# Dalpiciclib combined with pyrotinib and endocrine therapy in women with ER-positive, HER2-positive advanced breast cancer: A prospective, multicenter, single-arm, phase 2 trial

## TL;DR

A combination of dalpiciclib, pyrotinib, and endocrine therapy showed promising anti-tumor activity and a manageable safety profile in treating ER-positive, HER2-positive advanced breast cancer.

## Contribution

This is the first phase 2 trial to evaluate the combination of a CDK4/6 inhibitor (dalpiciclib), a HER2-targeted tyrosine kinase inhibitor (pyrotinib), and endocrine therapy in the frontline setting for ER+/HER2+ advanced breast cancer.

## Key findings

- The combination achieved a 70.2% objective response rate with a median progression-free survival of 22.0 months.
- Safety was manageable with no new safety signals observed, despite high rates of myelosuppression.
- Patients with BRCA mutations or increased 68Ga-HER2 affibody uptake showed no objective response.

## Abstract

Combination of HER2-targeted therapy and endocrine therapy offers a more tolerable alternative to HER2-targeted chemotherapy regimens for estrogen receptor (ER)-positive, HER2-positive advanced breast cancer (ABC), but with compromised efficacy. The addition of cyclin-dependent kinase 4/6 (CDK4/6) inhibition may enhance the durability of anti-tumor responses, offering a potential chemotherapy-sparing alternative, although its role in the frontline setting remains uncertain. We performed a multicenter, single-arm, phase 2 clinical trial (PLEASURABLE) to assess the activity and safety of combining dalpiciclib with pyrotinib and endocrine therapy in patients receiving first- or second-line treatment for ER-positive and HER2-positive ABC.

We enrolled patients with ER-positive and HER2-positive ABC between August 1, 2019, and November 28, 2022 in this prospective, investigator-initiated trial conducted at six centers in China. Patients received dalpiciclib (125 mg once daily, on days 1–21 of each 28-day cycle) and pyrotinib (320 mg once daily) plus endocrine therapy determined by the physician’s choice (letrozole or fulvestrant). The primary endpoint was the objective response rate (ORR), while secondary endpoints included progression-free survival (PFS), duration of response (DOR), disease control rate (DCR), clinical benefit rate (CBR), safety, plasma pharmacokinetics (PK), and biomarker analysis. Efficacy was analyzed in the modified intention-to-treat population, comprising patients with at least one post-baseline tumor assessment. Safety was assessed in all patients who received at least one dose. A total of 51 patients were screened, and 48 were evaluable (median age was 52.5 years [range, 29–74]); 31 (64.6%) had prior HER2-target therapy, and 37 (77.1%) had received prior endocrine therapy. Thirty (62.5%) and 18 (37.5%) patients received the study treatment as first- and second-line HER2-targeted treatment for ABC, respectively. As of the data cutoff on December 11, 2024, six patients were lost to follow-up, and the median follow-up was 27.3 months (interquartile range, 24.8–30.5). The investigator confirmed ORR was 70.2% (95% CI [55.1, 82.7]), with a DCR of 100% (95% CI [92.5, 100]) and a CBR of 87.2% (95% CI [74.3, 95.2]). The median PFS was 22.0 months (95% CI [16.6, 26.6]), and the median DOR was 22.3 months (95% CI [16.4, 26.9]). No new safety signals were observed, and no treatment-related deaths occurred with only one (2.1%) grade 1 alopecia and no interstitial lung disease. Grade 3 or 4 treatment-related adverse events occurred in 68.8% and 12.5% of patients, respectively, mostly myelosuppression. PK analysis showed no major drug accumulation for dalpiciclib or pyrotinib over the treatment period. Of interest, no objective response was observed in three patients with detected BRCA mutations (n = 2) or increased 68Ga-HER2 affibody uptake over the initial two cycles (n = 2). The findings of this study should be interpreted with caution due to the limited patient cohort and sample size in exploratory analyses.

The non-intravenous, chemotherapy-sparing combination of dalpiciclib, pyrotinib, and endocrine therapy demonstrated anti-tumor activity with a manageable safety profile in the frontline treatment of ER-positive, HER2-positive ABC, supporting its further evaluation as a potential alternative.

ClinicalTrials.gov Identifier: NCT03772353

The integration of HER2-targeted therapies with chemotherapy is the standard treatment for HER2-positive advanced breast cancer (ABC). However, not all patients are suitable for chemotherapy.

HER2-targeted therapy combined with endocrine therapy is a treatment option for ER-positive, HER2-positive ABC, offering lower toxicity but with compromised efficacy.

The addition of cyclin-dependent kinase 4/6 (CDK4/6) inhibition to HER2-targeted therapy and endocrine therapy has shown efficacy in ER-positive/HER2-positive later-line ABC, providing a potential chemotherapy-free alternative.

To the best of our knowledge, the role of CDK4/6 inhibition in combination with HER2-targeted and endocrine therapy in the frontline setting remains uncertain.

We recruited 48 patients with ER-positive, HER2-positive ABC across multiple centers to receive a combination of dalpiciclib, pyrotinib, and endocrine therapy as first- or second-line treatment.

70 % (33 of 47) of patients achieved an objective response, with a median progression-free survival of 22.0 months.

The safety profile was manageable, with no new safety signals observed.

Exploratory analysis suggested a potential lack of response in patients with increased 68Ga-HER2 affibody uptake or BRCA mutation.

The combination of dalpiciclib, pyrotinib, and endocrine therapy appears to be clinically active in ER-positive, HER2-positive advanced breast cancer, with a manageable safety profile, albeit in a relatively small patient cohort.

The potential effectiveness of CDK4/6 inhibitors dalpiciclib in this study suggests they might potentially be an effective chemotherapy-free option for patients with ER-positive, HER2-positive breast cancer. However, since this study included a small number of patients and did not compare this treatment with standard therapies, more research is needed to confirm the findings.

Jian Zhang, Yanchun Meng and colleagues assess the activity and safety of combining dalpiciclib with pyrotinib and endocrine therapy in patients receiving first- or second-line treatment for ER-positive and HER2-positive advanced breast cancer.