Experiencing an immune-related adverse event (irAE) during immune checkpoint inhibitor therapy was associated with improved recurrence-free survival for patients with melanoma, a secondary analysis of a phase III trial indicated.
Among over 1,000 stage III patients treated in KEYNOTE-054 with the anti-PD-1 agent pembrolizumab (Keytruda), those who had an irAE survived longer without recurrence compared to those without these events (HR 0.61, 95% CI 0.39-0.95, P=0.03), reported researchers led by Alexander Eggermont, MD, PhD, of Gustave Roussy Cancer Campus Grand Paris.
Yet as described in JAMA Oncology, there was no difference in the placebo arm of the trial between patients who experienced an irAE and those who did not (HR 1.37, 95% CI 0.82-2.29, P=0.21).
“Our study observed a strong association between irAEs and outcomes of patients with high-risk stage III melanoma who were treated with ICIs [immune checkpoint inhibitors], which adds to the growing amount of evidence that irAEs are indicators of greater ICI activity,” Eggermont and co-authors wrote. “However, in the absence of an irAE, patients in the pembrolizumab arm had a lower risk of recurrence or death compared with those in the placebo arm.”
The main analysis of KEYNOTE-054, which was previously reported, showed that adjuvant pembrolizumab for patients with resected high-risk melanoma led to an 18-month recurrence-free survival of 71.4%, as compared with 53.2% for those assigned to placebo (HR 0.57, 98.4% CI 0.43-0.74).
When compared to the placebo arm of the trial, the new analysis showed that patients on pembrolizumab had a significantly reduced hazard for recurrence or death following an irAE:
- After onset (HR 0.37, 95% CI 0.24-0.57)
- Before or without (HR 0.62, 95% CI 0.49-0.78)
No significant differences were seen when examining specific irAEs, but the effect was consistent when restricted to the most common group of irAEs, endocrine disorders (hypothyroidism, hyperthyroidism, thyroiditis, hypophysitis, type 1 diabetes, adrenal insufficiency):
- After onset (HR 0.34, 95% CI 0.20-0.57)
- Before or without (HR 0.60, 95% CI 0.48-0.75)
“Knowledge about the indicators of ICI activity in patients with adjuvant melanoma is of substantial importance,” Eggermont’s team wrote. “Treatment with ICIs has been previously associated with improved outcomes for patients with advanced melanoma, has indicated efficacy in the adjuvant setting, and is becoming the standard of care among patients with high-risk stage III melanoma.”
The observed effect was attenuated by use of steroids, which are immunosuppressive, the authors noted. Compared with the placebo group, those on pembrolizumab who had an irAE had an HR for recurrence or death of 0.34 (95% CI 0.21-0.56) with no systemic steroid use or by day 30 of use, as compared with an HR of 0.50 (95% CI 0.23-1.07) after 30 days of steroid use.
The findings add to a growing body of evidence that irAEs during anti-cancer immunotherapy are linked with better outcomes for patients. For example, a recent study on a small cohort of lung cancer patients showed that immune-related skin toxicities were associated with improved treatment response.
“Unfortunately, many of these studies analyzed the data by comparing patients with and without irAEs using a log-rank test or a standard Cox model, which introduces a bias owing to the different follow-up times and treatment exposures between patients who did and did not develop irAEs,” the authors cautioned. “As previously reported, the size of that bias may be large enough to dramatically change the study conclusion. In this analysis, we dealt with this problem by using a time-dependent Cox model.”
From August 2015 to November 2017, the KEYNOTE-054 randomly assigned 1,019 stage III melanoma patients (61.5% men and 38.5% women) to the pembrolizumab arm of the placebo-controlled study. Ultimately, 1,011 underwent treatment with the anti-PD-1 checkpoint inhibitor.
In all, 37.4% of patients in the pembrolizumab arm had an irAE, led by endocrine disorders (21.4%), skin disorders (5.3%), respiratory or thoracic events (4.7%), and gastrointestinal events (3.9%). In the placebo arm, 9.0% experienced an irAE.
Incidence of irAEs was similar for men and women in the pembrolizumab arm (36.6% and 38.6%, respectively), and the main findings were largely similar for both. When compared to the placebo arm, the HRs for recurrence-free survival after onset of an irAE were 0.36 (95% CI 0.21-0.63) for men and 0.42 (95% CI 0.22-0.82) for women on treatment. The HRs for those without an irAE or before one occurred were 0.59 (95% CI 0.44-0.79) for men and 0.71 (95% CI 0.48-1.04) for women.
The study was funded by Merck.
Eggermont disclosed being the study chair of EORTC 18071, a phase III trial testing ipilimumab (Yervoy) in melanoma, as well as financial relationships with Actelion, Agenus, Amgen, Bayer, BioInvent, Bristol-Myers Squibb, CatalYm, Celldex, Gilead, GlaxoSmithKline, HalioDx, Incyte, IO Biotech, ISA Pharmaceuticals, MedImmune, Merck, Nektar, Novartis, Pfizer, Polynoma, Regeneron, Sanofi, and SkylineDx. Co-authors reported various relationships with industry.
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Source: MedicalNewsToday.com
