Robert L. Comis

Independent Review of E2100: A Phase III Trial of Bevacizumab Plus Paclitaxel Versus Paclitaxel in Women With Metastatic Breast Cancer

PURPOSE E2100, an open-label, randomized, phase III trial conducted by the Eastern Cooperative Oncology Group (ECOG), demonstrated a significant improvement in progression-free survival (PFS) and overall response rate (ORR) with paclitaxel plus bevacizumab compared with paclitaxel alone as initial chemotherapy for patients with HER2-negative metastatic breast cancer. METHODS An independent, blinded review of radiologic and clinical data was performed, assessing progression and response according to Response Evaluation Criteria in Solid Tumors. In addition, ECOGs investigator assessments were reanalyzed using the same methods applied to the independent review. The primary end point was PFS as assessed by an independent review facility (IRF). RESULTS The addition of bevacizumab to paclitaxel resulted in a statistically significant improvement in PFS using both the IRF and investigator assessments. Hazard ratios for PFS (0.48, 95% CI, 0.385 to 0.607; P < .0001 for the IRF v 0.42, 95% CI, 0.34 to 0.52; P < .0001 for ECOG investigators) and the improvement in median PFS (11.3 v 5.8 months for the IRF v 11.4 v 5.8 months for ECOG investigators) were similar. Among patients with measurable disease at baseline, the IRF-assessed ORR was significantly higher in patients treated with paclitaxel and bevacizumab (48.9% v 22.2%; P < .0001). CONCLUSION The risk of progression was reduced by more than half and the ORR more than doubled with the addition of bevacizumab to weekly paclitaxel in both analyses, confirming a substantial and robust bevacizumab treatment effect. The consistency between the IRF and ECOG analyses validates the original data previously reported by ECOG in this open-label trial.

Activity of docetaxel in platinum-treated non-small-cell lung cancer: results of a phase II multicenter trial.

PURPOSE Although several new chemotherapeutic agents are promising as primary therapy in non-small-cell lung cancer (NSCLC), few have demonstrated activity in platinum-refractory disease. Based on encouraging results reported in two single-institution studies of docetaxel in this setting, we performed a multicenter phase II trial evaluating this novel taxane in previously treated NSCLC patients prospectively categorized by platinum response status. PATIENTS AND METHODS Eighty patients with NSCLC previously treated with platinum-based chemotherapy received docetaxel at a dose of 100 mg/m(2) intravenously over 1 hour, repeated every 21 days, accompanied by dexamethasone 8 mg orally twice daily for 5 days. Forty-seven patients (59%) were defined as platinum-refractory based on response status to prior therapy. RESULTS The median number of cycles delivered per patient was four (range, one to 21 cycles). Partial response was observed in 13 (16%) of 80 of patients, with similar response rates in platinum-sensitive and platinum-refractory patients. The median survival time was 7 months, and the 1-year survival rate was 25%. Docetaxel was relatively well tolerated in this previously treated population. Grade IV neutropenia was common in patients (77%) but typically of brief duration. Febrile neutropenia was observed in 11 patients (14%), with no fatal infections. Severe fluid retention was rare (4% of patients). CONCLUSIONS This multicenter phase II trial confirms antitumor activity and encouraging survival with docetaxel therapy in platinum-treated and platinum-refractory NSCLC. To validate these results, a phase III trial randomizing platinum-treated patients to docetaxel or best supportive care is underway.

Evaluating Antiangiogenesis Agents in the Clinic: The Eastern Cooperative Oncology Group Portfolio of Clinical Trials

Recent evidence indicates that treatment with a humanized monoclonal antibody (bevacizumab) directed at vascular endothelial growth factor improves response and survival in metastatic colorectal cancer when added to standard chemotherapy, validating angiogenesis as a therapeutic target. Investigators from the Eastern Cooperative Oncology Group (ECOG) have initiated a number of Phase III studies that will help further define the role of antiangiogenic agents for the treatment of breast, colon, lung, renal, and head and neck cancer, as well as melanoma and myeloma. The agents being evaluated target various biological functions involved in angiogenesis, including vascular endothelial growth factor (bevacizumab), endothelial cell proliferation (thalidomide, IFN-α), and matrix metalloproteinases (marimastat). These clinical trials include correlative laboratory studies aimed at elucidating how these agents may exert their clinical effects. The portfolio of Eastern Cooperative Oncology Group studies will serve to further define the role of this therapeutic strategy for patients with advanced cancer.

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.

A retrospective analysis of outcomes by age in a three-arm phase III trial of gemcitabine in combination with carboplatin or paclitaxel vs. paclitaxel plus carboplatin for advanced non-small cell lung cancer

PURPOSE Sufficient data are currently unavailable to assist in defining suitable regimens for patients ≥ 70 years with advanced non-small cell lung cancer (NSCLC). METHODS Chemonaïve patients with a performance status (PS) of 0 or 1 and stage IIIB or IV NSCLC were randomized to gemcitabine 1000mg/m(2) on days 1 and 8 plus carboplatin area under the curve (AUC) 5.5 on day 1; the same schedule of gemcitabine plus paclitaxel 200mg/m(2) on day 1; or paclitaxel 225mg/m(2) on day 1 plus carboplatin AUC 6.0 on day 1. Cycles were every 21 days up to 6. Efficacy and toxicity results were compared by age groups. RESULTS Overall survival (OS) between patients <70 years (8.6 months, 95% CI: 7.9, 9.5) and ≥ 70 years (7.9 months, 95% CI: 7.1, 9.5) was similar. OS was 8.8 months (95% CI: 7.5, 10.3) among patients 70-74 years, 6.5 months (95% CI: 5.6, 9.3) among patients 75-79 years, and 7.9 months (95% CI: 6.3, 10.3) among patients ≥ 80 years. OS was lower among patients 75-79 years compared with patients 70-74 years (P=0.04). Compared with patients <70 years, patients ≥ 70 years experienced similar rates of myelosuppresion, but younger patients experienced more vomiting and nausea. There was no clear pattern with respect to differences in efficacy by treatments across age groups. CONCLUSIONS Based on the similarity of patient outcomes across age groups, doublet chemotherapy is feasible among carefully selected elderly patients with good PS.

Development of Clinical Trials in a Cooperative Group Setting: The Eastern Cooperative Oncology Group

Purpose: We examine the processes and document the calendar time required to activate phase II and III clinical trials by an oncology group: the Eastern Cooperative Oncology Group (ECOG). Methods: Setup steps were documented by (a) interviewing ECOG headquarters and statistical center staff, and committee chairs, (b) reviewing standard operating procedure manuals, and (c) inspecting study records, documents, and e-mails to identify additional steps. Calendar time was collected for each major process for each study in this set. Results: Twenty-eight phase III studies were activated by ECOG during the January 2000 to July 2006 study period. We examined a sample from 16 of those studies in detail. More than 481 distinct processes were required for study activation: 420 working steps, 61 major decision points, 26 processing loops, and 13 stopping points. Median calendar days to activate a trial in the phase III subset was 783 days (range, 285-1,542 days) from executive approval and 808 days (range, 435-1,604 days) from initial conception of the study. Data were collected for all phase II and phase III trials activated and completed during this time period (n = 52) for which development time represented 43.9% and 54.1% of the total trial time, respectively. Conclusion: The steps required to develop and activate a clinical trial may require as much or more time than the actual completion of a trial. The data shows that to improve the activation process, research should to be directed toward streamlining both internal and external groups and processes.

The Cooperative Groups : Past and future

The Cooperative Group system of the National Cancer Institute (NCI) has been in existence since the 1950s and has evolved to comprise 11 groups, the membership of which includes universities, Community Clinical Oncology Programs, and Cooperative Group Outreach Programs. The Cooperative Groups serve as models for cancer clinical trials throughout the world. However, in today’s changing healthcare environment in the USA the Cooperative Groups need to adjust how they operate to ensure the continuation of their leadership role in cancer clinical trials. Government funds, the main source of support for the Cooperative Groups’ activities, are shrinking and currently funding is only 50% of the recommended level. If the Cooperative Groups are to remain at the forefront, adjustments must be made in several areas: the Cooperative Groups need to provide an efficient and rapid scientific and legal mechanism to execute large phase III studies of the increasingly important portfolio of compounds being developed by industry more effectively. Industry has come to rely on contract research organizations for expedited testing of their products due to perceived inefficiency in these areas in the Cooperative Group mechanism. The Cooperative Groups are uniquely situated to provide in-depth evaluation of the newest therapies for regulatory agencies and interested health insurers, as well as provide health outcomes data, which are now much sought after by the healthcare industry. Managed care is shaping medical practice, including cancer care, throughout the USA. Finally, the Cooperative Groups need to foster greater international cooperation to speed technology transfers. The leaders of the Cooperative Groups are discussing new approaches to address these deficiencies, while complementing the existing NCI structure and recognizing the independence of each group. The objectives of these new approaches would be: to establish a structure whereby better contracts with industry for conducting trials can be established; to enhance international cooperation in clinical trials; to encourage greater involvement of third-party payers in clinical trials; to build on the scientific breadth of the members; to identify the most appropriate therapies to consider for reimbursement; to establish a framework which builds on the strengths of each of the members; and to integrate health outcomes and economic measures into the protocol activities. The Cooperative Groups are making changes to ensure they remain the leaders in cancer clinical trials well into the 21st century. The benefits of these adjustments will be realized not only by patients, but also by health professionals and the healthcare industry.

Recommendations for research priorities in breast cancer by the Coalition of Cancer Cooperative Groups Scientific Leadership Council: systemic therapy and therapeutic individualization

Over 9,000 women with breast cancer are enrolled annually on clinical trials sponsored by the National Cancer Institute (NCI), accounting for about one-third of all patients enrolled on NCI-sponsored trials. Thousands are also enrolled on pharmaceutical-sponsored studies. Although breast cancer mortality rates have recently declined for the first time in part due to systemic therapeutic advances, coordinated efforts will be necessary to maintain this trend. The Coalition of Cancer Cooperative Groups convened the Scientific Leadership Council in breast cancer (BC), an expert panel, to identify priorities for future research and current trials with greatest practice-changing potential. Panelists formed a consensus on research priorities for chemoprevention, development and application of molecular markers for predicting therapeutic benefit and toxicity, intermediate markers predictive of therapeutic effect, pathogenesis-based therapeutic approaches, utilization of adaptive designs requiring fewer patients to achieve objectives, special and minority populations, and effects of BC and treatment on patients and families. Panelists identified 13 ongoing studies as High Priority and identified gaps in the current trial portfolio. We propose priorities for current and future clinical breast cancer research evaluating systemic therapies that may serve to improve the efficiency of clinical trials, identify individuals most likely to derive therapeutic benefit, and prioritize therapeutic strategies.

A Comparison of White and African American Outcomes from a Three-Arm, Randomized, Phase III Multicenter Trial of Advanced or Metastatic Non-small Cell Lung Cancer

Purpose: To investigate the effect of race on the efficacy and safety of standard chemotherapy doublet regimens in African American patients, we conducted a subgroup analysis of a phase III randomized trial. Patients and Methods: Chemonaïve patients with a performance status of 0 or 1 and stage IIIB or IV non-small cell lung cancer were randomized to arm A: gemcitabine 1000 mg/m2 on days 1 and 8 plus carboplatin area under the curve 5.5 on day 1; arm B: the same schedule of gemcitabine plus paclitaxel 200 mg/m2 on day 1; or arm C: paclitaxel 225 mg/m2 on day 1 plus carboplatin area under the curve 6.0 on day 1. Cycles were repeated every 21 days up to 6. A site selection tool identified institutions with potential to recruit a minority population. Outcome and toxicity data of white and African American patients were compared. Results: Of 1135 total patients, 972 were white (85.6%) and 138 were African American (12.2%). Median survival was 8.3 months for white patients (95% confidence interval [CI]: 7.7–9.3) and 9.1 months for African American patients (95% CI: 8.2–11.1). Response rates were 29.1 and 29.0%, respectively. Rates of grade 3 or 4 toxicities were comparable. Among African Americans, median survival was 7.2 months (95% CI: 5.1–10.1) for gemcitabine-carboplatin (n = 47), 10.5 months (95% CI: 7.1–15.4) for gemcitabine-paclitaxel (n = 42), and 10.2 months (95% CI: 8.5–13.2) for paclitaxel-carboplatin (n = 49). Conclusion: Whites and African Americans had similar outcomes, although there was some variability in survival among African Americans across the three treatment groups.

The role of oral etoposide in non-small cell lung cancer.

Oral etoposide has been tested alone and in combination in a number of tumour types since the late 1980s because of its mild toxicity, high response rates, ease of administration, and comparatively low cost. Encouraging early results with protracted oral etoposide therapy in small cell lung cancer have not been borne out in non-small cell lung cancer (NSCLC), particularly in the advanced-disease setting. However, in stage IV NSCLC, oral etoposide does appear to be as compatible with most of the newer agents as it has been with platinum compounds; these combinations continue to be explored, although they have not penetrated into standard usage. In stage III NSCLC, large combined-modality studies are ongoing. Other investigations examining protracted administration in combination with radiation ‘sensitisers’ are planned. It is possible that by exploiting the ‘radiosensitising effect’ of prolonged low dose oral etoposide, combined with that of other proven radiosensitisers such as paclitaxel, gemcitabine, and topotecan, we may identify a niche for oral etoposide in the future.