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Combination Afatinib and Cetuximab Yields Benefit in Lung Cancer Patients Resistant to EGFR Inhibitors

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Key Points

  • A combination of afatinib and cetuximab yielded clinical responses in 29% of patients with EGFR-mutant lung cancer that had stopped responding to erlotinib and gefitinib.
  • The combination therapy benefited patients regardless of whether their cancer had acquired resistance to erlotinib or gefitinib due to a second-site EGFR T790M mutation.
  • The study provides clinical proof-of-concept for the preclinical hypothesis that a significant proportion of tumors in patients with acquired resistance to gefitinib/erlotinib remain dependent on EGFR signaling for survival.

A phase Ib study has found that a combination of the EGFR-targeted agents afatinib (Gilotrif) and cetuximab (Erbitux) yielded clinical responses in patients with EGFR-mutant lung cancer that had stopped responding to the EGFR inhibitors erlotinib (Tarceva) and gefitinib (Iressa). The combination benefited patients regardless of whether their cancer had acquired resistance to erlotinib or gefitinib due to a second-site EGFR T790M mutation. The study by Janjigian et al is published in Cancer Discovery.

Study Methodology and Results

Between March 2010 and April 2013, researchers enrolled 201 heavily pretreated patients with advanced EGFR-mutant lung cancer and acquired resistance to erlotinib/gefitinib from cancer centers in the Netherlands and the United States into a phase Ib study. Of these patients, 126 were treated with the maximum-tolerated dose of afatinib plus cetuximab (40 mg daily; 500 mg/m2 every 2 weeks). The patients provided post–acquired-resistance tumor samples for profiling EGFR mutations.

Of the 126 patients treated with the combination therapy, 37 (29%) had a confirmed objective response. Among the 37 patients who had a confirmed objective response, 22 had their tumors shrink by 50% or more. In addition, there was no significant difference in the objective response rate between patients harboring T790M-positive and T790M-negative tumors (32%, 95% confidence interval [CI] = 21.8–44.5 vs 25%, 95% CI = 13.8–38.3; P = .341). The overall median duration of the responses was 5.7 months.

Benefit Seen Regardless of EGFR T790M Mutation Status

One of the most common causes of resistance to erlotinib or gefitinib is that the tumors acquire the EGFR T790M mutation. In this study, the objective response rates were not statistically different for patients with EGFR T790M–positive and EGFR T790M–negative tumors (32% vs 25%, 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 [to the therapy],” said Yelena Y. Janjigian, MD, Assistant Attending Physician at Memorial Sloan Kettering Cancer Center in New York, in a statement. “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.”

She continued, “Another important point from this study is that it provides for the first time 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 gefitinib are still dependent on EGFR signaling for their growth and survival.” 

Dr. Janjigian is the corresponding author for the Cancer Discovery article.

The study was funded by Boehringer Ingelheim Pharmaceuticals and the Conquer Cancer Foundation of the American Society of Clinical Oncology. Dr. Janjigian has received or has pending grants from Boehringer Ingelheim Pharmaceuticals, Bayer, Genentech, and Eli Lily.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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