The revised guideline (Version 2.2016) for the management of advanced melanoma, released by the National Comprehensive Cancer Network (NCCN), shows increasing appreciation for the use of immune checkpoint inhibitors and targeted agents, as more data establish these drug classes as having superior efficacy to traditional chemotherapy.
“We’ve seen the approval by the FDA of the [programmed death-1] PD-1–targeted agents and also molecular-targeted agents to treat patients with mutations in the BRAF gene, and the rate of change continues apace,” said John A. Thompson, MD, University of Washington, Seattle, at the NCCN 21st Annual Conference.
The new guideline adds the cytotoxic T-lymphocyte antigen 4 inhibitor ipilimumab as a second-line option in patients with metastatic or unresectable disease. Intralesional talimogene laherparepvec (T-VEC) has been added for primary treatment of stage III in-transit disease.
Recommended first-line systemic therapy for metastatic or unresectable disease includes:
- Monotherapy with an anti–PD-1 agent, either pembrolizumab or nivolumab (category 1)
- Targeted therapy for patients with BRAF mutations using combinations (preferred) of either dabrafenib and trametinib or vemurafenib and cobimetinib (category 1 for both)
- Single-agent therapy with either vemurafenib or dabrafenib (category 1)
- Enrollment into a clinical trial
For patients with good performance status (0-2) and disease progression, or patients who have derived their maximum clinical benefit from BRAF-targeted therapy, second-line or subsequent therapy consists of:
- Anti–PD-1 monotherapy (pembrolizumab or nivolumab)
- Ipilimumab (category 1) alone or in combination with nivolumab
- Targeted therapy with BRAF inhibitor combinations (as with first-line treatment)
- Single-agent therapy with vemurafenib or dabrafenib
Alternate second-line options for patients with good performance status include high-dose interleukin-2, biochemotherapy, cytotoxic agents, and imatinib for tumors with activating c-KIT mutations.
Although the combination of nivolumab and ipilimumab is associated with improved relapse-free survival compared with single-agent nivolumab or ipilimumab, the guideline states that improvement comes “at the expense of significantly increased toxicity.” In addition, the impact of the nivolumab/ipilimumab combination on overall survival (OS) compared with either agent as monotherapy is not known. The combination is especially advantageous among treatment-naive patients who express <5% PD-L1 (PD-1 ligand 1) protein, Dr Thompson noted.
In previously untreated patients with unresectable stage IIIC or stage IV disease, the combination of vemurafenib/cobimetinib is associated with an improvement in progression-free survival compared with vemurafenib alone, but the effect of the combination on OS compared with single-agent vemurafenib is uncertain.
When treating patients with immune checkpoint inhibitors, Dr Thompson advised clinicians to be aware of a phenomenon known as “pseudoprogression,” in which the disease can progress until the immune response has been sufficiently activated.
Ipilimumab can be considered for adjuvant therapy in resected high-risk stage III melanoma based on an improvement in recurrence-free survival, which prompted its approval for this indication.
For treatment of recurrent disease, T-VEC is a new recommendation contained in the guideline. T-VEC is a genetically modified herpes simplex-1 virus that is administered intralesionally into accessible tumors. It works by replicating in tumors, promoting secretion of granulocyte-macrophage colony-stimulating factor by tumor cells, which leads to cell lysis.
In patients with BRAF-mutated melanoma in whom a rapid antitumor response is necessary, the combination of a BRAF/MEK inhibitor is a preferred first-line therapy, Dr Thompson said.