Ceritinib Approved for Metastatic ALK-Positive Lung Cancer

Alice T. Shaw, MD, PhD

The FDA has granted an accelerated approval to the next-generation ALK inhibitor ceritinib (Zykadia; LDK378) as a treatment for patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) following progression on crizotinib (Xalkori). The approval arrives 4 months earlier than expected, under the FDA's priority review program.

The FDA's decision was based on an analysis of 163 patients with ALK-positive NSCLC treated with single-agent ceritinib at 750 mg daily. In these select patients, the overall response rate was 54.6% with a 7.4-month median duration of response, according to investigator-assessed criteria. Based on these findings, the FDA granted ceritinib a breakthrough therapy designation, priority review, and orphan product designation.

"Zykadia represents an important treatment option for ALK-positive NSCLC patients who relapse after starting initial therapy with crizotinib," Alice Shaw, MD, PhD, of the Massachusetts General Hospital Cancer Center and lead author of the report, said in a statement. "This approval will affect the way we manage and monitor patients with this type of lung cancer, as we will now be able to offer them the opportunity for continued treatment response with a new ALK inhibitor."

In the study that was the basis for the approval, the median age of patients with primarily adenocarcinoma histology was 52 years, with 91% of patients having progressed on crizotinib. The majority of patients (84%) enrolled in the trial had been treated with 2 prior therapies. The primary endpoint was ORR by RECIST criteria with a secondary outcome measure of duration of response.

Treatment with ceritinib resulted in an ORR of 54.6% by investigator assessment with a median duration of response of 7.4 months. The complete response (CR) rate was 1.2% and the partial response (PR) rate was 53.4%. By blinded independent central review, the ORR was 43.6% and the duration of response was 7.1 months. The CR rate was 2.5% and the PR rate was 41.1%.

The most common grade 3/4 toxicities in a total of 255 patients treated with ceritinib across clinical trials were increased alanine transaminase (27%), aspartate transaminase (13%), glucose (13%), and lipase (10%).

The most common all-grade side effects were diarrhea (86%), hemoglobin decrease (84%), increased alanine transaminase (80%), nausea (80%), and increased aspartate transaminase (75%). Dose modifications related to gastrointestinal toxicity occured in 38% of patients. Additionally, 4% of patients developed pneumonitis, resulting in permanent discontinuation of ceritinib.

“Today’s approval illustrates how a greater understanding of the underlying molecular pathways of a disease can lead to the development of specific therapies aimed at these pathways,” 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. “It also demonstrates the FDA’s commitment to working cooperatively with companies to expedite a drug’s development, review and approval, reflecting the promise of the breakthrough therapy designation program.”

Two phase III studies are enrolling patients to further explore the efficacy and safety of ceritinib in patients with ALK-positive NSCLC. These studies will likely act as confirmation for the accelerated approval. In the first, ceritinib will be compared with chemotherapy in untreated patients with ALK-rearranged NSCLC (NCT01828099). The second will compare ceritinib to chemotherapy in ALK-positive patients with NSCLC following progression on chemotherapy and crizotinib (NCT01828112).

Approximately 224,210 new diagnoses of lung cancer will be made in the United States this year, of which 85% will be NSCLC, according to the National Cancer Institute. In general, ALK mutations are present in up to 7% of patients with NSCLC.