On December 11, 2015, the U. S. Food and Drug Administration granted accelerated approval to alectinib (ALECENSA capsules, Hoffmann-La Roche Inc.) for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.
The approval was based on two multicenter, single arm, open-label clinical trials in patients with metastatic ALK rearrangement-positive NSCLC who had progressed on or were intolerant to the ALK inhibitor crizotinib (Study 1 and 2) and the majority also received previous systemic chemotherapy. All patients received alectinib 600 mg twice daily. The major efficacy outcome measure was objective response rate (ORR) according to RECIST v1.1 as evaluated by an independent review committee (IRC) and by Investigator. Additional outcome measures included duration of response (DOR), central nervous system (CNS) ORR according to RECIST v1.1 in patients with baseline measurable lesions in the CNS, and CNS DOR.
Study 1 (n=87) showed an ORR of 38% (95% CI: 28%, 49%) by IRC and 46% (95% CI: 35%, 57%) by Investigator. In Study 2 (n=138) the ORR was 44% (95% CI: 36%, 53%) by IRC and 48% (95% CI: 39%, 57%) by Investigator. The median DOR was 7.5 months in Study 1 and 11.2 months in Study 2 after a median duration of follow-up of 4.8 months and 10.9 months, respectively. In a pooled analysis of patients from Study 1 and Study 2 with baseline measurable lesions in the CNS, the CNS ORR was 61% (95% CI: 46%, 74%) and the median CNS DOR was 9.1 months.
Safety data was evaluated in 253 patients who received alectinib at a dose of 600 mg twice daily. The most common adverse reactions were fatigue, constipation, edema, and myalgia. The majority of these adverse reactions were grade 1-2. The most common grade 3-4 adverse reaction was dyspnea. The most common laboratory abnormalities were anemia, elevations in aspartate aminotransferase (AST), elevations in alkaline phosphatase, and elevations in creatine phosphokinase (CPK). The majority of the above laboratory abnormalities were grade 1-2. The most common grade 3-4 laboratory abnormalities were elevations in alanine aminotransferase (ALT), lymphopenia, and elevations in CPK.
Serious adverse events (SAEs) were reported in 19% of patients. The most common SAEs (reported in 3 patients each) included dyspnea, pulmonary embolism, and elevations in bilirubin. The most frequent adverse reactions leading to dose reductions or interruptions were elevations in bilirubin, CPK, ALT, AST, and vomiting. The most common adverse events leading to discontinuation included ALT elevations (1.6%), and bilirubin elevations (1.6%). Fatal adverse events occurred in 2.8% of patients, including 1 case each of hemorrhage and intestinal perforation attributed to alectinib.
The recommended dose and schedule for alectinib is 600 mg orally with food twice daily.
This application was approved before the Prescription Drug User Fee Act (PDUFA) goal date of March 4, 2016. Alectinib received Breakthrough Therapy Designation, and the current indication was approved under FDA’s accelerated approval program. The application was granted Priority Review. A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.
Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208434s000lbl.pdf.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).