Безопасность иммунных модуляторов точек контроля за пределами PD-1/PD-L1 и CTLA-4 в твердых опухолях: мета-анализ.

Introduction

Immune checkpoint blockade (ICB), including programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) blockade, has revolutionized cancer treatment and is now a standard of care for multiple types of solid tumors. 1 Despite these advancements, a substantial proportion of patients exhibit primary resistance or eventually develop resistance after an initial response. 2 , 3 To overcome these limitations, novel immunotherapeutic agents targeting alternative co-stimulatory and co-inhibitory immune checkpoints are under development. 4 Activation of co-stimulatory immune receptors, such as OX40, 4-1BB, glucocorticoid-induced tumor necrosis factor receptor (GITR), and inducible T cell costimulatory (ICOS), has been shown to enhance T cell activation and promote antitumor immunity. 5 Concurrently, several co-inhibitory immune checkpoints, such as T cell immunoglobulin and immunoreceptor-tyrosine-based-inhibitory-motif domain (TIGIT), lymphocyte activation gene-3 (LAG-3), and T cell immunoglobulin and mucin-domain containing-3 (TIM-3), have emerged as key regulators of immune suppression. 6 Multiple clinical trials are currently being conducted to assess the efficacy of agents targeting immune checkpoints to overcome resistance to anti PD-1/PD-L1 or CTLA-4 ICB. 7 For instance, the phase 2 to 3 RELATIVITY-047 trial ( NCT03470922 ) demonstrated that nivolumab with relatlimab, a human IgG4 LAG-3-blocking antibody, improved progression-free survival compared to nivolumab monotherapy in patients with previously untreated advanced melanoma, leading to the U.S. Food and Drug Administration approval. 8 , 9

Conventional ICB is known to cause adverse events (AEs) deemed to be immune-mediated, called immune-related adverse events (irAEs), which presents another critical challenge in ICB therapy. IrAEs are inflammatory toxicities that can affect multiple organ systems and are believed to result from reactivated cellular immunity. 10 While most irAEs are mild and self-limiting, severe cases can lead to life-threatening organ dysfunction and impact ongoing treatment. 11 , 12 The incidence and profile of irAEs associated with PD-1, PD-L1, and CTLA-4 blockades have been well-characterized; however, the safety profiles of novel immunotherapeutic agents remain poorly defined. 13 Additionally, as novel immunotherapy combinations are increasingly explored, a comprehensive understanding of their toxicity profiles is crucial, particularly given the higher incidence of irAEs with ICB combination therapy compared to monotherapy. 14 , 15

To address these gaps, we performed a systematic review and meta-analysis to report the safety profile of novel immunotherapeutic agents in patients with solid tumors. Our study aims to provide a comprehensive overview of the incidence and severity of irAEs as well as the impact of the addition of these agents to standard of care on the incidence of irAEs and to inform clinicians as these therapies progress toward broader clinical approval across multiple tumor types.

Methods

Search strategy and study selection

Database search was performed to identify eligible articles in PubMed/MEDLINE, Embase, and Web of Science, published up to December 1, 2024 ( Table S1 ). The protocol of this study was registered in PROSPERO (CRD42024628470) and conducted following the PRISMA guideline. 16 Clinical trials that evaluated agents targeting co-inhibitory checkpoints (B7-H3, CD47, TIGIT, LAG-3, and TIM-3) or co-stimulatory checkpoints (OX40, 4-1BB, CD27, ICOS, GITR, CD70, and CD40) in solid tumors and reported safety information were included. 17 We included phase 2 and 3 clinical trials, and phase 1 trials that reported safety results of agents administered at the recommended phase 2 dose. If several studies reported the results of the same clinical trial, an article that reported the latest safety outcomes was chosen for data extraction. Studies evaluating patients with hematological malignancies were excluded. Details of inclusion and exclusion criteria are available in Table S2 .

Data extraction and study outcome

Systematic review and data extraction were performed by 2 or more independent reviewers and any conflicts that arose among reviewers were resolved by a third reviewer. The Covidence web platform ( https://www.covidence.org/ ) was utilized to conduct the systematic review. From each eligible study, information on first author, publication year, cancer type, clinical setting, immunotherapy agents and their subclass based on mechanisms of action, treatment patterns such as monotherapy and combination with other agents, clinical trial phase, study design, the number of patients in the experimental and control arms, and the number of patients who developed AEs of interest, were collected. Outcomes of interest in this study were any AEs, treatment-related AEs (trAEs), and specific irAEs including pneumonitis, colitis, diarrhea, aspartate aminotransferase (AST) elevation, alanine aminotransferase (ALT) elevation, hepatitis, diabetes, hypophysitis, hyperthyroidism, hypothyroidism, adrenal insufficiency, nephritis, rash, arthralgia, anemia, and neutropenia. For each AE, the number of Common Terminology Criteria for Adverse Events (CTCAE) any-grade and grade 3-5 (G3-5) incidences was collected and analyzed. CTCAE versions were either 4.0 or 5.0 depending on each eligible trial. The definition of AEs was according to each clinical trial but usually as follows: any AEs: AEs that arise during the study period regardless of treatment; trAEs: AEs that were deemed associated with the study agents; irAEs: AEs with potential immune-mediated pathophysiology that arise during the treatment period regardless of the treatment drug attribution. AE information without clear information on these AE classifications was excluded from the analysis.

Statistical analysis

Among the eligible studies, we first performed a meta-analysis to evaluate the impact of adding either LAG-3 blockade or TIGIT blockade to the control arm treatment. In this analysis, studies with a design “LAG-3 or TIGIT blockade + Treatment X vs Treatment X” were chosen to accurately assess the add-on effect of these agents on AEs as performed in the previous studies. 12 , 18 The odds ratios (ORs) of AEs of interest were calculated from eligible studies and pooled using a random-effects model meta-analysis. To capture AE differences, multiple testing correction to account for testing of various AEs was not performed. Next, the incidences of targeted AEs were calculated from treatment arms evaluating immunotherapy agents, and pooled incidences with their 95% CI were reported for each immunotherapy subtype using a random-effects proportional meta-analysis. A meta-regression analysis was further performed to compare the incidences of AEs of interest and the predicted incidence of AEs as well as study-level ORs were reported in this analysis. Particularly, we compared AE incidences between co-inhibitory antagonists and co-stimulatory agonists as these strategies engage distinct immunological mechanisms. 19 Although heterogeneity exists within each categorization, co-inhibitory blockade generally acts to overcome peripheral immune tolerance, often leading to systemic autoimmunity, while co-stimulatory agonism is designed to enhance T-cell activation, which may skew the toxicity profile toward cytokine-mediated or enhanced inflammatory responses. 17

A P value of < .05 was considered statistically significant and heterogeneity among studies was evaluated using I 2 statistics with 50% or more considered high heterogeneity. All statistical analyses were performed in R (version 4.3.2) using publicly available packages (meta v8.0.2, dplyr v1.1.4, and metafor v4.8.0), without using any custom codes.

Quality and risk of bias assessment

The Cochrane Risk of Bias assessment tool was used to assess the quality of randomized controlled trials (RCTs) and the Newcastle Ottawa Scale (NOS) was used to evaluate the quality of non-RCTs, respectively. 20 , 21 Because the number of studies (maximum number: 4) included in the meta-analysis of 2-arm trials for assessing the add-on effect of LAG-3 or TIGIT blockade was limited, and the rest of the meta-analyses were performed to report the pooled incidences of AEs, publication bias assessment was omitted.

Results

Study characteristics

In total, the systematic review identified 27 clinical trials with 40 treatment cohorts comprising 3946 patients ( Figure 1 , Tables S3 and S4 ). 8 , 22-47 These studies assessed agents targeting in total of 10 immune checkpoints (B7-H3, LAG-3, TIGIT, CD47, OX40, CD137, TIM-3, CD40, CD27, ICOS). LAG-3 was the most common drug target evaluated in 11 studies, followed by TIGIT evaluated in 3 studies. In total, 19 trials evaluated these novel agents in the advanced or metastatic disease setting and 8 trials in the perioperative setting. Most studies were phase 1/2 or phase 2 trials, and 2 studies contained the phase 3 portion ( Table S4 ).

Meta-analysis of the contribution of LAG-3 or TIGIT blockade to adverse events

We first performed a meta-analysis to evaluate the contribution of LAG-3 or TIGIT blockade to the incidence of AEs. In total, 7 studies (LAG-3: n = 4; TIGIT: n = 3) comprising 2462 patients (LAG-3: n = 1271; TIGIT: n = 791) were included in this meta-analysis ( Table 1 ). Meta-analyses showed that the addition of LAG-3 blockade to the control arm therapy was associated with a comparative increase in G3-5 trAEs (OR = 1.79, 95% CI = 1.26 to 2.54, P = .001), G3-5 adrenal insufficiency (OR = 8.43, 95% CI = 1.04 to 68.37, P = .046), and any-grade adrenal insufficiency (OR = 4.81, 95% CI = 1.81 to 12.78, P = .002) and arthralgia (OR = 2.07, 95% CI = 1.29 to 3.30, P = .002). The addition of TIGIT blockade was correlated with increased any-grade rash (OR = 2.32, 95% CI = 1.01 to 5.34, P = .048), but was not associated with an increase in any G3-5 AEs ( Figure 2 ).

Meta-analysis of the incidence rates of adverse events across immunotherapy subtypes

Absolute incidence rates of a variety of AEs were pooled using the proportional meta-analysis, and 24 studies from 22 articles, comprising 30 treatment cohorts with 2462 patients, were included in this analysis ( Tables S3 and S4 ). The incidence rates of grade 3-5 any AEs ranged from 45.5% to 66.7% in agents targeting co-inhibitory checkpoints, and 18.0% to 50.8% in agents targeting co-stimulatory checkpoints, respectively. G3-5 trAEs occurred in 6.1% to 21.2% in most agents targeting co-inhibitory checkpoints except for CD47 blockade with a 60.0% incidence of G3-5 trAEs ( Table 2 ). Incidence rates of each irAE varied across all immunotherapy agents. Major G3-5 AEs are as follows with details of both any-grade and G3-5 AEs available in Tables 2 and 3 : G5 trAEs (0.9%-2.9%, highest in CD47 blockade), G3-5 pneumonitis (0.5%-5.5%, highest in TIM-3 blockade), G3-5 colitis (0.2%-5.4%, highest in LAG-3 blockade), G3-5 diarrhea (0.4%-3.8%, highest in OX40 agonist), G3-5 AST elevation (1.1%-7.4%, highest in LAG-3 blockade), G3-5 ALT elevation (0.9%-7.4%, highest in LAG-3 blockade), G3-5 hepatitis (1.5%-5.5%, highest in TIM-3 blockade), G3-5 adrenal insufficiency (1.7%-8.4%, highest in TIGIT blockade), G3-5 rash (0.8%-18.4%, highest in CD40 agonists), G3-5 myocarditis (0.7%-0.8%), and G3-5 arthralgia (0.4%-1.9%, highest in LAG-3 blockade). Overall, the incidence rates of G3-5 trAEs and major G3-5 irAEs are not negligible, underscoring the need for vigilant monitoring when treating patients with agents targeting co-inhibitory or co-stimulatory immune checkpoints.

Meta-regression analysis comparing the incidences of adverse events between agents targeting co-inhibitory and co-stimulatory immune checkpoints

Study arm-level comparison was performed to evaluate the incidences of each AE between studies evaluating drugs targeting co-inhibitory and co-stimulatory checkpoints. Studies evaluating agents targeting co-stimulatory checkpoints demonstrated significantly higher incidences of G3-5 diarrhea (Study-level OR = 3.01, 95% CI = 1.13 to 8.03, P = .03) with low heterogeneity among studies ( I 2 = 0%) and significantly lower incidences of any-grade irAEs (Study-level OR = 0.19, 95% CI = 0.04 to 0.90, P = .04), any-grade hypothyroidism (study-level OR = 0.41, 95% CI = 0.2 to 0.86, P = .02), with high heterogeneity among studies ( I 2 = 87.6%, 65.2% for each), and any-grade arthritis (study-level OR = 0.52, 95% CI = 0.31 to 0.87, P = .01) with moderate heterogeneity among studies ( I 2 = 28.5%), respectively ( Table S5 ).

Summary of grade 5 adverse events

The incidence rate of grade 5 AEs was reported in 21 studies, including those reporting zero grade 5 AEs. Details of grade 5 adverse events were available in 8 studies with a total of 15 grade 5 events ( Table S6 ). Among these, pulmonary events such as pneumonitis, acute respiratory failure, and pulmonary embolism were seen in 7 cases. The majority of cases were reported from studies evaluating either LAG-3 blockade or TIGIT blockade due to a relatively larger number of studies and participants.

Quality and risk of bias assessment

Risk of bias assessment for RCTs and quality assessment for non-RCTs are summarized in Figure S1 and Table S7 . The overall quality of RCTs was good although 10 studies in 8 articles with an open-label design potentially carry a risk of reporting bias. Ten out of 15 non-RCTs had an NOS score of 6 or above, indicating that the majority of non-RCT studies were of good quality. The overall NOS score became low due to a single-arm trial design.

Discussion

Toxicity from ICB often disrupts ongoing systemic antineoplastic therapy and potentially impairs the quality of life in patients with cancer, and thus, understanding safety profiles of ICB agents is imperative for physicians to actively monitor for signs of irAEs and proactively manage irAEs to prevent severe outcomes. The incidences of specific irAEs such as colitis, rash, and thyroid-related AEs have been well documented; for example, CTLA-4 blockade tends to cause colitis more frequently than PD-1/PD-L1 blockade. 15 The recent development of newer agents targeting other immune checkpoints has demonstrated promising results, such as the development of LAG-3 blockade showing survival benefit when combined with PD-1 blockade in advanced melanoma, indicating that novel immunotherapy agents will be increasingly used for solid tumors over the next few years. 8 , 9 Our study reports incidence rates of various AEs from newer agents targeting immune checkpoints, thereby providing timely updated information on AEs from these agents to clinicians to prepare for further approvals of these agents. The non-negligible incidence rates of overall G3-5 trAEs and individual irAEs across the evaluated treatment regimens in our study underscore the essential need for rigorous safety monitoring in ongoing and future early-phase and phase 3 clinical trials, as well as in the clinical management of patients receiving recently approved treatments such as the combination of PD-1 and LAG-3 blockade.

Specifically, the addition of LAG-3 blockade to either PD-1 blockade monotherapy or PD-1 blockade plus chemotherapy was associated with an increase in both any-grade and G3-5 adrenal insufficiency. The incidences of adrenal insufficiency from PD-1/PD-L1 blockade and CTLA-4 blockade were reported to be 1.8% and 2.9%, respectively. 48 Additionally, dual ICB (PD-1 plus CTLA-4 blockade) was reported to cause any-grade adrenal insufficiency in about 4.8%-9.3% of cases, aligned with the pooled incidence of 5.2% (any-grade) and 1.7% (G3-5) from LAG-3 blockade-based therapy shown in our study. 48 , 49 Generally, LAG-3 blockade-based therapy is thought to be more tolerable than CTLA-4-based therapy, but this finding indicates that clinicians should vigilantly monitor for any signs of adrenal insufficiency such as nonspecific fatigue and electrolyte abnormalities while patients are treated with LAG-3 blockade therapy. 6 , 9 , 13

TIGIT blockade is another agent that has entered large phase 3 clinical trials compared to agents targeting other immune checkpoints. 6 However, studies such as the SKYSCRAPER-02 trial evaluating the addition of TIGIT blockade to chemoimmunotherapy in small cell lung cancer did not demonstrate a benefit in improving overall survival. 38 In our study, the addition of TIGIT blockade was associated with an increased incidence of any-grade rash only. Several studies have reported that the incidence of irAEs such as acute irAEs, endocrine-related AEs, and cutaneous AEs, was associated with longer survival in patients treated with PD-1/PD-L1 blockade and/or CTLA-4 blockade. 50-54 Several ongoing trials evaluating TIGIT blockade as well as translational findings from the completed clinical trials will further inform us of the reasons for limited efficacy as well as the mechanisms of irAEs from TIGIT blockade. 55

Cancer immunotherapy targeting immune checkpoints has been recognized as “tolerable” therapy compared to conventional chemotherapy. 56 After its efficacy was seen in patients with advanced disease, ICB has been evaluated in neoadjuvant and adjuvant settings, where it has also demonstrated an overall survival benefit in multiple cancer types. 57 , 58 However, utilizing ICB in the perioperative setting increases the risk of severe trAEs and overtreatment, and thus, patient selection is becoming more important. 12 In this study, G3-5 trAEs occurred in 6.1% to 21.2% in most agents targeting co-inhibitory checkpoints beyond PD-1/PD-L1 and CTLA-4, and 8 out of 27 trials were undertaken in the perioperative setting. Although it is not predictable at this moment whether novel agents would be approved as either neoadjuvant or adjuvant therapy, these findings imply and confirm that close observation for a variety of immune-mediated toxicities is still important in the perioperative setting. Findings from our study will further inform treating physicians about which irAEs should be carefully monitored for each novel immunotherapy agent.

The present study also investigated incidences of AEs between agents targeting co-stimulatory and co-inhibitory immune checkpoints and demonstrated that while agents targeting co-stimulatory checkpoints were associated with higher incidences of G3-5 diarrhea, drugs targeting co-inhibitory checkpoints were associated with lower incidences of any-grade irAEs, any-grade hypothyroidism, and any-grade arthritis at the study level. This observed pattern is consistent with AE differences between CTLA-4 blockade and PD-1/PD-L1 blockade: higher incidences of colitis with CTLA-4 blockade and higher incidences of hypothyroidism and arthralgia with PD-1/PD-L1 blockade. 59 This is likely due to the difference in mechanisms; CTLA-4 blockade unlocks the co-stimulatory signal via CD28 whereas PD-1/PD-L1 blockade primarily reactivates the interaction between a T cell receptor and major histocompatibility complex. 60 Literature describing the mechanisms of irAEs from novel agents targeting immune checkpoints other than CTLA-4 and PD-1/PD-L1 remains scarce, which warrants further research in this field.

Several limitations are applied to our study. First, except for LAG-3 blockade, the number of trials evaluated for each agent was small, and the statistical power to detect any significant differences may have been underpowered. The limited number of studies also widens the CIs for pooled incidences of each AE, making it difficult to calculate the accurate incidence rates of AEs from these agents. Thus, caution should be applied for pooled incidence rates of AEs among drug classifications, particularly for the results derived from only 1 or 2 studies. For example, high incidences of G3-5 trAEs were observed in CD47 blockade though this was calculated based on only one study evaluating the combination of CD47 blockade plus atezolizumab, and thus the true effect of CD47 blockade was not fully isolated. Second, most immunotherapy agents included in this study were evaluated as a combination treatment with other agents such as PD-1/PD-L1 blockade and chemotherapy. Thus, the obtained findings can be confounded by treatment type, and this limits the ability to isolate the contribution of novel agents to each AE assessed in our study. To overcome this limitation, we performed a meta-analysis evaluating the add-on effect of either LAG-3 blockade or TIGIT blockade to the control arm therapy. Other than for LAG-3 or TIGIT blockade, we could not perform such analyses; thus, the attribution of toxicity for other immunoregulatory agents could not be clarified. Furthermore, in this analysis, we did not adjust the P value for multiple testing of various adverse events, which could lead to a false discovery of statistical significance. Therefore, our study is more hypothesis-generating rather than confirmatory, and further large-scale research is needed to validate our findings. Additionally, agents targeting other immune checkpoints could not be included in this meta-analysis due to their single-arm trial designs and a limited number of comparative studies assessing these agents. Obtaining AE information from early-phase, single-arm studies or open-label RCTs introduces a risk of reporting bias, particularly for subjective or low-grade irAEs, which ultimately affect AE data reported in each trial. Furthermore, inherent variability of AE reporting across trials cannot be avoided, necessitating the validation of our findings using data from future double-blinded RCTs. Furthermore, novel immunotherapy agents such as newer generations of PD-1/PD-L1 and CTLA-4 blockade agents as well as bispecific antibodies are currently being evaluated, with some showing promising preliminary efficacy in early-phase clinical trials. 61 , 62 These studies were not included in our study to focus on agents solely targeting immune checkpoints; however, further studies are needed to investigate the safety profiles of these immunotherapy agents.

Conclusion

Toxicity profiles vary among novel immunotherapy agents targeting co-stimulatory or co-inhibitory immune checkpoints beyond PD-1/PD-L1 and CTLA-4. The addition of LAG-3 blockade to standard-of-care immunotherapy was associated with an increased incidence of adrenal insufficiency. These findings provide essential safety information for clinicians to manage irAEs from these agents.

Supplementary Material

Acknowledgments

Not applicable.

Author contributions

Yu Fujiwara, MD (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Visualization, Writing—original draft), Yui Okamura, MD (Data curation, Investigation, Writing—review & editing), Mrinalini Ramesh, DO (Data curation, Investigation, Writing—review & editing), Yasmin Fakhari Tehrani, DO (Data curation, Investigation, Writing—review & editing), Riona Aburaki, MD (Investigation, Writing—review & editing), Toshiaki Takahashi, MD (Data curation, Investigation, Writing—review & editing), Manmeet S. Ahluwalia, MD, MBA, FASCO (Investigation, Writing—review & editing), and Sarbajit Mukherjee, MD, MS (Conceptualization, Investigation, Supervision, Writing—review & editing)

Supplementary material

Supplementary material is available at JNCI Cancer Spectrum online.

Funding

This study was not funded by any research funds.

Conflicts of interest

Y.F. reports research expenses from American Association for Cancer Research, Conquer Cancer Foundation of the American Society of Clinical Oncology, and JMSA Korin Scholarship, outside this work. Y.O., M.R., Y.F.T., R.A., and T.T. do not have competing interests. M.S.A. has received consulting fees from Bayer, Xoft, Apollomics, Menarini Richerche, Sumitomo Pharma Oncology, Autem Therapeutics, GT Medical Technologies, Modifi Biosciences, Allovir, EquilliumBio, VBI Vaccines, Servier Pharmaceuticals, Incyte, Recordati and has stock/stock options from Mimivax, Trisalus Lifesciences, LiveAI, and Bugworks. His institution has received research funding from Pfizer. S.M. serves as a volunteer guidelines panel member at the National Comprehensive Cancer Network and American Society of Clinical Oncology. He received research funding from the National Comprehensive Cancer Network and Ipsen Biopharmaceuticals/North American Neuroendocrine Tumor Society that were paid to the institute, and received consulting fees from Merck, Eisai, and BeiGene Ltd.

Data availability

All data were obtained from the articles published in public databases. Data used for the analysis in this study were summarized and included in tables, figures, and supplementary materials.

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