Systemic treatment of melanoma has changed rapidly since the introduction of ipilimumab in 2011. Newer therapies approved for melanoma since that time include immunotherapy, targeted therapy for mutation-bearing tumors, and injectional therapy for cutaneous or palpable lesions. ASCO has released the first clinical practice guideline to provide evidence- and expert-based recommendations on systemic therapy for melanoma across all stages in response to the rapid changes in therapy options.1
The expert panel was unable to make recommendations for or against the routine use of neoadjuvant therapy for adults with resectable regional or distant metastatic cutaneous melanoma due to a lack of strong evidence.
The expert panel included ASCO members as well as oncologists and researchers from cancer centers, academic institutions, and foundations in the United States, Italy, France, the Netherlands, and Australia.
Adjuvant Setting
In the adjuvant setting, for patients with resected stages IIIA, IIIB, IIIC, and IIID cutaneous melanoma that is BRAF wild-type, the guideline recommends nivolumab or pembrolizumab, regardless of BRAF-mutation status. Either of these two agents or the combination of dabrafenib and trametinib is recommended for patients with BRAF-mutant disease.
Pauline Funchain, MD
“Stage III data became available mainly in the past couple of years, so not all practitioners may be aware that adjuvant treatment for stage III melanoma is standard of care and very well supported by evidence,” said Pauline Funchain, MD, of the Cleveland Clinic Taussig Cancer Center and Guideline Co-Chair.
“A side point to these recommendations is that obtaining BRAF status is important in these patients because that can open up a whole new set of therapies,” Dr. Funchain said. “Every [patient with a] new stage III or IV melanoma diagnosis should have BRAF testing ordered. Of note, the guideline also states that, if the decision has been made to start with immunotherapy, treatment can be started prior to return of the BRAF results.”
The guideline revealed a lack of strong data to support or reject the use of neoadjuvant therapy in cutaneous melanoma.
“Not all practitioners may be aware that adjuvant treatment for stage III melanoma is standard of care and very well supported by evidence.”— Pauline Funchain, MD
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Unresectable/Metastatic Setting
In the unresectable/metastatic setting, ipilimumab plus nivolumab, nivolumab alone, or pembrolizumab alone should be offered to patients with BRAF wild-type cutaneous melanoma, whereas one of those three therapies—or combination BRAF/MEK inhibitor therapy with dabrafenib/trametinib, encorafenib/binimetinib, or vemurafenib/cobimetinib—should be offered in BRAF-mutant disease. Talimogene laherparepvec, a U.S. Food and Drug Administration (FDA)-approved injectional oncolytic therapy, is an alternate option for melanoma that is accessible for injection and not eligible for other systemic therapies.
Among several gaps that exist in the guideline is whether to choose immunotherapy or targeted therapy first in the metastatic setting, but the expert panel concluded that the data still do not exist to make a definitive recommendation. However, Dr. Funchain said clinical trials are currently underway that will address some of these gaps.
For example, she specifically called attention to the DREAMseq phase III trial (ClinicalTrials.gov identifier NCT02224781) in patients with stages III to IV BRAF V600 melanoma, which is exploring treatments in the first-line setting. “Participants are randomly assigned to immunotherapy first or BRAF therapy and, if the disease progresses, they switch to the other,” Dr. Funchain said. “The results of this trial will be really important to cover that data gap.” Publicly available data are expected in 2022.
The new guideline also recommends that patients with mucosal melanoma be offered the same therapies recommended for cutaneous melanoma. No recommendation could be made for or against specific therapy for uveal melanoma.
Extended Pembrolizumab Dosing
Recommendations on extended pembrolizumab dosing were not possible due to a lack of sufficient data. “In Europe, pembrolizumab has been approved for every-6-week dosing. Here, in the United States, the FDA-approved dose is still every-3-week dosing. There will be more to come on that in the next year or so. Things will likely change,” Dr. Funchain said.
Similarly, not enough data are available to recommend alternative dosing for the combination of ipilimumab and nivolumab. The guideline recommends using the FDA-approved dosing of ipilimumab at 3 mg/kg and nivolumab at 1 mg/kg every 3 weeks for the first four cycles.
Due to a rapidly evolving treatment landscape, Dr. Funchain sees this guideline as a foundation for standardizing first-line melanoma care, and it is expected to change rapidly over the next 5 years. “This guideline lays out strict evidence-driven treatment recommendations,” Dr. Funchain said. “In clinical settings where a clear recommendation is not given, the data were insufficient for guideline-based care. In these situations, we highly encourage referral to an academic center.”
DISCLOSURE: For full disclosures of the panel members, visit ascopubs.org.
REFERENCE
1. Seth R, Messersmith H, Kaur V, et al: Systemic therapy for melanoma: ASCO guideline. J Clin Oncol. March 31, 2020 (early release online).
Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, April 1, 2020. All rights reserved.
