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Immune Checkpoint Inhibitor Rechallenge Safety and Efficacy in Stage IV Non-Small Cell Lung Cancer Patients After Immune-Related Adverse Events

Open AccessPublished:August 07, 2022DOI:https://doi.org/10.1016/j.cllc.2022.07.015

      Abstract

      Background

      Despite their anti-tumor efficacy, immune checkpoint inhibitors (ICIs) are associated with a variety of immune-related adverse events (irAEs). Grade ≥ 2 irAEs require ICI discontinuation. The decision to resume ICI treatment often remains challenging.

      Methods

      We retrospectively studied 1051 adult patients with stage IV non-small cell lung cancer (NSCLC) treated with ICIs at a single institution between January 2015 and December 2020, and identified 99 (9.4%) patients with grade≥2 irAEs necessitating treatment interruption. Forty patients underwent retreatment (rechallenged group), while 59 discontinued the treatment (discontinued group).

      Results

      Baseline characteristics of patients in the 2 groups were similar. Initial irAEs were less severe in the rechallenged group. After rechallenging, 24 of 40 (60%) patients had recurrence of the same or de-novo irAEs. Twenty (50%) developed second grade≥ 2 irAEs. No grade 4 irAE or irAE-related death occurred after rechallenging. Using multivariate analysis, no statistically significant differences in overall survival (OS) (HR: 1.10, 95% CI: 0.57-2.15, P = .77) or progression-free survival (PFS) (HR: 0.87, 95% CI: 0.45-1.71, P = .69) were noted between the 2 groups, while the best objective response prior to the initial irAEs was the only variable affecting OS and PFS.

      Conclusions

      Rechallenge was associated with a relative high risk of second grade≥ 2 irAEs. The risk was less if the initial irAEs were resolved. No differences were seen in survival outcomes of patients who had ICI rechallenge and those who did not. Permanent ICI discontinuation is an appropriate strategy after grade≥ 2 irAEs, especially severe irAEs.

      Keywords

      Introduction

      Lung cancer is the leading cause of cancer death worldwide, with an estimated 1.8 million people dying of lung cancer in 2020.
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      The 5-year relative survival rate for stage IV non-small cell lung cancer (NSCLC) is dismal.

      National Institutes of Health, N.C.I., Surveillance epidemiology, and end results cancer statistics, SEER cancer statistics review 2011-2018: Cancer Stat Facts: Lung and Bronchus Cancer, survival by Stage. Bethesda, Maryland. Available at: https://seer.cancer.gov/statfacts/html/lungb.html (Accessed: March 23, 2022).

      Immune checkpoint inhibitors (ICIs) include programmed cell death-1/ programmed cell death ligand-1 (PD-1/PD-L1) inhibitors, and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitors. They are monoclonal antibodies that target several key immune suppressive proteins, promoting T cells to attack cancer cells.
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      In the past decade, ICIs have been increasingly used as the first-line or early-line treatment in patients with stage IV NSCLC,
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      resulting in durable responses and improved survival outcomes.
      Despite their anti-tumor efficacy, ICIs are associated with a variety of distinct inflammatory autoimmune tissue damages, referred to as immune-related adverse events (irAEs). These irAEs can involve nearly every organ system with varying frequencies, timing of onset and degrees of severity.
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      Although ICIs are generally more tolerable than traditional chemotherapy, associated irAEs can be debilitating and fatal in severe cases. However, the occurrence of an irAE has been associated with a more favorable ICI response and better clinical outcomes.
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      Patients with grade 1 irAEs can usually continue ICI treatment with close monitoring. Grade ≥ 2 irAEs require temporary or permanent cessation of ICI treatment, and are often managed with immunosuppressants.
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      ICI resumption (ie, ICI rechallenge) is recommended only if irAEs have improved to grade 1 or lower. However, the likelihood of irAE recurrence after rechallenging and the efficacy of rechallenge remains uncertain. Data regarding the safety and efficacy of ICI rechallenge after a grade≥ 2 irAE are limited.
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      • Santini FC
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      Safety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC.
      • Allouchery M
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      Safety of immune checkpoint inhibitor rechallenge after discontinuation for grade≥ 2 immune-related adverse events in patients with cancer.
      • Dolladille C
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      Immune checkpoint inhibitor rechallenge after immune-related adverse events in patients with cancer.
      • Pollack MH
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      Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma.
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      Therefore, the decision to resume ICI treatment following improvement of irAEs often remains challenging.
      We conducted a single-center retrospective study to examine the safety and efficacy of patients with stage IV NSCLC who had ICI permanently discontinued or had ICI rechallenge after grade≥ 2 irAEs.

      Methods

      We conducted a retrospective single-center study and investigated all patients with stage IV NSCLC treated with ICIs at a single cancer center between January 2015 and December 2020. Adult patients with histologically confirmed stage IV NSCLC who received at least 1 cycle of PD-1 inhibitors, PD-L1 inhibitors or CTLA-4 inhibitors, either as monotherapy or as multiple-agent therapy, were eligible. Pharmacy records were reviewed to capture treatment interruption longer than 1 week between planned doses of ICI therapy, and individual chart reviews were then used to identify irAE-related interruptions. Exclusion criteria included interruptions due to reasons other than grade≥ 2 irAEs, any additional systemic anti-cancer treatment between ICI cessation and resumption, and any past medical history of autoimmune diseases. The decision for permanent ICI discontinuation or rechallenge was determined by each patient's treating oncologist. Patients who had ICI treatment permanently discontinued were defined as the discontinued group, while those who had cessation of ICI treatment and were later retreated with ICI were defined as the rechallenged group.
      Patient demographics, Eastern Cooperative Oncology Group (ECOG) performance status score at the time of ICI initiation, cancer treatment-related data, irAEs-related data, and survival outcomes were collected. The Common Terminology Criteria of Adverse Events (version 5.0) was used to grade irAE at its peak severity. ICI responses were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and categorized as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or not evaluable (NE).
      The first-ever irAE during the initial ICI treatment was defined as the initial irAE, and any irAE that occurred after rechallenging was defined as the second irAE. The time to the initial irAE was defined as the time between the start of initial ICI therapy to the onset of the initial irAE. The duration of the initial irAE was defined as the time between the initial irAE onset and symptom resolution. Time to rechallenge was defined as the time between the initial irAE onset and the date of ICI treatment resumption. Duration of steroid use was defined from the date of initiation of therapeutic-dose steroid for initial irAE to the date of steroid discontinuation or back to baseline maintenance dose if patient was on steroid prior. Overall response rate (ORR) was defined as the percentage of complete or partial responses obtained as the best response. Overall survival (OS) was defined as the time from initiation of the first ICI therapy to the date of death from any cause. Progression-free survival (PFS) was defined as the time from initiation of the first ICI therapy to the first documented disease progression or the date of death from any cause. Patients who were alive without disease progression at the time of the analysis were censored at the date of the last follow-up. The final censor date was set at December 31, 2021. The institutional review board at The University of Tennessee Health Science Center approved the study protocol.

      Statistical Analysis

      Descriptive statistics were used to describe patients’ socio-demographic and clinical characteristics, and unadjusted t-test was used for comparing continuous variables (natural logarithm transformation may be used if distribution is skewed), and x2test for comparing categorical variables between those discontinued and rechallenge groups, at the time of initial irAE occurrence and later recurrence after ICI rechallenge. The overall survival and progression-free survival were examined using Kaplan-Meier plot and compared with log-rank test between discontinued and rechallenge groups. Cox proportional hazard model was used to adjusted for patient's socio-economic and clinical characteristics, and irAEs. Due to small sample size, only clinical meaningful or statistically significant (at P < .10) variables during the unadjusted analysis were included in the final multivariate models. Additional analyses stratified by best overall response during the initial treatment were performed. All the analyses were done using Stata 16.1 (Stata Corp. College Station, TX) and R software (version 4.1.3).

      Results

      Patient Characteristics

      Out of 1051 consecutive stage IV NSCLC patients on ICI treatment, a total of 99 (9.4%) patients had ICI discontinuation due to irAEs and were included in our study. All experienced grade ≥ 2 irAEs. Among the 99 patients, 40 (41.4%) underwent rechallenging with ICI therapy (the rechallenged group), while 59 (59.6%) patients received no additional ICI therapy (the discontinued group). Table 1 presents patient sociodemographic and clinical characteristics, and the initial irAEs in these 2 groups. There was no difference in age, gender, ethnicity, ECOG performance status, smoking status, cancer histology, type of ICI, or PD-L1 status, except that patients in the rechallenged group were more likely to have ICI as first-line therapy rather than second line or later (75.0% vs. 55.9%, p = 0.05).
      Table 1Basic Characteristics for the Entire Study Group
      VariableDiscontinued(n = 59)Rechallenge(n = 40)P-value
      Age, median (range), y68 (55-88)68.5 (51-88).49
      Sex, n (%).87
       Male29 (49.2)19 (47.5)
       Female30 (50.8)21 (52.5)
      Ethnicity, n (%).11
       White45 (76.3)35 (87.5)
       African American14 (23.7)4 (10.0)
       Other0 (0.0)1 (2.5)
      ECOG, n (%).35
       0-150 (84.7)33 (82.5)
       2 and beyond9 (15.3)7 (17.5)
      Smoker, n (%).72
       Current13 (22.0)9 (22.5)
       Former39 (66.1)24 (60.0)
       Never7 (11.9)7 (17.5)
      Cancer type, n (%).06
       Adenocarcinoma47 (79.7)23 (57.5)
       Squamous cell11 (18.6)15 (37.5)
       Other1 (1.7)2 (5.0)
      PD-L1 status, n (%).46
       ≥ 50%19 (32.2)16 (40.0)
       ≥ 1% but <50%11 (18.6)3 (7.5)
       Negative16 (27.1)11 (27.5)
       Unknown13 (22.0)10 (25.0)
      Line of ICI therapy, n (%).05
       First line33 (55.9)30 (75.0)
       Second and beyond26 (44.1)10 (25.0)
      Type of ICI, n (%).08
       Nivolumab20 (33.9)14 (35.0)
       Pembrolizumab38 (64.4)21 (52.5)
       Ipilimumab + Nivolumab1 (1.7)4 (10.0)
       Atezolizumab0 (0.0)1 (2.5)
      Grade of irAE, n (%)<.001
       Grade 218 (30.5)32 (80.0)
       Grade 3-441 (69.5)8 (20.0)
      Corticosteroid use, n (%)53 (89.8)32 (80.0).25
      Route of corticosteroid, n (%).01
       Intravenous14 (23.7)1 (2.5)
       Oral39 (66.1)30 (75.0)
      Steroid ≥ 4 weeks, n (%).57
       Yes42 (71.2)24 (60.0)
       No11 (18.6)8 (20.0)
      Use of additional immunosuppressant.06
       Yes6 (10.2)1 (2.5)
       No53 (89.8)39 (97.5)
      Time to the initial irAE, median (range)
       Treatment cycle7 (1-31)16 (1-37).54
       Days115 (6-621)180 (7-987).49
      Death related to irAE, n (%).15
       Yes, due to initial irAE4 (6.8)0 (0.0)
       Yes, due to second irAE0 (0.0)0 (0.0)
       No55 (93.2)40 (100.0)
      Hospitalization for initial irAE, n (%)25 (42.4)3 (7.5)<.001
      Abbreviations: ECOG = Eastern Cooperative Oncology Group; ICI = immune checkpoint inhibitor; irAE= immune-related adverse event

      Initial ICI Treatment and irAEs

      During the initial ICI treatment, grade 2, 3 and 4 irAE were observed in 50 (50.5%), 45 (45.5%) and 4 (4%) patients, respectively (Table 1). The median time to the initial irAE onset from ICI initiation was 148 days. Among all patients, the most common initial irAEs that led to treatment interruption was pneumonitis, which occurred in 34 (34.3%) patients, followed by colitis in 16 (16.2%) patients, hepatitis in 13 (13.1%) patients and dermatitis in 12 (12.1%) patients. Eighty-one (81.8%) patients required systemic corticosteroid treatment for an irAE. Among them, 7 (7.1%) required additional immunosuppressive drugs, including infliximab, mycophenolate mofetil and intravenous immune globulin (IVIG).
      No difference in the timing of the initial irAEs was seen between the 2 groups (Table 1). In the discontinued group, the incidence of initial grade 3-4 pneumonitis was significantly higher (22% vs. 0%, P = .001), while the incidence of initial all-grade colitis/diarrhea was significantly lower (10.2% vs. 25.0%, P= .049) (Supplemental Table 1). Initial irAEs were less severe in the rechallenged group, with fewer grade 3 irAEs (20% vs. 62.7%, P < .001), no grade 4 irAEs (0% vs. 6.8%, P< .001), less intravenous (IV) corticosteroid use (2.5% vs. 23.7%, P= .01), less additional immunosuppressant use (2.5% vs. 10.2%, P= .06) and less frequent hospitalizations for initial irAEs (7.5% vs. 42.4%, P< .001). Four patients in the discontinued group developed grade 4 irAEs, with 3 cases of pneumonitis and 1 case of hepatitis, all eventually died due to complications related to irAEs.

      ICI Rechallenge

      Of the 40 patients in the rechallenged group, ICI was retreated due to cancer progression in 6 (15%) patients, and as continued treatment after irAE resolution in 34 (85%). Two patients initially on the combination regimen with nivolumab and ipilimumab were rechallenged with nivolumab monotherapy. All other patients in the rechallenged group resumed the initial ICI treatment regimen upon rechallenging.
      Three (7.5%) patients were on systemic corticosteroids when they resumed ICI treatment. The median duration from the onset of the initial irAE to ICI rechallenge was 59 (21-1143) days. Sixteen (40.0%) did not experience further irAEs. However, 24 (60.0%) experienced recurrence of the same or de-novo irAEs of any grade (Supplemental Figure 1). Twenty (50.0%) developed second grade≥ 2 irAEs. No grade 4 irAE occurred after rechallenging. No patient died from rechallenge-related second irAEs. Fifteen (37.5%) patients required treatment discontinuation due to second irAEs after rechallenging. Among the 24 patients with second irAEs, 6 (25%) still had residual grade 1 irAEs upon rechallenging, while none of the 16 patients without second irAEs had residual irAEs (P= .03) (Supplemental Table 2).
      In those 24 patients who developed second irAEs after rechallenging, 16 (66.7%) patients experience a recurrence of the same irAE, and 8 (33.3%) experienced a de-novo irAE. Of these, the worse grade was grade 1 in 4 (16.7%) patients, grade 2 in 13 (54.2%) patients and grade 3 in 7 (29.2%) patients. Nineteen (79.2%) required systemic corticosteroid for second irAEs, and none required other immunosuppressants.
      The second irAE affected most of the organs involved in the initial irAE, but with different frequencies (Figure 1 and Supplemental Table 3). Colitis/diarrhea, dermatitis/rash, pneumonitis, and hepatitis appeared to recur more often.
      Figure 1
      Figure 1Patient outcomes after immune checkpoint inhibitor rechallenge according to the type of immune-related adverse events (irAEs).

      Overall Response Rate (ORR) and Survival Outcomes

      Among the entire cohort, 14 (14.1%) experienced CR, 41 (41.4%) experienced PR, 38 (38.4%) experienced SD, 1 (1%) experienced PD and 5 (5.1%) were non-evaluable as their best objective response prior to the initial irAEs (Table 2). The ORR prior to the initial irAE was 67.5% in the rechallenged group vs. 47.4 % in the discontinued group. The ORR for the entire study period was 72.5% in the rechallenged group vs. 57.6% in the discontinued group.
      Table 2Best Objective Response to Immune Checkpoint Inhibitors
      VariableDiscontinued(n = 59)Rechallenged(n = 40)
      Best OR, n (%)Prior to Initial irAEEntire Study PeriodPrior to Initial irAEEntire Study Period
      CR8 (13.5)15 (25.4)6 (15.0)10 (25.0)
      PR20 (33.9)19 (32.2)21 (52.5)19 (47.5)
      SD26 (44.1)22 (37.3)12 (30.0)11 (27.5)
      PD1 (1.7)3 (5.1)0 (0.0)0 (0.0)
      NE4 (6.8)0 (0.0)1 (2.5)0 (0.0)
      Abbreviations: CR = complete response; irAE = immune-related adverse event; NE = not evaluable; OR = objective response; ORR, = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease.
      Among the patients who didn't achieve CR or PR prior to ICI interruption, we found that 1 patient (2.5% of the entire rechallenged group, 1 of 13 without CR or PR prior to rechallenge [7.7%]) later achieved PR following rechallenge. For comparison, in the discontinued group, 6 patients (10.2% of the entire discontinued group, 6 of 31 without CR or PR prior to discontinuation [19.4%]) had either PR or CR onset following permanent ICI discontinuation.
      At the time of analysis, a total of 54 (54.5%) patients had died. With a median follow-up of 572 days, the difference in OS between the 2 groups was not significant (P= .29), while the PFS for the rechallenged group was longer than the discontinued group (P= .02) (Figures 2A and 2B). However, in the multivariate analysis, after adjusted for age, gender, ethnicity, ECOG performance status, PD-L1 status, grade of initial irAEs, and best objective response (OR) prior to the initial irAEs, there were no statistically significant differences in PFS (HR: 0.87, 95% CI: 0.45-1.71, P= .69) or OS (HR: 1.10, 95% CI: 0.57-2.15, P= .77) between the 2 groups (Table 3). The only variable affecting OS and PFS in the multivariate analysis was the best objective response prior to the initial irAEs. Patients with CR or PR as the best response during the initial treatment had a longer PFS (HR: 0.37, 95% CI; 0.19-0.73, P= .004) and OS (HR: 0.45, 95%CI: 0.23-0.87, P= .02) than those with best objective response as SD, PD or unknown.
      Figure 2
      Figure 2Survival outcomes in the discontinued group and rechallenged group. (A) Progression-free survival. (B) Overall survival.
      Table 3Multivariate Cox Regression Analysis for Progression Free Survival and Overall Survival
      CovariatePFSOS
      HR (95% CI)P-valueHR (95% CI)P-value
      Rechallenge0.87 (0.45–1.71)0.691.10 (0.57-2.15).77
      Age1.01 (0.97–1.05)0.561.02 (0.98-1.06).32
      Male gender (vs. female)1.38 (0.74–2.56)0.311.41 (0.76-2.63).28
      White ethnicity (vs. non-white)0.51 (0.23–1.13)0.100.65 (0.29-1.46).30
      PD-L1 expression ≥50% (vs. <50%)0.70 (0.34–1.42)0.320.59 (0.28-1.22).15
      PD-L1 unknown (vs. <50%)1.53 (0.71–3.28)0.281.71 (0.78-3.75).18
      ECOG score 1 (vs. 0)0.63 (0.29–1.34)0.230.76 (0.34-1.66).49
      ECOG score ≥2 (vs. 0)1.13 (0.45–2.84)0.791.35 (0.52-3.52).54
      Best OR prior to initial irAEs as CR or PR (vs. SD+PD+NE)0.37 (0.19–0.73)0.0040.45 (0.23-0.87).02
      Initial grade 3 irAE (vs. 2)1.02 (0.52–2.00)0.961.16 (0.59-2.29).66
      Initial grade 4 irAE (vs. 2)1.82 (0.38–8.70)0.453.16 (0.63-15.71).16
      Abbreviations: CR = complete remission; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio; irAE = immune-related adverse event; NE = not evaluable; OR = objective response; OS = overall survival; PFS = progression-free survival; PD = progressive disease; PR = partial response; SD = stable disease.
      Furthermore, after stratifying the data by ORR status, there was no statistically significant differences between rechallenge and discontinued groups for both PFS and OS with each ORR stratum. Among the 44 patients who had CR or PR during initial treatment, no significant differences were found in PFS and OS (P= .10 and 0.84, for PFS and OS, respectively) (Supplemental Figure 2A and 2C). Moreover, among the 55 patients who didn't achieve CR or PR prior to the initial irAEs, PFS and OS were similar in the rechallenged and discontinued groups (P= .30 and 0.56, for PFS and OS, respectively) (Supplemental Figure 2B and 2D).

      Discussion

      In this retrospective study, we analyzed data from stage IV NSCLC patients receiving ICI therapy at a single cancer institution over a 6-year period. We found that 99 (9.4%) patients experienced a grade≥ 2 irAE that led to treatment interruption, and more than half of them had treatment permanently discontinued due to irAEs. Among the 40 patients who underwent rechallenge, 20 (50%) developed recurrent grade≥ 2 irAEs.
      In real-world settings, clinicians tend to rechallenge patients with less severe irAEs. This is consistent with our findings. Patients in the rechallenged group had less severe initial irAEs with the majority grade 2 (80%). The initial irAEs occurred more commonly in the first-line treatment settings, were more manageable with less intravenous corticosteroid use and less irAE-related hospitalizations. Immune-related pneumonitis are less likely to be rechallenged, and cardiac and neurologic irAEs are usually not rechallenged due to life-threatening risk. In our study, the incidence of immune-related pneumonitis was significantly higher in the discontinued group. Also, 1 patient with grade 2 pericarditis and another with grade 3 Guillain-Barré syndrome were not rechallenged. This reflects physicians’ judgment in the real-world settings, where cautions are taken into decision making for ICI retreatment vs. permanent discontinuation.
      Overall, after rechallenging with the initial ICI, we found that 60% of patients had a recurrence of second irAEs of any grade, which was comparable with prior studies with reported range of 49% to 55%.
      • Simonaggio A
      • Michot JM
      • Voisin AL
      • et al.
      Evaluation of readministration of immune checkpoint inhibitors after immune-related adverse events in patients with cancer.
      ,
      • Santini FC
      • Rizvi H
      • Plodkowski AJ
      • et al.
      Safety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC.
      ,
      • Pollack MH
      • Betof A
      • Dearden H
      • et al.
      Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma.
      37.5% of patients had recurrence of identical irAEs, while de-novo irAEs occurred in 17.5% of patients. Compare with other irAEs, the recurrence rates for colitis/diarrhea, dermatitis/rash, hepatitis and pneumonitis were higher after the rechallenge. Dolladill et al. retrospectively analyzed 452 patients with irAE-related ICI treatment interruption who resumed the initial ICI regimen using data acquired from VigiBase and reported a 28.8% recurrence rate of the same irAEs.
      • Dolladille C
      • Ederhy S
      • Sassier M
      • et al.
      Immune checkpoint inhibitor rechallenge after immune-related adverse events in patients with cancer.
      Santini et al. examined 68 patients with NSCLC who developed irAE with anti-PD-L1 cessation, and found that, of the 38 patients who were rechallenged, 52% experienced recurrence of irAEs with 26% identical and 26% de-novo irAEs.
      • Santini FC
      • Rizvi H
      • Plodkowski AJ
      • et al.
      Safety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC.
      With regard to the safety of ICI rechallenge, our study showed that rechallenge was associated with a relative high-risk (50%) of the recurrence of grade≥ 2 irAEs. This finding differed from the findings reported by Allouchery et al.
      • Allouchery M
      • Lombard T
      • Martin M
      • et al.
      Safety of immune checkpoint inhibitor rechallenge after discontinuation for grade≥ 2 immune-related adverse events in patients with cancer.
      In their study, 180 patients with varying types of cancer developed grade≥ 2 irAEs necessitating ICI interruption. After the rechallenge, 61.1% of the patients experienced no recurrent grade ≥ 2 irAEs. Such discrepancy could be related to under reporting of recurrent irAEs in their study, in which data were collected from a spontaneous reporting pharmacovigilance database. In our study, no grade 4 irAEs or irAE-related death occurred after retreatment. The recurrence rates for grade 3 irAE was 17.5%, which was comparable to the rate of initial grade 3 irAEs (20%) in the rechallenged group, indicating that the second irAEs were not more severe than the initial irAEs. Immunosuppressive treatments for the initial irAEs may have a ‘spill-over’ effect, leading to protection against severe recurrent irAEs after rechallenging.
      • Park R
      • Lopes L
      • Saeed A.
      Outcomes following immunotherapy re-challenge after immune-related adverse event: systematic review and meta-analysis.
      We also found that the recurrence of irAEs was more likely if the initial irAEs were still present upon rechallenging, while the severity/duration of initial irAE or duration of corticosteroid use for initial irAE was not associated with recurrent irAEs after rechallenge. Our study suggests that rechallenge can be performed under close monitoring, ideally, after the initial irAEs have completed resolved.
      In the rechallenged group, the time to the initial irAE was comparable between patients with recurrent irAEs and those without any recurrence. This finding differs from prior studies. Allouchery et al. observed a longer duration of the time to initial irAEs in patients with irAE recurrence compared to those without after ICI rechallenge.
      • Allouchery M
      • Lombard T
      • Martin M
      • et al.
      Safety of immune checkpoint inhibitor rechallenge after discontinuation for grade≥ 2 immune-related adverse events in patients with cancer.
      On the contrary, Simonaggio et al. reported a shorter duration of the time to initial irAEs in patients with irAE recurrence.
      • Simonaggio A
      • Michot JM
      • Voisin AL
      • et al.
      Evaluation of readministration of immune checkpoint inhibitors after immune-related adverse events in patients with cancer.
      Such discrepancy could be related to differences in cancer types, ICI regimen, and varying types of irAEs.
      Rechallenged or not, the ORRs were improved in both groups after the initial irAEs, which raised the question of the benefit of rechallenge. Prior studies have suggested that patients with irAEs tend to have high response rates and favorable outcomes after ICI discontinuation.
      • Horvat TZ
      • Adel NG
      • Dang TO
      • et al.
      Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center.
      Patients with ongoing stable or responding disease could potentially monitor off immunotherapy, avoiding risks of rechallenge-related irAEs. In our study, the PFS was statistically significant longer in the rechallenged group, which appears that rechallenge improves PFS. However, after stratifying the cohort by best objective repones prior to the initial irAE, this difference disappeared. In multivariate analysis, the only variable that contribute to a longer PFS was the initial best objective response prior to the initial irAEs. We noted a higher proportion of patients with CR and PR as the best objective response during the initial treatment period in the rechallenged group. In real-world practice, clinicians tend to rechallenge patient who has had a good response to ICIs after resolving of the initial irAEs, leading to a better PFS with the impression that rechallenge can improve PFS. However, rechallenge or not, the improvement of PFS actually relies on the initial response to ICIs.
      OS is one of the most efficient tools used to evaluate treatment response in cancer patients. Whether being rechallenged or not, the survival outcomes of ICI rechallenge and discontinuation were similar. Our data suggested that ICI discontinuation is often the best strategy after grade≥ 2 irAEs, especially after severe and life threatening irAEs.
      This study has several limitations. First, as it was a retrospective study, some mild second irAEs may be underreported. Second, although focusing exclusively on patients with stage IV NSCLC mitigated confounding and heterogeneity, it also limited the generalizability to other malignancies. Third, the study sample size is relatively small, again limiting the generatability of the findings. Forth, we didn't consider patient outcome in the discontinued group with further treatments after ICI was permanently discontinued, as patients who received alternative treatment might have different survival outcomes compared to patients who were only on surveillance. Fifth, the decision to rechallenge was primarily based on the treating oncologists. To rechallenge or not to after improvement of non-life-threatening but bothersome grade 2 irAE was physician and patient-specific. Finally, all but 2 patients were rechallenged with the initial ICI regimen, the efficacy and safety of retreatment with a different type of ICI was not evaluated.
      To rechallenge or not to is a dilemma every clinician facing when severe irAEs have resolved. Our study provides real-world data on the rechallenge safety and efficacy in stage IV NSCLC patients after developing grade≥2 irAEs. Our results shed light on the feasibility of permanent ICI discontinuation, since patient survival outcomes are affected mainly by the initial best objective response, not by rechallenge. Future prospective studies are warranted to further validate our results.

      Conclusions

      The survival outcomes of ICI rechallenge and discontinuation were similar. ICI discontinuation is a feasible strategy after grade≥ 2 irAEs, especially after severe and life-threatening irAEs. Rechallenge was associated with a relative high risk of second grade≥ 2 irAEs. However, the second irAEs were not more severe than the initial irAEs. Rechallenge can be performed under close monitoring, ideally, after complete resolution of the initial irAEs. Many questions remain unanswered surrounding immunotherapy rechallenge. Further prospective studies are required to further evaluate outcomes of ICI rechallenge in the setting of previous irAEs.

      Clinical Practice Points

      • Grade ≥ 2 irAEs often require ICI discontinuation. The decision to resume ICI treatment often remains challenging. Data regarding the safety and efficacy of ICI rechallenge after a grade≥ 2 irAE are limited.
      • In this retrospective study, rechallenge was associated with a relative high risk of second grade≥ 2 irAEs. However, the second irAEs were not more severe than the first.
      • The risk of second irAEs was less if the initial irAEs were resolved upon rechallenge. Rechallenge can be performed under close monitoring, ideally, after the initial irAEs have completed resolved.
      • After multivariate adjustment, OS and PFS were comparable in patients who had ICI rechallenge and those who did not. The best objective response prior to the initial irAEs was the only variable affecting OS and PFS.
      • This report shed light on the feasibility of permanent ICI discontinuation after grade≥2 irAEs, which will help physicians with clinical decision making.

      Author Contributions

      M.G.: Conceptualization, Methodology, Investigation, Data Curation, Writing - original draft, Visualization, A.V.: Methodology, Supervision, Writing - Review & Editing, X.Y.: Methodology, Formal analysis, Review, Editing, G.V.: Supervision, Resources, Review, Editing, G.T.: Conceptualization, Methodology, Investigation, Data Curation, Supervision, Writing - Review & Editing, Project Administration

      Acknowledgments

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Disclosure

      The authors have stated that they have no conflicts of interest.

      Appendix. Supplementary materials

      • Supplement Figure 2. A. PFS in patients with complete response or partial response as the best objective response prior to the initial irAEs. B. PFS in patients with stable disease, progressive disease or not evaluable as the best objective response prior to the initial irAEs. C. OS in patients with complete response or partial response as the best objective response prior to the initial irAEs. D. OS in patients with stable disease, progressive disease or not evaluable as the best objective response prior to the initial irAEs.

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