Paper 2
Paper 2
Paper 2
doi:10.1093/jjco/hyt054
Advance Access Publication 28 April 2013
*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
Key words: axitinib – renal cell carcinoma – vascular endothelial growth factor receptors –
clinical trial – phase III
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
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
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
Days on treatmenta
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
PFS, months
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
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
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
All grades Grade #3 All grades Grade #3 All grades Grade #3 All grades Grade #3
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
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.
39. Bonomi AE, Cella DF, Hahn EA, et al. Multilingual translation of the 46. Motzer RJ, Escudier B, Tomczak P, et al. Axitinib vs Sorafenib for
Functional Assessment of Cancer Therapy (FACT) quality of life advanced renal cell carcinoma: phase III overall survival results and
measurement system. Qual Life Res 1996;5:309– 20. analysis of prognostic factors. Ann Oncol 2012;23:ix262. (Suppl 9;
40. Eremenco SL, Cella D, Arnold BJ. A comprehensive method for the abstr 793PD).
translation and cross-cultural validation of health status questionnaires. 47. Pithavala YK, Tortorici M, Toh M, et al. Effect of rifampin on the
Eval Health Prof 2005;28:212– 32. pharmacokinetics of Axitinib (AG-013736) in Japanese and
41. Wild D, Grove A, Martin M, et al. Principles of Good Practice Caucasian healthy volunteers. Cancer Chemother Pharmacol
for the Translation and Cultural Adaptation Process for 2010;65:563– 70.
Patient-Reported Outcomes (PRO) Measures: report of the ISPOR 48. Mukohara T, Nakajima H, Mukai H, et al. Effect of axitinib