Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis

Abstract

Background: ALK gene rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). In a recent phase 1 clinical trial, the ALK tyrosine-kinase inhibitor (TKI) crizotinib showed marked antitumour activity in patients with advanced, ALK-positive NSCLC. To assess whether crizotinib affects overall survival in these patients, we did a retrospective study comparing survival outcomes in crizotinib-treated patients in the trial and crizotinib-naive controls screened during the same time period.

Methods: We examined overall survival in patients with advanced, ALK-positive NSCLC who enrolled in the phase 1 clinical trial of crizotinib, focusing on the cohort of 82 patients who had enrolled through Feb 10, 2010. For comparators, we identified 36 ALK-positive patients from trial sites who were not given crizotinib (ALK-positive controls), 67 patients without ALK rearrangement but positive for EGFR mutation, and 253 wild-type patients lacking either ALK rearrangement or EGFR mutation. To assess differences in overall survival, we assessed subsets of clinically comparable ALK-positive and ALK-negative patients.

Findings: Among 82 ALK-positive patients who were given crizotinib, median overall survival from initiation of crizotinib has not been reached (95% CI 17 months to not reached); 1-year overall survival was 74% (95% CI 63-82), and 2-year overall survival was 54% (40-66). Overall survival did not differ based on age, sex, smoking history, or ethnic origin. Survival in 30 ALK-positive patients who were given crizotinib in the second-line or third-line setting was significantly longer than in 23 ALK-positive controls given any second-line therapy (median overall survival not reached [95% CI 14 months to not reached] vs 6 months [4-17], 1-year overall survival 70% [95% CI 50-83] vs 44% [23-64], and 2-year overall survival 55% [33-72] vs 12% [2-30]; hazard ratio 0·36, 95% CI 0·17-0·75; p=0·004). Survival in 56 crizotinib-treated, ALK-positive patients was similar to that in 63 ALK-negative, EGFR-positive patients given EGFR TKI therapy (median overall survival not reached [95% CI 17 months to not reached] vs 24 months [15-34], 1-year overall survival 71% [95% CI 58-81] vs 74% [61-83], and 2-year overall survival 57% [40-71] vs 52% [38-65]; p=0·786), whereas survival in 36 crizotinib-naive, ALK-positive controls was similar to that in 253 wild-type controls (median overall survival 20 months [95% CI 13-26] vs 15 months [13-17]; p=0·244).

Interpretation: In patients with advanced, ALK-positive NSCLC, crizotinib therapy is associated with improved survival compared with that of crizotinib-naive controls. ALK rearrangement is not a favourable prognostic factor in advanced NSCLC.

Funding: Pfizer Inc, V Foundation for Cancer Research.

Trial registration: ClinicalTrials.gov NCT00585195.

Figure 1. Summary of study populations

The three study populations and subsets analysed are shown. Double-headed arrows highlight comparisons between specific patient subsets shown in subsequent figures. MGH=Massachusetts General Hospital.

Figure 2. Overall survival for ALK-positive, crizotinib-treated patients

Overall survival is shown for the subset of 82 ALK-positive patients who enrolled on the international, multicentre phase 1 clinical trial of crizotinib. Overall survival was calculated from the date of first crizotinib dose.

Figure 3. Overall survival for crizotinib-treated versus crizotinib-naive, ALK-positive patients

Overall survival was calculated from second-line or third-line crizotinib therapy in 30 ALK-positive patients, and from any second-line therapy in 23 ALK-positive controls.

Figure 4. Overall survival for ALK-positive versus ALK-negative patients

(A) Overall survival for 56 crizotinib-treated, ALK-positive patients compared with 63 ALK-negative, EGFR-positive patients who received erlotinib or gefitinib. Overall survival was calculated from the start of crizotinib or EGFR TKI therapy. (B) Overall survival comparison for ALK-positive vs ALK-negative, EGFR-negative (wild-type) patients. Overall survival was calculated from second-line or third-line crizotinib in 30 ALK-positive patients and from any second-line therapy in 23 ALK-positive controls and 125 wild-type controls. p value is for the difference in overall survival between crizotinib-treated, ALK-positive patients and wild-type controls. (C) Overall survival comparison for 36 ALK-positive, crizotinib-naive patients vs 253 wild-type controls. Overall survival was calculated from metastatic diagnosis. (D) Overall survival analysis in younger (≤60 years) never or light-smoking patients in the ALK-positive, crizotinib-naive vs wild-type groups. Overall survival was calculated from metastatic diagnosis.