Frontline treatment with alectinib reduced the risk of progression or death by 66% compared with crizotinib for patients with advanced or recurrent ALK-positive non-small cell lung cancer.
Objective response rates (ORRs) as determined by investigators were 85.4% in the alectinib group and 70.2% in the crizotinib group. As assessed by independent review, ORR was 91.6% in the alectinib arm, which was consistent with the phase I/II data, and 78.9% in the crizotinib arm. The median progression-free survival had not yet been reached at the time of data analysis in the arm receiving alectinib.
“Based on these results, we believe that alectinib is the new standard first-line therapy for ALK-positive NSCLC,” said lead study author Hiroshi Nokihara, MD, PhD, of the National Cancer Center Hospital in Tokyo, Japan.
Alectinib, a potent ALK inhibitor with activity in the central nervous system (CNS), was granted accelerated approval by the FDA in December 2015 for the treatment of patients with ALK-positive NSCLC who have progressed on or are intolerant to crizotinib, which is the current standard frontline treatment for ALK-positive NSCLC.
PFS with crizotinib in this patient population is approximately 11 months, Nokihara said. “All patients eventually relapse on crizotinib, mainly due to secondary ALK mutations, ALK amplification, or CNS metastases,” he said.
A previous Japanese phase I/II study established the early efficacy of alectinib in ALK inhibitor-naïve patients, with a median PFS that surpassed 29 months.
In the phase III J-ALEX study, 207 Japanese patients with ALK-positive advanced or recurrent NSCLC who had not been previously treated with an ALK inhibitor were randomized to alectinib, 300 mg twice daily, or crizotinib, 250 mg twice daily. Treatment was continued until disease progression or unacceptable toxicity.
Baseline characteristics were well balanced between the groups, with the exception that a higher proportion of patients randomized to crizotinib had brain metastases by independent review compared with those randomized to alectinib (27.9% vs 13.6%, respectively).
More than 90% of the patients were positive for ALK by immunohistochemistry and fluorescence in situ hybridization while the status of the remaining participants was confirmed with reverse transcription polymerase chain reaction testing. About one-third of patients in each arm had received 1 line of chemotherapy before entry. The duration of follow-up was 12.0 months in the alectinib arm and 12.2 months in the crizotinib arm.
The primary endpoint, median PFS as assessed by independent review, was significantly improved with alectinib. Median PFS not reached in the alectinib arm, with a lower confidence interval of 20.3 months, compared with a median PFS of 10.2 months in the crizotinib arm (HR, 0.34; P <.0001). In the subgroup of patients with brain metastases at baseline, the hazard ratio for the primary endpoint with alectinib versus crizotinib was 0.08 (95% CI, 0.01-0.61).
Grade 3-4 adverse events (AEs) occurred with greater frequency in the crizotinib arm compared with the alectinib arm (51.9% vs 26.2%, respectively). Discontinuation of study drug due to AEs occurred more frequently in the crizotinib arm compared with the alectinib arm (20.2% vs 8.7%, respectively), as did dose interruption due to AEs (74.0% vs 29.1%, respectively).
Constipation was the most common all-grade AE in the alectinib group (35.0%), followed by nasopharyngitis (20.4%), dysgeusia (18.4%), nausea (10.7%), aspartate aminotransferase (AST) increase (10.7%). In the crizotinib group, the most common adverse events were nausea (74.0%), diarrhea (73.1%), vomiting (57.5&), visual disturbance (54.8%), dysgeusia (51.9%), constipation (44.2%), and elevations in alanine aminotransferase (31.7%), and AST (30.8%).
Eight patients in each arm withdrew from the study due to interstitial lung disease. In the crizotinib arm, 5 patients discontinued due to impaired hepatic function and 4 discontinued following an increase in alanine aminotransferase level.
“This is the first investigational study to show Alecensa helped people live longer without their disease getting worse compared to crizotinib,” said Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech/Roche, which is the company developing the medication. “We believe these efficacy and safety results represent a clinically meaningful advancement for people with ALK-positive lung cancer, and we plan to discuss these data with health authorities, including the FDA.”
At the conference, discussant Shirish M. Gadgeel, MD, gave a cautious “yes” in answering the question of whether alectinib should be the new standard frontline therapy in this setting. “This was not a purely frontline study in that some of the patients had received one prior line of chemotherapy,” said Gadgeel, a professor at the Karmanos Cancer Institute at Wayne State University, Detroit.
He added that the 0.34 hazard ratio and the superior toxicity profile with alectinib were compelling but “there’s clearly a note of caution in that these results are based on an interim analysis, though planned, and we still await the results of the global ALEX study, and certain that some, if not many, might have reluctance in considering such a switch at this point.”
Nokihara H, Hida T, Kondo M, et al. Alectinib (ALC) versus crizotinib (CRZ) in ALK inhibitor naïve ALK-positive non-small cell lung cancer (ALK+ NSCLC): Primary results from the J-ALEX study. Presented at: 2016 ASCO Annual Meeting; June 3-7, 2016; Chicago. Abstract 9008.