Consistent benefit with first-line alectinib over crizotinib in Asians with ALK+ NSCLC
Alectinib shows significantly improved efficacy in terms of progression-free survival (PFS) over crizotinib in the first-line setting, yet again, this time involving Asian patients with ALK+ NSCLC in the ALESIA* study, consistent with previous findings in a global population.
Previously, alectinib has demonstrated superior efficacy with lower toxicity over crizotinib both in the ALEX study enrolling a global population with treatment-naïve ALK+ NSCLC (HR for PFS, 0.43) as well as in the J-ALEX study involving a Japanese population (HR 0.34).
“ALESIA study results are consistent with the global ALEX study and confirm the clinical benefit of alectinib in Asian patients with advanced ALK+ NSCLC,” said Professor Zhou Caicun of Tongji University in Shanghai, China. “ALESIA further confirms alectinib as standard of care in first-line treatment for ALK+ NSCLC.”
Patients treated with alectinib had a significantly improved PFS compared with the crizotinib arm, both as assessed by investigator (median, not estimable [NE] vs 11.1 months, HR, 0.22; p<0.0001) and by an independent review committee (IRC; median, NE vs 10.7 months, HR, 0.37; p<0.0001). Furthermore, the benefit in PFS remained across subgroups defined by age, sex, and baseline CNS** metastases. [ESMO 2018, LBA10]
Although overall survival (OS) data were immature, preliminary analysis showed that the risk of death was reduced by 72 percent reduction in favour of alectinib (HR, 0.28; p=0.0027), with an event rate of 6.4 percent vs 21.0 percent.
Alectinib also led to a significantly better overall response rate (91.2 percent vs 77.4 percent; p=0.0095), with NE median duration of response compared with 9.3 months in the crizotinib arm (HR, 0.22; p<0.0001).
“ALESIA met its primary objective of showing consistency with the global ALEX study,” said Zhou.
The phase III, open-label, multicentre study randomized 187 Asian patients (from China, South Korea, and Thailand; mean age 51 years) with ALK+ stage IIIB/IV NSCLC who were treatment-naïve in a 2:1 ratio to receive alectinib 600 mg or crizotinib 250 mg, both twice daily.
Being a highly selective CNS-active ALK inhibitor, treatment with alectinib yielded more than threefold higher CNS objective response rate than crizotinib in patients with measurable or nonmeasurable baseline CNS lesions (72.7 percent vs 21.7 percent). The time to CNS progression also favoured alectinib, whereby only 7.3 percent experienced CNS progression compared with 35.5 percent in the crizotinib arm at 1 year (cause-specific HR, 0.14; p<0.0001).
Fewer patients in the alectinib arm had serious adverse events (AEs; 15.2 percent vs 25.8 percent) and grade 3–5 AEs (28.8 percent vs 48.8 percent).
“The safety results in an Asian patient population were generally consistent with the known safety profile of alectinib,” said Zhou, noting that crizotinib was associated with more GI and liver related toxicities such as constipation, diarrhoea, nausea, decreased appetite, elevated alanine aminotransferase levels, and hyponatraemia; while alectinib was associated with more frequent sinus bradycardia, elevated blood creatinine phosphokinase, alkaline phosphatase, and bilirubin levels when analysing AEs with ≥10 percent difference between arms.
“ALESIA study confirmed the dose of 600 mg bd in an Asian population; however, there is no definitive evidence that 300 mg bd is associated with lesser outcomes,” said invited discussant Professor Tony Mok of The Chinese University of Hong Kong, who pointed out that J-ALEX which used 300 mg alectinib in the Japanese population showed similar PFS benefit of 0.34 in terms of HR.
“While J-ALEX provided suggestive evidence, the ALEX and ALESIA confirmed the … optimal CNS efficacy of alectinib at 600 mg bd,” he added.