Background
Phase III RCT (PROFILE 1014). N=343. Treatment-naïve advanced ALK-positive non-squamous NSCLC. First-line crizotinib vs platinum-pemetrexed chemotherapy.
Interventions and follow up
Arm A: Crizotinib 250 mg PO BID
Arm B: Pemetrexed 500 mg/m² + cisplatin 75 mg/m² (or carboplatin AUC 5–6) q3wk up to 6 cycles (84% crossed over to crizotinib)
Primary endpoint: PFS
mFollow up: ~17 mo at primary; 46 mo at OS update
Arm B: Pemetrexed 500 mg/m² + cisplatin 75 mg/m² (or carboplatin AUC 5–6) q3wk up to 6 cycles (84% crossed over to crizotinib)
Primary endpoint: PFS
mFollow up: ~17 mo at primary; 46 mo at OS update
Results
mPFS: 10.9 mo vs 7.0 mo, HR 0.45 (95% CI 0.35–0.60; P<.001)
ORR: 74% vs 45% (median DoR 11.3 mo vs 5.3 mo)
1-yr OS: 84% vs 79%
mOS (primary): not reached in either group, HR 0.82 (95% CI 0.54–1.26; P=.36)
mOS (update): not reached vs 47.5 mo, HR 0.760 (95% CI 0.548–1.053); crossover-adjusted HR 0.35 (95% bootstrap CI 0.08–0.72)
ORR: 74% vs 45% (median DoR 11.3 mo vs 5.3 mo)
1-yr OS: 84% vs 79%
mOS (primary): not reached in either group, HR 0.82 (95% CI 0.54–1.26; P=.36)
mOS (update): not reached vs 47.5 mo, HR 0.760 (95% CI 0.548–1.053); crossover-adjusted HR 0.35 (95% bootstrap CI 0.08–0.72)
Adverse events
Crizotinib, more frequent: Vision problems 71% vs 9%, diarrhea 61% vs 13%, edema 49% vs 12%, nausea 46% vs 36%, constipation 43% vs 30%
Chemo, more frequent (hematologic): Anemia 9% vs 32%, neutropenia 21% vs 30%, thrombocytopenia 1% vs 18%
Treatment duration: 10.9 mo vs 4.1 mo (median 6 cycles)
Chemo, more frequent (hematologic): Anemia 9% vs 32%, neutropenia 21% vs 30%, thrombocytopenia 1% vs 18%
Treatment duration: 10.9 mo vs 4.1 mo (median 6 cycles)
Conclusions
Crizotinib significantly improved PFS and response rate vs chemotherapy in treatment-naïve ALK-positive NSCLC; the related second-line trial (PROFILE 1007, Shaw AT et al, NEJM 2013) showed crizotinib superior to chemotherapy after progression.
Key Limitations
Open-label design; chemotherapy comparator. 84% crossover confounds OS, which was not statistically significant. No CNS-dedicated endpoints; crizotinib has limited intracranial activity. Now superseded by next-generation ALK TKIs in 1L.
Clinical Context
PROFILE 1014 established crizotinib as the first 1L ALK TKI standard (FDA 1L approval 2016). Now displaced by alectinib, brigatinib, and lorlatinib, which offer superior PFS and CNS control. Study update: Solomon BJ et al, JCO 2018, PMID: 29768118.