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Adverse Events Linked to Better Survival With ICIs in Melanoma

Among patients with metastatic melanoma who undergo treatment with single or combination immune checkpoint inhibitors (ICIs) and who experience immune adverse events, overall survival is significantly longer, regardless of the need for hospitalization. Survival is further improved if the immunotherapy is continued after the adverse event develops, a new study confirms.

“In the largest clinical cohort to date, our data support a positive association with overall survival for patients who develop clinically significant immune-related adverse events while receiving combination immune checkpoint blockade, in keeping with other reported series,” say the authors.

The study was published online on December 8 in JAMA Oncology.

Immune-related adverse events are common with these drugs. Severe events of grade 3 or higher occur in 59% of trial patients who receive combination ICI therapy.

The adverse events have increasingly been positively assocaited with survival. However, the effects for patients with metastatic melanoma, in particular, are less clear. There is little research on the effects in relation to combination therapy with ipilimumab and nivolumab, which is the standard of care for many patients with metastatic melanoma.

To investigate, Alexander S. Watson, MD, and colleagues evaluated data on 492 patients with metastatic melanoma who had been treated with one or more doses of an anti–programmed cell death protein 1 (PD-1) agent as single or combination immune checkpoint blockade in the multicenter Alberta Immunotherapy Database (AID), a retrospective cohort in Alberta, Canada, from August 2013 to May 2020.

Of these 492 patients, 198 patients (40%) developed immune-related adverse events. The mean age of the patients who developed adverse events was 61.8 years; of those who did not develop adverse events, the mean age was 65.5 years. Men made up 69.2% and 62.2%, respectively.

A total of 288 patients received pembrolizumab as their first ICI therapy, 80 received nivolumab, and 124 received combination blockade with ipilimumab-nivolumab.

Overall, with a median follow-up of 36.6 months, among patients who experienced clinically significant immune-related adverse events, defined as requiring systemic corticosteroids and/or a treatment delay, median overall survival was significantly improved, at 56.3 months, compared with 18.5 months among those who did not experience immune-related adverse events (P < .001).

In addition, among those who received combination ICI treatment, the median overall survival was 56.2 months for those who experienced adverse events, vs 19.0 months for those who did not (P < .001).

There were no significant differences in overall survival between those who were and those who were not hospitalized for their immune-related adverse events (P = .53).

For patients who resumed their ICI therapy following the adverse events, overall survival was longer compared with those who did not resume the therapy (median, 56.3 months vs 31.5 months; P = .009).

The improvements in overall survival seen with immune-related adverse events remained consistent after adjustment in a multivariable analysis (hazard ratio for death, 0.382; P < .001).

There were no significant differences in the median number of cycles of ICIs between those with and those without the adverse events.

The risk of recurrence of immune-related adverse events following the reintroduction of therapy after initial events was a concern, so the improved overall survival among those patients is encouraging, although further investigation is needed, commented lead author Watson, from the Department of Oncology, University of Calgary, Alberta, Canada..

“It may be, for certain patients with immune-related adverse events, that continued immune-priming is safe and optimizes anticancer response,” he told Medscape Medical News. “However, in a retrospective analysis such as ours, selection bias can have an impact,” he added.

“Confirming this finding and better identifying patients who may benefit from resumption will be an area for future investigation,” he said.  

Patients who developed immune-related adverse events were more likely to be younger than 50 years (21.8% vs 13.9%), have normal albumin levels (86.4% vs 74.8%), and have a more robust Eastern Cooperative Oncology Group status, which is consistent with other studies that have shown survival benefits among those who experience adverse events.

“We, and others, speculate this could be due to such groups having immune systems more ready to respond strongly to immunotherapy,” Watson explained.

He noted, however, that after controlling for age and performance status in the multivariable analysis, “immune-related adverse events remained strongly associated with survival, potentially [indicating] that robust responses to immunotherapy lead to both cancer control and immune-related adverse events.”

Overall, “we feel these findings will help clinicians in discussions with patients and in clinical decision-making after adverse events develop,” Watson said.

Watson has received personal fees from Apobiologix Canada Inc. The other authors’ relevant financial relationships are detailed in the original article.

JAMA Oncol. Published December 8, 2022. Full text

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