Alectinib promise for crizotinib-resistant NSCLC

By Lucy Piper, Senior medwireNews Reporter

Alectinib has shown promising antitumour activity in patients with ALK-rearranged non-small-cell lung cancer (NSCLC) that is resistant to crizotinib, researchers report.

“[A]lmost all patients with ALK-rearranged NSCLC invariably progress, with the CNS [central nervous system] being a common site of relapse”, note researcher Sai-Hong Ou (University of California Irvine School of Medicine, Orange, USA) and team.

Progression in the CNS and resistance to crizotinib mean that “we urgently need novel ALK inhibitors that can overcome acquired ALK resistance, can cross the blood–brain barrier, and are well tolerated”, the researchers add.

In the current dose-finding part of the AF-002JG study, 47 patients with ALK-rearranged NSCLC began oral alectinib twice a day a median of 18 days after discontinuing crizotinib. The dose varied from 300 to 900 mg.

Dose-limiting side effects of grade 3 headache and grade 3 neutropenia were reported by one patient each given a twice-daily dose of 900 mg, and 26% of the patients needed dose reduction or interrupted treatment due to side effects, the researchers say.

Nevertheless, grade 3 or 4 adverse events were rare, most commonly elevated gamma-glutamyl transpeptidase (4%), neutrophil decrease (4%) and hypophosphatemia (4%). Four other serious grade 4 events were reported in three patients but judged as unrelated to alectinib (acute renal failure, pleural and pericardial effusion and brain metastases).

At data cutoff after a median of 126 days, 55% of the 44 patients assessed for treatment activity were found to have had an objective response to alectinib including a confirmed complete response in one (2%) patient given a 900 mg dose. In addition, 32% of patients had a confirmed partial response to treatment, 20% had an unconfirmed partial response, 36% had stable disease and 9% experienced progression.

Twenty-one patients had progressive CNS metastasis on entering the trial and cerebral spinal fluid samples taken from five patients showed alectinib had crossed into the CNS compartment.

After a median follow-up of 187 days, 52% of the patients with CNS metastases had an objective response to alectinib including a complete response in 29% and a partial response in 24%. Disease had stabilised in 38% of patients and progressed in 10%.

“Alectinib was well tolerated, with promising antitumour activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases”, the authors write in The Lancet Oncology.

The results indicate that phase II of the trial should use an alectinib dose of 600 mg twice daily, they conclude.

In an accompanying comment, Karen Reckamp (City of Hope Comprehensive Cancer Center, Duarte, California, USA) says: “These early results indicate some CNS activity from second-generation ALK inhibitors, but the number of patients with untreated brain metastases and measurable disease are small.”

She concludes that trial design must take into account ALK inhibitor efficacy against CNS metastases as well as overall activity and the impact of side effects on patient quality of life.

“Ultimately, patients and clinicians will ascertain the value of these types of drugs as researchers establish the best timing, sequence, and possible combinations”, she adds.

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