melanoma patients, but other patients whose cancers harbor RAS mutations as well,” Flaherty stated.Immunotherapy has been another successful area of research in the treatment of advanced melanoma. Because ipilimumab, an antibody targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4), received FDA approval in 2011 for use in patients with late-stage melanoma, agents targeting immune checkpoints to restore antitumor activity by the immune system have generated significant interest from researchers.

Checkpoint inhibitors that target the programmed cell death-1 receptor (PD-1) and its ligand (PD-L1) have demonstrated synergistic effects with BRAF inhibitors in a mouse model of melanoma.¹⁰This suggests that such combinations might be an alternative way to avoid the resistance that often develops in patients receiving BRAF inhibitors as monotherapy.

The anti-PD-1 antibody pembrolizumab (lambrolizumab; MK-3475), was approved by the FDA for metastatic melanoma in September 2014 and is being tested in clinical trials. Phase I results have demonstrated that it has efficacy in advanced, ipilimumab-refractory melanoma.^11,12Human trials are underway to test combinations of pembrolizumab with inhibitors of the MAPK pathway, including trametinib and dabrafenib.¹³

Clinical Pearls

• One strategy to prevent or overcome acquired resistance in melanoma treatment is vertical cotargeting of the MAPK cascade by inhibiting the pathway at multiple points simultaneously.
• Activating mutations ofNRAShave been identified in 15% to 20% of melanomas.
• Binimetinib (MEK162) is a MEK 1/2 inhibitor that is the first targeted therapy to demonstrate activity in patients withNRAS-mutated melanoma.
• Inhibitors targeting first BRAF and now MEK have increased the number of patients who are able to benefit from targeted agents.
• The propensity of currently approved targeted therapies to generate resistance is being studied through combinations of MAPK inhibitors that target the pathway at multiple points and by combining these inhibitors with agents that target immune checkpoints.

“MAPK pathway inhibitors have a high, quick response rate, but the responses typically don’t last as long as desired,” noted Michael A. Postow, MD, an attending physician in the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center, who was involved in some of the phase I studies of pembrolizumab. “Adding immunotherapy may improve the durability of these responses, but we need additional trials to see if this is the case,” Postow said.

“There is reason for great optimism in the treatment of advanced melanoma,” said Postow. “We are also eager to know if these approaches, which have proven benefits in the metastatic setting, can help patients with stage 3 melanoma in the adjuvant setting as well.” Conclusion The development of new therapies for advanced melanoma has made significant progress since the importance of MAPK pathway dysfunction was first identified. Inhibitors targeting first BRAF and now MEK have increased the number of patients who are able to benefit from targeted agents. The most significant weakness of these inhibitors, their propensity to generate resistance, is now being addressed by combinations of MAPK inhibitors that target the pathway at multiple points and by combining these inhibitors with agents that target immune checkpoint molecules.

References

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