Suppressing Immune-Related Toxicity and Survival in Melanoma

Roxanne Nelson, RN, BSN

November 07, 2022

Treating severe, immune-related adverse events (AEs) with second-line immunosuppressants may impair survival among patients with advanced melanoma, according to new findings.

Patients who received second-line immunosuppressants along with steroids to manage the toxic effects of the checkpoint inhibitors ipilimumab and nivolumab had shorter progression-free survival (PFS) and overall survival than those who received only steroids.

These results further "validate our general belief that profound and prolonged immunosuppression [can] compromise the beneficial effects of immunotherapy against cancer," said Shailender Bhatia, MD, director of the melanoma and renal cancer team, Fred Hutchinson Cancer Center, Seattle, who was not involved in the current research.

Bhatia explained that several studies have demonstrated a link between the development of immunotherapy side effects and improved cancer outcomes, perhaps signaling that the immune system has been activated.

"However, too much immune activation can lead to severe, harder-to-treat side effects that generally require prolonged courses of steroids and additional immunosuppressants," he said. An important caveat regarding the suppression of these adverse events is that doing so may "negate the benefits of immune activation."

The study was published online late last month in JAMA Oncology.

The prognosis for patients with advanced melanoma has improved through the use of immune checkpoint inhibitors, but they can cause severe immune-related AEs. Data on how immunosuppressive therapy affects immune checkpoint inhibitor efficacy is limited, and managing these AEs is often at the discretion of the treating physician.

In the current study, the authors wanted to determine whether managing immune-related AEs affected PFS and overall survival among patients with advanced melanoma who received first-line ipilimumab-nivolumab combination therapy.

Using data from the Dutch Melanoma Treatment Registry, the researchers conducted a population-based, multicenter cohort study that included 771 patients with advanced melanoma who had experienced immune-related AEs of grade 3 or higher.

Of this group, 235 received steroids alone, and 115 received steroids along with a second-line immunosuppressant. In the subset who received a second-line immunosuppressant, 67 received an anti–tumor necrosis factor (TNF) agent, and 35 received a non-anti-TNF agent.

Overall, among patients treated with steroids alone, median PFS was significantly longer compared with patients who received steroids plus any second-line immunosuppressant (11.3 vs 5.4 months; hazard ratio [HR], 1.43; P = .01). This PFS benefit held when comparing the steroids-only group to each second-line immunosuppressant arm (HR, 1.44 for those receiving steroids plus an anti-TNF agent; and HR, 1.65 for those receiving steroids plus a non-anti-TNF immunosuppressant).

In a multivariate analysis, the authors also observed a strong trend of a higher risk of progression or death among patients who received any second-line immunosuppressant (adjusted HR [aHR], 1.40; P = .05).

More specifically, median overall survival was significantly longer among patients who received steroids alone compared with those who received steroids plus any second-line immunosuppressant (46.1 vs 22.5 months; HR, 1.64). When adjusted for potential confounders, the risk of death remained significantly higher for patients who received any second-line immunosuppressant along with steroids (aHR, 1.54).

The significant overall survival findings held when patients received steroids alone in comparison with patients who received steroids along with an anti-TNF agent (HR,1.62) but not when patients received steroids plus a second-line immunosuppressant, excluding anti-TNF agents (HR, 1.59; P = .08).

Additionally, median melanoma-specific survival was higher among patients who received steroids alone compared with patients who received steroids plus any second-line immunosuppressant (not reached vs 28.8 months; P = .006).

Colitis and hepatitis were the most frequently reported types of toxicities, and significantly more patients who received steroids plus immunosuppression discontinued treatment because of toxic effects — 102 of 115 patients (88.7%) vs 171 of 235 patients who received steroids only (72.8%).

The authors highlight two limitations of the study: they did not know which specific immunosuppressants patients received, nor did they know the duration or dosage of the immunosuppressants.

Overall, the authors conclude that the "current results suggest harmful effects of escalated immunosuppression rather than a specific anti–TNF-related effect."

Commenting on the study, Andrew Pecora, MD, an oncologist at Hackensack Meridian's John Theurer Cancer Center in New Jersey, noted that patients need to be better educated about the signs and symptoms of immune-related AEs and to report them immediately.

"Many [patients] come in when the effects are already advanced," said Pecora, who is also president of biotechnology company Celularity Inc. "If we can catch it early and begin treating with steroids, then immunosuppression can often be avoided," he said.

Carman A. Giacomantonio, MD, of Dalhousie University, Halifax, Nova Scotia, who was also not involved in the research, noted that he "would continue to advocate for [the] addition of steroids in the treatment of patients experiencing severe immune-related AEs due to checkpoint inhibition" and that he would only add "second-line immunosuppression for patients who fail to improve following optimal first-line steroid therapy."

JAMA Oncol. Published online October 27, 2022. Abstract

No outside source of funding for the research was disclosed. Bhatia has received research grants to his institution from EMD Serono, Bristol-Myers Squibb, Exicure, Xencor, 4SC, NantKwest, Novartis, TriSalus Life Sciences, Merck, and other companies, and he has participated in advisory committees for Genentech, Bristol- Myers Squibb, Sanofi Genzyme, Regeneron, and EMD Serono. Several co-authors have relationships with industry, as noted in the original article.

Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.

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