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The FDA granted Alecensa a breakthrough therapy designation to be used in the frontline setting for some patients with non small-cell lung cancer.
Alecensa (alectinib) was granted a breakthrough therapy designation by the U.S. Food and Drug Administration (FDA) 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 3 J-ALEX study, in which Alecensa reduced the risk of disease progression or death by 66 percent compared with the current first-line standard, Xalkori (crizotinib), 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, M.D., 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 Alecensa at 300 mg twice daily, or Xalkori 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 Xalkori arm had brain metastases by independent review compared with those randomized to Alecensa (27.9 percent vs 13.6 percent, respectively).
Greater than 90 percent 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 one line of chemotherapy before entry. The median follow-up was approximately one year in each arm.
The median progression-free survival (PFS) was not reached in the Alecensa cohort compared with 10.2 months in the Xalkori arm. In the subgroup of patients with brain metastases at baseline, the hazard ratio for PFS with Alecensa versus Xalkori was 0.08.
The investigator-assessed objective response rates (ORRs) were 85.4 percent in the Alecensa group and 70.2 percent in the Xalkori arm. By the independent review, the ORR was 91.6 percent in Alecensa cohort.
The most common all-grade adverse event (AE) in the Alecensa group was constipation (36 percent), followed by nasopharyngitis (20.4 percent), dysgeusia (18.4 percent), nausea (10.7 percent) and AST increase (10.7 percent).
In the Xalkori group, the most common all-grade AEs were nausea (74 percent), diarrhea (73 percent), vomiting (59 percent), visual disturbance (55 percent), dysgeusia (52 percent), constipation (46 percent), ALT increase (32 percent) and AST increase (31 percent).
Eight patients in each arm withdrew from the study due to interstitial lung disease. In the Xalkori arm, five patients discontinued due to impaired hepatic function and four discontinued following an increase in ALT level.
The rate of grade 3/4 AEs was higher in the Xalkori arm compared with the Alecensa cohort, at 51 percent versus 26.2 percent, respectively. Discontinuations due to AEs also occurred more frequently in the Xalkori arm compared with the Alecensa arm (20.2 percent vs 8.7 percent), as did dose interruptions due to AEs (74.0 percent vs 29.1 percent).
In 2013, Alecensa received a breakthrough therapy designation from the FDA as a treatment for patients with ALK-positive NSCLC following progression on Xalkori. The FDA subsequently granted an accelerated approval to Alecensa in December 2015 as a treatment for patients with metastatic ALK-positive NSCLC following progression on Xalkori. The ongoing phase 3 ALEX trial is comparing Alecensa with Xalkori 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.