Regulatory Decision Summary for ALECENSARO

Anaplastic lymphoma kinase (ALK)-positive, locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) is a life-threatening, incurable disease. There are limited treatment options for patients who have progressed on or are intolerant to crizotinib therapy.

The efficacy and safety of Alecensaro were investigated in two Phase I/II, single arm, multicentre studies (NP28761 and NP28673) enrolling patients with ALK-positive, mostly metastatic NSCLC who have progressed on or were intolerant to prior crizotinib. Objective response rate (ORR), determined by an Independent Review Committee (IRC) was the primary efficacy endpoint in both studies. Both studies were ongoing at the time of submission.

The IRC-determined ORRs in the Response Evaluable Population were 47.8% and 50% with corresponding median duration of response (DOR) of 7.5 and 11.2 months in pivotal studies NP28761 and NP28673, respectively. Patients with stable metastases in the central nervous system (CNS) were enrolled in the studies and CNS ORR was a pre-specified efficacy endpoint. In pooled analyses, CNS ORR was 60.8% with a median CNS DOR of 9.1 months. The complete response rate of CNS lesions was 25%. This level of anti-tumor activity is considered clinically significant and promising evidence of clinical effectiveness. The uncertainties about Alecensaros efficacy included lack of robust evidence of survival or quality of life benefit and insufficient representation of patients with locally advanced disease (not amenable to curative therapy) or who discontinued crizotinib due to toxicities.

Serious Adverse Reactions (SARs) were reported in 19% of patients (dyspnoea and hyperbilirubinemia being the most common in 1.2% of patients each). Adverse events resulting in Alecensaro discontinuation occurred in 6% of patients (blood bilirubin increased being the most frequent in 1.6% of patients). Fatal adverse events occurred in 2.8% of patients, consisting of hemorrhage (0.8%, 2 patients) and 1 patient each of intestinal perforation, dyspnea, pulmonary embolism, endocarditis and death unspecified. The serious identified risks of Alecensaro included gastrointestinal perforation, bradycardia, hepatotoxicity, severe myalgia and blood creatine phosphokinase (CPK) elevation and interstitial lung disease.

Alecensaro has not been studied in pregnant women; however, non-clinical reproductive studies indicated a risk of fetal harm and loss. New significant adverse reactions (for example, complete atrioventricular block and eosinophilic pneumonia) were identified in the post-marketing safety database. Alecensaro has not been studied in patients with moderate or severe hepatic impairment or severe renal impairment. There is limited safety evidence of Alecensaro in patients with significant co-morbidities or unrecovered toxicities from previous therapies, as these patients were excluded according to pivotal study inclusion/exclusion criteria. These safety findings and uncertainties, as well as monitoring and management recommendations were adequately described in the final Product Monograph (PM). The safety profile of Alecensaro is considered acceptable for the proposed indication. A Risk Management Plan (RMP) containing pharmacovigilance measures was submitted by the sponsor, Roche, and considered acceptable by the Marketed Health Products Directorate (MHPD).

Alecensaro demonstrated clinically significant anti-tumor activity against crizotinib-treated, ALK-positive, locally advanced (not amenable to curative therapy) or metastatic NSCLC with an acceptable safety profile for the proposed indication; the potential clinical benefit of Alecensaro is considered to outweigh the associated risks.

Based on the available data, Alecensaro has the potential to provide a significant increase in efficacy and/or decrease in risk such that the overall benefit/risk profile is improved over existing therapies. A Notice of Compliance with Conditions Qualifying Notice (NOC/c QN) was issued to Roche earlier, outlining confirmatory studies and post market surveillance commitments, as well as other measures in accordance with the NOC/c Guidance. In the response to the NOC/c QN, Roche agreed to have the Alecensaro submission considered under the NOC/c Guidance. The Letter of Undertaking (LOU), Dear Health Care Professional Letter (DHCPL), Product Monograph (PM) including Part III: Patient Medication Information and Inner and Outer Labels were prepared per the NOC/c Guidance and considered acceptable to Health Canada.

For more information on Health Canadas decision, please view the Summary Basis of Decision.