Rechallenge of immune checkpoint inhibitors: A systematic review and meta-analysis
Graphical abstract
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.
References (65)
- et al.
Patients with melanoma treated with an anti-PD-1 antibody beyond RECIST progression: a US Food and Drug Administration pooled analysis
Lancet Oncol.
(2018) - et al.
Outcomes of long-term responders to anti-programmed death 1 and anti-programmed death ligand 1 when being rechallenged with the same anti-programmed death 1 and anti-programmed death ligand 1 at progression
Eur. J. Cancer
(2018) - et al.
A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS)
Ann. Oncol.
(2015) - et al.
Efficacy of ipilimumab after anti-PD-1 therapy in sequential treatment of metastatic melanoma patients - Real world evidence
Adv. Med. Sci.
(2020) - et al.
Retrospective study of advanced melanoma patients treated with ipilimumab after nivolumab: analysis of 60 Japanese patients
J. Dermatol. Sci.
(2018) - et al.
Immunotherapy rechallenge after nivolumab treatment in advanced non-small cell lung cancer in the real-world setting: a national data base analysis
Lung Cancer
(2020) - et al.
Immune checkpoint inhibitors rechallenge efficacy in non–small-cell lung cancer patients
Clin. Lung Cancer
(2020) - et al.
Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity
Eur. J. Cancer
(2017) - et al.
Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma
Eur. J. Cancer
(2017) - et al.
Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab
Ann. Oncol.
(2017)
Safety and efficacy of nivolumab in patients with rare melanoma subtypes who progressed on or after ipilimumab treatment: a single-arm, open-label, phase II study (CheckMate 172)
Eur. J. Cancer
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
Ann. Oncol.
Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial
Lancet Oncol.
Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial
Lancet
Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study
Lancet Oncol.
Safety and efficacy of nivolumab in challenging subgroups with advanced melanoma who progressed on or after ipilimumab treatment: a single-arm, open-label, phase II study (CheckMate 172)
Eur. J. Cancer
Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma
Eur. J. Cancer
Resumption of immune checkpoint inhibitor therapy after immune-mediated colitis
J. Clin. Oncol.
Safety and efficacy of restarting immune checkpoint inhibitors after clinically significant immune-related adverse events in metastatic renal cell carcinoma
J. Immunother. Cancer
Immune-related adverse events (Irae) in cancer immune checkpoint inhibitors (ici) and survival outcomes correlation: to rechallenge or not?
Cancers
Anti-programmed cell death protein 1 tolerance and efficacy after ipilimumab immunotherapy: observational study of 39 patients
Melanoma Res.
Long-term outcomes and responses to retreatment in patients with melanoma treated with PD-1 blockade
J. Clin. Oncol.
Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy
Br. J. Cancer
Oncology meets immunology: the cancer-immunity cycle
Immunity
Ipilimumab retreatment in patients with pretreated advanced melanoma: the expanded access programme in Italy
Br. J. Cancer
Immune checkpoint inhibitor rechallenge after immune-related adverse events in patients with cancer
JAMA Oncol.
Retreatment with pembrolizumab in advanced non-small cell lung cancer patients previously treated with nivolumab: emerging reports of 12 cases
Cancer Chemother. Pharmacol.
Retreatment with Anti-PD-L1 antibody in advanced non-small cell lung cancer previously treated with Anti-PD-1 antibodies
Anticancer Res.
Real-world efficacy of atezolizumab in non-small cell lung cancer: a multicenter cohort study focused on performance status and retreatment after failure of anti-PD-1 antibody
Thorac. Cancer
Rechallenge patients with immune checkpoint inhibitors following severe immune-related adverse events: review of the literature and suggested prophylactic strategy
J. Immunother. Cancer
Long-term outcomes and retreatment among patients with previously treated, programmed death-ligand 1‒positive, advanced non‒small-cell lung cancer in the KEYNOTE-010 study
J. Clin. Oncol.
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Treatment Rechallenge With Immune Checkpoint Inhibitors in Advanced Urothelial Carcinoma
2023, Clinical Genitourinary CancerCitation Excerpt :Further, these results should be considered in the context of potentially greater motivation of patients with aUC to consider ICI rechallenge given the relatively limited therapeutic options. Prior literature additionally suggests potentially improved response rates35 and survival36 in patients with IRAEs in the context of ICI therapy. The results from our cohort seem consistent with this hypothesis, as all the patients (n = 4) who discontinued first ICI due to treatment-related toxicity had disease control at rechallenge however, additional data are needed to answer this question more definitively.
Immune checkpoint inhibitor-induced pure red cell aplasia: Case series and large‐scale pharmacovigilance analysis
2023, International ImmunopharmacologyCitation Excerpt :Moreover, among 15 patients, one patient was rechallenged with nivolumab with prednisone and experienced recurrence of PRCA [19]. To reduce the incidence of recurrent toxicity, some investigators have used an ICI-based rechallenge strategy combined with preventive immunosuppression [35]. In a recently published retrospective study of 20 patients with immune-related myositis, six patients initially received steroid coverage, one patient with severe atypical immune-related myositis also received methotrexate and intravenous immunoglobins, and no patients experienced recurrent myositis [36].
Drug allergy: A 2022 practice parameter update
2022, Journal of Allergy and Clinical ImmunologyCitation Excerpt :For grade 4 reactions rechallenge is typically considered contraindicated. Several studies have now looked at the recurrence of ICI toxicities with rechallenge with the same agent or same class of agent, or deescalation from dual ICI therapy to single therapy (eg, CTLA4/PD-1 inhibitor dual therapy to PD-1 therapy).547-551 The rates of recurrence with rechallenge with the same ICI have been ≤50% and more common with colitis, pneumonitis, and hepatitis.
Heterogeneous Outcomes of Immune Checkpoint Inhibitor Rechallenge in Patients With NSCLC: A Systematic Review and Meta-Analysis
2022, JTO Clinical and Research ReportsCitation Excerpt :Interestingly, our pooled analysis found that patients with irAE at initial ICI treatment had high therapeutic efficacy at ICI rechallenge among different reasons of initial ICI discontinuation (Fig. 4). Nevertheless, the ORR of ICI rechallenge in our NSCLC study is still lower than that in the pan-cancer studies.30,33 Although recent studies have begun to evaluate the clinical outcomes of ICI rechallenge in patients with cancer who had previously discontinued ICI treatment, the uncertain risks and benefits of ICI retreatment may impede the decision to resume ICI as an alternative therapy option in the clinical settings.34
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.