Efficacy of Next-Generation ALK Inhibitors

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The ALK translocation was identified as a potential target in non-small cell lung cancer (NSCLC) in 2007, with an effective treatment quickly gaining accelerated approval in 2011. The approval of crizotinib made a dramatic impact on the treatment of patients; however, it demonstrated some limitations, H. Jack West, MD, explains. To address this, next-generation ALK inhibitors have been developed to be more potent, not only in crizotinib-naive but also crizotinib-resistant patients, West notes.

The FDA approved the first next-generation ALK inhibitor, ceritinib, in April 2014 as a treatment for patients with ALK-positive NSCLC who progressed on crizotinib. In the phase I ASCEND-1 trial, 246 patients with ALK-positive NSCLC received treatment with ceritinib at 750 mg daily. Both crizotinib-naive and pretreated patients were enrolled in the trial.

For the total population, the ORR was 61.8% with a median progression-free survival of 9 months. The ORR was 72.3% in ALK inhibitor naive patients (n = 83) and 56.4% in pretreated patients (n = 163). At the approved 750-mg dose, the most frequent all grade adverse events were diarrhea (86.7%), nausea (82.7%) and vomiting (61.6%). However, in many situations, dose reductions can effectively manage these side effects, West points out.

Progression on crizotinib is commonly the result of brain metastases. One of the encouraging aspects of ceritinib and other ALK inhibitors is the level of activity observed in the CNS, West notes. In the ASCEND-1 trial, patients with brain metastases experienced similar results as the entire population following treatment with ceritinib.

Other agents, such as alectinib and AP26113 have also demonstrated promising CNS activity, West adds. With the many next-generation ALK inhibitors in development, it is likely that survival will be significantly prolonged for patients with ALK-positive NSCLC, West suggests.