Current treatment of metastatic breast cancer (MBC) aims to ameliorate symptoms and improve quality of life for patients. Intas Pharmaceuticals Ltd is forging the way ahead for MBC treatment with the world’s first fixed-dose combination (FDC) of two known chemotherapy drugs: ‘capecitabine’ and ‘cyclophosphamide’. This unique FDC formulation is based on patented tablet-in-tablet technology, which has been approved by the regulatory authorities in India based on THE ENCLOSE clinical trial. It is marketed by Intas as Comcapsy® (capecitabine 400/700 mg + cyclophosphamide 20/30 mg). The combined oral fixed-dose tablet provides the advantage of ease of dosing, better patient adherence, and a manageable tablet load for patients with breast cancer.
In India, breast cancer is the leading cause of cancer mortality, representing 11.1% of all cancer deaths. In this context, breast cancer mainly affects women of reproductive age, where its late diagnosis leads to a high mortality rate. When not treated promptly, breast cancer can result in the spread of disease from the breast to other organs and tissues, and is known as metastatic disease, or stage 4 breast cancer. The symptoms caused by metastatic breast cancer (MBC) depend on the site of metastasis. Common metastatic sites include the bones, liver, lungs, and brain.
Approximately half of patients with breast cancer in India are diagnosed in stages 3 and 4 when the chances of survival are significantly lower and treatment costs are high. Treatment is focused on palliation to offer relief from symptoms caused by the disease itself and by the aggressive cancer treatment. Although palliation helps the patient feel more comfortable and improves their quality of life, it does not cure the disease.
Currently, available treatments for breast cancer include surgery, radiation therapy, chemotherapy, hormonal therapy, and targeted therapy. Current chemotherapy medications for MBC include oral anticancer drugs, anthracyclines and/or taxanes. Within the body, the anticancer drug capecitabine is converted to 5-fluorouracil, a substance which blocks cancer cell multiplication and results in cancer cell death. Cyclophosphamide, besides slowing/stopping growth of cancer cells through the body’s immune system, also enhances the conversion of capecitabine to active 5-fluorouracil, suggesting a collaborative activity of the two medications (known as synergistic anti-tumour activity).
Through its patented tablet-in-tablet technology, Intas Pharmaceuticals Ltd has developed the first oral fixed-dose combination (FDC) tablet of capecitabine and cyclophosphamide. The FDC demonstrated promising results in THE ENCLOSE clinical trial recently published in the high-impact factor journal, The Breast. Following positive results from the trial, the combination treatment was marketed in India, after regulatory approval, in April 2020. The labelled dose of capecitabine alone can negatively impact the pill burden, and the addition of other oral drugs can further increase the tablet load, negatively affecting patients’ treatment adherence. This oral FDC provides the advantage of ease of dosing and better adherence as well as manageable tablet load for patients with breast cancer.
THE ENCLOSE study
THE ENCLOSE (capEcitabiNe CycLophOsphamide Synergism brEast cancer) study determined the efficacy and safety profile of the world’s first oral FDC tablet of capecitabine and cyclophosphamide. In this randomised, multicentre study, patients with MBC who previously experienced failure of first-line treatment (with anthracyclines and/or taxanes) were included.
The study was conducted in two parts between February 2015 and November 2018 at 15 centres across India. Sixty-six women were initially randomised into three dose groups: D1, D2, and D3.
These doses were calculated after considering the scientific literature on the specific medications. The FDC tablets were administered orally within 30 minutes after a meal in a regimen of 14 days on and seven days off in three-weekly cycles for up to six cycles.
Part I of THE ENCLOSE Study
Being a novel formulation, detailed pharmacokinetic assessment of the FDC was included as part of the trial. Part I of the study focused on the pharmacokinetics – to investigate how the body interacts with the drugs. Blood samples were collected from patients and the concentration of the drugs in their blood was calculated at different time points. The pharmacokinetic profiles were evaluated in 24 out of 66 patients and did not reveal any concerning findings. Pharmacokinetic parameters were greater than dose proportional for capecitabine.
Following a futility analysis, D1 dose was not considered optimal and discontinued. With additional patients recruited in D2 and D3 groups, a total of 144 patients’ data were available for analysis in part II of the study.
Part II of THE ENCLOSE Study
In part II of the study, the main aim was to identify the best overall response (BOR) to treatment rate, defined as the proportion of patients with complete response or partial response. The response to treatment rate was evaluated after three and six cycles of chemotherapy and was assessed using radiological imaging such as computer tomography, magnetic resonance imaging or bone scans. The study also evaluated the disease control rate (DCR), defined as the proportion of patients with complete response, partial response, or stable disease. The BOR rates in D2 and D3 groups were 29.63% and 22.41%, respectively. The DCR rates after three cycles in D2 and D3 groups were 87.04% and 82.76%, respectively.
Promising efficacy and safety of the FDC
The study highlights that capecitabine and cyclophosphamide combined in one oral tablet is an attractive chemotherapy option that could be preferred by patients, while the reduced pill burden could also improve treatment adherence. Additionally, the FDC’s synergistic antitumour effect is thought to add extra value to the treatment, potentially resulting in a reduced dose of capecitabine for MBC disease control, consequently ameliorating the side effects that are often associated with such treatments.
The pharmacokinetic data confirms the hypothesis of the synergistic antitumour effect of the two components of the FDC. When it comes to the drug’s safety, it is worth mentioning that the most common side effects were hand–foot syndrome (redness and blisters on the skin of the palms of the hands and the soles of the feet), vomiting, fever, and nausea. The incidence of these side effects was lower compared to previous studies and is thought to be related to the lower doses of these agents used in THE ENCLOSE trial.
About Intas Pharmaceuticals Ltd
Intas Pharmaceuticals Ltd is a leading multinational pharmaceutical company that highly values innovation and treatment affordability for everyone. The company is present in more than 85 countries worldwide with an extensive range of medications, including 35 oncological drugs available globally and five more under development that will be launched in the market over the next year. The company’s innovative approach has led to solutions that have transformed treatment approaches and improved the lives of millions of patients to date. Its progressive future strategy includes expansion of its highly automated facility in India. This modern manufacturing unit can produce more than one billion oral tablets per month as well as five million injectable drugs. With worldwide operations, and a strong pan-European footprint including more than 45 countries, Accord Healthcare (a wholly owned subsidiary of Intas Pharmaceuticals Ltd) develops, manufactures, and distributes affordable medicines, and has one of the most active launch programmes in the European pharmaceutical sector.
Intas’ mission is to provide affordable treatments all around the world in a variety of medical fields including oncology, ophthalmology, nephrology, rheumatology, and also hormone-based therapies. To achieve this goal, Intas is currently investing on multiple fronts, such as biosimilar (biologic medical products that are a copy of the original product) development, groundbreaking automation technology and also in attracting talented and ambitious researchers to continue raising the bar of healthcare excellence worldwide.
- Gupta, S, Biswas, G, Babu, S, et al (2021) Fixed dose combination of capecitabine and cyclophosphamide in metastatic breast cancer: results from THE ENCLOSE phase 2/3 randomized multicenter study. The Breast, 60, 147–54. doi.org/10.1016/j.breast.2021.09.012
Intas Pharmaceuticals Ltd is committed to fulfilling unmet medical and societal needs through innovation by developing processes and synthesising molecules that are the need of the hour for improving overall patient care.
Lambda Therapeutic Research Ltd
Intas Pharmaceuticals Ltd is one of the leading multinational pharmaceutical formulation, development, manufacturing, and marketing companies in the world. It crossed the $2.3 billion mark last year and is valued at over US $5 billion, with a geographic footprint spanning over 85 countries across the globe. Part of the Intas group, Accord Healthcare Ltd is one of the fastest-growing pharmaceutical and biosimilars companies in Europe, with one of the largest market footprints of any European generic company.
Intas Pharmaceuticals Ltd, Corporate Office
Corporate House, Near Sola Bridge
S G Highway, Thaltej, Ahmedabad – 380054, Gujarat, India