The anaplastic lymphoma kinase (ALK)-inhibitor crizotinib leads to longer progression-free survival than chemotherapy in patients with advanced ALK-positive non–small-cell lung cancer (NSCLC), according to results of a phase III clinical trial published in the New England Journal of Medicine.
Rearrangement of the ALK gene represents a distinct molecular subtype that accounts for approximately 5% of all lung cancer cases. Crizotinib has been developed by Pfizer as an inhibitor of several tyrosine kinases, ALK among them. Prior clinical studies using this agent had shown antitumor activity in advanced NSCLC, and in 2011 the drug was approved by the US Food and Drug Administration (FDA) to treat patients with late-stage NSCLC under the FDA’s accelerated approval program.
Crizotinib was evaluated in a randomized, open-label phase III trial, recruiting a total of 347 patients. Of the 347 patients recruited into the study, 173 were randomized to twice-daily oral crizotinib, and the other 174 patients received chemotherapy (intravenous pemetrexed or docetaxel every 3 weeks). Patients were eligible for the trial if they had locally advanced or metastatic NSCLC that tested positive for ALK gene rearrangement as assessed by fluorescence in situ hybridization and showed progression after at least one round of chemotherapy. The primary endpoint of the study was progression-free survival, with secondary outcomes of overall survival, response rate, safety, and patient-reported outcomes.
The results showed that median progression-free survival in the crizotinib cohort was significantly improved over chemotherapy (7.7 months vs 3 months, HR = 0.49, P < .001). In addition, the response rate was higher in the crizotinib-treated patients (65% in the crizotinib cohort vs 20% in the chemotherapy cohort, P < .001). Overall survival data were not fully matured at the time of publication, but an interim analysis showed no significant improvement with crizotinib treatment over chemotherapy. However, the authors remarked that the “analysis was immature, and it is likely that it was confounded by the high crossover rate among patients in the chemotherapy group,” referring to the opportunity for patients to switch over to crizotinib therapy if they failed to respond to the chemotherapy regimen.
Severe adverse and patient-reported events were shown to be related to crizotinib therapy, including visual disorders, gastrointestinal side effects (eg, diarrhea, nausea, and vomiting), and elevated liver enzyme levels. Patients treated with crizotinib experienced more adverse events than patients on chemotherapy, but these were mainly limited to grade 1 and 2 phenomena. The rate of grade 3 or 4 adverse events was similar between the two groups. Both crizotinib and chemotherapy produced similar rates of hair loss, fatigue, and shortness of breath.
While crizotinib has shown promising results, acquired resistance remains a possibility, as is common with kinase inhibitors in the treatment of different forms of cancer. The same issue of the New England Journal of Medicine described a case report of a woman in the trial with a CD74–ROS1 mutation, who initially responded to crizotinib therapy. However, after 3 months she experienced progression of disease. Researchers used reverse-transcriptase PCR and deep sequencing on a biopsy of the malignant tissue in an effort to determine the cause of acquired resistance. A replacement of the natural glycine residue by arginine in the ROS1 protein at the 2032 position was a mutation that had not been present prior to treatment. All sites of metastases carried this mutation. By expressing this mutant form of ROS1 into HEK293 cells, the researchers were able to demonstrate resistance to crizotinib treatment. Finally, a crystal structure revealed that the substitution created a steric clash between the ATP binding site and crizotinib, preventing effective binding without a significant loss of ATP binding.