J-ALEX Results Point to Alectinib For First-Line ALK-Positive NSCLC Treatment

Alectinib offers longer progression-free survival than crizotinib for anaplastic lymphoma kinase (ALK) inhibitor-naive Japanese patients with non-small-cell lung cancer that tests positive for the gene rearrangement

medwireNews: Progression-free survival (PFS) findings for the J-ALEX trial favour the use of alectinib over crizotinib in Japanese patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) who have not previously received an ALK inhibitor.

Tomohide Tamura, from St Luke’s International Hospital in Tokyo, Japan, and co-investigators say their results “provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard first-line treatment of ALK-positive non-small-cell lung cancer.”

At data cutoff for the second interim analysis of the phase III trial, the independent data monitoring committee declared that the primary endpoint of PFS had been achieved, with a significant hazard ratio (HR) of 0.34 in favour of alectinib.

Median PFS was unmet in the 103 patients randomly assigned to receive alectinib 300 mg twice daily compared with a median of 10.2 months for the 104 patients given crizotinib 250 mg twice daily, the authors report in The Lancet.

Objective response, as assessed by an independent review, was more common in the alectinib-treated patients with at least one measurable lesion than their crizotinib-treated counterparts (92 vs 79%), with complete responses in 2% of patients in both groups, and partial responses in 89% and 77%, respectively.

Alectinib was also associated with a lower rate of grade 3 or 4 adverse events than crizotinib (26 vs 52%) and alectinib-treated patients were less likely to experience adverse events leading to dose interruption (29 vs 74%) or treatment discontinuation (9 vs 20%).

The investigators note that alectinib is recommended at the higher dose of 600 mg twice daily and admit that “whether or not this dose might be associated with a higher frequency of adverse events than the 300 mg twice-daily dose remains unclear.”

However, the ongoing ALEX study – comparing the two ALK inhibitors in a multinational treatment-naive population of patients with ALK-positive NSCLC – will assess the efficacy and safety of the larger dose, they say.

The authors of an accompanying comment observe that, in a change from other ALK inhibitor studies, patients were selected for J-ALEX based on an ALK-positive reverse-transcriptase polymerase chain reaction or dual positivity on immunohistochemistry and fluorescent in situ hybridization (FISH).

“Since nearly all patients (90% in the crizotinib group, 93% in the alectinib group) had double ALK positivity by immunohistochemistry and FISH, J-ALEX might have theoretically selected for a subgroup of patients (eg, high ALK fusion expression) who might have derived greater benefit from alectinib than crizotinib, by more potent ALK inhibition”, they suggest.

Justin Gainor and Alice Shaw, both from Massachusetts General Hospital in Boston, USA, add that while the “apparent degree of benefit in in J-ALEX is striking, it should be viewed with cautious optimism”, citing the higher proportion of patients in the alectinib group with baseline brain metastases that “almost certainly favoured the more [central nervous system]-penetrable agent, alectinib.”

Nevertheless, they say that multiple analyses to correct for this imbalance found a similar HR in favour of alectinib as seen in the primary analysis.


Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet; Advance online publication 10 May 2017. DOI: http://dx.doi.org/10.1016/S0140-6736(17)30565-2

Gainor JF, Shaw AT. J-ALEX: alectinib versus crizotinib in ALK-positive lung cancer. Lancet; Advance online publication 10 May 2017. DOI: http://dx.doi.org/10.1016/S0140-6736(17)31074-7

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