Dataset Information

Survival benefit and biomarker analysis of pyrotinib or pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer: a pooled analysis of two phase I studies.

ABSTRACT:

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).

SUBMITTER: Guan X

PROVIDER: S-EPMC9940415 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

Survival benefit and biomarker analysis of pyrotinib or pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer: a pooled analysis of two phase I studies.

Guan Xiuwen X Ma Fei F Li Qiao Q Chen Shanshan S Lan Bo B Fan Ying Y Wang Jiayu J Luo Yang Y Cai Ruigang R Zhang Pin P Li Qing Q Xu Binghe B

Biomarker research 20230220 1

<h4>Background</h4>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, t ...[more]

PMID: 36803645

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Project description:PurposeNALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens.MethodsPatients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL).ResultsA total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups.ConclusionN+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

Project description:BackgroundHuman 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.MethodsPubMed, 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.ResultsIn 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).ConclusionsIn 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.

Dataset Information

Survival benefit and biomarker analysis of pyrotinib or pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer: a pooled analysis of two phase I studies.

Background

Methods

Results

Conclusions

Trial registration

Publications

Survival benefit and biomarker analysis of pyrotinib or pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer: a pooled analysis of two phase I studies.

Similar Datasets

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