What’s Next With Next-Generation BRAF Inhibitors?

Karl Lewis, MD

Targeted therapy for patients with activatingBRAFmutations has demonstrated the potential for personalized medicine in patients with metastatic melanoma. Initial study results were promising and dramatic. Vemurafenib was associated with improved response rates, progression-free survival (PFS) and overall survival (OS) in patients withBRAF^V600-mutated metastatic melanoma.^1,2Dabrafenib showed similar improvements in PFS when compared to dacarbazine in patients withBRAF^V600E-mutated metastatic melanoma.

Limitations of Current BRAF Inhibitors

Vemurafenib may be associated with cutaneous squamous-cell carcinoma, keratoacanthomas, and hepatic function abnormalities in a significant number of patients,^1,2and pancreatitis has also been reported.⁴Dabrafenib may be associated with dermatologic toxic effects, fever, fatigue, arthralgia, and headache.^4,5The adverse dermatologic manifestations associated with these agents are distinct from the cutaneous toxicities associated with EGFR and mTOR inhibitors.⁶

While these agents represent a significant advancement in the treatment of metastatic melanoma, their benefit is also limited by the frequent and rapid onset of resistance, with most patients eventually progressing.^7,8,9“Current limitations of BRAF-inhibitor monotherapy lie in their toxicity and duration of efficacy,” noted Karl Lewis, MD, associate professor, division of medical oncology, University of Colorado School of Medicine, Denver.

“Monotherapy can result in significant cutaneous toxicity, for example, leading to secondary malignancies—cutaneous squamous cell carcinomas. Although response rates are quite high with monotherapy, duration of response is limited with resistance developing in most patients,” Lewis added.

These limitations provide the rationale for combination therapy with BRAF inhibitors and MEK inhibitors. For example, dabrafenib plus trametinib therapy significantly improves PFS and response rates compared to dabrafenib monotherapy inBRAF-mutant metastatic melanoma.^10,11,12“Currently, the combination of BRAF inhibitors and MEK inhibitors is, in my opinion, the standard of care,” noted Lewis. “Although data are pending, early studies demonstrate that the combination is more efficacious and less toxic, particularly in terms of cutaneous toxicities, than BRAF monotherapy.”

Continued efforts to develop safer, more tolerable and more effective therapies are ongoing.

Investigational Next-generation BRAF Inhibitors

LGX818 is a potent, oral, selective BRAF inhibitor that has shown promising activity in metastatic melanoma. Data show that LGX818 has a dissociation half-life more than 10 times longer than other BRAF inhibitors, with a maximum-tolerated dose/recommended phase II dose (MTD/RP2D) of 450 mg/day.¹³Preliminary data show that LGX818 can be safely combined with MEK162, a selective MEK1/2 inhibitor, with complete responses (CR) in 14% and partial responses (PR) in 71% of patients with metastatic melanoma who were BRAF-inhibitor naïve and in 22% PR in patients who were previously treated with a BRAF-inhibitor.¹⁴Importantly, no febrile events or photosensitivity were observed in this study, which suggests a distinct safety profile for this combination.¹⁵LGX818 is being assessed in a phase III trial as monotherapy and in combination with MEK162 against vemurafenib in patients with unresectable or metastaticBRAF^V600-mutant melanoma.

RAF265 is a novel, orally bioavailable dual inhibitor of RAF kinase and VEGFR2 that may predict prognosis and treatment response in patients with melanoma.^16,17Preliminary phase I results suggest an overall response rate (ORR) of 16% for patients with advanced cutaneous melanoma who haveBRAF-mutant disease and an ORR of 13% for patients with wild-type/unknownBRAFmutations; delayed dose-limiting hematologic toxicities were also observed.¹⁸RAF265 has been evaluated in combination with MEK162 in patients withRASorBRAF^V600Emutations; study results have not been published.¹⁹

References

Building on the foundation of previous combination therapies, clinical trials of combination strategies of BRAF inhibitors with ipilimumab are ongoing.³Combination targeted therapies appear to be the focus for future treatment for metastatic melanoma. “Although next-generation BRAF inhibitors are encouraging in preclinical models, their clinical potential remains to be determined,” cautioned Lewis. “Whether they are equivalent or superior to current BRAF inhibitors is being asked in ongoing trials. It is likely that their greatest utility will come in the form of combination regimens,” Lewis concluded.

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19. MEK162 and RAF265 in adult patients with advanced solid tumors harboring RAS or BRAFV600E mutations. www.clinicaltrials.gov. Accessed March 18, 2014.