"The overall response rate and progression-free survival were significantly improved with pyrotinib plus capecitabine."
Improvement in progression-free survival (PFS) was demonstrated with the combination of pyrotinib plus capecitabine versus lapatinib (Tykerb) plus capecitabine as treatment of patients with HER2-positive metastatic breast cancer (MBC) in the phase 3 PHOEBE trial who received prior treatment with trastuzumab and chemotherapy. The results were presented as part of the 2020 ASCO Virtual Scientific Program.
The median PFS was 12.5 months (95% CI, 9.7-not reached) with pyrotinib plus capecitabine versus 6.8 months (95% CI, 5.4-8.1) with lapatinib plus capecitabine (HR, 0.39; 95% CI, 0.27-0.56; P <.0001), which met the criterion for statistical significance (≤.0066).
While multiple HER2-directed treatments are approved, several therapies—including ado-trastuzumab emtansine (T-DM1; Kadcyla) and fam-trastuzumab deruxtecan-nxki (Enhertu)—are not available in all regions of the world, said Binghe Xu, MD, PhD, professor and director of the department of medical oncology at the Cancer Hospital and Institute of the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing. Inevitable drug resistance requires additional irreversible tyrosine kinase inhibitor options.
Pyrotinib is a small molecule, irreversible, pan-ErbB receptor tyrosine kinase inhibitor targeting EGFR, HER2, and HER4. Pyrotinib plus capecitabine has shown clinically meaningful benefits and acceptable tolerability in patients with HER2+ metastatic breast cancer in phase 1 and phase 2 studies.
"In the previous phase 2 study, we compared pyrotinib plus capecitabine versus lapatinib plus capecitabine in pretreated patients," he said. "The overall response rate and progression-free survival were significantly improved with pyrotinib plus capecitabine."
PHOEBE, an open-label, multicenter, randomized phase 3 study enrolled patients with HER2-positive MBC after trastuzumab and taxanes, and/or anthracyclines. Patients were randomly assigned (1:1) to receive pyrotinib 400 mg or lapatinib 1250 mg once daily continuously plus capecitabine 1000 mg/m2 twice daily on days 1-14 of 21-day cycles. The primary end point was PFS per blinded independent central review.1
From July 2017 through October 2018, the study enrolled 267 patients. There were 134 patients in the pyrotinib plus capecitabine group; 133 patients were in the pyrotinib and lapatinib, including 1 patient in who did not receive study treatment and was excluded from analyses. At baseline, 42.5% and 34.8% of patients in the pyrotinib and lapatinib arm had no prior chemo for metastatic disease, 41.8% and 49.2% had 1 prior line, and 15.7% and 15.9% had 2 lines, respectively.
Among trastuzumab-resistant patients, prolonged PFS with pyrotinib plus capecitabine was also observed (12.5 months [95% CI 6.9 to not reached] versus 6.9 months [95% CI 5.4 to not reached]; HR 0.60 [95% CI 0.29 to 1.21]). Benefits in objective response rate, clinical benefit rate, and duration of response with pyrotinib plus capecitabine were also indicated.
The objective response rate was 67.2% (95% CI, 58.5%-75.0%) in the pyrotinib arm and 51.5% (95% CI, 42.7%-60.3%) in the lapatinib arm. Partial response was observed in 61.9% and 50.8% of patients and complete response in 5.2% and 0.8% of patients, respectively. The clinical benefit rate was 73.1% (95% CI, 64.8%-80.4%) in the pyrotinib arm versus 59.1% (95% CI, 50.2%-67.6%) in the lapatinib arm. Further, the duration of response was 11.1 months (95% CI, 9.7-NR) versus 7.0 months (95% CI, 5.6-9.8) with response ongoing in 70.0% versus 48.5% in the pyrotinib and lapatinib arms, respectively.
"OS data were not yet mature, but we found that there was a strong trend toward prolonged survival with the pyrotinib plus capecitabine, and safety profile was manageable," Xu said.
The overall survival (OS) data were not yet mature, but a strong trend toward prolonged survival was observed in the pyrotinib group, with an OS rate of 91.3% (95% CI, 82.3%-95.9%) versus 77.4% (95% CI, 65.5%-85.6%) in the lapatinib group.
Treatment related adverse events (AEs) grade 3 or higher were observed in 57.5% of patients in the pyrotinib arm and 34.1% of patients in the lapatinib arm. The most common grade 3 AEs were diarrhea (30.6% vs 8.3%) and hand-foot syndrome (16.4% vs 15.2%) in the pyrotinib versus lapatinib arms, respectively. No AEs grade 4 or 5 occurred in either arm.
"As the study progressed, the incidence of diarrhea in the pyrotinib group showed a decreasing trend," Xu said. "In general, diarrhea was low severity, short duration, and rarely led to treatment termination."
In the pyrotinib group, 61 discontinued treatment, including 53 for disease progression and 4 4 due to AEs. At the time of data analysis, 73 patients were continuing with treatment. In the lapatinib group, 101 patients discontinued treatment, including 95 for disease progression and 3 for AEs, with 31 patients continuing on treatment.
Pyrotinib plus capecitabine was approved as a second-line standard-of-care therapy for metastatic HER2-positive breast cancer in China in 2018. This was based on data from a phase 2 trial that demonstrated the a superior investigator-assessed overall response rate in patients treated with pyrotinib compared with the lapatinib group (78.5% vs 57.1%); the difference was statistically significant (P = .01). In addition, the pyrotinib group had a nearly 11-month longer median PFS and 64% lower likelihood of disease progression or death compared with the lapatinib group (18.1 vs 7.0 months; HR, 0.36; 95% CI, 0.23-0.58; P = .001).1,2
1. Xu B, Yan M, Ma F, et al. Pyrotinib or lapatinib plus capecitabine for HER2+ metastatic breast cancer (PHOEBE): a randomized phase III trial. 2020 ASCO Virtual Scientific Program. https://meetinglibrary.asco.org/record/184810/abstract
2. Ma F, Ouyang Q, Li W, et al. Pyrotinib or lapatinib combined with capecitabine in HER2–positive metastatic breast cancer with Prior taxanes, anthracyclines, and/or trastuzumab: a randomized, phase II study. J Clin Oncol. 2019;37(29):2610-2619. doi./10.1200/JCO.19.00108