Pyrotinib therapy in HER2+ breast cancer
Breast cancer with human epidermal growth factor receptor 2 (HER2) occurs in almost 15-20% of all breast cancers. This type of cancer also shows aggressive clinical behavior and has a poor prognosis. The development and use of anti-HER2 drugs have improved outcomes for patients with HER2-positive breast cancer. However, patients eventually develop resistance to these drugs and relapse. This is why it’s important to develop new anti-HER2 targeted drugs to overcome drug resistance. Pyrotinib is an irreversible ErbB receptor tyrosine kinase inhibitor that targets HER1, HER2, and HER4. It also helps improve the progression-free survival in HER2-positive metastatic breast cancer.
From the data gathered from studies of pyrotinib, the two common complications that arise after therapy are diarrhea and palmar-plantar erythrodysesthesia. Because of this, physicians have modified doses, sometimes interrupted treatment, and even discontinued therapy altogether. In this study, the researchers investigated the effectiveness and safety of pyrotinib in complex real-world clinical practice.
Methods
The study is a retrospective, single-center study of HER2-positive patients at Shandong Cancer Hospital and Institute in China. The study date began in October 2018 and ended in October 2020. These are the eligibility criteria for patients:
(1) female patients with HER2- positive MBC (HER2 positivity was histologically confirmed by immunohistochemistry category of 3+ or fluorescence in situ hybridization with HER2 gene amplification; if a re-biopsy of the metastatic site was infeasible, HER2 status was determined based on the latest primary tumor specimen);
(2) not less than one measurable lesion based on Response Evaluation Criteria in Solid Tumors guidelines version 1.1 (RECIST 1.1);
(3) complete medical records. Patients were excluded from the study if they had previously enrolled in any pyrotinib- related clinical trial settings or refused to provide written informed consent.
A total of 248 patients were enrolled. Patients who discontinued pyrotinib for severe adverse events or economic reasons and were lost to follow-up were excluded from the efficacy analysis. The study was approved by the institutional review board and all the individual participants confirmed their informed consent.
The patients then received pyrotinib in routine clinical practice, accompanied by chemotherapeutic drugs and/or anti- HER2- targeted agents. The initial dose of pyrotinib, dose modification, and treatment termination were determined by the physicians’ clinical decision according to clinical trial results, grade of adverse events (AEs), physical performance status, and willingness of the patient.
All patients were evaluable for PFS analysis. The median follow-up time was 9.5 months (interquartile range, 5.0– 10.0 months). The median PFS was 9.3 months (95% CI, 8.6– 10.0 months). OS data were not achieved at the time of analysis. Menstrual status, ECOG score, BMI, and hormone receptor status had no significant correlation with PFS in the log-rank analysis (p = 0.638, p = 0.723, p = 0.751, and p = 0.968, respectively). Patients who received pyrotinib- based therapy as first, second, and later lines of metastatic treatment had a median PFS of 15.0 (13.2– 16.8), 10.3 (9.3– 11.3), and 6.8 (6.4– 7.3) months, respectively.
Patients with one or two metastatic sites achieved a longer PFS time (11.4 (10.0– 12.8) months) than patients with >2 metastatic sites (8.3 (7.6– 9.0) months). Fifty- three patients with brain metastases showed a median PFS of 7.0 (6.1– 7.8) months. A total of 118 patients with visceral metastases, not including those who had brain metastases, and 47 patients with soft tissue and/or bone metastases only had median PFS of 9.1 (8.4– 9.9) months and 12.3 (10.3– 14.3) months, respectively.
Results
267 patients with HER2-positive advanced breast cancer were reviewed. From these, only 218 patients were included in the efficacy cohort. The median age at diagnosis was 51 years (range, 34– 75 years) and 144 (66.1%) were premenopausal. The ECOG performance status was 0– 1 in 203 (93.1%) patients at the time of therapy. The majority (191, 87.6%) of patients had IDC and the positivity of HR status was 52.8%. Thirty- nine patients (17.9%) had de novo stage IV breast cancer.
The median number of metastatic sites was 3.0, with 107 (49.1%) patients exhibiting local involvement, 152 (69.7%) exhibiting node metastasis, 109 (50.0%) exhibiting bone metastasis, 159 (72.9%) exhibiting visceral metastasis, and 53 (24.3%) exhibiting brain metastasis. All patients except 10 (4.6%) had previously received anti-HER2 therapy, with 208 (95.4%) patients receiving trastuzumab, 11 (5.0%) patients receiving pertuzumab, and 89 (40.8%) patients receiving lapatinib.
The patients were exposed to trastuzumab in either (neo)adjuvant (82, 37.6%) or metastatic settings (186, 85.3%). Of the pa-tients with trastuzumab in the (neo)adjuvant setting, 71 received trastuzumab over a 1-year standard schedule, while 11 received less trastuzumab therapy due to primary resistance, intolerable toxicity, or other reasons.
Trastuzumab resistance and trastuzumab refractoriness occurred in 25.2% and 67.9% of patients in the efficacy cohort, respectively. Thirty-three (15.1%) and fifty (22.9%) patients received pyrotinib- based therapy as first-line or second-line systematic treatment, respectively. A total of 135 (62.0%) patients received two or more lines of prior treatment for MBC before pyrotinib, representing the heavily pretreated group.
Conclusion
Dual anti-HER2 therapy and taxane have become the standard first-line treatment for HER2-positive MBC and T-DM1 was the most used therapy for patients who exhibit progression after prior trastuzumab-based treatment.
However, pertuzumab and T-DM1 weren’t approved for the metastatic setting in China resulting in limitations in the ability to use these drugs in clinical practice. The alternative is pyrotinib or lapatinib, especially for those patients that show resistance.
From the results of PHENIX and PHBOB studies, HER2 positive MBC patients treated with pyrotinib plus capecitabine after trastuzumab and chemotherapy have been shown to improve the outcomes.
Primary populations of HER2 positive MBC patients who were previously treated with multiple anti-HER2 therapies still respond to pyrotinib-based treatment in clinical practice and combined agents such as vinorelbine and Abraxane are incorporated into various chemotherapy regimens.
The safety and efficacy of clinical trials are applicable for later line pyrotinib-based therapy is still questionable. This study shows real-world data that strengthens the results of previous clinical trials. It also serves as a foundation to further explore pyrotinib treatment patterns.
The study showed that the median PFS for all patients who received pyrotinib- based treatment was 9.3 months, and the ORR was 44.0%, with a CR of 6.4% and PR of 37.6%, while the PFS time was 18.1 months and 12.5 months and the ORR was 67% and 78.5% for pyrotinib plus capecitabine, in PHENIX and PHBOBE studies, respectively.
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