- •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.
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.
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.
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.
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
The date of registration
March 6, 2018.
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- Clinical presentation, histology, and prognoses of malignant melanoma in ethnic Chinese: a study of 522 consecutive cases.BMC Canc. 2011; 11: 85https://doi.org/10.1186/1471-2407-11-85
- Acral lentiginous melanoma: incidence and survival patterns in the United States, 1986-2005.Arch Dermatol. 2009; 145: 427-434https://doi.org/10.1001/archdermatol.2008.609
- Prevalence of BRAF V600E mutation in Chinese melanoma patients: large scale analysis of BRAF and NRAS mutations in a 432-case cohort.Eur J Canc. 2012; 48: 94-100https://doi.org/10.1016/j.ejca.2011.06.056
- Safety, efficacy and biomarker analysis of toripalimab in previously treated advanced melanoma: results of the POLARIS-01 multicenter phase II trial.Clin Canc Res. 2020; (clincanres.3922.2019)https://doi.org/10.1158/1078-0432.CCR-19-3922
- Immunohistochemical analysis of molecular drivers in melanoma identifies p16 as an independent prognostic biomarker.J Clin Pathol. 2014; 67: 520-528
- Increased prevalence of lung, breast, and pancreatic cancers in addition to melanoma risk in families bearing the cyclin-dependent kinase inhibitor 2A mutation: implications for genetic counseling.J Am Acad Dermatol. 2014; 71: 888-895https://doi.org/10.1016/j.jaad.2014.06.036
- Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines.Pigment Cell Melanoma Res. 2014; 27: 590-600https://doi.org/10.1111/pcmr.12228
- Cell cycle control as a promising target in melanoma.Curr Opin Oncol. 2015; 27: 141-150https://doi.org/10.1097/CCO.0000000000000159
- Frequent genetic aberrations in the CDK4 pathway in acral melanoma indicate the potential for CDK4/6 inhibitors in targeted therapy.Clin Canc Res. 2017; 23: 6946-6957https://doi.org/10.1158/1078-0432.CCR-17-0070
- Genetic aberrations in the CDK4 pathway are associated with innate resistance to PD-1 blockade in Chinese patients with non-cutaneous melanoma.Clin Canc Res. 2019; 25: 6511-6523https://doi.org/10.1158/1078-0432.CCR-19-0475
- FDA approval: palbociclib for the treatment of postmenopausal patients with estrogen receptor-positive, HER2-negative metastatic breast cancer.Clin Canc Res. 2015; 21: 4760-4766https://doi.org/10.1158/1078-0432.CCR-15-1185
- Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.Lancet Oncol. 2016; 17: 425-439https://doi.org/10.1016/S1470-2045(15)00613-0
- Targeting cell cycle in breast cancer: CDK4/6 Inhibitors.Int J Mol Sci. 2020; 21E6479
- Therapy after cyclin-dependent kinase inhibition in metastatic hormone receptor-positive breast cancer: resistance mechanisms and novel treatment strategies.Cancer. 2020; 126: 3400-3416
- Palbociclib for treatment of metastatic melanoma with copy number variations of CDK4 pathway: case report.Chin Clin Oncol. 2018; 7: 62https://doi.org/10.21037/cco.2018.06.08
- Optimal two-stage designs for phase II clinical trials.Contr Clin Trials. 1989; 10: 1-10https://doi.org/10.1016/0197-2456(89)90015-9
- Cancer genome landscapes.Science. 2013; 339: 1546-1558https://doi.org/10.1126/science.1235122
- Cell cycle progression without cyclin E/CDK2: breaking down the walls of dogma.Canc Cell. 2003; 4: 160-162https://doi.org/10.1016/s1535-6108(03)00217-4
- Cell cycle proteins as promising targets in cancer therapy.Nat Rev Canc. 2017; 17: 93-115https://doi.org/10.1038/nrc.2016.138
- Post-translational modifications of the mini-chromosome maintenance proteins in DNA replication.Genes. 2019; 10: 331https://doi.org/10.3390/genes10050331
- Ribociclib as first-line therapy for HR-positive, advanced breast cancer.N Engl J Med. 2018; 379: 2582https://doi.org/10.1056/NEJMoa1609709
- Phase-2 trial of palbociclib in adult patients with recurrent RB1-positive glioblastoma.J Neuro Oncol. 2018; 140: 477-483https://doi.org/10.1007/s11060-018-2977-3
- Hypoxia. Cross talk between oxygen sensing and the cell cycle machinery.Am J Physiol Cell Physiol. 2011; 301: C550-C552https://doi.org/10.1152/ajpcell.00176.2011
- MCM7 silencing promotes cutaneous melanoma cell autophagy and apoptosis by inactivating the AKT1/mTOR signaling pathway.J Cell Biochem. 2020; 121: 1283-1294https://doi.org/10.1002/jcb.29361
- Mutations associated with acquired resistance to PD-1 blockade in melanoma.N Engl J Med. 2016; 375: 819-829https://doi.org/10.1056/NEJMoa1604958
- Primary resistance to PD-1 blockade mediated by JAK1/2 mutations.Canc Discov. 2017; 7: 188-201https://doi.org/10.1158/2159-8290.CD-16-1223
- LNK suppresses interferon signaling in melanoma.Nat Commun. 2019; 10: 2230https://doi.org/10.1038/s41467-019-09711-y
- Cyclin-dependent kinase activity is required for type I interferon production.Proc Natl Acad Sci U S A. 2018; 115: E2950-E2959https://doi.org/10.1073/pnas.1720431115
- The CDK4/6 inhibitor LY2835219 overcomes vemurafenib resistance resulting from MAPK reactivation and cyclin D1 upregulation.Mol Canc Therapeut. 2014; 13: 2253-2263https://doi.org/10.1158/1535-7163
- Phase I-II open label multicenter study of PD0332991 in BRAF V600mut metastatic melanoma patients harboring CDKN2A loss and RB1 expression and treated with vemurafenib.J Clin Oncol. 2019; 37 (abstr 9545)https://doi.org/10.1200/JCO.2019.37.15_suppl.9545
- Cyclin D–CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance.Nature. 2018; 553: 91-95https://doi.org/10.1038/nature25015
Published online: March 23, 2021
Accepted: February 14, 2021
Received in revised form: January 22, 2021
Received: June 25, 2020
© 2021 Elsevier Ltd. All rights reserved.