Reports from the European Cancer Conference

Oncology & Biotech News, November 2007, Volume 1, Issue 9

The 14th annual European Cancer Conference, sponsored by the European Cancer Organisation (ECCO), was held September 23-27 in Barcelona, Spain. The results of numerous major clinical trials were presented, along with an increasing wealth of new preclinical and translational data.

REPORTS FROM THE EUROPEAN CANCER CONFERENCE

Latest advances in cancer research highlighted at annual meeting

The 14th annual European Cancer Conference, sponsored by the European Cancer Organisation (ECCO), was held September 23- 27 in Barcelona, Spain. The results of numerous major clinical trials were presented, along with an increasing wealth of new preclinical and translational data. This exciting new information offers opportunities to consider new treatment approaches both in the research and practice settings.

ECCO is a consortium of societies and organizations involved in day-to- day oncology throughout Europe. ECCO seeks to take a wide approach to oncology—one that brings together major players in cancer research, treatment, and care in order to create awareness of patients’ wishes and needs; encourage progressive thinking in cancer policy, education, and training; and continue to promote European cancer research and its application through the multidisciplinary meetings and conferences.

ADVANCES IN LUNG CANCER

Gemcitabine Provides Efficacy Similar to Pemetrexed When Combined With Cisplatin for First-Line Treatment of Advanced NSCLC

Dr. Christian Manegold, Medical Center University of Mannheim, Interdisciplinary Thoracic Oncology, Mannheim, Germany, reported the results of a study evaluating pemetrexed (Alimta) plus cisplatin (PC; N=862) versus gemcitabine (Gemzar) plus cisplatin (GC; N=863) in chemonaive patients with locally advanced or metastatic non—small cell lung cancer (NSCLC). Patients in both arms received dexamethasone prophylaxis, folic acid, and vitamin B12 supplementation. Overall survival for patients randomized to PC was similar to that in those who received GC (10.3 months vs 10.3 months). Progression-free survival was also similar in the two arms (4.8 months in the PC group vs 5.1 months in the GC group).

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The rates of Grade 3/4 hematologic toxicity were significantly lower ( ≤ 0.001) with PC than with GC, including neutropenia (15% vs 27%), anemia (6% vs 10%), and thrombocytopenia (4% vs 13%). Grade 3/4 febrile neutropenia (1% vs 4%) and alopecia (12% vs 21%) were also significantly ( < 0.001) less common in the PC group. Less grade 3/4 nausea (7% vs 4%, = 0.004) and anorexia (2% vs 1%, = 0.009) were observed in the GC group. This study showed that for the first-line treatment of advanced NSCLC, PC provides efficacy similar to that of GC, with better tolerability (as well as more convenient administration) than GC.

Gefitinib Is as Effective as Docetaxel in Patients with Pretreated Advanced NSCLC

Dr. Jean-Yves Douillard, Centre Rene Gauducheau, Site Hospitalier Nord, Nantes-Saint-Herblain, France, reported the results of the INTEREST (Iressa Non—Small-Cell Lung Cancer Trial Evaluating Response and Survival against Taxotere) trial— a Phase III, randomized, open-label, parallel-group study of oral gefi- tinib (Iressa) versus intravenous docetaxel (Taxotere) in patients with locally advanced or metastatic NSCLC who have previously received platinum-based chemotherapy. Dr. Douillard was Co- Principal Investigator and lead author of the study.

Patients ≥18 years of age with locally advanced or metastatic NSCLC that progressed or recurred following 1 or 2 prior chemotherapy regimens (≥1 of which were platinumbased) were randomized to receive either gefitinib (250 mg/day orally) or docetaxel (75 mg/m2 IV every 3 weeks). A total of 1466 patients were enrolled. Gefitinib-treated patients had survival equivalent to those treated with intravenous docetaxel. Gefitinib demonstrated a more favorable tolerability profile, and gefitinib-treated patients experienced superior quality of life for patients compared with docetaxel.

This is the largest Phase III study ever reported comparing two active treatments for pretreated, advanced NSCLC. It is also the first time an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), such as gefitinib, has demonstrated non-inferiority for overall survival relative to chemotherapy in a head-to-head Phase III study in patients with pretreated advanced NSCLC.

Dr. Edward Kim, Assistant Professor of Medicine, MD Anderson Cancer Center, Houston, Texas, and Co-Principal Investigator of the INTEREST study said, “This large study validates the role of targeted therapy when compared to chemotherapy in previously treated advanced NSCLC patients. The study showed that IRESSA was as effective as docetaxel but with a more favorable tolerability profile, resulting in significantly more IRESSA-treated patients experiencing clinically important improvements in quality of life compared with patients who received docetaxel. Clearly, improving efficacy while minimizing toxicity is the direction advanced cancer therapy is going.”

Oral or IV Vinorelbine plus Cisplatin Achieves Efficacy Similar to That of Docetaxel plus Cisplatin in Chemonaïve Patients with Advanced NSCLC

The GLOB 3 trial was a multinational, randomized, Phase III trial of oral and IV vinorelbine (Navelbine) plus cisplatin versus docetaxel (Taxotere) plus cisplatin as first-line treatment for advanced NSCLC in chemonaive patients. Results of the GLOB 3 trial were reported by Dr. J. Rolski, Maria Curie Sklodowska Institute, Oncology, Krakow, Poland. Dr. Rolski was lead investigator and lead author of the study.

Both regimens were given in 3-week cycles. A total of 390 patients were randomized, and 381 were treated. Objective response was seen in 27.4% of vinorelbine- treated patients, compared with 27.2% of those who received docetaxel. Median progression-free survival was 4.9 months versus 5.0 months, and median survival was 9.9 months versus 9.8 months in the two groups, respectively. Tolerability was similar in the two groups, and quality-of-life assessments yielded similar results in the two groups.

In this trial, oral or IV vinorelbine plus cisplatin achieved efficacy similar to that of docetaxel plus cisplatin, with similar and acceptable tolerability, when given as front-line chemotherapy for chemonaive patients with advanced NSCLC. Quality of life was also similar in the two groups in this first headto- head comparison of vinorelbine/cisplatin and docetaxel/cisplatin given in 3-week cycles.

Addition of Bevacizumab to Cisplatin/Gemcitabine Significantly Improves Progression- Free Survival and Response Rate in Patients with Advanced NSCLC

Dr. Christian Manegold, Klinikum Mannheim, Germany, reported the results of a randomized, placebo-controlled, Phase III study of bevacizumab (Avastin) in combination with cisplatin and gemcitabine (Gemzar) in patients with advanced or recurrent non-squamous NSCLC. Dr. Manegold was lead investigator and lead author of the study.

Patients were randomized to receive cisplatin (80 mg/m2) on Day 1 and gemcitabine (1250 mg/m2) on Days 1 and 8 every 3 weeks for up to 6 cycles plus either bevacizumab (7.5 mg/kg or 15 mg/kg) or placebo every 3 weeks. Treatment was continued to disease progression. Median progression-free survival was 6.1 months in the placebo/cisplatin/gemcitabine group (N=347), 6.7 months in the bevacizumab 7.5-mg/kg/cisplatin/gemcitabine group (N=345), and 6.5 months in the bevacizumab 15-mg/kg/cisplatin/gemcitabine group (N=351). The response rate was 20.1%, 34.1%, and 30.4% in these three groups, respectively. The frequency of serious adverse events was comparable between study arms.

In this trial, the addition of bevacizumab (7.5 or 15 mg/kg) to cisplatin/gemcitabine signifi- cantly improved progression-free survival and response rate in patients with advanced NSCLC.

IV Vinflunine Provides Efficacy and Tolerability Similar to That of IV Docetaxel in Patients With Advanced NSCLC Treated Previously With a Platinum-Containing Regimen

The results of an open-label Phase III study evaluating IV vinflunine versus IV docetaxel (Taxotere) in patients with advanced or metastatic NSCLC treated previously with a platinum- containing regimen were reported by Dr. Jean-Yves Douillard, Centre Rene Gauducheau, Site Hospitalier Nord, Nantes-Saint- Herblain, France.

Five hundred fifty-one patients were randomized to receive either vinflunine (320 mg/m2, 20-minute infusion; N=274) or docetaxel (75 mg/m2, 1-hour infusion with dexamethasone over 3 days; N=277) every 3 weeks. All patients were platinum-pretreated. A total of 950 vinflunine cycles and 1025 docetaxel cycles were given. Median progression- free survival in each group was 2.3 months. The response rates in the vinflunine and docetaxel groups was 4.4% and 5.5%, respectively, and median overall survival in the two groups was 6.7 months and 7.2 months, respectively. Grade 3/4 toxicities in the two groups, respectively, included neutropenia (33% vs 30%), anemia (8% vs 3%), thrombocytopenia (2% vs <1%), febrile neutropenia (3% vs 5%), fatigue (10% vs 6%), vomiting (2% vs 1%), abdominal pain (4% vs <1%), and constipation (7% vs <1%).

The investigators concluded that the efficacy and tolerability of IV vinflunine and IV docetaxel were similar in patients with advanced or metastatic NSCLC treated previously with a platinum-containing regimen, and suggested that vinflunine be further evaluated as a therapeutic option in the second-line setting.

ADVANCES IN HEPATOCELLULAR CARCINOMA

Favorable Results of a Phase II Trial Evaluating Sorafenib in Combination with Doxorubicin in Patients with Advanced Hepatocellular Carcinoma Warrant Extension Study

Dr. Ghassan K. Abou Alfa, Memorial Sloan-Kettering Cancer Center, New York, NY, reported preliminary results of a Phase II, randomized, double-blind study of sorafenib (Nexavar) plus doxorubicin versus placebo plus doxorubicin in patients with advanced hepatocellular carcinoma. Patients had received no prior systemic therapy.

Patients received doxorubicin 60 mg/m2 IV every 21 days plus either sorafenib 400 mg po bid (N=47) or placebo (N=49), for a maximum of 6 cycles (18 weeks) of doxorubicin. Patients could continue on single-agent sorafenib or placebo beyond 18 weeks until disease progression. Median time to progression was 8.5 months in the sorafenib group, compared with 2.8 months in the placebo group. Median overall survival in the two groups was 14.0 months and 5.6 months, respectively. Response rate (complete response partial response) was 4.3% in the sorafenib group, compared with 2.0% in the placebo group. Grade 3/4 neutropenia was more common in the placebo group (41.7% vs 36.25). Grade 3/4 fatigue occurred in 10.6% of sorafenib-treated patients, compared with 6.3% of those who received placebo.

Based on these encouraging preliminary results, the trial has been unblinded and remaining patients in the control arm have been crossed over to sorafenib.

Sorafenib Improves Survival in a Large Multicenter, Randomized, Placebo-Controlled, Phase III trial in Patients with Advanced Hepatocellular Carcinoma

Dr. Josep Llovet, University of Barcelona, Spain, reported the results of the SHARP study, a multicenter, randomized, placebocontrolled, Phase III trial evaluating the effi- cacy and safety of sorafenib in patients with advanced hepatocellular carcinoma. Patients had no prior systemic treatment.

A total of 602 patients were randomized, 299 of whom were treated with sorafenib and 303 of whom received placebo. Median overall survival was 10.7 months in the sorafenib group, compared with 7.9 months in the placebo group. Median time to progression was longer in the sorafenib group (5.5 vs 2.8 months) and the disease-control rate (complete response partial response standard deviation for at least 2 cycles) was greater in the sorafenib group (43% vs 32%). The most frequent grade 3/4 events in the sorafenib and placebo groups, respectively, were diarrhea (11% vs 2%), hand—foot skin reaction (8% vs 1%), fatigue (10% vs 15%), and bleeding (6% vs 9%).

This is the first Phase III trial to demonstrate a statistically significant improvement in overall survival in patients with advanced hepatocellular carcinoma treated with sorafenib, with good tolerability, and establishes sorafenib as a first-line treatment for these patients.

ADVANCES IN BREAST CARCINOMA

Addition of Trastuzumab to Neoadjuvant Chemotherapy Significantly Improves Outcome in HER2- Positive Patients with Inflammatory Breast Carcinoma

There is currently no standard therapy for women diagnosed with HER2-positive inflammatory breast carcinoma (IBC). Dr. Jose Baselga, Vall d’Hebron University Hospital, Barcelona, Spain, reported interim results of the NOAH (Neoadjuvant Herceptin) trial—a Phase III study of neoadjuvant trastuzumab (Herceptin) in combination with chemotherapy in patients with IBC.

All enrollees in the trial received neoadjuvant chemotherapy consisting of 3 cycles of doxorubicin/paclitaxel, 4 cycles of paclitaxel, and 3 cycles of cyclophosphamide/ methotrexate/5-fluorouracil (CMF). Patients with HER2-positive disease were randomized to receive either concomitant trastuzumab (8 mg/kg IV loading dose, then 6 mg/ kg q3w for 1 year) or chemotherapy only.

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Sixty-one of 228 patients with HER2-positive disease and 14 of 99 with HER2-negative disease had IBC; 31 of those with HER2-positive IBC received chemotherapy with trastuzumab. The objective clinical response rate was 77.4% in HER2-positive patients treated with trastuzumab, 77.4% in HER2-positive patients not treated with trastuzumab, and 57.1% in HER2-negative patients. The in-breast pathological eradication rate in these three groups, respectively, was 54.8% ( = 0.004), 19.3%, and 28.6%, and the nodal pathological eradication rate in the three groups, respectively, was 48.4% ( = 0.002), 12.9%, and 28.6%.

In this trial, the clinical response rate was similar with or without trastuzumab in patients with HER2-positive IBC, but the addition of trastuzumab significantly improved the in-breast and nodal pathological eradication rates compared with chemotherapy alone. These interim results suggest that the addition of trastuzumab to neoadjuvant chemotherapy may significantly improve outcome in HER2- positive patients with IBC.

First-Line Therapy with Trastuzumab plus Docetaxel, With or Without Carboplatin, Significantly Improves Survival in Patients with HER2-Positive Metastatic Breast Cancer

Dr. Tadeusz Pienkowski, Maria Sklodowska Curie, Warsaw, Poland, presented a survival analysis of results from a Phase III trial of trastuzumab (Herceptin) plus docetaxel (Taxotere), with or without carboplatin, as first-line therapy in HER2-positive metastatic breast cancer.

Enrollees were randomized to receive either trastuzumab plus docetaxel (TH; N=131) or trastuzumab plus carboplatin plus docetaxel (TCH; N=131). At a median follow-up of 39 months, median overall survival was 36.40 months and 36.57 months in TH and TCH arms, respectively. More patients on TCH than on TH received the maximum number of chemotherapy cycles, and numerically fewer patients on TCH than TH discontinued treatment as a result of nonhematological toxicity. The most common grade 3/4 toxicities in the TH and TCH groups, respectively, were neutropenic infection (16.8% vs 9.2%), thrombocytopenia (2% vs 15%), asthenia (5% vs 12%),

anemia (5% vs 11%), and diarrhea (2% vs 10%).

The investigators concluded that both TH and TCH were highly effective treatment regimens in women with HER2-positive metastatic breast cancer.

Ixabepilone plus Capecitabine in Patients with Metastatic Breast Cancer Progressing After Anthracyclines and Taxanes: Subgroup Analysis of Patients Receiving Ixabepilone in the First-Line Setting

Dr. Jacek Jassem, Medical University of Gdansk, Department of Oncology and Radiotherapy, Gdansk, Poland, presented a subgroup analysis of results from a Phase III study of ixabepilone (Ixempra) plus capecitabine in patients with metastatic breast cancer progressing after anthracyclines and taxanes. Ixabepilone, a semi-synthetic analog of epothilone B, was developed to overcome tumor resistance mechanisms. This trial evaluated ixabepilone plus capecitabine versus capecitabine alone.

A total of 752 patients with metastatic breast cancer resistant to anthracyclines and taxanes were randomized to receive either ixabepilone (40 mg/m2 IV over 3 hours on Day 1, every 3 weeks) plus capecitabine (2000 mg/m2 po in 2 divided doses, on Days 1—14 of a 21- day cycle), or capecitabine alone (2500 mg/m2 on the same schedule). Resistance was defined as disease progression within 3—4 months following anthracycline/taxane in the metastatic setting and 6–12 months following adjuvant anthracycline/ taxane therapy. A prospectively-defined subset analysis was performed in patients who received ixabepilone plus capecitabine as first-line treatment after adjuvant anthracycline/ taxane.

Ixabepilone plus capecitabine was superior to capecitabine alone, with a 40% prolongation of median progression-free survival (P < 0.001). Fifty-five patients received ixabepilone plus capecitabine or capecitabine as first-line therapy. Progression-free survival was again prolonged for patients receiving combination therapy, with a 54% reduction in the estimated risk of disease progression. Grade 3/4 sensory neuropathy (21% vs 0%), fatigue (9% vs 3%), and neutropenia (68% vs 11%) were more frequent with combination therapy in the total population.

The investigators concluded that ixabepilone plus capecitabine is superior to capecitabine alone in patients with metastatic breast cancer who progress rapidly after anthracycline/taxane treatment. This benefit was also confirmed in first-line patients who progress after adjuvant anthracycline/taxane therapy.

ADVANCES IN COLORECTAL CARCINOMA

Interim Safety Analysis of Phase III Study of Capecitabine, Oxaliplatin and Bevacizumab (CAPOXB) With or Without Cetuximab in Advanced Colorectal Cancer (CAIRO2)

Preliminary safety results of the Dutch Colorectal Cancer Group (DCCG) CAIRO2 study—a Phase III study of capecitabine (Xeloda), oxaliplatin (Eloxatin), and bevacizumab (Avastin) (CAPOXB), with or without cetuximab (Erbitux), in patients with advanced colorectal cancer—were presented by Dr. Jolien Tol, University Medical Centre St. Radboud, Nijmegen, The Netherlands.

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A total of 755 patients were randomized to receive either CAPOXB (Arm A) or CAPOXB plus cetuximab (Arm B). Of the 755 patients, 381 were safety-evaluable in the interim analysis. The overall incidence of Grade 3/4 toxicity in arms A and B was 66% and 76%, respectively ( = 0.12). Toxicity was the main reason for treatment discontinuation for 30 patients (15%) in Arm A and 35 patients (19%) in Arm B ( = 0.70). Grade 3/4 toxicities in Arms A and B, respectively, included hand—foot syndrome (12% vs 13%) diarrhea (16% vs 23%), vomiting (7% vs 6%), febrile neutropenia (1% vs 0%), cardiovascular events (4% vs 3%), thromboembolic events (5% vs 7%), with none of these differences being statistically significant. In Arm B, the incidence of all grade and grade 3/4 acneiform skin reactions was 80% and 20%, respectively, and all grade and grade 3/4 nail changes, 27% and 4%, respectively.

Toxicity was considered acceptable in both treatment arms. Except for skin toxicity due to cetuximab, no difference in the incidence of other grade 3/4 toxicities was observed between the two treatment arms.

Cetuximab Plus Irinotecan Results in Significantly Longer Progression-Free Survival Than Irinotecan Alone in Patients With Metastatic Colorectal Cancer who Failed on Oxaliplatin

Dr. Werner Scheithauer, Vienna University Medical School, Department of Internal Medicine, Vienna, Austria, reported results of the EPIC trial—a multinational, randomized, Phase III trial of cetuximab (Erbitux) plus irinotecan (Camptosar) in patients with metastatic epidermal growth factor receptor (EGFR)— expressing colorectal cancer who failed prior oxaliplatin-based therapy.

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A total of 1,298 patients were randomized to receive either cetuximab (400 mg/ m2 initial dose, then 250 mg/m2 weekly) plus irinotecan (350 mg/m2 every 3 weeks) (Arm A; N=648) or irinotecan alone (350 mg/m2 every 3 weeks) (Arm B; N=650). Median overall survival in Arm A was found to correlate with the presence of acne-like rash: grade 0, 5.8 months; grade 1/2, 11.7 months; grade 3/4, 15.6 months. The most common grade-3/4 adverse events in Arms A and B, respectively, were neutropenia (31.8% vs 25.4%), diarrhea (28.4% vs 15.7%), and acneiform rash (8.0% vs 0.2%). Baseline health-related quality-of-life (HRQoL) scores for social functioning, fatigue, dyspnea, and appetite loss showed significant differences in favor of Arm A. Patients in Arm A had significantly improved Global Health Status ( = 0.047), as well as significant improvements in 10 of 15 HRQoL scales, including pain ( = 0.006), nausea/vomiting (P < 0.001), insomnia ( < 0.001), and physical (P = 0.023) and cognitive functioning ( = 0.008).

In this trial, cetuximab plus irinotecan in patients with metastatic colorectal cancer who failed on oxaliplatin resulted in a significantly longer progression-free survival, greater response rates and improved HRQoL than irinotecan alone.