Aiming for Precision Medicine in NSCLC - Episode 7

Development of Rociletinib and AZD9291 in NSCLC

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First- and second-generation epidermal growth factor receptor (EGFR) agents target both mutant and wild-type receptors, accounting for the typical EGFR inhibitor toxicities of rash and diarrhea. Third-generation EGFR inhibitors are more specific for mutant EGFR than wild-type EGFR, says Mark A. Socinski, MD, and are associated with less skin and gastrointestinal toxicity.

The third-generation agents were developed with the intent to possess activity against the T790M mutation, the major secondary mutation for resistance. This mutation occurs in about 50% to 60% of patients with known EGFR mutations after exposure to first- and second-generation EGFR inhibitors, states Socinski.

Two third-generation agents currently in development are rociletinib and AZD9291. In T790M-positive tumors, response rates are over 50% with these investigational agents. Socinski notes that patients with T790M-negative disease also receive some benefit, and thus these 2 agents should not be ruled out as a treatment in that population. Rociletinib may cause hyperglycemia that is typically well manageable, and both agents may cause minor cardiac abnormalities.

Given the level of activity seen with these agents, they are being explored in earlier treatment settings. With growing options, Socinski suggests that the most effective sequencing of treatments will also need to be determined.