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FDA Grants Alectinib Priority Review in NSCLC

Jason M. Broderick @jasoncology
Published: Wednesday, Sep 09, 2015

Dr. Sandra Horning

Sandra Horning, MD

Alectinib has received an FDA priority review designation for patients with ALK-positive, locally advanced or metastatic no­n–small cell lung cancer (NSCLC) who have progressed or are intolerant to crizotinib (Xalkori), according to Genentech, the manufacturer of the oral second-generation ALK inhibitor. The FDA’s action date for an approval decision is March 4, 2016.

The priority review is based on two phase II trials (NP286731and NP287612) which demonstrated that alectinib had robust activity in patients with ALK-positive NSCLC following progression on crizotinib (Xalkori), including individuals with CNS metastases.

“Alectinib was granted priority review by the FDA based on results from two studies showing the medicine shrank tumors in people with ALK-positive NSCLC that progressed on crizotinib,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, said in a statement. “There is a need for new treatment options in this patient population, especially because the disease often spreads to the brain at progression.”

Data from the phase II NP28673 and NP28761 studies were presented at the 2015 ASCO Annual Meeting. 

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

The overall response rate (ORR) in the full population by independent review was 50% (95% CI, 40.8%-59.1%), which consisted of all partial responses. ORR by investigator assessment was 47.8% (95% CI, 39.3%-56.5%). The median duration of response by independent review was 11.2 months. The median progression-free survival (PFS) with alectinib was 8.9 months (95% CI, 5.6-11.3). 

"Alectinib achieved a robust response rate in crizotinib-resistant patient populations, a majority of whom received a platinum-based chemotherapy," said Sai-Hong Ignatius Ou, MD, PhD, a health science associate clinical professor at the University of California, Irvine, when presenting the data at ASCO 2015.

In all patients enrolled in the study with CNS metastases, the CNS-specific ORR was 57.1% (95% CI, 39.4%-73.7%), with a complete response (CR) rate of 27.4%. In those with untreated CNS metastases, the CR rate was 43.5%.

"The disease control rate in the CNS was excellent, with a sustained median duration of 10.3 months," Ou commented. "These data taken together may signal a new standard of care for CNS metastases in ALK-positive non–small cell lung cancer."

The safety profiled of alectinib was consistent with previous research. Grade 3/4 adverse events were relatively infrequent. Dyspnea, which occurred in 4% of patients, was the most frequently reported grade ≥3 adverse event.

Dose reductions due to adverse events were required in 8.7% of patients. Dose delays or interruptions were needed in 19.6% of patients.

"More than 90% of patients were able to tolerate alectinib without dose reductions," Ou said.

The second pivotal phase II study, NP28761, was an open-label, single-arm, multicenter trial that included 87 patients with ALK-positive NSCLC who progressed on crizotinib. As in NP28673, patients received alectinib at 600 mg orally twice daily until progression.

ORR by independent review was 47.8%  (95% CI, 35.6%-60.2%) and 46.0% by investigator assessment (95% CI, 35.2%-57.0%). In patients with CNS metastases, ORR was 68.8% by independent review (95% CI, 41.3%-89.0%).

The median duration of response was 7.5 months. Median PFS, although not yet mature, was 6.3 months.

The safety profile for alectinib was similar to adverse event reports with the ALK-inhibitor in previous studies. The most frequently reported grade ≥3 adverse events were increased blood levels of creatine phosphokinase (8%), increased ALT levels (6%), increased AST levels (5%), and dyspnea (3%).

Alectinib is also being examined in the phase III ALEX study, which is comparing the drug with crizotinib in chemotherapy-naive patients with ALK-positive NSCLC. In this study, alectinib will be administered at the same dose as in the phase II studies, 600 mg twice daily. 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, under the name Alecensa, for patients with ALK-positive NSCLC.


  1. Ou IS-H, Ahn JS, Petris LD, et al. Efficacy and safety of the ALK inhibitor alectinib in ALK+ non-small-cell lung cancer (NSCLC) patients who have failed prior crizotinib: An open-label, single-arm, global phase 2 study (NP28673). J Clin Oncol. 2015;33 (suppl; abstr 8008).
  2. 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).



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