Researchers are attempting to determine if targeting more than one tyrosine kinase provide a greater benefit in several clinical trials involving the investigational drug afatinib.
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.
Chih-Hsin (James) Yang, MD
Germany-based Boehringer Ingelheim is sponsoring a group of studies of afatinib in different tumor types, collectively known as the LUX Clinical Trial Program.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.
Nancy Lin, MD
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.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.”
Lin served as one of the investigators in a phase II trial of afatinib in HER2-positive breast cancer patients who were refractory to trastuzumab.2 The study found that among 41 patients treated with afatinib alone, four patients (10%) had partial response, 15 patients (37%) had stable disease as best response, and 19 (46%) achieved some level of clinical benefit. The toxicity profile was as expected, with diarrhea as the most commonly reported adverse event. Lin called the results “respectable for a single-agent study in reasonably pretreated patients.”
Currently, three trials are under way to further determine the efficacy of afatinib in HER2- positive breast cancer. The phase III LUX-Breast 1 trial is investigating the drug in combination with vinorelbine as a second-line treatment after trastuzumab failure, the phase II LUX-Breast 2 trial is looking at afatinib monotherapy after failure with other HER2-targeted therapies, and the phase II LUX-Breast 3 trial is examining patients with brain metastases after trastuzumab or lapatinib failure.
Lin said that systemic therapy has significantly improved the survival of breast cancer patients whose disease has metastasized to the central nervous system, with patients who have a good performance status surviving for a median of 2 years, irrespective of the number of brain metastases they have. However, if patients do not respond or their disease recurs after treatment with radiotherapy, there are very few options. This is where afatinib may be important in this setting, especially since monoclonal antibodies like trastuzumab appear to have no effect on these particular metastases.
“I think there’s a lot of interest in this space because it’s a place where potentially the small-molecule inhibitors have a particular role that would be distinct from what you might expect from monoclonal antibodies,” Lin said.The LUX-Head & Neck 1 and the LUX-Head & Neck 2 trials are currently assessing the efficacy of afatinib in head and neck cancer. The first trial is evaluating the drug in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) after failure of platinum-based therapy, and the second trial is investigating how patients with unresected stage III/IV advanced SCCHN perform with the drug after receiving chemoradiotherapy.
“In lung cancer, we’re talking about mutations in EGFR that drive the activity. In head and neck cancer, it’s still EGFR that’s relevant, but it’s not necessarily a mutation in EGFR, it’s the expression levels of EGFR,” said William Goeckeler, PhD, director of Oncology Medical Affairs at Boehringer Ingelheim, in an interview. “So EGFR is overexpressed in head and neck cancers, and it’s been found that overexpression of EGFR is a bad prognostic factor, and it’s thought to drive the growth of these tumors.”
Approximately half of all patients with SCCHN experience recurrent disease. Goeckeler explained that LUX-Head & Neck 1 is designed to determine whether patients can receive afatinib instead of additional chemotherapy to keep their disease under control. For patients with locally advanced disease, chemoradiation followed by repeat chemoradiation is often employed to keep the disease from spreading. Goeckeler said that the LUX-Head & Neck 2 trial is designed to assess whether patients experienced an improved outcome and may not need repeat chemoradiation treatments.