[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.
—Alice T. Shaw, MD, PhD
In a phase III trial reported by Alice T. Shaw, MD, PhD, a thoracic oncologist at Massachusetts General Hospital, Boston, 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).1 Crizotinib treatment was also associated with a higher response rate and greater patient-reported reductions in symptoms and improvement in global quality of life.
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 IV pemetrexed (Alimta) at 500 mg/m2 (n = 99) or docetaxel 75 mg/m2 (n = 72) every 3 weeks (1 crizotinib and 3 chemotherapy patients 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, 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%), 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 in the intention-to-treat population were 65% with crizotinib and 20% with chemotherapy (P < .001). In the as-treated population, response rates were higher with crizotinib than with either type of chemotherapy (66% with crizotinib compared with 29% for pemetrexed and 7% for docetaxel; both P < .001).At the time of data cutoff, the median follow-up for overall survival was 12.2 months in the crizotinib group and 12.1 months in the chemotherapy group.
On interim analysis, median overall survival did not differ between the crizotinib and chemotherapy groups (20.3 months, 95% confidence interval [CI] = 18.1 months to not reached, vs 22.8 months, 95% CI = 18.6 months to not reached, HR = 1.02, P = .54). The authors noted that the overall survival findings are likely influenced by the high degree of crossover to crizotinib from the chemotherapy group.
High Crossover Rate
The duration of study drug treatment was longer in the crizotinib group (median, 31 vs 12 weeks). Of the 174 patients randomized to chemotherapy, 112 (64%) received crizotinib after disease progression. A total of 85 patients (49%) in the crizotinib group and 28 patients (16%) in the chemotherapy group were still receiving the study treatment at the time of data cutoff. More patients in the crizotinib group than in the chemotherapy group (58 vs 17) continued treatment beyond RECIST-defined progression, and the duration of such therapy was longer with crizotinib than with chemotherapy (median, 15.9 vs 6.9 weeks).
The safety analysis was not adjusted for the longer duration of treatment with crizotinib. The most common adverse events of any grade with crizotinib with an incidence ≥ 5% greater than that with chemotherapy were vision disorder (60% vs 9%), diarrhea (60% vs 19%), nausea (55% vs 37%), vomiting (47% vs 18%), constipation (42% vs 23%), elevated liver aminotransferases (38% vs 15%), edema (31% vs 16%), upper respiratory infection (26% vs 13%), dysgeusia (26% vs 9%), and dizziness (22% vs 8%). The most common adverse events with chemotherapy with an incidence ≥ 5% greater than that with crizotinib were fatigue (33% vs 27%), alopecia (20% vs 8%), dyspnea (19% vs 13%), and rash (17% vs 9%).
The most common grade 3 or 4 adverse events were elevated aminotransferases (16%) and dyspnea (4%) in crizotinib patients and fatigue (4%) and dyspnea (3%) in chemotherapy patients. Grade 3 or 4 neutropenia occurred in 13% of crizotinib patients, including one with febrile neutropenia, and in 19% of chemotherapy patients, including 9% (n = 16) with febrile neutropenia. 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 crizotinib patients and 10% of chemotherapy patients. Treatment-related death occurred in three patients in the crizotinib group (including the two who died from interstitial lung disease and one patient who died from ventricular arrhythmia) and in one patient in the chemotherapy group (due to sepsis). An additional crizotinib patient had hepatic dysfunction and subsequently died from hepatic failure after the data cutoff date.
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 patients 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).
With regard to global quality of life, the crizotinib group showed a statistically significant and clinically meaningful (≥ 10-point) improvement from baseline in cycle 4 and a statistically significant (but < 10-point) improvement in cycles 2 through 12 and cycle 14. In contrast, the chemotherapy group showed no significant change from baseline at any time point. The crizotinib group had a significantly greater overall improvement from baseline compared with the chemotherapy group for all functional domains except for cognitive functioning.
With regard to the high crossover rate from chemotherapy to crizotinib and the absence of a difference in overall survival at interim analysis, the investigators noted that median overall survival among all study patients from the time that second-line therapy was initiated was “remarkably high, at longer than 20 months, suggesting that the addition of crizotinib either before or after second-line chemotherapy may contribute to improving survival.”
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.” ■
Disclosure: The study was supported by Pfizer. For full disclosures of the study authors, visit www.nejm.org.
1. Shaw AT, Kim D-W, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385-2394, 2013.