Background
Phase III RCT (ASCEND-4). N=376. Treatment-naïve stage IIIB/IV ALK-positive non-squamous NSCLC. First-line ceritinib vs platinum-pemetrexed chemotherapy.
Interventions and follow up
Arm A: Ceritinib 750 mg/day fasted (later 450 mg with food reduces GI AEs)
Arm B: Cisplatin 75 mg/m² (or carboplatin AUC 5–6) + pemetrexed 500 mg/m² q3wk ×4 cycles, then pemetrexed maintenance
Primary endpoint: PFS by blinded independent review
Arm B: Cisplatin 75 mg/m² (or carboplatin AUC 5–6) + pemetrexed 500 mg/m² q3wk ×4 cycles, then pemetrexed maintenance
Primary endpoint: PFS by blinded independent review
Results
mPFS: 16.6 mo vs 8.1 mo, HR 0.55 (95% CI 0.42–0.73; P<.00001)
mOS: not reached vs 26.2 mo, HR 0.73 (95% CI 0.50–1.08; P=.056)
ORR: 72.5% vs 26.7%
Treatment duration: 26.9 wk vs 6.4 wk
mOS: not reached vs 26.2 mo, HR 0.73 (95% CI 0.50–1.08; P=.056)
ORR: 72.5% vs 26.7%
Treatment duration: 26.9 wk vs 6.4 wk
Adverse events
Overall: Grade 3–4 AEs 65% (ceritinib) vs 40% (chemo)
GI: Diarrhea 85% vs 69%, nausea 69% vs 66%, abdominal pain 24% vs 16%
Lab changes: ALT increased 53% vs 22%, AST increased 60% vs 36%
Hematologic: Anemia 15% vs 35%, neutropenia 5% vs 18%
Respiratory: Cough 24% vs 16%
GI: Diarrhea 85% vs 69%, nausea 69% vs 66%, abdominal pain 24% vs 16%
Lab changes: ALT increased 53% vs 22%, AST increased 60% vs 36%
Hematologic: Anemia 15% vs 35%, neutropenia 5% vs 18%
Respiratory: Cough 24% vs 16%
Conclusions
Ceritinib significantly improved PFS and ORR vs chemotherapy in treatment-naïve ALK-positive NSCLC, validating first-line ALK TKI therapy.
Key Limitations
Open-label design; chemotherapy comparator rather than another ALK TKI. OS not statistically significant (P=.056). High GI toxicity at the 750 mg fasted dose limited tolerability; the modern 450 mg with-food dose was not used. Now superseded by alectinib, brigatinib, and lorlatinib in 1L.
Clinical Context
FDA approved ceritinib 1L ALK+ NSCLC (2017). Largely displaced by alectinib, brigatinib, and lorlatinib, which offer superior PFS, CNS activity, and tolerability. ESMO no longer favors ceritinib over later-generation ALK TKIs in 1L.