Dataset Information

Evaluation of Readministration of Immune Checkpoint Inhibitors After Immune-Related Adverse Events in Patients With Cancer.

ABSTRACT:

Importance

Although immune checkpoint inhibitors (ICIs), such as anti-PD-1 (programmed cell death 1) or anti-PD-L1 (programmed cell death 1 ligand 1), have proved effective in treating many cancers, patients receiving ICIs may experience immune-related adverse events (irAEs). Little evidence exists on the safety of resuming these treatments after an irAE.

Objective

To investigate the safety of a rechallenge with anti-PD-1 or anti-PD-L1 immunotherapies after an irAE.

Design, setting, and participants

This cohort study of the safety of an ICI rechallenge involved consecutive adult patients (n?=?93) who were referred to the ImmunoTOX assessment board at the Gustave Roussy cancer center in Villejuif, France, between August 1, 2015, and December 31, 2017. Data were analyzed from May 28 to November 25, 2018.

Main outcomes and measures

Incidence of a second irAE in patients who had a readministration of an anti-PD-1 or anti-PD-L1 inhibitor after an initial grade 2 or higher irAE. Characteristics of the patients and the irAEs were reviewed, and the primary end point was the rate of occurrence of second irAEs.

Results

A total of 93 patients were included, among whom 48 (52%) were female, and the median (range) age was 62.5 (33-85) years. The main cancer types or tumor sites were melanoma (31 [33%]), lung (15 [16%]), colorectal (8 [9%]), and lymphoma (8 [9%]). For the initial irAE, 43 grade 2 events (46%), 36 grade 3 events (39%), and 14 grade 4 events (15%) were found, presenting primarily as hepatitis (17 [18%]), skin toxic effect (14 [15%]), pneumonitis (13 [14%]), colitis (11 [12%]), or arthralgia (7 [7.5%]). Forty patients (43%) were rechallenged with the same anti-PD-1 or anti-PD-L1 agent. The rechallenged and non-rechallenged groups did not differ in terms of median (range) age (61 [34-84] years vs 63 [33-85] years; P?=?.37), time to initial irAE (5 [1-40] treatment cycles vs 3 [1-22] treatment cycles; P?=?.32), irAE severity (grade 2: 18 [47.5%] vs 27 [51%]; grades 3-4: 22 [52.5%] vs 26 [49%]; P?=?.70), or steroid use (17 [42.5%] vs 32 [60%]; P?=?.09). With a median follow-up period of 14 months, the same irAE or a different irAE occurred in 22 patients (55%). Shorter time to the initial irAE was linked to the occurrence of a second irAE (9 vs 15 weeks; P?=?.04). The second irAEs were not found to be more severe than the first.

Conclusions and relevance

The risk-reward ratio for an anti-PD-1 or anti-PD-L1 rechallenge appears to be acceptable, although these patients require close monitoring; further investigation into rechallenge conditions through a prospective clinical trial is needed.

SUBMITTER: Simonaggio A

PROVIDER: S-EPMC6555478 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

Evaluation of Readministration of Immune Checkpoint Inhibitors After Immune-Related Adverse Events in Patients With Cancer.

Simonaggio Audrey A Michot Jean Marie JM Voisin Anne Laure AL Le Pavec Jérome J Collins Michael M Lallart Audrey A Cengizalp Geoffray G Vozy Aurore A Laparra Ariane A Varga Andréa A Hollebecque Antoine A Champiat Stéphane S Marabelle Aurélien A Massard Christophe C Lambotte Olivier O

JAMA oncology 20190901 9

<h4>Importance</h4>Although immune checkpoint inhibitors (ICIs), such as anti-PD-1 (programmed cell death 1) or anti-PD-L1 (programmed cell death 1 ligand 1), have proved effective in treating many cancers, patients receiving ICIs may experience immune-related adverse events (irAEs). Little evidence exists on the safety of resuming these treatments after an irAE.<h4>Objective</h4>To investigate the safety of a rechallenge with anti-PD-1 or anti-PD-L1 immunotherapies after an irAE.<h4>Design, set ...[more]

PMID: 31169866

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Project description:ImportanceLimited information is available on the safety of a rechallenge with an immune checkpoint inhibitor (ICI) after an immune-related adverse event (irAE).ObjectiveTo identify the recurrence rate of the same irAE that prompted discontinuation of ICI therapy after an ICI rechallenge in patients with cancer and to identify the clinical features associated with such recurrences.Design, setting, and participantsThis observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database VigiBase, which contains case reports from more than 130 countries. Case reports were extracted from database inception (1967) to September 1, 2019. All consecutive ICI cases with at least 1 associated irAE were included.Main outcomes and measuresThe primary outcome was the rate of recurrence of the initial irAE after an ICI rechallenge. Secondary outcomes included the factors associated with the recurrence after a rechallenge among informative rechallenges, the recurrence rate according to the ICI regimen (anti-programmed cell death 1 or anti-programmed cell death ligand 1 monotherapy, anti-cytotoxic T-lymphocyte antigen-4 monotherapy, or combination therapy), and the rate of occurrence of a different irAE after a rechallenge.ResultsA total of 24 079 irAE cases associated with at least 1 ICI were identified. Among the irAEs, 452 of 6123 irAEs associated with ICI rechallenges (7.4%) were informative rechallenges. One hundred thirty recurrences (28.8%; 95% CI, 24.8-33.1) of the initial irAE were observed. In a rechallenge, colitis (reporting odds ratio [OR], 1.77; 95% CI, 1.14-2.75; P = .01), hepatitis (reporting OR, 3.38; 95% CI, 1.31-8.74; P = .01), and pneumonitis (reporting OR, 2.26; 95% CI, 1.18-4.32; P = .01) were associated with a higher recurrence rate, whereas adrenal events were associated with a lower recurrence rate (reporting OR, 0.33; 95% CI, 0.13-0.86; P = .03) compared with other irAEs.Conclusions and relevanceThis cohort study found a 28.8% recurrence rate of the same irAE associated with the discontinuation of ICI therapy after a rechallenge with the same ICI. Resuming ICI therapy could be considered for select patients, with appropriate monitoring and use of standard treatment algorithms to identify and treat toxic effects.

Project description:Although immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for patients with many advanced malignancies, only 15-60% of patients respond, leaving a broad swath of patients who do not derive benefit. Identifying biomarkers to optimally identify patients who will benefit from ICIs is a major research focus for the oncology community. Thus far, predictive biomarker research has focused on tumor signatures such as microsatellite instability, programmed death-ligand 1 (PD-L1) expression and tumor mutational burden; clinical biomarkers have been far less studied. One potential clinical biomarker for ICI response in patients is immune-related adverse event (IRAE) onset.IRAEs are thought to represent bystander effects from activated T-cells and it is plausible that patients responding to ICIs would have greater likelihood of autoimmune toxicities (e.g. due to a more competent/treatment-responsive immune system, or cross-reactivity between tumor and host tissue). Earlier studies in melanoma patients however, suggested no association between IRAE onset and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody efficacy. In contrast, a growing body of literature suggests IRAE onset is predictive of anti-programmed cell death protein 1 (PD-1) and anti-PD-L1 antibody response across a variety of solid tumors. Most of these studies report that patients who experienced IRAEs demonstrate marked improvements in progression-free survival, overall survival and overall response rate compared to those lacking toxicity.Key questions regarding the association between IRAE onset and ICI efficacy remain. The most pertinent of these involve whether the association is only relevant for patients treated with anti-PD-1 and anti-PD-L1 antibodies and whether IRAE site, severity, timing of onset and management influence ICI efficacy. Herein, we discuss the seminal studies which have begun to address these questions and have shaped the narrative about the predictive value of IRAE onset for patients on ICIs, in this review.

Dataset Information

Evaluation of Readministration of Immune Checkpoint Inhibitors After Immune-Related Adverse Events in Patients With Cancer.

Importance

Objective

Design, setting, and participants

Main outcomes and measures

Results

Conclusions and relevance

Publications

Evaluation of Readministration of Immune Checkpoint Inhibitors After Immune-Related Adverse Events in Patients With Cancer.

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