Trial Information

A Phase II Study of Erlotinib in Combination With Capecitabine as First-line Treatment in Elderly Patients With Stage IIIB/IV Adenocarcinoma Non-small Cell Lung Cancer (NSCLC)

1. BACKGROUND AND RATIONALE 1.1 Background Lung cancer is the leading cause of
cancer-related mortality in the world. Non-small-cell lung cancer (NSCLC), the most common
type of lung cancer, comprises about 80% of all lung cancer cases, and five-year survival
across all stages is about 12%. More than 60% of all NSCLC patients have advanced or
metastatic disease that is not suitable for curative resection at diagnosis. Platinum-based
chemotherapy remains the cornerstone of treatment for these patients and results in a small
but statistically significant improvement in survival compared with supportive care
alone.But the regimen is also associated with moderate to severe hematological and
non-hematological toxic effects in a majority of patients.

Approximately two-thirds of patients diagnosed with non-small cell lung cancer (NSCLC) are
65 years or older, and nearly 50% are 70 years or older. And greater than 90% of elderly
patients experience a grade 3/4 toxicity when treated with a platinum-based
doublet..Moreover，a group of patients with the performance status ≥2 is intolerant
intravenous chemotherapy. Availability of an effective,less toxic therapy might help extend
potentially beneficial treatment to a greater proportion of elderly or patients whose
performance status ≥2.

1.2 Rationale 1.2.1 Capecitabine for NSCLC Capecitabine is an oral prodrug of 5-Fu.It is
absorbed through the intestine and converted to 5'-deoxy-S-fluorocytidine (5'-DFCR) by
carboxylesterase and then to 5'-deoxy-S-fluorouridine (5'-DFUR) by cytidine deaminase, both
steps taking place in the liver. Finally,it is converted to the only active metabolite, FU,
by thymidine phosphorylase（TP）. This occurs in both tumor and normal tissues; however, the
TP is found at higher concentrations in some tumor tissue compared with normal healthy
tissue.The expression of this enzymes may influence the effect of the capecitabine. Han et
al examined the TP expression in tumor tissue samples from NSCLC patients who enrolled in a
previous phase II study of capecitabine/docetaxel chemotherapy and found that the patients
with high tumour cell thymidine phosphorylase expression show a better response to
capecitabine based chemotherapy .

The thymidylate synthase (TS) is an important target enzyme for antifolate drugs, such as
5-FU、UFT and capecitabine,because it catalyzes an essential step in DNA synthesis. The
predictive role of the expression of thymidylate synthase (TS) in tumors treated with
antifolate drugs has been extensively reported in NSCLC.In 2006, Nakano et al performed an
immunohistochemical study on the clinical significance of TS expression using 151 resected
non-small-cell lung cancer (NSCLC) patients postoperatively treated with UFT.They found that
the 5-year survival rate of patients with TS-negative tumours was significantly higher than
that with TS-positive tumours (P=0.0133).Miyoshi et al reported that the oral administration
of UFT after surgery might improve the survival of NSCLC patients when TS levels in tumor
tissues are low,with the 5-year survival rates of patients positive and negative for TS were
50.0 and 89.5%(p<0.001).Some research still found that TS expression was significantly
higher in squamous cell carcinoma compared with adenocarcinoma when both mRNA levels and
protein levels.

Recently，a Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus
Pemetrexed in Chemotherapy-Naïve Patients With Advanced-Stage Non-Small- Cell Lung Cancer
showed that Overall survival was statistically superior for cisplatin/ pemetrexed versus
cisplatin/gemcitabine in patients with adenocarcinoma.The result reminded us that patients
with adenocarcinoma were most likely to benefit from antifolate drugs.

In the preclinical study, we examined tumor specimens for TS and TP expression obtained from
171 Chinese NSCLC patients who were operated without any preoperative chemotherapy or
radiation at our institute. We categorized Grades 0 and 1 as negative, Grades 2 and 3 as
positive for both enzymes. As for TS staining, 14.6% (n = 25) were classified as Grade 0,
28.7% (n = 49) as Grade 1, 32.7% (n = 56) as Grade 2 and 24.0% (n = 41) as Grade 3. And for
TP staining, 12.3% (n = 21) were classified as Grade 0, 17.0% (n = 29) as Grade 1, 13.5% (n
= 23) as Grade 2 and 57.3% (n =98) as Grade 3. Although the anti-tumor activity of
capecitabine has not been well evaluated in NSCLC, the relatively high expression of TP
(70.8%) and low expression TS (43.3%) in NSCLC provided a rationale for the use of
capecitabine in patients with this tumor.

1.2.2 Erlotinib for NSCLC Erlotinib is a novel small molecule inhibitor of the EGFR tyrosine
kinase (TK). It has been approved as monotherapy for the treatment of patients with advanced
NSCLC who have progressed following first- and second-line chemotherapy.It is fairly well
tolerated and the salient adverse effects are mild to moderate skin rash and diarrhea. And
the further study showed that adenocarcinoma histology predicted the better survival.

Recently a trial of erlotinib as first-line therapy in elderly patients has been reported by
investigators at the Dana-Farber Cancer Center. In 76 patients over the age of 70, the vast
majority with adenocarcinoma histology, the response rate was 12% and a median survival was
11 months.

1.2.3 The synergistic interaction of erlotinib and capecitabine in NSCLC. Giovannetti et al
reported that erlotinib significantly reduced TS expression and activity, possibly via E2F-1
reduction, as detected by RT-PCR and western blot, and the combination decreased TS in situ
activity in NSCLC cells. Furthermore, Van SS. et al found TS inhibitor (5-FU) increases
EGFR phosphorylation which potentially favors EGFR-TKIs activity.Thus, erlotinib and
capecitabine may have a strong synergism in NSCLC.

Because of the effect in the treatment of NSCLC, the capecitabine and erlotinib may compose
to a new regimen for NSCLC. Based on the preclinical observation and the confirmed clinical
synergistic anti-tumor activity of combined capecitabine and erlotinib in gemzar refractory
APC, we previously conducted a phase II study of erlotinib in combination with capecitabine
against NSCLC.