1108691 research-article20222022 TAM0010.1177/17588359221108691Therapeutic Advances in Medical OncologyD Castellano, AB Apolo Therapeutic Advances in Medical Oncology Systematic Review Cabozantinib combination therapy for the Ther Adv Med Oncol 2022, Vol. 14: 1­–37 treatment of solid tumors: a systematic DOI: 10.1177/ https://doi.org/10.1177/17588359221108691 https://doi.org/10.1177/17588359221108691 17588359221108691 review © The Author(s), 2022. Article reuse guidelines: sagepub.com/journals- permissions Daniel Castellano , Andrea B. Apolo, Camillo Porta, Jaume Capdevila, Santiago Viteri, Cristina Rodriguez-Antona, Lidia Martin and Pablo Maroto Abstract Background: Cabozantinib monotherapy is approved for the treatment of several types of solid tumors. Investigation into the use of cabozantinib combined with other therapies is increasing. To understand the evidence in this area, we performed a systematic review of cabozantinib combination therapy for the treatment of solid tumors in adults. Methods: This study was designed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses, and the protocol was registered with PROSPERO (CRD42020144680). On 9 October 2020, we searched for clinical trials and observational studies of cabozantinib as part of a combination therapy for solid tumors using Embase, MEDLINE, and Cochrane databases, and by screening relevant congress abstracts. Eligible studies reported clinical or safety outcomes, or biomarker data. Randomized Correspondence to: Daniel Castellano and observational studies with a sample size of fewer than 25 and studies of cabozantinib Medical Oncology monotherapy were excluded. For each study, quality was assessed using National Institute Department, University Hospital 12 de Octubre, for Health and Care Excellence methodology, and the study characteristics were described Av Cordoba s/n, Madrid qualitatively. This study was funded by Ipsen. 28041, Spain daniel.castellano@salud. Results: Of 2421 citations identified, 32 articles were included (6 with results from randomized madrid.org studies, 24 with results from non-randomized phase I or II studies, and 2 with results from Andrea B. Apolo Center for Cancer both). The most commonly studied tumor types were metastatic urothelial carcinoma/ Research, National genitourinary tumors and castration-resistant prostate cancer (CRPC). Findings from Cancer Institute, National Institutes of Health, randomized studies suggested that cabozantinib combined with other therapies may lead to Bethesda, MD, USA better progression-free survival than some current standards of care in renal cell carcinoma, Camillo Porta Interdisciplinary CRPC, and non-small-cell lung cancer. The most common adverse events were hypertension, Department of Medicine, University of Bari ‘Aldo diarrhea, and fatigue. Moro’, Bari, Italy Conclusion: This review demonstrates the promising efficacy outcomes of cabozantinib Jaume Capdevila combined with other therapies, and a safety profile similar to cabozantinib alone. However, the Department of Medical Oncology, Vall d’Hebron findings are limited by the fact that most of the identified studies were reported as congress University Hospital, Vall d’Hebron Institute of abstracts only. More evidence from randomized trials is needed to explore cabozantinib as a Oncology, Barcelona, combination therapy further. Spain Santiago Viteri Dr. Rosell Oncology Institute, Teknon Medical Keywords: cabozantinib, non-small-cell lung cancer, renal cell carcinoma, solid tumor, Center, QuironSalud tyrosine kinase inhibitor, vascular endothelial growth factor Group, Barcelona, Spain Cristina Rodriguez- Antona Received: 13 November 2021; revised manuscript accepted: 6 June 2022. National Cancer Research Center, Madrid, Spain Lidia Martin Ipsen Pharma, Barcelona, Spain Introduction only available multitargeted vascular endothelial Pablo Maroto Medical Oncology Service, Cabozantinib, approved as monotherapy for the growth factor receptor (VEGFR) tyrosine kinase Hospital de la Santa Creu i treatment of several types of solid tumors, is the inhibitor (TKI) that targets VEGFR (VEGF-1, Sant Pau, Barcelona, Spain journals.sagepub.com/home/tam 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Medical Oncology Volume 14 VEGFR-2, and VEGFR-3) and also MET and modulated dendritic cells, suggesting an immu- AXL.1 By targeting VEGFR, cabozantinib inhib- nostimulatory role.22 its tumor blood vessel growth (angiogenesis) and promotes the vascular normalization of the Mouse models have been used to investigate the tumor.2 Simultaneous inhibition of abnormal combination of cabozantinib with anti-pro- MET signaling, which is associated with cell inva- grammed cell death protein 1 (anti-PD1) therapy, sion, metastasis, tumor proliferation, and angio- a type of immunotherapy, in HCC. Results genesis, and AXL signaling, which is linked with showed that the combination led to a higher increased proliferation, invasion, and metastasis, objective response rate (ORR) than cabozantinib allows cabozantinib to target multiple parallel key alone.23 This was explained by the enhanced pathways involved in tumor vascularization and effect of both therapies working to counteract growth.3–5 Cabozantinib also targets other spe- tumor-induced immunosuppression: cabozan- cific receptor tyrosine kinases involved in tumori- tinib by acting as an anti-angiogenic agent, and genesis, including RET, KIT, FLT3, ROS1, anti-PD1 by acting as a checkpoint inhibitor.23 A MER, TYRO3, TRKB, and TIE-2.6–8 The effi- recent study using machine-learning-based tech- cacy of cabozantinib monotherapy has been dem- nology investigated the potential synergistic onstrated in several solid tumor types, including effects of cabozantinib and anti-PD1 therapy in renal cell carcinoma (RCC),9,10 hepatocellular the treatment of metastatic RCC (mRCC) and carcinoma (HCC)11 and medullary thyroid can- reported that cabozantinib may enhance the cer12 based on data from phase II and III rand- impact of anti-PD1 therapy on immunosurveil- omized controlled trials (RCTs). Based on the lance via its actions on the innate and adaptive results from the COSMIC-311 study,13 the immune system, and that anti-PD1 therapy may Committee for Medicinal Products for Human enhance the anti-angiogenic and pro-apoptotic Use recently recommended the use of cabozan- effects of cabozantinib via action on angiogenesis tinib in differentiated thyroid carcinoma (DTC) and T-cell cytotoxicity.24 and a decision is pending in the European Union (EU). Evidence from these trials has supported In patients with metastatic urothelial carcinoma the approval of cabozantinib in these indications, (mUC) treated with cabozantinib, reductions in under specific conditions, in the EU14,15 and in the number of regulatory T cells and myeloid- the United States.16,17 derived suppressor cells were observed after treat- ment and were associated with clinical responses21; Cabozantinib also has the potential to be effective similar associations have been demonstrated in in combination with other therapies. Inhibition of patients with RCC treated with cabozantinib.25 In tumor angiogenesis and vascular normalization of addition, cabozantinib has been shown to increase the tumor allows for a synergistic effect when the number of CD8+ T cells in patients with combined with immunotherapy because, in a RCC.26 One study of patients with mRCC demon- normalized vascular network, it favors infiltration strated that patients treated with cabozantinib fol- and accumulation of immune effector cells within lowing immune checkpoint blockade (ICB) had the tumor.2,18 Given that it has multiple targets, higher response rates than patients who received cabozantinib may lead to additional synergistic ICB before treatment with cabozantinib.27 The US effects with immunotherapy beyond those of Food and Drug Administration and European other TKIs. For example, it blocks intracellular Medicines Agency have recently approved cabo- signaling pathways that drive epithelial–mesen- zantinib plus nivolumab for the first-line treatment chymal transition, which is associated with an of patients with advanced RCC (aRCC), based on immunosuppressive state and reduced sensitivity the evidence of a significant improvement in pro- to checkpoint inhibitors.19 Furthermore, cabo- gression-free survival (PFS; primary) and overall zantinib reduces the number of immunosuppres- survival (OS; secondary) with the combination sive cells, such as myeloid-derived suppressor compared with sunitinib in previously untreated cells and regulatory T cells, and increases the patients with clear-cell aRCC.28 number of peripheral and tumor-infiltrating cyto- toxic cluster of differentiation 8 (CD8)+ T In addition to immunotherapy, there is some sug- cells.20,21 In addition, a recent in vitro study gestion of cabozantinib having synergistic activity showed that cabozantinib triggered immunogenic with glutaminase inhibitors, which reduce glu- cell death in prostate cancer cells and directly tamine metabolism that is upregulated in some 2 journals.sagepub.com/home/tam D Castellano, AB Apolo et al. tumors and supports tumor angiogenesis.3,29,30 Association for Cancer Research. Prior to sub- There is also evidence that the activity of andro- mission of the article, searches were conducted gen deprivation therapy is likely to be enhanced for the full publication of studies already included by concomitant inhibition of angiogenesis with as abstracts. If the full manuscript was identified cabozantinib.31 Furthermore, combination treat- later, both the congress abstract and full article ment with cabozantinib may serve to block the are cited in the review; the data presented are development of MET-driven resistance observed from the more recent full article. with some therapies, such as endothelial growth factor receptor (EGFR) inhibitors,32–35 and the To identify the ongoing and planned trials for resistance to VEGFR inhibition with other TKIs cabozantinib as part of a combination therapy, driven by additional targets of cabozantinib, such searches of ClinicalTrials.gov were performed in as AXL and fibroblast growth factor receptor.36 November 2020 to identify ‘not yet recruiting’, ‘recruiting’, ‘enrolling’, and ‘active’ studies. The To consolidate the available evidence in this area, status of these trials was checked prior to final we performed a systematic literature review submission of the article (February 2022). (SLR) to identify the published clinical and observational data examining cabozantinib ther- apy in combination with other therapies for the Study selection and data collection treatment of solid tumors in adults. From these Citations identified by the searches were screened studies, we aimed to assess the evidence on the against prespecified criteria in accordance with clinical efficacy and safety profile of cabozantinib the 2009 Preferred Reporting Items for Systematic as part of a combination therapy for solid tumors. Reviews and Meta-Analyses guidelines.38 During screening, abstracts and titles were reviewed by a single reviewer against the inclusion/exclusion Materials and methods criteria to identify the relevant studies, and any uncertainties were resolved by a second reviewer. Search strategy Inclusion and exclusion criteria are presented in Published studies relating to the use of cabozan- Table 1. tinib as part of a combination therapy for the treat- ment of solid tumors were identified through a For the data extraction stage, study population systematic search. MEDLINE In-Process & Other data and key results relating to efficacy, safety, Non-Indexed Citations and Ovid MEDLINE and biomarkers were extracted manually for each (1946–present), Embase (1974–present), and the included study into an Excel worksheet. Cochrane Library were searched on 9 October 2020 using the Ovid platform (see Supplemental Resource 1 for search terms used in Embase). The Results protocol for the SLR is registered with the International Prospective Register of Systematic Overview of evidence Reviews (PROSPERO; registration name: An SLR Results of SLR. The electronic searches identified of cabozantinib for the treatment of solid tumors; 2421 citations (excluding duplicates), which were registration number: CRD42020144680).37 then screened. Of these, 386 were selected for full paper review. In addition, 19 articles were consid- ered relevant from the congress searches, and Supplementary searches three articles were identified from bibliographies The bibliographies of studies identified in the of studies identified in the electronic searches. electronic searches were reviewed to identify the After full paper review and review of congress additional relevant references. Congress abstracts abstracts and additional articles, 376 articles were were searched from 1 January 2016 to 9 October excluded; 58 of these were excluded according to 2020. The congresses included were American post hoc exclusion criteria (i.e. RCTs with a sam- Society of Clinical Oncology (ASCO), ASCO ple size of fewer than 25, and biomarker studies Gastrointestinal Cancers Symposium, ASCO carried out in cell lines, in vitro cultures or in vivo Genitourinary Cancers Symposium, European models). The final number of studies considered Society for Medical Oncology, and American relevant was 32 (Figure 1). journals.sagepub.com/home/tam 3 Therapeutic Advances in Medical Oncology Volume 14 Table 1. Eligibility criteria for studies identified by an SLR. Category Inclusion criteria Exclusion criteria Population • Patients with a solid tumor • Patients with non-solid tumors • Healthy volunteers • Non-human subjects Interventions • Cabozantinib in combination with other • No cabozantinib therapies • Cabozantinib monotherapy Comparator • Any • No exclusions • No comparator (i.e. single-arm studies) Outcomes • Clinical outcomes (ORR, OS, PFS, other • Outcomes not listed in inclusion criteria survival, and response outcomes) • Safety outcomes (AEs, number of dose reductions/discontinuations) • Outcomes related to biomarkers Study designs • Randomized trials (any phase) • Editorials and narrative reviews • Non-randomized phase I or II studies • Systematic reviews • Any study reporting data on biomarkers • MAs/NMAs (except those stated under exclusion criteria) • Non-randomized, non-observational studies that were not described as a phase I or phase II study Post hoc exclusion criteria* • Randomized or observational studies with sample size of fewer than 25 • Biomarker studies carried out in cell lines, in in vitro cultures or using models Date restrictions • Studies published between January 2012 and • Studies published before January 2012 date of search (9 October 2020) Country restrictions • No restriction Language • English language • Non-English language *These criteria were applied after the full paper review stage, prior to data extraction stage. AE, adverse event; MA, meta-analysis; NMA, network meta-analysis; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; SLR, systematic literature review. Characteristics of included studies. Of the 32 with another therapy, all but one of which also included articles, there were five articles reporting reported safety outcomes, and four articles that findings from RCTs, one reporting findings from reported safety outcomes only. Disease types a randomized discontinuation trial, 24 reporting studied for efficacy were as follows: RCC (6 arti- findings from non-randomized phase I or II stud- cles); non-small-cell lung cancer (NSCLC; 4 arti- ies and two reporting results from both a non-ran- cles); mUC (2 articles, 1 with RCC subgroup) or domized phase I study and a randomized phase II other genitourinary tumors (5 articles); castra- study. The characteristics of all included studies tion-resistant prostate cancer (CRPC; 6 articles); are presented in Table 2. In terms of quality assess- pancreatic ductal adenocarcinoma (PDAC; 2 ment, none of the 32 references had the highest articles); and metastatic colorectal cancer rating for internal validity. Poorer ratings were pre- (mCRC), high-grade gliomas, advanced HCC dominantly owing to a lack of study details (aHCC), hormone-naive metastatic prostate can- reported in congress abstracts (23 of the included cer, breast cancer brain metastases, metastatic references were abstracts, and nine were articles). triple-negative breast cancer, and recurrent endo- metrial cancer (1 article each). In addition, one The SLR identified 28 articles that include effi- article covered gastroesophageal adenocarcinoma cacy outcomes for cabozantinib in combination (GEA), colorectal cancer (CRC), and HCC. 4 journals.sagepub.com/home/tam D Castellano, AB Apolo et al. Figure 1. PRISMA diagram of included and excluded studies in the SLR. ITC, indirect treatment comparison; MA, meta-analysis; NMA, network meta-analysis; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCT, randomized controlled trial; SLR, systematic literature review. Prior to submission, six recently published full or a glutaminase inhibitor (telaglenastat) articles on studies included in the SLR as con- reported favorable efficacy outcomes with cabo- gress abstracts were identified and included in the zantinib combination therapy in patients with results. RCC.39,46,47,53,55,59,61,66 In the phase III study CheckMate 9ER, patients Efficacy of cabozantinib in combination with previously untreated aRCC [1:1, stratified Renal cell carcinoma. One phase III RCT inves- by International Metastatic RCC Database tigating the combination of cabozantinib and Consortium (IMDC) risk score, PD-L1 expres- nivolumab and four phase I/Ib studies assessing sion and region] were randomly assigned to the combination of cabozantinib with anti-PD-1/ receive nivolumab in combination with cabozan- PD-L1 immunotherapies [atezolizumab, pem- tinib (40 mg/day) (n = 323) or sunitinib (50 mg/ brolizumab, or nivolumab with or without ipili- day for 4 weeks of each 6-week cycle) (n = 328).46,47 mumab (anti-CTLA-4 monoclonal antibody)] All three efficacy endpoints were met. Nivolumab journals.sagepub.com/home/tam 5 6 Table 2. Study characteristics and quality assessment of included studies. First Country Study design Tumor type Line of therapy or Treatment dose Study Total number Number of patients Median Female, n (%) Quality author, patient treatment endpoints of patients receiving Cabo (range)* assessment publication history (primary/ age, years checklist (NICE)/ year secondary internal validity indicated if rating/external applicable) validity rating$ Medical Oncology Agarwal Multinational Phase Ib aRCC First line Cabo 40 or ORR, safety 12 12 65.5 (49–77) 4 (33) Cohort/–/– et al.39 study 60 mg/day; atezolizumab 1200 mg Q3W Agarwal Multinational Phase Ib mCRPC Overall, 27% of Cabo 40 mg/ ORR, DOR, 44 44 70 (49–90) 0 (0) Cohort/–/– Therapeutic Advances in et al.40 study patients had prior day orally; PFS, OS, safety docetaxel and atezolizumab 52% had ⩾2 prior 1200 mg IV Q3W novel hormonal therapies Al Harthy The United Pooled mCRPC No prior Fixed dose PFS, safety 44 32 Cabo + DP Not reported RCT/–/– et al.41 States analysis of a chemotherapy of docetaxel arm, 69 phase I study in the castrate (75 mg/m2 IV (45–84); DP and a phase setting day 1 of each only arm, 69 II RCT [RDT 21-day cycle) (50–83) because and prednisone 23 patients (5 mg orally (72%) re- BID), and quired dose Cabo at three reduction or escalating discontinua- dose levels in tion of Cabo] the Cabo + DP group: 20, 40. or 60 mg/day in the phase I cohort (all orally) and 40 mg/day in the phase II cohort Apolo The United Phase I study Advanced or Patients had 0 Escalating DLT, RP2D, 54 Cabo and nivolumab, 56 (20–82) 6 (11.1) Cohort/–/– et al.42 States metastatic (9%), 1 (35%), doses. Results ORR, PFS, OS, 24 (Cabo 40 mg, 12; UC and other or ⩾ 2 (56%) based on 40 and DCR, DOR Cabo 60 mg, 12); genitourinary prior systemic 60 mg doses of Cabo + tumors regimens Cabo nivolumab + ipilimumab, 30 (Cabo 40 mg, 24; Cabo 60 mg, 6) Barroso- The United Phase II mTNBC Median (range) Nivolumab ORR, PFS, 18 18 58 (41–71) 18 (100) Cohort/–/– Sousa States study number of 480 mg IV on clinical benefit et al.43,44‡ prior cytotoxic day 1, then rate (objective therapies, 1 (0–3) every 28 days; response or SD Cabo 40 mg/day ⩾24 weeks), orally safety (toxicity) (Continued) journals.sagepub.com/home/tam Volume 14 Table 2. (Continued) First Country Study design Tumor type Line of therapy or Treatment dose Study Total number Number of patients Median Female, n (%) Quality author, patient treatment endpoints of patients receiving Cabo (range)* assessment publication history (primary/ age, years checklist (NICE)/ year secondary internal validity indicated if rating/external applicable) validity rating$ Choudhury The United Phase I, mCRPC Patients had Three dose Safety, 27 27 [9 in the dose- 64 (61–70); 0 (0) Cohort/–/– journals.sagepub.com/home/tam et al.45 States open-label, 0–2 prior levels of antitumor escalation phase Cabo 20 mg dose- chemotherapy Cabo (20, 40, effect – (Part A) with 3 at (n = 12), 66 escalation regimens and 60 mg serologic each Cabo dose level (61–72); (3 + 3 design; orally QD); response and of 20, 40, and 60 mg; 40 mg Part A) abiraterone radiographic an additional 9 (n = 12), 62 and dose- acetate response patients were in each (61–67); expansion 1000 mg/day of the two expansion 60 mg (n = 3), (Part B) cohorts at Cabo 65 (60–68) study 20 and 40 mg dose levels (Part B)] Choueiri Multinational Randomized, aRCC First line Nivolumab PFS, OS, ORR, 651 323 (nivolumab and 62 (29–90) 74 (22.9) RCT/–/– et al.46,47‡ phase III (previously 240 mg IV safety Cabo) (Cabo + (Cabo + study untreated Q2W and Cabo nivolumab nivolumab patients) 40 mg orally QD cohort) cohort) versus sunitinib 50 mg orally for 4 weeks (6-week cycles) Corn et al.48 The United Phase II HNMPCa First line Cabo 60 mg/day Castrate- 62 62 62 (47–84) 0 (0) Cohort/–/– States study orally (starting resistant PFS, dosage; OS, safety, reductions to 40 radiographic and 20 mg/day responses, were allowed) biomarker and ADT (LHRH modulation agonist or in blood and antagonist) tumor tissues Da Motta The United Phase I mUC Median (range) Cabo 40 mg/day; ORR, OS, PFS, 30 29 (nivolumab and 64.5 (47–80) 8 (26.7) Cohort/–/– Girardi States expansion number of prior nivolumab 3 mg/ DOR, DCR, Cabo) et al.49,50‡ cohort study therapies, 2 (0–8) kg Q2W safety Karzai Not reported Phase I study mCRPC Not reported Fixed dose Safety, PFS 13 13 (Cabo/DP) Not reported Not reported Cohort/–/– et al.51 of docetaxel probability (75 mg/m2 IV day 1 of each 21-day cycle) and prednisone (5 mg orally Q12H) with Cabo at three escalating dose levels: 20, 40, or 60 mg/day (all orally) (Continued) 7 D Castellano, AB Apolo et al. 8 Table 2. (Continued) First Country Study design Tumor type Line of therapy or Treatment dose Study Total number Number of patients Median Female, n (%) Quality author, patient treatment endpoints of patients receiving Cabo (range)* assessment publication history (primary/ age, years checklist (NICE)/ year secondary internal validity indicated if rating/external applicable) validity rating$ Medical Oncology Keeler Not reported Phase I study mRCC Median (range) Cabo 40 and Safety, ORR 8 8 (pembrolizumab/ 52.5 (40–68) 2 (25) Cohort/–/– et al.52 number of prior 60 mg QD in Cabo) therapies, 1 (1–3) the first and second cohorts, respectively; pembrolizumab Therapeutic Advances in 200 mg IV Q3W in all cohorts Leone The United Two-stage Breast cancer Patients could Cabo 60 mg/day ORR in 36 36 (21 in cohort 1, Overall, 50 36 (100) Cohort/–/– et al.53 States phase II brain metastases have received orally, during patients with 7 in cohort 2, 8 in (28–69); study prior surgery, a 21-day cycle; HER2-positive cohort 3) cohort 1, radiation, trastuzumab metastatic 52 (28–69); or systemic 8 mg/kg IV breast cancer cohort 2, therapy for CNS loading dose and CNS 48 (40–62); metastases followed by metastases cohort 3, 48 6 mg/kg IV Q3W (primary); ORR (33–62) in hormone- receptor- positive and triple-negative breast cancer (secondary); also OS, PFS, and clinical benefit rate at 12 weeks Lheureux The United Randomized, Recurrent Second- or Cabo 40 mg/day PFS, ORR, 76 Arm A, 36; arm Not reported 76 (100) RCT/–/– et al.54 States and phase II endometrial later-line therapy and nivolumab response B, 18; arm C, 9 Canada study cancer for patients; at 240 mg on day outcomes carcinosarcoma least one prior 1 and day 15 of and 20 post- platinum-based a 28-day cycle immunotherapy, chemotherapy; for four cycles, including seven 55% received followed by patients crossed over ⩾3 prior lines of 480 mg every from arm B therapy 4 weeks (arm A) Nivolumab 240 mg on day 1 and day 15 of a 28-day cycle for four cycles, followed by 480 mg every 4 weeks (arm B) Patients with carcinosarcoma or prior immunotherapy were enrolled in an exploratory cohort and received combination treatment (arm C) journals.sagepub.com/home/tam Volume 14 (Continued) Table 2. (Continued) First Country Study design Tumor type Line of therapy or Treatment dose Study Total number Number of patients Median Female, n (%) Quality author, patient treatment endpoints of patients receiving Cabo (range)* assessment publication history (primary/ age, years checklist (NICE)/ year secondary internal validity indicated if rating/external applicable) validity rating$ McGregor Multinational Phase Ib nccRCC 7 patients (22%) Cabo 40 mg ORR, PFS, OS, 32 (2 from 32 (2 from dose 62 (37–78) 6 (19) Cohort/–/– journals.sagepub.com/home/tam et al.55 and study had received orally QD; DOR, safety dose escala- escalation and 30 Pal et al.56‡ prior VEGFR TKI atezolimib tion and 30 from dose expansion) therapy 1200 mg IV Q3W from dose expansion) Madan The United Phase I/II mCRPC Any prior Phase I study: PFS (for phase 44 [phase I Phase I study, 19; Phase I 0 (0) Cohort/–/– et al.31 States multicenter abiraterone for escalating II study) study, 19; phase II study, 13 study, study (initial mCRPC, n (%): doses of Cabo phase II study, 67 (45–84); phase I, phase I study, 20, 40, and 25 phase II open-label, 16 (84); phase 60 mg/day orally (arm study dose- II study arm 1, plus docetaxel 1 − Cabo + arm 1 escalation 4 (31); phase II (75 mg/m2 docetaxel + (Cabo + study study arm 2, 6 (50) IV Q3W with prednisone, docetaxel + followed by a Any prior prednisone 5 mg 13; arm 2 − prednisone), randomized, enzalutamide for orally BID) docetaxel + 69 (54–80); phase II trial) mCRPC, n (%): Phase II study: prednisone, phase II phase I study, based on the 12)] study arm 2 7 (37); phase II results of (docetaxel + study arm 1, 5 the phase I prednisone), (38); phase II study, study 69 (50–83) study arm 2, 8 (67) expanded into Any prior a randomized abiraterone and study of enzalutamide: docetaxel/ phase I study, prednisone with 4 (21); phase II the maximum study arm 1, 2 tolerated dose (15); phase II (40 mg) of study arm 2, 4 (33) Cabo versus Prior docetaxel/ chemotherapy prednisone (in castration- sensitive disease or as part of [neo] adjuvant clinical trials): phase I study, 2 (11); phase II study arm 1, 0 (0); phase II study arm 2, 2 (17) Marandino Italy Phase II UC Second- or later- Cabo 40 mg/ OS, PFS, ORR, 16 16 62 4 (25) Cohort/–/– et al.57,58‡ study line therapy for day orally; DOR, safety (interquartile patients; 4 (28%) durvalumab range, had received two 1500 mg IV 51–67) prior systemic every 28 days anticancer therapies (Continued) 9 D Castellano, AB Apolo et al. 10 Table 2. (Continued) First Country Study design Tumor type Line of therapy or Treatment dose Study Total number Number of patients Median Female, n (%) Quality author, patient treatment endpoints of patients receiving Cabo (range)* assessment publication history (primary/ age, years checklist (NICE)/ year secondary internal validity indicated if rating/external applicable) validity rating$ Medical Oncology Meric- Not reported Phase I study mRCC Median (range) Escalating Safety, ORR, 13 13 (Cabo/ Not reported Not reported Cohort/–/– Bernstam number of prior doses of the response telaglenastat) et al.59 therapies, 3 (0–7) glutaminase Patients with inhibitor clear-cell disease telaglenastat were required to (CB-839; Therapeutic Advances in have treatment 600–800 mg with ⩾1 prior orally BID) plus anti-VEGF therapy Cabo (60 mg orally QD) were evaluated using a 3 + 3 design Nadal Not reported Phase I Chemotherapy- Not reported Escalating Safety, ORR, 30 Patients with mUC Not reported Not reported Cohort/–/– et al.60 dose plus refractory mUC, doses DOR, PFS, OS nCPI: escalating expansion either naive or doses of Cabo/ cohorts study rCPI nivolumab, 15; Cabo/nivolumab/ ipilimumab, 8 patients with mUC rCPI: Cabo 40 mg/kg/ nivolumab 3 mg/kg, 7 Nadal Not reported Phase I plus mUC and other Not reported Seven dose Safety, ORR, 75 Cabo/nivolumab, 47; 59 (not Not reported Cohort/–/– et al.61 expansion genitourinary levels DOR, PFS, OS Cabo/nivolumab/ reported) (17) cohorts malignancies ipilimumab, 28 (including RCC) Neal et al.62 The United Phase II RCT Metastatic Patients had Oral daily doses Primary: PFS 115 76 Not reported Not reported RCT/–/– States (ECOG- non-squamous received of: erlotinib Secondary: ACRIN 1512) EGFR-wild-type 1–2 previous 150 mg; OS, RECIST NSCLC treatments Cabo 60 mg; v1.1 response, or erlotinib CTCAE v4 150 mg + Cabo toxicity 40 mg Neal et al.63 The United Phase II RCT Advanced Patients had Oral daily doses Primary: PFS 111 73 Mean 61 (55) RCT/+/+ States (ECOG- non-squamous received of: erlotinib Secondary: OS, (standard ACRIN 1512) EGFR-wild-type 1–2 previous 150 mg; best objective deviation), NSCLC treatments Cabo 60 mg; response, AEs 65.3 (9.6) or erlotinib 150 mg + Cabo 40 mg Neal et al.64 Multinational Phase 1b NSCLC After prior ICB Cabo 40 Primary: ORR, 30 30 67 (41–81) Not reported Cohort/–/– study mb/day; RECIST v1.1 (57) (COSMIC- atezolizumab Other: safety, 021, cohort 7) 1200 mg IV Q3W DOR, PFS, OS (Continued) journals.sagepub.com/home/tam Volume 14 Table 2. (Continued) First Country Study design Tumor type Line of therapy or Treatment dose Study Total number Number of patients Median Female, n (%) Quality author, patient treatment endpoints of patients receiving Cabo (range)* assessment publication history (primary/ age, years checklist (NICE)/ year secondary internal validity indicated if rating/external applicable) validity rating$ Pal et al.65 Multinational Phase 1b UC After prior Cabo 40 mb/day; Primary: ORR, 30 30 66 (44–84) Not reported Cohort/–/– journals.sagepub.com/home/tam study platinum- atezolizumab RECIST v1.1 (27) (COSMIC- containing 1200 mg IV Q3W Other: safety, 021, cohort 2) chemotherapy DOR, PFS, OS Pal Multinational Phase Ib ccRCC First line Cabo 40 or ORR, PFS, OS, 70 (10 70 (40 mg, 34; 60 mg, 40 mg 40 mg cohort: Cohort/–/– et al.66,56‡ study 60 mg orally QD; safety from dose 36) cohort: 68 7 (21) atezolizumab escalation and (39–87) 60 mg cohort: 1200 mg IV Q3W 60 from dose 60 mg 10 (28) expansion) cohort: 60 (42–82) Saeed The United Phase Ib, GEA, CRC, HCC Median (range) Cabo 20, 40, DLT, RP2D, 23 (8 GEA, 13 23 60 (33–79) 7 (30.4) Cohort/–/– et al.67 States gastrointes- number of prior and 60 mg/ ORR, PFS, OS, CRC, 2 HCC) tinal chemotherapies, day in the first, safety dose- 3 (1–3) second and escalation third cohorts, and respectively; expansion durvalumab basket trial 1500 mg IV Q4W in all cohorts Schiff The United Phase I, High-grade Patients had a Cabo 40 or Safety 26 26 56.5 (30–72) 10 (38.5) Cohort/–/– et al.68 States dose- gliomas newly diagnosed 60 mg/day; TMZ Arm 1 escalation (glioblastoma disease 200 mg/m2/day (Cabo + RT + TMZ): and or anaplastic on a 5-day cycle 60 mg, 3; 40 mg, 7 pharmacoki- glioma) Arm 2 (Cabo + TMZ): netic study arm 2a, 60 mg, 3; 40 mg, 7; arm 2c, 60 mg, 3; arm 2d, 60 mg, 3 Strickler Not reported Phase Ib mCRC Not reported 60 mg orally QD; OS, PFS, 25 25 (panitumumab/ 52.4 17 (68) Cohort/–/– et al.32,69‡ study panitumumab response, Cabo) (30.0–72.6) 6 mg/kg IV Q2W safety Sweeney Not reported Phase I study mCRPC Not reported Escalating Safety 21 21 (Cabo/ 60 Not reported Cohort/–/– et al.70 doses of Cabo abiraterone) (20, 40, and 60 mg/day); abiraterone 1000 mg/day Turk et al.71 The United Phase II PDAC Second line Cabo 40 mg/ ORR, PFS, OS, 7 7 62 (51–76) Not reported Cohort/–/– States study (median of day; erlotinib DCR one line of 100 mg/day prior systemic continuously chemotherapy) (Continued) 11 D Castellano, AB Apolo et al. 12 Table 2. (Continued) First Country Study design Tumor type Line of therapy or Treatment dose Study Total number Number of patients Median Female, n (%) Quality author, patient treatment endpoints of patients receiving Cabo (range)* assessment publication history (primary/ age, years checklist (NICE)/ year secondary internal validity indicated if rating/external applicable) validity rating$ Medical Oncology Wakelee The United Phase I/IIb NSCLC Patients enrolled Different dose AEs (primary), 92 28 Cabo arm, Cabo arm, 12 RCT/+/– et al.72 States study in phase I must levels depending ORR 54.7 (36–74); (80.0); Cabo/ have had failed on cohort: cohort Cabo/ erlotinib arm, prior treatment 1, Cabo 60 mg, erlotinib 7 (53.8) with erlotinib erlotinib 150 mg; arm, 64.8 cohort 2A, Cabo (44–78) Therapeutic Advances in 60 mg, erlotinib 100 mg; cohort 2B, Cabo 40 mg, erlotinib 150 mg; cohort 3A, Cabo 100 mg, erlotinib 100 mg; cohort 4A, Cabo 100 mg, erlotinib 50 mg Yau et al.73 Multinational Randomized aHCC First or later line Arm 1: ORR, safety 71 71 (arm 1, 36; arm Not reported Not reported Cohort/–/– study (sorafenib-naive nivolumab 2, 35) or -experienced) 240 mg Q2W; Cabo 40 mg/day Arm 2: nivolumab 3 mg/kg Q2W; ipilimumab 1 mg/ kg Q6W; Cabo 40 mg/day Zhen et al.74 The United Phase I study PDAC Patients were Escalating Primary: 12 12 (Cabo/ 61 (41–74) 6 (50) Cohort/–/– States excluded if they doses of Cabo maximum gemcitabine) had received >1 from 20 to tolerated dose prior systemic 80 mg/day; Other: safety, treatment gemcitabine OS, PFS, regimen for 1000 mg/m2 IV response locally advanced over 30 min on or metastatic days 1, 8 and 15 PDAC every 28 days *Median (range) age unless stated otherwise. $Quality assessment was performed on all articles identified in the systematic and initial supplementary searches. Internal validity addresses whether there is a risk of bias in the study findings, including selection bias, performance bias, attrition bias, and detection bias. External validity addresses whether the findings for the study participants apply to the whole source population and if similar findings are likely to be replicated in a different setting with a similar population. For both types of validity, the ratings are defined as follows: ++, all or most of the checklist criteria have been fulfilled and, for those that have not been fulfilled, the conclusions are very unlikely to alter; +, some of the checklist criteria have been fulfilled and, for those that have not been fulfilled or adequately described, the conclusions are unlikely to alter; −, few or no checklist criteria have been fulfilled, and the conclusions are likely or very likely to alter. Source: NICE checklists for randomized controlled trials, cohort studies and systematic reviews and meta-analyses.75 ‡Recent full articles identified prior to final submission and presenting updated data from included congress abstracts are cited together with the abstracts, and study information has been updated; quality assessment was only performed on the congress abstracts identified in the initial searches. ADT, androgen deprivation therapy; AE, adverse event; aHCC, advanced hepatocellular carcinoma; aRCC, advanced renal cell carcinoma; BID, twice daily; Cabo, cabozantinib; ccRCC, clear-cell renal cell carcinoma; CNS, central nervous system; CRC, colorectal cancer; CTCAE, Common Terminology Criteria for Adverse Events; DCR, disease control rate; DLT, dose-limiting toxicity; DOR, duration of response; DP, docetaxel plus prednisone; EGFR, epidermal growth factor receptor; GEA, gastroesophageal adenocarcinoma; HCC, hepatocellular carcinoma; HER2, human epidermal growth factor receptor 2; HNMPCa, hormone-naive metastatic prostate cancer; ICB, immune checkpoint blockade; IV, intravenously; LHRH, luteinizing hormone-releasing hormone; mCRC, metastatic colorectal cancer; mCRPC, metastatic castration-resistant prostate cancer; mRCC, metastatic renal cell carcinoma; mTNBC, metastatic triple-negative breast cancer; mUC, metastatic urothelial carcinoma; nccRCC, non-clear-cell renal cell carcinoma; nCPI, naive to checkpoint inhibitor; NICE, National Institute for Health and Care Excellence; NSCLC, non-small-cell lung cancer; ORR, objective response rate; OS, overall survival; PDAC, pancreatic ductal adenocarcinoma; PFS, progression-free survival; QD, once daily; Q2W, every 2 weeks; Q3W, every 3 weeks; Q12H, every 12 h; RCC, renal cell carcinoma; rCPI, refractory to checkpoint inhibitor; RCT, randomized controlled trial; RDT, randomized discontinuation trial; RECIST, Response Evaluation Criteria in Solid Tumors; RP2D, recommended phase II dose; RT, radiotherapy; SD, stable disease; TKI, tyrosine kinase inhibitor; TMZ, temozolomide; UC, urothelial carcinoma; VEGFR, vascular endothelial growth factor. journals.sagepub.com/home/tam Volume 14 D Castellano, AB Apolo et al. plus cabozantinib versus sunitinib significantly cabozantinib (40 mg/day) plus nivolumab and improved PFS (primary endpoint) by blinded ipilimumab (n = 6). Among all 13 patients, the central review [median: 16.6 months versus ORR was 53.9% and the DCR, defined as 8.3 months; hazard ratio (HR) for disease pro- CR + PR + stable disease (SD), was 100%.61 gression or death 0.51; 95% confidence interval Another study evaluated telaglenastat (CB-839, a (CI): 0.41–0.64; p < 0.001] and OS (probability glutaminase inhibitor) plus cabozantinib (60 mg/ at 12 months of 85.7% versus 75.6%; HR for day) as a second-line therapy (following treat- death, 0.60; 98.89% CI: 0.40–0.89; p = 0.0010). ment with mammalian target of rapamycin inhib- The ORR (95% CI) was significantly higher in itors or one or more anti-VEGFR therapies) in 13 the combination group than in the sunitinib group patients with mRCC (clear-cell or papillary his- [55.7% (50.1–61.2%) versus 27.1% (22.4– tology), and demonstrated an ORR of 42% and a 32.3%); p < 0.0001]; complete response (CR) DCR of 100%.59 In a study of eight patients was achieved in 8.0% and 4.6% of patients, receiving pembrolizumab and cabozantinib respectively, and the median duration of response (40 mg/day or 60 mg/day), the ORR was 25%, (DOR) was 20.2 months and 11.5 months, and the median number of prior therapies was 1 respectively. In subsequent analysis, with an (range: 1–3).52 extended median follow-up for OS of 32.9 (range: 25.4–45.4) months nivolumab plus cabozantinib Urothelial carcinoma. One single-arm phase II, versus sunitinib improved OS (median one phase Ib and one phase I study reported posi- 37.7 months versus 34.3; HR, 0.70; 95% CI: tive efficacy outcomes with the combination of 0.55–0.90); in addition, PFS and ORR benefits cabozantinib and anti-PD1 immunotherapy (dur- with N + C were sustained with minimum 2-year valumab, atezolizumab, or nivolumab with or follow-up.76 without ipilimumab) in patients with advanced urothelial carcinoma (UC) or mUC.42,49,50,57,58,65 Three abstracts and one recent full publication from the phase Ib COSMIC-021 study, which is In an interim analysis of a single-arm, phase II evaluating cabozantinib plus atezolizumab in var- study of 16 patients with advanced UC who ious solid tumors, reported efficacy outcomes in received cabozantinib (40 mg/day) and dur- patients with aRCC. In the dose-escalation stage valumab after platinum-based chemotherapy, in patients with treatment-naive aRCC [n = 12; objective responses were observed in six patients 10 with clear-cell RCC (ccRCC) and 2 with non- (37.5%) including two CRs (12.5%) and four clear cell RCC (nccRCC)], an ORR of 67% [1 PRs; response was ongoing at 8 months in one CR and 7 partial responses (PRs)] was observed patient with a RET short variant alteration with cabozantinib (40 mg/day or 60 mg/day) plus (P117T).57,58 atezolizumab.39 In a further analysis of treatment- naive patients with ccRCC receiving atezoli- Results from cohort 2 of the phase Ib zumab plus cabozantinib 40 mg/day (n = 34) or COSMIC-021 study, which is investigating cabo- 60 mg/day (n = 36), ORRs were 53% (80% CI: zantinib plus atezolizumab, showed an ORR of 41–65%) and 58% (80% CI: 46–70%), disease 27% in patients with locally advanced or mUC control rates (DCRs) were 94% and 92%, and who had received prior platinum-containing median PFS was 19.5 months and 15.1 months, chemotherapy (n = 30). The DCR was 64% and respectively.66 In the cohort of 32 patients with the median (range) PFS was 5.4 (0–17.3) nccRCC (two from dose escalation and 30 from months.65 dose expansion), of whom seven had received prior VEGFR TKI therapy, cabozantinib 40 mg/ One phase I dose-escalation study compared out- day plus atezolizumab was associated with an comes in 54 patients with mUC and other meta- ORR of 31% (80% CI: 20–44%; all confirmed static genitourinary tumors following treatment PRs), a DCR of 94%, and a median DOR of with cabozantinib plus nivolumab, and cabozan- 8.3 months.55 tinib plus nivolumab and ipilimumab.42 The median (95% CI) PFS and OS were 5.1 (3.5–6.9) Three other phase I studies measured ORR in months and 12.6 (6.9–18.8) months, respec- patients with mRCC treated with cabozantinib in tively. In the 49 patients evaluable for tumor combination with another therapy.52,59,61 Of response, ORR (95% CI) was 30.6% (18.3– these, one study included patients receiving cabo- 45.4%), and four patients (8.2%) had a CR. ORR zantinib (40 mg/day) plus nivolumab (n = 7), or was numerically higher in patients (n = 23) who journals.sagepub.com/home/tam 13 Therapeutic Advances in Medical Oncology Volume 14 received cabozantinib plus nivolumab than in DP. Patients in each arm had the same median those (n = 26) who received cabozantinib plus age (69 years), but those in the cabozantinib com- nivolumab and ipilimumab (39.1% versus 23.1%). bination arm (n = 32) had lower median prostate- Among those with evaluable responses, the DCR specific antigen than patients in the DP arm (95% CI) was 77.6% (63.4–88.2%) and the (n = 12) (74.8 ng/mL versus 309.5 ng/mL). median (95% CI) DOR was 21.0 (5.4–24.1) Patients in the cabozantinib combination arm months. DCR was 82.6% in patients who received had a longer median (95% CI) PFS [13.6 (8.31– cabozantinib plus nivolumab and 73.1% in those 21.0) months] than those in the DP arm [6.6 who received cabozantinib plus nivolumab and (2.9–10.4) months; p value not reported].41 In the ipilimumab. In the expansion study, involving 29 original phase I study, which included 13 patients patients with mUC who received prior ICB treat- receiving a combination of cabozantinib and DP, ment with cabozantinib 40 mg/day and nivolumab, the probability of PFS was 90% at 6 months and the median (95% CI) PFS and OS were 3.6 (2.1– 67.5% at 8 months.51 5.5) months and 10.4 (5.8–19.5) months, respec- tively; ORR was 13.8% (one patient with CR, In another phase I/II study, 19 patients with three patients with PR).49,50 mCRPC received escalating doses of cabozan- tinib (20, 40, and 60 mg/day) plus DP in the Gynecological cancer. In one randomized phase II phase I part of the study, with a median time to study of cabozantinib (40 mg/day) and nivolumab progression (TTP) and OS of 13.6 months and (n = 36) versus nivolumab (n = 18) in women with 16.3 months, respectively. In the randomized recurrent endometrial cancer, median (95% CI) phase II expansion part of the study, which was PFS was significantly longer in those receiving terminated early owing to poor accrual, compari- cabozantinib plus nivolumab than in those receiv- son of cabozantinib plus DP (n = 13) with DP ing nivolumab alone [5.3 (3.5–9.5) months versus (n = 12) showed a median TTP of 21.0 months 1.9 (1.6–3.8) months; log-rank p = 0.07]. Analysis versus 6.6 months (p = 0.035) and a median OS of of the tumor microenvironment to identify pre- 23.8 months versus 15.6 months (p = 0.072), dictive immune biomarkers of response is ongo- respectively.31 ing in this study.54 Interim results from cohort 6 of the phase Ib Prostate cancer. A phase II study reported prom- COSMIC-021 study, which is evaluating cabo- ising clinical activity with the combination of zantinib (40 mg/day) plus atezolizumab in patients cabozantinib and androgen deprivation therapy with a range of solid tumors, including 44 patients in patients with hormone-naive metastatic pros- with mCRPC, demonstrated an ORR of 32% (2 tate cancer.48 Two phase I/II studies demonstrated CRs and 12 PRs).40 Recently reported results for a clinical benefit of the combination with cabo- the expanded cohort 6 of 132 mCRPC patients zantinib and prednisone (DP) compared with DP with a median (range) follow-up of 15.2 months alone in patients with metastatic CRPC showed ORR by investigator among all patients (mCRPC).31,41,51 In addition, a phase Ib study per RECIST 1.1 was 23%, ORR by independent showed clinically relevant activity with the combi- review (BIRC) was 15% and DCR was 84% by nation of cabozantinib and atezolizumab in investigator, and 81% by BIRC (Blinded patients with mCRPC.40 Independent Central Review).77 Evaluation of cabozantinib (60 mg/day) plus Gastrointestinal cancers. Five studies reported androgen deprivation therapy in a phase II study outcomes in patients with gastrointestinal can- of 62 patients with hormone-naive metastatic cers, including three that showed encouraging prostate cancer (median follow-up: 31.2 months) clinical activity with: cabozantinib in combination showed that median (95% CI) PFS was 16.1 with either nivolumab or durvalumab in patients (14.6–22.7) months, whereas median OS was not with HCC; cabozantinib plus durvalumab in reached.48 patients with advanced GEA and CRC; and cabo- zantinib plus panitumumab in patients with A pooled analysis of a phase I study and a rand- mCRC.32,67,69,71,73,74 omized phase II study reported outcomes in 44 patients with mCRPC with no prior chemother- In the phase I/II CheckMate 040 study, patients apy, who had received docetaxel plus DP or a with aHCC were randomized to receive cabozan- combination of cabozantinib (20–60 mg/day) and tinib (40 mg/day) and nivolumab, or cabozantinib 14 journals.sagepub.com/home/tam D Castellano, AB Apolo et al. plus nivolumab and ipilimumab. In the cabozan- progression in the 1–2 months after initiating tinib and nivolumab arm, ORR was 17% (6 PRs), treatment, and the trial was stopped owing to DCR was 81%, and median PFS was 5.5 months, futility.71 whereas, in the cabozantinib plus nivolumab and ipilimumab arm, ORR was 26% (9 PRs), DCR Non-small-cell lung cancer. One RCT and one was 83%, and median PFS was 6.8 months. phase Ib/II study investigated the efficacy out- Median OS was not reached in either arm.73 comes with cabozantinib plus erlotinib in patients with NSCLC but reported inconsistent results; In a phase Ib study of 25 patients with chemo- one phase Ib study reported the encouraging effi- therapy refractory KRAS wild-type mCRC, out- cacy outcomes with the combination of cabozan- comes were measured after treatment with tinib and atezolizumab in patients with NSCLC. cabozantinib (60 mg/day) and panitumumab.32,69 Median (95% CI) OS and PFS were 12.1 (7.5– In the analyses of a phase II RCT of patients who 14.3) months and 3.7 (2.3–7.1) months, respec- received cabozantinib (60 mg/day) (n = 39), cabo- tively. Of the 25 patients treated, 13 had received zantinib (40 mg/day) plus erlotinib (n = 37), or prior anti-epidermal growth factor receptor (anti- erlotinib alone (n = 39) in a second- or third-line EGFR) therapy, and four patients (16%) had a setting (with no prior erlotinib or MET TKI ther- confirmed PR.32 apy),62,63 the primary endpoint was PFS, with 91% power to detect an HR of 0.5. Cabozantinib Cabozantinib (20, 40, and 60 mg/day) in combi- and cabozantinib plus erlotinib both had signifi- nation with durvalumab was assessed in patients cantly better PFS than erlotinib alone [HRs 0.39 with advanced GEA, CRC, and HCC in the (80% CI: 0.27–0.55) and 0.37 (80% CI: 0.25– phase Ib CAMILLA study. Preliminary analysis 0.53), respectively].63 Cabozantinib groups also of the 19 patients with evaluable responses demonstrated significantly better OS (secondary showed an ORR of 21% (four PRs: two in patients endpoint) than erlotinib alone. In a phase Ib/II with GEA and two in patients with CRC), a clini- study of cabozantinib (40–100 mg/day) with or cal benefit rate of 84% and a median time to pro- without erlotinib in 64 patients with no prior gressive disease (PD) of 16 weeks (range: 8–40+ VEGFR TKI therapy, the ORR was 6.7% (90% weeks).67 In recently report results on the phase II CI: 0.3–27.9%) in the cabozantinib group and CRC cohort of the 36 patients, cabozantinib plus 0% in the combination group.72 durvalumab demonstrated the promising efficacy with an ORR of 27.6% (8/29), DCR of 86.2% Results from cohort 7 of the phase Ib (25/29), median PFS of 4.4 months, and a median COSMIC-021 study, which is investigating cabo- OS of 9.1 months.78 zantinib plus atezolizumab, showed an ORR of 23% in patients with metastatic non-squamous A phase I study of 26 patients with advanced NSCLC (n = 30). The time to response (range) PDAC and no more than one prior systemic was 1.4 (1–3) months, the median (range) DOR treatment regimen assessed cabozantinib treat- was 5.6 (2.6–6.9) months, and the DCR was ment (escalating doses: 20–80 mg) in combina- 83%.64 tion with gemcitabine. Of the eight patients evaluable, three had PR, three had SD, and two Breast cancer. One phase II study investigated the had PD; the median (95% CI) OS and PFS were efficacy outcomes with the combination of cabo- 10.1 (3.6–20.6) months and 4.7 (1.4–9.7) zantinib and nivolumab in patients with metastatic months, respectively.74 Further investigation of triple-negative breast cancer, and a phase II study this combination was not recommended, how- assessed cabozantinib alone and in combination ever, owing to safety issues. with trastuzumab in heavily pretreated patients with breast cancer and brain metastases.43,44,53 Finally, cabozantinib (40 mg/day) and erlotinib in patients with metastatic PDAC (with EGFR and In the phase II, single-arm study of cabozantinib c-Met overexpression) that had progressed while (40 mg/day) plus nivolumab in patients with met- patients had been receiving at least one chemo- astatic triple-negative breast cancer who had therapy regimen was evaluated in a phase II study. received 0–3 prior cytotoxic therapies, only one of Overall, 43 patients were screened, and seven the first 18 patients had a PR (ORR, 6%; 95% patients were enrolled and treated; however, all CI: 0–27%), and the study was closed to further patients had clinical and/or radiographic accrual; the primary endpoint was not met.43,44 journals.sagepub.com/home/tam 15 Therapeutic Advances in Medical Oncology Volume 14 The median (95% CI) PFS was 3.6 (1.9–6.9) (cabozantinib 40 mg/day and escalating doses of months. In all, 14 patients (78%) had SD and other treatments) grade 3–4 treatment-related two patients (11%) had PD as best response. The AEs with cabozantinib plus nivolumab and with clinical benefit rate was 17% (95% CI: 4–41%). cabozantinib plus nivolumab and ipilimumab, In the single-arm, phase II study of 36 patients respectively, occurred in 75% and 87% of [median (range) prior lines of therapy: 3 (1–9)] patients, and in 42% and 71% of patients in the with breast cancer and brain metastases, patients CheckMate 040 aHCC study.42,73 Among the with human epidermal growth factor receptor 2 patients with aHCC, these AEs led to discontinu- (HER2)-positive disease (n = 21; cohort 1) ation in 3% of patients receiving cabozantinib received cabozantinib (60 mg/day) in combina- plus nivolumab and 20% of those treated with tion with trastuzumab, and those with hormone- cabozantinib plus nivolumab and ipilimumab. receptor-positive/HER2-negative (n = 7; cohort 2) and triple-negative disease (n = 8; cohort 3) In a study of 18 patients with metastatic triple- received cabozantinib (60 mg/day) alone. Central negative breast cancer and 0–3 prior cytotoxic nervous system ORR was 5% in cohort 1 (pri- therapies, all-cause AEs occurred in 100% of mary outcome), and 14% and 0% in cohorts 2 patients and grade 3–4 AEs in 83% of patients.43 and 3, respectively (secondary outcomes). The authors concluded that cabozantinib had insuffi- The most commonly reported AEs and treat- cient activity in these patients.53 ment-related AEs with the combination of cabo- zantinib and nivolumab included diarrhea, palmar–plantar erythrodysesthesia (PPES), Safety of cabozantinib in combination hypertension, fatigue, and elevated liver enzyme Cabozantinib plus nivolumab. Safety outcomes levels (Table 3). Diarrhea related to cabozantinib with the combination of cabozantinib and and nivolumab combination therapy was recorded nivolumab were reported in six studies: a phase in 56.9% of patients with aRCC and 47.2% of III study in patients with aRCC; a phase I study patients with recurrent endometrial cancer; a in patients with advanced or mUC or other geni- grade 3 or above treatment-related AE of diarrhea tourinary tumors; a phase I expansion study in with cabozantinib plus nivolumab was reported patients with mUC; a phase II study in patients for 5.6% of patients with aRCC.46,54 A grade 3 or with recurrent endometrial cancer; a phase I/II above or grade 3–4 treatment-related AE of study in patients with aHCC; and a phase II study hypertension with cabozantinib plus nivolumab in patients with metastatic triple-negative breast was reported in 10.9% of patients with aRCC and cancer (Table 3).42,43,46,47,49,50,54,73 in 21% (cabozantinib plus nivolumab) and 10% (cabozantinib plus nivolumab and ipilimumab) of In the phase III CheckMate 9ER study of patients with advanced or mUC and other geni- nivolumab (240 mg every 2 weeks) plus cabozan- tourinary tumors.42,46,50 In patients with aRCC, tinib (40 mg/day) versus sunitinib (50 mg/day for the incidence of treatment-related PPES with 4 weeks in 6-week cycles) in previously untreated cabozantinib plus nivolumab was 38.1% overall patients with clear-cell aRCC, 96.6% of patients (any grade) and the incidence of grade 3 or above receiving nivolumab plus cabozantinib and 93.1% treatment-related PPES was 7.5%; 17% of of those receiving sunitinib experienced treatment- patients with metastatic triple-negative breast related adverse events (AEs); grade 3 treatment- cancer had a grade 3–4 AE of PPES.43,46 related AEs occurred in 60.6% and 50.9% of Treatment-related elevations in liver enzyme lev- patients, respectively. Treatment-related AEs led els with cabozantinib and nivolumab were found to discontinuation of nivolumab in 5.6%, cabozan- in 44.4% of patients with recurrent endometrial tinib in 6.6%, and sunitinib in 8.8% of patients. cancer, and grade 3–4 AEs of elevated aspartate One and two treatment-related deaths were aminotransferase (AST) and alanine aminotrans- reported in the nivolumab plus cabozantinib and ferase (ALT) levels were reported in 17% and sunitinib groups, respectively.46,47 In recently 11% of patients, respectively, in the metastatic reported analysis of patients with a 2-year follow- triple-negative breast cancer study.43,54 up, no new safety signals emerged with extended follow-up in either arm among all treated patients.76 In addition to hypertension, grade 3–4 treatment- related AEs in patients with advanced or mUC In a Phase I study involving patients with mUC and other genitourinary tumors who were treated and other metastatic genitourinary tumors with cabozantinib plus nivolumab or cabozantinib 16 journals.sagepub.com/home/tam Table 3. Safety outcomes with cabozantinib combination therapies. Tumor type (N) Line of therapy or Treatment dose Rate of AEs Rate of dose reductions and/or Deaths patient treatment discontinuations history Cabozantinib plus nivolumab  aRCC46,47 First line (previously Nivolumab 240 mg IV Q2W and TRAEs: Cabo + nivolumab, 96.6%; sunitinib, 93.1% TRAEs leading to discontinuations: Number of (N = 651) untreated patients) Cabo 40 mg orally QD versus Grade 3 TRAEs: Cabo + nivolumab, 60.6%; sunitinib, Cabo, 6.6%; nivolumab, 5%; sunitinib, treatment- journals.sagepub.com/home/tam sunitinib 50 mg orally QD for 50.9% 8.8% related 4 weeks (6-week cycles) Most common TRAEs with Cabo + nivolumab and deaths: sunitinib, respectively: diarrhea, 56.9% and 42.5%; Cabo + PPES, 38.1% and 40.3%; hypothyroidism, 33.4% and nivolumab, 1; 28.1%; hypertension, 30.3% and 33.4% sunitinib, 2 Most common grade ⩾3 TRAEs with Cabo + nivolumab and sunitinib, respectively: diarrhea, 5.6% and 4.4%; PPES, 7.5% and 7.5%; and hypertension, 10.9% and 12.2%  Advanced or Patients had 0 (9%), 1 Escalating doses. Results based Grade 3–4 TRAEs: Cabo + nivolumab, 75%; mUC and other (35%), or ⩾2 (56%) prior on 40 and 60 mg doses of Cabo Cabo + nivolumab + ipilimumab, 87% genitourinary systemic regimens Grade 3–4 TRAEs in Cabo + nivolumab and tumors42 (N = 54) Cabo + nivolumab + ipilimumab groups, respectively: fatigue, 17% and 10%; hypertension, 21% and 10%; thromboembolic events, 4% and 10% Grade 3–4 immune-related AEs in Cabo + nivolumab and Cabo + nivolumab + ipilimumab groups, respectively: hepatitis, 0% and 13%; colitis, 0% and 7% mUC49,50 (N = 29) Median (range) number Cabo 40 mg/day; nivolumab Grade 3–4 TRAEs: 16 patients [15 (52%) grade 3; 1 (3%) TRAEs leading to reduction of Cabo of prior therapies, 3 mg/kg Q2W grade 4]. There were no grade 5 TRAEs dose to 20 mg/day: 12 patients 2 (0–8); all patients Grade 3–4 TRAEs: decrease in lymphocyte count, 14%; (41.4%); 3 of these patients (10.3%) received prior ICB fatigue, 10%; hypophosphatemia, 10%; thromboembolic required further reduction to 20 mg event, 10%; hypertension, 7%; diarrhea, 7%; increase in every other day amylase, 7% Two patients discontinued treatment (one owing to physician discretion, the other owing to a grade 3 cardiomyopathy and grade 3 thromboembolic event requiring hospitalization)  Recurrent Second- or later-line Cabo 40 mg/day and nivolumab Most common TRAEs with Cabo + nivolumab: diarrhea, endometrial therapy for patients; at 240 mg on days 1 and 15 of a 47.2%; elevated liver enzymes, 44.4%; fatigue, 38.9%; cancer54 (N = 76) least 1 prior platinum- 28-day cycle for four cycles, anorexia, 30.6%; hypertension, 30.6%; nausea, 30.6% based chemotherapy; followed by 480 mg every 55% received ⩾3 prior 4 weeks (arm A) lines of therapy Nivolumab 240 mg on days 1 and 15 of a 28-day cycle for four cycles, followed by 480 mg every 4 weeks (arm B) Patients with carcinosarcoma or prior immunotherapy were enrolled in an exploratory cohort and received combination treatment (arm C) (Continued) 17 D Castellano, AB Apolo et al. 18 Table 3. (Continued) Tumor type (N) Line of therapy or Treatment dose Rate of AEs Rate of dose reductions and/or Deaths patient treatment discontinuations history aHCC73 (N = 71) First or later line Arm 1: nivolumab 240 mg Q2W; Grade 3–4 TRAEs: Cabo + nivolumab, 15 patients (42%); Discontinuation due to grade 3–4 (sorafenib-naive or Cabo 40 mg/day Cabo + nivolumab + ipilimumab, 25 patients (71%) TEAEs: Cabo + nivolumab, 1 patient -experienced) Arm 2: nivolumab 3 mg/kg Q2W; Medical Oncology (3%); Cabo + nivolumab + ipilimumab, ipilimumab 1 mg/kg Q6W; Cabo 7 patients (20%) 40 mg/day  mTNBC43,44 Median (range) number Nivolumab 480 mg IV on day 1, All-cause AEs, 100%; grade 3–4 AEs, 83% Dose reduction of Cabo: 9 patients (N = 18) of prior cytotoxic then every 28 days; Cabo 40 mg/ Grade 3–4 AEs: elevated AST levels, 17%; PPES, Discontinuation of Cabo due to Therapeutic Advances in therapies, 1 (0–3) day orally 17%; back pain, 17%; thromboembolic events, 11%; toxicity: 5 patients hypertension, 11%; fatigue, 11%; elevated ALT levels, 11% Cabozantinib plus atezolizumab aRCC39 (N = 12) First line Cabo 40 mg/day or 60 mg/day; Grade 3 AEs: 11/12 patients (92%) Dose reductions due to AEs: 9 patients atezolizumab 1200 mg Q3W Hypertension: three patients in the 40 mg group, two (75%) patients in the 60 mg group Hypophosphatemia: one patient in each of the 40 and 60 mg groups Diarrhea: zero patients in the 40 mg group, two patients in the 60 mg group  ccRCC66,56 First line (with the Cabo 40 or 60 mg orally QD; Grade 3–4 TRAEs: 71% (40 mg), 67% (60 mg) TRAEs leading to discontinuation of (N = 70) exception of two atezolizumab 1200 mg IV Q3W Grade 3–4 TRAEs in the 40 and 60 mg dose groups, either study drug: 24% (40 mg), 19% patients enrolled in the respectively: hypertension, 24% and 14%; diarrhea, 9% (60 mg) dose-escalation stage and 19%; hypophosphatemia, 15% and 3%; elevated who had received prior ALT levels, 3% and 14% adjuvant sunitinib or pazopanib)  nccRCC55,56 7 patients (22%) had Cabo 40 mg orally QD; Grade 3–4 TRAEs: 38% TRAEs leading to discontinuation of (N = 32) received prior VEGFR atezolizumab 1200 mg IV Q3W Grade 3–4 TRAE hypophosphatemia: 13% either study drug, 16% TKI therapy UC65 (N = 30) After prior Cabo 40 mb/day; atezolizumab Grade 3–4 TRAEs: 57% platinum-containing 1200 mg IV Q3W Most common TRAEs (any grade): asthenia, 37%; chemotherapy diarrhea, 27%; decreased appetite, 23%; increased levels of transaminases, 23%; mucosal inflammation, 20% mCRPC40 (N = 44) Overall, 27% of patients Cabo 40 mg/day orally; Most common any-grade TEAEs: fatigue, 57%; nausea, had prior docetaxel and atezolizumab 1200 mg IV Q3W 48%; decreased appetite, 45%; diarrhea, 39%; PPES, 52% had ⩾2 prior novel 32%; vomiting, 32% hormonal therapies One grade 5 TRAE of dehydration occurred in a 90-year- old patient NSCLC64 (N = 30) After prior ICB Cabo 40 mb/day; atezolizumab Grade 3–4 TRAEs: 14/30 patients (46.7%) 1200 mg IV Q3W One patient (3.3%) had grade 5 TRAEs of myocarditis and pneumonitis (Continued) journals.sagepub.com/home/tam Volume 14 Table 3. (Continued) Tumor type (N) Line of therapy or Treatment dose Rate of AEs Rate of dose reductions and/or Deaths patient treatment discontinuations history Cabozantinib plus pembrolizumab mRCC52 (N = 8) Median (range) number Cabo 40 mg QD and 60 mg QD No. of patients with the following grade 3 AEs: No. of patients needing a dose of prior therapies, 1 in the first and second cohorts, leukoencephalopathy syndrome, 1; hypertension, 1; reduction: 40 mg dose, 0/5; 60 mg journals.sagepub.com/home/tam (1–3) respectively; pembrolizumab anorexia, 1; confusion, 1 dose, 1/3 200 mg IV Q3W in all cohorts Cabozantinib plus durvalumab UC57,58 (N = 16) Second- or later-line Cabo 40 mg/day orally; TRAEs: 14 patients (87.5%); no grade 3 or 4 TRAEs Dose reduction of Cabo to 20 mg/day: therapy for patients; durvalumab 1500 mg IV every Most common grade 1 and 2 TRAEs: fatigue (43.8%), 2 patients (12.5%) four patients had 28 days diarrhea (31.3%) and dysphonia (31.3%) Discontinuation: one patient (6.3%) received two prior who developed a duodenal fistula systemic anticancer within a bulky abdominal mass therapies GEA, CRC, HCC67 Median (range) Cabo 20, 40, and 60 mg/ No DLTs were observed (N = 23) number of prior day in the first, second and Grade 1 and 2 TRAEs: fatigue, 83%; abnormal liver chemotherapies, 3 (1–3) third cohorts, respectively; function tests, 39%; anorexia, 26%; diarrhea, 26%; durvalumab 1500 mg IV Q4W in nausea, 13%; PPES, 13% all cohorts Three patients developed grade 3 TRAEs hypertension, hyperthyroidism, and thrombocytopenia and a thromboembolic event (one patient each), all occurring outside the DLT window Cabozantinib plus panitumumab mCRC32,69 (N = 25) Not reported 60 mg orally QD; panitumumab No grade 5 TRAEs Discontinuations due to toxicity: 5 6 mg/kg IV Q2W Most common grade 2–4 TRAEs: acneiform rash, 64%; patients (20%) fatigue, 48%; diarrhea, 48% Dose reduction of Cabo: 18 patients (72%) Cabozantinib plus trastuzumab  Breast Patients could have Cabo 60 mg/day orally, during a Most common grade 3–4 AEs: elevations in lipase cancer brain received prior surgery, 21-day cycle; trastuzumab 8 mg/ levels, 11%; elevations in AST levels, 8%; elevations in metastases53 radiation, or systemic kg IV loading dose followed by ALT levels, 6%; hyponatremia, 8%; hypertension, 6% (N = 36) therapy for CNS 6 mg/kg IV Q3W metastases Cabozantinib plus erlotinib PDAC71 (N = 7) Second line Cabo 40 mg/day; erlotinib Most common any-grade AEs attributable to (median of one line 100 mg/day continuously Cabo + erlotininb: diarrhea, 71%; increase in AST of prior systemic levels, 43%; fatigue, 43%; nausea, 43%; rash, 43% chemotherapy)  Advanced Patients had received Oral daily doses of: erlotinib Grade 3 AEs: Cabo, 70%; Cabo + erlotinib, 72% Proportion of patients undergoing non-squamous one to two previous 150 mg; Cabo 60 mg; or erlotinib AEs in the Cabo versus Cabo + erlotinib groups, planned or unplanned dose EGFR-wild-type treatments 150 mg + Cabo 40 mg respectively: hypertension, 25% versus 3%; oral modification: Cabo, 95% NSCLC63 (N = 111) mucositis, 10% versus 3%; thromboembolic events, 8% Cabo + erlotinib, 97% versus 5%; diarrhea, 8% versus 28% 19 D Castellano, AB Apolo et al. (Continued) 20 Table 3. (Continued) Tumor type (N) Line of therapy or Treatment dose Rate of AEs Rate of dose reductions and/or Deaths patient treatment discontinuations history NSCLC72 (N = 92) Patients enrolled in Different dose levels depending Most common AEs in the Cabo group: hypertension, 2 Dose interruption or reduction: Cabo, phase I must have had on cohort: cohort 1, Cabo 60 mg, patients; hyponatremia, 2 patients; fatigue, 2 patients 10/15 patients (66.7%) Medical Oncology failed prior treatment erlotinib 150 mg; cohort 2A, Most common AEs in the Cabo + erlotinib group: Cabo + erlotinib, 9/13 patients (69.2%) with erlotinib Cabo 60 mg, erlotinib 100 mg; diarrhea, 4 patients (30.8%); dehydration, 3 patients cohort 2B, Cabo 40 mg, erlotinib (23.1%) 150 mg; cohort 3A, Cabo 100 mg, erlotinib 100 mg; cohort 4A, Cabo 100 mg, erlotinib 50 mg Therapeutic Advances in Cabozantinib plus telaglenastat (glutaminase inhibitor) mRCC59 (N = 13) Median (range) number Escalating doses of No. of events for the following grade 3 AEs: of prior therapies, 3 telaglenastat (CB-839; hypertension, 1; diarrhea, 1; decrease in platelet count, (0–7) 600–800 mg orally BID) plus 1; hallucination, 1 Patients with clear-cell Cabo (60 mg orally QD) were disease were required evaluated using a 3 + 3 design to have treatment with ⩾1 prior anti-VEGF therapy Cabozantinib plus androgen ablation  HNMPCa48 First line Cabo 60 mg/day orally (starting Most common grade 3 AEs: hypertension, 19%; Proportion of patients with dose (N = 62) dosage; reductions to 40 and diarrhea, 6%; thromboembolic events, 6% reductions, 85% 20 mg/day were allowed) and ADT (LHRH agonist or antagonist) Cabozantinib plus abiraterone mCRPC70 (N = 21) Not reported Escalating doses of Cabo (20, Grade 3 AEs: six patients 40, and 60 mg/day); abiraterone Grade 3 AEs included: 20 mg cohort: diarrhea, anemia, 1000 mg/day and increased AST/ALT levels 40 mg cohort: hypertension, low phosphate levels, and increased lipase levels mCRPC45 (N = 27) Patients had 0–2 Three dose levels of Cabo Patients with grade 3 AEs: infection, 3 (11%); Dose reductions due to toxicity: Cabo prior chemotherapy (20, 40, and 60 mg orally QD); hypophosphatemia, 2 (11%) 20 mg, 3/12 patients regimens abiraterone acetate 1000 mg/ Some grade 4 AEs occurred but were not related to Cabo 40 mg, 8/12 patients day treatment Cabo 60 mg, 3/3 patients Cabozantinib plus docetaxel (Continued) journals.sagepub.com/home/tam Volume 14 Table 3. (Continued) Tumor type (N) Line of therapy or Treatment dose Rate of AEs Rate of dose reductions and/or Deaths patient treatment discontinuations history mCRPC31 (N = 44) Any prior abiraterone Phase I study: escalating doses Among patients receiving Cabo 40 mg + docetaxel: Among for mCRPC, n (%): of Cabo 20, 40, and 60 mg/day grade 3–4 myelosuppression, hypophosphatemia, and patients phase I study, 16 (84); orally plus docetaxel (75 mg/m2 neuropathy were observed in at least three patients receiving phase II study arm 1, 4 IV Q3W with prednisone 5 mg DLTs were neutropenic fever and PPES Cabo 40 mg + journals.sagepub.com/home/tam (31); phase II study arm orally BID) docetaxel: 2, 6 (50) Phase II study: based on one death Any prior enzalutamide the results of the phase I from a for mCRPC, n (%): study, study expanded into a thromboembolic phase I study, 7 (37); randomized study of docetaxel/ event phase II study arm 1, 5 prednisone with the maximum (38); phase II study arm tolerated dose (40 mg) of Cabo 2, 8 (67) versus docetaxel/prednisone Any prior abiraterone and enzalutamide: phase I study, 4 (21); phase II study arm 1, 2 (15); phase II study arm 2, 4 (33) Prior chemotherapy (in castration-sensitive disease or as part of [neo]adjuvant clinical trials): phase I study, 2 (11); phase II study arm 1, 0 (0); phase II study arm 2, 2 (17) Cabozantinib plus gemcitabine PDAC74 (N = 12) Patients were excluded Escalating doses of Cabo from Most common grade 3 AEs: neutropenia, 5/11 Discontinuations due to toxicity: 7/12 if they had received 20 to 80 mg/day; gemcitabine patients; elevated AST/ALT levels, 5/11 patients; patients (64%) >1 prior systemic 1000 mg/m2 IV over 30 min on thrombocytopenia, 2/11 patients treatment regimen for days 1, 8, and 15 every 28 days No grade 4 AEs locally advanced or metastatic PDAC Cabozantinib plus temozolomide  High-grade Patients had a newly Cabo 40 or 60 mg/day; TMZ Most common grade 3–4 AEs: thrombocytopenia, Proportion of patients with dose gliomas diagnosed disease 200 mg/m2/day on a 5-day cycle 31%; leukopenia, 27%; deep vein thrombosis and/or modifications: 80.8% (glioblastoma pulmonary embolism, 23% Events leading to dose modification: or anaplastic Thrombocytopenia, 11 patients glioma)68 (N = 26) (42.3%) Neutropenia, 5 patients (19.2%) ADT, androgen deprivation therapy; AE, adverse event; aHCC, advanced hepatocellular carcinoma; ALT, alanine aminotransferase; aRCC, advanced renal cell carcinoma; AST, aspartate aminotransferase; BID, twice daily; Cabo, cabozantinib; ccRCC, clear-cell renal cell carcinoma; CNS, central nervous system; CRC, colorectal cancer; DLT, dose-limiting toxicity; EGFR, epidermal growth factor receptor; GEA, gastroesophageal adenocarcinoma; HCC, hepatocellular carcinoma; HNMPCa, hormone-naive metastatic prostate cancer; ICB, immune checkpoint blockade; IV, intravenously; LHRH, luteinizing hormone-releasing hormone; mCRC, metastatic colorectal cancer; mCRPC, metastatic castration-resistant prostate cancer; mRCC, metastatic renal cell carcinoma; mTNBC, metastatic triple-negative breast cancer; mUC, metastatic urothelial carcinoma; nccRCC, non-clear-cell renal cell carcinoma; NSCLC, non-small-cell lung cancer; PDAC, pancreatic ductal adenocarcinoma; PPES, palmar–plantar erythrodysesthesia syndrome; QD, once daily; Q2W, every 2 weeks; Q3W, every 3 weeks; Q12H, every 12 hours; RCC, renal cell carcinoma; RT, radiotherapy; TEAE, treatment-emergent adverse event; TKI, tyrosine kinase inhibitor; TMZ, temozolomide; TRAE, treatment-related adverse event; UC, urothelial carcinoma; VEGFR, vascular endothelial growth factor. 21 D Castellano, AB Apolo et al. Therapeutic Advances in Medical Oncology Volume 14 plus nivolumab and ipilimumab included fatigue 40 mg/day plus atezolizumab, treatment-related (17% and 10%, respectively) and thromboem- grade 3–4 AEs were reported in 38% of patients, bolic events (4% and 10%, respectively); grade most commonly hypophosphatemia (13%).56 3–4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, Grade 3–4 treatment-related AEs with cabozan- respectively). The recommended phase II dosage tinib (40 mg/day) plus atezolizumab occurred in was cabozantinib 40 mg/day and nivolumab 3 mg/ 57% of patients with locally advanced or mUC kg for cabozantinib plus nivolumab, and cabozan- who had received prior platinum-containing tinib 40 mg/day, nivolumab 3 mg/kg, and ipili- chemotherapy (n = 30) and in 47% of patients mumab 1 mg/kg for cabozantinib plus nivolumab with NSCLC (n = 30).64,65 In the patients with and ipilimumab.42 In the expansion study, in 30 NSCLC, 3% of patients had grade 5 treatment- patients with mUC with PD following ICB, 52% related AEs of myocarditis and pneumonitis. treated with cabozantinib (40 mg/day) plus nivolumab had a grade 3 treatment-related AE The most common treatment-related AEs (any and 3% a grade 4 treatment-related AE; the most grade) with cabozantinib and atezolizumab com- common were fatigue (10%), hypophosphatemia bination therapy were asthenia (37%), increased (10%), lymphocyte count decrease (10%), throm- transaminases (23%), and mucosal inflammation boembolic event (10%), hypertension (7%), diar- (20%) in patients with UC, and fatigue (57%), rhea (7%), and increased amylase (7%).49,50 The nausea (48%), PPES (32%), and vomiting (32%) management of overlapping toxicities of combina- in patients with mCRPC.40,65 In the UC and tion cabozantinib and nivolumab using the 9ER mCRPC studies, respectively, treatment-related phase III trial, the phase 1 combination study, and decreased appetite was reported in 23% and 45% published guidelines is discussed in a recently of patients, and treatment-related diarrhea in published review.79 27% and 39% of patients. Cabozantinib plus atezolizumab. Six congress Cabozantinib plus other immunotherapies. Two abstracts presenting safety data from the phase studies reported the safety profile of cabozantinib Ib COSMIC-021 study of cabozantinib plus and durvalumab combination therapy: one study atezolizumab in patients with RCC, UC, in patients with advanced UC and the second mCRPC, and NSCLC were retrieved from the study in patients with advanced GEA, CRC, or searches, and a recently published manuscript HCC.47,58,67 Single studies were found investigat- later identified.39,40,55,56,64,65,66 ing the safety of cabozantinib and pembrolizumab in patients with mRCC; cabozantinib plus pani- Three of the six congress abstracts and the full tumumab in patients with mCRC; and cabozan- manuscript reported safety outcomes in patients tinib plus trastuzumab in patients with breast with aRCC. In the dose-escalation stage in cancer and brain metastases (Table 3).32,52,53,69 patients with treatment-naive aRCC, 11/12 patients (92%) experienced grade 3 AEs, includ- In a phase I study of cabozantinib and pembroli- ing hypertension (three patients and two patients zumab in patients with mRCC who had a median in the 40 mg and 60 mg dose groups, respec- of one prior therapy, dose reductions were not tively), hypophosphatemia (one patient in each required in the cabozantinib 40 mg dose cohort dose group) and diarrhea (two patients, both in (n = 5), whereas dose reductions were needed for the 60 mg dose group). There were nine dose one patient in the 60 mg dose cohort (n = 3). reductions (75%) due to AEs.39 Among all Grade 3 AEs included reversible posterior leu- patients with ccRCC enrolled in the study (treat- koencephalopathy syndrome, hypertension, ano- ment-naive with the exception of two patients rexia, and confusion (occurring in one patient from the dose-escalation stage), grade 3–4 treat- each).52 ment-related AEs were reported in 71% and 67% of patients in the 40 mg and 60 mg dose groups, In the two studies (phase Ib and phase II studies) respectively, the most common being hyperten- of cabozantinib plus durvalumab, diarrhea was sion (24% and 14%, respectively), diarrhea (9% one of the most common grade 1–2 treatment- and 19%, respectively), hypophosphatemia (15% related AEs, occurring in 31.3% of patients with and 3%, respectively), and increased ALT (3% advanced UC after platinum chemotherapy and 14%, respectively).56 In the cohort of 32 (n = 16; cabozantinib 40 mg/day) and 26% of patients with nccRCC who received cabozantinib patients with GEA, CRC, or HCC.58,67 Other 22 journals.sagepub.com/home/tam D Castellano, AB Apolo et al. common grade 1–2 treatment-related AEs with hypertension, oral mucositis, and thromboem- this combination therapy included fatigue bolic events were more common in the mono- (43.8%) and dysphonia (31.3%) in patients with therapy group than in the combination group UC, and fatigue (83%), abnormal liver function (25% versus 3%, 10% versus 3% and 8% versus tests (39%), and anorexia (26%) in patients with 5%, respectively), whereas diarrhea was more GEA, CRC, or HCC. Three of the patients with common in the combination group (28%) than in GEA, CRC, or HCC developed grade 3 treat- the monotherapy group (8%).63 Wakelee et al. ment-related hypertension, hyperthyroidism, and conducted a phase Ib/II study of cabozantinib thrombocytopenia and a thromboembolic event (40–100 mg) with or without erlotinib in patients (one patient each), all outside the dose-limiting with no prior VEGFR TKI therapy. Dose inter- toxicity (DLT) window. ruption or reduction occurred in 67% of patients receiving cabozantinib only and in 69% of patients In a phase Ib study of 25 patients with mCRC receiving cabozantinib and erlotinib. In the com- receiving cabozantinib (60 mg/day) and panitu- bination group, the most common grade 3–4 AEs mumab, there were no grade 5 treatment-related were diarrhea [n = 4 (31%)] and dehydration AEs and one grade 4 treatment-related AE [n = 3 (23%)]. In the monotherapy group, the (hypertension).32,69 The most common grade 2–4 most common AEs were hypertension, hypona- treatment-related AEs were acneiform rash tremia, and fatigue [n = 2 (13%) each].72 (64%), fatigue (48%), and diarrhea (48%). Five patients (20%) discontinued treatment owing to Cabozantinib plus telaglenastat. Safety outcomes toxicity. were reported in a phase I study of cabozantinib in combination with telaglenastat as second- or Results from a phase II study of cabozantinib later-line therapy in patients with mRCC (n = 13). (60 mg/day) alone or in combination with trastu- The grade 3 AEs that occurred were diarrhea, zumab in patients with breast cancer with brain hypertension, decrease in platelet count, and hal- metastases showed that the most common grade lucination (one event each).59 In primary analysis 3–4 AEs included elevations in lipase (11%), from CANTATA, rates of AEs were similar AST (8%), ALT (6%), hyponatremia (8%), and between cabozantinib plus telaglenastat and hypertension (6%).53 cabozantinib plus placebo arms, with grade 3-4 AEs occurred in 71% and 79% of patients with Cabozantinib plus erlotinib. Safety data on the mRCC, respectively.80 combination of cabozantinib and erlotinib were available from three studies: one phase II study in Cabozantinib plus hormone therapy. One phase II patients with pancreatic adenocarcinoma and one study evaluated the safety of the combination of phase II RCT and one phase Ib study in patients cabozantinib and androgen ablation in patients with NSCLC (Table 3).63,71,72 with hormone-naive metastatic prostate cancer, and a dose-finding study investigated the safety of In the phase II study evaluating cabozantinib cabozantinib and abiraterone combination ther- (40 mg/day) and erlotinib in EGFR- and c-Met- apy in patients with mCRPC.45,48,70 expressing pancreatic adenocarcinoma following at least one chemotherapy regimen, the most In the phase II study of cabozantinib (starting common any-grade AEs attributable to cabozan- dosage: 60 mg/day) and androgen ablation in 62 tinib and erlotinib included diarrhea (71%), AST patients with hormone-naive metastatic prostate increase (43%), fatigue (43%), nausea (43%), cancer, the most common grade 3 AEs were and rash (43%).71 hypertension (19%), diarrhea (6%), and throm- boembolic events (6%), and dose reductions The RCT randomized patients to receive cabo- occurred in 85% of patients.48 zantinib (60 mg/day) (n = 39) or cabozantinib (40 mg/day) plus erlotinib (n = 37) in a second- or In the initial analysis of the phase I dose-finding third-line setting.62,63 The rate of grade 3 AEs was study (n = 21) of cabozantinib (20, 40, or 60 mg/ similar in the monotherapy and combination day) plus abiraterone in patients with progressive groups (70% and 72%, respectively).63 The rate mCRPC (before or after chemotherapy), six of planned or unplanned dose modification was patients had grade 3 AEs, which included diar- also similar (95% in the monotherapy group and rhea, anemia, and increased AST/ALT in the 97% in the combination group). Grade 3 or 4 20 mg cohort, and hypertension, low phosphate, journals.sagepub.com/home/tam 23 Therapeutic Advances in Medical Oncology Volume 14 and increased lipase in the 40 mg cohort.70 In the or preparing for recruitment (Table 4). Tumor final analysis of this phase I study including 27 types studied include RCC (16), NSCLC (6), patients treated with cabozantinib plus abirater- genitourinary (not RCC) (4), prostate (5), breast one, the most common treatment-related grade 3 cancer (3), HCC (3), neuroendocrine tumors (3), AEs were infection and hypophosphatemia [n = 3 solid tumors (3), muscle or soft tissue sarcoma (11%) each]. Some grade 4 AEs occurred, but (4), head and neck squamous cell cancer (2), these were not treatment related. Dose reductions melanoma (2), thyroid cancer (2), UC (2), gas- due to toxicity occurred in 3/12 patients receiving trointestinal (2), gynecologic cancers (2), liver cabozantinib 20 mg, 8/12 patients receiving cancer (2), melanoma (2), and myeloma (1). 40 mg, and 3/3 patients receiving 60 mg.45 Seven studies include various types of tumors. Among the ongoing studies are: the six phase III Cabozantinib plus chemotherapy. Three studies studies PDIGREE, COSMIC-313 in mRCC reported safety outcomes with cabozantinib in (cabozantinib plus nivolumab and ipilimumab combination with three different chemotherapy versus nivolumab and ipilimumab), COSMIC-312 drugs: a phase I/II study of cabozantinib plus in aHCC (cabozantinib plus atezolizumab versus docetaxel in patients with mCRPC; a phase I cabozantinib monotherapy versus sorafenib), study of cabozantinib plus gemcitabine in patients CONTACT-01 in NSCLC, CONTACT-02 in with PDAC; and a phase I study of cabozantinib mCRPC, and CONTACT-03 in aRCC; and the plus temozolomide in patients with high-grade seven phase II studies ARCADIA and gliomas (Table 3).31,68,74 NICARAGUA including patients with advanced UC, the CANTATA study in mRCC, and Among patients with mCRPC who received CABATEN in patients with advanced and pro- cabozantinib 40 mg with docetaxel in a phase I/II gressive neoplasms of the endocrine system, study,31,41,51 DLTs were neutropenic fever and LOLA, NCT04079712, and NCT04197310 in PPES, and there was one death due to a throm- patients with neuroendocrine tumors. An expan- boembolic event. In addition, grade 3–4 myelo- sion of the COSMIC-021 phase I study suppression, hypophosphatemia, and neuropathy (NCT03170960) is ongoing in multiple tumor were observed in at least three patients.31 types. A phase I study in 12 patients with advanced At the time of final submission of the article, five PDAC who had received no more than one prior of the studies identified in this search had com- systemic treatment regimen showed that, follow- pleted. Published results from four of these stud- ing treatment with cabozantinib (escalating doses: ies are included in this review; data from the fifth 20–80 mg) and gemcitabine, 7/12 patients (64%) study, the CANTATA study in mRCC, are discontinued therapy owing to toxicity. The most reviewed in the discussion section. Four studies common grade 3 AEs were neutropenia and AST had been withdrawn or terminated since the and/or ALT elevation (5/11 patients each) and searches were performed, leaving a total of 56 thrombocytopenia (2/11 patients); there were no studies ongoing at the time of submission of this grade 4 AEs.74 article (Table 4). In another phase I study, patients with newly diagnosed high-grade gliomas were treated with Discussion cabozantinib (40 or 60 mg/day), either concur- This SLR was designed to capture the evidence of rent with temozolomide followed by radiotherapy the efficacy and safety of cabozantinib in combina- or following completion of radiotherapy and at tion with other therapies for the treatment of solid least one cycle of temozolomide. Dose modifica- tumors. To our knowledge, this is the first SLR to tions occurred in 80.8% of patients, mainly owing summarize the evidence of cabozantinib in combi- to the occurrence of thrombocytopenia [n = 11 nation, and it complements a separate manuscript (42.3%)] and neutropenia [n = 5 (19.2%)].68 in which we discuss studies of cabozantinib as monotherapy identified from the same SLR Moher et al.81 Searching from 2012 onwards, 32 articles Ongoing studies were identified that report findings for cabozan- At the time of the searches, 67 studies of cabozan- tinib in combination with immunotherapy, chem- tinib in a combination therapy were identified on otherapy and other targeted agents in patients with ClinicalTrials.gov that are either active, recruiting a range of cancers, including RCC, NSCLC, 24 journals.sagepub.com/home/tam D Castellano, AB Apolo et al. Table 4. Ongoing studies of cabozantinib in combination with other therapies. ClinicalTrials.gov Trial title Status registry number Phase III NCT04338269 A Study of Atezolizumab in Combination With Cabozantinib Compared to Recruiting Cabozantinib Alone in Participants With Advanced Renal Cell Carcinoma After Immune Checkpoint Inhibitor Treatment NCT03755791 Study of Cabozantinib in Combination With Atezolizumab Versus Sorafenib Recruiting in Subjects With Advanced HCC Who Have Not Received Previous Systemic Anticancer Therapy NCT04471428 Study of Atezolizumab in Combination With Cabozantinib Versus Docetaxel Recruiting in Patients With Metastatic Non-Small Cell Lung Cancer Previously Treated With an Anti-PD-L1/PD-1 Antibody and Platinum-Containing Chemotherapy NCT03937219 Study of Cabozantinib in Combination With Nivolumab and Ipilimumab in Active, not recruiting Patients With Previously Untreated Advanced or Metastatic Renal Cell Carcinoma NCT04446117 Study of Cabozantinib in Combination With Atezolizumab Versus Second Recruiting NHT in Subjects With mCRPC NCT03793166 Immunotherapy With Nivolumab and Ipilimumab Followed by Nivolumab or Recruiting Nivolumab With Cabozantinib for Patients With Advanced Kidney Cancer, The PDIGREE Study NCT03141177 A Study of Nivolumab Combined With Cabozantinib Compared to Sunitinib Active, not recruiting in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma NCT04471428 Study of Atezolizumab in Combination With Cabozantinib Versus Docetaxel Recruiting* in Patients With Metastatic Non-Small Cell Lung Cancer Previously Treated With an Anti-PD-L1/PD-1 Antibody and Platinum-Containing Chemotherapy (CONTACT-01) NCT04446117 Study of Cabozantinib in Combination With Atezolizumab Versus Second Recruiting NHT in Subjects With mCRPC (CONTACT-02) NCT04338269 A Study of Atezolizumab in Combination With Cabozantinib Compared to Recruiting Cabozantinib Alone in Participants With Advanced Renal Cell Carcinoma After Immune Checkpoint Inhibitor Treatment (CONTACT-03) Phase II NCT03463681 A Study of CaBozantinib in Patients With Advanced or Unresectable Renal Recruiting† cEll cArcinoma NCT04400474 Trial of Cabozantinib Plus Atezolizumab in Advanced and Progressive Recruiting Neoplasms of the Endocrine System. The CABATEN Study NCT04164979 Ph II Study of Cabozantinib With Pembrolizumab in Metastatic Gastric and Recruiting Gastroesophageal Adenocarcinoma NCT03824691 hARnessing CAbozantinib and Durvalumab Immuno-oncology Association: Recruiting ARCADIA Study NCT04091750 Nivolumab/Ipilimumab Plus Cabozantinib in Patients With Unresectable Recruiting Advanced Melanoma NCT04197310 Cabozantinib and Nivolumab for Carcinoid Tumors Recruiting (Continued) journals.sagepub.com/home/tam 25 Therapeutic Advances in Medical Oncology Volume 14 Table 4. (Continued) ClinicalTrials.gov Trial title Status registry number NCT03635892 A Study of Nivolumab In Combination With Cabozantinib in Patients With Recruiting Non-Clear Cell Renal Cell Carcinoma NCT04427787 A Trial Aiming to Assess the Safety and Activity of the Combination of Recruiting Cabozantinib Plus Lanreotide in GEP and NET (LOLA) NCT04230954 Cabozantinib Plus Pembrolizumab for Recurrent, Persistent and/or Recruiting Metastatic Cervical Cancer NCT01630590 Cabozantinib and Androgen Ablation in Patients With Androgen-Dependent Active, not recruiting† Metastatic Prostate Cancer NCT04289779 Study of Cabozantinib in Combination With AtezolizumaB for Muscle- Recruiting Invasive BladdEr Cancer (ABATE) NCT03316586 A Phase II Study of Nivolumab in Combination With Cabozantinib for Active, not recruiting† Metastatic Triple-negative Breast Cancer NCT03534804 Cabozantinib Plus Pembrolizumab as First-Line Therapy for Cisplatin- Recruiting Ineligible Advanced Urothelial Carcinoma NCT04413123 Cabozantinib In Combo With NIVO + IPI In Advanced NCCRCC Recruiting NCT03634540 A Trial of Belzutifan (PT2977, MK-6482) in Combination With Cabozantinib Recruiting in Patients With Clear Cell Renal Cell Carcinoma (ccRCC) NCT03468218 Pembrolizumab & Cabozantinib in Patients With Head and Neck Squamous Recruiting Cell Cancer NCT04149275 Cabozantinib Plus Nivolumab and Ipilimumab in Women With Recurrent Not yet recruiting‡ Gynecologic Carcinosarcoma NCT01441947 Cabozantinib in Women With Metastatic Hormone-Receptor-Positive Active, not recruiting Breast Cancer NCT04442581 Cabozantinib and Pembrolizumab for the First-Line Treatment of Advanced Not yet recruiting§ Liver Cancer NCT04472767 Cabozantinib Combined With Ipilimumab/Nivolumab and TACE in Patients Recruiting With Hepatocellular Carcinoma NCT04551430 Cabozantinib Combined With PD-1 and CTLA-4 Inhibition in Metastatic Soft Not yet recruiting§ Tissue Sarcoma NCT04079712 Testing the Combination of XL184 (Cabozantinib), Nivolumab, and Recruiting* Ipilimumab for Poorly Differentiated Neuroendocrine Tumors NCT03866382 Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Recruiting Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare Genitourinary Tumors NCT02260531 Cabozantinib ± Trastuzumab In Breast Cancer Patients w/ Brain Active, not recruiting† Metastases NCT03914300 Testing the Combination of Cabozantinib, Nivolumab, and Ipilimumab Recruiting|| (CaboNivoIpi) for Advanced Differentiated Thyroid Cancer NCT04310007 Testing the Addition of the Pill Chemotherapy, Cabozantinib, to Recruiting the Standard Immune Therapy Nivolumab Compared to Standard Chemotherapy for Non-small Cell Lung Cancer (Continued) 26 journals.sagepub.com/home/tam D Castellano, AB Apolo et al. Table 4. (Continued) ClinicalTrials.gov Trial title Status registry number NCT04071223 Testing the Addition of a New Anti-cancer Drug, Radium-223 Dichloride, to Recruiting the Usual Treatment (Cabozantinib) for Advanced Renal Cell Cancer That Has Spread to the Bone, the RadiCaL Study NCT04200443 Cabozantinib and Temozolomide for the Treatment of Unresectable or Recruiting Metastatic Leiomyosarcoma or Other Soft Tissue Sarcoma NCT03428217 CANTATA: CB-839 With Cabozantinib vs. Cabozantinib With Placebo in Active, not recruiting† Patients With Metastatic Renal Cell Carcinoma NCT01708954 Erlotinib Hydrochloride and Cabozantinib-s-Malate Alone or in Combination Active, not recruiting as Second or Third Line Therapy in Treating Patients With Stage IV Non- small Cell Lung Cancer NCT04322955 CYTO Reductive Surgery in Kidney Cancer Plus Immunotherapy and Recruiting Targeted Kinase Inhibition NCT03468985 Nivolumab, Cabozantinib S-Malate, and Ipilimumab in Treating Patients Active, not recruiting With Recurrent Stage IV Non-small Cell Lung Cancer NCT04339738 Testing the Addition of Nivolumab to Chemotherapy in Treatment of Soft Recruiting Tissue Sarcoma NCT03630120 Adaptive Tyrosine Kinase Inhibitor (TKI) Therapy in Patients With Thyroid Active, not recruiting¶ Cancer Phase I/II NCT03149822 Study of Pembrolizumab and Cabozantinib in Patients With Metastatic Recruiting* Renal Cell Carcinoma NCT03957551 Cabozantinib and Pembrolizumab for Advanced Metastatic Melanoma Recruiting NCT03201250 Cabozantinib as a Targeted Strategy to Reverse Carfilzomib Resistance in Recruiting¶ Refractory Multiple Myeloma NCT04220229 Cabozantinib With Radiation Therapy for the Treatment of Sarcomas of the Recruiting Extremities NCT03425201 Niraparib in Combination With Cabozantinib (XL184) in Patients With Recruiting Advanced Urothelial Cancer (NICARAGUA) NCT03539822 Cabozantinib in Combination With Durvalumab in Patients With Recruiting Gastroesophageal Cancer and Other Gastrointestinal Malignancies NCT03170960 Study of Cabozantinib in Combination With Atezolizumab to Subjects With Recruiting Locally Advanced or Metastatic Solid Tumors NCT04300140 Safety and Efficacy Study of AVB-S6-500 in Patients With Advanced Clear Not yet recruiting§ Cell Renal Cell Carcinoma NCT01658878 An Immuno-therapy Study to Evaluate the Effectiveness, Safety and Active, not recruiting Tolerability of Nivolumab or Nivolumab in Combination With Other Agents in Patients With Advanced Liver Cancer NCT04151563 A Clinical Study Evaluating Nivolumab-containing Treatments in Patients Not yet recruiting‡ With Advanced Non-small Cell Lung Cancer After Failing Previous PD-1/ (L)1 Therapy and Chemotherapy (Continued) journals.sagepub.com/home/tam 27 Therapeutic Advances in Medical Oncology Volume 14 Table 4. (Continued) ClinicalTrials.gov Trial title Status registry number Phase I NCT03611595 Cabozantinib in Combination With 13-cis-Retinoic Acid in Children With Recruiting Relapsed or Refractory Solid Tumors NCT03667482 Cabozantinib in Combination With Cetuximab in Patients With Recurrent or Recruiting Metastatic Head and Neck Squamous Cell Cancer NCT04173338 Cabozantinib With Pemetrexed in Advanced Non-small Cell Lung Cancer, Recruiting Urothelial Cancer and Malignant Mesothelioma NCT03299946 Feasibility and Efficacy of Neoadjuvant Cabozantinib Plus Nivolumab Active, not recruiting (CaboNivo) Followed by Definitive Resection for Patients With Locally Advanced Hepatocellular Carcinoma (HCC) NCT04514484 Testing the Combination of the Anti-cancer Drugs XL184 (Cabozantinib) and Not yet recruiting§ Nivolumab in Patients With Advanced Cancer and HIV NCT03200587 Cabometyx and Avelumab in Patients With Metastatic Renal Cell Carcinoma Active, not recruiting (mRCC) NCT02496208 Cabozantinib S-malate and Nivolumab With or Without Ipilimumab in Recruiting* Treating Patients With Metastatic Genitourinary Tumors NCT01574937 XL-184+Abiraterone in Post-Chemo CRPC Active, not recruiting$ NCT04477512 Cabozantinib and Abiraterone With Checkpoint Inhibitor Immunotherapy in Not yet recruiting§ Metastatic Hormone Sensitive Prostate Cancer (CABIOS Trial) NCT02293980 A Phase 1, Dose-Escalation Trial of PT2385 Tablets in Patients With Active, not recruiting Advanced Clear Cell Renal Cell Carcinoma NCT03138538 M8891 First in Human in Solid Tumors Active, not recruiting NCT03798626 Gevokizumab With Standard of Care Anti-cancer Therapies for Metastatic Recruiting Colorectal, Gastroesophageal, and Renal Cancers NCT03878524 Serial Measurements of Molecular and Architectural Responses to Therapy Recruiting (SMMART) PRIME Trial Registry was searched in November 2020. The status of all trials was then checked prior to final submission in February 2022; any further updates are detailed in the footnotes below. *Status updated to active, not recruiting. $Now completed. ‡Subsequently withdrawn. §Status updated to recruiting. ||Status updated to suspended (for scheduled interim monitoring); ¶Status updated to terminated (owing to lack of efficacy). ¶Status updated to terminated (unexpected response to treatment in phase I). CRPC, castration-resistant prostate cancer; NR, not recruiting. prostate cancer, breast cancer, gastrointestinal immunotherapy, make cabozantinib an attractive cancers, and UC and other genitourinary cancers. candidate for combination therapy.19 The immu- Overall, studies demonstrate promising findings nosuppressive effects have been demonstrated in for cabozantinib as part of a combination therapy. patient correlative studies of cabozantinib mono- therapy in mUC21 and RCC,25,26 and the synergis- The anti-angiogenic and immunosuppressive tic potential of cabozantinib plus immunotherapy effects of cabozantinib, which lead to a potential has been shown in preclinical mouse models of synergistic effect with other therapies, especially HCC.23 This enhanced efficacy could be achieved 28 journals.sagepub.com/home/tam D Castellano, AB Apolo et al. in a range of disease types. Although our SLR Several ongoing studies aim to investigate the shows that the evidence of cabozantinib in combi- cabozantinib combination therapy in RCC fur- nation is relatively limited at present (32 articles ther. Initial results from the CANTATA study published from 2012 until 2020), our supplemen- suggest that a combination of cabozantinib plus tary searches indicate that there are many ongoing telaglenastat offers no PFS benefit compared with or planned studies in indications for which cabo- cabozantinib alone in patients with mRCC or zantinib is approved as monotherapy, as well as in aRCC who have received one to two prior anti- unapproved tumor types, and this is a research cancer systemic therapies.89 An expansion stage topic of much interest. of the COSMIC-021 study is underway to inves- tigate cabozantinib plus atezolizumab in tumor In the current review, we identified the studies of types beyond RCC. This expansion includes patients with RCC, HCC, UC, CRPC, CRC, 1732 patients in 24 cohorts and will include 12 pancreatic cancer, prostate cancer, GEA, tumor types: RCC, UC, NSCLC, CRPC, triple- NSCLC, breast cancer, endometrial cancer, and negative breast cancer, ovarian cancer, endome- gliomas. Cabozantinib has been most studied in trial cancer, HCC, gastric or gastroesophageal patients with RCC; there is strong evidence sup- junction adenocarcinoma, colorectal adenocarci- porting the efficacy of cabozantinib monother- noma, head and neck cancer and DTC. Interim apy in RCC from the METEOR9,82–86 and efficacy and safety results are positive from CABOSUN10,87 trials. This review highlights patients with mCRPC (cohort 6)40 and aRCC that RCC is also well studied in terms of the use (cohort 10)55 and NSCLC (cohort 7).64 In addi- of cabozantinib as part of a combination ther- tion, based on the positive outcomes from the apy, including cabozantinib plus anti-PD1/anti- original COSMIC-021 study, a phase III trial PD-L1 immunotherapies [pembrolizumab, (NCT04338269), designed to evaluate the effi- atezolizumab, or nivolumab with or without cacy of cabozantinib plus atezolizumab versus ipilimumab (anti-CTLA-4 monoclonal anti- cabozantinib in patients with aRCC after immu- body)39,52,61] and glutaminase inhibitors (telagle- notherapy failure, is currently active. Also, several nastat).59 The available evidence suggests phase III RCTs (PDIGREE and COSMIC-313 promising results for all combinations, with an trials) are investigating the doublet and triplet ORR of 25% for pembrolizumab;52 ORR and combinations of cabozantinib plus nivolumab, DCR of 53% and 94%, respectively, in patients and cabozantinib plus nivolumab and ipilimumab with ccRCC treated with atezolizumab;39,56 further, following the positive findings from a ORR and DCR of 54% and 100%, respectively, phase I study. The phase I study by Apolo et al. for cabozantinib plus nivolumab, or cabozan- was the first to report on these doublet and triplet tinib plus nivolumab and ipilimumab;61 and combinations in patients with mRCC, carcinoma, ORR and DCR of 42% and 100%, respectively, and urothelial and rare tumors, such as bladder for telaglenastat.59 squamous cell carcinoma, urachal adenocarci- noma, and penile cancer;42,90 the study resulted in This review includes evidence identified by sys- recommended phase II and expansion cohort temic bibliometric searches and subsequent doses of 40 mg (cabozantinib) and 3 mg/kg searches for full publication of data presented in (nivolumab), with or without ipilimumab 1 mg/ the retrieved congress abstracts. In addition, for kg. The Alliance for Clinical Trials in Oncology91 the phase I study of cabozantinib plus nivolumab is supporting the PDIGREE trial, in which versus cabozantinib plus nivolumab and ipili- patients with mRCC will be treated in the first- mumab in patients with metastatic genitourinary line setting with nivolumab and ipilimumab for cancers, a report of the final data for the expan- 3 months, then those with CR will continue sion cohorts was presented at the genitourinary nivolumab monotherapy, those with PD will be symposium 2021, which reported updated ORRs changed to cabozantinib monotherapy and those for the 33 patients with UC of 42.2% and for the with PR or SD will be randomized to nivolumab 16 patients with RCC of 62.5% (efficacy results monotherapy or cabozantinib plus nivolumab.92 are not reported by therapy for the expansion In COSMIC-313, cabozantinib plus nivolumab cohorts). Overall, grade 3–4 treatment-related and ipilimumab will be compared with nivolumab AEs occurred in 84% of patients treated with and ipilimumab in patients with previously cabozantinib plus nivolumab versus 80% of untreated mRCC with intermediate or poor risk, patients treated with cabozantinib plus nivolumab according to IMDC categorization.93 and ipilimumab.88 COSMIC-313 will be the first RCT in aRCC, journals.sagepub.com/home/tam 29 Therapeutic Advances in Medical Oncology Volume 14 with nivolumab and ipilimumab as the standard has also demonstrated favorable results in patients of care comparator. CONTACT-03 is an ongo- with hormone-I metastatic prostate cancer; can- ing phase III study of cabozantinib plus atezoli- didate prognostic and predictive markers of cabo- zumab versus cabozantinib monotherapy in zantinib benefit were identified and have provided patients with RCC. insights for rational therapy combinations.48 For UC, published findings show that cabozan- At the time of the searches for the current review, tinib plus nivolumab is clinically active and well two studies were identified that had presented tolerated in heavily pretreated patients with pro- findings in HCC.67,73 Results from the CheckMate gressive mUC following ICB.49 In another study, 040 trial showed that cabozantinib plus nivolumab initial data show encouraging clinical activity with and ipilimumab led to higher investigator- an acceptable safety profile in patients with assessed ORR than cabozantinib plus nivolumab advanced UC treated with cabozantinib in com- alone (26% versus 17%) in patients with advanced bination with durvalumab.57 Following the phase liver cancer. Results also favored the triple combi- I findings on cabozantinib plus nivolumab nation arm for DCR and PFS.73 HCC is also reported by Apolo et al.,90 a cooperative group being studied in the randomized phase III study run by the Alliance for Clinical Trials in COSMIC-312 trial. The primary endpoint of Oncology initiated enrollment in April 2019 for PFS in the first 372 patients randomized to the phase II ICONIC study (NCT03866382) to receive cabozantinib plus atezolizumab or investigate cabozantinib plus nivolumab and ipili- sorafenib was met: the combination therapy sig- mumab in rare genitourinary tumors.94 In a trial nificantly improved PFS compared with sorafenib currently in development, the same group will monotherapy (median PFS, 6.8 months versus also investigate cabozantinib plus pembrolizumab 4.2 months; HR 0.63; 95% CI: 0.44–0.91; versus pembrolizumab after first-line chemother- p = 0.0012).97 However, in a prespecified interim apy in patients with mUC. In terms of other com- analysis of the second primary endpoint, OS in all binations, the PemCab study (NCT03534804, randomized patients, there was not a statistically estimated completion date September 2023)95 is significant benefit of cabozantinib and atezoli- a non-randomized phase II study that will evalu- zumab combination therapy versus sorafenib ate cabozantinib plus pembrolizumab in patients monotherapy (HR 0.90; 96% CI: 0.69–1.18; with mUC who are ineligible for cisplatin. p = 0.438). Final OS analysis, announce in March 2022, reported neither improvement nor detri- For endometrial cancer, a published randomized ment in OS for cabozantinib in combination with phase II trial, comparing the combination of atezolizumab versus sorafenib.98 cabozantinib and nivolumab versus nivolumab in recurrent endometrial cancer, has reported that In pancreatic cancer, one phase I study evalu- cabozantinib plus nivolumab demonstrated ated the combination of cabozantinib with gem- improved PFS compared with nivolumab in heav- citabine, which is a standard chemotherapy for ily pretreated women with recurrent endometrial advanced PDAC, and cabozantinib;74 the cancer.54 authors did not recommend further exploration of this combination because of DLTs.74 In For prostate cancer, two studies investigated the CRC, one phase Ib study reported promising triple combination therapy of cabozantinib plus safety and efficacy findings for cabozantinib in DP in patients with CRPC and found positive combination with the EGFR inhibitor results.41,51 One of these was a randomized phase panitumumab.32,69 II study, which showed that cabozantinib plus DP was associated with longer PFS than DP in For NSCLC, there were mixed results for the patients with CRPC.41 In the expansion of the combination of cabozantinib and erlotinib,63,72 COSMIC-021 trial, which originally investigated but promising findings were reported for cabo- cabozantinib and atezolizumab in RCC, prelimi- zantinib plus atezolizumab in patients with nary data on the CRPC cohort have been encour- advanced NSCLC who had progressed after prior aging, leading to the decision to expand this ICB in the expansion of the COSMIC-021 cohort further.96 A phase III trial (CONTACT-02) study.64 A phase III trial (CONTACT-01) is cur- is also currently recruiting to investigate cabozan- rently recruiting to investigate cabozantinib plus tinib plus atezolizumab in patients with CRPC. atezolizumab versus docetaxel monotherapy in Cabozantinib plus androgen deprivation therapy patients with CRPC. 30 journals.sagepub.com/home/tam D Castellano, AB Apolo et al. For breast cancer, there was a lack of evidence for from randomized phase III trials is expected in the benefits of cabozantinib combination therapy the coming years, across a range of disease areas. from the two available studies, one assessing The ongoing studies will expand our understand- combination with nivolumab in patients with ing of the potential benefits of cabozantinib com- metastatic triple-negative breast cancer and the bination therapy in the near future. other investigating combination with trastuzumab in heavily pretreated patients with breast cancer and brain metastases.43,44,53 Declarations Several ongoing studies aimed at evaluating the Ethics approval and consent to participate combination of cabozantinib with other therapies Not applicable. will increase evidence on the observed safety pro- files of different combinations in various tumor Consent for publication types. In the current review, the most common Not applicable. AEs reported across all included studies were diarrhea, hypertension, fatigue, and lipase eleva- Author contributions tion, which are also commonly observed with Daniel Castellano: Conceptualization; cabozantinib monotherapy. AEs appeared to be Methodology; Writing – original draft; Writing – manageable with dose reductions, although the review & editing. range of patients requiring dose reductions while Andrea B. Apolo: Methodology; Writing – orig- receiving cabozantinib 40–100 mg varied widely inal draft; Writing – review & editing. from 0% to 100%. Camillo Porta: Methodology; Writing – original This SLR is a comprehensive review of cabozan- draft; Writing – review & editing. tinib as part of a combination therapy for the treat- Jaume Capdevila: Methodology; Writing – ment of solid tumors. Inclusion criteria were original draft; Writing – review & editing. broad, with no restriction on disease type and all phases of clinical trial included. Only nine pub- Santiago Viteri: Methodology; Writing – origi- lished manuscripts were identified in the system- nal draft; Writing – review & editing. atic searches, eight of which reported Cristina Rodriguez-Antona: Methodology; non-randomized phase I and II studies. Most of Writing – original draft; Writing – review & the studies identified in the searches were reported editing. as congress abstracts only. For six of these studies, published full articles were identified later and the Lidia Martin: Methodology; Writing – original relevant data updated. Evidence from randomized draft; Writing – review & editing. trials was identified in five tumor types: aRCC, Pablo Maroto: Conceptualization; Methodo­ CRPC, NSCLC, aHCC, and endometrial cancer. logy; Writing – original draft; Writing – review & Numerous planned and ongoing trials across a editing. range of disease areas indicate that this area of research continues to be of interest. These include the aforementioned studies CONTACT-01, Acknowledgements CONTACT-02, CONTACT-03, COSMIC-021, The authors thank Lisa Law and Obaro COSMIC-312/313, and PDIGREE. The pub- Evuarherhe of Oxford PharmaGenesis, Oxford, lished evidence in this review, together with emerg- UK, for performing the literature review and pro- ing findings from ongoing trials, will strengthen viding medical writing support. This support was our understanding of the potential benefits to funded by Ipsen UK in accordance with Good patients using cabozantinib in combination. Publication Practice (GPP3) guidelines (http:// www.ismpp.org/gpp3). In conclusion, research is increasing for the use of cabozantinib as part of a combination therapy to Funding treat solid tumors. The current review identified The authors disclosed receipt of the following evidence from phase I, II, and III trials, demon- financial support for the research, authorship, strating promising response to treatment and and/or publication of this article: This study was manageable safety profiles. Further evidence funded by Ipsen. journals.sagepub.com/home/tam 31 Therapeutic Advances in Medical Oncology Volume 14 Competing Interests References DC has received institutional research funding 1. Atkins MB and Tannir NM. Current and from Janssen Oncology; has received travel and emerging therapies for first-line treatment of accommodation expenses from AstraZeneca metastatic clear cell renal cell carcinoma. Cancer (Spain), Bristol Myers Squibb, Pfizer and Roche; Treat Rev 2018; 70: 127–137. and has a consulting or advisory role with 2. Fukumura D, Kloepper J, Amoozgar Z, et al. Astellas, AstraZeneca, Bayer, Boehringer Enhancing cancer immunotherapy using Ingelheim, Bristol Myers Squibb, Eli Lilly, antiangiogenics: opportunities and challenges. Ipsen, Janssen Oncology, MSD Oncology, Nat Rev Clin Oncol 2018; 15: 325–340. Novartis, Pfizer, Pierre Fabre, Roche/Genentech, 3. Santoni M, Iacovelli R, Colonna V, et al. and Sanofi. ABA has no interests to declare. CP Antitumor effects of the multi-target tyrosine has an advisory role with AstraZeneca, Bristol kinase inhibitor cabozantinib: a comprehensive Myers Squibb, Eisai, EUSA Pharma, General review of the preclinical evidence. Expert Rev Electric Healthcare, Ipsen, Janssen, MSD, Anticancer Ther 2021; 21: 1029–1054. Novartis, and Pfizer; has been a speaker for 4. Zhang Y, Xia M, Jin K, et al. Function of the Bristol Myers Squibb, EUSA Pharma, General c-Met receptor tyrosine kinase in carcinogenesis Electric Healthcare, Ipsen, and Pfizer; has been and associated therapeutic opportunities. Mol a protocol steering committee member for Cancer 2018; 17: 45. Bristol Myers Squibb, Eisai and EUSA Pharma; 5. Reichl P, Dengler M, van Zijl F, et al. Axl and has provided expert testimony for EUSA activates autocrine transforming growth factor- Pharma and Pfizer. JC has a scientific consul- beta signaling in hepatocellular carcinoma. tancy role (speaker and advisory roles) for Hepatology 2015; 61: 930–941. Advanced Accelerator Applications, Amgen, Bayer, Eisai, Exelixis, Ipsen, ITM, Merck 6. Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 Serono, Novartis, Pfizer, Sanofi, and Sirlex, and inhibitor, simultaneously suppresses metastasis, has received research grants from Advanced angiogenesis, and tumor growth. Mol Cancer Ther Accelerator Applications, AstraZeneca, Bayer, 2011; 10: 2298–2308. Eisai, Novartis, and Pfizer. SV reports personal fees and non-financial support from Bristol 7. Osanto S and Van der Hulle T. Cabozantinib in Myers Squibb, personal fees and non-financial the treatment of advanced renal cell carcinoma in adults following prior vascular endothelial growth support from Roche, personal fees from MSD, factor targeted therapy: clinical trial evidence and personal fees from AbbVie, non-financial sup- experience. Ther Adv Urol 2018; 10: 109–123. port from OSE PHARMA, and non-financial support from Merck. CR-A has no interests to 8. DrugBank. Cabozantinib, https://go.drugbank.com/ declare. LM is an employee of Ipsen. PM is on drugs/DB08875 (2022, accessed 19 January 2022). advisory boards for Astellas, AstraZeneca, Bayer, 9. Choueiri TK, Escudier B, Powles T, et al. Bristol, Ipsen, Janssen, Novartis, Pfizer, and Cabozantinib versus everolimus in advanced Roche, and has received research grants from renal-cell carcinoma. N Engl J Med 2015; 373: Bayer and Roche. 1814–1823. 10. Choueiri TK, Halabi S, Sanford BL, et al. Availability of data and material Cabozantinib versus sunitinib as initial targeted Not applicable. therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol ORCID iDs 2017; 35: 591–597. Daniel Castellano https://orcid.org/0000- 11. Abou-Alfa GK, Meyer T, Cheng AL, et al. 0002-9106-0687 Cabozantinib in patients with advanced and Pablo Maroto https://orcid.org/0000-0002- progressing hepatocellular carcinoma. N Engl J 0030-0412 Med 2018; 379: 54–63. 12. Schlumberger M, Elisei R, Müller S, et al. Overall survival analysis of EXAM, a phase III trial of Supplemental material cabozantinib in patients with radiographically Supplemental material for this article is available progressive medullary thyroid carcinoma. Ann online. Oncol 2017; 28: 2813–2819. 32 journals.sagepub.com/home/tam D Castellano, AB Apolo et al. 13. Brose MS, Robinson B, Sherman SI, et al. and immune modulatory activity of anti-PD1 Cabozantinib for radioiodine-refractory treatment in a syngeneic mouse model of HCC. J differentiated thyroid cancer (COSMIC-311): a Hepatol 2020; 73: S40 (abstract AS053). randomised, double-blind, placebo-controlled, 24. Duran I, Castellano D, Puente J, et al. Exploring phase 3 trial. Lancet Oncol 2021; 22: 1126–1138. the synergistic effects of cabozantinib and a 14. Ipsen Pharma. Cabometyx (summary of product programmed cell death protein 1 inhibitor in characteristics). European Medicines Agency, metastatic renal cell carcinoma with machine https://www.ema.europa.eu/en/documents/ learning. Oncotarget 2022; 13: 237–256. product-information/cabometyx-epar-product- 25. Adotevi O, Pere H, Ravel P, et al. A decrease of information_en.pdf (2021, accessed 25 June regulatory T cells correlates with overall survival 2021). after sunitinib-based antiangiogenic therapy in 15. Ipsen Pharma. Cometriq (summary of product metastatic renal cancer patients. J Immunother characteristics). European Medicines Agency, https:// 2010; 33: 991–998. www.ema.europa.eu/en/documents/product- 26. Verzoni E, Ferro S, Procopio G, et al. Potent information/cometriq-epar-product-information_ natural killer (NK) and myeloid blood cell en.pdf (2021, accessed 25 June 2021). remodeling by cabozantinib (cabo) in pretreated 16. Exelixis Inc. Cabometyx (highlights of prescribing metastatic renal cell carcinoma (mRCC) patients information). Food & Drug Administration, (pts). Ann Oncol 2018; 29: VIII312 (abstract https://www.accessdata.fda.gov/drugsatfda_docs/ 882P). label/2021/208692s012lbl.pdf (2022, accessed 7 27. Alves Costa Silva C, Le Teuff G, Hirsch L, et al. April 2022). Improved response rate of cabozantinib after 17. Exelixis Inc. Cometriq (highlights of prescribing immune checkpoint therapy in patients with information). Food & Drug Administration, metastatic renal cell carcinoma. Kidney Cancer https://www.accessdata.fda.gov/drugsatfda_docs/ 2020; 4: S26–S27 (abstract 34). label/2020/203756s009lbl.pdf (2020, accessed 25 28. Choueiri TK, Powles T, Burotto M, et al. June 2021). Nivolumab plus cabozantinib versus sunitinib 18. Bergerot P, Lamb P, Wang E, et al. Cabozantinib for advanced renal-cell carcinoma. N Engl J Med in combination with immunotherapy for 2021; 384: 829–841. advanced renal cell carcinoma and urothelial 29. Polet F and Feron O. Endothelial cell metabolism carcinoma: rationale and clinical evidence. Mol and tumour angiogenesis: glucose and glutamine Cancer Ther 2019; 18: 2185–2193. as essential fuels and lactate as the driving force. 19. Patel SA and Minn AJ. Combination cancer J Intern Med 2013; 273: 156–165. therapy with immune checkpoint blockade: 30. Emberley E, Bennett M, Chen J, et al. CB-839, mechanisms and strategies. Immunity 2018; 48: a selective glutaminase inhibitor, has anti-tumor 417–433. activity in renal cell carcinoma and synergizes 20. Kwilas AR, Ardiani A, Donahue RN, et al. with cabozantininb and everolimus. In: Keystone Dual effects of a targeted small-molecule symposia, tumor metabolism: mechanisms and inhibitor (cabozantinib) on immune-mediated targets, Whistler, BC, Canada, 5–9 March killing of tumor cells and immune tumor 2017, https://www.calithera.com/wp-content/ microenvironment permissiveness when uploads/2017/12/03.2017-Keystone-poster- combined with a cancer vaccine. J Transl Med Emberley-2017.pdf (accessed 20 January 2022). 2014; 12: 294. 31. Madan RA, Karzai FH, Al Harthy M, et al. 21. Apolo AB, Nadal R, Tomita Y, et al. Cabozantinib plus docetaxel and prednisone in Cabozantinib in patients with platinum-refractory metastatic castrate resistant prostate cancer. BJU metastatic urothelial carcinoma: an open-label, Int 2020; 127: 435–434. single-centre, phase 2 trial. Lancet Oncol 2020; 32. Strickler JH, Rushing CN, Uronis HE, et al. 21: 1099–1109. Cabozantinib and panitumumab for RAS wild- 22. Scirocchi F, Napoletano C, Pace A, et al. type metastatic colorectal cancer. Oncologist 2021; Immunogenic cell death and immunomodulatory 26: 465–e917. effects of cabozantinib. Front Oncol 2021; 11: 33. Bardelli A, Corso S, Bertotti A, et al. 755433. Amplification of the MET receptor drives 23. Esteban-Fabró R, Willoughby CE, Piqué-Gili resistance to anti-EGFR therapies in colorectal M, et al. Cabozantinib enhances the efficacy cancer. Cancer Discov 2013; 3: 658–673. journals.sagepub.com/home/tam 33 Therapeutic Advances in Medical Oncology Volume 14 34. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. and biomarker study. NPJ Breast Cancer 2021; 7: Cetuximab for the treatment of colorectal cancer. 110. N Engl J Med 2007; 357: 2040–2048. 45. Choudhury AD, Gray KP, Supko JG, et al. 35. Van Cutsem E, Peeters M, Siena S, et al. Open- A dose finding clinical trial of cabozantinib label phase III trial of panitumumab plus best (XL184) administered in combination with supportive care compared with best supportive abiraterone acetate in metastatic castration- care alone in patients with chemotherapy- resistant prostate cancer. Prostate 2018; 78: refractory metastatic colorectal cancer. J Clin 1053–1062. Oncol 2007; 25: 1658–1664. 46. Choueiri TK, Powles T, Burotto M, et al. 36. Lai Y, Zhao Z, Zeng T, et al. Crosstalk between Nivolumab plus cabozantinib versus sunitinib VEGFR and other receptor tyrosine kinases for for advanced renal-cell carcinoma. N Engl J Med TKI therapy of metastatic renal cell carcinoma. 2021; 384: 829–841. Cancer Cell Int 2018; 18: 31. 47. Choueiri TK, Powles T, Burotto M, et al. 696O_ 37. National Institute for Health Research (NIHR). PR Nivolumab + cabozantinib vs sunitinib PROSPERO. International prospective register of in first-line treatment for advanced renal cell systematic reviews, https://www.crd.york.ac.uk/ carcinoma: first results from the randomized PROSPERO/ (2019, accessed 11 November phase III CheckMate 9ER trial. Ann Oncol 2020; 2019). 31: S1159. 38. PRISMA. Transparent reporting of systematic 48. Corn PG, Zhang M, Nogueras-Gonzalez GM, reviews and meta-analyses, http://www.prisma- et al. A phase II study of cabozantinib and statement.org/ (2019, accessed 19 November androgen ablation in patients with hormone-naive 2019). metastatic prostate cancer. Clin Cancer Res 2020; 26: 990–999. 39. Agarwal N, Vaishampayan U, Green M, et al. Phase Ib study (COSMIC-021) of cabozantinib 49. Da Motta Girardi D, Niglio SA, Mortazavi A, in combination with atezolizumab: results of et al. Phase I expansion study of cabozantinib the dose escalation stage in patients (pts) with plus nivolumab (CaboNivo) in metastatic treatment-naıve advanced renal cell carcinoma urothelial carcinoma (mUC) patients (pts) with (RCC). Ann Oncol 2018; 29: VIII308 (abstract progressive disease following immune checkpoint 872P). inhibitor (ICI) therapy. J Clin Oncol 2020; 38: abstract 5037. 40. Agarwal N, Loriot Y, McGregor BA, et al. Cabozantinib (C) in combination with 50. Girardi DM, Niglio SA, Mortazavi A, et al. atezolizumab (A) in patients (pts) with metastatic Cabozantinib plus nivolumab phase I expansion castration-resistant prostate cancer (mCRPC): study in metastatic urothelial carcinoma patients results of cohort 6 of the COSMIC-021 study. J refractory to immune checkpoint inhibitor Clin Oncol 2020; 38: abstract 139. therapy. Clin Cancer Res 2022; 28: 1353–1362. 41. Al Harthy M, Madan RA, Karzai F, et al. A phase 51. Karzai FH, Shah AA, Ojemuyiwa MA, et al. I and randomized phase II study of cabozantinib A phase I study of the multikinase inhibitor plus docetaxel and prednisone (C + DP) cabozantinib (C) plus docetaxel (D) and versus docetaxel and prednisone (DP) alone prednisone (P) in metastatic castrate-resistant in metastatic castrate-resistant prostate cancer prostate cancer (mCRPC). J Clin Oncol 2014; 32: (mCRPC). J Clin Oncol 2019; 37: 173. abstract 108. 42. Apolo AB, Nadal R, Girardi DM, et al. Phase 52. Keeler ME, Kessler ER, Bernard B, et al. I study of cabozantinib and nivolumab alone Pembrolizumab (pembro) and cabozantinib or with ipilimumab for advanced or metastatic (cabo) in patients (pts) with metastatic renal cell urothelial carcinoma and other genitourinary carcinoma (mRCC): phase I results. J Clin Oncol tumors. J Clin Oncol 2020; 38: 3672–3684. 2019; 37: abstract 600. 43. Barroso-Sousa R, Trippa L, Li T, et al. A phase 53. Leone JP, Duda DG, Hu J, et al. A phase II study II study of nivolumab in combination with of cabozantinib alone or in combination with cabozantinib for metastatic triplenegative breast trastuzumab in breast cancer patients with brain cancer (mTNBC). Cancer Res 2020; 80: abstract metastases. Breast Cancer Res Treat 2020; 179: P3-09-10. 113–123. 44. Barroso-Sousa R, Keenan TE, Li T, et al. 54. Lheureux S, Matei D, Konstantinopoulos Nivolumab in combination with cabozantinib for PA, et al. A randomized phase II study of metastatic triple-negative breast cancer: a phase II cabozantinib and nivolumab versus nivolumab in 34 journals.sagepub.com/home/tam D Castellano, AB Apolo et al. recurrent endometrial cancer. J Clin Oncol 2020; cabozantinib as second-line or third-line 38: abstract 6010. treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG- 55. McGregor BA, Agarwal N, Suarez C, et al. ACRIN 1512): a randomised, controlled, open- Cabozantinib (C) in combination with label, multicentre, phase 2 trial. Lancet Oncol atezolizumab (A) in non-clear cell renal cell 2016; 17: 1661–1671. carcinoma (nccRCC): results from cohort 10 of the COSMIC-021 study. Ann Oncol 2020; 31: 64. Neal JW, Lim FL, Felip E, et al. Cabozantinib in S558 (abstract 709P). combination with atezolizumab in non-small cell lung cancer (NSCLC) patients previously treated 56. Pal SK, McGregor B, Suarez C, et al. with an immune checkpoint inhibitor: Results Cabozantinib in combination with atezolizumab from cohort 7 of the COSMIC-021 study. J Clin for advanced renal cell carcinoma: results from Oncol 2020; 38: abstract 9610. the COSMIC-021 study. J Clin Oncol 2021; 39: 3725–3736. 65. Pal SK, Agarwal N, Loriot Y, et al. Cabozantinib in combination with atezolizumab in urothelial 57. Marandino L, Raggi D, Giannatempo P, carcinoma previously treated with platinum- et al. Cabozantinib (CABO) plus durvalumab containing chemotherapy: results from cohort 2 (DURVA) in patients (pts) with advanced of the COSMIC-021 study. J Clin Oncol 2020; urothelial carcinoma (UC) after platinum 38: abstract 5013. chemotherapy: safety and preliminary activity of the open-label, single-arm, phase II ARCADIA 66. Pal S, Tsao CK, Suarez C, et al. Cabozantinib trial. Ann Oncol 2020; 31–33. (C) in combination with atezolizumab (A) as first-line therapy for advanced clear cell renal 58. Marandino L, Raggi D, Calareso G, et al. cell carcinoma (ccRCC): results from the Cabozantinib plus durvalumab in patients with COSMIC-021 study. Ann Oncol 2020; 31: S554 advanced urothelial carcinoma after platinum (abstract 702O). chemotherapy: safety and preliminary activity of the open-label, single-arm, phase 2 ARCADIA 67. Saeed A, Phadnis M, Park R, et al. Cabozantinib trial. Clin Genitourin Cancer 2021; 19: 457–465. (cabo) combined with durvalumab (durva) in gastroesophageal (GE) cancer and other 59. Meric-Bernstam F, Lee RJ, Carthon BC, et al. gastrointestinal (GI) malignancies: preliminary CB-839, a glutaminase inhibitor, in combination phase Ib CAMILLA study results. J Clin Oncol with cabozantinib in patients with clear cell and 2020; 38: abstract 4563. papillary metastatic renal cell cancer (mRCC): results of a phase I study. J Clin Oncol 2019; 37: 68. Schiff D, Desjardins A, Cloughesy T, et al. abstract 549. Phase 1 dose escalation trial of the safety and pharmacokinetics of cabozantinib concurrent with 60. Nadal R, Mortazavi A, Stein MN, et al. Clinical temozolomide and radiotherapy or temozolomide efficacy of cabozantinib plus nivolumab after radiotherapy in newly diagnosed patients (CaboNivo) and CaboNivo plus ipilimumab with high-grade gliomas. Cancer 2016; 122: (CaboNivoIpi) in patients (pts) with 582–587. chemotherapy-refractory metastatic urothelial carcinoma (mUC) either naive (n) or refractory 69. Strickler JH, Rushing CN, Uronis HE, (r) to checkpoint inhibitor (CPI). J Clin Oncol et al. Phase 1b study of cabozantinib plus 2018; 36: abstract 4528. panitumumab in KRAS wild-type (WT) metastatic colorectal cancer (mCRC). J Clin 61. Nadal RM, Mortazavi A, Stein M, et al. Results Oncol 2016; 34: abstract 3548. of phase I plus expansion cohorts of cabozantinib (Cabo) plus nivolumab (Nivo) and CaboNivo 70. Sweeney C, Gray KP, Harshman LC, et al. Phase plus ipilimumab (Ipi) in patients (PTS) with with 1 dose-finding study of cabozantinib (cabo) metastatic urothelial carcinoma (mUC) and other plus abiraterone (abi) combination therapy in genitourinary (GU) malignancies. J Clin Oncol castration resistant prostate cancer (CRPC): an 2018; 36: abstract 515. investigator-sponsored study. J Clin Oncol 2014; 32: abstract 5027. 62. Neal JW, Dahlberg SE, Wakelee HA, et al. A randomized phase 2 trial of cabozantinib, 71. Turk AA, Sehdev A, Shahda S, et al. A phase II erlotinib or the combination as 2nd or 3rd line trial of cabozantinib and erlotinib for patients therapy in EGFR wild-type NSCLC: ECOG- with EGFR and c-Met co-expressing metastatic ACRIN E1512. J Thorac Oncol 2015; 10: S373 pancreatic adenocarcinoma (PDAC). J Clin Oncol (abstract MINI30.04). 2020; 38: abstract e16764. 63. Neal JW, Dahlberg SE, Wakelee HA, et al. 72. Wakelee HA, Gettinger S, Engelman J, et al. A Erlotinib, cabozantinib, or erlotinib plus phase Ib/II study of cabozantinib (XL184) with journals.sagepub.com/home/tam 35 Therapeutic Advances in Medical Oncology Volume 14 or without erlotinib in patients with non-small reviews and meta-analyses: the PRISMA cell lung cancer. Cancer Chemother Pharmacol statement. J Clin Epidemiol 2009; 62: 1006–1012. 2017; 79: 923–932. 10.1016/j.jclinepi.2009.06.005 73. Yau T, Zagonel V, Santoro A, et al. Nivolumab 82. Choueiri TK, Escudier B, Powles T, et al. (NIVO) + ipilimumab (IPI) + cabozantinib Cabozantinib versus everolimus in advanced renal (CABO) combination therapy in patients (pts) cell carcinoma (METEOR): final results from with advanced hepatocellular carcinoma (aHCC): a randomised, open-label, phase 3 trial. Lancet results from CheckMate 040. J Clin Oncol 2020; Oncol 2016; 17: 917–927. 38: abstract 478. 83. Escudier B, Powles T, Motzer RJ, et al. 74. Zhen DB, Griffith KA, Ruch JM, et al. A phase I Cabozantinib, a new standard of care for patients trial of cabozantinib and gemcitabine in advanced with advanced renal cell carcinoma and bone pancreatic cancer. Invest New Drugs 2016; 34: metastases? Subgroup analysis of the METEOR 733–739. trial. J Clin Oncol 2018; 36: 765–772. 75. National Institute for Health and Care 84. Mainwaring P, Powles T, Escudier BJ, et al. Excellence. The social care guidance manual. Overall survival (OS) in meteor, a randomised Appendices B to D, https://www.nice.org.uk/ phase III trial of cabozantinib versus everolimus process/pmg10/chapter/introduction (2019, in patients with advanced renal cell carcinoma accessed 11 November 2019). (RCC). Asia Pac J Clin Oncol 2017; 13–14. 76. Powles T, Choueiri TK, Burotto M, et al. Final 85. Motzer RJ, Escudier B, Powles T, et al. Long- overall survival analysis and organ-specific target term follow-up of overall survival for cabozantinib lesion assessments with two-year follow-up in versus everolimus in advanced renal cell CheckMate 9ER: nivolumab plus cabozantinib carcinoma. Br J Cancer 2018; 118: 1176–1178. versus sunitinib for patients with advanced renal 86. Powles T, Escudier B, Mainwaring PN, et al. cell carcinoma. J Clin Oncol 2022; 40: 350. METEOR: results from the randomized phase 3 77. Agarwal N, McGregor BA, Maughan BL, trial of cabozantinib versus everolimus in pts with et al. Cabozantinib (C) in combination with advanced renal cell carcinoma (RCC). BJU Int atezolizumab (A) in patients (pts) with metastatic 2015; 116: 19. castration-resistant prostate cancer (mCRPC): 87. Choueiri TK, Hessel C, Halabi S, et al. results of expanded cohort 6 of the COSMIC-021 Cabozantinib versus sunitinib as initial study. Ann Oncol 2021; 32: S1283–S1346 therapy for metastatic renal cell carcinoma of (abstract LBA24). intermediate or poor risk (Alliance A031203 78. Saeed A, Park R, Dai J, et al. Phase II trial of CABOSUN randomised trial): progression- cabozantinib (Cabo) plus durvalumab (Durva) in free survival by independent review and overall chemotherapy refractory patients with advanced survival update. Eur J Cancer 2018; 94: mismatch repair proficient/microsatellite stable 115–125. (pMMR/MSS) colorectal cancer (CRC): 88. Apolo AB, Girardi DdM, Niglio SA, et al. Final CAMILLA CRC cohort results. J Clin Oncol results from a phase I trial and expansion cohorts 2022; 40: abstract 135. of cabozantinib and nivolumab (CaboNivo) alone 79. McGregor B, Mortazavi A, Cordes L, et al. or with ipilimumab (CaboNivoIpi) for metastatic Management of adverse events associated genitourinary tumors. J Clin Oncol 2021; 39: with cabozantinib plus nivolumab in renal cell abstract 3. carcinoma: a review. Cancer Treat Rev 2022; 103: 89. Tannir NM, Agarwal N, Porta C, et al. 102333. CANTATA: primary analysis of a global, 80. Tannir NM, Agarwal N, Porta C, et al. randomized, placebo (Pbo)-controlled, CANTATA: Primary analysis of a global, double-blind trial of telaglenastat (CB- randomized, placebo (Pbo)-controlled, 839) + cabozantinib versus Pbo + cabozantinib double-blind trial of telaglenastat (CB- in advanced/metastatic renal cell carcinoma 839) + cabozantinib versus Pbo + cabozantinib (mRCC) patients (pts) who progressed on in advanced/metastatic renal cell carcinoma immune checkpoint inhibitor (ICI) or anti- (mRCC) patients (pts) who progressed on angiogenic therapies. J Clin Oncol 2021; 39: immune checkpoint inhibitor (ICI) or anti- abstract 4501. angiogenic therapies. J Clin Oncol 2021; 39: 4501 90. Apolo AB, Mortazavi A, Stein MN, et al. A (abstract 4501). phase I study of cabozantinib plus nivolumab 81. Moher D, Liberati A, Tetzlaff J, et al., PRISMA (CaboNivo) and cabonivo plus ipilimumab Group . Preferred reporting items for systematic (CaboNivoIpi) in patients (pts) with refractory 36 journals.sagepub.com/home/tam D Castellano, AB Apolo et al. metastatic (m) urothelial carcinoma (UC) and 95. U.S. National Library of Medicine. Cabozantinib other genitourinary (GU) tumors. J Clin Oncol plus pembrolizumab as first-line therapy for cisplatin- 2017; 35: abstract 4562. ineligible advanced urothelial carcinoma (PemCab), https://clinicaltrials.gov/ct2/show/NCT03534804 91. Alliance for Clinical Trials in Oncology. Alliance (2020, accessed 9 March 2020). for Clinical Trials in Oncology home, https:// www.allianceforclinicaltrialsinoncology.org/main/ 96. Exelixis. Exelixis further expands prostate (2020, accessed 12 March 2020). cancer cohort in phase 1b COSMIC-021 trial of 92. U.S. National Library of Medicine. cabozantinib in combination with atezolizumab Immunotherapy with nivolumab and ipilimumab in patients with advanced solid tumors, https:// followed by nivolumab or nivolumab with ir.exelixis.com/news-releases/news-release-details/ cabozantinib for patients with advanced kidney exelixis-further-expands-prostate-cancer-cohort- cancer: the PDIGREE study, https://clinicaltrials. phase-1b-cosmic (2020, accessed February 2020). gov/ct2/show/NCT03793166 (2020, accessed 6 97. Kelley RK, Yau T, Cheng A-L, et al. VP10- March 2020). 2021: cabozantinib (C) plus atezolizumab 93. Ko JJ, Xie W, Kroeger N, et al. The International (A) versus sorafenib (S) as first-line systemic Metastatic Renal Cell Carcinoma Database treatment for advanced hepatocellular carcinoma Consortium model as a prognostic tool in (aHCC): results from the randomized phase patients with metastatic renal cell carcinoma III COSMIC-312 trial. Ann Oncol 2022; 33: previously treated with first-line targeted therapy: P114–P116. a population-based study. Lancet Oncol 2015; 16: 98. Exelixis. Exelixis announces final overall survival 293–300. results from phase 3 COSMIC-312 trial of 94. U.S. National Library of Medicine. Testing the cabozantinib in combination with an immune effectiveness of two immunotherapy drugs (nivolumab checkpoint inhibitor in patients with previously and ipilimumab) with one anti-cancer targeted drug untreated advanced liver cancer, https:// Visit SAGE journals online (cabozantinib) for rare genitourinary tumors, https:// ir.exelixis.com/news-releases/news-release-details/ journals.sagepub.com/ home/tam clinicaltrials.gov/ct2/show/NCT03866382 (2020, exelixis-announces-final-overall-survival-results- accessed 9 March 2020). phase-3-cosmic (2022, accessed April 2022). SAGE journals journals.sagepub.com/home/tam 37