A phase 3 randomized clinical trial has found that adding the tyrosine kinase inhibitor pyrotinib to standard trastuzumab and docetaxel therapy significantly improves progression-free survival in patients with previously untreated HER2-positive metastatic breast cancer. The study, published October 31, 2023 in The BMJ, provides evidence for a potential new first-line treatment option for this patient population.
The PHILA trial was a randomized, double-blind, placebo-controlled phase 3 study conducted at 40 centers in China between May 2019 and January 2022. It was funded by Jiangsu Hengrui Pharmaceuticals and partly supported by the CAMS Innovation Fund for Medical Sciences. The study aimed to assess the efficacy and safety of adding pyrotinib, an irreversible pan-HER tyrosine kinase inhibitor, to standard trastuzumab and docetaxel therapy as first-line treatment for HER2-positive metastatic breast cancer.
A total of 590 female patients with untreated HER2-positive metastatic breast cancer were enrolled in the trial. The median age was 52 years (interquartile range 46-58 years). Key inclusion criteria were histologically confirmed HER2-positive (immunohistochemistry 3+ or in situ hybridization positive) recurrent or metastatic breast cancer, no prior systemic treatment for metastatic disease, at least one measurable lesion according to RECIST v1.1 criteria, ECOG performance status of 0-1, and adequate organ function. Patients were excluded if they had prior anti-HER2 therapy (except trastuzumab in the neoadjuvant/adjuvant setting), disease-free interval less than 12 months from completion of neoadjuvant/adjuvant treatment, central nervous system metastases, or other malignancies.
Patients were randomized 1:1 to receive either oral pyrotinib 400 mg once daily or placebo, both in combination with intravenous trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and docetaxel (75 mg/m2) given on day 1 of each 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, death, withdrawal of consent, or investigator decision. Randomization was stratified by prior trastuzumab use in the neoadjuvant/adjuvant setting and hormone receptor status.
The primary endpoint was progression-free survival as assessed by investigators. Secondary endpoints included progression-free survival assessed by independent review, overall survival, objective response rate, duration of response, clinical benefit rate, and safety.
At the data cutoff of May 25, 2022, after a median follow-up of 15.5 months, the study met its primary endpoint. Median progression-free survival was significantly longer in the pyrotinib group compared to the placebo group (24.3 months vs 10.4 months; hazard ratio 0.41, 95% CI 0.32-0.53, p<0.001). The 12-month progression-free survival rate was 74.3% vs 44.0% and the 24-month rate was 50.3% vs 16.6% for the pyrotinib and placebo groups, respectively.
The progression-free survival benefit with pyrotinib was consistent across all pre-specified subgroups analyzed. Notably, the benefit appeared more pronounced in patients who had received prior trastuzumab in the neoadjuvant/adjuvant setting (hazard ratio 0.23, 95% CI 0.12-0.46) compared to those who had not (hazard ratio 0.45, 95% CI 0.34-0.59).
Objective response rates were also significantly higher with pyrotinib (83% vs 71%, p<0.001). The median duration of response was 25.9 months in the pyrotinib group compared to 9.5 months in the placebo group.
Results assessed by independent review were consistent with the investigator-assessed findings. Independent review-assessed median progression-free survival was 33.0 months vs 10.4 months (hazard ratio 0.35, 95% CI 0.27-0.46, p<0.001) for pyrotinib vs placebo.
The safety profile was generally consistent with known adverse events of pyrotinib-based regimens. Grade 3 or higher treatment-related adverse events occurred in 90% of patients in the pyrotinib group compared to 76% in the placebo group. The most common grade 3 or higher adverse events with pyrotinib were decreased neutrophil count (63%), decreased white blood cell count (53%), and diarrhea (46%).
Diarrhea was the most common adverse event associated with pyrotinib, occurring in 99% of patients (46% grade 3). However, grade 3 diarrhea occurred primarily during the first treatment cycle and decreased substantially thereafter. No grade 4 or 5 diarrhea was reported. Diarrhea was generally manageable with antidiarrheal medications.
Treatment-related adverse events led to dose reductions in 26% of patients in the pyrotinib group vs 3% in the placebo group. Treatment discontinuation due to adverse events occurred in 13% vs 7% of patients, respectively. No treatment-related deaths occurred in the pyrotinib group.
The study authors concluded that pyrotinib in combination with trastuzumab and docetaxel demonstrated superior efficacy by significantly improving progression-free survival compared to placebo plus trastuzumab and docetaxel in patients with previously untreated HER2-positive metastatic breast cancer. They noted that the toxicity profile was manageable and suggested this dual anti-HER2 regimen could be an alternative first-line treatment option for this patient population.
The authors highlighted several limitations of the study. First, at the time of study design in 2018, the current standard of care using pertuzumab plus trastuzumab and docetaxel was not yet approved in China, so the control arm did not include pertuzumab. Second, only 15% of patients had received prior trastuzumab in the neoadjuvant/adjuvant setting and none had received pertuzumab, which may limit generalizability to populations with higher rates of prior anti-HER2 therapy. Third, HER2 status was assessed locally rather than by central confirmation. Finally, overall survival data were immature at the time of this analysis and require further follow-up.
Despite these limitations, the PHILA trial provides important evidence supporting the efficacy of combining an oral tyrosine kinase inhibitor with intravenous anti-HER2 therapy in the first-line metastatic setting. The significant improvement in progression-free survival, with a hazard ratio of 0.41, compares favorably to the benefit seen in previous landmark trials like CLEOPATRA (hazard ratio 0.69 for pertuzumab plus trastuzumab and docetaxel). The apparent increased benefit in patients with prior trastuzumab exposure is also noteworthy and warrants further investigation.
The potential clinical impact of these findings is substantial. If confirmed in further studies and real-world use, the addition of pyrotinib to trastuzumab and docetaxel could provide a valuable new first-line option for patients with HER2-positive metastatic breast cancer. The oral administration of pyrotinib may be more convenient for some patients compared to intravenous pertuzumab. Additionally, the possible increased efficacy in patients previously treated with trastuzumab could be particularly beneficial as rates of adjuvant anti-HER2 therapy use continue to increase.
However, the increased toxicity, particularly rates of diarrhea, will need to be carefully considered and managed. While most diarrhea events were low-grade and occurred early in treatment, the high rate of grade 3 diarrhea (46%) is notable. Proactive management strategies and patient education will be crucial if this regimen sees widespread adoption.
It will also be important to see how these results compare to the current global standard of care using pertuzumab. Direct comparative trials would be ideal, but in their absence, careful cross-trial comparisons and real-world evidence will be needed to determine the optimal sequencing and selection of HER2-targeted therapies.
The compelling efficacy seen in this trial has already led to regulatory approval of pyrotinib in combination with trastuzumab and docetaxel as first-line therapy for HER2-positive advanced breast cancer in China. As more data emerge on long-term outcomes, overall survival, and use in broader patient populations, this regimen may become an important new option in the evolving treatment landscape for HER2-positive metastatic breast cancer. Ongoing research into biomarkers of response and resistance will be crucial to further refine patient selection and maximize the impact of this promising approach.
References
Ma F, Yan M, Li W, et al. Pyrotinib versus placebo in combination with trastuzumab and docetaxel as first line treatment in patients with HER2 positive metastatic breast cancer (PHILA): randomised, double blind, multicentre, phase 3 trial [published correction appears in BMJ. 2023 Nov 16;383:p2665. doi: 10.1136/bmj.p2665]. BMJ. 2023;383:e076065. Published 2023 Oct 31. doi:10.1136/bmj-2023-076065
