Rechallenge of immune checkpoint inhibitors: A systematic review and meta-analysis

https://doi.org/10.1016/j.critrevonc.2021.103434Get rights and content

Highlights

  • Rechallenge ICI is an active and feasible strategy.

  • Rechallenge ICI could be considered on an individual basis.

  • Prospective studies are needed to clarify the role of rechallenge ICI.

Abstract

Background

The role of immune checkpoint inhibitors (ICI) rechallenge in cancer patients is not defined. 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 definitive conclusions. Here we report the results of a meta-analysis evaluating efficacy and safety of ICI rechallenge.

Methods

PubMed, Embase, and Cochrane library were searched for studies reporting efficacy 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.

Introduction

Monoclonal antibodies directed against cytotoxic T-lymphocyte antigen 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 fixed duration course of treatment. After ICIs discontinuation, the opportunity of a retreatment with ICIs is debated, since the efficacy-safety balance of the rechallenge has not been yet clarified.

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 immunotherapy. 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 benefit 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 discontinued due to treatment completion, results from clinical trials suggest that another course of ICIs is feasible, but the amount of data is still quite limited to draw definitive conclusions (Herbst et al., 2020).

In the present systematic review, we assessed the available evidence on efficacy and safety of the rechallenge with ICIs in patients with solid tumors.

Section snippets

Search strategy and inclusion criteria

A systematic review was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.12 A bibliographical search was performed in Medline (PubMed), Embase, and Cochrane library—Cochrane Central Register of Controlled Trials (CENTRAL). The last search date was April 25th, 2021. The following terms were used in combination with Boolean operators (AND, OR, NOT): (PD-1 OR PD-L1 OR "immune checkpoint inhibitors" OR CTLA-4) AND (rechallenge OR

Results

Overall, after selection, 49 studies (n = 13,027 patients) were included in qualitative and quantitative pooled analysis (Abu-Sbeih et al., 2019; Alaiwi et al., 2020, Amode et al., 2017, Beaver et al., 2018, Bernard-Tessier et al., 2018, Bowyer et al., 2016, Chiarion-Sileni et al., 2014, Cybulska-Stopa et al., 2020, Dolladille et al., 2020, Fujisawa et al., 2018, Fujita et al., 2018, Giaj Levra et al., 2020, Gobbini et al., 2020, Gul et al., 2020, Gutzmer et al., 2017, Hamid et al., 2017,

Discussion

In the present analysis, among patients who had previously discontinued treatment due to disease progression or irAEs, rechallenge ICIs translated into an approximately 20 % ORR and, more interestingly, into a survival benefit as compared to patients who did not receive the rechallenge. Moreover, rechallenge has acceptable tolerability. In fact, the incidence of any grade and grade 3−4 irAEs in rechallenged patients was respectively 57.5 % and 21.3 %, and this is somewhat comparable to that

Conclusion

The present analysis suggests that rechallenge ICIs may represent a feasible and effective strategy for select patients with solid tumors who have previously discontinued ICIs due to disease progression or adverse events. However, the choice of rechallenge should be made weighing benefits and risks carefully on an individual basis, taking into account several factors including performance status, comorbidities, and preference of the patient, the response obtained with previous ICIs, the type

Declaration of Competing Interest

The authors report no declarations of interest.

Alessandro Inno, MD. Medical oncologist at the Sacro Cuore Hospital in Negrar (VR), Italy. He is interested in immunotherapy for cancer disease.

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    Alessandro Inno, MD. Medical oncologist at the Sacro Cuore Hospital in Negrar (VR), Italy. He is interested in immunotherapy for cancer disease.

    Giandomenico Roviello MD PHD. Assistant Professor at the University of Florence. He is interested in immunotherapy for cancer disease.

    Antonio Ghidini, MD. Medical oncologist at Casa di cura Igea in Milan, Italy. Author of 44 systematic review and meta-analysis about soldi tumors.

    Andrea Luciani, MD. He is the chief of medical oncology unit at ASST Bergamo ovest, Treviglio (BG), Italy. Skilled in oncogeriatry and lung cancer.

    Martina Catalano, MD. She is a resident physician in medical oncology at the university of Florence.

    Stefania Gori, MD. She is the chief of medical oncology at the Sacro Cuore Hospital in Negrar (VR), Italy. She was a past president of AIOM society.

    Fausto Petrelli, MD. Medical oncologist at ASST Bergamo ovest, Treviglio (BG), Italy. He is author of more than 200 systematic review and meta-analysis.

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