Efficacy, safety, and predictive biomarkers of dalpiciclib combined with letrozole, pertuzumab and trastuzumab as neoadjuvant therapy in HR+/HER2+ breast cancer: A phase II study.

person Xinrui Liang Chongqing University Cancer Hospital, Chongqing, China, China info_outline Xinrui Liang, Jing Wu, Ningning Zhang, Xiaohua Zeng

Authors person Xinrui Liang Chongqing University Cancer Hospital, Chongqing, China, China info_outline Xinrui Liang, Jing Wu, Ningning Zhang, Xiaohua Zeng Organizations Chongqing University Cancer Hospital, Chongqing, China, China, Chongqing University Cancer Hospital, Chongqing, China, Chongqing University Cancer Hospital, Chonqqing, China Abstract Disclosures Research Funding Beijing Science and Technology Innovation Medical Development Foundation Beijing Medical Award Fund, Chongqing University Cancer Hospital Special Project for Improving Scientific Research Ability Background: HR+/HER2+ breast cancer is a unique subtype of breast cancer. Between ER and HER2 crosstalk pathways may affect the sensitivity to both HER2-targeted and endocrine therapy in patients with HR+/HER2+ breast cancer. Current therapies for HER2-positive breast cancer have demonstrated limited efficacy in patients with HR+/HER2+ breast cancer. This Phase II trial aimed to assess the efficacy and safety of a neoadjuvant regimen combining trastuzumab, pertuzumab, dalpiciclib (a cyclin dependent kinase 4/6 inhibitor) and letrozole in patients with HR+/HER2+ breast cancer, alongside the exploration of efficacy biomarkers. Methods: Patients were administered six 28-day cycles of dalpiciclib (150 mg once daily on days 1-21) and letrozole (2.5 mg once daily), plus six 21-day cycles of trastuzumab (8 mg/kg loading dose followed by 6 mg/kg maintenance dose on day 1), pertuzumab (840mg loading dose followed by 420mg maintenance dose on day 1), prior to surgery. The primary endpoint was total pathological complete response (tpCR, ypT0/is, ypN0) rate. Secondary endpoints were objective response rate (ORR), breast pathological complete response (bpCR; ypT0/is) rate, change in Ki-67 level from baseline to one cycle of treatment and to surgery, and safety. For biomarkers analysis, next-generation sequencing was performed on pre-treatment tissue and circulating tumor DNA (ctDNA) at various time points before surgery. Results: A total of 14 patients who completed the neoadjuvant treatment and surgery between July 12, 2022 and August 12, 2023 were enrolled. A 50.0% (7 out of 14) tpCR and bpCR rate was observed, with an ORR of 92.9%. Significant reductions in Ki-67 levels were noted after both one ( P <0.05) and six cycles of neoadjuvant therapy ( P <0.05). Grade 4 neutropenia was reported in one case, with no fatalities. The most common grade 3 adverse events were neutropenia (10 [71.4%]) and leukopenia (8 [57.1%]). NGS identified frequent mutations in TP5 3 (84.6%), PIK3CA (53.8%), and ARID1A (30.8%). Cell cycle pathway gene alterations correlated with a higher pCR rate (80% vs 25%, P =0.103). Eight (61.5%) patients had positive ctDNA at baseline, and ctDNA positivity decreased significantly post-neoadjuvant treatment ( P <0.05). Patients with positive ctDNA at baseline without clearance post-treatment exhibited a trend towards a lower pCR rate. Conclusions: This combination neoadjuvant regimen of dalpiciclib, letrozole, pertuzumab and trastuzumab demonstrated promising pathological responses and manageable safety in patients with HR+/HER2+ breast cancer. The predictive value of genetic alterations and ctDNA status for treatment efficacy warrants further investigation. Clinical trial information: ChiCTR2200062114.

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