Second-Generation ALK Inhibitors in NSCLC

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Many patients with ALK-positive non-small cell lung cancer (NSCLC) develop resistance to crizotinib warranting the investigation of several second-generation agents. One of these agents, ceritinib (LDK378), demonstrated an overall response rate of nearly 60% in both crizotinib-resistant and -naive patients, notes Benjamin P. Levy, MD. Moreover, the progression-free survival (PFS) was nearly 9 months with low levels of serious adverse events. Based on these data, the FDA granted ceritinib a Breakthrough Therapy designation in March 2013.

AP26113 is another second-generation TKI in development for ALK-positive patients with NSCLC, notes moderator Corey J. Langer, MD. Following progression on crizotinib, patients saw an ORR of 56% with AP26113, Langer notes. Moreover, radiographic improvement in CNS abnormalities were observed in patients with pre-existing brain metastases.

Adding to the collection of positive data, the second-generation ALK inhibitor alectinib demonstrated over a 90% response rate in crizotinib-naive patients with NSCLC, states Heather A. Wakelee, MD. This impressive benefit resulted in a Breakthrough Therapy designation from the FDA in September, which coincided with the presentation of updated data at the ECCO/ESMO Annual Congress. Following progression on crizotinib, the ORR rate with alectinib was 60%, notes Wakelee.

In general, crizotinib is not the most potent ALK inhibitor, and was initially developed as a MET inhibitor, notes Mark A. Socinski, MD. The high-level of response seen with alectinib could be a result of more accurate ALK testing. In general, the FISH ALK assay is challenging for pathologists to interpret, with several intricacies that could give false positives, such as KRAS status, Socinski suggests.