Irreversible pan-ErbB Receptor Tyrosine Kinase Research Articles

Abstract PO2-01-05: Neoadjuvant pyrotinib plus trastuzumab, and chemoterapy in patients with HER2-positive early breast cancer: a real-world study

Abstract Background Pyrotinib is a new oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor that targets human epidermal growth factor receptor 1 (HER1), HER2, and HER4. Previous studies have confirmed it combined with capecitabine is safe and well-tolerated in advanced breast cancer. And also PHEDRA trial had demonstrated the efficacy and safety of pyrotinib combined with trastuzumab and docetaxel neoadjuvant therapy early HER2-positive breast cancer. However, the efficacy of pyrotinib plus trastuzumab-based in real-world neoadjuvant therapy for early breast cancer is unknown. Purpose The present study aimed to explore the efficacy of pyrotinib-based in neoadjuvant therapy for early breast cancer in real-world. Method This is investigator-initiated phase 2 real-world study recruited eligible patients, aged 18–70 years with invasive carcinoma, cT2-3N0-3M0 stage, HER2-positive breast cancer. The patients received 400 mg pyrotinib orally once per day for 21 days and trastuzumab (8 mg/kg loading dose, 6 mg/kg maintenance dose) plus different standard chemotherapy, including six 21-day cycles of docetaxel (75 mg/m2) plus carboplatin (6 mg/mL/min), or four cycles of epirubicin (90 mg/m2) plus cyclophosphamide (600 mg/m2) and four cycles paclitaxel (80 mg/m2). The primary endpoint was to calculate the number of patients who achieved a pathological complete response (pCR, ypT0/is, ypN0). (ChiCTR2100052892). Result The results of the 23 patients were reported, The pCR of 12 (52.2%) patients, who reached the threshold for the design, was noted. The study is ongoing. The most frequent grade 3 to 4 adverse events were diarrhea (35.6%), which all the patients received primary prevention of diarrhea, leukopenia (44.8%), and anaemia (23.7%). However, no treatment-related deaths were recorded. Conclusion Previous studies have shown the efficacy and safety of pyrotinib plus trastuzumab and docetaxel in neoadjuvant therapy of HER2-positive early breast cancer. The current trial suggests that pyrotinib plus trastuzumab-based standard chemotherapy in real-world has promising efficacy and manageable toxicity in patients with HER2-positive early breast cancer in a neoadjuvant setting, the trial is ongoing, we will enroll more patients. Citation Format: Jun Zhou, Rui Wang. Neoadjuvant pyrotinib plus trastuzumab, and chemoterapy in patients with HER2-positive early breast cancer: a real-world study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-01-05.

Abstract OT3-29-01: A Phase Ib/II Study of anlotinib combined with pyrotinib and capecitabine for HER2-Positive Metastatic Breast Cancer

Abstract Background: Preclinical data showed that high levels of vascular endothelial growth factor (VEGF) may lead to aggressive behavior in breast tumors that overexpress HER2. AVEREL study demonstrated that bevacizumab in combination with trastuzumab and docetaxel as first-line treatment increased progression-free survival (PFS) in HER2 postive metastatic breast cancer (BC) patients (BTH vs TH:16.5m vs 13.7m, HR=0.82, P=0.0775). It is necessary to exploring new effective and tolerable strategy of targeting both HER2 signaling and angiogenesis. PHENIX and PHOEBE studies proved pyrotinib (an irreversible pan-ErbB receptor tyrosine kinase inhibitor) plus capecitabine improved prognosis for patients with advanced HER2 positive BC. Anlotinib is a novel multi-target tyrosine kinase inhibitor that effectively inhibits VEGFR, FGFR, c-KIT, c-MET and RET. This study is aimed to evaluate safety, tolerability and efficacy of anlotinib combined with pyrotinib and capecitabine for HER2-Positive metastatic BC. Methods: This open-label study is designed to include patients with pathologically confirmed HER2-positive metastatic breast cancer that have progressed or relapsed after treatment with trastuzumab or inability to receive trastuzumab in West China Hospital, Sichuan University. Eligible patients have at least one measurable lesion according to RECIST v1.1; previously received taxanes regimen and had ≤2 line of chemotherapy for advanced disease; an ECOG performance status of 0-1; adequate organ function. In the “3+3” dose-exploring phase, pyrotinib and capecitabine are given at a fixed dose of 400mg qd and 1000 mg/m2 bid respectively. Anlotinib is initially given at a dose of 10mg/d (Level I). If the initial dose level could be tolerated, subsequent patients are assigned to the higher level (Level H) with anlotinib 12mg/d; otherwise, to Level L with anlotinib 8 mg/d. Primary endpoints of phase Ib are dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and efficacy. Phase II is an expansion cohort at the recommended phase II dose (RP2D). The primary endpoint for phase II is one-year PFS rate by investigator-assessed, and secondary endpoints include PFS, overall response rate (ORR), clinical benefit rate (CBR), duration of response (DoR), overall survival (OS) and quality of life. A sample size of 23 provided 80% power at 2-sided alpha = 0.20 to detect a minimum of 20% improvement (45% vs. 65%) in one-year PFS. The phase Ib portion of the trial is currently enrolling in China. Clinical trial information: ChiCTR2100045962. Funding: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Citation Format: Ting Luo, Xiaorong Zhong, Jie Chen. A Phase Ib/II Study of anlotinib combined with pyrotinib and capecitabine for HER2-Positive Metastatic Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-29-01.

Pyrotinib Targeted EGFR-STAT3/CD24 Loop-Mediated Cell Viability in TSC.

Pyrotinib is an irreversible pan-ErbB receptor tyrosine kinase inhibitor, designed for the therapy of HER2-positive breast cancers. Inhibition of the epidermal growth factor receptor (EGFR, HER family) efficiently and selectively suppresses the proliferation of human TSC2-deficient smooth muscle cells and reverses lung changes in LAM/TSC. Our pilot study indicated that pyrotinib dramatically restrained the vitality of TSC2-deficient cells compared to its limited impact on TSC2-expression cells. Pyrotinib induced G1-phase arrest and triggered apoptosis by blocking abnormally activated CD24 in TSC2-deficient cells. CD24 is not only an important immune checkpoint, but is also involved in the regulation of signaling pathways. Pyrotinib inhibited the nuclear import of pEGFR and restrained the pEGFR/pSTAT3 signals, which directly boosted the transcriptional expression of CD24 by binding to its promoter region. In reverse, CD24 enhanced pEGFR function by directly binding. Pyrotinib specifically targeted TSC2-deficient cells, inhibited tumor cell viability and induced apoptosis through EGFR-STAT3/CD24 Loop in vivo and in vitro. Thus, pyrotinib may be a promising new therapeutic drug for TSC treatment.

Abstract OT1-12-06: Neoadjuvant pyrotinib versus pertuzumab in combination with trastuzumab and nab-Paclitaxel for patients with HER2-positive early or locally advanced breast cancer (Pyramid): A randomized, multicenter, open-label, phase 2 trial

Abstract Background: Pyrotinib is an irreversible pan-ErbB receptor tyrosine kinase inhibitor targeting human epidermal growth factor receptor 1 (HER1), HER2, and HER4. Exploratory studies of neoadjuvant pyrotinib combined with trastuzumab-based standard chemotherapy for HER2-positive (HER2+) early or locally advanced breast cancer (BC) showed promising pathological complete response (pCR) rates of 51.6%-71%, with a manageable toxicity profile. We are to further investigate this combination strategy versus standard therapy in a randomized trial. Trial design: Pyramid is a randomized, multicenter, open-label, two-stage adaptive enrichment phase 2 trial to evaluate the efficacy and safety of pyrotinib plus trastuzumab and nab-Paclitaxel versus pertuzumab plus trastuzumab and nab-Paclitaxel as neoadjuvant treatment in patients with HER2+ early or locally advanced BC (NCT04900311). Eligible patients will be randomized 1:1 to receive four 21-day cycles of pyrotinib (400 mg, po, qd) or pertuzumab (840 mg loading dose, 420 mg maintenance doses, i.v., day 1) with trastuzumab (8 mg/kg loading dose, 6 mg/kg maintenance doses, i.v., day 1) and nab-Paclitaxel (260 mg/m2, day 1 or 125 mg/m2, i.v., day 1/8/15). After completion of neoadjuvant treatment, patients will undergo surgery, followed by standard EC regime for 4 cycles. Subsequent adjuvant therapy will be decided by investigators. Randomization was stratified by hormone receptor (HR) status (ER and/or PR positive vs. negative) and primary tumor size (2<T≤5 cm vs. T>5 cm). There will be two stage of this trial, and population may be enriched to HR-positive based on the results of interim analysis at Stage I. Eligibility criteria: Key inclusion criteria include female, treatment-naïve, histologically confirmed HER2+ invasive BC (cT2-4/cN0-3/cM0), the diameter of primary tumor > 2 cm, known HR status (ER and PR). Specific aims: Primary endpoint is total pathologic complete response (tpCR) rate per central review assessment. Secondary endpoints include invasive disease-free survival, event-free survival, objective response rate, breast-conserving surgery rate, safety. Exploratory endpoint is to investigate the possible predictive biomarkers of efficacy. Statistical methods: A sample size of 220 patients per arm is calculated to provide a power of 80% with a significance level of 0.1 (one-sided) to detect an estimated increase in the tpCR rate from 39% in the pertuzumab group to 49% in the pyrotinib group. Considering a dropout rate of 10%, 490 patients (245 per arm) will be required to be enrolled. A two-stage adaptive enrichment design will be used. The trial will enroll 186 patients at Stage I and an interim analysis will be conducted by an independent data monitoring committee (IDMC) when the pathologic response has been evaluated in at least 132 patients (including at least 66 HR-positive patients) at Stage I. Then, one of five options might be adapted at Stage II depending on the results, including: i. Continue study as planned in whole population; ii. Re-estimate sample size in whole population; iii. Enrich to HR-positive population with pre-defined sample size; iv. Enrich to HR-positive population and re-estimate sample size; v. Early termination. The Clopper-Pearson method will be used to calculate a 95% confidence interval (CI) for the tpCR rate. The CMH chi-square test will be used to compare the tpCR rate between groups and 95% CIs for the difference will be estimated using the Miettinen-Nurminen method. Present accrual and target accrual: Target enrollment will be 490 patients at approximately 20 sites in China. As of June 24, 2021, 4 patients have been enrolled. Contact information: Jin Zhang, MD, Email: zhangjin@tjmuch.com. Citation Format: Jin Zhang, Qiang Liu, Hongchuan Jiang, Jianguo Zhang, Jianghua Ou, Dedian Chen, Fuguo Tian, Yongqing Li, Xiaoming Cheng, Zhong Ouyang. Neoadjuvant pyrotinib versus pertuzumab in combination with trastuzumab and nab-Paclitaxel for patients with HER2-positive early or locally advanced breast cancer (Pyramid): A randomized, multicenter, open-label, phase 2 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-12-06.

Abstract P2-13-32: Pyrotinib in combination with letrozole for estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer: A multicenter, single-arm, phase II trial

Abstract Background: HER2-targeted agents combined with endocrine therapy (ET) has been recommended as an optional therapeutic strategy for hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) co-positive metastatic breast cancer (MBC). Pyrotinib is an oral irreversible pan-ErbB receptor tyrosine kinase inhibitor targeting EGFR, HER2 and HER4, with proven efficacy in combination with chemotherapy in HER2-positive MBC. This multicenter, single-arm phase 2 trial aimed to investigate the efficacy and safety of pyrotinib plus letrozole in patients with estrogen receptor (ER)-positive, HER2-positive MBC (NCT04407988). Methods: Pre-/perimenopausal or postmenopausal women with histologically confirmed HER2-positive (immunohistochemistry [IHC] 3+ or 2+ with fluorescence in situ hybridization positive) and ER-positive (the percentage of ER+ cells ≥ 10% by IHC) MBC were enrolled. Prior treatment for metastatic disease was not allowed. Eligible patients received pyrotinib (400 mg, po, qd) plus letrozole (2.5 mg, po, qd) until disease progression or unacceptable toxicity. For pre-/perimenopausal patients, additional treatment with ovarian function suppression (OFS) was required. The primary endpoint was clinical benefit rate (CBR), defined as the rate of patients with complete response (CR), partial response (PR), or stable disease (SD) for at least 24 weeks per RECIST 1.1. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between December 3, 2019 and April 2, 2021, 26 patients were enrolled. As of July 5, 2021, CBR was 76.9% (20 of 26; 95% CI 56.4% to 91.0%) and ORR was 57.7% (15 of 26; 95% CI 36.9% to 76.6%). One of the 26 patients (3.8%) had CR, 14 (53.8%) had PR, 5 (19.2%) had SD, 5 (19.2%) had progressive disease, and 1 (3.8%) had not evaluable disease. The benefits in CBR and ORR were observed across all subgroups. The most common any grade AEs were diarrhea (25 of 26, 96.2%), vomiting (8 of 26, 30.8%), nausea (6 of 26, 23.1%), and oral ulceration (6 of 26, 23.1%). Diarrhea was the only reported grade 3 AE that occurred in 5 patients (19.2%). No grade 4 or 5 AEs occurred during this study. Conclusions: Pyrotinib combined with letrozole showed an encouraging antitumor activity with good tolerance in patients with ER/HER2 co-positive MBC, promising as an alternative treatment option for this disease. The study is ongoing. Citation Format: Quchang Ouyang, Huihua Xiong, Min Yan, Jincai Zhong, Li Ran, Ting Luo, Liping Liu, Jing Li, Xiaohong Yang, Huawu Xiao, Ning Xie, Hui Wu, Jianxiang Gao, Jun Lu, Xuming Hu, Zheyu Hu, Can Tian, Zhengrong Shui, Min Cao. Pyrotinib in combination with letrozole for estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer: A multicenter, single-arm, phase II trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-32.

155P The addition of pyrotinib in early or locally advanced HER2-positive breast cancer patients with no response to two cycles of neoadjuvant therapy: A prospective, multicenter study

Early assessment of clinical response to treatment would facilitate individualized therapy, with ineffective therapy changed. Pyrotinib is a new oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor that targets human epidermal growth factor receptor (HER) 1, HER2, and HER4. Whether the addition of pyrotinib to TCH (trastuzumab, docetaxel, carboplatin) regimen can bring benefit to non-responder after 2 neoadjuvant cycles of TCH is unclear. This prospective, open-label, multicenter study (NCT03847818) explored the efficacy and safety of neoadjuvant pyrotinib + TCH in patients with early or locally advanced HER2-positive breast cancer who did not respond after 2 neoadjuvant cycles of TCH.

285P Real-world outcomes associated with pyrotinib-based therapy for HER2-positive metastatic breast cancer

Pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, has shown promising antitumor activity and manageable toxicity in HER2-positive metastatic breast cancer. However, the efficacy and safety of pyrotinib-based treatment in the real-world setting in China is limited. The aim of this study was to evaluate actual clinical outcomes in HER2-positive metastatic breast cancer treated with pyrotinib.

The Efficacy of Pyrotinib as a Third- or Higher-Line Treatment in HER2-Positive Metastatic Breast Cancer Patients Exposed to Lapatinib Compared to Lapatinib-Naive Patients: A Real-World Study.

Background: Pyrotinib is a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor. Evidence of the efficacy of pyrotinib-based treatments for HER2-positive metastatic breast cancer (MBC) in patients exposed to lapatinib is limited.Methods: Ninety-four patients who received pyrotinib as a third- or higher-line treatment for HER2-positive MBC were included in this retrospective study. The primary and secondary endpoints were overall survival (OS) and progression‐free survival (PFS). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analysis were implemented to balance important patient characteristics between groups.Results: Thirty (31.9%) patients were pretreated with lapatinib and subsequently received pyrotinib as an anti-HER2 treatment, and 64 (68.1%) patients did not receive this treatment. The OS and PFS indicated a beneficial trend in lapatinib-naive group compared to lapatinib-treated group in either the original cohort (PFS: 9.02 vs 6.36 months, p = 0.05; OS: 20.73 vs 14.35 months, p = 0.08) or the PSM (PFS: 9.02 vs 6.08 months, p = 0.07; OS: 19.07 vs 18.00 months, p = 0.61) or IPTW (PFS: 9.90 vs 6.17 months, p = 0.05; OS: 19.53 vs 15.10 months, p = 0.08) cohorts. Subgroup analyses demonstrated lapatinib treatment-related differences in PFS in the premenopausal subgroup and the no prior trastuzumab treatment subgroup, but no significant differences were observed in OS.Conclusion: Pyrotinib-based therapy demonstrated promising effects in HER2-positive MBC patients in a real-world study, especially in lapatinib-naive patients, and also some activity in lapatinib-treated patients.

Pyrotinib in the treatment of women with advanced HER2 positive breast cancer: A multicenter, prospective, real-world study.

e13012 Background: Pyrotinib is a newly-developed irreversible pan-ErbB receptor tyrosine kinase inhibitor. The efficacy of pyrotinib in patients with different baseline characteristics in the actual clinical practice has been rarely reported. This study analyzed the efficacy and safety of pyrotinib in the real world. Methods: Patients with histologically confirmed advanced HER2 positive breast cancer were included in the analyses. All patients received pyrotinib-based therapy were given pyrotinib once a day in a 21-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints included adverse events (AE), objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Results: A total of 132 patients (median age: 52 years [29-78]) were enrolled from February 2019 to March 2020. 94(71.21%) patients had visceral metastatic lesions and 20 (15.15%) had brain metastases. HR+, HR-, or unknown HR status for primary tumor accounted for 56.82%, 42.42%, 0.76%, respectively. 115(87.12%) patients were previously administered with trastuzumab. 96(72.73%) patients received pyrotinib-based therapy as a second or further line of treatment. 94(71.21%) patients initiated pyrotinib treatment at 400 mg. Treatment regimens were pyrotinib plus capecitabine (55.30%), pyrotinib combined with trastuzumab (18.18%), and pyrotinib monotherapy (8.33%), pyrotinib combined with endocrine therapy, radiotherapy or antiangiogenic drugs (3.79%). A total of 132 patients were included in PFS analysis. mPFS was 12.0 months (95%CI 8.1-18.8). mPFS for patients without primary trastuzumab-resistant breast cancer was 14.1 months (95%CI 8.7-23.3). Patients receiving pyrotinib-based therapy as their ≥3 lines treatment had lower mPFS than those receiving pyrotinib-based therapy as their < 3 lines treatment (8.8 vs. 15.1 months, P= 0.119). mPFS in patients receiving regimen with and without capecitabine were 15.1 months and 8.4 months, respectively ( P= 0.081). As of data cutoff, mOS has not yet been reached. Among the 65 patients available for efficacy evaluation, 1 (1.54%) patient achieved complete response (CR), 24 (36.92%) patients had partial response (PR), 30 (46.15%) patients achieved stable disease (SD), and 10 (15.38%) patients had progression disease (PD), resulting in an ORR of 38.46% and DCR of 84.62%. The most common AE was diarrhea (84.17%), but only 5 (4.17%) patients were reported grade ≥ 3 diarrhea which could be well controlled. Other AEs with an incidence higher than 20.00% were anemia (36.67%), leukopenia (25.83%), vomiting (25.00%), neutropenia (22.50%). No treatment-related death occurred. Conclusions: Pyrotinib demonstrated an encouraging efficacy and manageable safety in patients with advanced HER2+ breast cancer. More data would be analyzed and reported in the future. Clinical trial information: ChiCTR1900021819.

Abstract PS10-43: Pyrotinib in the treatment of women with advanced HER2 positive breast cancer: A multicenter, prospective, real world study

Abstract Backgrounds: Pyrotinib (an irreversible pan-ErbB receptor tyrosine kinase inhibitor) plus capecitabine have been approved for patients with advanced HER2 positive breast cancer in China. However, the efficacy of pyrotinib in patients with different baseline characteristics in the actual clinical practice has not been reported. This study analyzed the anti-tumor activity and toxicity of pyrotinib in real world setting. Methods: Total 36 hospitals in China participated in the real-world study. Patients with histologically confirmed advanced HER2 positive breast cancer were included in the analyses. All patients received pyrotinib-based therapy were given pyrotinib once a day in a 21-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints included adverse events (AE), objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Results: Periodic analysis results were reported in this study. A total of 231 patients (median age: 53 years [26-78]) were enrolled from February 17, 2019 to June 11, 2020. Among them, 156 (67.53%) patients had visceral metastatic lesions and 39 (16.88%) had brain metastases. HR+, HR-, or unknown HR status for primary tumor accounted for 52.82%, 45.45%, 1.73%, respectively. 206 (89.18%) patients were previously administered with anti-HER2 drugs. Among them, 156 patients had received single type of anti-HER2 drug (153 patients with trastuzumab, 3 patients with trastuzumab biosimilar); 50 patients had received trastuzumab and some other drugs (lapatinib, pertuzumab, T-DM1, trastuzumab biosimilar, and antibody-drug conjugate). 88 (65.67%) patients received pyrotinib-based therapy as a second or further line of treatment. 177 (76.62%) patients initiated pyrotinib treatment at 400 mg, 52 (22.51%) patients started with 320 mg, and 2 (0.87%) patients had a starting dose of 160mg. Treatment regimens were pyrotinib plus capecitabine (95/231), pyrotinib combined with other chemotherapy drugs (41/231), pyrotinib combined with anti-HER2 treatments (57/231), and pyrotinib monotherapy (30/231), pyrotinib combined with endocrine therapy, radiotherapy or antiangiogenic drugs (8/231). Among the 134 patients available for efficacy evaluation, 1 (0.75%) patient achieved complete response (CR), 30 (22.39%) patients had partial response (PR), 86 (64.18%) patients achieved stable disease (SD), and 17 (12.69%) patients had progression disease (PD), resulting in an ORR of 23.14% and DCR of 87.31%. Patients received pyrotinib-based therapy as their first, second, and later lines of treatment had a DCR of 82.05%, 90.91%, and 87.27%, respectively. Among patients receiving ≥3 lines treatment, no statistical significance of the DCR was observed, nonetheless, patients received pyrotinib plus capecitabine had a numerically lower DCR than those received pyrotinib combined with other chemotherapy drugs (85% vs. 92.86%, P=0.704). This is an early stage of data analysis, median progression-free survival has not yet been reached. The most common AE was diarrhea (81.68%), but only 16 (7.93%) patients reported Grade ≥ 3 diarrhea which could be well controlled. Other AEs included leukopenia (31.69%), neutropenia (30.69%), anemia (27.23%), increased alanine aminotransferase (15.36%), decreased appetite (11.39%), and stomatitis (6.44%). No treatment-related death occurred. Conclusions: Pyrotinib demonstrated an encouraging efficacy and manageable safety profile in patients with advanced HER2+ breast cancer. More data would be analyzed and reported in the future. Citation Format: Jifeng Feng, Lili Zhang, Zhaoji Guo, Jun Zhou, Mingzhen Zhu, Xiaohong Wu, Tongbo Yi, Yujiang Guo, Xiaoqin Li, Hao Yu, Weidong Mao, Bei Gu, Zhengxiang Han, Yun Zuo, Yanhua Liu, Xufen Wang. Pyrotinib in the treatment of women with advanced HER2 positive breast cancer: A multicenter, prospective, real world study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-43.

Durable clinical benefit from pyrotinib combined with carboplatin in HER2-positive relapsed breast cancer previously treated with taxanes, anthracyclines, and trastuzumab.

Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer inevitably progressed after a short response to initial trastuzumab treatment, suggesting a possibility of acquired-resistance to trastuzumab. Pyrotinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor (TKI), has been reported as an effective and safe drug for the treatment of HER2-positive relapsed or metastatic breast cancer. Pyrotinib combined with capecitabine is widely used to treat HER2-positive metastatic breast cancer in patients who have been previously treated with anthracyclines, taxanes, and trastuzumab. However, the efficacy of pyrotinib combined with other chemotherapy drugs is still unclear. Here we report pyrotinib combined with carboplatin in treating a patient with HER2-positive relapsed breast cancer who had acquired resistance to trastuzumab. The patient received three cycles of treatments of pyrotinib (400 mg, orally once per day, days 1-21) combined with carboplatin (600 mg, iv drip, day 1, cycled every 21 days). The patient showed an excellent response to the therapy, including faded rashes on the skin of her breast, no obvious signs of recurrence from the breast magnetic resonance imaging (MRI), decreased skin thickness and cord shadow of the right breast, unchanged degree of right pleural effusion, and no enlarged LN. The patient had a stable disease time of more than four months. Our case provides evidence for the feasibility and efficacy of pyrotinib with carboplatin in treating patients with HER2-positive relapsed or metastatic breast cancer who may develop resistance to trastuzumab.

224P Neoadjuvant pyrotinib plus trastuzumab, docetaxel, and carboplatin in patients with HER2-positive early breast cancer: A single-group, multicenter, phase II study

Pyrotinib is a new oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor that targets human epidermal growth factor receptor 1 (HER1), HER2, and HER4. Previous studies have confirmed that progression-free survival (PFS) is safe and well-tolerated in advanced breast cancer. However, the efficacy of pyrotinib plus trastuzumab-based dual HER2 blockade in neoadjuvant therapy for early breast cancer is unknown. The present study aimed to explore the efficacy of pyrotinib in neoadjuvant therapy for early breast cancer.

Real-World Data of Pyrotinib-Based Therapy in Metastatic HER2-Positive Breast Cancer: Promising Efficacy in Lapatinib-Treated Patients and in Brain Metastasis.

PurposePyrotinib is a newly-developed irreversible pan-ErbB receptor tyrosine kinase inhibitor. This study reported the first real-world data of pyrotinib-based therapy in metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC), focusing on efficacy in lapatinib-treated patients and in brain metastasis.Materials and MethodsOne hundred thirteen patients with metastatic HER2-positive BC treated with pyrotinib-based therapy in Fudan University Shanghai Cancer Center under non-clinical trial settings from September 1, 2018 to March 1, 2019 were included.ResultsOver half patients have received more than two lines of systematic therapy and exposed to two or more kinds of anti-HER2 agents. Most patients received a combined therapy, commonly of pyrotinib plus capecitabine, or vinorelbine or trastuzumab. Median progression-free survival (PFS) was 6.3 months (range, 5.54 to 7.06 months) and objective response rate (ORR) was 29.5%, with two patients (1.9%) achieving complete response. Lapatinib-naïve patients had significantly longer PFS than lapatinib-treated patients (9.0 months vs. 5.4 months, p=0.001). ORR for lapatinib-treated patients was 23.2%. Thirty-one of 113 patients have brain metastasis. Median PFS was 6.7 months and intracranial ORR was 28%. For patients without concurrent radiotherapy and/or brain surgery, the ORR was very low (6.3%). But for patients receiving concurrent radiotherapy and/or brain surgery, the ORR was 66.7%, and three patients achieved complete response. Most common adverse event was diarrhea.ConclusionPyrotinib-based therapy demonstrated promising effects in metastatic HER2-positive BC and showed activity in lapatinib-treated patients. For patients with brain metastasis, pyrotinib-based regimen without radiotherapy showed limited efficacy, but when combined with radiotherapy it showed promising intracranial control.

Efficacy and safety of oral pyrotinib in HER2 positive metastatic breast cancer: real-world practice

Pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, showed promising antitumor activity and acceptable tolerability in phase II and phase III randomized clinical trials. We assessed the activity and safety of oral pyrotinib for human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer patients in the real world. We retrospectively analyzed 72 HER2 positive metastatic breast cancer (MBC) patients who received oral pyrotinib based regimens at Beijing Cancer Hospital and other four hospitals (Peking University First Hospital, China-Japan Friendship Hospital, General Hospital of PLA, Peking University Third Hospital) from August 2018 to September 2019. Progression free survival (PFS), objective response rate (ORR), adverse events (AE) of pyrotinib were investigated. Seventy-two patients with HER2 positive MBC were enrolled. The median age of the patients was 55 years (range: 32-79 years). Sixty-nine (95.8%) patients had received anti-HER2 treatment in the metastatic and/or (neo) adjuvant settings; 61 (84.7%) patients had received anti-HER2 treatments in the metastatic setting in terms of trastuzumab 56 (77.8%) patients, lapatinib 36 (50.0%) patients, and T-DM1 4 (5.6%) patients. Among these 72 patients who received oral pyrotinib based regimens, 62 (86.1%) patients received pyrotinib (±trastuzumab) in combination with chemotherapy, 6 (8.3%) patients received pyrotinib (± trastuzumab) in combination with endocrine therapy and 4 (5.6%) patients received pyrotinib (±trastuzumab). Sixty-five (90.3%) patients received 400 mg pyrotinib once daily as initial dose, and 7 (9.7%) patients received 320 mg. OBJECTIVE response and safety to pyrotinib based therapy were evaluable in all the 72 patients. One (1.4%) patient achieved complete response (CR), 18 (25.0%) patients achieved partial response (PR), 41 (56.9%) patients had stable disease (SD), and 12 (16.7%) patients had progressive disease (PD). The ORR (CR+PR) was 26.4% and the median PFS was 7.6 months (95%CI: 5.5-9.7 months). Among the 36 patients with prior lapatinib therapy, the median PFS was 7.9 months (95%CI: 4.1-11.7 months). Among the 15 patients with brain metastasis, the median PFS was 6.0 months (95%CI: 2.2-9.8 months). The main toxicities related to pyrotinib were diarrhea in 57 (79.2%) cases, and 48 (66.7%) cases with grade 1-2 as well as 9 (12.5%) cases with grade 3. Pyrotinib based therapy is an effective treatment for patients with HER2 positive MBC, including patients with lapatinib treatment failure and brain metastasis, and the toxicities can be tolerated.

Pyrotinib combined with capecitabine in women with HER2+ metastatic breast cancer previously treated with trastuzumab and taxanes: A randomized phase III study.

1001 Background: Pyrotinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor, showed promising anti-tumour activity and acceptable tolerability in patients with HER2+ metastatic breast cancer (MBC) in phase 1/2 trials. Methods: This double-blinded, multicentre, randomised phase 3 trial was conducted in Chinese patients with HER2+ MBC previously treated with taxanes and trastuzumab. Patients were randomly assigned (2:1) to receive 400 mg pyrotinib or placebo orally once daily for 21-day cycles in combination with capecitabine (1000 mg/m2 orally twice daily on days 1–14). The primary endpoint (IRC-assessed progression free survival [PFS]) was assessed in patients who received ≥1 dose of study treatment. Patients whose disease progressed on placebo plus capecitabine received subsequent single agent pyrotinib. Results: Between July, 2016 and November, 2017, 279 patients were randomised to pyrotinib plus capecitabine (n = 185) or placebo plus capecitabine (n = 94) arms. The median PFS was 11.1 months (95% CI 9.66, 16.53) in the pyrotinib plus capecitabine arm and 4.1 months (95% CI 2.79, 4.17) in the placebo plus capecitabine arm. seventy-one patients in placebo plus capecitabine arm received subsequent pyrotinib, showing single-agent response rate of 38.0% (95%CI 26.7%, 49.3%) and median PFS of 5.5 months (95% CI 4.07, 6.90). The most frequent (≥5%) treatment-related ≥ grade 3 adverse events were diarrhoea (30.8% vs 12.8% ) and hand-foot syndrome (15.7% vs 5.3%). Conclusions: In women with HER2+ MBC previously treated with taxanes and trastuzumab, pyrotinib plus capecitabine yield statistically significant better PFS. Pyrotinib monotherapy showed anti-tumour activity. Clinical trial information: NCT02973737. [Table: see text]

Pyrotinib treatment on HER2-positive gastric cancer cells promotes the released exosomes to enhance endothelial cell progression, which can be counteracted by apatinib.

Aims: Pyrotinib is a newly developed irreversible pan-ErbB receptor tyrosine kinase inhibitor for treatment of human epidermal growth factor receptor 2 (HER2)-positive cancers, and clinic trials of pyrotinib in treatment of HER2-positive gastric cancer (GC) are underway. Exosomes are tiny vesicles secreted by cancer cells and take essential roles in the progression of carcinoma. Whether pyrotinib application has any effect on the cancer cell-released exosomes has not been studied. The aim of our work was to address if pyrotinib treatment impacts the effect of HER2-positive GC cell-derived exosomes on endothelial cell (EC) progression.Methods: Isolation of exosomes released by HER2-positive NCI-N87 and MKN45 lines after pyrotinib treatment was performed. Then, human umbilical vein endothelial cells (HUVECs) were incubated with different concentrations of exosomes to address their proliferation by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS). Effect of pyrotinib-treated exosomes at concentration of 10 µg/mL was compared to that without pyrotinib treatment over 96-hr time course. Transwell assay and wound-healing assay were carried out by incubating with exosomes released by NCI-N87 and MKN45 cells with/without pyrotinib treatment over 24-hr time course. The aforementioned experiments were done under same conditions in order to evaluate the combined effect of apatinib and pyrotinib on HUVEC motility and invasive capacity.Results: We showed that HUVEC proliferation, motility and invasive capacity were further enhanced upon incubation with exosomes released by pyrotinib-treated GC cell lines, compared to those without pyrotinib treatment. Significantly, this effect was counteracted by the vascular endothelial growth factor receptor (VEGFR)-2 inhibitor apatinib which inhibits EC progression.Conclusion: Our study suggests that pyrotinib application on HER2-positive GC produces stronger exosomes that promote the proliferation and motility of vascular ECs, and combination of pyrotinib with apatinib provides potentially better therapy.

Pyrotinib or Lapatinib Combined with Capecitabine in Women with HER2-Positive Metastatic Breast Cancer Previously Treated with Taxanes, Anthracyclines, And/Or Trastuzumab: An Open-Label, Randomised, Phase 2 Study

Background: Pyrotinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor, showed promising antitumour activity and acceptable tolerability in a phase 1 breast cancer trial. We assessed the efficacy and tolerability of pyrotinib versus lapatinib, both with capecitabine, in women with HER2-positive metastatic breast cancer. Methods: This open-label, multicentre, randomised phase 2 study was conducted at 11 hospitals in China in patients with HER2-positive relapsed or metastatic breast cancer previously treated with taxanes, anthracyclines and/or trastuzumab, and two or fewer chemotherapy regimens. Using stratified block randomisation, patients were assigned (1:1) to receive either 400 mg pyrotinib or 1250 mg lapatinib orally once daily for 21-day cycles in combination with capecitabine (1000 mg/m2 orally twice daily on days 1-14). The primary endpoint (investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1) and safety were assessed in patients who received ≥1 dose of study treatment. Findings: Between May 29, 2015 and March 15, 2016, 128 eligible patients were randomly assigned to the pyrotinib (n=65) or lapatinib (n=63) treatment groups. The objective response rate was 78·5% (95% CI 68·5-88·5) with pyrotinib and 57·1% (95% CI 44·9-69·4) with lapatinib (treatment difference 21·3%, 95% CI 4·0-38·7; p=0·01). The most frequent grade 3-4 adverse events were hand-foot syndrome in 16 (24·6%) of 65 patients in the pyrotinib group vs 13 (20·6%) of 63 in the lapatinib group; diarrhoea (ten [15·4%] vs three [4·8%]); and decreased neutrophil count (six [9·2%] vs two [3·2%]). Interpretation: These findings support the use of pyrotinib plus capecitabine as an effective treatment option for pre-treated relapsed or metastatic breast cancer. Clinical Trial Number: This trial is registered with ClinicalTrials.gov (NCT02422199) and is closed to new participants Funding Statement: Jiangsu Hengrui Medicine Co., Ltd., CAMS Initiative for Innovative Medicine (CAMS-12M-1-010) and Grant No. 2015ZX09101007003 from National Science and Technology Major. Declaration of Interests: JZ and XZ are employed by Jiangsu Hengrui Medicine Co., Ltd. All other authors report no potential conflicts. Ethics Approval Statement: If a patient agreed to participate, she was required to provide written informed consent before enrollment. Investigations were performed in accordance with Chinese laws and regulations and the Helsinki declaration, after approval by the local ethics committee at each participating site.

Abstract PD3-08: A randomized phase II trial of pyrotinib plus capecitabine versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer previously treated with taxanes, anthracyclines and/or trastuzumab

Abstract Background:Pyrotinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor (TKI) with activity against epidermal growth factor receptor (EGFR) / HER1, HER2, and HER4. Lapatinib in combination with capecitabine is one of the standards of care for patients with HER2-positive metastatic breast cancer (MBC) who have received prior taxanes, anthracyclines and/or trastuzumab. Methods: We conducted an open label, multicenter, randomized phase II trial to comparatively evaluate efficacy and safety of pyrotinib + capecitabine (PC) or lapatinib + capecitabine (LC) in women with HER2-positive MBC. Key eligibility criteria included prior treatment with taxanes, anthracyclines and/or trastuzumab, ≤2 prior chemotherapies for metastatic disease, no CNS metastases, and no prior treatment with HER2 targeted TKI. Eligible patients were randomized 1:1 to PC Arm (P 400 mg QD D1–21 + C 1000 mg/m2BID D1–14, 21-D cycle) or LC Arm (L 1250 mg QD D1–21 + C 1000 mg/m2BID D1–14, 21-D cycle). The primary endpoint was objective response rate (ORR) as assessed by investigator, and secondary endpoints included progression-free survival (PFS), time to progression (TTP), duration of response (DoR), overall survival (OS), and safety. Results: Between May 2015 and Mar 2016, 128 patients (65 in PC arm and 63 in LC arm) were enrolled in this study. Median age was 48 years (range 25-70), ECOG performance status was 0 (53.9%) or 1 (46.1%), 62.5% had hormone receptor-positive disease, 76.6% had visceral disease and 53.9% had received prior trastuzumab in (neo)adjuvant and/or mestastatic setting. Baseline characteristics were well balanced in two arms. Median follow-up time was 15.0 months. ORR was 78.5% in PC arm and 57.1% in LC arm (p=0.01), Median PFS was 18.1 months in PC arm and 7.0 months in LC arm (hazard ratio 0.363; 95% CI 0.228, 0.579; p<0.0001), PFS benefit in PC arm compared to LC arm was observed irrespective of prior trastuzumab or not. Treatment related Grade 3-4 toxicities occurred in >2% patients in PC arm vs LC arm included hand-foot syndrome (21.5% vs 19.0%), diarrhea (13.8% vs 4.8%), decreased neutrophil (7.7% vs 1.6%), decreased WBC (6.2% vs 1.6%), vomiting (4.6% vs 0%), increased AST (3.1% vs 1.6%), decreased hemoglobin (3.1% vs 1.6%), increased total bilirubin (0% vs 4.8%) and increased conjugated bilirubin (0% vs 3.2%). Conclusions: In women with HER2-positive MBC previously treated with taxanes, anthracyclines and/or trastuzumab, pyrotinib + capecitabine yield statistically significant better PFS and ORR than lapatinib + capecitabine in this randomized phase II trial. Phase III study is ongoing to validate this finding. Citation Format: Xu B, Ma F, Ouyang Q, Li W, Jiang Z, Tong Z, Liu Y, Li H, Yu S, Feng J, Wang S, Hu X, Zhu X, Zou J. A randomized phase II trial of pyrotinib plus capecitabine versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer previously treated with taxanes, anthracyclines and/or trastuzumab [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-08.

Abstract P4-14-18: Phase I study of single-agent pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, in patients with ErbB2+ metastatic breast cancer

Abstract Pyrotinib is a novel small molecule irreversible pan-ErbB receptor tyrosine kinase inhibitor. This phase I study was designed to evaluate the safety, pharmacokinetics and antitumor activity of pyrotinib in Chinese patients with ErbB2+ metastatic breast cancer (n=38). The majority of patients were previously treated with multiple lines (≤5) of anti-tumor regimens including trastuzumab. The dose-escalation study was conducted at 80, 160, 240, 320, 400 and 480 mg levels in patients receiving oral pyrotinib with food once daily on a 28-day cycle. Dose-limiting toxicity (DLT) was grade 3 diarrhea, which occurred in two out of two patients treated with 480mg pyrotinib during the dose-escalation. Therefore, the maximum tolerated dose (MTD) of pyrotinib was determined to be 400 mg per day. In general, pyrotinib was safe and well tolerated when administered to patients. The majority of adverse events which occurred in the study were grade I and II. The pharmacokinetic results showed linear characteristics along the range of doses tested, and supports a once daily dosing regimen. The overall objective response rate (ORR) was 52.8% and disease control rate (DCR) was 80.6% in 36 patients (19 PR and 10 SD), with the highest ORR of 55.6% (5/9) and 87.5% (7/8) observed in 320 mg and 400 mg cohorts, respectively. The median duration of response was 32.3 weeks. In addition, 3 (8.3%) subjects achieved stable disease for at least 24 weeks. Kaplan-Meier median progression-free survival (PFS) was 35.3 weeks (95%CI: 23.6∼39.9 weeks) among all subjects treated with 80-400 mg, and the median PFS for 320 mg and 400 mg cohorts was 39.9 weeks (95%CI: 31.1∼47.4 weeks). Based on tolerability, safety, PK and efficacy data of 6 dose-cohorts, 320 mg and 400mg of pyrotinib once daily could be considered a recommended regimen for Phase II studies. The promising antitumor activity of pyrotinib observed in patients with ErbB2+ metastatic breast cancer, who had previous treatment with anthracyclines, taxanes, and trastuzumab, warrants its further study (ClinicalTrials.gov number, NCT01937689). Citation Format: Xu B, Ma F, Chen S, Li Q, Yang F, Zhang Y, Chen X, Zhong D, Zhang G. Phase I study of single-agent pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, in patients with ErbB2+ metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-18.

Dacomitinib (PF-00299804), a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor, demonstrates remarkable activity against HER2-amplified uterine serous endometrial cancer in vitro.

Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that carries an extremely poor prognosis. Up to 35 % of USC may overexpress the epidermal growth factor receptor-2 (HER2/neu) at strong (i.e., 3+) level by immunohistochemistry (IHC) or harbor HER2/neu gene amplification by fluorescence in situ hybridization (FISH). In this study, we assessed the sensitivity of a panel of USC cell lines with and without HER2/neu gene amplification to dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor tyrosine kinase inhibitor. Eight primary cell lines (i.e., four harboring HER2/neu gene amplification by FISH and four FISH- cell lines), all demonstrating similar in vitro growth rates, were evaluated in viability/proliferation assays. The effect of dacomitinib on cell growth, cell cycle distribution, and signaling was determined using flow cytometry-based assays. Dacomitinib caused a significantly stronger growth inhibition in HER2/neu FISH+ USC cell lines when compared to FISH- USC (dacomitinib half maximal inhibitory concentration (IC50) mean ± SEM = 0.02803 ± 0.003355 μM in FISH+ versus 1.498 ± 0.2209 μM in FISH- tumors, P < 0.0001). Dacomitinib growth inhibition was associated with a significant and dose-dependent decline in phosphorylated HER2/neu and S6 transcription factor and a dose-dependent and time-dependent cell cycle arrest in G0/G1 in FISH+ USC. Dacomitinib is remarkably effective against chemotherapy-resistant HER2/neu gene-amplified USC. Clinical studies with dacomitinib in HER2/neu FISH+ USC patients resistant to standard salvage chemotherapy are warranted.