Could targeting more than one tyrosine kinase provide a greater benefit to patients with a wide variety of tumors? That’s the question researchers are attempting to answer through several clinical trials involving the investigational drug afatinib.
Afatinib is a pan-HER inhibitor, meaning that its target is the entire ErbB/HER family of receptors, which includes epidermal growth factor receptor (EGFR, or ErbB1) and human epidermal growth factor receptor 2 (HER2, or ErbB2). Each of these tyrosine kinases is implicated in varying ways among different cancers.
Germany-based Boehringer Ingelheim is sponsoring a group of studies of afatinib in different tumor types, collectively known as the LUX Clinical Trial Program.
Chih-Hsin (James) Yang, MD
Among the studies of afatinib in various tumor types, the drug is in the latest stage of clinical development in non–small cell lung cancer (NSCLC).
While other EGFR-targeted therapies have been approved for the treatment of patients with NSCLC, afatinib’s mechanism of action could offer certain advantages, Chih-Hsin (James) Yang, MD, said in an interview.
“EGFR of course is the most important pathway for non–small cell lung cancer, but some lung cancers may use HER2 to increase the activity of the cancer, so blocking all HER1 to HER4 [receptors] actually has the advantage of amending possible escape-resistant patterns,” said Yang, professor at the Graduate Institute of Oncology and director of the Cancer Research Center at National Taiwan University in Taipei, and Deputy Director of the Department of Oncology at National Taiwan University Hospital, who serves as lead investigator on several of the afatinib trials in lung cancer.
At the 2012 ASCO Annual Meeting, Yang presented preliminary results from the pivotal phase III LUX-Lung 3 trial.1 The trial found that chemotherapy-naïve patients with stage IIIB/IV lung adenocarcinoma experienced a median progression-free survival (PFS) of 11.1 months with afatinib compared with 6.9 months in patients who received a combination of pemetrexed and cisplatin (hazard ratio = 0.58).
The difference was even more pronounced for patients whose tumors had deletion 19 or L858R mutations. In those patients, afatinib nearly doubled PFS compared with chemotherapy (13.6 months vs 6.9 months, respectively). These patients accounted for approximately 90% of patients in the trial who were included in this analysis.
“Afatinib is the first drug that has shown to have a progression-free survival time more than one year in a registration study in [patients with] EGFR mutations,” Yang said. “So I think for those patients who want to have disease control stabilization for a median of over a year, afatinib is certainly a very good choice.”
Based on the LUX-Lung 3 results, the FDA is currently reviewing afatinib for approval in EGFR-positive advanced NSCLC, with an action date of July 15.
Yang said the results of the LUX-Lung 6 trial, which was similar in design to LUX-Lung 3, but used gemcitabine plus cisplatin as the control, will likely be presented at the 2013 ASCO Annual Meeting.
Additionally, LUX-Lung 7 is continuing to enroll patients with EGFR-mutated NSCLC for first-line treatment with either afatinib or gefitinib, and LUX-Lung 8 is comparing afatinib with erlotinib as a second-line treatment for patients with NSCLC who have advanced squamous cell carcinoma.
Nancy Lin, MD
While numerous HER2-targeted therapies in breast cancer have been approved or are under clinical investigation, there still may be a niche for afatinib in HER2-positive metastatic breast cancer, Nancy Lin, MD, said in an interview. For example, it could be used when patients develop resistance to other treatments, such as lapatinib.
“There clearly is resistance with lapatinib, both as a single agent and in combination, so I think there is room for additional agents,” said Lin, clinical director of the Breast Cancer Treatment Center at Dana-Farber Cancer Institute and an assistant professor of Medicine at Harvard Medical School in Boston, Massachusetts. “In the HER2-positive metastatic space, people commonly receive multiple lines of therapy, so we actually do need multiple regimens that are efficacious because people do go through many different lines.”