Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer

By Eunice Lee Kwak, Y. Bang, D. Camidge, Alice T. Shaw, B. Solomon, Robert G. Maki, Sai-Hong Ignatius Ou, B. Dezube, P. Jänne, D. B. Costa and 21 more. New England Journal of Medicine, 2010

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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.

Subfields: Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/71060c8283cb3a03c940867923f4851a816d77b0

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Citations in the corpus

Rociletinib in EGFR-mutated non-small-cell lung cancer. (2015, neutral): “Decreased appetite 19 (15) 1 (3) 6 (32) 4 (24) 3 (19) 3 (9) 2 (33) 18 (20)”
Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. (2015, background): “As with EGFR, ALK rearrangements are more likely to be seen in specific populations; younger patients who are light or never-smokers with adenocarcinoma and frequent signet ring cells seen on histology (97-101).”
First-line crizotinib versus chemotherapy in ALK-positive lung cancer. (2014, neutral): “Thrombocytopenia§ 2 (1) 0 31 (18) 11 (7)”
Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors (2013, neutral): “A recent report of a large clinical series indicated that ALK rearrangements were seen in about 5% of 1500 NSCLC patients screened.(13) Moreover, ALK rearrangement-positive patients treated with a novel ALK inhibitor, crizotinib, showed an overall response rate of 57%, with 72% having a PFS of 6 mon”
Systematic identification of genomic markers of drug sensitivity in cancer cells (2012, methodology): “PD0332991CDK4/6 (RB1) AxatinibPDGFR,KIT,VEGFR (BCR-ABL) AZD6244MEK (BRAF) GW441756NTRK1 (FLT3) WH-4-023SRC,ABL (CDKN2A) (2) (1) 1 × 10–28 (1)”