A Phase I Study of the CDK4/6 Inhibitor Palbociclib in Combination with Cetuximab and Radiotherapy for Locally...

Palbociclib, a cyclin D kinase 4 (CDK4)/6 inhibitor, has shown radiosensitizing effects in preclinical studies. There is a strong rationale for adding palbociclib to cetuximab and radiotherapy in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), especially in p16-negative HNSCC.

We conducted a phase I dose-escalation study (NCT03024489) using a classical 3+3 design to determine safety, tolerability, and MTD of palbociclib, cetuximab, and intensity-modulated radiotherapy (IMRT) combination. At the recommended phase II dose (RP2D), additional p16-negative patients were enrolled.

Twenty-seven patients with LA-HNSCC (13 in dose escalation, 14 in expansion) with oropharyngeal (41%) and hypopharyngeal (30%) cancers were enrolled. The MTD was not reached, and the RP2D of palbociclib was established at the full standard palbociclib dose of 125 mg/day for 21 days per cycle, administered for two cycles during IMRT. The most common grade 3-4 toxicities were mucositis (59%), radiation dermatitis (22%), and neutropenia (22%), with a febrile neutropenia rate of 7%. Common genomic alterations included mutations in TP53 (57%), GNAQ (35%), and PIK3CA (17%), and copy-number gains in CCND1 (22%), CCND2 (9%), and EGFR (9%). Overall, p16 expression was positive in 15% of patients. No correlation was observed between p16 status, genomic alterations, and preliminary efficacy. The objective response rate was 84%. The rates for 2-year locoregional control, event-free survival, and overall survival were 73%, 48%, and 71%, respectively.

The palbociclib, cetuximab, and IMRT combination was well tolerated. The RP2D was established, while no MTD was determined. The regimen demonstrated promising preliminary efficacy, suggesting further investigation is warranted in patients with cisplatin-ineligible p16/human papilloma virus-unrelated LA-HNSCC.