Regulatory Decision Summary for Xalkori

Pre-clinical studies have identified ROS1 rearrangements as a potential target in patients with NSCLC. Xalkori (crizotinib) demonstrated antitumor activity in mouse xenograft studies. The antitumor efficacy of crizotinib was dose dependent and demonstrated a correlation with inhibition of ROS1 phosphorylation in vivo. The clinical benefit of crizotinib in ROS1 rearranged NSCLC is based on study A8081001, a Phase 1/2 Safety, Pharmacokinetic and Pharmacodynamic Study. An investigator assessed Objective Response Rate (ORR) of 69.8% based on Response Evaluation Criteria In Solid Tumors (RECIST) criteria was observed in the 53 patients treated, including 5 complete responses. Responses were demonstrated in 6 of 7 treatment naïve patients (85.7%) and in 31 of 46 patients (67.4%) who had been previously treated for advanced disease. The investigator assessed median Duration of Response (DoR) was not reached but the lower end of the 95% confidence interval was 15.2 months. The ORR and DoR were confirmed by Independent Radiology Review (IRR) based on 50 patients and found to be 66% and 18.3 months, respectively.

The safety profile of crizotinib in patients with ROS1 rearranged NSCLC was similar to the profile previously characterized in the ALK mutation positive NSCLC population. The most common adverse reactions (≥25%) in patients with ROS1-positive NSCLC from Study A8081001 were vision disorder, nausea, edema, vomiting, diarrhea, constipation, dizziness, elevated transaminases, fatigue, neuropathy, bradycardia, and rash. The most common Grade 3 or 4 adverse reactions (>3%) were neutropenia, syncope, vomiting, elevated transaminases, and electrocardiogram QT prolongation. Dose interruptions to manage adverse events (AEs) were required by 25% of patients, primarily for neutropenia and vomiting. Eleven percent of patients required dose reductions to manage AEs, primarily for elevated transaminases. There were no deaths related to treatment.

The small sample size in Study A8081001 (i.e., n = 53) along with the lack of a comparator arm led to uncertainty related to the efficacy of crizotinib in the ROS1 positive NSCLC population. In addition, only 7 patients in Study A8081001 were receiving crizotinib as front line treatment (previously untreated patients). Despite those uncertainties, the magnitude of the ORR benefits in this rare patient population was substantial. Evidence in public literature with regard to the molecular biology suggesting the resemblance in clinical benefits of Xalkori in ROS1- and ALK-positive NSCLC patients and the recent USFDA and EMA approvals further mitigated the uncertainty.

The product monograph (PM) has been updated to reflect additional data from the final Overall Survival analysis of Study A8081007 in previously treated ALK-Positive Metastatic NSCLC and from a pharmacokinetic study in a paediatric population. The benefit-risk profile of Xalkori in the new indication is deemed to be favorable.