U.S. Regulatory Actions and Marketing History
Lorlatinib is a new molecular entity (NME) and is not currently marketed in the U.S.
Summary of Presubmission/Submission Regulatory
ActivityFollowing the receipt of final written responses for a Type B pre-IND meeting on June 14, 2013, regarding the design of the first-in-patient trial of lorlatinib (PF-06463922) under IND 118296, the original IND was filed on August 15, 2013. A list outlining the pertinent regulatory history for lorlatinib is included in the table below.
Table 2: Regulatory history for lorlatinib
Date Description
June 14, 2013 Pre-IND/written response only (WRO) meeting to discuss the development program for lorlatinib and the proposed initial open-label, multicenter, multiple-dose study in advanced ALK or ROS1-positive NSCLC (Study B7461001)
September 13, 2013 New IND containing study B7461001 allowed to proceed
June 23, 2015 Orphan Drug Designation granted for the treatment of ALK or ROS1-positive NSCLC
December 18, 2015 Type B EOP1/pre-phase 3 meeting to discuss the clinical development program for lorlatinib, evidence that would support a request for breakthrough therapy designation (BTD) and advice on proposed revisions to Study B7461001 to support a request for the accelerated approval of lorlatinib
April 26, 2017 BTD granted for the development of lorlatinib for the treatment of ALK-positive NSCLC previously treated with one or more ALK inhibitors August 30, 2017 Type B pre-NDA meeting to discuss and reach agreement on the
content and format of an NDA for lorlatinib for the proposed indication of the treatment of patients with ALK-positive NSCLC previously treated with one or more ALK inhibitors
February 12, 2018 Priority review granted for NDA 210868 for lorlatinib
During the December 18, 2015 Type B EOP1/pre-phase 3 meeting, FDA agreed that the demonstration of an ORR that is clinically meaningful in magnitude and durability in
approximately 160 planned patients with ALK-positive NSCLC who have been treated with prior
crizotinib or other ALK inhibitor(s) with or without prior chemotherapy, enrolled in four cohorts in Study B7461001 could support the filing of a marketing application seeking accelerated approval for the indication of the treatment of patients with ALK-positive NSCLC with disease progression following crizotinib. The ability of such data to support accelerated approval would be contingent upon there being no available therapies for the indication at the time of the NDA submission or demonstration of significant improvement over any available therapies. FDA recommended that Pfizer consider providing data in populations not covered by drugs such as alectinib or ceritinib, such as patients who received more than one prior ALK inhibitor or
specific ALK mutations where lorlatinib may have superior efficacy. FDA agreed that a subset of 80 patients with two or more prior lines of therapy with an ALK inhibitor could represent the primary analysis population, supported by the results from 160 patients. FDA further stated that the analysis of ORR should be conducted in the intent-to-treat (ITT) population based on independent review committee (IRC) assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
FDA also agreed that pooled analyses of estimated intracranial ORR and DOR per RECIST v1.1, as determined by independent radiology assessment, in a subgroup of patients with CNS
metastases at baseline across cohorts 1-5 in Study B7461001 may support inclusion of CNS ORR results in product labeling. FDA also stated that the clinical significance of a “time to intracranial progression” endpoint cannot be interpreted in a single arm study and would not be included in product labeling.
During the August 30, 2017 pre-NDA meeting, FDA agreed that the study results from Study B7461001 proposed for inclusion in an NDA submitted under the provisions of 21 CFR 314 Subpart H (accelerated approval) may provide sufficient clinical evidence to characterize the benefit and risks of lorlatinib in patients with ALK-positive metastatic NSCLC previously treated with one or more ALK inhibitors. FDA stated that the safety population should include all 275 patients treated in the dose expansion portion of Study B7461001 and all 54 patients from the dose escalation portion of the study, and that separate safety analyses should be performed and provided for the 292 patients across both parts of Study B7461001 who received lorlatinib at the recommended phase 2 dose (RP2D) of 100 mg daily. FDA also stated that the proposed ITT population should include all patients in expansion cohorts 2-5 (patients with ALK-positive NSCLC previously treated with one or more ALK inhibitors) who received at least one dose of lorlatinib, including one patient enrolled in cohort EXP-3 for whom ALK positivity was not confirmed. Pfizer agreed to provide analyses of ORR and DOR in the following populations: all patients with documented ALK mutation enrolled in the dose expansion portion of the study, all patients with documented ALK mutation receiving lorlatinib 100 mg across the entire study, all patients enrolled in the dose expansion portion of the study purported to be ALK positive and who received prior treatment, and all patients receiving lorlatinib 100 mg across the entire study purported to be ALK positive and who received prior treatment. The results to be
presented in the product labeling will be determined during review of the application. Overall, agreement was reached regarding the contents of a complete application.
On October 25, 2017, Pfizer submitted a clarification to the Type B meeting minutes from the August 30, 2017 Type B pre-NDA meeting. Pfizer stated that a total of three Japanese patients were enrolled in the Japanese lead-in cohort (LIC), which was not part of the dose escalation or dose expansion portions of the study but was described in the protocol for Study B7461001.
Pfizer believed that since these patients received lorlatinib 100 mg daily, they should be included in the pooled analyses of safety and efficacy; specifically, the Pfizer proposed that all three patients be included in the pooled analyses of safety and two patients who had ALK-positive NSCLC be included in the pooled analyses of efficacy. The addition of these patients would bring the total numbers of patients to 295 and 215, respectively, for the pooled analyses of safety and efficacy in patients receiving lorlatinib 100 mg daily. FDA responded with their acknowledgment that the Japanese LIC patients were included in the analyses.