Outcomes after resumption of immune checkpoint inhibitor therapy after high-grade immune-mediated hepatitis.

In the current study, the authors assessed the risks and outcomes of immune checkpoint inhibitor (ICI) rechallenge in patients with resolved grade 3 to 4 ICI hepatitis because current guidelines recommend permanent ICI discontinuation in these patients. The authors performed a retrospective cohort study from 2010 through 2019 of patients with melanoma who were treated with ≥1 ICIs and who recovered from grade 3 to 4 ICI hepatitis. The primary outcome was hepatitis recurrence and the secondary outcome was the development of any immune-related adverse event (irAE) requiring the discontinuation of ICI rechallenge. Best overall response and time to all-cause death were compared between the patients who did and those who did not undergo ICI rechallenge. Grading was performed using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Of the 102 patients with melanoma who developed high-grade ICI hepatitis, 31 underwent ICI rechallenge. Although 15 of 31 patients (48%) developed an irAE of any grade, only 6 patients (19%) required ICI discontinuation due to irAE severity (4 of 29 patients [14%] rechallenged with anti-PD-1 or anti-PD-L1 and 2 of 2 patients [100%] rechallenged with ipilimumab). Recurrent hepatitis accounted for 4 of these 6 cases. Rechallenged patients who did not require ICI discontinuation were found to be significantly less likely to receive ipilimumab rather than anti-PD-1 or anti-PD-L1 monotherapy (0% vs 33%; relative risk (RR), 0.1 [95% CI, 0.1-0.3; P = .032]) and significantly less likely to be rechallenged with their original ICI (8% vs 50%; RR, 0.2 [95% CI, 0.1-0.7; P = .038]). There was no difference noted with regard to best overall response or time to death between rechallenged and non-rechallenged patients. ICI therapy can be resumed in patients with melanoma who have recovered from grade 3 to 4 ICI hepatitis with a modest risk of serious irAEs. It remains unclear whether ICI retreatment improves clinical outcomes.

Li M ，Sack JS ，Rahma OE ，Hodi FS ，Zucker SD ，Grover S ... -  《-》

Patterns and outcomes of immune-related adverse events in solid tumor patients treated with immune checkpoint inhibitors in Thailand: a multicenter analysis.

Most immune-related adverse event (irAE) patterns and treatment guidelines are based on western clinical data. We evaluated the incidence and patterns of irAEs in patients treated with immune-checkpoint inhibitors (ICI) in Thailand. All solid tumor patients treated with ICIs were retrospectively reviewed in a multicenter analysis. The study aims to evaluate the incidence of irAEs and their characteristics, treatments, outcomes, and impact on survival. All irAEs were graded using the CTCAE version 4.0. Characteristics of irAEs including time to onset, duration of irAEs, specific treatments, and outcomes of irAEs were reviewed. The Chi-square or Fisher's exact test was used to compare variables. Overall survival (OS) was estimated by the Kaplan-Meier method, and compared by the log-rank test. A p-value < 0.05 was considered statistically significant. irAEs of any grade were observed in 98 of 414 patients (24%), whereas grades 3-4 irAEs were observed in 5.6%. The majority of patients (78%) were treated with monotherapy ICI (anti-PD1/PD-L1 92%). The most common all-grade irAEs were hypothyroidism (7.5%), hepatitis (6.5%), and rash (4.8%). Median onset of overall irAEs was 63 days. Pancreatitis and pneumonitis had the earliest onset at 30 and 34 days, respectively. ICIs were rechallenged in 68 of 98 patients with irAE. Eleven of sixty-eight patients (11.2%) with initial irAE had reoccurrence after ICI rechallenge. Based on a multivariate analysis, pre-existing hypothyroidism, ICI used in a clinical trial setting, and combinations of ICI/ICI were independent factors predicting irAE occurrence. Patients with irAE had a statistically significant longer overall survival (OS) when compared to patients without irAE (p = 0.019). A multivariate analysis revealed that occurrence of irAE was an independent prognostic factor for OS (HR 0.70, 95% CI 0.51-0.96; p = 0.028). irAE was commonly observed in Thai cancer patients treated with ICIs. Most irAEs were low-grade and manageable. Re-occurrence of irAE after re-challenging ICI was not uncommonly observed. Patients who experienced irAEs might have significantly longer OS compared to patients without irAEs. However, OS in this study should be interpreted with caution since it might be affected by various tumor types, treatment settings, dosing schedule, and ICI combinations.

Ngamphaiboon N ，Ithimakin S ，Siripoon T ，Sintawichai N ，Sriuranpong V ... -  《BMC CANCER》

Safety of immune checkpoint inhibitor rechallenge after discontinuation for grade ≥2 immune-related adverse events in patients with cancer.

Safety of rechallenge of immune checkpoint inhibitor (ICI) after grade ≥2 immune-related adverse events (irAEs) leading to ICI discontinuation remains unclear. All adverse drug reactions involving at least one ICI reported up to December 31, 2019 were extracted from the French pharmacovigilance database. Patients were included if they experienced at least one grade ≥2 irAE resulting in ICI discontinuation, with subsequent ICI rechallenge. The primary outcome was the recurrence of at least one grade ≥2 irAE in these patients after ICI rechallenge. We included 180 patients: 61.1% were men (median age of 66 years), 43.9% had melanoma and 78.9% were receiving anti-programmed cell death 1. First ICI discontinuation was related to 191 irAEs. After ICI rechallenge, 38.9% of the patients experienced at least one grade ≥2 irAE. Among them, 70.0% experienced the same irAE, 25.7% a distinct irAE, and 4.3% both the same and a distinct irAE. Lower recurrence rates of irAEs were associated with rechallenge with the same ICI treatment (p=0.02) or first endocrine irAEs (p=0.003). Gastrointestinal irAEs were more likely to recur (p=0.007). The median duration from ICI discontinuation to rechallenge and the severity of the initial irAE did not predict recurrent irAEs after ICI rechallenge (p=0.53 and p=0.40, respectively). In this study, 61.1% of the patients who discontinued ICI treatment for grade ≥2 irAEs experienced no recurrent grade ≥2 irAEs after ICI rechallenge. Although ICI rechallenge appears to be safe under close monitoring, it should always be discussed balancing usefulness of rechallenge, patient comorbidities and risk of recurrence of first irAE(s). Due to inherent bias associated with pharmacovigilance studies, further prospective studies are needed to assess risk factors that may influence patient outcomes after ICI rechallenge.

Allouchery M ，Lombard T ，Martin M ，Rouby F ，Sassier M ，Bertin C ，Atzenhoffer M ，Miremont-Salame G ，Perault-Pochat MC ，Puyade M ，French Network of Regional Pharmacovigilance Centers ... -  《Journal for ImmunoTherapy of Cancer》

Safety and Efficacy Outcomes in Immune Checkpoint Inhibitor-Treated Patients With Metastatic Urothelial Carcinoma Requiring Treatment Interruption or Discontinuation Due to Immune-Related Adverse Events.

Nizam A ，Rader RK ，Tzeng A ，Wei W ，Sheng IY ，Martin A ，Wee CE ，Gilligan TD ，Gupta S ，Ornstein MC ... -  《-》

Systematic review and meta-analysis efficacy and safety of immune checkpoint inhibitors in advanced melanoma patients with anti-PD-1 progression: a systematic review and meta-analysis.

More than half of melanoma patients taking first-line anti-PD-1 therapy either express transient or no response at all. The efficacy and safety of secondary treatments for these patients are still not well established. Here, we evaluate the efficacy and safety of different melanoma FDA-approved ICI modalities used in post-anti-PD-1 refractory settings. We searched the PubMed database and the ASCO meetings library for studies on advanced melanoma patients with cancer progression on anti-PD-1 therapy and were then treated with ipilimumab, nivolumab/ipilimumab combination, or retreated with anti-PD-1. Primary and secondary endpoints were efficacy and toxicity, respectively. Pooled estimates for each treatment group were obtained using a random or fixed effects model according to detected heterogeneity. Fourteen studies, of which 10 on ipilimumab, 2 on anti-PD-1 treatment, and 6 on combination therapies, were included, involving a total of 1460 patients. Twelve studies reported objective response rates (ORRs) and nine of them reported immune-related adverse events (irAEs). As for ORR, patients experienced a response that was inferior compared to the same therapy in treatment -naïve patients, with combination therapy having the best ORR of a pooled 23.08% (95% CI: 16.75% to 30.03%), followed by ipilimumab with a pooled ORR of 8.19% (95% CI: 5.78% to 10.92%). Survival data were also inferior in the ipilimumab cohort (mOS: 5.1 to 7.4 months) compared to ipilimumab in anti-PD-1 naive patients. As for grade 3/4 irAE occurrence, the ipilimumab cohort showed an estimate of 43.77% (95% CI 22.55% to 66.19%). Our findings provide the best current evidence that patients who progress on anti-PD-1 can still respond to different ICI modalities (ipilimumab with or without nivolumab, and retreatment or continuation beyond progression with anti-PD-1) with tolerable grade 3/4 irAEs. However, more prospective clinical trials are needed to confirm these results.

Alrabadi NN ，Abushukair HM ，Ababneh OE ，Syaj SS ，Al-Horani SS ，Qarqash AA ，Darabseh OA ，Al-Sous MM ，Al-Aomar SR ，Ahmed YB ，Haddad R ，Al Qarqaz FA ... -  《-》