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Purpose: To explore the efficacy and safety of pyrotinib combined with different radiotherapy modes in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) patients with brain metastasis (BM)., Patients and Methods: This study is a retrospective analysis of patients diagnosed with BM who underwent treatment with pyrotinib between November 2018 and April 2023. A total of 66 patients were administered radiotherapy in conjunction with pyrotinib (Group A), while 26 patients received pyrotinib as a standalone treatment (Group B). Within Group A, 18 patients underwent conventional fractionated radiotherapy (2Gy/F), while 48 patients received hyperfractionated radiotherapy (HFRT) (≥3Gy/F). The primary endpoints were intracranial progression-free survival (IC-PFS) and overall survival (OS). The secondary endpoints were objective response rate (ORR) and clinical benefit rate (CBR)., Results: The ORR of Group A was 54.5% (36/66), while the ORR of Group B was 34.6% (9/26) (P= 0.047). The CBR of Group A was 89.4% (59/66) and that of Group B was 69.2% (18/26) (P= 0.041). The IC-PFS between Group A and Group B were 12 months and 8 months, respectively (P< 0.001), and the OS were 20 months and 16 months, respectively (P= 0.065). In Group A, the IC-PFS and OS between the conventional fractionation radiotherapy group and the HFRT group were 10 months and 12 months, respectively (P= 0.001) and 16 months and 24 months, respectively (P< 0.001). No serious adverse reactions were observed in Group A and Group B., Conclusion: For HER2-positive BC patients with BM, it is recommended to adopt the treatment mode of HFRT combined with pyrotinib, which can improve the local control and survival of patients., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Huang et al.)

Pyrotinib, an irreversible pan-ErbB inhibitor, has been approved for treating HER2-positive advanced breast cancer in China. We conducted a nationwide, prospective observational study to examine the real-world data of pyrotinib-based therapy in this population. Patients from 61 sites across China were included. Pyrotinib-based regimens were prescribed at local physician's discretion. Demographics, treatment patterns, prognosis and safety were evaluated. The primary outcome was real-world progression-free survival (rwPFS). Of 1129 patients, pyrotinib-based therapy was prescribed as first-, second- and third- or later-line treatment in 437 (38.7%), 476 (42.2%) and 216 (19.1%) patients, respectively. Median rwPFS (mrwPFS) was 14.3 (95% CI, 13.3-15.2) months in the total population, with the longest mrwPFS of 17.8 (95% CI, 15.2-24.9) months in the first-line setting, followed by 14.4 (95% CI, 12.9-15.3) months in the second-line setting. Patients with third- or later-line treatment also achieved a mrwPFS of 9.3 (95% CI, 8.4-11.8) months. Patients with trastuzumab- or trastuzumab-pertuzumab-treated disease achieved a mrwPFS of 14.3 and 13.6 months, respectively. Dual HER2 blockade with pyrotinib plus trastuzumab showed a mrwPFS of 16.2 months in the total population, with data not mature in the first-line setting. For patients with baseline brain metastases, the mrwPFS was 11.7 months. The most common adverse event was diarrhea (any grade, 73.5%; grade ≥ 3, 15.3%). In real world, pyrotinib-based therapy shows promising effectiveness in the first-, as well as second- and later-line treatment, with acceptable tolerability. Further investigations regarding front-line use or novel combinations of pyrotinib might facilitate to maximize its anti-tumor potential., (© 2023 UICC.)

Background: Although some targeted therapies have been shown to be effective in treating HER2-altered non-small cell lung cancer (NSCLC), the survival demands have not yet been met due to the high cost and limited availability. This study aimed to assess the effectiveness and safety of pyrotinib plus antiangiogenic agents, including apatinib, anlotinib, and bevacizumab, in previously treated patients with HER2-altered advanced NSCLC., Methods: In this retrospective real-world study, patients with HER2-altered NSCLC who received pyrotinib plus antiangiogenic agents as a second- or later-line treatment between November 2015 and January 2022 were reviewed. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety profiles of patients were analyzed., Results: A total of 107 patients were included in the analysis, of which 59 patients (55.1%) had received at least two lines of prior chemotherapy or tyrosine kinase inhibitors. Most of them (87.9%) were identified as harboring HER2 exon 20 insertions. At the data cutoff date (May 13, 2022), the ORR, DCR, median PFS, and median OS were 19.6% (21/107), 94.4% (101/107), 7.13 months (95% confidence interval [CI]: 6.26-8.01), and 19.50 months (95% CI: 12.83-26.17), respectively. There was no difference in the PFS between patients receiving apatinib or anlotinib/bevacizumab (median PFS, 7.13 vs. 6.27 months, hazard ratio [HR] = 1.49, 95% CI: 0.87-2.54, p = 0.15). The most frequent grade 3 or higher treatment-related adverse events was diarrhea (17.6%), followed by hypertension (11.0%) and nausea (3.3%). No treatment-related death occurred., Conclusion: In this study, pyrotinib plus antiangiogenic agents demonstrated promising efficacy and were tolerable in HER2-altered NSCLC patients., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Peripheral blood biomarkers have been reported to be associated with the prognosis of breast cancer (BC) patients, but a few findings remain controversial. This study aimed to explore the correlation between peripheral blood indicators and treatment outcomes in human epidermal growth factor receptor 2 (HER2)-positive advanced BC patients treated with pyrotinib., Methods: This was a retrospective cohort study including 156 HER2-positive advanced BC patients who treated with pyrotinib between March 2019 and May 2021. The baseline clinical characteristics including age, hormone receptor (HR) status, Ki-67, sites of metastasis, antitumor therapies and peripheral blood parameters including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR), the product of neutrophil, platelet, and monocyte counts divided by lymphocyte count [pan-immune-inflammation value (PIV)] were collected. Tumor response was assessed every two cycles during treatment period. Follow-up was performed every 2 months to record survival status. All patients were followed up until death or time of data lock., Results: Low PLR was associated with better disease control rate (P=0.005). Univariate analysis showed that high MLR (P=0.004), PLR (P=0.003), or PIV (P=0.02), low lymphocyte count (P=0.025), more than two metastatic sites (P<0.001), and presence of liver metastasis (P<0.001) or brain metastasis (P<0.001) were associated with poor progression-free survival (PFS). Multivariate analysis showed that only high PLR was an independent factor for poor PFS [hazard ratio =0.63; 95% confidence interval (CI): 0.41-0.97; P=0.038]. For overall survival (OS), univariate analysis showed that high NLR (P=0.001), MLR (P=0.005), PLR (P<0.001), or PIV (P=0.018), more than two metastatic sites (P=0.001), presence of liver metastasis (P=0.004) or brain metastasis (P=0.007), and pyrotinib monotherapy (P=0.036) were associated with worse OS. Multivariate analysis showed that PLR (hazard ratio =0.37; 95% CI: 0.14-0.94; P=0.037), number of metastatic sites (hazard ratio =2.84; 95% CI: 1.02-7.94; P=0.046) and treatment regimens (hazard ratio =0.15; 95% CI: 0.03-0.73; P=0.019) were independent factors., Conclusions: High PLR is associated with poor treatment response and is an independent unfavorable prognostic factor in HER2-positive advanced BC patients treated with pyrotinib. The findings herein indicate that patients with higher PLR are less likely to benefit from pyrotinib-based therapy and may be helpful in identifying the effective population in clinical practice., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1078/coif). The authors have no conflicts of interest to declare., (2023 Translational Cancer Research. All rights reserved.)

Background: Human epidermal growth factor receptor 2 (HER2)-targeted agents have significantly improved the outcomes of patients with HER2-positive breast cancer; however, a large proportion of patients still develop resistance to trastuzumab. In this study, we investigated the efficacy and safety of inetetamab, another anti-HER2 antibody, combined with pyrotinib and oral vinorelbine in patients with HER2-positive advanced breast cancer so as to provide new ideas for the treatment., Methods: In this prospective, single-arm, phase 2 trial, patients with HER2-positive advanced breast cancer with disease progression after trastuzumab were recruited. Patients received a combination of inetetamab (loading dose of 8 mg/kg and subsequent doses of 6 mg/kg intravenously once every 3 weeks), pyrotinib (400 mg orally once daily), and vinorelbine (60 mg/m 2 orally once weekly) until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), overall survival (OS), disease control rate (DCR), and safety., Results: Between February 13, 2022 and December 25, 2022, 30 patients were screened and enrolled in this study. The median age of the patients at enrollment was 54 years, 12 patients (40.0 %) had hormone-receptor-positive disease and 23 patients (76.7 %) had visceral metastasis. The median PFS was 8.63 months (95 % confidence interval [CI] 4.15-13.12 months). The median OS was not reached. The ORR was 53.3 % (16/30) and the DCR was 96.7 % (29/30). The most common Grade III/IV adverse events were leukopenia ( n  = 5, 16.7 %), neutropenia ( n  = 4, 13.3 %), and diarrhea ( n  = 3, 10 %). No treatment-related serious adverse events or deaths occurred., Conclusions: The combination regimen of inetetamab, pyrotinib, and oral vinorelbine showed encouraging efficacy and favorable safety in patients with HER2-positive advanced breast cancer and could be considered as an alternative treatment option for the patients., Trial Registration: No.NCT05823623; https://www.clinicaltrials.gov/., Competing Interests: None., (© 2023 The Author(s).)

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) is a highly aggressive subtype associated with poor prognosis. The advent of HER2-targeted drugs, including monoclonal antibodies, tyrosine-kinase inhibitors (TKIs) and antibody-drug conjugates, has yielded improved prognosis for patients. Compared with widely used monoclonal antibodies, small-molecule TKIs have unique advantages including oral administration and favorable penetration of blood-brain barrier for brain metastatic BC, and reduced cardiotoxicity. Pyrotinib is an irreversible TKI of the pan-ErbB receptor, and has recently been shown to be clinically effective for the treatment of HER2-positive BC in metastatic and neoadjuvant settings. This review highlights the development on the application of pyrotinib-based therapeutic approaches in the clinical settings of HER2-positive BC., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: Pyrotinib is a newly developed tyrosine kinase inhibitor whose in vivo clearance relies heavily on cytochrome P450 3A4 (CYP3A4) activity. Clinical trials are ongoing to explore the effects of coadministration with CYP3A4 perpetrators on pyrotinib exposure. The present study aims to utilize physiologically based pharmacokinetic (PBPK) modeling to predict CYP3A4-based drug interactions of pyrotinib., Methods: Pyrotinib PBPK model was developed in the PK-Sim ® multicompartmental physiology structure. Physiochemical parameters were obtained from the literature, and clearance-related parameters were optimized by fitting clinical single-dose pharmacokinetic data. Pharmacokinetic parameters from the model output were compared with the observed data to validate the model predictive performance. Using validated CYP3A4 perpetrator models, we conducted PBPK simulations for drug interactions in a virtual population to explore the impacts of comedication with these perpetrators., Results: The PBPK model accurately describes pyrotinib single- and multi-dose pharmacokinetics. The model also predicts dramatic exposure change of pyrotinib in the presence of itraconazole and rifampicin, though the impact of rifampicin is somewhat underestimated. According to model predictions, coadministration with typical potent or moderate CYP3A4 perpetrators increases pyrotinib concentration by over sixfold, extinguishing the possibility of dose adjustment for pyrotinib. A weak CYP3A4 inhibitor has minimal influence on pyrotinib pharmacokinetics., Conclusion: PBPK modeling provides valuable information to avoid irrational medication when receiving pyrotinib chemotherapy., (© 2023. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Human epidermal growth factor receptor 2 (HER2) plays a critical role in breast cancer progression in patients with HER2 overexpression, thereby driving the development of targeted drugs and advancing therapy strategies targeting this gene. Pyrotinib is a novel irreversible pan-ErbB kinase inhibitor, primarily suppresses the downstream MAPK and PI3K/AKT pathways. Alpelisib, a selective PI3K p110α inhibitor, has been approved for clinical application in HR+, HER2-, PIK3CA mutated breast cancers and is also being developed for use in other breast cancer subtypes. In this study, we hypothesised that combining pyrotinib with alpelisib would yield superior results compared to single-drug treatment. Our data demonstrated that the combination of alpelisib and pyrotinib exhibited a synergistic effect in HER2+ breast cancer both in vitro and in vivo. This combination led to decreased cell proliferation and migration, G0-G1 cell cycle arrest, and increased apoptosis rates. Additionally, the deactivation of ErbB receptors and sustained activation of PI3K/AKT pathway by upstream compensatory pathways induced acquired pyrotinib resistant cells resistant to pyrotinib treatment, thus alpelisib combined with pyrotinib showed a tremendous synergistic effect and reverse pyrotinib resistance in acquired pyrotinib resistant cells by suppressing the activated PI3K/AKT pathway. Our results revealed a combination of pyrotinib and alpelisib as an effective therapeutic strategy in treating HER2+ breast cancer, whether sensitive or resistant to pyrotinib treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer and primary resistance to trastuzumab have a poor clinical outcome and lack good evidence to inform clinical decision. This study investigated the efficacy and safety of pyrotinib plus capecitabine in this population., Methods: This phase 2 trial was conducted at 16 sites in China. Patients received oral pyrotinib 400 mg once daily and capecitabine 1000 mg/m 2 twice a day on days 1-14 of each 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS)., Results: Between June 2019 and September 2021, 100 patients were enrolled with a median age of 51 years (range, 24-69). All patients had been treated with trastuzumab and 21 (21.0%) patients had prior use of pertuzumab. As of August 31, 2022, the median follow-up duration was 20.1 months (range, 1.3-38.2). The median PFS was 11.8 months (95% confidence interval [CI], 8.4-15.1), which crossed the pre-specified efficacy boundary of 8.0 months. The objective response rate was 70.0% (70/100), with a median duration of response of 13.8 months (95% CI, 10.2-19.3). The disease control rate was 87.0% (87/100). The median overall survival was not reached. The most common grade ≥ 3 treatment-emergent adverse event was diarrhea (24 [24.0%]). No treatment-related deaths occurred., Conclusions: Pyrotinib plus capecitabine can be considered to be a treatment option in HER2-positive advanced breast cancer patients who have shown primary resistance to trastuzumab. Even in the era of modern anti-HER2 treatments, this clinical setting warrants more investigations to meet unmet needs., Trial Registration: ClinicalTrials.gov, NCT04001621. Retrospectively registered on June 28, 2019., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: We report a case of metastatic human epidermal growth factor receptor-2 (HER2) positive breast cancer who achieved encouraging clinical benefits across multiple pyrotinib-based anti-HER2 therapies., Case Description: A 33-year-old woman was diagnosed with hormone receptor (HR) positive, HER2-positive breast cancer in June 2018, and did not receive adjuvant radiotherapy, chemotherapy, or anti-HER2 targeted therapy post-breast conserving surgery. By May 2020, she developed recurrence of the left breast mass with metastases in liver, bone and lymph nodes. She then received pyrotinib plus trastuzumab and nab-paclitaxel as first-line therapy. Both the left breast mass and liver metastases showed noticeable improvement, with the disease evaluated as partial response (PR). Despite this promising result, the patient developed brain metastases after first-line treatment. A combination regimen of pyrotinib retention plus inetetamab and vinorelbine were administered as second-line anti-HER2 therapy, and the brain metastases visibly shrunk, leading to PR, with the extracranial lesions remaining stable. Ultimately, due to brain lesions progression, the treatment was transitioned to trastuzumab deruxtecan. We applied next generation sequencing (NGS) to illustrate the efficacy of anti-HER2 therapy and minimal residual disease (MRD) to detect the disease status., Conclusions: Pyrotinib is a promising antineoplastic agent for HER2-positive advanced breast cancer patients. Under the guidance of precision medicine, it is encouraged to utilize novel diagnostic and therapeutic methods to manage advanced breast cancer patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-23-26/coif). XW serves as an unpaid editorial board member of Translational Breast Cancer Research from March 2022 to February 2024. The other authors have no conflicts of interest to declare., (2023 Translational Breast Cancer Research. All rights reserved.)

HER2 signaling is activated in response to somatic HER2 mutations, which are often found in invasive lobular breast cancer (ILC) and are associated with poor prognosis. Tyrosine kinase inhibitors (TKIs) have demonstrated considerable antitumor activity in patients with HER2-mutated advanced breast cancer (BC). Further, several clinical trials have indicated that HER2-targeted antibody-drug conjugates (ADCs) exhibit promising efficacy in lung cancer with HER2 mutations, and the efficacy of ADCs against HER2-mutated BC is currently being evaluated. Several preclinical studies have demonstrated that the therapeutic efficacy of ADCs in HER2-mutated cancer can be enhanced by the addition of irreversible TKIs, but the potential of such a combined treatment regimen for the treatment of HER2-mutated BC has not been reported. Herein, we describe a case in which a patient with estrogen receptor-positive/HER2-negative metastatic ILC with 2 activating HER2 mutations (D769H and V777L) exhibited a significant and durable response to anti-HER2 treatment with pyrotinib (an irreversible TKI) in combination with ado-trastuzumab emtansine, which was administered after multiple lines of therapy that had resulted in disease progression. Further, based on the evidence from the present case, TKI plus ADC seems to be a promising combination anti-HER2 regimen for patients with HER2-negative/HER2-mutated advanced BC, although further rigorous studies are warranted to confirm these findings., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Human epidermal growth factor receptor 2 (HER2) targeted therapy combined with endocrine therapy has been recommended as an alternative treatment strategy for patients with hormone receptor (HR)-positive, HER2-positive metastatic breast cancer (MBC). This study aimed to evaluate the role of pyrotinib, an oral pan-HER irreversible tyrosine kinase inhibitor, in combination with letrozole for patients with HR-positive, HER2-positive MBC., Methods: In this multi-center, phase II trial, HR-positive and HER2-positive MBC patients who were not previously treated for metastasis disease were enrolled. Patients received daily oral pyrotinib 400 mg and letrozole 2.5 mg until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the clinical benefit rate (CBR) assessed by an investigator according to the Response Evaluation Criteria in Solid Tumors version 1.1., Results: From November 2019 to December 2021, 53 patients were enrolled and received pyrotinib plus letrozole. As of August 2022, the median follow-up duration was 11.6 months (95% confidence interval [CI], 8.7-14.0 months). The CBR was 71.7% (95% CI, 57.7-83.2%), and the objective response rate was 64.2% (95% CI, 49.8-76.9%). The median progression-free survival was 13.7 months (95% CI, 10.7-18.7 months). The most common treatment-related adverse event of grade 3 or higher was diarrhea (18.9%). No treatment-related deaths were reported, and one patient experienced treatment discontinuation due to adverse event., Conclusions: Our preliminary results suggested that pyrotinib plus letrozole is feasible for the first-line treatment of patients with HR-positive and HER2-positive MBC, with manageable toxicities., Trial Registration: ClinicalTrials.gov, NCT04407988., (© 2023. The Author(s).)

Introduction: Pyrotinib is a novel irreversible pan-HER tyrosine kinase inhibitor (TKI). However, real-world data of pyrotinib-containing therapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and developing brain metastases (BMs) are limited, and the genomic profile of this subpopulation is almost undefined., Methods and Materials: Patients with BM of HER2-positive MBC (n = 35) treated with pyrotinib-containing therapy were enrolled in this analysis. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and toxicity profiles were evaluated. Hazard ratios (HRs) and 95% confidence intervals (CIs) for disease progression were estimated using the Cox proportional hazards models. Targeted next-generation sequencing of 618 cancer-relevant genes was performed on plasma and primary breast tumors from patients with BM and without BM., Results: The median PFS time was 8.00 (95% CI, 5.98-10.017) months, and the median OS time was 23 (95% CI, 10.412-35.588) months. The ORR was 45.7%, and the DCR was 74.3%. In the Cox multivariate analysis, prior exposure to brain radiotherapy (HR = 3.268), received pyrotinib as third- or higher-line treatment (HR = 4.949), subtentorial brain metastasis (HR = 6.222), and both supratentorial and subtentorial brain metastases (HR = 5.863) were independently associated with increased risk of progression. The frequent grade 3-4 adverse event was increased direct bilirubin (14.3%), and two patients suffered from grade 3-4 diarrhea. In the exploratory genomic analysis, altered frequencies of FGFR3, CD276, CDC73, and EPHX1 were higher in the BM group. The consistency of mutated profiles of plasma and primary lesion in the BM group was significantly lower (30.4% vs. 65.5%; p = 0.0038)., Conclusions: Pyrotinib-containing therapy shows favorable effectiveness and tolerable safety in patients with BM of HER2-positive MBC, particularly in a population that is brain radiotherapy-naïve, received pyrotinib as first- or second-line treatment, and developed supratentorial brain metastasis. In the exploratory genomic analysis, patients with BM showed distinct genomic features from patients without BM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Liu, Zhang, Zhang, Ran, Ma, Yang, Wang, He, Zhao, Wang, Zhang, Dong and Yang.)

Background: Non-small cell lung cancer (NSCLC) with HER2 mutation has entered into the era of targeted therapy. However, both anti-HER2 antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs) showed moderate objective response rate (ORR) and median progression-free survival (PFS). The aim of this study was to investigate the molecular features of responders to pyrotinib in advanced NSCLC with HER2 mutation., Methods: Patients from our two previous phase II trials were pooled analyzed. Their circulating tumor DNA (ctDNA) were detected by next-generation sequencing (NGS) panels, and the correlation with the efficacy of pyrotinib was investigated., Results: This pooled analysis included 75 patients, and 50 of them with baseline plasma samples were finally enrolled with a median age of 57 years old. The overall ORR and median PFS were 28% and 7.0 months respectively. Biomarker analysis showed that 5 patients were ctDNA nonshedding. Patients with TP53 wild type were significantly associated with higher disease control rate (97.1%vs. 68.8%, p = 0.010), PFS (median 8.4 vs. 2.8 months, p = 0.001) and overall survival (OS, median 26.7 vs. 10.4 months, p < 0.001) than those with mutations. ctDNA of nonshedding and clearance exhibited significantly longer PFS (median: 10.2 vs. 9.8 vs. 5.6 months, p = 0.036) and a trend of longer OS (median: 35.3 vs. 18.1 vs. 14.6 months, p = 0.357) than those not., Conclusion: Patients with TP53 wild type, ctDNA nonshedding, or clearance showed superior efficacy of pyrotinib in patients with HER2-mutated advanced NSCLC, which might be helpful to guide the utility of pyrotinib in clinical setting., Trial Registration: The patients were from two registered clinical trials (ClinicalTrials.gov: NCT02535507, NCT02834936)., (© 2023. The Author(s).)

Pyrotinib is a novel irreversible tyrosine kinase inhibitor developed for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The results of phase I clinical trial demonstrated that pyrotinib was well tolerated and exhibited potent antitumor activity. As a promising therapeutic agent for HER2-positive breast cancer, it is of great importance to investigate the biotransformation of pyrotinib in humans and identify the major enzymes involved in its metabolism during its early stage of development for safety consideration. For this purpose, a robust analytical method based on ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) was established to characterize the metabolites of pyrotinib in human plasma, feces, and urine, and identify the primary enzymes responsible for its metabolism. As a result, a total of 24 metabolites were identified, including 16 phase I metabolites resulting from dealkylation, oxidation, dehydrogenation, and carbonylation, and 8 phase II metabolites originating from cysteine and N -acetylcysteine conjugation. Pyrotinib was absorbed into blood by 1 h, reached its peak level at 4 h, and afterwards underwent slow elimination. The principal metabolites detected in humans (M1, M2, and M5) were products resulting from O -depicoline and pyrrolidine lactam formation, whose structures have been confirmed by the synthetic references. In addition, fecal clearance was the major route of excretion for pyrotinib. Further phenotyping experiment proved that CYP3A4 was the most active enzyme responsible for the biotransformation of pyrotinib, implying the vital necessity of the assessment of the potential CYP3A-mediated drug–drug interactions in humans. Taken together, this study provided valuable metabolic data to explicate the dynamic process of pyrotinib in humans, and important reference basis for its safety evaluation and rational clinical application. The results will also benefit the assessment of the contributions to the overall activity or toxicity from the key metabolites. [ABSTRACT FROM AUTHOR]

The body of evidence investigating human epidermal growth factor receptor-2 (HER2) directed therapy in patients with breast cancer (BC) has been growing within the last decade. Recently, the use of tyrosine kinase inhibitors (TKIs) has been of particular interest in the treatment of human malignancies. This literature commentary is intended to highlight the most recent findings associated with the widely-studied TKI agents and their clinical significance in improving the outcomes of HER2 positive BC., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Aim: Pyrotinib (an irreversible pan-ErbB small-molecular tyrosine kinase inhibitor) was approved in human epidermal growth factor receptor 2 (HER2)-positive breast cancer and showed great antitumor activity in preclinical studies of gastric cancer (GC). This study was first designed to prospectively assess pyrotinib in pretreated HER2-positive GC., Methods: This multicenter, phase I study followed a standard "3 + 3" design and included two parts. In the pyrotinib part, pyrotinib was administered orally, once per day at dose levels of 240, 320, 400, and 480 mg. In the pyrotinib plus docetaxel part, patients received pyrotinib (qd, d1-21, q3W) combined with docetaxel (60 mg/m 2 , d1, q3W) at dose levels of 240, 320, and 400 mg. Primary endpoints were to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of pyrotinib as monotherapy or coadministered with docetaxel., Results: A total of 25 patients were enrolled and received pyrotinib (n = 15) or pyrotinib plus docetaxel (n = 10). One DLT was observed in pyrotinib monotherapy part (Grade 3 uncontrolled diarrhea after supportive care) and pyrotinib plus docetaxel part (Grade 4 neutropenia and leukopenia). In the pyrotinib monotherapy part, MTD was not reached. Diarrhea, anemia, neutropenia, and leukopenia were the most common treatment-related adverse events (TRAEs). The RP2D for pyrotinib monotherapy was recommended as 400 mg. After combining with docetaxel, the risk of leukopenia and neutropenia was increased. Grade ≥3 TRAEs were reported for four patients in the monotherapy part and for eight patients in the combination part. Mean t 1/2 was approximately 20 h. Pyrotinib exposure was dose-dependent with a nonlinear relationship versus dose. There were five patients who had confirmed partial response (monotherapy: one each at 240, 400, and 480 mg dose cohort; combination therapy: two at 240 mg dose cohort), resulting in an objective response rate of 21% and 20%, respectively., Conclusions: Pyrotinib alone and combined with docetaxel showed acceptable toxicities in patients with pretreated HER2-positive GC., Trial Registration: This study was registered with ClinicalTrials.gov, NCT02378389., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Pyrotinib, a novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor, shows encouraging anticancer activity and acceptable tolerability in multiple phase II and phase III randomized clinical trials, but the real-world data of pyrotinib, especially the outcomes in HER2-positive metastatic breast cancer, have been rarely reported. Here, we evaluated the treatment outcomes of pyrotinib in real-world practice in patients with HER2-positive metastatic breast cancer (MBC). Methods: This was a prospective, real-world, observational cohort study. Through the Breast Cancer Information Management System, HER-2 positive MBC patients treated with pyrotinib between 2017/06 and 2020/09 were included. Provider-reported objective response rate, progression-free survival (PFS), and overall survival (OS) were considered in the assessment of treatment outcomes. Tumor responses to pyrotinib treatment were calculated using RECIST 1.1. Adverse events were evaluated using clinical records. Results: The trial involved 113 individuals who were receiving pyrotinib treatment, with an average age of 51 years. Complete response, partial response and stable disease were observed in 9 (8.0%), 66 (58.4%), and 17 (15.0%) patients, respectively, while progressive disease was recorded in 20 (17.7%) patients. After a median follow-up of 17.2 months, the median PFS was 14.1. The most common adverse events of any grade were diarrhea (87.6%), vomiting (31.9%), and palmar-plantar erythrodysesthesia (26.6%). Among the patients with brain metastases, the median PFS and OS were 15.2 and 19.8 months, respectively. In addition, pyrotinib has similar efficacy in various subtypes of HER2-positive MBC patients, as shown by the lack of a significant difference of PFS and OS among pyrotinib-treated patients with or without brain metastases, or patients using pyrotinib as first-line, second-line, third-line or beyond therapies. Conclusion: Our real-world results demonstrated equivalent clinical efficacy in HER-2 positive MBC patients compared to phase II and phase III clinical trials with pyrotinib, and promising outcomes in patients with brain metastases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, He, Tian, Yan, Huang, Zhang, Zheng, Zhong and Luo.)

This trial was initiated to evaluate the efficacy and safety of pyrotinib in combination with trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent/metastatic colorectal cancer (CRC). In this single-arm, open-label, multicenter, phase 2 trial patients with HER2-positive recurrent/metastatic CRC were enrolled and received oral pyrotinib 400 mg once a day plus intravenous trastuzumab 8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks. The primary endpoint was the objective response rate (ORR). Disease control rate (DCR), progression-free survival (PFS), duration of response, and safety were assessed as secondary endpoints. From December 2019 to October 2021, a total of 20 patients were enrolled and 18 of them were evaluable for response. All patients were B-rapidly accelerated fibrosarcoma (BRAF) wild type. Four patients achieved partial response, with an ORR of 22.2% (4/18, 95% confidence interval [CI] 6.4-47.6) and DCR of 61.1% (11/18, 95% CI 35.8-82.7), while the ORR and DCR were 33.3% (4/12, 95% CI 13.8-60.9) and 83.3% (10/12, 95% CI 51.6-97.9), respectively, in RAS wild-type patients. At the time of cut-off day, median follow-up was 10.7 months (range 3.8-13.8). The median PFS was 3.4 months (95% CI 1.8-4.3) in the overall population and 4.3 months (95% CI 3.2-8.5) in the RAS wild-type group. The most common adverse event of grade ≥3 was diarrhea (13/20, 65.0%). Pyrotinib combined with trastuzumab showed promising antitumor activity and a manageable safety profile in patients with RAS/BRAF wild-type HER2-positive advanced CRC., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Pyrotinib combined with capecitabine has been approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer in China. To date, the management of early-stage or locally advanced HER2-positive breast cancer in the clinic remains challenging. We conducted this trial to investigate the efficacy and safety of pyrotinib combined with capecitabine as neoadjuvant therapy (NAT) in elderly patients with HER2-positive breast cancer. Due to the stimulation of blood vessels by chemotherapy drugs, the elasticity of blood vessels in the elderly decreases, and then chemotherapy infusion is more likely to lead to phlebitis. Both pyrotinib and capecitabine can be taken to facilitate home treatment for elderly patients with HER2-positive breast cancer (BC)., Methods: From January 2020 to March 2021, patients aged between 70 and 81 years old with stage IIA-IIIB HER2-positive breast cancer were screened, enrolled, and assigned to receive six cycles of pyrotinib (320-400 mg, orally, once daily) plus capecitabine (1,250 mg/m 2 , orally, twice daily) on days 1-14 in every 21-day cycle. The primary endpoint was the objective response rate (ORR). Adverse events (AEs) were assessed in every neoadjuvant cycle. Surgery was performed after the last cycle, and the total pathological complete response (tpCR) was evaluated postoperatively., Results: Of the 23 patients enrolled, the ORR was 100% (23/23; 95% confidence intervals: 85 to 100). All patients underwent surgery with a tpCR rate of 43.5% (10/23; 95% confidence intervals: 23 to 66). The most common AE was diarrhea, occurring in 19 of 23 patients (82.6%); most of these patients sustained mild diarrhea (Grade 1 or Grade 2) and only three had moderate diarrhea (Grade 3). The incidences of other AEs, including weakness, loss of appetite, leukopenia, nausea, vomiting, hand-foot syndrome, etc., were low and the symptoms were mild. No severe AEs (Grade 4 or 5) were observed throughout the treatment., Conclusion: In our study, pyrotinib combined with capecitabine as neoadjuvant therapy in elderly women with HER2-positive breast cancer is safe and showed efficacy in this population, which may be widely used as a protocol for clinical neoadjuvant therapy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-23-11/coif). The authors have no conflicts of interest to declare., (2023 Gland Surgery. All rights reserved.)

Background: Trastuzumab (H) and pertuzumab (P) plus chemotherapy is the standard guideline-recommended neoadjuvant therapy recommended for patients with human epidermal growth factor receptor 2 (HER2)-positive locally advanced breast cancer (BC), which has dramatically improved patient prognosis. However, over 10% of patients develop primary drug resistance to HP and did not respond to treatment. There is no standard second-line neoadjuvant therapy approach for these individuals at the present. Pyrotinib and vinorelbine have shown promising efficacy in HER2-positive metastatic breast cancer, but their usage in neoadjuvant therapy has not been reported so far., Case Description: Here, we present a case of a 58-year-old female patient with locally advanced HER2-positive BC who was initially resistant to HP neoadjuvant therapy. Following the failure of the treatment, this patient was given pyrotinib plus trastuzumab and vinorelbine as second-line neoadjuvant therapy. The patient tolerated this treatment well, with mild symptoms of diarrhea. After 6 cycles of neoadjuvant therapy, the efficacy was assessed to be partial remission (PR), and a modified radical mastectomy was finally conducted. This patient remained disease-free for 23 months after surgery., Conclusions: This is the first report to present a case of neoadjuvant pyrotinib plus trastuzumab and vinorelbine in a patient with HER2-positive locally advanced BC, suggesting that the combination could be a new option for patients who have developed resistance to HP neoadjuvant treatment., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-22-751/coif). Both authors report that this study was supported by the Special Project of Scientific and Technological Innovation for Social Undertakings and People’s Livelihood Security of Chongqing (No. cstc2017shmsA130093) and the Chongqing Natural Science Foundation (No. CSTB2022NSCQ-MSX0842). The authors have no other conflicts of interest to declare., (2023 Gland Surgery. All rights reserved.)

Background: Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer patients continue to progress despite multiple anti-HER2-targeted treatments. A number of studies have found that Pyrotinib, a small-molecule pan-ErbB receptor tyrosine kinase inhibitor (TKI), is effective in treating patients with HER2-positive metastatic breast cancer. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of Pyrotinib in the treatment of HER2-positive metastatic breast cancer., Methods: PubMed, Embase, Web of Science, and Cochrane Library databases were searched until February 2022. Research on HER2-positive metastatic breast cancer being treated with Pyrotinib in any line of therapy was included, both prospective and retrospective. Statistical pooling and meta-analysis of data from the included studies were performed to explore the efficacy and safety of Pyrotinib in HER2-positive metastatic breast cancer., Results: In this meta-analysis, 23 studies were included. The overall objective response rate was 0.49 (95% CI: 0.40, 0.58) for Pyrotinib in HER2-positive metastatic breast cancer and 0.52 (95% CI: 0.32, 0.71) in those with brain metastases. The objective response rate of Pyrotinib was superior to that of other second-line therapeutics in comparison (RR =1.38, 95% CI: 1.25, 1.52), but was relatively inferior to trastuzumab emtansine (T-DM1) (RR =0.82, 95% CI: 0.36, 1.85). The combined median progression-free survivals (PFSs) for Pyrotinib in metastatic breast cancer and those with brain metastases were 8.2 (95% CI: 6.8, 9.5) months and 8.9 (95% CI: 6.2, 11.7) months, respectively. The most common adverse reaction was diarrhea with an all-grade incidence of 0.84 (95% CI: 0.74, 0.92), followed by nausea and vomiting of 0.52 (95% CI: 0.36, 0.68)., Conclusions: In any line of treatment for HER2-positive metastatic breast cancer, the Pyrotinib-containing regimens demonstrated considerable tumor response, disease control, and survival with manageable adverse effects., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-1746/coif). The authors have no conflicts of interest to declare., (2023 Translational Cancer Research. All rights reserved.)

Background: Pyrotinib, a novel irreversible tyrosine kinase inhibitor (TKI), has demonstrated promising antitumor activity to improve the overall response rate and progression-free survival (PFS) in patients with HER2-positive metastatic breast cancer (MBC). However, the survival data of pyrotinib or pyrotinib plus capecitabine in HER2-positive MBC remains scarce. Thus, we summarized the updated individual patient data from the phase I trials of pyrotinib or pyrotinib plus capecitabine, to provide a cumulative assessment on long-term outcomes and associated biomarker analysis of irreversible TKIs in HER2-positive MBC patients., Methods: We performed a pooled analysis of the phase I trials for pyrotinib or pyrotinib plus capecitabine based on the updated survival data from individual patients. Next-generation sequencing was performed on circulating tumor DNA for predictive biomarkers., Results: A total of 66 patients were enrolled, including 38 patients from the phase Ib trial for pyrotinib and 28 patients from the phase Ic trial for pyrotinib plus capecitabine. The median follow-up duration was 84.2 months (95% CI: 74.7-93.7 months). The estimated median PFS in the entire cohort was 9.2 months (95% CI: 5.4-12.9 months) and median OS was 31.0 months (95% CI: 16.5-45.5 months). The median PFS was 8.2 months in the pyrotinib monotherapy cohort and 22.1 months in the pyrotinib plus capecitabine group, while the median OS was 27.1 months in the pyrotinib monotherapy group and 37.4 months in the pyrotinib plus capecitabine group. Biomarker analysis suggested that the patients harbored concomitant mutations from multiple pathways in HER2-related signaling network (HER2 bypass signaling pathways, PI3K/Akt/mTOR pathway and TP53) were observed with significantly poorer PFS and OS when compared to those with none or one genetic alteration (median PFS, 7.3 vs. 26.1 months, P = 0.003; median OS, 25.1 vs. 48.0 months, P = 0.013)., Conclusions: The updated survival results based on individual patient data from the phase I trials of pyrotinib-based regimen revealed promising PFS and OS in HER2-positive MBC. Concomitant mutations from multiple pathways in HER2-related signaling network may be a potential efficacy and prognosis biomarker for pyrotinib in HER2-positive MBC., Trial Registration: ClinicalTrials.gov. (NCT01937689, NCT02361112)., (© 2023. The Author(s).)

Background: Pyrotinib, a novel irreversible epidermal growth factor receptor 2 (EGFR)/HER2 dual tyrosine kinase inhibitor, has shown promising antitumor efficacy with tolerable toxicity in HER2-positive metastatic breast cancer (MBC) in several clinical trials. However, the clinical trials do not usually well reflect the patients in real clinical settings. Despite several small-sample studies in real world, the data on pyrotinib as first-line and third-or-later-line treatment and the efficacy comparison of pyrotinib combined with different regimens are still lacking. Therefore, this study aimed to investigate the efficacy and safety of pyrotinib for the HER2-positive MBC in real world to replenish more comprehensive data., Methods: A total of 172 HER2-positive MBC patients treated with pyrotinib-based therapy were recruited from multiple centers in nonclinical trial settings from September 2017 to June 2020., Results: The median progression-free survival (mPFS) of 172 patients was 8.83 months. The patients, receiving first-line pyrotinib treatment, had the longest mPFS (20.93 months) compared with those receiving second-line (8.67 months, p = 0.0339) and third-or-later-line (7.13 months, p = 0.0075) treatments, respectively. Prior treatment with lapatinib (p = 0.012) and site of metastasis (visceral vs. nonvisceral) (p = 0.033) were the independent prognostic factors for PFS. The prior treatment with lapatinib compared with lapatinib-native treatment (5.96 vs. 10.97 months, p = 0.0036) and those with visceral metastasis compared with nonvisceral metastasis (8.40 vs. 23.70 months, p = 0.0138) had worse mPFS. Among 146 patients evaluated for efficacy, 2.1%, 58.9%, and 32.9% showed complete response, partial response, and stable disease, respectively. Adverse events occurred in 92.4% of the patients with 33.3% Grade 3 and higher adverse events and diarrhea (57.0%), anemia (44.8%), and leukopenia (40.7%) as the most frequent ones., Conclusions: Pyrotinib-containing regimen could effectively treat HER2-positive MBC with acceptable toxicity, including the patients who progressed after lapatinib treatment and with brain metastasis., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

For HER2-positive metastatic breast cancer patients with the brain involved at initial diagnosis, there was no standard regimen before 2022 when the HER2CLIMB trial published its final overall survival analysis, and the prognosis is relatively poor under the current treatment strategy. We herein reported a case of a female patient who was initially diagnosed with HER2-positive metastatic breast cancer with brain metastases, receiving pyrotinib and trastuzumab-based systematic therapy after palliative craniocerebral radiotherapy as the first-line systematic therapy. During the treatment, the tumor lesions showed obvious regression, and chemotherapy drugs were gradually removed from the regimen. The patient continued receiving trastuzumab and pyrotinib for HER2-targeted therapy. She had achieved more than 26 months of progression-free survival and the disease was stable during the evaluation in April 2022. Radiotherapy followed by dual HER2-targeted therapy of macromolecular monoclonal antibodies trastuzumab and micromolecular TKI pyrotinib plus chemotherapy could be an alternative option for this subtype of patients and need to be further verified by future clinical trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Yu, Cui, Yu and Ma.)

Introduction: This multicenter, randomized, double-blind, placebo-controlled phase 2 trial compared the efficacy, and safety of adding pyrotinib to trastuzumab, docetaxel, and carboplatin versus placebo, trastuzumab, docetaxel, and carboplatin in Chinese patients with human epidermal receptor 2 (HER2)-positive early or locally advanced breast cancer (ClinicalTrials.gov identifier: NCT03756064)., Methods: Sixty-nine women with HER2-positive early (T1-3, N0-1, M0) or locally advanced breast cancer (T2-3, N2 or N3, M0; T4, any N, M0) were recruited from October 1, 2019, to June 1, 2021. Before surgery, patients received 6 cycles of orally pyrotinib (400 mg once per day), trastuzumab (8-mg/kg loading dose and 6-mg/kg maintenance doses), docetaxel (75 mg/m2), and carboplatin (AUC = 6 mg/mL·min) or orally placebo, trastuzumab, and docetaxel, and carboplatin every 3 weeks. The primary end point was independent review committee-assessed total pathologic complete response rate. The 2-sided Cochran-Mantel-Haenszel test, stratified by age, hormone receptor status, tumor stage, nodal status, cTNM stage, and Ki-67 level was used to compare rates between treatment groups., Results: In total, 69 female patients were randomized (pyrotinib, 36; and placebo, 33; median age, 53 [31-69] years). In the intention-to-treat population, total pathologic complete response rates were 65.5% (19/29) in the pyrotinib group and 33.3% (10/30) in the placebo group (difference, 32.2%, p = 0.013). Diarrhea was been reported in 86.1% of patients (31/36) in the pyrotinib group as the most common adverse events (AEs) and 15.2% of patients (5/33) in the placebo group. But no grade 4 or 5 AEs were reported., Conclusion: Treatment with pyrotinib, trastuzumab, docetaxel, and carboplatin resulted in a statistically significant improvement in the total pathologic complete response rate versus placebo, trastuzumab, docetaxel, and carboplatin for the neoadjuvant treatment of HER2-positive early or locally advanced breast cancer in Chinese patients. Safety data were in line with the known pyrotinib safety profile and generally comparable between treatment groups., (© 2023 S. Karger AG, Basel.)

Background: Radiotherapy has an unsatisfactory effect on gastric cancer. The purpose of this study was to investigate the effect of pyrotinib, a highly effective human epidermal growth factor receptor (HER) family inhibitor, on the radiosensitivity of HER2-positive gastric cancer and its mechanism in vivo and in vitro., Methods: NCI-N87 and SNU-216 were HER2-positive gastric cancer cell lines; these cell lines were treated with or without 0.01 μM pyrotinib 12 h before irradiation. The proliferation capacity was determined by CCK8, and clone formation experiments were used to test the radiosensitization effect of pyrotinib. The expression of HER2, γ-H2AX, apoptosis protein, senescence-associated proteins, and AKT/ERK signaling pathway changes were determined by Western blot. Cell cycle and apoptosis were established by flow cytology. Immunofluorescence was utilized to detect the expression of HER2 and γ-H2AX. Senescence cells were stained by β-galactosidase staining method. Pathway enrichment analysis was tested by RNA sequencing. Next, a xenograft tumor model was constructed in nude mice for verification in vivo., Results: The clone formation experiment indicated the radiosensitivity of pyrotinib. The combined treatment can inhibit the entry of HER2 protein into the nucleus and reduce the phosphorylation of the ERK signaling pathway caused by irradiation. Pyrotinib also enhances DNA damage; induces apoptosis, G2/M phase arrest; and promotes senescence. In the xenograft model, the tumor inhibition rate was significantly stronger in the combined treatment group., Conclusions: Our results demonstrated that pyrotinib can induce radiosensitivity in HER2-positive gastric cancer in vivo and in vitro. This effect is through reducing irradiation-induced HER2 entry into the nucleus and inhibiting ERK1/2 signaling pathway., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

With the extensive application of anti-human epidermal growth factor receptor-2 (HER2) targeted therapy, the prognosis of HER2-positive breast cancer brain metastasis (BCBM) has been improved greatly. Due to the lack of prospective randomized controlled studies; however, the treatment of active brain metastasis (BM) remains a difficulty in clinic. Based upon the retrospective studies, an effective approach of radiotherapy combined with pyrotinib in HER2-positive BCBM treatment was investigated in present research. In all, 29 patients who had active BM in HER2-positive breast cancer (BC) and underwent whole-brain radiotherapy (WBRT) combined with pyrotinib from January 2019 to May 2021 were enrolled. The progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR), objective response rate (ORR), and drug-related adverse events (AEs) were analyzed among patients undergoing WBRT combined with concurrent or sequence pyrotinib + capecitabine. After the systematic treatments using WBRT combined with pyrotinib + capecitabine, the mPFS and mOS of BM patients were 6.5 months and 15.5 months, respectively. PFS (7.2 vs 6.2 months, p  = 0.038) and OS (19.0 vs 14.0 months, p  = 0.014) were longer after sequence treatments than those after concurrent treatment. The central nervous system (CNS) ORR of sequence treatment was superior to that of concurrent treatment (80.4% vs 58.6%, p  < 0.05). Vomiting (17.2%) and diarrhea (10.3%) were the most common adverse reactions ⩾ grade 3. WBRT combined with pyrotinib is safe and effective for the treatments of active BM in HER2-positive BC. WBRT combined with sequence pyrotinib + capecitabine is more effective and less toxic than concurrent treatment. Therefore, sequence treatment is potentially a preferred regimen for patients with active BM in HER2-positive BC. The size and number of BM lesions, presence or absence of hepatic metastasis, and combination mode of radiotherapy and targeted therapy are independent risk factors for active BM prognosis.

Purpose: A substantial need for effective and safe treatment options is still unmet for patients with heavily pre-treated human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Herein, we assessed the efficacy and safety of pyrotinib plus trastuzumab and chemotherapy in patients with heavily treated HER2-positive MBC., Methods: In this single-arm exploratory phase II trial, patients with HER2-positive MBC previously treated with trastuzumab plus lapatinib or pertuzumab, received pyrotinib plus trastuzumab and chemotherapy. The primary end point was progression-free survival (PFS) in the total population (TP). Secondary end points included PFS in the subgroup with brain metastases (Sub-BrM), confirmed objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), exploration of predictive factors of PFS, and safety., Results: Between November 1, 2018, and March 31, 2021, 40 patients were eligible for this study. The median PFS reached 7.5 months (95% confidence interval [CI] 4.7 to 9.9 months) and 9.4 months (95% CI 6.6 to 12.1 months) in the TP and Sub-BrM, respectively. ORR was 50.5% (20/40). CBR was 75.5% (30/40) and DCR reached 97.5% (39/40). Cox univariate and multivariate analyses demonstrated that liver or/and lung metastases was the significant adverse prognostic factor for PFS (p = 0.018; p = 0.026; respectively). The most frequent grade 3 or 4 treatment-related adverse events were diarrhea, neutropenia and leukopenia. No new safety signals were observed., Conclusion: Pyrotinib plus trastuzumab and chemotherapy offered a promising option with manageable safety profile for heavily pre-treated HER2-positive MBC, especially for those without liver or/and lung metastases., (© 2022. The Author(s).)