Guideline Update Reflects Recent Surge of New Data in Systemic Therapy for Melanoma

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A guideline update on systemic treatment for melanoma offers new guidance in several areas, including the selection of front-line therapy for patients with metastatic disease with and without BRAF mutations, treatment of patients with earlier-stage disease in the adjuvant setting, and emerging neoadjuvant therapies.1

Rahul Seth, DO

Rahul Seth, DO

“I think it’s noteworthy that since 2021, data [on melanoma] have been immense, and that’s why it was important to review the data and update the guideline,” said Rahul Seth, DO, of SUNY Upstate Medical University and Guideline Expert Panel Co-Chair. “Data for melanoma have changed so much and so fast, readers should not be surprised if another round of guideline updates comes out in a few years.”

Responding to Recent Research

The rapid advancement of the management of melanoma over the past several years can be attributed to numerous discoveries. The emergence of new immunotherapy, particularly immune checkpoint inhibitors, has improved survival outcomes and given oncologists a new, effective set of tools.2

“Also, the recognition of molecular testing for BRAF mutations as well as the availability of effective combination treatments have become increasingly important,” Dr. Seth said.

As a result of the surge in melanoma research, the Expert Panel was faced with reviewing data from 21 new randomized controlled trials in cutaneous and noncutaneous melanoma published since the previous guideline was released in 2020.3 The recommendations reflected new evidence in three areas in particular—the treatment of unresectable or metastatic melanoma, therapy in the adjuvant setting, and novel treatments in the neoadjuvant space.

For advanced or unresectable disease in patients with BRAF mutations, the Expert Panel was finally able to address a long-standing question about whether to use immunotherapy or targeted therapy first, thanks to new data from the phase III DREAMseq trial—also known as the ECOG-ACRIN EA6134 trial.4

“This trial showed that combination immunotherapy would be the right first choice, and then you can switch patients to targeted therapy if they [experience disease] progression, instead of the other way around,” said Sanjiv S. Agarwala, MD, of Temple University, and Guideline Expert Panel Co-Chair.

Sanjiv S. Agarwala, MD

Sanjiv S. Agarwala, MD

Further, data from 12 clinical trials informed recommendations for new treatment regimens for advanced or unresectable disease in patients with mutant or wild-type BRAF. These new regimens involve various monotherapies and drug combinations with nivolumab, ipilimumab, relatlimab, and pembrolizumab, depending on BRAF status.

In the adjuvant space, the guideline update added a new treatment recommendation of nivolumab or pembrolizumab for patients with stage IIB–C melanoma. Dr. Agarwala noted this change could potentially cause some debate among oncologists because many of these lower-risk patients are cured without any adjuvant therapy—that is, with surgery alone.

“However, we don’t have a good way—with a biomarker, for example—to pick the patients who only need surgery,” he said. “So, with this recommendation, we are going to be treating a lot more patients, and some might experience side effects from treatment. That is unfortunately a tradeoff.”

Finally, the Panel recommended neoadjuvant treatment for the first time—specifically, pembrolizumab followed by resection and adjuvant pembrolizumab—for patients with resectable stage IIIB–IV cutaneous disease. “What we were trying to do with these recommendations was take out the confusion, and we were hoping to streamline the guideline more effectively for community oncologists, and I think we were able to achieve that goal,” Dr. Seth added.

More Data Lead to More Questions

The rush of innovative treatment options for melanoma is exciting but also has the unintended consequence of potentially muddying the waters when it comes to treatment decision-making. For instance, Dr. Agarwala noted that although the Panel provided recommendations on new treatment regimens for metastatic and unresectable disease, the guideline update is silent on treatment selection.

“The problem right now is, we can’t tell people which, if any, of these regimens are better because they have never been compared head-to-head. So, the Panel couldn’t resolve that,” he said. “The data clearly show that as front-line therapy, these treatments work, but we can’t tell you which way to go. They’ve never been compared to one another, but hopefully by the next guideline, they will.”

Although neoadjuvant therapy was considered investigational during the 2020 guideline, the Panel was able to provide updated guidance on therapies in this setting. However, its recommendation was based on a small amount of data, underscoring the importance of further developing this research area to give oncologists more definitive answers about how best to manage this subpopulation. In patients with late-stage, resectable disease, for example, the discovery of effective neoadjuvant treatments could be beneficial in reducing metastatic disease burden and improving resectability.5

Notably, the phase III NADINA trial ( identifier NCT04949113) is currently recruiting and will compare outcomes from neoadjuvant nivolumab plus ipilimumab vs adjuvant nivolumab. But the trial does not conclude until 2025, so results are still several years off.

In the meantime, a plethora of unanswered questions remain, giving researchers plenty to consider and clinicians much to anticipate. “A lot of new results will come out in the next few months, hopefully, or the next year or two that might make things clearer. [For example], what do you do when you’re looking for an option for patients when a treatment in the guideline fails?” Dr. Agarwala said. “There are still plenty of unmet needs in melanoma, especially in metastatic disease.” 


1. Seth R, Agarwala SS, Messersmith H, et al: Systemic therapy for melanoma: ASCO Guideline Update. J Clin Oncol. August 14, 2023 (early release online).

2. Carlino MS, Larkin J, Long GV: Immune checkpoint inhibitors in melanoma. Lancet 398:1002-1014, 2021.

3. Seth R, Messersmith H, Kaur V, et al: Systemic therapy for melanoma: ASCO Guideline. J Clin Oncol 38:3947-3970, 2020.

4. Atkins MB, Lee SJ, Chmielowski B, et al: Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma: The DREAMseq Trial—ECOG-ACRIN EA6134. J Clin Oncol 41:186-197, 2023.

5. Witt RG, Erstad DJ, Wargo JA: Neoadjuvant therapy for melanoma: Rationale for neoadjuvant therapy and pivotal clinical trials. Ther Adv Med Oncol 14:17588359221083052, 2022.

Originally published in ASCO Daily News © American Society of Clinical Oncology. ASCO Daily News, September 6, 2023. All rights reserved.