1. 腎臓がんに対する分子標的薬
～最新の話題～
15/02/27
Department of Medical Oncology, Nippon Medical School Musashikosugi Hospital

2. 本日のお話
• Current therapy for advanced renal cancer
• 1st line treatment
• 2nd line treatment
• How to overcome for resistant disease
• New agents
• Dose Titration
15/02/27
Department of Medical Oncology, Nippon Medical School Musashikosugi Hospital

3. 腎臓がんに対する分子標的薬
• Anti-VEGF
• tyrosine kinase (TK) inhibitors
- Sunitinib
- Sorafenib
- Pazopanib
- Axitinib
• monoclonal antibody
- Bevacizuzumab
• mTOR inhibitor
- Temsirolimus
- Everolimus
15/02/27
Department of Medical Oncology, Nippon Medical School Musashikosugi Hospital

4. Biological pathways and the resulting
therapeutic targets in renal cell carcinoma
15/02/27
Department of Medical Oncology, Nippon Medical School Musashikosugi Hospital
Lancet 2009; 373:1119

5. Algorithm for Clear Cell RCC Therapy
Setting
Phase III
Alternative
1st
line
Good or
intermediate risk
Sunitinib
Pazopanib
Bevacizumab+IFN
HD IL-2
Poor risk
Temsirolimus
Sunitinib
2nd
line
Prior cytokine
Sorafenib
Pazopanib
Sunitinib or
Bevacizumab
Prior VEGFR
inhibitor
Everolimus
Axitinib
Clinical trials
Prior mTOR
inhibitor
Clinical trials
3rd line
Clinical trials
15/02/27
Department of Medical Oncology, Nippon Medical School Musashikosugi Hospital
ASCO 2014

6. Which is the best first-line treatment?
15/02/27
Department of Medical Oncology, Nippon Medical School Musashikosugi Hospital

7. Pazopanib 800 mg QD
continuous dosing
Dose reductions to
600 mg or 400 mg
Sunitinib 50 mg QD
4 wks on/2 wks off
Dose reductions to
37.5 mg or 25 mg
Key Eligibility Criteria
§ Advanced/metastatic RCC
§ Clear-cell histology
§ No previous systemic therapy
§ Measurable disease (RECIST 1.0)
§ KPS ≥ 70
§ Adequate organ function
Stratification factors
§ KPS 70/80 vs 90/100
§ Previous nephrectomy
§ Baseline LDH > 1.5 vs ≤ 1.5 x ULN
COMPARZ: Phase III Noninferiority Trial of
Pazopanib vs Sunitinib in First-line mRCC
Randomized
1:1
Motzer RJ, et al. N Engl J Med 2013;369:722-31.

8. Primary Endpoint: PFS (Independent Review)
N Median PFS, Mos
(95% CI)
Pazopanib 557 8.4 (8.3-10.9)
Sunitinib 553 9.5 (8.3-11.1)
HR: 1.047 (95% CI: 0.898-1.220)
Pts at Risk, n
557
553
361
351
245
249
136
147
105
111
61
69
46
48
19
18
13
10
1
3
Pazopanib
Sunitinib
1.0
0.8
0.6
0.4
0.2
0
ProportionofPtsProgressionFree
0 4 8 12 16 20 24 28 32 36 40
Mos

9. Interim Analysis of OS
N Median OS, Mos
(95% CI)
Pazopanib 557 28.4 (26.2-35.6)
Sunitinib 553 29.3 (25.3-32.5)
HR: 0.908 (95% CI: 0.762-1.082;
P = .275)
Motzer RJ, et al. ESMO 2012. Abstract 2325.
Pazopanib
Sunitinib
1.0
0.8
0.6
0.4
0.2
0
EstimatedSurvivalFunction
00 4 8 12 16 20 24 28 32 36 40
Mos
44
Pts at Risk, n
557
553
521
501
458
431
384
354
327
313
274
269
223
225
142
148
82
69
3
3
28
28

10. Most Common Adverse Events
(Treatment Emergent)
Adverse Event,* % Pazopanib (n = 554) Sunitinib (n = 548)
All Grades Grade 3/4 All Grades Grade 3/4
Any event† > 99 59/15 > 99 57/17
Diarrhea 63 9/0 57 7/< 1
Fatigue 55 10/< 1 63 17/< 1
Hypertension 46 15/< 1 41 15/< 1
Nausea 45 2/0 46 2/0
Decreased appetite 37 1/0 37 3/0
ALT increased 31 10/2 18 2/< 1
Hair color changes 30 0/0 10 < 1/0
Hand–foot syndrome 29 6/0 50 11/< 1
Taste alteration 26 < 1/0 36 0/0
Thrombocytopenia 10 2/< 1 34 12/4
Motzer RJ, et al. N Engl J Med 2013;369:722-31.

11. SWITCH Phase III Study:
Sorafenib → Sunitinib vs Sunitinib → Sorafenib in mRCC
• Primary endpoint: total PFS (from randomization to confirmed progression or
death during second-line therapy, or first line for pts who did not receive
second-line treatment)
• Pts enrolled in Germany, Austria, and The Netherlands
• Efficacy assessed every 12 wks (per RECIST 1.0) and at end of treatment
Michel M, et al. ASCO GU 2014. Abstract 393.
Pts with mRCC,
unsuitable for
cytokines, no prior
systemic therapy,
ECOG PS 0-1, ≥ 1
lesion
Sorafenib
400 mg BID
Sunitinib
50 mg QD
Progression
or
intolerable
toxicity Sorafenib
400 mg BID
Sunitinib
50 mg QD
Stratified by MSKCC prognostic group
(favorable or intermediate)

12. SWITCH Study of Sorafenib → Sunitinib
vs Sunitinib → Sorafenib in mRCC: PFS
Michel M, et al. ASCO GU 2014. Abstract 393.
Median PFS
So → Su (n = 182): 12.5 mos (95% CI: 11.5-15.0)
Su → So (n = 183): 14.9 mos (95% CI: 10.5-17.2)
HR: 1.01; P = .54
100
80
60
40
20
0
0 5 10 15 20 25 30 35 40 45 50
Mos From Randomization
ProbabilityofPFS(%)
Pts at Risk, n
So → Su
→ So
182
183
127
116
83
85
66
62
45
43
30
26
17
19
14
16
7
10
6
9
Intent-to-treat population

13. SWITCH Study of Sorafenib → Sunitinib
vs Sunitinib → Sorafenib in mRCC: OS
Michel M, et al. ASCO GU 2014. Abstract 393.
100
80
60
40
20
0
0 5 10 15 20 25 30 35 40 45 50
Mos From Randomization
ProbabilityofOS(%)
Pts at Risk, n
So → Su
→ So
182
183
148
147
123
119
105
95
79
80
58
59
36
37
25
29
17
18
9
12
Median OS
So→ Su (n = 182): 31.5 mos (95% CI: 23.3-36.9)
Su → So (n = 183): 30.2 mos (95% CI: 23.6-50.1)
HR: 1.00; P = .49
55
6
7

14. Sorafenib → Sunitinib vs Sunitinib →
Sorafenib in mRCC: Conclusions
• Sorafenib and sunitinib both benefited patients with
mRCC in both treatment sequences
• Primary endpoint not met: PFS of sorafenib → sunitinib
not superior to sunitinib → sorafenib (HR: 1.01)
• OS comparable in both arms (HR: 1.00)
• Adverse events for both agents generally less frequent in
second-line vs first-line treatment
Michel M, et al. ASCO GU 2014. Abstract 393.

15. RECORD-3: Phase II Sequential Study
of Sunitinib and Everolimus
• Primary endpoints: first PFS noninferiority of everolimus
• Secondary endpoints: second PFS, ORR, duration of response, patient-
reported outcomes, OS
Everolimus
10 mg/day
Sunitinib
50 mg/day
(schedule 4/2)
Sunitinib
50 mg/day
(schedule 4/2)
Everolimus
10 mg/day
Eligibility
§ Patients with
advanced RCC
(N = 390)
Stratification
§ KPS ≥70%
§ No previous
systemic therapy for
advanced or mRCC
R
A
N
D
O
M
I
Z
A
T
I
O
N
ClinicalTrials.gov. NCT01784978.
Discontinuation
(due to progressive disease/toxicity)

16. RECORD-3: PFS
15/02/27
Department of Medical Oncology, Nippon Medical School Musashikosugi Hospital

17. Which is the best second treatment?
15/02/27
Department of Medical Oncology, Nippon Medical School Musashikosugi Hospital

18. NCCN. Clinical practice guidelines in oncology: kidney cancer. v.1.2013.
Current Management of Advanced RCC
First-line Therapy Second-line Therapy
Favorable risk Sunitinib
or pazopanib
Everolimus
or axitinib
(or TKI, temsirolimus, bevacizumab)
Intermediate risk Sunitinib
or pazopanib
Everolimus
or axitinib
(or TKI, temsirolimus, bevacizumab)
Poor risk
Temsirolimus
Unknown
((sunitinib, clinical trial, supportive care)

19. Drug Control Study Design ORR, % PFS, Mos OS, Mos
VEGFInhibitors
Sorafenib[1,
2] Placebo
Randomized 1:1;
patients previously
treated with
IL-2 or IFN-α
10 vs 2
(P < .001)
5.5 vs 2.8
(HR: 0.44;
P < .01)
17.8 vs 15.2
(HR: 0.88;
P = .146)
(17.8 vs
14.3‡;
HR: 0.78;
P = .029)
Axitinib[3] Sorafenib
Randomized 1:1;
patients previously
treated with
sunitinib,
bevacizumab with
IFN-α, temsirolimus,
or cytokines
19 vs 9
(P = .
0001)
6.7 vs 4.7
(HR: 0.665;
P < .0001)
20.1 vs 19.2
(HR: 0.969;
P = .374)
mTORi
Everolimus[4] Placebo
Randomized 2:1;
patients previously
treated with VEGFR
TKI
2.0 vs 0
4.9 vs 1.9*
(HR: 0.33;
P < .001)*
5.5 vs 1.9†
(HR: 0.32;
P < .001)†
14.8 vs 14.4
(HR: 0.87;
P = .162)
1. Escudier B, et al. N Engl J Med. 2007;356:125-134. 2. Escudier B, et al. J Clin Oncol.
2009;27:3312-3318. 3. Rini BI, et al. Lancet. 2011;378:1931-1939. 4. Motzer R, et al. Cancer.
2010;116:4256-4265.
Pivotal Phase III Data in Second Line

20. AXIS Trial: Axitinib Superior to Sorafenib
in Second-line mRCC Therapy
Rini BI, et al. Lancet. 2011;378:1931-1939.
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 2 4 6 8 10 12 14 16 18 20
ProbabilityofPFS
Axitinib
Sorafenib
Median PFS, Mos (95% CI)
6.7 (6.3-8.6)
4.7 (4.6-5.6)
Stratified HR: 0.665
(95% CI: 0.544-0.812;
P < .0001)
Pts at Risk, n
Axitinib
Sorafenib
256
224
361
362
202
157
145
100
96
51
64
28
38
12
20
6
10
3
1
1
0
0
Months

21. Patients with mRCC and PD
on first-line sunitinib
(N = 512)
Stratification factors:
§ Duration of sunitinib therapy
(≤ or > 6 mos)
§ MSKCC risk group
§ Histology (clear cell or
non–clear cell)
§ Nephrectomy status
R
A
N
D
O
M
I
Z
E
Temsirolimus
25 mg IV weekly*
(n = 259)
1:1
Sorafenib
400 mg oral BID*
(n = 253)
Treat until PD, unacceptable toxicity, or
discontinuation for any other reason
Primary
endpoint:
PFS
(per IRC)
ClinicalTrials.gov. NCT00474786.
*Dose reductions were allowed: temsirolimus (to 20 mg, then 15 mg), sorafenib (to 400 mg/
day, then every other day).
INTORSECT Study Design
J Clin Oncol 2014;32:760-767

22. Hutson T, et al. ESMO 2012. Abstract LBA22.
Temsirolimus
Sorafenib
ProbabilityofPFS
252 72 22 11 6 0
259 96 28 9 5 0
Sorafenib
Temsirolimus
Mos
0 5 10 15 20 25
PFS (IRC Assessment)
Stratified HR: 0.87 (95% CI: 0.71-1.07;
log rank P = .1933)
Median PFS, Mos
(95% CI)
4.28 (4.01-5.43)
3.91 (2.80-4.21)
Pts at Risk, n
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
J Clin Oncol 2014;32:760-767

23. ProbabilityofOS
253 158 74 34 13 0
259 132 54 22 8 0
Sorafenib
Temsirolimus
0 10 20 30 40 50
Temsirolimus
Sorafenib
Pts at Risk, n
Mos
Stratified HR: 1.31 (95% CI: 1.05-1.63;
log rank P = .014)
12.27 (10.13-14.80)
16.64 (13.55-18.72)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Median OS, Mos
(95% CI)
Hutson T, et al. ESMO 2012. Abstract LBA22.
Overall Survival
J Clin Oncol 2014;32:760-767

24. OS by Duration of Previous Sunitinib
(ITT Population)
Previous Sunitinib Use
Temsirolimus
(n = 259)
Sorafenib
(n = 253)
HR (95% CI)
P
Value*
< 90 days, n (%)
Median OS, mos (95% CI)
38 (15)
8.0 (5.3-14.7)
29 (12)
10.3 (5.7-13.8)
1.11
(0.64-1.93)
.708
90-270 days, n (%)
Median OS, mos (95% CI)
99 (38)
11.6 (10.1-16.1)
97 (38)
16.8 (11.1-19.8)
1.32
(0.95-1.84)
.096
> 270 days, n (%)
Median OS, mos (95% CI)
121 (47)
14.4 (10.9-17.6)
126 (50)
17.6 (15.3-22.9)
1.40
(1.02-1.92)
.036
*Unstratified log rank test.
Longer time on first-line TKI predicts for greater benefit from
second-line TKI
Hutson T, et al. ESMO 2012. Abstract LBA22. J Clin Oncol 2014;32:760-767

25. Second-line Post-TKI Results
Agent PFS, Mos OS, Mos Comments
Everolimus
4.9
(5.4 in second line only)
14.8 Second and third line
Temsirolimus 4.3 12.3 Shorter OS than sorafenib
Axitinib 4.8 15.2
Substantially higher in
non-sunitinib subgroups
Sorafenib
3.4 (AXIS)
3.9 (INTORSECT)
16.5 (AXIS)
16.6 (INTORSECT)
Consistent low PFS but
high OS results
Placebo 1.9 14.4
80% crossover to
everolimus
(5.0 mos PFS)
Motzer RJ, et al. Cancer. 2010;116:4256-4265. Rini et al, Lancet Oncology.
2011;378:1931-1936. Hutson T, et al. ESMO 2012. Abstract LBA22.

26. How to Overcome for Resistant
Disease in Advanced RCC？

27. Sorafenib treatment
Baseline Follow-up 1 Follow-up 2
Tumor volume (cm3) 295 341 285
Tumor necrosis (%) 2.09 53.07 51.03
Abou-Alfa G, et al. EORTC-NCI-AACR 2004, Geneva, Switzerland
RECIST vs. Progressive Disease

28. Placebo
0
20
40
60
80
100
120
140
160
180
200
0 20 40 60 80
TumorBurdenComparedtoBaseline(%)
Low Dose
0
20
40
60
80
100
120
140
160
180
200
0 20 40 60 80
Weeks of Treatment
High Dose
0
20
40
60
80
100
120
140
160
180
200
0 20 40 60 80
Change in tumor burden in mRCC patients
Adapted from Elaraj et al. J Immunotx 27(4), 2004
Easy to call PD
Easy to say NOT PD
???? PD

29. Patterns of Tumor Progression vs.
Selection of Subsequent Therapy
ChangeinTumor
Measurements(%)
ChangeinTumor
Measurements(%)
ChangeinTumor
Measurements(%)
Primary Refractory Early Progression Late Progression
Rini BI and Flaherty K, Urol Oncol 2008
New agent Synergic combination Single agent

30. Slide 8

31. Cabozantinib
• Inhibitor of MET and VEGF receptor
• Striking response seen in bone of patients with prostate
cancer
• Agent is being explored in multiple other cancers,
including RCC
• Currently FDA approved for use in patients with
progressive, metastatic medullary thyroid cancer

32. Cabozantnib in RCC

33. Tumor Response<br />Best Response in Patients With ≥1 Post-Baseline Scan (n = 21)*

34. Response Example: RCC with Sarcomatoid Differentiation

35. <br />Example of Partial Bone Scan Resolution in a Symptomatic Patient With Predominantly Osteolytic Bone Metastases

36. Cabozantinib (CaboSun)

37. Cabozantinib

38. Novel Immunotherapy

39. Slide 40

40. Nivolumab in mRCC

41. Nivolumab in mRCC

42. Nivolumab Phase 3 Trial

43. Slide 47

44. Novel Immunotherapy: Combinations

45. Second-line Trials to Watch
• Phase III Nivolumab (anti-PD1) vs everolimus
• Phase III cabozantinib (XL184) vs everolimus
• Phase III dovitinib vs sorafenib (completed, third line)
• Phase III everolimus with or without bevacizumab
(CALGB, closed)

46. Combination with approved drugs
in randomized trials
• 4 important comparative (II/III) studies:
– BeST study phase II (6 arm trial of
Combination Targeted Therapy With
Bevacizumab, Sorafenib and Temsirolimus)
– TORAVA study phase II
– IFN-Bev vs TEMS-Bev phase III
– IFN-Bev vs EVER-Bev phase II

47. Pts with mRCC, no
prior systemic
therapy, > 75%
clear cell, prior
nephrectomy
R
A
N
D
O
M
I
Z
E
Arm A
Bevacizumab 10mg/kg IV q2wks
(n = 89)
Primary endpoint:
PFS
ASCO GU 2013 (suppl 6; abstr 345)
BEST trial (E2804)
Arm B
Bevacizumab 10mg/kg IV q2wks
Temsirolimus 25mg IV wkly
(n = 91)
Arm C
Bevacizumab 5mg/kg IV q2wks
Sorafenib 200mg PO bid d1-15, 8-12
(n = 90)
Arm D
Sorafenib 200mg PO bid d1-28
Temsirolimus 25mg IV wkly
(n = 91)

48. BEST trial (E2804): PFS
15/02/27
Department of Medical Oncology, Nippon Medical School Musashikosugi Hospital

49. BEST trial (E2804): OS
15/02/27
Department of Medical Oncology, Nippon Medical School Musashikosugi Hospital

50. Temsirolimus and Avastin (TORAVA) study
(Phase II)
• Objectives
– primary: PFS
– secondary: safety, ORR (independently assessed), OS
– tertiary: circulating endothelial cells, functional imaging
Avastin + temsirolimus
(n=80)
Sunitinib
(n=40)
Metastatic RCC
patients (n=160)
Avastin + IFN-α2a
(n=40)
2:1:1 PD
PD
PD

51. Review of Other Ongoing and Planned
Trials (Phase II/III)
Temsirolimus +
bevacizumab
IFN-α +
Bevacizumab
Patients
with mRCC
Randomized phase III trial of
temsirolimus + bevacizumab vs
IFN-α + bevacizumab in mRCC
Everolimus +
bevacizumab
IFN-α +
Bevacizumab
Patients
with mRCC
Randomized phase II trial of
everolimus + bevacizumab vs
IFN-α + bevacizumab in mRCC
R
A
N
D
O
M
I
S
E
R
A
N
D
O
M
I
S
E

52. Hypertension as Marker of Efficacy in Pts With
Metastatic RCC After Sunitinib Treatment
Rini BI, et al. J Natl Cancer Inst. 2011;103:763-773.
With HTN (n = 442)
Median OS: 30.9 mos (95% CI: 27.9-33.7)
Without HTN (n = 92)
Median OS: 7.2 mos (95% CI: 5.6-10.7)
Mos
ProbabilityofOS
1.0
0.8
0.6
0.4
0.2
0
0 5 10 15 35 45 5030 4020 25
442 418 377 308 257 224 190 106 29
92 55 38 21 15 7 5 3 1
Pts at Risk, n
P < .0001
With HTN
Without HTN
With HTN Without HTN
Month N S, % 95% CI N S, % 95% CI
10 377 86.3 (82.7-89.2) 38 43.5 (33.0-53.5)
20 257 66.3 (61.5-70.6) 15 21.4 (13.1-31.0)
30 190 51.9 (46.9-56.7) 5 8.2 (3.2-16.1)

53. Axitinib With or Without Dose Titration
for First-line Metastatic Renal Cell
Carcinoma: Unblinded Results From a
Randomized Phase II Study
BI Rini,1 V Grünwald,2 MN Fishman,3 B Melichar,4 T Ueda,5
AH Bair,6 Y Chen,6 P Bycott,6 D Pavlov,7 S Kim,6 E Jonasch8
1Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; 2Hannover Medical School, Hannover,
Germany; 3H. Lee Moffitt Cancer Center, Tampa, FL; 4Palacky University Hospital, Olomouc, Czech
Republic; 5Chiba Cancer Center, Urology, Chiba, Japan; 6Pfizer Oncology, San Diego, CA; 7Pfizer Inc,
New York, NY; 8The University of Texas M. D. Anderson Cancer Center, Houston, TX
Rini BI, et al. ASCO GU 2013. Abstract LBA349.

54. Axitinib With or Without Dose Titration for
First-line Metastatic RCC
Assessments
Tumor assessments performed according to RECIST
version 1.0 at screening, Wks 8, 16, and 24 of therapy, and
every 12 wks thereafter
Safety assessed throughout the study period with adverse
events graded according to CTCAE v3.0
Rini BI, et al. ASCO GU 2013. Abstract LBA349.
* For at least 2 consecutive wks.
†Titrated stepwise to 7 mg BID and then to a maximum of 10 mg BID if criteria for randomization to dose
titration were met.
1:1
Lead-in period
(Cycle 1)
Axitinib 5 mg
BID
(4 wks)
Arm C
Axitinib ≤ 5 mg BID
(no dose titration)
Arm B
Axitinib 5 mg BID
+
Placebo dose
titration†
(blinded therapy)
Arm A
Axitinib 5 mg BID
+
Active (axitinib) dose
titration†
(blinded therapy)
Randomization Criteria*
BP ≤ 150/90 mm Hg and
≤ 2 concurrent anti-HTN
medications and
no grade 3 or 4
axitinib-related toxicities and
no dose reduction
RandomizeAssign
Yes
No

55. Axitinib With or Without Dose Titration:
Study Objectives
• Primary objective
• To compare the ORR in patients randomized to axitinib plus axitinib
titration vs axitinib plus placebo titration
• Secondary objectives
• PFS, OS, safety, duration of response, axitinib plasma
pharmacokinetics, BP measurements, biomarker and
pharmacogenetic analyses
Rini BI, et al. ASCO GU 2013. Abstract LBA349.

56. Clinical Efficacy of Axitinib in First-line
Metastatic RCC
Total*
(N = 213)
Active Titration
(n = 56)
Placebo Titration
(n = 56)
Nonrandomized
(n = 91)
ORR, %
(95% CI)
48
(42-55)
54
(40-67)
34
(22-48)
59
(49-70)
P value† .019
Median PFS, mos
(95% CI)
14.6
(11.5-17.5)
14.5
(9.2-24.5)
15.7
(8.3-19.4)
16.6
(11.2-22.5)
HR (95% CI)‡ 0.85 (0.54-1.35)
P value§ .244
*Includes 10 patients who withdrew during lead-in period.
†P value is from a 1-sided Cochran-Mantel-Haenszel test stratified by ECOG PS from randomization
system.
‡Assuming proportional hazards, HR < 1 indicates a reduction in favor of active titration; HR > 1 indicates
a reduction in favor of placebo titration.
§P value is from a 1-sided log-rank test stratified by ECOG PS from randomization system.
Rini BI, et al. ASCO GU 2013. Abstract LBA349.

57. Axitinib With or Without Dose Titration:
Adverse Events
Treatment-Emergent,
All-Causality AEs in
> 30% of Treated
Patients, %
Total*
(N = 213)
Active
Titration
(n = 56)
Placebo
Titration
(n = 56)
Nonrandomized
(n = 91)
All
Grades
Grade
≥ 3
All
Grades
Grade
≥ 3
All
Grades
Grade
≥ 3
All
Grades
Grade
≥ 3
Hypertension 65 30 61 18 43 9 82 50
Diarrhea 60 8 61 13 63 4 63 9
Fatigue 49 7 45 5 46 4 54 8
Dysphonia 40 1 32 2 36 0 48 0
Decreased appetite 36 3 38 5 30 0 39 4
Hypothyroidism 35 0 32 0 23 0 45 0
Nausea 34 2 38 5 34 0 34 1
Hand–foot syndrome 32 4 32 4 18 2 44 6
Proteinuria 30 1 20 4 20 0 43 0
*Includes 10 patients who withdrew during lead-in period.
Rini BI, et al. ASCO GU 2013. Abstract LBA349.

58. Axitinib With or Without Dose Titration:
Conclusions
• Axitinib dose titration significantly improved ORR
compared with placebo
• Median PFS was not altered in randomized dose
escalation group compared with control
• The nonrandomized group did best of all highest response
rate and PFS
• High proportion of Asian patients in this group, suggestive of host
genomic features that predispose to benefit from VEGF pathway
targeting agents
Rini BI, et al. ASCO GU 2013. Abstract LBA349.