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Palbociclib in advanced acral melanoma with genetic aberrations in the cyclin-dependent kinase 4 pathway
Lili Mao1, Jie Dai1, Yabin Cao2
1Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma, Peking University Cancer Hospital & Institute, Beijing, China.
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.
Insights
Palbociclib showed preliminary effectiveness in advanced acral melanoma (AM) patients with CDK4 pathway aberrations. MCM7 amplification may predict benefit, while JAK2 deletions suggest resistance to this targeted therapy.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Acral melanoma (AM) is the most common melanoma subtype in China, with 82% of patients exhibiting genetic aberrations in the cyclin-dependent kinase (CDK)4 pathway.
- Targeting the CDK4 pathway presents a potential therapeutic strategy for advanced AM.
Purpose of the Study:
- To evaluate the anti-tumour activity and safety of palbociclib, a selective CDK4/6 inhibitor, in patients with advanced AM harboring CDK4 pathway gene aberrations.
- To identify potential predictive biomarkers for palbociclib response in this patient population.
Main Methods:
- A phase II clinical trial involving patients with advanced AM and specific CDK4 pathway gene alterations (CDK4/CCND1 gain or CDKN2A loss).
- Patients received oral palbociclib (125 mg) on a 21/28-day cycle.
- Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs).
- Whole-exome sequencing and immunohistochemistry were used to explore predictive biomarkers.
Main Results:
- Fifteen patients were enrolled; 20% (3/15) achieved tumour shrinkage, with one partial response.
- Median PFS was 2.2 months and median OS was 9.5 months.
- Most common TRAEs included leukopenia (87%), neutropenia (80%), and fatigue (53%).
- JAK2 deletions and SH2B3 amplifications were associated with lack of clinical benefit, whereas MCM7 amplification/expression correlated with benefit.
Conclusions:
- Palbociclib monotherapy demonstrates preliminary efficacy and an acceptable safety profile in advanced AM with CDK4 pathway aberrations.
- MCM7 amplification or high protein levels may indicate a higher likelihood of benefiting from palbociclib treatment.
- The JAK-STAT pathway may be involved in palbociclib's mechanism of action in AM.
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