Immune-Related Side Effects After Keytruda Treatment Could Indicate Improved Responses

January 22, 2020

Patients with high-risk stage 3 melanoma who experienced an immune-related side effect after treatment with adjuvant Keytruda had reduced risk for disease recurrence, compared with those on the placebo arm.

The occurrence of an immune-related side effect following treatment with Keytruda (pembrolizumab) could be an indicator of improved relapse-free survival in patients with high-risk stage 3 melanoma, according to study findings published in JAMA Oncology.

“Immune-related adverse events are commonly observed in patients treated with immunotherapies that include immune checkpoint inhibitors, such as anti—CTLA-4 (anti-cytotoxic T-lymphocyte–associated protein 4) and anti–PD-L1 (anti-programmed cell death ligand 1),” the researchers explained. “Adverse events related to autoimmunity have also been recognized in the context of treatments with other agents, such as interleukin-2 and interferon.”

Although previous studies have demonstrated a correlation between immune-related side effects and improved outcomes in both melanoma and lung cancer, such an association has not yet been explained.

“These associations reported in advanced disease require validation in larger studies with prospectively collected data and a control group of patients who are not treated with (immune checkpoint inhibitors),” the researchers wrote. “…little is known regarding the impact of sex on the association between (immune-related side effects) and outcomes of patients treated with (immune checkpoint inhibitors); sex is a factor that has been reported to be associated with outcomes of patients treated with (immune checkpoint inhibitors).

In the double-blind EORTC 1325/KEYNOTE-054 trial, treatment with adjuvant Keytruda, compared with placebo, demonstrated prolonged recurrence-free survival. In a secondary analysis, the researchers investigated the association between immune-related side effects with improved recurrence-free survival.

The majority of patients were male (61.5%). In total, 386 patients (38.2%) were aged 50 to 64 years, 377 (37.3%) were younger than 50 years and 248 (24.5%) were 65 years and older.

The incidence of grade 1 or higher immune-related side effects in the Keytruda arm was 19.4% at three months and 37.4% at 15 months and 4.0% and 9.0%, respectively, in the placebo arm.

Immune-related side effects occurred in 190 patients (37.4%) in the Keytruda arm and 45 patients (9.0%) in the placebo arm.

Between both arms, the incidence of these side effects was similar for men (36.6%) and women (38.6%). The researchers found that the occurrence of an immune-related side effect was associated with longer recurrence-free survival in both sexes, reducing the risk for recurrence by 39%. Moreover, the incidence of immune-related side effects was similar among younger and older patients, as well as across different disease stages.

Among those treated with Keytruda, the reduction of the risk for recurrence or death was greater than the placebo arm (63%) after the onset of an immune-related side effect than without or before such an event. Similar results were seen in each sex group.

“Our study observed a strong association between (immune-related side effects) and outcomes of patients with high-risk stage 3 melanoma who were treated with (immune checkpoint inhibitors), which adds to the growing amount of evidence that (immune-related side effects) are indicators of greater (immune checkpoint inhibitor) activity,” the researchers concluded. “However, in the absence of an (immune-related side effects), patients in the pembrolizumab arm had a lower risk of recurrence or death compared with those in the placebo arm.”


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