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.

Little 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. We 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. A 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). ICI rechallenge after irAEs showed lower safety and similar efficacy outcomes compared with initial ICI treatment. PROSPERO, identifier CRD42020191405.

Zhao Q ，Zhang J ，Xu L ，Yang H ，Liang N ，Zhang L ，Zhang F ，Zhang X ... -  《Frontiers in Immunology》

Safety and efficacy of retreatment with immune checkpoint inhibitors in non-small cell lung cancer: a systematic review and meta-analysis.

Retreatment with immune checkpoint inhibitors (ICIs) might be a subsequent therapeutic option for patients with non-small cell lung cancer (NSCLC) who discontinued initial ICIs treatment because of disease progression, immune-related adverse events (irAEs) or completion of a fixed course, yet little evidence exists on the safety and efficacy of ICIs retreatment to support this strategy. We searched PubMed, Web of Science, Embase, Cochrane and major meeting libraries for articles about ICIs retreatment in NSCLC for systematic review and meta-analysis. The outcomes included objective response rate (ORR) and disease control rate (DCR) for efficacy and the incidence of all-grade and high-grade irAEs for safety. ICIs rechallenge implies retreatment that can be applied to patients who progressed, while ICIs resumption refers to retreatment for patients who discontinued prior treatment due to an irAE or completion of a fixed course of immunotherapy. Eighteen studies were enrolled in our analysis. The pooled ORR and DCR of ICIs retreatment were respectively 20% and 54%. ICIs retreatment was associated with a decrease in ORR and DCR compared to prior ICIs treatment (ORR: OR, 0.29, 95% CI: 0.14, 0.63, P=0.002; DCR: OR, 0.53, 95% CI: 0.28-0.99, P=0.05). The pooled ORR and DCR of ICIs rechallenge were 8% and 39%. ICIs rechallenge showed a lower ORR compared with initial ICIs treatment (P<0.05). ICIs resumption presented an ORR of 34% and a DCR of 71%, showing no significant difference in ORR and DCR compared with initial ICIs treatment (P>0.05). Retreated with the same type of ICIs as before showed no difference in ORR and DCR (P>0.05), while with different ICIs was associated with a decrease in ORR and DCR in contrast to initial treatment (P<0.05). The pooled incidence of all-grade and high-grade irAEs after ICIs retreatment in patients with NSCLC were separately 41% and 13% which showed a similar incidence compared with initial ICIs treatment (P>0.05). Retreatment with ICIs is feasible for patients with NSCLC in consideration of its encouraging efficacy and tolerable safety, especially in resumption with ICIs. When it comes to ICIs rechallenge, it is necessary to accurately identify the potential targeted beneficiary population. More large-scale prospective studies are warranted to confirm our discoveries. More attention could be paid to further exploring the efficacy and safety of retreatment concurrently with ICIs and chemotherapy.

Cai Z ，Zhan P ，Song Y ，Liu H ，Lv T ... -  《-》

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》

Switching administration of anti-PD-1 and anti-PD-L1 antibodies as immune checkpoint inhibitor rechallenge in individuals with advanced non-small cell lung cancer: Case series and literature review.

Based on several phase III studies, immune checkpoint inhibitors (ICIs) are essential and promising drugs for the treatment of non-small cell lung cancer (NSCLC). However, in patients previously treated with ICI, the efficacy and safety of rechallenging the same or another type of ICI inhibitor remain unclear. Moreover, clinical data about the efficacy of switching the administration of anti-programmed death-1 (PD-1) antibodies (e.g. nivolumab, pembrolizumab) and anti-programmed death-ligand 1 (PD-L1) antibodies (e.g. atezolizumab) as ICI rechallenge are limited. Thus, the current study aimed to evaluate the efficacy and safety of such treatment strategy in NSCLC patients. We retrospectively reviewed the medical records of 17 patients with advanced or recurrent NSCLC who received both anti-PD-1 and anti-PD-L1 antibodies during their clinical courses. Among the 17 patients, one (5.9%) and nine (52.9%) achieved partial response and stable disease, respectively, after ICI rechallenge. The median progression-free survival of ICI rechallenge in these patients was 4.0 (range: 0.4-8.0) months, and the median overall survival from the start of the initial ICI was 31.0 (range: 7.6-46.8) months. Of the 10 patients who developed immune-related adverse events (irAEs) during the first ICI treatment, five presented with these events after the readministration of ICI. Among them, four experienced relapsed irAEs and two patients had pneumonitis, which is a grade 3 or higher irAE. Almost all irAEs during the rechallenge treatment were manageable. Switching the administration of anti-PD-1 and anti-PD-L1 antibodies as ICI rechallenge could be a treatment option for some NSCLC patients. • Significant findings of the study In this study, switching the administration of anti-PD-1 and anti-PD-L1 antibodies as ICI rechallenge could be an effective and safe treatment option for some patients with advanced or recurrent NSCLC. • What this study adds Switching the administration of ICI may increase the efficacy of readministration. However, the mechanism is unknown. Thus, further accumulation of cases is required, and extensive investigations must be conducted to elucidate the mechanism and benefits of such treatment.

Kitagawa S ，Hakozaki T ，Kitadai R ，Hosomi Y ... -  《-》

Immune Checkpoint Inhibitor Rechallenge After Immune-Related Adverse Events in Patients With Cancer.

Dolladille C ，Ederhy S ，Sassier M ，Cautela J ，Thuny F ，Cohen AA ，Fedrizzi S ，Chrétien B ，Da-Silva A ，Plane AF ，Legallois D ，Milliez PU ，Lelong-Boulouard V ，Alexandre J ... -  《-》