First-Line Crizotinib Improves Progression-Free Survival vs Chemotherapy in ALK-Positive NSCLC
In a phase III PROFILE 1014 trial reported in The New England Journal of Medicine, Solomon et al found that the ALK inhibitor crizotinib (Xalkori) improved progression-free survival vs standard chemotherapy in first-line treatment of advanced ALK-positive non–small cell lung cancer (NSCLC). Crizotinib was associated with significant improvements in patient-reported outcomes. Median overall survival had not been reached in either group.
Study Details
In this open-label international trial, 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease were randomly assigned between January 2011 and July 2013 to receive oral crizotinib at 250 mg twice daily (n = 172) or intravenous chemotherapy (n = 171) consisting of pemetrexed (Alimta) at 500 mg/m2 plus either cisplatin at 75 mg/m2 or carboplatin at an area under the curve of 5 to 6 mg/mL/min every 3 weeks for up to six cycles.
Randomization was stratified according to Eastern Cooperative Oncology Group (ECOG) performance status, Asian or non-Asian race, and presence or absence of brain metastases. Crossover to crizotinib after disease progression was permitted. The primary endpoint was progression-free survival assessed by independent radiologic review.
The crizotinib and chemotherapy groups were generally balanced for age (median, 52 and 54 years), sex (60% and 63% female), race (53% and 50% white, 45% and 47% Asian), smoking status (never for 62% and 65%, former for 33% and 32%, and current for 6% and 3%), histology (adenocarcinoma in 94% in both), ECOG performance status (0 or 1 in 94% and 95%), extent of disease (locally advanced in 2% in both, metastatic in 98% in both), brain metastases (26% and 27%), and time since initial diagnosis (median, 1.2 months in both). Among evaluable intravenous chemotherapy patients, 91 received pemetrexed/cisplatin and 78 received pemetrexed/carboplatin.
Significantly Improved Progression-Free Survival
At the time of data cutoff, median duration of follow-up for overall survival was 17.4 months in the crizotinib group and 16.7 months in the chemotherapy group. The median duration of treatment was 10.9 months (range, 0.4–34.3 months) in the crizotinib group (median of 16 cycles started) and 4.1 months (range, 0.7–6.2 months ) in the chemotherapy group (median of six cycles of chemotherapy started).
Progression-free survival was significantly longer with crizotinib than with chemotherapy (median, 10.9 vs 7.0 months; hazard ratio [HR] = 0.45, P < .001). Subgroup analysis showed that hazard ratios significantly favored crizotinib in almost all stratification and baseline characteristic subgroups, including Asian (HR = 0.44) and non-Asian patients (HR = 0.53), age < or ≥ 65 years, sex, never and current/former smokers, and presence or absence of brain metastases.
Response Rates and Overall Survival
Objective response rates were significantly different (P < .001) at 74% (including complete response in 2%) vs 45% (including complete response in 1%). Median duration of response was 11.3 vs 5.3 months.
Median overall survival was not reached in either group (HR = 0.82, P = .36), likely reflecting the low rate of all-cause mortality in the population (26%) and the fact that 70% of patients in the chemotherapy group crossed over to crizotinib treatment. The probability of 1-year survival was 84% vs 79% with chemotherapy. After adjustment for crossover with a rank-preserving structural failure time model, the hazard ratio for death with crizotinib was 0.60 (95% confidence interval = 0.27–1.42).
Among patients in the crizotinib group, 74 (83%) of 89 with progression continued to receive crizotinib for a median of 3.0 months (range, 0.7–22.6 months); 21 crizotinib recipients (12%) subsequently received platinum-based chemotherapy.
Adverse Events
The most common adverse events of any grade with a frequency ≥ 5% greater in the crizotinib group were vision disorder (71% vs 9%), diarrhea (61% vs 13%), edema (49% vs 12%), vomiting (46% vs 36%), and constipation (43% vs 30%); the most common with a frequency ≥ 5% greater in the chemotherapy group were fatigue (38% vs 29%), anemia (32% vs 9%), and neutropenia (30% vs 21%). The most common grade 3 or 4 adverse events were elevated aminotransferases (14%) and neutropenia (11%) in the crizotinib group and neutropenia (15%), anemia (9%), and thrombocytopenia (7%) in the chemotherapy group.
Adverse events led to treatment discontinuation in 12% of the crizotinib group and 14% of the chemotherapy group; events leading to discontinuation in the crizotinib group included hepatic events in four patients and interstitial lung disease in two patients. One case of fatal pneumonitis occurred in a patient who crossed over to crizotinib and was considered related to crizotinib treatment.
Patient-Reported Outcomes
Patient-reported outcomes were assessed by the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life core questionnaire (QLQ-C30) and corresponding lung cancer module (QLQ-LC13) and the EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D). Crizotinib treatment was associated with greater overall improvement from baseline in global quality of life (P < .001), overall improvement in physical, social, emotional, and role functioning domains (P < .001), and overall reduction in the symptoms of pain, dyspnea, and insomnia assessed by QLQ-C30 and in dyspnea, cough, chest pain, arm or shoulder pain, and pain in other parts of the body assessed by QLQ-LC13 (P < .001 for all comparisons). The crizotinib group also had a significantly greater delay in worsening of lung cancer symptoms (HR = 0.62, P = .002), with estimated probability of being event-free at 6 months of 38% vs 22%, and a greater improvement in EQ-5D general health status scores (P = .002).
The investigators concluded: “[I]in patients with previously untreated ALK-positive NSCLC, crizotinib treatment was superior to pemetrexed-plus-platinum chemotherapy with respect to progression-free survival, objective response rate, reduction of lung-cancer symptoms, and improvement in quality of life.”
Benjamin J. Solomon, MB, BS, PhD, of Peter MacCallum Cancer Centre, Melbourne, is the corresponding author for The New England Journal of Medicine article. Dr. Solomon and Tony Mok, MD, of Chinese University of Hong Kong, contributed equally to the article.
The study was funded by Pfizer. For full disclosures of the study authors, visit www.nejm.org.
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