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Phase II Trial of Palbociclib in Patients with Advanced Esophageal or Gastric Cancer
Thomas Benjamin Karasic1, Mark H O'Hara1, Ursina R Teitelbaum1
1Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Lessons Learned:
Palbociclib monotherapy demonstrated minimal clinical activity in patients with previously treated gastroesophageal cancers. Further clinical evaluation of palbociclib monotherapy is not warranted in gastroesophageal cancers, but improved understanding of resistance mechanisms may permit rational combination approaches.
Background:
Dysregulation of the cell cycle is a hallmark of cancer. Progression through the G1/S transition requires phosphorylation of retinoblastoma (RB) by cyclin-dependent kinases (CDKs) 4 and 6, which are regulated by cyclins D and E. Amplifications of cyclin D loci and activating mutations in CDKs are frequent molecular aberrations in gastroesophageal malignancies. We conducted a phase II trial of the CDK4/6 inhibitor palbociclib as an initial test of efficacy.
Methods:
Patients with previously treated metastatic gastroesophageal cancers with intact RB nuclear expression by immunohistochemistry were treated with 125 mg daily of palbociclib for days 1-21 of 28-day cycles. The primary endpoint was overall response rate.
Results:
We screened 29 patients and enrolled 21 patients: 5 with gastric adenocarcinoma, 3 with gastroesophageal junction adenocarcinoma, 8 with esophageal adenocarcinoma, and 5 with esophageal squamous cell carcinoma. All 29 tumors screened had intact nuclear RB expression, and four treated patients tested positive for CCND1 overexpression. No objective responses were seen. Median progression-free survival was 1.8 months, and median overall survival was 3.0 months. All recurrent grade 3 or 4 toxicities were hematologic, with neutropenia in eight patients (38%), anemia in four patients (19%), and thrombocytopenia in two patients (10%).
Conclusion:
Palbociclib has limited single-agent activity in gastroesophageal tumors.
Insights
Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, showed minimal activity in patients with gastroesophageal cancers. Further study of palbociclib monotherapy is not recommended, but combination therapies may be viable.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Cell cycle dysregulation is a key feature of cancer.
- Cyclin-dependent kinases (CDKs) 4 and 6 regulate the G1/S transition, crucial for cell proliferation.
- Gastroesophageal malignancies frequently exhibit alterations in cyclin D and CDK pathways.
Purpose of the Study:
- To evaluate the efficacy of palbociclib, a CDK4/6 inhibitor, as a monotherapy in patients with previously treated gastroesophageal cancers.
- To assess the overall response rate as the primary endpoint.
Main Methods:
- A phase II trial was conducted involving patients with metastatic gastroesophageal cancers.
- Patients received 125 mg of palbociclib daily on a 21/28-day cycle schedule.
- Inclusion criteria required intact retinoblastoma (RB) nuclear expression.
Main Results:
- Twenty-one patients were enrolled, including those with gastric, gastroesophageal junction, and esophageal adenocarcinomas, and esophageal squamous cell carcinoma.
- No objective responses were observed in any patients.
- Median progression-free survival was 1.8 months, and median overall survival was 3.0 months.
- Hematologic toxicities, primarily neutropenia, were the most common severe adverse events.
Conclusions:
- Palbociclib demonstrated limited single-agent efficacy in gastroesophageal tumors.
- Further clinical investigation of palbociclib monotherapy in this patient population is not warranted.
- Understanding resistance mechanisms could inform future combination therapy strategies.
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