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First-line pyrotinib in advanced HER2-mutant non-small-cell lung cancer: a patient-centric phase 2 trial

Nature Medicine volume 29, pages 2079–2086 (2023)Cite this article

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Abstract

To explore targeted treatment options in patients with non-small-cell lung cancer (NSCLC) with rare genetic mutations in the context of a patient-centric clinical trial, we initiated, in parallel, a phase 2 adaptive umbrella trial consisting of a criteria-fulfilled (CF) cohort and a compassionate use (CU) cohort under expanded eligibility criteria, and a prospective real-world study (RWS). Here, we present efficacy and safety data from 48 patients with treatment-naive, advanced HER2-mutant NSCLC treated with the pan-HER receptor tyrosine kinase inhibitor pyrotinib (CF and CU cohorts) or physician’s therapy of choice (RWS cohort). In the phase 2 trial CF cohort (n = 28), the primary endpoint was reached with an objective response rate of 35.7% after pyrotinib treatment. Secondary endpoints included disease control rate (89.3%), median progression-free survival (PFS) (7.3 months), median overall survival (OS) (14.3 months) and toxicity, which was acceptable, with grade 3 or 4 treatment-related adverse events occurring in three patients (10.7%). The phase 2 trial CU cohort (n = 12) showed an objective response rate of 16.7%, disease control rate of 83.4%, median PFS of 4.7 months and median OS of 14.2 months after pyrotinib treatment. The RWS cohort (n = 8) had no responses to physician’s therapy of choice, while median PFS and OS were 3.0 and 12.2 months, respectively. Phase 2 umbrella trial, clinicaltrials.gov identifier: NCT03574402. RWS, clinicaltrials.gov identifier: NCT03605602.

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Fig. 1: Patient recruitment.
Fig. 2: Individual tumor response and treatment duration waterfall and swimming plots for patients with the HER2 mutation treated with pyrotinib.
Fig. 3: Survival analysis outcomes in three cohorts and subgroup analyses of the ORR to pyrotinib.

Data availability

For eligible studies, qualified researchers may request access to individual patient-level clinical data. The datasets generated and/or analyzed during the current study are not publicly available due to proprietary considerations. All data will be shared in aggregate form and can be requested once the article has been published, if there is not a reasonable likelihood of participant reidentification. Access to patient-level data can be requested by contacting the lead investigator Y.-L.W. (syylwu@live.cn), who will decide whether the data can be provided. Requests will be processed within 8 weeks.

Change history

  • 27 July 2023

    In the version of this article initially published, the Abstract did not list the ClinicalTrials.gov identifiers NCT03574402 and NCT03605602, which are now amended in the HTML and PDF versions of the article.

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Acknowledgements

This work was funded by the National Natural Science Foundation of China (grant no. 82202997, S.-Y.M.L.), Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (grant no. 2017B030314120, Y.-L.W.), Guangdong Provincial People’s Hospital Scientific Research Funds for Leading Medical Talents in Guangdong Province (no. KJ012019426, Y.-L.W.), National Natural Science Foundation of China (grant no. 82072562, Q.Z.) and the High-Level Hospital Construction Project (grant no. DFJH201810, Q.Z.). Medical writing assistance and figure processing for this manuscript were provided by W. Shi and H. Dong of Jiangsu Hengrui Pharmaceuticals.

Author information

Author notes

  1. These authors contributed equally: Si-Yang Maggie Liu, Hai-Yan Tu, Xue-Wu Wei.

Authors and Affiliations

  1. Department of Hematology, The First Affiliated Hospital, Jinan University, Guangzhou, China

    Si-Yang Maggie Liu & Yangqiu Li

  2. Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

    Hai-Yan Tu, Xue-Wu Wei, Hong-Hong Yan, Chong-Rui Xu, Ming-Ying Zheng, Yang-Si Li, Zhen Wang, Xiao-Yan Bai, An-Na Li, Yue-Li Sun, Jie Huang, Jia-Xin Lin, E. E. Ke, Bing-Fei Xu, Chang Lu, Bin-Chao Wang, Hua-Jun Chen, Jin-Ji Yang, Qing Zhou & Yi-Long Wu

  3. Chinese Thoracic Oncology Group (CTONG), Guangzhou, China

    Hong-Hong Yan, Qing Zhou & Yi-Long Wu

  4. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Xiao-Rong Dong

  5. Cancer Center, The First Hospital of Jilin University, Jilin University, Changchun, China

    Jiu-Wei Cui

  6. Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China

    Zhen Zhou

  7. Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China

    Yingying Du

  8. Department of Oncology, Tongji Hospital, Tongji, Medical College, Huazhong, University of Science and Technology, Wuhan, China

    Yuan Chen

  9. Medical Oncology Department of Thoracic Cancer, Liaoning Cancer Hospital, Shenyang, China

    Rui Ma

  10. Department of Oncology, Northern Jiangsu People’s Hospital, Yangzhou, China

    Bu-Hai Wang

  11. Department of Oncology, Henan Provincial People’s Hospital, Zhengzhou, China

    Shun-Dong Cang

  12. Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China

    Yangqiu Li

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  1. Si-Yang Maggie Liu
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Contributions

Y.-L.W., Q.Z. and S.-Y.M.L. conceived and designed the study. S.-Y.M.L., H.-Y.T., X.-W.W. and C.L. collected and assembled the data. Y.-L.W., Y.L., Q.Z., H.-Y.T., S.-Y.M.L. and H.-H.Y. carried out the data analysis. H.-H.Y. performed the statistical analysis. J.-J.Y., H.-J.C., X.-R.D., J.-W.C., Z.Z., C.-R.X., M.-Y.Z., Y.-S.L., Z.W., A.-N.L., Y.-L.S., Y.D., Y.C., R.M., B.-H.W. and S.-D.C. recruited the patients. All authors were involved in data interpretation and in the writing, revision and critical review of the manuscript. All authors approved the submitted version and are accountable for their contributions and the integrity of the work.

Corresponding authors

Correspondence to Yangqiu Li, Qing Zhou or Yi-Long Wu.

Ethics declarations

Competing interests

Y.-L.W. reports getting honoraria from AstraZeneca, Lily, Roche, Pfizer, Boehringer Ingelheim, MSD Oncology, Bristol-Myers Squibb/China, Hengrui Pharmaceutical and BeiGene Beijing; consulting and advisory services for AstraZeneca, Roche and Takeda; and getting research funding from Roche, Boehringer Ingelheim, Pfizer and BMS. Q.Z. reports honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, MSD, Pfizer, Roche and Sanofi outside the submitted work. The remaining authors declare no competing interests.

Peer review

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Nature Medicine thanks Patrick Forde and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ulrike Harjes, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Table 1 Demographics, disease characteristics and antitumor therapy in HER2-mutant patients of the RWS cohort
Full size table
Extended Data Table 2 Clinical efficacy of pyrotinib in HER2-mutant patients with or without brain metastasis
Full size table
Extended Data Table 3 Clinical efficacy of pyrotinib in HER2-mutant patients with or without exon 20 insertion
Full size table
Extended Data Table 4 Acquired genomic alterations to 1st line pyrotinib treatment
Full size table
Extended Data Table 5 Reasons for ineligibility for the inclusion or exclusion criteria of patients in the phase 2 CU cohort
Full size table
Extended Data Table 6 The key eligibility criteria for the three cohorts
Full size table

Supplementary information

Supplementary Information

General Protocol for CTONG1702, sub-protocol of arm 7 of CTONG1702, general protocol of CTONG1705, statistical analysis of arm 7 of CTONG1702 and statistical analysis of CTONG1705.

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Liu, SY.M., Tu, HY., Wei, XW. et al. First-line pyrotinib in advanced HER2-mutant non-small-cell lung cancer: a patient-centric phase 2 trial. Nat Med 29, 2079–2086 (2023). https://doi.org/10.1038/s41591-023-02461-x

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