Alectinib, an oral, small-molecule, ATP-competitive tyrosine kinase inhibitor of ALK, demonstrated good clinical activity in crizotinib-refractory patients with advanced non–small-cell lung cancer (NSCLC) harboring ALK rearrangements.
The overall response rate (ORR) for all 122 evaluable patients was 49%: 44% for the 96 patients who had received prior chemotherapy, and 69% for the 26 chemotherapy-naive patients. The median duration of response (DOR) for the 61 patients with a partial response was 11.2 months.
“The clinically meaningful ORR and DOR in patients with crizotinib-resistant disease and the sustained CNS response reported from this study, as well as the good tolerability profile, support the additional development of this promising new ALK inhibitor,” wrote Dr. Sai-Hong Ignatius Ou, clinical professor at the University of California, Irvine, and colleagues (J Clin Oncol. 2015 Nov. 23. doi:10.1200/JCO.2015.63.9443).
The observed clinical activity of alectinib in the CNS was consistent with preclinical data showing high CNS tissue penetration and earlier phase I/II results. Among 35 patients with baseline measurable CNS lesions, the ORR was 57%, including seven complete responses. CNS complete responses were observed in 10 of 23 patients (43%) who had no prior brain radiation.
The cumulative incidence rates of CNS progression were lower than were those of non-CNS progression, “which seems to suggest that alectinib can prevent or delay the emergence of CNS metastases,” the authors wrote. At 12 months, 33 patients had a CNS progression and 43 had a non-CNS progression.
Alectinib showed an acceptable safety profile. The most common adverse events were myalgia, fatigue, and gastrointestinal events, usually grade 1 or 2. Grade 3 or 4 adverse events occurred at a rate less than 5%. Most patients maintained therapeutic levels of alectinib throughout the study, indicated by a mean dose intensity of 97%.
The phase II study evaluated 122 patients who had locally advanced or metastatic NSCLC harboring an ALK rearrangement and who had progressed on crizotinib treatment.
Multiple oral doses at 600 mg twice daily produced an overall flat PK profile, supporting sustained alectinib exposure throughout the dosing interval. In contrast to results from the U.S. phase I/II study that reported differences in alectinib exposures between white and Asian patients, this study showed no marked differences between white (n = 6) and Asian (n = 20) patients evaluated.
F. Hoffmann-La Roche supported the study. Dr. Ou disclosed ties with Pfizer, F. Hoffmann-La Roche, Boehringer Ingelheim, ARIAD, AstraZeneca, Clovis Oncology, Astellas Pharma, Ignyta, and Daichi Sankyo. Several of his coauthors reported ties to industry.