Immune checkpoint inhibitors (ICIs) are the new standard of care in the treatment of many different types of cancer.1 ICIs promote antitumor immune response by inhibiting cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed cell death 1 or ligand 1 (PD-1/PDL-1) or both, leading to durable responses when compared with standard chemotherapy.2–9 Because of the rapid and broad expansion of their indications, ICIs have been prescribed to a growing number of patients, resulting in increased understanding of their safety profile.

ICI use is associated with immune-related adverse events (irAEs), related to their T-cell mechanism of action. IrAEs can affect nearly any organ system, with varying degrees of severity.10 ICI therapy can generally be continued with close monitoring in the presence of grade 1 irAEs. Grade ≥2 irAEs require corticosteroids and temporary or permanent ICI discontinuation.11–13 Severe irAEs leading to ICI discontinuation affect approximately 15%, 10% and 5% of patients receiving anti-CTLA4, anti-PD-1 or anti-PD-L1 agents, respectively, and 50% of patients receiving both nivolumab and ipilimumab.10 11 13 14 According to the current guidelines, permanent discontinuation of ICI treatment is generally recommended for grade 4 irAEs. The decision to resume ICI treatment after grade ≥2 irAEs often remains challenging. Indeed, ICI rechallenge can be associated not only with significant antitumor response,15 16 but also with a theoretically increased significant risk of irAE(s) in comparison with naïve patients. Indeed, few studies have explored the issue of ICI rechallenge after an irAE. The largest series of ICI rechallenges after an irAE focused only on the recurrence rate of the same irAE after the rechallenge of the same ICI, thereby covering only part of the possible clinical scenario.17 Many other studies have also been based on small samples of patients.15 16 18 19 So far, the recurrence rate of irAEs varies from 39% to 55%.20 In this study, we aimed to characterize the safety of ICI rechallenge after initial grade ≥2 irAEs, which led to subsequent ICI discontinuation.

This study aimed to provide complementary data on safety of ICI rechallenge after grade ≥2 irAE(s), which have led to substantial ICI discontinuation in 180 patients. Herein, we found that 61.1% of the patients who discontinued ICI treatment for grade ≥2 irAE(s) experienced no recurrent grade ≥2 irAE(s) after ICI rechallenge.

Data on safety of ICI rechallenge after grade ≥2 irAE(s) leading to ICI discontinuation are scarce. Recent studies with small sample sizes were mainly focused on the rechallenge of anti-PD-1 or anti-PD-L1 after discontinuation for irAEs. Anti-PD-1 and anti-PDL-1 rechallenge was associated with occurrence of a second grade ≥2 irAE in 55.0% of patients treated for various types of cancers.18 In 68 patients with anti-PD-L1 for advanced non-small cell lung cancer who stopped treatment due to irAEs, 55.0% experienced the same or a distinct irAE after anti-PD-L1 rechallenge.15 In the largest published series of ICI rechallenges after irAEs (n=452), Dolladille et al explored recurrence of the same irAE after rechallenge with the same ICI and found a 28.8% recurrence rate of the same irAE, which is quite similar to the rate observed in our study.17

In the present study, no patient died after ICI rechallenge. Almost half of the patients experienced initial grade ≥3 irAEs, while a third of the patients with recurrent irAEs experienced grade ≥3 irAEs, suggesting that ICI rechallenge was not associated with more severe irAEs. Furthermore, we did not observe any statistically significant difference between the group with irAE recurrence and the group with no irAE recurrence with regard to first irAE(s) severity. ICI rechallenge should always be considered with caution after a grade 4 irAE.11 ICI rechallenge was associated with recurrence of a distinct irAE in 1 of 3 patients with initial grade 4 irAEs. In addition, due to life-threatening risk, ICI rechallenge after neurological or cardiac irAEs is not recommended. In our study, 1 out of 6 patients and 1 out of 2 patients experienced recurrent encephalitis and myocarditis respectively, raising the question of the benefit/risk ratio of ICI rechallenge in these patients.

In this study, the time to first irAE was longer in the recurrence group compared the free-recurrence group. By contrast, Simonaggio et al observed that the first irAEs occurred earlier in the patients who experienced new or recurrent irAEs after ICI rechallenge.18 Such discrepancy could be related to the wide profile of irAEs, and to the longer duration between ICI discontinuation and rechallenge in our cohort (median of 8 weeks vs 3.8 weeks). This latter aspect could lead to exclude early worsening of pre-existing irAEs after ICI rechallenge, wrongly considered as irAEs recurrence.

Patients with initial gastrointestinal irAEs were more likely to have recurrent grade ≥2 irAEs after ICI rechallenge compared with those with no gastrointestinal irAEs. By contrast, initial endocrine disorders were less likely to recur. These findings are consistent with those previously reported by Dolladille et al.17 These authors observed a higher recurrence rate for colitis compared with others irAEs, while the recurrence rate of adrenal irAEs was lower than that for other irAEs.

The question of which ICI should be restarted after ICI discontinuation for severe irAEs is essential. In our study, the rechallenge of the same ICI drug or the same ICI combination was associated with a lower rate of irAE recurrence. This finding is particularly interesting for patients who progress after ICI discontinuation for irAE. Most studies have only reported the safety of PD-1 rechallenge as maintenance therapy after anti-PD-1/anti-CTLA-4 discontinuation for severe irAEs. For example, Pollack et al concluded that patients who experienced colitis or hypophysitis after anti-PD-1/anti-CTLA-4 combination could safely resume anti-PD-1.19 In a retrospective multicenter study in 167 patients, Abu-Sbeih et al also found that anti-PD-1/anti-PDL-1 rechallenge was associated with a lower risk of recurrent colitis (OR 0.30, 95% CI 0.11 to 0.81).23

This study has several strengths. First, all irAEs reports in the FPVD had been diagnosed by healthcare specialists and validated by a pharmacologist with expertize in the field. Second, this study provides additional data on safety of ICI rechallenge in a large cohort of patients treated in real-life practice with a broad spectrum of ICI regimens for varying types of cancers. It is also the first study to propose a standard definition of ICI rechallenge after discontinuation for irAEs. ICI rechallenge was only considered if the patients discontinued ICI treatment for a period at least equal to twice the duration of a cycle. Delyon et al suggested that the median duration between ICI discontinuation and rechallenge should be taken into account when considering ICI rechallenge.24 Indeed, as discussed earlier, a short temporary discontinuation could be associated with worsening of pre-existing irAEs, rather than recurrence of irAEs. However, in this study, the duration from ICI discontinuation to rechallenge was not associated with a higher risk of recurrence of irAEs.

Our study presents some limitations. The pharmacovigilance system is based on spontaneous reporting of ADRs, which can result in under reporting of less severe, for example, grade 2 irAEs, and/or expected ADRs.25 26 Given retrospective data collection, several data, such as number of prior courses or BMI were missing. Although the recurrence rate of irAEs in our study is quite similar to that previously reported, it could have been underestimated in the cases with insufficient retrospective update or when under-reporting concerned recurrent irAEs after ICI rechallenge. Despite these limitations, our results highlight the value of spontaneously reporting databases to characterize the safety profile of ICIs.

In conclusion, 61.1% of the patients who discontinued ICI treatment for grade ≥2 irAEs experienced no recurrent grade ≥2 irAEs after ICI rechallenge. ICI rechallenge after discontinuation for irAEs was not associated with more severe recurrent irAEs. Gastrointestinal disorders were more likely to recur after ICI rechallenge, whereas endocrine disorders had a lower recurrence rate. Due to inherent bias associated with pharmacovigilance studies, further prospective studies are needed to assess risk factors that influence patient outcomes after ICI rechallenge. Hence, even though ICI rechallenge appears to be safe under close monitoring, it should always be discussed in a multidisciplinary team meeting in light of usefulness of rechallenge, patient comorbidities and risk of recurrence of first irAE(s).