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November 2, 2018

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf

On November 2, 2018, the Food and Drug Administration granted accelerated approval to lorlatinib (LORBRENA, Pfizer, Inc.) for patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on crizotinib and at least one other ALK inhibitor for metastatic disease or whose disease has progressed on alectinib or ceritinib as the first ALK inhibitor therapy for metastatic disease.

Approval was based on a subgroup of 215 patients with ALK-positive metastatic NSCLC, previously treated with one or more ALK kinase inhibitors, enrolled in a non‑randomized, dose-ranging and activity-estimating, multi‑cohort, multicenter study (Study B7461001; NCT01970865). The major efficacy measures were overall response rate (ORR) and intracranial ORR, according to RECIST 1.1, as assessed by an independent central review committee.

The ORR was 48% (95% CI: 42, 55), with 4% complete and 44% partial responses. The estimated median response duration was 12.5 months (95% CI: 8.4, 23.7). The intracranial ORR in 89 patients with measurable lesions in the CNS according to RECIST 1.1 was 60% (95% CI: 49, 70) with 21% complete and 38% partial responses. The estimated median response duration was 19.5 months (95% CI: 12.4, not reached).

Most common adverse reactions (incidence ≥20%) in patients receiving lorlatinib were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea. The most common laboratory abnormalities were hypercholesterolemia and hypertriglyceridemia.

The FL indication is based on a single-arm multicenter trial of duvelisib (NCT02204982) enrolling 83 patients with FL who were refractory to rituximab and to either chemotherapy or radioimmunotherapy. The ORR, determined by an IRC, was 42% (95% CI: 31, 54), with 41% of patients experiencing partial responses and one patient having a complete response. Of the 35 responding patients,15 (43%) maintained responses for at least 6 months and 6 (17%) maintained responses for at least 12 months. Continued approval for the FL indication may be contingent upon verification of clinical benefit demonstrated in a planned randomized trial.

The recommended lorlatinib dose is 100 mg orally once daily.

View full prescribing information for LORBRENA.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. FDA granted this application priority review and granted breakthrough therapy designation for this development program. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

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).

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