Overcoming EGFR Inhibitor Resistance in NSCLC

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Following progression on a frontline EGFR TKI as a treatment for non-small cell lung cancer (NSCLC), it is becoming a common practice to rebiopsy the tumor for potential resistance mechanisms, notes Roy S. Herbst, MD, PhD. Approximately 50% to 60% of tumors develop resistance to EGFR therapy through an acquired mutation in T790M. This resistance mechanism can occasionally exist at the start of treatment, which underlines the importance of moving newer agents that target T790M, like rociletinib and AZD9291, into the frontline setting for patients with EGFR-mutant NSCLC, Herbst suggests.

Rebiopsying the tumor at the time of progression is essential for understanding the cause of resistance to frontline therapy, notes Herbst. The third-generation EGFR inhibitors AZD9291 and rociletinib have demonstrated promising results in early phase clinical trials, with larger studies ongoing. For patients with confirmed T790M mutations, the overall response rate was 64% with AZD9291 and 58% with CO-1686. As a result of these early findings, both therapies received the FDA's breakthrough therapy designation. Furthermore, the third-generation TKIs are selective to T790M, resulting in less skin and gastrointestinal side effects, which are commonly associated with EGFR inhibitors, Herbst notes.

In addition to novel agents, clinical trials have demonstrated promise with the combination of cetuximab and afatinib for patients with EGFR-mutant NSCLC who developed resistance to frontline therapy. This combination seemed to overcome resistance, regardless of the mechanism, but was associated with toxicity. The SWOG 1403 trial is examining cetuximab plus afatinib versus afatinib alone as a frontline treatment for patients with newly diagnosed EGFR-mutant NSCLC.

Other combination strategies have shown promise in clinical trials, including erlotinib plus bevacizumab, notes Thomas E. Stinchcombe, MD. In a phase II trial of 150 patients with NSCLC who harbored confirmed exon 19 or exon 21 mutations, the combination of erlotinib and bevacizumab resulted in a significant improvement in progression-free survival (PFS) compared with erlotinib alone. In the study, the median PFS was 16 months with the combination versus 9.7 months in the erlotinib monotherapy arm.

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