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An open-label, phase IB/II study of abemaciclib with paclitaxel for tumors with CDK4/6 pathway genomic alterations
1Department of Internal Medicine, Division of Medical Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea.
Background:
Disruption of cyclin D-dependent kinases (CDKs), particularly CDK4/6, drives cancer cell proliferation via abnormal protein phosphorylation. This open-label, single-arm, phase Ib/II trial evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, combined with paclitaxel against CDK4/6-activated tumors.
Patients And Methods:
Patients with locally advanced or metastatic solid tumors with CDK4/6 pathway aberrations were included. Based on phase Ib, the recommended phase II doses were determined as abemaciclib 100 mg twice daily and paclitaxel 70 mg/m2 on days 1, 8, and 15, over 4-week-long cycles. The primary endpoint for phase II was the overall response rate (ORR). The secondary endpoints included the clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. Tissue-based next-generation sequencing and exploratory circulating tumor DNA analyses were carried out.
Results:
Between February 2021 and April 2022, 30 patients received abemaciclib/paclitaxel (median follow-up: 15.7 months), and 27 were included in the efficacy analysis. CDK4/6 amplification (50%) and CCND1/3 amplification (20%) were common activating mutations. The ORR was 7.4%, with two partial responses, and the CBR was 66.7% (18/27 patients). The median OS and PFS were 9.9 months [95% confidence interval (CI) 5.7-14.0 months] and 3.5 months (95% CI 2.6-4.3 months), respectively. Grade 3 adverse events (50%, 21 events) were mainly hematologic. Genetic analysis revealed a 'poor genetic status' subgroup characterized by mutations in key signaling pathways (RAS, Wnt, PI3K, and NOTCH) and/or CCNE amplification, correlating with poorer PFS.
Conclusion:
Abemaciclib and paclitaxel showed moderate clinical benefits for CDK4/6-activated tumors. We identified a poor genetic group characterized by bypass signaling pathway activation and/or CCNE amplification, which negatively affected treatment response and survival. Future studies with homogeneous patient groups are required to validate these findings.
Insights
Abemaciclib combined with paclitaxel showed moderate clinical benefits for CDK4/6-activated tumors. A subgroup with bypass signaling pathway activation experienced poorer progression-free survival.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Cyclin D-dependent kinases (CDKs), especially CDK4/6, are crucial in cancer cell proliferation through abnormal protein phosphorylation.
- Targeting CDK4/6 is a strategy for treating CDK4/6-activated tumors.
Purpose of the Study:
- To evaluate the efficacy and safety of abemaciclib in combination with paclitaxel in patients with CDK4/6-activated solid tumors.
- To identify potential biomarkers predictive of treatment response.
Main Methods:
- An open-label, single-arm, phase Ib/II trial was conducted.
- Patients received abemaciclib (100 mg twice daily) and paclitaxel (70 mg/m2 on days 1, 8, 15) in 4-week cycles.
- Overall Response Rate (ORR), Clinical Benefit Rate (CBR), Progression-Free Survival (PFS), Overall Survival (OS), and safety were assessed. Genetic analyses included next-generation sequencing and circulating tumor DNA.
Main Results:
- The study included 30 patients, with 27 in the efficacy analysis. CDK4/6 and CCND1/3 amplifications were common.
- The ORR was 7.4%, and the CBR was 66.7%. Median PFS was 3.5 months, and median OS was 9.9 months.
- A 'poor genetic status' subgroup (RAS, Wnt, PI3K, NOTCH mutations, and/or CCNE amplification) showed significantly poorer PFS.
Conclusions:
- Abemaciclib plus paclitaxel demonstrated moderate clinical benefit in CDK4/6-activated tumors.
- Bypass signaling pathway activation and CCNE amplification define a subgroup with a negative impact on treatment outcomes.
- Future research should focus on homogeneous patient populations to validate these findings.
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