Clinically meaningful improvement in symptoms and quality of life for patients with non-small-cell lung cancer receiving gefitinib in a randomized controlled trial.

PURPOSE Evaluation of disease-related symptom improvement rate by the Lung Cancer Subscale (LCS) of the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire was a coprimary end point of the pivotal phase II trial of gefitinib (Iressa; AstraZeneca, Wilmington, DE) conducted in the United States. This report includes the results of analyses exploring the relationship between weekly LCS scores and radiographic response and survival, as well as detailed protocol-specified analysis of symptom and quality-of-life data. PATIENTS AND METHODS In this trial, 216 symptomatic patients with advanced non-small-cell lung cancer (NSCLC) who had at least two prior chemotherapy regimens received gefitinib 250 or 500 mg/d. Disease-related symptoms were assessed weekly and quality of life was assessed monthly by LCS and FACT-L, respectively. Results Symptom improvement was rapid and correlated with tumor response and survival. At the recommended gefitinib dose of 250 mg/d, median overall survival times were 13.6 and 4.6 months for patients with and without symptom improvement, respectively, and 9.7 months for patients with symptom improvement without tumor response. Among patients with stable disease or disease progression, those with symptom improvement had significantly better overall survival than those without improvement. At 250 mg/d, 30% of patients showed a quality-of-life improvement that was correlated with tumor response. CONCLUSION This triadic analysis of response, survival, and symptom data supports the hypothesis that tumor response and symptom response are related and that each predicts survival. Among these NSCLC patients treated with gefitinib, symptom improvement was complementary to and, for most patients, preceded evidence of radiographic regression.

TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer.

PURPOSE: Erlotinib is a potent reversible HER1/epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor with single-agent activity in patients with non-small-cell lung cancer (NSCLC). Erlotinib was combined with chemotherapy to determine if it could improve the outcome of patients with NSCLC. PATIENTS AND METHODS: TRIBUTE randomly assigned patients with good performance status and previously untreated advanced (stage IIIB/IV) NSCLC to erlotinib 150 mg/d or placebo combined with up to six cycles of carboplatin and paclitaxel, followed by maintenance monotherapy with erlotinib. Random assignment was stratified by stage, weight loss in the previous 6 months, measurable disease, and treatment center. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response (OR), and duration of response. RESULTS: There were 1,059 assessable patients (526 erlotinib; 533 placebo). Median survival for patients treated with erlotinib was 10.6 v 10.5 months for placebo (hazard ratio, 0.99; 95% CI, 0.86 to 1.16; P = .95). There was no difference in OR or median TTP. Patients who reported never smoking (72 erlotinib; 44 placebo) experienced improved OS in the erlotinib arm (22.5 v 10.1 months for placebo), though no other prespecified factors showed an advantage in OS with erlotinib. Erlotinib and placebo arms were equivalent in adverse events (except rash and diarrhea). CONCLUSION: Erlotinib with concurrent carboplatin and paclitaxel did not confer a survival advantage over carboplatin and paclitaxel alone in patients with previously untreated advanced NSCLC. Never smokers treated with erlotinib and chemotherapy seemed to experience an improvement in survival and will undergo further investigation in future randomized trials.

Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial.

CONTEXT: More persons in the United States die from non-small cell lung cancer (NSCLC) than from breast, colorectal, and prostate cancer combined. In preclinical testing, oral gefitinib inhibited the growth of NSCLC tumors that express the epidermal growth factor receptor (EGFR), a mediator of cell signaling, and phase 1 trials have demonstrated that a fraction of patients with NSCLC progressing after chemotherapy experience both a decrease in lung cancer symptoms and radiographic tumor shrinkages with gefitinib. OBJECTIVE: To assess differences in symptomatic and radiographic response among patients with NSCLC receiving 250-mg and 500-mg daily doses of gefitinib. DESIGN, SETTING, AND PATIENTS: Double-blind, randomized phase 2 trial conducted from November 2000 to April 2001 in 30 US academic and community oncology centers. Patients (N = 221) had either stage IIIB or IV NSCLC for which they had received at least 2 chemotherapy regimens. INTERVENTION: Daily oral gefitinib, either 500 mg (administered as two 250-mg gefitinib tablets) or 250 mg (administered as one 250-mg gefitinib tablet and 1 matching placebo). MAIN OUTCOME MEASURES: Improvement of NSCLC symptoms (2-point or greater increase in score on the summed lung cancer subscale of the Functional Assessment of Cancer Therapy-Lung [FACT-L] instrument) and tumor regression (>50% decrease in lesion size on imaging studies). RESULTS: Of 221 patients enrolled, 216 received gefitinib as randomized. Symptoms of NSCLC improved in 43% (95% confidence interval [CI], 33%-53%) of patients receiving 250 mg of gefitinib and in 35% (95% CI, 26%-45%) of patients receiving 500 mg. These benefits were observed within 3 weeks in 75% of patients. Partial radiographic responses occurred in 12% (95% CI, 6%-20%) of individuals receiving 250 mg of gefitinib and in 9% (95% CI, 4%-16%) of those receiving 500 mg. Symptoms improved in 96% of patients with partial radiographic responses. The overall survival at 1 year was 25%. There were no significant differences between the 250-mg and 500-mg doses in rates of symptom improvement (P =.26), radiographic tumor regression (P =.51), and projected 1-year survival (P =.54). The 500-mg dose was associated more frequently with transient acne-like rash (P =.04) and diarrhea (P =.006). CONCLUSIONS: Gefitinib, a well-tolerated oral EGFR-tyrosine kinase inhibitor, improved disease-related symptoms and induced radiographic tumor regressions in patients with NSCLC persisting after chemotherapy.

A phase 2 randomized trial of paclitaxel and carboplatin with or without panitumumab for first-line treatment of advanced non-small-cell lung cancer.

INTRODUCTION: This two-part phase 2 study evaluated the efficacy and safety of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, combined with carboplatin/paclitaxel in patients with previously untreated advanced non-small-cell lung cancer. METHODS: In part 1, patients were sequentially enrolled to receive paclitaxel 200 mg/m(2) and carboplatin (area under the concentration-versus-time curve, 6 mg/min/ml) plus panitumumab (1.0, 2.0, or 2.5 mg/kg). In part 2, patients were randomized 2:1 to receive paclitaxel/carboplatin with (arm A) or without (arm B) the maximum tolerated dose of panitumumab identified in part 1. Primary endpoints in parts 1 and 2 were the incidence of dose-limiting toxicities and time to progression (TTP), respectively. RESULTS: In part 1, four of 19 patients had dose-limiting toxicities: three at 2.0 mg/kg (fatigue, pain in extremity, dyspepsia) and one at 2.5 mg/kg (rash). The maximum tolerated dose was not reached; panitumumab 2.5 mg/kg was selected for part 2. In part 2, TTP was 18.1 weeks (95% confidence interval [CI], 13.6-23.3) in arm A and 23.0 weeks (95% CI, 15.9-24.1) in arm B (hazard ratio, 0.9; 90% CI, 0.66-1.21; p = 0.555). Progression-free survival in arms A and B was 17.6 weeks and 18.3 weeks, respectively, and the objective response rate was 15.2% and 11.1%. Adverse events occurring more frequently in arm A than in arm B included skin toxicity, diarrhea, stomatitis, vomiting, and dizziness. Exploratory analyses did not demonstrate associations between potential biomarkers and outcomes. CONCLUSION: Although toxicity was predictable and manageable, the addition of panitumumab to paclitaxel/carboplatin did not improve TTP in patients with previously untreated advanced non-small-cell lung cancer.

Phase III, randomized study of the effects of parenteral iron, oral iron, or no iron supplementation on the erythropoietic response to darbepoetin alfa for patients with chemotherapy-associated anemia.

PURPOSE: Functional iron deficiency may impair response to erythropoiesis-stimulating agents (ESAs) in iron-replete patients with chemotherapy-associated anemia (CAA). This study evaluated whether coadministration of parenteral iron improves ESA efficacy in patients with CAA. PATIENTS AND METHODS: This prospective, multicenter, randomized trial enrolled 502 patients with hemoglobin (Hb) less than 11 g/dL who were undergoing chemotherapy for nonmyeloid malignancies. All patients received darbepoetin alfa once every 3 weeks and were randomly assigned to receive either ferric gluconate 187.5 mg intravenously (IV) every 3 weeks, oral daily ferrous sulfate 325 mg, or oral placebo for 16 weeks. RESULTS: There was no difference in the erythropoietic response rate (ie, proportion of patients achieving Hb ≥ 12 g/dL or Hb increase ≥ 2 g/dL from baseline): 69.5% (95% CI, 61.9% to 76.5%) of IV iron-treated patients achieved an erythropoietic response compared with 66.9% (95% CI, 59.1% to 74.0%) who received oral iron and 65.0% (95% CI, 57.2% to 72.3%) who received oral placebo (P = .75). There were also no differences in the proportion of patients requiring red cell transfusions, changes in quality of life, or the dose of darbepoetin administered. Adverse events (AEs) tended to be more common in the IV iron arm: grade 3 or higher AEs occurred in 54% (95% CI, 46% to 61%) of patients receiving IV iron compared with 44% (95% CI, 36% to 52%) who received oral iron and 46% (95% CI, 38% to 54%) who received oral placebo (P = .16). CONCLUSION: In patients with CAA, addition of IV ferric gluconate to darbepoetin failed to provide additional benefit compared with oral iron or oral placebo.

Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated non small-cell lung cancer.

PURPOSE: Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor kinase activity. The activity of vandetanib plus docetaxel was assessed in patients with previously treated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This two-part study comprised an open-label run-in phase and a double-blind randomized phase. Eligible patients had locally advanced or metastatic (stage IIIB/IV) NSCLC after failure of first-line platinum-based chemotherapy. The primary objective of the randomized phase was to prolong progression-free survival (PFS) in patients receiving vandetanib (100 or 300 mg/d) plus docetaxel (75 mg/m2 intravenous infusion every 21 days) versus placebo plus docetaxel. The study was designed to have more than 75% power to detect 50% prolongation at a one-sided significance level of P < .20. Secondary objectives included objective response rate, overall survival, safety and tolerability. RESULTS: In the randomized phase (n = 127), median PFS was 18.7 weeks for vandetanib 100 mg plus docetaxel (n = 42; hazard ratio v docetaxel = 0.64; one-sided P = .037); 17.0 weeks for vandetanib 300 mg plus docetaxel (n = 44; hazard ratio v docetaxel = 0.83; one-sided P = .231); and 12 weeks for docetaxel (n = 41). There was no statistically significant difference in overall survival among the three treatment arms. Common adverse events included diarrhea, rash, and asymptomatic prolongation of corrected QT (QTC) interval. CONCLUSION: The primary objective was achieved, with vandetanib 100 mg plus docetaxel demonstrating a significant prolongation of PFS compared with docetaxel in relation to the prespecified significance level. On the basis of these encouraging data, phase III evaluation of vandetanib 100 mg plus docetaxel in second-line NSCLC has been initiated.

Randomized phase II trial of pemetrexed combined with either cisplatin or carboplatin in untreated extensive-stage small-cell lung cancer.

PURPOSE: Given the activity and tolerability of pemetrexed/platinum combinations in non-small-cell lung cancer, and the success of novel therapeutic strategies employed in recent extensive-stage small-cell lung cancer (ES-SCLC) trials, a randomized phase II trial was initiated to evaluate the use of cisplatin or carboplatin plus pemetrexed in previously untreated ES-SCLC. PATIENTS AND METHODS: Patients were randomly assigned to receive pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or pemetrexed plus carboplatin area under the concentration curve 5. Treatment was administered once every 21 days for a maximum of six cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis. RESULTS: Between December 19, 2002, and May 17, 2004, 78 patients were enrolled onto this multicenter trial. Median age was 63 years (range, 46 to 82 years) for cisplatin/pemetrexed and 66 years (range, 47 to 75 years) for carboplatin/pemetrexed. Median survival time (MST) for cisplatin/pemetrexed was 7.6 months, with a 1-year survivorship of 33.4% and a response rate of 35% (95% CI, 20.6% to 51.7%). The MST for carboplatin/pemetrexed was 10.4 months, with a 1-year survivorship of 39.0% and a response rate of 39.5% (95% CI, 24.0 to 56.6). Median time to progression for cisplatin/pemetrexed was 4.9 months and for carboplatin/pemetrexed was 4.5 months. Median dose-intensity (actual/planned dose) was 98.94% for cisplatin and 99.95% for pemetrexed in the cisplatin/pemetrexed group and 93.21% for carboplatin and 98.50% for pemetrexed in the carboplatin/pemetrexed group. Grade 3/4 hematologic toxicities included neutropenia (15.8% v 20.0%) and thrombocytopenia (13.2% v 22.9%) in the cisplatin/pemetrexed and carboplatin/pemetrexed treatment groups, respectively. CONCLUSION: Pemetrexed/platinum doublets had activity and appeared to be well-tolerated in first-line ES-SCLC.

Phase II trial of irinotecan in combination with amifostine in patients with advanced colorectal carcinoma.

BACKGROUND: Irinotecan is effective in patients with advanced colorectal carcinoma in both first-line and salvage settings but its use can be limited by serious side effects. Amifostine has been shown to reduce the incidence of cisplatin-induced cumulative renal toxicity in patients with advanced ovarian carcinoma and nonsmall cell lung carcinoma. In the current pilot Phase II trial, the authors examined the potential role of amifostine as a protective agent against irinotecan-induced diarrhea and myelosuppression and evaluated an every-2-weeks regimen as an alternative schedule for the administration of irinotecan in patients with previously treated metastatic colorectal carcinoma. METHODS: All patients received amifostine, 740 mg/m2, followed by irinotecan, 250 mg/m2, every 2 weeks. A 6-week cycle of chemotherapy (every 2 weeks for 3 treatments) was chosen to assess toxicity and response. The main objective of the current study was to evaluate the impact of amifostine on gastrointestinal and hematologic toxicity. RESULTS: A total of 22 patients entered the current study. Six of these 22 patients (27%) had WHO Common Toxicity Criteria Grade 3 or 4 diarrhea, including 2 patients (9%) with Grade 4 diarrhea. Eight of 22 patients (36.3%) developed Grade 3 or 4 neutropenia (Grade 4 in 4 of the 22 patients [18%]). Dose reduction was required in 25% of the treatment cycles. Five of the 22 patients (23%) withdrew from the trial due to amifostine toxicity. Of the 15 patients who were evaluable for response, 4 patients (26.6%) had achieved a partial response and 9 (60%) had stable disease as their best response. CONCLUSIONS: The combination of irinotecan with amifostine in patients with previously treated metastatic colorectal carcinoma did not appear to reduce irinotecan toxicity. Amifostine did not appear to interfere with the cytotoxic effect of irinotecan. The results of the current study did demonstrate efficacy and safety of the every-2-weeks irinotecan schedule that was comparable to other established regimens and these results support its feasibility as a reasonable alternative in this disease setting.