Yelena Y. Janjigian, MD
Results of an early-phase study have shown the combination of afatinib (Gilotrif) and cetuximab (Erbitux) has utility in EGFR-mutant lung cancer patients who have developed resistance to gefitinib (Iressa) and erlotinib (Tarceva), with the afatinib–cetuximab regimen eliciting a 29% response in patients receiving the combination.
“Treatment with erlotinib and gefitinib leads to dramatic tumor regression and has improved survival for patients with EGFR-mutant lung adenocarcinoma,” noted Yelena Y. Janjigian, MD, assistant attending physician at Memorial Sloan Kettering Cancer Center and assistant professor of medicine at Weill Cornell Medical College, in a statement. “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.”
The phase Ib trial enrolled patients across six centers in the Netherlands and the United States. All participants had received prior erlotinib or gefitinib for a median of 1 year (range, 1 month–7 years) before study entry. Of the 201 enrolled patients, 126 were treated with the maximum tolerated dose of oral afatinib (40 mg daily) plus intravenous cetuximab (500 mg/m2
every 2 weeks).
Thirty-seven patients (29%) treated with the maximum tolerated dose had a confirmed objective response (OR) with an overall median duration of confirmed OR of 5.7months (range, 1.8–24.4). Of those patients, 22 had their tumors shrink by 50% or more.
This level of tumor shrinkage is clinically significant because it results in regression of cancer-related symptoms and improvement in the patient’s quality of life, noted Janjigian.
“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 gefitinib as a result of a secondary mutation in EGFR called T790M.”
The status for EGFR-sensitizing mutations was known for all patients. Exon 19-deletion, found in 78 patients, was the most frequent EGFR mutation detected, followed by L858R-positive (n = 41). Of the 124 patients whose baseline T790M mutation status was known, 71 patients were T790M positive whereas 53 patients were T790M negative.
OR rates were not statistically different for patients with and without the EGFR T790M mutation in their tumors: 32% and 25%, respectively [(95% CI, 21.8–44.5) vs (95% CI, 13.8–38.3); P
= .341]). 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.”
Nearly all patients (99%) experienced treatment-related adverse events, the most common of which were rash (90%), diarrhea (71%), nail effects (57%), stomatitis (56%), fatigue (47%), and nausea (42%). The most common grade 3 events were rash (20%) and diarrhea (6%); grade 4 events (fatigue, pneumonitis, and lung infiltration) occurred in two patients. Overall, 13% of patients discontinued therapy due to treatment-related adverse events, and two patients died because of treatment-related adverse events (dyspnea and pneumonitis).
The authors of the study noted that to their knowledge, “this trial is the first study to demonstrate robust and durable clinical activity of a targeted treatment regimen in EGFR-mutant lung cancers with acquired resistance to erlotinib or gefitinib.”
This study also provided a clinical confirmation of a controversial topic in the field, Janjigian said.
“A significant proportion of EGFR-mutant lung adenocarcinomas with acquired resistance to erlotinib and gefitinib are still dependent on EGFR signaling for their growth and survival,” she said.
Cetuximab, a monoclonal antibody directed against EGFR with antineoplastic activity, is currently approved for the treatment of KRAS wild-type, EGFR-expressing metastatic colorectal cancer and recurrent or metastatic head and neck cancer.
Afatinib, a pan-HER inhibitor, is approved for the treatment of patients with metastatic non-small cell lung cancer who harbor EGFR mutations.
Findings of the study are published in the journal Cancer Discovery.