Efficacy of ceritinib administered to patients with crizotinib-refractory, ALK-positive, advanced NSCLC within the Italian compassionate use program

Abstract

Background: Ceritinib is an effective treatment for patients (pts) with anaplastic lymphoma kinase (ALK)-positive advanced non-small cel lung cancer (NSCLC) who progress on crizotinib. We assessed the efficacy of ceritinib administered within a compassionate use (CU) program. Patients and methods: This collaborative study involved pts with crizotinib-refractory, ALK-positive, advanced NSCLC treated at multiple Institutions. The clinical data of pts for whom ceritinib was requested as CU at the recommended dose of 750 mg/d without food were collected and analyzed. Results: Twenty-five Centers took part to the study, for a total of 70 pts who received at least one dose of ceritinib from July 2014 to March 2017. Pts characteristics were as follows: median age 56 years (22-86), 67/70 (95.5%) adenocarcinomas, 36/70 (51.5%) female, 47/70 (67%) never smokers, 14/70 (20%) ECOG PS≥2, 17/70 (24.5%) pretreated with ≥ 2 lines of chemotherapy, 49/70 (70%) metastatic to the brain. Median time on prior crizotinib was 359 days (51-1644). The starting dose of ceritinib was 750 mg/d in 63/70 (90%) pts. The most common any grade treatment-related adverse events (TRAEs) were nausea and/or vomiting (60%, 7%grade 3 or 4), diarrhea (50%, 1.5% grade 3 or 4), ALT and/or AST elevation (47%, 18.5% grade 3 or 4) and fatigue (57%, 8.5% grade 3 or 4). Unusual TRAEs considered to be drug-related consisted of an increase in serum creatinine in 2 pts. Dose reduction due to TRAEs occurred in 31/ 63 (49%) pts who started at 750 mg/d. Of them, 17/63 (27%) pts reduced to 600 mg/d, 8/63 (12.5%) pts to 450 mg/d, and 6/63 (9.5%) pts to 300 mg/d. Permanent dose discontinuation due to toxicity occurred in 4/70 (5.5%) pts. Of the 61 evaluable pts, 27 (44.5%, 95%CI: 31.5-57.6) responded to treatment, the median duration of response being 11.2 months. At a median follow-up of 6.7 months (<1-26), the median progression- free survival (PFS) was 7.2 months, with 6- and 12-month PFS rates being 54.5% and 31.5%, respectively. No statistically significant difference in terms of PFS was observed between pts with (n=38) or without (n=32) dose adjustements (8.2 months vs. 4.2 months, respectively, P=0.20). Conclusions: Ceritinib CU program in Italy confirms the efficacy of the drug in a “realworld” setting, with a sefety profile that is similar to that observed in clinical trials. A high rate of dose adjustments due to TRAEs was observed, which, however, did not appear to affect the activity of the drug.