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.

Conflict of interest statement

Conflicts of interest

ATS, BJS, DBC, RGM, Y-JB, ELK, and AJI received honoraria or consulting fees from Pfizer. RGM served as a paid expert witness for Pfizer. BJS, GJR, GIS, RGM, and Y-JB received research funding from Pfizer. KK, PS, YT, and KDW are employees and stockholders of Pfizer. AJI received honoraria or consulting fees from Abbott Laboratories. ATS, GJR, JAE, and JWC received honoraria or consulting fees from ARIAD. ATS and GJR received honoraria or consulting fees from Chugai. GJR received honoraria or consulting fees from Merck, Boehringer-Ingelheim, and Tragara. JAE received consulting fees and research funding from Novartis and AstraZeneca. All other authors declared no conflicts of interest.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

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.