A phase I study of the anaplastic lymphoma kinase inhibitor ceritinib in combination with gemcitabine‐based chemotherapy in patients with advanced solid tumors. Issue 12 (27th August 2021)

• Record Type: Journal Article
• Authors: Fountzilas, Christos; Adjei, Alex; Opyrchal, Mateusz; Evans, Rachel; Ghasemi, Mohammad; Attwood, Kristopher; Groman, Adrienne; Bshara, Wiam; Goey, Andrew; Wilton, John; Ma, Wen Wee; Iyer, Renuka
• Is Part Of: International journal of cancer. Volume 149:Issue 12(2021)
• Page Start: 2063
• Page End: 2074
• Publication Date: 2021-08-27
• Subjects: biomarkers -- ceritinib -- cisplatin -- gemcitabine -- pharmacokinetics -- phase I; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.33754
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract: In this phase I, dose‐escalation study, we sought to determine the maximum tolerated dose (MTD) of the anaplastic lymphoma kinase/c‐ROS oncogene 1 receptor (ALK/ROS1) inhibitor ceritinib in combination with gemcitabine‐based chemotherapy in patients with advanced solid tumors. Secondary objectives were characterization of the safety profile, pharmacokinetics and preliminary efficacy of these combinations, and identification of potential biomarkers of efficacy. Ceritinib was combined with gemcitabine (Arm 1), gemcitabine/nab‐paclitaxel (Arm 2) or gemcitabine/cisplatin (Arm 3). Drug concentrations in plasma were measured by tandem mass spectrometric detection (LC‐MS/MS). We analyzed archival tumor tissue for ALK, ROS1, hepatocyte growth factor receptor (c‐MET) and c‐Jun N‐terminal kinase (JNK) expression by immunohistochemistry. Arm 2 closed early secondary to toxicity. Twenty‐one patients were evaluable for dose‐limiting toxicity (DLT). There was one DLT in Arm 1 (grade 3 ALT increase) and three DLTs in Arm 3 (grade 3 acute renal failure, grade 3 thrombocytopenia, grade 3 dyspnea). The MTD of ceritinib was determined to be 600 mg (Arm 1) and 450 mg orally daily (Arm 3). Main toxicities were hematologic, constitutional and gastrointestinal as expected by the chemotherapy backbone. The apparent clearance for ceritinib decreased substantially after repeated dosing; cisplatin did not significantly affect the pharmacokinetics of ceritinib. The overall response rate was 20%; the median progression‐free survival was 4.8 months. Three out of five response‐evaluable cholangiocarcinoma patients had clinical benefit. Increased expression of c‐MET was associated with a lack of clinical benefit. Ceritinib in combination with gemcitabine and gemcitabine/cisplatin has a manageable toxicity profile. Further development of this strategy in tumors with ALK or ROS1 fusions is warranted. Abstract : What's new? ALK/ROS1 inhibitors have in vitro and in vivo synergy with cytotoxic agents and can effectively kill tumour cell subpopulations that either lack ALK/ROS1 aberrations or are resistant to ALK/ROS1 inhibition. In this phase I trial, the authors show that the highly selective oral ALK/ROS1 inhibitor ceritinib can be combined with gemcitabine‐based chemotherapy in humans with a manageable toxicity profile. Furthermore, c‐MET expression as measured by immunohistochemistry could be a potential negative predictive biomarker for treatment benefit. The results pave the way for further development of this combination strategy in tumours with ALK or ROS1 fusions.