Kidney Disease Patient Representation in Trials of Combination Therapy With VEGF-Signaling Pathway Inhibitors and Immune Checkpoint Inhibitors: A Systematic Review

Combination therapy with vascular endothelial growth factor signaling pathway inhibitors (VSPIs) and immune checkpoint inhibitors (ICIs) has led to major improvements in cancer survival. These survival improvements have not been observed to the same degree in people with chronic kidney disease (CKD) and cancer. CKD is highly prevalent in people with cancer1Launay-Vacher V. Oudard S. Janus N. et al.Prevalence of renal insufficiency in cancer patients and implications for anticancer drug management: the renal insufficiency and anticancer medications (IRMA) study.Cancer. 2007; 110: 1376-1384https://doi.org/10.1002/cncr.22904Crossref PubMed Scopus (341) Google Scholar and is associated with reduced survival in those diagnosed with some types of cancer.2Lees J.S. Ho F. Parra-Soto S. et al.Kidney function and cancer risk: an analysis using creatinine and cystatin C in a cohort study.EClinicalMedicine. 2021; 38101030https://doi.org/10.1016/j.eclinm.2021.101030Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar People with CKD have been poorly represented in cancer trials,3Kitchlu A. Shapiro J. Amir E. et al.Representation of patients with chronic kidney disease in trials of cancer therapy.JAMA. 2018; 319: 2437-2439https://doi.org/10.1001/jama.2018.7260Crossref PubMed Scopus (37) Google Scholar and the evidence base for the use of ICI and VSPI in people with CKD is important because of their association with adverse kidney events.4Gao L. Yang X. Yi C. Zhu H. Adverse events of concurrent immune checkpoint inhibitors and antiangiogenic agents: a systematic review.Front Pharmacol. 2019; 10: 1173https://doi.org/10.3389/fphar.2019.01173Crossref PubMed Scopus (23) Google Scholar We assessed the extent to which people with markers of kidney disease are represented in clinical trials of combination therapy with ICI and VSPI. We systematically searched MEDLINE, EMBASE, and Cochrane library databases (PROSPERO CRD42022337942) and followed Preferred Reporting Items for Systematic Reviews and Meta-analyses statement guidelines. The inclusion criteria used the PICO (population, intervention, comparison, and outcome) framework and included adult populations with any solid organ cancer receiving concurrent ICI and VSPI treatment in phase II-IV trials. Two reviewers independently assessed published articles and extracted data. The study did not require ethics approval and used a systematic narrative synthesis with quantitative analysis. The primary outcomes of interest were: i) exclusion criteria related to kidney disease from trial protocols and ii) information about the representation of people with kidney disease in trials of combination therapy with ICI and VSPI. Initial search identified 4,893 references, of which 32 trials spanning April 6, 2018 to December 4, 2022 and evaluating 11,066 participants met our pre-specified inclusion criteria. Most participants were assessed in Phase III trials (12 of 32 trials, 87.5% of participants); the remaining participants were assessed in phase II trials. There were 10 different combinations of ICI and VSPI. We could not obtain 1 trial’s full eligibility criteria (Zhang et al 2021, representing 0.3% of participants); this trial was excluded from the analysis (Table 1).Table 1Trials that met eligibility criteria, with trial characteristics and exclusion criterion usedStudyVSPIICITrial Population (n)Tumor SiteExcluded With any Form of Kidney DiseaseExclusion Criterion DefinitionCreatinine Clearance Cut-off (mL/min)Were Patients with Proteinuria Excluded?Was Baseline Kidney Function Available?Were Patients on Immunosuppression Excluded?Were Patients With Solid Organ Transplants ExcludedPhase III randomized controlled trialsMotzer 2019AxitinibAvelumab886Renal cellYesCreatinine clearance50YesNoYesNoChoueiri 2021CabozantinibNivolumab651Renal cellYesSerum Creatinine in relation to upper limit of normal or Creatinine clearance40YesNoYesNoColombo 2021BevacizumabPembrolizumab617GynaeYesSerum Creatinine in relation to upper limit of normal or Creatinine clearance60UnspecifiedNoYesNoAndre 2020BevacizumabPembrolizumab307ColorectalYesSerum Creatinine in relation to upper limit of normal or Creatinine clearance60UnspecifiedNoYesNoMakker 2022LenvatinibPembrolizumab827GynaeYesSerum Creatinine in relation to upper limit of normal or Creatinine clearance30YesNoYesYesMoore 2021BevacizumabAtezolizumab1301GynaeYesSerum Creatinine in relation to upper limit of normalNAYesNoYesYesMotzer 2021LenvatinibPembrolizumab1069Renal cellYesCreatinine clearance30YesNoYesYesRini 2019 - keynoteAxitinibPembrolizumab861Renal cellYesSerum Creatinine or Creatinine clearance40YesNoYesYesFinn 2020BevacizumabAtezolizumab501LiverYesSerum Creatinine or Creatinine clearance50YesNoYesYesSugawara 2021BevacizumabNivolumab550LungYesSerum Creatinine or Creatinine clearance50UnspecifiedNoYesUnspecifiedSocinski 2018BevacizumabAtezolizumab1202LungYesSerum Creatinine in relation to upper limit of normalNAYesNoYesYesRini 2019 - ImmotionBevacizumabAtezolizumab915Renal cellYesMeasured or Creatinine clearance30YesNoYesYesPhase II randomized controlled trialsLheureux 2022CabozantinibNivolumab82GynaeYesSerum Creatinine in relation to upper limit of normal or Creatinine clearance50YesNoYesYesMettu 2022BevacizumabAtezolizumab133ColorectalYesCreatinine clearance50YesNoYesYesNayak 2021BevacizumabPembrolizumab80GBMYesSerum Creatinine in relation to upper limit of normalNAYesNoYesNoMcDermott 2018BevacizumabAtezolizumab305Renal cellYesSerum Creatinine in relation to upper limit of normal or Creatinine clearance40YesNoYesYesRedman 2022BevacizumabAvelumab26ColorectalYesCreatinine clearance30UnspecifiedNoYesYesPhase II non-randomized multi-arm trialsNayak 2022BevacizumabDurvalumab159GBMYesSerum Creatinine in relation to upper limit of normal or Creatinine clearance50YesNoYesYesAwada 2020AxitinibAvelumab54GBMYesCreatinine clearance30YesNoYesNoPhase II non-randomized single-arm trialsCousin 2021RegorafenibAvelumab46ColorectalYesCreatinine clearance30YesNoYesYesCousin 2022RegorafenibAvelumab34OtherYesCreatinine clearance30YesNoYesYesKawazoe 2020LenvatinibPembrolizumab29GastricYesSerum Creatinine in relation to upper limit of normalNAYesNoYesNoLam 2021BevacizumabAtezolizumab40LungYesSerum Creatinine in relation to upper limit of normal or Creatinine clearance50YesNoYesNoLee C 2022CabozantinibNivolumab47Renal cellYesSerum Creatinine in relation to upper limit of normal or Creatinine clearance30YesNoYesNoLee J2022BevacizumabAtezolizumab42LungYesCreatinine clearance30YesNoYesNoLiu 2019BevacizumabNivolumab38GynaeYesSerum Creatinine in relation to upper limit of normal or Creatinine clearance60YesNoYesNoMakker 2019LenvatinibPembrolizumab54GynaeYesSerum Creatinine in relation to upper limit of normal or Creatinine clearance40YesNoYesYesMcGregor 2019BevacizumabAtezolizumab60Renal cellYesCreatinine clearance30YesNoYesYesSeto 2022BevacizumabAtezolizumab39LungYesSerum CreatinineNAYesNoYesUnspecifiedWilky 2019AxitinibPembrolizumab33OtherYesSerum Creatinine in relation to upper limit of normal or Creatinine clearance60UnspecifiedNoYesUnspecifiedZhang 2021LenvatinibPembrolizumab38OtherUnspecifiedUnspecifiedNAUnspecifiedNoUnspecifiedUnspecifiedZsiros 2021BevacizumabPembrolizumab40GynaeYesCreatinine clearance60YesNoYesYesAbbreviations: n, number; VSPI, VEGF-signaling pathway inhibitor; ICI, immune checkpoint inhibitor; GBM, Glioblastoma; Gyne, Gynecological cancers; NA, not applicable. Open table in a new tab Abbreviations: n, number; VSPI, VEGF-signaling pathway inhibitor; ICI, immune checkpoint inhibitor; GBM, Glioblastoma; Gyne, Gynecological cancers; NA, not applicable. All trials contained at least 1 exclusion criterion pertaining to kidney disease. Creatinine Clearance (CrCl) was the most common exclusion criterion, either alone or in combination with another criterion (26 of 31 trials, 75.7% of participants). No trials using the criterion CrCl included people with CrCl of <30 mL/min. The CrCl cut-off values were inconsistent by trial phase, tumor site, publication year, and agents used in combination (Figure 1, Fig S1-S3). Six trials (6 of 31, 17.2% of participants) accepted alternatives measures of glomerular filtration rate (GFR). Participants with evidence of proteinuria were excluded in 26 of 31 trials (85.9% of participants). Semi-quantitative detection on urinalysis (24 of 31 trials, 84.9% of participants) was the most used exclusion criterion, either alone (3 of 31 trials, 1.1% of participants) or in combination with quantitative methods. All trials excluded people on immunosuppressive therapy. No trial published participants’ baseline kidney function or proteinuria in the primary results article. We found that all published trials of combination therapy with ICI and VSPI excluded people with evidence of kidney disease. No study included people with advanced CKD and few studies included people with proteinuria. The findings are concerning given that both drugs are associated with adverse kidney effects when used alone, and in combination.4Gao L. Yang X. Yi C. Zhu H. Adverse events of concurrent immune checkpoint inhibitors and antiangiogenic agents: a systematic review.Front Pharmacol. 2019; 10: 1173https://doi.org/10.3389/fphar.2019.01173Crossref PubMed Scopus (23) Google Scholar The under-representation of people with CKD in trials may undermine external validity of the trial and the generalizability of results. The evidence for administration of VSPI or ICI in advanced CKD is mainly from published case series or retrospective analysis. The paucity of safety data may deny the access of people with CKD to effective anti-cancer therapy or unnecessarily expose them to excess risk of adverse effects. All identified trials excluded people treated with immunosuppressive medications; however, the use of these agents in kidney transplant recipients is increasing. A recent analysis demonstrated high rates of transplant rejection following ICI initiation.5Murakami N. Mulvaney P. Danesh M. et al.A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant.Kidney Int. 2021; 100: 196-205https://doi.org/10.1016/j.kint.2020.12.015Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Concerns have been raised about heterogeneity regarding laboratory measurements used for cancer trial eligibility, including kidney function.6Sprangers B. Perazella M.A. Lichtman S.M. Rosner M.H. Jhaveri K.D. Improving cancer care for patients with CKD: the need for changes in clinical trials.Kidney Int Rep. 2022; 7: 1939-1950https://doi.org/10.1016/j.ekir.2022.06.005Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar The accuracy of creatinine-based GFR estimating equations is susceptible to several factors. Moreover, cancer patients may have reduced creatinine generation because of sarcopenia, leading to overestimation of GFR.7Chancharoenthana W. Wattanatorn S. Vadcharavivad S. Eiam-Ong S. Leelahavanichkul A. Agreement and precision analyses of various estimated glomerular filtration rate formulae in cancer patients.Sci Rep. 2019; 919356https://doi.org/10.1038/s41598-019-55833-0Crossref PubMed Scopus (20) Google Scholar Inaccuracies in GFR estimation could expose patients to potentially toxic doses or, conversely, to inadequate dosing of medications with reduced anti-cancer efficacy. Renalism, the systematic undertreatment of people with CKD, is not unique to cancer therapies.8Konstantinidis I. Nadkarni G.N. Yacoub R. et al.Representation of patients with kidney disease in trials of cardiovascular interventions.JAMA Intern Med. 2016; 176: 121-124https://doi.org/10.1001/jamainternmed.2015.6102Crossref PubMed Scopus (91) Google Scholar,9Major R. Selvaskandan H. Makkeyah Y.M. Hull K. Kuverji A. Graham-Brown M. The exclusion of patients with CKD in prospectively registered interventional trials for COVID-19—a rapid review of international registry data.J Am Soc Nephrol. 2020; 31: 2250-2252https://doi.org/10.1681/ASN.2020060877Crossref PubMed Scopus (21) Google Scholar Given that CKD is more common among older people, ethnic minorities, and those from socioeconomically deprived backgrounds,10Lees J.S. Hanlon P. Butterly E.W. et al.Effect of age, sex, and morbidity count on trial attrition: meta-analysis of individual participant level data from phase 3/4 industry funded clinical trials.BMJ Med. 2022; 1e000217https://doi.org/10.1136/bmjmed-2022-000217Crossref PubMed Google Scholar improving the evidence base of people with CKD is crucial in reducing health care inequalities. Limitations to this review include its strategy to capture eligibility criteria for original trials, potentially missing post-licensing data or pre-trial safety data. We may not have captured efforts to report the representation of participants with kidney disease in secondary trial publications. We could not find 1 of 32 full trial protocols; however, this trial included only 0.3% of the total number of participants. In conclusion, no trial included people with advanced CKD or kidney transplant recipients and few included people with proteinuria. Given CKD’s high prevalence in people with cancer and its association with worse cancer outcomes, targeted efforts should improve the representation of people with CKD in cancer trials to enhance external validity. Where exclusions are biologically justified, standardizing the approach using relevant markers of kidney function would improve the clinical application. Study design: all authors; search design: BMPE, SR, JSL; search performance, extraction and collation of data: BMPE, SR; data analysis: BMPE, JSL; data analysis and figures: BMPE; supervision: PBM, NNL, RJJ. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. This work was in part funded by a Chief Scientist Office Lectureship (number PCL/20/10) to Dr Lees. Outside the submitted work, Dr Lees reports personal fees from Pfizer, Astra Zeneca, and Bristol-Myers Squibb; Professor Mark reports personal fees and/or non-financial support from Vifor, Napp, Pharmacosmos, Astra Zeneca, Astellas, Novartis, and grants from Boehringer Ingelheim; Dr Lang reports personal fees and non-financial support from Roche, Pfizer, Novartis, Astra Zeneca, Pharmacosmos, Vifor Pharma, and grant support from Roche Diagnostics, Astra Zeneca, and Boehringer (all paid to the University of Glasgow, his employing institution). Professor Jones reports research support from Clovis, Astellas, Exelixis, AstraZeneca, and Roche, honoraria from Clovis, Astellas, AstraZeneca, Roche, Ipsen, Bristol-Myers-Squibb, Pfizer, Merck Serono, Merck Sharp Dohme, Janssen, Bayer, and Novartis. The remaining authors declare that they have no relevant financial interests. The views expressed in the submitted article are the authors’ and not an official position of the institution or funder. Received December 19, 2022. Evaluated by 2 external peer reviewers, with direct editorial input from the Editor-in-Chief. Accepted in revised form March 19, 2023. Download .pdf (.62 MB) Help with pdf files Supplementary File (PDF)Figure S1-S3.