A phase 1 study of everolimus + weekly cisplatin + intensity modulated radiation therapy in head-and-neck cancer.
OBJECTIVE
Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation.


METHODS
This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m(2) weekly × 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and-neck cancer. The study had a standard 3 + 3 dose-escalation design.


RESULTS
Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer-free margins. The most common grade ≥3 treatment-related adverse event was lymphopenia (92%), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximum tolerated dose was everolimus 5 mg/day.


CONCLUSIONS
Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins.
Department of Medicine, Head and Neck Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.
Matthew G
MG
Fury
Nancy Y
NY
Lee
Eric
E
Sherman
Alan L
AL
Ho
Shyam
S
Rao
Adriana
A
Heguy
Ronglai
R
Shen
Susan
S
Korte
Donna
D
Lisa
Ian
I
Ganly
Snehal
S
Patel
Richard J
RJ
Wong
Ashok
A
Shaha
Jatin
J
Shah
Sofia
S
Haque
Nora
N
Katabi
David G
DG
Pfister
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000628:therapy*; D059248:Chemoradiotherapy / Q000009:adverse effects / Q000379:methods; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects; D004334:Drug Administration Schedule; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D000068338:Everolimus; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011446:Prospective Studies; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000009:adverse effects; D011879:Radiotherapy Dosage; D050397:Radiotherapy, Intensity-Modulated / Q000379:methods*; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000077195:Squamous Cell Carcinoma of Head and Neck; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D039561:Eukaryotic Initiation Factor-4E; D009363:Neoplasm Proteins; D011838:Radiation-Sensitizing Agents; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D002945:Cisplatin; D020123:Sirolimus