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.
Authors: Fayette Jerome , Saada-Bouzid Esma , Cropet Claire , Daste Amaury , Treilleux Isabelle , Pissaloux Daniel , Pilleul Frank , Mastier Charles , Neidhardt Eve-Marie , Karabajakian Andy , Grinand Elodie , Mayet Romaine , Bernardin Mathilde , Celse Clothilde , Garin Gwenaelle , Pérol David 
Published: June 2023

6044 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 (PFR8W) 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 PFR8W 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 (PFR8w: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 .