The ALK inhibitor crizotinib is more effective that first- or second-line chemotherapy in patients with advanced ALK plus NSCLC.a Thus, targeting ALK is a valid approach in patients with ALK plus NSCLC. Ceritinib, a second-generation, oral ALK inhibitor, demonstrated clinical activity in advanced ALK inhibitor (ALKi)-pretreated and -naïve patients with ALK plus NSCLC, including those with brain metastases.b Felip and colleaguesc now presented results from ASCEND-3, a single-arm, open-label, multicenter, phase 2 study which evaluated efficacy and safety of ceritinib in ALKi-naïve patients. At the time of presentation, 124 patients had enrolled worldwide and received oral ceritinib 750 mg/d. Investigators assessed whole body (WB) and intracranial (I) responses. Prior chemotherapy (?3 lines) was permitted. The median time from initial diagnosis to treatment start was 13.5 (1.0–283.1) months; median exposure duration was 8.0 (0.1–16.2) months; median follow-up (range) was 8.3 (0.6-16.3) months. The primary endpoint of the study was overall response rate (ORR) by RECIST criteria, with secondary objectives including duration of response (DOR), safety, progression-free survival (PFS), overall survival (OS), and patient-reported outcomes (PRO).
The study met its primary endpoint, with a WB ORR of 63.7%. Investigator-assessed efficacy outcomes are shown in the Table. At baseline, 10 patients had investigator-assessed measurable brain lesions (MBL); Intracranial Disease Control Rate (IDCR) was 80.0% (95% CI: 44.4, 97.5); in 6 patients with MBL and no prior brain radiation therapy (BRT), all responses in the brain matched or exceeded the WB response. The median time to first response was 1.8 months, and for patients with measurable baseline disease, 93.9% had a decrease in tumor burden from baseline. The most common adverse events (AEs; mostly Grade 1/2) were diarrhea, nausea, and vomiting, and 7.3% of the patients discontinued treatment due to AEs, with 73% requiring dose adjustment or interruption. Serious AEs were reported in 22% of patients, including pericarditis. PRO included symptom improvement in 82% of treated patients and stable global quality of life scores. This study demonstrates that ceritinib achieved a robust ORR and promising DOR and PFS in ALKi-naïve patients with advanced NSCLC, with and without baseline brain metastases. Indeed, ceritinib showed brain responses even in those patients with no prior BRT. Safety outcomes were similar to those observed in the ASCEND-1 trial.a
