Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study

Abstract

Background: ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively identified to have an ALK fusion within the first-in-man phase 1 crizotinib study.

Methods: In this phase 1 study, patients with ALK-positive stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles. Endpoints included tumour responses, duration of response, time to tumour response, progression-free survival (PFS), overall survival at 6 and 12 months, and determination of the safety and tolerability and characterisation of the plasma pharmacokinetic profile of crizotinib after oral administration. Responses were analysed in evaluable patients and PFS and safety were analysed in all patients. This study is registered with ClinicalTrials.gov, number NCT00585195.

Findings: Between Aug 27, 2008, and June 1, 2011, 149 ALK-positive patients were enrolled, 143 of whom were included in the response-evaluable population. 87 of 143 patients had an objective response (60·8%, 95% CI 52·3-68·9), including three complete responses and 84 partial responses. Median time to first documented objective response was 7·9 weeks (range 2·1-39·6) and median duration of response was 49·1 weeks (95% CI 39·3-75·4). The response rate seemed to be largely independent of age, sex, performance status, or line of treatment. Median PFS was 9·7 months (95% CI 7·7-12·8). Median overall survival data are not yet mature, but estimated overall survival at 6 and 12 months was 87·9% (95% CI 81·3-92·3) and 74·8% (66·4-81·5), respectively. 39 patients continued to receive crizotinib for more than 2 weeks after progression because of perceived ongoing clinical benefit from the drug (12 for at least 6 months from the time of their initial investigator-defined disease progression). Overall, 144 (97%) of 149 patients experienced treatment-related adverse events, which were mostly grade 1 or 2. The most common adverse events were visual effects, nausea, diarrhoea, constipation, vomiting, and peripheral oedema. The most common treatment-related grade 3 or 4 adverse events were neutropenia (n=9), raised alanine aminotransferase (n=6), hypophosphataemia (n=6), and lymphopenia (n=6).

Interpretation: Crizotinib is well tolerated with rapid, durable responses in patients with ALK-positive NSCLC. There seems to be potential for ongoing benefit after initial disease progression in this population, but a more formal definition of ongoing benefit in this context is needed.

Conflict of interest statement

Conflicts of interest

DRC, Y-JB, ELK, AJI, BS, S-HIO, D-WK, PAJ, DBC, PLR, and ATS received honoraria or consulting fees from Pfizer. ELK, GJR, BS, and JWC received research funding from Pfizer. AJI, MV-G, and GJR received honoraria or consulting fees from Abbott Molecular. GJR, LG, and ATS received honoraria or consulting fees from Chugai. GJR received research funding from Chugai, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Infinity Pharmaceuticals, and Merck; and honoraria or consulting fees from Daiichi and Tragara. GJR and ATS received honoraria or consulting fees from Novartis and Ariad and research funding from Novartis. PF received honoraria or consulting fees from Genentech. DBC received honoraria or consulting fees from AstraZeneca and Roche. KR, YT, and KW are employees and stockholders of Pfizer. ATS received research funding from AstraZeneca. SBF, RS, JAE, GIS, and PS declare that they have no conflicts of interest.

Copyright © 2012 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Waterfall plot of best percent change in target lesions from baseline for 133* patients on the basis of investigator assessment

*Excludes patients with early death before re-imaging, non-measurable non-target disease, or indeterminate responses: five patients with a best overall response of indeterminate either had available on-study scans that could not be assessed or discontinued the study before to obtaining adequate scans to assess response; three patients died within 42 days from first dose; and two patients had non-target lesions only.

Figure 2. Kaplan–Meier plot of progression-free survival

64 patients were censored, of whom 52 remained in follow-up for progression-free survival.

Figure 3. Duration of initial response or stable disease and of ongoing crizotinib treatment in patients who continued to receive crizotinib after progression

Patients are ordered by initial best response before progression and duration of crizotinib treatment after progression (n=39). *Defined as the time (in weeks) from the first documentation of objective tumour response (complete response or partial response) that was subsequently confirmed, to the first documentation of progressive disease or death. Stable disease duration was calculated from the date of the first dose to the date of first documented disease progression. †Defined as time from investigator-documented progressive disease to the last date of crizotinib dose or censor at the time of analysis. Disease progression and best objective response were derived according to Response Evaluation Criteria in Solid Tumors. ‡Treatment ongoing at the time of analysis. §Received crizotinib as first-line treatment.

Figure 4. Prevalence of common treatment-related grade 1 or 2 adverse events during crizotinib treatment

Prevalence of adverse events for cycle 7 and beyond is presented as the proportion of patients at risk who experienced a particular event.