Dalpiciclib Combined With Pyrotinib and Letrozole in Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer (LORDSHIPS): A Phase Ib Study

Jian Zhang, Yanchun Meng, Biyun Wang, Leiping Wang, Jun Cao, Zhonghua Tao, Ting Li, Wenqing Yao, Xichun Hu, Jian Zhang, Yanchun Meng, Biyun Wang, Leiping Wang, Jun Cao, Zhonghua Tao, Ting Li, Wenqing Yao, Xichun Hu

Abstract

Purpose: The LORDSHIPS study aimed to explore the safety and efficacy of a novel fully oral triplet combination of dalpiciclib (a potent cyclin-dependent kinase 4/6 inhibitor), pyrotinib (a HER2 tyrosine kinase inhibitor) and endocrine therapy letrozole in patients with HER2-positive, hormone receptor (HR)-positive metastatic breast cancer (MBC) in the front-line setting.

Patients and methods: Postmenopausal women with HER2-positive, HR-positive MBC were recruited in the dose-finding phase Ib trial. A standard 3 + 3 design was used to determine safety, tolerability, and recommended phase II dose (RP2D) for the combination.

Results: A total of 15 patients were enrolled to three dose combination cohorts (letrozole/pyrotinib/dalpiciclib, level/I: 2.5/400/125 mg, n=5; level/L1: 2.5/400/100 mg, n=6; level/L2: 2.5/320/125 mg, n=4). Three patients experienced dose-limiting toxicities (level/I, n=2; level/L1, n=1) and level/L2 was identified as RP2D. The most frequent grade 3-4 adverse events were neutropenia (46.7%), leukopenia (40.0%), oral mucositis (26.7%) and diarrhea (20.0%). The confirmed objective response rate (ORR) was 66.7% (95% CI: 38.4% to 88.2%). The confirmed ORR of study treatment as first line (1L) and second line (2L) HER2-targeted therapy was 85.7% (6/7) and 50.0% (4/8), respectively. Median progression-free survival (PFS) was 11.3 months (95% CI: 5.3 months to not reached). PFS in 1L setting was not reached yet, while PFS in 2L setting was 10.9 months (95% CI: 1.8 to 13.7 months).

Conclusions: The fully oral combination of dalpiciclib, pyrotinib and letrozole is a promising chemotherapy-sparing treatment option for HER2-positive, HR-positive MBC patients. The planned dose-expansion phase II study is ongoing.

Clinical trial registration: ClinicalTrials.gov, identifier NCT03772353.

Keywords: CDK4/6 inhibitor; HER2-positive; endocrine therapy; hormone receptor-positive; metastatic breast cancer; pyrotinib.

Conflict of interest statement

Author WY was employed by Jiangsu Hengrui Pharmaceuticals Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Zhang, Meng, Wang, Wang, Cao, Tao, Li, Yao and Hu.

Figures

Figure 1
Figure 1
Study design. HR, hormone receptor; HER2, human epidermal growth factor receptor 2; DLT, dose-limiting toxicity; RP2D, recommended phase II dose.
Figure 2
Figure 2
Clinical response to combination therapy in patients. (A) Maximum reduction of target lesions from baseline for patients in the Level/I, Level/L1, and Level/L2 dose cohorts. The best response for target lesions per patient was determined on the basis of RECIST 1.1 criteria. (B) Change in tumor burden over time, measured as the sum of longest diameters (SLD), in patients with MBC. PR was confirmed by investigator-assessed RECIST 1.1 criteria. PR, partial response; SD, stable disease; PD, progressive disease; HER2, human epidermal growth factor receptor 2.
Figure 3
Figure 3
PFS of combination therapy in patients with HER2+/HR+ MBC. (A) Kaplan-Meier estimates of PFS in all patients (N = 15). (B) Kaplan-Meier estimates of PFS in patients with 1L and 2L HER2-targeted therapy. PFS, progression-free survival; HR, hormone receptor; HER2, human epidermal growth factor receptor 2; 1L, first-line; 2L, second-line; CI, confidence interval; NR, not reached.

References

    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin (2021) 71(3):209–49. doi: 10.3322/caac.21660
    1. Wu VS, Kanaya N, Lo C, Mortimer J, Chen S. From Bench to Bedside: What do We Know About Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer? J Steroid Biochem Mol Biol (2015) 153:45–53. doi: 10.1016/j.jsbmb.2015.05.005
    1. Schettini F, Buono G, Cardalesi C, Desideri I, De Placido S, Del Mastro L. Hormone Receptor/Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Where We Are Now and Where We Are Going. Cancer Treat Rev (2016) 46:20–6. doi: 10.1016/j.ctrv.2016.03.012
    1. Zhao S, Liu XY, Jin X, Ma D, Xiao Y, Shao ZM, et al. . Molecular Portraits and Trastuzumab Responsiveness of Estrogen Receptor-Positive, Progesterone Receptor-Positive, and HER2-Positive Breast Cancer. Theranostics (2019) 9(17):4935–45. doi: 10.7150/thno.35730
    1. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al. . Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer. N Engl J Med (2015) 372(8):724–34. doi: 10.1056/NEJMoa1413513
    1. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. . Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. N Engl J Med (2012) 367(19):1783–91. doi: 10.1056/NEJMoa1209124
    1. Xu B, Li W, Zhang Q, Shao Z, Li Q, Wang X, et al. . Pertuzumab, Trastuzumab, and Docetaxel for Chinese Patients With Previously Untreated HER2-Positive Locally Recurrent or Metastatic Breast Cancer (PUFFIN): A Phase III, Randomized, Double-Blind, Placebo-Controlled Study. Breast Cancer Res Treat (2020) 182(3):689–97. doi: 10.1007/s10549-020-05728-w
    1. Saura C, Oliveira M, Feng YH, Dai MS, Chen SW, Hurvitz SA, et al. . Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With >/= 2 HER2-Directed Regimens: Phase III NALA Trial. J Clin Oncol (2020) 38(27):3138–49. doi: 10.1200/JCO.20.00147
    1. Johnston S, Pippen J, Jr., Pivot X, Lichinitser M, Sadeghi S, Dieras V, et al. . Lapatinib Combined With Letrozole Versus Letrozole and Placebo as First-Line Therapy for Postmenopausal Hormone Receptor-Positive Metastatic Breast Cancer. J Clin Oncol (2009) 27(33):5538–46. doi: 10.1200/JCO.2009.23.3734
    1. Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, 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: ALTERNATIVE. J Clin Oncol (2018) 36(8):741–8. doi: 10.1200/JCO.2017.74.7824
    1. Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, 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):5529–37. doi: 10.1200/JCO.2008.20.6847
    1. O’Sullivan CC, Suman VJ, Goetz MP. The Emerging Role of CDK4/6i in HER2-Positive Breast Cancer. Ther Adv Med Oncol (2019) 11:1758835919887665. doi: 10.1177/1758835919887665
    1. Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA, Li W, et al. . Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers With CDK4/6 Inhibitors. Cancer Cell (2016) 29(3):255–69. doi: 10.1016/j.ccell.2016.02.006
    1. Tolaney SM, Wardley AM, Zambelli S, Hilton JF, Troso-Sandoval TA, Ricci F, et al. . Abemaciclib Plus Trastuzumab With or Without Fulvestrant Versus Trastuzumab Plus Standard-of-Care Chemotherapy in Women With Hormone Receptor-Positive, HER2-Positive Advanced Breast Cancer (monarcHER): A Randomised, Open-Label, Phase 2 Trial. Lancet Oncol (2020) 21(6):763–75. doi: 10.1016/S1470-2045(20)30112-1
    1. Shagisultanova E, Gradishar W, Brown-Glaberman U, Chalasani P, Brenner AJ, Stopeck A, et al. . Abstract PS10-03: Interim Safety and Efficacy Analysis of Phase IB/II Clinical Trial of Tucatinib, Palbociclib and Letrozole in Patients With Hormone Receptor and HER2-Positive Metastatic Breast Cancer. Cancer Res (2021) 81(4 Supplement):PS10–03-PS10-03. doi: 10.1158/1538-7445.sabcs20-ps10-03
    1. Shagisultanova E, Gradishar W, Brown-Glaberman U, Chalasani P, Brenner A, Stopeck A, et al. . (2021). Abstract P1-18-26: Intracranial Efficacy of Tucatinib, Palbociclib and Letrozole Combination in Patients With HR+/HER2+ Breast Cancer and Brain Metastases, in: Presented at: 2021 San Antonio Breast Cancer Symposium, San Antonio, TX, December 7-10, 2021.
    1. Zhang P, Xu B, Gui L, Wang W, Xiu M, Zhang X, et al. . A Phase 1 Study of Dalpiciclib, A Cyclin-Dependent Kinase 4/6 Inhibitor in Chinese Patients With Advanced Breast Cancer. Biomark Res (2021) 9(1):24. doi: 10.1186/s40364-021-00271-2
    1. Xu B, Zhang Q, Zhang P, Hu X, Li W, Tong Z, et al. . Dalpiciclib or Placebo Plus Fulvestrant in Hormone Receptor-Positive and HER2-Negative Advanced Breast Cancer: A Randomized, Phase 3 Trial. Nat Med (2021) 27(11):1904–9. doi: 10.1038/s41591-021-01562-9
    1. Ma F, Li Q, Chen S, Zhu W, Fan Y, Wang J, et al. . 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. J Clin Oncol (2017) 35(27):3105–12. doi: 10.1200/JCO.2016.69.6179
    1. Xu B, Yan M, Ma F, Hu X, Feng J, Ouyang Q, et al. . 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):351–60. doi: 10.1016/S1470-2045(20)30702-6
    1. Long F, He Y, Fu H, Li Y, Bao X, Wang Q, et al. . Preclinical Characterization of SHR6390, a Novel CDK 4/6 Inhibitor, In Vitro and in Human Tumor Xenograft Models. Cancer Sci (2019) 110(4):1420–30. doi: 10.1111/cas.13957
    1. Chen Z, Xu Y, Gong J, Kou F, Zhang M, Tian T, et al. . Pyrotinib Combined With CDK4/6 Inhibitor in HER2-Positive Metastatic Gastric Cancer: A Promising Strategy From AVATAR Mouse to Patients. Clin Transl Med (2020) 10(4):e148. doi: 10.1002/ctm2.148
    1. Dellapasqua S, Colleoni M. Letrozole. Expert Opin Drug Metab Toxicol (2010) 6(2):251–9. doi: 10.1517/17425250903540246
    1. Xu B, Zhang Q, Zhang P, Hu X, Li W, Tong Z, et al. . Dalpiciclib Versus Placebo Plus Fulvestrant in HR+/HER2- Advanced Breast Cancer That Relapsed or Progressed on Previous Endocrine Therapy (DAWNA-1): A Multicenter, Randomized, Phase 3 Study. J Clin Oncol (2021) 39(15_suppl):1002–2. doi: 10.1200/JCO.2021.39.15_suppl.1002
    1. Yan M, Bian L, Hu X, Zhang Q, Ouyang Q, Feng J, et al. . Pyrotinib Plus Capecitabine for Human Epidermal Factor Receptor 2-Positive Metastatic Breast Cancer After Trastuzumab and Taxanes (PHENIX): A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study. Trans Breast Cancer Res (2020) 1. doi: 10.21037/tbcr-20-25
    1. Montemurro F, Di Cosimo S, Arpino G. Human Epidermal Growth Factor Receptor 2 (HER2)-Positive and Hormone Receptor-Positive Breast Cancer: New Insights Into Molecular Interactions and Clinical Implications. Ann Oncol (2013) 24(11):2715–24. doi: 10.1093/annonc/mdt287
    1. Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, et al. . Pertuzumab Plus Trastuzumab Plus Docetaxel for Metastatic Breast Cancer. N Engl J Med (2012) 366(2):109–19. doi: 10.1056/NEJMoa1113216
    1. Puglisi F, Minisini AM, De Angelis C, Arpino G. Overcoming Treatment Resistance in HER2-Positive Breast Cancer: Potential Strategies. Drugs (2012) 72(9):1175–93. doi: 10.2165/11634000-000000000-00000
    1. Giuliano M, Hu H, Wang YC, Fu X, Nardone A, Herrera S, 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. doi: 10.1158/1078-0432.CCR-14-2728
    1. Thanopoulou E, Khader L, Caira M, Wardley A, Ettl J, Miglietta F, et al. . Therapeutic Strategies for the Management of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Positive (HR+/HER2+) Breast Cancer: A Review of the Current Literature. Cancers (Basel) (2020) 12(11). doi: 10.3390/cancers12113317
    1. Statler AB, Hobbs BP, Wei W, Gupta A, Blake CN, Nahleh ZA. Real-World Treatment Patterns and Outcomes in HR+/HER2+ Metastatic Breast Cancer Patients: A National Cancer Database Analysis. Sci Rep (2019) 9(1):18126. doi: 10.1038/s41598-019-54402-9
    1. Cortés J, Kim S, Chung W, Im S, Park YH, Hegg R, et al. . LBA1 - Trastuzumab Deruxtecan (T-DXd) vs Trastuzumab Emtansine (T-DM1) in Patients (Pts) With HER2+ Metastatic Breast Cancer (mBC): Results of the Randomized Phase III DESTINY-Breast03 Study. Ann Oncol (2021) 32(suppl_5):S1283–346. doi: 10.1016/annonc/annonc741
    1. Gennari A, Andre F, Barrios CH, Cortes J, de Azambuja E, DeMichele A, et al. . ESMO Clinical Practice Guideline for the Diagnosis, Staging and Treatment of Patients With Metastatic Breast Cancer. Ann Oncol (2021) 32(12):1475–95. doi: 10.1016/j.annonc.2021.09.019

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner