A Phase I Study of the CDK4/6 Inhibitor Palbociclib in Combination with Cetuximab and Radiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma
Issued Date
2024-01-15
Resource Type
ISSN
10780432
eISSN
15573265
Scopus ID
2-s2.0-85182747455
Pubmed ID
37982827
Journal Title
Clinical Cancer Research
Volume
30
Issue
2
Start Page
294
End Page
303
Rights Holder(s)
SCOPUS
Bibliographic Citation
Clinical Cancer Research Vol.30 No.2 (2024) , 294-303
Suggested Citation
Ngamphaiboon N., Pattaranutaporn P., Lukerak S., Siripoon T., Jinawath A., Arsa L., Shantavasinkul P.C., Taonam N., Trachu N., Jinawath N., Kositwattanarerk A., Sananmuang T., Jiarpinitnun C. A Phase I Study of the CDK4/6 Inhibitor Palbociclib in Combination with Cetuximab and Radiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma. Clinical Cancer Research Vol.30 No.2 (2024) , 294-303. 303. doi:10.1158/1078-0432.CCR-23-2303 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/95641
Title
A Phase I Study of the CDK4/6 Inhibitor Palbociclib in Combination with Cetuximab and Radiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma
Corresponding Author(s)
Other Contributor(s)
Abstract
Purpose: 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. Patients and Methods: We conducted a phase I dose-escalation study (NCT03024489) using a classical 3þ3 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. Results: Twenty-seven patients with LA-HNSCC (13 in dose escalation, 14 in expansion) with oropharyngeal (41%) and hypo-pharyngeal (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. Conclusions: 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.