Highlights
- •This is the first phase II study of a cyclin-dependent kinase4/6 inhibitor in patients with advanced acral melanoma (AM).
- •Palbociclib was effective in individual patients with advanced AM.
- •MCM7 and JAK-STAT status may be used as predictive biomarkers of palbociclib in AM.
Abstract
Background
Genetic aberrations in the cyclin-dependent kinase (CDK)4 pathway occur in 82% of
patients with acral melanoma (AM), which is the predominant subtype of melanoma in
China. We aimed to evaluate the anti-tumour activity of palbociclib, a selective CDK4/6
inhibitor, in patients with advanced AM with CDK4 pathway gene aberrations.
Methods
In this phase II trial, patients with advanced AM with CDK4 or/and CCND1 gain or/and CDKN2A loss were treated with oral palbociclib (125 mg) on days 1–21 of a 28-day cycle.
The primary end-point was overall response rate (ORR). Secondary end-points were progression-free
survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs).
Whole-exome sequencing and multiplex immunohistochemistry of the available formalin-fixed,
paraffin-embedded samples of nine patients were analysed to explore the predictive
biomarkers of palbociclib response.
Results
Fifteen patients were enrolled. Three (20.0%) patients achieved tumour shrinkage at
8 weeks, including one with confirmed partial response. At data cut-off date, treatment
was ongoing for one patient. The median PFS was 2.2 mo (range: 1.5–13.3 mo; 95% confidence
interval [CI]: 1.9–2.5), and the median OS was 9.5 mo (range: 2.6–14.1 mo, 95% CI:
5.7–13.4). Eight patients died due to disease progression. The most common TRAEs were
leukopenia (87%; Grade III/IV, 27%), neutropenia (80%; grade III/IV, 27%), and fatigue
(53%; grade III/IV, 7%). Significant JAK2 deletions and SH2B3 amplifications were observed in patients who did not achieve any clinical benefit
(CB) with palbociclib treatment. MCM7 amplification or protein expression level was found to be associated with CB.
Conclusions
Palbociclib monotherapy demonstrated preliminary efficacy and an acceptable safety
profile in advanced AM patients with CDK4 pathway aberrations. Patients with amplification
or high protein levels of MCM7 were more prone to benefit from palbociclib. The JAK-STAT pathway might play a role
in the mechanism of action of palbociclib in AM.
Trial registration number
NCT03454919.
The date of registration
March 6, 2018.
Keywords
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Article info
Publication history
Published online: March 23, 2021
Accepted:
February 14,
2021
Received in revised form:
January 22,
2021
Received:
June 25,
2020
Identification
Copyright
© 2021 Elsevier Ltd. All rights reserved.
