PLEASURABLE: Results and biomarkers analysis from the phase II study of dalpiciclib combined with pyrotinib and endocrine therapy (ET) in women with dual-receptor positive (ER+/HER2+) metastatic breast cancer (MBC)

1046 Background: In the front-line setting, our previous work demonstrated an impressive median progression-free survival (PFS) of 11.3 months with 66.7% response rate, and concluded a recommended phase 2 dose of pyrotinib 320mg/d, dalpiciclib (SHR6390, a novel CDK4/6i) 125mg/d, and letrozole 2.5mg/d for HR+/HER2+ MBC patients (pts) (Xichun Hu, FRONT ONCOL 2022). Results and biomarkers analysis from phase II dose expansion study are presented. Methods: ER+/HER2+ MBC Pts eligible for first- or second-line treatment were enrolled to receive dalpiciclib combined with pyrotinib and ET (letrozole or fulvestrant determined by physician’s choice). The primary endpoint was objective response rate (ORR). For biomarkers analysis, 68 Ga-HER2 affibody, pre-treatment tissue-derived DNA and circulating tumor DNA (ctDNA) were assessed by PET/CT, and next-generation sequencing (NGS), respectively. Results: As of January 19, 2023, 48 pts were enrolled. 17 pts (35.4%) were treatment naïve, and 31 pts (64.6%) had received prior trastuzumab. The ORR was 68.1% (32/47) and disease control rate was 100% (47/47). In trastuzumab-naïve and trastuzumab-pretreated patients, ORR was 81.3% (13/16) and 61.3% (19/31), respectively. PFS and OS data were not mature by cut-off date. No new safety signals were observed. The most frequent treatment-related adverse events were neutropenia (95.8%; G3:60.4%, G4:6.3%), leukopenia (91.7%; G3:45.8%), diarrhea (87.5%; G3:2.1%), anemia (79.2%; G3:4.2%), oral mucositis (68.8%, G3:2.1%) and platelet count decreased (41.7%; G3:2.1%, G4:2.1%). The heterogeneity of 68 Ga-HER2 affibody uptake was observed among patients, both at baseline (N=16，median SUV max 7.5, range, 2.3-34.9) and after 2 cycles of therapy (N=12，median SUV max 4.0, range, 0-14.9). All patients with a decline in 68 Ga-HER2 affibody uptake (N=8) achieved partial response, while the uptake in non-responders was elevated (N=2). NGS was conducted to detect somatic and germline mutations in baseline tissue (n=10) and ctDNA (n=10) samples. Two patients with BRCA mutation (one had somatic BRCA1/ 2 mutation and another with germline BRCA2 mutation) had no tumor response. Conclusions: The chemotherapy-sparing regimens showed significant anti-tumor activity for ER+/HER2+ MBC pts in the front-line setting. The 68 Ga-HER2 affibody PET/CT may be a potential predictive biomarker of therapy response. Additional analysis including correlation of biomarkers with long-term outcomes is underway. Clinical trial information: NCT03772353 .