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FDA Grants Alectinib Breakthrough Designation for Frontline ALK+ NSCLC

The FDA has granted a breakthrough therapy designation to alectinib (Alecensa) as a frontline treatment for patients with ALK-positive non–small cell lung cancer.

Sandra Horning, MD

The FDA has granted a breakthrough therapy designation to alectinib (Alecensa) as a frontline treatment for patients with ALK-positive non—small cell lung cancer (NSCLC), according to Genentech, the manufacturer of the ALK inhibitor.

The designation, which is meant to expedite the development of promising new therapies, was based on findings from the phase III J-ALEX study, in which alectinib reduced the risk of disease progression or death by 66% compared with the current first-line standard, crizotinib (Xalkori), in patients with advanced or recurrent ALK-positive NSCLC.

“The J-ALEX study that supports the second breakthrough designation for Alecensa showed superior efficacy versus the standard of care, crizotinib, in Japanese people with advanced ALK-positive disease,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, said in a statement.

“The decision by the FDA to grant a second breakthrough therapy designation is recognition of the clinically meaningful improvement in efficacy and safety that Alecensa brings to the care of people with advanced ALK-positive lung cancer who have not received prior treatment with an ALK inhibitor,” Horning added.

The J-ALEX study, randomized 207 Japanese patients with ALK-positive advanced or recurrent NSCLC who had not previously received an ALK inhibitor to alectinib at 300 mg twice daily, or crizotinib at 250 mg twice daily. Patients continued treatment until disease progression or unacceptable toxicity.

Overall, baseline characteristics were similar between the treatment arms; however, a higher proportion of patients in the crizotinib arm had brain metastases by independent review compared with those randomized to alectinib (27.9% vs 13.6%, respectively).

Greater 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 median follow-up was approximately 1 year in each arm.

The median progression-free survival (PFS) was not reached (95% CI, 20.3—not estimated) in the alectinib cohort compared with 10.2 months (95% CI, 8.2-12) in the crizotinib arm (HR, 0.34; 99% CI, 0.17-0.70; P <.0001). In the subgroup of patients with brain metastases at baseline, the hazard ratio for PFS with alectinib versus crizotinib was 0.08 (95% CI, 0.01-0.61).

The investigator-assessed objective response rates (ORRs) were 85.4% in the alectinib group and 70.2% in the crizotinib arm. By the independent review, the ORR was 91.6% in alectinib cohort.

The most common all-grade adverse event (AE) in the alectinib group was constipation (36%), followed by nasopharyngitis (20.4%), dysgeusia (18.4%), nausea (10.7%), and AST increase (10.7%).

In the crizotinib group, the most common all-grade AEs were nausea (74%), diarrhea (73%), vomiting (59%), visual disturbance (55%), dysgeusia (52%), constipation (46%), ALT increase (32%), and AST increase (31%).

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 ALT level.

The rate of grade 3/4 AEs was higher in the crizotinib arm compared with the alectinib cohort, at 51% versus 26.2%, respectively. Discontinuations due to AEs also occurred more frequently in the crizotinib arm compared with the alectinib arm (20.2% vs 8.7%), as did dose interruptions due to AEs (74.0% vs 29.1%).

In 2013, alectinib received a breakthrough therapy designation from the FDA as a treatment for patients with ALK-positive NSCLC following progression on crizotinib. The FDA subsequently granted an accelerated approval to alectinib in December 2015 as a treatment for patients with metastatic ALK-positive NSCLC following progression on crizotinib. The ongoing phase III ALEX trial is comparing alectinib with crizotinib in the first-line setting for patients with advanced ALK-positive NSCLC.

“This study (ALEX) is part of the company’s commitment to convert the current accelerated approval in people with ALK-positive, metastatic NSCLC who have progressed on or are intolerant to crizotinib to a full approval as an initial treatment,” Genentech reported in a statement.

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.