Phase II Study of Palbociclib in Patients with Tumors with CDK4 or CDK6 Amplification: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1C.

in Clinical cancer research : an official journal of the American Association for Cancer Research by Mark H O'Hara, Opeyemi Jegede, Mark A Dickson, Angela M DeMichele, Richard Piekarz, Robert J Gray, Victoria Wang, Lisa M McShane, Lawrence V Rubinstein, David R Patton, P Mickey Williams, Stanley R Hamilton, Adedayo Onitilo, James V Tricoli, Barbara A Conley, Carlos L Arteaga, Lyndsay N Harris, Peter J O'Dwyer, Alice P Chen, Keith T Flaherty

TLDR

  • The study evaluated palbociclib in CDK4- or CDK6-amplified tumors and found limited activity, with only one partial response and four patients achieving stable disease.
  • The study highlights the need for further research into the molecular characteristics that predict response to CDK4/6 inhibitors and suggests that central nervous system tumors may be a promising area for future investigation.

Abstract

Amplification of cyclin-dependent kinase 4 (CDK4) and CDK6 is a feature of a variety of malignancies, and preclinical evidence suggests that inhibition of CDK4/6 is a plausible treatment strategy in these tumors. Subprotocol Z1C of the NCI-Molecular Analysis for Therapy Choice trial was designed to evaluate the CDK4/6 inhibitor palbociclib in CDK4- or CDK6-amplified tumors. Patients had a solid malignancy or lymphoma with progression on at least one systemic therapy for advanced disease or with no standard-of-care therapy available. Tumors with ≥7 copies of CDK4 or CDK6 were considered amplified and molecularly eligible. Enrolled patients were treated with palbociclib 125 mg daily on days 1 to 21 of a 28-day cycle. The primary endpoint was objective response rate. Forty-three patients were enrolled on subprotocol Z1C, and 38 patients were deemed eligible, treated, and included in analyses; 25 patients were eligible, treated, and centrally confirmed to have CDK4 or CDK6 amplification and comprised the primary analysis cohort for objective response rate endpoint. Among the 25 patients in the primary cohort, one patient had a partial response, 4 patients had stable disease, and 16 patients had progressive disease as best response. Four patients were not evaluable due to lack of follow-up scans. Among the 38 evaluable patients, one patient had a partial response, 10 patients had stable disease, and 21 patients had progressive disease as best response. Partial response and stable disease were seen only in patients with CDK4 amplification. Median progression-free survival was 2.0 months, and median overall survival was 8.8 months. Palbociclib showed limited activity in histology-agnostic CDK4- or CDK6-amplified tumors, although central nervous system tumors may be worthy of future investigation.

Overview

  • The study evaluates the CDK4/6 inhibitor palbociclib in CDK4- or CDK6-amplified tumors, specifically, solid malignancies or lymphomas with progressive disease or no standard-of-care therapy available.
  • The study aimed to assess palbociclib's activity in histology-agnostic CDK4- or CDK6-amplified tumors, with the primary endpoint being objective response rate.
  • A total of 25 patients with centrally confirmed CDK4 or CDK6 amplification were included in the primary analysis cohort, with the study evaluating palbociclib's efficacy and survival outcomes in this patient population.

Comparative Analysis & Findings

  • The study found that palbociclib showed limited activity in histology-agnostic CDK4- or CDK6-amplified tumors, with only one partial response and four patients achieving stable disease as best response.
  • Partial response and stable disease were observed only in patients with CDK4 amplification, with no responses seen in patients with CDK6 amplification.
  • The median progression-free survival was 2.0 months, and median overall survival was 8.8 months, indicating that palbociclib may have some clinical benefit, albeit limited, in patients with CDK4- or CDK6-amplified tumors.

Implications and Future Directions

  • The study suggests that CDK4/6 inhibition may not be an effective treatment strategy for all CDK4- or CDK6-amplified tumors, and future studies may be warranted to identify specific subgroups that are more responsive to this therapy.
  • Central nervous system tumors, which were not well-represented in this study, may be a promising area for future investigation, given the observed limited activity of palbociclib in solid malignancies and lymphomas.
  • The study highlights the importance of molecularly guided treatment approaches in cancer care, emphasizing the need for further research into the molecular characteristics that predict response to CDK4/6 inhibitors.
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