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A multicentre single arm phase 2 trial of neoadjuvant pyrotinib and letrozole plus dalpiciclib for triple-positive breast cancer.

ABSTRACT: Current therapies for HER2-positive breast cancer have limited efficacy in patients with triple-positive breast cancer (TPBC). We conduct a multi-center single-arm phase 2 trial to test the efficacy and safety of an oral neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib (a CDK4/6 inhibitor) in patients with treatment-naïve, stage II-III TPBC with a Karnofsky score of ≥70 (NCT04486911). The primary endpoint is the proportion of patients with pathological complete response (pCR) in the breast and axilla. The secondary endpoints include residual cancer burden (RCB)-0 or RCB-I, objective response rate (ORR), breast pCR (bpCR), safety and changes in molecular targets (Ki67) from baseline to surgery. Following 5 cycles of 4-week treatment, the results meet the primary endpoint with a pCR rate of 30.4% (24 of 79; 95% confidence interval (CI), 21.3-41.3). RCB-0/I is 55.7% (95% CI, 44.7-66.1). ORR is 87.4%, (95% CI, 78.1-93.2) and bpCR is 35.4% (95% CI, 25.8-46.5). The mean Ki67 expression reduces from 40.4% at baseline to 17.9% (P < 0.001) at time of surgery. The most frequent grade 3 or 4 adverse events are neutropenia, leukopenia, and diarrhoea. There is no serious adverse event- or treatment-related death. This fully oral, chemotherapy-free, triplet combined therapy has the potential to be an alternative neoadjuvant regimen for patients with TPBC.

SUBMITTER: Niu N

PROVIDER: S-EPMC9672048 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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A multicentre single arm phase 2 trial of neoadjuvant pyrotinib and letrozole plus dalpiciclib for triple-positive breast cancer.

Niu Nan N Qiu Fang F Xu Qianshi Q He Guijin G Gu Xi X Guo Wenbin W Zhang Dianlong D Li Zhigao Z Zhao Yi Y Li Yong Y Li Ke K Zhang Hao H Zhang Peili P Huang Yuanxi Y Zhang Gangling G Han Hongbin H Cai Zhengang Z Li Pengfei P Xu Hong H Chen Guanglei G Xue Jinqi J Jiang Xiaofan X Jahromi Alireza Hamidian AH Li Jinshi J Zhao Yu Y de Faria Castro Fleury Eduardo E Huo Shiwen S Li Huajun H Jerusalem Guy G Tripodi Domenico D Liu Tong T Zheng Xinyu X Liu Caigang C

Nature communications 20221117 1

Current therapies for HER2-positive breast cancer have limited efficacy in patients with triple-positive breast cancer (TPBC). We conduct a multi-center single-arm phase 2 trial to test the efficacy and safety of an oral neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib (a CDK4/6 inhibitor) in patients with treatment-naïve, stage II-III TPBC with a Karnofsky score of ≥70 (NCT04486911). The primary endpoint is the proportion of patients with pathological complete response (pCR) in the ...[more]

PMID: 36396665

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Project description:BackgroundHormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common subtype of breast cancer, yet its response to traditional chemotherapy remains limited, posing a challenge in achieving optimal therapeutic outcomes. In this study, we aimed to evaluate the clinical efficacy and safety of dalpiciclib, a novel CDK4/6 inhibitor, combined with letrozole as neoadjuvant therapy (NAT) in postmenopausal patients with HR+/HER2- stage II-III breast cancer. Additionally, we explored potential predictive biomarkers for treatment response using gene analysis.MethodsThis single-arm, open-label, exploratory phase II trial involved 35 postmenopausal women with HR+/HER2- breast cancer (ClinicalTrials.gov identifier NCT05512780). Patients received four cycles of dalpiciclib (125 mg/day for 3 weeks, followed by 1 week off) plus continuous letrozole (2.5 mg/day). The primary endpoint was objective response rate (ORR), and secondary endpoints included changes in Ki-67 expression, complete cell cycle arrest (CCCA) rate, residual cancer burden (RCB), and safety profiles. Gene expression profiling and least absolute shrinkage and selection operator (LASSO) regression were conducted to identify biomarkers predictive of response to NAT.ResultsAmong the 35 enrolled patients, 31 completed the full treatment course. Of the 29 patients with evaluable response data after 4 cycles, 16 achieved partial response (PR), resulting in an ORR of 55.2%. Following two weeks of treatment, the mean Ki-67 expression significantly decreased from a baseline of 17.5-1.8%, and CCCA was observed in 75% of patients. Grade ≥ 3 treatment-emergent adverse events (TEAEs) were mainly decreased neutrophil count (45.7%), with a median duration of 3 days. The NAT predictive model, developed using gene expression analysis and clinicopathological factors, achieved an area under the curve (AUC) of 0.928, indicating that TFRC, SCUBE2, and MMP11A could serve as novel predictive biomarkers for response to NAT.ConclusionsDalpiciclib combined with letrozole demonstrated promising antitumor activity and an acceptable safety profile in postmenopausal patients with HR+/HER2- breast cancer. The identification of TFRC, SCUBE2, and MMP11A as predictive biomarkers provides insights into the potential for personalized neoadjuvant treatment strategies.

Dataset Information

A multicentre single arm phase 2 trial of neoadjuvant pyrotinib and letrozole plus dalpiciclib for triple-positive breast cancer.

Publications

A multicentre single arm phase 2 trial of neoadjuvant pyrotinib and letrozole plus dalpiciclib for triple-positive breast cancer.

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