Reference Detail

Ref Type

Journal Article

PMID

(31678634)

Authors

Dunn LA, Riaz N, Fury MG, McBride SM, Michel L, Lee NY, Sherman EJ, Baxi SS, Haque SS, Katabi N, Wong RJ, Xiao H, Ho AL, Pfister DG

Title

A Phase 1b Study of Cetuximab and BYL719 (Alpelisib) Concurrent with Intensity Modulated Radiation Therapy in Stage III-IVB Head and Neck Squamous Cell Carcinoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
International journal of radiation oncology, biology, physics	106	3	2020 03 01	564-570	Int J Radiat Oncol Biol Phys

URL

Abstract Text

Activation of the PI3K/mTOR signaling pathway is common in head and neck squamous cell carcinoma (HNSCC). BYL719 is an α-specific PI3K inhibitor that is synergistic and efficacious when combined with cetuximab, a Food and Drug Administration-approved radiosensitizing agent in the treatment of HNSCC. The agent independently has been shown to enhance radiosensitivity. This study evaluates the addition of BYL719 to cetuximab and radiation in the treatment of locally advanced HNSCC.This is a single-institution, phase 1 study. Patients with American Joint Committee on Cancer seventh edition stage III to IVB HNSCC received standard cetuximab (400 mg/m2 intravenous loading dose) before intensity modulated radiation therapy (IMRT) followed by 250 mg/m2 weekly infusions during IMRT. BYL719 was given orally during IMRT in 3 dose levels: (1) 200 mg/d, (2) 250 mg/d, or (3) 300 mg/d in a standard 3 + 3 dose-escalation design.Eleven patients were evaluable. Dose level 2 was the maximum tolerated dose for BYL719. Two patients on dose level 3 had dose-limiting toxicities of oral mucositis that required a dose reduction of BYL719. One patient on dose level 2 had a dose-limiting toxicity of nausea that led to withdrawal of on-study treatment. Related grade 3 or higher adverse events consisted of decreased lymphocyte count, oral mucositis, dysphagia, hyperglycemia, maculopapular rash, and palmar-plantar erythrodysesthesia syndrome. All 11 patients had a complete response on posttreatment imaging, and 10 remain disease free. Of the 8 patients with mutational analysis, 1 had an activating PIK3CA mutation associated with a rapid response on serial intratreatment magnetic resonance imaging scans.The recommended phase 2 dose of BYL719 is 250 mg/d in combination with cetuximab and IMRT in patients with locally advanced HNSCC. Further evaluation of the addition of BYL719 to the platinum-sparing regimen of cetuximab and IMRT in the treatment of locally advanced HNSCC is warranted.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA E542K	head and neck squamous cell carcinoma	predicted - sensitive	Alpelisib + Cetuximab + Radiotherapy	Case Reports/Case Series	Actionable	In a Phase Ib trial, 11 of 11 patients with metastatic head and neck squamous cell carcinoma demonstrated no evidence of disease at 3 to 4 months following treatment with Piqray (alpelisb) in combination with Erbitux (cetuximab) and intensity modulated radiation therapy (IMRT), and PIK3CA E542K was identified in one patient with oropharyngeal squamous cell carcinoma who had a near complete radiologic response within 8 days of starting IMRT (PMID: 31678634).	31678634