irAEs Linked To Adjuvant Pembrolizumab Response In Melanoma Patients

Author: By Shreeya Nanda, Senior medwireNews Reporter
 
medwireNews: Analysis of a phase III trial has shown “a strong association” between the occurrence of an immune-related adverse event (irAE) and improved recurrence-free survival (RFS) in individuals with resected stage III melanoma who received adjuvant therapy with pembrolizumab, report researchers.

This observation “is in line with previous studies of patients with advanced melanoma and lung cancer” and “adds to the growing amount of evidence that irAEs are indicators of greater [immune checkpoint inhibitor] activity”, they comment.

But the investigators emphasize that pembrolizumab treatment was associated with a reduced risk of recurrence or death relative to placebo regardless of the development of an irAE.

The team drew on the EORTC 1325/KEYNOTE-054 trial of adjuvant pembrolizumab versus placebo in stage IIIA–IIIC melanoma that previously demonstrated significantly prolonged RFS with the PD-1 inhibitor, as well as a higher incidence of grade 1–5 irAEs at 15 months, at rates of 37.4% and 9.0% for pembrolizumab and placebo, respectively.

Using a time-dependent Cox model for the current analysis, the investigators showed that the incidence of an irAE was associated with prolonged RFS in the pembrolizumab arm, but not in the placebo arm, with a significant hazard ratio (HR) for recurrence or death of 0.61 and a nonsignificant HR of 1.37, respectively.

Furthermore, the magnitude of the reduction in risk with pembrolizumab versus placebo was greater after the onset of an irAE (HR=0.37) than in the absence of or before irAE onset (HR=0.62).
Of interest, the findings were similar for men and women. Specifically, the HRs for recurrence or death with pembrolizumab were 0.36 after irAE onset and 0.59 without or before irAE onset in men, while the corresponding HRs were 0.42 and 0.71 in women.

These results are in contrast to recent data indicating that immune checkpoint inhibitors may be more efficacious in men than women receiving treatment for advanced melanoma, and that toxicity profiles may also differ by sex, comment Stefan Suciu, from EORTC Headquarters in Brussels, Belgium, and co-investigators in JAMA Oncology.

Discussing the strengths of their study, the authors note that “the data were prospectively collected in the framework of a clinical trial with high-quality standards regarding assessment of disease and evaluation of AEs.”

The researchers additionally highlight that they “used adequate statistical methods to avoid bias that may have resulted from the differences in the duration of follow-up and the treatment exposure between patients who did and did not develop irAEs”.
 
Reference

Eggermont AMM, Kicinski M, Blank CU, et al. Association between immune-related adverse events and recurrence-free survival among patients with stage III melanoma randomized to receive pembrolizumab or placebo. A secondary analysis of a randomized clinical trial. JAMA Oncol; Advance online publication 2 January 2020. doi: 10.1001/jamaoncol.2019.5570