Next-Generation ALK Inhibitors in NSCLC

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More than 10 next-generation ALK inhibitors are currently being explored as treatments for patients with non-small cell lung cancer (NSCLC), Alice T. Shaw, MD, PhD, states. Many of these therapies have been designed to have extensive CNS activity and greater ALK-selectivity.

In April 2014, the next-generation ALK inhibitor ceritinib received an accelerated approval as a treatment for patients with ALK-positive NSCLC following progression on crizotinib. This approval was based on phase I data from the ASCEND-1 trial showing an overall response rate (ORR) of 58.5%. The early median duration of response was near 7.5 months, Shaw notes.

In order to move this therapy into the frontline setting, ceritinib would need to show a vast improvement over crizotinib, Shaw states. At this point, it is clear that ceritinib is effective following crizotinib; however, it remains unknown whether crizotinib has efficacy following ceritinib. As a result, ceritinib needs to show a median progression-free survival of 16 to 18 months in order to move into the frontline setting, Shaw believes.

The most common all-grade side effects in the ASCEND-1 trial were diarrhea (86%), hemoglobin decrease (84%), ALT increase (80%), nausea (80%), AST increase (75%), and vomiting (60%). A majority of these side effects are seen at the maximum tolerated dose of 750 mg but can diminish with dose reductions, Shaw notes. In clinical trials, responses were seen in patients treated with 300-mg ceritinib and higher, suggesting the dose can be lowered substantially if needed. In the phase I trial, nearly 80% of patients were dose reduced, Shaw states.

The ALK inhibitor AP26113 was one of the first next-generation therapies to enter development but suffered setbacks as the result of side effects. In early studies, 10% of patients experienced pulmonary symptoms at a 180 mg or higher daily dose. To address these concerns, a phase II study is currently comparing 180-mg and 90-mg AP26113.

In early studies, the ORR with AP26113 was 69% in crizotinib resistant patients. This included high response rates in patients with CNS metastases, notes D. Ross Camidge, MD, PhD. For these patients, the ORR was the same as the entire population, at 69%. This activity is promising, since the CNS is an area were crizotinib has shown less activity, Camidge suggests.