Pyrotinib: First Global Approval
Hannah A. Blair1
Pyrotinib is an irreversible dual pan-ErbB receptor tyrosine kinase inhibitor developed for the treatment of HER2-positive advanced solid tumours. Based on positive results in a phase II trial, the drug recently received conditional approval in China for use in combination with capecitabine for the treatment of HER2-positive, advanced or metastatic breast cancer in patients previously treated with anthracycline or taxane chemotherapy. This article summarizes the milestones in the development of pyrotinib leading to this first global approval for the treatment of HER2-positive advanced breast cancer.
Approximately 15–20% of breast cancer patients have over- expression of HER2 [1, 2], which is associated with more aggressive disease . Clinical outcomes in patients with breast cancer have improved greatly with the development of HER2-targeted therapies, including (primarily) anti- HER2 antibodies and their derivatives . Tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates such as trastuzumab-emtansine have so far played a lesser role . Additional agents need to be developed further to improve on current results and overcome resistance .
Pyrotinib is an orally administered irreversible dual pan- ErbB TKI developed by Shanghai Hengrui Pharmaceutical (a subsidiary of Jiangsu Hengrui Medicine) for the treat- ment of advanced solid tumours with overexpression of HER2, including breast cancer . In August 2018, pyro- tinib received its first global conditional approval in China for use in combination with capecitabine for the treatment of HER2-positive, advanced or metastatic breast cancer in patients previously treated with anthracycline or taxane chemotherapy . In China, a conditional approval permits the early marketing of new drugs where there is an urgent
clinical need to treat patients in a critical condition . The priority review was based on data from a phase II trial (NCT02422199). The recommended dosage of oral pyro- tinib is 400 mg once daily after a meal . Interruption, cessation or downward dosage titration of pyrotinib may be necessary to manage adverse events; the minimum dosage of pyrotinib is 240 mg once daily .
Pyrotinib, as part of neoadjuvant combination therapy, is currently undergoing phase III clinical trials for HER2- positive early stage or locally advanced breast cancer in China. In addition, phase I and II development for use in HER2-positive gastric cancer and non-small cell lung cancer (NSCLC) is underway in China and the USA.
Jiangsu Hengrui Medicine owns a patent application cover- ing the method of preparation and pharmaceutical uses of 3-cyanoquinolone derivatives. The application is granted in Canada, China, Japan, South Korea, the USA and Europe (including Denmark, Russia and Spain).
This profile has been extracted and modified from the AdisInsight database. AdisInsight tracks drug development worldwide through the entire development process, from discovery, through pre- clinical and clinical studies to market launch and beyond.
The 3-cyanoquinoline derivative pyrotinib is a novel, irre- versible TKI with activity against EGFR/HER1, HER2 and
HER4 . Pyrotinib binds to and inhibits EGFR (ErbB1/
HER1) and ErbB2/HER2, with a half maximal inhibitory
1 Springer, Private Bag 65901, Mairangi Bay, Auckland 0754, New Zealand
concentration (IC50) of 5.6 and 8.1 nM, respectively . In
Phase I trials in HER2-positive advanced breast cancer (NCT01937689) (Jan)
NDA submitted to CFDA in China (Aug)
Fast track designation granted by the CFDA for breast cancer (Dec)
Approved in China for recurrent or metastatic breast cancer (Aug)
2013 2014 2015 2016 2017 2018 2019 2020 2021 2022
NCT02422199 (Phase I/II)
NCT02973737 (Phase III)
NCT03080805 (Phase III)
NCT03412383 (Phase II)
NCT03588091 (Phase III)
HER2-positive metastatic breast cancer
HER2 non-amplified but HER2 mutant metastatic breast cancer HER2-positive early stage or locally advanced breast cancer
Clinical development of pyrotinib for the treatment of HER2-positive breast cancer
mouse models of breast, lung and ovarian cancer, pyrotinib significantly inhibited HER2 factor-driven tumour growth and HER2-mediated downstream signalling, and blocked tumour cells in the G1 phase of the cell cycle .
Pyrotinib demonstrated high potency in HER2-overex- pressing mouse xenograft models of breast (IC50 5.1 nM) and ovarian (IC50 43 nM) cancer, with much weaker inhi- bition in a HER2-negative breast cancer cell line (IC50 3500 nM) . Pyrotinib significantly inhibited the growth of tumour cells in HER2-dependent xenograft models. The tumour growth inhibition (TGI %) of pyrotinib on day 21 was 109, 157 and 159% at doses of 5, 10 and 20 mg/kg, respectively. The antitumour efficacy of pyrotinib 10 mg/
kg was confirmed in a secondary ovarian xenograft model (TGI % on day 21 of 2, 12 and 83% at doses of 2.5, 5 and 10 mg/kg, respectively) .
In vivo, pyrotinib 80 mg/kg inhibited HER2 to a signif- icantly greater extent than pyrotinib 5 or 20 mg/kg (both
increase in a dose-dependent manner. Steady-state plasma concentrations are reached on day 8 of repeated administra- tion. Multiple-dose exposure is 1.22- to 1.57-fold greater than single-dose exposure, suggesting that there is no major accumulation of pyrotinib following repeated daily admin- istration . When pyrotinib is administered with a high-fat meal, Cmax and AUC0–∞ increase by 79 and 43% . The apparent volume of distribution of pyrotinib is 4200 L. Pyro- tinib is highly (86.9–99.7%) bound to plasma proteins .
The metabolism of pyrotinib is catalyzed primarily by CYP3A4 and, to a lesser extent, by CYP1B1, CYP2C8, CYP2C19, CYP2D6 and CYP3A5 [3, 9]. High-resolu- tion mass spectrometry analysis detected 24 metabolites in human plasma, faeces and urine . These included 16 phase I metabolites resulting from dealkylation,
p ≤ 0.0001), afatinib 15 mg/kg (p = 0.0471) and trastuzumab emtansine 10 mg/kg (p = 0.0138) in a patient-derived xen- ograft model of lung cancer . Pyrotinib 80 mg/kg also
demonstrated robust inhibition of phosphorylated HER2, ERK and Akt .
N Cl NH
Pyrotinib is absorbed relatively slowly following administra- N
tion of a single dose of pyrotinib (80–400 mg) in patients with HER2-positive metastatic breast cancer, with a median time to maximum plasma concentration of 3–5 h . At steady state, the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC)
Chemical structure of pyrotinib
Features and properties of pyrotinib
Alternative names BLTN; pyrroltinib maleate; SHR1258
Class Antineoplastics; pyridines; pyrrolidines; quinolones
Mechanism of action EGFR antagonist; ErbB2 receptor antagonist
Route of administration Oral
Binds to and inhibits EGFR (ErbB1/HER1) and ErbB2/HER2; inhibits HER2 factor-driven tumour growth and
HER2-mediated downstream signalling; blocks tumour cells in the G1 phase of the cell cycle
Median time to maximum plasma concentration is 3–5 h; steady state plasma concentrations reached on day 8 of repeated administration; human plasma protein binding ratio is 86.9–99.7%; apparent volume of distribution is 4200 L; elimination half-life is 18.2 h; clearance is 141 L/h
Most common adverse events Diarrhoea, vomiting, nausea, hand and foot syndrome, leukopenia, neutropenia ATC codes
WHO ATC code L01X-E (protein kinase inhibitors)
EphMRA ATC code L1H (protein kinase inhibitor antineoplastics)
Chemical name (E)-N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl]-3-[(2R)-1-methylpyrrolidin-
oxidation, dehydrogenation and carbonylation, and 8 phase II metabolites originating from cysteine and N-ace- tylcysteine conjugation. The primary circulating metabolites were O-depicolyl metabolite M1, O-depicolyl and pyrroli- dine lactam metabolite M2 and pyrrolidine lactam metabo- lite M5. No metabolites were detected in plasma after 36 h . Pyrotinib is mainly excreted in the faeces . Following the administration of radiolabeled pyrotinib in healthy sub- jects, 90.9% of the radioactivity was recovered in the urine and 1.72% was recovered in the faeces. The mean elimina- tion half-life of pyrotinib is 18.2 h and the mean clearance is 141 L/h .
Formal drug interaction studies with pyrotinib have not been conducted . However, as pyrotinib is metabolized primarily by CYP3A4, caution is advised when the drug is coadministered with strong CYP3A4 inhibitors or inducers. Pyrotinib is a weak inhibitor of CYP2C19 (IC50 18.52 μM) and is also a substrate of P-glycoprotein. Therefore, the
plasma concentration of pyrotinib may be increased when it is coadministered with drugs that are metabolized by CYP2C19 or drugs that inhibit P-glycoprotein .
In the first-in-human, open-label phase I study (NCT01937689) in patients with HER2-positive metastatic breast cancer, pyrotinib 400 mg once daily demonstrated promising antitumour activity; this dosage was determined to be the maximum tolerated dose and was subsequently taken forward into future studies . All studies discussed further in this section used this dosage.
The efficacy of pyrotinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer
Key clinical trials of pyrotinib (Jiangsu Hengrui Medicine)
Drug(s) Indication Phase Status Location Identifier
Pyrotinib HER2-positive advanced breast cancer I Completed China NCT01937689
Pyrotinib + capecitabine HER2-positive metastatic breast cancer I Completed China NCT02361112
Pyrotinib HER2-positive advanced solid tumours I Ongoing USA NCT02500199
Pyrotinib + SHR6390 HER2-positive advanced gastric cancer I Ongoing China NCT03480256
Pyrotinib + capecitabine vs lapatinib + capecitabine HER2-positive metastatic breast cancer I/II Completed China NCT02422199
Pyrotinib HER2-positive advanced NSCLC II Ongoing China NCT02834936
Pyrotinib HER2 mutant breast cancer II Ongoing China NCT03412383
Pyrotinib + capecitabine vs placebo + capecitabine HER2-positive metastatic breast cancer III Ongoing China NCT02973737
Pyrotinib + capecitabine vs lapatinib + capecitabine HER2-positive metastatic breast cancer III Ongoing China NCT03080805
Pyrotinib + trastuzumab + docetaxel vs placebo +
trastuzumab + docetaxel
NSCLC non-small cell lung cancer
HER2-positive early stage or locally
advanced breast cancer
III Ongoing China NCT03588091
previously treated with taxanes, anthracyclines and/or tras- tuzumab was demonstrated in a randomized, open-label, active comparator-controlled, multicentre phase II trial (NCT02422199) . Patients were randomized to pyro- tinib 400 mg once daily on days 1–21 plus capecitabine 1000 mg/m2 twice daily on days 1–14 (n = 65) or lapat- inib 1250 mg once daily on days 1–21 plus capecitabine 1000 mg/m2 twice daily on days 1–14 (n = 63) until disease progression or intolerable toxicity. Pyrotinib plus capecit- abine was associated with a significantly greater objective response rate (ORR) than lapatinib plus capecitabine, as assessed by the investigator (79 vs. 57%; p = 0.01; primary endpoint). With the exception of three patients in the pyro- tinib plus capecitabine group and one patient in the lapatinib plus capecitabine group who had complete responses, all ORRs were partial responses . Similar findings were reported for ORR when assessed by independent imag- ing assessment (71 vs. 49%; p = 0.0117) . Duration of response was 16.7 months with pyrotinib plus capecitabine and 8.4 months with lapatinib plus capecitabine [hazard ratio (HR) 0.402] .
Pyrotinib plus capecitabine significantly prolonged median progression-free survival (PFS) versus lapatinib plus capecitabine (18.1 vs. 7.0 months; adjusted HR 0.363; 95% CI 0.228–0.579; p < 0.0001) . The PFS benefit of pyrotinib plus capecitabine was seen in patients with (not reached vs. 7.1 months; HR 0.374; 95% CI 0.190–0.738; p = 0.0031) and without (18.1 vs. 5.6 months; HR 0.366; 95% CI 0.192–0.696; p = 0.0013) prior trastuzumab. Median time to progression was 19.5 months with pyrotinib plus capecitabine and 7.0 months with lapatinib plus capecitabine (HR 0.349) .
2.3.2Non‑Small Cell Lung Cancer
The efficacy of pyrotinib in patients with HER2 mutant advanced NSCLC was demonstrated in a single-arm, pro- spective, phase II trial (NCT02535507) . Preliminary results were available in 11 evaluable patients. The best ORR (primary endpoint) was partial response in 55% of patients, stable disease in 27% of patients and progressive disease in 18% of patients. Median PFS was 6.2 months .
Pyrotinib had a manageable tolerability profile in patients with HER2-positive metastatic breast cancer (NCT02422199) . The most common treatment-emer- gent adverse events (TEAEs) of any grade (occurring in ≥ 20% of patients and with a numerically higher incidence in the pyrotinib plus capecitabine group than the lapatinib plus capecitabine group) were diarrhoea (97 vs. 44%), hand-foot syndrome (79 vs. 73%), vomiting (46 vs. 21%), leukopenia
(46 vs. 35%), neutropenia (43 vs. 37%), nausea (39% vs. 21%), decreased appetite (32 vs. 6%), increased ALT (29 vs. 27%), anaemia (22 vs. 3%) and asthenia (20 vs. 14%). The most common (≥ 10% incidence) grade 3–4 TEAEs were hand-foot syndrome (25 vs. 21%) and diarrhoea (15 vs. 5%) . Diarrhoea generally occurred during the first 4 days of treatment, lasted for 2–3 days and was managed with symptomatic treatment (e.g. loperamide, montmorillon- ite) or by suspending or decreasing the dosage of pyrotinib . Serious adverse events occurred in 8% of pyrotinib plus capecitabine recipients and 6% of lapatinib plus capecitabine recipients .
In patients with HER2 mutant advanced NSCLC (NCT02535507), pyrotinib was associated with mild (grade 1–2) toxicities, including diarrhoea (36%), fatigue (18%), rash (18%) and dyspnea (9%) .
2.5Ongoing Clinical Trials
Jiangsu Hengrui Medicine is conducting two randomized phase III trials in China to investigate the efficacy of pyro- tinib plus capecitabine in patients with HER2-positive met- astatic breast cancer (NCT02973737 and NCT03080805). One trial plans to enrol approximately 350 patients and the other 240 patients. Both trials have an estimated completion date of December 2019. In February 2018, a phase II trial was initiated in patients with HER2 mutant breast cancer (NCT03412383). The trial is enrolling 14 patients in China, and has an estimated completion date of June 2019.
A phase III trial is also underway to evaluate the efficacy of pyrotinib plus trastuzumab and docetaxel as neoadju- vant therapy in women with HER2-positive early stage or locally advanced breast cancer (NCT03588091). Initiated in July 2018, the randomized, double-blind study is recruiting approximately 294 patients in China. The estimated study completion date is June 2022.
Several other studies are underway to assess the efficacy and safety of pyrotinib in other HER2-positive advanced solid tumours (breast cancer, NSCLC or gastric can- cer), including a phase II trial in China (NCT02834936) and phase I trials in China (NCT03480256) and the USA (NCT02500199).
Pyrotinib received its first global conditional approval in China in August 2018 for use in combination with capecit- abine for the treatment of HER2-positive, advanced or metastatic breast cancer in patients previously treated with anthracycline or taxane chemotherapy .
Compliance with Ethical Standards
Funding The preparation of this review was not supported by any external funding.
Conflict of interest During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the author on the basis of scientific completeness and accuracy. Hannah Blair is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.
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