METEOR: A Study of Cabozantinib (XL184) vs Everolimus in Subjects With Metastatic Renal Cell Carcinoma

• Sponsor: Exelixis (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01865747
• Collaborator: (none)
• Enrollment: 658
• Locations: 205
• Arms: 2
• Duration (Months): 91.5
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effect of Cabozantinib (XL184) compared with Everolimus (Afinitor) on progression-free survival (PFS) and overall survival (OS) in subjects with advanced renal cell cancer that has progressed after prior VEGFR tyrosine kinase inhibitor therapy.

Condition or Disease	Intervention/Treatment	Phase
Renal Cell Carcinoma	Drug: Cabozantinib tablets; Drug: Everolimus (Afinitor) tablets	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 658 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Controlled Study of Cabozantinib (XL184) vs Everolimus in Subjects With Metastatic Renal Cell Carcinoma That Has Progressed After Prior VEGFR Tyrosine Kinase Inhibitor Therapy
• Study Start Date: Jun 1, 2013
• Actual Primary Completion Date: May 22, 2015
• Actual Study Completion Date: Jan 15, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cabozantinib (XL184) Cabozantinib (XL184) 60 mg tablet once daily.	Drug: Cabozantinib tablets; Other Names: XL184
Active Comparator: Everolimus (Afinitor) Everolimus (Afinitor) 10 mg tablet once daily.	Drug: Everolimus (Afinitor) tablets

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) [PFS is measured from the date of randomization until the date of first documented disease progression or date of death from any cause as determined by the Independent Radiology Committee (IRC) per RECIST 1.1, assessed for up to 17 months.]

   The primary analysis of PFS is the time from randomization to date of first documented tumor progression as determined by investigator (per RECIST 1.1 criteria) or death due to any cause, whichever occurred first. A Kaplan-Meier analysis was performed to estimate the median duration.

Secondary Outcome Measures

1. Overall Survival (OS) [OS was measured from the time of randomization until 320 deaths, approximately 28 months]

   Overall Survival (OS) is defined as the time from randomization to the date of death. Participants that had not died were censored at last known date alive. Median OS was calculated using Kaplan-Meier estimates. Interim analyses for OS occurred after 320 deaths (78% of the total OS events needed for final analysis).

2. Objective Response Rate (ORR) [ORR was assessed at 8 weeks post-randomization, every 8 weeks for 12 months, and every 12 weeks until date of disease progression or death, up to May 2015 (approximately 21 months)]

   Objective Response Rate (ORR) is the number of participants with a best response of complete response (CR) or partial response (PR) divided by number of randomized participants. ORR was assessed by the Independent Radiology Committee (IRC) per RECIST 1.1 which was confirmed by a subsequent visit >= 28 days later, and was analyzed in the Intent to Treat (ITT) population at the time of the primary analysis of Progression Free Survival (PFS). The data cutoff date was 22 May 2015.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Select Inclusion Criteria:

1. Documented histological or cytological diagnosis of renal cell cancer with a clear-cell component.

2. Measurable disease as determined by the investigator.

3. Must have received at least one VEGFR-targeting TKI (eg, sorafenib, sunitinib, axitinib, pazopanib or tivozanib).

4. Recovery from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.

5. Adequate organ and marrow function.

6. Sexually active fertile subjects(male and female)must agree to use medically accepted methods of contraception during the course of the study and for 4 months after the last dose of study treatment.

7. Female subjects of childbearing potential must not be pregnant at screening.

Select Exclusion Criteria:

1. Prior treatment with everolimus, or any other specific or selective TORC1/PI3K/AKT inhibitor (eg, temsirolimus), or cabozantinib.

2. Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before randomization.

3. Receipt of any type of anticancer antibody (including investigational antibody) within 4 weeks before randomization.

4. Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before randomization. Systemic treatment with radionuclides within 6 weeks before randomization. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.

5. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 3 months before randomization.

6. Concomitant anticoagulation at therapeutic doses with oral anticoagulants or platelet inhibitors.

7. Chronic treatment with corticosteroids or other immunosuppressive agents.

8. Serious illness other than cancer.

9. Major surgery within 3 months before randomization. Complete wound healing from major surgery must have occurred 1 month before randomization and from minor surgery at least 10 days before randomization.

10. Pregnant or lactating females.

11. Diagnosis of another malignancy within 2 years before randomization, except for superficial skin cancers, or localized, low grade tumors.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Anchorage	Alaska	United States	99503
3		Gilbert	Arizona	United States	85234
4		Scottsdale	Arizona	United States	85259
5		Tucson	Arizona	United States	85724
6		Duarte	California	United States	91010
7		La Jolla	California	United States	92093
8		Los Angeles	California	United States	90048
9		Los Angeles	California	United States	90095
10		Vallejo	California	United States	94589
11		Aurora	Colorado	United States	80045
12		Denver	Colorado	United States	80218
13		New Haven	Connecticut	United States	06520
14		Washington	District of Columbia	United States	20007
15		Boca Raton	Florida	United States	33486
16		Miami	Florida	United States	33136
17		Miami	Florida	United States	33176
18		Orlando	Florida	United States	06520
19		Tampa	Florida	United States	33612
20		Chicago	Illinois	United States	60611
21		Chicago	Illinois	United States	60612
22		Chicago	Illinois	United States	60637
23		Iowa City	Iowa	United States	52242
24		Westwood	Kansas	United States	66205
25		Baltimore	Maryland	United States	21201
26		Baltimore	Maryland	United States	21287
27		Boston	Massachusetts	United States	02215
28		Ann Arbor	Michigan	United States	48109
29		Detroit	Michigan	United States	48201
30		Detroit	Michigan	United States	48202
31		Rochester	Minnesota	United States	55905
32		Saint Louis	Missouri	United States	63110
33		Las Vegas	Nevada	United States	89148
34		Albany	New York	United States	12206
35		New York	New York	United States	10065
36		Durham	North Carolina	United States	22710
37		Cleveland	Ohio	United States	44106
38		Cleveland	Ohio	United States	44195
39		Columbus	Ohio	United States	43210
40		Portland	Oregon	United States	97213
41		Portland	Oregon	United States	97239
42		Philadelphia	Pennsylvania	United States	19111
43		Pittsburgh	Pennsylvania	United States	15232
44		Charleston	South Carolina	United States	29425
45		Knoxville	Tennessee	United States	37920
46		Memphis	Tennessee	United States	38120
47		Nashville	Tennessee	United States	37203
48		Nashville	Tennessee	United States	37232
49		Austin	Texas	United States	78731
50		Bedford	Texas	United States	76022
51		Dallas	Texas	United States	75246
52		Fort Worth	Texas	United States	76104
53		Houston	Texas	United States	77024
54		Houston	Texas	United States	77030
55		San Antonio	Texas	United States	78229
56		Salt Lake City	Utah	United States	84112
57		Seattle	Washington	United States	98109
58		Vancouver	Washington	United States	98684
59		Yakima	Washington	United States	98902
60		La Plata	Buenos Aires	Argentina	B1900BAJ
61		Mar Del Plata		Argentina	B7600LTO
62		Concord	New South Wales	Australia	2139
63		Darlinghurst	New South Wales	Australia	2010
64		Kogarah	New South Wales	Australia	2217
65		Port Macquarie	New South Wales	Australia
66		Randwick	New South Wales	Australia	2031
67		Wahroonga	New South Wales	Australia	2076
68		Westmead	New South Wales	Australia	2145
69		Milton	Queensland	Australia	4064
70		Wooloongabba	Queensland	Australia	4102
71		Adelaide	South Australia	Australia	5000
72		Hobart	Tasmania	Australia	7000
73		Bentleight East	Victoria	Australia	3165
74		Box Hill	Victoria	Australia	3128
75		Wodonga	Victoria	Australia	3690
76		Linz	Oberösterreich	Austria	4010
77		Wien		Austria	1090
78		Wien		Austria	1100
79		Bonheiden	Antwerpen	Belgium	2820
80		Brasschaat	Antwerpen	Belgium	2930
81		Bruxelles	Brussels	Belgium	1000
82		Leuven	Vlaams Brabant	Belgium	3000
83		Roeselare	West-Vlaanderen	Belgium	8800
84		Antwerpen		Belgium	2020
85		Liege		Belgium	4000
86		Calgary	Alberta	Canada	T2N 4N2
87		Edmonton	Alberta	Canada	T6G 1Z2
88		Vancouver	British Columbia	Canada	V5Z 4E6
89		Winnepeg	Manitoba	Canada	R3A 1R9
90		Halifax	Nova Scotia	Canada	B3H 1V7
91		Hamilton	Ontario	Canada	L8V 5C2
92		Kingston	Ontario	Canada	K7L 5P9
93		London	Ontario	Canada	N6A 4L6
94		Oshawa	Ontario	Canada	L1G 2B9
95		Ottawa	Ontario	Canada	K1H 8L6
96		Toronto	Ontario	Canada	M4N 3M5
97		Toronto	Ontario	Canada	M5G 2N2
98		Montreal	Quebec	Canada	H2L 4M1
99		Saskatoon	Saskatchewan	Canada	S7N 4H4
100		Santiago		Chile
101		Olomouc	Olomoucký Kraj	Czechia	775 20
102		Brno		Czechia	656 91
103		Prague		Czechia	128 08
104		Herlev	Hovedstaden	Denmark	DK-2730
105		Aarhus	Midtjylland	Denmark	DK-8000
106		Odense	Syddanmark	Denmark	DK-5000
107		Turku	Länsi-Suomen Lääni	Finland	FI-20520
108		Helsinki		Finland	290
109		Caen	Calvados	France	14076
110		Besancon	Doubs	France	25030
111		Bordeaux	Gironde	France	33075
112		Toulouse	Haute-Garonne	France	31052
113		Rennes	Ille-et-Vilaine	France	35042
114		Nantes	Loire-Atlantique	France	44805
115		Lyon	Rhône	France	96008
116		Le Mans	Sarthe	France	72000
117		Villejuif	Val-de-Marne	France	94805
118		Marseille		France	13273
119		Paris		France	75908
120		Freiburg	Baden Wuttemberg	Germany	79106
121		Tubingen	Baden-Württemberg	Germany	72076
122		Ulm	Baden-Württemberg	Germany	89075
123		Erlangen	Bayern	Germany	91054
124		Aachen	Nordrhein-Westfalen	Germany	52074
125		Essen	Nordrhein-Westfalen	Germany	45122
126		Mainz	Rheinland-Pfalz	Germany	55131
127		Jena	Thuringen	Germany	99089
128		Erfurt	Thüringen	Germany	99089
129		Berlin		Germany	12200
130		Dresden		Germany	01307
131		Frankfurt am Main		Germany	60590
132		Guetersloh		Germany	33332
133		Hamburg		Germany	20246
134		Hannover		Germany	30605
135		Heidelberg		Germany	69120
136		Munchen		Germany	81675
137		Munich		Germany	81377
138		Budapest		Hungary	1122
139		Szolnok		Hungary	5004
140		Dublin		Ireland	24
141		Dublin		Ireland	7
142		Meldola	Emilia-Romagna	Italy	47014
143		Modena	Emilia-Romagna	Italy	41124
144		Ravenna	Emilia-Romagna	Italy	48100
145		Rome	Lazio	Italy	00128
146		Rome	Lazio	Italy	00152
147		Genova	Liguria	Italy	16132
148		Cremona	Lombardia	Italy	Lombardia
149		Bari	Puglia	Italy	70124
150		Arezzo	Toscana	Italy	52100
151		Terni	Umbria	Italy	05100
152		Seoul		Korea, Republic of	110-744
153		Seoul		Korea, Republic of	120-752
154		Seoul		Korea, Republic of
155		Maastricht	Limburg	Netherlands	6229 HX
156		Amsterdam	Noord-Holland	Netherlands	1066 CX
157		Leiden	Zuid-Holland	Netherlands	2333 ZA
158		Rotterdam	Zuid-Holland	Netherlands	3045 PM
159		Bialystok	Podlaskie	Poland	15-027
160		Gdansk	Pomorskie	Poland	80-210
161		Poznan	Wielkopolskie	Poland	60-569
162		Warsaw		Poland	04-909
163		Lisbon		Portugal	1500-650
164		Lisbon		Portugal	1649-035
165		Porto		Portugal	200-072
166		Moscow		Russian Federation	115478
167		Omsk		Russian Federation	644013
168		St. Petersburg		Russian Federation	196247
169		Yaroslavl		Russian Federation	150040
170		Presov		Slovakia	08001
171		Zilina		Slovakia	01207
172		Oviedo	Asturias	Spain	33006
173		Barcelona	Cataluna	Spain	08025
174		Badalona	Cataluña	Spain	08003
175		L'Hospitalet de Llobregat	Cataluña	Spain	08907
176		Pamplona	Navarra	Spain	31008
177		Barcelona		Spain	08035
178		Madrid		Spain	28034
179		Madrid		Spain	28041
180		Madrid		Spain	28922
181		Málaga		Spain	Málaga
182		Santiago de Compostela		Spain	15706
183		Seville		Spain	28050
184		Valencia		Spain	46010
185		Lund	Skane Lan	Sweden	SE-22185
186		Stockholm	Sodermanlands Lan	Sweden
187		Umea		Sweden
188		Taichung		Taiwan
189		Taipei		Taiwan
190		Ankara		Turkey	6500
191		Gaziantep		Turkey	27100
192		Istanbul		Turkey	34365
193		Izmir		Turkey	35100
194		Birmingham	England	United Kingdom	B15 2TH
195		Derby	England	United Kingdom	DE22 3NE
196		Guildford	England	United Kingdom	GU2 7XX
197		London	England	United Kingdom	EC1A 7BE
198		London	England	United Kingdom	SE1 9ER
199		London	England	United Kingdom
200		Manchester	England	United Kingdom	M20 4BX
201		Northwood	England	United Kingdom	HA6 2RN
202		Wirral	England	United Kingdom	CH63 4JY
203		Aberdeen	Scotland	United Kingdom	AB25 2ZN
204		Edinburgh	Scotland	United Kingdom	EH4 2XU
205		Glasgow	Scotland	United Kingdom

Sponsors and Collaborators

• Exelixis

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Exelixis
• ClinicalTrials.gov Identifier: NCT01865747
• Other Study ID Numbers: XL184-308
• First Posted: May 31, 2013
• Last Update Posted: Apr 27, 2021
• Last Verified: Apr 1, 2021

• Keywords provided by Exelixis: renal cell cancer; kidney; vascular endothelial growth factor receptor 2 (VEGFR2); tyrosine kinase inhibitor; hepatocyte growth factor receptor protein (MET); von Hippel-Lindau gene
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Everolimus

Study Results

Participant Flow

Recruitment Details	First patient enrolled: 08 August 2013, Data cut off date: 22 May 2015

Arm/Group Title	Cabozantinib (XL184)	Everolimus (Afinitor)
Arm/Group Description	Cabozantinib (XL184) 60 mg tablet once daily. Cabozantinib tablets	Everolimus (Afinitor) 10 mg tablet once daily. Everolimus (Afinitor) tablets
Period Title: Overall Study (ITT)
STARTED	330	328
COMPLETED	132	73
NOT COMPLETED	198	255
Period Title: Overall Study (ITT)
STARTED	187	188
COMPLETED	56	36
NOT COMPLETED	131	152

Baseline Characteristics

Arm/Group Title	Cabozantinib (XL184)	Everolimus (Afinitor)	Total
Arm/Group Description	Cabozantinib (XL184) 60 mg tablet once daily. Cabozantinib tablets	Everolimus (Afinitor) 10 mg tablet once daily. Everolimus (Afinitor) tablets	Total of all reporting groups
Overall Participants	330	328	658
Age, Customized (participants) [Number]
<65	196 59.4%	198 60.4%	394 59.9%
65 to <75	107 32.4%	94 28.7%	201 30.5%
75 to <85	26 7.9%	36 11%	62 9.4%
=>85	1 0.3%	0 0%	1 0.2%
Sex/Gender, Customized (participants) [Number]
Male	253 76.7%	241 73.5%	494 75.1%
Female	77 23.3%	86 26.2%	163 24.8%
Missing	0 0%	1 0.3%	1 0.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	19 5.8%	18 5.5%	37 5.6%
Not Hispanic or Latino	278 84.2%	273 83.2%	551 83.7%
Unknown or Not Reported	33 10%	37 11.3%	70 10.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	21 6.4%	26 7.9%	47 7.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	6 1.8%	3 0.9%	9 1.4%
White	269 81.5%	263 80.2%	532 80.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	34 10.3%	36 11%	70 10.6%
Geographic Region (Count of Participants)
Europe	167 50.6%	153 46.6%	320 48.6%
North America	118 35.8%	122 37.2%	240 36.5%
Asia Pacific	39 11.8%	47 14.3%	86 13.1%
Latin America	6 1.8%	6 1.8%	12 1.8%
Randomization Stratification Factors per CRF (Count of Participants)
Prior VEGFR-TKI = 1	235 71.2%	229 69.8%	464 70.5%
Prior VEGFR-TKI ≥ 2	95 28.8%	99 30.2%	194 29.5%
MSKCC risk factors = 0	150 45.5%	150 45.7%	300 45.6%
MSKCC risk factors = 1	139 42.1%	135 41.2%	274 41.6%
MSKCC risk factors = 2 or 3	41 12.4%	43 13.1%	84 12.8%
Prior VEGFR-TKI = 1, MSKCC risk factors = 0	102 30.9%	100 30.5%	202 30.7%
Prior VEGFR-TKI = 1, MSKCC risk factors = 1	107 32.4%	103 31.4%	210 31.9%
Prior VEGFR-TKI = 1, MSKCC risk factors = 2 or 3	26 7.9%	26 7.9%	52 7.9%
Prior VEGFR-TKI ≥ 2, MSKCC risk factors =0	48 14.5%	50 15.2%	98 14.9%
Prior VEGFR-TKI ≥ 2, MSKCC risk factors = 1	32 9.7%	32 9.8%	64 9.7%
Prior VEGFR-TKI ≥ 2, MSKCC risk factors = 2 or 3	15 4.5%	17 5.2%	32 4.9%
Karnofsky performance status (KPS) (Count of Participants)
100 (normal activity)	99 30%	74 22.6%	173 26.3%
90 (normal activity, minor signs and symptoms)	127 38.5%	142 43.3%	269 40.9%
80 (normal w/effort, minor signs/symptoms)	75 22.7%	90 27.4%	165 25.1%
70 (unable to work, cares for self)	29 8.8%	22 6.7%	51 7.8%
Heng Prognostic Criteria (Count of Participants)
0 adverse factors (favorable risk)	66 20%	62 18.9%	128 19.5%
1-2 adverse factors (intermediate risk)	210 63.6%	214 65.2%	424 64.4%
3-6 adverse factors (poor risk)	54 16.4%	52 15.9%	106 16.1%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	The primary analysis of PFS is the time from randomization to date of first documented tumor progression as determined by investigator (per RECIST 1.1 criteria) or death due to any cause, whichever occurred first. A Kaplan-Meier analysis was performed to estimate the median duration.
Time Frame	PFS is measured from the date of randomization until the date of first documented disease progression or date of death from any cause as determined by the Independent Radiology Committee (IRC) per RECIST 1.1, assessed for up to 17 months.

Outcome Measure Data

Analysis Population Description

The pre-specified primary analysis of PFS was based on the first 375 randomized subjects (187 cabozantinib and 188 everolimus).

Arm/Group Title	Cabozantinib (XL184)	Everolimus (Afinitor)
Arm/Group Description	Cabozantinib (XL184) 60 mg tablet once daily. Cabozantinib tablets	Everolimus (Afinitor) 10 mg tablet once daily. Everolimus (Afinitor) tablets
Measure Participants	187	188
Number (95% Confidence Interval) [months]	7.4	3.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cabozantinib (XL184), Everolimus (Afinitor)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments	The Log-Rank Test was stratified by the Memorial Sloan-Kettering Cancer Center (MSKCC) group and number of prior VEGFR TKIs.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95%; 0.45 to 0.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall Survival (OS) is defined as the time from randomization to the date of death. Participants that had not died were censored at last known date alive. Median OS was calculated using Kaplan-Meier estimates. Interim analyses for OS occurred after 320 deaths (78% of the total OS events needed for final analysis).
Time Frame	OS was measured from the time of randomization until 320 deaths, approximately 28 months

Outcome Measure Data

Analysis Population Description

The Intent to Treat (ITT) population was used and included 658 randomized subjects (330 cabozantinib, 328 everolimus) in the second interim analysis with a cutoff date of 31 December 2015.

Arm/Group Title	Cabozantinib (XL184)	Everolimus (Afinitor)
Arm/Group Description	Cabozantinib (XL184) 60 mg tablet once daily. Cabozantinib tablets	Everolimus (Afinitor) 10 mg tablet once daily. Everolimus (Afinitor) tablets
Measure Participants	330	228
Number (95% Confidence Interval) [months]	21.4	16.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cabozantinib (XL184), Everolimus (Afinitor)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Log Rank
	Comments	The Log-Rank test was stratified by the Memorial Sloan-Kettering Cancer Center (MSKCC) risk group and number of prior VEGFR TKIs.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; 0.53 to 0.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	Objective Response Rate (ORR) is the number of participants with a best response of complete response (CR) or partial response (PR) divided by number of randomized participants. ORR was assessed by the Independent Radiology Committee (IRC) per RECIST 1.1 which was confirmed by a subsequent visit >= 28 days later, and was analyzed in the Intent to Treat (ITT) population at the time of the primary analysis of Progression Free Survival (PFS). The data cutoff date was 22 May 2015.
Time Frame	ORR was assessed at 8 weeks post-randomization, every 8 weeks for 12 months, and every 12 weeks until date of disease progression or death, up to May 2015 (approximately 21 months)

Outcome Measure Data

Analysis Population Description

The analysis of ORR was performed in the ITT population (all randomized: 330 cabozantinib, 328 everolimus) based upon response determined by Independent Radiology Committee (IRC) per RECIST 1.1.

Arm/Group Title	Cabozantinib (XL184)	Everolimus (Afinitor)
Arm/Group Description	Cabozantinib (XL184) 60 mg tablet once daily. Cabozantinib tablets	Everolimus (Afinitor) 10 mg tablet once daily. Everolimus (Afinitor) tablets
Measure Participants	330	328
Number [percentage of participants]	17 5.2%	3 0.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cabozantinib (XL184), Everolimus (Afinitor)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

Adverse Events

Time Frame	08 August 2013 - 22 May 2015
Adverse Event Reporting Description	The safety data includes subjects who were randomized and treated. Of 658 patients, 330 were randomized to receive cabozantinib and 328 everolimus. Five subjects in the everolimus arm were randomized but not treated. One subject randomized to the everolimus arm received cabozantinib only as study treatment and was evaluated in the cabozantinib arm for the Safety population (331 cabozantinib, 322 everolimus).
Arm/Group Title	Cabozantinib (XL184)		Everolimus (Afinitor)
Arm/Group Description	Cabozantinib (XL184) 60 mg tablet once daily. Cabozantinib tablets		Everolimus (Afinitor) 10 mg tablet once daily. Everolimus (Afinitor) tablets
All Cause Mortality
	Cabozantinib (XL184)		Everolimus (Afinitor)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Cabozantinib (XL184)		Everolimus (Afinitor)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	131/331 (39.6%)		139/322 (43.2%)
Blood and lymphatic system disorders
Abdominal lymphadenopathy	1/331 (0.3%)	1	0/322 (0%)	0
Anaemia	6/331 (1.8%)	6	12/322 (3.7%)	12
Haemorrhagic anaemia	1/331 (0.3%)	1	0/322 (0%)	0
Lymphadenopathy	1/331 (0.3%)	1	0/322 (0%)	0
Cardiac disorders
Acute coronary syndrome	0/331 (0%)	0	1/322 (0.3%)	1
Atrial fibrillation	2/331 (0.6%)	2	3/322 (0.9%)	3
Cardiac failure	1/331 (0.3%)	1	0/322 (0%)	0
Cardiac failure congestive	0/331 (0%)	0	1/322 (0.3%)	1
Cardiac tamponade	1/331 (0.3%)	1	1/322 (0.3%)	1
Conduction disorder	0/331 (0%)	0	1/322 (0.3%)	1
Myocardial infarction	0/331 (0%)	0	1/322 (0.3%)	1
Palpitations	1/331 (0.3%)	1	0/322 (0%)	0
Pericardial effusion	1/331 (0.3%)	1	0/322 (0%)	0
Ventricular arrhythmia	1/331 (0.3%)	1	0/322 (0%)	0
Ear and labyrinth disorders
Tinnitus	1/331 (0.3%)	1	0/322 (0%)	0
Endocrine disorders
Adrenal Insufficiency	1/331 (0.3%)	1	0/322 (0%)	0
Hypercalcaemia of Malignancy	0/331 (0%)	0	1/322 (0.3%)	1
Gastrointestinal disorders
Abdominal Pain	10/331 (3%)	10	2/322 (0.6%)	2
Abdominal Pain Upper	1/331 (0.3%)	1	0/322 (0%)	0
Anal Fistula	1/331 (0.3%)	1	0/322 (0%)	0
Ascites	1/331 (0.3%)	1	1/322 (0.3%)	1
Colitis	0/331 (0%)	0	1/322 (0.3%)	1
Colitis Ulcerative	1/331 (0.3%)	1	0/322 (0%)	0
Constipation	1/331 (0.3%)	1	1/322 (0.3%)	1
Diarrhoea	7/331 (2.1%)	7	2/322 (0.6%)	2
Faecaloma	1/331 (0.3%)	1	0/322 (0%)	0
Gastric Haemorrhage	1/331 (0.3%)	1	1/322 (0.3%)	1
Gastritis	0/331 (0%)	0	1/322 (0.3%)	1
Gastrointestinal Perforation	1/331 (0.3%)	1	1/322 (0.3%)	1
Inguinal Hernia	1/331 (0.3%)	1	0/322 (0%)	0
Intestinal Perforation	0/331 (0%)	0	1/322 (0.3%)	1
Nausea	7/331 (2.1%)	7	2/322 (0.6%)	2
Oesophageal Pain	1/331 (0.3%)	1	0/322 (0%)	0
Pancreatitis	2/331 (0.6%)	2	1/322 (0.3%)	1
Pancreatitis Acute	1/331 (0.3%)	1	0/322 (0%)	0
Proctitis	1/331 (0.3%)	1	0/322 (0%)	0
Rectal Haemorrhage	1/331 (0.3%)	1	0/322 (0%)	0
Small Intestine Obstruction	1/331 (0.3%)	1	0/322 (0%)	0
Small Intestinal Perforation	1/331 (0.3%)	1	0/322 (0%)	0
Stomatitis	1/331 (0.3%)	1	0/322 (0%)	0
Swollen Tongue	1/331 (0.3%)	1	0/322 (0%)	0
Upper Gastrointestinal Haemorrhage	0/331 (0%)	0	1/322 (0.3%)	1
Vomiting	6/331 (1.8%)	6	4/322 (1.2%)	4
General disorders
Asthenia	4/331 (1.2%)	4	1/322 (0.3%)	1
Death	2/331 (0.6%)	2	0/322 (0%)	0
Device Occlusion	1/331 (0.3%)	1	0/322 (0%)	0
Fatigue	6/331 (1.8%)	6	5/322 (1.6%)	5
General Physical Health Deterioration	4/331 (1.2%)	4	6/322 (1.9%)	6
Generalised Oedema	0/331 (0%)	0	1/322 (0.3%)	1
Hypothermia	1/331 (0.3%)	1	0/322 (0%)	0
Local Swelling	1/331 (0.3%)	1	0/322 (0%)	0
Malaise	1/331 (0.3%)	1	0/322 (0%)	0
Mucosal Inflammation	0/331 (0%)	0	2/322 (0.6%)	2
Mutli-Organ Failure	0/331 (0%)	0	1/322 (0.3%)	1
Non-Cardiac Chest Pain	1/331 (0.3%)	1	1/322 (0.3%)	1
Oedema	0/331 (0%)	0	1/322 (0.3%)	1
Oedema Peripheral	0/331 (0%)	0	1/322 (0.3%)	1
Pain	5/331 (1.5%)	5	4/322 (1.2%)	4
Pyrexia	3/331 (0.9%)	3	4/322 (1.2%)	4
Ulcer Haemorrhage	1/331 (0.3%)	1	0/322 (0%)	0
Hepatobiliary disorders
Bile Duct Obstruction	2/331 (0.6%)	2	0/322 (0%)	0
Cholangitis	1/331 (0.3%)	1	1/322 (0.3%)	1
Cholecystitis	0/331 (0%)	0	1/322 (0.3%)	1
Cholecystitis Acute	1/331 (0.3%)	1	1/322 (0.3%)	1
Hepatitis Cholestatic	1/331 (0.3%)	1	0/322 (0%)	0
Infections and infestations
Abdominal Abscess	1/331 (0.3%)	1	0/322 (0%)	0
Abscess Neck	0/331 (0%)	0	1/322 (0.3%)	1
Acute Sinusitis	1/331 (0.3%)	1	0/322 (0%)	0
Anal Abscess	2/331 (0.6%)	2	0/322 (0%)	0
Anorectal Cellulitis	1/331 (0.3%)	1	0/322 (0%)	0
Appendicitis	1/331 (0.3%)	1	0/322 (0%)	0
Appendicitis Perforated	1/331 (0.3%)	1	0/322 (0%)	0
Aspergillus Infection	0/331 (0%)	0	1/322 (0.3%)	1
Bacteraemia	1/331 (0.3%)	1	0/322 (0%)	0
Bacterial Sepsis	1/331 (0.3%)	1	0/322 (0%)	0
Bronchitis	1/331 (0.3%)	1	2/322 (0.6%)	2
Bronchopneumonia	0/331 (0%)	0	1/322 (0.3%)	1
Device Related Infection	1/331 (0.3%)	1	0/322 (0%)	0
Diverticulitis	0/331 (0%)	0	1/322 (0.3%)	1
Empyema	1/331 (0.3%)	1	1/322 (0.3%)	1
Gastroenteritis	0/331 (0%)	0	1/322 (0.3%)	1
Implant Site Infection	1/331 (0.3%)	1	0/322 (0%)	0
Infection	1/331 (0.3%)	1	0/322 (0%)	0
Kidney Infection	1/331 (0.3%)	1	0/322 (0%)	0
Klebsiella Infection	1/331 (0.3%)	1	0/322 (0%)	0
Lower Respiratory Tract Infection	1/331 (0.3%)	1	3/322 (0.9%)	3
Lung Infection	2/331 (0.6%)	2	1/322 (0.3%)	1
Otitis Externa	0/331 (0%)	0	1/322 (0.3%)	1
Periorbital Cellulitis	0/331 (0%)	0	1/322 (0.3%)	1
Peritonitis	0/331 (0%)	0	1/322 (0.3%)	1
Peritonitis Bacterial	0/331 (0%)	0	1/322 (0.3%)	1
Pleural Infection	1/331 (0.3%)	1	0/322 (0%)	0
Pneumocystis Jirovecii Pneumonia	0/331 (0%)	0	1/322 (0.3%)	1
Pneumonia	6/331 (1.8%)	6	13/322 (4%)	13
Pyelonephritis	0/331 (0%)	0	1/322 (0.3%)	1
Respiratory Tract Infection	0/331 (0%)	0	2/322 (0.6%)	2
Sepsis	1/331 (0.3%)	1	3/322 (0.9%)	3
Septic Shock	1/331 (0.3%)	1	0/322 (0%)	0
Skin Infection	0/331 (0%)	0	1/322 (0.3%)	1
Tuberculosis	0/331 (0%)	0	1/322 (0.3%)	1
Urinary Tract Infection	1/331 (0.3%)	1	1/322 (0.3%)	1
Urosepsis	2/331 (0.6%)	2	0/322 (0%)	0
Viral Pharyngitis	0/331 (0%)	0	1/322 (0.3%)	1
Vulval Cellulitis	1/331 (0.3%)	1	0/322 (0%)	0
Wound Infection	0/331 (0%)	0	1/322 (0.3%)	1
Injury, poisoning and procedural complications
Acetabulum Fracture	0/331 (0%)	0	1/322 (0.3%)	1
Contusion	0/331 (0%)	0	1/322 (0.3%)	1
Extradural Haematoma	1/331 (0.3%)	1	0/322 (0%)	0
Fall	3/331 (0.9%)	3	2/322 (0.6%)	2
Femoral Neck Fracture	0/331 (0%)	0	2/322 (0.6%)	2
Foreign Body in Eye	1/331 (0.3%)	1	0/322 (0%)	0
Fracture	2/331 (0.6%)	2	0/322 (0%)	0
Humerus Fracture	1/331 (0.3%)	1	0/322 (0%)	0
Incisional Hernia	1/331 (0.3%)	1	0/322 (0%)	0
Post Procedural Haemorrhage	1/331 (0.3%)	1	0/322 (0%)	0
Rib Fracture	1/331 (0.3%)	1	0/322 (0%)	0
Stress Fracture	0/331 (0%)	0	1/322 (0.3%)	1
Thoracic Vertebral Fracture	1/331 (0.3%)	1	0/322 (0%)	0
Investigations
Blood Bilirubin Increased	1/331 (0.3%)	1	0/322 (0%)	0
Blood Cholesterol Increased	0/331 (0%)	0	1/322 (0.3%)	1
Haemoglobin Decreased	0/331 (0%)	0	1/322 (0.3%)	1
Weight Decreased	0/331 (0%)	0	1/322 (0.3%)	1
Metabolism and nutrition disorders
Decreased Appetite	2/331 (0.6%)	2	1/322 (0.3%)	1
Dehydration	3/331 (0.9%)	3	7/322 (2.2%)	7
Diabetes Mellitus	0/331 (0%)	0	1/322 (0.3%)	1
Diabetes Mellitus Inadequate Control	1/331 (0.3%)	1	0/322 (0%)	0
Electrolyte Imbalance	1/331 (0.3%)	1	0/322 (0%)	0
Hypercalcaemia	4/331 (1.2%)	4	4/322 (1.2%)	4
Hyperglycaemia	0/331 (0%)	0	1/322 (0.3%)	1
Hyperkalaemia	2/331 (0.6%)	2	2/322 (0.6%)	2
Hypocalcaemia	1/331 (0.3%)	1	0/322 (0%)	0
Hypokalaemia	2/331 (0.6%)	2	0/322 (0%)	0
Hypomagnesaemia	4/331 (1.2%)	4	0/322 (0%)	0
Hyponatraemia	4/331 (1.2%)	4	2/322 (0.6%)	2
Type 2 Diabetes Mellitus	0/331 (0%)	0	1/322 (0.3%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/331 (0%)	0	1/322 (0.3%)	1
Back Pain	6/331 (1.8%)	6	4/322 (1.2%)	4
Flank Pain	0/331 (0%)	0	1/322 (0.3%)	1
Haemarthrosis	1/331 (0.3%)	1	0/322 (0%)	0
Lumbar Spinal Stenosis	0/331 (0%)	0	1/322 (0.3%)	1
Musculoskeletal Chest Pain	1/331 (0.3%)	1	2/322 (0.6%)	2
Osteolysis	1/331 (0.3%)	1	0/322 (0%)	0
Osteonecrosis of Jaw	1/331 (0.3%)	1	2/322 (0.6%)	2
Pain in Extremity	1/331 (0.3%)	1	0/322 (0%)	0
Pathological Fracture	1/331 (0.3%)	1	0/322 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma	1/331 (0.3%)	1	0/322 (0%)	0
Adenocarcinoma of Colon	1/331 (0.3%)	1	0/322 (0%)	0
Chronic Lymphocytic Leukaemia	1/331 (0.3%)	1	0/322 (0%)	0
Leiomyoma	1/331 (0.3%)	1	0/322 (0%)	0
Malignant Melanoma	0/331 (0%)	0	1/322 (0.3%)	1
Malignant Neoplasm of Orbit	0/331 (0%)	0	1/322 (0.3%)	1
Metastases to Bone	2/331 (0.6%)	2	2/322 (0.6%)	2
Metastases to Central Nervous System	1/331 (0.3%)	1	5/322 (1.6%)	5
Metastases to Ovary	1/331 (0.3%)	1	0/322 (0%)	0
Metastases to Pelvis	1/331 (0.3%)	1	0/322 (0%)	0
Metatases to Spine	2/331 (0.6%)	2	2/322 (0.6%)	2
Metatases to Testicle	1/331 (0.3%)	1	0/322 (0%)	0
Metastatic Pain	0/331 (0%)	0	1/322 (0.3%)	1
Metastatic Renal Cell Carcinoma	2/331 (0.6%)	2	1/322 (0.3%)	1
Renal Cancer	1/331 (0.3%)	1	1/322 (0.3%)	1
Renal Cell Carcinoma	11/331 (3.3%)	11	11/322 (3.4%)	11
Tumour Associated Fever	0/331 (0%)	0	1/322 (0.3%)	1
Tumour Thrombosis	0/331 (0%)	0	1/322 (0.3%)	1
Nervous system disorders
Carotid Artery Occlusion	1/331 (0.3%)	1	0/322 (0%)	0
Carotid Artery Thrombosis	1/331 (0.3%)	1	0/322 (0%)	0
Cerebral Haematoma	1/331 (0.3%)	1	0/322 (0%)	0
Cerebrovascular Disorder	1/331 (0.3%)	1	0/322 (0%)	0
Cognitive Disorder	1/331 (0.3%)	1	0/322 (0%)	0
Convulsion	2/331 (0.6%)	2	0/322 (0%)	0
Dizziness	2/331 (0.6%)	2	1/322 (0.3%)	1
Epilepsy	1/331 (0.3%)	1	0/322 (0%)	0
Intracranial Venous Sinus Thrombosis	1/331 (0.3%)	1	0/322 (0%)	0
Miller Fisher Syndrome	1/331 (0.3%)	1	0/322 (0%)	0
Somnolence	1/331 (0.3%)	1	1/322 (0.3%)	1
Spinal Cord Compression	1/331 (0.3%)	1	4/322 (1.2%)	4
Syncope	1/331 (0.3%)	1	1/322 (0.3%)	1
Transient Ischaemic Attack	1/331 (0.3%)	1	0/322 (0%)	0
Psychiatric disorders
Confusional State	2/331 (0.6%)	2	1/322 (0.3%)	1
Delirium	1/331 (0.3%)	1	1/322 (0.3%)	1
Renal and urinary disorders
Haematuria	1/331 (0.3%)	1	1/322 (0.3%)	1
Renal Failure	1/331 (0.3%)	1	2/322 (0.6%)	2
Renal Failure Acute	0/331 (0%)	0	5/322 (1.6%)	5
Renal Haemorrhage	0/331 (0%)	0	1/322 (0.3%)	1
Renal Impairment	0/331 (0%)	0	1/322 (0.3%)	1
Renal pain	1/331 (0.3%)	1	0/322 (0%)	0
Reproductive system and breast disorders
Pelvic Pain	1/331 (0.3%)	1	1/322 (0.3%)	1
Prostatitis	0/331 (0%)	0	1/322 (0.3%)	1
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure	0/331 (0%)	0	1/322 (0.3%)	1
Cough	0/331 (0%)	0	1/322 (0.3%)	1
Dyspnoea	6/331 (1.8%)	6	13/322 (4%)	13
Haemoptysis	1/331 (0.3%)	1	1/322 (0.3%)	1
Hydrothorax	0/331 (0%)	0	3/322 (0.9%)	3
Hypoxia	0/331 (0%)	0	1/322 (0.3%)	1
Interstitial Lung Disease	0/331 (0%)	0	1/322 (0.3%)	1
Obstructive Airways Disorder	0/331 (0%)	0	1/322 (0.3%)	1
Pleural Effusion	10/331 (3%)	10	6/322 (1.9%)	6
Pneumonia Aspiration	0/331 (0%)	0	3/322 (0.9%)	3
Pneumonitis	0/331 (0%)	0	8/322 (2.5%)	8
Pneumothorax	4/331 (1.2%)	4	1/322 (0.3%)	1
Pulmonary Embolism	6/331 (1.8%)	6	1/322 (0.3%)	1
Pulmonary Haemorrhage	0/331 (0%)	0	1/322 (0.3%)	1
Respiratory Distress	1/331 (0.3%)	1	0/322 (0%)	0
Respiratory Failure	1/331 (0.3%)	1	1/322 (0.3%)	1
Skin and subcutaneous tissue disorders
Dermatitis Bullous	1/331 (0.3%)	1	0/322 (0%)	0
Hyperhidrosis	1/331 (0.3%)	1	0/322 (0%)	0
Pruritus	0/331 (0%)	0	1/322 (0.3%)	1
Rash	0/331 (0%)	0	1/322 (0.3%)	1
Rash Maculo-Papular	0/331 (0%)	0	1/322 (0.3%)	1
Vascular disorders
Circulatory Collapse	0/331 (0%)	0	1/322 (0.3%)	1
Deep Vein Thrombosis	4/331 (1.2%)	4	0/322 (0%)	0
Hypertension	1/331 (0.3%)	1	0/322 (0%)	0
Orthostatic Hypotension	0/331 (0%)	0	1/322 (0.3%)	1
Pelvic Venous Thrombosis	1/331 (0.3%)	1	0/322 (0%)	0
Peripheral Ischaemia	1/331 (0.3%)	1	0/322 (0%)	0
Other (Not Including Serious) Adverse Events
	Cabozantinib (XL184)		Everolimus (Afinitor)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	328/331 (99.1%)		270/322 (83.9%)
Endocrine disorders
Hypothyroidism	68/331 (20.5%)	68	2/322 (0.6%)	2
Gastrointestinal disorders
Abdominal Pain	50/331 (15.1%)	50	30/322 (9.3%)	30
Abdominal Pain Upper	26/331 (7.9%)	26	7/322 (2.2%)	7
Constipation	83/331 (25.1%)	83	61/322 (18.9%)	61
Diarrhoea	245/331 (74%)	245	88/322 (27.3%)	88
Dyspepsia	40/331 (12.1%)	40	15/322 (4.7%)	15
Flatulence	32/331 (9.7%)	32	6/322 (1.9%)	6
Nausea	164/331 (49.5%)	164	89/322 (27.6%)	89
Vomiting	105/331 (31.7%)	105	44/322 (13.7%)	44
General disorders
Fatigue	185/331 (55.9%)	185	149/322 (46.3%)	149
Investigations
Alanine Aminotransferase Increased	53/331 (16%)	53	19/322 (5.9%)	19
Aspartate Aminotransferase Increased	58/331 (17.5%)	58	18/322 (5.6%)	18
Blood Thyrpod Stimulating Hormone Increased	23/331 (6.9%)	23	3/322 (0.9%)	3
Weight Decreased	104/331 (31.4%)	104	39/322 (12.1%)	39
Metabolism and nutrition disorders
Decreased Appetite	152/331 (45.9%)	152	108/322 (33.5%)	108
Hypomagnesaemia	50/331 (15.1%)	50	5/322 (1.6%)	5
Musculoskeletal and connective tissue disorders
Muscle Spasms	42/331 (12.7%)	42	16/322 (5%)	16
Pain in Extremity	46/331 (13.9%)	46	25/322 (7.8%)	25
Nervous system disorders
Dysgeusia	78/331 (23.6%)	78	30/322 (9.3%)	30
Respiratory, thoracic and mediastinal disorders
Dysphonia	66/331 (19.9%)	66	12/322 (3.7%)	12
Skin and subcutaneous tissue disorders
Palmar-Plantar Erythrodysaesthesia Syndrome	139/331 (42%)	139	19/322 (5.9%)	19
Vascular disorders
Hypertension	122/331 (36.9%)	122	23/322 (7.1%)	23

Limitations/Caveats

[Not Specified]

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Principal Investigators are NOT employed by the organization sponsoring the study.

Our agreements with investigators vary; constant is our right to review results communications prior to public release, and embargo communications for a period of ≤60 days from submittal for review. We do not prohibit investigators from publishing, but we may require previously undisclosed confidential information, other than study results, to be removed from publications, and single-center publications are postponed until after publication of the trial's primary multicenter publication.