X-7/7 trial: Alternative fixed dosing of capecitabine associated with similar efficacy with better safety profile
By Drs. Arya Mariam Roy & Shipra Gandhi
Roswell Park Comprehensive Cancer Center
The approved dose of oral capecitabine for metastatic breast cancer by the US Food and Drug Administration (FDA) is 1250 mg/m2 twice daily, administered in a 14-day on, 7-day off schedule, cycled every 21 days [1]. However, this dose has been associated with poor tolerability and increased toxicities, often leading to treatment discontinuation. There has been a growing question regarding oral capecitabine’s optimal dosing and duration, aiming to minimize toxicity while maintaining efficacy.
Khan et al. presented the randomized clinical trial X-7/7 comparing the standard dose capecitabine (1250 mg/m2 twice daily 14 days on followed by 7 days off) with fixed-dose (1500 mg orally twice daily, 7 days on followed by 7 days off) [2]. Female patients with metastatic breast cancer were randomized in a 1:1 model to receive fixed dose vs. standard dose capecitabine between October 2015 and April 2021. Patients with any breast cancer subtypes and any prior number of chemotherapy or endocrine therapies could enroll in the trial. HER2-positive patients were allowed to receive concurrent trastuzumab. The primary endpoint of the trial was 3-month progression-free survival (PFS). The secondary endpoints were PFS, overall survival (OS), objective response rate, and toxicity. Patients were stratified by the line of chemotherapy (first vs. subsequent lines), measurable or non-measurable disease, and estrogen receptor status. Out of the 153 patients enrolled (80 patients in fixed-dose and 73 in standard dose arms), 78% were hormone receptor-positive HER2-negative, and 11% each were HER2-positive and triple-negative breast cancer patients. There was no difference in the primary endpoint in both standard and fixed-dose arms (3-month PFS=76%, hazard dose (HR) 1.01 (0.52 – 1.94), p=0.99). The restricted mean OS at 36 months was 21.2 and 19.6 months in the fixed and standard dose arms respectively (HR 0.80 (0.55 – 1.81, p=0.27)). More importantly, higher treatment-related discontinuations (28.8% vs. 7.5%, p <0.006) and dose modifications (23.3 % vs. 7.5%, p=0.0063) were observed in the standard dose arm compared to the fixed-dose. Similarly, all grade 2-4 toxicities occurred more frequently in the standard dose compared to the fixed-dose capecitabine arm (49.3% vs. 25.0%, p=0.0018).
This patient-centered research is practice-changing, in our opinion. The X-7/7 trial findings indicate that a fixed dose of capecitabine (1500 mg twice daily) on a 7/7 schedule offers a better toxicity profile, improved tolerability, and comparable efficacy to the current FDA-approved standard dose. This highlights the importance of considering optimal doses for patients in the real world, as the maximum tolerable dose recommended in clinical trials may not always be the most suitable. Given the higher costs of cancer therapeutics and the financial burden on healthcare systems due to drug-related hospitalizations, particularly in low- and middle-income countries, it becomes crucial to identify appropriate drug doses and schedules that minimize toxicity and enhance tolerability without compromising efficacy.
- Bajetta, E.; Procopio, G.; Celio, L.; Gattinoni, L.; Della Torre, S.; Mariani, L.; Catena, L.; Ricotta, R.; Longarini, R.; Zilembo, N.; et al. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol 2005, 23, 2155-2161, doi:10.1200/JCO.2005.02.167.
- Bohnenkamp, C.; Monson, T.; Smith, H.E.; Phadnis, M.A.; Raja, V.; Elia, M.; O’Dea, A.; Crane, G.J.; Fesen, M.R.; Nye, L.E.; et al. Randomized trial of fixed dose capecitabine compared to standard dose capecitabine in metastatic breast cancer: The X-7/7 trial. Journal of Clinical Oncology 2023, 41, 1007-1007, doi:10.1200/JCO.2023.41.16_suppl.1007.
