Afatinib with Post-Operative Radiation in Head and Neck Cancer
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the United States. These cancers are usually treated with either surgery or radiation, and patients who are at risk of recurrence after surgery also receive follow-up radiation therapy. High-risk patients may also receive chemotherapy, typically cisplatin, with their post-operative radiation. However, many patients cannot tolerate a complete round of cisplatin, and have little recourse. Also, cisplatin does not lower the risk of distant metastases outside the head and neck when given with radiation therapy after surgery. “
There’s an urgent need for more tolerable and efficacious therapies after surgery,” says Danielle Margalit, MD, MPH, (BWH/DFCI). She is leading a phase I dose escalation clinical trial to test a new strategy to improve the outcome for these patients and reduce the risk of recurrence: combining afatinib, a new investigational targeted therapy, with radiation. For the high-risk group, she wants to know if combining afatinib with a different chemotherapy, docetaxel instead of cisplatin, is more easily tolerated and ultimately more effective.
Prior Evidence and Rationale
In laboratory studies, researchers found that EGFR inhibitors make HNSCC cells more sensitive to radiation. Several large trials have shown the benefit of adding EGFR inhibitors to therapy. In one, EGFR inhibition combined with radiation improved the survival of patients compared to radiation alone. In another, adding an EGFR inhibitor to chemotherapy improved survival for patients with recurrent or metastatic head and neck cancer. For patients treated with surgery, adding docetaxel instead of cisplatin in combination with EGFR inhibition and radiation was better tolerated and more effective.
Afatinib is a novel, oral, irreversible dual inhibitor of several members of the ErbB family of receptors to which EGFR belongs. This family includes the related Human Epidermal Growth Factor Receptor 2 (HER2/ErbB2), which can bind with the EGFR to promote the downstream signaling that makes EGFR lead to cell growth and proliferation. Because afatinib is a small molecule, it can enter the cell and more directly shut down the active site where these receptors relay growth signals to intracellular pathways than antibody EGFR inhibitors can. Also, as a potent inhibitor of a variety of EGFR mutations, afatinib can potentially evade resistance mechanisms that have limited the results of other small molecule oral inhibitors. Finally, EGFR can become internalized and travel to the nucleus of cells to affect expression of different genes, and afatinib can inhibit this nuclear EGFR as well.
Afatinib is being tested in HNSCC and lung and breast cancer, both as a single agent and in combination with chemotherapy. This is the first study to combine afatinib with radiation therapy.
Study Aim and Design
The objective of the current trial is to test the safety of afatinib in combination with radiation therapy in post-operative head and neck cancer patients. The trial is open and accruing head and neck cancer patients who are treated with surgery and are candidates for post-operative radiation or radiation plus chemotherapy. Using a 3-plus-3 design, the study will begin with the intermediate risk group on afatinib and radiation, and will establish safety at the first dose before beginning the high-risk group on a combination of radiation, afatinib and docetaxel.
“We want to extend the potential benefits of EGFR inhibition to patients who are first treated with surgery, since that is such a common treatment plan,” Margalit explains. “Our goal is to reduce the risk of recurrence of these head and neck cancers, and at the same time increase the tolerability of treatment, so we’re excited to be able to test this promising new drug in combination with radiation therapy.”
Phase I Trial
Title: Safety Study of Afatinib and Postoperative Radiation Therapy to Treat Head and Neck Cancer
Principal Investigator: Danielle Margalit, MD, MPH (DFCI)
NIH Trial Number: NCT01783587
DF/HCC Protocol Number: 12-267
The trial is open and recruiting patients.
For information on ClinicalTrials.gov, go to http://clinicaltrials.gov/show/NCT01783587
— Cathryn Delude