The accelerated path of ceritinib: Translating pre-clinical development into clinical efficacy

Abstract The discovery of anaplastic lymphoma kinase ( ALK )-rearranged non–small-cell lung cancer (NSCLC) in 2007 led to the development and subsequent approval of the ALK inhibitor crizotinib in 2011. However, despite its clinical efficacy, resistance to crizotinib invariably develops. There is now a next generation of ALK inhibitors, including two that have been approved—ceritinib and alectinib—and others that are in development—brigatinib, lorlatinib and X-396. Ceritinib and the other next-generation ALK inhibitors are more potent than crizotinib and can overcome tumor cell resistance mechanisms. Ceritinib gained US Food and Drug Administration approval in 2014 following accelerated review for the treatment of patients with ALK -positive ( ALK +) metastatic NSCLC who have progressed on or are intolerant to crizotinib. In pre-clinical studies, it demonstrated more potent inhibition of ALK than crizotinib in enzymatic assays, more durable responses in xenograft models and the ability to potently overcome crizotinib resistance mutations in vitro (including the gatekeeper mutation). There is also evidence for ceritinib penetration across the blood-brain barrier. In clinical trials, ceritinib has demonstrated durable responses and progression-free survival in ALK-inhibitor–pre-treated and –naive NSCLC patients, including high overall and intracranial response rates in those with central nervous system metastases. Selective gastrointestinal toxicity of ceritinib, such as diarrhea, nausea and vomiting is generally manageable with prophylactic medication and prompt dose reduction or interruption. Future progress in treating ALK + NSCLC will focus on determining the optimal sequencing of therapies and strategies to overcome acquired resistance, an ongoing challenge in treating ALK -mutation–driven tumors

ASCEND-7: Efficacy and Safety of Ceritinib Treatment in Patients with ALK-Positive Non-Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges

Purpose:Central nervous systemmetastases are a prominent cause of morbidity and mortality in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC). The phase II ASCEND-7 (NCT02336451) study was specifically designed to assess the efficacy and safety of the ALK inhibitor (ALKi) ceritinib in patients with ALK+ NSCLC metastatic to the brain and/or leptomeninges. Patients and Methods: Patients with active brain metastases were allocated to study arms 1 to 4 based on prior exposure to an ALKi and/or prior brain radiation (arm 1: prior radiotherapy/ALKipretreated; arm 2: no radiotherapy/ALKi-pretreated; arm 3: prior radiotherapy/ALKi-naïve; arm 4: no radiotherapy/ALKi-naïve). Arm 5 included patients with leptomeningeal carcinomatosis. Patients received ceritinib 750 mg once daily (fasted condition). Primary endpoint was investigator-assessed whole-body overall response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR) and intracranial/extracranial responses. Results: Per investigator assessment, in arms 1 (n = 42), 2 (n = 40), 3 (n = 12), and 4 (n = 44), respectively: whole-body ORRs [95% confidence interval (CI)] were 35.7% (21.6-52.0), 30.0% (16.6-46.5), 50.0% (21.1-78.9), and 59.1% (43.2-73.7); whole-body DCR (95% CI): 66.7% (50.5-80.4), 82.5% (67.2- 92.7), 66.7% (34.9-90.1), and 70.5% (54.8-83.2); intracranial ORRs (95% CI): 39.3% (21.5-59.4), 27.6% (12.7-47.2), 28.6% (3.7-71.0), and 51.5% (33.5-69.2). In arm 5 (n = 18), whole-body ORR was 16.7% (95% CI, 3.6-41.4) and DCR was 66.7% (95% CI, 41.0-86.7). Paired cerebrospinal fluid and plasma sampling revealed that ceritinib penetrated the human blood-brain barrier. Conclusions: Ceritinib showed antitumor activity in patients with ALK+ NSCLC with active brain metastases and/or leptomeningeal disease, and could be considered in the management of intracranial disease

LDK378 in Anaplastic Lymphoma Kinase-Rearranged Non–Small-Cell Lung Cancer

Background: Non–small-cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangement is sensitive to the ALK inhibitor crizotinib, but invariably resistance develops. LDK378 is a novel ALK inhibitor with greater preclinical antitumor potency than crizotinib. Methods: In this phase 1 study, patients with advanced malignancies harboring genetic alterations in ALK received oral LDK378 at doses of 50 to 750 mg once daily. Expansion cohorts received the maximum tolerated dose (MTD). Patients were assessed for safety, pharmacokinetics, and antitumor activity. Tumor biopsies were performed pre-LDK378 treatment to identify ALK resistance mutations in a group of patients with NSCLC who had progressed on crizotinib. Results: Fifty-nine patients were enrolled in the dose-escalation part. The MTD of LDK378 was 750 mg once daily; dose-limiting toxicities included diarrhea, vomiting, dehydration, transaminase elevation, and hypophosphatemia. Seventy-one additional patients were treated in the expansion part, totaling 130 patients. Among 114 patients with NSCLC who received LDK378 ≥400 mg per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 79 crizotinib-treated patients, the response rate was 57% (95% CI, 45 to 68). Responses were observed in patients with different ALK resistance mutations, and in patients without detectable mutations. Among patients with NSCLC who received LDK378 ≥400 mg per day, median progression-free survival was 8.6 months (95% CI, 5.7 to 9.9). Conclusions: LDK378 is highly active in patients with advanced, ALK-rearranged NSCLC, including patients who progressed on crizotinib, with and without ALK resistance mutations. (Funded by Novartis; ClinicalTrials.gov number, NCT01283516