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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Adverse Events of Concurrent Immune Checkpoint Inhibitors and Antiangiogenic Agents: A Systematic Review</title><author><name sortKey="Gao, Ling" sort="Gao, Ling" uniqKey="Gao L" first="Ling" last="Gao">Ling Gao</name></author><author><name sortKey="Yang, Xi" sort="Yang, Xi" uniqKey="Yang X" first="Xi" last="Yang">Xi Yang</name></author><author><name sortKey="Yi, Cheng" sort="Yi, Cheng" uniqKey="Yi C" first="Cheng" last="Yi">Cheng Yi</name></author><author><name sortKey="Zhu, Hong" sort="Zhu, Hong" uniqKey="Zhu H" first="Hong" last="Zhu">Hong Zhu</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31680957</idno><idno type="pmc">6812341</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812341</idno><idno type="RBID">PMC:6812341</idno><idno type="doi">10.3389/fphar.2019.01173</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000B22</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000B22</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Adverse Events of Concurrent Immune Checkpoint Inhibitors and Antiangiogenic Agents: A Systematic Review</title><author><name sortKey="Gao, Ling" sort="Gao, Ling" uniqKey="Gao L" first="Ling" last="Gao">Ling Gao</name></author><author><name sortKey="Yang, Xi" sort="Yang, Xi" uniqKey="Yang X" first="Xi" last="Yang">Xi Yang</name></author><author><name sortKey="Yi, Cheng" sort="Yi, Cheng" uniqKey="Yi C" first="Cheng" last="Yi">Cheng Yi</name></author><author><name sortKey="Zhu, Hong" sort="Zhu, Hong" uniqKey="Zhu H" first="Hong" last="Zhu">Hong Zhu</name></author></analytic><series><title level="j">Frontiers in Pharmacology</title><idno type="eISSN">1663-9812</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><bold>Background:</bold> Immune checkpoint blockade has revolutionized the treatment of multiple malignancies. Currently, however, the effect is not universal, with objective response rates (ORR) of about 15–25%, and even lower for some cancers. Abnormal vasculature is a hallmark of most solid tumors and plays a role in immune evasion. Growing body of evidence suggests that vascular normalization and immune reprogramming could operate synergistic effect, resulting in an enhanced therapeutic efficacy. However, the benefit of antitumor efficacy must be weighed against the risk of added toxicity. In this systematic review, we summarize severe toxicity observed in such a kind of combination regimen.</p><p><bold>Methods:</bold> PubMed and Embase were searched for English references published up to May 31, 2019, with MeSH and keywords search terms of immune checkpoint inhibitors (ICIs) and antiangiogenic agents approved for using in solid tumors. Studies performing concomitant use of ICIs and antiangiogenic agents, and also reporting severe treatment-related adverse events (trAEs) (≥grade 3), were included for further analysis.</p><p><bold>Results:</bold> A total of 32 studies including a total of 2,324 participants were analyzed. Limited available data suggests that both antiangiogenic monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) show potential risk of increasing treatment-related toxicity when combined with ICIs. Overall, the total incidence of severe adverse events (AEs) associated with ICIs plus mAbs (44.5%) is lower than that of ICIs plus TKIs (60.1%). However, the trAEs observed in combination therapy are mostly consistent with the known safety profiles of corresponding monotherapy, and they seem to be largely related to antiangiogenic agents, rather than a true immune-related adverse event (irAE) predominantly due to ICIs. The majority of trAEs are intervened by holding ICI treatment and adding corticosteroids, as well as reducing dose or adjusting administration frequency of the antiangiogenic drugs.</p><p><bold>Conclusions:</bold> Concurrent use of ICIs and antiangiogenic agents shows potential treatment-related toxicity. Further research is required to compare the efficacy and safety of the combination regimen and corresponding monotherapy and identify predictive biomarkers, as well as explore dose, duration, and sequencing schedules of drugs.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Allen, E" uniqKey="Allen E">E. Allen</name></author><author><name sortKey="Jabouille, A" uniqKey="Jabouille A">A. Jabouille</name></author><author><name sortKey="Rivera, L B" uniqKey="Rivera L">L. B. Rivera</name></author><author><name sortKey="Lodewijckx, I" uniqKey="Lodewijckx I">I. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Front Pharmacol</journal-id><journal-id journal-id-type="iso-abbrev">Front Pharmacol</journal-id><journal-id journal-id-type="publisher-id">Front. Pharmacol.</journal-id><journal-title-group><journal-title>Frontiers in Pharmacology</journal-title></journal-title-group><issn pub-type="epub">1663-9812</issn><publisher><publisher-name>Frontiers Media S.A.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31680957</article-id><article-id pub-id-type="pmc">6812341</article-id><article-id pub-id-type="doi">10.3389/fphar.2019.01173</article-id><article-categories><subj-group subj-group-type="heading"><subject>Pharmacology</subject><subj-group><subject>Systematic Review</subject></subj-group></subj-group></article-categories><title-group><article-title>Adverse Events of Concurrent Immune Checkpoint Inhibitors and Antiangiogenic Agents: A Systematic Review</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Gao</surname><given-names>Ling</given-names></name><xref ref-type="author-notes" rid="fn003"><sup>†</sup></xref><uri xlink:type="simple" xlink:href="https://loop.frontiersin.org/people/561828"></uri></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Xi</given-names></name><xref ref-type="author-notes" rid="fn003"><sup>†</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yi</surname><given-names>Cheng</given-names></name><xref ref-type="author-notes" rid="fn001"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhu</surname><given-names>Hong</given-names></name><xref ref-type="author-notes" rid="fn001"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><institution>Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University</institution>,<addr-line>Chengdu</addr-line>,<country>China</country></aff><author-notes><fn fn-type="edited-by"><p>Edited by: Shuang Zhou, University of Houston, United States</p></fn><fn fn-type="edited-by"><p>Reviewed by: Feng Tian, Harvard Medical School, United States; Robert L. Lins, Retired, Antwerp, Belgium</p></fn><corresp id="fn001">*Correspondence: Cheng Yi, <email xlink:href="mailto:yicheng6834@163.com" xlink:type="simple">yicheng6834@163.com</email>; Hong Zhu, <email xlink:href="mailto:441695131@qq.com" xlink:type="simple">441695131@qq.com</email></corresp><fn fn-type="other" id="fn002"><p>This article was submitted to Pharmaceutical Medicine and Outcomes Research, a section of the journal Frontiers in Pharmacology</p></fn><fn fn-type="equal" id="fn003"><p>†These authors have contributed equally to this work</p></fn></author-notes><pub-date pub-type="epub"><day>17</day><month>10</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>10</volume><elocation-id>1173</elocation-id><history><date date-type="received"><day>30</day><month>6</month><year>2019</year></date><date date-type="accepted"><day>12</day><month>9</month><year>2019</year></date></history><permissions><copyright-statement>Copyright © 2019 Gao, Yang, Yi and Zhu</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Gao, Yang, Yi and Zhu</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</license-p></license></permissions><abstract><p><bold>Background:</bold> Immune checkpoint blockade has revolutionized the treatment of multiple malignancies. Currently, however, the effect is not universal, with objective response rates (ORR) of about 15–25%, and even lower for some cancers. Abnormal vasculature is a hallmark of most solid tumors and plays a role in immune evasion. Growing body of evidence suggests that vascular normalization and immune reprogramming could operate synergistic effect, resulting in an enhanced therapeutic efficacy. However, the benefit of antitumor efficacy must be weighed against the risk of added toxicity. In this systematic review, we summarize severe toxicity observed in such a kind of combination regimen.</p><p><bold>Methods:</bold> PubMed and Embase were searched for English references published up to May 31, 2019, with MeSH and keywords search terms of immune checkpoint inhibitors (ICIs) and antiangiogenic agents approved for using in solid tumors. Studies performing concomitant use of ICIs and antiangiogenic agents, and also reporting severe treatment-related adverse events (trAEs) (≥grade 3), were included for further analysis.</p><p><bold>Results:</bold> A total of 32 studies including a total of 2,324 participants were analyzed. Limited available data suggests that both antiangiogenic monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) show potential risk of increasing treatment-related toxicity when combined with ICIs. Overall, the total incidence of severe adverse events (AEs) associated with ICIs plus mAbs (44.5%) is lower than that of ICIs plus TKIs (60.1%). However, the trAEs observed in combination therapy are mostly consistent with the known safety profiles of corresponding monotherapy, and they seem to be largely related to antiangiogenic agents, rather than a true immune-related adverse event (irAE) predominantly due to ICIs. The majority of trAEs are intervened by holding ICI treatment and adding corticosteroids, as well as reducing dose or adjusting administration frequency of the antiangiogenic drugs.</p><p><bold>Conclusions:</bold> Concurrent use of ICIs and antiangiogenic agents shows potential treatment-related toxicity. Further research is required to compare the efficacy and safety of the combination regimen and corresponding monotherapy and identify predictive biomarkers, as well as explore dose, duration, and sequencing schedules of drugs.</p></abstract><kwd-group><kwd>immune checkpoint inhibitor</kwd><kwd>antiangiogenic monoclonal antibody</kwd><kwd>tyrosine kinase inhibitor</kwd><kwd>concurrent therapy</kwd><kwd>treatment-related adverse event</kwd><kwd>immune-related adverse event</kwd><kwd>systematic review</kwd></kwd-group><counts><fig-count count="2"></fig-count><table-count count="4"></table-count><equation-count count="0"></equation-count><ref-count count="92"></ref-count><page-count count="20"></page-count><word-count count="9992"></word-count></counts></article-meta></front><body><sec sec-type="intro" id="s1"><title>Introduction</title><p>Interventions for local advanced or metastatic solid tumors have evolved rapidly in recent years, among which immune checkpoint blockade therapy may be the most notable strategy (<xref rid="B66" ref-type="bibr">Pardoll, 2012</xref>; <xref rid="B39" ref-type="bibr">Hoos, 2016</xref>; <xref rid="B65" ref-type="bibr">Papaioannou et al., 2016</xref>). Indeed, immune checkpoint inhibitors (ICIs) targeting the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), a T-cell immune checkpoint receptor, or its ligand PD-L1 may be effective for various types of cancer and have brought significant improvements in clinical prognosis (<xref rid="B37" ref-type="bibr">Hodi et al., 2010</xref>; <xref rid="B35" ref-type="bibr">Herbst et al., 2014</xref>; <xref rid="B3" ref-type="bibr">Ansell et al., 2015</xref>; <xref rid="B75" ref-type="bibr">Sharma and Allison, 2015</xref>). However, these therapies benefit just a few of patients, with objective response rates (ORR) of about 15–25%, and even lower for pancreatic carcinoma, prostate cancer, ovarian carcinoma, triple negative breast cancer, and microsatellite stable colorectal cancer. It may be attributed to insufficient abundance of tumor neoantigens, tumor heterogeneity, and genetic variation among individuals. Besides, acquired tumor resistance of ICIs is also a challenge (<xref rid="B50" ref-type="bibr">Ma et al., 2016</xref>; <xref rid="B84" ref-type="bibr">Wang and Wu, 2017</xref>). Therefore, it is necessary to seek combination therapy strategy which can activate anti-tumor immunity and enhance treatment efficacy.</p><p>Researches have identified that abnormal tumor vasculature in the tumor microenvironment (TME) not only fuels tumor progression but also has a negative impact on the effectiveness of all types of anticancer therapies, especially immunotherapy. Elevated interstitial fluid pressure of the TME caused by the leaky nature of tumor vessels and dysfunctional lymphatic drainage, along with low expression level of cell adhesion molecules, such as vascular cell adhesion protein 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1), limits the entry of drugs and the trafficking of immune effector cells into tumors (<xref rid="B32" ref-type="bibr">Griffioen et al., 1996</xref>; <xref rid="B11" ref-type="bibr">Buckanovich et al., 2008</xref>; <xref rid="B42" ref-type="bibr">Jain, 2013</xref>). Besides, angiogenic molecules presenting in the TME, such as vascular endothelial growth factor (VEGF), act as a mediator of tumor-associated immunosuppression. Firstly, VEGF directly prevent mobilization, trafficking, development, proliferation, and effector function of CD8-positive cytotoxic T lymphocytes (CTLs) (<xref rid="B62" ref-type="bibr">Ohm and Carbone, 2001</xref>; <xref rid="B82" ref-type="bibr">Voron et al., 2015</xref>). Secondly, VEGF could promote the recruitment and proliferation of immunosuppressive cells, including regulatory T (Treg) cells, myeloid-derived suppressor cells (MDSCs), and M2-like tumor-associated macrophages (TAMs) (<xref rid="B79" ref-type="bibr">Terme et al., 2013</xref>; <xref rid="B14" ref-type="bibr">Chaudhary et al., 2014</xref>; <xref rid="B51" ref-type="bibr">Maenhout et al., 2014</xref>). Thirdly, maturation and antigen presentation of dendritic cells (DCs) might be suppressed by elevated VEGF (<xref rid="B29" ref-type="bibr">Gabrilovich et al., 1996</xref>; <xref rid="B28" ref-type="bibr">Gabrilovich et al., 1998</xref>). Thus, strategies inducing vascular normalization may restore immune cell functions and help to attenuate the immunosuppression of the TME, thereby improve the activity of immunotherapy. For example, sunitinib could increase T-cell and B-cell levels and decrease PD-1 expression in tumor-infiltrating T-cells as well as inhibit MDSCs and Treg cells into tumor (<xref rid="B34" ref-type="bibr">Heine et al., 2011</xref>; <xref rid="B82" ref-type="bibr">Voron et al., 2015</xref>). Bevacizumab and pazopanib could increase the infiltration or activity of CD8-positive and CD4-positive T-cells and enhance the maturation of DCs (<xref rid="B25" ref-type="bibr">Elamin et al., 2015</xref>; <xref rid="B92" ref-type="bibr">Zizzari et al., 2018</xref>). However, recent studies have also shown that an adaptive immunosuppression caused by the up-regulation of PD-L1 in endothelial cells (ECs) and tumor cells after antiangiogenic therapies limits the activity of antiangiogenesis (<xref rid="B1" ref-type="bibr">Allen et al., 2017</xref>). It suggests that combination of antiangiogenesis and immune checkpoint blockade targeting PD-1/PD-L1 may be a good choice. More interestingly, bioinformatic analyses revealed that gene expression features related to vascular normalization correlate with immunostimulatory pathways, especially the activation and infiltration of T-cells. As a result, activating of CD4-positive T-cells by ICIs promoted the normalization of tumor vessels in return (<xref rid="B80" ref-type="bibr">Tian et al., 2017</xref>). Therefore, it demonstrates that vascular normalization and immune reprogramming have synergistic effect, which provides a basis for the rationality of the combination of ICIs and antiangiogenic agents.</p><p>Indeed, preclinical evidences have confirmed the efficacy of these combination regimens (<xref rid="B89" ref-type="bibr">Yasuda et al., 2013</xref>; <xref rid="B59" ref-type="bibr">Motoshima et al., 2015</xref>; <xref rid="B23" ref-type="bibr">Du Four et al., 2016</xref>; <xref rid="B45" ref-type="bibr">Kimura et al., 2018</xref>; <xref rid="B48" ref-type="bibr">Laubli et al., 2018</xref>). For instance, in a mouse model of colon adenocarcinoma, treatment with axitinib led to an improved T-cell response, and it resulted in a synergistic therapeutic efficacy when combined with anti-PD-1 antibody (<xref rid="B48" ref-type="bibr">Laubli et al., 2018</xref>). On the basis of preclinical data, these combination therapies have been tested in dozens of clinical trials, which reported promising outcomes in patients with metastatic melanoma, non-squamous non-small-cell lung carcinoma (NSCLC), and renal cell carcinoma (RCC). Among them, IMpower150 trial showed that atezolizumab plus chemotherapy plus bevacizumab significantly improved progression-free survival (PFS) and overall survival (OS) of patients with metastatic non-squamous NSCLC, regardless of mutational status and checkpoint expression of tumor (<xref rid="B72" ref-type="bibr">Reck et al., 2019</xref>). Similarly, in other two phase 3 trials on the first-line treatment of advanced or metastatic RCC, concomitant use of pembrolizumab and axitinib improved OS, PFS, and ORR over the standard of care (<xref rid="B73" ref-type="bibr">Rini et al., 2019a</xref>), while combining avelumab with axitinib improved PFS and ORR (<xref rid="B60" ref-type="bibr">Motzer et al., 2019</xref>).</p><p>However, despite the enhanced anti-tumor efficacy, the combination treatment is not without challenge, including the risk of added toxicity and increasing of immune-related adverse events (irAEs). As is well known, toxic effects associated with ICIs manifesting with autoimmune-like side-effects are commonly seen in the skin, gastrointestinal tract, pulmonary, hepatic, renal, nervous, hematologic, cardiovascular, and endocrine systems (<xref rid="B31" ref-type="bibr">Gordon et al., 2017</xref>; <xref rid="B69" ref-type="bibr">Puzanov et al., 2017</xref>). Likewise, antiangiogenic monoclonal antibodies (mAbs) and small-molecule tyrosine kinase inhibitors (TKIs), the two main types of antiangiogenic agent, also have diverse adverse effects, mainly including hypertension, arterial thromboembolic events, proteinuria, bowel perforation, reversible posterior leukoencephalopathy syndrome, wound complications, and hemorrhage (<xref rid="B15" ref-type="bibr">Chen and Cleck, 2009</xref>). At present, there is no systematic analysis of the toxicity of such a kind of combination. This review will focus on the severe treatment-related adverse events (trAEs) and irAEs of the concomitant use of ICIs and antiangiogenic agents.</p></sec><sec sec-type="materials|methods" id="s2"><title>Material and Methods</title><sec id="s2_1"><title>Search Strategy and Eligibility</title><p>The study was performed according to the “PRISMA” statement. Search was done on 31 May 2019. PubMed and Embase databases were searched for relevant literatures published in English using MeSH and keywords “nivolumab,” “pembrolizumab,” “atezolizumab,” “avelumab,” “ipilimumab,” “durvalumab,” “immune checkpoint inhibition” or “immune checkpoint inhibitors,” combined with “bevacizumab,” “ramucirumab,” “anlotinib,” “apatinib,” “axitinib,” “cabozantinib,” “cediranib,” “fruquintinib,” “lenvatinib,” “motesanib,” “nintedanib,” “pazopanib,” “regorafenib,” “sorafenib,” “sunitinib,” “vandetanib,” “aflibercept,” or “endostar.” Studies included in this review were limited to clinical trial of any phase, retrospective study, or case report involving adult patients with solid tumors. Only original articles were included. Duplicates, conference abstracts or poster presentations, commentaries, reviews, and secondary reporting of clinical trials were excluded.</p><p>Studies involving concurrent treatment of ICIs and antiangiogenic agents were eligible. The study should properly describe the safety of the combination treatment. Studies not describing toxicity or the timing of antiangiogenic therapy in relation to ICIs were excluded. AEs should be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). If not, authors rated them accordingly. When more than one article reported the same trial, the most recent data was used. When patients in case report were from the same cohort of a clinical trial and were reported with the same AEs, the case report was excluded. All relevant articles underwent evaluation for eligibility by two independent authors (LG and XY) and then were verified by senior author (HZ and CY). Titles and abstracts were preliminary screened. Subsequently, full-text reading was used to check whether the study met inclusion or exclusion criteria.</p></sec><sec id="s2_2"><title>Data Extraction</title><p>Two authors (LG and XY) collected all data for included studies. Data was sought on authors, year of publication, study type, number of patients, as well as the type, dose, and treatment duration of ICIs and antiangiogenic agents. Tumor types and stages, follow-up time, toxicity, and management were also collected. Only grade 3–5 trAEs and irAEs were included for analysis.</p></sec></sec><sec sec-type="results" id="s3"><title>Results</title><sec id="s3_1"><title>Included Studies and Overview</title><p>We initially identified a total of 1,883 references from database search. There were 348 papers excluded due to duplication, and the remaining 1,535 references were read with title and abstract. Subsequently, 104 relevant articles were further assessed for eligibility by full-text reviewing. Finally, 32 articles meeting the inclusion criteria were included into this systematic review (<xref ref-type="fig" rid="f1"><bold>Figure 1</bold></xref>). Among them, there were 17 prospective studies (n = 2186), 5 retrospective studies (n = 104), and 10 case reports (n = 34), with the median number of patient as 70 per study. Studies of the combination of ICIs and anlotinib, fruquintinib, motesanib, nintedanib, regorafenib, vandetani, or aflibercept were not found. The concurrent use of ICIs and mAbs was reported in 15 studies (<xref rid="T1" ref-type="table"><bold>Table 1</bold></xref>), while concurrent use of ICIs and TKIs was in 17 studies (<xref rid="T2" ref-type="table"><bold>Table 2</bold></xref>).</p><fig id="f1" position="float"><label>Figure 1</label><caption><p>Search flow diagram.</p></caption><graphic xlink:href="fphar-10-01173-g001"></graphic></fig><table-wrap id="T1" position="float"><label>Table 1</label><caption><p>Included articles with concurrent ICIs and antiangiogenic mAbs.</p></caption><table frame="hsides" rules="groups"><thead><tr><th valign="top" rowspan="1" colspan="1">Authors</th><th valign="top" rowspan="1" colspan="1">Study year</th><th valign="top" rowspan="1" colspan="1">Study type</th><th valign="top" rowspan="1" colspan="1">Patients (n)</th><th valign="top" rowspan="1" colspan="1">Compounds and dosage</th><th valign="top" rowspan="1" colspan="1">Treatment timing</th><th valign="top" rowspan="1" colspan="1">Primary tumor</th><th valign="top" rowspan="1" colspan="1">Follow-up (median time)</th><th valign="top" rowspan="1" colspan="1">Toxicity (≥3)</th></tr></thead><tbody><tr><td valign="top" rowspan="1" colspan="1">Wallin et al.</td><td valign="top" rowspan="1" colspan="1">2016</td><td valign="top" rowspan="1" colspan="1">Prospective</td><td valign="top" rowspan="1" colspan="1">10</td><td valign="top" rowspan="1" colspan="1">Bevacizumab 15 mg/kg i.v./3 w * 1 cycle, and then atezolizumab 20 mg/kg i.v., bevacizumab 15 mg/kg i.v./3 w</td><td valign="top" rowspan="1" colspan="1">Renal cell carcinoma (RCC)</td><td valign="top" rowspan="1" colspan="1">Advanced; metastatic</td><td valign="top" rowspan="1" colspan="1">17.2 months</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">McDermott et al.</td><td valign="top" rowspan="1" colspan="1">2018</td><td valign="top" rowspan="1" colspan="1">Phase 2 trial</td><td valign="top" rowspan="1" colspan="1">101</td><td valign="top" rowspan="1" colspan="1">Atezolizumab 1,200 mg i.v., bevacizumab 15 mg/kg i.v./3 w</td><td valign="top" rowspan="1" colspan="1">RCC</td><td valign="top" rowspan="1" colspan="1">Advanced; metastatic</td><td valign="top" rowspan="1" colspan="1">20.7 months</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Rini et al.</td><td valign="top" rowspan="1" colspan="1">2019</td><td valign="top" rowspan="1" colspan="1">Phase 3 trial</td><td valign="top" rowspan="1" colspan="1">451</td><td valign="top" rowspan="1" colspan="1">Atezolizumab 1,200 mg i.v., bevacizumab 15 mg/kg i.v./3 w</td><td valign="top" rowspan="1" colspan="1">RCC</td><td valign="top" rowspan="1" colspan="1">Advanced; metastatic</td><td valign="top" rowspan="1" colspan="1">15 months</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Reck et al.</td><td valign="top" rowspan="1" colspan="1">2019</td><td valign="top" rowspan="1" colspan="1">Phase 3 trial</td><td valign="top" rowspan="1" colspan="1">394</td><td valign="top" rowspan="1" colspan="1">Atezolizumab + bevacizumab + carboplatin + paclitaxel (atezolizumab 1,200 mg i.v., bevacizumab 15 mg/kg i.v./3 w)</td><td valign="top" rowspan="1" colspan="1">Non-squamous non-small-cell lung cancer (NSCLC)</td><td valign="top" rowspan="1" colspan="1">Chemotherapy-naïve metastatic</td><td valign="top" rowspan="1" colspan="1">19.6 months</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Wu et al.</td><td valign="top" rowspan="1" colspan="1">2017</td><td valign="top" rowspan="1" colspan="1">Case report</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">Pembrolizumab + bevacizumab + cisplatin + gemcitabine (pembrolizumab 1 mg/kg i.v., bevacizumab 4 mg/kg i.v.)</td><td valign="top" rowspan="1" colspan="1">Urothelial carcinoma (UC)</td><td valign="top" rowspan="1" colspan="1">Recurrent</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">N</td></tr><tr><td valign="top" rowspan="1" colspan="1">Gadgeel et al.</td><td valign="top" rowspan="1" colspan="1">2018</td><td valign="top" rowspan="1" colspan="1">Phase 1 trial</td><td valign="top" rowspan="1" colspan="1">24</td><td valign="top" rowspan="1" colspan="1">Pembrolizumab + bevacizumab + carboplatin + paclitaxel (pembrolizumab 2(n = 11) or 10 mg/kg (n = 13) i.v., bevacizumab 15 mg/kg i.v./3 w * 4 cycles, and then pembrolizumab + bevacizumab for 2 years)</td><td valign="top" rowspan="1" colspan="1">Non-squamous NSCLC</td><td valign="top" rowspan="1" colspan="1">Stage IIIB/IV without EGFR mutations or ALK translocations</td><td valign="top" rowspan="1" colspan="1">16.4 months</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Blumenthal et al.</td><td valign="top" rowspan="1" colspan="1">2016</td><td valign="top" rowspan="1" colspan="1">Retrospective</td><td valign="top" rowspan="1" colspan="1">10</td><td valign="top" rowspan="1" colspan="1">Pembrolizumab 150 mg i.v., bevacizumab, dosage NR i.v.,/3 w</td><td valign="top" rowspan="1" colspan="1">Central nervous system (CNS) tumor</td><td valign="top" rowspan="1" colspan="1">Recurrent</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">N</td></tr><tr><td valign="top" rowspan="1" colspan="1">Kurz et al.</td><td valign="top" rowspan="1" colspan="1">2018</td><td valign="top" rowspan="1" colspan="1">Retrospective</td><td valign="top" rowspan="1" colspan="1">28</td><td valign="top" rowspan="1" colspan="1">Pembrolizumab 2 mg/kg i.v./3 w (n = 19), or nivolumab 3 mg/kg i.v./2 w (n = 12), bevacizumab 10 mg/kg i.v./2 w (n = 28)</td><td valign="top" rowspan="1" colspan="1">High-grade gliomas (HGGs)</td><td valign="top" rowspan="1" colspan="1">Recurrent</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">N</td></tr><tr><td valign="top" rowspan="1" colspan="1">Mantica et al.</td><td valign="top" rowspan="1" colspan="1">2018</td><td valign="top" rowspan="1" colspan="1">Retrospective</td><td valign="top" rowspan="1" colspan="1">43</td><td valign="top" rowspan="1" colspan="1">Nivolumab 3 mg/kg i.v./2 w, bevacizumab, dosage NR</td><td valign="top" rowspan="1" colspan="1">HGGs</td><td valign="top" rowspan="1" colspan="1">Advanced</td><td valign="top" rowspan="1" colspan="1">6.4 months</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Kanda et al.</td><td valign="top" rowspan="1" colspan="1">2016</td><td valign="top" rowspan="1" colspan="1">Phase 1b trial</td><td valign="top" rowspan="1" colspan="1">6</td><td valign="top" rowspan="1" colspan="1">Nivolumab+paclitaxel+carboplatin+bevacizumab (nivolumab 10 mg/kg i.v., bevacizumab 15 mg/kg i.v./3 w * 6 cycles, and then pembrolizumab + bevacizumab maintain)</td><td valign="top" rowspan="1" colspan="1">Non-squamous NSCLC</td><td valign="top" rowspan="1" colspan="1">Stage IIIB without indication for definitive thoracic radiotherapy; stage IV; recurrent</td><td valign="top" rowspan="1" colspan="1">7.54 months</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Normann et al.</td><td valign="top" rowspan="1" colspan="1">2019</td><td valign="top" rowspan="1" colspan="1">Prospective</td><td valign="top" rowspan="1" colspan="1">5</td><td valign="top" rowspan="1" colspan="1">Nivolumab 3 mg/kg i.v./2 w, bevacizumab dosage NR</td><td valign="top" rowspan="1" colspan="1">Platinum resistant ovarian cancer</td><td valign="top" rowspan="1" colspan="1">Recurrent</td><td valign="top" rowspan="1" colspan="1">30 weeks</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Shirali et al.</td><td valign="top" rowspan="1" colspan="1">2016</td><td valign="top" rowspan="1" colspan="1">Case report</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">Nivolumab 3 mg/kg i.v., bevacizumab 15 mg/kg i.v./3 w)</td><td valign="top" rowspan="1" colspan="1">NSCLC</td><td valign="top" rowspan="1" colspan="1">Progression</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Hodi et al.</td><td valign="top" rowspan="1" colspan="1">2014</td><td valign="top" rowspan="1" colspan="1">Prospective</td><td valign="top" rowspan="1" colspan="1">46</td><td valign="top" rowspan="1" colspan="1">Ipilimumab 10 mg/kg i.v./3 w *4 cycles, and then 10 mg/kg i.v./12 w + bevacizumab 7.5 mg/kg (cohort 1) or 15 mg/kg (cohort 2) i.v./3 w; ipilimumab 3 mg/kg i.v./3 w *4 cycles, and then 3 mg/kg i.v./12 w + bevacizumab 7.5 mg/kg (cohort 3) or 15 mg/kg (cohort 4) i.v./3 w</td><td valign="top" rowspan="1" colspan="1">Melanoma</td><td valign="top" rowspan="1" colspan="1">Unresectable stage III; stage IV</td><td valign="top" rowspan="1" colspan="1">17.3 months</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Carter et al.</td><td valign="top" rowspan="1" colspan="1">2016</td><td valign="top" rowspan="1" colspan="1">Case series</td><td valign="top" rowspan="1" colspan="1">20</td><td valign="top" rowspan="1" colspan="1">Ipilimumab 3 mg/kg i.v./3 w *4 cycles, and then 3 mg/kg i.v./12 w, bevacizumab 10 mg/kg i.v./2 w</td><td valign="top" rowspan="1" colspan="1">Glioblastoma</td><td valign="top" rowspan="1" colspan="1">Grade IV disease or recurrent astrocytoma (grade II); progression or after first-line therapy</td><td valign="top" rowspan="1" colspan="1">≥12 weeks</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Arkenau et al.</td><td valign="top" rowspan="1" colspan="1">2018</td><td valign="top" rowspan="1" colspan="1">Phase 1 trial</td><td valign="top" rowspan="1" colspan="1">26</td><td valign="top" rowspan="1" colspan="1">Pembrolizumab 200 mg i.v. d1, ramucirumab 8 mg/kg i.v. d1, d8/3 w</td><td valign="top" rowspan="1" colspan="1">Biliary tract cancer (BTC)</td><td valign="top" rowspan="1" colspan="1">Advanced; metastatic</td><td valign="top" rowspan="1" colspan="1">15.7 months</td><td valign="top" rowspan="1" colspan="1">Y</td></tr></tbody></table></table-wrap><table-wrap id="T2" position="float"><label>Table 2</label><caption><p>Included articles with concurrent ICIs and TKIs.</p></caption><table frame="hsides" rules="groups"><thead><tr><th valign="top" rowspan="1" colspan="1">Authors</th><th valign="top" rowspan="1" colspan="1">Study year</th><th valign="top" rowspan="1" colspan="1">Study type</th><th valign="top" rowspan="1" colspan="1">Patients (n)</th><th valign="top" rowspan="1" colspan="1">Compounds and dosage</th><th valign="top" rowspan="1" colspan="1">Primary tumor</th><th valign="top" rowspan="1" colspan="1">Treatment timing</th><th valign="top" rowspan="1" colspan="1">Follow-up (median time)</th><th valign="top" rowspan="1" colspan="1">Toxicity (≥3)</th></tr></thead><tbody><tr><td valign="top" rowspan="1" colspan="1">Atkins et al.</td><td valign="top" rowspan="1" colspan="1">2018</td><td valign="top" rowspan="1" colspan="1">Phase 1b trial</td><td valign="top" rowspan="1" colspan="1">52</td><td valign="top" rowspan="1" colspan="1">Axitinib 3,5 or 7 mg p.o. bid continuously, (median dose: 8.8 mg/day), pembrolizumab 2 mg/kg i.v. d8/3 w</td><td valign="top" rowspan="1" colspan="1">RCC</td><td valign="top" rowspan="1" colspan="1">Advanced</td><td valign="top" rowspan="1" colspan="1">20.4 months</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Rini et al.</td><td valign="top" rowspan="1" colspan="1">2019</td><td valign="top" rowspan="1" colspan="1">Phase 3 trial</td><td valign="top" rowspan="1" colspan="1">429</td><td valign="top" rowspan="1" colspan="1">Axitinib 5 mg (2–10 mg) p.o. bid continuously, pembrolizumab 200 mg i.v./3 w</td><td valign="top" rowspan="1" colspan="1">RCC</td><td valign="top" rowspan="1" colspan="1">Advanced, recurrent</td><td valign="top" rowspan="1" colspan="1">12.8 months</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Wilky et al.</td><td valign="top" rowspan="1" colspan="1">2019</td><td valign="top" rowspan="1" colspan="1">Phase 2 trial</td><td valign="top" rowspan="1" colspan="1">33</td><td valign="top" rowspan="1" colspan="1">Axitinib 5 mg (2–10 mg) p.o. bid continuously, pembrolizumab 200 mg i.v. d8/3 w up to 2y</td><td valign="top" rowspan="1" colspan="1">Sarcomas, including alveolar soft-part sarcoma (ASPS)</td><td valign="top" rowspan="1" colspan="1">Advanced; metastatic</td><td valign="top" rowspan="1" colspan="1">14.7 months</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Choueiri et al.</td><td valign="top" rowspan="1" colspan="1">2018</td><td valign="top" rowspan="1" colspan="1">Phase 1b trial</td><td valign="top" rowspan="1" colspan="1">55</td><td valign="top" rowspan="1" colspan="1">Axitinib 5 mg p.o. bid, d1–7 (lead-in period), axitinib 5 mg p.o. bid continuously, avelumab 10 mg/kg i.v./2 w</td><td valign="top" rowspan="1" colspan="1">RCC<break></break></td><td valign="top" rowspan="1" colspan="1">Advanced</td><td valign="top" rowspan="1" colspan="1">52.1 weeks</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Motzer et al.</td><td valign="top" rowspan="1" colspan="1">2019</td><td valign="top" rowspan="1" colspan="1">Phase 3 trial</td><td valign="top" rowspan="1" colspan="1">434</td><td valign="top" rowspan="1" colspan="1">Axitinib 5 mg p.o. bid, avelumab 10 mg/kg i.v./2 w</td><td valign="top" rowspan="1" colspan="1">RCC</td><td valign="top" rowspan="1" colspan="1">Advanced</td><td valign="top" rowspan="1" colspan="1">11.6 months</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Qiao et al.</td><td valign="top" rowspan="1" colspan="1">2018</td><td valign="top" rowspan="1" colspan="1">Case report</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">Pazopanib + pembrolizumab + RAK cells (pazopanib 200 mg p.o. qd for 2 days, 400 mg qd for 5 days, then 600 mg qd up to now, pembrolizumab 100 mg i.v./3 w)</td><td valign="top" rowspan="1" colspan="1">Primary hepatic angiosarcoma (PHA)</td><td valign="top" rowspan="1" colspan="1">Advanced</td><td valign="top" rowspan="1" colspan="1">About 15 months</td><td valign="top" rowspan="1" colspan="1">N</td></tr><tr><td valign="top" rowspan="1" colspan="1">Amin et al.</td><td valign="top" rowspan="1" colspan="1">2018</td><td valign="top" rowspan="1" colspan="1">Phase 1 trial</td><td valign="top" rowspan="1" colspan="1">20(P+N)33(S+N)</td><td valign="top" rowspan="1" colspan="1">Pazopanib 800 mg p.o. qd, nivolumab 2 mg/kg i.v./3 w; sunitinib 50 mg p.o. qd/4 weeks on and 2 weeks off, nivolumab 2 mg/kg i.v./3 w</td><td valign="top" rowspan="1" colspan="1">RCC</td><td valign="top" rowspan="1" colspan="1">Advanced</td><td valign="top" rowspan="1" colspan="1">27.1 months (P+N); 50 months (S+N)</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Paoluzzi et al.</td><td valign="top" rowspan="1" colspan="1">2016</td><td valign="top" rowspan="1" colspan="1">Retrospective</td><td valign="top" rowspan="1" colspan="1">18</td><td valign="top" rowspan="1" colspan="1">Pazopanib 400–800 mg p.o. qd, nivolumab 3 mg/kg i.v./2 w</td><td valign="top" rowspan="1" colspan="1">Sarcomas</td><td valign="top" rowspan="1" colspan="1">Relapsed metastatic; unresectable</td><td valign="top" rowspan="1" colspan="1">≥13 months</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Yu-Li Su et al.</td><td valign="top" rowspan="1" colspan="1">2017</td><td valign="top" rowspan="1" colspan="1">Case report</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">Pazopanib 400 mg p.o. qd continuingly, nivolumab 3 mg/kg i.v./2 w</td><td valign="top" rowspan="1" colspan="1">RCC</td><td valign="top" rowspan="1" colspan="1">Metastatic</td><td valign="top" rowspan="1" colspan="1">≥4 months</td><td valign="top" rowspan="1" colspan="1">N</td></tr><tr><td valign="top" rowspan="1" colspan="1">Chen et al.</td><td valign="top" rowspan="1" colspan="1">2017</td><td valign="top" rowspan="1" colspan="1">Case report</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">Sorafenib 200 mg p.o. bid, pembrolizumab 2 mg/kg i.v. d1/3 w (4 w starting in cycle 3)</td><td valign="top" rowspan="1" colspan="1">Hepatocellular carcinoma (HCC)</td><td valign="top" rowspan="1" colspan="1">End-stage</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">N</td></tr><tr><td valign="top" rowspan="1" colspan="1">Feng et al.</td><td valign="top" rowspan="1" colspan="1">2017</td><td valign="top" rowspan="1" colspan="1">Case series</td><td valign="top" rowspan="1" colspan="1">6</td><td valign="top" rowspan="1" colspan="1">Sorafenib 200 mg p.o. bid, nivolumab 3 mg/kg i.v. d1/3 w</td><td valign="top" rowspan="1" colspan="1">HCC</td><td valign="top" rowspan="1" colspan="1">Advanced</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">N</td></tr><tr><td valign="top" rowspan="1" colspan="1">Mahmoud et al.</td><td valign="top" rowspan="1" colspan="1">2016</td><td valign="top" rowspan="1" colspan="1">Case report</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">Sunitinib 50 mg p.o. qd/4 weeks on and 2 weeks off, nivolumab NR</td><td valign="top" rowspan="1" colspan="1">RCC</td><td valign="top" rowspan="1" colspan="1">Metastatic</td><td valign="top" rowspan="1" colspan="1">≥11 months</td><td valign="top" rowspan="1" colspan="1">N</td></tr><tr><td valign="top" rowspan="1" colspan="1">Lee et al.</td><td valign="top" rowspan="1" colspan="1">2017</td><td valign="top" rowspan="1" colspan="1">Phase 1 trial</td><td valign="top" rowspan="1" colspan="1">14</td><td valign="top" rowspan="1" colspan="1">Cediranib 20/30 mg p.o. qd, + durvalumab 10 mg/kg i.v./2 w; cediranib 20 mg p.o. qd/5 days on and 2 days off, + durvalumab 1,500 mg i.v./4 w</td><td valign="top" rowspan="1" colspan="1">Solid tumors</td><td valign="top" rowspan="1" colspan="1">Recurrent; metastatic</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Zhao et al.</td><td valign="top" rowspan="1" colspan="1">2019</td><td valign="top" rowspan="1" colspan="1">Case report</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">Apatinib 500 mg p.o. qd, nivolumab 3 mg/kg i.v./2 w</td><td valign="top" rowspan="1" colspan="1">Liver carcinosarcoma</td><td valign="top" rowspan="1" colspan="1">Advanced</td><td valign="top" rowspan="1" colspan="1">About 15 months</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Makker et al.</td><td valign="top" rowspan="1" colspan="1">2019</td><td valign="top" rowspan="1" colspan="1">Phase 2 trial</td><td valign="top" rowspan="1" colspan="1">53</td><td valign="top" rowspan="1" colspan="1">Lenvatinib 20 mg p.o. bid, pembrolizumab 200 mg i.v./3 w</td><td valign="top" rowspan="1" colspan="1">Endometrial cancer</td><td valign="top" rowspan="1" colspan="1">Metastatic</td><td valign="top" rowspan="1" colspan="1">13.3 months</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Iyer et al.</td><td valign="top" rowspan="1" colspan="1">2018</td><td valign="top" rowspan="1" colspan="1">Retrospective</td><td valign="top" rowspan="1" colspan="1">12</td><td valign="top" rowspan="1" colspan="1">Lenvatinib 20 mg p.o. bid, pembrolizumab 200 mg i.v./3 w</td><td valign="top" rowspan="1" colspan="1">Anaplastic thyroid carcinoma (ATC)</td><td valign="top" rowspan="1" colspan="1">Progression</td><td valign="top" rowspan="1" colspan="1">13.74 months (8.14 + 5.6)</td><td valign="top" rowspan="1" colspan="1">Y</td></tr><tr><td valign="top" rowspan="1" colspan="1">Bhat et al.</td><td valign="top" rowspan="1" colspan="1">2019</td><td valign="top" rowspan="1" colspan="1">Case report</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">Cabozantinib, nivolumab, dosage NR</td><td valign="top" rowspan="1" colspan="1">RCC</td><td valign="top" rowspan="1" colspan="1">Metastatic</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">N</td></tr></tbody></table></table-wrap><p>The reported treatment-related toxicities of included studies were listed in <xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>. When ICIs combined with mAbs (n = 1166), severe toxicity reported as grade 3/4 and grade 5 AEs was observed in 501 (43%) and 18 (1.5%) patients, respectively (<xref ref-type="fig" rid="f2"><bold>Figures 2A, B</bold></xref>), while for ICIs plus TKIs (n = 1158), grade 3/4 and grade 5 AEs were in 687 (59.3%) and 9 (0.8%) patients, respectively (<xref ref-type="fig" rid="f2"><bold>Figures 2A, C</bold></xref>). Overall, the total incidence of severe trAEs associated with ICIs plus mAbs was lower than that of ICIs plus TKIs (<xref ref-type="fig" rid="f2"><bold>Figures 2B, C</bold></xref>).</p><table-wrap id="T3" position="float"><label>Table 3</label><caption><p>Treatment-related toxicity as observed within the included articles.</p></caption><table frame="hsides" rules="groups"><thead><tr><th valign="top" rowspan="1" colspan="1">Antiangiogenic agents</th><th valign="top" rowspan="1" colspan="1">ICIs</th><th valign="top" rowspan="1" colspan="1">Study</th><th valign="top" rowspan="1" colspan="1">Median treatment duration</th><th valign="top" rowspan="1" colspan="1">Patients (n)</th><th valign="top" rowspan="1" colspan="1">Grade 3 (n) trAE/irAE</th><th valign="top" rowspan="1" colspan="1">Grade 4 (n) trAE/irAE</th><th valign="top" rowspan="1" colspan="1">Grade 5 (n) trAE/irAE</th><th valign="top" rowspan="1" colspan="1">Total toxicity (≥3)</th><th valign="top" rowspan="1" colspan="1">Management</th></tr></thead><tbody><tr><td valign="top" rowspan="1" colspan="1">Bevacizumab</td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">1,140</td><td valign="top" colspan="2" rowspan="1">494</td><td valign="top" rowspan="1" colspan="1">18</td><td valign="top" rowspan="1" colspan="1">512</td><td valign="top" rowspan="1" colspan="1"></td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Ipilimumab</td><td valign="top" rowspan="1" colspan="1">Hodi et al.</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">46</td><td valign="top" rowspan="1" colspan="1">ALT (n = 2), AST (n = 2), abdomen pain (n = 2), adrenal insufficiency (n = 2), allergic reaction (n = 1), colitis (n = 2), endocrine-other (n = 1), fatigue (n = 1), head or headache (n = 1), hemorrhage-other (n = 1), hepatic-other (n = 1), hypertension (n = 4), hyponatremia (n = 2), lipase (n = 2), lymphopenia (n = 1), mucostomatitis by exam, oral cavity (n = 1), rash or desquamation (n = 2), thrombosis or thrombus or embolism (n = 1), vascular-other (n = 1). Among them, 5 trAEs were observed in cohort 1, 8 were in cohort 2, 6 were in cohort 3, and 10 in cohort 4.</td><td valign="top" rowspan="1" colspan="1">Hepatic-other (n = 1), proteinuria (n = 2)<break></break>All above were observed in cohort 2<break></break>Number of patient was 13 (grade 3/4)</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">13</td><td valign="top" rowspan="1" colspan="1">NR</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Carter et al.</td><td valign="top" rowspan="1" colspan="1">65% patients complete four cycles</td><td valign="top" rowspan="1" colspan="1">20</td><td valign="top" rowspan="1" colspan="1">Diarrhea (n = 1), abscess formation (dental, uterine, diverticular) (n = 3), intracerebral bleed (n = 1), pulmonary embolism (n = 2)</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">7</td><td valign="top" rowspan="1" colspan="1">Three abscess were managed surgically; corticosteroids (diarrhea), dosage NR; NO discontinued treatment.</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Pembrolizumab</td><td valign="top" rowspan="1" colspan="1">Gadgeel et al.</td><td valign="top" rowspan="1" colspan="1">Pemb: 10 doses (30 weeks)</td><td valign="top" rowspan="1" colspan="1">24</td><td valign="top" rowspan="1" colspan="1">Thrombocytopenia (n = 1), neutrophil count decreased (n = 1), white blood cell count decreased (n = 2)/colitis (n = 1), pneumonitis (n = 1), pancreatitis (n = 1). Grade 3 trAEs occurred in 10 (42%) and 10 (40%) patients with or without bevacizumab, respectively. Grade 3 irAEs and infusion reactions occurred in 5 (20.8%) and 1 (4%) patients with or without bevacizumab, respectively.</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">10</td><td valign="top" rowspan="1" colspan="1">Discontinuation: pembrolizumab 2 mg/kg group (n = 2, 18%); 10 mg/kg group (n = 3, 23%)</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Blumenthal et al.</td><td valign="top" rowspan="1" colspan="1">Pemb: 3 doses (9 weeks)</td><td valign="top" rowspan="1" colspan="1">10</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">Steroids weaned off or minimal 2 mg/d</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Wu et al.</td><td valign="top" rowspan="1" colspan="1">11 cycle (about 7.7 months)</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">A mild immune-related skin was resolved completely with anti-histamines.</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Pembrolizumab or nivolumab</td><td valign="top" rowspan="1" colspan="1">Kurz et al.</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">28</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">On steroids when pembrolizumab initiated: n = 17 (55%), dosage NR<break></break>Discontinuation: n = 1 (3%)</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Nivolumab</td><td valign="top" rowspan="2" colspan="1">Mantica et al.</td><td valign="top" rowspan="2" colspan="1">8 cycle (about 16 weeks)</td><td valign="top" rowspan="2" colspan="1">43</td><td valign="top" rowspan="2" colspan="1">Pneumonitis (n = 1) / irAEs (including colitis and pneumonitis): n = 3</td><td valign="top" rowspan="1" colspan="1">Pneumonitis (n = 2), colitis (n = 1)</td><td valign="top" rowspan="2" colspan="1">0</td><td valign="top" rowspan="2" colspan="1">4</td><td valign="top" rowspan="2" colspan="1">Discontinuation: n = 4 (8%)</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Kanda et al.</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">6</td><td valign="top" colspan="2" rowspan="1">White blood cell count decreased (n = 3), neutrophil count decreased (n = 6), lymphocyte count decreased (n = 1), anemia (n = 1), platelet count decreased (n = 2), febrile neutropenia (n = 1)/select adverse events (those with a potential immunologic cause) (n = 0); number of patient was 6.</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">6</td><td valign="top" rowspan="1" colspan="1">No discontinuation.<break></break>NR</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Normann et al.</td><td valign="top" rowspan="1" colspan="1">Bev: 16 weeks<break></break>Nivo: 12 weeks</td><td valign="top" rowspan="1" colspan="1">5</td><td valign="top" rowspan="1" colspan="1">Hepatitis (n = 1)<break></break>There was a tendency toward increased toxicity when using concomitant bevacizumab [2 (40%) of 5 vs. 1 (11%) of 9].</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">Intestinal perforation (n = 1);<break></break>Believed to cause by bevacizumab</td><td valign="top" rowspan="1" colspan="1">3</td><td valign="top" rowspan="1" colspan="1">Grade 2 events continued treatment after administration of steroids (dosage NR)<break></break>Discontinuation because of nivolumab: n = 2 (14%)</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Shirali, et al.</td><td valign="top" rowspan="1" colspan="1">10 months</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">Acute interstitial nephritis (n = 1)</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">Hospitalization: methylprednisolone 125 mg i.v. for 3 days, followed by prednisone 60 mg/d p.o., which was tapered over the next month.</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Atezolizumab</td><td valign="top" rowspan="1" colspan="1">Wallin et al.</td><td valign="top" rowspan="1" colspan="1">Atez: 15.9 months</td><td valign="top" rowspan="1" colspan="1">10</td><td valign="top" colspan="2" rowspan="1">Hypertension (n = 3), acute respiratory failure (n = 1), hypercalcemia (n = 1), abdominal pain (n = 1)/n = 0</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">6</td><td valign="top" rowspan="1" colspan="1">NR</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">McDermott et al.</td><td valign="top" rowspan="1" colspan="1">Bev: 10.3 months<break></break>Atezb: 11.8 months</td><td valign="top" rowspan="1" colspan="1">101</td><td valign="top" colspan="2" rowspan="1">Fatigue (n = 2), diarrhea (n = 4), nausea (n = 1), palmar–plantar erythrodysaesthesia syndrome (PPE) (n = 2), decreased appetite (n = 2), stomatitis (n = 2), headache (n = 1), arthralgia (n = 1), proteinuria (n = 8)/elevated liver enzymes or hepatitis (n = 4).<break></break>TrAEs significantly increased with addition of bevacizumab (40 vs. 17%), but frequencies of irAEs were similar (5 [5%] of 101 vs. 3[3%] of 103).</td><td valign="top" rowspan="1" colspan="1">Intracrinal hemorrhage (n = 1)</td><td valign="top" rowspan="1" colspan="1">41</td><td valign="top" rowspan="1" colspan="1">Discontinuation: n = 9 (9%)<break></break>Dose modification or interruption: n = 61 (60%)</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Rini et al.</td><td valign="top" rowspan="1" colspan="1">12 months</td><td valign="top" rowspan="1" colspan="1">451</td><td valign="top" colspan="2" rowspan="1">Hypertension (n = 63), fatigue (n = 6), hypothyroidism (n = 1), diarrhea (n = 7), proteinuria (n = 15), rush (n = 3), arthralgia (n = 10), decreased appetite (n = 2), nausea (n = 1), stomatitis (n = 2), mucosal inflammation (n = 1), anemia (n = 1), thrombocytopenia (n = 3), neutropenia (n = 2)/rush (n = 3), hypothyroidism (n = 1), hyperthyroidism (n = 1), LFT abnormalities (n = 13), colitis (n = 4), pneumonitis (n = 4).<break></break>Frequency of trAEs was lower than that of sunitinib [182 (40%) of 451 vs. 240 (54%) of 446].</td><td valign="top" rowspan="1" colspan="1">Cerebral infarction (n = 1, with known hypercholesterolaemia), intracranial hemorrhage (n = 1, following a fall), adrenal insufficiency (n = 1, with a history of coronary artery disease and myocardial infarction), multiple organ dysfunction syndrome (n = 1, following a post-radiation ulcer with cecum perforation), sepsis (n = 1, following pneumonia)</td><td valign="top" rowspan="1" colspan="1">187</td><td valign="top" rowspan="1" colspan="1">Discontinuation:treatment regimen n = 24 (5%), any treatment component n = 53 (12%)<break></break>Systemic corticosteroids: n = 74 (16%)<break></break>High-dose systemic corticosteroids (prednisone ≥40 mg/d or equivalent): n = 42 (9%)</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Reck et al.</td><td valign="top" rowspan="1" colspan="1">Bev: 6.7 months<break></break>Atez: 8.2 months</td><td valign="top" rowspan="1" colspan="1">394</td><td valign="top" colspan="2" rowspan="1">Peripheral neuropathy (n = 11), nausea (n = 15), fatigue (n = 13), anemia (n = 24), decreased appetite (n = 10), diarrhea (n = 11), neutropenia (n = 54), hypertension (n = 25), arthralgia (n = 3), asthenia (n = 5), epistaxis (n = 4), vomiting (n = 6), decreased platelet count (n = 20), myalgia (n = 2), thrombocytopenia (n = 16), proteinuria (n = 10), decreased neutrophil count (n = 34), rush (n = 5), stomatitis (n = 4), febrile neutropenia (n = 33), decreased white blood cell count (n = 13), decreased weight (n = 4), alt increased (n = 4), dehydration (n = 8), AST increased (n = 4), leukopenia (n = 7), hypokalemia (n = 7), pulmonary embolism (n = 7), hyponatremia (n = 8), pneumonia (n = 7), pneumonitis (n = 4), colitis (n = 5), transaminases increased (n = 4), cerebrovascular accident (n = 1), sepsis (n = 1)/rash (n = 9), hepatitis (laboratory abnormalities) (n = 16), hypothyroidism (n = 1), hyperthyroidism (n = 1), pneumonitis (n = 6), colitis (n = 5), hepatitis (diagnosis) (n = 4), adrenal insufficiency (n = 1), pancreatitis (n = 2), hypophysitis (n = 1), nephritis (n = 1), ocular inflammatory toxicity (n = 1), myositis (n = 1), encephalitis (n = 1), meningoencephalitis (n = 1); information was from an article reporting the same trial (Socinski et al., 2018). TrAEs elevated with addition of bevacizumab or atezolizumab (56.7 vs. 43%, 56.7 vs. 48.5%). But the addition of bevacizumab did not significantly increased irAEs (12.5 vs. 9.5%).</td><td valign="top" rowspan="1" colspan="1">Febrile neutropenia (n = 3), hemoptysis (n = 3), pulmonary hemorrhage (n = 2), cerebrovascular accident (n = 1), aortic dissection (n = 1), intestinal obstruction (n = 1).<break></break>Information was from an article reporting the same trial (Socinski et al., 2018).<break></break>Treatment-related death elevated with addition of bevacizumab (2.8 vs. 1%), but the addition of atezolizumab did not significantly increased it (2.8 vs. 2.3%).</td><td valign="top" rowspan="1" colspan="1">234</td><td valign="top" rowspan="1" colspan="1">Discontinuation or interruption<break></break>No dose reduction for atezolizumab or bevacizumab<break></break>Steroids, dosage NR</td></tr><tr><td valign="top" rowspan="1" colspan="1">Ramucirumab</td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">26</td><td valign="top" colspan="2" rowspan="1">7</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">7</td><td valign="top" rowspan="1" colspan="1"></td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Pembrolizumab</td><td valign="top" rowspan="1" colspan="1">Arkenau et al.</td><td valign="top" rowspan="1" colspan="1">Ramu: 9 weeks<break></break>Pemb: 9.3 weeks</td><td valign="top" rowspan="1" colspan="1">26</td><td valign="top" rowspan="1" colspan="1">Hypertension (n = 5), alanine aminotransferase increased (n = 1), aspartate aminotransferase increased (n = 1)</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">7</td><td valign="top" rowspan="1" colspan="1">Discontinuation: n = 1 (3.8%)</td></tr><tr><td valign="top" rowspan="1" colspan="1">Apatinib</td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" colspan="2" rowspan="1">1</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1"></td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Nivolumab</td><td valign="top" rowspan="1" colspan="1">Zhao et al.</td><td valign="top" rowspan="1" colspan="1">About 7 months</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">Elevated aminotransferases (n = 1)</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">Discontinued and received liver-protecting drugs with magnesium isoglycyrrhizinate injection and transmetil for 3 weeks.</td></tr><tr><td valign="top" rowspan="1" colspan="1">Axitinib</td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">1003</td><td valign="top" colspan="2" rowspan="1">594</td><td valign="top" rowspan="1" colspan="1">8</td><td valign="top" rowspan="1" colspan="1">602</td><td valign="top" rowspan="1" colspan="1"></td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Pembrolizumab</td><td valign="top" rowspan="1" colspan="1">Atkins et al.</td><td valign="top" rowspan="1" colspan="1">14.5 months</td><td valign="top" rowspan="1" colspan="1">52</td><td valign="top" rowspan="1" colspan="1">Fatigue (n = 5), diarrhea (n = 5), hypertension (n = 12), increased alanine aminotransferase concentration (n = 4), decreased appetite (n = 1), nausea (n = 1), palmar–plantar erythrodysaesthesia (n = 2), increased aspartate aminotransferase concentration (n = 2), weight decreased (n = 2), proteinuria (n = 1), oral pain (n = 1), headache (n = 2), vomiting (n = 1), dizziness (n = 1)/diarrhea (n = 4), increased alanine aminotransferase concentration (n = 2), increased aspartate aminotransferase concentration (n = 2), fatigue (n = 2), weight decreased (n = 1), colitis (n = 1), lymphocyte count decreased (n = 1)</td><td valign="top" rowspan="1" colspan="1">Hyperuricemia (n = 1)/hyperuricemia (n = 1)</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">34</td><td valign="top" rowspan="1" colspan="1">Axitinib dose modification + symptomatic treatment: axitinib starting dose: 5 mg bid; dose level-1: 3 mg bid; dose level-2: 2 mg bid; permanently discontinued.<break></break>For pembrolizumab: hold treatment until toxicity was </td> </tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Rini et al.</td><td valign="top" rowspan="1" colspan="1">Pemb+axi: 8.3 months<break></break>Pemb: 9.2 months<break></break>Axi: 9.6 months</td><td valign="top" rowspan="1" colspan="1">429</td><td valign="top" colspan="2" rowspan="1">Diarrhea (n = 31), hypertension (n = 91), hypothyroidism (n = 1), fatigue (n = 10), palmar–plantar erythrodysesthesia (n = 22), alanine aminotransferase increased (n = 52), dysphonia (n = 1). Aspartate aminotransferase increased (n = 29), decreased appetite (n = 9), nausea (n = 2), proteinuria (n = 11), stomatitis (n = 3), mucosal inflammation (n = 4), pruritus (n = 1), arthralgia (n = 3), hyperthyroidism (n = 4), asthenia (n = 6), rash (n = 1), dysgeusia (n = 1), vomiting (n = 1), platelet count decrease (n = 1), anemia (n = 1), neutrophil (n = 1), neutrophil count decreased (n = 1)/hypothyroidism (n = 1), hyperthyroidism (n = 5), adrenal insufficiency (n = 3), hepatitis (n = 10, pneumonitis (n = 2), thyroiditis (n = 1), colitis (n = 8), severe skin reactions (n = 5), infusion reactions (n = 1), nephritis (n = 1), hypophysitis (n = 4), myasthenic syndrome (n = 2), myositis (n = 1), myocarditis (n = 2), pancreatitis (n = 2), type 1 diabetes mellitus (n = 1)</td><td valign="top" rowspan="1" colspan="1">Myasthenia gravis (n = 1), myocarditis (n = 1), necrotizing fasciitis (n = 1), pneumonitis (n = 1)/myasthenia gravis (n = 1), myocarditis (n = 1), pneumonitis (n = 1)<break></break>Incidence of treatment-related death was lower than that of sunitinib [4(0.9%) vs. 7 (1.6%)].</td><td valign="top" rowspan="1" colspan="1">270</td><td valign="top" rowspan="1" colspan="1">Interruption: n = 267 (62.2%)<break></break>Discontinuation of both pembrolizumab and axitinib: n = 35 (8.2%)<break></break>Dose reduction of axitinib: n = 86 (20%)<break></break>Steroids, dosage NR</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Wilky et al.</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">33</td><td valign="top" rowspan="1" colspan="1">Oral mucositis (n = 1), nausea or vomiting (n = 2), diarrhea (n = 1), abdominal pain or dyspepsia (n = 1), hypertension (n = 5), hemoptysis (n = 1), pneumothorax (n = 1), seizures (n = 2)/hyperglycemia (n = 1), autoimmune hepatitis (n = 1), autoimmune colitis (n = 1), autoimmune arthritis (n = 2)</td><td valign="top" rowspan="1" colspan="1">Elevated ALT, AST, or AP (n = 1), hypertriglyceridemia or hyperlipidemia (n = 1)</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">16</td><td valign="top" rowspan="1" colspan="1">Axitinib dose modification + symptomatic treatment: axitinib starting dose: 5 mg bid. If grade 2 or greater toxicity, dose level-1: 4 mg bid; dose level-2: 3 mg bid; dose level-3: 2 mg bid; permanently discontinued.<break></break>Steroids and discontinuation of study treatment: n = 3 (9%).<break></break>One patient with autoimmune arthritis was also given methotrexate and hydroxychloroquine.</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Avelumab</td><td valign="top" rowspan="1" colspan="1">Choueiri et al.</td><td valign="top" rowspan="1" colspan="1">Axi: 66.6 weeks<break></break>Ave: 66.0 weeks</td><td valign="top" rowspan="1" colspan="1">55</td><td valign="top" rowspan="1" colspan="1">Diarrhea (n = 2), hypertension (n = 16), fatigue (n = 2), PPE syndrome (n = 4), ALT increased (n = 4), rush (n = 1), AST increased (n = 1), amylase increased (n = 3), decreased appetite (n = 1), mucosal inflammation (n = 1), infusion-related reaction (n = 1), lipase increased (n = 1), nausea (n = 1), arthralgia (n = 1), weight decreased (n = 1), proteinuria (n = 2), hypophosphatemia (n = 2), blood triglycerides increased (n = 1), dehydration (n = 1), pain in extremity (n = 1), drug eruption (n = 1), dyslipidemia (n = 1), urticaria (n = 1), venous thrombosis (n = 1)/rash (n = 2), hepatitis (n = 2), colitis (n = 1)</td><td valign="top" rowspan="1" colspan="1">Amylase increased (n = 1), lipase increased (n = 3), hematoma (n = 1), pulmonary embolism (n = 1)</td><td valign="top" rowspan="1" colspan="1">Myocarditis (n = 1)</td><td valign="top" rowspan="1" colspan="1">33</td><td valign="top" rowspan="1" colspan="1">Dose interruption of avelumab: n = 1 (1.8%)<break></break>Discontinuation of avelumab: n = 7 (13%)<break></break>Discontinuation of axitinib: n = 4 (7%)<break></break>Dose reductions of axitinib: n = 28 (51%)<break></break>Steroids, dosage NR</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Motzer et al.</td><td valign="top" rowspan="1" colspan="1">Axi: 9.0 months<break></break>Ave: 8.6 months</td><td valign="top" rowspan="1" colspan="1">434</td><td valign="top" colspan="2" rowspan="1">Diarrhea (n = 22), hypertension (n = 106), fatigue (n = 13), PPE syndrome (n = 25), dysphonia (n = 2), nausea (n = 3), hypothyroidism (n = 1), stomatitis (n = 8), decreased appetite (n = 7), chills (n = 1), mucosal inflammation (n = 5), alanine aminotransferase increased (n = 21), rash (n = 2), dyspnea (n = 6), arthralgia (n = 1), infusion-related reaction (n = 7), aspartate aminotransferase increased (n = 12), weight decreased (n = 7), vomiting (n = 1), asthenia (n = 5), thrombocytopenia (n = 1), anemia (n = 1), neutropenia (n = 1)/n = 39, events NR</td><td valign="top" rowspan="1" colspan="1">Sudden death (n = 1), myocarditis (n = 1), necrotizing pancreatitis (n = 1)/n = 0</td><td valign="top" rowspan="1" colspan="1">249</td><td valign="top" rowspan="1" colspan="1">Discontinuation of both avelumab and axitinib: n = 33 (7.6%)<break></break>Dose reduction of axitinib: n = 183 (42.2%)<break></break>High-dose glucocorticoids (≥40 mg total daily dose of prednisone or equivalent): n = 48 (11.1%)</td></tr><tr><td valign="top" rowspan="1" colspan="1">Cabozantinib</td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1"></td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Nivolumab</td><td valign="top" rowspan="1" colspan="1">Bhat et al.</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">NR</td></tr><tr><td valign="top" rowspan="1" colspan="1">Cediranib</td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">14</td><td valign="top" rowspan="1" colspan="1">7</td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">7</td><td valign="top" rowspan="1" colspan="1"></td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Durvalumab</td><td valign="top" rowspan="1" colspan="1">Lee et al.</td><td valign="top" rowspan="1" colspan="1">>15 months</td><td valign="top" rowspan="1" colspan="1">14</td><td valign="top" rowspan="1" colspan="1">(1) Once-daily cediranib: lymphopenia (n = 1), anemia (n = 2), nausea (n = 1), diarrhea (n = 3), colitis (n = 1), fatigue (n = 1), headache (n = 1), hypertension (n = 3), pulmonary thromboembolism (n = 1), pulmonary hypertension (n = 1). Number of patient was 7; (2) intermittent cediranib:fatigue (n = 1)</td><td valign="top" rowspan="1" colspan="1">(1) Once-daily cediranib: lymphopenia (n = 1), pulmonary thromboembolism (n = 1); (2) intermittent cediranib: hypertension (n = 1)</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">7</td><td valign="top" rowspan="1" colspan="1">Discontinued or dose reduced of daily cediranib: n = 7 (87.5%)<break></break>Systemic corticosteroids, dosage NR</td></tr><tr><td valign="top" rowspan="1" colspan="1">Lenvatinib</td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">58</td><td valign="top" colspan="2" rowspan="1">40</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">41</td><td valign="top" rowspan="1" colspan="1"></td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Pembrolizumab</td><td valign="top" rowspan="1" colspan="1">Makker et al.</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">53</td><td valign="top" rowspan="1" colspan="1">Fatigue (n = 3), diarrhea (n = 4), palmar–plantar erythrodysesthesia syndrome (n = 3), hypertension (n = 18), proteinuria (n = 1), oral pain (n = 1), dehydration (n = 1), increased aspartate aminotransferase (n = 1), anemia (n = 1), hyponatremia (n = 2), increased lipase (n = 1), increased alanine aminotransferase (n = 1), prolonged electrocardiogram qt interval (n = 1), hypocalcaemia (n = 1), acute kidney injury (n = 2), pulmonary embolism (n = 2), syncope (n = 2), adrenal insufficiency (n = 1), cardiac failure (n = 1), colitis (n = 1), dysarthria (n = 1), hypertensive encephalopathy (n = 1), ischemic colitis (n = 1), neutropenia, pancreatitis (n = 1), retinal vein occlusion (n = 1), small intestinal obstruction (n = 1), upper abdominal pain (n = 1)/n = 30, irAEs (including skin, endocrine, gastrointestinal, pulmonary, hepatic, and renal adverse events), but grade NR</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">Intracranial hemorrhage (n = 1)</td><td valign="top" rowspan="1" colspan="1">37</td><td valign="top" rowspan="1" colspan="1">Discontinued: n = 5 (9%)<break></break>High-dose glucocorticoids (≥40 mg/d of prednisone or equivalent): n = 3 (10%)</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Iyer et al.</td><td valign="top" rowspan="1" colspan="1">5.6 months</td><td valign="top" rowspan="1" colspan="1">5</td><td valign="top" rowspan="1" colspan="1">Fatigue (n = 1), hypokalemia (n = 1), weakness (n = 1), altered mental status (n = 1), hypophosphatemia (n = 1)/2 patients had mild irAEs, including a grade 2 hepatic</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">4</td><td valign="top" rowspan="1" colspan="1">Grade 2 colitis: n = 1(20%), budesonide, dosage NR, and continued pembrolizumab<break></break>Grade 2 hepatitis: n = 1(20%), high dose of prednisone, and discontinued pembrolizumab.</td></tr><tr><td valign="top" rowspan="1" colspan="1">Pazopanib</td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">40</td><td valign="top" rowspan="1" colspan="1">18</td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">18</td><td valign="top" rowspan="1" colspan="1"></td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Pembrolizumab</td><td valign="top" rowspan="1" colspan="1">Qiao et al.</td><td valign="top" rowspan="1" colspan="1">About 15 months</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">NR</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Nivolumab</td><td valign="top" rowspan="1" colspan="1">Amin et al.</td><td valign="top" rowspan="1" colspan="1">Pazo: 13.9 months<break></break>Nivo: 15.1 months</td><td valign="top" rowspan="1" colspan="1">20</td><td valign="top" colspan="2" rowspan="1">Fatigue (n = 3), diarrhea (n = 4), hypertension (n = 2), increased alt (n = 4), increased AST (n = 4), hypothyroidism (n = 1), arthralgia (n = 1)/endocrine (n = 2), gastrointestinal (n = 4), hepatic (n = 4)</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">14</td><td valign="top" rowspan="1" colspan="1">Discontinuation: n = 5 (25%)<break></break>Systemic corticosteroid: n = 12(60%), including prednisone [n = 11 (55%)], dexamethasone [n = 2 (10%)], and methylprednisolone [n = 2 (10%)].</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Paoluzzi et al.</td><td valign="top" rowspan="1" colspan="1">Nivo: 8 cycles (16 weeks)</td><td valign="top" rowspan="1" colspan="1">18</td><td valign="top" rowspan="1" colspan="1">AST elevation (n = 1), ALT elevation (n = 3), alkaline bilirubin elevation (n = 2), pneumonitis (n = 1), colitis (n = 1).<break></break>The total number of patient who suffered grade 3/4 trAEs was 4.<break></break>The frequencies of trAEs significantly increased with addition of pazopanib [4 (22%) of 18 vs. 0 (0%) of 10].</td><td valign="top" rowspan="1" colspan="1">Bilirubin elevation (n = 1), AST elevation (n = 1)</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">4</td><td valign="top" rowspan="1" colspan="1">Discontinuation of both nivolumab and pazopanib: n = 4 (22%), among which, two patients restarted on treatment with both drugs, while one patient restart pazopanib only<break></break>High-dose steroids (prednisone 1 mg/kg/daily), with a slow taper over about 2 months: n = 3<break></break>One patients needed intubation.</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Yu-Li Su et al.</td><td valign="top" rowspan="1" colspan="1">4 months</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">NR</td></tr><tr><td valign="top" rowspan="1" colspan="1">Sorafenib</td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">7</td><td valign="top" colspan="2" rowspan="1">0</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1"></td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Pembrolizumab</td><td valign="top" rowspan="1" colspan="1">Chen et al.</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">To avoid tumor rupture, the schedule of pembrolizumab was changed to every 4 weeks starting in cycle three.</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Nivolumab</td><td valign="top" rowspan="1" colspan="1">Feng et al.</td><td valign="top" rowspan="1" colspan="1">Nivo: 7.1 cycles</td><td valign="top" rowspan="1" colspan="1">6</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">NR</td></tr><tr><td valign="top" rowspan="1" colspan="1">Sunitinib</td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">34</td><td valign="top" rowspan="1" colspan="1">27</td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">27</td><td valign="top" rowspan="1" colspan="1"></td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Nivolumab</td><td valign="top" rowspan="1" colspan="1">Amin et al.</td><td valign="top" rowspan="1" colspan="1">Suni: 28 months<break></break>Nivo: 45.1 months</td><td valign="top" rowspan="1" colspan="1">33</td><td valign="top" colspan="2" rowspan="1">Fatigue (n = 3), diarrhea (n = 3), nausea (n = 1), hypertension (n = 6), decreased appetite (n = 1), increased alt (n = 6), increased AST (n = 3), blood creatinine increased (n = 2), vomiting (n = 1)/skin (n = 2), gastrointestinal (n = 3), hepatic (n = 8), renal (n = 4), pulmonary (n = 1)</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">27</td><td valign="top" rowspan="1" colspan="1">Discontinuation of both nivolumab and sunitinib: n = 13(39.4%)<break></break>Systemic corticosteroid n = 13 (39.4%) (prednisone, dexamethasone, and methylprednisolone)</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Mahmoud et al.</td><td valign="top" rowspan="1" colspan="1">Suni: ≥11 months<break></break>Nivo: ≥8 months</td><td valign="top" rowspan="1" colspan="1">1</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">NR</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">0</td><td valign="top" rowspan="1" colspan="1">NR</td></tr></tbody></table></table-wrap><fig id="f2" position="float"><label>Figure 2</label><caption><p><bold>(A)</bold> Included studies and patients; X-axis: n, number of included studies. Severe trAE evaluation of concurrent use of antiangiogenic mAbs <bold>(B)</bold> or TKIs <bold>(C)</bold> with each class of ICIs.</p></caption><graphic xlink:href="fphar-10-01173-g002"></graphic></fig></sec><sec id="s3_2"><title>Toxicity of Concurrent ICIs and Antiangiogenic mAbs (Bevacizumab and Ramucirumab)</title><sec id="s3_2_1"><title>Anti-CTLA-4 (Ipilimumab)</title><p>One prospective study (<xref rid="B36" ref-type="bibr">Hodi et al., 2014</xref>) and one case series (<xref rid="B12" ref-type="bibr">Carter et al., 2016</xref>) were identified (<xref rid="T1" ref-type="table"><bold>Table 1</bold></xref>), examining concurrent ipilimumab and bevacizumab in melanoma and glioblastoma, respectively. The median dose of bevacizumab ranged from 7.5 to 15 mg/kg, and the dose of ipilimumab was 3 or 10 mg/kg every 3 weeks. Hodi et al. reported a total of 32 grade 3/4 trAEs in 13 patients, including one grade 4 hepatic and two grade 4 proteinuria. Among them, grade 3/4 trAEs in four cohorts were 5 (15.6%), 11 (34.4%), 6 (18.8%), and 10 (31.3%), respectively (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>). It seemed that the incidence of severe trAEs tended to elevate with the increase dose of bevacizumab. But it did not seem to increase the incidence of dermatologic or gastrointestinal side effects such as colitis, which were more concerning for ipilimumab treatment (<xref rid="B36" ref-type="bibr">Hodi et al., 2014</xref>). In addition, one case series reporting the combination regimen in glioblastoma observed seven grade 3 trAEs. However, all immune-related toxicities were manageable with corticosteroids, without diagnosing of endocrinopathies (<xref rid="B12" ref-type="bibr">Carter et al., 2016</xref>).</p><p>In summary, limited available data indicated potential toxicity of concurrent ipilimumab and bevacizumab. But at least, it did not seem to increase the incidence of some special interest irAEs. Data on the combination of ipilimumab and ramucirumab is lacking.</p></sec><sec id="s3_2_2"><title>Anti-PD-1 (Pembrolizumab and Nivolumab)</title><p>For pembrolizumab, there were two phase 1 trials (<xref rid="B4" ref-type="bibr">Arkenau et al., 2018</xref>; <xref rid="B30" ref-type="bibr">Gadgeel et al., 2018</xref>), two retrospective studies (<xref rid="B8" ref-type="bibr">Blumenthal et al., 2016</xref>; <xref rid="B46" ref-type="bibr">Kurz et al., 2018</xref>), and one case report (<xref rid="B88" ref-type="bibr">Wu et al., 2017</xref>). Among them, four were concerning combined with bevacizumab, and one was with ramolumab. In the study of Gadgeel et al. where 24 patients with advanced non-squamous NSCLC received concurrent pembrolizumab, bevacizumab, and chemotherapy, grade 3 trAEs occurred in 10 (42%) patients, which was similar to patients treated without bevacizumab [10 (40%)]. But the grade 3 irAEs (colitis, pneumonitis, and pancreatitis) and infusion reaction occurred in five (20.8%) and one (4%) patients treated with or without addition of bevacizumab (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>) (<xref rid="B30" ref-type="bibr">Gadgeel et al., 2018</xref>). In the two retrospective studies, concomitant use of pembrolizumab and bevacizumab in recurrent central nervous system (CNS) tumor was well tolerated, with no significant toxicity (<xref rid="B8" ref-type="bibr">Blumenthal et al., 2016</xref>; <xref rid="B46" ref-type="bibr">Kurz et al., 2018</xref>). The only one case report by <xref rid="B88" ref-type="bibr">Wu et al., 2017</xref> observed no grade 3–5 trAEs in one patient with urothelial carcinoma (UC) receiving such a concurrent regimen (<xref rid="B88" ref-type="bibr">Wu et al., 2017</xref>). There was only one phase 1 trial, treating a total of 26 patients with concurrent pembrolizumab and ramucirumab for advanced or metastatic biliary tract cancer (BTC). A total of seven (27%) grade 3 trAEs of 26 patients were observed, with hypertension accounting for 71% (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>) (<xref rid="B4" ref-type="bibr">Arkenau et al., 2018</xref>).</p><p>As for nivolumab, two retrospective studies on recurrent high-grade gliomas (HGGs) (<xref rid="B46" ref-type="bibr">Kurz et al., 2018</xref>; <xref rid="B54" ref-type="bibr">Mantica et al., 2018</xref>), one phase 1b trial and one case report on non-squamous NSCLC (<xref rid="B44" ref-type="bibr">Kanda et al., 2016</xref>; <xref rid="B77" ref-type="bibr">Shirali et al., 2016</xref>) and one prospective trial on platinum resistant ovarian cancer (<xref rid="B61" ref-type="bibr">Normann et al., 2019</xref>) were identified (<xref rid="T1" ref-type="table"><bold>Table 1</bold></xref>). In the two retrospective studies (n = 71 patients), a total of four (5.6%) patients experienced grade 3/4 trAEs, among which there were three cases of irAEs including colitis and pneumonitis (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>) (<xref rid="B46" ref-type="bibr">Kurz et al., 2018</xref>; <xref rid="B54" ref-type="bibr">Mantica et al., 2018</xref>). The phase 1b trial of concurrent nivolumab, bevacizumab, and chemotherapy for NSCLC patients observed a total of 14 grade 3/4 trAEs of 6 patients. However, all of them were hematological AEs, and no grade 3/4 irAEs were reported (<xref rid="B44" ref-type="bibr">Kanda et al., 2016</xref>). The prospective trial by Normann et al. observed a grade 3 hepatitis, and one death (grade 5) of intestinal perforation which was believed to be caused by bevacizumab in recurrent ovarian cancer patients. They also found that there was a tendency to increase toxicity when using concomitant nivolumab and bevacizumab [2 (40%) of 5 vs. 1 (11%) of 9] (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>) (<xref rid="B61" ref-type="bibr">Normann et al., 2019</xref>). Besides, Shirali, et al. reported one event of grade 3 acute interstitial nephritis in a progressive NSCLC patient treated with concurrent nivolumab and bevacizumab (<xref rid="B77" ref-type="bibr">Shirali et al., 2016</xref>).</p><p>In summary, although the available data was limited, it suggested that concurrent use of pembrolizumab/nivolumab and bevacizumab is relatively safe. The data on the combination of pembrolizumab/nivolumab and ramucirumab is insufficient for conclusions.</p></sec><sec id="s3_2_3"><title>Anti-PD-L1 (Atezolizumab)</title><p>Bevacizumab was combined with atezolizumab in four prospective studies (<xref rid="B83" ref-type="bibr">Wallin et al., 2016</xref>; <xref rid="B57" ref-type="bibr">McDermott et al., 2018</xref>; <xref rid="B72" ref-type="bibr">Reck et al., 2019</xref>; <xref rid="B74" ref-type="bibr">Rini et al., 2019b</xref>). Three were associated with unresectable or metastatic RCC, and one was about chemotherapy-naïve metastatic non-squamous NSCLC (<xref rid="T1" ref-type="table"><bold>Table 1</bold></xref>). The median follow-up ranged from 15 to 20.7 months. In total, 468 severe trAEs (≥grade 3), including 17 treatment-related deaths (grade 5), were reported of 956 patients (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>). But our search did not find studies on concurrent atezolizumab and ramucirumab.</p><p>In patients with RCC, grade 3/4 trAEs were observed in 228 (40.6%) of 562 patients, and also 6 (1.1%) grade 5 trAEs were reported, consisting of 2 intracranial hemorrhage, 1 cerebral infarction, 1 adrenal insufficiency, 1 multiple organ dysfunction syndrome, and 1 sepsis (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>). An early clinical trial reported six grade 3/4 trAEs, but none of them were deemed related to atezolizumab (<xref rid="B83" ref-type="bibr">Wallin et al., 2016</xref>). McDermott et al found that concurrent atezolizumab and bevacizumab led to a significantly increase of the incidence of grade 3–5 trAEs (40 <italic>vs</italic>. 17%), but the incidence of irAEs was similar (5 <italic>vs</italic>. 3%) (<xref rid="B57" ref-type="bibr">McDermott et al., 2018</xref>). The phase 3 trial of Rini et al. observed that patients given atezolizumab plus bevacizumab had lower frequency of grade 3/4 trAEs than that of sunitinib (40 <italic>vs</italic>. 54%) (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>) (<xref rid="B74" ref-type="bibr">Rini et al., 2019b</xref>). Regarding NSCLC, the only one phase 3 trial suggested that when adding atezolizumab to bevacizumab and chemotherapy, grade 3/4 trAEs and treatment-related death (grade 5) slightly elevated, while the increase degree was higher when adding bevacizumab to atezolizumab and chemotherapy. However, the addition of bevacizumab did not significantly increase the incidence of irAEs (12.5 <italic>vs</italic>. 9.5%) (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>) (<xref rid="B72" ref-type="bibr">Reck et al., 2019</xref>). Information about the AEs was from an article that reporting the same trial (<xref rid="B78" ref-type="bibr">Socinski et al., 2018</xref>).</p><p>In summary, concurrent atezolizumab and bevacizumab might increase trAEs, but not irAEs. In addition, no unexpected patterns of toxicity emerged in the combination therapy. Data about the combination of atezolizumab and ramucirumab is not available.</p></sec></sec><sec id="s3_3"><title>Toxicity of Concurrent ICIs and Antiangiogenic TKIs (Apatinib, Axitinib, Cabozantinib, Cediranib, Lenvatinib, Pazopanib, Sorafenib, Sunitinib)</title><sec id="s3_3_1"><title>Anti-PD-1 (Pembrolizumab, Nivolumab)</title><p>The concomitant use of pembrolizumab and antiangiogenic TKIs was examined in seven studies (<xref rid="B16" ref-type="bibr">Chen et al., 2017</xref>; <xref rid="B5" ref-type="bibr">Atkins et al., 2018</xref>; <xref rid="B41" ref-type="bibr">Iyer et al., 2018</xref>; <xref rid="B70" ref-type="bibr">Qiao et al., 2018</xref>; <xref rid="B53" ref-type="bibr">Makker et al., 2019</xref>; <xref rid="B73" ref-type="bibr">Rini et al., 2019a</xref>; <xref rid="B85" ref-type="bibr">Wilky et al., 2019</xref>), which were highly diverse in research and tumor types (<xref rid="T2" ref-type="table"><bold>Table 2</bold></xref>). In a phase 1b study, where a total of 52 RCC patients received concurrent pembrolizumab and axitinib, grade 3/4 trAEs were observed in 34 patients. The most common trAEs, such as diarrhea (8%) and elevations in liver-enzyme levels (8%), seemed to be largely related to axitinib rather than a true irAE predominantly due to pembrolizumab (<xref rid="B5" ref-type="bibr">Atkins et al., 2018</xref>). Similarly, the phase 3 trial by Rini et al. reported 270 (51%) grade 3 or higher toxicities of 429 patients (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>), which were as expected on the basis of the known profiles of each drug. Although there were four (0.9%) patients died from trAEs, none of them related to hepatic adverse that might be more challenging due to the overlapping toxicities of axitinib and pembrolizumab. Moreover, combined group had fewer treatment-related death than sunitinib [4 (0.9%) <italic>vs</italic>. 7 (1.6%)] (<xref rid="B73" ref-type="bibr">Rini et al., 2019a</xref>). We also found a phase 2 trial of this combined regimen for soft-part sarcoma. A total of 16 grade 3/4 trAEs occurred in 33 patients, and grade 3/4 irAEs in 5 (15%) patients (<xref rid="B85" ref-type="bibr">Wilky et al., 2019</xref>). Two studies examining concurrent pembrolizumab and lenvatinib were identified. In a phase 2 trial of metastatic endometrial cancer, Makker et al. observed 36 (68%) patients with grade 3 trAEs and a grade 5 intracranial hemorrhage. Among them, there were 30 irAEs in total, but the grade was not described in detail (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>) (<xref rid="B53" ref-type="bibr">Makker et al., 2019</xref>). One retrospective study for progressive anaplastic thyroid carcinoma (ATC) reported four grade 3 trAEs of five patients and some mild irAEs (such as grade 2 hepatitis) (<xref rid="B41" ref-type="bibr">Iyer et al., 2018</xref>). Two case reports about concurrent pembrolizumab and pazopanib for primary hepatic angiosarcoma (PHA) (<xref rid="B70" ref-type="bibr">Qiao et al., 2018</xref>) and pembrolizumab plus sorafenib for HCC (<xref rid="B16" ref-type="bibr">Chen et al., 2017</xref>) did not observe any significant toxicity.</p><p>Regarding nivolumab, there were three studies examining concurrent nivolumab and pazopanib (<xref rid="B64" ref-type="bibr">Paoluzzi et al., 2016</xref>; <xref rid="B2" ref-type="bibr">Amin et al., 2018</xref>; <xref rid="B90" ref-type="bibr">Yu-Li Su, 2018</xref>), two for combining with sunitinib (<xref rid="B52" ref-type="bibr">Mahmoud et al., 2016</xref>; <xref rid="B2" ref-type="bibr">Amin et al., 2018</xref>), and one for combining with apatinib (<xref rid="B91" ref-type="bibr">Zhao et al., 2019</xref>), cabozantinib (<xref rid="B7" ref-type="bibr">Bhat et al., 2019</xref>) or sorafenib (<xref rid="B26" ref-type="bibr">Feng et al., 2017</xref>), respectively (<xref rid="T2" ref-type="table"><bold>Table 2</bold></xref>). Zhao et al. observed grade 3 elevated aminotransferases in a patient with advanced liver carcinosarcoma treated with nivolumab plus apatinib (<xref rid="B91" ref-type="bibr">Zhao et al., 2019</xref>), while Bhat et al. did not observe severe trAEs in a patients treated with nivolumab plus cabozantinib (<xref rid="B7" ref-type="bibr">Bhat et al., 2019</xref>). In the phase 1 trial of Amin et al. 27 (81.8%) and 14 (70.0%) patients in arms nivolumab plus sunitinib and nivolumab plus pazopanib, respectively, experienced grade 3/4 trAEs, and 18 (55%) and 10 (50%) patients, respectively, experienced grade 3/4 irAEs (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>). The rate of arm nivolumab plus pazopanib was higher than that of arm nivolumab or pazopanib monotherapy in previous reports (<xref rid="B2" ref-type="bibr">Amin et al., 2018</xref>. Paoluzzi et al. reported 10 grade 3/4 trAEs in 4 (22.2%) patients receiving concomitant nivolumab and pazopanib, but no grade 3/4 trAEs occurred in nivolumab monotherapy group (<xref rid="B64" ref-type="bibr">Paoluzzi et al., 2016</xref>). Yu-Li Su et al. observed no toxicity after treatment of concurrent nivolumab and pazopanib in a patient with metastatic RCC (<xref rid="B90" ref-type="bibr">Yu-Li Su, 2018</xref>). Feng et al. analyzed nivolumab combined with sorafenib for advanced HCC in six patients and observed no severe toxicity (<xref rid="B26" ref-type="bibr">Feng et al., 2017</xref>), while Mahmoud et al. did not observe severe trAEs in a patient treated with nivolumab plus sunitinib (<xref rid="B52" ref-type="bibr">Mahmoud et al., 2016</xref>).</p><p>In summary, data on the toxicity of concurrent anti-PD-1 antibody and TKIs was conflicting. Some severe trAEs of the combination seemed to be largely related to TKIs, rather than a true irAE predominantly due to anti-PD-1 monotherapy. However, most studies were early phase clinical trials or case report, not randomized controlled studies with a large population, so the data is insufficient for conclusions.</p></sec><sec id="s3_3_2"><title>Anti-PD-L1 (Avelumab, Durvalumab)</title><p>Two prospective studies (<xref rid="B18" ref-type="bibr">Choueiri et al., 2018</xref>; <xref rid="B60" ref-type="bibr">Motzer et al., 2019</xref>) evaluated concurrent use of avelumab and axitinib on advanced RCC. A total of 282 (57.7%) in 489 patients experienced grade 3–5 trAEs, of which the most frequent were diarrhea, hypertension, fatigue, palmar–plantar erythrodysesthesia syndrome, and changes of liver enzymes (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>). In addition, in the phase 1b trial of Choueiri et al. where 55 patients received avelumab plus axitinib, one patient developed a fatal treatment-related autoimmune myocarditis (<xref rid="B18" ref-type="bibr">Choueiri et al., 2018</xref>). In the prospective phase 3 trial of Motzer et al., three (0.7%) treatment-related deaths were attributed to sudden death, myocarditis, and necrotizing pancreatitis, respectively (<xref rid="B60" ref-type="bibr">Motzer et al., 2019</xref>) (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>). However, the trAEs observed with combination therapy were generally consistent with the known safety profiles of monotherapy. No new toxicities were reported.</p><p>Currently, only one phase 1 trial, treating a total of 14 patients with concurrent durvalumab and cediranib for several recurrent or metastatic solid tumors, was found (<xref rid="T2" ref-type="table"><bold>Table 2</bold></xref>). Lee et al. observed 19 grade 3/4 trAEs occurred in 7 patients. In durvalumab plus intermittent cediranib, the severe AEs were only one grade 3 fatigue and one grade 4 hypertension. In contrast, daily cediranib with durvalumab was not well tolerated (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>) (<xref rid="B49" ref-type="bibr">Lee et al., 2017</xref>).</p><p>In summary, the very small number of patients treated with avelumab plus axitinib or durvalumab plus cediranib and lack of compared monotherapy group make it difficult to draw conclusions about their safety.</p></sec></sec><sec id="s3_4"><title>Management of irAEs</title><p>In the included literatures, holding the ICI treatment was the first thing for managing grade 3/4 irAEs, and most of studies did not reduce the dose of ICIs, with an exception for one. In the case, a patient with HCC had a low-grade fever relating to remarkable tumor necrosis. Thus, to avoid tumor rupture, the schedule of pembrolizumab was changed to every 4 weeks (<xref rid="B16" ref-type="bibr">Chen et al., 2017</xref>). Besides, high-dose corticosteroids (including prednisone, methylprednisolone, and dexamethasone) were the first line for treating irAEs, and often effective in alleviating symptoms (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>). As some severe trAEs that were largely related to the addition of antiangiogenic agents, reducing or holding dose, as well as adjusting administration frequency of the antiangiogenic drugs, were the other common ways to deal with treatment-related toxicity (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>) (<xref rid="B12" ref-type="bibr">Carter et al., 2016</xref>; <xref rid="B49" ref-type="bibr">Lee et al., 2017</xref>; <xref rid="B2" ref-type="bibr">Amin et al., 2018</xref>; <xref rid="B5" ref-type="bibr">Atkins et al., 2018</xref>; <xref rid="B18" ref-type="bibr">Choueiri et al., 2018</xref>; <xref rid="B60" ref-type="bibr">Motzer et al., 2019</xref>; <xref rid="B73" ref-type="bibr">Rini et al., 2019a</xref>; <xref rid="B85" ref-type="bibr">Wilky et al., 2019</xref>). In addition, the rest of trAEs were managed with symptomatic treatment such as drugs or surgery (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>).</p></sec></sec><sec sec-type="discussion" id="s4"><title>Discussion</title><p>In this review, we demonstrated the risk of added toxicity of concurrent ICIs and antiangiogenic agents, but there are not abundant of data from multi-institutional randomized controlled trials (RCTs) to draw an exact conclusion. From the available data, bevacizumab and axitinib were the most commonly used antiangiogenic agents for concomitant treatment. For other antiangiogenic drugs, available safety information is primarily based on small, retrospective single institution experiences, and even case report. In terms of tumor types, the three most numerous studies on concurrent ICIs and antiangiogenic agents were RCC, non-squamous NSCLC, and CNS tumors (including glioblastoma) (<xref rid="T1" ref-type="table"><bold>Tables 1</bold></xref> and <xref rid="T2" ref-type="table"><bold>2</bold></xref>). However, the combination of the two types of therapies is indeed a research hotspot at present, with a huge amount of ongoing trials (<xref rid="T4" ref-type="table"><bold>Table 4</bold></xref>).</p><table-wrap id="T4" position="float"><label>Table 4</label><caption><p>Parts of ongoing phase 2/3 clinical trials of ICIs combined with antiangiogenic agents.</p></caption><table frame="hsides" rules="groups"><thead><tr><th valign="top" rowspan="1" colspan="1">ICIs</th><th valign="top" rowspan="1" colspan="1">Antiangiogenic agents</th><th valign="top" rowspan="1" colspan="1">Primary tumor</th><th valign="top" rowspan="1" colspan="1">Status and end points</th><th valign="top" rowspan="1" colspan="1">CliniclTrials.gov identifier</th></tr></thead><tbody><tr><td valign="top" rowspan="1" colspan="1">Nivolumab</td><td valign="top" rowspan="1" colspan="1">Bevacizumab</td><td valign="top" rowspan="1" colspan="1">Glioblastoma</td><td valign="top" rowspan="1" colspan="1">Phase 2: recruiting (OS, ORR, DOR, and PFS)</td><td valign="top" rowspan="1" colspan="1">NCT03452579</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Ramucirumab</td><td valign="top" rowspan="1" colspan="1">Mesothelioma, malignant</td><td valign="top" rowspan="1" colspan="1">Phase 2: recruiting (ORR, AEa, PFS, and OS)</td><td valign="top" rowspan="1" colspan="1">NCT03502746</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Axitinib</td><td valign="top" rowspan="1" colspan="1">Renal cell carcinoma</td><td valign="top" rowspan="1" colspan="1">Phase 2: recruiting (AEs, ORR, DOR, PFS, OS, PD-L1 expression, and tumor infiltrating lymphocyte assessments, pharmacodynamic effect of study treatment including cytokines)</td><td valign="top" rowspan="1" colspan="1">NCT03172754</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Cabozantinib</td><td valign="top" rowspan="1" colspan="1">Renal cell carcinoma</td><td valign="top" rowspan="1" colspan="1">Phase 3: recruiting (PFS, OS, ORR, AEs, SAEs)</td><td valign="top" rowspan="1" colspan="1">NCT03141177</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Lenvatinib</td><td valign="top" rowspan="1" colspan="1">Advanced hepatocellular carcinoma</td><td valign="top" rowspan="1" colspan="1">Phase 2: recruiting (ORR, AEs, SAEs, TTP, PFS, OS, and translational research)</td><td valign="top" rowspan="1" colspan="1">NCT03841201</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Regorafenib</td><td valign="top" rowspan="1" colspan="1">Advanced and metastatic solid tumor</td><td valign="top" rowspan="1" colspan="1">Phase 1/2: recruiting (RD, MTD, ORR, PFS, DCR, OS, and AEs)</td><td valign="top" rowspan="1" colspan="1">NCT03406871</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Sunitinib</td><td valign="top" rowspan="1" colspan="1">Soft tissue sarcoma, bone sarcoma</td><td valign="top" rowspan="1" colspan="1">Phase 1/2: recruiting (PFSR, OS, ORR, immune response, tumor response, AEs, and clinical outcome)</td><td valign="top" rowspan="1" colspan="1">NCT03277924</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Sorafenib</td><td valign="top" rowspan="1" colspan="1">Hepatocellular carcinoma</td><td valign="top" rowspan="1" colspan="1">Phase: recruiting (MTD, ORR, DOR, AEs, irAEs, OS, and PFS)</td><td valign="top" rowspan="1" colspan="1">NCT03439891</td></tr><tr><td valign="top" rowspan="1" colspan="1">(Nivolumab + ipilimumab)</td><td valign="top" rowspan="1" colspan="1">Cabozantinib</td><td valign="top" rowspan="1" colspan="1">Genitourinary tumors</td><td valign="top" rowspan="1" colspan="1">Phase 2: recruiting (ORR, DOR, PFS, OS, CBR, AEs, and effects of treatment in patients with bone-only disease)</td><td valign="top" rowspan="1" colspan="1">NCT03866382</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Nintedanib</td><td valign="top" rowspan="1" colspan="1">Non-small-cell lung cancer metastatic</td><td valign="top" rowspan="1" colspan="1">Phase 1/2: recruiting (MTD, ORR, DCR, OS, and PFS)</td><td valign="top" rowspan="1" colspan="1">NCT03377023</td></tr><tr><td valign="top" rowspan="1" colspan="1">SHR 1210 (anti-PD-1 mAb)</td><td valign="top" rowspan="1" colspan="1">Apatinib</td><td valign="top" rowspan="1" colspan="1">Gastric cancer and HCC</td><td valign="top" rowspan="1" colspan="1">Phase 1/2: recruiting (OSR, tumor control rate, DCR, DOR, and AEs)</td><td valign="top" rowspan="1" colspan="1">NCT02942329</td></tr><tr><td valign="top" rowspan="1" colspan="1">Pembrolizumab</td><td valign="top" rowspan="1" colspan="1">Bevacizumab</td><td valign="top" rowspan="1" colspan="1">Colorectal cancer, metastatic cancer</td><td valign="top" rowspan="1" colspan="1">Phase 2: recruiting (ORR, PFS, OS, and AEs)</td><td valign="top" rowspan="1" colspan="1">NCT03475004</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Ramucirumab</td><td valign="top" rowspan="1" colspan="1">Head and neck squamous cell carcinoma</td><td valign="top" rowspan="1" colspan="1">Phase 1/2: recruiting (RP2D, ORR, AEs, DOR, PFS, OS, and changes in quality of life)</td><td valign="top" rowspan="1" colspan="1">NCT03650764</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Apatinib</td><td valign="top" rowspan="1" colspan="1">Advanced urothelial carcinoma, advanced MSI-H or dMMR solid tumors, advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma</td><td valign="top" rowspan="1" colspan="1">Phase 1/2: recruiting (DLTs, ORR, and PFS)</td><td valign="top" rowspan="1" colspan="1">NCT03407976</td></tr><tr><td valign="top" rowspan="1" colspan="1">(Pembrolizumab+ D-CIK)</td><td valign="top" rowspan="1" colspan="1">Axitinib</td><td valign="top" rowspan="1" colspan="1">Renal cancer metastatic</td><td valign="top" rowspan="1" colspan="1">Phase 2: recruiting (ORR, PFS, OS, DOR, the quality of life, and AEs)</td><td valign="top" rowspan="1" colspan="1">NCT03736330</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Anlotinib</td><td valign="top" rowspan="1" colspan="1">Advanced solid tumor</td><td valign="top" rowspan="1" colspan="1">Phase 2/3: recruiting (PFS, ORR, DCR, and OS)</td><td valign="top" rowspan="1" colspan="1">NCT03975036</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Cabozantinib</td><td valign="top" rowspan="1" colspan="1">Advanced metastatic melanoma</td><td valign="top" rowspan="1" colspan="1">Phase 1/2: not yet recruiting (DLTs, ORR, DCR, PFS, and OS)</td><td valign="top" rowspan="1" colspan="1">NCT03957551</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Lenvatinib</td><td valign="top" rowspan="1" colspan="1">Thyroid gland carcinoma</td><td valign="top" rowspan="1" colspan="1">Phase 2: recruiting (CR, AEs, PFS, OS, AEs, and biomarker levels)</td><td valign="top" rowspan="1" colspan="1">NCT02973997</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Regorafenib</td><td valign="top" rowspan="1" colspan="1">Metastatic colorectal cancer</td><td valign="top" rowspan="1" colspan="1">Phase 1/2: not yet recruiting (DLTs, PFS, and OS)</td><td valign="top" rowspan="1" colspan="1">NCT03657641</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Sunitinib</td><td valign="top" rowspan="1" colspan="1">Thymic carcinoma</td><td valign="top" rowspan="1" colspan="1">Phase 2: recruiting (ORR, AEs, OS, PFS, and PD-L1 expression)</td><td valign="top" rowspan="1" colspan="1">NCT03463460</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Sorafenib</td><td valign="top" rowspan="1" colspan="1">Hepatocellular carcinoma</td><td valign="top" rowspan="1" colspan="1">Phase 1b/2: recruiting (ORR, OS. TTP, change in functional activity of effector T cells, and levels of immunosuppressive cell PFS)</td><td valign="top" rowspan="1" colspan="1">NCT03211416</td></tr><tr><td valign="top" rowspan="1" colspan="1">Atezolizumab (MPDL3280A)</td><td valign="top" rowspan="1" colspan="1">Bevacizumab+chemotherapy</td><td valign="top" rowspan="1" colspan="1">Ovarian cancer</td><td valign="top" rowspan="1" colspan="1">Phase 3: recruiting (efficacy, TSST, OS, and AEs)</td><td valign="top" rowspan="1" colspan="1">NCT02891824</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Ramucirumab</td><td valign="top" rowspan="1" colspan="1">Non-small-cell lung cancer</td><td valign="top" rowspan="1" colspan="1">Phase 2: recruiting (OS, CBR, and irAEs)</td><td valign="top" rowspan="1" colspan="1">NCT03689855</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Cabozantinib</td><td valign="top" rowspan="1" colspan="1">Hepatocellular carcinoma</td><td valign="top" rowspan="1" colspan="1">Phase 3: recruiting (PFS and OS)</td><td valign="top" rowspan="1" colspan="1">NCT03755791</td></tr><tr><td valign="top" rowspan="1" colspan="1">Avelumab</td><td valign="top" rowspan="1" colspan="1">Ramucirumab++paclitaxel</td><td valign="top" rowspan="1" colspan="1">Gastroesophageal junction Adenocarcinoma/adenocarcinoma of the stomach</td><td valign="top" rowspan="1" colspan="1">Phase 2: recruiting (OSR, OS, PFS, PFSR, DOR, ORR et al.)</td><td valign="top" rowspan="1" colspan="1">NCT03966118</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Axitinib</td><td valign="top" rowspan="1" colspan="1">Non-small-cell lung cancer; urothelial cancer</td><td valign="top" rowspan="1" colspan="1">Phase 2: recruiting (ORR, TTR, tumor tissue biomarker status, ADA, DOR, PFS, Cmax of axitinib or avelumab, OS et al.)</td><td valign="top" rowspan="1" colspan="1">NCT03472560</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Regorafenib</td><td valign="top" rowspan="1" colspan="1">Metastatic solid tumors</td><td valign="top" rowspan="1" colspan="1">Phase 1/2: recruiting (pharmacokinetics, RP2D, antitumor activity, MTD, DLT, toxicity, ORR, PFS, and blood biomarkers et al.)</td><td valign="top" rowspan="1" colspan="1">NCT03475953</td></tr><tr><td valign="top" rowspan="1" colspan="1">Durvalumab</td><td valign="top" rowspan="1" colspan="1">Bevacizumab</td><td valign="top" rowspan="1" colspan="1">Hepatocellular carcinoma</td><td valign="top" rowspan="1" colspan="1">Phase 3: recruiting (RFS, OS, RFS24 h/36 h, TTR)</td><td valign="top" rowspan="1" colspan="1">NCT03847428</td></tr><tr><td valign="top" rowspan="1" colspan="1"></td><td valign="top" rowspan="1" colspan="1">Pazopanib</td><td valign="top" rowspan="1" colspan="1">Sarcoma</td><td valign="top" rowspan="1" colspan="1">Phase 2: not yet recruiting (progression free rate: antitumor efficacy)</td><td valign="top" rowspan="1" colspan="1">NCT03798106</td></tr><tr><td valign="top" rowspan="1" colspan="1">MEDI4736 (anti-PD-L1 mAb)</td><td valign="top" rowspan="1" colspan="1">Cediranib</td><td valign="top" rowspan="1" colspan="1">Colorectal neoplasms; breast neoplasms</td><td valign="top" rowspan="1" colspan="1">Phase 1/2: recruiting (RP2D and ORR)</td><td valign="top" rowspan="1" colspan="1">NCT02484404</td></tr></tbody></table></table-wrap><p>Usually, immune checkpoint blockade treatment is associated with multitude and atypical types of tumor responses and has specific toxicity profiles which are termed irAEs (<xref rid="B87" ref-type="bibr">Wolchok et al., 2009</xref>; <xref rid="B31" ref-type="bibr">Gordon et al., 2017</xref>). In general, within the first 3–4 months of treatment, 80% patients may experience irAEs (<xref rid="B17" ref-type="bibr">Chen et al., 2015</xref>; <xref rid="B58" ref-type="bibr">Michot et al., 2016</xref>). Because of the different functions of CTLA-4 and PD-1/PD-L1, the types and frequency of irAEs related to various checkpoint inhibitors were different (<xref rid="B58" ref-type="bibr">Michot et al., 2016</xref>). Anti-CTLA-4 antibodies mostly affect the skin (44%) and the gastrointestinal tract (35%), whereas the endocrine (6%) and hepatic (5%) systems are rarely affected (<xref rid="B9" ref-type="bibr">Boutros et al., 2016</xref>; <xref rid="B19" ref-type="bibr">Cousin and Italiano, 2016</xref>; <xref rid="B24" ref-type="bibr">Eggermont et al., 2016</xref>). The side effects of anti-PD-1/PD-L1 antibodies are less frequent and less severe than those of anti-CTLA-4 antibodies (<xref rid="B13" ref-type="bibr">Champiat et al., 2016</xref>; <xref rid="B69" ref-type="bibr">Puzanov et al., 2017</xref>). The main AEs of PD-1 and PD-L1 blocking agents are pneumonia, myalgia, hypothyroidism, arthralgia, and vitiligo (<xref rid="B9" ref-type="bibr">Boutros et al., 2016</xref>; <xref rid="B19" ref-type="bibr">Cousin and Italiano, 2016</xref>). In this review, the frequencies, types, and severities of irAEs that mentioned in most of studies were consistent with previous data for ICI treatment alone, and trAEs of combination regimen were largely consistent with the known safety profiles of each monotherapy. Besides, the data of included literatures suggested that some severe trAEs of the concurrent treatment were largely related to the addition of antiangiogenic agents, rather than a true irAEs caused by ICIs (<xref rid="B36" ref-type="bibr">Hodi et al., 2014</xref>; <xref rid="B5" ref-type="bibr">Atkins et al., 2018</xref>; <xref rid="B78" ref-type="bibr">Socinski et al., 2018</xref>; <xref rid="B72" ref-type="bibr">Reck et al., 2019</xref>). In addition, frequency of severe trAEs in ICI plus TKI groups was a little higher than that of ICIs plus mAbs groups, which may be explained by the multiple targets of TKIs. The toxicities consist of not only AEs related to the blockade of VEGR/VEGFR pathway but also AEs caused by additional targets inhibition (<xref rid="B15" ref-type="bibr">Chen and Cleck, 2009</xref>; <xref rid="B71" ref-type="bibr">Qin et al., 2019</xref>). For example, sunitinib (targeting VEGFR-1/2, PDGFR-α/β, Flt-3, and c-kit) is known to cause both neutropenia and thrombocytopenia as a result of VEGF inhibition and simultaneous inhibition of c-kit (<xref rid="B21" ref-type="bibr">Demetri et al., 2006</xref>; <xref rid="B15" ref-type="bibr">Chen and Cleck, 2009</xref>). Similarly, anemia and decrease of both platelet and neutrophil counts were observed in an included study of concurrent avelumab and axitinib (targeting VEGFR-1–3, PDGFR, and c-kit) (<xref rid="B55" ref-type="bibr">Matias et al., 2017</xref>; <xref rid="B73" ref-type="bibr">Rini et al., 2019a</xref>). Therefore, the selection of optimal components for combination therapy is worthy of further research.</p><p>In general, most irAEs are mild and manageable, although a few patients treated with ICIs develop severe irAEs (grade 3/4), even immune-related death (grade 5). Recommendations on the management of irAEs have been published as the guidelines in Europe and the United States (<xref rid="B69" ref-type="bibr">Puzanov et al., 2017</xref>; <xref rid="B10" ref-type="bibr">Brahmer et al., 2018</xref>; <xref rid="B33" ref-type="bibr">Haanen et al., 2018</xref>). Firstly, successful management of irAEs requires standardize grading based on the common terminology criteria for adverse events (CTCAE 4.0) grading. As for intervention, patients with grade 1 irAEs can continue immunotherapy, except for some neurologic, hematologic, and cardiac toxicities. Holding ICI treatment should be considered for most grade 2 irAEs until symptoms and/or laboratory values reduce to grade 1 or less and then treat them with locally or orally small doses of corticosteroids (0.5–1 mg/kg/d of prednisone or equivalent). For grade 3 irAEs, discontinuation of the ICI therapy and giving moderate to high-dose corticosteroids (prednisone 1–2 mg/kg/d or methylprednisolone i.v. 1 to 2 mg/kg/d) are recommended. Resuming treatment should be caution depending on the risk/benefit ratio. Regarding to life-threatening events (grade 4), hospitalization and high-dose corticosteroids (methylprednisolone i.v. 1-2 mg/kg/d) or other immunosuppressive measures (infliximab 5 mg/kg) are necessary. And ICI treatment should be permanently discontinued (<xref rid="B13" ref-type="bibr">Champiat et al., 2016</xref>; <xref rid="B69" ref-type="bibr">Puzanov et al., 2017</xref>; <xref rid="B10" ref-type="bibr">Brahmer et al., 2018</xref>). In the included studies, most of immune-related toxicities of the concurrent treatment were managed <italic>via</italic> holding ICI treatment and adding corticosteroids. Reducing dose or adjusting the administration frequency of the antiangiogenic drugs was also used to alleviate some symptoms of trAEs (<xref rid="T3" ref-type="table"><bold>Table 3</bold></xref>). However, the information concerning the new advances and management of irAEs are limited.</p><p>Recently, irAEs were considered as therapy-induced loss of tolerance, similar to autoimmune disorders (<xref rid="B9" ref-type="bibr">Boutros et al., 2016</xref>; <xref rid="B68" ref-type="bibr">Postow et al., 2018</xref>; <xref rid="B67" ref-type="bibr">Pauken et al., 2019</xref>). Thus, the known risk factors for autoimmunity may also predict the risk of irAEs. <xref rid="B38" ref-type="bibr">Hoefsmit et al. 2019</xref> searched for susceptible loci associated with various autoimmune diseases and pooled them in groups most likely to be associated with ICIs-induced irAEs (<xref rid="B38" ref-type="bibr">Hoefsmit et al., 2019</xref>), which may help to screening out patients with pre-existing subclinical autoimmune disorders or susceptibility to autoimmune diseases and guide physicians in a more refined and personal manner. Besides, depending on the degree of similarity between irAEs and autoimmune disorders, we can find reference in therapies developed for autoimmunity to manage irAEs (<xref rid="B67" ref-type="bibr">Pauken et al., 2019</xref>). For example, anti-TNF-α antibodies are usually used to treat steroid-refractory inflammatory bowel disease and could also alleviate ICIs-induced colitis (<xref rid="B22" ref-type="bibr">Dougan, 2017</xref>). Also, experts in autoimmune disorders should be involved in the care of cancer patients receiving ICIs. In addition, studies have found that gut microbiome is not only associated with the efficacy of immunotherapy but also with some specific irAEs, such as colitis (<xref rid="B63" ref-type="bibr">Osman and Luke, 2019</xref>). Thus, the ability to predict which patient has a high risk of developing ICI-induced colitis is very valuable to clinicians who have to weigh the potential risks and benefits of ICI therapy. Regarding to the combination of ICIs and antiangiogenic agents, the problem also includes the dose, optimal duration of treatment, and sequencing of each therapy. As is well known, anti-VEGF therapies have the window of normalization (<xref rid="B86" ref-type="bibr">Winkler et al., 2004</xref>; <xref rid="B40" ref-type="bibr">Huang et al., 2012</xref>), with the dose and duration time of antiangiogenic agents being the key modulating factors (<xref rid="B40" ref-type="bibr">Huang et al., 2012</xref>; <xref rid="B14" ref-type="bibr">Chaudhary et al., 2014</xref>). High dose or long duration time of antiangiogenic therapy are associated with aggressive ablation of the vasculature, leading to higher degree of hypoxia and immunosuppression (<xref rid="B40" ref-type="bibr">Huang et al., 2012</xref>; <xref rid="B1" ref-type="bibr">Allen et al., 2017</xref>). Thus, reducing the dose of antiangiogenic agents has been taken into account in the design of some clinical trials with the combination of ICIs (<xref rid="B27" ref-type="bibr">Fukumura et al., 2018</xref>). Besides, as vascular normalization can enhance delivery and distribution of ICIs in the tumor tissues, the low dose of ICIs may help to reduce the incidence and severity of irAEs (<xref rid="B27" ref-type="bibr">Fukumura et al., 2018</xref>). In addition, identification of predictive or prognostic markers is also expected to help screening suitable patients in order to prevent unnecessary side effects of combination therapy. Previous study found that expression level of PD-L1 was a predictive marker of the response to immunotherapy and also a negative prognostic marker in RCC patients receiving VEGF-targeted therapy (<xref rid="B76" ref-type="bibr">Shin et al., 2015</xref>). Angiopoietin 2 (ANG2), a vessel-destabilizing ligand of TIE2 and a critical regulator of blood vessel maturation, is a potential biomarker of resistance to anti-VEGF therapy (<xref rid="B6" ref-type="bibr">Bauerschlag et al., 2013</xref>; <xref rid="B43" ref-type="bibr">Jain, 2014</xref>; <xref rid="B47" ref-type="bibr">Labussiere et al., 2016</xref>). At the same time, evidence showing high serum level of ANG2 was inversely correlated with treatment response and prognosis of ICI treatment in metastatic melanoma patients (<xref rid="B20" ref-type="bibr">De Palma and Jain, 2017</xref>). Therefore, it is not so sensible to provide such a combined strategy for this kind of patients.</p><p>The current review has limitations that the number of available studies, especially RCTs, is insufficient. Even for some drugs, the data is lacking. These may partly due to the fact that many studies assessing the combination treatment of ICIs and antiangiogenic agents are still ongoing for this emerging area of research. Besides, the information about the new advances and management of irAEs in the included studies are limited. In addition, the review mainly focuses on three well known immune checkpoints, CTLA-4, PD-1, and PD-L1. However, identification of better biomarkers or therapeutic agents aimed at improving the clinical response in refractory patients and reducing irAEs is also necessary, which has led to the development of “next-generation” ICIs, such as T cell immunoglobulin mucin 3 (TIM-3), lymphocyte activation gene 3 (LAG-3), T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), indoleamine-2,3-dioxygenase 1 (IDO1), and so on (<xref rid="B56" ref-type="bibr">Mazzarella et al., 2019</xref>). Hundreds of registered past and ongoing clinical trials investigate the mechanism and efficiency of “next-generation” ICIs either as monotherapy or combining with other ICIs (<xref rid="B56" ref-type="bibr">Mazzarella et al., 2019</xref>; <xref rid="B81" ref-type="bibr">Tundo et al., 2019</xref>). Therefore, updated information is still required in the future.</p></sec><sec sec-type="conclusions" id="s5"><title>Conclusion</title><p>In summary, concurrent ICIs and antiangiogenic agents show potential treatment-related toxicity. Further research is required to compare the efficacy and safety of the combined regimen and the corresponding monotherapy. It is also necessary to explore dose, duration, and sequencing schedule of drugs, as well as identify predictive or prognostic biomarkers.</p></sec><sec id="s6"><title>Author Contributions</title><p>LG, XY and HZ conceived and designed the study. LG and XY screened, extracted the data, and wrote the manuscript. HZ and CY contributed to the revise of the manuscript.</p></sec><sec sec-type="funding-information" id="s7"><title>Funding</title><p>This research was supported by the Post-Doctor Research Project, West China Hospital, Sichuan University (NO. 2018HXBH032) and Sichuan Science and Technology Program (NO. 2019YFS0109).</p></sec><sec id="s8"><title>Conflict of Interest</title><p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p></sec></body><back><ref-list><title>References</title><ref id="B1"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Allen</surname><given-names>E.</given-names></name><name><surname>Jabouille</surname><given-names>A.</given-names></name><name><surname>Rivera</surname><given-names>L. 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