ALK Inhibition in NSCLC

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Various forms of ALK rearrangements exist in patients with non-small cell lung cancer (NSCLC), with at least seven ALK gene rearrangement variants involving different EML4-ALK breakpoints. ALK translocations may involve different partners, rather than one set mutation, notes Heather A. Wakelee, MD.

In patients with ALK-rearranged NSCLC, crizotinib resulted in higher objective response rates (ORR) and longer progression-free survival (PFS) compared with doublet chemotherapy, notes Thomas E. Stinchcombe, MD. The Median PFS was 10.9 versus 7.0 months (P <.001) and the ORR was 74% compared with 45% (P <.001), for crizotinib and chemotherapy, respectively.

Ceritinib is another ALK-specific therapy, which is approved for patients following progression or intolerance on crizotinib. This therapy is effective in patients, regardless of whether they have received frontline crizotinib or not, explains Wakelee.

In the phase I ASCEND-1 study, ceritinib demonstrated an ORR of 72.3% and a median PFS of 18.4 months in ALK-inhibitor naïve patients with NSCLC. In ALK inhibitor treated patients, the ORR was 56.4% and the median PFS was 6.9 months.

Ceritinib appears to target certain ALK alterations that crizotinib does not, allowing it to be effective following the development of resistance to crizotinib. The key question facing researchers now is an optimal sequence for these agents. In clinical studies, ceritinib appears to have activity in patients with brain metastases, suggesting ceritinib may be a better choice for these patients than crizotinib, notes Anne Tsao, MD.

In addition to the approved ALK inhibitors, several other next-generation agents are under exploration, explains Wakelee. The two leading agents in development are alectinib and brigatinib (AP26113). These treatments have demonstrated promising response rates in patients with ALK-rearranged NSCLC, including those with brain metastases.