Abstract
Abemaciclib in recurrent/metastatic head and neck squamous cell carcinoma (RM-HNSCC) harboring CDKN2A loss, and/or CCND1 and/or CDK6 amplification: A phase II multicenter trial.
Author
person
Jerome Fayette
Centre Léon Bérard, Lyon, France
info_outline
Jerome Fayette, Esma Saada-Bouzid, Claire Cropet, Amaury Daste, Isabelle Treilleux, Daniel Pissaloux, Frank Pilleul, Charles Mastier, Eve-Marie Neidhardt, Andy Karabajakian, Elodie Grinand, Romaine Mayet, Mathilde Bernardin, Clothilde Celse, Gwenaelle Garin, David Pérol
Full text
Authors
person
Jerome Fayette
Centre Léon Bérard, Lyon, France
info_outline
Jerome Fayette, Esma Saada-Bouzid, Claire Cropet, Amaury Daste, Isabelle Treilleux, Daniel Pissaloux, Frank Pilleul, Charles Mastier, Eve-Marie Neidhardt, Andy Karabajakian, Elodie Grinand, Romaine Mayet, Mathilde Bernardin, Clothilde Celse, Gwenaelle Garin, David Pérol
Organizations
Centre Léon Bérard, Lyon, France, Centre de Lutte Contre le Cancer Antoine Lacassagne, Nice, France, Centre Léon Bérard, and GINECO, Lyon, France, Department of Medical Oncology, Hôpital Saint-André, University of Bordeaux-CHU Bordeaux, Bordeaux, France, Deeplink Medical, Lyon, France
Abstract Disclosures
Research Funding
Pharmaceutical/Biotech Company
Lilly
Background:
More than half of HPV negative HSNCC harbor genomic aberrations (i.e.
CDKN2A
loss, cyclin D amplification (ampl.)) that activate the cyclin-dependent kinase 4 and 6 (CDK4/6) – retinoblastoma protein (Rb) signalling pathway. Hyperactivated CDK4/6-Rb pathway leads to acceleration of G1/S transition of cell cycle and ultimately to uncontrolled cellular proliferation. We hypothesized that abemaciclib, a CDK4/6 inhibitor, could be a potent targeted strategy by inhibiting this commonly dysregulated pathway in HNSCC.
Methods:
This single arm, multicentre Phase II evaluated the efficacy of abemaciclib (200mg/d orally BID) in molecularly-selected, HPV negative (HPV
-
), RM-HNSCC patients (pts) progressing after at least 1 prior line of platinum and cetuximab. A molecular screening step through centralised CGH-assay was required before treatment start: only pt with tumor harboring CDKN2A loss and/or CCND1 and/or CDK6 ampl. without homozygous deletion of RB1 were eligible to the therapeutic step. The primary endpoint was 8-week non-progression rate (PFR
8W
) as per central imaging review according to RECIST V.1.1. Secondary endpoints included best overall response rate (BORR), progression free survival (PFS), overall survival (OS) and adverse event (AE) according to NCI-CTCAE V5.0. The study used a Fleming A’Hern design with an inefficacy bound of 15% and a target PFR
8W
of 40% (α = 5% one sided, 1-β = 90%).
Results:
Twenty-six HPV
-
RM-HNSCC pts (M: 23, F: 3, median age: 59 [range, 42-78], heavily pre-treated [84.6% ≥ 2 prior lines]) received at least one dose of abemaciclib. According to central CGH-assay, molecular alterations were
CDKN2A
loss +
CCND1
ampl. +
CDK6
ampl. (n = 1),
CDKN2A
loss +
CCND1
ampl. (n = 10),
CDKN2A
loss (n = 6) or
CCND1
ampl. (n = 9), all with intact Rb. Among the 24 evaluable pts, 7 pts were progression-free at 8 weeks (PFR
8w
:29.2% (95% CI 14.6-)). BORR according to central imaging review was stable disease for 7 pts (31.8%) and progressive disease for 11 pts (50%); no objective response was observed. Median PFS and OS were 7.1 weeks (95% CI: 6.9-10.4) and 4.8 months (95% CI: 2.4-7.3), respectively. Most common related AEs (≥20% of pts, all grade) were diarrhea/nausea/vomiting, fatigue and hematological toxicity (anemia, lymphocyte and neutrophil count decreased). Two fatal serious AE potentially related to abemaciclib according to both investigator and sponsor were reported: a case of pulmonary hemorrhage also possibly related to abemaciclib-induced tumor necrosis and a case of myocardial infarction.
Conclusions:
Abemaciclib had limited antitumor activity in RM-HNSCC harboring molecular alteration in CDK4/6 pathway. Clinical trial information: NCT03356223.
Clinical status
Clinical
7 organizations
1 drug
2 targets
Organization
Centre Léon BérardOrganization
Hôpital Saint-AndréOrganization
University of Bordeaux-CHU BordeauxOrganization
Deeplink MedicalDrug
abemaciclibTarget
CDK6Target
CDK4 & 6