The investigational drug alpelisib, previously known as BYL719, was able to overcome head and neck cancer resistance to the anti-EGFR treatment cetuximab, and combining alpelisib with cetuximab was found to be beneficial, according to data from a phase Ib/II trial presented at the AACR special conference Targeting the PI3K-mTOR Network in Cancer, held Sept. 14-17.

"Most of head and neck cancers are driven by activation of the EGFR pathway. Cetuximab is a drug that targets EGFR and is effective in this setting, but cancers often become resistant to this therapy," said Pamela Munster, MD, professor of medicine and director of the Early Phase Clinical Trials Unit at the UCSF Helen Diller Family Comprehensive Cancer Center. "Treatment resistance is often conveyed through activation of the PI3K/AKT/mTOR pathway, and alpelisib is an inhibitor of this pathway."

"In this clinical trial, we treated patients with recurrent and metastatic head and neck cancer with a combination of cetuximab and alpelisib, and about 25 percent of the patients benefited from this therapy. Further, the treatment was fairly well tolerated," said Munster. "We are very encouraged by the study findings, and we are now conducting the phase II part of the trial."

In the phase Ib study, Munster and colleagues recruited 37 patients with recurrent/metastatic squamous cell carcinoma of the head and neck resistant to platinum-based chemotherapy. Of these patients, 32 received 300 mg alpelisib once daily and five received 400 mg alpelisib once daily, plus cetuximab.

Of the 32 patients who received alpelisib alone, four patients had a confirmed partial response and 16 had stable disease, of which five had unconfirmed partial responses.

Among the 37 patients, the overall response rate was 11 percent and the disease control rate was 54 percent. Of the seven patients who had relapsed on prior cetuximab therapy, treatment with alpelisib resulted in one partial response and disease control in five, with a disease control rate of 71 percent.

To study the effect of a combination of alpelisib and cetuximab, the researchers conducted preclinical studies using mice bearing cetuximab-sensitive and cetuximab-resistant esophageal cancer cells and found that a combination of alpelisib and cetuximab had an additive effect in mice with cetuximab-sensitive cancer cells leading to tumor regression. In mice with cetuximab-resistant cancer cells, this combination restored sensitivity to cetuximab.

Based on the data from preclinical studies and phase Ib results testing the combination, the team is currently conducting the phase II part of the trial to test a combination of cetuximab and 300 mg alpelisib once daily in patients who have squamous cell carcinoma of the head and neck.

This study was funded by Novartis Pharmaceuticals Corporation. Munster declares no conflicts of interest.