Development of ALK Inhibitors in Advanced NSCLC

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The ALK inhibitor crizotinib initially gained accelerated approval from the FDA in August 2011 based on an improvement in objective response rates (ORR) for patients with ALK-positive non-small cell lung cancer (NSCLC). In November 2013, crizotinib was granted a full regulatory approval based on an improvement in PFS and ORR when compared with chemotherapy in a phase III study.

The approval of crizotinib was a game-changer in the treatment of NSCLC, notes Mark G. Kris, MD. Moreover, data has indicated that continuing crizotinib after disease progression may improve survival for patients with advanced ALK-positive NSCLC, notes Kris. This is particularly true in the case of oligoprogression, notes Corey J. Langer, MD. In addition to patients with ALK translocations, crizotinib also appears effective in patients with MET amplifications and ROS1 alterations.

At this point, the mechanism of resistance to ALK inhibition remains unclear, notes Kris. As a result, it is difficult to ascertain whether new ALK inhibitors are truly effective in patients who are resistant or if they are just more potent. The investigation of resistance in this setting is complicated, since the mechanism appears to be heterogeneous, notes Mark A. Socinski, MD.

The side effect profile for crizotinib has become familiar since the 2011 approval, particularly the management of GI toxicities. In most situations, these side effects can be ameliorated by dose reductions, notes Socinski. In studies comparing the two agents, it appears that the ALK inhibitor ceritinib (LDK378) may have more GI toxicity than crizotinib, suggests Langer.