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Alectinib highly active in advanced ALK-positive NSCLC
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Alectinib showed promising activity in patients with advanced, crizotinib-refractory, ALK-positive non–small cell lung cancer, according to results of a global phase 2 study.
The regimen also appeared well tolerated.
In December, the FDA granted accelerated approval to alectinib (Alecensa, Genentech) — an oral, small molecule, ATP-competitive tyrosine kinase inhibitor of ALK — for treatment of patients with metastatic ALK-positive NSCLC who progressed on or are intolerant to crizotinib (Xalkori, Pfizer).
This approval was based on results of this study by Sai-Hong Ignatius Ou, MD, PhD, clinical professor of health science in the school of medicine at University of California Irvine, and colleagues.
Sai-Hong Ignatius Ou
“The development of resistance to crizotinib is a major barrier to the successful long-term treatment of patients with ALK-rearranged NSCLC,” Ou and colleagues wrote. “Progression with crizotinib can be due to acquired resistance mutations in ALK, activation of other signaling bypass pathways, and, in approximately half the patients treated with crizotinib, development and/or progression of brain metastases. Therefore, novel ALK inhibitors should not only be more potent than crizotinib and able to inhibit the clinically relevant acquired resistance mutations in ALK but also confer sustained clinical activity in the central nervous system.”
Ou and colleagues enrolled 138 patients between June 2013 and April 2014. All patients received 600 mg alectinib twice daily.
Objective response rate (ORR) served as the primary endpoint. Secondary endpoints included PFS, OS, and alectinib’s effects on the central nervous system.
Overall, 61% of the patients had central nervous system metastases at baseline. Among 122 evaluable patients, the ORR was 50% (95% CI, 41-59) and the median duration of response was 11.2 months (95% CI, 9.6-not yet reached).
Median PFS was 8.9 months (95% CI, 5.6-11.3), and the control rate of central nervous system disease was 83% (95% CI, 74-91). The median duration of response for the central nervous system was 10.3 months (95% CI, 7.6-11.2), and the ORR for the 35 patients who had measureable lesions in the central nervous system at baseline was 57% (95% CI, 39-74).
Twenty-three patients had baseline central nervous system metastases without prior radiation. In that subgroup, 43% had a complete central nervous system response. The cumulative 12-month central nervous system progression rate was 24.8%, which was lower than the cumulative progression rate for non-central nervous system progression (33.2%).
The most common adverse events were constipation (33%), fatigue (26%) and peripheral edema (25%), and most of these toxicities were either grade1 or grade 2.
“The clinically meaningful ORR and duration of response in [these] patients … and the sustained central nervous system response reported in this study, as well as the good tolerability profile, support the additional development of this promising new ALK inhibitor,” Ou and colleagues concluded. – by Anthony SanFilippo
Disclosure: Ou reports honoraria from, consultant/advisory roles with, speakers bureau roles with and research funding from Ariad, Astellas, AstraZeneca, Boehringer Ingelheim, Clovis, Daiichi Sankyo, Hoffmann-La Roche, Ignyta and Pfizer. Please see the full study for the other researchers’ relevant financial disclosures.
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