CHMP Recommends Approval of Alectinib for ALK+ NSCLC

Sandra Horning, MD

The Committee for Medicinal Products for Human Use (CHMP) has recommended approval of alectinib (Alecensa) as a treatment for patients with metastatic ALK-positive non—small cell lung cancer (NSCLC) following progression on crizotinib (Xalkori), according to Roche, the developer of the second-generation ALK inhibitor.

The application is based on data from 2 phase II trials. In the first study, labeled NP28761, the overall response rate (ORR) with alectinib was 52.2% (95% CI, 39.7%-64.6%) and the median progression-free survival (PFS) was 8.2 months (95% CI, 6.3-12.6).¹ For the second trial, known as NP28673, the ORR was 50.8% (95% CI, 41.6%-59.9%) and the median PFS was 8.9 months (95% CI, 5.6-12.8).²

The positive opinion will now be reviewed by the European Commission. A final approval decision for use in the European Union is anticipated in early 2017.

“Most people living with ALK-positive NSCLC develop resistance to the current standard of care, and nearly half see their tumors spread to the central nervous system within one year of treatment,” Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development, Roche, said in a statement. “Today’s positive CHMP opinion is great news for people living with ALK-positive NSCLC and brings us one step closer to providing a much needed new treatment option for people and physicians in Europe.”

NP28761 was an open-label, single-arm multicenter trial that included 87 patients with ALK-positive NSCLC who progressed on crizotinib. In this study, which was conducted in North America, patients received alectinib at 600 mg orally twice daily until progression.

The median duration of response in the study was 14.9 months (95% CI, 6.9-NE) and the safety profile was consistent with previous trials.

The most common grade ≥3 adverse events (AEs) were an increase in blood levels of creatine phosphokinase (8%), increased ALT (6%), increased AST (5%), dyspnoea (3%), hypertriglyceridaemia (3%), hypokalaemia (3%), hypophosphatemia (3%), and thromboplastin (2%).

In the NP28673 study, crizotinib-pretreated patients received alectinib at 600 mg orally twice daily until progression. One hundred thirty-eight patients were evaluable for response. The median age of patients was 51.6 years and 60% had baseline CNS metastases. Most patients (80%) received prior chemotherapy.

The median duration of response in the trial was 15.2 months (95% CI, 11.2-24.9) and the safety profile was in line with prior studies of the drug. The most common grade ≥3 AE was dyspnoea (4%).

A pooled analysis of the 2 studies was conducted for patients with CNS metastases. The ORR in these patients was 64% (95% CI, 49.2%-77.1%). The complete response rate was 22% and the median duration of response in these patients was 11.1 months (95% CI, 7.6-NE).

Additional studies are also exploring alectinib as a first-line option. Findings from the phase III J-ALEX study presented at the 2016 ASCO Annual Meeting showed that frontline alectinib reduced the risk of disease progression or death by 66% versus crizotinib in patients with advanced or recurrent ALK-positive NSCLC (HR, 0.34; 99% CI, 0.17-0.70, P <.0001).³

References

1. Gandhi L, Shaw AT, Gadgeel SM, et al. A phase II, open-label, multicenter study of the ALK inhibitor alectinib in an ALK+ non-small-cell lung cancer (NSCLC) U.S./Canadian population who had progressed on crizotinib (NP28761). J Clin Oncol. 2015;33 (suppl; abstr 8019).
2. Ou S-HI, Ahn JS, Petris LD, et al. Alectinib in Crizotinib-Refractory ALK-Rearranged Non—Small-Cell Lung Cancer: A Phase II Global Study [Published online November 23, 2015]. J Clin Oncol. doi:10.1200/JCO.2015.63.9443.
3. Nokihara H, Hida T, Kondo M, et al. Alectinib (ALC) versus crizotinib (CRZ) in ALK inhibitor naïve ALK-positive non-small cell lung cancer (ALK+ NSCLC): Primary results from the J-ALEX study. Presented at: 2016 ASCO Annual Meeting; June 3-7, 2016; Chicago. Abstract 9008.