Melinda L. Yushak, MD, MPH

CLINICIANS ARE now well acquainted with BRAF mutations in advanced melanoma, but there is more to genomics in this disease than identifying BRAF and prescribing a BRAF inhibitor. 

At the 2017 Debates and Didactics Conference, held at Sea Island, Georgia, Melinda L. Yushak, MD, MPH, of Emory University, discussed mutations beyond BRAF V600E—where to expect them, how and when to test for them, and how to treat patients who have them. 

Mutation Frequency Varies by Site 

MUTATIONS ARE COMMON in melanoma, and they are often mutually exclusive. “You generally find only one mutation in a patient,” she said, namely, BRAF (50%), NRAS (13.25%), MEK1 (6%), KIT (2.6%), CTNNB1 (2%–3%), GNA11 (2%), or GNAQ (1%). 

More than 90% of melanomas diagnosed in the clinic are cutaneous. Cutaneous melanomas often harbor BRAF mutations (40%–50%) and to a lesser degree NRAS mutations (15%–20%). KIT aberrations are occasionally seen as well, usually arising in sun-damaged sites. 

Much less common are mucosal and acral melanomas—ie, lesions in vaginal, anal, sinonasal, and palmar or plantar sites. In these patients, BRAF and NRAS mutations are rare, but 15% to 40% of patients will have KIT mutations. 

Even less common are uveal melanomas, accounting for 5%. More than 80% of these patients have GNAQ or GNA11 mutations, and they lack targeted drugs. Primary uveal therapy is local: brachytherapy, proton beam, and enucleation. Generally, the overall prognosis is poor, with 5- and 10-year cumulative metastasis rates of 25% and 34%, respectively. Median time from diagnosis to death is 6 months. 

Surveillance in Uveal Melanoma 

“UNLIKE OTHER CANCERS, metastatic disease in uveal melanoma goes almost exclusively to the liver. This is important when you think about local treatment options and what kind of surveillance to do,” Dr. Yushak said. 

In determining prognosis, TNM (tumor, nodal, metastasis) staging is not particularly helpful, but chromosome analysis is informative, as follows: 

• BRCA1-associated protein (BAP1 gene), located on chromosome 3: Monosomy is associated with poor prognosis. 

• Chromosome 8q: Gain is associated with poor prognosis. 

• Chromosome 6p: Gain is associated with better survival. 

• Chromosome 6q: Loss is associated with better survival. 

Polymerase chain reaction (PCR)-based gene-expression profiling that tests for 15 different genes has been able to separate uveal melanoma into two classes. Class 1 patients have more than a 95% chance of being free of metastasis at 5 years; however, class 2 patients have less than a 20% chance. There are efforts to further subclassify class 1 patients to determine which of them are in the good-prognosis group (class 1A) and which are the 5% with worse outcomes (class 1B). 

“This information is very helpful in counseling patients in the clinic, as it allows us to stratify high- and low-risk patients,” she said. “Class 1A patients really do not need to see a medical oncologist on a regular basis because they have a low risk for metastasis, but class 2 patients need to see someone, at least for a discussion about surveillance.” 

There is currently no recommendation for adjuvant therapy for class 2 patients, but this is an active area of research, she added. 

The surveillance interval remains controversial. With early detection of oligometastatic disease, targeted intervention might be helpful, but this must be weighed against its cost and the risk of false-positives. Low-cost options for screening, such as liver function tests, have low sensitivity. 

“Because uveal melanoma almost exclusively goes to the liver, our algorithm for class 2 patients is surveillance every 3 months, generally alternating between [magnetic resonance imaging] and liver ultrasound,” she said. 

Focus on BRAF 

THE MOST CRITICAL mutation in melanoma is, of course, BRAF. More than 90% of BRAF mutations are located at codon 600; of them, more than 90% are at V600E; about 5% are at V600K; and a few are at V600R, V600E2, or V600D. 

“I would argue that all our metastatic melanoma patients should be tested for actionable mutations.”

— Melinda L. Yushak, MD, MPH

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Testing for BRAF mutations can change patient outcomes. “There are different treatment options for patients with certain mutations, and some have shown improvements in overall survival,” Dr. Yushak emphasized. Three BRAF/MEK inhibitor combinations are available for these patients: vemurafenib (Zelboraf) plus cobimetinib (Cotellic), and dabrafenib (Tafinlar) plus trametinib (Mekinist) are approved by the U.S. Food and Drug Administration; encorafenib plus binimetinib are in clinical trials. 

Update on COMBI Trials 

UPDATED ANALYSES of the COMBI trials have confirmed multiple benefits of dabrafenib plus trametinib in patients with V600 mutations. 

In COMBI-d, at 3 years, 22% of patients on the combination were progression-free, compared to 12% receiving dabrafenib alone (hazard ratio [HR] = 0.71).¹ Patients with normal lactate dehydrogenase (LDH) levels had 3-year progression-free survival rates of 27% with the combination vs 17% with dabrafenib alone (HR = 0.70). For the subgroup with normal LDH and oligometastatic disease (≤ 3 lesions), these numbers were 38% and 16%, respectively (HR = 0.53). For overall survival, the trends were similar, with the combination yielding 3-year survival rates of 44% overall (HR = 0.75) and 62% among patients with normal LDH and oligometastases (HR = 0.63). 

“This is a big deal for melanoma,” she commented. “We continue to see patients deriving benefit from this combination 2 to 3 years out.” 

This combination is also effective against brain metastases, according to the phase II COMBI-MB trial, where intracranial responses occurred in 44% to 59% of patients (depending on the cohort), and intracranial disease control rates ranged from 75% to 88%.² 

“They saw some pretty dramatic intracranial responses,” Dr. Yushak reported. For the 76 patients who were asymptomatic, of good performance status, and without prior local therapy, the intracranial response rate was 58%, median progression-free survival rates were 44% and 19%, respectively. 

The lowest response rate—44%—was observed in patients with V600D, K, and R mutations, “but still, 44% is impressive,” she noted. “This trial, though it’s with a limited number of patients, gives us another option for the 50% to 90% of our patients who develop metastases to the brain.” 

Retreatment Can Be Effective 

PATIENTS WHO DEVELOP resistance to BRAF/MEK inhibition— as most do—can sometimes be successfully re-treated with the same drugs, according to a phase II study of 25 patients.³ Patients had received a BRAF inhibitor with or without a MEK inhibitor and had been off treatment for at least 12 weeks. Retreatment with dabrafenib and trametinib yielded partial responses in 32% and stable disease in 40%. 

“Even patients who had received the BRAF/MEK inhibitor combination had a response to retreatment,” she said. “This could be a valuable benefit in some patients, especially those with rapidly progressive disease or pain.” 

Mutations in KIT 

MUTATIONS AND AMPLIFICATIONS in KIT are seen in mucosal, acral, or chronically sun-damaged melanoma. These patients may respond to a KIT inhibitor. In a study of 25 total patients who received imatinib at 400 mg daily or more, the response rate was 29%, rising to 54% in patients with KIT mutations, whereas none of the patients with KIT-amplified disease responded.⁴ 

Similarly, in a study of 42 patients with KIT gene mutations treated with nilotinib (Tasigna) at 400 mg twice daily, the response rate was 26%, and 48% achieved stable disease.⁵ Almost all patients with exon 11 mutations responded to the treatment. Median progression-free survival was 4.2 months, and overall survival was 18 months. 

Mutation Testing: Which Patients, Which Tests? 

“ALL OUR METASTATIC melanoma patients should be tested for actionable mutations,” Dr. Yushak suggested. 

Companion diagnostic assays are available for vemurafenib— the cobas 4800 BRAF V600 mutation test—and for dabrafenib—the THxID assay, which tests for V600E and V600K. Both are PCR-based, but more comprehensive testing can be achieved with next-generation sequencing, which can identify all the relevant mutations. This is important because patients with V600D and V600R mutations can derive benefit from BRAF/MEK inhibition, “and you’ll miss them with a PCR-based assay,” she pointed out. ■

DISCLOSURE: Dr. Yushak reported no conflicts of interest. 

REFERENCES 

1. Long GV, Flaherty KT, Stroyakovskiy D, et al: Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: Long-term survival and safety analysis of a phase 3 study. Ann Oncol 28:1631-1639, 2017. 

2. Davies MA, Saiag P, Robert C, et al: Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): A multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 18:863-873, 2017. 

3. Schreuer M, Jansen Y, Planken S, et al: Combination of dabrafenib plus trametinib for BRAF and MEK inhibitor pretreated patients with advanced BRAF V600-mutant melanoma: An open-label, single arm, dual-centre, phase 2 clinical trial. Lancet Oncol 18:464-472, 2017. 

4. Hodi SF, Corless CL, Giobbie-Hurder A, et al: Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol 31:3182-3190, 2013. 

5. Lee SJ, Kim TM, Kim YJ, et al: Phase II trial of nilotinib in patients with metastatic malignant melanoma harboring KIT gene aberration: A multicenter trial of Korean Cancer Study Group (UN10-06). Oncologist 20:1312-1319, 2015.