Next-Generation EGFR Inhibitors in NSCLC

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Frontline treatment with EGFR and ALK targeted therapies has revolutionized the care of select patients with non-small cell lung cancer (NSCLC). In general, actionable mutations are apparent in approximately 25% of patients with non-squamous histology; however, despite this promising treatment approach, resistance is inevitable, notes Corey J. Langer, MD.

Next-generation targeted therapies are being developed to counter acquired resistance. In the case of EGFR inhibitors, these therapies primarily include rociletinib (CO-1686) and AZD9291, notes Langer. In early phase clinical trials, AZD9291 demonstrated an ORR of 64% and rociletinib had an ORR of 58% in patients with NSCLC who received prior treatment with frontline EGFR inhibitors. Based on this early promise, both therapies have received the FDA's breakthrough therapy designation.

The most common resistance mechanism in patients with EGFR-mutant NSCLC is an acquired mutation in T790M, which occurs in approximately 50-60% of patients, notes D. Ross Camidge, MD, PhD. These mutations alter the binding kinetics for traditional frontline EGFR inhibitors, preventing them from eliciting responses.

The assays and biopsy procedures used for the detection of the T790M mutation continue to be explored, in order to ascertain true positives and negatives, Camidge notes. Noninvasive techniques that utilize circulating DNA are being investigated as a possible approach for T790M detection.

Many of the side effects associated with wild-type EGFR inhibition are not apparent with the third-generation EGFR inhibitors, due to the highly selective nature of these agents, notes Camidge. The skin rash and gastrointestinal side effects that are common with traditional EGFR inhibitors were not present with the new agents. However, novel side effects, such as hyperglycemia, have been seen in clinical trials. The exact mechanism for these adverse events is unclear, notes Camidge.

Each company has a unique strategy for approaching FDA approval, with the rociletinib’s plan appearing to be the most aggressive, believes Camidge. This development program, labeled TIGER, is exploring the drug as a second-line treatment in patients with EGFR T790M mutations and as a frontline therapy in comparison to erlotinib.