Is Re-Administration of Immune Checkpoint Blockade Safe?

For cancer patients who have experienced a grade 2 or higher immune-related adverse event (irAE), re-administration of immune checkpoint blockade may be safe, a retrospective cohort study published in JAMA Oncology found. Additional studies are needed to validate these findings.

“It’s excellent that somebody actually looked at this group of patients because we do know that there is a toxicity rate associated with giving checkpoint inhibitors,” said Sapna Patel, MD, associate professor in the Department of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center, during an interview with Cancer Network.

Approximately 8% of patients who receive programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor monotherapy have a grade 3 or 4 irAE, and with combination therapy, the rate is even higher, with approximately 50% of patients having a grade 3 or 4 irAE.  

The study included a cohort of 93 adults who had a grade 2 or higher irAE while on PD-1 or PD-L1 inhibitor therapy. Of the 93 patients, 40 had re-administration of PD-1 or PD-L1 inhibitor therapy and 53 patients permanently discontinued treatment.   

Overall, 45% of patients (18 of 40) who had re-administration of PD-1 or PD-L1 inhibitor therapy did not have an irAE. Among the 55% of patients (22 of 40) who did have additional irAEs, most (17 of 22) had the same type of event and a minority had a different type of event (5 of 22). For patients who had a second irAE, 38% were of grade 2, 48% were of grade 3, and 14% were of grade 4, and the event was not worse than the first event.

If a blanket statement were made that patients who have had a side effect cannot have more therapy, Patel said, “we would be withholding [therapy] from 45% of people who potentially will not have another side effect to this.”

The study also showed that, for patients who had recurrence of an irAE after re-administration, the time interval between starting PD-1 or PD-L1 inhibitor therapy and having an irAE was a median of 6 weeks shorter than those who did not experience a second irAE after re-administration (9 vs 15 weeks; P = .04).  “These are things we’ve often anecdotally felt,” said Patel.

Although re-administration may be safe, patients who had re-administration of PD-1 or PD-L1 inhibitor therapy had no statistically significant difference in progression-free survival compared with patients who permanently discontinued therapy. “It’s not clear that re-challenge gives you more of a benefit yet,” said Patel. She cautioned, “Of course, it was a small study, so if they had more patients, maybe that [benefit] would tease out.”

While the study provides insights, Patel noted that there’s “still a little bit of a gap” in terms of the safety of re-administering PD-1 or PD-L1 inhibitor therapy. She explained that the guidelines and the prescribing information for most immune checkpoint inhibitors specify when to permanently discontinue the drug, which is typically with a grade 4 side effect. However, if a patient had a high-grade side effect, such as a grade 3/4, she asked, “Do you resume therapy, even when the package insert states to permanently discontinue for grade 4 side effects?”