Best Practices Established for Melanoma Neoadjuvant Therapy

Field: Medicine (Health Sciences)

Melanoma: MelanomaThe past 5 years have seen an explosion of research and treatment advances for melanoma patients, particularly for those with stage IV. A multitude of clinical trials have provided new targeted therapies and immunotherapies, bringing hope to patients with resected stage III disease as well. However, patients with stage III melanoma, representing approximately 10-20 percent of all melanoma patients, still face a 70 percent risk of relapse when treated with standard surgery and adjuvant therapy (CA Cancer J Clin 2017; doi: 10.3322/caac.21409). To help address these patients' needs, researchers have been exploring the potential benefits of using many different new drugs for neoadjuvant therapy. So far, the data is promising—but with disparate trial designs, study cohorts and treatment regimens, it's hard to really know the true benefits this treatment approach may provide. Recently, researchers from the University of Texas MD Anderson Cancer Center in Houston gathered experts in the field to create the International Neoadjuvant Melanoma Consortium (INMC), which then set out to develop recommendations to improve research strategies for neoadjuvant therapy. “We developed the INMC to organize the investigators who are interested in neoadjuvant therapy so that we can, as a group, navigate the challenges poised from this therapeutic approach with the ultimate goal of making neoadjuvant therapy a standard practice in melanoma,” noted Rodabe Amaria, MD, an MD Anderson melanoma oncologist and a co-first author of the paper recently published in Lancet Oncology (2019; doi: 10.1016/S1470-2045(19)30332-8). The team—which includes experts in medical oncology, surgical oncology, pathology, radiation oncology, radiology, and translational research—pooled their knowledge of neoadjuvant therapy and laid out a playbook to help streamline future research efforts, providing investigators everything they need to know to conduct top-notch investigations. Treat Before You Remove Neoadjuvant therapy has a number of potential benefits and is already the standard for other malignancies. Not only could it reduce the tumor burden and help improve surgical resection, it may also provide researchers crucial information about pathological response, mechanisms of disease resistance, and biomarkers linked to treatment response and survival. “This type of treatment is a powerful research tool in which blood and tumor specimens can be collected throughout the course of therapy and then interrogated to find immune and molecular mechanisms of treatment response and resistance,” explained Amaria. Neoadjuvant treatment response may also help guide clinicians on their choice of adjuvant therapy after surgical resection, potentially improving overall outcomes. Despite these benefits, many remain wary of the treatment approach, considering it delays resection, possibly leading to progression to unresectable disease in some patients. Even if patients don't necessarily progress, treatment toxicity may take a toll, further delaying surgery and exposing patients to higher surgical risks. All of the pros and cons of neoadjuvant therapy require extensive study, as early data suggests it can provide improved pathological response, with complete pathological response correlating with improved relapse-free survival, Amaria and her team noted in their study. But the investigations that provided this data included varying study protocols, making direct comparison a challenge. Better-designed trials could create more reliable data and provide researchers the information they need to move forward with promising therapy regimens. “If trials are designed similarly, it is possible to potentially pool data across trials with the hopes of providing larger data sets to help understand fundamental questions regarding neoadjuvant therapy,” Amaria explained. “The goal is for our data to be compelling enough to potentially lead to regulatory approval of drugs in the neoadjuvant setting and to thus firmly establish neoadjuvant therapy as a standard option for high-risk clinical stage III patients.” Trial Recommendations Amaria and her team identified numerous disparities in the current body of literature and came to a consensus on proper study protocols for just about all of them. The resulting paper provides “granular recommendations regarding how best to conduct neoadjuvant trials in melanoma,” according to Amaria. “We specifically focused on disease characteristics that would make patients eligible for treatment, how long the treatment should be given, which biospecimens should be collected at specific time points during therapy, how the disease should be imaged, how pathology should be evaluated, and considerations for surgical intervention,” she said. Following are some highlights. Patient selection. Because outcomes are highly dependent on the stage of the disease, the INMC recommends researchers limit their study cohorts to those with surgically resectable disease, diagnosed as clinically detectable stage IIIB, IIIC, and IIID melanoma. Clinicians should consider stratifying patients when including more than one group of patients and take into account any prior therapies. Regardless of the study population, researchers should closely monitor patients with clinical follow-up and imaging. Although high treatment toxicity might be acceptable for patients with a low 5-year overall survival, the same isn't true for patients with low-risk disease considering neoadjuvant therapy, the study authors stressed. Treatment duration. Trials should stick to treatment windows of 6-8 weeks, according to the INMC. While longer treatment—up to 12 weeks in some clinical studies—may improve response, the team felt the shorter duration maximizes the possible benefits of the therapy while minimizing the chance of toxicity. Amaria and her team also recommend trials include conventional post-op adjuvant therapy for up to 1 year, which would help standardize long-term follow-up data and allow better pooled analyses. Endpoints. All neoadjuvant trials should carefully document a number of endpoints, including drug toxicity (containing any potential delays in surgery or increased post-op complications); radiographical and pathological response; 1-, 2- and 3-year relapse-free, event-free, distant metastasis-free, and overall or melanoma-specific survival; and neoadjuvant therapy's effects on surgical resection. Biospecimens. The INMC recommends clinicians collect specimens at four key time points: baseline, early treatment (weeks 3-5 of treatment), surgical resection, and relapse. Trials should also include longitudinal blood sampling, the paper said. Whenever possible, researchers should analyze the samples as soon as possible to ensure accuracy. “The paper is meant to serve as a template for how investigators should design neoadjuvant trials for patients with clinical stage III disease,” Amaria highlighted. A Consistent Body of Work If researchers follow these best practices when designing and conducting neoadjuvant therapy trials, “it is possible to potentially pool data across trials with the hopes of providing larger data sets to help understand fundamental questions regarding neoadjuvant therapy,” Amaria explained. Such a robust body of literature is crucial to help facilitate and accelerate research—and hopefully lead to regulatory approval for neoadjuvant therapies, which would establish the novel approach as a standard option for high-risk clinical stage III patients, Amaria said. Rebecca Hepp is a contributing writer.