Crizotinib Improves Progression-free Survival vs Pemetrexed or Docetaxel in Advanced ALK-positive NSCLC
In a phase III trial reported by Alice T. Shaw, MD, PhD, of Massachusetts General Hospital, and colleagues in The New England Journal of Medicine, crizotinib (Xalkori) improved progression-free survival compared with standard chemotherapy in previously treated patients with advanced ALK-positive non–small cell lung cancer (NSCLC). Crizotinib treatment was also associated with a higher response rate and greater patient-reported reductions in symptoms and improvement in global quality of life.
Study Details
In this open-label trial, 347 patients with locally advanced or metastatic ALK-positive NSCLC who had received one prior platinum-based regimen were randomly assigned to receive oral crizotinib at 250 mg twice daily (n = 173) or chemotherapy (n = 174) consisting of intravenous pemetrexed (Alimta) at 500 mg/m2 (n = 99) or docetaxel at 75 mg/m2 (n = 72) every 3 weeks (1 patient in the crizotinib group and 3 patients in the chemotherapy group did not receive study treatment). Patients in the chemotherapy group received pemetrexed unless their prior chemotherapy regimen contained pemetrexed or their tumor had predominantly squamous histologic features. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study.
Patients in the crizotinib and chemotherapy groups were well matched for age (median of 51 and 49 years, 84% and 87% < 65 years), sex (43% and 45% male), race (52% white in both, 46% and 45% Asian), smoking status (62% and 64% never smokers), histology (95% and 94% adenocarcinoma), Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 in 91% and 92%, respectively), metastatic disease (95% and 91%), and presence of brain metastases (35% and 34%).
Prolonged Progression-free Survival
Median progression-free survival, the primary endpoint, was 7.7 months in the crizotinib group vs 3.0 months in the chemotherapy group (hazard ratio [HR] = 0.49, P < .001). In a subgroup analysis, crizotinib was associated with significantly prolonged progression-free survival compared with both pemetrexed (HR = 0.59, P < .001) and docetaxel (HR = 0.30, P < .001). Crizotinib was associated with progression-free survival benefit in subgroup analyses according to ECOG performance status, presence or absence of brain metastases and prior epidermal growth factor receptor kinase inhibitor therapy, and other baseline characteristics.
Response rates were 65% with crizotinib and 20% with chemotherapy (P < .001); on as-treated analysis, response rates were 66% with crizotinib compared with 29% with pemetrexed and 8% with docetaxel (both P < .001). Median overall survival did not differ between the crizotinib (20.3 months, 95% confidence interval [CI] = 18.1 months to not reached) and chemotherapy groups (22.8 months, 95% CI = 18.6 months to not reached, HR = 1.02, P = .54). Of the 174 patients randomly assigned to chemotherapy, 112 (64%) received crizotinib after disease progression.
Adverse Events
The most common adverse events of any grade with crizotinib with an incidence ≥ 5% greater than that with chemotherapy were vision disorder, diarrhea, nausea, vomiting, constipation, elevated liver aminotransferases, edema, upper respiratory infection, dysgeusia, and dizziness. The most common adverse events with chemotherapy with an incidence ≥ 5% greater than that with crizotinib were fatigue, alopecia, dyspnea, and rash. The most common grade 3 or 4 adverse events were elevated aminotransferases (16%) and dyspnea (4%) in crizotinib-treated patients and fatigue (4%) and dyspnea (3%) in chemotherapy recipients.
Three patients in the crizotinib group (2%) had treatment-related interstitial lung disease of grade 3 or higher, with two of the cases being fatal. Treatment-related adverse events led to discontinuation of study drug in 6% of the crizotinib group and 10% of the chemotherapy group.
Improved Symptoms, Global Quality of Life
Evaluation with the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire (QLQ-C30) and corresponding lung cancer instrument (QLQ-LC13) showed that crizotinib recipients had significantly greater overall reductions from baseline in the symptoms of alopecia, cough, dyspnea, fatigue, chest pain, arm or shoulder pain, and other pain (all P < .001); a significant delay in median time to deterioration in cough, dyspnea, and chest pain (5.6 vs 1.4 months, HR = 0.54, P < .001); and a significantly greater overall improvement from baseline in global quality of life (P < .001).
The investigators concluded, “[T]his study showed that crizotinib … prolonged progression-free survival, increased response rates, and improved the quality of life in patients with advanced, previously treated ALK-positive NSCLC. The apparent lack of a survival benefit probably reflects the confounding effects of crossover, effects that have been observed in other randomized trials of molecularly targeted agents in patients with NSCLC.”
The study was supported by Pfizer. For full disclosures of the study authors, visit www.nejm.org.
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