Elsevier

The Lancet Oncology

Volume 12, Issue 11, October 2011, Pages 1004-1012
The Lancet Oncology

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

https://doi.org/10.1016/S1470-2045(11)70232-7Get rights and content

Summary

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.

Introduction

Anaplastic lymphoma kinase (ALK) is one of the newest tyrosine-kinase targets in non-small-cell lung cancer (NSCLC). In about 4% of NSCLC tumours, ALK is aberrantly activated because of a chromosomal rearrangement, leading to expression of an oncogenic fusion kinase, such as EML4–ALK.1, 2, 3, 4, 5 Chromosomal rearrangements and other genetic alterations of ALK also occur in anaplastic large-cell lymphoma,6 inflammatory myofibroblastic tumour,7, 8 and paediatric neuroblastoma.9, 10, 11 In NSCLC, ALK rearrangement is associated with distinct clinicopathological features, including young age of onset, absent or minimal smoking history, and adenocarcinoma histology.4, 12, 13, 14, 15 EML4–ALK and other oncogenic drivers such as mutant EGFR and oncogenic KRAS are generally mutually exclusive,12 consistent with the notion that ALK rearrangement defines a unique molecular subset of NSCLC.

Preclinical and clinical studies have shown that cancer cells harbouring EML4ALK and other ALK abnormalities are exquisitely sensitive to ALK inhibition.3, 16 In a recent phase 1 clinical trial, crizotinib (PF-02341066), the first clinically available tyrosine-kinase inhibitor (TKI) targeting ALK, showed marked antitumour activity in patients with advanced, ALK-positive NSCLC.17 Response and survival data from this trial were recently updated; among 119 evaluable patients, most of whom had received more than one previous line of therapy, the objective response rate was 61% and median progression-free survival (PFS) was 10 months.18 By comparison, standard single-agent chemotherapies for previously treated, unselected metastatic NSCLC are associated with an objective response rate of less than 10% and a median PFS of less than 3 months.19, 20 In the phase 1 trial, crizotinib also showed substantial activity in one patient with ALK-rearranged inflammatory myofibroblastic tumour.21 Furthermore, the side-effects of crizotinib were generally mild and well tolerated.17 Based on these results and those from an ongoing phase 2 trial (NCT00932451), crizotinib has received accelerated approval in the USA.

The effect of crizotinib on overall survival in patients with ALK-positive NSCLC is not yet known. Overall survival has traditionally been regarded as the gold standard for evaluating clinical benefit in clinical trials. However, in the era of targeted therapies, prospective genotyping, and rapid drug development, assessing overall survival benefit poses unique challenges. For example, in the IPASS study,22 gefitinib was associated with a higher response rate and improved PFS compared with standard carboplatin plus paclitaxel chemotherapy in newly diagnosed, EGFR-mutation-positive patients. However, in the final analysis of IPASS, overall survival (a secondary endpoint) was similar between patients who received gefitinib and those who received carboplatin plus paclitaxel.23 Several factors might account for the similar survival outcomes. In particular, a large proportion of chemotherapy-treated patients received subsequent post-study treatments including gefitinib, effectively crossing over to the other study group. A similar issue might also confound evaluation of overall survival in the ongoing phase 3 registration trials of crizotinib, since ALK-positive patients randomised to receive chemotherapy who experience disease progression are eligible to cross over to receive crizotinib. With the recent approval of crizotinib in the USA, crizotinib might become a standard therapy for patients with ALK-positive NSCLC. As a result, assessment of overall survival benefit using a traditional randomised controlled trial with no crossover will not be possible.

In the absence of data from a randomised controlled trial, we addressed whether crizotinib improves survival by comparing overall survival in crizotinib-treated, ALK-positive patients with that in a control group consisting of patients who were retrospectively or prospectively shown to be ALK positive but never received crizotinib. Additionally, we examined overall surival in control groups of ALK-negative patients, including a TKI-sensitive, EGFR-mutant cohort and EGFR wild-type patients, to examine the survival effect of crizotinib in the context of other well defined subsets of NSCLC.

Section snippets

Study populations and procedures

Three populations were used in these retrospective analyses (figure 1). The crizotinib group consisted of a subgroup of 82 patients with advanced ALK-positive NSCLC who received crizotinib in the phase 1 clinical trial (NCT00585195).17 These patients were enrolled at one of seven study sites between Dec 26, 2007, and Feb 10, 2010. For all patients, ALK positivity was confirmed by fluorescence in-situ hybridisation (FISH).12 ALK FISH was done before trial enrolment, using the initial diagnostic

Results

We assessed overall survival in the subgroup of 82 patients with advanced, ALK-positive NSCLC who had enrolled on the multicentre phase 1 clinical trial of crizotinib.17 These patients were mainly young (median age 51 years [range 25–78]), never smokers with adenocarcinoma histology, as previously reported.17 Among the 82 patients, 50 (61%) were enrolled at US study sites, 26 (32%) at the Korean site, and the remaining six (7%) in Australia. Since the protocol placed no restriction on the

Discussion

Our data suggest that overall survival for patients with advanced ALK-positive NSCLC was significantly longer in the subset of patients given second-line or third-line crizotinib than in clinically comparable, crizotinib-naive controls. Thus, crizotinib might prolong overall survival in ALK-positive NSCLC. Additionally, crizotinib-naive, ALK-positive patients had a generally poor outcome, similar to that of the general population of NSCLC patients. Thus, ALK rearrangement is not a favourable

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