By ecancer reporter Clare Sansom

A large majority of lung cancer patients are diagnosed with non-small cell lung cancer (NSCLC); this tumour type has a better prognosis than small-cell lung cancer, although five-year survival rates only range from 50% for very early cancer to 2% for stage IV disease.

Rearrangements of the anaplastic lymphoma kinase (ALK) gene are detected in 3-7% of patients with NSCLC.

This genetic aberration is more common in younger patients, in never-smokers or light smokers, and in adenocarcinomas.

Patients with ALK rearrangements can be treated with small-molecule inhibitors of the protein product of this gene, ALK.

The first ALK inhibitor, crizotinib, has been shown to be superior to the standard platinum-based chemotherapy in untreated patients and has been licensed as a first-line treatment in the US and some other countries.

However, patients taking crizotinib almost always progress, and further inhibitors are under development.

The second-generation inhibitor ceritinib, which has been developed by Novartis, is more potent than crizotinib in vitro, and clinical trials have already shown it to be effective in delaying progression in pre-treated patients with advanced disease.

Results of a randomised Phase III trial of ceritinib against platinum therapy in previously untreated patients with advanced NSCLC have now been published.

This trial, ASCEND-4, was set up by a large research consortium headed by Jean-Charles Sonia from University Paris-Sud, Orsay, France and involved 134 clinical centres in 28 countries.

A total of 376 chemotherapy-naïve patients diagnosed with advanced NSCLC with ALK rearrangements were randomised between August 2013 and May 2015 to receive either oral ceritinib or the control treatment of a standard platinum-based chemotherapy protocol.

At least 95% of patients in both groups were classified as having metastatic (stage IV) disease, with the bones, brain and liver the main metastasis sites.

Patients in the control group received either cisplatin or carboplatin plus the anti-metabolite pemetrexed for four cycles, followed by a maintenance dose of pemetrexed.

All patients received their initial therapy until disease progression; patients with progressive disease were allowed to continue while they still received some clinical benefit, and post-progression crossovers from chemotherapy to ceritinib were allowed.

The primary endpoint of the trial was progression-free survival, with overall survival, response rate, time to response and safety among the secondary endpoints.

A full analysis took place after the data cutoff point in June 2016.

Median progression-free survival of the patients on the ceritinib arm was 16.6 months compared to 8.1 months for those on the control arm [95% confidence interval (CI) 5.8-11.1 months].

This represent a risk reduction of 45% in progression-free survival [hazard ratio 0.55; 95% CI 0.42-0.73; p < 0.00001)].

These robust results showed without doubt that ceritinib is superior to platinum-based chemotherapy in terms of progression-free survival in this patient group, thus meeting the primary objective of the study.

Longer progression-free survival on ceritinib was recorded in almost all patient subgroups, and the few groups with different results were small enough for the significance of those results to be uncertain.

The benefit was particularly high in those patients without brain metastases at the baseline, where the median progression-free survival was 25.2 months with ceritinib compared to 8.3 months with chemotherapy.

Too few patients in the ceritinib arm had died by the data cutoff point for their median overall survival to be determined; in contrast, the median overall survival in the chemotherapy arm was 26.2 months.

Furthermore, the median time to response was shorter and the median duration of response was longer in the ceritinib arm.

Almost all patients in both arms reported some drug-related adverse events, but these were mainly mild or moderate (grade 1 or 2); 85% of patients in the ceritinib arm reported at least mild diarrhoea, and 69% of these patients reported nausea.

The most frequent severe adverse events in the ceritinib arm were increases in enzyme levels, particularly alanine aminotransferase and gamma-glutamyltransferase.

Taken together, the results of this trial suggest that the superiority of ceritinib over platinum drugs in chemotherapy-naïve patients with ALK-rearranged NSCLC is statistically significant; that its toxicity is acceptable; and that it should therefore be considered as a new first-line treatment for these patients.

Reference
Soria, J-C., Tan, D.S.W., Chiari, R. and 19 others (2017). First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet, published online ahead of print 23 January 2017.
doi: 10.1016/S0140-6736(17)30123-X