Safety and Efficacy of the Rechallenge of Immune Checkpoint Inhibitors After Immune-Related Adverse Events in Patients With Cancer: A Systemic Review and Meta-Analysis

Abstract

IntroductionLittle evidence exists on the safety and efficacy of the rechallenge of immune checkpoint inhibitors (ICIs) after immune-related adverse events (irAEs) in patients with cancer.MethodsWe searched PubMed, Web of Science, Embase, and Cochrane for articles on ICI rechallenge after irAEs for systemic review and meta-analysis. The outcomes included the incidence and associated factors for safety and objective response rate (ORR) and disease control rate (DCR) for efficacy.ResultsA total of 789 ICI rechallenge cases from 18 cohort studies, 5 case series studies, and 54 case reports were included. The pooled incidence of all-grade and high-grade irAEs after rechallenge in patients with cancer was 34.2% and 11.7%, respectively. Compared with initial ICI treatment, rechallenge showed a higher incidence for all-grade irAEs (OR, 3.81; 95% CI, 2.15–6.74; p < 0.0001), but similar incidence for high-grade irAEs (p > 0.05). Types of initial irAEs (pneumonitis and global irAEs) and cancer (non-small cell lung cancer and multiple cancer) recapitulated these findings. Gastrointestinal irAEs and time interval between initial irAEs and ICI rechallenge were associated with higher recurrence of high-grade irAEs (p < 0.05), whereas initial anti-PD-1/PD-L1 antibodies were associated with a lower recurrence (p < 0.05). Anti-PD-1/PD-L1 antibodies rechallenge was associated with a lower all-grade irAE recurrence (p < 0.05). The pooled ORR and DCR after rechallenge were 43.1% and 71.9%, respectively, showing no significant difference compared with initial ICI treatment (p > 0.05).ConclusionsICI rechallenge after irAEs showed lower safety and similar efficacy outcomes compared with initial ICI treatment.Systematic Review RegistrationPROSPERO, identifier CRD42020191405.

Heterogeneous Outcomes of Immune Checkpoint Inhibitor Rechallenge in Patients With NSCLC: A Systematic Review and Meta-Analysis

“…Recurrent or new irAE after ICI retreatment seems mild and manageable in comparison with initial immune checkpoint therapy. 29,30 On the basis of the durable response in previous ICI treatment, patients with disease progression in treatmentfree period are supposed to have a more favorable efficacy at ICI rechallenge. Consistently, the present pooled study revealed that patients with disease progression in treatment-free period after ICI treatment had the best therapeutic efficacy of ICI rechallenge.…”

“…Nevertheless, the ORR of ICI rechallenge in our NSCLC study is still lower than that in the pan-cancer studies. 30,33 Although recent studies have begun to evaluate the clinical outcomes of ICI rechallenge in patients with cancer who had previously discontinued ICI treatment, the uncertain risks and benefits of ICI retreatment may impede the decision to resume ICI as an alternative therapy option in the clinical settings. 34 In the studies included in the present meta-analysis, the switch from PD-1/PD-L1 to PD-L1/PD-1 at disease progression that occurred during ICI treatment revealed limited clinical efficacy.…”

Immune Checkpoint Inhibitor Rechallenge After Prior Immune Toxicity

“…No prospective clinical trials have been initiated or published on this topic in the National Institutes of Health registry [27]. The highest level of evidence to date comes from a systematic review and meta-analysis by Zhao et al (2021) [28•]. Results from this publication and a multitude of cohort studies will be discussed in this section.…”

Efficacy, prognosis and safety analysis of anti-PD-1/PD-L1 inhibitor rechallenge in advanced lung cancer patients: a cohort study

“…Pembrolizumab (an anti-PD-1 inhibitor) was approved as a second-line treatment for advanced non-small-cell lung cancer (NSCLC) by the U.S. Food and Drug Administration in 2015; since then, several anti-PD-1/PD-L1 inhibitors have shown promising antitumor effects against lung cancers (3). Despite the considerable clinical benefits of ICIs in lung cancer patients, some patients discontinue ICIs due to disease progression, toxicity, or completion of a fixed treatment course (4,5). To achieve better clinical outcomes of ICIs in these patients, ICI rechallenge, using the same or another ICI after the initial discontinuation, has attracted much attention in clinical practice (6)(7)(8).…”

“…A multicenter cohort enrolled 69 patients with metastatic renal cell carcinoma, and it showed an overall response rate (ORR) of 23% and an irAEs rate of 16% during the ICI rechallenge (13). A meta-analysis included patients who retreated ICI after irAEs, and the results showed lower safety and similar efficacy outcomes compared with initial ICI treatment (5).…”