Trial Information

A Phase II Study of Axitinib in Metastatic Non-clear Cell Renal Cell Carcinoma Patients Previously Treated With Temsirolimus

1. Renal Cell Carcinoma Renal cell carcinoma is a malignant tumor occurring most
frequently of primary malignant tumors in kidney.1 According to Korea Central Cancer
Registry (KCCR) data, renal cancer affects 4.4 out of 100,000 males and 2.1 out of
100,000 females. About 30% of renal cancer patients accompany remote metastasis at the
time of diagnosis and renal cancer even recurs in about 40% of the patients who
underwent surgery for radical treatment of renal cancer as a local disease.1 New
treatment strategies against renal cell carcinoma have been developed, but they have
not obtained satisfactory therapeutic outcomes. Thus, constant clinical studies are
necessary to improve therapeutic efficacy.

2. Treatment of Metastatic Renal Cell Carcinoma The treatment for metastatic renal cell
carcinoma has been improved a lot for the recent few years, which is, however, limited
to clear cell renal cell carcinoma. The drugs showing antitumor activity against clear
cell renal cell carcinoma include axitinib, sunitinib, sorafenib, bevacizumab,
temsirolimus, and everolimus.

Of them, axitinib, sunitinib, sorafenib, bevacizumab, etc. are neovascularization
inhibitors which inhibit vascular endothelial growth factor (VEGF) and its receptor
(VEGFR). As a first-line treatment, sunitinib prolongs progression-free survival (PFS)
compared to interferon-alpha, being recognized as a first-line standard therapy.
Sorafenib, a second-line treatment, shows significant prolongation of PFS against clear
cell renal cell carcinoma compared to the placebo control group, establishing itself as
a second-line drug. Concomitantly administered with interferon-alpha, bevacizumab shows
significant prolongation of PFS compared to the single use of interferon-alpha,
establishing itself as another first-line therapy. Temsirolimus, an mammalian target of
rapamycin (mTOR) inhibitor, extended survival time in a clinical study of both clear
and non-clear cell renal cell carcinoma. However, this clinical study was limited to
patients with renal cell carcinoma having bad prognostic factors. This renal cell
carcinoma with bad prognostic factors only accounts for 10-20% of entire metastatic
renal cell carcinoma. Everolimus, an another mTOR inhibitor, showed a significant
prolongation of PFS in the placebo-controlled phase III clinical study of patients with
clear cell renal cell carcinoma in whom sunitinib therapy failed, establishing itself
as a second-line therapy in case the first-line standard sunitinib therapy fails.

3. Treatment of Metastatic Non-clear Cell Renal Cell Carcinoma (nccRCC) In fact, VEGF
antagonists are shown to have some efficacy also in nccRCC. Sunitinib was effective
against nccRCC. A worldwide expanded access trial of sunitinib has been undertaken. A
subgroup analysis of patients with non-clear-cell histology was performed and 276
patients (11.8%) with non-clear-cell histology were identified, although distinction
between different subtypes was not made. A response rate of 5.4%, clinical benefit
(defined as response and stable disease was more than 3 months) of 47% and median PFS
of 6.7 months was seen in this subgroup. This result compared with an overall response
rate for the entire patient group of 9.3%, clinical benefit of 52.3%, and median PFS of
8.9 months. The investigators concluded that sunitinib was active in the non-clear-cell
subgroup; however, these data need to be interpreted with caution because of the
nonrandomization of patients in the expanded access trial and the lack of pathology
verification. Also, recently, phase 2 trial of sunitinib in non-clear cell renal cell
carcinoma showed remarkable efficacy with response rate of 36% and median PFS of 6.4
months. The study enrolled non-clear cell RCC patients who did not receive previous
anti-angiogenic treatment.

Sorafenib also showed some efficacy in nccRCC, though not so efficacious. The Advanced
Renal Cell Carcinoma Sorafenib Expanded Access Program allowed patients in the United
States and Canada with metastatic RCC to receive treatment with sorafenib prior to its
regulatory approval. This non-randomized, open-label program treated 158 subjects with
papillary RCC of a total of 1891 evaluable subjects (81% clear cell, 8% non-clear, and
11% unclassified histology). Of the 107 evaluable subjects with papillary RCC, 90 (84%)
had a measurable response to treatment with 3 partial responders and 87 with stable
disease for at least 8 weeks, while 17 (16%) subjects demonstrated early progression on
treatment. The side effect profile for sorafenib was similar across histologic
subtypes, and the authors concluded that sorafenib has some activity in papillary
tumors.

On the other hand, in randomized phase 3 trial of single-agent Axitinib in 723 renal
cell carcinoma patients who progressed despite first-line therapy containing sunitinib,
bevacizumab plus interferon-alpha, temsirolimus or cytokines, the median PFS duration
was significantly longer with axitinib than with sorafenib in the entire population
(6.7 months versus 4.7 months, respectively: p less than 0.0001).

4. Rationale In short,

1. There is no standard treatment option for non-clear cell RCC.

2. Patients with non-clear cell RCC is strongly assumed to have benefit from
anti-VEGF treatment.

3. There is no trial of axitinib for non-clear cell RCC.

4. Axitinib is expected to show more potent efficacy over sorafenib or sunitinib in
renal cell carcinoma.

Based on above, this clinical study is designed to examine efficacy and adverse events of
axitinib for non-clear cell renal cell carcinoma.