Ceritinib ‘highly active’ in advanced ALK-rearranged NSCLC

By Sara Freeman, medwireNews Reporter

Phase I study findings suggest the investigational drug ceritinib is effective in patients with advanced non-small-cell lung cancer (NSCLC) with anaplastic lymphoma kinase gene (ALK) rearrangement, even in those who develop resistance to crizotinib.

Ceritinib was associated with an overall response rate (ORR) of 58% and a median progression-free survival of 7 months. Importantly, the ORR was high, at 56%, even in patients who had disease progression during prior crizotinib treatment, including patients who had and had not acquired further ALK mutations or amplification.

“Ceritinib (LDK378) is a new ALK inhibitor that has shown greater anti-tumor potency than crizotinib in preclinical studies,” explain study investigator Alice Shaw (Massachusetts General Hospital Cancer Center, Boston, USA) and colleagues.

While crizotinib is established as an effective treatment for ALK-positive tumors – which constitute around 5% of all NSCLC cases – most patients relapse within 1 year due to acquired resistance, Shaw et al explain in the New England Journal of Medicine.

“Treatment options after the failure of crizotinib are limited”, the researchers add, so the aim of the present study was to see if the promise ceritinib had shown in preclinical studies would translate into a clinical benefit.

Initially, 59 patients participated to find the maximum tolerated dose (MTD), which was 750 mg once daily. This dose was then used in a further 71 patients to determine the safety and tolerability and potential antitumor activity of ceritinib.

The median age of the combined 130 patients treated was 53 years, 60% of the study population were women and 75% were White. Patients were treated with ceritinib in 21-day cycles until disease progression, unacceptable toxicity occurred or consent was withdrawn. The majority (68%) had received prior crizotinib treatment.

Dose-limiting toxicities included hypophosphatemia and elevated alanine aminotransferase levels, dehydration, diarrhoea, nausea and vomiting at doses of 400 mg and above. All of these resolved with treatment discontinuation or interruption.

“Among patients with ALK-rearranged NSCLC for whom crizotinib is no longer effective, more potent inhibition of the target by a structurally distinct ALK kinase inhibitor such as ceritinib can induce substantial and durable responses in the majority of cases,” Shaw and team conclude.

Editorialist Roman Thomas (University of Cologne, Germany) notes that the findings are “good news for patients with ALK-rearranged lung cancer.” The study, he says is “an example of how mechanistically inspired and rationally designed trials involving large, genotypically defined patients cohorts can lead to dramatic steps forward in the care of patients with cancer.”

Licensed from medwireNews with permission from Springer Healthcare Ltd. ©Springer Healthcare Ltd. All rights reserved. Neither of these parties endorse or recommend any commercial products, services, or equipment.


The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
Post a new comment
You might also like...
Three genetic mutations seen in individuals with KCNMA1-linked channelopathy successfully mirrored in mice