Sosman, Jeffrey A. MD; Johnson, Douglas B. MD
Metastatic melanoma traditionally has had limited treatment options and almost universally poor outcomes. Recent advances in our understanding of melanoma biology and novel melanoma therapeutics, however, have radically altered treatment paradigms.
Approximately 40 to 50 percent of advanced melanomas harbor a BRAF V600 mutation. Selective BRAF inhibitors (vemurafenib and dabrafenib) and a MEK inhibitor (trametinib) are now available and are effective treatment options in this genetically defined cohort of melanoma patients. However, the remaining 50 to 60 percent of melanoma patients without BRAF wild-type mutations (BRAF WT) do not benefit from BRAF inhibitors and remain a challenge to treat. We will review the treatment options for this population, which largely consist of immune-based therapies.
Prior to determining that a melanoma is BRAF WT, accurate molecular profiling should be performed. BRAF V600E Cobas testing is commonly used in clinical practice and is highly sensitive and specific for BRAF V600E mutations. However, many of the 20 percent of alternative BRAF mutations may not be identified with this testing platform (V600K, V600D, V600R, V600M, V600E'). Since these mutations are generally sensitive to BRAF inhibitors, extended molecular testing should be considered to determine if a melanoma is truly BRAF wild type.
Assessment of CKIT mutation status should also be performed in some cases, especially if the primary was from mucosal and acral surfaces or cutaneous sites with chronic sun exposure (head and neck; see “Imatinib” section below).
Ipilimumab is a monoclonal antibody directed against the immune checkpoint CTLA-4, which activates the immune system by blocking this key negative T-cell regulator. Ipilimumab is the only agent that has shown an overall survival benefit in the BRAF WT population, and that has demonstrated increased overall survival in pre-treated melanoma patients compared with use of an experimental vaccine in a Phase III study (10 vs. 6.4 months).
A trial in therapy-naïve metastatic melanoma also demonstrated a survival benefit compared with chemotherapy (DTIC). Most impressive is the finding from both trials that at 24 and 36 months, the overall survival had nearly doubled (from 10-15 percent to 20-25 percent). Only approximately 10 percent of patients achieve classic tumor regression, although other patients may have delayed responses or even apparent progression prior to tumor shrinkage.
In view of these delayed responses, defining whether a patient will benefit is difficult to assess prior to 18 to 24 weeks after treatment initiation. Patients with rapidly progressive disease, elevated LDH, and visceral organ involvement appear to be less likely to benefit from ipilimumab.
Side effects are primarily caused by aberrant immune stimulation and auto-immune toxicity. Colitis, hepatitis, dermatitis, and endocrinopathies are the most frequent immune-related adverse events, although more uncommon side effects have been described as well. Severe toxicities should be treated promptly with corticosteroids.
We use this agent commonly both in treatment-naïve or pre-treated patients with BRAF WT melanoma. This agent is generally better tolerated than interleukin-2 (see below) and appears to cause prolonged remissions in a similar number of patients.
High-dose IL-2 has been a cornerstone of advanced melanoma therapy for many years. The overall response rate is in the range of 15 to 20 percent, with durable complete responses occurring in only six to eight percent of treated patients. Severe acute multiorgan toxicities and shock due to the vascular leak syndrome may occur during treatment. Therefore, we consider IL-2 only in young patients with normal organ function. Age greater than 65, untreated brain metastases, and poor performance status are generally exclusion criteria.
Despite the advent of newer therapies, we continue to use IL-2 in selected patients. There are several reasons to consider IL-2 as a first-line agent as opposed to ipilimumab. It appears that ipilimumab is equally effective following IL-2 use as in IL-2 naïve patients. However, there is significant theoretical concern to using IL-2 following ipilimumab, as the extreme immune activation caused by IL-2 may unleash severe delayed ipilimumab toxicities.
Therefore, if IL-2 is an option, it should be given upfront, with ipilimumab reserved for second-line therapy. Another benefit to using IL-2 first is that responses are generally evaluable sooner than in patients treated with ipilimumab (8-10 weeks vs. 18-24 weeks). Finally, the long-term complete remission rate of IL-2 is better established than for ipilimumab.
Activating CKIT mutations, primarily in exon 11, predict sensitivity to imatinib. Although infrequent in cutaneous melanoma (less than 2% of patients), these mutations do occur in up to 20 percent of mucosal or acral (nail beds and soles of feet) melanomas. In these rare melanoma subtypes, molecular profiling for CKIT mutation should be strongly considered.
Unfortunately, the clinical activity of imatinib in melanoma does not appear to be as high as in gastrointestinal stromal tumor (GIST), the other major CKIT-mutant tumor. Imatinib may cause objective responses in 16 to 23 percent of CKIT-mutant melanoma, with some patients achieving disease control for more than a year.
The clinical benefit is considerably better if patients with exon 11 mutations in CKIT are selected. Cases demonstrating responses to sunitinib and dasatinib have also been reported.
Chemotherapy was traditionally a mainstay in melanoma therapy although response rates are very low (less than 10%) and no improvements in overall survival have been demonstrated. Dacarbazine and temozolomide have been shown to be equivalent, with occasional durable disease control. We occasionally use cytotoxic chemotherapy in selected patients with no other treatment options.
Some patients may present with a limited number of metastases, which may be amenable to surgical resection. We favor an aggressive surgical approach in these cases as approximately one third of patients with complete resections may experience long-term survival.
This decision is influenced by the number of metastases, the organ site, time from prior surgery or disease-free period, and the number of prior surgeries. In some cases we will give systemic therapy for a short period of three to six months prior to the surgical resection. This may provide an opportunity to make certain that other lesions are not likely to occur rapidly, and to treat microscopic disease while treating measurable or evaluable disease.
Surgery may also play a role in patients treated with immune therapy who experience regression of all their sites of disease other than one or two lesions. Resection of these persistent lesions may cause “surgical complete responses.”
Anti PD-1/PD-L1 Therapy—Future Directions
Novel immune checkpoint inhibitors targeting the programmed cell death-1 receptor and its ligand (PD-1/PD-L1) are currently in clinical trials (nivolumab, lambrolizumab, MPDL3280A). These promising agents have similar mechanisms of action to ipilimumab and have demonstrated objective response rates in the range of 30 to 50 percent, many of which appear durable.
Anti-PD-1/PD-L1 therapies are well tolerated, with pneumonitis emerging as the most concerning toxicity. Although these treatments are not currently approved, patients should be considered for referral to a clinical trial after failure of approved agents or even for first-line therapy.
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