FDA Approves Ceritinib for ALK-Positive NSCLC

Richard Pazdur, MD

Acting 4 months ahead of schedule, the FDA has granted an accelerated approval to ceritinib (Zykadia; LDK378) as a treatment for patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) following treatment with crizotinib (Xalkori), based on a single-arm clinical trial demonstrating a durable improvement in overall response rates (ORR).

The approval for the second-generation ALK inhibitor was supported by results from an analysis of 163 patients treated with single-agent ceritinib at 750 mg daily following progression on crizotinib. In these select patients, the ORR was 54.6% with a 7.4-month median duration of response, according to data submitted to the FDA by Novartis, the company developing the drug. Based on these findings, the FDA granted ceritinib a Breakthrough Therapy designation, Priority Review, and orphan product designation.

“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.”

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%.

Earlier this year, results from a dose escalation study that examined ceritinib in 130 patients who were untreated or refractory to crizotinib were published in the New England Journal of Medicine. In this analysis for patients who received doses of at least 400 mg (n = 114), the ORR was 58%. Patients who had progressed on crizotinib (n = 80) experienced an ORR of 56% and those who were crizotinib-naïve (n =34) had an ORR of 62%.

The median progression-free survival was 7.0 months and the median duration of response was 8.2 months (95% CI; 6.9-11.4). Additionally, responses were seen in patients with untreated metastatic brain lesions who progressed on prior therapy with crizotinib, the authors of the study noted.

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.

"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 (MGH) Cancer Center, 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."

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).

"The approval of Zykadia less than three and a half years after the first patient entered our clinical trial exemplifies what is possible with a highly focused approach to drug development and strong collaboration," Alessandro Riva, MD, president of Novartis Oncology ad interim and global head of Oncology Development and Medical Affairs, said in a statement. "The dedication of clinical investigators, patients, the FDA and others has enabled us to bring this medicine to patients in need as swiftly as possible."