Jpn J Clin Oncol 2013;43(6)616 – 628

doi:10.1093/jjco/hyt054
Advance Access Publication 28 April 2013

Efficacy and Safety of Axitinib Versus Sorafenib in Metastatic

Renal Cell Carcinoma: Subgroup Analysis of Japanese Patients

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from the Global Randomized Phase 3 AXIS Trial
Takeshi Ueda1,*, Hirotsugu Uemura2, Yoshihiko Tomita3, Taiji Tsukamoto4, Hiroomi Kanayama5,
Nobuo Shinohara6, Jamal Tarazi7, Connie Chen8, Sinil Kim7, Seiichiro Ozono9, Seiji Naito10 and Hideyuki Akaza11
1
Prostate Center and Division of Urology, Chiba Cancer Center, Chiba, 2Department of Urology, Kinki University
School of Medicine, Osaka, 3Department of Urology, Yamagata University Faculty of Medicine, Yamagata,
4
Department of Urology, Sapporo Medical University School of Medicine, Hokkaido, 5Department of Urology, The
University of Tokushima Graduate School, Tokushima, 6Department of Urology, Hokkaido University Graduate
School of Medicine, Hokkaido, Japan, 7Clinical Oncology, Pfizer, Inc., San Diego, CA, 8Global Outcomes Research,
Pfizer, Inc., New York, NY, USA, 9Department of Urology, Hamamatsu University School of Medicine, Shizuoka,
10
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka and 11Research
Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan

*For reprints and all correspondence: Takeshi Ueda, Prostate Center and Division of Urology, Chiba Cancer Center,
666-2 Nitona-cho, Chuo-ku, Chiba-shi, Chiba 260-8717, Japan. E-mail: [email protected]
Received November 27, 2012; accepted March 24, 2013

Objective: Axitinib is a potent and selective second-generation inhibitor of vascular endothe-

lial growth factor receptors 1, 2 and 3. The efficacy and safety of axitinib in Japanese patients
with metastatic renal cell carcinoma were evaluated.
Methods: A subgroup analysis was conducted in Japanese patients enrolled in the rando-
mized Phase III trial of axitinib versus sorafenib after failure of one prior systemic therapy for
metastatic renal cell carcinoma.
Results: Twenty-five (of 361) and 29 (of 362) patients randomized to the axitinib and soraf-
enib arms, respectively, were Japanese and included in this analysis. Median progression-
free survival in Japanese patients was 12.1 months (95% confidence interval 8.6 to not
estimable) for axitinib and 4.9 months (95% confidence interval 2.8 – 6.6) for sorafenib
(hazard ratio 0.390; 95% confidence interval 0.130 – 1.173; stratified one-sided P ¼ 0.0401).
The objective response rate was 52.0% for axitinib and 3.4% for sorafenib (P ¼ 0.0001). The
common all-causality adverse events (all grades) in Japanese patients were dysphonia
(68%), hypertension (64%), hand – foot syndrome (64%) and diarrhea (56%) for axitinib, and
hand – foot syndrome (86%), hypertension (62%) and diarrhea (52%) for sorafenib. The
safety profiles of axitinib and sorafenib in Japanese patients were generally similar to those
observed in the overall population, with the exceptions of higher incidences of hypertension,
dysphonia, hand– foot syndrome, hypothyroidism and stomatitis.
Conclusions: Axitinib is efficacious and well tolerated in Japanese patients with previously
treated metastatic renal cell carcinoma, consistent with the results in the overall population,
providing a new targeted therapy for these Japanese patients.

Key words: axitinib – renal cell carcinoma – vascular endothelial growth factor receptors –
clinical trial – phase III

# The Author 2013. Published by Oxford University Press.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/
licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is
properly cited. For commercial re-use, please contact [email protected]
 Jpn J Clin Oncol 2013;43(6) 617

INTRODUCTION minimizing potential toxicities. The aim of this subgroup

analysis was to evaluate the efficacy and safety of axitinib
Kidney cancer accounts for 2.2% of all malignancies world-
compared with sorafenib in Japanese patients with mRCC
wide (1), with steady increases in global incidence over the
enrolled in AXIS trial.
past several decades (2 – 5). Renal cell carcinoma (RCC) is
the most common form of kidney cancer (5). When RCC is
diagnosed early, surgical resection of localized tumors is the
PATIENTS AND METHODS

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primary and often curative treatment (6 – 8). However, due to
lack of symptoms with early stage RCC, !30% of patients STUDY DESIGN
are not diagnosed until their disease is advanced or metastat-
ic (2,9). Until recently, immunotherapy with interleukin-2 or AXIS was a two-arm, multicenter, open-label, randomized,
interferon (IFN)-a was the established systemic therapy for controlled Phase III clinical trial to evaluate efficacy and
patients with metastatic RCC (mRCC), generally with safety of axitinib versus sorafenib (as an active comparator) in
modest clinical benefits (10). Advanced understanding of the patients with mRCC whose disease progressed following one
molecular biology of RCC led to the development and prior systemic cytokine-, sunitinib-, bevacizumab/IFN-a- or
approval of several drugs that inhibit vascular endothelial temsirolimus-based regimen (15). The study was conducted at
growth factor receptor (VEGFR) signaling pathways (i.e. sor- 175 centers in 22 countries, including 18 centers in Japan.
afenib, sunitinib, bevacizumab/IFN-a, pazopanib and axiti- Patients were stratified by Eastern Cooperative Oncology
nib) (9,11 – 17) or mammalian target of rapamycin pathways Group (ECOG) performance status (0 vs. 1) and by prior
(i.e. temsirolimus and everolimus) (18,19). therapy and randomized in a 1:1 ratio to receive either axitinib
Axitinib is a potent and selective second-generation in- or sorafenib. The study protocol, all amendments and
hibitor of VEGFR-1, 2 and 3 (20 – 24). Axitinib has shown informed consent forms were approved by the Institutional
anti-tumor activity as a single agent with acceptable safety Review Boards or Independent Ethics Committees at each
profile against several advanced solid tumors, including pre- center. The study was conducted in compliance with Good
viously treated mRCC, in Phase II clinical trials conducted Clinical Practice Guidelines, the Declaration of Helsinki and
in the United States and Europe (25 – 29). Axitinib has local regulatory requirements.
also been evaluated in a Phase II clinical trial for
cytokine-refractory mRCC in Japan, with promising out- PATIENTS
comes (9). A pivotal randomized Phase III trial (AXIS trial;
ClinicalTrials.gov identifier: NCT00678392) was conducted Inclusion and exclusion criteria for patients enrolled in
globally to compare effectiveness of axitinib against another AXIS have previously been described in detail (15). In brief,
targeted agent, sorafenib, in patients with previously treated key eligibility criteria were aged 18 years (20 years in Japan)
mRCC (15). Results from AXIS demonstrated a significant or older; histologically or cytologically confirmed mRCC of
improvement in progression-free survival (PFS) for axitinib clear-cell subtype; Response Evaluation Criteria in Solid
over sorafenib; median PFS assessed by Independent Review Tumors (RECIST, v1.0)-defined progressive disease after
Committee (IRC) was 6.7 vs. 4.7 months, respectively one prior systemic first-line regimen; ECOG performance
(hazard ratio [HR] 0.665; 95% confidence interval [95% CI] status 0 or 1; adequate bone marrow, hepatic and renal
0.544 – 0.812; P , 0.0001, stratified one-sided log-rank test), function; baseline proteinuria ,2þ by urine dipstick or
leading to its recent approval in several countries including ,2 g/24 h urine collection; and no uncontrolled hyperten-
the United States and Japan. sion, i.e. blood pressure (BP) "140/90 mmHg at baseline
Epidemiologic studies have shown that incidence and ( prior anti-hypertensive medications were permitted).
mortality rates for RCC vary substantially among different Written informed consent was obtained from each patient
ethnic and geographical populations in the world (1,30,31). prior to enrollment.
The reasons for such differences are not fully understood,
but may include differences in the use of diagnostic surveil-
STUDY TREATMENT
lance, inherited susceptibility due to genetic variations in
key genes involved in the pathophysiology of the disease Axitinib was administered orally at a starting dose of 5 mg
and environmental risk factors such as cigarette smoking, twice daily (bid) taken with food. Axitinib dose could be
obesity and hypertension. Advanced RCC is less common in increased to 7 mg bid, and then to a maximum of 10 mg bid,
Japan than in countries in Europe and North America, but is in patients who tolerated the starting dose with no
more prevalent than in other Asian countries; the incidence treatment-related adverse events (AEs) above grade 2 accord-
of RCC is also increasing in Japan (30,32). With disparities ing to the National Cancer Institute Common Terminology
in efficacy and toxicities reported for some anti-cancer Criteria for Adverse Events version 3.0 (NCI-CTCAE, v3.0)
agents in different ethnic populations (33,34), it is critical to for a consecutive 2-week period, at the discretion of a treat-
evaluate new anti-cancer agents in different ethnic popula- ing physician, unless the patient had BP .150/90 mmHg or
tions in order to optimize their clinical benefits while was receiving anti-hypertensive medications (15,35).
618 AXIS: Japanese subgroup analysis of axitinib

Axitinib dose reduction (3 mg bid, and then to 2 mg bid) or translators according to established Functional Assessment
temporary interruption was permitted in patients to manage of Chronic Illness Therapy (FACIT) Multilingual
toxicities. Translations Methodology (39 – 41). The minimally import-
Sorafenib was administered at a dose of 400 mg bid taken ant difference (MID) was predefined as 5 points for the
orally without food (at least 1 h before or 2 h after eating). FKSI-15 and 3 points for the FKSI-DRS subscale, as previ-
Sorafenib dose could be reduced to 400 mg once daily, and ously established (37,38). Lastly, a pre-specified time to de-
then to 400 mg once every other day, if necessary (15,36). terioration (TTD) composite endpoint was examined, which

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Patients were treated with assigned drugs in 28-day cycles, was comprised of the combined endpoints of death, disease
until disease progression, occurrence of intolerable AE or progression or clinically meaningful worsening of symptoms
withdrawal of consent. Patients and investigators were not (worsening in symptom scores greater than the MID), which-
masked to study treatment and crossover between study ever occurred first.
drugs was not allowed.
STATISTICAL ANALYSES
ASSESSMENTS
The sample size was calculated in the overall population
The primary efficacy evaluation was PFS assessed by a based on the assumption that axitinib treatment would result
blinded IRC and secondary evaluations included overall sur- in a 40% improvement in median PFS to 7 months from 5
vival (OS), objective response rate (ORR), safety, tolerabil- months with sorafenib in patients with mRCC whose disease
ity, and patient-reported outcomes (PROs) consisting of progressed after one prior systemic therapy, as described pre-
kidney-specific symptoms and health status. Tumors were viously (15). The full analysis set included all randomized
radiologically assessed at baseline, 6 and 12 weeks and patients and was used for efficacy and PROs analyses.
every 8 weeks thereafter and responses were evaluated Median PFS was estimated using Kaplan – Meier methods,
according to RECIST v1.0. and a one-sided (a ¼ 0.025) log-rank test stratified by both
Safety was assessed throughout the study by monitoring all ECOG performance status and prior therapy was used to
AEs and conducting physical examinations, clinical labora- compare the two treatment arms. Similar survival analysis
tory tests and BP measurements. Severity of AEs was graded methods (without stratification) were used to compare TTD
according to NCI-CTCAE v3.0. Thyroid function tests (free between treatments. ORRs between the two treatment groups
tri-iodothyronine [T 3], free thyroxine [T 4] and thyroid- were compared using a one-sided Cochran – Mantel –
stimulating hormone [TSH]) were performed at baseline. Haenszel test stratified by ECOG performance status and
Subsequently, TSH measurements were repeated at 2, 4, 8 prior therapy. All patients who received at least one dose of
and 12 weeks and every 8 weeks thereafter, whereas free T3 study medication were included in safety and treatment ad-
and free T4 measurements were performed when clinically ministration assessments. East version 5 was used to calcu-
indicated. Protein, glucose and blood urinalysis were done at late the sample size; all other statistical analyses were done
baseline and every 4 weeks. If patients had #2þ proteinuria with SAS version 9.2.
by semi-quantitative method (e.g. urine dipstick), protein was
quantified by 24-h urine protein determination. BP readings
were taken with patient in a seated position after 5-min rest at RESULTS
each clinic visit. Additionally, patients were provided with a
PATIENT BASELINE CHARACTERISTICS AND DISPOSITION
BP monitor and instructed to measure BP at home prior to
taking each dose and contact their physicians if systolic BP Baseline characteristics of patients randomly assigned to axi-
was .150 mmHg or diastolic BP .100 mmHg. tinib (n ¼ 361) and sorafenib (n ¼ 362) were well balanced
PROs were assessed using the validated Functional in the overall population and included 25 and 29 Japanese
Assessment of Cancer Therapy Kidney Symptom Index patients, respectively (Table 1). Baseline characteristics of
(FKSI) and the FKSI – Disease-Related Symptoms (DRS) Japanese patients were generally comparable to those of the
subscale, a validated questionnaire which measures quality overall population, except that a higher percentage of
of life (QOL) and symptoms related to advanced kidney Japanese patients had ECOG performance status 0, favorable
cancer disease (37,38), at baseline and every 4 weeks. They Memorial Sloan-Kettering Cancer Center (MSKCC) risk and
were measured as the summary scores of the 15-item (i.e. prior cytokine-based therapy. There were no Japanese
lack of energy, bone pain, short of breath, coughing, hema- patients with prior temsirolimus or bevacizumab/IFN-a
turia, bothered by fever, pain, fatigue, losing weight, appe- therapy enrolled in this study since temsirolimus was
tite, side effects, enjoying life, worsened condition, ability to approved in Japan after the enrollment period for this study
work and sleep) FKSI-15 and 9-item (i.e. the first nine items and bevacizumab/IFN-a therapy is not available in Japan.
listed under FKSI-15) FKSI-DRS questionnaires, respective- At the time of data cutoff date of 31 August 2010, five
ly. A higher score is better (i.e. less symptoms). Japanese (20%) of 25 Japanese patients in the axitinib arm discontin-
patients completed a validated Japanese translation of the ued study treatment either due to an AE (n ¼ 1 transient is-
FKSI questionnaire, conducted by experienced and trained chemic attack), disease progression (n ¼ 3) or death
 Jpn J Clin Oncol 2013;43(6) 619

Table 1. Baseline demographics and clinical characteristics

Characteristics Overall population Japanese patients P valuea

Axitinib (n ¼ 361) Sorafenib (n ¼ 362) Total (n ¼ 723) Axitinib (n ¼ 25) Sorafenib (n ¼ 29) Total (n ¼ 54)

Age, median (range) (years) 61 (20– 82) 61 (22–80) 61 (20– 82) 62 (32– 82) 63 (28– 77) 62 (28– 82) 0.2059b

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Gender, n (%) 0.5284
Male 265 (73) 258 (71) 523 (72) 16 (64) 21 (72) 37 (69)
Female 96 (27) 104 (29) 200 (28) 9 (36) 8 (28) 17 (31)
ECOG PS, n (%) ,0.001
0 195 (54) 200 (55) 395 (55) 23 (92) 24 (83) 47 (87)
1 162 (45) 160 (44) 322 (45) 2 (8) 5 (17) 7 (13)
.1 1 (,1) 0 1 (,1) 0 0 0
Site of metastases, n (%)
Lung 274 (76) 292 (81) 566 (78) 22 (88) 26 (90) 48 (89) 0.0580
Lymph node 209 (58) 202 (56) 411 (57) 13 (52) 10 (34) 23 (43) 0.0321
Bone 119 (33) 107 (30) 226 (31) 4 (16) 7 (24) 11 (20) 0.0923
Liver 102 (28) 103 (28) 205 (28) 1 (4) 6 (21) 7 (13) 0.0075
MSKCC risk groupc, n (%) ,0.001
Favorable 100 (28) 101 (28) 201 (28) 14 (56) 13 (45) 27 (50)
Intermediate 134 (37) 130 (36) 264 (37) 7 (28) 12 (41) 19 (35)
Poor 118 (33) 120 (33) 238 (33) 1 (4) 2 (7) 3 (6)
NA 9 (2) 11 (3) 20 (3) 3 (12) 2 (7) 5 (9)
Prior treatment, n (%)
Nephrectomy 327 (91) 331 (91) 658 (91) 24 (96) 28 (97) 52 (96) 0.2160
Radiotherapy 75 (21) 73 (20) 148 (20) 1 (4) 5 (17) 6 (11) 0.0811
Systemic therapy ,0.001
Sunitinib 194 (54) 195 (54) 389 (54) 5 (20) 9 (31) 14 (26)
Cytokines 126 (35) 125 (35) 251 (35) 20 (80) 20 (69) 40 (74)
Bevacizumab 29 (8) 30 (8) 59 (8) 0 0 0
Temsirolimus 12 (3) 12 (3) 24 (3) 0 0 0

ECOG PS, Eastern Cooperative Oncology Group performance status; MSKCC, Memorial Sloan-Kettering Cancer Center; NA, not available.
a
Fisher’s exact test comparing baseline demographics and clinical characteristics (except age) between all non-Japanese versus all Japanese patients.
b
t-test comparing baseline mean age between all non-Japanese and all Japanese patients.
c
Derived using three risk factors: serum hemoglobin ("130 vs. .130 g/l for men and "115 vs. .115 g/l for women), corrected serum calcium (,2.5 vs. #
2.5 mmol/l) and ECOG PS (0 vs. 1). MSKCC risk groups were defined as: favorable ¼ 0 risk factor; intermediate ¼ 1 risk factor or poor ¼ 2 or 3 risk factors.

associated with disease progression (n ¼ 1), compared with compared with Japanese patients receiving sorafenib, as in
20 (69%) of 29 Japanese patients in the sorafenib arm who the overall population (Table 2). The majority of Japanese
discontinued study treatment either due to an AE (n ¼ 5; 1 patients had one or more dose interruptions of treatment
each for angina pectoris, periodontitis and hepatic function drug (96% in the axitinib arm and 83% in the sorafenib
abnormality and 2 for erythema multiforme) or disease pro- arm), compared with overall population (77 and 80%, re-
gression (n ¼ 15). In the overall population, 221 (61%) of spectively). At least one dose reduction was reported in 32%
361 patients in the axitinib arm and 256 (71%) of 362 of Japanese patients treated with axitinib, compared with
patients in the sorafenib arm discontinued study treatment. 66% of Japanese patients treated with sorafenib. A similar
percentage of patients had at least one dose reduction in the
overall population (31% in the axitinib arm and 52% in the
TREATMENT
sorafenib arm). Three (12%) Japanese patients had their axi-
Japanese patients receiving axitinib generally remained on tinib dose increased above 5 mg bid, whereas 37% of
treatment longer and received study drug on more days patients in the overall population received axitinib doses
620 AXIS: Japanese subgroup analysis of axitinib

Table 2. Exposure to study drugs

Overall population Japanese patients

Axitinib (n ¼ 359) Sorafenib (n ¼ 355) Axitinib (n ¼ 25) Sorafenib (n ¼ 29)

Days on treatmenta

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Median (range) 196 (1 –670) 152 (1– 610) 161 (23–405) 130 (11–365)
b
Days on drug
Median (range) 186 (1 –670) 141 (1– 609) 157 (23–372) 84 (9 –338)
Average daily dose
Mean (standard deviation) (mg) 10.6 (3.3) 677.9 (148.8) 9.3 (2.2) 627.6 (154.1)
Relative dose intensity
Median (range) (%) 99 (32– 194) 92 (27–100) 89 (35–151) 69 (38–100)

a
Time period starting from date of the first dose to date of the last dose or data cutoff.
b
Total number of days in which axitinib or sorafenib was actually administered.

above 5 mg bid. Mean daily dose as well as median relative PATIENT-REPORTED OUTCOMES
dose intensity of axitinib or sorafenib were slightly lower in
Nearly 100% of the eligible Japanese patients completed
Japanese patients compared with the corresponding values in
FKSI questionnaires, which was higher than the 90% for the
the overall population (Table 2).
overall population. In Japanese patients, the pre-defined TTD
composite endpoint utilizing the FKSI-15 or FKSI-DRS in
addition to death and progression, demonstrated a 47% (P ¼
EFFICACY 0.0258) and 19% (P ¼ 0.2613) respective reduction in risk
In the overall population, IRC-assessed median PFS was for axitinib compared with sorafenib patients (Fig. 4) favor-
significantly longer with axitinib than sorafenib treatments ing axitinib; the corresponding risk reductions in the overall
(Fig. 1A, Table 3) (15). In the Japanese subgroup analysis, population were 17 and 16%, respectively (15).
IRC-assessed median PFS with axitinib was 12.1 months
(95% CI 8.6 to not estimable) compared with 4.9 months
SAFETY
(95% CI 2.8 – 6.6) with sorafenib (HR 0.390; 95% CI
0.130 – 1.173; P ¼ 0.0401, stratified one-sided log-rank Hypertension, hand – foot syndrome and diarrhea were the
test) (Fig. 1B, Table 3). Among patients who had received most common (#50% of patients) all-causality AEs (all
previous cytokine treatment, differences between median grades) in both axitinib and sorafenib arms in the Japanese
PFS for axitinib and sorafenib were statistically significant subgroup (Table 5). Dysphonia, fatigue, hypothyroidism,
in favor of axitinib in the Japanese subgroup, as in the decreased appetite, dysgeusia and weight decrease were
overall population (Table 3). In patients with prior suniti- more frequently reported by Japanese patients receiving axi-
nib treatment, axitinib demonstrated significantly longer tinib whereas hand – foot syndrome, rash and alopecia were
median PFS than sorafenib in the overall population more common with sorafenib (Table 5). Fewer laboratory
whereas the number of Japanese patients with prior suniti- abnormalities (all grades) were associated with axitinib than
nib therapy was too small to compare PFS between the sorafenib in Japanese patients (Table 5). The common all-
two arms (Table 3). causality grade #3 AEs in Japanese patients were hyperten-
A total of 15 (60%) of 25 Japanese patients in the axitinib sion, hand – foot syndrome, decreased appetite and fatigue
arm and 2 (7%) of 29 in the sorafenib arm had a #30% with axitinib and hypertension, hand – foot syndrome and
decrease in target lesions (Fig. 2). IRC-assessed ORR was lipase elevation with sorafenib (Table 5).
significantly higher with axitinib than that with sorafenib in The safety profiles of axitinib and sorafenib in Japanese
Japanese patients (52.0 vs. 3.4%, respectively, P ¼ 0.0001) patients were generally similar to those observed in the
(Fig. 3, Table 4). In the overall population, IRC-assessed overall population, with few exceptions. Hypertension, dys-
ORR was 19.4 vs. 9.4%, respectively (P ¼ 0.0001) (Fig. 3, phonia, hand – foot syndrome, hypothyroidism and stomatitis
Table 4) (15,42). When stratified by prior therapy, ORR for occurred more frequently among Japanese patients treated
axitinib was statistically significantly higher in Japanese with either axitinib or sorafenib than in the overall popula-
patients previously treated with cytokines, but the number of tion. On the other hand, incidences of nausea and asthenia
Japanese patients with prior sunitinib therapy was too small were lower among Japanese patients compared with the
to compare ORR (Table 4). overall population (Table 5).
 Jpn J Clin Oncol 2013;43(6) 621

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Figure 1. Kaplan – Meier plot of progression-free survival assessed by Independent Review Committee (IRC) in (A) the overall population and (B) Japanese
patients [(A) was reprinted from Rini et al. (15), Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised
phase 3 trial, p 1931 – 9, Copyright 2011, with permission from Elsevier. All rights reserved]. P values based on one-sided log-rank test stratified by ECOG
performance status and prior therapy. CI, confidence interval; HR, hazard ratio; NE, not estimable; PFS, progression-free survival.

HYPERTENSION dose of existing anti-hypertensive medication was adminis-

tered to 55% of patients after treatment with axitinib.
All-causality hypertension (all grades) was more common
with axitinib than sorafenib in the overall population (40 vs.
29%, respectively), whereas it was similarly higher in both
HYPOTHYROIDISM
treatment arms in Japanese patients (64 vs. 62%, respective-
ly). Incidence of grade #3 hypertension was also more At baseline, a similar percentage of Japanese patients in the
common with axitinib than sorafenib in the overall popula- axitinib and sorafenib arms were receiving medications such
tion (16 vs. 11%, respectively) whereas it was similarly as levothyroxine for hypothyroidism (12 and 14%, respect-
higher in both treatment arms in the Japanese subgroup (44 ively). However, during study treatment, more patients admi-
vs. 45%, respectively). In the Japanese subgroup, 36% of nistered axitinib were diagnosed with hypothyroidism than
patients received anti-hypertensive medications before treat- those receiving sorafenib (44 and 24%, respectively)
ment with axitinib and 80% started new or increased their (Table 5). The diagnosis of hypothyroidism in either arm
dose of existing anti-hypertensive medication during was more common among Japanese than in the overall popu-
treatment with axitinib. In the overall population, anti- lation, although the incidence of TSH elevation to #10 mIU/
hypertensive medications were administered to 47% of ml among patients who had TSH , 5 mIU/ml before treat-
patients prior to treatment with axitinib and new or increased ment was comparable between Japanese patients and the
622 AXIS: Japanese subgroup analysis of axitinib

Table 3. IRC-assessed progression-free survival (overall or stratified by prior therapy)

Overall population Japanese patients

Axitinib Sorafenib Axitinib Sorafenib

PFS, months

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Overall n ¼ 361 n ¼ 362 n ¼ 25 n ¼ 29
Median PFS (95% CI) 6.7 (6.3–8.6) 4.7 (4.6– 5.6) 12.1 (8.6–NE) 4.9 (2.8– 6.6)
HR (95% CI) 0.665 (0.544–0.812) 0.390 (0.130–1.173)
P valuea ,0.0001 0.0401
Stratified by prior therapy
Prior cytokine therapy n ¼ 126 n ¼ 125 n ¼ 20 n ¼ 20
Median PFS (95% CI) 12.1 (10.1– 13.9) 6.5 (6.3– 8.3) 12.1 (8.6–NE) 6.6 (4.7– 8.5)
HR (95% CI) 0.464 (0.318–0.676) 0.171 (0.034–0.858)
P valueb ,0.0001 0.0085
Prior sunitinib therapy n ¼ 194 n ¼ 195 n¼5 n¼9
Median PFS (95% CI) 4.8 (4.5–6.4) 3.4 (2.8– 4.7) 4.7 (1.3– 4.7) 2.8 (1.4– 4.9)
HR (95% CI) 0.741 (0.573–0.958) 1.033 (0.229–4.671)
P valueb 0.0107 0.5175

IRC, Independent Review Committee; PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; NE, not estimable.
a
Based on one-sided log-rank test stratified by ECOG PS and prior therapy.
b
Based on one-sided log-rank test stratified by ECOG PS.

Figure 2. IRC assessed maximum percent change in target lesions in Japanese patients treated with (A) axitinib (n ¼ 24; 1 indeterminate) and (B) sorafenib
(n ¼ 25; 4 indeterminate). Dotted lines represent 30% decrease in target lesions.
 Jpn J Clin Oncol 2013;43(6) 623

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Figure 3. Objective response rate assessed by IRC. P values based on one-sided Cochran– Mantel – Haenszel test stratified by ECOG performance status and
prior therapy.

Table 4. IRC-assessed objective tumor response (overall or stratified by Japanese patients was managed with thyroid replacement
prior therapy)
therapy as the protocol recommended that hypothyroidism be
treated per standard medical practice to maintain euthyroid
Overall population Japanese patients
state. In the Japanese subgroup, 12% of patients received
thyroid medications before starting treatment with axitinib
Axitinib Sorafenib Axitinib Sorafenib
and 48% of patients started thyroid medications or increased
the dose of existing thyroid medications during treatment
Best-observed RECIST response, n (%) with axitinib. In the overall population, the corresponding
Overall n ¼ 361 n ¼ 362 n ¼ 25 n ¼ 29 values were 19 and 26%, respectively.
CR 0 0 0 0
PR 70 (19.4) 34 (9.4) 13 (52.0) 1 (3.4)
PROTEINURIA
SD 180 (49.9) 197 (54.4) 9 (36.0) 16 (55.2)
PD 78 (21.6) 76 (21.0) 2 (8.0) 6 (20.7) Incidences of all-causality proteinuria (all grades) were
similar between axitinib- and sorafenib-treated Japanese
Indeterminate 22 (6.1) 42 (11.6) 1 (4.0) 4 (13.8)
patients (12 and 10%, respectively), which were comparable
ORR (CR þ PR) 70 (19.4) 34 (9.4) 13 (52.0) 1 (3.4)
to those observed in the overall population (11 and 7%, re-
95% CI 15.4– 23.9 6.6–12.9 31.3– 72.2 0.1–17.8 spectively). One Japanese patient each in the axitinib and
P valuea 0.0001 0.0001 sorafenib arms had grade 3 proteinuria. No patient receiving
Stratified by prior therapy axitinib or sorafenib developed grade 4 proteinuria in the
Prior cytokine therapy n ¼ 126 n ¼ 125 n ¼ 20 n ¼ 20 Japanese subgroup or in the overall population. Incidence of
proteinuria #2þ in the axitinib arm was similar between the
ORR (CR þ PR) 41 (32.5) 17 (13.6) 13 (65.0) 1 (5.0)
Japanese and overall population (20 vs. 21%, respectively).
95% CI 24.5– 41.5 8.1–20.9 40.8– 84.6 0.1–24.9
P valueb 0.0002 0.0001
Prior sunitinib therapy n ¼ 194 n ¼ 195 n¼5 n¼9 DISCUSSION
ORR (CR þ PR) 22 (11.3) 15 (7.7) 0 0
The globally conducted AXIS trial has established clinical
95% CI 7.2–16.7 4.4–12.4 – –
benefit and superiority of axitinib compared with sorafenib
P valueb 0.1085 – in patients with previously treated mRCC in the overall
population (15). The current analysis demonstrated that in
RECIST, Response Evaluation Criteria in Solid Tumors; CR, complete the Japanese subgroup, axitinib treatment resulted in a
response; PR, partial response; SD, stable disease; PD, progressive disease;
ORR, objective response rate. longer PFS and higher ORR compared with sorafenib, con-
a
Based on one-sided Cochran– Mantel–Haenszel test stratified by ECOG PS sistent with the results obtained in the overall population.
and prior therapy. Furthermore, median PFS and ORR achieved in axitinib-
b
Based on one-sided Cochran –Mantel– Haenszel test stratified by ECOG PS.
treated Japanese patients were longer and higher than those
achieved in the overall population treated with axitinib. The
higher percentage of the patients with ECOG performance
status 0 and favorable MSKCC risk, as well as lower inci-
overall population (31 vs. 32%, respectively, in the axitinib dence of hepatic metastasis in the Japanese subgroup might
arm and 18 vs. 11%, respectively, in the sorafenib arm). As have accounted for better efficacy compared with the overall
with patients in the overall population, hypothyroidism in population (43,44). In addition, the majority (80%) of
624 AXIS: Japanese subgroup analysis of axitinib

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Figure 4. Kaplan – Meier analysis of time to deterioration (TTD) composite endpoint in Japanese patients. Composite endpoint of TTD was defined as time
between the date of randomization to date of first occurrence of progression of disease, death or deterioration of symptoms, as measured by (A) FKSI-15 and
(B) FKSI-DRS. P values based on one-sided log-rank test.

Japanese patients treated with axitinib had prior cytokine patients in the sorafenib arm of the AXIS trial were previ-
therapy, whereas in the overall population, 62% of patients ously treated with sunitinib whereas none of patients en-
treated with axitinib had prior sunitinib or bevacizumab/ rolled in the previous sorafenib Phase II study received prior
IFN-a therapy, both of which have the similar mode of sunitinib. In addition, only investigator-assessed PFS was
action as axitinib. available in the previous sorafenib Phase II study (45).
While cross-study comparisons are difficult due to meth- It should be noted that the median days on drug and rela-
odological differences, median PFS and ORR in cytokine- tive dose intensity in the sorafenib arm in Japanese patients
pretreated Japanese patients who received axitinib in this were shorter and lower, respectively, compared with the
study were comparable to those observed in the previous overall population (84 vs. 141 days, 69 vs. 92%, respective-
Phase II study of axitinib in cytokine-pretreated Japanese ly). The mean percentage of the total number of sorafenib
patients conducted in Japan (median PFS, 11.0 months; dose interruption was almost twice as high in Japanese
ORR, 50.0%) (9). On the other hand, values for PFS and patients as in the overall population (20.5 vs. 10.6%, respect-
ORR were slightly lower in Japanese patients treated with ively), which likely resulted in shorter days on drug and a
sorafenib in this study compared with those reported in a lower relative dose intensity in Japanese patients treated with
Phase II study of sorafenib in Japanese RCC patients sorafenib. Furthermore, this also could have affected the effi-
(median PFS, 7.4 months; ORR, 12.4%) (45). One possible cacy of sorafenib in Japanese patients, as seen in a lower
reason for the differences may be the fact that 9 of 29 ORR in Japanese patients compared with the overall
 Jpn J Clin Oncol 2013;43(6) 625

Table 5. Summary of common all-causality adverse events and laboratory abnormalities

AE, n (%) Overall population Japanese patients

Axitinib (n ¼ 359) Sorafenib (n ¼ 355) Axitinib (n ¼ 25) Sorafenib (n ¼ 29)

All grades Grade #3 All grades Grade #3 All grades Grade #3 All grades Grade #3

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Diarrhea 197 (55) 38 (11) 189 (53) 26 (7) 14 (56) 1 (4) 15 (52) 2 (7)
Hypertension 145 (40) 56 (16) 103 (29) 39 (11) 16 (64) 11 (44) 18 (62) 13 (45)
Fatigue 140 (39) 41 (11) 112 (32) 18 (5) 11 (44) 3 (12) 7 (24) 0
Decreased appetite 123 (34) 18 (5) 101 (28) 13 (4) 8 (32) 4 (16) 3 (10) 2 (7)
Nausea 116 (32) 9 (3) 77 (22) 4 (1) 2 (8) 0 2 (7) 0
Dysphonia 111 (31) 0 48 (14) 0 17 (68) 0 8 (28) 0
Hand–foot syndrome 98 (27) 18 (5) 181 (51) 57 (16) 16 (64) 4 (16) 25 (86) 7 (24)
Weight decrease 89 (25) 8 (2) 74 (21) 5 (1) 6 (24) 0 1 (3) 0
Vomiting 85 (24) 12 (3) 61 (17) 3 (1) 4 (16) 0 3 (10) 0
Asthenia 74 (21) 19 (5) 50 (14) 9 (3) 0 0 0 0
Constipation 73 (20) 4 (1) 72 (20) 3 (1) 4 (16) 0 7 (24) 0
Hypothyroidism 69 (19) 1 (,1) 29 (8) 0 11 (44) 0 7 (24) 0
Stomatitis 54 (15) 5 (1) 44 (12) 1 (,1) 9 (36) 0 5 (17) 0
Dysgeusia 38 (11) 0 29 (8) 0 7 (28) 0 2 (7) 0
Rash 45 (13) 1 (,1) 112 (32) 14 (4) 4 (16) 0 13 (45) 2 (7)
Alopecia 14 (4) 0 115 (32) 0 2 (8) 0 11 (38) 0
a
Laboratory abnormalities , n (%)
Anemia 113/320 (35) 1/320 (,1) 165/316 (52) 12/316 (4) 5/25 (20) 0 12/26 (46) 0
b
Hemoglobin elevation 31/320 (10) NA 3/316 (1) NA 2/25 (8) NA 0 NA
Neutropenia 19/316 (6) 2/316 (1) 26/308 (8) 2/308 (1) 4/24 (17) 0 8/25 (32) 0
Thrombocytopenia 48/312 (15) 1/312 (,1) 44/310 (14) 0 6/25 (24) 0 7/26 (27) 0
Lymphopenia 106/317 (33) 10/317 (3) 111/309 (36) 11/309 (4) 5/25 (20) 0 10/26 (38) 1/26 (4)
Creatinine elevation 185/336 (55) 0 131/318 (41) 1/318 (,1) 12/25 (48) 0 9/26 (35) 0
Hypocalcemia 132/336 (39) 4/336 (1) 188/319 (59) 5/319 (2) 13/25 (52) 0 16/26 (62) 0
Lipase elevation 91/338 (27) 16/338 (5) 148/319 (46) 47/319 (15) 9/25 (36) 2/25 (8) 17/26 (65) 3/26 (12)

a
The number of patients for each laboratory abnormality differed depending on the availability of baseline and at least one on-study test result.
b
Defined as hemoglobin value above the upper limit of normal.

population, respectively (3.4 vs. 9.4%), although median between Japanese patients and the overall population
PFS was similar (4.9 vs. 4.7 months). (the percentage of patients who had AEs above grade 2 or
The dose-uptitration rate was lower in Japanese patients received anti-hypertensive medications were similar between
treated with axitinib compared with the overall population Japanese patients and the overall population [4 vs. 6% and
(12 vs. 37%, respectively). In this study, axitinib dose could 64 vs. 59%, respectively]).
be increased in patients who met dose-titration criteria: no In the overall population, the OS was similar between the
treatment-related AEs above grade 2 according to the axitinib arm and sorafenib arm (46). The OS events occurred
NCI-CTCAE v3.0 for a consecutive 2-week period; BP in less than 50% of Japanese subgroup at the final analysis
"150/90 mmHg; and not taking any anti-hypertensive medi- of OS. The OS in Japanese subgroup has not been matured
cation. The percentage of Japanese patients who experienced yet and will be evaluated when additional OS events have
at least one systolic BP .150 mmHg or diastolic BP occurred.
.90 mmHg during the first 2 weeks of starting axitinib was A treatment goal in a metastatic disease where there is no
44%, which was !2-fold higher than the overall population cure as of yet is to delay symptom worsening. It is also im-
(21%), and likely led to the difference in dose-titration rate portant for an improvement in PFS not to be offset by a
626 AXIS: Japanese subgroup analysis of axitinib

worsening in symptoms or toxicity. In the AXIS trial, kidney treatment. Primary endpoint of the study, IRC-assessed PFS,
cancer-specific symptoms and QOL of patients were com- was achieved in Japanese patients, as in the overall popula-
pared between the axitinib and sorafenib arms in a pre- tion. Secondary endpoints, which included ORR and PROs,
specified composite endpoint, including death, progression supported the finding that axitinib improved efficacy over
or worsening of symptoms and QOL. Importantly, results sorafenib in Japanese patients. While nature and incidence of
demonstrated the PFS advantage of axitinib over sorafenib AEs observed in Japanese patients were generally similar to
was maintained in Japanese patients when time to symptom those reported in the overall population, there were some

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deterioration was included with the overall efficacy assess- notable differences. AEs more frequently reported by
ment, consistent with the overall population (15) and indi- Japanese patients treated with axitinib included hypertension
cated that axitinib provides extended symptom and disease and hypothyroidism, which were effectively managed with
control for these patients. anti-hypertensive medications and/or axitinib dose reduction/
AEs observed in Japanese patients as well as in the overall interruption and thyroid medications, respectively. Thus, axi-
population receiving axitinib were those expected for this tinib provides a new targeted therapy option for Japanese
class of drugs, which include diarrhea, hypertension and patients with advanced RCC following prior systemic
fatigue. Axitinib was generally well tolerated in Japanese therapy.
patients and its safety profile was comparable to that in the
overall population, with the exceptions of hypertension, dys-
phonia, hand – foot syndrome, hypothyroidism and stomatitis, Acknowledgements
which occurred more frequently in Japanese patients.
Hypertension and hypothyroidism in Japanese patients were We acknowledge the following investigators and investiga-
generally managed with use of anti-hypertensive and thyroid tional sites that also participated in this study: Y. Horikawa
medications, respectively, as in the overall population. Both (Akita University School of Medicine, Akita, Japan),
anti-hypertensive and thyroid medications were more fre- S. Takahashi (Nihon University School of Medicine, Tokyo,
quently administered to Japanese patients during axitinib Japan), H. Fujimoto (National Cancer Center Hospital,
treatment compared with the overall population. Other AEs Tokyo, Japan), M. Eto (Kumamoto University, Graduate
with higher incidences in Japanese patients were mostly School of Medical Sciences, Kumamoto, Japan), K. Tanabe
managed with axitinib dose interruption and/or reduction, as (Tokyo Women’s Medical University, Tokyo, Japan),
evidenced by the fact that no Japanese patients in the axiti- M. Oya (Keio University School of Medicine, Tokyo,
nib arm discontinued study treatment due to these AEs. Japan), J. Miyazaki (University of Tsukuba, Ibaraki, Japan),
It is unclear as to the cause(s) for slight differences in H. Nakazawa (Tokyo Women’s Medical University Medical
AEs reported by Japanese patients and the overall popula- Center East, Tokyo, Japan), M. Niwakawa (Shizuoka Cancer
tion. A follow-up analysis to further investigate differences Center Hospital, Shizuoka, Japan), H. Matsuyama
and similarities in AEs between Japanese patients and the (Yamaguchi University, Graduate School of Medicine,
overall population is warranted. It is noteworthy that no Yamaguchi, Japan). We thank Paul Bycott, Brad Rosbrook
major differences in axitinib plasma pharmacokinetics have and Helen Bhattacharyya of Pfizer, Inc. (San Diego, CA,
been observed between Japanese and Caucasians in Phase I USA) for assistance with statistical analyses. Medical writing
pharmacokinetic studies of axitinib in healthy volunteers and support was provided by Mariko Nagashima, PhD, of UBC
in patients with advanced solid tumors, including mRCC Scientific Solutions, Southport, CT, USA, and was funded
(47 – 49). Furthermore, a population pharmacokinetic ana- by Pfizer, Inc.
lysis and a fixed effects meta-analysis of datasets pooled
from a large number of axitinib clinical studies in healthy
volunteers showed that none of the several common genetic Funding
polymorphisms in cytochrome P450 (CYP) 3A4/5, This work was funded by Pfizer, Inc.
CYP2C19 or uridine diphosphate glucuronosyltransferase
1A1, which are known to metabolize axitinib, were signifi-
cant predictors of variability in axitinib plasma pharmaco-
Conflict of interest statement
kinetics (50,51). Factors such as age, gender and body
weight did not significantly affect axitinib systemic clearance T.U. has received speaker honoraria from Pfizer and Bayer.
either. Other factors are responsible for inter-individual vari- H.U. has served as a consultant for Pfizer, and received
ability observed in axitinib plasma pharmacokinetics, which speaker honoraria and research funding from Pfizer and
in turn, may impact AEs. The differences in AEs observed Bayer. Y.T. has served as a consultant for Pfizer and Bayer
may be contributed by differences in genetics as well as in and received speaker honoraria and research funding from
meticulousness of AE tracking. Pfizer and Bayer. T.T. has received speaker honoraria from
In conclusion, the current analysis indicated that axitinib Pfizer and Bayer. H.K. has served as a consultant for Pfizer
is efficacious and well tolerated in Japanese patients with and Bayer and received speaker honoraria from Pfizer and
mRCC, whose disease progressed after one prior systemic Bayer. N.S. has served as a consultant for Pfizer and received
 Jpn J Clin Oncol 2013;43(6) 627

speaker honoraria from Pfizer. S.O. has received speaker 15. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of
axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a
honoraria and research funding from Pfizer and Bayer. S.N. randomised phase 3 trial. Lancet 2011;378:1931– 9.
has served as a consultant for Pfizer and received speaker 16. Ueda T, Imamura Y, Komaru A, et al. Treatment outcomes of sorafenib
honoraria from Pfizer and Bayer. H.A. has served as a con- for first line or cytokine refractory advanced renal cell carcinoma in
sultant for Pfizer and Bayer and received speaker honoraria Japanese patients. Int J Urol 2010;17:811– 5.
17. Suyama T, Ueda T, Fukasawa S, et al. Efficacy and safety of sunitinib
from Pfizer and Bayer. J.T., C.C., S.K., K.I. and Y.U. are in Japanese patients with metastatic renal cell carcinoma. J Cancer Ther
employees of Pfizer and own stock in Pfizer. 2011;2:335 –41.

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