Combined pyrotinib and fulvestrant for hormone receptor-positive and HER2-positive metastatic breast cancer: A multicenter, single-arm, phase II trial

Abstract

This multicenter, single-arm, phase II clinical trial (NCT04034589) evaluated the efficacy and safety of pyrotinib combined with fulvestrant in patients with HR-positive/HER2-positive metastatic breast cancer who had experienced trastuzumab treatment failure. A total of 46 patients were enrolled, receiving pyrotinib orally once daily and fulvestrant intramuscularly on days 1 and 15 of cycle 1, followed by monthly doses on day 1. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. The median PFS was 18.2 months (95% CI, 11.9–31.1) overall, 19.5 months (95% CI, 10.6–NA) for those receiving the combination as first-line therapy, and 18.4 months (95% CI, 16.7–NA) for patients with brain metastases. Median OS was not reached, with a 3-year OS rate of 75.2% (95% CI, 62.8–90.2%). The ORR was 32.5%, and the DCR was 97.5%. Responses were observed in patients with low tumor mutation burden and ZNF217 mutation. Importantly, no grade 4 or higher treatment-related adverse events or deaths were reported, indicating a favorable safety profile. In conclusion, the combination of pyrotinib and fulvestrant demonstrated promising antitumor activity and acceptable safety in HR-positive/HER2-positive metastatic breast cancer patients.

References

[1] Ma F, Yan M, Li W, et al, PHILA Investigators. Pyrotinib versus placebo in combination with trastuzumab and docetaxel as first line treatment in patients with HER2 positive metastatic breast cancer (PHILA): randomised double blind, multicentre, phase 3 trial. BMJ. 2023; 383: e076065.

[2] Howlader N, Altekruse SF, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014; 106(5).

[3] Cardoso F, Paluch-Shimon S, Senkus E, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol. 2020; 31(12): 1623-1649.

[4] Giordano SH, Temin S, Chandarlapaty S, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: ASCO Clinical Practice Guideline update. J Clin Oncol. 2018; 36(26): 2736-2740.

[5] Gennari A, André F, Barrios CH, et al. ESMO Guidelines Committee. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021; 32(12): 1475-1495.

[6] Niu N, Qiu F, Xu Q, et al. A multicentre single arm phase 2 trial of neoadjuvant pyrotinib and letrozole plus dalpiciclib for triple-positive breast cancer. Nat Commun. 2022; 13(1): 7043.

[7] Kaufman B, Mackey JR, Clemens MR, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009; 27(33): 5529-5537.

[8] Johnston SRD, Toi M, O’Shaughnessy J, et al, monarchE Committee Members. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023; 24(1): 77-90.

[9] Finn RS, Press MF, Dering J, et al. Quantitative ER and PgR assessment as predictors of benefit from lapatinib in postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res. 2014; 20(3): 736-743.

[10] Hu ZY, Yan M, Xiong H, et al. Pyrotinib in combination with letrozole for hormone receptor-positive, human epidermal growth factor receptor 2-positive metastatic breast cancer (PLEHERM): a multicenter, single-arm, phase II trial. BMC Med. 2023; 21(1): 226.

[11] Hua X, Bi XW, Zhao JL, et al. Trastuzumab plus endocrine therapy or chemotherapy as first-line treatment for patients with hormone receptor-positive and HER2-positive metastatic breast cancer (SYSUCC-002). Clin Cancer Res. 2022; 28(4): 637-645.

[12] Giuliano M, Hu H, Wang YC, et al. Upregulation of ER signaling as an adaptive mechanism of cell survival in HER2-positive breast tumors treated with anti-HER2 therapy. Clin Cancer Res. 2015; 21(17): 3995-4003.

[13] Wang YC, Morrison G, Gillihan R, et al. Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers–role of estrogen receptor and HER2 reactivation. Breast Cancer Res. 2011; 13(6): R121.

[14] Li X, Yang C, Wan H, et al. Discovery and development of pyrotinib: a novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor with favorable safety profiles for the treatment of breast cancer. Eur J Pharm Sci. 2017; 110: 51-61.

[15] Wu J, Jiang Z, Liu Z, et al. Neoadjuvant pyrotinib, trastuzumab, and docetaxel for HER2-positive breast cancer (PHEDRA): a double-blind, randomized phase 3 trial. BMC Med. 2022; 20(1): 498.

[16] Mayer EL, Ren Y, Wagle N, et al. PACE: a randomized phase II study of fulvestrant, palbociclib, and avelumab after progression on cyclin-dependent kinase 4/6 inhibitor and aromatase inhibitor for hormone receptor-positive/human epidermal growth factor receptor-negative metastatic breast cancer. J Clin Oncol. 2024; 42(17): 2050-2060.

[17] Tolaney SM, Goel S, Nadal J, et al. Overall survival and exploratory biomarker analyses of abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus chemotherapy in HR+, HER2+ metastatic breast cancer patients. Clin Cancer Res. 2024; 30(1): 39-49.

[18] Baselga J, Cortés J, Kim SB, et al, CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012; 366(2): 109-119.

[19] Yao H, Yan M, Tong Z, et al. Safety, efficacy, and pharmacokinetics of SHR-A1811, a human epidermal growth factor receptor 2-directed antibody-drug conjugate, in human epidermal growth factor receptor 2-expressing or mutated advanced solid tumors: a global phase i trial. J Clin Oncol. 2024; 20: JCO2302044.

[20] Hurvitz SA, Hegg R, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023; 401(10371): 105-117.

[21] Boire A, Brastianos PK, Garzia L, Valiente M. Brain metastasis. Nat Rev Cancer. 2020; 20(1): 4-11.

[22] Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013; 14(1): 64-71.

[23] Yan M, Ouyang Q, Sun T, et al. Pyrotinib plus capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases (PERMEATE): a multicentre, single-arm, two-cohort, phase 2 trial. Lancet Oncol. 2022; 23(3): 353-361.

[24] Xu B, Yan M, Ma F, et al, PHOEBE Investigators. Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021; 22(3): 351-360.

[25] Chen H, Hu X, Wang D, Wang Y, Yu Y, Yao H. Association of PIK3CA mutation with outcomes in HER2-positive breast cancer treated with anti-HER2 therapy: a meta-analysis and bioinformatic analysis of TCGABRCA data. Transl Oncol. 2023; 37: 101738.

[26] Topham JT, O’Callaghan CJ, Feilotter H, et al. Circulating tumor DNA identifies diverse landscape of acquired resistance to anti-epidermal growth factor receptor therapy in metastatic colorectal cancer. J Clin Oncol. 2023; 41(3): 485-496.

[27] Yu Y, Zhang W, Li A, et al. Association of long noncoding RNA biomarkers with clinical immune subtype and prediction of immunotherapy response in patients with cancer. JAMA Netw Open. 2020; 3(4): e202149.

[28] Acosta JN, Falcone GJ, Rajpurkar P, Topol EJ. Multimodal biomedical AI. Nat Med. 2022; 28(9): 1773-1784.

[29] Zhao J, Sun Z, Yu Y, et al. Radiomic and clinical data integration using machine learning predict the efficacy of anti-PD-1 antibodies-based combinational treatment in advanced breast cancer: a multicentered study. J Immunother Cancer. 2023; 11(5).

[30] Yu Y, Ren W, He Z, et al. Machine learning radiomics of magnetic resonance imaging predicts recurrence-free survival after surgery and correlation of LncRNAs in patients with breast cancer: a multicenter cohort study. Breast Cancer Res. 2023; 25(1): 132.

[31] Yu Y, Chen H, Ouyang W, et al. Unraveling the role of M1 macrophage and CXCL9 in predicting immune checkpoint inhibitor efficacy through multicohort analysis and single-cell RNA sequencing. MedComm. 2024; 5(3): e471.

[32] Hutson M. How AI is being used to accelerate clinical trials. Nature. 2024; 627(8003): S2-S5.

[33] Xia K, Wang J. Recent advances of transformers in medical image analysis: a comprehensive review. MedComm—Future Med. 2023; 2: e38.26.

[34] Wang D, Feng L, Ye J, et al. Accelerating the integration of ChatGPT and other large-scale AI models into biomedical research and healthcare. MedComm—Future Med. 2023; 2: e43.

[35] Johnston SRD, Hegg R, Im SA, et al. Phase III, randomized study of dual human epidermal growth factor receptor 2 (HER2) blockade with lapatinib plus trastuzumab in combination with an aromatase inhibitor in postmenopausal women with HER2-positive, hormone receptor-positive metastatic breast cancer: updated results of ALTERNATIVE. J Clin Oncol. 2021; 39(1): 79-89.

[36] Robertson JFR, Bondarenko IM, Trishkina E, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016; 388(10063): 2997-3005.

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