Immunotherapy Takes Center Stage in the Updated NCCN Melanoma Guideline

The updated National Comprehensive Cancer Network (NCCN) guideline (version 2.2016) for the management of advanced melanoma reflects the increasing role of immune checkpoint inhibitors and targeted agents, as more data establish their superior efficacy over traditional chemotherapy.

“We have seen the approval by the FDA of the 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, Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, WA, at the 2016 NCCN annual conference.

Among the many changes to the guideline, the cytotoxic T-lymphocyte antigen-4 inhibitor ipilimumab (Yervoy) was added as a second-line treatment for patients with metastatic or unresectable melanoma, and talimogene laherparepvec (Imlygic, also known as T-VEC)—the first oncolytic viral therapy approved by the FDA—is recommended for primary treatment of patients with stage III in-transit metastasis.

Primary and Adjuvant Treatment

Talimogene laherparepvec, a genetically modified herpes simplex-1 virus that is administered by intralesional injection into accessible tumors, is recommended for the pri­mary treatment of patients with stage III in-transit metastasis. Talimogene laherparepvec replicates in tumors, promoting the secretion of granulocyte-macrophage colony-stimulating factor by tumor cells, which leads to cell lysis.

Ipilimumab can be considered for adjuvant therapy in patients with resected, high-risk stage III melanoma, based on an improvement in recurrence-free survival, which prompted ipilimumab’s approval for this indication.

First-Line Systemic Therapy

The recommended first-line systemic therapies for metastatic or unresectable melanoma include:

  • Monotherapy with a PD-1 inhibitor, either pembrolizumab (Keytruda) or nivolumab (Opdivo): category 1 recommendation
  • Nivolumab plus ipilimumab
  • Targeted combination therapy for patients with a BRAF mutation with (preferred) dabrafenib (Tafinlar) plus trametinib (Mekinist) or with vemurafenib (Zelboraf) plus cobimetinib (Cotellic): category 1 for both
  • Monotherapy with vemurafenib or dabrafenib: category 1
  • Enrollment in a clinical trial.
The vemurafenib plus cobimetinib combination in patients with previously untreated, unresectable stage IIIC or stage IV melanoma is associated with improved progression-free survival versus vemurafenib alone, but its effect on overall survival compared with vemurafenib alone is unknown.

The combination of a BRAF/MEK inhibitor is a preferred first-line therapy in patients with a BRAF mutation in whom a rapid antitumor response is necessary, Dr Thompson said.

Second-Line or Subsequent Systemic Therapy

Second-line or subsequent systemic therapy for metastatic or unresectable melanoma in patients with a good performance status (0-2) and disease progression, or those who have derived the maximum benefit from a BRAF inhibitor includes:

  • A PD-1 inhibitor monotherapy (pembrolizumab or nivolumab)
  • Ipilimumab (category 1) alone or in combination with nivolu­mab (category 2A)
  • Targeted therapy with a BRAF inhibitor combination (as for first-line treatment)
  • Monotherapy with vemurafenib or dabrafenib.
Alternate second-line options for patients with a good performance status include high-dose interleukin-2, biochemotherapy, cytotoxic agents, imatinib (Gleevec) for tumors with activating cKIT mutations, and participation in clinical trials.

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 this improvement comes “at the expense of significantly increased toxicity.”

In addition, the impact of the nivolumab and ipilimumab combination on overall survival compared with either agent alone is not known. This combination is especially advantageous among treatment-naïve patients whose tumors express <5% PD-1 ligand 1 protein, Dr Thompson advised.

When treating patients with immune checkpoint inhibitors, providers should be aware of a phenomenon known as “pseudoprogression,” in which the disease can progress until the immune response has been sufficiently activated, Dr Thompson emphasized.

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