ASCO Updates Systemic Therapy Guidelines for Melanoma

Since 2011, twelve new drugs have been approved to treat unresectable melanoma—including 4 regimens approved in the adjuvant setting—and research into the neoadjuvant setting continues to be underway.

These advances in the field have been associated with substantial improvements in overall survival and long-term survival. However, the clinical burden associated with treating melanoma has also increased, underscoring the need for rational evidence-based treatment selections.

As such, an expert panel with has reviewed 21 newly published randomized clinical trials and updated the American Society of Clinical Oncology (ASCO) guideline regarding the use of systemic therapies in melanoma accordingly.

Neoadjuvant Therapy Updates

In the new recommendations, neoadjuvant pembrolizumab (Keytruda) is recommended for patients with resectable stage IIIB or IV cutaneous melanoma. The recommended maximum dose is three courses of 200 mg once every 3 weeks. Moreover, it is advised that these patients be referred to clinical trial enrollment for neoadjuvant therapy when possible.

Adjuvant Therapy Updates

Adjuvant nivolumab (Opdivo) or pembrolizumab is now recommended for patients with stage IIB-C resected cutaneous melanoma. This recommendation is supported by the conference abstract publication for CheckMate76K (NCT04099251). The panel is operating under the assumption that the full publication of those data will be consistent with the results of the abstract. The guidelines also assert that adjuvant therapy should not be offered to patients with resected stage IIA melanoma outside of clinical trial enrollment.

Moreover, for patients with resected stage IIIA-D disease that is BRAF wild-type, the guidelines recommend—in no particular order—either 52 weeks of nivolumab or 52 weeks of pembrolizumab. The guidelines do not support ipilimumab (Yervoy) and high-dose interferon for routine use in the adjuvant setting. The guidelines also acknowledge that the evidence supporting this update did not include patients with stage IIIA disease whose microscopic sentinel nodal metastasis were less 1 mm in diameter. As patients with <1 mm involvement in the sentinel lymph node has generally better prognoses and a lower risk of relapse, individualized conversations about the risks and benefits of adjuvant therapy are advised.

For those with resected IIIA-D disease that is BRAF mutant (V600E), the guidelines advise the following adjuvant therapy options—in no particular order—52 weeks of nivolumab, 52 weeks of pembrolizumab, 52 weeks of dabrafenib or trametinib. The guidelines recommend adjuvant therapy for patients with resected stage IV melanoma.

Updates by BRAF Mutation Status

The new guidelines include nivolumab plus relatlimab (Opdualag) as a potential treatment option for patients with unresectable or metastatic cutaneous melanoma—regardless of BRAF mutation status. For the same population, nivolumab plus ipilimumab followed by nivolumab is now preferred over BRAF/MEK inhibitor therapy. Overall, the guidelines state that nivolumab plus ipilimumab, followed by nivolumab; or nivolumab plus relatlimab; or nivolumab alone; or pembrolizumab alone may be offered to patients with BRAF wild-type, unresectable and/or metastatic cutaneous melanoma.

The guidelines no longer recommend talimogene laherparepvec (Imlygic) as an option for patients with BRAF wild-type disease who have already received anti-PD-1 therapy.

For patients with BRAF mutant V600 unresectable or metastatic cutaneous melanoma, the guidelines support a number of first-line therapies, including nivolumab plus ipilimumab followed by nivolumab; nivolumab plus relatlimab; nivolumab as monotherapy; pembrolizumab as monotherapy; dabrafenib (Tafinlar) plus trametinib (Mekinist); encorafenib (Braftovi) plus binimetinib (Mektovi); and vemurafenib (Zelboraf) plus cobimetinib (Cotellic).

The recommendations no longer support ipilimumab and ipilimumab-containing regimens for pretreated patients with BRAF-mutated disease.

Updates in Uveal Melanoma

The guidelines state that all patients with HLA-A*02:01-positive metastatic uveal melanoma should be offered tebentafusp (Kimmtrak). The guidelines support the following dosing schedule: 20 ug on day 1, 30 ug once on day 8, and 68 ug once weekly thereafter.

The panel noted that there are several ongoing trials scheduled to conclude by 2025 that will help further clarify the existing guidelines.

Reference

Seth R, Agarwala SS, Messersmith, Alluri, et al. Systemic therapy for melanoma: ASCO guideline update. Published online August 14, 2023. J Clin Oncol. doi:10.1200/JCO.23.01136