HOLLYWOOD, FLA. –The remarkable changes that have occurred in the treatment of advanced malignant melanoma over the last several years are reflected in revised National Comprehensive Cancer Network guidelines.
“Gone are the days where our active agents were interferon and dacarbazine,” said Dr. John A. Thompson of the Fred Hutchinson Cancer Research Center, Seattle.
Dr. John A. Thompson
“We’ve 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,” he said at the annual conference of the National Comprehensive Cancer Network.
Among the changes in the 2016 guidelines are the addition of high-dose ipilimumab (Yervoy) as an option for stage III (node-positive) disease, and intralesional talimogene laherparepvec (T-VEC) for primary treatment of stage III in-transit disease.
Guidelines for first-line systemic therapy for metastatic or unresectable disease recommend treatment based on evaluation of individual patients and include:
• Monotherapy with an anti-PD-1 (programmed death-1) agent, either pembrolizumab (Keytruda) or nivolumab (Opdivo) (category 1 recommendation).
• Targeted therapy for BRAF-mutated disease with combinations (preferred) of either dabrafenib (Tafinlar) and trametinib (Mekinist) or vemurafenib (Zelboraf)and cobimetinib (Cotellic); both are category 1 recommendations.
• Single-agent therapy with either vemurafenib or dabrafenib (category 1), or clinical trial.
For patients with disease progression or those who have had their maximum clinical benefit from BRAF-targeted therapy and good performance status (0-2), the guidelines recommend second-line or subsequent therapy with anti-PD-1 agents as above, ipilimumab, or a combination of nivolumab and ipilimumab.
The guidelines note, however, that “nivolumab/ipilimumab combination therapy is associated with improved relapse-free survival compared with single-agent nivolumab or ipilimumab, at the expense of significantly increased toxicity. Compared to single-agent therapy, the impact of nivolumab/ipilimumab combination therapy on overall survival is not known.”
Also recommended are targeted therapy with the BRAF-inhibitor combinations listed above (preferred) or single-agent therapy with vemurafenib or dabrafenib.
“In previously untreated patients with unresectable stage IIIC or stage IV disease, the combination of vemurafenib/cobimetinib was associated with improved PFS [progression-free survival] and response rate when compared to vemurafenib alone. The impact on overall survival compared to single-agent vemurafenib is unknown,” the guidelines state.
Other second-line options for patients with good performance status include high-dose interleukin-2 (not suitable for patients with inadequate organ reserve, poor performance status, or untreated or active brain metastases), biochemotherapy and cytotoxic agents (dacarbazine or temozolomide, and cisplatin or carboplatin, with or without vinblastine or nitrosourea, and IL-2 and interferon alfa-2b; paclitaxel, albumin-bound paclitaxel).
For patients with poor performance status (3-4) the guidelines call for best supportive care according to guidelines for palliative care.
Oncolytic immunotherapy
For treatment of recurrent disease, the guidelines newly recommend use of T-VEC, a genetically modified herpes simplex-1 virus that is injected intralesionally into accessible tumors. The attenuated virus does not kill healthy cells, but replicates in tumors and causes the cells to secrete granulocyte macrophage–colony stimulating factor (GM-CSF), leading to lysis of the tumor cells.
“It is hypothesized that the GM-CSF works with the immune system to boost a resident immune response against the destroyed melanoma cells and antigens that are released from this process,” Dr. Thompson said.
In a recent clinical trial (J Clin Oncol. 2015;33:2780-8), patients with injectable melanoma that was not surgically resectable were randomized to either intralesional T-VEC injections on week 0, 3, and then every 2 weeks (295 patients), or subcutaneous GM-CSF 125 mcg/m2 on days 1 to 14 for every 28 days (141 patients).
T-VEC was associated with significantly more durables responses (16% vs. 2.1% for GM-CSF, P less than .001) and a significantly higher overall response rate (26.4% vs. 5.7%, respectively, P less than .001).
In the primary analysis in an intent-to-treat population, T-VEC had a borderline significant association with better overall survival (median 23.2 vs. 18.9 months, hazard ratio [HR] 0.70, log-rank P = .051).
In subanalyses of outcomes in patient subgroups, however, the benefits of T-VEC were seen in patients with stage IIIB IIIC, and IV M1a disease (HR 0.57, P less than .001), but not in patients with IV M1b or M1c disease. In addition, patients treated with T-VEC in first-line therapy had significantly better overall survival compared with GM-CSF (HR 0.50, P less than .001), but those who received it in second or subsequent lines of therapy saw no survival benefit from intralesional injection.
Future directions for the treatment of advanced melanoma include identification of predictive biomarkers to guide the choice of therapy, new immune agonist antibodies or checkpoint inhibitors to act in concert with PD-1 inhibitors, adaptive T-cell therapies, and lymphokines, cytokines, vaccines, and targeted therapies that can overcome mechanisms of resistance and work in combination with immunomodulators, Dr. Thompson said.