After decades of being considered the “graveyard of drug development,” melanoma has now become one of the hottest fields in oncologic research. In response to this rapid change in the treatment landscape, the Society for Immunotherapy of Cancer has issued updated consensus guidelines to help clinicians stratify patients, choose optimal treatment regimens, and manage immune-related adverse events in patients with stage II to IV disease.
Howard L. Kaufman, MD
After decades of being considered the “graveyard of drug development,” melanoma has now become one of the hottest fields in oncologic research. In response to this rapid change in the treatment landscape, the Society for Immunotherapy of Cancer (SITC) has issued updated consensus guidelines to help clinicians stratify patients, choose optimal treatment regimens, and manage immune-related adverse events (irAEs) in patients with stage II to IV disease.
The FDA has approved 11 potential drugs or drug 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 the treatment of patients with melanoma. Howard L. Kaufman, MD, chief medical officer at Replimune and corresponding author for the SITC Cancer Immunotherapy GuidelineMelanoma Subcommittee, said the development of all these new options is great for patients, but the draw-back now 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-size-fits-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,” said Dr. Kaufman, who is a surgeon in the Division of Surgical Oncology at Massachusetts General Hospital, 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 are unique to that individual patient, addressing the specific issues in that patient.”
Dr. Kaufman said the purpose of the updated guidelines is to provide the best consensus thinking 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 offer less drug resistance.
An example of how the SITC melanoma guidelines have evolved over time concerns patients with higher-risk stage IIB-C disease. In 2013, a majority of subcommittee members recommended standard one year high-dose interferon-α2b for high-risk patients. Now in 2018, 55 percent of the panel recommends enrollment onto a clinical trial for these patients, with or without selection by a prognostic or predictive biomarker. Among those who did not recommend a clinical trial, they were twice as likely to recommend observation over adjuvant interferon α-2b (20 percent vs. 10 percent).
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, however, the Subcommittee had to balance recent updates to the American Joint Committee on Cancer (AJCC) staging system for melanoma. In all, 30 percent of the Subcommittee felt that stage III patients should still be treated similarly, but the majority of the panel believed that cancer behaves differently in patients with microscopic metastasis to a single lymph node (stage N1a, AJCC 7th), especially when the node has been excised by sentinel lymphadenectomy, compared with patients who have more extensive lymph node involvement (stages N1b-3, AJCC 7th). As such, independent treatment algorithms were generated for each population.
In light of the new AJCC 8th edition of melanoma staging, the Subcommittee recommended that patients with stage IIIA disease (AJCC 8th) be treated in a similar manner as patients with stage N1a (AJCC 7th) disease. Furthermore, the Subcommittee combined treatment recommendations for patients with stage N1b-3 disease (AJCC 7th) or stage IIIB-D (AJCC 8th) disease. However, 30 percent 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 US Food and Drug Administration (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 2018 treatment algorithms.
The consensus panel identified five immunotherapy agents that may provide clinical benefit in the adjuvant setting: interferon-α2b, pegylated interferon-α2b, 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) were 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-α2b for patients with N1a disease. Now in 2018, the majority of the panel recommends a clinical trial as treatment for these patients. In the event an appropriate trial could not be identified, 67 percent of the experts recommended observation, and no panelists recommended interferon-α2b for these patients.
Patients with stage NIB and N2IINIII disease (AJCC 7th)/ stage IIIB-IIID (AJCC 8th) are at significant risk for melanoma recurrence, and 56 percent of the panel in 2018 recommended enrollment into a clinical trial. In contrast, 73 percent of the panel recommended one year of interferon-α2b 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 MK-3475-054/ 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 percent vs. 60.8 percent; HR, 0.65; 95 percent CI, 0.51-0.83; P <.001). Nivolumab was also associated with a significantly lower rate of treatment-related grade 3/4 adverse events (14.4 percent vs 42.6 percent).
Data from MK-3475-054/KEYNOTE-054 demonstrated that pembrolizumab extended RFS compared with placebo for patients with resected high-risk stage III disease. At a median follow-up of 15 months, the median RFS was 75.4 percent in the pembrolizumab group compared with 61.0 percent for placebo (HR for recurrence or death, 0.57; 98.4 percent CI, 0.43-0.74; P <.001). However, patients assigned to pembrolizumab did experience more grade three or greater AEs (14.7 percent vs. 3.4 percent).
Based on these findings, the panel concluded that antiPD-1 therapy with nivolumab or pembrolizumab (46 percent), anti–CTLA-4 ipilim- umab at three mg/kg (8 percent), dabrafenib/ trametinib in patients with BRAF mutation (13 percent), or high-dose interferon (IFN; four percent) were acceptable options for patients with stage NIB-3 (AJCC 7th)/ IIIB-D (AJCC 8th) melanoma. However, 29 percent of the panel was unable to make a specific recommendation.
“The treatment of patients with stage III and even high-risk stage II disease is rapidly evolving,” Dr. 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 available 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, antiPD-1 monotherapy has been shown to produce superior outcomes for patients with non–small cell lung cancer and high PD-L1 expression. In support, MK-3475 054/KEYNOTE-054 included 853 patients with PD-L1+ tumors. The one-year RFS rate was 77.1 percent in the pembrolizumab treated group compared with 62.6 percent in the placebo group (HR 0.54; 95 percent CI: 0.42-0.69).
Despite these data, 58 percent 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.
Other potential biomarkers, including tumor mutation burden, DNA mismatch repair deficiency, microsatellite instability, and the pres- ence of IFN-γ-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,” Dr. 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 these 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 for clinical guidelines, but Dr. Kaufman noticed in his own practice that those guidelines 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 Immu- notherapy 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.