A combination of the EGFR-targeted anticancer therapeutics afatinib (Gilotrif) and cetuximab (Erbitux) yielded clinical responses in 29% of patients who had lung cancer harboring epidermal growth factor receptor (EGFR) mutations that had stopped responding to the EGFR inhibitors erlotinib (Tarceva) and gefitinib (Iressa), according to data from a Phase 1b clinical trial published in Cancer Discovery, a journal of the American Association for Cancer Research.
“Treatment with erlotinib and gefitinib leads to dramatic tumor regression and has improved survival for patients with EGFR-mutant lung adenocarcinoma,” said Yelena Janjigian, assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, and assistant professor of medicine at Weill Cornell Medical College in New York. “Unfortunately, these cancers invariably acquire resistance to these drugs and the patient’s disease progresses. There are currently no effective therapies for patients in this situation.”
Each year, nearly 20,000 people in the United States are diagnosed with lung adenocarcinomas that harbor EGFR mutations. Mutations in the EGFR tyrosine kinase domain result in aberrant activation of the protein kinase enabling the cancer cells’ signaling.
“Our study shows that a combination of afatinib and cetuximab can yield durable and robust clinical responses in the setting of acquired resistance, although larger, randomized trials are needed to confirm the results,” Janjigian continued. “Importantly, the afatinib/cetuximab combination benefited patients whether or not their cancer had acquired resistance to erlotinib or gefitinb as a result of a secondary mutation in EGFR called T790M.”
Of the 201 patients enrolled in the clinical trial by Janjigian and colleagues, 126 received the maximum-tolerated dose of combined afatinib and cetuximab. All these patients had EGFR-mutant lung cancer that had progressed during treatment with erlotinib or gefitinib, and 37 of them had a confirmed objective response to afatinib plus cetuximab. The overall median duration of the responses was 5.7 months.
Among the 37 patients who had a confirmed objective response, 22 had their tumors shrink by 50% or more. According to Janjigian, this level of tumor shrinkage is clinically significant as it results in regression of cancer-related symptoms and improvement in the patient’s quality of life.
One of the most common causes of resistance to erlotinib or gefitinib is that the tumors acquire the EGFR T790M mutation. In the study, the objective response rates were not statistically different for patients with and without the EGFR T790M mutation in their tumors: 32 and 25%, respectively. The median durations of the responses were 5.6 months for patients with EGFR T790M-positive tumors and 9.5 months for those with EGFR T790M-negative tumors.
“We were pleased to observe that EGFR T790M-positive and T790M-negative tumors responded,” said Janjigian. “This is important because there are third-generation EGFR inhibitors under development that can target EGFR T790M but it is not likely that these will benefit patients with EGFR T790M-negative disease.
“Another important point from our study is that it provides for the first time a clinical confirmation of a concept that has been controversial in the field: that a significant proportion of EGFR-mutant lung adenocarcinomas with acquired resistance to erlotinib and gefitinb are still dependent on EGFR signaling for their growth and survival,” Janjigian added.
Date: July 29, 2014