Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First-line and Second-line Treatment of Patients With Metastatic Renal Cell Carcinoma (RECORD-3)

• ClinicalTrials.gov Identifier: NCT00903175
• Recruitment Status: Completed
• First Posted: May 18, 2009
• Results First Posted: June 28, 2016
• Last Update Posted: November 8, 2016
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Renal Cell Carcinoma
• Interventions: Drug: everolimus; Drug: sunitinib
• Enrollment: 471

Participant Flow

Recruitment Details	238 patients were randomized to everolimus as 1st line followed by 2nd line sunitinib. All patients in this group were treated. 233 patients were randomized to the sunitinib as 1st line followed by 2nd line everolimus. However 2 of the 233 patients were not treated in this group.
Pre-assignment Details	The trial had a crossover design: first-line therapy until disease progression followed by second-line therapy until disease progression.Patients were randomized 1:1 to either everolimus-sunitinib or sunitinib-everolimus treatment sequence and were stratified by MSKCC risk criteria

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description	everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)	sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment
Period Title: Period 1 - First Line
Started	238	231
Completed	161 [1]	142 [1]
Not Completed	77	89
Reason Not Completed
Adverse Event	36	50
Abnormal lab value(s)	0	1
Abnormal test procedure result(s)	1	0
Protocol Violation	3	3
Withdrawal by Subject	8	12
Administrative problems	12	13
Death	17	10
[1] Completed = Disease progression (completed 1L)
Period Title: Period 2 - Second Line
Started	128 [1]	116 [2]
Completed	79 [3]	80 [3]
Not Completed	49	36
Reason Not Completed
Missing	1	0
Adverse Event	16	20
Withdrawal by Subject	7	5
Lost to Follow-up	1	0
Administrative problems	19	9
Death	5	2
[1] 139 from everolimus 1L planned to enter 2L period and cross over to sunitinib but only 128 did.; [2] 130 from Sunitinib 1L planned to enter 2L period and cross over to everolimus but only 116 did.; [3] Completed = Disease progression - (completed 2L)

Baseline Characteristics

Arm/Group Title		Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L	Total
Arm/Group Description		everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)	sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment	Total of all reporting groups
Overall Number of Baseline Participants		238	233	471
Baseline Analysis Population Description		The Full Analysis Set (FAS) consists of all randomized patients. Following the intent-to-treat principle, patients are analyzed according to the treatment sequence and stratum they were assigned to at randomization.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	238 participants	233 participants	471 participants
		61.36 (12.102)	60.84 (11.627)	61.10 (11.860)
Sex/Gender, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	238 participants	233 participants	471 participants
Female		72	57	129
Male		166	176	342

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival First-Line (PFS 1-L)
Description	PFS_1L based on investigator assessment of radiology data by RECIST 1.0, was defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause during or after first-line treatment with everolimus or sunitinib. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	based on radiological assessments every 3 months until disease progression, start of another antineoplastic therapy or for any other reason up to 35 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description:	everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)	sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment
Overall Number of Participants Analyzed	238	233
Median (95% Confidence Interval); Unit of Measure: Months
	7.85; (5.55 to 8.25)	10.71; (8.18 to 11.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Everolimus 1L/Sunitinib 2L, Sunitinib 1L/Everolimus 2L
	Comments	[Not Specified]
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Primary objective was to assess the non-inferiority of everolimus as compared to Sunitinib in terms of PFS-1L & was based on Bayesian methodology. If the estimated HR for PFS-1L had a value ≤ 1.1, non-inferiority of everolimus to Sunitinib would be declared. Non-inferiority of everolimus compared with Sunitinib as a first-line therapy was not achieved. The estimated HR for PFS-1L was 1.43 which did not satisfy the protocol-defined non-inferiority margin of a HR ≤ 1.1.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.43
	Confidence Interval	(2-Sided) 95%; 1.15 to 1.77
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Progression-free Survival Combined (PFS-C)
Description	PFS-C (1L and 2L study drugs combined) was a composite endpoint which combined both lines of study treatment. It was defined as the time from the date of randomization to the first of the following: date of death due to any cause, or date of the first radiologically documented progression disease during or after the second-line treatment period for patients with a radiologically documented progression disease in the first-line treatment period and who had crossed-over to second-line treatment no more than 6 weeks after progression.
Time Frame	based on radiological assessments every 3 months until disease progression, start of another antineoplastic therapy or for any other reason up to about 56 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description:	everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)	sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment
Overall Number of Participants Analyzed	238	233
Median (95% Confidence Interval); Unit of Measure: Months
	21.68; (15.05 to 26.71)	22.18; (16.03 to 29.83)

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival was defined as the time from date of randomization to date of death due to any cause. The analysis of OS included all deaths in the FAS regardless of when they were observed.
Time Frame	Every 2 months from randomization up to 3 years after last patient randomized

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description:	everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)	sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment
Overall Number of Participants Analyzed	238	233
Median (95% Confidence Interval); Unit of Measure: Months
	22.41; (18.60 to 33.28)	29.47; (22.83 to 33.05)

4. Secondary Outcome

Title	Overall Response Rate (ORR) - First -Line (1-L)
Description	ORR was defined as the number of participants with best overall response (BOR) of complete response (CR) or partial response (PR) and was based on investigator assessment of radiology data per RECIST. Participants with best overall response of 'Unknown' were treated as non-responders in the calculation of the ORR. Confirmed CR = at least two determinations of CR at least 4 weeks apart before progression. Confirmed PR = at least two determinations of PR or better at least 4 weeks apart before progression. CR required a disappearance of all target and non-target lesions. PR required at least a 30% decrease in the sum of the longest diameters of all target lesions, taking as a reference the baseline sum of the longest diameters. Radiological assessments : every 12 weeks until disease progression, the start of another antineoplastic therapy or for any other reason.
Time Frame	based on radiological assessments every 3 months until disease progression, start of another antineoplastic therapy or for any other reason up to 35 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description:	everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)	sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment
Overall Number of Participants Analyzed	238	233
Measure Type: Number; Unit of Measure: percentage of participants
Complete Response (CR)	1	3
Partial Response (PR)	18	59
Overall Response Rate (CR + PR)	19	62

5. Secondary Outcome

Title	Duration of Response (DoR) - First-Line (1-L)
Description	Duration of overall response (CR or PR) applies only to patients whose Best Overall Response (BOR) was Complete Response (CR) or Partial Response (PR) during the first-line treatment period. The start date was the date of first documented response (CR or PR) during the first-line treatment and the end date was the date of the event defined as the first documented progression or death due to underlying cancer during or after the same treatment line.
Time Frame	based on radiological assessments every 3 months until disease progression, start of another antineoplastic therapy or for any other reason up to 35 months

Outcome Measure Data

Analysis Population Description

The analysis population corresponds to the patients included in the Full analysis set (i.e. randomized patients analyzed according to the treatment and stratum they were assigned to at randomization) and who achieved a best overall response of CR or PR during the first-line treatment period.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description:	everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)	sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment
Overall Number of Participants Analyzed	19	62
Median (95% Confidence Interval); Unit of Measure: Months
	13.37 [1]; (8.3 to NA)	17.25 [1]; (11.4 to NA)

[1]

N/A = Data not estimable due to few number of patient at this time point

6. Secondary Outcome

Title	Time to Definitive Deterioration of the FKSI-DRS Risk Score by at Least 3 Score Units by First-line Drug
Description	The Functional Assessment of Cancer Therapy - Kidney Symptom Index, Disease Related Symptoms (FKSI-DRS) is a set of items to assess symptoms experienced by patients with advanced kidney cancer. These symptoms include fatigue, pain, weight loss, dyspnea, cough, fever and hematuria. Each item is scored on a 5-point scale (0 = not at all; 4 = very much). The FKSI-DRS total score ranges from 0 (most severe symptoms) to 36 (no symptoms). Definitive deterioration was defined as a decrease by at least 3 units compared to baseline, with no later increase above this threshold observed during the 1-L of treatment. A single measure reporting a decrease of at least 3 units was considered definitive only if it was the last one available for the patient.
Time Frame	<=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description:	everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)	sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment
Overall Number of Participants Analyzed	238	233
Median (95% Confidence Interval); Unit of Measure: Months
	12.65; (7.9 to 19.4)	16.66 [1]; (13.7 to NA)

[1]

N/A = Data not estimable due to few number of patient at this time point

7. Secondary Outcome

Title	Time to Definitive Deterioration of the FKSI-DRS Risk Score by at Least 3 Score Units by First and Second-line Drugs Combined
Description	The Functional Assessment of Cancer Therapy - Kidney Symptom Index, Disease Related Symptoms (FKSI-DRS) is a set of items to assess symptoms experienced by patients with advanced kidney cancer. These symptoms include fatigue, pain, weight loss, dyspnea, cough, fever and hematuria. Each item is scored on a 5-point scale (0 = not at all; 4 = very much). The FKSI-DRS total score ranges from 0 (most severe symptoms) to 36 (no symptoms). Definitive deterioration was defined as a decrease by at least 3 units compared to baseline, with no later increase above this threshold observed during the 1-L or 2-L treatment. A single measure reporting a decrease of at least 3 units was considered definitive only if it was the last one available for the patient.
Time Frame	<=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description:	everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)	sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment
Overall Number of Participants Analyzed	238	233
Median (95% Confidence Interval); Unit of Measure: Months
	14.23; (12.0 to 19.4)	15.97; (13.7 to 20.4)

8. Secondary Outcome

Title	Time to Definitive Deterioration of the Physical Functioning (PF) Scale of the EORTC QLQ-C30 - by First-Line (1L) Drug
Description	The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items. The standardized score for the PF, fatigue subscales and global health status ranges from 0 to 100, with a higher score representing a high level of functioning/high level of symptom/high quality of life. Definitive deterioration by at least 10% was defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the first line of treatment. A single measure reporting a decrease of at least 10% was considered definitive only if it was the last one available for the participant.
Time Frame	<=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description:	everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)	sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment
Overall Number of Participants Analyzed	238	233
Median (95% Confidence Interval); Unit of Measure: Months
	13.47; (7.9 to 20.6)	14.03; (12.1 to 17.7)

9. Secondary Outcome

Title	Time to Definitive Deterioration of the Physical Functioning Scale of the EORTC QLQ-C30 - by First and Second-Line Drugs Combined
Description	The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items.The standardized score for the PF, fatigue subscales and global health status ranges from 0 to 100, with a higher score representing a high level of functioning/high level of symptom/high quality of life. Definitive deterioration by at least 10% was defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the first line or second line treatment. A single measure reporting a decrease of at least 10% was considered definitive only if it was the last one available for the participant.
Time Frame	<=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description:	everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)	sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment
Overall Number of Participants Analyzed	238	233
Median (95% Confidence Interval); Unit of Measure: Months
	12.25; (9.5 to 16.3)	14.03; (12.0 to 17.7)

10. Secondary Outcome

Title	Time to Definitive Deterioration of the Global Health Status/QoL Scores of the EORTC QLQ-C30 by First-Line Drug
Description	The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items.The standardized score for the PF, fatigue subscales and global health status ranges from 0 to 100, with a higher score representing a high level of functioning/high level of symptom/high quality of life. Definitive deterioration by at least 10% was defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the first line of treatment. A single measure reporting a decrease of at least 10% was considered definitive only if it was the last one available for the participant.
Time Frame	<=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description:	everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)	sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment
Overall Number of Participants Analyzed	238	233
Median (95% Confidence Interval); Unit of Measure: Months
	7.92; (5.6 to 12.1)	12.25; (7.9 to 14.1)

11. Secondary Outcome

Title	Time to Definitive Deterioration of the Global Health Status/QoL Scores of the EORTC QLQ-C30 by First and Second-Line Drugs Combined
Description	The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items. The standardized score for the PF, fatigue subscales and global health status ranges from 0 to 100, with a higher score representing a high level of functioning/high level of symptom/high quality of life. Definitive deterioration by at least 10% was defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the first line or second line treatment. A single measure reporting a decrease of at least 10% was considered definitive only if it was the last one available for the participant.
Time Frame	<=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description:	everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)	sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment
Overall Number of Participants Analyzed	238	233
Median (95% Confidence Interval); Unit of Measure: Months
	10.84; (7.5 to 13.8)	12.71; (10.5 to 14.8)

12. Secondary Outcome

Title	Time to Definitive Deterioration of the Fatigue Scale of the EORTC QLQ-C30 by First-Line Drug
Description	The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items.The standardized score for the PF, fatigue subscales and global health status ranges from 0 to 100, with a higher score representing a high level of functioning/high level of symptom/high quality of life. Definitive deterioration by at least 10% was defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the first line of treatment. A single measure reporting a decrease of at least 10% was considered definitive only if it was the last one available for the participant.
Time Frame	<=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description:	everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)	sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment
Overall Number of Participants Analyzed	238	233
Median (95% Confidence Interval); Unit of Measure: Months
	9.20; (6.2 to 12.6)	11.37; (9.3 to 13.4)

13. Secondary Outcome

Title	Time to Definitive Deterioration of the Fatigue Scale of the EORTC QLQ-C30 by First and Second-Line Drugs Combined
Description	The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items. The standardized score for the PF, fatigue subscales and global health status ranges from 0 to 100, with a higher score representing a high level of functioning/high level of symptom/high quality of life. Definitive deterioration by at least 10% was defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the first line or second line treatment. A single measure reporting a decrease of at least 10% was considered definitive only if it was the last one available for the participant.
Time Frame	<=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description:	everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)	sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment
Overall Number of Participants Analyzed	238	233
Mean (95% Confidence Interval); Unit of Measure: Months
	11.56; (7.9 to 14.1)	13.34; (10.8 to 15.9)

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description	everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)	sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment
All-Cause Mortality
	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
	Affected / at Risk (%)	Affected / at Risk (%)
Total	139/238 (58.40%)	131/231 (56.71%)
Blood and lymphatic system disorders
Anaemia † 1	16/238 (6.72%)	9/231 (3.90%)
Coagulopathy † 1	1/238 (0.42%)	0/231 (0.00%)
Disseminated intravascular coagulation † 1	0/238 (0.00%)	1/231 (0.43%)
Febrile neutropenia † 1	0/238 (0.00%)	1/231 (0.43%)
Lymph node pain † 1	0/238 (0.00%)	1/231 (0.43%)
Lymphopenia † 1	0/238 (0.00%)	1/231 (0.43%)
Thrombocytopenia † 1	2/238 (0.84%)	9/231 (3.90%)
Cardiac disorders
Acute myocardial infarction † 1	1/238 (0.42%)	2/231 (0.87%)
Arrhythmia supraventricular † 1	0/238 (0.00%)	1/231 (0.43%)
Atrial fibrillation † 1	7/238 (2.94%)	0/231 (0.00%)
Atrial flutter † 1	1/238 (0.42%)	0/231 (0.00%)
Atrioventricular block second degree † 1	1/238 (0.42%)	0/231 (0.00%)
Bradycardia † 1	0/238 (0.00%)	1/231 (0.43%)
Cardiac arrest † 1	1/238 (0.42%)	0/231 (0.00%)
Cardiac failure † 1	0/238 (0.00%)	2/231 (0.87%)
Cardiac failure congestive † 1	3/238 (1.26%)	0/231 (0.00%)
Cardio-respiratory arrest † 1	2/238 (0.84%)	0/231 (0.00%)
Cardiomyopathy † 1	0/238 (0.00%)	1/231 (0.43%)
Cardiopulmonary failure † 1	0/238 (0.00%)	2/231 (0.87%)
Myocardial infarction † 1	3/238 (1.26%)	3/231 (1.30%)
Myocardial ischaemia † 1	1/238 (0.42%)	1/231 (0.43%)
Pericardial effusion † 1	2/238 (0.84%)	0/231 (0.00%)
Sinus bradycardia † 1	0/238 (0.00%)	1/231 (0.43%)
Sinus tachycardia † 1	0/238 (0.00%)	1/231 (0.43%)
Stress cardiomyopathy † 1	1/238 (0.42%)	0/231 (0.00%)
Supraventricular tachycardia † 1	1/238 (0.42%)	0/231 (0.00%)
Ventricular dysfunction † 1	1/238 (0.42%)	0/231 (0.00%)
Ear and labyrinth disorders
Vertigo † 1	0/238 (0.00%)	1/231 (0.43%)
Endocrine disorders
Hypothyroidism † 1	0/238 (0.00%)	2/231 (0.87%)
Eye disorders
Corneal disorder † 1	0/238 (0.00%)	1/231 (0.43%)
Diplopia † 1	0/238 (0.00%)	1/231 (0.43%)
Optic ischaemic neuropathy † 1	1/238 (0.42%)	0/231 (0.00%)
Visual impairment † 1	0/238 (0.00%)	1/231 (0.43%)
Gastrointestinal disorders
Abdominal distension † 1	2/238 (0.84%)	1/231 (0.43%)
Abdominal pain † 1	6/238 (2.52%)	8/231 (3.46%)
Abdominal pain lower † 1	0/238 (0.00%)	1/231 (0.43%)
Abdominal pain upper † 1	3/238 (1.26%)	1/231 (0.43%)
Anal fissure † 1	2/238 (0.84%)	0/231 (0.00%)
Anal fistula † 1	1/238 (0.42%)	1/231 (0.43%)
Ascites † 1	2/238 (0.84%)	2/231 (0.87%)
Colitis † 1	1/238 (0.42%)	3/231 (1.30%)
Constipation † 1	1/238 (0.42%)	3/231 (1.30%)
Diarrhoea † 1	6/238 (2.52%)	5/231 (2.16%)
Diverticulum † 1	1/238 (0.42%)	0/231 (0.00%)
Duodenal obstruction † 1	1/238 (0.42%)	0/231 (0.00%)
Dyspepsia † 1	0/238 (0.00%)	1/231 (0.43%)
Dysphagia † 1	0/238 (0.00%)	1/231 (0.43%)
Enteritis † 1	1/238 (0.42%)	0/231 (0.00%)
Enterocolitis † 1	1/238 (0.42%)	0/231 (0.00%)
Gastritis † 1	1/238 (0.42%)	0/231 (0.00%)
Gastrointestinal erosion † 1	1/238 (0.42%)	0/231 (0.00%)
Gastrointestinal haemorrhage † 1	3/238 (1.26%)	2/231 (0.87%)
Gastrointestinal inflammation † 1	0/238 (0.00%)	1/231 (0.43%)
Gingival bleeding † 1	1/238 (0.42%)	0/231 (0.00%)
Haematemesis † 1	1/238 (0.42%)	1/231 (0.43%)
Haematochezia † 1	3/238 (1.26%)	0/231 (0.00%)
Haemorrhoids † 1	0/238 (0.00%)	1/231 (0.43%)
Ileus † 1	0/238 (0.00%)	1/231 (0.43%)
Intestinal ischaemia † 1	0/238 (0.00%)	1/231 (0.43%)
Intestinal obstruction † 1	3/238 (1.26%)	0/231 (0.00%)
Localised intraabdominal fluid collection † 1	0/238 (0.00%)	1/231 (0.43%)
Melaena † 1	1/238 (0.42%)	1/231 (0.43%)
Nausea † 1	4/238 (1.68%)	5/231 (2.16%)
Oesophageal ulcer † 1	0/238 (0.00%)	1/231 (0.43%)
Oral pain † 1	1/238 (0.42%)	0/231 (0.00%)
Pancreatitis † 1	3/238 (1.26%)	0/231 (0.00%)
Peritoneal adhesions † 1	1/238 (0.42%)	0/231 (0.00%)
Rectal haemorrhage † 1	1/238 (0.42%)	1/231 (0.43%)
Small intestinal obstruction † 1	0/238 (0.00%)	1/231 (0.43%)
Stomatitis † 1	6/238 (2.52%)	0/231 (0.00%)
Upper gastrointestinal haemorrhage † 1	1/238 (0.42%)	0/231 (0.00%)
Vomiting † 1	5/238 (2.10%)	8/231 (3.46%)
General disorders
Asthenia † 1	6/238 (2.52%)	6/231 (2.60%)
Fatigue † 1	6/238 (2.52%)	5/231 (2.16%)
General physical health deterioration † 1	3/238 (1.26%)	4/231 (1.73%)
Generalised oedema † 1	1/238 (0.42%)	0/231 (0.00%)
Impaired healing † 1	1/238 (0.42%)	1/231 (0.43%)
Influenza like illness † 1	1/238 (0.42%)	1/231 (0.43%)
Localised oedema † 1	0/238 (0.00%)	1/231 (0.43%)
Malaise † 1	3/238 (1.26%)	1/231 (0.43%)
Mucous membrane disorder † 1	1/238 (0.42%)	0/231 (0.00%)
Multi-organ failure † 1	1/238 (0.42%)	1/231 (0.43%)
Non-cardiac chest pain † 1	2/238 (0.84%)	3/231 (1.30%)
Oedema peripheral † 1	2/238 (0.84%)	3/231 (1.30%)
Pelvic mass † 1	0/238 (0.00%)	1/231 (0.43%)
Performance status decreased † 1	1/238 (0.42%)	1/231 (0.43%)
Peripheral swelling † 1	1/238 (0.42%)	2/231 (0.87%)
Pyrexia † 1	10/238 (4.20%)	7/231 (3.03%)
Sudden death † 1	0/238 (0.00%)	1/231 (0.43%)
Hepatobiliary disorders
Cholangitis † 1	0/238 (0.00%)	1/231 (0.43%)
Cholecystitis † 1	2/238 (0.84%)	4/231 (1.73%)
Cholecystitis acute † 1	2/238 (0.84%)	0/231 (0.00%)
Cholelithiasis † 1	1/238 (0.42%)	1/231 (0.43%)
Haemobilia † 1	0/238 (0.00%)	1/231 (0.43%)
Hepatic function abnormal † 1	0/238 (0.00%)	1/231 (0.43%)
Hepatic haemorrhage † 1	0/238 (0.00%)	1/231 (0.43%)
Hyperbilirubinaemia † 1	0/238 (0.00%)	1/231 (0.43%)
Jaundice † 1	0/238 (0.00%)	1/231 (0.43%)
Jaundice cholestatic † 1	1/238 (0.42%)	1/231 (0.43%)
Immune system disorders
Drug hypersensitivity † 1	1/238 (0.42%)	0/231 (0.00%)
Hypersensitivity † 1	1/238 (0.42%)	0/231 (0.00%)
Infections and infestations
Abdominal abscess † 1	0/238 (0.00%)	1/231 (0.43%)
Abscess oral † 1	0/238 (0.00%)	1/231 (0.43%)
Anal abscess † 1	0/238 (0.00%)	1/231 (0.43%)
Aspergillus infection † 1	0/238 (0.00%)	1/231 (0.43%)
Bacteraemia † 1	0/238 (0.00%)	1/231 (0.43%)
Bacterial prostatitis † 1	0/238 (0.00%)	1/231 (0.43%)
Bacterial sepsis † 1	1/238 (0.42%)	0/231 (0.00%)
Bronchitis † 1	1/238 (0.42%)	1/231 (0.43%)
Bronchopneumonia † 1	1/238 (0.42%)	0/231 (0.00%)
Cellulitis † 1	3/238 (1.26%)	3/231 (1.30%)
Clostridium difficile infection † 1	1/238 (0.42%)	0/231 (0.00%)
Diverticulitis † 1	1/238 (0.42%)	2/231 (0.87%)
Empyema † 1	1/238 (0.42%)	0/231 (0.00%)
Endocarditis † 1	1/238 (0.42%)	1/231 (0.43%)
Escherichia sepsis † 1	1/238 (0.42%)	0/231 (0.00%)
Gastrointestinal viral infection † 1	0/238 (0.00%)	1/231 (0.43%)
Hepatitis A † 1	1/238 (0.42%)	0/231 (0.00%)
Herpes zoster † 1	1/238 (0.42%)	0/231 (0.00%)
Infected bites † 1	0/238 (0.00%)	1/231 (0.43%)
Kidney infection † 1	0/238 (0.00%)	1/231 (0.43%)
Localised infection † 1	0/238 (0.00%)	1/231 (0.43%)
Lower respiratory tract infection † 1	2/238 (0.84%)	0/231 (0.00%)
Lung infection † 1	2/238 (0.84%)	1/231 (0.43%)
Pneumonia † 1	18/238 (7.56%)	15/231 (6.49%)
Respiratory tract infection † 1	2/238 (0.84%)	0/231 (0.00%)
Salmonella sepsis † 1	0/238 (0.00%)	1/231 (0.43%)
Sepsis † 1	3/238 (1.26%)	4/231 (1.73%)
Septic shock † 1	4/238 (1.68%)	2/231 (0.87%)
Urinary tract infection † 1	3/238 (1.26%)	5/231 (2.16%)
Wound infection † 1	1/238 (0.42%)	0/231 (0.00%)
Wound sepsis † 1	0/238 (0.00%)	1/231 (0.43%)
Injury, poisoning and procedural complications
Femoral neck fracture † 1	1/238 (0.42%)	0/231 (0.00%)
Femur fracture † 1	1/238 (0.42%)	2/231 (0.87%)
Head injury † 1	1/238 (0.42%)	0/231 (0.00%)
Heat stroke † 1	1/238 (0.42%)	0/231 (0.00%)
Hip fracture † 1	1/238 (0.42%)	0/231 (0.00%)
Humerus fracture † 1	3/238 (1.26%)	0/231 (0.00%)
Pneumothorax traumatic † 1	1/238 (0.42%)	0/231 (0.00%)
Post procedural haematoma † 1	0/238 (0.00%)	1/231 (0.43%)
Post-traumatic pain † 1	0/238 (0.00%)	1/231 (0.43%)
Rib fracture † 1	2/238 (0.84%)	0/231 (0.00%)
Road traffic accident † 1	0/238 (0.00%)	1/231 (0.43%)
Scar † 1	1/238 (0.42%)	0/231 (0.00%)
Subdural haematoma † 1	1/238 (0.42%)	1/231 (0.43%)
Subdural haemorrhage † 1	1/238 (0.42%)	0/231 (0.00%)
Investigations
Blood creatinine increased † 1	3/238 (1.26%)	3/231 (1.30%)
Body temperature increased † 1	1/238 (0.42%)	0/231 (0.00%)
C-reactive protein increased † 1	1/238 (0.42%)	0/231 (0.00%)
Creatinine renal clearance decreased † 1	0/238 (0.00%)	1/231 (0.43%)
Eastern cooperative oncology group performance status worsened † 1	1/238 (0.42%)	0/231 (0.00%)
Electrocardiogram T wave abnormal † 1	0/238 (0.00%)	1/231 (0.43%)
Gamma-glutamyltransferase increased † 1	0/238 (0.00%)	1/231 (0.43%)
Haemoglobin decreased † 1	1/238 (0.42%)	2/231 (0.87%)
Hepatic enzyme increased † 1	0/238 (0.00%)	1/231 (0.43%)
Troponin † 1	0/238 (0.00%)	1/231 (0.43%)
Troponin I increased † 1	1/238 (0.42%)	0/231 (0.00%)
Troponin increased † 1	1/238 (0.42%)	0/231 (0.00%)
Metabolism and nutrition disorders
Decreased appetite † 1	3/238 (1.26%)	0/231 (0.00%)
Dehydration † 1	13/238 (5.46%)	6/231 (2.60%)
Diabetes mellitus † 1	1/238 (0.42%)	1/231 (0.43%)
Electrolyte imbalance † 1	1/238 (0.42%)	0/231 (0.00%)
Failure to thrive † 1	1/238 (0.42%)	1/231 (0.43%)
Feeding disorder † 1	1/238 (0.42%)	0/231 (0.00%)
Food intolerance † 1	1/238 (0.42%)	0/231 (0.00%)
Gout † 1	1/238 (0.42%)	0/231 (0.00%)
Hypercalcaemia † 1	2/238 (0.84%)	5/231 (2.16%)
Hyperglycaemia † 1	4/238 (1.68%)	5/231 (2.16%)
Hyperkalaemia † 1	1/238 (0.42%)	1/231 (0.43%)
Hypoalbuminaemia † 1	1/238 (0.42%)	1/231 (0.43%)
Hypocalcaemia † 1	1/238 (0.42%)	0/231 (0.00%)
Hypoglycaemia † 1	2/238 (0.84%)	1/231 (0.43%)
Hypokalaemia † 1	1/238 (0.42%)	1/231 (0.43%)
Hypomagnesaemia † 1	1/238 (0.42%)	0/231 (0.00%)
Hyponatraemia † 1	0/238 (0.00%)	1/231 (0.43%)
Hypovolaemia † 1	0/238 (0.00%)	1/231 (0.43%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	1/238 (0.42%)	2/231 (0.87%)
Back pain † 1	5/238 (2.10%)	3/231 (1.30%)
Bone pain † 1	2/238 (0.84%)	1/231 (0.43%)
Flank pain † 1	3/238 (1.26%)	0/231 (0.00%)
Fracture pain † 1	0/238 (0.00%)	1/231 (0.43%)
Muscular weakness † 1	0/238 (0.00%)	1/231 (0.43%)
Musculoskeletal chest pain † 1	1/238 (0.42%)	0/231 (0.00%)
Myalgia † 1	1/238 (0.42%)	0/231 (0.00%)
Osteonecrosis of jaw † 1	0/238 (0.00%)	1/231 (0.43%)
Pain in extremity † 1	0/238 (0.00%)	2/231 (0.87%)
Pathological fracture † 1	4/238 (1.68%)	3/231 (1.30%)
Spinal column stenosis † 1	1/238 (0.42%)	0/231 (0.00%)
Spinal pain † 1	0/238 (0.00%)	1/231 (0.43%)
Vertebral lesion † 1	0/238 (0.00%)	1/231 (0.43%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain † 1	0/238 (0.00%)	1/231 (0.43%)
Endometrial adenocarcinoma † 1	0/238 (0.00%)	1/231 (0.43%)
Gastrointestinal stromal tumour † 1	1/238 (0.42%)	0/231 (0.00%)
Lung neoplasm malignant † 1	1/238 (0.42%)	0/231 (0.00%)
Lymphangiosis carcinomatosa † 1	1/238 (0.42%)	0/231 (0.00%)
Malignant ascites † 1	1/238 (0.42%)	0/231 (0.00%)
Malignant neoplasm progression † 1	1/238 (0.42%)	0/231 (0.00%)
Metastases to bone † 1	2/238 (0.84%)	0/231 (0.00%)
Metastases to central nervous system † 1	1/238 (0.42%)	1/231 (0.43%)
Renal cell carcinoma † 1	0/238 (0.00%)	1/231 (0.43%)
Squamous cell carcinoma † 1	0/238 (0.00%)	1/231 (0.43%)
Tumour associated fever † 1	0/238 (0.00%)	1/231 (0.43%)
Tumour pain † 1	0/238 (0.00%)	1/231 (0.43%)
Waldenstrom's macroglobulinaemia † 1	1/238 (0.42%)	0/231 (0.00%)
Nervous system disorders
Balance disorder † 1	0/238 (0.00%)	1/231 (0.43%)
Brain oedema † 1	0/238 (0.00%)	1/231 (0.43%)
Cerebral haemorrhage † 1	3/238 (1.26%)	1/231 (0.43%)
Cerebrovascular accident † 1	2/238 (0.84%)	1/231 (0.43%)
Coma † 1	0/238 (0.00%)	1/231 (0.43%)
Dizziness † 1	1/238 (0.42%)	1/231 (0.43%)
Dysgeusia † 1	1/238 (0.42%)	0/231 (0.00%)
Generalised tonic-clonic seizure † 1	0/238 (0.00%)	1/231 (0.43%)
Haemorrhagic stroke † 1	0/238 (0.00%)	1/231 (0.43%)
Headache † 1	2/238 (0.84%)	0/231 (0.00%)
Hemiparesis † 1	2/238 (0.84%)	0/231 (0.00%)
Hypoaesthesia † 1	0/238 (0.00%)	1/231 (0.43%)
Intracranial pressure increased † 1	0/238 (0.00%)	1/231 (0.43%)
Lethargy † 1	1/238 (0.42%)	0/231 (0.00%)
Loss of consciousness † 1	0/238 (0.00%)	2/231 (0.87%)
Meningorrhagia † 1	0/238 (0.00%)	1/231 (0.43%)
Neuralgia † 1	0/238 (0.00%)	1/231 (0.43%)
Seizure † 1	0/238 (0.00%)	2/231 (0.87%)
Somnolence † 1	0/238 (0.00%)	1/231 (0.43%)
Spinal cord compression † 1	4/238 (1.68%)	3/231 (1.30%)
Status epilepticus † 1	0/238 (0.00%)	1/231 (0.43%)
Syncope † 1	1/238 (0.42%)	2/231 (0.87%)
Transient ischaemic attack † 1	1/238 (0.42%)	1/231 (0.43%)
Visual field defect † 1	1/238 (0.42%)	0/231 (0.00%)
Psychiatric disorders
Anxiety † 1	1/238 (0.42%)	0/231 (0.00%)
Completed suicide † 1	1/238 (0.42%)	0/231 (0.00%)
Confusional state † 1	1/238 (0.42%)	2/231 (0.87%)
Disorientation † 1	0/238 (0.00%)	1/231 (0.43%)
Mental status changes † 1	1/238 (0.42%)	0/231 (0.00%)
Panic attack † 1	1/238 (0.42%)	0/231 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	11/238 (4.62%)	10/231 (4.33%)
Anuria † 1	0/238 (0.00%)	1/231 (0.43%)
Azotaemia † 1	2/238 (0.84%)	3/231 (1.30%)
Calculus ureteric † 1	0/238 (0.00%)	1/231 (0.43%)
Chronic kidney disease † 1	0/238 (0.00%)	1/231 (0.43%)
Dysuria † 1	1/238 (0.42%)	1/231 (0.43%)
Haematuria † 1	4/238 (1.68%)	0/231 (0.00%)
Hydronephrosis † 1	0/238 (0.00%)	1/231 (0.43%)
Nephrotic syndrome † 1	1/238 (0.42%)	0/231 (0.00%)
Proteinuria † 1	0/238 (0.00%)	1/231 (0.43%)
Renal failure † 1	5/238 (2.10%)	3/231 (1.30%)
Renal vein thrombosis † 1	0/238 (0.00%)	1/231 (0.43%)
Tubulointerstitial nephritis † 1	1/238 (0.42%)	0/231 (0.00%)
Urinary retention † 1	2/238 (0.84%)	0/231 (0.00%)
Urinary tract obstruction † 1	1/238 (0.42%)	0/231 (0.00%)
Reproductive system and breast disorders
Oedema genital † 1	0/238 (0.00%)	1/231 (0.43%)
Pelvic pain † 1	0/238 (0.00%)	1/231 (0.43%)
Uterine haemorrhage † 1	0/238 (0.00%)	1/231 (0.43%)
Uterine polyp † 1	0/238 (0.00%)	1/231 (0.43%)
Vaginal haemorrhage † 1	0/238 (0.00%)	1/231 (0.43%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome † 1	0/238 (0.00%)	1/231 (0.43%)
Acute respiratory failure † 1	0/238 (0.00%)	1/231 (0.43%)
Bronchial disorder † 1	0/238 (0.00%)	1/231 (0.43%)
Chronic obstructive pulmonary disease † 1	2/238 (0.84%)	1/231 (0.43%)
Cough † 1	2/238 (0.84%)	1/231 (0.43%)
Dyspnoea † 1	12/238 (5.04%)	13/231 (5.63%)
Dyspnoea exertional † 1	2/238 (0.84%)	0/231 (0.00%)
Epistaxis † 1	2/238 (0.84%)	3/231 (1.30%)
Haemoptysis † 1	4/238 (1.68%)	0/231 (0.00%)
Hypoxia † 1	2/238 (0.84%)	1/231 (0.43%)
Interstitial lung disease † 1	3/238 (1.26%)	0/231 (0.00%)
Obstructive airways disorder † 1	1/238 (0.42%)	0/231 (0.00%)
Pleural effusion † 1	10/238 (4.20%)	12/231 (5.19%)
Pneumonia aspiration † 1	1/238 (0.42%)	1/231 (0.43%)
Pneumonitis † 1	4/238 (1.68%)	0/231 (0.00%)
Pneumothorax † 1	1/238 (0.42%)	2/231 (0.87%)
Pulmonary embolism † 1	0/238 (0.00%)	3/231 (1.30%)
Pulmonary granuloma † 1	0/238 (0.00%)	1/231 (0.43%)
Pulmonary haemorrhage † 1	0/238 (0.00%)	1/231 (0.43%)
Pulmonary oedema † 1	1/238 (0.42%)	3/231 (1.30%)
Respiratory failure † 1	6/238 (2.52%)	1/231 (0.43%)
Skin and subcutaneous tissue disorders
Angioedema † 1	2/238 (0.84%)	0/231 (0.00%)
Dermatitis † 1	1/238 (0.42%)	0/231 (0.00%)
Generalised erythema † 1	1/238 (0.42%)	0/231 (0.00%)
Skin ulcer † 1	0/238 (0.00%)	1/231 (0.43%)
Vascular disorders
Aortic aneurysm † 1	0/238 (0.00%)	1/231 (0.43%)
Aortic dissection † 1	0/238 (0.00%)	1/231 (0.43%)
Hypertension † 1	0/238 (0.00%)	4/231 (1.73%)
Hypertensive crisis † 1	0/238 (0.00%)	2/231 (0.87%)
Hypotension † 1	3/238 (1.26%)	1/231 (0.43%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 18.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
	Affected / at Risk (%)	Affected / at Risk (%)
Total	231/238 (97.06%)	228/231 (98.70%)
Blood and lymphatic system disorders
Anaemia † 1	75/238 (31.51%)	70/231 (30.30%)
Leukopenia † 1	11/238 (4.62%)	14/231 (6.06%)
Neutropenia † 1	21/238 (8.82%)	45/231 (19.48%)
Thrombocytopenia † 1	37/238 (15.55%)	58/231 (25.11%)
Endocrine disorders
Hyperthyroidism † 1	4/238 (1.68%)	14/231 (6.06%)
Hypothyroidism † 1	30/238 (12.61%)	57/231 (24.68%)
Eye disorders
Periorbital oedema † 1	9/238 (3.78%)	12/231 (5.19%)
Gastrointestinal disorders
Abdominal discomfort † 1	13/238 (5.46%)	8/231 (3.46%)
Abdominal distension † 1	19/238 (7.98%)	16/231 (6.93%)
Abdominal pain † 1	49/238 (20.59%)	41/231 (17.75%)
Abdominal pain upper † 1	32/238 (13.45%)	38/231 (16.45%)
Aphthous stomatitis † 1	14/238 (5.88%)	2/231 (0.87%)
Constipation † 1	66/238 (27.73%)	68/231 (29.44%)
Diarrhoea † 1	131/238 (55.04%)	140/231 (60.61%)
Dry mouth † 1	16/238 (6.72%)	22/231 (9.52%)
Dyspepsia † 1	37/238 (15.55%)	59/231 (25.54%)
Dysphagia † 1	16/238 (6.72%)	12/231 (5.19%)
Gastritis † 1	8/238 (3.36%)	13/231 (5.63%)
Gastrooesophageal reflux disease † 1	14/238 (5.88%)	28/231 (12.12%)
Mouth ulceration † 1	18/238 (7.56%)	14/231 (6.06%)
Nausea † 1	114/238 (47.90%)	125/231 (54.11%)
Oral pain † 1	12/238 (5.04%)	12/231 (5.19%)
Stomatitis † 1	134/238 (56.30%)	146/231 (63.20%)
Toothache † 1	15/238 (6.30%)	8/231 (3.46%)
Vomiting † 1	73/238 (30.67%)	76/231 (32.90%)
General disorders
Asthenia † 1	44/238 (18.49%)	63/231 (27.27%)
Chills † 1	29/238 (12.18%)	20/231 (8.66%)
Face oedema † 1	16/238 (6.72%)	19/231 (8.23%)
Fatigue † 1	124/238 (52.10%)	131/231 (56.71%)
Non-cardiac chest pain † 1	33/238 (13.87%)	30/231 (12.99%)
Oedema peripheral † 1	79/238 (33.19%)	58/231 (25.11%)
Pain † 1	14/238 (5.88%)	11/231 (4.76%)
Peripheral swelling † 1	15/238 (6.30%)	10/231 (4.33%)
Pyrexia † 1	66/238 (27.73%)	48/231 (20.78%)
Infections and infestations
Bronchitis † 1	12/238 (5.04%)	6/231 (2.60%)
Influenza † 1	16/238 (6.72%)	8/231 (3.46%)
Nasopharyngitis † 1	26/238 (10.92%)	18/231 (7.79%)
Pneumonia † 1	16/238 (6.72%)	10/231 (4.33%)
Upper respiratory tract infection † 1	25/238 (10.50%)	38/231 (16.45%)
Urinary tract infection † 1	21/238 (8.82%)	23/231 (9.96%)
Investigations
Alanine aminotransferase increased † 1	16/238 (6.72%)	18/231 (7.79%)
Aspartate aminotransferase increased † 1	14/238 (5.88%)	12/231 (5.19%)
Blood alkaline phosphatase increased † 1	4/238 (1.68%)	12/231 (5.19%)
Blood creatinine increased † 1	34/238 (14.29%)	39/231 (16.88%)
Gamma-glutamyltransferase increased † 1	12/238 (5.04%)	16/231 (6.93%)
Haemoglobin decreased † 1	21/238 (8.82%)	26/231 (11.26%)
Neutrophil count decreased † 1	7/238 (2.94%)	15/231 (6.49%)
Platelet count decreased † 1	6/238 (2.52%)	17/231 (7.36%)
Weight decreased † 1	63/238 (26.47%)	49/231 (21.21%)
Metabolism and nutrition disorders
Decreased appetite † 1	93/238 (39.08%)	101/231 (43.72%)
Dehydration † 1	19/238 (7.98%)	23/231 (9.96%)
Hypercholesterolaemia † 1	19/238 (7.98%)	12/231 (5.19%)
Hyperglycaemia † 1	41/238 (17.23%)	30/231 (12.99%)
Hyperkalaemia † 1	12/238 (5.04%)	14/231 (6.06%)
Hypertriglyceridaemia † 1	21/238 (8.82%)	15/231 (6.49%)
Hypoalbuminaemia † 1	13/238 (5.46%)	10/231 (4.33%)
Hypokalaemia † 1	14/238 (5.88%)	13/231 (5.63%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	50/238 (21.01%)	46/231 (19.91%)
Back pain † 1	60/238 (25.21%)	66/231 (28.57%)
Bone pain † 1	8/238 (3.36%)	15/231 (6.49%)
Flank pain † 1	23/238 (9.66%)	17/231 (7.36%)
Muscle spasms † 1	17/238 (7.14%)	11/231 (4.76%)
Muscular weakness † 1	15/238 (6.30%)	13/231 (5.63%)
Musculoskeletal chest pain † 1	15/238 (6.30%)	11/231 (4.76%)
Musculoskeletal pain † 1	29/238 (12.18%)	20/231 (8.66%)
Myalgia † 1	19/238 (7.98%)	22/231 (9.52%)
Neck pain † 1	10/238 (4.20%)	15/231 (6.49%)
Pain in extremity † 1	47/238 (19.75%)	44/231 (19.05%)
Nervous system disorders
Dizziness † 1	40/238 (16.81%)	30/231 (12.99%)
Dysgeusia † 1	73/238 (30.67%)	75/231 (32.47%)
Headache † 1	58/238 (24.37%)	50/231 (21.65%)
Hypoaesthesia † 1	16/238 (6.72%)	10/231 (4.33%)
Neuropathy peripheral † 1	12/238 (5.04%)	14/231 (6.06%)
Paraesthesia † 1	12/238 (5.04%)	12/231 (5.19%)
Psychiatric disorders
Anxiety † 1	21/238 (8.82%)	19/231 (8.23%)
Depression † 1	22/238 (9.24%)	13/231 (5.63%)
Insomnia † 1	41/238 (17.23%)	41/231 (17.75%)
Renal and urinary disorders
Dysuria † 1	19/238 (7.98%)	15/231 (6.49%)
Haematuria † 1	12/238 (5.04%)	17/231 (7.36%)
Proteinuria † 1	6/238 (2.52%)	13/231 (5.63%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	96/238 (40.34%)	76/231 (32.90%)
Dysphonia † 1	13/238 (5.46%)	6/231 (2.60%)
Dyspnoea † 1	68/238 (28.57%)	57/231 (24.68%)
Dyspnoea exertional † 1	18/238 (7.56%)	14/231 (6.06%)
Epistaxis † 1	53/238 (22.27%)	54/231 (23.38%)
Nasal congestion † 1	12/238 (5.04%)	5/231 (2.16%)
Oropharyngeal pain † 1	28/238 (11.76%)	22/231 (9.52%)
Pleural effusion † 1	14/238 (5.88%)	11/231 (4.76%)
Pneumonitis † 1	16/238 (6.72%)	7/231 (3.03%)
Productive cough † 1	24/238 (10.08%)	19/231 (8.23%)
Rhinorrhoea † 1	26/238 (10.92%)	17/231 (7.36%)
Skin and subcutaneous tissue disorders
Alopecia † 1	15/238 (6.30%)	15/231 (6.49%)
Dermatitis † 1	4/238 (1.68%)	12/231 (5.19%)
Dermatitis acneiform † 1	20/238 (8.40%)	9/231 (3.90%)
Dry skin † 1	34/238 (14.29%)	38/231 (16.45%)
Erythema † 1	11/238 (4.62%)	18/231 (7.79%)
Hair colour changes † 1	6/238 (2.52%)	16/231 (6.93%)
Nail disorder † 1	13/238 (5.46%)	10/231 (4.33%)
Night sweats † 1	9/238 (3.78%)	13/231 (5.63%)
Palmar-plantar erythrodysaesthesia syndrome † 1	46/238 (19.33%)	92/231 (39.83%)
Pruritus † 1	43/238 (18.07%)	38/231 (16.45%)
Rash † 1	95/238 (39.92%)	67/231 (29.00%)
Swelling face † 1	12/238 (5.04%)	6/231 (2.60%)
Yellow skin † 1	12/238 (5.04%)	28/231 (12.12%)
Vascular disorders
Hypertension † 1	61/238 (25.63%)	84/231 (36.36%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 18.0

Limitations and Caveats

PRO Tools - completed on Days 1 & 28 of a cycle. Assessments on D1 coincided with end of a 14-day break for patients on sunitinib but not everolimus. So D1 assessments of patients in sunitinib arm may be less impacted by potential toxicity effects.

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.

Results Point of Contact

• Name/Title: Study Director
• Organization: Novartis Pharmaceuticals
• Phone: 862-778-8300
• EMail: trialandresults.registries@novartis.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Voss MH, Chen D, Reising A, Marker M, Shi J, Xu J, Ostrovnaya I, Seshan VE, Redzematovic A, Chen YB, Patel P, Han X, Hsieh JJ, Hakimi AA, Motzer RJ. PTEN Expression, Not Mutation Status in TSC1, TSC2, or mTOR, Correlates with the Outcome on Everolimus in Patients with Renal Cell Carcinoma Treated on the Randomized RECORD-3 Trial. Clin Cancer Res. 2019 Jan 15;25(2):506-514. doi: 10.1158/1078-0432.CCR-18-1833. Epub 2018 Oct 16.

Knox JJ, Barrios CH, Kim TM, Cosgriff T, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page RD, Beck JT, Cheung F, Yadav S, Patel P, Geoffrois L, Niolat J, Berkowitz N, Marker M, Chen D, Motzer RJ. Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC. Ann Oncol. 2017 Jun 1;28(6):1339-1345. doi: 10.1093/annonc/mdx075. Erratum in: Ann Oncol. 2018 Nov 1;29(11):2269.

Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. doi: 10.1200/JCO.2013.54.6911. Epub 2014 Jul 21.

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• ClinicalTrials.gov Identifier: NCT00903175
• Other Study ID Numbers: CRAD001L2202; 2009-011056-21 ( EudraCT Number )
• First Submitted: April 24, 2009
• First Posted: May 18, 2009
• Results First Submitted: May 20, 2016
• Results First Posted: June 28, 2016
• Last Update Posted: November 8, 2016