The authors’ full names, academic de-
`grees, and affiliations are listed in the Ap-
`pendix. Address reprint requests to Dr.
`Choueiri at the Dana–Farber Cancer In-
`stitute, 450 Brookline Ave. (DANA 1230),
`Boston, MA 02215, or at toni_choueiri@
` dfci . harvard . edu.
`
`* A complete list of investigators in the
`Metastatic RCC Phase 3 Study Evaluat-
`ing Cabozantinib versus Everolimus
`(METEOR) is provided in the Supplemen-
`tary Appendix, available at NEJM.org.
`
`This article was published on September
`25, 2015, at NEJM.org
`
`N Engl J Med 2015;373:1814-23.
`DOI: 10.1056/NEJMoa1510016
`Copyright © 2015 Massachusetts Medical Society.
`
`Original Article
`
`Cabozantinib versus Everolimus in Advanced
`Renal-Cell Carcinoma
`T.K. Choueiri, B. Escudier, T. Powles, P.N. Mainwaring, B.I. Rini, F. Donskov,
`H. Hammers, T.E. Hutson, J.-L. Lee, K. Peltola, B.J. Roth, G.A. Bjarnason,
`L. Géczi, B. Keam, P. Maroto, D.Y.C. Heng, M. Schmidinger, P.W. Kantoff,
`A. Borgman-Hagey, C. Hessel, C. Scheffold, G.M. Schwab, N.M. Tannir,
`and R.J. Motzer, for the METEOR Investigators*
`
`ABS TR ACT
`
`BACKGROUND
`Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vas-
`cular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each
`of which has been implicated in the pathobiology of metastatic renal-cell carci-
`noma or in the development of resistance to antiangiogenic drugs. This random-
`ized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared
`with everolimus, in patients with renal-cell carcinoma that had progressed after
`VEGFR-targeted therapy.
`
`METHODS
`We randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg
`daily or everolimus at a dose of 10 mg daily. The primary end point was progres-
`sion-free survival. Secondary efficacy end points were overall survival and objective
`response rate.
`
`RESULTS
`Median progression-free survival was 7.4 months with cabozantinib and 3.8 months
`with everolimus. The rate of progression or death was 42% lower with cabozantinib
`than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75;
`P<0.001). The objective response rate was 21% with cabozantinib and 5% with
`everolimus (P<0.001). A planned interim analysis showed that overall survival was
`longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95%
`CI, 0.51 to 0.89; P = 0.005) but did not cross the significance boundary for the
`interim analysis. Adverse events were managed with dose reductions; doses were
`reduced in 60% of the patients who received cabozantinib and in 25% of those
`who received everolimus. Discontinuation of study treatment owing to adverse events
`occurred in 9% of the patients who received cabozantinib and in 10% of those who
`received everolimus.
`
`CONCLUSIONS
`Progression-free survival was longer with cabozantinib than with everolimus among
`patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy.
`(Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747.)
`
`1814
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`The New England Journal of Medicine
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`Downloaded from nejm.org on June 4, 2017. For personal use only. No other uses without permission.
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`
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`

`Cabozantinib in Advanced Renal-Cell Carcinoma
`
`Renal-cell carcinoma is the most
`
`common form of kidney cancer, with
`more than 330,000 cases diagnosed and
`more than 140,000 deaths attributed to it world-
`wide every year.1 Approximately one third of
`patients present with metastatic disease at diag-
`nosis,2 and in about one third of treated patients
`with localized disease, the disease will relapse.3-5
`Inactivation of the von Hippel–Lindau (VHL)
`tumor-suppressor protein characterizes clear-cell
`tumors, the predominant histologic subtype in
`patients with renal-cell carcinoma, and results
`in the up-regulation of vascular endothelial
`growth factor (VEGF) production.6,7 Antiangio-
`genic drugs that target VEGF (bevacizumab) and
`its receptors (sunitinib, sorafenib, pazopanib,
`and axitinib) are standard treatments, owing to
`improved progression-free survival in random-
`ized, phase 3 trials as compared with interferon
`alfa, placebo, or other targeted drugs.8-12 Sunitinib,
`pazopanib, and bevacizumab (with interferon
`alfa) were investigated in the first-line setting,
`and sorafenib and axitinib were investigated af-
`ter progression with a first-line treatment.
`Resistance develops in nearly all patients
`treated with one or more of these drugs, as evi-
`denced by disease progression. The median
`progression-free survival ranges from 8 to 11
`months with first-line sunitinib or pazopanib8-10
`and from 3 to 5 months with sorafenib or ax-
`itinib after progression with first-line sunitinib
`treatment.12,13 In the second-line setting or later,
`the mammalian target of rapamycin (mTOR)
`inhibitor everolimus was associated with longer
`progression-free survival than placebo (median,
`4.9 vs. 1.9 months) in a phase 3 trial involving
`patients with renal-cell carcinoma that had pro-
`gressed during or after treatment with sunitinib,
`sorafenib, or both.14 However, no significant im-
`provement in overall survival was observed.
`Cabozantinib is an oral, small-molecule in-
`hibitor of tyrosine kinases, including MET,
`VEGF receptors (VEGFRs), and AXL, and is cur-
`rently approved for the treatment of patients
`with progressive, metastatic medullary thyroid
`cancer.15,16 MET and AXL are up-regulated in
`renal-cell carcinoma as a consequence of VHL
`inactivation, and high expression of each is as-
`sociated with poor prognosis.17,18 In addition,
`increased expression of MET and AXL has been
`implicated in the development of resistance to
`VEGFR inhibitors in preclinical models of sev-
`
`eral cancers, including renal-cell carcinoma.19-22
`A single-group trial showed objective responses
`and prolonged disease control with cabozantinib
`in patients with renal-cell carcinoma with tumors
`resistant to VEGFR and mTOR inhibitors.23
`On the basis of these results, we conducted a
`randomized, open-label, phase 3 trial that com-
`pared cabozantinib with everolimus in patients
`with advanced renal-cell carcinoma that had
`progressed after VEGFR tyrosine kinase inhibi-
`tor therapy. The trial design allowed for appro-
`priate statistical power for both a primary end
`point of progression-free survival and a second-
`ary end point of overall survival while avoiding
`overrepresentation of patients with rapidly pro-
`gressing disease for the primary end point.
`
`Methods
`
`Patients
`Eligible patients were 18 years of age or older
`with advanced or metastatic renal-cell carcinoma
`with a clear-cell component and measurable
`disease. Patients must have received prior treat-
`ment with at least one VEGFR-targeting tyrosine
`kinase inhibitor and must have had radiographic
`progression during treatment or within 6 months
`after the most recent dose of the VEGFR inhibi-
`tor. Patients with known brain metastases that
`were adequately treated and stable were eligible.
`There was no limit to the number of previous
`anticancer therapies, which could include cyto-
`kines, chemotherapy, and monoclonal antibod-
`ies, including those targeting VEGF, the pro-
`grammed death 1 (PD-1) receptor, or its ligand
`PD-L1. Eligible patients also had a Karnofsky
`performance-status score of at least 70% (on a
`scale from 0 to 100%, with higher scores indi-
`cating better performance status) and adequate
`organ and marrow function. Key exclusion crite-
`ria were previous therapy with an mTOR inhibi-
`tor or cabozantinib or a history of uncontrolled,
`clinically significant illness.
`
`Study Design and Treatment
`Patients were randomly assigned in a 1:1 ratio to
`receive either cabozantinib or everolimus. Ran-
`domization was stratified according to the num-
`ber of previous VEGFR-targeting tyrosine kinase
`inhibitors (1 or ≥2) and prognostic risk category
`(favorable, intermediate, or poor) according to the
`Memorial Sloan Kettering Cancer Center (MSKCC)
`
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`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`criteria24 (for details on the MSKCC criteria, see
`Table S1 in the Supplementary Appendix, available
`with the full text of this article at NEJM.org).
`Cabozantinib and everolimus were provided
`by the sponsor (Exelixis). Cabozantinib was ad-
`ministered orally at a dose of 60 mg once daily,
`and everolimus was administered orally at a
`dose of 10 mg once daily. Dose reductions for
`cabozantinib (40 mg, then 20 mg) and everoli-
`mus (5 mg, then 2.5 mg) and interruptions of
`study treatment were specified for management
`of adverse events. Treatment was continued as
`long as clinical benefit was observed by the in-
`vestigator or until the development of unaccept-
`able toxic effects. Crossover between treatment
`groups was not allowed.
`
`End Points and Assessments
`The primary end point was duration of progres-
`sion-free survival, defined as the interval be-
`tween the dates of randomization and first
`documentation of disease progression (assessed
`by an independent radiology review committee)
`or death from any cause. Secondary efficacy end
`points were duration of overall survival and ob-
`jective response rate. Tumor response and pro-
`gression were assessed according to Response
`Evaluation Criteria in Solid Tumors, version 1.1,25
`in all patients at screening, every 8 weeks after
`randomization during the first 12 months, and
`every 12 weeks thereafter. Routine safety evalua-
`tions were performed and adverse-event severity
`was assessed by the investigator with the use of
`the National Cancer Institute Common Termi-
`nology Criteria for Adverse Events, version 4.0.26
`
`Study Oversight
`The protocol was approved by the institutional
`review board or ethics committee at each center,
`and the study was conducted in accordance with
`Good Clinical Practice guidelines and the Decla-
`ration of Helsinki. Safety was monitored by an
`independent data monitoring committee. Data
`were collected by the sponsor and were analyzed
`in collaboration with the authors. The authors
`vouch for the accuracy and completeness of the
`data and for the fidelity of the study to the pro-
`tocol. The first draft of the manuscript was writ-
`ten by the first and last authors, with all the
`authors contributing to subsequent drafts. Med-
`ical-writing support, funded by the sponsor, was
`provided by Bellbird Medical Communications.
`
`All the authors made the decision to submit the
`manuscript for publication. The study protocol
`and statistical analysis plan are available at
`NEJM.org.
`
`Statistical Analysis
`The trial was designed to provide adequate
`power for assessment of both the primary end
`point of progression-free survival and the sec-
`ondary end point of overall survival. For the
`primary end point, we estimated that 259 events
`(disease progression or death) would be required
`to provide 90% power to detect a hazard ratio of
`0.667 (7.5 months with cabozantinib vs. 5 months
`with everolimus), using the log-rank test and a
`two-sided significance level of 0.05. For the
`overall-survival end point, assuming a single
`interim analysis at the time of the primary end-
`point analysis and a subsequent final analysis,
`we estimated that 408 deaths would be required
`to provide 80% power to detect a hazard ratio of
`0.75 (20 months with cabozantinib vs. 15 months
`with everolimus), using the log-rank test and a
`two-sided significance level of 0.04.
`Efficacy was evaluated in two populations ac-
`cording to the intention-to-treat principle. To
`evaluate the secondary end point of overall sur-
`vival, 650 patients were planned (the overall-sur-
`vival population). However, only 375 patients were
`required to achieve appropriate statistical power
`for the primary end point of progression-free
`survival. Thus, the study was designed to evalu-
`ate the primary end point in the first 375 patients
`who underwent randomization (the progression-
`free–survival population) to allow longer follow-
`up of progression-free survival (Fig. 1).
`Hypothesis testing for progression-free and
`overall survival was performed with the use of
`the stratified log-rank test according to the
`stratification factors used at randomization.
`Median duration of progression-free survival
`and overall survival and associated 95% confi-
`dence intervals for each treatment group were
`estimated with the Kaplan–Meier method. Haz-
`ard ratios were estimated with a Cox regression
`model. A prespecified interim analysis for over-
`all survival was conducted at the time of the
`primary end-point analysis. The type I error for
`the interim analysis was controlled by a Lan–
`DeMets alpha spending function, with O’Brien–
`Fleming boundaries, to account for the fraction
`of planned events at the time of the analysis.
`
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`Cabozantinib in Advanced Renal-Cell Carcinoma
`
`R esults
`
`Patients
`From August 2013 through November 2014, a total
`of 658 patients from 173 centers in 26 countries
`were randomly assigned to receive cabozantinib
`(330 patients) or everolimus (328 patients); these
`patients together compose the overall-survival
`population (Fig. S1 in the Supplementary Appen-
`dix). The first 375 patients who underwent ran-
`domization (187 assigned to cabozantinib and
`188 assigned to everolimus) compose the pro-
`gression-free–survival population for the primary
`end-point analysis (Fig. S2 in the Supplementary
`Appendix). The safety population comprises all
`patients who received study treatment (331 re-
`ceived cabozantinib and 322 received everolimus)
`(Fig. S1 in the Supplementary Appendix).
`As of the data-cutoff date of May 22, 2015, a
`total of 133 patients assigned to cabozantinib
`and 67 patients assigned to everolimus were
`continuing to receive study treatment. Minimum
`follow-up time was 11 months in the progres-
`sion-free–survival population and 6 months in
`the overall-survival population. The most com-
`mon reason for discontinuing treatment was
`progression of disease on radiography.
`The treatment groups were balanced with re-
`spect to baseline demographic and disease char-
`acteristics (Table 1). The most common previous
`therapy was sunitinib, and the majority of patients
`had received only one prior VEGFR inhibitor.
`
`Efficacy
`The duration of progression-free survival was
`determined by an independent radiology review
`committee in the first 375 patients who under-
`went randomization. The estimated median pro-
`gression-free survival was 7.4 months (95% con-
`fidence interval [CI], 5.6 to 9.1) with cabozantinib
`and 3.8 months (95% CI, 3.7 to 5.4) with evero-
`limus. The rate of disease progression or death
`was 42% lower with cabozantinib than with
`everolimus (hazard ratio for progression or death,
`0.58; 95% CI, 0.45 to 0.75; P<0.001) (Fig. 2). The
`results were similar in a supportive analysis in-
`volving investigator assessment of progression-
`free survival (median, 7.4 months [95% CI, 6.3 to
`7.6] with cabozantinib vs. 5.3 months [95% CI,
`3.8 to 5.6] with everolimus; hazard ratio for
`progression or death, 0.60; 95% CI, 0.47 to 0.76;
`P<0.001) (Fig. S3 in the Supplementary Appendix).
`
`Advanced renal-cell carcinoma
`Clear-cell histology
`Measurable disease
`Progression after prior VEGFR tyrosine kinase inhibitor
`
` 1:1 Randomization
`
`Cabozantinib,
`60 mg once daily
`
`Everolimus,
`10 mg once daily
`
`Progression-free–survival
`population
`(first 375 patients who
`underwent randomization)
`
`Overall-survival
`population
`(650 patients)
`
`Figure 1. Study Design.
`VEGFR denotes vascular endothelial growth factor receptor.
`
`A progression-free survival benefit associated
`with cabozantinib was consistently observed in
`prespecified subgroups defined according to the
`number of prior VEGFR inhibitors and MSKCC
`prognostic risk category (Fig. S4 in the Supple-
`mentary Appendix). In a post hoc analysis of the
`subgroup of 153 patients who received sunitinib
`as their only prior VEGFR inhibitor, the estimated
`median progression-free survival was 9.1 months
`(95% CI, 5.6 to 11.2) with cabozantinib and 3.7
`months (95% CI, 1.9 to 4.2) with everolimus
`(hazard ratio for progression or death, 0.41).
`Among the first 375 patients who underwent
`randomization, the objective response rate, as
`assessed by an independent radiology review com-
`mittee, was significantly higher with cabozan-
`tinib than with everolimus (partial responses in
`40 of the 187 patients [21%] assigned to cabo-
`zantinib vs. 9 of the 188 patients [5%] assigned
`to everolimus; P<0.001) (Table S2 in the Supple-
`mentary Appendix). A best response of stable
`disease occurred in 116 patients (62%) in each
`group, and progressive disease occurred in 26
`patients (14%) assigned to cabozantinib versus
`51 patients (27%) assigned to everolimus. In the
`subgroup of 153 patients who received sunitinib
`as their only prior VEGFR inhibitor, objective re-
`sponses occurred in 17 of the 76 patients assigned
`
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`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Table 1. Baseline Demographic and Clinical Characteristics.*
`
`Characteristic
`
`Progression-free–Survival Population
`
`Overall-Survival Population
`
`Cabozantinib
`(N = 187)
`
`Everolimus
`(N = 188)
`
`Cabozantinib
`(N = 330)
`
`Everolimus
`(N = 328)
`
`Age — yr
`Median
`Range
`Sex — no. (%)
`Male
`Female
`Not reported
`Geographic region — no. (%)
`Europe
`North America
`Asia–Pacific
`Latin America
`Race — no. (%)†
`White
`Asian
`Black
`Other
`Not reported
`Missing data
`ECOG performance-status score — no. (%)‡
`0
`1
`MSKCC prognostic risk category — no. (%)§
`Favorable
`Intermediate
`Poor
`Prior VEGFR tyrosine kinase inhibitors — no. (%)
`1
`≥2
`Previous systemic therapy — no. (%)
`Sunitinib
`Pazopanib
`Axitinib
`Sorafenib
`Bevacizumab
`Interleukin-2
`Interferon alfa
`Nivolumab
`Radiotherapy — no. (%)
`Nephrectomy — no. (%)
`
`62
`36–83
`
`142 (76)
`45 (24)
`0
`
`83 (44)
`76 (41)
`25 (13)
`3 (2)
`
`157 (84)
`12 (6)
`4 (2)
`10 (5)
`4 (2)
`0
`
`129 (69)
`58 (31)
`
`80 (43)
`80 (43)
`27 (14)
`
`137 (73)
`50 (27)
`
`114 (61)
`87 (47)
`28 (15)
`11 (6)
`1 (<1)
`11 (6)
`6 (3)
`9 (5)
`56 (30)
`156 (83)
`
`61
`31–84
`
`130 (69)
`57 (30)
`1 (<1)
`
`84 (45)
`64 (34)
`36 (19)
`4 (2)
`
`147 (78)
`20 (11)
`2 (1)
`6 (3)
`12 (6)
`1 (<1)
`
`116 (62)
`72 (38)
`
`83 (44)
`75 (40)
`30 (16)
`
`136 (72)
`52 (28)
`
`113 (60)
`78 (41)
`28 (15)
`19 (10)
`7 (4)
`13 (7)
`13 (7)
`11 (6)
`61 (32)
`153 (81)
`
`63
`32–86
`
`253 (77)
`77 (23)
`0
`
`167 (51)
`118 (36)
`39 (12)
`6 (2)
`
`269 (82)
`21 (6)
`6 (2)
`19 (6)
`15 (5)
`0
`
`226 (68)
`104 (32)
`
`150 (45)
`139 (42)
`41 (12)
`
`235 (71)
`95 (29)
`
`210 (64)
`144 (44)
`52 (16)
`21 (6)
`5 (2)
`20 (6)
`19 (6)
`17 (5)
`110 (33)
`282 (85)
`
`62
`31–84
`
`241 (73)
`86 (26)
`1 (<1)
`
`153 (47)
`122 (37)
`47 (14)
`6 (2)
`
`263 (80)
`26 (8)
`3 (<1)
`13 (4)
`22 (7)
`1 (<1)
`
`217 (66)
`111 (34)
`
`150 (46)
`135 (41)
`43 (13)
`
`229 (70)
`99 (30)
`
`205 (62)
`136 (41)
`55 (17)
`31 (9)
`11 (3)
`29 (9)
`24 (7)
`14 (4)
`108 (33)
`279 (85)
`
`* Statistical testing of differences in baseline characteristics between groups was not included in the statistical analysis plan. VEGFR denotes
`vascular endothelial growth factor receptor.
`† Race was self-reported.
`‡ Eastern Cooperative Oncology Group (ECOG) performance-status scores range from 0 to 5, with 0 indicating no symptoms, 1 indicating
`mild symptoms, and higher numbers indicating increasing degrees of disability.
`§ The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk category24 was determined by the number of three factors (anemia,
`hypercalcemia, and poor performance) that were present. Patients with zero factors had a favorable prognosis, patients with one factor had
`an intermediate prognosis, and patients with two or three factors had a poor prognosis.
`
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`Cabozantinib in Advanced Renal-Cell Carcinoma
`
`to cabozantinib (22%; 95% CI, 14 to 33) and in
`2 of the 77 patients assigned to everolimus (3%;
`95% CI, 0 to 9).
`At the prespecified interim analysis of overall
`survival, 202 deaths had occurred in the overall-
`survival population. A trend toward longer over-
`all survival with cabozantinib than with everoli-
`mus was observed (hazard ratio for death, 0.67;
`unadjusted 95% CI, 0.51 to 0.89; P = 0.005) (Fig. 3).
`The P value of ≤0.0019 required to achieve sta-
`tistical significance at the time of the interim
`analysis was not reached, and survival follow-up
`is continuing to the planned final analysis after
`408 deaths occur. The trend toward longer sur-
`vival with cabozantinib occurred despite more
`frequent use of subsequent anticancer therapies
`in the everolimus group (155 of 328 patients
`[47%]) than in the cabozantinib group (126 of
`330 patients [38%]) (Table S3 in the Supplemen-
`tary Appendix). The most common subsequent
`anticancer therapies were axitinib in the everoli-
`mus group (74 patients [23%]) and everolimus in
`the cabozantinib group (75 patients [23%]).
`
`Safety
`The median duration of treatment was 7.6 months
`among patients who received cabozantinib and
`4.4 months among patients who received evero-
`limus. Dose reductions occurred among 197 of
`the 331 patients (60%) treated with cabozantinib
`and 79 of the 322 patients (25%) treated with
`everolimus (Table S4 in the Supplementary Appen-
`dix). The median average daily dose was 44 mg
`of cabozantinib and 9 mg of everolimus. The
`rate of treatment discontinuation due to adverse
`events not related to renal-cell carcinoma was
`9% (31 patients) in the cabozantinib group and
`10% (31 patients) in the everolimus group.
`The incidence of adverse events (any grade),
`regardless of whether the event was considered
`by the investigator to be related to the study
`treatment, was 100% with cabozantinib and more
`than 99% with everolimus, and the incidence of
`adverse events of grade 3 or 4 was 68% with
`cabozantinib and 58% with everolimus (Table 2).
`The most common grade 3 or 4 adverse events
`with cabozantinib were hypertension (15%), diar-
`rhea (11%), and fatigue (9%) and with everoli-
`mus were anemia (16%), fatigue (7%), and hyper-
`glycemia (5%). The most common adverse events
`(any grade) leading to dose reductions with
`cabozantinib were diarrhea (16%), the palmar–
`
`Figure 2. Kaplan–Meier Estimates of Progression-free Survival.
`Disease progression was assessed by an independent radiology review
`committee.
`
`Cabozantinib
`
`Everolimus
`
`Hazard ratio for death, 0.67 (95% CI, 0.51–0.89)
`P=0.005
`
`0
`
`3
`
`6
`
`9
`
`12
`Months
`
`15
`
`18
`
`21
`
`24
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`OverallSurvival(%)
`
`00
`
`11
`
`65
`
`330
`328
`
`317
`306
`
`294
`260
`
`189
`156
`
`101
`88
`
`32
`24
`
`No.atRisk
`Cabozantinib
`Everolimus
`
`Figure 3. Kaplan–Meier Estimates of Overall Survival.
`
`plantar erythrodysesthesia syndrome (11%), and
`fatigue (10%), and the most common with evero-
`limus were pneumonitis (4%), fatigue (3%), and
`stomatitis (3%). Grade 5 adverse events occurred
`in 22 patients (7%) in the cabozantinib group
`and in 25 patients (8%) in the everolimus group
`and were primarily related to disease progres-
`sion. Grade 5 events that were considered to be
`
`n engl j med 373;19 nejm.org November 5, 2015
`
`1819
`
`No.of
`Patients
`
`Median
`Progression-free
`Survival
`mo (95% CI)
`
`No.of
`Events
`
`Cabozantinib
`Everolimus
`
`187
`188
`
`7.4 (5.6–9.1)
`3.8 (3.7–5.4)
`
`121
`126
`
`Hazard ratio for progression or death,
`0.58 (95% CI, 0.45–0.75)
`P<0.001
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`Progression-freeSurvival(%)
`
`Cabozantinib
`
`Everolimus
`
`15
`
`18
`
`20
`
`62
`
`6
`
`92
`46
`
`9
`Months
`
`68
`29
`
`12
`
`20
`10
`
`0
`
`3
`
`No.atRisk
`Cabozantinib
`Everolimus
`
`187
`188
`
`152
`99
`
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`
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`
` Copyright © 2015 Massachusetts Medical Society. All rights reserved.
`
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`

`

`Table 2. Adverse Events.*
`
`Event
`
`Any adverse event
`Diarrhea
`Fatigue
`Nausea
`Decreased appetite
`Palmar–plantar erythrodysesthesia syndrome
`Hypertension
`Vomiting
`Weight decreased
`Constipation
`Dysgeusia
`Stomatitis
`Hypothyroidism
`Dysphonia
`Mucosal inflammation
`Asthenia
`Dyspnea
`Cough
`Back pain
`Abdominal pain
`Rash
`Pain in arms or legs
`Muscle spasms
`Dyspepsia
`Dry skin
`Headache
`Arthralgia
`Dizziness
`Peripheral edema
`Pyrexia
`Pruritus
`Epistaxis
`Pneumonitis
`Laboratory abnormality
`Aspartate aminotransferase increased
`Anemia
`Alanine aminotransferase increased
`Hypomagnesemia
`Proteinuria
`Hypokalemia
`Hypophosphatemia
`Hypertriglyceridemia
`Serum creatinine increased
`Hyperglycemia
`
`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Cabozantinib (N = 331)
`
`Everolimus (N = 322)
`
`Any Grade
`
`Grade 3 or 4
`
`Any Grade
`
`Grade 3 or 4
`
`331 (100)
`245 (74)
`186 (56)
`165 (50)
`152 (46)
`139 (42)
`122 (37)
`106 (32)
`102 (31)
`83 (25)
`78 (24)
`73 (22)
`67 (20)
`65 (20)
`63 (19)
`62 (19)
`62 (19)
`61 (18)
`56 (17)
`53 (16)
`50 (15)
`47 (14)
`41 (12)
`40 (12)
`37 (11)
`37 (11)
`36 (11)
`36 (11)
`31 (9)
`28 (8)
`25 (8)
`12 (4)
`0
`
`58 (18)
`56 (17)
`53 (16)
`52 (16)
`41 (12)
`38 (11)
`33 (10)
`20 (6)
`15 (5)
`15 (5)
`
`number of patients with an event (percent)
`226 (68)
`321 (>99)
`38 (11)
`88 (27)
`30 (9)
`148 (46)
`13 (4)
`90 (28)
`8 (2)
`108 (34)
`28 (8)
`19 (6)
`49 (15)
`23 (7)
`7 (2)
`45 (14)
`6 (2)
`40 (12)
`1 (<1)
`60 (19)
`0
`30 (9)
`8 (2)
`77 (24)
`0
`1 (<1)
`2 (<1)
`12 (4)
`3 (<1)
`73 (23)
`14 (4)
`50 (16)
`10 (3)
`90 (28)
`1 (<1)
`107 (33)
`7 (2)
`47 (15)
`12 (4)
`31 (10)
`2 (<1)
`89 (28)
`3 (<1)
`26 (8)
`0
`16 (5)
`1 (<1)
`15 (5)
`0
`32 (10)
`1 (<1)
`38 (12)
`1 (<1)
`45 (14)
`0
`21 (7)
`0
`72 (22)
`2 (<1)
`51 (16)
`0
`47 (15)
`0
`46 (14)
`0
`33 (10)
`
`6 (2)
`18 (5)
`8 (2)
`16 (5)
`8 (2)
`15 (5)
`12 (4)
`5 (2)
`1 (<1)
`2 (<1)
`
`18 (6)
`122 (38)
`19 (6)
`5 (2)
`30 (9)
`21 (7)
`18 (6)
`40 (12)
`35 (11)
`62 (19)
`
`187 (58)
`7 (2)
`22 (7)
`1 (<1)
`3 (<1)
`3 (<1)
`10 (3)
`3 (<1)
`0
`1 (<1)
`0
`7 (2)
`0
`0
`11 (3)
`7 (2)
`13 (4)
`3 (<1)
`7 (2)
`4 (1)
`2 (<1)
`1 (<1)
`0
`0
`0
`1 (<1)
`4 (1)
`0
`5 (2)
`1 (<1)
`1 (<1)
`0
`6 (2)
`
`1 (<1)
`50 (16)
`1 (<1)
`0
`1 (<1)
`6 (2)
`7 (2)
`9 (3)
`0
`16 (5)
`
`* Shown are adverse events that were reported in at least 10% of the patients in either study group, regardless of whether the event was con-
`sidered by the investigator to be related to the study treatment. The severity of adverse events was graded according to the National Cancer
`Institute Common Terminology Criteria for Adverse Events, version 4.0.26
`
`1820
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`Downloaded from nejm.org on June 4, 2017. For personal use only. No other uses without permission.
`
` Copyright © 2015 Massachusetts Medical Society. All rights reserved.
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`

`

`Cabozantinib in Advanced Renal-Cell Carcinoma
`
`treatment-related occurred in 1 patient in the
`cabozantinib group (death not otherwise speci-
`fied) and in 2 patients in the everolimus group
`(aspergillus infection and aspiration pneumonia).
`
`Discussion
`
`Progression-free survival was longer with cabo-
`zantinib than with everolimus in this random-
`ized, phase 3 trial involving patients with renal-
`cell carcinoma that had previously progressed
`during at least one VEGFR-targeted therapy. The
`efficacy with cabozantinib was robust, with an
`estimated median progression-free survival of
`7.4 months, as compared with 3.8 months with
`everolimus, and a hazard ratio of 0.58, corre-
`sponding to a 42% reduction in the rate of dis-
`ease progression or death. Objective tumor re-
`sponses were observed in 21% of the patients
`assigned to cabozantinib, as compared with 5%
`of the patients assigned to everolimus.
`Data pertaining to overall survival, a second-
`ary end point in this trial, were immature at the
`prespecified interim analysis. Nonetheless, the
`rate of death was 33% lower with cabozantinib
`than with everolimus, a finding that indicates a
`strong trend toward longer survival. The interim
`boundary for significance was not reached, and
`follow-up for survival is continuing to the
`planned final analysis.
`The safety profile of cabozantinib in this
`trial was similar to previous experience in this
`patient population.23 Common adverse events
`with cabozantinib included diarrhea, fatigue,
`nausea, decreased appetite, the palmar–plantar
`erythrodysesthesia syndrome, and hypertension,
`which are also observed with other VEGFR tyro-
`sine kinase inhibitors in patients with renal-cell
`carcinoma.8,12 Adverse events that occurred at
`higher rates and with greater severity with
`everolimus than with cabozantinib included
`pneumonitis, peripheral edema, anemia, and
`hyperglycemia. Dose reductions for management
`of adverse events occurred more frequently with
`cabozantinib than with everolimus, underlining
`the need for careful adverse-event monitoring, as
`is the case with other VEGFR inhibitors. Discon-
`tinuation of study treatment owing to adverse
`events not related to renal-cell carcinoma oc-
`curred in 9% of the patients who received cabo-
`zantinib and in 10% of the patients who received
`everolimus.
`This study used a “trial within a trial” design
`
`because the sample size required to properly
`evaluate the primary end point of progression-
`free survival is too small to adequately assess
`the important secondary end point of overall
`survival. An event-driven analysis of progres-
`sion-free survival in the larger sample required
`for overall survival could have been overweight-
`ed with patients who have early progression, and
`patients with longer times to progression might
`not have been sufficiently represented. There-
`fore, to provide longer follow-up for an event-
`driven analysis of progression-free survival, the
`primary analysis of this end point was prespeci-
`fied to occur in the first 375 patients who under-
`went randomization.
`Everolimus was used as the comparator be-
`cause it is a standard treatment for patients who
`previously had disease progression with a VEGFR-
`targeted therapy. A growing body of evidence
`suggests greater efficacy with VEGFR inhibitors
`than with mTOR inhibitors in patients with renal-
`cell carcinoma.13,27,28 However, owing to the ab-
`sence of comparative data from phase 3 trials,
`an area of controversy has been the relative ben-
`efit of a VEGFR inhibitor as compared with
`everolimus as a second-line treatment.29 More
`than 70% of our study population were previously
`treated with only one VEGFR inhibitor, primar-
`ily sunitinib. A benefit with respect to progres-
`sion-free survival was observed with cabozan-
`tinib in the subgroup of patients who received
`one prior VEGFR-targeted therapy, a finding that
`is consistent with the overall results.
`Axitinib is also an option as a second-line
`treatment for patients with renal-cell carcinoma,
`given the results of the phase 3 AXIS trial, which
`showed a benefit in progression-free survival as
`compared with sorafenib as a second-line ther-
`apy.12 The eligibility criteria of the AXIS trial
`allowed varied first-line therapies, and the two
`largest populations were patients who were previ-
`ously treated with sunitinib (54%) or cytokines
`(35%). The estimated median progression-free
`survival in the overall population was 6.7 months
`with axitinib, as compared with 4.7 months with
`sorafenib, and the benefit was strongest among
`patients previously treated with cytokines. The
`subgroup of patients who received sunitinib as
`their first-line therapy had an estimated median
`progression-free survival of 4.8 months and an
`objective response rate of 11% with axitinib.12,30
`Thus, the estimated median progression-free sur-
`vival of 9.1 months and the objective response
`
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