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SINGAPORE-A subanalysis of the phase III ALEX study has shown that alectinib 600 mg twice daily is more effective than standard-of-care crizotinib in Asian patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), researchers reported at the ESMO Asia 2017 Congress (Abstract 410O_PR).

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The J-ALEX study demonstrated that alectinib 300 mg twice daily improved progression-free survival compared to crizotinib in Japanese patients with ALK-positive NSCLC (Lancet 2017;390(10089):29-39). The ALEX study subsequently showed improvement in progression-free survival with alectinib 600 mg twice daily compared to crizotinib in a global population of ALK-positive NSCLC patients (N Engl J Med 2017;377:829-838).


This subanalysis of the ALEX study investigated the efficacy and safety of alectinib 600 mg twice daily compared to crizotinib in Asian versus non-Asian patients with ALK-positive NSCLC. As previously reported, the ALEX study included 303 patients who were randomized in a 1:1 ratio to receive alectinib or standard-of-care crizotinib. There were 69 Asian patients in each treatment group. The primary endpoint was progression-free survival.


A distinguishing feature of the study was that all patients underwent MRI of the brain every 6 months, regardless of whether or not they had brain metastases at the start of the study. The time to progression in the brain was measured and compared between the two treatment groups.


"Around 50 percent of NSCLC patients with ALK mutations will develop brain metastases, so it is very important to demonstrate the efficacy of alectinib in the brain," said lead author Tony S.K. Mok, MD, Chairman, Department of Clinical Oncology, The Chinese University of Hong Kong.


The subanalysis showed similar efficacy and safety with alectinib in Asian and non-Asian patients. Progression-free survival was longer with alectinib compared to crizotinib in Asian and non-Asian populations, with hazard ratios (HRs) of 0.46 and 0.49, respectively. Alectinib reduced central nervous system (CNS) progression compared to crizotinib in the Asian and non-Asian groups, with cause-specific HRs of 0.21 and 0.16, respectively. Median overall survival was not reached in either subgroup.


Response rates to alectinib and crizotinib were 81.2 percent versus 76.8 percent, respectively, for the Asian subgroup and 84.3 percent versus 74.4 percent, respectively, for the non-Asian subgroup.


The rates of nausea, vomiting, and grade III toxicities overall were lower with alectinib compared to crizotinib, and similar between the Asian and non-Asian subgroups. Liver toxicity due to alectinib was slightly higher in the Asian compared to the non-Asian subgroup.


"Alectinib 600 mg twice daily was similarly effective in Asian and non-Asian patients in the ALEX study in terms of progression-free survival, CNS progression, and response rate. The rates of toxicities were also comparable. The findings suggest that 600 mg should be the standard dose of alectinib across Asia," Mok said.


Expert Commentary

Commenting on the research, Pilar Garrido, MD, PhD, Head of the Thoracic Tumour Section, Medical Oncology Department, Ramon y Cajal University Hospital, Madrid, Spain, said: "ALK rearrangements emerged as important therapeutic targets in NSCLC in 2007, defining a distinct molecular subset of tumors. Around 5 percent of NSCLC patients harbor ALK mutations and are highly sensitive to ALK tyrosine kinase inhibitors, which efficiently induce apoptosis. Patients with advanced ALK-positive NSCLC have a high lifetime risk of CNS metastases and a high frequency of brain metastases at diagnosis, with the CNS being the most common site of disease progression.


"The first approved ALK inhibitor, crizotinib, significantly increased response rate and prolonged progression-free survival compared to first- and second-line chemotherapy. However, patients almost invariably relapse on crizotinib, commonly within 1 year," Garrido noted. "Alectinib is a highly selective and potent next-generation ALK inhibitor-with high CNS penetration-that has demonstrated significant anti-tumor activity against ALK-rearranged NSCLC in several trials.


"The phase III ALEX and J-ALEX trials showed the superiority of alectinib compared with crizotinib in progression-free survival and reducing the risk of progression in both non-CNS and CNS lesions. Alectinib also had a favorable adverse event profile compared to crizotinib in both studies although in the J-ALEX trial the dose of alectinib (300 mg twice daily) was lower than the approved dose in countries other than Japan."


This subgroup analysis presented at the ESMO Asia 2017 Congress confirms that alectinib can be safely used at the standard dose of 600 mg twice daily in the Asian population, said Garrido. "We now have an extremely efficacious drug to be added to our first-line armamentarium without differences in efficacy or safety based on ethnicity."


Regarding the need for further research, Garrido said: "Although next-generation ALK inhibitors are extremely potent, eventually all patients relapse. Our next step is to better identify the underlying mechanisms of resistance to provide the best sequence of available agents to our patients."