FDA expands approval of Zykadia for ALK–positive metastatic NSCLC

The FDA expanded the approval of ceritinib to include the first-line treatment of patients with metastatic non–small cell lung cancer, according to the drug’s manufacturer.

This approval is intended for patients who harbor ALK mutations, as detected by an FDA–approved test. Approximately 3% to 7% of all patients with NSCLC harbor an ALK gene rearrangement.

The first-line approval of ceritinib (Zykadia, Novartis) is based on results from the open-label, randomized, multicenter, phase 3 ASCEND-4 trial. The trial included 376 patients with stage IIIb or IV ALK–positive NSCLC who had received no prior therapy for their advanced disease. Patients received 750 mg daily ceritinib (total, n = 189; with brain metastases, n = 59) or standard pemetrexed-based platinum doublet chemotherapy for four cycles followed by pemetrexed maintenance (total, n = 187; with brain metastases, n = 62).

Approximately 70% of patients with measurable brain metastases at baseline did not have prior radiation therapy, which is the current standard of treatment.

Results showed patients assigned ceritinib achieved longer median PFS than patients assigned chemotherapy (16.6 months vs. 8.1 months; HR = 0.55; 95% CI, 0.42-0.73). Ceritinib prolonged PFS in patients without brain metastases (26.3 months vs. 8.3 months; HR = 0.48; 95% CI, 0.33-0.69) and with brain metastases (10.7 months vs. 6.7 months; HR = 0.7; 95% CI, 0.44-1.12).

Researchers reported a whole-body overall response rate of 73% (95% CI, 66-79) with ceritinib and 27% (95% CI, 21-34) with chemotherapy. Among patients with measurable brain metastases, a greater proportion of those assigned ceritinib achieved intracranial ORR (57% vs. 22%).

Researchers estimated median response durations of 23.9 months (95% CI, 16.6 to not estimable) in the ceritinib arm and 11.1 months (95% CI, 7.8-16.4) in the chemotherapy arm.

The most common adverse reactions included diarrhea (85%), nausea (69%), vomiting (67%), fatigue (45%), abdominal pain (40%), decreased appetite (34%) and cough (25%). Grade 3 and grade 4 adverse reaction included fatigue (7%), vomiting (5%), diarrhea (4.8%), abdominal pain (3.7%), weight loss (3.7%), nausea (2.6%) and prolonged QT interval (2.6%).

“Today’s approval represents the next step in the development of Zykadia as a treatment option for ALK–positive metastatic NSCLC, bringing this important medication to a patient population where a need still exists,” Bruno Strigini, CEO of Novartis Oncology, said in a company-issued press release. “At Novartis, we are tireless in our pursuit of developing novel medicines to treat lung cancer, and the first-line approval of Zykadia for ALK–positive metastatic NSCLC illustrates our commitment to cancer patients.”

Ceritinib first received accelerated approval in 2014 for patients with ALK–positive metastatic NSCLC who progressed on or are intolerant to crizotinib (Xalkori; Pfizer Oncology, EMD Serono). FDA granted ceritinib breakthrough therapy designation for the first-line treatment of patients with ALK–positive metastatic NSCLC with metastases to the brain, and priority review for first-line ALK–positive metastatic NSCLC.