Toxicities of PD-1/PD-L1 Inhibitors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

BackgroundImmunotherapy, especially immune-checkpoint inhibitors (PD-1 and PD-L1 inhibitors), is now one of the mainstays of cancer treatment. Several studies have analyzed treatment-related toxicities of immunotherapy. However, small sample size, rough and unspecific stratification, and lack of comparison (pure sing-arm studies) are common limitations. Detailed organ- and system-specific toxicities remain not clear enough. MethodsWe systematically searched PubMed, Embase, Cochrane Library, Web of Science and others (CNKI), from database inception to Mar 31, 2020, for randomized controlled trials (RCTs) related to PD-1/PD-L1 inhibitors that had available toxicity data. We excluded non-randomized trials. The primary endpoint was to assess the difference in the incidences of toxicities between cancer patients who did and did not receive PD-1/PD-L1 inhibitors. We calculated the pooled relative risks (RRs) and corresponding 95% confidence intervals (95% CIs) using a random-effects model and assessed the heterogeneity between different groups. The subgroup analyses were conducted based on toxicity grade (severity), system and organ, treatment regimens in the intervention arm and control arm, PD-1/PD-L1 inhibitor drug type, and cancer histotype. We applied the five-point Jadad ranking system to evaluate the quality of the selected studies. We performed multivariate meta-regression analyses to explore the proportion of between-study variance. FindingsA total of 29 eligible RCTs including 8067 patients were selected for the meta-analysis based on specified inclusion and exclusion criteria. Patients treated with PD-1/PD-L1 inhibitors were at lower risks of overall toxicities (all grades: RR 0.91, 95% CI 0.89-0.92; grade 3[~]4: RR 0.76, 95% CI 0.74-0.78), including gastrointestinal toxicity (all grades: RR 0.68, 95% CI 0.60-0.77; grade 3[~]4: RR 0.71, 95% CI 0.43-1.20), hematologic toxicity (all grades: RR 0.66, 95% CI 0.51-0.85; grade 3[~]4: RR 0.55, 95% CI 0.37-0.83), and treatment event leading to discontinuation (all grades: RR 0.78, 95% CI 0.72-0.84; grade 3[~]4: RR 0.58, 95% CI 0.49-0.67); but were at higher risks for respiratory toxicity (all grades: RR 1.74, 95% CI 1.33-2.28; grade 3[~]4: RR 1.92, 95% CI 1.45-2.55) and endocrine toxicity (all grades: RR 1.70, 95% CI 0.62-4.69; grade 3[~]4: RR 1.29, 95% CI 0.45-3.69). The subgroup analyses indicated that when compared with the control, toxicity comparison tendency for PD-1/PD-L1 inhibitors varied with the toxicity grade, affected system and organ, treatment regimens in the intervention arm and control arm, drug type, and cancer histotype. The male-female ratio was a statistically significant variable in the Meta-Regression analysis (I2=89.1,{tau} 2=0.01, and P=0.001). InterpretationFor most toxicity types based on system and organ, the incidence proportions for patients in the intervention arm were lower than those in the control arm, which suggested the general safety of PD-1/PD-L1 inhibitors against conventional chemotherapy and CTLA-4 inhibitors. However, for some specific toxicities including respiratory, cutaneous, and endocrine toxicities, the case was the opposite. The toxicity grade, system and organ, treatment regimens, drug type, and cancer histotype were all influencing factors. To our knowledge, this was by far the most comprehensive meta-analysis of RCTs on toxicities of immune-checkpoint inhibitors. Future research should focus on taking effective targeted measures to decrease the risks of different toxicities for different patient populations. Author ContributionsConceptualization, Xiangyi Kong, Yi Fang, Jing Wang; Data Collection, Xiangyi Kong, Li Chen; Methodology, Lin Zhang, Zhihong Qi, Yulu Liu; Supervision, Lin Zhang, Ryan J Sullivan; Writing - original draft, Xiangyi Kong, Lin Zhang; Writing - review & editing, Ryan J Sullivan, Xiangyi Kong, Lin Zhang. All authors have read and agreed to the published version of the manuscript. FundingThis work was supported by the Beijing Municipal Natural Science Foundation (No. 7204293 and No. 19G10077), the Special Research Fund for Central Universities, Peking Union Medical College (No. 3332019053), the Beijing Hope Run Special Fund of Cancer Foundation of China (No. LC2019B03 and No. LC2019L07), the Natural Science Foundation of China (No. 81872160), and National Key R&D Program of China (No. 2018YFC1315000 and No. 2018YFC1315003). The funders have no conflicts of interests. AcknowledgmentsNone. Conflicts of InterestThe authors declare no conflict of interest. Ethical ApprovalThe analysis followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College institutional review board approved this study as exempt. RegistrationWe registered the research protocol with PROSPERO (registration number CRD42019135113). Copyright(C) 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. O_TEXTBOXResearch in context Evidence before this studyPD-1/PD-L1 inhibitors have increasingly become a mainstay of cancer treatment in recent years. Growing evidence supports the existence of a different pattern of toxicities for PD-1/PD-L1 inhibitors in comparison with the conventional chemotherapy. However, the organ- and system-specific toxicity spectrum remained not clear enough. We hypothesized that the types and severities of such toxicities varied with the agents used as well as the cancer histotypes. We systematically searched PubMed, Embase, Cochrane Library, Web of Science and others (CNKI), from database inception to Mar 31, 2020, for randomized controlled trials (RCTs) related to PD-1/PD-L1 inhibitors that had available toxicity data. The search terms included "PD-1", "programmed death receptor 1", "PD-L1", "programmed cell death 1 ligand 1", "immunotherapy", "immune checkpoint inhibitor", "durvalumab", "avelumab", "ipilimumab", "tremelimumab", "nivolumab", "pembrolizumab", "atezolizumab". A few previous meta-analyses investigated the incidences of immunotherapy-related toxicities among a variety of cancer histotypes, drugs, and dosing schedules. However, most of them were single-arm analyses, thus we could not conclude whether the toxicity incidence was higher or lower than patients who did not receive PD-1/PD-L1 inhibitors. Also, their stratification standards were easy and rough, hence not sufficient enough to provide a detailed toxicity spectrum. Added value of this studyTo the best of our knowledge, our study was by far the most comprehensive meta-analysis of randomized controlled trials (RCTs) on toxicities of PD-1 and PD-L1 inhibitors, providing evidence of a significant difference in the toxicities in PD-1/PD-L1 inhibitors and the control. Using published data from 29 RCTs, for more than 15162 patients with several types of advanced cancers, we showed that for most toxicity types, the incidence proportions for patients in the intervention arm were lower than those in the control arm, which suggested the general safety of PD-1/PD-L1 inhibitors. However, for some specific toxicities such as respiratory, cutaneous, and endocrine toxicities, the case was the opposite. The toxicities varied with the toxicity-grade, system and organ, treatment regimens, drug type, and cancer histotype. Implications of all the available evidenceOur findings have several potential implications for clinical practice and future research. It is interesting that there are differences in the toxicity profiles in patients treated with PD-1/PD-L1 inhibitors based on specific drug types and cancer histotypes. Comparing with the control, when administering PD-1/PD-L1 inhibitors, possible respiratory toxicities (cough and dyspnea), mild cutaneous toxicities (pruritus, rash, and vitiligo), and endocrine toxicity (hypothyroidism and hyperthyroidism) should be given more attention. For instance, patients treated with pembrolizumab were more likely to experience rash, hepatitis, and pneumonitis than nivolumab; patients treated with PD-L1 inhibitors were at higher risks for developing cough and colitis. The first future research direction is to conduct a further meta-analysis to assess the heterogeneity of PD-1/PD-L1 inhibitor toxicities between different sexes, ages, races and Eastern Cooperative Oncology Group (ECOG) scores to obtain a better and unbiased estimation of the toxicities. The second direction should focus on taking effective targeted measures to decrease the risks of different toxicities for different patient populations. C_TEXTBOX