supplementary online content€¦ · clinical trial. jama oncol. published online december 1, 2016....

© 2016 American Medical Association. All rights reserved.

Supplementary Online Content

Cirkel GA, Hamberg P, Sleijfer S, et al. Alternating treatment with pazopanib and everolimus vs continuous pazopanib to delay disease progression in patients with metastatic clear cell renal cell cancer: the ROPETAR randomized clinical trial. JAMA Oncol. Published online December 1, 2016. doi:10.1001/jamaoncol.2016.5202.

eFigure 1. Study Design. eFigure 2. Kaplan-Meier analysis of PFS2II in the intention-to-treat population. eFigure 3. Kaplan-Meier analysis of Overall Survival in the intention-to-treat population. eFigure 4. FKSI-DRS symptom scale. eFigure 5. QLQ-C30 Physical Functioning. eFigure 6. QLQ-C30 Global Health Status / Quality of Life scale. eFigure 7. Time to first 20% deterioration in Physical Functioning. eTable 1. Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic factors at baseline. eTable 2. Toxicities during first-line treatment assessed as at least possible related to study treatment. eTable 3. Drug administration and modifications.

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Supplementary Online Content

eFigure 1: Study Design. eFigure 2: Kaplan-Meier analysis of PFS2II in the intention-to-treat population. eFigure 3: Kaplan-Meier analysis of Overall Survival in the intention-to-treat

population. eFigure 4: FKSI-DRS symptom scale. eFigure 5: QLQ-C30 Physical Functioning. eFigure 6: QLQ-C30 Global Health Status / Quality of Life scale. eFigure 7: Time to first 20% deterioration in Physical Functioning. eTable 1: Memorial Sloan Kettering Cancer Center (MSKCC) and

International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic factors at baseline

eTable 2: Toxicities during first-line treatment assessed as at least possible related to study treatment eTable 3: Drug administration and modifications


screen

randomize

8 weeks everolimus 10 mg/day

8 weeks pazopanib 800 mg/day

1st line pazopanib 800 mg/day until progression

Pazopanib monotherapy 800mg/day

Everolimus monotherapy 10 mg/day

2nd line everolimus 10 mg/day until progression

Secondary

study

endpoints

PFS2

Time to se-

cond pro-

gression

Toxicity

QoL

Overall Sur-

vival

After PD one rotation to continuous

monotherapy

Primary study endpoint

PFS1

eFigure 1. Study Design.

PD indicates progressive disease according RECIST 1.1; PFS1, progression-free survival 1, defined as time between randomization and first PD or death; PFS2, progression-free survival 2, defined as time between randomization and second PD or death; QoL: Quality of Life.

©American Medical Association. All rights reserved.



eFigure 2: Kaplan-Meier analysis of PFS2II in the intention-to-treat population.



eFigure 3: Kaplan-Meier analysis of Overall Survival in the intention-to-treat population.



eFigure 4-6: At each cycle a boxplot is constructed describing the distribution of scores of patients in each arm as well as the mean (line) of these scores. The bold black line in the middle of the boxplot indicates the median. eFigure 4: FKSI-DRS symptom scale.

Development of the FKSI-DRS symptom scale over the treatment cycles during first line treatment. Scores range from 0 to 36 and are the sum of the scores on the 9 individual symptom outcome. Higher scores correspond to less symptoms.



eFigure 5: QLQ-C30 Physical Functioning.

Development of the QLQ-C30 PF scale during first line treatment. Scores range from 0 to 100 and are based on the scores on 5 individual questions. Higher score corresponds to better quality of life.



eFigure 6: QLQ-C30 Global Health Status / Quality of Life scale.

Development of the QLQ-C30 QoL scale during first line treatment. Scores range from 0 to 100 and are based on the scores on 2 questions. Higher score corresponds to better quality of life.



eFigure 7: Time to first 20% deterioration in Physical Functioning compared to baseline.



eTable 1: Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic factors at baseline Rotating arm Control arm Total *p-value

N % N % N %

Karnofsky performance status < 80%

No 52 100% 42 86% 94 93% 0.005

Yes 0 0% 7 14% 7 7%

Corrected serum calcium > 10mg/dL

No 44 85% 41 84% 85 84% 0.89

Yes 8 15% 7 14% 15 15%

NA 0 0% 1 2% 1 1%

Haemoglobin level below the lower limit of normal

No 29 56% 28 57% 57 56% 1

Yes 23 44% 21 43% 44 44%

Lactate dehydrogenase > 1.5 times upper limit of normal

No 51 98% 45 92% 96 95% 0.2

Yes 1 2% 4 8% 5 5%

Time from initial diagnosis < 1 year

No 20 38% 21 43% 41 41% 0.69

Yes 32 62% 28 57% 60 59%

Neutrophilia above the upper limit of normal

No 41 84% 38 78% 79 78% 0.41

Yes 6 12% 10 20% 16 16%

NA 5 10% 1 2% 6 6%

Platelets above the upper limit of normal

No 43 83% 37 76% 80 79% 0.46

Yes 9 17% 12 24% 21 21%

*Fisher’s exact test



eTable 2: toxicities during first-line treatment assessed as at least possible related to study treatment Grade∞ All grades Grade ≥ 3 All grades Grade ≥ 3

Everolimus related

Pazopanib related

Everolimus related

Pazopanib related

Toxicity, n(%)

Rot (N=51)

Con (N=49)

Total (N=100)

Rot (N=51)

Con (N=49)

Total (N=100)

Rot (N=51)

Rot (N=51)

Rot (N=51)

Rot (N=51)

Fatique 27(53)

24(49)

51(51)

2(4) 2(4) 4(4) 11(22) 25(49) 1(2) 1(2)

Diarrhea 17(33)

25(51)

42(42)

4(8) 3(6) 7(7) 6(12) 14(27) 2(4) 3(6)

Nausea 22(43)

15(31)

37(37)

1(2) 2(4) 3(3) 6(12) 18(35) 1(2) 0(0)

Anorexia 20(39)

11(22)

31(31)

1(2) 1(2) 2(2) 8(16) 17(33) 0(0) 1(2)

Hypertension

17(33)

14(29)

31(31)

11(22)

10(20)

21(21)

1(2) 17(33) 1(2) 11(22)

ALT 15(29)

16(33)

31(31)

7(14)

11(22)

18(18)

6(12) 14(27) 0(0) 7(14)

AST 13(25)

16(33)

29(29)

7(14)

9(18)

16(16)

5(10) 12(24) 0(0) 7(14)

GGT 12(24)

10(20)

22(22)

7(14)

5(10)

12(12)

6(12) 10(20) 4(8) 6(12)

Headache

14(27)

10(20)

24(24)

0(0) 0(0) 0(0) 6(12) 9(18) 0(0) 0(0)

Mucositis

18(35)

4(8) 22(22)*

3(6) 0(0) 3(3) 15(29) 5(10) 2(4) 1(2)

Dysgeusia

10(20)

11(22)

21(21)

1(2) 0(0) 1(1) 2(4) 10(20) 0(0) 1(2)

Rot: rotating arm; con: control arm; ALT= Alanine aminotransferase; AST= Asparate aminotransferase; GGT= Gammaglutamyltransferase *p<0,01; ∞ According Common Terminology Criteria for Adverse Events (CTCAE) v4.03.


13

eTable 3: Drug administration and modifications Arm Rotating Control Both

Drug Pazopanib

Everolimus

Pazopanib

Everolimus

Both

Total number of cycles before 1st PD

Sample size before 1st PD

52 52 49 NA 101

Median 2 1 4 NA 3

Range 0.0 - 10.0 0.0 - 9.0 1.0 - 18.0 NA 0.0 - 19.0

Total number of cycles after 1st PD

Samples size after 1st PD

16 4 2 18 40

Median 3.0 1.5 7.0 2.0 2.0

Range 1 - 11 1.0 - 5.0 7.0 - 7.0 1.0 - 8.0 1.0 - 11.0

Dose reductions before 1st PD (Safety population), n(%)

Samples size before 1st PD

51 51 49 NA 100

Yes, n(%) 18(35) 7(14) 19(39) NA 44(44)

Dose reductions after 1st PD, n(%)

Yes, n(%) 4(25) 0(0) 1(50) 4(22) 9(23)

Dose interruption in one or more cycles before 1st PD (Safety population), n(%)

Yes, n(%) 30 (59%) 18(35) 33 (67%) NA 81(81)


supplementary online content€¦ · clinical trial. jama oncol. published online december 1, 2016....

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