Final Overall Survival Analysis of First-Line Crizotinib vs Chemotherapy in Advanced ALK-Positive NSCLC


Key Points

  • The unadjusted survival benefit of crizotinib was not significant, likely reflecting the high rate of crossover to crizotinib in the chemotherapy group.
  • The longest survival was among patients treated with crizotinib who subsequently received ALK inhibitor therapy. 

As reported by Solomon and colleagues in the Journal of Clinical Oncology, the final overall survival results of the phase III PROFILE 1014 trial showed evidence of survival benefit of first-line crizotinib (Xalkori) vs chemotherapy in advanced ALK-positive non–small cell lung cancer (NSCLC). A prior report of the primary analysis of the trial showed that crizotinib significantly prolonged progression-free survival (10.9 vs 7.0 months, hazard ratio [HR] = 0.45, P < .001).

Study Details

In the open-label trial, 343 patients were randomized between January 2011 and July 2013 to receive crizotinib (n = 172) or investigator choice of chemotherapy (n = 171), with 91 receiving pemetrexed (Alimta)/cisplatin and 78 receiving pemetrexed/carboplatin. Treatment consisted of oral crizotinib 250 mg twice daily or intravenous pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin area under the curve = 5 every 3 weeks for a maximum of 6 cycles. Crossover to crizotinib was permitted after disease progression. Overall survival was analyzed by stratified log-rank test and a prespecified rank-preserving structural failure time model to account for patient crossover.

Overall Survival

Median follow-up for overall survival was approximately 46 months in both groups. In the chemotherapy group, 144 patients (84%) received crizotinib in subsequent treatment lines after progression. Median overall survival was not reached in the crizotinib group vs 45.8 to 47.5 months in the chemotherapy group (HR = 0.760, P = .0978). Overall survival at 4 years was 56.6% vs 49.1%. After adjustment for crossover to crizotinib treatment, the crizotinib group showed an overall survival benefit (HR = 0.346, 95% bootstrap confidence interval = 0.081–0.718). Median overall survival was not reached among 57 patients in the crizotinib group who received at least one ALK inhibitor in subsequent treatment, 49.5 months among 145 patients in the chemotherapy group who received at least one ALK inhibitor, and 20.8 months among 37 patents in the crizotinib group who did not receive subsequent ALK inhibitor treatment.

The investigators concluded, “The final analysis of the PROFILE 1014 study provides a new benchmark for [overall survival] in patients with ALK-rearranged non–small-cell lung cancer and highlights the benefit of crizotinib for prolonging survival in this patient population.” They noted: “The absence of a statistically significant difference in [overall survival] despite the significant effect of crizotinib on [progression-free survival] likely highlights the effect of crossover and the impact of highly effective post-progression therapy on the outcome.”

The study was sponsored by Pfizer.

Benjamin J. Solomon, MBBS, PhD, of the Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, is the corresponding author for the Journal of Clinical Oncology article. 

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