The second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) alectinib demonstrated promising efficacy with a durable response rate (objective response rate,: 93.5%; 95% CI, 82.1–98.6) and a favorable toxic profile in patients with ALK-rearranged advanced non-small cell lung cancer in a clinical phase II study. This reagent could also overcome acquired resistance to the first-generation ALK TKI crizotinib. Two randomized phase III studies comparing alectinib with crizotinib in treatment-naÃ¯ve ALK-positive advanced lung cancer are currently ongoing. However, even for this promising agent, as well as for other TKIs, acquired resistance is a major limitation of its efficacy. In order to overcome acquired resistance to alectinib, we investigated the mechanisms of resistance.
We established an alectinib-resistant cell line, ABC-11/CHR, by continuous exposure to alectinib, from our original cell line ABC-11 (EML4-ALK variant 3b E6; A20), which was derived from the pleural effusion of a treatment-naÃ¯ve patient. Using these cell lines, we determined the mechanisms of resistance to alectinib.
ABC-11/CHR was 40-fold more resistant to alectinib than the parental ABC-11. MET was activated in ABC-11/CHR as a result of autocrine hepatocyte growth factor (HGF) signaling. An anti-HGF antibody or a selective MET inhibitor SGX523 effectively inhibited growth when combined with alectinib. In addition, crizotinib, which targets both ALK and MET, inhibited the growth both in vitro and in vivo. Finally, in order to determine if our observations are clinically relevant, we investigated a pair of tissue specimens obtained from a patient pre- and post-alectinib. Immunostaining showed HGF overexpression in the post-alectinib specimen, but not in the pre-alectinib specimen.
We found that HGF autocrine caused acquired resistance to alectinib in the preclinical model and that crizotinib could overcome the resistance. Furthermore, HGF-induced acquired resistance was clinically relevant. Based on these observations, we have started a phase II clinical trial validating the efficacy of crizotinib in alectinib-refractory patients (UMIN registration number 000015984).
Clinical trial identification
N. Takigawa: Boehringer Ingelheim, Chugai Pharma, Pfizer, Sanofi, AstraZeneca, Taiho Pharmaceutical, Kyowa-Hakko Kirin Lilly Nipponkayaku Nihon Shinyaku Taisho Toyama. K. Hotta: Honoraria from Speakers Bureau 1, Taiho Pharmaceutical 2, Lilly 3, Daiichi-Sankyo 4, Pfizer 5, Nipponkayaku 6, Boehringer Ingelheim 7, Chugai Pharma 8, AstraZeneca 9, Sanofi 10, MSD. K. Kiura: Chugai Pharma Pfizer Novartis Pharma. All other authors have declared no conflicts of interest.