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Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer
Eunice L Kwak1, Yung-Jue Bang, D Ross Camidge
1Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA. ekwak@partners.org
Background:
Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase.
Methods:
After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy.
Results:
Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects.
Conclusions:
The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
Insights
Crizotinib effectively treats non-small-cell lung cancer with anaplastic lymphoma kinase (ALK) rearrangements, showing significant tumor shrinkage and stable disease. This targeted therapy offers a promising option for ALK-positive lung cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Clinical Trials
Background:
- Non-small-cell lung cancer (NSCLC) harbors oncogenic EML4-anaplastic lymphoma kinase (ALK) fusion genes in 2-7% of cases.
- Targeting ALK tyrosine kinase presents a therapeutic strategy for ALK-rearranged NSCLC.
Purpose of the Study:
- To evaluate the therapeutic efficacy of crizotinib, an ALK inhibitor, in patients with advanced ALK-positive NSCLC.
- To assess response rates, progression-free survival, and adverse events associated with crizotinib treatment.
Main Methods:
- Screening of approximately 1500 NSCLC tumor samples identified 82 patients with advanced ALK rearrangements.
- An expanded cohort received crizotinib 250 mg twice daily; patients were assessed for adverse events and treatment response.
Main Results:
- Patients with ALK rearrangements were often younger, non-smokers, and had adenocarcinomas.
- An overall response rate of 57% (47/82) was observed, with 33% (27/82) achieving stable disease.
- Estimated 6-month progression-free survival was 72%, with 77% of patients continuing treatment.
Conclusions:
- Inhibition of ALK in lung tumors with ALK rearrangements leads to tumor shrinkage or stable disease in the majority of patients.
- Crizotinib demonstrates significant efficacy in treating ALK-positive NSCLC with manageable gastrointestinal side effects.
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