Immunotherapy Rechallenge After Immune-Related AEs

Veronica Hackethal, MD

April 29, 2020

For some cancer patients, immune checkpoints inhibitors (ICIs) can dramatically improve outcomes, leading some oncologists to talk about "functional cure."

But these immunotherapies come with drawbacks: not everyone responds, and some patients develop severe ― sometimes fatal ― immune-related adverse events (AEs) that lead to discontinuance of the therapy.

For these patients, can therapy be resumed? This was the question addressed by the largest study so far ― which analyzed 6234 cases of ICI rechallenge after immune-related AEs.

"We found that one quarter to one third of patients who had an immune-related adverse event during initial ICI therapy had a recurrence of the same immune-related adverse event after a rechallenge with the same ICI," lead author Charles Dolladille, MD, told Medscape Medical News.

"The recurrences were broadly consistent across the different ICI regimens that we studied, and across immune-related adverse event types," continued Dolladille, who is affiliated with Normandie University and the PICARO cardio-oncology program, in France.

The study was published online on April 26 in JAMA Oncology.

The results from this study can only indicate general patterns and should be considered as hypothesis-generating, Dollaidille cautioned.

"We don’t know much about the clinical efficacy of ICI rechallenge. Where we need to go next is to look at cancer prognosis," he commented. "We need prospective clinical cohorts that evaluate both safety and efficacy of ICI rechallenge after an initial immune-related adverse event."

Analyzing the Data on Rechallenge

The observational, cross-sectional study included a wide range of settings, ICI regimens, and immune-related AEs.

Using VigiBase, a worldwide database that contains over 20 million safety reports, researchers searched for safety case reports from inception (1967) to September 1, 2019.

The analysis included 6123 immune-related AEs associated with ICI rechallenge. Of these, informative data on recurrence status were available for 7.4% (452/6123). Among these, 28.8% of patients (130/452; 95% confidence interval [CI], 24.8 – 33.1) experienced recurrences of the same immune-related AE.

Rates of recurrence were highest after combination therapy rechallenge (43.5%; n = 18; 95% CI, 29.1% to 57.8%), followed by rechallenge with anti-CTLA-4 therapy (47.4%; n = 7; 95% CI, 24.8% to 69.9%), and then anti-PD-1 or anti-PD-L1 resumption (28.6%; n = 105; 95% CI, 24.0% to 33.2%). However, the odds of recurrence were only statistically significant for anti-CTLA-4 rechallenge (odds ratio [OR], 3.5; 1.05 – 11.64; P = .04).

Some AEs More Likely to Recur

One of the most important results, says Dolladille, is that some of the immune-related AEs were more likely to recur than others. In analyses that were adjusted for age, sex, ICI regimen, follow-up status, and adverse event type, ORs were highest for colitis (OR, 2.99; 95% CI, 1.60 – 5.59; P < .001), hepatitis (OR, 3.38; 95% CI, 1.31 – 8.74; P = .01), and pneumonitis (OR, 2.26; 95% CI, 1.18 – 4.32; P = .01).

ORs were lowest for diabetes (OR, N/A) and adrenal immune-related AEs (OR, 0.33; 95% CI, 0.13 – 0.86; P = .03).

Dolladille said that these results could help guide physicians in selecting patients and medication types for ICI rechallenge. For example, anti-CTLA-4 therapy is very likely to cause colitis. So, in a patient who has experienced colitis with initial anti-CTLA-4 therapy, clinicians might consider rechallenging with a different type of ICI that is less likely to cause colitis.

"Minimizing recurrence is mostly about selecting a good candidate. It is really important for the clinician to identify the situation in which the adverse event is likely to recur, to weigh the benefits of treatment against the potential risks of recurrence, and to be transparent about these issues when counseling patients," he said.

The authors highlight the importance of a multidisciplinary review board and use of appropriate monitoring and standard treatment algorithms to identify and treat side effects of ICIs. They add that the study had limited data on initial serious AEs, such as myocarditis and neurologic conditions. They stress that clinicians should use extreme caution when resuming ICIs in patients who experience these problems initially.

Another limitation of the study is that the collected data were for recurrence of the same type of immune-related AE after rechallenge with the same ICI. Therefore, the researchers could not evaluate recurrence of immune-related AEs after rechallenge with a different ICI or development of a different type of immune-related AE upon ICI rechallenge.

The study was funded by CHU Caen Normandie and Université de Caen Normandie. One coauthor has received consultant and lecture fees from Novartis. Dolladille and the other coauthors have disclosed no relevant financial relationships.

JAMA Oncol. Published online April 16, 2020. Abstract

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