Types of EGFR Therapy in NSCLC

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Each generation of EGFR inhibitor has unique attributes and potency, which defines these classifications, notes Heather A. Wakelee, MD. The first-generation EGFR TKIs target wild-type polymorphisms as well as sensitive mutants but not T790M, an acquired resistance mutation. These agents include erlotinib and gefitinib. The second-generation agents, such as afatinib, have some activity against T790M, but are more potent against standard sensitizing mutations. The third-generation agents have increased sensitivity to T790M and standard EGFR mutations, but not wild-type targets.

At this time, the FDA has not yet approved a third-generation agent, notes Wakelee. The experimental agents AZD9291 and rociletinib have shown significant activity in patients with non-small cell lung cancer (NSCLC) with T790M resistance mutations. Based on evidence from early phase clinical trials, both third-generation agents have received breakthrough therapy designations from the FDA.

For both agents, the overall response rates in patients with NSCLC who harbor an EGFR T790M mutation ranges from 50% to 60%, and with T790M-negative tumors, from 20% to 30%. Anne S. Tsao, MD, notes that because these third-generation inhibitors are more targeted, there is less toxicity, including the diarrhea and rash that is common with the earlier-generation TKIs.