A“one-two punch” that features a BRAF inhibitor plus a MEK inhibitor is an effective strategy to treat metastatic cutaneous melanoma, according to Dr. Jean Bolognia, professor of dermatology at Yale School of Medicine, New Haven, Conn.
“Use a ‘one-two punch’ to inhibit the [mitogen-activated protein kinase] MAPK pathway,” Dr. Bolognia recommendef during a presentation at the annual Atlantic Dermatological Conference, held this year in Toronto.
“If you combine a BRAF inhibitor with a MEK inhibitor, you actually get less cutaneous side effects than with either drug alone. This is especially important in the case of cutaneous squamous cell carcinomas or keratocanthomas, as well as plantar hyperkeratoses.”
Dr. Bolognia stressed that combination therapy is a strategy to avoid the development of resistance to selective BRAF inhibitors and to prolong duration of response. One of the major mechanisms of melanoma resistance is enhanced MEK activity, hence the combination with a MEK inhibitor. The reduced side effect profile is an additional benefit to the patient.
Selective BRAF inhibitors are small molecules taken orally daily,” said Dr. Bolognia. “They have a rapid response rate, but their Achilles’ heel is the development of resistance.”
Specific activating BRAF mutations that lead to an amino acid substitution in BRAF (BRAFV600E) are detected in up to 50% of cutaneous melanomas, in particular those that arise in intermittently sun-exposed skin. These activating mutations lead to uncontrolled activation of the MAPK pathway and increased expression of genes involved in proliferation.
Pathology reports of cutaneous metastases often contain a BRAF analysis and the selective BRAF inhibitors were designed specifically to interact with these altered proteins, noted Dr. Bolognia.
MAPK pathway key
Cutaneous toxicities associated with selective BRAF inhibitors such as vemurafenib and dabrafenib include morbilliform eruptions that have a follicular accentuation, said Dr. Bolognia. Patients on vemurafenib also develop ultraviolet A-induced photosensitivity. Other side effects include squamous papillomas, widespread keratosis pilaris and regressing melanocytic nevi, noted Dr. Bolognia.
"In some series, the median time for the development of keratoacanthomas and squamous cell carcinomas was six to eight weeks after beginning a selective BRAF inhibitor,” said Dr. Bolognia. “As a result, dermatologists may asked by their oncology colleagues to screen these patients prior to or soon after they begin therapy.”
"In addition, patients receiving selective BRAF inhibitors can develop new melanocytic nevi and even additional primary cutaneous melanomas, so clinicians should have a low threshold for biopsy,” Dr. Bolognia said.
“If a patient develops a grade 1 or 2 morbilliform eruption while on a selective BRAF inhibitor, you do not reflexively discontinue the drug,” she explained. “These are life-saving drugs. A dose reduction, or in the case of a grade 3 reaction a drug holiday, can be instituted. StevensJohnson syndrome and toxic epidermal necrolysis represent grade 4 reactions and of course, the drug must be discontinued.”
In commparison to kinase inhibitors, immune checkpoint inhibitors, which lead to immune stimulation, have a slower and reduced response rate, but patients who do have a complete response to checkpoint inhibitors often have a long-term durable response, explained Dr. Bolognia.
Immune checkpoint inhibitors that are currently approved for the treatment of metastatic melanoma include ipilimumab, nivolumab, and pembrolizumab, Ipilimumab, an antiCTLA-4 antibody, inhibits the interaction between a dendritic cell and a Tcell, while nivolumab and prembrolizumab, anti-PD-1 antibodies, target the interaction between a T-cell and a tumour cell, explained Dr. Bolognia.
Common cutaneous side effects associated with checkpoint inhibitors include dermatitis, leukoderma and lichenoid or sarcoidal reactions. Patients can also experience systemic autoimmune reactions including the acute onset of diabetes mellitus as well as hypothroidism and adrenal insufficiency, said Dr. Bolognia.
The highest incidence of grad III/IV side effects is seen with the combination of ipilimumab and nivolumab. As single agents, nivolumab and pembrolizumab have fewer side effects than does ipilimumab, said Dr. Bolognia. However, the highest response rates are seen with the combination of ipilimumab with nivolumab, but this regimen is usually reserved for younger patients with few, if any, comorbidities.
One new facet of assessing response to advanced therapies for melanoma is considering the patient’s microbiome, noted Dr. Bolognia. It has been hypothesized that identifying different microbiome profiles may aid in determining categories of responders to therapy (Oncotarget 2017 Jan 31; 8(5): 8890–8899).
“Further studies are needed, but the patient’s microbiome may influences their response to these drugs,” she said.
Non-proprietary and brand names of therapies:vemurafenib (Zelboraf, Roche Canada); cobimetinib (Cotellic, Roche Canada); dabrafenib (PrTafinlar, Novartis); trametinib (PrMekinist, Novartis); ipilimumab (Yervoy, Bristol-Myers Squibb Canada); nivolumab (Opdivo, BristolMyers Squibb Canada); pembrolizumab (Keytruda, Merck Canada).