New Melanoma Guideline Adds BRAF Inhibitor, MEK Inhibitor to First-Line Systemic Therapy Options

John A. Thompson, MD

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The BRAF inhibitor dabrafenib has been added as a category 1 recommendation for the primary treatment of BRAF-mutated metastatic melanoma in the latest version of the National Comprehensive Cancer Network (NCCN) guidelines. MEK inhibition with trametinib in BRAF-mutated melanoma was also added to the systemic therapy options for the treatment of advanced or metastatic melanoma.

NCCN melanoma guidelines were updated by John A. Thompson, MD, at the 2014 meeting of the NCCN.

Dabrafenib was added as a recommendation only for patients with V600 mutation of the BRAF gene (as is vemurafenib), whereas the principal indication for primary treatment of BRAF-mutated melanoma with trametinib (plus dabrafenib) is intolerance to BRAF inhibitors. Single-agent trametinib is not indicated for the treatment of patients who have experienced progression of disease on prior BRAF inhibitor therapy.

The category 1 preferred regimens for advanced or metastatic melanoma now include ipilimumab, vemurafenib, and dabrafenib. The new guidelines note that dabrafenib can be associated with significant episodic and recurrent fevers, low-grade squamous carcinoma, and little if any significant photosensitivity.

The data to support these recommendations were presented by Thompson, medical director of the Phase 1 Clinical Trials Program and member of the Melanoma Clinic, Seattle Cancer Care Alliance.

Dabrafenib was compared with dacarbazine in a randomized study in 250 patients with BRAF-mutated metastatic melanoma (Lancet. 2012;380:358-365); median progression-free survival (PFS) was 5.1 months in the dabrafenib arm compared with 2.7 months in the dacarbazine arm, for a hazard ratio of 0.30.

Further downstream from BRAF, the next signaling molecule in melanoma is MEK. The first targeted MEK inhibitor to achieve FDA approval is trametinib. In a study in which 322 previously untreated patients with metastatic melanoma were randomized to trametinib or chemotherapy (dacarbazine or paclitaxel) (N Engl J Med. 2012;367:107-114), median PFS was 1.5 months in the chemotherapy arm and 4.8 months in the trametinib arm, and overall survival at 6 months was 67% and 81%, respectively.

A study of combined BRAF and MEK inhibition at 2 doses versus dabrafenib monotherapy in patients with metastatic melanoma revealed superior PFS with the combination regimens (~9.0 to 9.5 months) compared with dabrafenib monotherapy (~6 months) (N Engl J Med. 2012;367:1694-1703). The benefit of the combination regimen extended to all the clinical subgroups that were tested. Dual blockade increased the incidence of fever and chills compared with dabrafenib monotherapy. “Oftentimes, the fever and chills require temporary cessation and resumption of therapy at lower doses and supportive therapy such as acetaminophen,” he said.

Potential for Immune-Related Adverse Events
Thompson updated the field of immune checkpoint inhibitors in the treatment of melanoma. A recent multicenter retrospective review of ipilimumab in 39 patients with metastatic uveal melanoma resulted in a median overall survival of 9.6 months (Cancer. 2013;119:3687-3695). Grade 3/4 toxicity occurred in 18% of the patients.

“In treating patients with ipilimumab, we have to be very careful in managing the potential for immune-related adverse events,” said Thompson. Skin, gastrointestinal (GI), liver, endocrine system, and neurologic toxicities may develop. The median time to skin toxicity is about 3 weeks, whereas GI toxicity tends to manifest at about week 6 and endocrine toxicity in the later stages of treatment, he said. GI toxicity, which occurs in up to 25% of patients treated with ipilimumab, can progress rapidly and requires active intervention.

Anti–PD-1 agents in development for the treatment of advanced melanoma are lambrolizumab and nivolu­mab. The responses observed with lambrolizumab (N Engl J Med. 2013;369:134-144) were “quite dramatic,” he said, with approximately two-thirds of patients experiencing tumor shrinkage. The median duration of response had not been reached at the 11-month follow-up.

In patients with advanced melanoma, nivolumab received concurrently with ipilimumab was associated with a 53% objective response rate; a like percentage had immune-related grade 3/4 toxicities (N Engl J Med. 2013;369:122-133). Sixteen of 53 patients in this arm had tumor reduction >80% at 12 weeks.

First-Line Therapeutic Decisions
At present, it is recommended that patients with BRAF wild type who have low-volume metastatic melanoma and a performance status of 0 receive high-dose interleukin-2 (IL-2) or ipilimumab as first-line systemic therapy or be entered into a clinical trial. For those with BRAF wild type who have more aggressive and symptomatic disease, ipilimumab or clinical trial enrollment (combining cytotoxic agents with immune checkpoint inhibitors) are recommended, said Thompson.

For patients with a documented mutation of BRAF, it is recommended that those with low-volume disease and a performance status of 0 receive IL-2, ipilimumab, or a targeted agent as first-line systemic therapy, or be enrolled into a clinical trial. Molecular targeted therapy (or enrollment into a clinical trial) is suggested for those with bulky disease who are symptomatic

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