A phase II Randomized Controlled Trial to test the impact of two different dose levels of maintenance CAPEcitabine on progression-free survival in patients with persistent/recurrent/metastatic CERVical cancer not progressing on platinum-based chemotherapy

1 Introduction-

Cervical cancer is the second most common cancer in Indian women. In 2020, 123907 new cases were diagnosed, accounting for 18.3% of all new cancer cases in females. It’s also the second most common cause of cancer deaths in India, causing 77348 cancer deaths in 2020 as per GLOBOCAN India 2020 data. The 5-year survival rate for carcinoma (Ca) cervix reported from India is approximately 46%2 compared to 60-79% in more developed countries like China and South Korea.

The lack of widespread and readily accessible screening and the paucity of HPV vaccination coverage in India is among the significant reasons for the high prevalence of the disease. In India, most cervical cancer patients present at a locally advanced stage, leading to poor outcomes.

Five-year survival rates decrease with stage at diagnosis, from 91.5% for localized disease to 17.3% for metastatic disease.5 Before the availability of anti-VEGF antibody bevacizumab and recently approved PD-1 inhibitor Pembrolizumab, patients with distant metastases and/or recurrent disease had a poor prognosis, with a median overall survival(OS) between 6.4 and 9.4 months. Patients with advanced (persistent, recurrent, or metastatic) cervical cancer have limited, mainly palliative, treatment options. Standard first-line chemotherapy for advanced cervical cancer consists of paclitaxel combined with cisplatin or carboplatin. 2014 Bevacizumab was approved based on a randomized phase III trial demonstrating a median OS benefit of 3.7 months over chemotherapy alone. However, Indian data using a model economic analysis showed that bevacizumab isn’t cost-effective for patients in India. The next breakthrough came in 2021 when Pembrolizumab was approved in persistent, metastatic, recurrent cervical cancer patients in combination with chemotherapy and bevacizumab as the addition of Pembrolizumab improved 2-year survival by 11.3%, making it the new standard of care. Two major studies from India reported that only 1.6% to less than 3% of eligible patients were able to afford immunotherapy in non-melanoma solid cancers, head and neck cancers, and thoracic cancers due to the prohibitive cost of immunotherapy drugs.

The majority of Indian cancer patients fund their treatment out of pocket and can’t afford expensive drugs like bevacizumab and/or pembrolizumab, which are approved based on Western data. Pembrolizumab costs INR 8.85 lakhs/patient/year, and bevacizumab costs INR 3.5- 4 lakhs/patient/year.

Therefore, we need to find more cost-effective alternatives for our patient population which the majority can benefit from,

Capecitabine is an oral prodrug of 5-FU with good bioavailability. Phase II studies have shown objective response rates varying from 15%-36% either as monotherapy or combined with other drugs in doses ranging from 500 mg twice daily to 2500 mg/m2/day D1-D14 q21 days. It is a relatively well-tolerated oral drug with manageable and predictable toxicities. The cost of generic Capecitabine In India is approximately INR 300-400/strip ( 10 tablets). Therefore, it is an attractive cheap alternative that we want to test as maintenance therapy to see if it can offer a low-cost alternative to more expensive drugs approved yet unavailable to most of our patients. If our study is positive, it will give us a robust rationale to test it in a phase III randomized controlled trial(RCT).

In oncology trials, progression-free survival is often used as a surrogate for overall survival, especially in metastatic settings where patients are treated with palliative chemotherapy. Our study’s primary endpoint is a 6-month progression-free survival rate.

It is a pilot study to test a cheap alternative ( Oral Capecitabine) for standard-of-care expensive drugs ( Pembrolizumab- INR 8.85 lakhs/year and Bevacizumab- INR 15000/ dose, both given three weekly until progressive disease) which are out of reach for the majority of Indian patients, who bear the cost of cancer treatment out of pocket. Cervical cancer, being the third most common cancer in Indian females with a median survival of only 13 months with palliative chemotherapy, needs more accessible and cheaper treatment options for low-middle income countries like India.

Suppose we can reject the null hypothesis. In that case, we will conduct a phase III randomized controlled trial to establish oral capecitabine maintenance as a cheaper alternative to Pembrolizumab and Bevacizumab in patients with persistent/recurrent/metastatic cervical cancer not progressing on platinum-based chemotherapy.

2 Research Hypothesis:

The addition of oral capecitabine maintenance until progressive disease in patients with persistent/recurrent/metastatic cervical cancer not progressing on platinum-based chemotherapy will improve 6 months PFS rate by 15% compared to bevacizumab alone.