A randomized trial of TLR-2 agonist CADI-05 targeting desmocollin-3 for advanced non-small-cell lung cancer.

Background: Randomized controlled trial to evaluate synergy between taxane plus platinum chemotherapy and CADI-05, a Toll like receptor-2 agonist targeting desmocollin-3 as a first-line therapy in advanced non-small-cell lung cancer (NSCLC). Patients and methods: Patients with advanced NSCLC (stage IIIB or IV) were randomized to cisplatin-paclitaxel (chemotherapy group, N = 112) or cisplatin-paclitaxel plus CADI-05 (chemoimmunotherapy group, N = 109). CADI-05 was administered a week before chemotherapy and on days 8 and 15 of each cycle and every month subsequently for 12 months or disease progression. Overall survival was compared using a log-rank test. Computed tomography was carried out at baseline, end of two cycles and four cycles. Response rate was evaluated using Response Evaluation Criteria in Solid Tumors criteria by an independent radiologist. Results: As per intention-to-treat analysis, no survival benefit was observed between two groups [208 versus 196 days; hazard ratio, 0.86; 95% confidence interval (CI) 0.63-1.19; P = 0.3804]. In a subgroup analysis, improvement in median survival by 127 days was observed in squamous NSCC with chemoimmunotherapy (hazard ratio, 0.55; 95% CI 0.32-0.95; P = 0.046). In patients receiving planned four cycles of chemotherapy, there was improved median overall survival by 66 days (299 versus 233 days; hazard ratio, 0.64; 95% CI 0.41 to 0.98; P = 0.04) in the chemoimmunotherapy group compared with the chemotherapy group. This was associated with the improved survival by 17.48% at the end of 1 year, in the chemoimmunotherapy group. Systemic adverse events were identical in both the groups. Conclusion: There was no survival benefit with the addition of CADI-05 to the combination of cisplatin-paclitaxel in patients with advanced NSCLC; however, the squamous cell subset did demonstrate a survival advantage.

A multicenter phase II study of cetuximab in combination with chest radiotherapy and consolidation chemotherapy in patients with stage III non-small cell lung cancer.

BACKGROUND: Cetuximab has demonstrated improved efficacy in combination with chemotherapy and radiotherapy. We evaluated the integration of cetuximab in the combined modality treatment of stage III non-small cell lung cancer (NSCLC). METHODS: Patients with surgically unresectable stage IIIA or IIIB NSCLC were treated with chest radiotherapy, 73.5 Gy (with lung and tissue heterogeneity corrections) in 35 fractions/7 weeks, once daily (63 Gy without heterogeneity corrections). Cetuximab was given weekly during radiotherapy and continued during consolidation therapy with carboplatin and paclitaxel up to a maximum of 26 weekly doses. The primary endpoint was overall survival. Baseline tumor tissue was analyzed for EGFR by fluorescence in situ hybridization (FISH). RESULTS: Forty patients were enrolled in this phase II study. The median overall survival was 19.4 months and the median progression-free survival 9.3 months. The best overall response rate in 31 evaluable patients was 67%. No grade 3 or 4 esophagitis was observed. Three patients experienced grade 3 rash; 16 patients (69%) developed grade 3/4 neutropenia during consolidation therapy. One patient died of pneumonitis, possibly related to cetuximab. EGFR gene copy number on baseline tumor tissues, analyzed by FISH, was not predictive of efficacy outcomes. CONCLUSIONS: The addition of cetuximab to chest radiotherapy and consolidation chemotherapy was tolerated well and had modest efficacy in stage III NSCLC. Taken together with the lower incidence of esophagitis, our results support evaluation of targeted agents instead of chemotherapy with concurrent radiotherapy in this setting.

Identifying the target NSCLC patient for maintenance therapy: an analysis from a placebo-controlled, phase III trial of maintenance pemetrexed (H3E-MC-JMEN).

BACKGROUND: This was a post hoc analysis of patients with non-squamous histology from a phase III maintenance pemetrexed study in advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: The six symptom items' [average symptom burden index (ASBI)] mean at baseline was calculated using the lung cancer symptom scale (LCSS). Low and high symptom burden (LSB, ASBI < 25; HSB, ASBI ≥ 25) and performance status (PS: 0, 1) subgroups were analyzed for treatment effect on progression-free survival (PFS) and overall survival (OS) using the Cox proportional hazard models adjusted for demographic/clinical factors. RESULTS: Significantly longer PFS and OS for pemetrexed versus placebo occurred in LSB patients [PFS: median 5.1 versus 2.4 months, hazard ratio (HR) 0.49, P < 0.0001; OS: median 17.5 versus 11.0 months, HR 0.63, P = 0.0012] and PS 0 patients (PFS: median 5.5 versus 1.7 months, HR 0.36, P < 0.0001; OS: median 17.7 versus 10.3 months, HR 0.54, P = 0.0019). Significantly longer PFS, but not OS, occurred in HSB patients (median 3.7 versus 2.8 months, HR 0.50, P = 0.0033) and PS 1 patients (median 4.4 versus 2.8 months, HR 0.60, P = 0.0002). CONCLUSIONS: ASBI and PS are associated with survival for non-squamous NSCLC patients, suggesting that maintenance pemetrexed is useful for LSB or PS 0 patients following induction.

Phase Ib safety and pharmacokinetic study of volociximab, an anti-α5ß1 integrin antibody, in combination with carboplatin and paclitaxel in advanced non-small-cell lung cancer.

BACKGROUND: This phase Ib study evaluated volociximab, an anti-α5ß1 integrin antibody, in combination with carboplatin (Eli Lilly and Co., Indianapolis, IN) and paclitaxel (Taxol) in advanced, untreated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Three cohorts were treated with volociximab (10, 20, or 30 mg/kg) for up to six 3-week cycles in combination with carboplatin-paclitaxel chemotherapy and continued as maintenance therapy for patients with stable disease (SD) or better. Dose-limiting toxic effects, adverse events (AEs), pharmacokinetics, and anti-volociximab antibodies were assessed. RESULTS: A maximum tolerated dose was not reached up to the maximum planned dose of 30 mg/kg. In 29 patients who received volociximab, the most common grade≥3 AEs were neutropenia (24%), hyponatremia (17%), and fatigue (10%). Three patients experienced volociximab-related serious AEs. No hemorrhages were observed. Of 33 patients enrolled, 8 (24%) achieved a partial response and 17 (52%) had SD. The median progression-free survival was 6.3 months (95% confidence interval 5.5-8.1). Levels of potential biomarkers of angiogenesis or metastasis were reduced following six cycles of treatment. CONCLUSIONS: Volociximab combined with carboplatin and paclitaxel was generally well-tolerated and showed preliminary evidence of efficacy in advanced NSCLC.

Differential effect of age on survival in advanced NSCLC in women versus men: analysis of recent Eastern Cooperative Oncology Group (ECOG) studies, with and without bevacizumab.

BACKGROUND: The impact of age on prognosis in advanced stage non-small cell lung cancer (NSCLC) may differ by sex. PATIENTS AND METHODS: Eligible patients (N=1590) from E1594, a 4-arm platinum-based chemotherapy trial, and E4599 (carboplatin/paclitaxel ± bevacizumab) chemotherapy arm were divided into male and female cohorts and separated into age groups of <60 or ≥60 years old. Eligible E4599 patients (N=850) were similarly separated by age and sex and by treatment (± bevacizumab). Survival was calculated separately for each cohort. RESULTS: The median survival time (MST) for women ≥60 years old treated with chemotherapy alone on E1594 and E4599 was 11.6 months versus 9.0 months for women <60 (p=0.03). MST was 7.4 and 8.3 months for men ≥60 and <60 years old respectively (NS). In E4599 the age <60 by bevacizumab treatment interaction was statistically significant (p=0.03) for women (younger had greater benefit), with no age effect in men. CONCLUSIONS: In this unplanned, exploratory subgroup analysis of advanced stage NSCLC ECOG trials, women ≥60 years old treated with chemotherapy live longer than men and younger women. In contrast, bevacizumab survival benefit was more pronounced in men of any age and in younger women on E4599.

Recent clinical developments and rationale for combining targeted agents in non-small cell lung cancer (NSCLC).

While chemotherapy has been the standard of care for patients with advanced non-small cell lung cancer (NSCLC), efforts have shifted toward evaluating novel targeted agents in an attempt to improve outcome. These targeted agents are directed toward key components in several signalling pathways such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-IR). There is also increasing interest in using combinations of targeted agents to inhibit more than one pathway; for example, inhibition of VEGFR + EGFR and VEGFR + PDGFR + EGFR. Further investigation is needed to identify the most appropriate combinations of these targeted agents in select patient subgroups, and to define optimal treatment doses to thereby achieve the best therapeutic index. This review outlines the rationale for combining targeted agents for the treatment of advanced NSCLC.

EORTC Elderly Task Force and Lung Cancer Group and International Society for Geriatric Oncology (SIOG) experts' opinion for the treatment of non-small-cell lung cancer in an elderly population.

Non-small-cell lung cancer (NSCLC) represents a common health issue in the elderly population. Nevertheless, the paucity of large, well-conducted prospective trials makes it difficult to provide evidence-based clinical recommendations for these patients. The present paper reviews the currently available evidence regarding treatment of all stages of NSCLC in elderly patients. Surgery remains the standard for early-stage disease, though pneumonectomy is associated with higher incidence of postoperative mortality in elderly patients. Given the lack of demonstrated benefit for the use of adjuvant radiotherapy, it is also not recommended in elderly patients. Elderly patients seem to derive the same benefit from adjuvant chemotherapy as younger patients do, with no significant increase in toxicity. For locally advanced NSCLC, concurrent chemoradiotherapy may be offered to selected elderly patients as there is a higher risk for toxicity reported in the elderly population. Third-generation single-agent treatment is considered the standard of care for patients with advanced/metastatic disease. Platinum-based combination chemotherapy needs to be evaluated in prospective trials. Unfortunately, with the exception of advanced/metastatic NSCLC, prospective elderly-specific NSCLC trials are lacking and the majority of recommendations made are based on retrospective data, which might suffer from selection bias. Prospective elderly-specific trials are needed.

A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer.

BACKGROUND: Paclitaxel-carboplatin is used as the standard regimen for patients with advanced or metastatic non-small-cell lung cancer (NSCLC). This trial was designed to compare gemcitabine + carboplatin or gemcitabine + paclitaxel to the standard regimen. PATIENTS AND METHODS: A total of 1135 chemonaive patients with stage IIIB or IV NSCLC were randomly allocated to receive gemcitabine 1000 mg/m(2) on days 1 and 8 plus carboplatin area under the concentration-time curve (AUC) 5.5 on day 1 (GC), gemcitabine 1000 mg/m(2) on days 1 and 8 plus paclitaxel 200 mg/m(2) on day 1 (GP), or paclitaxel 225 mg/m(2) plus carboplatin AUC 6.0 on day 1 (PC). Stratification was based on disease stage, baseline weight loss, and presence or absence of brain metastases. Cycles were repeated every 21 days for up to six cycles or disease progression. RESULTS: Median survival (months) with GC was 7.9 compared with 8.5 for GP and 8.7 for PC. Response rates (RRs) were as follows: GC, 25.3%; GP, 32.1%; and PC, 29.8%. The GC arm was associated with a greater incidence of grade 3 or 4 hematologic events but a lower rate of neurotoxicity and alopecia when compared with GP and PC. CONCLUSIONS: Non-platinum and non-paclitaxel gemcitabine-containing doublets demonstrate similar overall survival and RR compared with the standard PC regimen. However, the treatment arms had distinct toxicity profiles.

Pharmacokinetic study of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced malignancies.

S-CKD602 is a pegylated liposomal formulation of CKD-602. This study is the first to evaluate the factors affecting the high interpatient variability in the pharmacokinetic disposition of S-CKD602. S-CKD602 was administered intravenously (i.v.) every 3 weeks as part of a phase I study. Pharmacokinetics studies of the liposomal encapsulated and released CKD-602 in plasma were performed. The pharmacokinetic variability of S-CKD602 is associated with both linear and nonlinear clearances. Patients > or =60 years of age have a 2.7-fold higher exposure of S-CKD602 as compared with patients <60 years of age (P = 0.02). Patients with a lean body composition have a higher plasma exposure of S-CKD602 (P = 0.02). Patients who have received prior therapy with pegylated liposomal doxorubicin (PLD) have a 2.2-fold higher exposure of S-CKD602 as compared with patients who have not received PLD (P = 0.045). Prolonged exposure of the encapsulated drug in plasma over 1-2 weeks provides significant pharmacologic advantages. The high interpatient variability in the pharmacokinetic disposition of S-CKD602 was associated with age, body composition, saturable clearance, and prior PLD therapy.

Randomized phase II trial of gemcitabine plus weekly versus three-weekly paclitaxel in previously untreated advanced non-small-cell lung cancer.

INTRODUCTION: Gemcitabine and paclitaxel (Taxol) each provides an efficacious non-platinum option for the treatment of advanced non-small-cell lung cancer (NSCLC), but the optimal dosage and schedule of the two agents used in combination are not well defined. METHODS: Previously untreated patients with advanced NSCLC were randomized to receive gemcitabine-paclitaxel on a traditional three-weekly schedule (Arm A) or a novel weekly schedule (Arm B) as follows-Arm A (three-weekly): gemcitabine 1000 mg/m2 infused>30 min on days 1 and 8 and paclitaxel 200 mg/m2 infused>3 h on day 1 of a 21-day cycle or Arm B (weekly): gemcitabine 1000 mg/m2 infused>30 min and paclitaxel 100 mg/m2 infused>1 h, both administered on days 1 and 8 of a 21-day cycle. RESULTS: One hundred patients received at least one dose of treatment. The weekly schedule, Arm B, was more efficacious and less hematologically toxic than Arm A. Confirmed complete and partial response rates were 28.2% and 26.8%, respectively. Median survival was 10.3 months on Arm B and 7.9 months on Arm A (log-rank P=0.10); 1- and 2-year survival rates also favor Arm B: 42.0% versus 34.0% and 18.0% versus 6.0%. Progression-free survival was 5.8 versus 4.8 months, again favoring Arm B (log-rank P=0.06). There was a two-fold lower frequency of grade 3/4 hematologic events with Arm B as follows: neutropenia (16% versus 30%), thrombocytopenia (4% versus 8%), and anemia (2% versus 6%). One patient (2%) in each treatment group developed febrile neutropenia. CONCLUSION: In this trial, both schedules were efficacious and tolerable, although the weekly schedule resulted in improved survival and lower hematologic toxicity compared with a three-weekly schedule. The weekly schedule of gemcitabine-paclitaxel indicates an improved therapeutic index.

Randomized phase III trial comparing cisplatin-etoposide to carboplatin-paclitaxel in advanced or metastatic non-small cell lung cancer.

BACKGROUND: The present study was designed to evaluate the efficacy and safety of the regimen of carboplatin plus paclitaxel (investigational arm) versus the reference regimen of cisplatin plus etoposide for the treatment of advanced or metastatic non-small-cell lung cancer. PATIENTS AND METHODS: A total of 369 patients were enrolled, 179 on arm A (cisplatin 75 mg/m2 and etoposide 100 mg/m2) and 190 on arm B (carboplatin AUC=6 mg/ml min and paclitaxel 225 mg/m2), with cycles repeated every 3 weeks. The arms were well balanced with respect to age, performance status, weight loss, stage of disease and disease measurability. However, significantly more women were randomized to arm A than to arm B (P=0.039). RESULTS: The objective response rate (ORR) was 15% on arm A compared with 23% on arm B (P=0.061). Median survival time, time to progression and 1-year survival rates for arms A and B were 274 days and 233 days (P=0.086), 111 days and 121 days (P=0.877), and 37% and 32%, respectively. The most prevalent toxicities were neutropenia and leukopenia and they occurred at a higher rate in arm A than in arm B. CONCLUSION: There was no statistically significant survival advantage for carboplatin-paclitaxel compared with cisplatin-etoposide. However, there was an overall benefit in quality of life with the carboplatin-paclitaxel regimen.

Skin rash and good performance status predict improved survival with gefitinib in patients with advanced non-small cell lung cancer.

BACKGROUND: Gefitinib (Iressa) is active as a single agent in the treatment of select patients with recurrent non-small cell lung cancer (NSCLC). The clinical characteristics of patients treated with gefitinib on an Expanded Access Program (EAP) at our institution identified predictive variables associated with better outcome. PATIENTS AND METHODS: Patients (n=199) with advanced NSCLC were treated with gefitinib (250 mg) upon progression with chemotherapy. Baseline patient characteristics were: median age, 69 years; males, 57%; adenocarcinoma, 56%. RESULTS: Partial responses were noted in two patients (1%) and disease stabilization in 66 (35%) patients. The median survival (MS) was 5.9 months [95% confidence interval (CI) 4.1-7.1] and median time to progression was 3 months (95% CI 2.0-3.0). The predictive factors analyzed were gender, skin rash, diarrhea, tumor histology and performance status (PS). Patients who developed skin rash (any grade) had MS of 10.8 months versus 4.0 months for those without rash (P <0.0001, log rank test). Patients with PS 0, 1 and 2 had MS of 8.4, 6.2 and 2.8 months, respectively (P <0.0002). The other factors did not impact survival. CONCLUSIONS: Occurrence of skin rash and baseline PS of 0/1 were associated with improved survival with gefitinib for recurrent NSCLC patients at our institution.

Phase II study of topotecan and paclitaxel for patients with previously untreated extensive stage small-cell lung cancer.

BACKGROUND: This phase II study was conducted to evaluate the safety and efficacy of the combination of paclitaxel and topotecan for patients with extensive stage small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: Previously untreated ED-SCLC patients with Eastern Coperative Oncology Group performance status <2 were eligible. Treatment consisted of topotecan 1 mg/m2 (first three patients received 1.25 mg/m2), on days 1-5, and paclitaxel 135 mg/m2 over 24 h on day 5, every 4 weeks. Prophylactic granulocyte colony-stimulating factor was administered to all patients. RESULTS: Thirty-two patients received a median of four cycles of chemotherapy. Grade 4 anemia, neutropenia and thrombocytopenia occurred in 13, 31 and 18 patients, respectively. Thirty episodes of febrile neutropenia occurred in 22 patients. Grade 3 fatigue, esophagitis, stomatitis and hypotension occurred in one patient each. Of 26 patients eligible for response evaluation, there were six complete and 12 partial responses (overall response rate 69%). The median survival was 54 weeks. The 1-, 2- and 3-year survival rates were 50%, 10% and 3%, respectively. CONCLUSIONS: The combination of topotecan and paclitaxel is active as initial therapy in SCLC, but the efficacy is similar to 'standard therapy'. This combination was associated with a high incidence of myelosuppression and febrile neutropenia, at the doses evaluated.

Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a Phase II trial in patients with metastatic nonsmall cell lung carcinoma .

BACKGROUND: Eastern Cooperative Oncology Group (ECOG) Study E1594 compared paclitaxel and cisplatin with three newer chemotherapy doublets in the treatment of patients with advanced nonsmall cell lung carcinoma (NSCLC). The accrual of patients with an ECOG performance status (PS) of 2 was discontinued due to a perceived rate of unacceptable toxicity. METHODS: Patients were stratified by PS and randomized to one of the following treatments: 1) paclitaxel (135 mg/m2) over 24 hours with cisplatin (75 mg/m2) on a 21-day cycle; 2) cisplatin (100 mg/m2) with gemcitabine (1 g/m2) on Days 1, 8, and 15 on a 28-day cycle; 3) cisplatin (75 mg/m2) with docetaxel (75 mg/m2) on a 21-day cycle; and 4) paclitaxel (225 mg/m2) over 3 hours with carboplatin (area under the curve, 6). All tests of statistical significance were two-sided. RESULTS: Sixty-eight patients with an ECOG PS of 2 were enrolled, and 64 patients were evaluable for toxicity and response. Fifty-six percent of 64 evaluable patients were male, and 81% had Stage IV disease. Grade 3-4 hematologic toxicities occurred in > 50% of the patients in each treatment group. Nonhematologic Grade 3-4 toxicities occurred significantly less often in the paclitaxel and carboplatin arm (P = 0.0032). The overall rate of toxicity did not differ significantly from the rate of toxicity in the PS-0 or PS-1 cohorts. There were 5 deaths (7.35%) among 68 patients with a PS of 2 during therapy; however, only 2 of those deaths were attributed to therapy. The overall response rate for the 64 evaluable patients was 14%. The overall median survival of all 68 patients with a PS of 2, as determined by an intent-to-treat analysis, was 4.1 months. CONCLUSIONS: Patients with advanced NSCLC and a PS of 2 experienced a large number of adverse reactions and overall poor survival. A comparison with patients with a PS of 0-1 suggests that these events and the shorter survival were related to disease process rather than treatment. Alternative strategies need to be explored with therapy specifically tailored for this group of patients.

Interim analysis of a phase II study of induction weekly paclitaxel/carboplatin regimens followed by maintenance weekly paclitaxel for advanced and metastatic non-small cell lung cancer.

This multi-institutional randomized phase II study was designed to compare the efficacy and toxicity of three different weekly paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin schedules in patients with advanced and metastatic non-small cell lung cancer. The second part of the trial evaluated the role of maintenance weekly paclitaxel for those with response or stable disease after 16 weeks of initial treatment. Patients in arm 1 received paclitaxel 100 mg/m(2)/wk for 3 weeks along with carboplatin (area under the curve of 6) on day 1 every 4 weeks. The treatment in arm 2 was the same as in arm 1 except that carboplatin was also administered weekly (area under the curve of 2) for 3 weeks. Patients in arm 3 received paclitaxel 150 mg/m(2)/wk and carboplatin (area under the curve of 2 per week) during the second 8-week cycle. The total duration of this initial therapy was 16 weeks. All regimens were well tolerated. Arm 1 has the best therapeutic index and will exceed the median survival seen in previous phase III trials with traditional schedules of paclitaxel and carboplatin.

The role of positron emission tomography in evaluating mediastinal lymph node metastases in non-small-cell lung cancer.

Positron emission tomography (PET) is a modality that differentiates malignant from benign processes based upon metabolism rather than anatomy. A number of studies have confirmed improved accuracy of PET over computed tomography (CT), but until a few recent studies, most had failed to include satisfactory histologic confirmation. The objective of this study was to compare PET and CT to histologic staging of the mediastinum in patients with non-small-cell lung cancer (NSCLC). Histologic examination of mediastinal lymph nodes (MLNs) was performed on 40 patients with NSCLC at mediastinoscopy and/or at surgical resection. PET scans were interpreted by one of two nuclear medicine physicians, blinded to histology, using CT scans for anatomic localization. CT scans were independently evaluated for mediastinal lymphadenopathy. The overall accuracy, sensitivity, and specificity of PET were 78% (31 of 40), 67% (four of six), and 79% (27 of 34), respectively. The overall accuracy, sensitivity, and specificity of CT were 68% (27 of 40), 50% (three of six), and 71% (24 of 34), respectively. PET was superior to CT at correctly identifying mediastinal nodal metastases; however, both modalities were inferior to the gold standard of surgical staging. PET is more accurate than CT in staging the mediastinum of patients with NSCLC. PET failed to identify lymph node metastasis in 33% of patients with histologically proven MLN involvement, and false positives were present in 15%. At present, mediastinoscopy should remain the standard of care for preoperative mediastinal staging for NSCLC.