Advances in precision medicine for the treatment of melanoma include novel small-molecule inhibitors targeting signal transduction pathways in BRAF and NRAS mutations and cutting-edge drugs in the area of immune-modulation, whereby the patient's own immune system is mobilized to attack the tumor.
MBA, RN, MSN, APRN-BC
Advances in precision medicine for the treatment of melanoma include novel small-molecule inhibitors targeting signal transduction pathways in BRAF and NRAS mutations and cutting-edge drugs in the area of immune-modulation, whereby the patient’s own immune system is mobilized to attack the tumor. Despite improved efficacy with these new therapies, both as monotherapy or in combinations, they provide new challenges to nurses in managing side effects and adjusting treatment; these advances and subsequent challenges were detailed May 2, 2014, during a presentation at the ONS 39th Annual Congress.
Brianna Hoffner, MSN, AOCNP, nurse practitioner and supervisor of Clinical Research Operations at The Angeles Clinic and Research Institute in Santa Monica, California, and Matthew Burke, MBA, RN, MSN, APRN-BC from Yale-New Haven Hospital in Connecticut, both presented on the topic.
Melanoma is the fifth most common cancer in the United States, with over 75,000 new cases in 2013 and nearly 1 million melanoma patients currently living with the disease. Although melanoma accounts for only a small percentage of skin cancers overall, it is responsible for the majority of skin cancer deaths, and incidence of melanoma is increasing faster than that of any other cancer. Fortunately, melanoma is also one of the most active research areas in oncology in terms of emerging treatment modalities.
Ipilimumab (antiâ€CLTAâ€4) is a first-in-class humanized monoclonal antibody approved for treatment of melanoma. Ipilimumab may activate a patient’s immune system for a vigorous and sustained antitumor response by blocking the activity of the CTLAâ€4 receptor on T lymphocytes. Unlike targeted therapies, where tumor cells can evolve to circumvent various types of signaling inhibition, immunotherapy, such as ipilimumab, provides a durable response that may last for years.
However, this same mechanism can lead to potentially severe or life-threatening adverse events. “The introduction of ipilimumab onto the market has led to a whole new area of immune-mediated adverse events. Our role as nurses and nurse practitioners in understanding how to manage patients through this therapy has become vital,” said Burke.
Side effects from immunotherapies such as ipilimumab are characterized as immuneâ€mediated adverse events (IMAEs). The most common IMAEs from ipilimumab include enterocolitis, hepatitis, dermatitis, and endocrinopathies. Toxicity may emerge after several weeks of therapy, and 10% to 15% of patients experience a severe or life-threatening (grade 3 or 4) toxicity. Treatment interruption and early administration of corticosteroids are essential for effective management of IMAEs.
Important variances in tumor response may occur with immune modulators, which can be disturbing to caregivers; namely, initial post-treatment growth of tumors prior to shrinkage or the temporary development of additional distant tumors. Response Evaluation Criteria in Solid Tumors (RECIST) criteria may not accurately capture tumor responses seen on radiographic imaging after administration of immunotherapy. A useful alternative to RECIST that has been developed is immune-related response criteria (irRC), which addresses response patterns characteristic of those observed post-administration of immunotherapies.
The next generation of immune-modulating antibodies that are currently in clinical trials target either the programmed death-1 receptor (PDâ€1) or one of its ligands, PD-L1. PD-1 is also a Tâ€cell receptor and has a structure similar to that of CLTAâ€4. While PD-1 has a distinct biologic function and ligand specificity, inhibiting binding of PD-L1 to the PD-1 receptor also has the effect of activating an immune response against the tumor. Durable responses and promising improvements in overall response rates and overall survival have been seen in trials of these agents. While antiâ€PDâ€1/L1 toxicity has been somewhat lower than that observed with anti-CTLA-4, grade 3 or 4 IMAEs have been seen, along with a variety of autoimmune side effects. The most commonly observed events included pneumonitis, vitiligo, colitis, and hepatitis.
Combining antiâ€CTLAâ€4 and antiâ€PDâ€1 therapy appears to provide a higher level of antiâ€melanoma activity than does either agent alone. Once anti-PD-1 antibodies are approved, concurrent antiâ€CLTAâ€4 and antiâ€PDâ€1 treatment will become more common, resulting in a slightly different suite of issues for nurses to address. Most common severe AEs involved in combining immune-modulatory agents include hepatotoxicity, gastrointestinal issues, and renal toxicity.
BRAF mutations are found in approximately 50% of melanomas, with mutations to NRAS are found in another 25%. There have been dramatic advances in the development of signaling inhibitors to counteract mutations in melanomas. Numerous therapies targeting the Rasâ€Rafâ€MEKâ€ERK signaling pathway, such as BRAF inhibitors for V600 mutations and MEK inhibitors for both BRAF- and NRAS-mutated melanomas, are now available. BRAF inhibitor therapy can display response rates as high as 50%, and these may occur rapidly. The FDA has approved two BRAF inhibitors, vemurafenib and dabrafenib. While effective, dermatologic side effects to these treatments may include severe photosensitivity, and development of rashes, squamous cell carcinomas, or additional melanomas.
Inhibition of MEK provides another angle for treating not only BRAF-mutated melanoma, but also NRAS-mutations. Currently trametinib is the only FDA-approved MEK inhibitor. Single-agent trametinib therapy is associated with a nearly 50% response rate. Side effects can be ocular, dermatologic, hepatic, or cardiac in nature. BRAF inhibitors can now be combined with MEK inhibitors, since combination therapy of dabrafenib plus trametinib was FDA approved earlier this year based on response rates of over 75% seen in clinical trials.
Addressing the issue of side effects with dual therapy, Hoffner said, “The side effects with the combined agents is similar to the monotherapy. However, the really interesting thing about BRAF plus MEK is that oftentimes the combination is tolerated better than a single agent.”
The complexity of emerging melanoma therapies continues to increase with the prospect of combining targeted inhibitors with one or more immuno-modulatory agent. An additional layer of complexity has arisen from agent sequencing strategies, and a multitude of permutations are currently being tested in clinical trials.