Phase I Study and Biomarker Analysis of Pyrotinib, a Novel Irreversible Pan-ErbB Receptor Tyrosine Kinase Inhibitor, in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

Ma, Fei; Li, Qiao; Chen, Shanshan; Zhu, Wenjie; Fan, Ying; Wang, Jiayu; Luo, Yang; Xing, Puyuan; Lan, Bo; Li, Meiying; Yi, Zongbi; Cai, Rong; Yuan, Peng; Zhang, Pin; Li, Qing; Xu, Bo

doi:10.1200/jco.2016.69.6179

Cited by 177 publications

(223 citation statements)

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“…The incidence of AEs observed in this combination regimen phase I study was higher than that in pyrotinib monotherapy study (16). Diarrhea, leukopenia, neutropenia, PPE, hyperbilirubinemia, nausea, vomiting, and anemia were more frequent when capecitabine was added to pyrotinib.…”

Section: Discussionmentioning

confidence: 67%

“…In the biomarker analysis of previous pyrotinib monotherapy trial (16), PIK3CA and/or TP53 mutations predicted a poorer response from pyrotinib. Because this correlation is not observed in this combination study, this inconsistency is probably due to the addition of capecitabine.…”

Section: Discussionmentioning

confidence: 99%

“…Pyrotinib was administered within 30 minutes after breakfast in the morning; the capecitabine dose was split into two equal doses and administered every 12 hours. The initial dose of pyrotinib was based on preclinical data (14,15) and on the results of a phase I monotherapy study in patients with breast cancer (16) in China. The study reported an MTD for pyrotinib monotherapy as 400 mg daily.…”

Section: Study Treatment and Dose-escalation Protocolmentioning

confidence: 99%

“…Preclinical data of pyrotinib demonstrate effective proliferation inhibition of HER2-overexpressing cells both in vivo and in vitro (14,15). In a phase I pyrotinib monotherapy study (16), the MTD of pyrotinib was determined to be 400 mg daily. The study also suggests that pyrotinib is safe and highly effective in patients with HER2-positive MBC, with an overall response rate (ORR) of 50.0% and a median progression-free survival (PFS) of 35.4 weeks in the dosage range of 80 to 400 mg per day.…”

Section: Introductionmentioning

confidence: 99%

“…The most common adverse events with pyrotinib monotherapy are diarrhea, nausea, oral ulceration, asthenia, and leukopenia. This study revealed that PIK3CA and TP53 mutations in circulating tumor DNA (ctDNA) are associated with a worse efficacy of pyrotinib monotherapy (16).…”

Section: Introductionmentioning

confidence: 99%

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Safety, Efficacy, and Biomarker Analysis of Pyrotinib in Combination with Capecitabine in HER2-Positive Metastatic Breast Cancer Patients: A Phase I Clinical Trial

Guan

Chen

et al. 2019

Clinical Cancer Research

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Purpose: This phase I study assessed the safety, tolerability, MTD, pharmacokinetics, antitumor activity, and predictive biomarkers of pyrotinib, an irreversible pan-ErbB inhibitor, in combination with capecitabine in patients with HER2positive metastatic breast cancer (MBC).Patients and Methods: Patients received oral pyrotinib 160 mg, 240 mg, 320 mg, or 400 mg once daily continually plus capecitabine 1,000 mg/m 2 twice daily on days 1 to 14 of a 21-day cycle. Pharmacokinetic blood samples were collected on days 1 and 14. Next-generation sequencing was performed on circulating tumor DNA to probe for predictive biomarkers.Results: A total of 28 patients were enrolled, 22 patients were treated at the two top-level doses. Among 17 (60.7%) trastuzumab-pretreated patients, 11 received trastuzumab for metastatic disease and 6 received adjuvant trastuzumab. No dose-limited toxicity was observed. Grade 3 treatment-related adverse events (AE) occurred in 12 (42.9%) patients; anemia (14.3%) and diarrhea (10.7%) were the most common grade 3 AEs. The overall response rate (ORR) was 78.6% [95% confidence interval (CI): 59.0%-91.7%], and the clinical benefit rate was 85.7% (95% CI: 67.3%-96.0%). The median progression-free survival (PFS) was 22.1 months (95% CI: 9.0-26.2 months). ORR was 70.6% (12/17) in trastuzumabpretreated patients and 90.9% (10/11) in trastuzumab-na€ ve patients. Analysis of all genetic alterations in HER2-related signaling network in baseline blood samples suggested that multiple genetic alterations were significantly associated with poorer PFS compared with none or one genetic alteration (median, 16.8 vs. 29.9 months, P ¼ 0.006).Conclusions: In a population largely na€ ve to HER2-targeted therapy, pyrotinib in combination with capecitabine was well-tolerated and demonstrates promising antitumor activity in patients with HER2-positive MBC.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Study Treatment and Dose-escalation Protocolmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Safety, Efficacy, and Biomarker Analysis of Pyrotinib in Combination with Capecitabine in HER2-Positive Metastatic Breast Cancer Patients: A Phase I Clinical Trial

Guan

Chen

et al. 2019

Clinical Cancer Research

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Principles of Dose, Schedule, and Combination Therapy

Hait

Eder

2019

Holland‐Frei Cancer Medicine

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Overview The discovery and development of oncology drugs are complex and associated with a high failure rate. For example, the chance of a new drug that enters clinical trial has an approximately 10% chance of achieving regulatory approval and ultimately becoming available for patients. Determining the proper dose and schedule of a drug are arguably the two most important determinants of both safety and efficacy, the primary determinants of regulatory approval. Understanding how to best estimate the proper dose and schedule for the many types of therapeutic agents now widely available and in development is a critical skill for those in the drug discovery and development field. This area of expertise has been made more complex with the addition of biological agents such as monoclonal antibodies, alternative protein scaffolds, and vaccines to that of hormones and small molecule platforms. In this chapter, we review the basic principles that underlie the appropriate selection of dose and schedule, with a major focus on cytotoxic chemotherapy. In addition, we discuss the many variables that can underlie the dose–response relationship including characteristics of the tumor, the tumor microenvironment, the host including enzymes of drug metabolism, and mechanisms of drug clearance. Finally, we review the clinical trial designs that have been successfully used to properly select dose and schedule for oncology drugs. The field of dose, schedule, and combination of chemotherapy agents has seen comparatively few developments in the past few years, as the focus of oncology progressively shifted from the so‐called traditional cytotoxic agents to target agents, and more recently to immunotherapy. Nevertheless, notably in the breast cancer field, dose dense chemotherapy regimens have come to the fore following the GIM‐2 trial. 1 It would be valuable to cite this published study, the ovarian cancer study GOG–0252 and breast cancer PANTHER study, as well as the recently presented meta‐analysis of dose dense trial by the EBCTCG presented at SABCS 2017. 2,3 ( ) Furthermore, two additional strategies have risen in the recent decades—in the advanced setting, the use of maintenance chemotherapy with either the reduction of current regimens or switching for non‐cross‐resistant drugs. 4–9 In the early setting, the combination of neoadjuvant therapy followed by postneoadjuvant therapy for select patients without adequate response at surgery, 10 and citing the potential of precision medicine to contribute to dose and combination design, chiefly through the evolving field of pharmacogenomics as well tumor mutation panels that are currently being tested. 11–14 The final segment, giving a panoramic view of an “integrated approach to cancer chemotherapy” should also mention the potential contributions of liquid biopsy strategies. 15,16 Finally, the field of immunotherapy has grown exponentially. Though a specific chapter is likely dedicated to the topic of immunotherapy, the potential of chemotherapy + immunotherapy combinations, both concomitant and sequentially, with chemotherapy acting as a “booster” would be interesting. 17 The TONIC trial presented during ESMO 2017 serves as a good example of the potential of this strategy.( )

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Breast cancer: an up‐to‐date review and future perspectives

Hong

2022

Cancer Communications

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Breast cancer is the most common cancer worldwide. The occurrence of breast cancer is associated with many risk factors, including genetic and hereditary predisposition. Breast cancers are highly heterogeneous. Treatment strategies for breast cancer vary by molecular features, including activation of human epidermal growth factor receptor 2 (HER2), hormonal receptors (estrogen receptor [ER] and progesterone receptor [PR]), gene mutations (e.g., mutations of breast cancer 1/2 [BRCA1/2] and phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha [PIK3CA]) and markers of the immune microenvironment (e.g., tumor‐infiltrating lymphocyte [TIL] and programmed death‐ligand 1 [PD‐L1]). Early‐stage breast cancer is considered curable, for which local‐regional therapies (surgery and radiotherapy) are the cornerstone, with systemic therapy given before or after surgery when necessary. Preoperative or neoadjuvant therapy, including targeted drugs or immune checkpoint inhibitors, has become the standard of care for most early‐stage HER2‐positive and triple‐negative breast cancer, followed by risk‐adapted post‐surgical strategies. For ER‐positive early breast cancer, endocrine therapy for 5‐10 years is essential. Advanced breast cancer with distant metastases is currently considered incurable. Systemic therapies in this setting include endocrine therapy with targeted agents, such as CDK4/6 inhibitors and phosphoinositide 3‐kinase (PI3K) inhibitors for hormone receptor‐positive disease, anti‐HER2 targeted therapy for HER2‐positive disease, poly(ADP‐ribose) polymerase inhibitors for BRCA1/2 mutation carriers and immunotherapy currently for part of triple‐negative disease. Innovation technologies of precision medicine may guide individualized treatment escalation or de‐escalation in the future. In this review, we summarized the latest scientific information and discussed the future perspectives on breast cancer.

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Phase I Study and Biomarker Analysis of Pyrotinib, a Novel Irreversible Pan-ErbB Receptor Tyrosine Kinase Inhibitor, in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

Cited by 177 publications

References 28 publications

Safety, Efficacy, and Biomarker Analysis of Pyrotinib in Combination with Capecitabine in HER2-Positive Metastatic Breast Cancer Patients: A Phase I Clinical Trial

Safety, Efficacy, and Biomarker Analysis of Pyrotinib in Combination with Capecitabine in HER2-Positive Metastatic Breast Cancer Patients: A Phase I Clinical Trial

Principles of Dose, Schedule, and Combination Therapy

Breast cancer: an up‐to‐date review and future perspectives

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