On Pembrolizumab Therapy for Stage III Melanoma, Side Effects Linked to Longer Recurrence-Free Survival

By Marilynn Larkin

January 09, 2020

NEW YORK (Reuters Health) - In patients taking adjuvant pembrolizumab for stage III melanoma, immune-related adverse events (irAE) are associated with longer recurrence-free survival (RFS), a secondary analysis of trial data suggests.

Dr. Stefan Suciu of the European Organization for Research and Treatment of Cancer in Brussels and colleagues analyzed data from adults participating the the double-blind EORTC 1325/KEYNOTE-054 clinical trial. Participants were scheduled to receive 200 mg of pembrolizumab or placebo every three weeks, for a total of 18 doses for approximately one year or until disease recurrence, unacceptable toxic effects or withdrawal from the study.

Among the irAEs considered were endocrine, pneumonitis/interstitial lung disease, sarcoidosis, vitiligo, severe skin reaction, colitis, pancreatitis, hepatitis, nephritis, uveitis, myositis, and or myocarditis.

As reported in JAMA Oncology and presented at ASCO in June 2019, 1,011 patients were included. About 62% were men; 38% were ages 50-64; 37% were under age 50; and 25% were 65 and older. (http://bit.ly/303QSz5)

In keeping with findings from the main analysis, RFS was longer with pembrolizumab compared with placebo (hazard ratio, 0.56). The incidence of irAEs was 37.4% in the pembrolizumab arm and 9% in the placebo arm, with a similar incidence in men and women.

Occurrence of an irAE was associated with a longer RFS for those on pembrolizumab (HR, 0.61) in both men and women. However, the association was not significant for those on placebo.

Compared with the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater after an irAE than without or before one (HR, 0.37 vs. HR, 0.61, respectively).

"Pembrolizumab is still working even if an irAE has not been reported, (although) somehow less as compared to those with an irAE," Dr. Suciu noted in an email to Reuters Health. Nonetheless, even patients without an irAE should continue on the medication, he advised, because the estimated reduction in the risk of recurrence in the trial was "still important, and statistically significant, as compared to those treated with placebo."

Dr. Sabina Sandigursky, an instructor in the Division of Rheumatology at Perlmutter Cancer Center in New York City, commented in an email to Reuters Health, "I read this manuscript with interest. The data strongly suggest that patients with stage III melanoma have a significant RFS benefit after treatment with adjuvant pembrolizumab. In addition, it is convincing that the irAEs are due to an immunotherapeutic effect and seem to be associated with prolonged RFS."

"The irAEs may be an indication of immune anti-cancer effects, especially with grade 1 and grade 2 irAEs," she said, "(although) it is unclear whether (overall) survival will be influenced by the occurrence of irAEs."

"The authors pointed out that the association between irAEs and RFS was not apparent in patients who developed grade 3 and grade 4 toxicities," she noted. "The reason for this is unclear, but perhaps survival advantage is negated by the high-dose steroids used to treat grade 3/4 irAEs. However, this has not been replicated in other trials."

"In addition," she pointed out, "these data are not consistent with irAE data from the Checkmate-238 trial presented at ASCO 2019 from Mandala et al, in which no relationship was found between RFS and occurrence of irAEs." (http://bit.ly/35yRttL)

The study was supported by Merck. Dr. Suciu and numerous coauthors received grants or fees from the company.

SOURCE: http://bit.ly/2QB2cQc JAMA Oncology, online January 2, 2020.