The highly selective CNS-active ALK inhibitor, alectinib, demonstrated superior efficacy compared to crizotinib when administered first-line in Asian patients with advanced ALK-positive non-small cell lung cancer (NSCLC), according to findings from the phase III ALESIA trial presented at the ESMO 2018 Congress in Munich, Germany.
Caicun Zhou, Medical Oncology, Shanghai Pulmonary Hospital in Shanghai, China and colleagues conducted the phase III open-label ALESIA (NCT02838420) trial of alectinib compared to crizotinib in Asian patients. Enrolled patients had ALK-positive stage IIIB/IV NSCLC (by central immunohistochemstry testing), and ECOG performance status 0 to 2. Patients with asymptomatic CNS metastases were allowed. The patients were randomly assigned in a 2:1 ratio to receive alectinib at 600 mg daily (n=125) or crizotinib at 250 mg daily (n=62). Tumour and CNS imaging was performed at regular intervals.
The primary endpoint was progression-free survival (PFS) by investigator according to RECIST v1.1, and secondary endpoints included PFS by an independent review committee (IRC), time to CNS progression, objective response rate (ORR), duration of response (DoR), overall survival (OS), CNS ORR, quality of life (QoL), and safety.
The primary objective was to demonstrate that PFS in Asian patients was consistent with that reported in the global ALEX trial, wherein median PFS was 34.8 months with alectinib compared to 10.9 months with critzotinib (hazard ratio [HR] 0.43; 95% confidence interval [CI], 0.32 – 0.58).
Alectinib significantly reduced the risk of disease progression over crizotinib
After a median follow-up of 16.2 months for alectinib and 15.0 months for crizotinib, the risk of progression or death was significantly reduced with alectinib compared to crizotinib, according to investigator assessed median PFS of not estimable (NE) versus 11.1 months, HR 0.22; 95% CI, 0.13 – 0.38 (p < 0.0001), respectively.
The secondary endpoints were met and supported the primary endpoint.
Median PFS by IRC was NE with alectinib versus 10.7 months with crizotinib, HR 0.37; 95% CI, 0.22 – 0.61 (p < 0.0001).
In the respective treament arms, investigator assessed ORR was 91.2% versus 77.4% (p = 0.0095), and median DoR was NE versus 9.3 months, HR 0.22; 95% CI, 0.12 – 0.40 (p < 0.0001).
Although OS data were immature, the event rates favoured alectinib; event rates were 6.4% with alectinib versus 21.0% with crizotinib. Median OS was NE in both groups, HR 0.28; 95% CI, 0.12 – 0.68 (p = 0.0027).
CNS activity demonstrated by alectinib
Evaluation of the data from patients with measurable or non-measurable CNS baseline lesions revealed that the CNS ORR (IRC) was 72.7% with alectinib versus 21.7% with crizotinib. Complete responses were achieved by 50.0% versus 13.0% of patients in the respective arms. The time to CNS progression according to IRC review favoured alectinib, cause-specific HR 0.14, 95% CI, 0.06 – 0.30 (p < 0.0001).
Although patients were on alectinib for a longer time they showed fewer grades 3 to 5 adverse events (AEs). Treatment duration was 14.7 versus 12.6 months with alectinib versus crizotinib, respectively. Grades 3 to 5 AEs occurred in 29% versus 48%, and serious AEs occurred in 15% versus 26% of patients on alectinib versus crizotinib, respectively. Seven percent of alectinib versus 10% of crizotinib patients discontinued treatment due to an AE.
Tony Mok, Li Shu Fan Medical Foundation Professor of Clinical Oncology at the Department of Clinical Oncology in The Chinese University of Hong Kong who discussed the study findings said that there are differences in study design in three studies ALEX, J-ALEX and ALESIA in terms of dose, population and stratification, but there are similar primary efficacy outcomes that confirm the significant improvement in PFS. While J-ALEX provided suggestive evidence, the ALEX and ALESIA confirmed the CNS efficacy of alectinib. 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. In terms of CNS efficacy, both ALESIA and ALEX confirmed the optimal CNS efficacy of alectinib at 600 mg bd.
The investigators concluded that the findings from the ALESIA study were consistent with the global ALEX study. This study confirms the clinical benefit of alectinib in first-line treatment in Asian patients with advanced ALK-positive NSCLC.
This trial was sponsored by F. Hoffmann-La Roche Ltd.
LBA10 - Zhou C, Lu Y, Kim S-W, et al. Primary results of ALESIA: A randomised, phase III, open-label study of alectinib vs crizotinib in Asian patients with treatment-naïve ALK+ advanced NSCLC.