Shrividya Iyer

BACKGROUND: In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. METHODS: We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. RESULTS: The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. CONCLUSIONS: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.).

BACKGROUND: The efficacy of the ALK inhibitor crizotinib as compared with standard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC) is unknown. METHODS: We conducted an open-label, phase 3 trial comparing crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease. Patients were randomly assigned to receive oral crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy (pemetrexed, 500 mg per square meter of body-surface area, plus either cisplatin, 75 mg per square meter, or carboplatin, target area under the curve of 5 to 6 mg per milliliter per minute) every 3 weeks for up to six cycles. Crossover to crizotinib treatment after disease progression was permitted for patients receiving chemotherapy. The primary end point was progression-free survival as assessed by independent radiologic review. RESULTS: Progression-free survival was significantly longer with crizotinib than with chemotherapy (median, 10.9 months vs. 7.0 months; hazard ratio for progression or death with crizotinib, 0.45; 95% confidence interval [CI], 0.35 to 0.60; P<0.001). Objective response rates were 74% and 45%, respectively (P<0.001). Median overall survival was not reached in either group (hazard ratio for death with crizotinib, 0.82; 95% CI, 0.54 to 1.26; P=0.36); the probability of 1-year survival was 84% with crizotinib and 79% with chemotherapy. The most common adverse events with crizotinib were vision disorders, diarrhea, nausea, and edema, and the most common events with chemotherapy were nausea, fatigue, vomiting, and decreased appetite. As compared with chemotherapy, crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life. CONCLUSIONS: Crizotinib was superior to standard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC. (Funded by Pfizer; PROFILE 1014 ClinicalTrials.gov number, NCT01154140.).

PURPOSE: In the initial PALOMA-2 (NCT01740427) analysis with median follow-up of 23 months, palbociclib plus letrozole significantly prolonged progression-free survival (PFS) in women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) [hazard ratio (HR) 0.58; P < 0.001]. Herein, we report results overall and by subgroups with extended follow-up. METHODS: In this double-blind, phase 3 study, post-menopausal women with ER+/HER2- ABC who had not received prior systemic therapy for their advanced disease were randomized 2:1 to palbociclib-letrozole or placebo-letrozole. Endpoints include investigator-assessed PFS (primary), safety, and patient-reported outcomes (PROs). RESULTS: After a median follow-up of approximately 38 months, median PFS was 27.6 months for palbociclib-letrozole (n = 444) and 14.5 months for placebo-letrozole (n = 222) (HR 0.563; 1-sided P < 0.0001). All subgroups benefited from palbociclib treatment. The improvement of PFS with palbociclib-letrozole was maintained in the next 2 subsequent lines of therapy and delayed the use of chemotherapy (40.4 vs. 29.9 months for palbociclib-letrozole vs. placebo-letrozole). Safety data were consistent with the known profile. Patients' quality of life was maintained. CONCLUSIONS: With approximately 15 months of additional follow-up, palbociclib plus letrozole continued to demonstrate improved PFS compared with placebo plus letrozole in the overall population and across all patient subgroups, while the safety profile remained favorable and quality of life was maintained. These data confirm that palbociclib-letrozole should be considered the standard of care for first-line therapy in patients with ER+/HER2- ABC, including those with low disease burden or long disease-free interval. Sponsored by Pfizer; ClinicalTrials.gov: NCT01740427.

BACKGROUND: Postoperative ileus, a transient impairment of gastrointestinal motility, is a common cause of delay in return to normal bowel function after abdominal surgery. Colectomy surgery patients who develop postoperative ileus could have greater health care resource utilization, including prolonged hospitalization, compared with those who do not develop postoperative ileus. Very few studies have assessed the impact of postoperative ileus on resource utilization and costs using retrospective analysis of administrative databases. OBJECTIVE: To assess health care utilization and costs in colectomy surgery patients who developed postoperative ileus versus those who did not. METHODS: A retrospective cohort study design was used. Adult patients with a principal procedure code for colectomy (ICD-9-CM procedure codes 45.71-45.79), discharged between January 1, 2004, and December 31, 2004, were identified from the Premier Perspective database of inpatient records from more than 500 hospitals in the United States. The colectomy patients were further classified for the presence of postoperative ileus, identified by the presence, in any diagnosis field on the administrative patient records, of a code for paralytic ileus (ICD-9-CM code 560.1) and/or digestive system complications (ICD-9-CM code 997.4) during the inpatient stay. Code 997.4 was used to account for cases in which postoperative ileus would be reported as a complication of anastomosis, as could be the case in colectomy surgeries. Hospital length of stay (LOS) and hospitalization costs were compared using t-tests. Multivariate analyses were performed with log-transformed LOS and log-transformed cost as the dependent variables. Patient demographics, mortality risk, disease severity, admission source, payment type (retrospective/prospective), and hospital characteristics were used as covariates. RESULTS: A total of 17,876 patients with primary procedure code for colectomy were identified, of whom 3115 (17.4%) patients were classified for presence of postoperative ileus (including paralytic ileus only [n=1216; 6.8%], digestive system complications only [n=383; 2.1%], or both [n=1516; 8.5%]). A majority of the colectomy patients with and without postoperative ileus, respectively, were male (54.1% vs. 50.3%, P < 0.001), Caucasian (70.5% vs. 69.3%, P = 0.170), and aged 51-64 years (51.1% vs. 49.7%, P = 0.143). The mean [SD] hospital LOS was significantly longer in patients with postoperative ileus (13.8 [13.3] days) compared with patients without postoperative ileus (8.9 [9.5] days; P < 0.001). Presence of postoperative ileus was found to be a significant predictor of LOS (P < 0.001) in the regression model, controlling for covariates. Female gender (P = 0.002), greater severity level (P < 0.001), and hospital bed size of more than 500 (P = 0.013) were other significant predictors of hospital LOS. Presence of postoperative ileus was found to be a significant predictor of hospitalization costs (P < 0.001), controlling for covariates. CONCLUSION: Postoperative ileus in colectomy patients is a significant predictor of hospital resource utilization.