Metronomic Capecitabine Continues Efficacy With Pyrotinib in HER2+ Advanced Breast Cancer


Results from an international phase 2 study show that using metronomic capecitabine in combination with the tyrosine kinase inhibitor pyrotinib continued to have promising efficacy results for patients with HER2-positive metastatic breast cancer.

3d rendered medically accurate illustration of a breast cancer: © SciePro -

3d rendered medically accurate illustration of a breast cancer: © SciePro -

The use of oral metronomic capecitabine (Xeloda) in combination with the tyrosine kinase inhibitor (TKI) pyrotinib (SHR1258) showed promising efficacy for patients with HER2-positive metastatic breast cancer warranting further investigation, according to conclusions from data published in The Breast.1

A prospective, single-arm phase II trial (NCT03923166) found that the use of 500 mg of capecitabine given 3 times a day alongside 400 mg of pyrotinib daily had an objective response rate (ORR) of 34.7% and a clinical benefit rate of 81.6% among 49 assessable patients with HER2-positive metastatic breast cancer. Two patients had a complete response to the therapy compared with 15 patients who had a partial response. Additionally, 23 patients had stable disease and 9 patients had progressive disease.

Differing from past uses of capecitabine when combined with pyrotinib, this phase 2 study used the metronomic delivery method for the chemotherapy. According to the researchers, metronomic chemotherapy is when the chemotherapy is given at a low-dose but a high frequency continuously without prolonged drug-free breaks. Recent research has shown that this method allows for a prolonged treatment cycle and can reduce adverse events (AEs).2 Further, the use of metronomic capecitabine for patients with advanced breast cancer has been previously explored, but for patients with triple-negative breast cancer or metastatic breast cancer regardless of their HER2 status.1

After a follow-up of 3 years, 15 patients died due to tumor progression and the researchers calculated a median overall survival (OS) of 29.3 months (95% CI, 24.4-34.8) and a median progression-free survival (PFS) of 11.9 months (95% CI, 8.8-14.6). The longest duration of PFS was 40.1 months for 1 patient. Comparing patients who were given the combination therapy as a first- or second-line therapy vs those given it after the second-line, researchers found patients had a longer median PFS if they were given the therapy a first- or second-line regimen at 12.2 months (95% CI, 10.5-20.1) vs 2.9 months (95% CI, 1.5-20.5), respectively (P =.02).

Further, a subgroup analysis found that patients who were postmenopausal had a median PFS of 12.1 months (95% CI, 10.1-14.6) compared with 8.7 months (95% CI, 3.6-20.5) in premenopausal patients, however, this was not deemed significant. The only significant difference found in the subgroup analysis was in the line of therapy the regimen was given.

The combination of pyrotinib and capecitabine had been previously studied in the open-label, randomized, controlled, phase 3 PHOEBE trial (NCT03080805), but in that trial capecitabine was administered in a 21 day cycle at 1000 mg/m2 twice daily on days 1-14 of the cycle.3 This was given alongside 400 mg of pyrotinib compared with 1250 mg of daily lapatinib (Tykerb) as a comparator. The phase 3 trial enrolled 267 patients with HER2-positive metastatic breast cancer, randomly assigning 134 patients to receive pyrotinib plus capecitabine compared with 132 patients given lapatinib plus capecitabine.

At the time of the interim analysis of PHOEBE, the ORR in the capectibine and pyrotinib arm was 67% (95% CI, 58.5%-75.0%) compared with 52% (95% CI, 42.7%-60.3%) in the lapatinib group. The clinical benefit rate between the 2 arms was 73% (95% CI, 64.8%-80.4%) vs 59% (95% CI, 50.2-67.6%), respectively.3 This was higher than the rate found on the phase 2 study, but researchers noted there the smaller population they had to work with. Further, the primary end point of PHOEBE was PFS, which the study met as patients in the pyrotinib arm had a median PFS of 12.5 months (95% CI, 9.7-not reached) compared with 6.8 months (95% CI, 5.4-8.1) in the lapatinib arm (HR, 0.39; 95% CI, 0.27-0.56, P <.0001).3

Safety was also looked at in the phase 3 and phase 2 trials, with researches in the PHOEBE trial noting that serious AEs were seen in 14 patients in the pyrotinib arm compared with 11 in the lapatinib arm, but only 1 sudden death was observed in the lapatinib group and deemed treatment-related.3 In the phase 2 study, 1 grade 4 AE was reported of diarrhea, and this was the only patient to discontinue treatment on the trial.1

Eight patients had a dose reduction, with 5 patients reducing their 400 mg dose of pyrotinib to 320 mg due to diarrhea. Three patients reduced their 500 mg dose of capecitabine from 3 times a day to twice a day due to hand-foot syndrome. After these dose adjustments, the majority of patients found relief from their AEs with just 1 patient sill having grade 3 hand-foot syndrome, and no grade 4 AE occurred after the dose adjustment.1 The most common grade 1 or 2 AEs included nausea, vomiting, diarrhea, and hand-foot syndrome, with 6 patients experiencing grade 3 hand-foot syndrome symptoms.1

“Oral metronomic capecitabine with pyrotinib is an anti-HER2 regimen with comparable efficacy and good adverse events profile in HER2-positive metastatic breast cancer patients,” the researchers concluded in their discussion of the data. “This combination expanded the patient population who can benefit from pyrotinib-based regimen, and worth further evaluation in trials with larger population.”

1. He M, Liu J, Wang Z, et al. Safety and efficacy study of oral metronomic capecitabine combined with pyrotinib in HER2-positive metastatic breast cancer: A phase II trial. Breast. 2023;72:103581. doi:10.1016/j.breast.2023.103581
2. Cazzaniga ME, Cordani N, Capici S, et al. Metronomic Chemotherapy. Cancers (Basel). 2021;13(9):2236. doi:10.3390/cancers13092236.
3. Xu B, Yan M, Ma F, et al; PHOEBE Investigators. Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22(3):351-360. doi:10.1016/S1470-2045(20)30702-6
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