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.

Dalpiciclib Partially Abrogates ER Signaling Activation Induced by Pyrotinib In HER2+HR+Breast Cancer

“…We found significant elevations in the nuclear ER expression levels of patients who received chemotherapy(doxetaxel+carboplatin) and anti-HER2 therapy (trastuzumab), compared with the levels in patients who only received chemotherapy (doxetaxel+carboplatin) (Figure 2b, c). However, in our clinical trial (NCT04486911, an open-label, multicentre phase II clinical study of pyrotinib maleate combined with CDK4/6 inhibitor and letrozole in neoadjuvant treatment of stage II-III triple positive breast cancer)( Niu et al, 2022 ), the nuclear ER expression levels of patients did not show significant elevations after the HER2-targeted therapy combined with dalpiciclib (Figure 2b, c). These findings verified that the ER receptor may have shifted to the nucleus after anti-HER2 therapy, which could be abrogated with the introduction of dalpiciclib.…”

“…The copyright holder for this preprint this version posted December 11, 2022. ; https://doi.org/10.1101/2022.12.07.519433 doi: bioRxiv preprint neoadjuvant therapy for HER2 + HR + patients (Niu et al, 2022). The molecular mechanism how the combination of pyrotinib, letrozole and dalpiciclib achieved optimal therapeutic effect remained further investigation.…”

“…Hence, with the rapid development of small-molecule drugs such as tyrosine kinase inhibitors (TKIs) and CDK4/6 inhibitors, additional chemo-free strategies are being developed for the treatment of HER2 + /HR + breast cancer ( Gianni et al, 2018; Pascual et al, 2021; Saura et al, 2014 ). In the recent MUKDEN 01 clinical trial (NCT04486911), the combination of pyrotinib, letrozole and dalpiciclib achieved satisfactory clinical response in HER2 + HR + patients with minimal adverse effects and offered novel chemo-free neoadjuvant therapy for HER2 + HR + patients( Niu et al, 2022 ). The molecular mechanism how the combination of pyrotinib, letrozole and dalpiciclib achieved optimal therapeutic effect remained further investigation.…”

“…The combination of anti-HER2 drugs and CDK4/6 inhibitors showed strong synergistic effects and high efficacy in HER2 + breast cancer cells ( Goel et al, 2016; Zhang et al, 2019 ). Besides, in the recent MUKDEN 01 clinical trial (NCT04486911), the combination use of pyrotinib (anti-HER2 drug), letrozole (endocrine drug) and dalpiciclib (CDK4/6 inhibitor) exerted optimal therapeutic effect in HER2 + HR + breast cancer patients and offered novel chemo-free neoadjuvant therapy for the treatment of HER2 + HR + breast cancer ( Niu et al, 2022 ), yet the underlying mechanism remained to be investigated.…”

“…Herein, we investigated the underlying molecular mechanism how the combination of pyrotinib, letrzole and dalpiciclib achieved satisfactory therapeutic effect in MUKDEN 01 trial. We studied the combined effect of pyrotinib (anti-HER2 drug), tamoxifen (endocrine therapy), and dalpiciclib (CDK4/6 inhibitor) on the HER2 + /HR + breast cancer cell line BT474 to simulate the clinical therapy in MUKDEN 01 trial( Niu et al, 2022 ). We found that pyrotinib combined with dalpiciclib exerted better cytotoxic efficacy than pyrotinib combined with tamoxifen.…”