Pyrotinib in the Treatment of Women With HER2-Positive Advanced Breast Cancer: A Multicenter, Prospective, Real-World Study

Background HER2-positive breast cancer was aggressive, resulting in a poorer prognosis. This multicenter study analyzed the real-world data of women treated with pyrotinib-based therapy, aiming to describe their characteristics, treatment regimens, and to investigate the clinical outcomes. Methods A total of 141 patients with HER2-positive breast cancer were enrolled from February 2019 to April 2020. Last follow-up time was February 2021. All patients were treated with pyrotinib-based therapy in 21-day cycles. The primary endpoint was progression-free survival (PFS). Results The median PFS (mPFS) for pyrotinib-based therapy was 12.0 months (95%CI 8.1-17.8) in all patients. Among the patients with liver metastases, mPFS was 8.7 months (95%CI, 6.3-15.4) compared to 12.3 months (95%CI, 8.8-23.3) for patients without liver metastases (P=0.172). In addition, patients receiving pyrotinib-based therapy as their >2 lines treatment had a numerically lower mPFS than those receiving pyrotinib-based therapy as their ≤2 lines treatment [8.4 (95%CI, 5.9-15.4) vs. 15.1 (95%CI, 9.3-22.9) months, P=0.107]. The mPFS was 12.2 months (95%CI, 7.9-18.8) in patients with previous exposure to trastuzumab and 11.8 months (95%CI, 6.8-22.9) in patients without previous exposure to trastuzumab (P=0.732). Moreover, mPFS in patients receiving regimens with and without capecitabine were 15.1 months (95%CI, 10.0-18.8) and 8.4 months (95%CI, 6.7-22.9), respectively (P=0.070). Furthermore, in patients with brain metastases, estimated 6-month PFS rate was 70.0%, and rate at 12 months was 60.0%. Seventy patients with measurable lesions were evaluable for response. The objective response rate was 38.6% and disease control rate was 85.7%. The most common adverse event was diarrhea (85.0%). Conclusion Pyrotinib-based therapy showed promising efficacy in patients with HER2-positive breast cancer and was well tolerated, especially in patients treated with pyrotinib as ≤2 lines treatment and receiving regimens with capecitabine. The results of this real-world study further confirmed the intriguing efficacy of pyrotinib.


INTRODUCTION
Breast cancer is one of the most commonly diagnosed malignancy worldwide. Due to lifestyle changes, the incidence of breast cancer is rising in women (1). With the development of early detection and efficient therapies, mortality from breast cancer has decreased. Nevertheless, breast cancer remains an important cause of death (2,3). Human epidermal growth factor receptor 2 (HER2)-positive is a key oncogenic driver event, with pathogenesis mainly being the activation of the PI3K/Akt and MAPK pathways (4). Overexpression of HER2 occurs in 15%-20% of breast cancer (5).
Pyrotinib is a newly-developed irreversible pan-ErbB receptor tyrosine kinase inhibitor inhibiting HER1, HER2, and HER4 (12). In an open-label phase II study, pyrotinib plus capecitabine had significantly longer progression-free survival (PFS) (18.1 months vs. 7.0 months, P<0.001) and higher objective response rate (ORR) (78.5% vs. 57.1%, P<0.05) than lapatinib plus capecitabine in patients with HER2-positive breast cancer (13). In addition, a randomized phase III trial (PHOEBE) enrolled 267 patients previously treated with trastuzumab. The results showed that the median PFS (mPFS) was significantly longer in patients receiving pyrotinib plus capecitabine than in those receiving lapatinib plus capecitabine (12.5 months vs 6.8 months, P <0.0001), and ORR was higher for patients treated with pyrotinib plus capecitabine than those treated with lapatinib plus capecitabine (67.2% vs 51.5%). The most common adverse event was diarrhea which was well manageable (14). Several randomized trials showed the promising efficacy of pyrotinib in HER2-positive breast cancer. However, the efficacy of pyrotinib in patients with different baseline characteristics in the actual clinical practice was rarely reported.
This multicenter study analyzed the real-world data of women treated with pyrotinib-based therapy, aiming to describe their characteristics, treatment regimens, and to investigate the clinical outcomes.

Study Design and Treatment
This was a multicenter, prospective, real-world study conducted at 15 hospitals in China. Patients with HER2-positive breast cancer were enrolled from February 2019 to April 2020. Last follow-up time was February 2021. All patients were treated with pyrotinib-based therapy in 21-day cycles. Starting dose and combination therapy with chemotherapeutic drugs and/or HER2-targeted agents and/or radiotherapy were determined by physicians' choice based on previous clinical trials results, general health status and willing of patients, and collected in the electronic case report form (13)(14)(15). This study was registered with Chinese Clinical Trial Registry (ChiCTR1900021819).

Patient Population
Patients were eligible if they were aged ≥18 years and pathologically confirmed HER2-positive advanced breast cancer. HER2 status was evaluated according to the American Society of Clinical Oncology/College of American Pathologists guidelines (16). HER2-positive status was identified when (on observing within an area of tumor that amounts to >10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression by immunohistochemistry or gene amplification by in situ hybridization (HER2 copy number or HER2/CEP17 ratio based on counting at least 20 cells within the area) (16). Patients were excluded if they were pregnant or lactating; had been previously treated with pyrotinib; lost information of treatment; or received less than one cycle of treatment with pyrotinib. No limits on prior therapy were required.

Study Endpoints
The primary endpoint was PFS, which was defined as the time from the beginning of treatment with pyrotinib to confirmed disease progression or death, whichever came first. The secondary endpoints included ORR (defined as the proportion of patients with a best overall response of complete or partial response), disease control rate (DCR defined as the proportion of patients with a best overall response of complete response, partial response, or stable disease) and overall survival (OS, defined as the time from the beginning of treatment with pyrotinib to death from any cause). Tumor response assessments were conducted in patients with measurable lesions by the investigator according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Safety assessments were performed using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

Statistical Analysis
Patient characteristics, treatment regimens and starting dosages of pyrotinib were summarized as frequency count (percentage) or median (range). Median PFS was estimated by the Kaplan-Meier method, and its 95% confidence interval (CI) was calculated using the Brookmeyer-Crowley method. Median PFS between subgroups (brain metastasis, liver metastasis, the lines of pyrotinib-based therapy, prior exposure to trastuzumab, and regimen with capecitabine) were compared using the log-rank test, and the Cox proportional hazard model was used to analyze the hazard ratio (HR) and 95%CI. Analyses were performed using STATA statistical software version 15.1 or MedCalc version 18.2.1. P<0.05 was considered statistically significant.

Safety
There were 14 patients without available safety data, leaving 127 patients included in the safety assessments. The adverse events (AEs) of all grades and grade ≥3 were reported in 123 patients (96.9%) and 14 patients (11.0%), respectively ( Table 6). The most common AE was diarrhea (85.0%), but only 6 patients (4.7%) reported grade ≥3 diarrhea. Moreover, the AEs of all

DISCUSSION
HER2-positive breast cancer is a more aggressive phenotype (17). The anti-HER2 agents (trastuzumab, pertuzumab, lapatinib, and T-DM1) have dramatically improved the prognosis in patients with HER2-positive breast cancer (18). However, primary or acquired resistance to anti-HER2 agents remains a major challenge (10). Thus, the novel therapy is required to provide option to patients. This study was carried out to analyze the efficacy and safety of pyrotinib-based therapy in patients with HER2-positive breast cancer in the real world. The most inspiring result of the study was a mPFS of 12.0 months, higher than that of trastuzumab (10.9 months) and T-DM1 (10.0 months) in the real-world     setting (19,20), and close to the mPFS result (12.5 months) of pyrotinib in the phase III PHOEBE study (14). In addition, the ORR of pyrotinib-based therapy in this study was 38.6% was also superior to that of T-DM1 (20.0%) (15). Subgroup results confirmed that the mPFS in patients with liver metastases was 8.7 months, which was shorter than the 12.3 months found in patients without liver metastases. This result is concordant with previous report in which liver metastases correlated with worse survival in patients with breast cancer (21,22). Moreover, the mPFS was 15.1 months in patients receiving pyrotinib as ≤2 lines treatment, similar to the result of trastuzumab as first-line treatment reported in the phase III PUFFIN study (14.5 months) (23). Our study demonstrated the efficacy of pyrotinib, providing evidence for the patients treated with pyrotinib as ≤2 lines treatment. In addition, 87.9% of patients in our study received prior trastuzumab treatment, thus we assessed the benefit of pyrotinibbased therapy in patients progressed on trastuzumab. The results showed that patients could benefit from pyrotinib, regardless of whether they had been previously exposed to trastuzumab or not. Our results also confirmed that pyrotinib-based therapy with capecitabine achieved a numerically higher ORR and longer mPFS than that without capecitabine, which merits further assessment in the future. In addition, among patients with brain metastases, the 6-month and 12-month PFS rates were 70.0% and 60.0%, respectively, numerically better than that of anti-HER2 monoclonal antibodies in patients with brain metastases (19,24,25), indicating that pyrotinib is an important treatment option for patients with brain metastases.
Diarrhea was the most common AE (85.0%), but only 4.7% of patients reported grade ≥3 diarrhea which could be well controlled. The incidence of diarrhea in our study was lower than that in previously studies of pyrotinib (14,26), which may be the result of the relatively low dose of pyrotinib (only 70.92% of patients were treated with pyrotinib at a starting dose of 400 mg/day). The antidiarrhea treatment or dose reduction after diarrhea could well control the occurrence of diarrhea.
This study confirmed the advantages of pyrotinib. However, the data were acquired from an observational study which included potential information bias or incomplete data. The sample size was small, and the safety profile of 14 (9.9%) patients could not be evaluated due to the missing data. In addition, the median OS has not yet been reached, but the follow up is ongoing. Despite these limitations, the results of this study provide evidence for the real-world use of pyrotinib in patients with HER2-positive breast cancer.
In conclusion, pyrotinib-based therapy showed promising efficacy in patients with HER2-positive breast cancer and was well tolerated, especially in patients treated with pyrotinib as ≤2 lines treatment and receiving regimens with capecitabine. The results of the real-world study further confirmed the intriguing efficacy of pyrotinib.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by the Ethics Committee of Jiangsu Cancer Hospital. The patients/participants provided their written informed consent to participate in this study.

AUTHOR CONTRIBUTIONS
JF and LZ were involved in study conception and design. LZ, XHW, JZ, MZZ, HY, YSZ, YTZ, ZH, YG, XG, XFW, HX, LS, JXZ, MZ, LX, SY, PC, and JF were involved in the acquisition of data. LZ was involved in the analysis and interpretation of data. XHW was involved in drafting the manuscript. LZ was involved in revising the manuscript. All authors contributed to the article and approved the submitted version.

FUNDING
This work was supported by the Chinese Society of Clinical Oncology-Hengrui Oncology research foundation (grant number: Y-HR2019-0348). The funding source had no role in the study design, collection, analysis and interpretation of data, writing of the manuscript, or decision to submit the article for publication.