Alecensa Gains FDA Approval for ALK-Positive Lung Cancer

“FDA”

The ALK-inhibitor alectinib (Alecensa) was granted accelerated approval by the FDA for patients with metastatic non-small-cell lung cancer (NSCLC) whose disease progressed on crizotinib (Xalkori).

The approval was based on positive objective response rates (ORR) observed in two phase II clinical trials.

In the first study, labeled NP28761, the ORR with alectinib was 38% by independent review and 46% by investigator assessment. The duration of response was 7.5 months. For the second trial, known as NP28673, the ORR was 44% by independent review, 48% by investigator assessment, and the duration of response was 11.2 months.

“Today’s approval provides a new therapy for a group of patients who would have few treatment options once their disease no longer responds to treatment with Xalkori,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “In addition to the primary effect on tumors in the lung, Alecensa clinical trials provide evidence of an effect on tumors that had spread to the brain, which is an important effect for clinicians to understand.”

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.

In data presented during the 2015 ASCO Annual Meeting,¹ patients with CNS metastases treated with alectinib experience an ORR of 68.8% by independent review with alectinib (95% CI, 41.3%-89.0%). Additionally, median progression-free survival (PFS), although not yet mature, was 6.3 months.

In second pivotal phase II study, NP28673, 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.

In data published in the Journal of Clinical Oncology,² the median independently-reviewed PFS was 8.9 months (95% CI, 5.6-11.3). In 35 patients with CNS disease, the ORR was 57% (95% CI, 39-74) and the duration of response was 10.3 months.

A pooled analysis of the two studies was conducted for 51 patients with CNS metastases. Across the studies, 69% of patients had received prior brain radiation, with nearly half of patients completing radiation (49%) at least 6 months prior to receiving alectinib.

In this analysis, the ORR in patients with CNS metastases was 61% (95% CI, 46-74). In this same group, the CNS complete response rate was 18% and the duration of response was 9.1 months.

The most common adverse events (AEs) associated with alectinib across the two studies were fatigue, constipation, edema, and myalgia. Serious AEs included liver problems, severe or life-threatening inflammation of the lungs, very slow heartbeats, and severe muscle problems. Additionally, the FDA noted that alectinib was associated with photosensitivity and an increased risk of sunburn.

The most frequently observed grade ≥3 AEs were increased creatine phosphokinase (4.6%), dyspnea (3.6%), increased aspartate transaminase (3.6%), increased alanine transaminase (4.8%), hyperbilirubinemia (2.4%), hyperglycemia (2%), hypokalemia (4%), hypophosphatemia (2.8%), hyponatremia (2%), anemia (2%), and lymphopenia (4.6%).

“Alecensa is now approved as a new option for people with ALK-positive NSCLC who progress on or are intolerant to crizotinib,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, the company developing the drug, said in a statement. “Sixty percent of people enrolled in our studies had tumors that had spread to their central nervous systems, and Alecensa shrank tumors in many people in a subset of patients with CNS disease.”

The accelerated approval is contingent upon results from a confirmatory analysis, which the phase III ALEX study is meant to provide. In this trial, alectinib is being compared with crizotinib for chemotherapy-naive patients with ALK-positive NSCLC. The study hopes to enroll 286 patients, with early results expected in 2018.

In 2013, alectinib received a breakthrough therapy designation from the FDA as a treatment for patients with ALK-positive NSCLC following progression on crizotinib. Alectinib was approved in Japan in 2014, also under the name Alecensa, for patients with ALK-positive NSCLC.

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