A pilot trial of neoadjuvant pyrotinib plus trastuzumab, dalpiciclib, and letrozole for triple-positive breast cancer

Abstract

Triple-positive breast cancer (TPBC) poorly responds to current standard neoadjuvant therapy (trastuzumab plus pertuzumab and chemotherapy). Our previous MUKDEN 01 study showed a promising total pathological complete response (tpCR) rate of 30.4% with neoadjuvant pyrotinib (pan-human epidermal growth factor receptor tyrosine kinase inhibitor) plus dalpiciclib (cyclin-dependent kinase 4/6 inhibitor) and letrozole, but the efficacy remains suboptimal. This pilot study (NCT05228951) explored adding trastuzumab to this triplet neoadjuvant regimen in patients with stage II–III TPBC. The primary endpoint was tpCR (ypT0/is, ypN0) rate. Between February 2022 and June 2022, 12 patients were enrolled, and seven (58%; 95% confidence interval [CI], 27.7%–84.8%) patients achieved tpCR. The rate of residual cancer burden (RCB) 0–I was 75% (95% CI, 46.8%–91.1%). The objective response rate (ORR) was 92% (95% CI, 64.6%–98.5%). Mean Ki-67 level was significantly reduced from 45.0% (95% CI, 19.5%–70.5%) at baseline to 17.2% (95% CI, 0.7%–33.7%) after neoadjuvant therapy (p = 0.03). The most common grade 3 adverse events were diarrhea (four [33%]) and decreased neutrophil count (three [25%]). No grade 4 adverse events or treatment-related deaths occurred. This four-drug neoadjuvant regimen shows promising pathological response with an acceptable safety profile in patients with TPBC. A randomized controlled trial (NCT05638594) of this regimen is being conducted.

Keywords

dalpiciclib / letrozole / neoadjuvant therapy / pyrotinib / trastuzumab / triple-positive breast cancer

References

1	GM Choong, GD Cullen, CC O'Sullivan. Evolving standards of care and new challenges in the management of HER2-positive breast cancer. CA Cancer J Clin. 2020;70(5):355-374.
2	SM Swain, M Shastry, E Hamilton. Targeting HER2-positive breast cancer: advances and future directions. Nat Rev Drug Discov. 2023;22(2):101-126.
3	DJ Slamon, B Leyland-Jones, S Shak, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-792.
4	D Cameron, M Casey, M Press, et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat. 2008;112(3):533-543.
5	SM Swain, D Miles, S-B Kim, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530.
6	V Diéras, D Miles, S Verma, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732-742.
7	C Saura, M Oliveira, Y-H Feng, 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):3138-3149.
8	B Xu, M Yan, F Ma, 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):351-360.
9	G Curigliano, V Mueller, V Borges, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann Oncol. 2022;33(3):321-329.
10	SA Hurvitz, R Hegg, W-P Chung, 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.
11	F André, Y Hee Park, S-B Kim, et al. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023;401(10390):1773-1785.
12	F Ma, M Yan, W Li, et al. 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.
13	SA Hurvitz, M Martin, WF Symmans, et al. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2018;19(1):115-126.
14	J Wu, Z Jiang, Z Liu, 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.
15	WJ Gradishar, MS Moran, J Abraham, et al. Breast cancer, version 3.2022, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2022;20(6):691-722.
16	D Chen, L Jin, Y Xu, A Bhandari, O Wang. ErbB inhibitors as neoadjuvant therapy for triple-positive breast cancer: a network meta-analysis. Am J Transl Res. 2021;13(11):12129-12140.
17	P Vici, L Pizzuti, C Natoli, et al. Triple positive breast cancer: a distinct subtype? Cancer Treat Rev. 2015;41(2):69-76.
18	S Zhao, X-Y Liu, X Jin, et al. Molecular portraits and trastuzumab responsiveness of estrogen receptor-positive, progesterone receptor-positive, and HER2-positive breast cancer. Theranostics. 2019;9(17):4935-4945.
19	MF Rimawi, IA Mayer, A Forero, et al. Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: tBCRC 006. J Clin Oncol. 2013;31(14):1726-1731.
20	V Guarneri, MV Dieci, G Bisagni, et al. De-escalated therapy for HR+/HER2+ breast cancer patients with Ki67 response after 2-week letrozole: results of the PerELISA neoadjuvant study. Ann Oncol. 2019;30(6):921-926.
21	CC O'Sullivan, VJ Suman, MP Goetz. The emerging role of CDK4/6i in HER2-positive breast cancer. Ther Adv Med Oncol. 2019;11:1758835919887665.
22	L Gianni, G Bisagni, M Colleoni, et al. Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study. Lancet Oncol. 2018;19(2):249-256.
23	B Xu, Q Zhang, P Zhang, 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):1904-1909.
24	P Zhang, Q Zhang, Z Tong, et al. Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2023;24(6):646-657.
25	N Niu, F Qiu, Q Xu, 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.
26	J Wang, B Xu. Targeted therapeutic options and future perspectives for HER2-positive breast cancer. Signal Transduct Target Ther. 2019;4:34.
27	Z Jiang, J Li, J Chen, et al. Chinese society of clinical oncology (CSCO) Breast Cancer Guidelines 2022. Transl Breast Cancer Res. 2022;3:13.
28	L Gianni, T Pienkowski, YH Im, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25-32.
29	A Schneeweiss, S Chia, T Hickish, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24(9):2278-2284.
30	J Baselga, I Bradbury, H Eidtmann, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379(9816):633-640.
31	MS van Ramshorst, A van der Voort, ED van Werkhoven, et al. Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19(12):1630-1640.
32	SM Swain, MS Ewer, G Viale, et al. Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol. 2018;29(3):646-653.
33	MF Rimawi, P Niravath, T Wang, et al. TBCRC023: a randomized phase II neoadjuvant trial of lapatinib plus trastuzumab without chemotherapy for 12 versus 24 weeks in patients with HER2-positive breast cancer. Clin Cancer Res. 2020;26(4):821-827.
34	N Harbeck, O Gluz, M Christgen, et al. De-escalation strategies in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC): final analysis of the West German Study Group adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptor-positive phase II randomized trial-efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without endocrine therapy (ET) versus trastuzumab plus ET. J Clin Oncol. 2017;35(26):3046-3054.
35	DM Collins, SF Madden, N Gaynor, et al. Effects of HER family-targeting tyrosine kinase inhibitors on antibody-dependent cell-mediated cytotoxicity in HER2-expressing breast cancer. Clin Cancer Res. 2021;27(3):807-818.
36	MB Amin, S Edge, F Greene, et al. AJCC Cancer Staging Manual. 8th ed. Springer International Publishing; 2017.
37	Members of Breast Cancer Expert Panel on Consensus 2020. Expert panel consensus on pathological diagnosis of breast cancer with neoadjuvant therapy, the 2020 version. Zhonghua Bing Li Xue Za Zhi. 2020;49(4):296-304.
38	WF Symmans, F Peintinger, C Hatzis, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007;25(28):4414-4422.
39	NK Aaronson, S Ahmedzai, B Bergman, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-376.
40	MA Sprangers, M Groenvold, JI Arraras, et al. The European Organization for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from a three-country field study. J Clin Oncol. 1996;14(10):2756-2768.