Research in context
Evidence before this study
We searched PubMed on Dec 6, 2016, for reports on clinical trials in advanced untreated anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) using the following search string “(ALK AND NSCLC) AND (naïve OR naive OR untreated OR first-line)”. We did not limit our search by date or language. These searches indicated that the only phase 3 trial published for first-line treatment of ALK-positive NSCLC was for crizotinib (PROFILE 1014) that compared efficacy and safety of crizotinib, an ALK inhibitor with platinum-pemetrexed combination without maintenance treatment. Ceritinib is a next-generation, selective oral ALK inhibitor with 20 times greater potency than crizotinib in enzymatic assays. Results from the phase 1 ASCEND-1 study and phase 2 ASCEND-3 study demonstrated consistent, high, and durable antitumour efficacy of ceritinib 750 mg/day in ALK inhibitor-naive patients with ALK-rearranged NSCLC who had progressed on multiple lines of chemotherapy.
Added value of this study
Ceritinib demonstrated a statistically significant and clinically meaningful improvement in progression-free survival versus pemetrexed-platinum chemotherapy including maintenance pemetrexed in untreated patients with ALK-rearranged NSCLC. The study's primary objective, median progression-free survival as assessed by blinded independent review committee, was 16·6 months (95% CI 12·6–27·2) for ceritinib versus 8·1 months (5·8–11·1) for chemotherapy (with an estimated 45% risk reduction for progression-free survival [HR 0·55, 95% CI 0·42–0·73; p<0·00001]). Improvement in progression-free survival was observed both in patients with or without brain metastases at study entry. The overall response with ceritinib was high, rapid, and prolonged. Additionally, ceritinib had a higher overall intracranial response as compared with chemotherapy. Ceritinib significantly improved the general quality of life and significantly prolonged time to deterioration for lung cancer-specific symptoms compared with chemotherapy. The safety profile of ceritinib was consistent with previous reports.
Implications of all the available evidence
Patients with advanced ALK-rearranged NSCLC treated with first-line ceritinib had a statistically significant and clinically meaningful improvement in progression-free survival compared with chemotherapy. Overall, ceritinib should be considered as a new first-line therapeutic option in patients with ALK-rearranged NSCLC.