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Updated NCCN Melanoma Guideline Adds BRAF Inhibitor and MEK Inhibitor to First-Line Targeted Therapeutic Options

April 2014, Vol 5, No 3

Hollywood, FL—The updated National Comprehensive Cancer Network (NCCN) guidelines for the management of melanoma now include the BRAF inhibitor daBRAFenib (Tafinlar) as a Category 1 recommendation for the primary treatment of patients with metastatic melanoma and BRAF mutation, as well as the use of the mitogen-activated protein kinase (MEK) inhibitor trametinib (Mekinist) for the treatment of patients with melanoma and BRAF mutation. These 2 drugs, which received US Food and Drug Administration (FDA) approval last year, are now added to the NCCN targeted therapies for the treatment of patients with advanced or metastatic melanoma.

John A. Thompson, MD, Medical Director, Phase 1 Clinical Trials Program, and Codirector, Melanoma Clinic, Seattle Cancer Care Alliance, WA, presented the updated guidelines at the 2014 NCCN Conference.

Updated Recommendations
DaBRAFenib is now recommended by the NCCN for patients with the BRAF V600 mutation; trametinib is indicated for use with daBRAFenib in patients who are intolerant of a BRAF inhibitor. Single-agent trametinib use is not recommended for patients with disease progression who had previous BRAF inhibitor therapy.

The Category 1 preferred regimens for advanced or metastatic melanoma now include ipilimumab, vemurafenib, and daBRAFenib. The updated guideline notes that daBRAFenib can be associated with significant febrile toxicity, and both vemurafenib and daBRAFenib have the potential for significant dermatologic complications, including cutaneous squamous-cell carcinoma and extreme photosensitivity.

The Evidence
Dr Thompson presented data from the literature to support these recommendations. A randomized study compared the use of daBRAFenib with dacarbazine in 250 patients with metastatic BRAF-mutated metastatic melanoma; the median progression-free survival (PFS) was 5.1 months with daBRAFenib and 2.7 months with dacarbazine, for a hazard ratio of 0.30 (Hauschild A, et al. Lancet. 2012;380:358-365).

Downstream from BRAF mutation, the other signaling molecule in melanoma is MEK. The first targeted MEK inhibitor to receive FDA approval was trametinib. In a study of 322 previously untreated patients with metastatic melanoma who were randomized to trametinib or to dacarbazine or paclitaxel chemotherapy, the median PFS was improved from 1.5 months in the chemotherapy arm to 4.8 months with trametinib, and the overall survival (OS) at 6 months improved from 67% to 81%, respectively (Flaherty KT, et al. N Engl J Med. 2012;367:107-114).

In a follow-up study, Flaherty and colleagues examined the use of combined BRAF and MEK inhibitions at 2 doses in patients with metastatic melanoma, showing approximately 3 additional months of PFS with the 2 com­bination regimens compared with daBRAFenib monotherapy; the benefit extended to all the subgroups. How­ever, dual blockade increased the incidence of fever and chills compared with daBRAFenib monotherapy. “Often- times, the fever and chills require temporary cessation and resumption of therapy at lower doses, and supportive therapy such as acetaminophen, should be used,” Dr Thompson said.

Potential for Immune-Related Adverse Events
Dr Thompson updated the field of immune checkpoint inhibitors in the treatment of melanoma. A 2013 multicenter retrospective review by Luke and colleagues of 39 patients with metastatic uveal melanoma who received ipilimumab showed a median OS of 9.6 months; 18% of patients had grade III or IV toxicity.

“In treating patients with ipilimu­mab, we have to be very careful in managing the potential for immune-related adverse events,” said Dr Thompson. Toxicities include skin, gastrointestinal (GI), liver, endocrine system, and neurologic. The median time to skin toxicity is approximately 3 weeks, whereas GI toxicity manifests at approximately week 6, and endocrine events 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.

The programmed death (PD)-1 medications in development for the treatment of patients with advanced melanoma are lambrolizumab and nivolumab. The responses observed with the PD-1 lambrolizumab in a 2013 study by Hamid and colleagues were “quite dramatic,” Dr Thompson said, with approximately 66% of patients demonstrating tumor shrinkage. The median duration of response had not yet been reached at 11 months of follow-up.

In a 2013 study by Wolchok and colleagues in patients with advanced melanoma, the PD-1 agent nivolumab, used concurrently with ipilimumab, was associated with a 53% objective response rate, and a similar percentage of patients had immune-related grade III to IV toxicities. Of 53 patients in this arm, 16 had tumor reduction of more than 80% by 12 weeks.

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

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

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