A Review of the Great Journey of Capecitabine that Has Been Marketed in China for 20 Years

Fluorouracil has been used in clinical treatment for more than half a century. Capecitabine, an oral prodrug of fluorouracil, is very convenient to use and is one of the classical chemotherapeutics widely used in clinical practice. Since marketed in China in 2001, the applied range of capecitabine has continued to expand from advanced-stage therapy to adjuvant and neoadjuvant therapy, providing benefits for both HER2-negative/triple-negative breast cancer and HER2-positive breast cancer. It has been playing an indispensable role in the whole-process management of breast cancer in the recent two decades. Today, let’s review the great journey that this classical chemotherapeutic drug has been through.

Unique administration method of capecitabine making it an ideal option for metronomic chemotherapy

Metronomic chemotherapy is an emerging maintenance treatment method which controls the growth of tumors with low-dose, high-frequency, non-intermittent or short-intermittent drug administration modes in recent years. Capecitabine is an ideal option for metronomic chemotherapy owing to its convenience in oral administration and flexible dosage. Metronomic chemotherapy with capecitabine has achieved important progress in treating HER2-negative advanced breast cancer: the VICTOR-2 study enrolled patients with locally advanced or metastatic HER2-negative breast cancer, who were divided into first-line and second-line treatment groups based on whether they had received prior salvage chemotherapy; all patients received 40mg/d of oral vincristine soft capsules on day 1, 3, and 5 of each week and 500mg of capecitabine three times a day, continuous medication until progression of disease; the primary endpoint was the clinical benefit rate (CBR) at 24 weeks; the study enrolled 86 patients, of which 65% were HR-positive patients and 35% had triple-negative breast cancer; in HR-positive patients receiving combination metronomic chemotherapy, the CBR was 55.8%, with the CBR of first-line patients and second-line patients being separately 50% and 60%.

Capecitabine in combination with targeted therapy regimens achieving superior results in HER2-positive advanced breast cancer

In terms of combination with other targeted drugs, the phase II clinical study of pyrotinib showed that in patients with HER2-positive advanced breast cancer who were previously treated or not treated with trastuzumab and received not more than 2 lines of chemotherapy, the combination of capecitabine and pyrotinib was superior to the combination of capecitabine and lapatinib (median PFS was separately 18.1 months and 7.0 months). In patients with HER2-positive advanced breast cancer who failed trastuzumab treatment, the PHENIX study showed that the combination of capecitabine and pyrotinib had better efficacy than pyrotinib monotherapy (the median PFS was separately 11.1 months and 4.1 months).

Based on the results of the above two studies, the Guidelines of CSCO for the Diagnosis and Treatment of Breast Cancer 2020 mentions that the combination of pyrotinib and capecitabine is increased for people who have not used trastuzumab or who are eligible for reusing it; the recommendation for the combination of pyrotinib and capecitabine is adjusted to Level I for people who have failed trastuzumab treatment.

The CREATE-X study establishing capecitabine’s position as the standard postsurgical adjuvant therapy for TNBC

The New England Journal of Medicine published a JBCRG04 (CREATE-X) study of Japan and South Korea in 2017, which was designed to investigate the efficacy and safety of capecitabine, as an adjuvant therapy, in patients who have not reached pCR (pathologic complete response) after the preoperative neoadjuvant chemotherapy. As a multicenter phase III clinical study, it enrolled 910 patients with HER2 breast cancer who had not reached pCR after neoadjuvant chemotherapy. The patients who received standard treatment were assigned to the control group, and the other patients, who received capecitabine at a dose of 2,500mg/m2/d, on days 1–14, every 3 weeks for 8 cycles in addition to the standard treatment, were assigned to the treatment group. The primary endpoint was DFS, and the secondary endpoint was OS and safety.

According to the study, the 5-year DFS in the treatment group that also received capecitabine and the control group was separately 74.1% and 67.7% (HR=0.7, one-sided P=0.005), with significant statistical differences; the 5-year OS of the two groups also had significant differences: 89.2% vs 83.9% (HR=0.6, P＜0.01), with the benefits of using capecitabine shown in all subgroups, especially for triple-negative breast cancer patients.

This study is of high practical value as it is closely related to clinical practice and can quickly aid clinical decision-making. It has therefore been evaluated as a significant finding in patients who have not achieved pCR after neoadjuvant chemotherapy, breaking the idea that more chemotherapy would not bring survival benefits before the CREATE-X study.

The CBCSG-010 study opening a new chapter in TNBC adjuvant therapy

The CBCSG-010 study was conducted in 35 centers in China, with the eligibility criteria being females age 18-70 years with newly diagnosed, unilateral invasive breast cancer after surgery, who had not received neoadjuvant therapy and was histologically and immunohistologically confirmed as having triple-negative early-stage (M0) breast cancer.

Between June 2012 and Dec. 2013, 636 patients were enrolled, and 585 patients with triple-negative breast cancer (TNBC) met the entry criteria. Patients were randomly assigned to two groups, with the control group (n=288) receiving 3 cycles of docetaxel followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide (T-CEF), and the capecitabine group (n=297) receiving 3 cycles of capecitabine and docetaxel followed by 3 cycles of capecitabine, epirubicin, and cyclophosphamide (TX-CEX). The primary endpoint was 5-year DFS; the secondary endpoints included recurrence-free survival (RFS), distant disease-free survival (DDFS), overall survival (OS), and safety.

The median follow-up was 67 months. In capecitabine group, the 5-year DFS (86.3% vs. 80.4%; HR=0.66; 95% CI: 0.44~0.99; P=0.044), 5-year RFS (89.5% vs. 83.1%; HR=0.59; 95% CI: 0.38~0.93; P=0.02), and 5-year DDFS (89.8% vs. 84.2%; HR=0.63; 95% CI: 0.40~1.0; P=0.048) were all significantly higher than those of the control group; the 5-year OS of the two groups (93.3% vs. 90.7%; HR=0.67; 95% CI: 0.37~1.22; P=0.186) was similar. No interaction was found in any subgroup, however, patients with extremely high risk factors (such as N+, T3) might benefit more from the treatment added with capecitabine.

As the world’s first clinical study adding capecitabine into the standard docetaxel/anthracycline adjuvant chemotherapy for TNBC, CBCSG-010’s TX-CEX regimen could significantly improve the survival outcome of TNBC patients and is hopeful to change the clinical treatment patterns.

Formally published in the Journal of Clinical Oncology (JCO, IF=28) in 2020, the CBCSG-010 study is the first Chinese clinical study in the adjuvant therapy field of breast cancer published in the JCO. The study confirms that the TX-CEX regimen could significantly improve the survival outcome of TNBC patients, which is important for the improvement of clinical efficacy in treating TNBC. Capecitabine has become an indispensable part of the whole-process management of breast cancer in China after nearly two decades of development. Capecitabine can provide benefits for both HER2-negative and HER2-positive breast cancer, and it is pushing the boundaries of breast cancer treatment. Let’s wait and see.

References:

1.M E Cazzaniga, L Cortesi , A Ferzi, et al. Metronomic Chemotherapy With Oral Vinorelbine (mVNR) and Capecitabine (mCAPE) in Advanced HER2-negative Breast Cancer Patients: Is It a Way to Optimize Disease Control? Final Results of the VICTOR-2 Study[J].Breast Cancer Res Treat.2016 ;160(3):501-509.

2. Working Committee for the Guidelines of Chinese Society of Clinical Oncology. Guidelines of CSCO for the Diagnosis and Treatment of Breast Cancer [M]. Beijing: People’s Medical Publishing House, 2020.

3．Fei Ma, Quchang Ouyang, Wei Li, et al. Pyrotinib or Lapatinib Combined With Capecitabine in HER2-Positive Metastatic Breast Cancer With Prior Taxanes, Anthracyclines, and/or Trastuzumab: A Randomized, Phase II Study[J].J Clin Oncol .2019 ;37(29):2610-2619.

4． Zefei Jiang, et al. Pyrotinib combined with capecitabine in women with HER2+ metastatic breast cancer previously treated with trastuzumab and taxanes: A randomized phase III study. ASCO 2019 abstract 1001.

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