Critical Reviews in Oncology / Hematology 165 (2021) 103434 Available online 31 July 2021 1040-8428/© 2021 Elsevier B.V. All rights reserved. Rechallenge of immune checkpoint inhibitors: A systematic review and meta-analysis Alessandro Inno a , Giandomenico Roviello b, *, Antonio Ghidini c , Andrea Luciani d , Martina Catalano b , Stefania Gori a , Fausto Petrelli d a Medical Oncology, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar di Valpolicella, Verona, Italy b Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, viale Pieraccini, 6, 50139, Florence, Italy c Medical Oncology, Casa di cura Igea, Milano, Italy d Medical Oncology, ASST Bergamo Ovest, Treviglio, BG, Italy A R T I C L E INFO Keywords: Immune checkpoint inhibitors Solid tumors Rechallenge Outcome Meta-analysis ABSTRACT Background: The role of immune checkpoint inhibitors (ICI) rechallenge in cancer patients is not defned. When ICIs are discontinued due to treatment completion or toxicity, another course of ICIs is feasible in clinical practice, but the amount of data is still quite limited to draw defnitive conclusions. Here we report the results of a meta-analysis evaluating effcacy and safety of ICI rechallenge. Methods: PubMed, Embase, and Cochrane library were searched for studies reporting effcacy and safety of ICI rechallenge. Pooled analysis of response rate (ORR), median progression-free survival (mPFS) and median overall survival (mOS) were calculated. Results: A total of 49 studies were included in qualitative and quantitative pooled analysis Overall response rate, mPFS and mOS were 21.8 % (range 0–70 %), 4.9 months (range 0–19.1 months) and 15.6 months (range 5.1–39 months), respectively. Incidence of any grade and grade 34 adverse events were 52.2 % (range 4–100 %) and 21.5 % (range 0–97.8 %), respectively. In the subgroup of patients who had previously discontinued ICI because of disease progression ORR, mPFS and mOS were 15.2 %, 2.9 and 7.9 months. Patients who had previously discontinued ICI because of toxicity achieved an ORR of 44 % and a mPFS of 13.2 months with the rechallenge. Conclusions: Our results suggest that rechallenge ICI is an active and feasible strategy, and it could be considered on an individual basis. However, this analysis is based on non-randomized studies. Prospective studies are needed to clarify the role of rechallenge after disease progression or adverse events. 1. Introduction Monoclonal antibodies directed against cytotoxic T-lymphocyte an- tigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) or PD-1 ligand (PD-L1) are immune checkpoint inhibitors (ICIs) that represent now the cornerstone of treatment for many tumor types (Ribas and Wolchok, 2018). Usually, ICIs are administered until evidence of tumor progression, occurrence of severe toxicity, or completion of a fxed duration course of treatment. After ICIs discontinuation, the opportunity of a retreatment with ICIs is debated, since the effcacy-safety balance of the rechallenge has not been yet clarifed. When ICIs are discontinued due to tumor progression, there are no established strategies to overcome acquired resistance (Schoenfeld and Hellmann, 2020). A switch from one class of ICIs to another may represent an empirical attempt to restore tumor response to immuno- therapy. Also, mainly in case of oligoprogressive disease, treatment beyond progression possibly associated with local therapies to control progressive sites may represent a reasonable strategy to prolong beneft from ICI. When ICIs are discontinued due to immune-related adverse events (irAEs), once irAEs are fully recovered or meaningful improved, restarting ICIs could potentially improve tumor control but, on the other hand, may also increase the risk for occurrence of the same or different irAEs (Inno et al., 2017; Nakajima et al., 2019). When ICIs are dis- continued due to treatment completion, results from clinical trials sug- gest that another course of ICIs is feasible, but the amount of data is still quite limited to draw defnitive conclusions (Herbst et al., 2020). In the present systematic review, we assessed the available evidence on effcacy and safety of the rechallenge with ICIs in patients with solid * Corresponding author. E-mail address: giandomenicoroviello@hotmail.it (G. Roviello). Contents lists available at ScienceDirect Critical Reviews in Oncology / Hematology journal homepage: www.elsevier.com/locate/critrevonc https://doi.org/10.1016/j.critrevonc.2021.103434 Received 12 October 2020; Received in revised form 17 May 2021; Accepted 27 July 2021