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Immune Checkpoint Inhibitors Associated with Lower Risk of Developing Severe and Any Adverse Events Compared to Chemotherapy

Results from the largest and most comprehensive meta-analysis across multiple primary solid tumours
16 Jan 2020
Cytotoxic Therapy;  Immunotherapy

Results from a meta-analysis of 22 clinical trials of 12,727 included patients with advanced solid tumours reveal that those treated with immune checkpoint inhibitors were less likely to develop severe adverse events than those receiving chemotherapy. Fewer terminations due to adverse events or deaths due to adverse events occurred in the immunotherapy group. Fatigue and diarrhoea were more likely to occur in patients treated with chemotherapy. The findings are published on 6 January 2020 in the Annals of Oncology.

A group of Canadian and US researchers wrote in the study background that multiple phase II and III clinical trials have demonstrated the efficacy of immune checkpoint inhibitors compared with traditional chemotherapeutic agents. In terms of safety outcomes, although results from these studies typically show fewer adverse events overall with immune checkpoint inhibitors, the severity and type of adverse events differed underlying mechanism of action of the two classes of drugs.

As the use of immunotherapy continues to expand and these agents are moved forward in treatment algorithms, a comprehensive understanding of how the incidence of adverse events and manifestations differ compared with chemotherapy is crucial for clinical practice. The primary aim of this systematic review and meta-analysis was to evaluate the burden of severe adverse events in patients with advanced solid tumours treated with anti-PD1, anti-PD-L1, and anti-CTLA4 agents compared to patients who received chemotherapy.

The authors performed a systematic review of studies indexed in Medline (PubMed), Embase, Web of Science, and the Cochrane Databases from January 2000 to February 2019. Randomised clinical trials comparing immune checkpoint inhibitors with standard-of-care chemotherapy in the treatment of advanced solid organ neoplasms were included if adverse events were reported as an outcome.

Primary outcome was adverse events at least grade 3 in severity. Secondary outcomes were proportion of overall adverse events, treatment discontinuation due to adverse events, deaths due to adverse events, and specific adverse events, in particular fatigue, diarrhoea, acute kidney injury, colitis, pneumonitis, and hypothyroidism. Paule–Mandel pooling and a random effects model were used to produce odds ratios (ORs) for measures of effects.

Among 10 598 abstracts screened, the authors included 22 studies involving 12 727 patients. In the immune checkpoint inhibitors group, 16.5% of patients developed an adverse event ≥ grade 3 in severity, compared with 41.09% in the chemotherapy arm (OR 0.26, 95% confidence interval [CI] 0.19–0.35, I2 = 92%).

Patients receiving immune checkpoint inhibitors also had lower odds of developing an adverse event overall (OR 0.35, 95% CI 0.28–0.44; I2 = 77%), terminating therapy due to an adverse event (OR 0.55, 95% CI 0.39–0.78, I2 = 80%), or dying from a treatment-related adverse event (OR 0.67, 95% CI 0.46–0.98, I2 = 0%).

When treated with chemotherapy versus immune checkpoint inhibitor therapy, patients more frequently experienced fatigue (25.10% versus 15.83%), diarrhoea (14.97% versus 11.13%), and acute kidney injury (1.79% versus 1.31%). However, colitis (1.02% versus 0.26%), pneumonitis (3.36% versus 0.36%), and hypothyroidism (6.82% versus 0.37%) were more common in those treated with immune checkpoint inhibitors.

The authors concluded that it is the largest and most comprehensive meta-analysis comparing the risk of adverse events with immune checkpoint inhibitors to chemotherapy across multiple primary solid neoplasms. Immunotherapy was associated with a significant reduction in the likelihood of developing severe, and any, adverse events compared with chemotherapy. In addition, patients receiving immune checkpoint inhibitor therapy had reduced odds of death from an adverse event compared with chemotherapy. However, adverse events with immune-mediated mechanisms are more common in patients treated with immune checkpoint inhibitors and require formal clinical monitoring.

No funding was received to support the publishing of this study.



Magee DE, Hird AE, Klaassen Z, et al. Adverse event profile for immunotherapy agents compared with chemotherapy in solid organ tumors: a systematic review and meta-analysis of randomized clinical trialsAnnals of Oncology; Published online 6 January 2020.https://doi.org/10.1016/j.annonc.2019.10.008 

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