Alectinib delays disease progression for a significant 15 months longer than crizotinib in the first-line treatment of advanced ALK-positive NSCLC
The primary results of the phase III ALEX study demonstrate that the 2nd generation ALK inhibitor alectinib significantly prolongs the progression-free survival (PFS) compared to crizotinib in the first-line treatment of advanced NSCLC patients harboring an ALK rearrangement. With alectinib, patients remained free of progression for a median of 25.7 months, which was 15 months longer than the 10.4 months observed with crizotinib (p< 0.0001). In addition to this, alectinib also significantly delayed the time to progression in the central nervous system (CNS). At 12 months, 41.4% of the crizotinib patients had CNS progression as compared to 9.4% with alectinib (p< 0.0001). As such, these findings convincingly point to a more effective initial treatment for patients with ALK-positive NSCLC.
About 5% of all NSCLCs harbor a genetic rearrangement where the ALK gene is fused with another gene. Crizotinib, the first medicine to specifically target ALK, was approved by the FDA in 2011. Although the majority of patients initially benefit from crizotinib, the cancer typically starts growing again within a year. Alectinib is a more potent, next-generation inhibitor of ALK. It was initially approved in 2015 for use in patients with advanced NSCLC failing first-line crizotinib. Earlier this year, the J-ALEX trial showed superiority of alectinib over crizotinib in Japanese patients with crizotinib-naïve ALK-positive NSCLC (HR for PFS: HR: 0.34; p< 0.0001).
In the open label, phase III ALEX trial, researchers randomly assigned 303 patients with stage IIIB or IV, ALK-positive NSCLC to receive alectinib (600mg BID) or crizotinib (250mg BID). The patients had not received prior systemic therapy for advanced NSCLC and needed to have an ECOG score of 0-2.
At the primary data cut-off (9 Feb 2017), alectinib demonstrated statistically significant superiority over crizotinib with a reduction in the risk of progression, or death of 53%. The investigator assessed median PFS was not yet reached with alectinib and was reported to be 11.1 months with crizotinib (HR[95%CI]: 0.47[0.34–0.65], p<0.0001). The median PFS assessed by independent review reached 25.7 months with alectinib, which was 15 months longer than the 10.4 months reported for crizotinib (HR[95%CI]: 0.50[0.36–0.70]; p<0.0001). Both treatments cross the blood-brain barrier, but alectinib was significantly more effective in preventing CNS progression than crizotinib. At 12 months, the incidence of brain metastases was much lower with alectinib than with crizotinib at 9% and 41%, respectively (HR[95%CI]: 0.16[0.10–0.28]; p< 0.0001). Also the objective response rate was higher with alectinib at 83% as compared to76% with crizotinib (p= 0.09).
Overall, severe side effects were less common with alectinib than with crizotinib, occurring in 41% vs. 50% of patients, respectively. Fatal adverse events occurred in 3% of patients treated with alectinib and in 5% receiving crizotinib. Rates of AEs leading to discontinuation, dose reduction and interruption were also lower with alectinib than with crizotinib (see key slides on this site for details). The most common side effects of alectinib were fatigue, constipation, muscle aches, and swelling, whereas crizotinib caused gastrointestinal problems and liver enzyme abnormalities.
In summary, this is the first global study to compare alectinib with crizotinib in ALK-positive lung cancer and should establish alectinib as the new standard of care for first-line treatment in this setting. This study met its primary endpoint showing significantly longer PFS with alectinib compared with crizotinib. Alectinib was also beneficial in controlling and preventing brain metastases. The researchers will continue to follow patients on this study to see if alectinib also invokes an OS over crizotinib. Meanwhile, several ongoing clinical trials are comparing other next-generation ALK inhibitors to crizotinib in the first-line setting.
Shaw A, Peters S, Mok T, et al. Alectinib versus crizotinib in treatment-naive advanced ALK-positive non-small cell lung cancer (NSCLC): Primary results of the global phase III ALEX study. Presented at ASCO 2017, Abstract LBA9008.