Editor's Note: The 2024 Annual Meeting of the American Society of Clinical Oncology (ASCO) will be held from May 31 to June 4 in Chicago, Eastern Time. Two studies led by Professor Jiayu Wang from Academician Binghe Xu's team at the Cancer Hospital of the Chinese Academy of Medical Sciences (CAMS) have been selected for poster presentation at the ASCO Annual Meeting. This article introduces these studies (Abstract Numbers: 1058, 3117).Abstract Number: 1058 – Phase III Clinical Trial of Pirlocyclib Combined with Fulvestrant in the Treatment of HR+/HER2- Advanced Breast Cancer (BRIGHT-2 Study Interim Analysis)
Pirlocyclib is a novel selective CDK4/6 inhibitor that has shown good efficacy and safety in previous clinical trials. Led by Academician Binghe Xu from CAMS Cancer Hospital and Professor Jiayu Wang as the SubI, a multicenter phase III clinical trial (BRIGHT-2, NCT05077449) was conducted to evaluate the efficacy and safety of pirlocyclib combined with fulvestrant in HR+/HER2- advanced breast cancer patients who had failed previous endocrine therapy.
As of October 24, 2022, this randomized, double-blind, placebo-controlled phase III trial enrolled 305 HR+/HER2- advanced breast cancer patients, randomly assigned in a 2:1 ratio. Among them, 204 patients received pirlocyclib combined with fulvestrant, while 101 patients received placebo combined with fulvestrant. The baseline characteristics of the two groups were balanced, with 208 patients (68.2%) having visceral metastases, 78 patients (25.6%) with primary endocrine resistance, and 73 patients (23.9%) having received chemotherapy in the advanced stage.
By March 28, 2023, with a median follow-up of 8.7 months, the median PFS was 12.94 months (95% CI: 11.07 to not reached) in the pirlocyclib plus fulvestrant group, significantly better than 7.29 months (95% CI: 5.45-11.04) in the placebo plus fulvestrant group (HR, 0.561; 95% CI: 0.393-0.799; P=0.0012). All subgroups benefited, with significant efficacy observed in patients with primary endocrine resistance, liver metastases, and bone metastases.
In terms of safety, the most common TEAEs in the pirlocyclib plus fulvestrant group included diarrhea, neutropenia, leukopenia, and anemia. Most AEs were grade 1-2 and could be alleviated with symptomatic treatment, dose interruption, or dose reduction. Only three patients (1.5%) discontinued treatment due to TEAEs.
The BRIGHT-2 study demonstrated that pirlocyclib combined with fulvestrant is effective and well-tolerated in HR+/HER2- advanced breast cancer patients. As a novel CDK4/6 inhibitor, it is expected to become another effective treatment option for HR+/HER2- advanced breast cancer patients. Currently, a phase III clinical trial of pirlocyclib combined with aromatase inhibitors (NCT05257395) is ongoing to further evaluate its efficacy and safety in HR+/HER2- advanced breast cancer patients.
Abstract Number: 3117 – Phase Ia Dose Escalation Study of SPH5030 Tablets in HER2-Positive Advanced Solid Tumors
Despite advances in anti-HER2 targeted therapies for HER2-overexpressing advanced solid tumors, significant unmet clinical needs remain. SPH5030 is a novel tyrosine kinase inhibitor (TKI) that combines the structural advantages of tucatinib and pyrotinib, featuring high selectivity and irreversible efficacy. Led by Academician Binghe Xu from CAMS Cancer Hospital and Professor Jiayu Wang as the SubI, the phase Ia study of SPH5030 tablets explored the safety, pharmacokinetics, and preliminary efficacy in HER2-positive advanced solid tumors (NCT05245058).
As of February 2, 2024, this open-label, multicenter phase Ia study adopted a “3+3” dose-escalation design, enrolling 30 patients from the Cancer Hospital of CAMS, Tianjin Medical University Cancer Institute and Hospital, and Sun Yat-sen University Cancer Center, including 28 breast cancer patients and 2 colorectal cancer patients.
Results showed an objective response rate (ORR) of 21.4%, a disease control rate (DCR) of 78.6%, and a clinical benefit rate (CBR) of 35.7%. Six patients (21.4%) achieved partial response (PR), including five breast cancer patients and one colorectal cancer patient. The median duration of response (mDoR) had not been reached.
Notably, the ORR in the 600 mg dose group was 50%, indicating a dose-response relationship. Most patients who achieved PR and stable disease (SD) maintained long-term efficacy (SD ≥24 weeks in 4 patients, accounting for 14.3%). Patients previously treated with anti-HER2 therapies, including TKIs, also benefited from SPH5030 tablets.
In terms of safety, all patients experienced TEAEs during treatment, mostly grade 1-2. Ten patients experienced ≥ grade 3 TEAEs, with eight patients experiencing ≥ grade 3 TRAEs. The most common TRAEs were diarrhea (66.7%, with ≥ grade 3 accounting for 16.7%). Most AEs improved with symptomatic treatment. One patient in the 600 mg dose group experienced dose-limiting toxicity (DLT) with grade 3 diarrhea. No AEs led to study discontinuation or death.
This study demonstrated the potential of SPH5030 as a new treatment for HER2-positive advanced solid tumors, showing good tolerability and preliminary efficacy, laying a solid foundation for future clinical trials. SPH5030 has the potential to become a new treatment option for patients with advanced breast cancer.
