COPENHAGEN, Denmark — Ceritinib significantly prolonged PFS compared with chemotherapy in patients with anaplastic lymphoma kinase–rearranged non–small cell lung cancer previously treated with crizotinib, according to randomized phase 3 study results presented at the European Society for Medical Oncology Congress.
Ceritinib (Zykadia, Novartis) also conferred greater improvement in lung cancer–specific symptoms and overall health status, while demonstrating a manageable safety profile.
“Ceritinib demonstrated superior efficacy compared with standard second-line chemotherapy in crizotinib-resistant ALK–positive patients, establishing ceritinib as a preferred treatment option in this patient population,” Giorgio Scagliotti, MD, head of the department of oncology at University of Turin in Italy, said during a press conference.
Crizotinib (Xalkori, Pfizer), a first-generation anaplastic lymphoma kinase inhibitor, has demonstrated efficacy in patients with ALK–positive NSCLC. However, the majority of patients develop resistance and experience disease progression.
Prior phase 1 and phase 2 studies showed ceritinib, a second-generation ALK inhibitor, was highly active in crizotinib-pretreated patients.
In the international, multicenter, open-label ASCEND-5 study, Scagliotti and colleagues compared ceritinib with chemotherapy in patients with ALK–positive NSCLC who previously received crizotinib and up to two chemotherapy regimens.
Researchers randomly assigned 231 patients (median age, 54 years) to 750 mg oral ceritinib daily (n = 115) or chemotherapy (n = 116). Chemotherapy regimens included pemetrexed 500 mg/m2 or docetaxel 75 mg/m2.
Patients who discontinued chemotherapy due to disease progression were allowed to cross over to ceritinib.
Investigators stratified patients by WHO performance status (0 vs. 1 or 2) and presence of brain metastases at screening.
PFS assessed by blinded independent review served as the primary endpoint.
Median follow-up was 16.5 months.
Patients assigned ceritinib achieved significantly longer median PFS (5.4 months vs. 1.6 months; HR = 0.49; P < .001). Ceritinib also induced a higher overall response rate (39.1% vs. 6.9%), and significantly improved lung cancer–specific symptoms and overall health status (P < .05).
“The benefit [of ceritinib] really was quite striking,” Scagliotti said. “This study opens up a new treatment paradigm after crizotinib failure.”
Researchers reported no OS benefit with ceritinib compared with chemotherapy (median, 18.1 months vs. 20.1 months). However, the fact 75 patients assigned chemotherapy crossed over to ceritinib treatment likely diluted the potential OS benefit, Scagliotti said.
The most common grade 3 or grade 4 adverse events reported in ceritinib-treated patients were nausea (7.8%), vomiting (7.8%) and diarrhea (4.3%). The most common grade 3 to grade 4 adverse events reported in chemotherapy-treated patients were neutropenia (15%), fatigue (4.4%) and nausea (1.8%).
Six patients (5.2%) assigned ceritinib and eight patients (6.9%) assigned chemotherapy discontinued treatment due to adverse events.
Prior single-arm studies suggested that ceritinib or alectinib (Alcensa, Genentech) could be viable options in the second-line setting after crizotinib has failed, according to Alice T. Shaw, MD, PhD, director of thoracic oncology at Massachusetts General Hospital Cancer Center.
“The positive effect on PFS in this phase 3 study confirms that there is greater benefit using a second ALK inhibitor over standard chemotherapy,” Shaw, who was not involved with this study, said in a press release.
Results of two trials in the first-line setting — one designed to compare ceritinib vs. chemotherapy, and the other designed to compare alectinib vs. crizotinib — are eagerly anticipated, Shaw said.
“The latter trial addresses one of the most fundamental questions in the field, which is what should be the first ALK inhibitor that patients should receive,” Shaw said. – by Mark Leiser
For more information: Scagliotti G, et al. Abstract LBA42_PR. Presented at: European Society for Medical Oncology Congress; Oct. 7-11, 2016; Copenhagen, Denmark.
Disclosure: Novartis provided funding for this study. Scagliotti reports honoraria from AstraZeneca, Clovis Oncology, Eli Lilly, Pfizer and Roche; consultant/advisory roles and speakers bureau roles with Eli Lilly; and travel, accommodations or expenses from Bayer. Please see the abstract for a list of all other researchers’ relevant financial disclosures.