Expression of the EGFR and its ligand transforming growth factor alpha occurs early in the carcinogenesis of squamous cell carcinoma of the head and neck (SCCHN).
Pamela N. Munster, MD
Expression of the EGFR and its ligand transforming growth factor alpha occurs early in the carcinogenesis of squamous cell carcinoma of the head and neck (SCCHN).1Overexpression of EGFR is a strong and unfavorable prognostic factor.
Cetuximab is an EGFR-inhibitor with demonstrated efficacy in SCCHN in combination with radiotherapy or cisplatin.2-5However, patient response to cetuximab is variable and treatment resistance may be conveyed through activation of the PI3K/AKT/mTor pathway.
“Resistance may be immediate or occur gradually,” noted Pamela Munster, MD, professor of medicine, Helen Diller Cancer Center, University of California, San Francisco. “We are evaluating resistance patterns in individual tumors to better define who may become resistant and why.” Combining therapies with cetuximab that target this pathway may overcome cetuximab-resistance in SCCHN.3
Adjunct Treatment Option for Cetuximab Resistance
The investigational agent alpelisib, formerly known as BYL719, is a potent oral inhibitor of the α-isoform of class I PI3K.4Recent data presented at the American Association for Cancer Research conference, Targeting the PI3K-mTOR Network in Cancer, demonstrate that the combination of alpelisib and cetuximab was beneficial in 25% of patients with recurrent/metastatic head and neck cancer who were resistant to cetuximab.5
A total of 37 patients with cetuximab-resistant SCCHN received alpelisib 300 mg daily (n = 32) or alpelisib 400 mg daily plus cetuximab (n = 5). The overall response rate was 11% and the disease control rate was 54%. Of those patients receiving alpelisib monotherapy, 4 patients had confirmed partial response, and 16 patients had stable disease. Importantly, of those patients who had relapsed on previous cetuximab therapy (n = 7), alpelisib resulted in one partial response and disease control in 5 patients. The most common side effects were hyperglycemia, stomatitis, and dermatitis acneiform. According to Munster, the goal of the trial was to test the safety, tolerability, and preliminary efficacy of the combination, while future trials will determine which, and how many, patients may benefit.
Investigation in Multiple Cancers
Based on these results, the combination of cetuximab and alpelisib 300 mg once daily is being further evaluated in the phase II component of the same trial. These data suggest that resistance to cetuximab may be overcome with a PI3K inhibitor, observed Munster, summarizing the study results. “The PI3K pathway is activated and mutated in many cancers and may be a good therapeutic target in those cancers.” In addition to SSCHN, alpelisib is also being evaluated in metastatic breast cancer,6advanced or metastatic gastric cancer,7renal cell cancer,8and metastatic colorectal cancer,9as well as other carcinomas.