ASCEND-4

ASCEND-4 was an open-label, randomised phase 3 trial at 134 centres in 28 countries that compared ceritinib with platinum-based chemotherapy in 376 patients with untreated stage IIIB or IV ALK-rearranged non-squamous non-small-cell lung cancer. Patients received ceritinib 750 mg once daily (189) or cisplatin or carboplatin plus pemetrexed for four cycles followed by pemetrexed maintenance (187). Randomisation was stratified by performance status, previous neoadjuvant or adjuvant chemotherapy and brain metastases, and the primary endpoint was progression-free survival by blinded independent review.

Median progression-free survival was 16.6 months with ceritinib against 8.1 months with chemotherapy (hazard ratio 0.55, 95% CI 0.42 to 0.73; The Lancet 2017). By independent review 72.5 percent of patients responded on ceritinib against 26.7 percent on chemotherapy, and responses lasted a median of 23.9 against 11.1 months (registry results; the US label rounds these to 73 and 27 percent). Among 55 patients with measurable brain metastases, intracranial responses were seen in 57 percent against 22 percent (28 and 27 patients, US label). Overall survival did not differ significantly at the prespecified interim analysis at 42 percent of required events. Gastrointestinal effects dominated ceritinib's toxicity: diarrhoea in 85 percent, nausea in 69 percent, vomiting in 66 percent and raised alanine aminotransferase in 60 percent.

The trial supported the 2017 US first-line approval of ceritinib. It compared ceritinib with chemotherapy, not with crizotinib; ALEX, ALTA-1L and CROWN later tested newer ALK inhibitors against crizotinib, and those drugs displaced ceritinib first line.