BACKGROUNDBrigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, has robust efficacy in patients with ALK-positive non-small-cell lung cancer (NSCLC) that is refractory to crizotinib. The efficacy of brigatinib, as compared with crizotinib, in patients with advanced ALK-positive NSCLC who have not previously received an ALK inhibitor is unclear.
METHODSIn an open-label, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced ALK-positive NSCLC who had not previously received ALK inhibitors to receive brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg) or crizotinib at a dose of 250 mg twice daily. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included the objective response rate and intracranial response. The first interim analysis was planned when approximately 50% of 198 expected events of disease progression or death had occurred.
RESULTSA total of 275 patients underwent randomization; 137 were assigned to brigatinib and 138 to crizotinib. At the first interim analysis (99 events), the median followup was 11.0 months in the brigatinib group and 9.3 months in the crizotinib group. The rate of progression-free survival was higher with brigatinib than with crizotinib (estimated 12-month progression-free survival, 67% [95% confidence interval {CI}, 56 to 75] vs. 43% [95% CI, 32 to 53]; hazard ratio for disease progression or death, 0.49 [95% CI, 0.33 to 0.74]; P<0.001 by the log-rank test). The confirmed objective response rate was 71% (95% CI, 62 to 78) with brigatinib and 60% (95% CI, 51 to 68) with crizotinib; the confirmed rate of intracranial response among patients with measurable lesions was 78% (95% CI, 52 to 94) and 29% (95% CI, 11 to 52), respectively. No new safety concerns were noted.
CONCLUSIONSAmong patients with ALK-positive NSCLC who had not previously received an ALK inhibitor, progression-free survival was significantly longer among patients who received brigatinib than among those who received crizotinib. (Funded by Ariad Pharmaceuticals; ALTA-1L ClinicalTrials.gov number, NCT02737501.
Sugars, primarily glucose and fructose, are the main energy source of cells. Because of their hydrophilic nature, cells use a number of transporter proteins to introduce sugars through their plasma membrane. Cancer cells are well known to display an enhanced sugar uptake and consumption. In fact, sugar transporters are deregulated in cancer cells so they incorporate higher amounts of sugar than normal cells. In this paper, we compile the most significant data available about biochemical and biological properties of sugar transporters in normal tissues and we review the available information about sugar carrier expression in different types of cancer. Moreover, we describe the possible pharmacological interactions between drugs currently used in anticancer therapy and the expression or function of facilitative sugar transporters. Finally, we also go into the insights about the future design of drugs targeted against sugar utilization in cancer cells.
In this prospective phase III trial, afatinib combined with paclitaxel improved progression-free survival and objective response, compared with single-agent chemotherapy, in patients with NSCLC who were clinically enriched for ErbB dependency having failed platinum-based chemotherapy, gefitinib/erlotinib and afatinib monotherapy after initial benefit on each tyrosine kinase inhibitor.
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