In the JournalsPerspective

Checkpoint inhibitor rechallenge appears safe, with monitoring, after immune-related adverse events

Readministration of anti-PD-1 or anti-PD-L1 inhibitors after mild or severe immune-related adverse events appeared to carry acceptable risks vs. rewards, according to study results published in JAMA Oncology.

“According to the European Society for Medical Oncology Clinical Practice Guidelines on diagnosis, treatment and follow-up and the American Society of Clinical Oncology Clinical Practice Guideline, most grade 2 immune-related adverse events will require systemic oral or IV steroid therapy, and the temporary discontinuation of the immune checkpoint inhibitor until the adverse event grade falls below 2,” Audrey Simonaggio, MD, of the department of drug development at Gustave Roussy in Villejuif, France, and colleagues wrote. “Grade 3 immune-related adverse events require high-dose IV steroids and the temporary or permanent discontinuation of the [inhibitor]. After grade 4 [events], immune checkpoint inhibitors are generally discontinued permanently. The resumption of [immune checkpoint inhibitor] treatment will depend on the physician’s estimation of the risk-reward ratio and the availability of other treatment options.”

In the retrospective cohort study, Simonaggio and colleagues evaluated 93 consecutive adults (median age, 62.5 years; range, 33-85; 52% women) referred to ImmunoTOX, a multidisciplinary immunotoxicity assessment board at Gustave Roussy cancer center, between August 2015 and December 2017.

All patients had grade 2 or higher immune-related adverse events after either anti-PD-1 or anti-PD-L1 treatment. Primary tumor types or sites included melanoma (33%), lung (16%), colorectal (9%) and lymphoma (9%). Patients receivedanti-PD-1 agents (50%), anti-PD-L1 agents (10%) anti-CTLA-4 and anti-PD-1 combination regimens (9%), or an anti-PD-L1 combined with another immune checkpoint inhibitor (27%).

Initial immune-related adverse events included 43 grade 2 events (46%), 36 grade 3 events (39%), and 14 grade 4 events (15%). Among these were hepatitis (18%), skin toxicity (15%), pneumonitis (14%), colitis (12%) and arthralgia (7.5%).

Forty-three percent of patients (n = 40) were rechallenged with the same anti-PD-1 or anti-PD-L1 agent. Researchers observed no significant differences between the rechallenged and nonrechallenged groups in terms of median age (61 years vs. 63 years), time to initial immune-related adverse event (treatment cycles, 5 vs. 3), event severity (grade 2, 47.5% vs. 51%; grade 3 to grade 4, 52.5% vs. 49%) or steroid use (42.5% vs. 60%).

The rate of occurrence of second immune-related adverse events served as the study’s primary endpoint.

Median follow-up was 14 months.
rechallenged group, 18 (45%) did not experience subsequent immune-related adverse events, whereas 22 (55%) had a recurrence of the same type (n = 17) and/or a different type (n = 5) of immune-related adverse event.

Second immune-related adverse events were not more severe than the original events (grade 2, 38%; grade 3, 48%; grade 4, 14%).

“As long as patients are closely monitored, anti-PD-1 or anti-PD-L1 rechallenge appears to have an acceptable toxic event profile,” the researchers wrote. “Myocarditis and neurological toxic events should remain a contraindication. Rechallenge conditions require further investigation in a prospective clinical trial.” – Jennifer Byrne

Disclosures: Simonaggio reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

 

Readministration of anti-PD-1 or anti-PD-L1 inhibitors after mild or severe immune-related adverse events appeared to carry acceptable risks vs. rewards, according to study results published in JAMA Oncology.

“According to the European Society for Medical Oncology Clinical Practice Guidelines on diagnosis, treatment and follow-up and the American Society of Clinical Oncology Clinical Practice Guideline, most grade 2 immune-related adverse events will require systemic oral or IV steroid therapy, and the temporary discontinuation of the immune checkpoint inhibitor until the adverse event grade falls below 2,” Audrey Simonaggio, MD, of the department of drug development at Gustave Roussy in Villejuif, France, and colleagues wrote. “Grade 3 immune-related adverse events require high-dose IV steroids and the temporary or permanent discontinuation of the [inhibitor]. After grade 4 [events], immune checkpoint inhibitors are generally discontinued permanently. The resumption of [immune checkpoint inhibitor] treatment will depend on the physician’s estimation of the risk-reward ratio and the availability of other treatment options.”

In the retrospective cohort study, Simonaggio and colleagues evaluated 93 consecutive adults (median age, 62.5 years; range, 33-85; 52% women) referred to ImmunoTOX, a multidisciplinary immunotoxicity assessment board at Gustave Roussy cancer center, between August 2015 and December 2017.

All patients had grade 2 or higher immune-related adverse events after either anti-PD-1 or anti-PD-L1 treatment. Primary tumor types or sites included melanoma (33%), lung (16%), colorectal (9%) and lymphoma (9%). Patients receivedanti-PD-1 agents (50%), anti-PD-L1 agents (10%) anti-CTLA-4 and anti-PD-1 combination regimens (9%), or an anti-PD-L1 combined with another immune checkpoint inhibitor (27%).

Initial immune-related adverse events included 43 grade 2 events (46%), 36 grade 3 events (39%), and 14 grade 4 events (15%). Among these were hepatitis (18%), skin toxicity (15%), pneumonitis (14%), colitis (12%) and arthralgia (7.5%).

Forty-three percent of patients (n = 40) were rechallenged with the same anti-PD-1 or anti-PD-L1 agent. Researchers observed no significant differences between the rechallenged and nonrechallenged groups in terms of median age (61 years vs. 63 years), time to initial immune-related adverse event (treatment cycles, 5 vs. 3), event severity (grade 2, 47.5% vs. 51%; grade 3 to grade 4, 52.5% vs. 49%) or steroid use (42.5% vs. 60%).

The rate of occurrence of second immune-related adverse events served as the study’s primary endpoint.

Median follow-up was 14 months.
rechallenged group, 18 (45%) did not experience subsequent immune-related adverse events, whereas 22 (55%) had a recurrence of the same type (n = 17) and/or a different type (n = 5) of immune-related adverse event.

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Second immune-related adverse events were not more severe than the original events (grade 2, 38%; grade 3, 48%; grade 4, 14%).

“As long as patients are closely monitored, anti-PD-1 or anti-PD-L1 rechallenge appears to have an acceptable toxic event profile,” the researchers wrote. “Myocarditis and neurological toxic events should remain a contraindication. Rechallenge conditions require further investigation in a prospective clinical trial.” – Jennifer Byrne

Disclosures: Simonaggio reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

 

    Perspective
    Hossein Borghaei

    Hossein Borghaei

    This is an interesting retrospective study. I have seen data from other groups also suggesting a roughly 50% chance of recurrence of adverse events after a patient has an adverse event due to the use of checkpoint inhibitors. This study highlights the importance of close and multidisciplinary monitoring of these patients. It also suggests that if there is an alternative treatment after the occurrence of an adverse events, it should be discussed with the patients before rechallenge.

    If a patient is having a great response to these drugs when they suffer an adverse event, then the rechallenge might be considered over other treatment options that might not work. A 50% chance of having another event is high and the treatment outcome must be “worth” the attempt to retry the same drug. These decisions are not easy and patient engagement is needed so that they are aware of the potential 50% chance of having a similar side effect.

    • Hossein Borghaei, DO, MS
    • Fox Chase Cancer Center

    Disclosures: Borghaei reports no relevant financial disclosures.

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