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The addition of pyrotinib to trastuzumab and docetaxel significantly improved progression-free survival vs trastuzumab/docetaxel alone in patients with HER2-positive metastatic breast cancer.
The addition of pyrotinib to trastuzumab (Herceptin) and docetaxel significantly improved progression-free survival (PFS) vs trastuzumab/docetaxel alone in patients with HER2-positive metastatic breast cancer, according to data from the phase 3 PHILA trial (NCT03863223).1
Data presented at the 2022 ESMO Congress showed that the median PFS was 24.3 months (95% CI, 19.1-33.0) per investigator assessment with the pyrotinib regimen vs 10.4 months (95% CI, 9.3-12.3) with trastuzumab plus docetaxel alone, translating to 59% reduction in the risk of disease progression or death (HR, 0.41; 95% CI, 0.32-0.53; P < .0001). The 12-month PFS rates in the investigative and control arms were 74.3% and 44.0%, respectively; at 24 months, these rates were 50.3% and 16.6%, respectively.
“To our knowledge, this is the second phase 3 trial to demonstrate PFS benefit from dual HER2 inhibition in the first-line treatment of HER2-positive metastatic breast cancer,” lead study author Binghe Xu, of the Department of Medical Oncology, Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, and colleagues, said in a presentation of the data.
The irreversible pan-HER inhibitor, pyrotinib, has previously demonstrated encouraging antitumor activity when paired with capecitabine in patients with HER2-positive metastatic breast cancer. Specifically, data from the phase 3 PHOEBE trial (NCT03080805), showed that the doublet resulted in a median PFS of 12.5 months (95% CI, 9.7-NR) vs 6.8 months (95% CI, 5.4-8.1) with lapatinib (Tykerb) plus capecitabine (HR, 0.39; 95% CI, 0.27-0.56; P < .0001).2
The double-blind, placebo-controlled, multicenter, phase 3 PHILA trial enrolled patients with pathologically confirmed, HER2-positive metastatic breast cancer who were treatment naïve. These patients were required to have measurable disease per RECIST v1.1 criteria and an ECOG performance status of 0 or 1.
A total of 590 participants were randomly assigned 1:1 to receive oral pyrotinib at a once-daily dose of 400 mg (n = 297) or placebo (n = 293) plus intravenous (IV) trastuzumab at 8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles and IV docetaxel at 75 mg/m2 on day 1 of each 21-day cycle. Treatment was continued until disease progression, intolerable toxicity, patient withdrawal, or investigator decision.
Patients were stratified by prior neoadjuvant or adjuvant trastuzumab (yes vs no) and hormone receptor status (estrogen receptor (ER)– and/or progesterone receptor–positive disease vs ER-negative and progesterone receptor–negative disease.
The primary end point of the trial was PFS per investigator assessment. Key secondary end points comprised PFS per independent review committee assessment, overall survival, objective response rate (ORR), duration of response (DOR), clinical benefit rate, and safety.
The data cutoff for the prespecified interim analysis was May 25, 2022. The median follow-up for the pyrotinib regimen was 15.8 months (range, 0.4-36.2) and 14.9 months (range, 0.4-35.3) with trastuzumab plus docetaxel.
Per IRC assessment, the median PFS with pyrotinib plus trastuzumab/docetaxel was 33.0 months (95% CI, 19.4–not reached [NR]) vs 10.4 months with trastuzumab plus docetaxel alone, translating to a 65% reduction in the risk of disease progression or death (HR, 0.35; 95% CI, 0.27-0.46; P < .0001). The PFS rates at 12 months were 77.3% and 44.5%, respectively; the 24-month rates were 55.3% and 13.3%, respectively.
Within the subgroup of patients who received prior (neo)adjuvant trastuzumab, those who received the pyrotinib regimen experienced a median PFS that was not yet reached (95% CI, 14.6-NR) vs 9.3 months (95% CI, 6.3-12.4) with trastuzumab/docetaxel (HR, 0.23; 95% CI, 0.12-0.46). In those who did not receive prior (neo)adjuvant trastuzumab, the median PFS in the investigative and control arms was 21.9 months (95% CI, 16.5-30.5) and 10.4 months (95% CI, 9.5-12.4), respectively (HR, 0.45; 95% CI, 0.34-0.59).
Additionally, in those who had a treatment-free interval with prior adjuvant therapy of at least 12 months and less than 24 months who received the pyrotinib regimen, the median PFS was not yet reached (95% CI, 14.7-NR) vs 8.3 months (95% CI, 6.2-11.8) with trastuzumab plus docetaxel (HR, 0.22; 95% CI, 0.10-0.50). In those who had a treatment-free interval of at least 24 months and who received the pyrotinib regimen or the control regimen, the median PFS was 22.2 months (95% CI, 12.5-NR) and 13.0 months (95% CI, 10.3-16.6), respectively (HR, 0.57; 95% CI, 0.37-0.87).
The addition of pyrotinib to trastuzumab and docetaxel elicited an ORR of 82.8% (95% CI, 78.1%-86.9%) per investigator assessment vs 70.6% (95% CI, 65.1%-75.8%) with trastuzumab plus docetaxel. Of those who responded to the pyrotinib regimen, 6.4% achieved a complete response, 76.4% experienced a partial response, and 10.4% had stable disease; 2.7% of patients experienced disease progression. The median DOR in the investigative and control arms were 25.9 months (95% CI, 17.3-NR) and 9.5 months (95% CI, 8.3-10.6), respectively.
The safety profile of the pyrotinib regimen was manageable, and the adverse effects (AEs) were consistent with prior reports of each agent.
All patients experienced treatment-related AEs (TRAEs) in the investigative arm vs 99.7% of those in the control arm; these effects were grade 3 or higher in 89.9% and 76.5% of patients, respectively. Serious TRAEs occurred in 24.9% of those in the investigative arm vs 6.1% of those in the control arm.
TRAEs resulted in treatment interruption, reduction, and discontinuation in 56.6%, 25.9%, and 13.1%, respectively, of patients who received the pyrotinib regimen; these rates were 24.2%, 3.1%, and 7.2%, respectively, in those who were given trastuzumab plus docetaxel. No patients in the investigative arm died from TRAEs vs 1 patient in the control arm.
The most frequently experienced TRAEs were diarrhea, decreased white blood cell count, decreased neutrophil count, anemia, vomiting, decreased weight, nausea, hypokalemia, increased aspartate aminotransferase, increased alanine aminotransferase, alopecia, increased blood creatinine, asthenia, decreased appetite, hypoalbuminemia, hypertriglyceridemia, and hypercholesterolemia.