Ceritinib in the treatment of brain metastases


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In contrast to crizotinib, ceritinib has demonstrated clinical responses in untreated CNS metastases in both crizotinib-naïve and -resistant ALK+-NSCLC patients. In the ASCEND-1 study of 246 ALK+-NSCLC patients, 124 patients harboring brain metastases were treated with ceritinib. An ORR of 54.0% and a median PFS of 6.9 months were observed in these patients.36 Tumor response was seen in 50.0% of patients with brain metastases who received prior crizotinib compared to 69.2% of patients who were crizotinib naïve.36 Shaw et al also reported that 64 patients harboring ALK+ brain metastases maintain a median PFS similar to 50 patients harboring only systemic tumors (6.9 months vs 7.0 months, with all patients receiving >400 mg of ceritinib daily).8

It appears that ceritinib has a tentative advantage over crizotinib regarding antitumor activity inALK+-NSCLC patients with brain metastases. While its penetration mechanism remains unknown, its capacity to cross the blood–brain barrier and offer tumor shrinkage in the CNS marks a significant milestone in the treatment of ALK+-NSCLC patients.

Future perspectives

Success with crizotinib in the treatment of ALK+-NSCLC patients has instigated continuous research and development of more potent ALK inhibitors. Ceritinib has demonstrated efficacy in the treatment of ALK+-NSCLC in both crizotinib-naïve and crizotinib-refractory patients. In addition, there are several ongoing trials as well as scheduled trials further investigating ceritinib (see Table 2 for details).

Table 2. Current list of ongoing trials of ceritinib (LDK378).

Trial
NCT02040870: a single-arm, Phase l/ll study testing tolerance, efficacy, and pharmacokinetics of ceritinib in 100 Chinese adult patients with ALK+NSCLC who are intolerant of crizotinib treatment
NCT02321501: a Phase l/Ib dose escalation and biomarker study of ceritinib (LDK378) and everolimus for locally advanced or metastatic solid tumors with an expansion in NSCLC characterized by abnormalities in ALK expression
NCT0l950481: a Phase I study designed to determine the safety, efficacy, and pharmacokinetics of ceritinib (750 mg daily) in patients with impaired and nonimpaired hepatic function
NCT0I634763: a Phase I study designed to determine the MTD of ceritinib as a single agent in Japanese ALK+-NSCLC patients
NCT0I772797: a Phase lb study designed to determine the MTD of combination therapy of LDK378 and AUY922. The study assesses safety. tolerability. and anti-tumor activity of combination therapy in ALK+NSCLC patients
NCT01828099: a Phase III study designed to compare the anti-tumor activity of ceritinib vs chemotherapy
NCT01828112: a Phase III study to compare the anti-tumor activity of ceritinib (750 mg daily) vs chemotherapy in patients already treated with platinum doublets and crizotinib
NCT02276027: a Phase ll. open-label. multiple arm study of AUY922. BYL7I9. INC280. LDK378. and MEKI62 in Chinese patients with advanced NSCLC
NCT01742286: a Phase I study determining the MTD of ceritinib as a single agent with and without food in pediatric patients harboring ALK+ tumors
NCT01947608: expanded treatment protocol with LDK378 in ALK(+) NSCLC
NCT01964157: a Phase II study investigating the anti-tumor activity and safety profile of ceritinib in patients harboring ROSI+-NSCLCs
NCT02186821: a modular Phase II study to link targeted therapy to patients with pathway activated tumors: module – 7. ceritinib (LDK378) for patients whose tumors have aberrations in ALK or ROSl
NCT02227940: a Phase I trial investigating ceritinib and combination chemotherapy in treating patients with advanced solid tumors or locally advanced or metastatic pancreatic cancer
NCT02289144: an open-label. multicenter Phase II study evaluating the anti-tumor activity of ceritinib (750 mg daily) against metastatic. anaplastic thyroid cancers
NCT02292550: a Phase lb/ll study of the ALK inhibitor ceritinib in combination with the CDK4/6 inhibitor LEEOI l in patients with ALK-positive NSCLC
NCT02299505: a Phase I study of lower doses of ceritinib taken with a low-fat meal vs 750 mg of ceritinib in the fasted state in adult patients with (ALK-positive) metastatic NSCLC
Abbreviations: ALK, anaplastic lymphoma kinase; NSCLC, non-small-cell lung cancer; MTD, maximum tolerated dose.

With the EML4–ALK fusion gene accounting for only 3%–7% of NSCLC patients, the method of precisely determining ALK positivity in tumors is a crucial step in the treatment of patients harboringALK+ tumors. While FISH is currently the primary mechanism for ALK+ detection, investigations into more cost-effective and accurate diagnostic tests could pave the road for improvements in the molecular identification of ALK positivity as well as the acquired resistance mechanisms resulting from TKI treatment.

There are other novel ALK inhibitors under development that have significantly demonstrated antitumor activity in advanced ALK+-NSCLC patients. The novel inhibitor alectinib is one such ALK inhibitor. In an ongoing Phase II study of 46 patients, 43 (93.5%) of them achieved overall responses (two complete, 41 partial response) with only mild reportable side effects.37 Alectinib also demonstrated significant anti-tumor response in CNS.38 Optimal treatment strategies for ALK+ NSCLC will continue to evolve with further investigations.

Finally, combination therapy involving ALK inhibitors and immune checkpoint inhibitors such as nivolumab, an anti-PD1 antibody that is currently approved for melanoma and squamous cell carcinoma of lung, may result in more effective and prolonged anti-tumor responses by optimizing anti-tumor T-cell responses. The study of safety and efficacy of ceritinib in combination with nivolumab in patients with ALK-positive NSCLC is being planned (NCT02393625).