Fovinaciclib for First-Line Therapy of Advanced Breast Cancer: A Randomized Clinical Trial.
Fovinaciclib significantly improves progression-free survival in hormone receptor-positive, ERBB2-negative advanced breast cancer, with manageable safety, but long-term survival benefits remain unclear.
Where it sits
this study against the rest of the goserelin corpusSummary and findings
This phase 3 randomized clinical trial evaluated the efficacy and safety of fovinaciclib plus an aromatase inhibitor in 417 women with hormone receptor-positive, ERBB2-negative advanced breast cancer. The primary endpoint was progression-free survival, with fovinaciclib showing a significant improvement compared to placebo. Secondary endpoints and safety profiles were also assessed.
Abstract
<h4>Importance</h4>Approximately 70% of patients with breast cancer (BC) have hormone receptor-positive, human epidermal growth factor receptor 2 (ERBB2; formerly HER2)-negative disease.<h4>Objective</h4>To evaluate the efficacy and safety of fovinaciclib plus an aromatase inhibitor as first-line treatment for hormone receptor-positive, ERBB2-negative advanced BC.<h4>Design, setting, and participants</h4>This double-blind, phase 3 randomized clinical trial enrolled patients from March 2, 2022, to June 28, 2023, from 63 centers in China. Eligible patients were adult women with hormone receptor-positive, ERBB2-negative advanced BC and no history of systemic therapy for advanced disease. The data cutoff date was June 25, 2024. Data were analyzed from September to October 2024.<h4>Intervention</h4>Patients were randomized (1:1) to receive fovinaciclib, 200 mg (orally once daily on days 1 to 21), or placebo plus letrozole, 2.5 mg, or anastrozole, 1 mg (orally once daily on days 1 to 28), in 28-day cycles. Premenopausal or perimenopausal patients also received goserelin, 3.6 mg (subcutaneously on day 1).<h4>Main outcomes and measures</h4>The primary end point was progression-free survival (PFS) per blinded independent central review (BICR). Secondary end points included other efficacy end points and safety. Exploratory end points included overall survival (OS) and quality of life.<h4>Results</h4>Of 417 randomized female patients, the median (range) age was 57.0 (32-84) years. A total of 208 were randomized to the fovinaciclib arm and 209 to the placebo arm. At prespecified interim analysis (median [range] follow-up, 16.6 [0.3-27.8] months), a significantly prolonged median PFS was observed with fovinaciclib compared with placebo (not reached vs 20.2 months [95% CI, 16.4 months to not evaluable]; hazard ratio, 0.55; 95% CI, 0.38-0.77; 1-sided P < .001) per BICR assessments. Consistent PFS benefit was observed in most patient subgroups. Fovinaciclib was also favored across secondary efficacy end points. OS data were immature, with only 40 events (9.6%). The most common treatment-emergent adverse events were hematologic toxic effects, none of which led to serious adverse events or study drug discontinuation. Incidence of discontinuation due to treatment-emergent adverse events was only 1.4% in both arms (3 of 208 receiving fovinaciclib and 3 of 209 receiving placebo). Longitudinal changes in global health status, function domains, and symptom domains of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 were similar between the 2 arms.<h4>Conclusions and relevance</h4>In this randomized clinical trial, adding fovinaciclib to first-line aromatase inhibitor conferred significant and clinically meaningful PFS benefit and consistent improvements in other efficacy outcomes, along with manageable safety and unaffected quality of life.<h4>Trial registration</h4>ClinicalTrials.gov Identifier: NCT05439499.
Background
This study addresses the need for effective first-line therapies in hormone receptor-positive, ERBB2-negative advanced breast cancer, a condition affecting approximately 70% of breast cancer patients. Prior treatments have focused on hormone therapy, but resistance and progression remain challenges. This trial evaluates the addition of fovinaciclib, a CDK inhibitor, to standard aromatase inhibitors to potentially improve outcomes.
Methods
The study was a double-blind, phase 3 randomized clinical trial conducted at 63 centers in China. It included 417 adult women with hormone receptor-positive, ERBB2-negative advanced breast cancer who had not received systemic therapy for advanced disease. Participants were randomized to receive either fovinaciclib, 200 mg orally once daily, or placebo, alongside letrozole or anastrozole, with goserelin for premenopausal or perimenopausal patients. The primary endpoint was progression-free survival assessed by blinded independent central review.
Results
The primary endpoint, progression-free survival, showed a significant improvement in the fovinaciclib arm compared to placebo, with a hazard ratio of 0.55 and a 95% confidence interval of 0.38 to 0.77 (1-sided P < .001). The median PFS was not reached in the fovinaciclib group, compared to 20.2 months in the placebo group. Secondary endpoints also favored fovinaciclib, though overall survival data were immature. Adverse events were primarily hematologic but did not lead to serious outcomes or high discontinuation rates.
Interpretation
The trial demonstrates a statistically significant and clinically meaningful improvement in progression-free survival with fovinaciclib, aligning with prior findings on CDK inhibitors in similar populations. However, the lack of mature overall survival data and the single-country study setting may limit broader applicability. The safety profile was manageable, suggesting potential for clinical use pending further data.
Key findings
- 417 randomized female patients, median age 57.0 years.
- Median PFS not reached vs 20.2 months with placebo, HR 0.55, 95% CI 0.38-0.77, 1-sided P < .001.
- OS data immature, with 40 events (9.6%).
- 1.4% discontinuation due to adverse events in both arms.
- Hematologic toxic effects were the most common treatment-emergent adverse events.
Limitations
- OS data immature.
- Single-country study (China).
- Limited generalizability.
- Short follow-up for OS.
- Potential regional treatment variations.