The single institution study compared fixed dose capecitabine to standard dose capecitabine to compare efficacy and tolerability in metastatic breast cancer.
The randomized X-7/7 trial (abstract 1007) from the American Society of Clinical Oncology 2023 Annual Meeting investigating fixed dose capecitabine (Xeloda; Genentech) compared to standard dose capecitabine in metastatic breast cancer (MBC) is a single institution study of particular interest, explained Danielle Roman, PharmD, BCOP, during the inaugural 2023 PTCE Oncology Pharmacists Connect conference in Austin, Texas. Roman explained further that the significance of this study may help to inform how capecitabine is prescribed.
“So that's one reason to discuss the X-7/7 trial [NCT02595320]. Another is that oncology pharmacist colleagues are the second and third authors on this trial, which is another reason to highlight it,” Roman, manager of Oncology Clinical Pharmacy Services at Allegheny Health Network, said during the presentation. “The relatively small patient population was 153 patients, and that included women with [MBC] who could have received any prior line of endocrine therapy or chemotherapy. If patients were HER2-positive [HER2+], they also had to have been receiving trastuzumab [Herceptin; Roche] to be included.”
For patients with MBC, oral capecitabine is prescribed at the FDA-approved dose of 1250 mg/m2 twice daily, 14 days on followed by 7 days off; however, this regimen is associated with poor tolerance and high rates of discontinuation. During the X-7/7 trial, patients were randomized to compare the efficacy and tolerability of fixed-dose capecitabine at 1500 mg twice daily, 7 days on, 7 days off (FD) to the FDA-approved dose and schedule (SD) of 1250 mg/m2 twice daily, 14 days on followed by 7 days off.
Patients were stratified by line of chemotherapy (first or subsequent), measurable disease, and ER status, and randomized 1:1 to either the FD or SD arm. The primary endpoint of the trial was 3-month progression-free survival (PFS), with an additional endpoint of overall survival (OS). At each patient visit, capecitabine-related toxicities were solicited and graded by investigators.
“So [the FD dose] is a pretty significant dose here. I know for any of you that have used this dose in practice, it can be quite toxic for patients, and really difficult to get through without dose reductions,” Roman said. “Mathematical models in some really early stage, non-randomized trials have looked at using a fixed dose, and what we're seeing in the mathematical models were that the 1500 mg dose given for 7 days appears to be that key cytotoxic effect, and continuing beyond 7 days just appears to increase toxicity.”
The trial was conducted between October 2015 and April 2021, with 153 patients enrolled (FD=80, SD =73). Of these patients, 78% were HR-positive (HR+)/HER2-negative (HER2-), 11% each were HER2+ and triple-negative. In the FD arm and in the SD arm, the 3-month PFS was 76% (hazard ratio (HR)=1.01; 95% CI, 0.52 to 1.94; p=0.99). The PFS at 36 months was 13.9 months in the FD arm vs 14.6 months in the SD arm (HR for progression or death, 1.31; 95% CI, 0.56 to 1.15; p=0.24). Additionally, OS at 36 months was 21.2 months in the FD arm vs 19.6 months in the SD arm (HR for death, 0.80; 95% CI, 0.55 to 1.81; p=0.27).
“What we're seeing here with the 3-month PFS is that it’s identical between these 2 arms, so the fixed dose and the standard dose are 76% across the board. You could see in the landmark analyses that the 12-month, 24-month, and 36-month PFS also show no statistically significant difference between these 2 arms, really showing us that the fixed dose appears to maintain the efficacy of the standard dose,” Roman said. “But what I would really like to draw your attention to is the toxicity profile.”
Roman explained further that toxicity-related treatment discontinuation occurred among 21 patients (28.8%) in the SD arm compared to 6 patients (7.5%) in the FD arm (p<0.0006). Notably, grade 2-4 toxicities occurred more frequently in patients receiving SD capecitabine (49.3%) as compared to FD capecitabine (25.0%) (p=0.0018).
“As you all know, we see a significant amount of diarrhea, hand-foot syndrome, and mucositis as particular toxicities of interest here, and you can see significant reductions in all 3 of these toxicities when you compare that FD to our SD arm,” Roman said. “There are also similar rates of neutropenia between the arms and significantly lower treatment discontinuation, which allowed patients to stay on treatment longer with less toxicity. We're seeing similar efficacy in a FD approach, with less toxicity. So it's an interesting approach here that I think could change some of the prescribing practices.”
Roman D. New Evidence in Breast Cancer and the Impact to Care. Presented at: 2023 PTCE Oncology Pharmacists Connect in Austin, Texas; June 16, 2023.