1107112 research-article20222022 TAM0010.1177/17588359221107112Therapeutic Advances in Medical OncologyP Maroto, C Porta Therapeutic Advances in Medical Oncology Systematic Review Cabozantinib for the treatment of solid Ther Adv Med Oncol 2022, Vol. 14: 1­–28 tumors: a systematic review DOI: 10.1177/ https://doi.org/10.1177/17588359221107112 https://doi.org/10.1177/17588359221107112 17588359221107112 © The Author(s), 2022. Article reuse guidelines: Pablo Maroto , Camillo Porta, Jaume Capdevila, Andrea B. Apolo, Santiago Viteri, sagepub.com/journals- permissions Cristina Rodriguez-Antona, Lidia Martin and Daniel Castellano Abstract Background: Cabozantinib is approved, in various settings, for the treatment of renal cell carcinoma, medullary thyroid cancer, and hepatocellular carcinoma, and it has been investigated for the treatment of other cancers. With the available evidence and the real-world performance of cabozantinib compared with clinical trial data, we performed a systematic review of cabozantinib monotherapy as treatment for solid tumors in adults. Methods: This study was designed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and registered with PROSPERO (CRD42020144680). We searched for clinical and observational studies of cabozantinib monotherapy for solid tumors using Embase, MEDLINE, and Cochrane databases (October 2020), and screened relevant congress abstracts. Eligible studies reported clinical or safety outcomes, or biomarker data. Small studies (n < 25) and studies of cabozantinib combination therapies were excluded. Quality was assessed using National Institute for Health and Care Excellence methodology, and study characteristics were described qualitatively. Correspondence to: Results: Of 2888 citations, 114 were included (52 randomized studies, 29 observational Pablo Maroto Medical Oncology Services, studies, 32 nonrandomized phase I or II studies or pilot trials, and 1 analysis of data from a Hospital de la Santa Creu i Sant Pau, Mas Casanovas, randomized study and a nonrandomized study). Beyond approved indications, other tumors Barcelona, 08025, Spain. studied were castration-resistant prostate cancer, urothelial carcinoma, Ewing sarcoma, JMaroto@santpau.cat Camillo Porta osteosarcoma, uveal melanoma, non-small-cell lung cancer, Merkel cell carcinoma, Interdisciplinary glioblastoma, pheochromocytomas and paragangliomas, cholangiocarcinoma, gastrointestinal Department of Medicine, University of Bari “Aldo stromal tumor, colorectal cancer, salivary gland cancer, carcinoid and pancreatic Moro,” Bari, Italy neuroendocrine tumors, and breast, endometrial and ovarian cancers. The most common Jaume Capdevila Department of Medical adverse events were hypertension, diarrhea, and fatigue. Oncology, Vall d’Hebron Conclusion: The identified evidence demonstrates the positive efficacy/effectiveness of University Hospital, Vall d’Hebron Institute cabozantinib monotherapy in various solid tumor types, with safety findings being consistent of Oncology (VHIO), with those observed with other VEGFR-targeting tyrosine kinase inhibitors. When available, Barcelona, Spain Andrea B. Apolo real-world findings were consistent with the data reported from clinical trials. A limitation of Center for Cancer this review is the high proportion of abstracts; however, this allowed us to capture the most Research, National Cancer Institute, National up-to-date findings. Institutes of Health, Bethesda, MD, USA Santiago Viteri Keywords: cabozantinib, hepatocellular carcinoma, renal cell carcinoma, solid tumor, UOMI Cancer Center, Clínica Mi Tres Torres, tyrosine kinase inhibitor, vascular endothelial growth factor Barcelona, Spain Cristina Rodriguez- Antona Received: 15 November 2021; revised manuscript accepted: 25 May 2022. National Cancer Research Center, Madrid, Spain Lidia Martin Ipsen Pharma, Barcelona, Spain Introduction regulate angiogenesis, epithelial to mesenchymal Daniel Castellano Vascular endothelial growth factor (VEGF) transition, cell proliferation, and cell migration.1 Medical Oncology Department, University receptor and hepatocyte growth factor receptor Overexpression of VEGF receptor and MET pro- Hospital 12 de Octubre, (MET) are involved in signaling pathways that motes tumor growth and metastasis.1 The kinase Madrid, 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 AXL is also linked to tumor pathogenesis, signal- in combination with nivolumab for the first-line ing to promote metastasis.2 As well as promoting treatment of adults with advanced RCC in the tumor growth, dysregulation of VEGF, MET, European Union and in the United States.6,10,15 and AXL signaling pathways is also associated with immune suppression, leading to inhibition of Cabozantinib has also been investigated for the antitumor immunity.3,4 Cabozantinib is the only treatment of other types of solid tumors. For approved tyrosine kinase inhibitor (TKI) that tar- example, the use of cabozantinib in metastatic gets VEGF receptors (VEGFRs), MET, and castration-resistant prostate cancer (mCRPC) AXL.5 has been investigated in two phase III randomized controlled trials (RCTs; COMET-1 and Cabozantinib is approved for several indications COMET-2),16,17 its use in non-small-cell lung both in the Europe and in the United States. In cancer (NSCLC) has been investigated in a phase Europe, cabozantinib monotherapy is approved II RCT,18,19 and has recently been assessed in for the treatment of the following patients: adult DTC in a phase III RCT (COSMIC-311).9 With patients with advanced renal cell carcinoma evidence growing in multiple disease areas, there (RCC) who are naive to treatment and have inter- is a need to establish an up-to-date understanding mediate or poor risk in terms of prognosis [tab- of the use of cabozantinib in the treatment of lets, 60 mg once daily (QD)]6; adults with solid tumors, focusing on the clinical efficacy, advanced RCC who have received prior VEGF- comparative effectiveness, and safety profile of targeted therapy (tablets, 60 mg QD)6; adults cabozantinib as a monotherapy for solid tumors. with progressive, unresectable locally advanced or metastatic medullary thyroid cancer (MTC; cap- To address these needs, we performed a system- sules, 140 mg QD)7; and adults with hepatocel- atic literature review (SLR) to identify the clinical lular carcinoma (HCC) who have previously been and observational data on cabozantinib mono- treated with sorafenib (tablets, 60 mg QD).6 In therapy for the treatment of different types of Europe, the Committee for Medicinal Products solid tumor in adults and to understand how the for Human Use endorsed the use of cabozantinib real-world performance of cabozantinib mono- in differentiated thyroid cancer (DTC), based on therapy compares with the data reported in piv- the results of the COSMIC-311 study; a decision otal clinical trials. As a secondary aim of this SLR, from the European Commission is awaited, at the we also assessed which biomarkers are being time of writing.8,9 In the United States, cabozan- explored to guide treatment decisions relating to tinib monotherapy is approved for the treatment the use of cabozantinib monotherapy. Although of patients with advanced RCC (tablets, 60 mg associations between biomarkers and patient QD)10; patients with progressive, metastatic response to cancer therapy have huge potential in MTC (capsules, 140 mg QD)11; and patients with guiding treatment decisions, a thorough evalua- HCC who have previously been treated with tion of this broad topic was beyond the scope of sorafenib (tablets, 60 mg QD)10 and adult and this review. pediatric patients (aged 12 years and older) with locally advanced or metastatic DTC that has pro- gressed following prior VEGFR-targeted therapy Materials and methods and who are radioiodine refractory, or ineligible (tablets, 60 mg QD).10 These approvals were Search strategy based on the following: a randomized phase III The protocol for this SLR was registered with the study demonstrated improved objective response International Prospective Register of Systematic rate (ORR), progression-free survival (PFS), and Reviews (PROSPERO; registration name: ‘A sys- overall survival (OS) in patients with advanced tematic literature review of cabozantinib for the RCC compared with everolimus; a phase III trial treatment of solid tumors’; registration number: comparing cabozantinib with placebo showed CRD42020144680). Published studies of cabo- improved ORR, PFS, and OS in patients with zantinib as a monotherapy for solid tumors were advanced progressive HCC; and a phase III trial identified through a systematic search. MEDLINE comparing cabozantinib with placebo showed In-Process & Other Non-Indexed Citations and improved PFS in progressive MTC.6,7,10–14 It Ovid MEDLINE (1946–present), Embase should be noted that cabozantinib capsules and (1974–present), and the Cochrane Library were tablets are not bioequivalent and cannot be used searched on 9 October 2020 (see Supplemental interchangeably.6,7 Cabozantinib is also approved Resource 1 for search terms used in Embase). 2 journals.sagepub.com/home/tam P Maroto, C Porta et al. Supplementary searches superseded by articles that were included. The Congress abstracts were searched from 1 January final number of studies included in this review 2016 to 9 October 2020. The congresses included was 114 (Figure 1). were as follows: American Society of Clinical Oncology (ASCO), ASCO Gastrointestinal Characteristics of included studies. Of the 114 Cancers Symposium, ASCO Genitourinary included articles, 106 reported efficacy, effective- Cancers Symposium, European Society for ness, and/or safety outcomes; of these, 47 reported Medical Oncology, and American Association for findings from RCTs or randomized discontinua- Cancer Research. The bibliographies of studies tion trials (RDTs), 28 reported findings from identified in the electronic searches were reviewed observational or retrospective studies, and 31 to identify the additional relevant references. reported findings from nonrandomized phase I or II studies (Supplemental Resource 2). Among the identified RCTs and RDTs, cabozantinib was Study selection and data collection evaluated versus placebo or versus the active com- Citations identified by the searches were screened parators everolimus, temozolomide, dacarbazine, against prespecified criteria in accordance with mitoxantrone, prednisone, or sunitinib. The most the 2009 Preferred Reporting Items for Systematic commonly studied disease type in terms of effi- Reviews and Meta-Analyses (PRISMA) guide- cacy was RCC (Figure 2). Among the included lines. During screening, abstracts and titles were studies, 54 articles contained data on biomarkers. reviewed by a single reviewer against the eligibil- ity criteria and uncertainties were resolved by a In terms of quality assessment, 21/114 studies second reviewer. Eligibility criteria are presented had the highest rating for internal validity. Poorer in Table 1. During data extraction, study popula- ratings were predominantly due to a lack of study tion data and key results relating to efficacy, safety details reported in congress abstracts (58 were and biomarkers were extracted manually for each abstracts, and 35 were articles). included study. Efficacy and effectiveness of cabozantinib Quality assessment monotherapy Quality was assessed using National Institute for Renal cell carcinoma. Evidence from randomized Health and Care Excellence methodology check- studies: Two RCTs evaluated cabozantinib in lists. Studies were given a rating according to patients with RCC: the phase III METEOR their level of potential bias in terms of internal trial13,21–27 and the phase II CABOSUN trial.28,29 and external validity.20 All studies are included in the Results section, regardless of their quality The METEOR trial compared cabozantinib rating. 60 mg (n = 330) with everolimus 10 mg (n = 328) QD in patients who received prior treatment with at least one VEGFR-targeting TKI; approxi- Results mately 70% of patients received study treatment as a second-line therapy. Results demonstrated a Overview of evidence superior efficacy for cabozantinib in all three end- Results of SLR. In total, 2888 citations were iden- points: PFS (primary endpoint, with 90% statisti- tified by the electronic searches after de-duplica- cal power), and OS and ORR (secondary tion; of these, 386 proceeded to full paper review. endpoints). The disease control rate [DCR; A further 20 articles were considered relevant for defined as complete response (CR) + partial full-text review, including 17 from congress response (PR) + stable disease (SD)] was 83% in searches and 3 from bibliographies of studies the cabozantinib group and 66% in the everoli- identified in the electronic searches. Following mus group. Subgroup analyses of patients in this full paper review, 292 articles were excluded, of study with or without prior nephrectomy showed which 77 were excluded according to post hoc cabozantinib improved PFS, ORR, and OS com- exclusion criteria, including RCTs and real-world pared with everolimus in patients with advanced studies with a sample size of fewer than 25; bio- RCC, irrespective of nephrectomy status.26 marker studies carried out in cell lines; in vitro Similarly, a retrospective analysis of patients in cultures or in vivo models; encores of abstracts the METEOR trial stratified by age group (<65, already included; or abstracts that had been 65–74, and ⩾75 years) reported improved PFS, journals.sagepub.com/home/tam 3 Therapeutic Advances in Medical Oncology Volume 14 Table 1. Eligibility criteria for studies identified by SLR. Category Inclusion criteria Exclusion criteria Population • Patients with a solid tumor • Patients with nonsolid tumors • Healthy volunteers • Nonhuman subjects Interventions • Cabozantinib monotherapy • No cabozantinib • Cabozantinib as part of combination therapy Comparator • Any • No exclusions • No comparator (i.e. single-arm studies) Outcomes • C linical outcomes (ORR, OS, PFS, other • Outcomes not listed in inclusion criteria survival, and response outcomes) and real- world proxies • Safety outcomes (AEs, number of dose reductions/discontinuations) • Outcomes related to biomarkers Study designs • Randomized trials (any phase) • Editorials and narrative reviews • Nonrandomized phase I or II studies • Systematic reviews • Real-world, observational studies • MAs/NMAs • A  ny study reporting data on biomarkers • N onrandomized, non-observational studies that (except those stated under exclusion were not described as a phase I or phase II study criteria) • 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 •  tudies published between January 2012 S • Studies published before January 2012 and 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, prior to data extraction. 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. ORR, and OS compared with everolimus, irre- respectively. Characteristics and key findings spective of age group.27 A post hoc pooled analysis from these studies are presented in Table 2. of patients from METEOR and a Japanese, open- label, phase II study showed similar efficacy Evidence from real-world studies: In all, 21 publica- results, irrespective of prior treatment with tions relating to 16 retrospective or observational immuno-oncology agents.30 analyses investigated OS, PFS, or response (pri- mary endpoints were not specified) of cabozan- The CABOSUN trial compared cabozantinib tinib (60 mg or not reported) in RCC (Figure 60 mg (n = 79), as a first-line therapy in patients at 3).35–55 Of the 16 studies, 13 were in patients with intermediate and poor risk only, with sunitinib advanced or metastatic RCC in which the histo- 50 mg (n = 78). Patients receiving cabozantinib logical subtypes were either mixed or not repor had a significantly lower risk of progression (pri- ted.35–52 Two studies evaluated patients with mary endpoint, with 85% statistical power) than advanced or metastatic non-clear-cell RCC,53,54 those receiving sunitinib (p = 0.0008). Risk of and one study was conducted in patients with death was not significantly different between metastatic clear-cell RCC.55 Effectiveness data treatment groups; however, the study was not reported in real-world studies were broadly simi- powered for survival differences.29 The DCRs for lar to the efficacy data reported in the RCTs cabozantinib and sunitinib were 75% and 47%, (Figure 3). OS was reported in 12 publications 4 journals.sagepub.com/home/tam P Maroto, C Porta 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. relating to 11 studies and ranged from 9.1 to failure was reported in four studies and ranged 25.4 months.35–43,53–55 PFS was reported in 10 from 5.7 to 7.4 months.39,43,53,55 studies and ranged from 5.6 to 12.5 mon ths.35–38,42,44,45,47,53,54 The ORR (or the proportion Subgroup analyses of a UK study (CERES) of of patients with CR + PR) was reported in 13 100 patients with advanced RCC reported found publications relating to 12 studies and ranged that patients who were enrolled early in the study from 14% to 52%.35,37–39,41–44,46,47,53–55 The DCR had similar outcomes to those that who enrolled or clinical benefit rate (or proportion of later,36 but lower (⩽6 versus >6) Charlson CR + PR + SD) was reported by 12 publications Comorbidity Index scores were associated with relating to 11 studies and ranged from 50% to longer OS and PFS.48 In a US-based retrospec- 96%.35,37–39,41–44,46,47,53–55 The time to treatment tive study (n = 65), increased body mass index journals.sagepub.com/home/tam 5 Therapeutic Advances in Medical Oncology Volume 14 Figure 2. Summary of clinical efficacy studies of cabozantinib monotherapy identified by the SLR, by study, and tumor type. CRPC, castration-resistant prostate cancer; HCC, hepatocellular carcinoma; MTC, medullary thyroid cancer; RCC, renal cell carcinoma; RCT, randomized controlled trial; RDT, randomized discontinuation trial; SLR, systematic literature review. 6 weeks after initiation of cabozantinib therapy Median (95% CI) OS was 30.7 (15.8–36.8), 17.8 was significantly associated with prolonged OS (11.9–23.3), 12.6 (9.3–21.7) and 14.9 (10.2– [hazard ratio (HR) 0.90; 95% confidence interval 21.7) months in the first-, second-, third- and (CI): 0.83–0.98; p = 0.016].52 The CABOREAL fourth-line settings, respectively. ORR was main- study investigated the real-world use of cabozan- tained over the different lines of treatment, at tinib in the French Early Access Program.40,49,50 32% in the first line, 26% in the second line, 51% A subgroup analysis of patients enrolled in in the third line, and 29% in the fourth line.51 CABOREAL by age showed similar clinical out- comes regardless of age; median (95% CI) OS Evidence from nonrandomized phase I and II clinical was 13.6 (10.2–15.4) months for patients younger studies: In phase I study, patients (n = 25) who than 65 years, 16.2 (14.1–19.5) months for those received prior therapies (median: two) received aged 65–75 years and 13.3 (6.5–18.3) months for cabozantinib (capsule, 140 mg QD). Median OS aged 75 years and older.49 A post hoc analysis in 47 and PFS were 15.0 months and 12.9 months, patients with non-clear-cell RCC enrolled in respectively. Numbers of patients with PR, SD, CABOREAL by subtype showed that cabozan- and PD were 7 (28%), 13 (52%), and 1 (4%), tinib is particularly effective in papillary RCC respectively.56 A phase II, open-label, single-arm type 1, with median OS of 16 months.50 Two study of cabozantinib (60 mg QD) in Japanese abstracts relating to the same French retrospec- patients (n = 35) with advanced RCC who had tive single-center study based on the Institut received at least one prior TKI (one prior TKI: Gustave Roussy RCC database were included,41,42 70%; two prior TKIs: 23%; three or more prior the second with an additional eight patients.42 TKIs: 9%) reported an ORR of 20%, a clinical This later abstract reported that ORR was higher benefit rate (CR + PR + SD) of 86% and a in patients who had received prior immune check- 6-month PFS estimate of 72.3% [median PFS point blockade (ICB; 49%; 54% clear-cell RCC and OS were not reached (NR)].57 versus 17% non-clear-cell RCC) than in those who had received prior TKI (21%; 27% clear-cell Hepatocellular carcinoma. Evidence from random- RCC versus 14% non-clear-cell RCC).42 Finally, ized studies: One phase III RCT (CELESTIAL another retrospective analysis, using a multina- trial) compared cabozantinib 60 mg (n = 470) with tional database, investigated the effectiveness of placebo (n = 237) in patients with HCC who had cabozantinib in patients with metastatic RCC. been treated with sorafenib and had received up to 6 journals.sagepub.com/home/tam Table 2. Summary of clinical efficacy and safety findings from key randomized controlled trials of cabozantinib. Trial name Tumor type Line of therapy or Treatment Details of statistical Findings for primary Findings for secondary Safety data for (and reference and patient patient treatment comparison and power endpoint(s) endpoint(s) cabozantinib arm of primary population history doses publication) METEOR13 aRCC or Patients must Cabozantinib Primary endpoint: under PFS: OS: 331 patients (100%) mRCC have received (n = 330) versus assumption of 259 events Median 7.4 (95% CI: Unadjusted HR at first had at least one AE journals.sagepub.com/home/tam Patients were prior treatment everolimus (disease progression or 5.6–9.1) months for interim analysis, 0.67 (95% (any grade) ⩾18 years with one or more (n = 328) death), there was 90% cabozantinib CI: 0.51–0.89; p = 0.005).13 226 patients (68%) had of age with VEGFR TKI and Cabozantinib power to detect an HR HR at first analysis Follow-up was at least grade 3–4 AEs a clear-cell must have had 60 mg orally QD; of 0.667 (cabozantinib (first 375 patients 6 months 31 patients (9%) component radiographic everolimus 10 mg versus everolimus), using who underwent PR was 40 (21%) for discontinued and progression orally QD the log-rank test and a randomization), 0.58 cabozantinib and 9 (5%) for treatment measurable during treatment two-sided significance (95% CI: 0.45–0.75; everolimus (p < 0.001)13 197 patients (60%) had disease or in the 6 months level of 0.05. Observed p < 0.001).13 Follow-up SD was 116 (62%) for a dose reduction after the most number of events was was at least 11 months cabozantinib and 116 (62%) Most common recent dose 247 HR for all randomized for everolimus (p value not grade 3–4 AEs were: of the VEGFR Secondary endpoint: patients, 0.51 (95% CI: reported)13 hypertension, 49 inhibitor. There under assumption of 408 0.41–0.62; p < 0.0001).21 PD was 26 (14%) for (15%); diarrhea, 38 was no limit deaths, there was 80% Median follow-up was cabozantinib and 51 (27%) (11%); fatigue, 30 (9%); to the number power to detect an HR of 18.7 months in the for everolimus (p value not PPES, 28 (8%) of previous 0.75 (cabozantinib versus cabozantinib arm and reported)13 anticancer everolimus), using the 18.8 months in the HR at second interim therapies log-rank test and a two- everolimus arm analysis, 0.66 (95% CI: 0.53– sided significance level of 0.83; p < 0.001).21 Median 0.04. Observed number of follow-up 21.4 months in deaths was 32021 the cabozantinib arm and 16.5 months in the everolimus arm Additional analysis with extended follow-up: HR, 0.70 (95% CI: 0.58–0.85; p = 0.0002).24 Median follow- up was 28 months (Continued) 7 P Maroto, C Porta et al. 8 Table 2. (Continued) Trial name Tumor type Line of therapy or Treatment Details of statistical Findings for primary Findings for secondary Safety data for (and reference and patient patient treatment comparison and power endpoint(s) endpoint(s) cabozantinib arm of primary population history doses publication) CABOSUN28 aRCC or First line Cabozantinib Under assumption of 123 PFS (progression or OS: 77 patients (98.7%) Medical Oncology mRCC (n = 79) versus events (progressions or death): Original analysis (median had at least one AE Patients were sunitinib (n = 78) deaths), there was 85% Adjusted HR, 0.66 follow-up, 21.4 months): (any grade) ⩾18 years Cabozantinib power to detect an HR of [95% CI: 0.46–0.95; median (95% CI) OS was 52 patients (66.7%) of age with 60 mg orally QD; 0.67 for PFS, using the p = 0.012; adjusted by 30.3 (14.6–35.0) months had grade 3–4 AEs a clear-cell sunitinib 50 mg log-rank test and a one- stratification factors for cabozantinib and 21.8 16 patients (20%) orally QD for sided type I error of 0.12. (IMDC risk groups and Therapeutic Advances in component (16.3–27.0) months for discontinued and 4 weeks, followed The required number of presence or absence sunitinib [adjusted HR 0.80 treatment measurable by a 2-week events (123) was reached of bone metastases)].28 (95% CI: 0.50–1.26); p value 36 patients (46%) had disease, break Median follow-up was not reported]28 a dose reduction and must 21.4 months Updated analysis (median Most common have been Additional analysis follow-up, 35.4 months): grade 3–4 AEs were classified as of PFS when PFS median (95% CI) OS was hypertension, 22 intermediate was assessed by 26.6 (14.6, upper limit (28.2%); diarrhea, or poor risk an investigator/ not estimable) months 8 (10.3%); PPES, 6 by IMDC independent radiology for cabozantinib and 21.2 (7.7%); fatigue, 5 criteria review committee. (16.3–27.4) months for (6.4%) Median follow-up was sunitinib [adjusted HR 0.80 25.0 months29 (95% CI: 0.53–1.21); p value Assessed by not reported]29 investigator, median Both of the HRs above were (95% CI) PFS was 8.3 adjusted by stratification (6.5–12.4) months for factors (IMDC risk groups and cabozantinib and 5.4 presence or absence of bone (limit not reported metastases) accurately) months ORR: for sunitinib [HR, 0.56 Original analysis: (95% CI: 0.37–0.83); cabozantinib, 33% (95% CI: p = 0.0042]29 23–44%); sunitinib, 12% (95% Assessed by an CI: 5.4–21%)28 independent Updated analysis: radiology review cabozantinib, 20% (95% CI: committee, median 12–31%); sunitinib, 9% (95% (95% CI) PFS was 8.6 CI: 4–18%)29 (6.8–14.0) months for cabozantinib and 5.3 (3.0–8.2) months for sunitinib [HR, 0.48 (95% CI: 0.31–0.74); p < 0.001]29 (Continued) journals.sagepub.com/home/tam Volume 14 Table 2. (Continued) Trial name Tumor type Line of therapy or Treatment Details of statistical Findings for primary Findings for secondary Safety data for (and reference and patient patient treatment comparison and power endpoint(s) endpoint(s) cabozantinib arm of primary population history doses publication) EXAM12 mMTC No limit on Cabozantinib For the OS analysis, PFS: OS: 22% of patients Adult number of (n = 219) versus there was 80% power to Median PFS was In the analysis of OS (44% discontinued patients with prior therapies, placebo (n = 111) detect an HR of 0.667, 11.2 months for of the 217 required events), treatment journals.sagepub.com/home/tam unresectable including MKIs 140 mg QD using the log-rank cabozantinib and there was no significant 82% of patients had a locally test and a two-sided 4.0 months for placebo. difference between dose reduction advanced or significance level of 0.04 Adjusted HR was 0.28 cabozantinib and placebo31 Most common grade metastatic (across interim and final [95% CI: 0.19–0.40; In the final analysis (minimum 3–4 AEs were diarrhea, MTC analyses) p < 0.0001; analyses follow-up, 42 months), median 46 (21.5%); PPES, 27 were stratified OS was 26.6 months for (12.6%); hypocalcemia, by randomization cabozantinib and 21.1 months 23 (10.7%); fatigue, stratification factors for placebo. The comparison 21 (9.8%); decreased (age and prior MKI between treatment arms was weight, 21 (9.8%) treatment)] only statistically significant in the patients with RET M918T [HR, 0.60 (95% CI: 0.38–0.94); p = 0.03]12 ORR was 28% in those receiving cabozantinib12 CELESTIAL14 aHCC Patients had Cabozantinib Under assumption of 621 OS: PFS: 460 patients (99%) had Patients were received previous (n = 470) versus deaths in a sample size Median (95% CI) Median (95% CI) PFS at least one AE14 ⩾18 years of treatment with placebo (n = 237) of 760, there was 90% OS was 10.2 (9.1– was 5.2 (4.0–5.5) months 316 patients (68%) had age and had sorafenib and 60 mg orally QD power to detect an HR of 12.0) months for for cabozantinib and 1.9 grade 3–4 AEs received a had experienced 0.76 (cabozantinib versus cabozantinib and 8.0 (1.9–1.9) months for placebo. 76 patients (16%) pathological disease placebo), using the log- (6.8–9.4) months for Unadjusted HR was 0.44 (95% discontinued treatment diagnosis of progression rank test and a two-sided placebo. Unadjusted CI: 0.36–0.52; p < 0.001)14 due to cabozantinib- HCC that was after at least significance level of 0.05. HR was 0.76 (95% CI: ORR was 4% (all PRs) for related AEs not amenable one systemic Observed number of 0.63–0.92; p = 0.005). cabozantinib and 0.4% for 291 patients (62%) had to curative treatment for deaths was 484 at time of Follow-up was up to placebo (p = 0.009)14 a dose reduction treatment HCC. They may second interim analysis 42 months Median TTP was 5.4 for Most common grade have up to two cabozantinib and 1.9 for 3–4 AEs were PPES, 79 previous systemic placebo32 (17%); hypertension, treatments HR for TTP was 0.41 (95% CI: 74 (16%); increase in 0.34–0.49)32 AST, 55 (12%); fatigue, 49 (10%); diarrhea, 46 (10%); asthenia, 32 (7%); increase in ALT, 23 (5%) Patients who had any- grade PPES had greater OS and PFS than those who did not have PPES (median OS, 14.4 versus 8.4 months; median PFS, 6.5 versus 3.7; p values not reported)33 Patients who had grade 3 or above hypertension had greater OS and PFS than those who did not have grade 3 or above hypertension (median OS, 16.1 versus 9.5 months; median PFS, 7.4 versus 4.4; p values not reported)33 9 P Maroto, C Porta et al. (Continued) 10 Table 2. (Continued) Trial name Tumor type Line of therapy or Treatment Details of statistical Findings for primary Findings for secondary Safety data for (and reference and patient patient treatment comparison and power endpoint(s) endpoint(s) cabozantinib arm of primary population history doses publication) COMET-117 mCRPC No limit on Cabozantinib Under assumption of 578 OS: PFS: 228 patients (33%) Medical Oncology Patients were the number (n = 682) versus deaths, there was 90% Median (95% CI) Median (95% CI) PFS was discontinued ⩾18 years of previous prednisone power to detect an HR OS was 11.0 (10.1– 5.6 (5.5–5.6) months for treatment of age with anticancer (n = 346) of 0.75, using a log-rank 11.6) months for cabozantinib and 2.8 (2.8–2.9) 67% of patients had a mCRPC and treatments Cabozantinib two-sided test at an cabozantinib and 9.8 months for prednisone. dose reduction had bone 60 mg orally QD; overall type I error level (9.0–11.5) months for Unadjusted HR was 0.48 (95% 680 patients (100%) prednisone 5 mg of 0.05. Observed number prednisone. Unadjusted had at least one AE Therapeutic Advances in metastases CI: 0.40–0.57; p < 0.001) and disease BID of deaths was 614 HR was 0.90 (95% CI: See COMET-2 row for 481 patients (71%) had progression 0.76–1.06; p = 0.213). findings on a pooled analysis grade 3–4 AEs after Follow-up was up to of COMET-1 and COMET-2 Most common docetaxel and 24 months grade 3–4 AEs were abiraterone hypertension, 135 acetate (20%); fatigue, 119 and/or (17%); anemia, 108 enzalutamide (16%); asthenia, 84 (12%); decreased appetite, 55 (8.1%) COMET-216 mCRPC Patients must Cabozantinib With the planned sample Primary endpoint was OS: 60 patients (100%) had Patients were have received (n = 61) versus MP size of 246, there was pain response – not Median OS was 9.0 months for at least one AE16 ⩾18 years of three or more (n = 58) ⩾90% power for the presented here cabozantinib and 7.9 months 42 patients (70%) had age with a cycles of Cabozantinib primary endpoint of pain for MP [stratified HR (95% grade 3–4 AEs pathological docetaxel or 60 mg orally QD; reduction and 80% power CI), 0.70 (0.44–1.10); p = 0.1]16 10 patients (17%) diagnosis of progressed mitoxantrone for OS using a two-sided In a combined analysis of discontinued mCRPC after docetaxel- 12 mg/m2 Q3W chi-squared test with a COMET-1 and COMET-2, treatment containing plus prednisone significance level of 0.05 adjusted HR for cabozantinib 52 patients (87%) had therapy and 5 mg orally BID versus prednisone or MP a dose reduction discontinued was 0. [95% CI: 0.67–0.95; Most common abiraterone or p = 0.0012; adjusted for grade 3–4 AEs were enzalutamide baseline prognostic anemia, 13 (22%); owing to disease factors (further details not hypertension, 13 progression reported)]34 (22%); fatigue, 11 Follow-up was up to (18%); increase in AST, approximately 28 months 6 (10%) AE, adverse event; aHCC, advanced hepatocellular carcinoma; ALT, alanine aminotransferase; aRCC, advanced renal cell carcinoma; AST, aspartate aminotransferase; BID, twice daily; CI, confidence interval; HCC, hepatocellular carcinoma; HR, hazard ratio; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; mCRPC, metastatic castration-resistant prostate cancer; MKI, multikinase inhibitor; mMTC, metastatic medullary thyroid cancer; MP, mitoxantrone plus prednisone; mRCC, metastatic renal cell carcinoma; MTC, medullary thyroid cancer; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PPES, palmar–plantar erythrodysesthesia syndrome; PR, partial response; Q3W, once every 3 weeks; QD, once daily; SD, stable disease; TKI, tyrosine kinase inhibitor; TTP, time to progression; VEGFR, vascular endothelial growth factor receptor. journals.sagepub.com/home/tam Volume 14 P Maroto, C Porta et al. Figure 3. (continued) journals.sagepub.com/home/tam 11 Therapeutic Advances in Medical Oncology Volume 14 Figure 3. Comparison of outcomes for key trials of cabozantinib in patients with RCC: (a) OS, (b) PFS, (c) ORR, and (d) DCR. Solid bars = cabozantinib; open bars = comparator (everolimus in METEOR11,20,23 and Santini et al.45; sunitinib in CABOSUN27,28; nivolumab in Stukalin et al.43); black = randomized controlled trial; gray = real-world study. N numbers are presented for the evaluable patients when available, and for the whole cohort if the number of evaluable patients has not been published. a60 mg dose. bColomba et al.41 and Alves Costa Silva et al.42 are reports from the same study at different time points. DCR, disease control rate; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RCC, renal cell carcinoma. two previous systemic treatments. The primary An analysis of patients in CELESTIAL who had endpoint was median (95% CI) OS (with 90% received prior transarterial chemoembolization power to detect an HR of 0.76), which was signifi- (TACE) showed that cabozantinib improved out- cantly greater with cabozantinib than with placebo comes versus placebo, irrespective of prior TACE. [10.2 (9.1–12.0) months versus 8.0 (6.8–9.4) Median OS was 11.4 months with cabozantinib months; HR 0.76; 95% CI: 0.63–0.92; p = 0.005]. versus 8.6 months with placebo for patients with Median (95% CI) PFS as 5.2 (4.0–5.5) for cabo- prior TACE and 9.5 months versus 7.2 months for zantinib versus 1.9 (1.9–1.9) for placebo (HR patients with no prior TACE.60 Characteristics 0.44; 95% CI: 0.32–0.52; p < 0.001).14 A further and key findings from the CELESTIAL study are analysis of tumor response reported that 47% of presented in Table 2. patients who received cabozantinib, versus 11% of those who received placebo, had a post-baseline Evidence from real-world studies: Two European reduction in tumor target lesion size; median time real-world studies of cabozantinib in HCC were to progression was 5.4 months for cabozantinib identified, the findings of which were consistent versus 1.9 months for placebo (HR 0.41; 95% CI: with data reported from the pivotal CELESTIAL 0.34–0.49).32 Further analyses of a subset of trial (Figure 4).61,62 Both real-world studies evalu- patients who received sorafenib as their only prior ated cabozantinib as a second or later line of ther- therapy demonstrated greater median (95% CI) apy, with median OS ranging from 7.761 to OS with cabozantinib, at 11.3 (9.5–13.9) months, 12.9 months.62 In the first study, conducted in than with placebo, at 7.2 (5.8–9.3) months (HR Austria and Germany, four patients (5%) 0.70; 95% CI: 0.55–0.88).58 Another retrospective achieved PR.61 The second study, conducted in analysis showed clinical efficacy in patients in Italy, reported a median (95% CI) PFS of 5.1 CELESTIAL who had deterioration of liver func- (2.7–7.5) months62 and DCR of 59%.62 tion to Child–Pugh B by study week 8. Median OS was 8.5 months with cabozantinib versus Evidence from nonrandomized phase I and II clinical 3.8 months with placebo (HR 0.32; 95% CI: studies: One phase II study evaluated cabozan- 0.18–0.58), and median PFS was 3.7 months ver- tinib in 41 patients with HCC, most (78%) of sus 1.9 months (HR 0.44; 95% CI: 0.25–0.76).59 whom had 1–2 lines of systemic therapy 12 journals.sagepub.com/home/tam P Maroto, C Porta et al. Figure 4. Comparison of outcomes for key trials of cabozantinib in patients with HCC: (a) OS, (b) PFS, (c) ORR, and (d) DCR. Solid bars = cabozantinib; open bars = comparator (placebo for CELESTIAL14]); black = randomized controlled trial; gray = real- world study. N numbers are presented for the evaluable patients when available, and for the whole cohort if the number of evaluable patients has not been published. DCR, disease control rate; HCC, hepatocellular carcinoma; ORR, objective response rate; OS, overall survival; PFS, progression-free survival. previously. At the end of a 12-week lead-in phase with an HR (95% CI) of 0.28 (0.19–0.40); there of an RDT, patients receiving cabozantinib was 80% power to detect an HR of 0.667. There 100 mg QD had an ORR (measured by Response was also a longer median OS with cabozantinib Evaluation Criteria in Solid Tumors version 1.0) than with placebo (26.6 months versus of 5%, and the DCR was 66% overall.63 21.1 months). Further characteristics and key findings of the EXAM study12,31,64–67 are pre- Medullary thyroid cancer. Evidence from random- sented in Table 2. ized studies: One phase III RCT (EXAM study) compared cabozantinib (140 mg as capsules; Evidence from real-world studies/nonrandomized n = 219) with placebo (n = 111) in patients with phase I and II clinical studies: No real-world studies MTC, with no limit on the number of prior thera- or phase I or II studies of cabozantinib monother- pies. The study met the primary endpoint (PFS) apy in MTC were identified. journals.sagepub.com/home/tam 13 Therapeutic Advances in Medical Oncology Volume 14 Differentiated thyroid cancer. Evidence from ran- In a phase II RDT, the primary endpoints were domized studies/real-world studies: No randomized ORR during the 12-week lead-in stage and PFS or real-world studies of cabozantinib monother- after randomization.72 Patients had received no apy in DTC were identified. The results of the more than one prior standard chemotherapy regi- phase III COSMIC-311 trial of cabozantinib in men, completed at least 4 weeks prior to study patients with radioiodine-refractory DTC previ- entry, and received cabozantinib 100 mg QD or ously treated with BEGFR-targeted therapy were placebo during the trial. At the end of the 12-week published after the searches for this review had lead-in phase, during which all 171 patients been conducted. For completeness, the key effi- received cabozantinib, numbers of patients with cacy results of COSMIC-311 are included in the PR, SD, and PD were 9 (5%), 127 (75%), and 18 Discussion.9 (11%), respectively. After randomization of 31 patients, median (95% CI) PFS was 23.9 (10.7– Evidence from nonrandomized phase I and II clinical 62.4) weeks in the cabozantinib arm (n = 14) and studies: Three phase I or II studies were identified 5.9 (5.4–6.6) weeks in the placebo arm (n = 17). for the evaluation of patients with DTC. In one HR for cabozantinib versus placebo was 0.12 phase II study, in the first-line setting, patients (p < 0.001). receiving cabozantinib 60 mg QD had a PR rate of 54% (19/35 patients).68 Cabanillas et al.69,70 Evidence from real-world studies: No real-world conducted a phase I study (n = 15) with cabozan- studies of cabozantinib monotherapy in CRPC tinib 140 mg and a phase II study (n = 25) with were identified. cabozantinib 60 mg. The phase I study measured response in patients who were refractory to stand- Evidence from nonrandomized phase I and II clinical ard therapy with radioactive iodine (RAI). The studies: Two phase II studies evaluated patients numbers of patients with PR and SD were 8 with mCRPC. One included 144 patients who (53%) and 6 (40%), respectively, out of a total of had received at least one previous docetaxel-con- 15 patients.69 In the phase II study of patients taining regimen and no more than three previous who received up to two lines of prior VEGFR- chemotherapy regimens. The primary endpoint targeted therapy, ORR (primary endpoint) was was bone scan response (not reported here), and 40% and median (95% CI) OS was 34.7 (18.3– further endpoints included OS. Median (95% upper limit NR) months.70 CI) OS was 12.1 (9.4–14.3) months in the cabo- zantinib 100 mg cohort (n = 93) and 9.1 (8.0– Castration-resistant prostate cancer. Evidence 12.9) months in the cabozantinib 40 mg cohort from randomized studies: The COMET-1 and (n = 51).73 In another study in patients with pro- COMET-2 trials were phase III RCTs that com- gressive CRPC and bone metastases who were pared cabozantinib 60 mg with prednisone, and naive to chemotherapy, 17/22 patients (77%) cabozantinib 60 mg with mitoxantrone plus pred- receiving cabozantinib 60 mg QD had PFS at nisone (MP), respectively. The study samples 12 weeks (primary endpoint; see Supplemental included men with mCRPC, more than 90% of Resource 2 for details of statistical power).74 whom had received three or more prior cancer therapies.17,34,71 COMET-1 did not meet its pri- Other tumor types. Evidence from randomized stud- mary endpoint (OS); there was no significant dif- ies: An RDT studied cabozantinib 100 mg QD in ference between cabozantinib (n = 682) and 526 patients with nine different tumor types, prednisone (n = 346; the study had 90% power to including CRPC, gastric/gastroesophageal junc- detect an HR of 0.75). However, there were favor- tion adenocarcinoma, HCC, metastatic breast able results for cabozantinib in terms of the sec- cancer, melanoma, NSCLC, small-cell lung can- ondary endpoint, PFS (Table 2).17 COMET-2 cer, ovarian cancer and pancreatic adenocarci- had a primary endpoint of pain response, which noma. Primary endpoints were ORR in the was not significantly different for cabozantinib 12-week lead-in phase and PFS after randomiza- versus MP (15% versus 17%; p = 0.8) and is out- tion. Overall, ORR and median PFS were 0–22% side the scope of this SLR. In terms of additional and 2.4–6.9 months, respectively.75 In a subgroup endpoints, patients receiving cabozantinib analysis of only patients with melanoma (n = 77), (n = 61) demonstrated longer OS than those 66% of whom had at least one line of prior sys- receiving MP (n = 58; 9.0 months versus temic therapy, ORR was 5% and median (95% 7.9 months; p = 0.1).16 Characteristics and key CI) PFS was 4.1 (1.8–upper limit NR) months. findings of these studies are presented in Table 2. The HR for PFS (cabozantinib versus placebo) 14 journals.sagepub.com/home/tam P Maroto, C Porta et al. was 0.59 and was not statistically significant to 60 mg QD after the first seven patients. The (p = 0.284).76 In another subgroup analysis of bone scan response rate (primary endpoint) was patients with ovarian cancer (n = 70) who had no 38%; 26 patients (50%) had SD as measured by more than three prior standard chemotherapy Response Evaluation Criteria in Solid Tumors. regimens, ORR (95% CI) was 21% (13–32%). Median (90% CI) OS and PFS were 19.6 (18.0– After randomization, median PFS was 5.9 months 26.8) months and 4.3 (2.8–5.5) months, respec- in the cabozantinib arm and 1.4 months in the tively.83 In one study of treatment of metastatic placebo arm (statistical significance not collecting-duct carcinoma in the first-line setting, reported).77 A randomized phase II trial com- response (primary endpoint) was partial in 2/9 pared cabozantinib with chemotherapy (temo- patients (22%), and there were SD and PD in 2/9 zolomide or dacarbazine) in 46 patients with patients (22%) and 3/9 patients (33%), respec- metastatic uveal melanoma. The primary end- tively.84 Two studies assessed patients with any point was to evaluate whether cabozantinib could number of prior therapies. The first study improve PFS at 4 months (PFS4) from 15% (pre- included patients with grade 1‒2 carcinoid viously described for temozolomide) to 40% with (n = 41) or pancreatic neuroendocrine tumors cabozantinib. PFS4 was not found to differ (n = 20),85 and reported an ORR (95% CI; pri- between the two groups, at 32% with cabozan- mary endpoint) of 15% (7–28%) and 15% (5– tinib and 27% with chemotherapy. Furthermore, 36%), respectively. The second study included there were no significant differences in PFS or OS patients with RET-rearranged lung cancers for cabozantinib versus chemotherapy (median (n = 26) and reported an ORR (95% CI) of 28% PFS: 60 days versus 59 days; median OS: (12–49%).86 One study, which also measured 6.4 months versus 7.3 months).78 response as the primary endpoint, evaluated patients with unresectable metastatic pheochro- Evidence from real-world studies: No real-world mocytomas and paragangliomas; results showed studies of cabozantinib monotherapy in other that 6/15 patients (40%) had PR.87 PFS was the tumor types were identified. primary endpoint in four studies that evaluated patients with recurrent/metastatic endometrial Evidence from nonrandomized phase I and II clinical cancer (n = 102),88 cholangiocarcinoma (n = 19),89 studies: In all, 18 phase II studies and one phase I uterine carcinosarcoma (n = 15),90 and gastroin- study evaluated patients with various types of testinal stromal tumor (n = 50).91 Prior to the tumor.79–96 In all but one of these studies,79 the studies, patients had progressed after one or two cabozantinib dose was 60 mg. In one study in 50 lines of therapy.88–91 Median PFS was 1.8– patients with relapsed or refractory metastatic 5.5 months. One study, in 44 patients with meta- urothelial carcinoma (mUC), the primary end- static colorectal cancer, had 12-week PFS rate as point, ORR (95% CI), was 19% (9–34%). the primary endpoint, which was 34%.92 Median (95% CI) OS and PFS were 8.1 (5.2– 10.3) months and 3.7 (3–6) months, respec- A retrospective analysis of phase II data measured tively.80 Another study evaluated 36 patients with OS in 108 patients with recurrent glioblastoma, breast cancer with brain metastases, with a in whom antiangiogenic therapy had not previ- median of three prior lines of therapy for meta- ously failed. After treatment with cabozantinib static disease. After treatment with cabozantinib 100 mg or 140 mg QD, median OS was 60 mg, the primary endpoint (central nervous sys- 11.0 months.79 tem ORR) was 5% in cohort 1 [human epidermal growth factor receptor 2 (HER2)+], 14% in A phase II study evaluated patients with advanced cohort 2 (hormone receptor+ HER2–), and 0% Ewing sarcomas and osteosarcomas, many of in cohort 3 (triple negative).81 In a study of meta- whom had received two or more prior lines of static triple-negative breast cancer only (n = 35), therapy (Ewing sarcomas: 67%; osteosarcomas: the primary endpoint, ORR (95% CI), was 9% 40%). In patients with osteosarcoma (n = 45), (2–26%) in patients with up to three prior chem- ORR was 12%, with median (95% CI) PFS of 6.7 otherapeutic regimens.82 In a study of 52 patients (5.4–7.9) months. In patients with Ewing sar- with hormone-receptor-positive breast cancer coma (n = 45), ORR was 26%, with median (95% with breast metastases (who had received at least CI) PFS of 4.4 (3.7–5.6) months.93 one prior line of hormonal therapy or chemother- apy for metastatic disease), cabozantinib had an A small phase II study in eight patients with initial dosage of 100 mg QD, but this was reduced advanced Merkel cell carcinoma was closed journals.sagepub.com/home/tam 15 Therapeutic Advances in Medical Oncology Volume 14 prematurely, partly due to lack of response (best 1–7%)53,54; mucosal inflammation or mucositis response was SD in one patient). Next-generation (3–5%)35,44; increased aspartate aminotransferase sequencing did not detect any genetic alteration (AST), alanine aminotransferase (ALT) or in either MET or VEGFR2.94 Another phase II transaminitis (1–5%)44,47,53; rash (4%)47; anemia study, in 25 patients with salivary gland cancer, (0–3%)44,47; and pneumonitis (1–2%).44,47 Nine reported ORRs of 6% for those with adenoid studies reported the proportions of patients who cystic carcinoma, 20% for those with salivary discontinued treatment owing to AEs, which duct carcinoma, and 0% for those with other sali- ranged from 4% to 16%35,41,44,46,47,53,55,99,100 and vary gland cancers; median (95% CI) PFS was were broadly similar to those reported in RCTs. 12.6 (6.8–18.4) months, 9.0 months (insufficient The proportions of patients who required dose events for 95% CI) and 6.9 (0–15.2) months, reductions owing to AEs were reported in nine respectively.95 Finally, a phase I study of cabozan- studies, which ranged from 23% to tinib in patients with advanced or metastatic solid 69%35,38,44,46,47,53–55,100 and were consistent with tumors included an expansion cohort of patients those seen in the RCTs. with NSCLC (cabozantinib was dosed at 60 mg in the expansion cohort). Objective responses In a retrospective analysis (n = 65), results showed were seen in 4/23 patients (17%) in the dose- that the rate of AEs was greater in patients who escalation cohorts and 4/20 patients (20%) in the received a reduced starting dose of cabozantinib NSCLC expansion cohort.96 than in those who received a starting dose of 60 mg (95% versus 66%).38 Another study observed a rate of dose reductions of 57% in 21 Safety of cabozantinib monotherapy patients receiving cabozantinib 60 mg.54 Renal cell carcinoma. Evidence from randomized studies: In two RCTs, the proportion of patients A European real-world study of 337 patients with who experienced grade 3–4 adverse events (AEs) advanced RCC (CASSIOPE) found that was 67–68%13,28; the most common grade 3–4 AE-related dose modifications were similar for AEs with cabozantinib 60 mg treatment were patients initiating cabozantinib at the recom- hypertension (15–28%), diarrhea (10–11%), mended 60 mg and for those initiating at any dose fatigue (6–9%), and palmar–plantar erythro- (dose reductions in 46% versus 39%; discontinu- dysesthesia syndrome (PPES; 8%).13,28 Overall, ations in 11% versus 10%).46 9–20% of patients discontinued treatment owing to AEs and 46–60% required a dose reduc- In two analyses (n = 91–96) of Italian real-world tion.13,28 All safety findings of the METEOR data for treatment beyond the first-line setting, trial13,21,22,24,25,27,30,97,98 and the CABOSUN rate of grade 3–4 AEs after treatment with cabo- trial28,29 are presented in Table 2. zantinib 60 mg was 21–36%44,99 (most common AEs were asthenia and diarrhea), and rate of dose Evidence from real-world studies: In all, 11 real- reduction was 42%.44 world studies that reported safety data relating to cabozantinib in patients with RCC were identi- In a UK study (n = 128), the most common grade fied. Six studies reported the overall proportions 3–4 AEs following treatment with cabozantinib of patients with grade 3–4 AEs, ranging from (dose not reported) were fatigue (11%) and diar- 15% to 49% of patients,35,44,46,47,55,99 which were rhea (9%), and 55% of patients required a dose lower than those reported in RCTs. Four real- reduction.35 In a North American observational world studies reported the most common grade study, 86 patients with metastatic clear-cell RCC 3–4AEs35,44,47,53,54: hypertension (4–7%),44,47,53,54 received cabozantinib following progression while diarrhea (3–10%),35,44,47,53 fatigue (2– undergoing ICB; dose reductions for AEs 23%), 35,47,53,54 and PPES (or hand–foot skin reac- occurred in 45% of patients [most commonly tion; 2–12%)35,44,47,53,54 that were all seen at fatigue (27%) and PPES (16%)].55 broadly similar levels to those reported in RCTs. Other grade 3–4 AEs reported in the real-world Fatigue was also the most common AE (52%) in studies in more than 2% of patients in at least one a study of patients with non-clear-cell RCC; the study were as follows: deep venous thrombosis or most common grade 3 AEs were skin toxicity pulmonary embolism (4–13%)44,54; asthenia (including PPES: 4%), hypertension (4%), and (7%)44; proteinuria (including nephrotic range; diarrhea (3%).53 16 journals.sagepub.com/home/tam P Maroto, C Porta et al. In a Polish real-world retrospective analysis of 115 Child–Pugh B by study week 8. In the Child– patients with metastatic RCC who had received Pugh B subgroup, versus the overall population, prior VEGF-targeted therapy, the most common there were similar rates of dose reductions (61% grade 3–4 AEs with cabozantinib 60 mg were versus 62%) and discontinuations due to AEs fatigue (23%), PPES (12%), and diarrhea (10%). (18% versus 16%). Rates of grade 3–4 PPES (17% Only 4% of patients discontinued treatment owing versus 8%) and hypertension (16% versus 8%) to AEs.47 An evaluation of cabozantinib in 91 were higher in the Child–Pugh B subgroup than patients with metastatic RCC in a real-world set- in the overall population.59 Further safety find- ting in France reported that 35% of patients had ings from the CELESTIAL study are presented more than 10% weight loss and that 11% experi- in Table 2. enced more than 20% weight loss.41 Fatigue was the most common AE (80%) in a US retrospec- Evidence from real-world studies: One real-world tive chart review of 35 patients with metastatic study of cabozantinib in HCC was identified. RCC, followed by gastrointestinal AEs (54%), This Italian study in patients with unresectable PPES (26%), and hypertension (23%). Four HCC (n = 52) reported that the most common patients (12%) discontinued owing to AEs.100 treatment-related grade 3–4 AEs were fatigue (10%), hand–foot skin reaction (8%), hyperten- Evidence from nonrandomized phase I and II clinical sion (6%), and increased ALT (6%).62 These studies: In a phase I study of 25 patients with were similar to those reported in the CELESTIAL clear-cell RCC with refractory tumors or tumors trial,14 but the RCT reports the overall event rate that progressed following standard therapies, the rather than the treatment-related events. most common grade 3 AEs were hypophos- Permanent dose reductions from 60 to 40 mg phatemia [n = 10 (40%)], fatigue [n = 5 (20%)], were required in 46% of patients, and from 60 to and hyponatremia [n = 5 (20%)] after treatment 20 mg in 17%. Permanent discontinuation for with cabozantinib 140 mg QD. There were three intolerance occurred in 17% of patients.62 Overall, reports of grade 4 AEs, including pulmonary the rates of dose reductions and discontinuations embolism, peritoneal hemorrhage, and a mental are in line with those reported in the CELESTIAL status change (not related to cabozantinib).56 A trial (62% and 16%, respectively).14 phase II, open-label, single-arm study of cabo- zantinib (60 mg QD) in Japanese patients (n = 35) Evidence from nonrandomized phase I and II clinical with advanced RCC who had received at least studies: In a phase II study (n = 41), the most com- one prior TKI reported a safety profile consistent mon AEs of grade 3 or above following cabozan- with those reported in other studies. Hypertension tinib 100 mg QD were diarrhea (20%), PPES was the most common AE of grade 3 or above (termed as hand-foot syndrome; 15%), thrombo- (11%), followed by PPES, diarrhea, proteinuria, cytopenia (15%), hypertension (10%), and abnormal hepatic function, decrease appetite, increased AST (10%).63 and fatigue (all 9%). Two patients (6%) discon- tinued owing to AEs.57 Medullary thyroid cancer. Evidence from random- ized studies: One RCT (cabozantinib arm, n = 219) Hepatocellular carcinoma. Evidence from random- identified diarrhea PPES and fatigue as the most ized studies: The phase III CELESTIAL trial of common grade 3–4 AEs with cabozantinib (cap- cabozantinib (tablets, 60 mg) in patients with sule,140 mg). Further safety findings from the advanced HCC following prior sorafenib therapy EXAM study are presented in Table 2.12,31,65,67,101 reported grade 3–4 AEs in 68% of the safety pop- ulation (n = 467).14 The most common grade 3–4 Evidence from real-world studies/nonrandomized AEs were PPES (17%), hypertension (16%), phase I and II clinical studies: No real-world studies increased AST (12%), fatigue (10%), and diar- or phase I or II studies of cabozantinib monother- rhea (10%).14 In a retrospective analysis of the apy in MTC were identified. AEs observed in the CELESTIAL trial, results showed that the development of any grade PPES Differentiated thyroid cancer. Evidence from ran- or hypertension of grade 3 or above was associ- domized studies/real-world studies: No randomized ated with prolonged OS and PFS.33 A retrospec- studies or real-world studies of cabozantinib tive analysis showed that cabozantinib may have a monotherapy in DTC were identified. As noted manageable safety profile in patients in CELES- earlier, the literature searches for this review were TIAL who had deterioration of liver function to conducted before the results of the COSMIC-311 journals.sagepub.com/home/tam 17 Therapeutic Advances in Medical Oncology Volume 14 trial were published. For completeness, however, discontinuation, which was 25% in the 100 mg the key safety results of COSMIC-311 are cohort and 18% in the 40 mg cohort.73 included in the Discussion.9 Other tumor types. Evidence from randomized stud- Evidence from nonrandomized phase I and II clinical ies: In an RDT of cabozantinib 100 mg QD of studies: In a phase I study (n = 15) by Cabanillas et various tumor types, the rates of dose reduction al.,69 rates of discontinuation and dose reduction were 74% (390/526 patients) overall,75 29% in were 7% and 93%, respectively, with cabozan- metastatic melanoma (22/77 patients),76 and 37% tinib 140 mg. In a subsequent phase II study in ovarian cancer (26/70).77 Fatigue and diarrhea (n = 25),70 the rate of dose reduction was 56% fol- were among the most common grade 3–4 AEs. In lowing a starting dose of 60 mg. With cabozan- a randomized phase II trial of cabozantinib in tinib 140 mg, the most common AEs (grade 3 or patients with mUC, grade 3–4 AEs were throm- above) were hyponatremia (27%), and diarrhea boembolic events (13%) and hypertension and increased lipase (both 20%). With cabozan- (20%).78 tinib 60 mg, the most common AEs (grade 3) were hypophosphatemia (16%), and fatigue, Evidence from real-world studies: No real-world weight loss, lipase or amylase elevation, and neu- studies of cabozantinib monotherapy in other tropenia (all 12%). tumor types were identified. Another phase II study (n = 35), in the first-line Evidence from nonrandomized phase I and II clinical setting, found that the most common treatment- studies: In all, 16 phase II studies evaluated the related AEs were hyperglycemia, diarrhea, fatigue/ safety of cabozantinib 60 mg in various tumor malaise, and weight loss, following treatment with types.80–83,85–95,103 The rate of dose reductions cabozantinib 60 mg.68 ranged from 34%82 to 87%87 in seven studies that reported these data. The most common grade Castration-resistant prostate cancer. Evidence 3–4 AEs included hypertension (⩽36% in 10 from randomized studies: In two RCTs that evalu- studies),80–83,85,86,88,90,91,95 diarrhea (⩽26% in ated 61 and 682 patients treated with cabozan- seven studies),80,81,83,85,90,91,95 and increased lipase tinib 60 mg, the most common grade 3–4 AEs (⩽15% in five studies).81,82,86,91,93 were found to be hypertension and fatigue. Fur- ther safety findings of COMET-117 and COMET- In a phase I study of patients with advanced or 216,71 are presented in Table 2. metastatic solid tumors, including an expansion cohort of patients with NSCLC, the most com- In a phase II RDT that evaluated 171 patients mon grade 3–4 AEs were gamma glutamyl trans- with mCRPC who received cabozantinib 100 mg ferase increase (17%), hypertension (13%), and and one or no prior standard chemotherapy regi- lymphopenia (13%) in the dose-escalation cohort, mens, fatigue [n = 27 (16%)] and hypertension and hypertension (30%), neutropenia (25%), and [n = 21 (12%)] were the most common grade 3 ALT increase, PPES, hypophosphatemia, and AEs. The rate of discontinuation during the lead- dyspnea (all 15%) in the NSCLC expansion in stage was 12%.72 cohort. The recommended phase II dose for cabozantinib was 60 mg.96 Evidence from real-world studies: No real-world studies of cabozantinib monotherapy in CRPC Biomarkers for response to cabozantinib. Of 114 were identified. articles identified from the SLR, 54 report find- ings related to biomarkers. The biomarkers iden- Evidence from nonrandomized phase I and II clinical tified include RET mutational status (seven studies: Three phase II studies (n = 19, 51, and studies),12,64–67,101,104 presence of bone metastases 144) examined AEs in patients with mCRPC (five studies),28,40,66,105,106 MET expression level receiving cabozantinib. Common AEs (grade 3 or (five studies),18,19,29,107,108 RAS mutational status above) were fatigue (14%73) and hypertension (four studies),67,92,101,104 circulating tumor cells (13%102) in those receiving 40 mg; venous throm- (two studies),73,102 and alpha-fetoprotein (three boembolism (23%) and diarrhea (14%)74 in those studies).109–111 Six studies investigated tumor receiving 60 mg; and fatigue (27%) in those characteristics, including diameter and vol- receiving 100 mg.73 One study reported the rate of ume.97,112–115 The remaining studies included 18 journals.sagepub.com/home/tam P Maroto, C Porta et al. various biomarkers, such as plasma and cell ⩾3 AEs (63% versus 72%), dose reductions (69% biomarkers.34,47,53,78,81,82,91,94,96,103,116–127 versus 81%), and discontinuations due to AEs (23% versus 36%). RET status was the most commonly investigated biomarker; all seven studies were subgroup anal- As well as approved indications, we identified yses of MTC study populations. Patients with studies of cabozantinib in additional tumor types. positive RET-mutation status (mainly RET Among these, CRPC was the most studied tumor M918T) generally experienced greater cabozan- type in randomized trials of cabozantinib; two tinib treatment benefit (prolonged OS and PFS RCTs (COMET-1 and COMET-2) did not pro- with cabozantinib versus placebo) than patients vide supporting evidence for cabozantinib versus without RET mutations.12,64,66,67,101,104 In a post prednisone or MP, while an RDT did demon- hoc analysis of the CABOSUN trial, including strate the improved efficacy of cabozantinib versus 131 patients with RCC in whom MET expres- placebo.16,17,72 Cabozantinib monotherapy in sion was determined by immunohistochemistry, CRPC is being studied further in two ongoing findings suggested the treatment effect (cabo- phase II studies. The aim of one randomized zantinib versus sunitinib) may be stronger in the study is to compare immediate prostatectomy group with MET overexpression than in the versus cabozantinib followed by prostatectomy in MET-negative group [HR (95% CI) for PFS: patients with high-risk prostate cancer 0.32 (0.16–0.63) versus 0.67 (0.37–1.23)], (NCT03964337), and the aim of the second sin- respectively.29 In another study (n = 90), higher gle-arm study is to determine the effectiveness of soluble MET (sMET) concentrations were cabozantinib in the treatment of patients with associated with improved PFS in patients with mCRPC (NCT04631744). Based on the 140 osteosarcoma (7.8 months versus 5·4 months for active cabozantinib monotherapy studies listed the sMET < 300.6 ng/mL and =300.6 ng/mL on ClinicalTrials.gov in May 2021, 27 are in indi- groups, respectively; log-rank p = 0.0167).93 No cations that are not yet approved, including the association has been observed between MET recently published COSMIC 311 trial expression and treatment response in patients (NCT03690388; estimated study completion, with Ewing sarcoma, NSCLC, or urothelial December 2022).9 COSMIC 311 was a phase III carcinoma.18,19,80 RCT comparing cabozantinib with placebo and focuses on patients with RAI-refractory DTC who progressed during or following treatment Discussion with ⩽2 prior VEGFR inhibitors. As is the case In carrying out a thorough systematic review of for other types of systemic therapy, there are rela- the literature, we have captured a wealth of evi- tively few studies of cabozantinib (and other dence from 114 articles reporting on the efficacy, TKIs) in DTC populations, probably because effectiveness, and safety of cabozantinib as a patients with DTC largely respond well to stand- monotherapy for the treatment of solid tumors. ard surgical treatment and RAI therapy.128 The COSMIC 311 results (published after the biblio- The review captured key efficacy evidence from metric searches were conducted and so not randomized trials that have supported the included in the quantitative analysis of the search approval of cabozantinib for RCC (METEOR results) reported significantly prolonged PFS and CABOSUN trials), MTC (EXAM trial), and with cabozantinib compared with placebo (HR HCC (CELESTIAL trial). Evidence for approved 0.22, 95% CI: 0.13–0.36; p < 0.0001); the safety indications is continuing to grow. The phase IV profile was manageable and consistent with the EXAMINER trial (NCT01896479) compared known safety profile of cabozantinib.9 cabozantinib (60 mg tablets and 140 mg capsules) in patients with metastatic MTC. Activity in A recent review emphasized that antiangiogenic patients with advanced MTC was shown for both drugs, such as cabozantinib, are of particular dose regimens, but the 60 mg tablet did not meet interest in ovarian cancer, in which immunother- the pre-specified non-inferiority criteria for PFS apy has achieved only modest results.129 Our SLR versus the 140 mg capsule (HR 1.24; 95% CI: supports the use of antiangiogenic therapy in 0.90–1.70). The safety profile was consistent with patients with ovarian cancer, albeit from a single that observed previously with cabozantinib the study that reported prolonged PFS with cabozan- 60 mg tablet versus 140 mg capsules associated tinib versus placebo (significance not reported) in with a non-significant lower frequency of Grade pretreated patients with ovarian cancer.77 journals.sagepub.com/home/tam 19 Therapeutic Advances in Medical Oncology Volume 14 Additionally, a phase II trial evaluating the effi- real-world studies (15–49%35,44,46,47,55,99) than in cacy of cabozantinib in the treatment of patients the RCTs (67–68%13,28). The report of the Italian with incurable, refractory, germ cell tumors, Managed Access Program proposed that the including ovarian germ cell tumors, started in lower tolerability in the real-world studies may be May 2021 (NCT04876456). related to bias due to the retrospective nature of the studies, the smaller sample sizes, and the The remaining tumor types identified in this improvements in management of dose and AEs SLR, which included breast cancer and mUC, because of better comprehension of the activity of were evaluated in single-arm, phase I and II stud- cabozantinib in the clinic.44 For both RCC and ies only; in breast cancer, ORR was 0–17%.81,82 HCC, rates of dose reductions and discontinua- In mUC, ORR was 19% and median OS was tions were consistent with clinical trials. 8.1 months.80 Across a variety of tumor types, clinical evidence continues to be generated. Almost half of the publications included in this review (54 of the 114) reported the results of bio- This SLR showed that AEs were similar across marker analyses. RET mutational status was the disease types and were in line with those com- most frequently studied biomarker; all studies monly observed for other TKIs.130 The most were in patients with MTC. Other biomarkers common AEs were hypertension, diarrhea, that featured in the eligible publications included fatigue, lipase elevation, and PPES. Cases of the following: bone metastases, MET expression hyponatremia mainly occurred with higher doses levels, RAS mutational status, circulating tumor of cabozantinib (140 mg versus 60 mg).69 AEs cells, alpha-fetoprotein, and tumor characteris- were managed well with dosing adjustments as tics. Detailed analysis of the biomarker evidence part of standard practice. Even with rates of dose was beyond the scope of this review, but it is an reduction of 46–62% in phase III RCTs (from a important area of research, given the potential starting dose of 60 mg), patients experienced value of cancer biomarkers in clinical practice. improved efficacy relative to everolimus, suni- Depending on the type, biomarkers could be used tinib, and placebo.13,14,28 for determining prognosis, monitoring progres- sion of the disease, or measuring response to Evidence of the real-world effectiveness of cancer treatment.131 More prospective studies are needed therapies is vital, because it demonstrates whether to explore predictive biomarkers for tumor findings observed during monitored clinical set- response to cabozantinib. tings and among selected patient populations can be translated to clinical practice. This review cap- The strength of this SLR is its comprehensive- tured several real-world studies of cabozantinib in ness. To our knowledge, given that there was no Europe, North America, Asia, and Australasia for restriction by disease type, this is the most com- patients with RCC,35,36,38,40,43,44,47,50–55,100 but prehensive review of cabozantinib monotherapy only two studies were identified that reported the to date. Although not included in this manuscript, effectiveness/safety data for HCC with cabozan- studies of cabozantinib used in combination with tinib as a single agent.61,62 We observed that real- other therapies have been discussed in a separate world findings in RCC are generally consistent manuscript (citation to be included once available). with the results from RCTs. In RCC, OS, PFS, The main limitation of the current review is the ORR, and DCR were similar in RCTs (21.2– high proportion of abstracts, in which informa- 30.3 months,21,24,28,29 7.4–8.6 months,13,28,29 17– tion is often incomplete and for which peer review 33%,13,21,28,29 and 75–83%,13,28,29 respectively) may have been less stringent. However, inclusion and real-world studies (9.1–25.4 months,35–43,53–55 of congress materials allowed us to capture the 5.6–12.5 months,35–38,42,44,45,47,53,54 14–52%,35,37– most up-to-date findings, even if full results have 39,41–44,46,47,53–55 and 50–96%,35,37,39,41–44,46,47,53–55 not yet been published, which is important for the respectively). Likewise, in HCC, OS, PFS, ORR, fast-moving field of oncology. and DCR were comparable between the CELESTIAL trial (10.2 months,14 5.2 months,14 In conclusion, in this extensive review of the lit- 4%14 and 64%,14 respectively) and the real-world erature, the efficacy and safety of cabozantinib studies (7.7–12.9 months,58,59 5.1 months,62 5%61 monotherapy has been demonstrated for the and 59%,62 respectively). In terms of safety data, treatment of various types of solid tumor. Real- the overall percentages of patients with RCC world effectiveness has been demonstrated for experiencing grade 3–4 AEs were lower in RCC, and initial data are encouraging for HCC, 20 journals.sagepub.com/home/tam P Maroto, C Porta et al. indicating that positive findings from clinical tri- funded by Ipsen UK in accordance with Good als do, indeed, translate into tangible benefits for Publication Practice (GPP3) guidelines (http:// patients in clinical practice. Ultimately, while evi- www.ismpp.org/gpp3). dence continues to be generated for various tumors, patient prognosis does not only rely on Funding effective treatments, but also on patient educa- The authors disclosed receipt of the following tion, consistent monitoring and early detection by financial support for the research, authorship, healthcare providers, and the application of and/or publication of this article: This study was emerging management strategies evidenced in the funded by Ipsen. literature. Conflict of interest statement Ethics approval PM is on advisory boards for Astellas, Not applicable. AstraZeneca, Bayer, Bristol, Ipsen, Janssen, Novartis, Pfizer, and Roche, and has received Consent to participate research grants from Bayer and Roche. CP has an Not applicable. advisory role with AstraZeneca, Bristol Myers Squibb, Eisai, EUSA Pharma, General Electric Consent for publication Healthcare, Ipsen, Janssen, MSD, Novartis and Not applicable. Pfizer; has been a speaker for Bristol Myers Squibb, EUSA Pharma, General Electric Author contributions Healthcare, Ipsen, and Pfizer; has been a protocol Pablo Maroto: Conceptualization; Methodology; steering committee member for Bristol Myers Writing – review & editing. Squibb, Eisai and EUSA Pharma; and has pro- vided expert testimony for EUSA Pharma and Camillo Porta: Methodology; Writing – review Pfizer. JC has a scientific consultancy role & editing. (speaker and advisory roles) for Advanced Jaume Capdevila: Methodology; Writing – Accelerator Applications, Amgen, Bayer, Eisai, review & editing. Exelixis, Ipsen, ITM, Merck Serono, Novartis, Pfizer, Sanofi and Sirlex, and has received Andrea B. Apolo: Methodology; Writing – research grants from Advanced Accelerator review & editing. Applications, AstraZeneca, Bayer, Eisai, Novartis, Santiago Viteri: Methodology; Writing – review and Pfizer. ABA has no interests to declare. SV & editing. reports personal fees and nonfinancial support from Bristol Myers Squibb, personal fees and Cristina Rodriguez-Antona: Methodology; nonfinancial support from Roche, personal fees Writing – review & editing. from MSD, personal fees from AbbVie, non- Lidia Martin: Methodology; Writing – original financial support from OSE PHARMA, and non- draft; Writing – review & editing. financial support from Merck. CR-A has no interests to declare. LM is an employee of Ipsen. Daniel Castellano: Conceptualization; DC has received institutional research funding Methodology; Writing – review & editing. from Janssen Oncology; has received travel and accommodation expenses from AstraZeneca ORCID iDs (Spain), Bristol Myers Squibb, Pfizer and Roche; Pablo Maroto https://orcid.org/0000- and has a consulting or advisory role with Astellas, 0002-0030-0412 AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Ipsen, Janssen Daniel Castellano https://orcid.org/0000- Oncology, MSD Oncology, Novartis, Pfizer, 0002-9106-0687 Pierre Fabre, Roche/Genentech, and Sanofi. Acknowledgements Availability of data and material The authors thank Lisa Law and Obaro Not applicable. Evuarherhe of Oxford PharmaGenesis, Oxford, UK, for performing the literature review and pro- Code availability viding medical writing support. 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