Howard L. Kaufman, MD
New therapeutic approaches for treating patients with earlier-stage melanoma who face a higher risk of recurrence are among the features of recently updated consensus guidelines from the Society for Immunotherapy of Cancer (SITC).1
The guidelines take stock of the extensive changes that have occurred in the field in less than a decade, with the goal of helping to stratify patients, choose optimal treatment regimens, and manage adverse events (AEs) in patients with stage II to IV disease.
The FDA has approved 11 drugs or combinations in the past decade for use in patients with melanoma, and the field has changed dramatically since 2013, when SITC issued its first iteration of immunotherapy guidelines for treating patients with melanoma. Howard L. Kaufman, MD, chief medical officer at Replimune and corresponding author for the SITC Cancer Immunotherapy Guideline– Cutaneous Melanoma Subcommittee, said the development of all these new options is great for patients—the drawback is that the field is racing to create treatment guidelines before clinical trial data are available.
“Each patient has to be individualized to some degree. I don’t think there’s a one-sizefits- all that we can apply to patients. I recently wrote an editorial that coined the term ‘precision immunology,’ similar to precision medicine, where if you understand the genetics of the cancer, you might be able to design the appropriate targeted therapy,” Kaufman, who is a surgeon in the Department of Surgical Oncology at Massachusetts General Hospital in Boston, said in an interview. “Similarly, if we really understood the immunology completely—if we were able to really identify appropriate biomarkers— we might be able to craft a drug regimen or treatment plan for patients that [is] unique to that individual patient, addressing the specific issues in that patient.”
Kaufman said the purpose of the updated guidelines is to provide the best consensus until investigators and clinicians have evidence-based data to help them make treatment decisions. He added that, for patients who are eligible for immunotherapy, these agents are generally preferred over targeted therapies because immunotherapy induces longer, more durable responses and offers less drug resistance.
An example of how the SITC melanoma guidelines have evolved concerns patients with higher-risk stage IIB-C disease. In 2013, a majority of subcommittee members recommended standard 1-year, high-dose interferon alfa-2b for high-risk patients. Now, in 2018, most members (55%) recommend enrollment onto a clinical trial for these patients, with or without selection by a prognostic or predictive biomarker. Those who did not recommend a clinical trial were twice as likely to recommend observation over adjuvant interferon alfa-2b (20% vs 10%).
Managing Stage III Disease
Perhaps the largest update within the new SITC melanoma guidelines concerns how to treat patients with stage III disease. In 2013, the subcommittee considered all stage III patients as a single group. In this update, the subcommittee had to balance recent updates to the American Joint Committee on Cancer (AJCC) staging system for melanoma. In all, 30% of the subcommittee felt that stage III patients should still be treated similarly, but the majority believed that cancer behaves differently in patients with microscopic metastasis to a single lymph node (stage NIa, AJCC seventh), especially when the node has been excised by sentinel lymphadenectomy, compared with patients who have more extensive lymph node involvement (stages NIb-III, AJCC seventh). As such, independent treatment algorithms were generated for each population.
In light of the new AJCC eighth edition of melanoma staging, the subcommittee recommended that patients with stage IIIA disease (AJCC eighth) be treated in a similar manner as patients with stage NIA (AJCC seventh) disease. Furthermore, the subcommittee combined treatment recommendations for patients with stage NIb-III (AJCC seventh) or IIIB-D (AJCC eighth) disease. However, 30% of the subcommittee felt that all stage III patients should be treated similarly.
Recommendations in the 2018 SITC guidelines state that clinicians should determine nodal status based on physical examination and sentinel lymph node biopsy (SNB) for patients with stage III disease. If SNB is positive, the treating physician can decide whether to proceed with complete lymphadenectomy.
Compared with 2013, providers now have more experience with immune checkpoint blockade. The immune checkpoint inhibitors ipilimumab (Yervoy), pembrolizumab (Keytruda), and nivolumab (Opdivo) have been approved by the FDA for the treatment of patients with melanoma, along with the combination of ipilimumab and nivolumab. As a result, these agents have moved into the new treatment algorithms.