ASCEND-1 Further Supports Ceritinib In ALK Inhibitor-Naive And -Pretreated NSCLC

Treatment with the anaplastic lymphoma kinase inhibitor ceritinib elicits extra- and intracranial responses among patients with ALK-rearranged non-small-cell lung cancer

medwireNews: Updated results of the ASCEND-1 trial show durable whole-body responses with ceritinib in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC), including those who have and have not received prior ALK inhibitor therapy.

The second-generation ALK inhibitor also shows intracranial activity among patients with untreated or locally treated asymptomatic or stable brain metastases at study entry, report the researchers, adding that these findings suggest that “ceritinib could be an alternative therapeutic approach to local ablative therapy in patients with ALK-rearranged NSCLC and brain metastases.”

Of 246 patients with locally advanced or metastatic ALK-rearranged NSCLC included in this phase I trial, 83 were naive to ALK inhibitors, while the remaining 163 had all received the first-generation ALK inhibitor crizotinib (five patients had also received alectinib). The majority of participants were heavily pretreated, having received several previous lines of anticancer treatments.

After a median follow-up of 11.1 months, treatment with ceritinib at the recommended dose of 750 mg/day given in 3-week cycles led to an overall whole-body (including brain) response, defined as all RECIST complete or partial responses, in 72% of ALK inhibitor-naive participants and 56% of ALK inhibitor-pretreated patients.

Median duration of response was 17.0 months for patients naive to prior ALK inhibitor therapy and 8.3 months for those who had received ALK inhibitors previously. The corresponding times for median progression-free survival were 18.4 and 6.9 months.

Furthermore, intracranial disease control was observed in 79% of 19 ALK inhibitor-naive patients with retrospectively confirmed brain metastases and in 65% of 75 ALK inhibitor-pretreated participants.

Notably, six of 11 patients with measurable brain lesions who had not received local radiotherapy also achieved a partial intracranial response following ceritinib therapy, “indicative of blood–brain barrier penetration of this highly potent ALK inhibitor”, say the authors.

Diarrhoea and nausea were the most frequent grade 3 or 4 non-laboratory toxicities, each occurring in 6% of patients. And elevated levels of alanine aminotransferase and aspartate aminotransferase were the most common laboratory abnormalities of grade 3 or worse, observed in 30% and 10% of participants, respectively.

Researcher Alice Shaw, from Massachusetts General Hospital in Boston, USA, and co-workers attribute two on-treatment deaths to the study drug – “one due to interstitial lung disease and the other due to multiorgan failure that occurred in the context of infection and ischaemic hepatitis.”

They conclude in The Lancet Oncology: “Clinical activity of ceritinib was noted in patients with ALK-rearranged NSCLC who had progressed on previous treatment with crizotinib, providing a therapeutic option for patients who might otherwise have limited choices.”

Reference

Kim D-W, Mehra R, Tan DSW, et al. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol 2016; Advance online publication 10 March. doi: http://dx.doi.org/10.1016/S1470-2045(15)00614-2

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