SITC Guidelines Provide a Fresh Look at Evolving Strategies for Melanoma

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.

Managing Stage III Disease

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%).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.

The consensus panel identified 5 immunotherapy agents that may provide clinical benefit in the adjuvant setting: interferon alfa- 2b, pegylated interferon alfa-2b, ipilimumab, nivolumab, and pembrolizumab. Recent trial results have also shown that the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) was superior for relapse-free survival (RFS) and overall survival (OS) compared with placebo in patients with BRAF V600E/K mutations and, as such, should be considered for patients with tumors harboring BRAF mutations.

In 2013, more than half the panel recommended interferon alfa-2b for patients with NIa disease. Now, in 2018, most members recommend a clinical trial as treatment for these patients. In the event an appropriate trial could not be identified, 67% of the experts recommended observation, and none recommended interferon alfa-2b for these patients.

Patients with stage NIb and NII—NIII disease (AJCC seventh)/stage IIIb-d (AJCC eighth) are at significant risk of melanoma recurrence, and 56% of the panel in 2018 recommended enrollment into a clinical trial. In contrast, 73% recommended 1 year of interferon alfa-2b treatment in the previous guidelines. If an appropriate clinical trial is not available, a plurality of the panel now recommends adjuvant nivolumab or pembrolizumab based on results from the phase III CheckMate 238 (NCT02388906) and phase III KEYNOTE-054 (NCT02362594) trials.

Results from CheckMate 238 showed that nivolumab improved 12-month RFS compared with ipilimumab for patients with resected stage IIIb-IV melanoma (70.5% vs 60.8%; HR, 0.65; 95% CI, 0.51-0.83; P <.001).

Nivolumab was also associated with a significantly lower rate of treatment-related grade 3/4 AEs (14.4% vs 42.6%).

Data from KEYNOTE-054 demonstrated that pembrolizumab extended RFS compared with placebo for patients with resected highrisk stage III disease. At a median follow-up of 15 months, the median RFS was 75.4% in the pembrolizumab group compared with 61.0% for placebo (HR for recurrence or death, 0.57; 98.4% CI, 0.43-0.74; P <.001). However, patients assigned to pembrolizumab did experience more grade 3 or greater AEs (14.7% vs 3.4%).

Based on these findings, the panel concluded that anti—PD-1 therapy with nivolumab or pembrolizumab (46%), anti– CTLA-4 ipilimumab at 3 mg/kg (8%), dabrafenib/trametinib in patients with BRAF mutation (13%), or high-dose interferon (4%) were acceptable options for patients with stage NIb-III (AJCC seventh)/IIIb-d (AJCC eighth) melanoma. However, 29% of the panel could not make a specific recommendation.

Developing a Predictive Biomarker Remains a High Priority

“The treatment of patients with stage III and even high-risk stage II disease is rapidly evolving,” Kaufman said. “This is now addressed in the current version of the guideline, but I anticipate that because this is so recent, we’ll probably have additional changes to make.”At present, and despite promising movement in the field, clinicians have no validated biomarkers to guide their treatment decisions.

Studies have demonstrated that patients with high tumor-infiltrating lymphocytes and PD-L1 expression in the tumor microenvironment have better response rates when treated with T-cell checkpoint inhibitors. For example, anti—PD-1 monotherapy has been shown to produce superior outcomes for patients with non–small cell lung cancer and high PD-L1 expression. In support, KEYNOTE-054 included 853 patients with PD-L1–positive tumors. The 1-year RFS rate was 77.1% in the pembrolizumab-treated group compared with 62.6% in the placebo group (HR 0.54; 95% CI, 0.42-0.69).

Despite these data, 58% of the expert panel did not consider PD-L1 as “valuable in clinical management of patients with melanoma” due to limited data validating its clinical applicability in melanoma settings.¹

Other potential biomarkers, including tumor mutation burden, DNA mismatch repair deficiency, microsatellite instability, and the presence of interferon-gamma—related gene signatures within the tumor microenvironment remain under investigation. Nonetheless, with the lack of prospective clinical trials that can validate the value of these parameters, the panel determined that it could not recommend using any of these potential biomarkers to guide clinical decision making for the treatment of patients with melanoma.

“We consider things such as the patient’s clinical performance status. We consider the tempo of the disease, how rapidly it’s progressing. We take into account the BRAF mutation status, which is the critical parameter,” Kaufman said. “We would like to have a biomarker. We don’t necessarily have a validated biomarker for immunotherapy yet in melanoma, but there’s a lot of work going on in that, so there are some clues as to why some patients might respond a little better or a little worse to an immunotherapy agent. That’s a very high priority.”

He added that the updated guidelines are designed to provide useful information to the practicing clinician, with recommendations on such matters as to which lab tests to choose or how often a patient will need imaging. The National Comprehensive Cancer Network (NCCN) Guidelines remain the gold standard, but Kaufman said that in his own practice, they don’t provide enough granular information for proper patient management, especially concerning immunotherapies.

“I think this information—these little details—are not found elsewhere,” he added. “Our goal with these guidelines is to supplement what’s coming out of NCCN and provide a bit more detail for the day-to-day management of the patient who is sitting right before you.”

Sullivan RJ, Atkins MB, Kirkwood JM, et al. An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0. J Immunother Cancer. 2018; 6(1):44. doi: 10.1186/s40425-018-0362-6.