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ASCO Meeting Highlights

OBTN, July 2008, Volume 2, Issue 7

The American Society of Clinical Oncology (ASCO) held its 44th Annual Clinical Meeting in Chicago. Leading oncologists and cancer researchers at centers from around the world presented new basic and clinical research findings to advance the care of cancer.

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Global Oncology Community Reviews the Latest Advances in Cancer Research and New Innovations in Cancer Care

The American Society of Clinical Oncology (ASCO) held its 44th Annual Clinical Meeting in Chicago. Leading oncologists and cancer researchers at centers from around the world presented new basic and clinical research findings to advance the care of cancer.

The ASCO Annual Meeting is the premier scientific and educational event in the field of oncology, drawing more than 30,000 attendees from around the world. As a forum for collaboration and communication, the ASCO Annual Meeting brings together oncologists of all disciplines, researchers, nurses, and patient advocates in the fight against cancer. The 2008 meeting united the global oncology community with the common goals of delivering the highest quality patient care and innovating treatment advances.

Advances in Lung Cancer

Platinum-Doublet Chemotherapy Followed by Gefitinib (Iressa) May Offer Improved Survival in Chemonaïve Patients With Advanced NSCLC

Toyoaki Hida, MD, PhD, who spoke on behalf of the West Japan Thoracic Oncology Group (WJTOG), presented the late-breaking results of a randomized phase III WJTOG study of platinum-doublet chemotherapy followed by gefitinib, a small molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, compared with continued platinum-doublet chemotherapy in patients with advanced non—small cell lung cancer (NSCLC).

Enrolled patients (N = 603) were chemotherapy-naïve, had advanced disease (stage IIIB or IV), had ECOG PS 0-1, and were randomized to receive either platinum-doublet chemotherapy for six cycles or platinumdoublet chemotherapy for three cycles followed by platinum-doublet chemotherapy.

Platinum-doublet chemotherapy consisted of one of the following regimens: (1) carboplatin AUC 6 + paclitaxel 200mg/m2 day1 q3w; (2) cisplatin 80 mg/m2 day1 + irinotecan 60 mg/ m2 days 1, 8, 15 q4W; (3) cisplatin 80 mg/m2 day 1 + vinorelbine 25 mg/m2 days 1, 8 q3W; (4) cisplatin 80 mg/m2 + docetaxel 60 mg/m2 day 1 q3W; or (5) cisplatin 80 mg/m2 day 1 + gemcitabine 1000 mg/m2 days 1, 8 q3W. The primary endpoint was overall survival (OS).

There was a statistically significant improvement in progression-free survival (PFS) (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.57-0.80; P < 0.001) in the gefitinib group; however, OS result did not reach statistical significance. In a prespecified analysis of OS by histologic groups, the gefitinib group had significantly better OS than the continued platinum-doublet treatment group in adenocarcinoma histology (N = 467; HR, 0.79; 95% CI, 0.65-0.98;

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= 0.03). The investigators concluded that platinum-doublet chemotherapy followed by gefitinib may offer clinical benefit, particularly in patients with adenocarcinoma.

First-line Sequential Administration of Erlotinib (Tarceva) With Chemotherapy Shows Promise in the Treatment of Stage IIIB/IV NSCLC: Results of the FAST-ACT

In a poster discussion, Jin S. Lee, MD, National Cancer Center, Seoul, South Korea, presented results of FAST-ACT—a phase II randomized, double-blind trial of sequential erlotinib and chemotherapy as first-line treatment in patients with stage IIIB/ IV NSCLC.

Study enrollees were chemonaïve and had an Eastern Cooperative Oncology Group performance status ECOG PS of 0-1. Patients were randomized to receive either erlotinib 150 mg/day (GC-E) or placebo (GC-P) on d 15-28 of 4-weekly chemotherapy cycles. Chemotherapy consisted of gemcitabine 1250 mg/m2 d1, eight plus either cisplatin 75 mg/m2 or carboplatin 5xAUC d1 for a maximum of six cycles. Responding pa- tients continued to receive erlotinib or placebo until progression or unacceptable toxicity. The primary endpoint was nonprogression rate (NPR: CR+PR+SD) at eight weeks based on Response Evaluation Criteria in Solid Tumors (RECIST).

A total of 154 patients from seven countries were enrolled. Median age was 57 years. Ninety- four percent of patients were Asian.

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At eight weeks, the nonprogression rate was 80.3% and 76.9% in the erlotinib and placebo groups, respectively ( = 0.51). At 16 weeks, the nonprogression rate in the two groups was 65.8% and 53.8%, respectively ( = 0.11). Median progression-free survival (PFS) was 31.3 weeks in the erlotinib group, compared with 23.7 weeks in the placebo group ( = 0.0175). The objective tumor response rate (based on partial responses) was 36.8% in the erlotinib group versus 24.4% in the placebo group ( = 0.089). Median OS has not yet been reached.

The median number of treatment cycles received was 6 versus 5 (GC-E vs. GC-P). Rash-like events were noted in 66% of GC-E versus 35% of GC-P patients, and diarrhea was observed in 24% and 18% of patients in these groups, respectively. The most common grade 3—5 adverse events (GC-E vs. GC-P) were neutropenia (20% vs. 15%), anemia (8% vs. 6%), thrombocytopenia (5% vs. 5%), and vomiting (3% vs. 8%). Overall safety profiles were similar between the two groups.

The investigators concluded that the first- line sequential administration of erlotinib with chemotherapy has demonstrated promising results, and suggested that this treatment be further investigated in patients with advanced NSCLC.

The FAST-ACT study is the first time that an epidermal growth factor receptor tyrosine kinase inhibitor has shown promise in the first-line treatment of NSCLC when administered sequentially with standard chemotherapy.

FLEX Results Demonstrate Superior Survival With Cetuximab (Erbitux) Plus Cisplatin/Vinorelbine Compared With Cisplatin/Vinorelbine Alone in the First-Line Treatment of Patients With Advanced, EGFR-Detectable NSCLC

Epidermal growth factor receptor dysregulation is common in NSCLC and is associated with poorer prognosis. In a plenary presentation, Robert Pirker, MD, Division of Oncology, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria disclosed the long-awaited results of the phase III FLEX (First- Line Trial for Patients with EGFR-Expressing Advanced NSCLC) Trial. This trial evaluated the efficacy and safety of the EGFR-targeted monoclonal antibody cetuximab in combination with cisplatin/vinorelbine compared with cisplatin/vinorelbine alone in patients with advanced NSCLC.

Patients with EGFR-detectable advanced NSCLC were randomized to cetuximab (400 mg/m2 initial dose, then 250 mg/m2 per week) plus cisplatin (80 mg/m2 d 1) and vinorelbine (25 mg/m2 d 1, d 8) q3w (N = 557) or cisplatin/ vinorelbin alone (N = 568). The primary endpoint was OS.

Median age was 59 years (range, 18-83 years), 94% had stage IV disease, 47% had adenocarcinoma, 34% had squamous-cell carcinoma, and 83% had ECOG PS 0/1. Survival analysis was performed after 868 events had occurred.

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Median OS was 11.3 months in the cetuximab group, compared with 10.1 months in the group receiving cisplatin/vinorelbine alone (HR, 0.871 [95% CI, 0.762-0.996], = 0.0441). Preliminary results of prespecified subgroup analyses suggested a greater benefit in Caucasians independent of histology and a general better prognosis in Asians. Analyses of secondary endpoints (PFS, tumor response, disease control, and safety) are ongoing.

The investigators concluded that cetuximab plus cisplatin/vinorelbine demonstrated superior survival over cisplatin/vinorelbine alone in patients with advanced EGFR-detectable NSCLC. This is the first study to demonstrate a survival benefit of an EGFR-targeted agent in combination with platinum-based chemotherapy in the first-line treatment of advanced NSCLC irrespective of histology, and confirms the clinical relevance of cetuximab in NSCLC.

Preoperative Gemcitabine (Gemzar)—Cisplatin Combination Is Well Tolerated and May Lead to Better Outcomes Than Surgery Alone for Patients With Early-Stage NSCLC: Follow-Up Data From ChEST

In an oral presentation, Giorgio Scagliotti, MD, PhD, University of Turin, Department of Clinical and Biological Sciences, San Luigi Hospital, Orbassano, Torino, Italy, provided updated results from the ChEST (Chemotherapy for Early Stages Trial). This was a phase III study that evaluated whether three preoperative cycles of gemcitabine— cisplatin followed by radical surgery provides a reduction in the risk of progression compared with surgery alone in patients with stage IB-IIIA NSCLC.

Chemotherapy-naïve patients with clinical stage T2N0, T1-2N1, or T3N0-1 received either preoperative cisplatin (75 mg/m2 d1) and gemcitabine (1250 mg/m2, d1, 8), q3week followed by surgery (N = 129), or surgery alone (N = 141). Enrollment was closed early after the inclusion of 270 out of 700 planned patients because, the investigators felt it would be unethical to complete the study treating patients with surgery alone due to positive adjuvant studies.

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Squamous-cell carcinoma was the most common histology. The response rate to chemotherapy was 35%. Progression of neoplastic disease during chemotherapy was reported in 5.5% of patients. The 3-year progression-free survival (PFS) rate was 48% in the group receiving surgery alone, compared with 53% in the group receiving preoperative chemotherapy plus surgery ( = 0.11). The overall three-year survival rate was 60% in the surgery- along group, compared with 67% in the chemotherapy-plus-surgery group ( = 0.053).

Eight deaths related to study drug or procedure were observed during the study (6 and 2 in the surgery-alone group and chemotherapy- plus-surgery groups, respectively).

This prematurely closed phase III study in early-stage NSCLC indicates the efficacy outcome estimates in the range of those reported from other neoadjuvant trials in similar patient populations.

Dr. Scagliotti provided further detail regarding PFS, stating, “For patients whose cancer was in an early stage at enrollment (IB to IIA), results told a somewhat different story. In the early-stage patients, PFS was 3.6 years in those who underwent surgery alone, compared with 2.9 years for those who had preoperative chemotherapy. Essentially, there were no differences in outcomes between the two treatment programs in patients who had early-stage disease.”

He added, “In terms of overall survival, 42% of patients in the surgery-only arm died, compared with 34% of those in the preoperative-chemotherapy arm. Median overall survival was 4.8 years for those in the surgery-only group, but was not available in the preoperative- chemotherapy arm.”

Dr. Scagliotti concluded the oral presentation by stating, “This study demonstrates that preoperative chemotherapy can be well tolerated and leads to better outcomes than surgery alone for patients with advanced NSCLC. However, these results were not as strong as what had been seen in previous studies looking at preoperative therapies, but consideration has to be given to the fact that the study was stopped early and, therefore, data from many patients were not included in the final analysis.”

Sorafenib (Nexavar) Is Active Against Relapsed NSCLC with Only One Prior Line of Systemic Treatment: Preliminary Results of a Phase II Study

Martin E. Gutierrez, MD, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, and colleagues reported the results of a phase II trial to determine the clinical and biological activity of sorafenib in patients with relapsed NSCLC.

Enrollees had recurrent NSCLC, no more than one prior chemotherapy regimen for metastatic disease, and ECOG PS 0-2. Sorafenib was administered at a starting dose of 400 mg bid continuously in 28-day cycles. Dynamic contrast enhanced MRI (DCE- MRI) was performed before cycle 1 and at cycle 1 day 15 to evaluate early changes in tumor vascularity.

Fifteen patients were enrolled, 14 of whom had one prior platinum-doublet regimen and one of whom had prior erlotinib. All 15 patients completed at least two cycles of therapy and were evaluable for response (>8 wk of treatment) and toxicity.

Two patients (13%) had partial response and seven (46%) had stable disease. Median time to progression was five months (range, 1 to 11+ mo). DCE-MRI showed a reduction in the parameters of permeability, with decreased values in Ktrans and kep, associated with reductions in tumor size.

No grade 4 toxicities were observed. Hematological toxicities included grade 3 anemia (1) and grade 1-2 leukopenia (4). Grade 3 non-hematological adverse events included hypo-natremia (3), hypokalemia (1), hypocalcemia (1), hypophosphatemia (2), nausea (1), dyspnea/ hypoxia (2), syncope (1), retinopathy (1) and hypertension (1). All toxicities have responded to temporary withdrawal of sorafenib and supportive care. Fifteen patients have completed at least two cycles of therapy and were evaluable for response (>8 wk of treatment) and toxicity.

The investigators concluded that sorafenib monotherapy is well tolerated, with manageable toxicity, and is active against relapsed NSCLC in patients who have had only one prior line of systemic treatment. Accrual to this phase II trial continues in the second stage.

Phase I Results of a Phase I-II Study Evaluating the Combination of RAD001 (Everolimus; Certican) and Erlotinib (Tarceva) as Second- and Third-Line Therapy in Patients With Advanced NSCLC

In a general poster session, Vassiliki Papadimitrakopoulou, MD, University of Texas M.D. Anderson Cancer Center, Houston, Texas, presented phase I results of a phase I-II study evaluating the combination of the rapamycin (mTOR) inhibitor RAD001 and the oral epidermal growth factor receptor inhibitor erlotinib as second- and third-line therapy in patients with advanced NSCLC.

Enrollees were patients with advanced NSCLC who had failed one or two prior chemotherapy regimens and had ECOG PS 0-2.

The phase 1 portion of the trial assessed the combination of rapamycin and erlotinib using a standard “6 + 6” dose-escalation design based on the rate of dose-limiting toxicity (DLT) and pharmacokinetic (PK) drug—drug interaction (DDI) during the first 28 days of combined treatment. A range of rapamycin doses administered in either a daily or weekly schedule were evaluated in combination with different daily doses of erlotinib.

Sixty-one patients were treated. Doses and schedules evaluated were rapamycin 2.5 mg qd, 5 mg qd, 30 mg qw, 50 mg qw in combination with qd doses of erlotinib (75 mg, 100 mg, and 150 mg). Rapamycin 2.5 mg qd + erlotinib 150 mg qd, rapamycin 5 mg qd + erlotinib 75 mg qd, and rapamycin 50 mg qw + erlotinib 150 mg qd were established as feasible dose regimens.

DLTs observed were: mucositis (5), rash (4), diarrhea (4), vomiting (1) and neutropenia (1). Available duration of exposure of the combination was 0.2—25.8 months in daily cohorts and 0.1–2.9 months in weekly cohorts. Preliminary best overall response based on RECIST as per Investigator lesion assessment was: CR (1), PR (3), SD (17), PD (18).

The investigators concluded that the phase 1 portion of the study established feasible doses of rapamycin in combination with erlotinib, with a promising early indication of clinical efficacy. Dr. Papadimitrakopoulou stated that the phase 2 portion of the study will evaluate the efficacy of dose regimens established in the phase 1 part.

ASCO Highlight — Advances in Lung Cancer

Sorafenib (Nexavar) May Prolong Progression-Free Survival in Heavily Pretreated Patients With NSCLC: Preliminary Results From ECOG 2501

In an oral presentation, Joan H. Schiller, MD, University of Texas Southwestern Medical Center, Dallas, Texas, summarized preliminary results from ECOG 2501—a phase II randomized discontinuation study of sorafenib versus placebo in patients with NSCLC who had failed at least two prior chemotherapy regimens.

The investigators utilized a unique randomized discontinuation design (Figure) in order to enrich for patients with slower growing disease, who theoretically might be more likely to derive benefit. Patients were required to have an ECOG PS of 0-1; at least two prior chemotherapy regimens; and progressing disease. All patients received sorafenib 400 mg orally bid for two cycles (2 months) (Step 1). Responding patients on Step 1 continued on sorafenib; progressing patients went off study, and patients with stable disease were randomized to receive either sorafenib or placebo (Step 2). Patients randomized to receive placebo were allowed to cross over to sorafenib upon progression. The primary endpoint of this study was the proportion of patients who had stable or responding disease two months after randomization.

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A total of 342 patients were enrolled in step 1; 97 eligible patients were subsequently randomized to step 2 and treated; 36 of 41 patients on placebo in step 2 were crossed over to sorafenib. Of 83 evaluable patients in step 2, 24 of 51 who received sorafenib (47%) and 6 of 32 who received placebo (19%) had stable or responding disease two months after randomization ( = 0.01).

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Median PFS in the sorafenib and placebo groups was 3.6 months and 2.0 months, respectively ( = 0.009). Median survival in the two groups was 11.9 months and 9.0 months, respectively ( = 0.18). Major grade 3—4 treatment-related toxicities among the 320 patients in step 1 included rash/hand–foot syndrome (15%); fatigue (11%); and international normalized ratio (INR) abnormalities (3%).

Two patients in Step 1 and one patient on maintenance sorafenib had grade 3, 5, and 5 hemoptysis, respectively.

This trial met its primary endpoint of disease stabilization at eight weeks following randomization to sorafenib. Single-agent sorafenib significantly improved PFS and maintained stable disease in a heavily pretreated, enriched NSCLC population. The trend toward improved survival was said by Dr. Schiller to be “promising,” and major toxicities were said to be “manageable and as expected.”

Dr. Schiller stated that these results warrant further investigation in larger randomized trials. She also commented about the positive results in the setting of numerous trials of combined chemotherapy and targeted therapy in advanced NSCLC failing to meet their endpoints, stating, “This phase II sorafenib monotherapy trial in advanced NSCLC demonstrated single-agent activity and clinical benefit. Possible explanations for the discrepancy with other trials include choice of drug, line of therapy, selection of enriched patient population, and single-agent benefit. Future studies should address these considerations.”

Advances in Prostate Cancer

Satraplatin (JM 216) Is Well Tolerated and Reduces Risk of Disease Progression in Men With Hormone-Refractory Prostate Cancer Progressing After Prior Chemotherapy

Satraplatin is an oral platinum compound previously reported to reduce the risk of disease progression in patients with hormone-refractory prostate cancer (HRPC) who progress after prior chemotherapy.

In a Clinical Science Symposium, A. Oliver Sartor, MD, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, presented results from the phase III SPARC trial, a multinational, randomized, doubleblind, placebo-controlled trial comparing satraplatin 80 mg/m2 per day x 5, q5 weeks) plus prednisone 5 mg bid with placebo + prednisone in patients with metastatic HRPC progressing after prior chemotherapy. PFS and OS were the primary endpoints.

A total of 950 patients were randomized—635 to the satraplatin plus prednisone group and 315 to the placebo plus prednisone group. Baseline demographic and disease characteristics were well-balanced between groups. Fifty-one percent of enrollees received prior docetaxel and 47% received post-SPARC chemotherapy.

Satraplatin plus prednisone was associated with statistically significant improvements in PFS, time to pain progression (TPP), prostatespecific antigen (PSA) response, objective tumor response, pain response, and duration of pain response. However, these improvements did not translate into an OS benefit. Median OS was 61.3 weeks and 61.4 weeks in the satraplatin and placebo groups respectively (HR = 0.97; 95% CI: 0.83-1.13). Trends for improved OS were observed in the subgroup of patients who received prior docetaxel (median OS, 66.1 vs. 62.9 mo; HR = 0.78; 95% CI: 0.61-0.99) as well as in patients who reported a PPI score of 2-5 at baseline (median PPI score, 45.7 vs. 43.0, HR = 0.88; 95% CI: 0.67-1.16) when models were adjusted for baseline prognostic factors.

In the satraplatin group; myelosuppression was the most common toxicity; grade 4 neutropenia was detected in 4% of patients, and only one patient experienced grade 4 thrombocytopenia. Grade 3/4 nonhematologic side effects in the satraplatin group included infection (4.5%), vomiting (1.6%), and diarrhea (1.9%).

The investigators concluded that satraplatin is well tolerated and reduces the risk of disease progression in men with HRPC who progress after prior CT. Dr. Sartor said that ongoing analyses are planned to more clearly define the relationships between PFS, pain response, and OS, as well as to elucidate factors (including post-SPARC chemotherapy) that may have confounded the survival analysis.

Erlotinib (Tarceva) Is Safe and Has Modest Single- Agent Activity in Chemotherapy-Naïve Patients with Androgen-Independent Prostate Cancer

T.M. Lestingi, MD, Department of Medicine, University of Chicago, Pritzker School of Medicine, Chicago, and Lutheran General Hospital, Park Ridge, Illinois, and colleagues reported the results of a phase II trials evaluating single-erlotinib for the treatment of chemotherapy-naïve patients with androgen-independent prostate cancer (AIPC). The primary endpoint was overall clinical benefit, defined as the sum of complete response (CR), partial response (PR), and stable disease (SD).

A total of 29 patients were enrolled. Median age was 78 years (range, 61 to 96 years). Median prostate-specific antigen (PSA) at enrollment was 64.1 ng/dL (range, 9.2 to 914.2 ng/dL). Median time from initial diagnosis to starting erlotinib was eight years (range, 1—14 yr). Erlotinib was given at a dose of 150 mg daily during 4-week cycles until disease progression or intolerability. Response assessment occurred every two cycles, and including computed tomography of measurable disease areas, bone scans, and serum PSA. Patients who progressed radiographically but maintained a PSA response or those who progressed biochemically but maintained a radiographic response were considered stable and continued on study.

Two patients achieved a PR and 3 patients demonstrated SD. The calculated overall clinical benefit was 26% (5 responses out of 19 patients). Although median TTP was 2 months (range, 2 to 20 months), the 2 PR patients responded for 20 and 13 months, respectively.

Erlotinib was well tolerated, and most toxicities were grade 1 or 2. Hematuria occurred in 3 patients, but was deemed unrelated to erlotinib. Grade 3 diarrhea and dehydration occurred in 2 patients (8%). One patient developed a grade 3 rash. One patient developed a venous thromboemblic event. One patient required a dose reduction secondary to grade 3 hand—foot syndrome. One patient was unable to tolerate therapy even at the reduced dose because of grade 3 fatigue. With a median follow up of 10 months (range, 1 to 23 months), 20 patients (72%) remain alive.

Dr. Lestingi and his co-investigators concluded that erlotinib is safe and has modest single-agent activity in AIPC. Further studies are warranted.

Advances in Colorectal Cancer

Adding Cetuximab (Erbitux) and Bevacizumab (Avastin) to Capecitabine and Oxaliplatin (CapOx) Results in Significant Decrease in Progression-Free Survival Compared With Bevacizumab and CapOx

In an oral presentation, Cornelis J. A. Punt, MD, PhD, Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands, reviewed the results of the CAIRO2 study—a randomized, phase III trial performed by the Dutch Colorectal Cancer Group (DCCG) to evaluate the effect of adding cetuximab and bevacizumab to capecitabine and oxaliplatin (CapOx) and in patients with advanced colorectal cancer.

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Seven hundred fifty-five patients were randomized to receive oxaliplatin, capecitabine, and bevacizumab with or without cetuximab. The median duration of follow-up was 18.7 months. The results of the study showed a significantly decreased PFS without affecting survival when adding cetuximab to the oxaliplatin, capecitabine, and bevacizumab therapy. The median PFS without and with cetuximab were 10.7 months and 9.6 months respectively ( = 0.018), and the response rate was 44% in both arms. Other additional observations were that the addition of cetuximab to chemotherapy plus bevacizumab significantly increased skin toxicity and diarrhea, and that the grade of the cetuximab-related skin toxicity significantly correlated with PFS.

In contrast to the CRYSTAL study, KRAS wildtype status did not influence the results with the addition of cetuximab in the CAIRO2 study. However, it was noted that patients with a KRAS mutation had a significant reduction in PFS with the addition of cetuximab.

Cathy Eng, MD, who discussed the presentation, suggested that the use of combined biologic therapy (anti-VEGF/EGFR) should only be conducted as part of a clinical trial. In addition, the use of anti-EGFR therapy in KRAS mutant tumors in combination with chemotherapy negatively affects PFS and possibly response rate.

Benefit From Adding Cetuximab (Erbitux) to Standard First-Line Chemotherapy for Metastatic Colorectal Cancer May Be Greater for Patients With Wild-Type K-Ras Mutation

KRAS mutation status has been related to the efficacy of anti-epidermal growth factor receptor (EGFR) targeted therapies in different cancer models.

In a Clinical Science Symposium, Prof. Carsten Bokemeyer, MD, Universitäres Cancer Center, Universitätsklinkum Eppendorf, Hamburg, Germany reported the results of a study in which he and his colleagues used genomic DNA isolated from archived tumor material to evaluate the relationship between KRAS mutation status and outcome in patients with metastatic colorectal cancer treated with standard chemotherapy with or without cetuximab.

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The OPUS trial evaluated the addition of cetuximab to first-line 5-fluorouracil, leucovorin, and oxaliplatin therapy (FOLFOX). This study showed no significant benefit in PFS with addition of cetuximab to FOLFOX-4 (HR 0.93, = 0.62). Dr. Bokemeyer presented a retrospective subgroup analysis of the role of KRAS mutational status in this study. Forty-two percent of patients were found to have KRAS mutation. In the KRAS wild-type subgroup, the addition of cetuximab produced significant improvement in the primary endpoint, response rate. The response rate was 37% with FOLFOX alone and 61% with the addition of cetuximab ( = 0.011). Similar improvement was seen in PFS for KRAS wild-type patients, with a HR of 0.57 ( = 0.016). This benefit was not observed in the KRAS mutant population, which sustained a response rate of 49% with FOLFOX alone and 33% with the addition of cetuximab ( = 1.06). As was observed in the CRYSTAL trial with leucovorin, 5-fluorouracil, and irinotecan (FOLFIRI), the KRAS wild-type and mutant subgroups in the OPUS trial showed no significant differences in response to FOLFOX alone, again suggesting that KRAS mutation is not an independent prognostic factor.

Dr. Bokemeyer concluded by saying, “These data suggest that the benefit from addition of cetuximab to standard treatment is higher for the population with wild-type KRAS. For patients with KRAS mutations, no benefit could be shown of adding cetuximab to FOLFOX in this study.”

KRAS is the first molecular marker for the selection of a targeted therapy in combination with a standard chemotherapy in firstline treatment of metastatic colorectal cancer. Cetuximab in combination with a standard first-line treatment for metastastic colorectal cancer is an important new option in patients with KRAS wild-type tumors.

Relationship Between Efficacy and KRAS Status in Patients With Irinotecan-Refractory Metastatic Colorectal Cancer Treated With Irinotecan and Escalating Doses of Cetuximab (Erbitux)

In a separate Clinical Science Symposium, Sabine Tejpar, MD, PhD, University Hospital Gasthuisberg, Leuvan, Belgium, analyzed the effect of KRAS mutation when doses of cetuximab were increased.

The EVEREST trial selected patients who showed little or no skin rash when treated with FOLFIRI and cetuximab, and randomly assigned them to continue the standard dose of cetuximab or have their dose increased until skin rash appeared.

Again, patients with wild-type KRAS did better. Response rate improved as dose increased. However, once more, those with mutant KRAS showed no benefit. Even with dose escalation, there were no responses to treatment. There was no difference in skin rash between wild-type and mutated KRAS groups.

Dr. Tejpar concluded by stating, “These data suggest that patients with KRAS wild-type achieve considerable benefit from irinotecan plus cetuximab treatment. Patients with KRAS mutation did not profit from irinotecan plus cetuximab treatment, and cetuximab dose escalation did not increase responses in these patients.”

KRAS mutational status is a biomarker for nonresponse to EGFR-targeted therapy in colorectal cancer, and should be incorporated into routine tumor testing and treatment decision making. Based upon the findings reported by Drs. Bokemeyer and Tejpar at ASCO, and the rationale that downstream activating KRAS mutation may render any upstream EGFR-targeted therapy futile, further study is warranted to more clearly define the role of KRAS mutation in all malignancies treated with EGFR-targeted therapies. Results from the CAIRO2 trial also emphasize the need for a better understanding of interactions between different targeted therapies. Ultimately, KRAS mutational status is a biomarker for nonresponse that represents an initial step toward personalized therapy for colorectal cancer—a finding that may help guide future research.

Addition of Either Bevacizumab (Avastin) or Bevacizumab plus Mitomycin-C to Capecitabine (Xeloda) Is Well Tolerated as First-Line Treatment for Metastatic Colorectal Cancer

In a poster discussion, Timothy J. Price, MD, FRACP, Queen Elizabeth Hospital, Woodville, South, Australia, reported the final safety results of the Australasian Gastro-Intestinal Trials Group (AGITG) MAX trial, a multinational, randomized, phase II—III study evaluating the role of mitomycin-C, bevacizumab, and capecitabine as first-line treatment in patients with untreated metastatic colorectal cancer.

Enrollees were patients with metastatic colorectal cancer who had not received prior chemotherapy or for whom six months had elapsed since adjuvant chemotherapy. Patients were randomized to receive capecitabine 2000 or 2500 mg/m2 in two divided doses, 14 days, q3w (Arm A); capecitabine plus bevacizumab 7.5 mg/kg q3w (Arm B); or capecitabine, bevacizumab, plus mitomycin-C 7 mg/m2, capped at 14 mg and a limit of 4 doses, q6w (Arm C). Dr. Price's final safety analysis included data on 471 patients.

Sixty-day all-cause mortality was 4.5% in Arm A, 5.7% in Arm B, and 2.5% in Arm C. The rates of stomatitis, hepatic toxicity, febrile neutropenia, and thrombocytopenia were <5% in all three arms. There were two patients in Arm C who had manageable, but delayed onset (10 and 11 months after the last dose of mitomycin-C) hemolytic uremic syndrome.

Dr. Price and his colleagues concluded that all treatment arms were well tolerated, and the addition of either bevacizumab or bevacizumab plus mitomycin-C to capecitabine was associated with little additional grade 3/4 toxicity, apart from higher rates of grade 3 hand— foot syndrome in Arms B and C. The rates of grade 3/4 proteinuria, venous thromboembolism, bleeding, and perforation observed in the bevacizumab arms were deemed acceptable. Dr. Price stated that efficacy results of the trial will be presented at next year’s ASCO meeting.

ASCO Highlight — Advances in Sarcoma

Maximum Tolerated Deforolimus Dose Evaluated in Phase I Trial

Monica M. Mita, MD, of the Cancer Therapy & Research Center (CTRC) at the University of Texas Health Science Center in San Antonio, Texas, reported on the preliminary results of an open-label single-arm dose-finding study. Patients in the phase I trial had advanced, metastatic solid tumors that were refractory to therapy. A total of seven treatment regimens, all over a 28-day cycle, were investigated. Definitions of dose limiting toxicity (DLT; Gr 4 or Gr 3 > 3 days) were based on common toxicity criteria. Antitumor activity was evaluated by modified RECIST criteria. Patients achieving stable disease (SD) or better lasting for at least four cycles of 28 days were classified as achieving clinical benefit response (CBR).

One hundred and forty seven patients (85 sarcoma) received deforolimus therapy. The median age of participants was 56 (range, 23-84 yr); 65 (44%) patients were male; patients had a median of two cytotoxic therapies at entry (range 0-7); and 77% (113) of the study population had documented progressing disease at enrollment.

The DLT for all regimens was aphthous-ulcer like mouth sores which were reversible by dose reduction or symptomatic therapy. Results indicated that 36 patients achieved a clinical-benefit response (CBR) (23 sarcomas). The maximum tolderated dose was increased with the addition of a weekly dose holiday interval. In all regimens, several types of sarcomas, and a variety of carcinomas, CBRs were seen. 24 patients received 40 mg QDx5/wk. In this group 3 of 13 (23%) sarcomas had CBR; 2 (liposarcoma, dendritic cell sarcoma) (15.4%) achieved PR. Pharmacodynamic analysis showed potent inhibition of mTOR. Seven patients remain on therapy after 6-24 cycles.

Researchers concluded that oral deforolimus has a safety and antitumor activity profile consistent with the intravenous form. Results indicated that 40 mg QDx5 each week is an active, well-tolerated regimen. The 40-mg dose has been selected for further evaluation in SUCCEED, a global phase III trial of patients with metastatic soft-tissue and bone sarcoma in the maintenance setting.

Managing Side Effects of Targeted Cancer Treatments

Preexisting Conditions Should Be Assessed Before Initiating Therapy

Molecularly targeted therapies represent a major advance in modern cancer care. These new agents hold great promise for cancer care professionals and their patients, but many of these recently developed therapies are presenting adverse-event profiles that differ from those typically observed with traditional cytotoxic chemotherapeutic agents. An Education Session entitled, “The Toxicity of Targeted Therapies: Specific Effects of New Agents” was held to address this issue.

Joanna M. Brell, MD, University Hospitals Case Medical Center, Cleveland, Ohio, served as Session Chair. She said that many oncologists are uncertain of the ways in which these therapies will affect patients because the drugs only recently have been developed and used in a broad population of patients with cancer. Dr. Brell explained, “More oncologists will be prescribing these drugs in the absence of years of clinical experience, as with any new agent. Some of the adverse events are unique compared with traditional cytotoxic chemotherapy and require a different management approach. That, coupled with the notion that these newer drugs are more successful at cancer stabilization rather than tumor response, means that the practicing oncologist will want to understand these adverse effects so that treatment can be continued for the patient.”

The session focused on the general management of adverse events that have been observed with molecularly targeted therapies recently approved by the FDA. Recent approvals include bevacizumab (Avastin), dasatinib (Sprycel), lapatinib (Tykerb), sorafenib (Nexavar), sunitinib (Sutent), and temsirolimus (Torisel).

Interestingly, side effects oncologists typically expect in patients receiving chemotherapy, such as nausea, vomiting, leukopenia, and thrombocytopenia, are notably absent with these new agents, unless they are incorporated with chemotherapy such as the combination of lapatinib and capecitabine. Some molecularly targeted agents have been associated with unique side effects, including a form of interstitial-like lung disease, pleural effusion, increases in pancreatic enzymes, and elevation of triglycerides.

Panelists discussed the pathophysiology of toxicities associated with targeted therapies, emphasizing that side effects either may be related directly to the mechanism of action of the drug or may simply be an incidental effect. The mechanisms of some side effects, such as hypertension, appear to be better understood than others. Many of the theories regarding the molecular mechanisms by which targeted agents attack their targets have not yet been fully elucidated. One panelist noted, “Typically, oncologists don’t focus on the mechanisms of the toxicities, just the toxicities themselves and how to work with them in patients.”

Cardiovascular events associated with some targeted agents have included hypertension, coronary syndromes, left ventricular dysfunction, and QTc interval prolongation, symptoms that also may be elevated in an adjuvant setting. Panelists stressed the importance of learning about the incidence, management, and prevention of cardiovascular side effects to improve overall cancer survivorship. One recommendation was for oncologists to adopt a risk-adaptive approach to anticancer treatment with newer agents in order to mitigate the risk of cardiovascular toxicity. The risk-adaptive approach includes thorough assessment of pre-existing conditions, such as hypertension and chronic obstructive pulmonary disease, before incorporating targeted drugs as anticancer treatments. Another element of the approach was a need to be comfortable working with other specialists, such as cardiologists, nephrologists, and other care providers who are experts in managing the more complicated side effects of anticancer therapy.

Although the incorporation of molecular targeted therapies into the traditional range of treatments presents many new challenges, the role they can play in the advancement of cancer treatment is unquestionably promising for many oncologists and their patients. Use of targeted therapies has allowed patients with a variety of tumor types to live longer and exhibit longer periods of progression- free survival. As experience with these new agents grows, so too should expertise in managing associated adverse events.

Advances in Breast Cancer

Paclitaxel and Bevacizumab (Avastin) With Gemcitabine (Gemzar) as First-Line Treatment for Metastatic Breast Cancer: Interim Safety Results

Adam M. Brufsky, MD, PhD, associate professor of medicine at the University of Pittsburgh School of Medicine and co-director of the Comprehensive Breast Program of the University of Pittsburgh Cancer Institute and Associate Chief of the Division of Hematology/ Oncology presented data from a phase II study for first-line treatment for metastatic breast cancer.

“Paclitaxel plus bevacizumab is a regimen that has shown significant improvement in progression-free survival (PFS) in patients with metastatic breast cancer (MBC),” said Dr. Brufsky, “and we are currently conducting a randomized phase II trial to examine the efficacy and safety of adding gemcitabine to the paclitaxel plus bevacizumab doublet.” Dr. Brufsky reported results of an interim safety analysis of the first 50 treated patients.

This multicenter, randomized, superiority trial is set to enroll 180 women. Eligible patients have locally advanced or metastatic breast cancer, PS 0 or 1, and have not received prior cytotoxic therapy for metastatic disease. Prior adjuvant or neoadjuvant treatment with a taxane or endocrine therapy is allowed. Patients assigned to Arm A receive paclitaxel 90 mg/m2 on days 1, 8, and 15, followed by bevacizumab 10 mg/kg on days 1 and 15 of a 28-day cycle. Patients assigned to Arm B receive the same regimen plus gemcitabine 1,500 mg/m2 on days 1 and 15. The primary outcome measure is response rate, and safety is one of the secondary endpoints.

Between May 2006 and January 2007, the researchers report that 50 qualified women were treated (Caucasian 70%, Hispanic 14%, African 8%, East Asian 8%). Arm A patients (N = 24): median age, 60 years (range, 37—75 years old); Arm B patients (N = 26): median age, 54 years (range 40–80).

There were no discontinuations in the study owing to adverse events in Arm A. Two Arm B patients discontinued from the study for treatment-related adverse events (rash, proteinuria). One on-study death has occurred in an Arm B patient, unrelated to treatment.

According to Dr. Brufsky, “Therapy with paclitaxel and bevacizumab with gemcitabine does not appear to be associated with significant bleeding or thrombotic events. As expected, the addition of gemcitabine to the paclitaxel and bevacizumab doublet appears to increase the incidence of neutropenia in patients with MBC. Enrollment is complete and we expect disclosure of full efficacy and safety results in the near future.”

First-Line Combination Therapy With Nab-Paclitaxel (Abraxane), Bevacizumab, and Gemcitabine Provides a 82% Overall Response Rate in Patients With HER2-Negative Metastatic Breast Cancer

Nab-paclitaxel (nab-pac) uses nanotechnology to bind paclitaxel to albumin. Since it is a nontoxic protein, albumin enables the paclitaxel to be delivered directly to the tumor with fewer side effects than paclitaxel and docetaxel, which are bound in a solution that causes side effects. The FDA approved Abraxane for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension; albumin-bound) in January 2005 for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

During a general poster session, Stefan Glück, MD, Department of Oncology, University of Calgary, Alberta, Canada, presented interim results from a phase II trial evaluating the efficacy of combination therapy with nab-pac, bevacizumab, and gemcitabine as first-line treatment for patients with HER2-negative metastatic breast cancer. A total enrollment of 30 evaluable patients and a 2.5-year study duration are planned.

To date, 15 patients (mean age, 54 yr) have been enrolled, 11 of whom received >2 cycles and were evaluated for efficacy and 13 of whom were evaluable for safety. All patients were HER2-negative; 80% were ER+, and 58% were PR+. Eighty-two percent of patients achieved PR. All adverse events were grade 1 or 2, and the most commonly reported side effects were alopecia (62%) and fatigue (38%). Two patients were hospitalized because of port-site infection and hematotoxicity.

The investigators concluded that despite the small sample size, the results suggest that combination therapy with nab-pac, bevacizumab, and gemcitabine may represent an important new option for the first-line treatment of patients with metastatic breast cancer.

Greater Efficacy but Similar Toxicity for Continuing Trastuzumab Beyond Trastuzumab (Herceptin) Progression When Second-Line Chemotherapy With Capecitabine Is Initiated in Patients With HER2-Positive, Locally Advanced or Metastatic Breast Cancer

In a poster discussion, Dr. Gunter Von Minckwitz, MD, PhD, German Breast Group, Frankfurt, Germany and Department of Gynecology and Obstetrics, Goethe University, Frankfurt, Germany, presented preliminary results of the phase II TBP Study.

In this trial, patients with HER2-positive, locally advanced or metastatic breast cancer that progressed during treatment with trastuzumab (with or without adjuvant and/or first-line metastatic chemotherapy) were prospectively randomized to receive either capecitabine (2500 mg/m2 on days 1-14, q21) or capecitabine plus continuation of trastuzumab (6 mg/kg, q3w). The primary endpoint was time to progression. With registration of lapatinib, the slowly accruing trial was closed prematurely.

A total of 156 patients (78 in each arm) were randomized and stratified according to pretreatment: taxane/trastuzumab as firstline therapy (N = 111), taxanes/trastuzumab as adjuvant therapy (N = 3), or trastuzumab alone or without taxanes as first-line treatment (N = 42). Seventy-five patients (48.1%) were pretreated with anthracyclines. One hundred nineteen (76.3%) showed visceral metastasis.

The current analysis (median follow-up, 11.8 mo) revealed a PFS of 5.6 months with 53 events for capecitabine, and 8.5 months with 48 events for capecitabine plus continuation of trastuzumab (HR = 0.71). Brain metastases were observed in 4 and 7 patients in the groups receiving capecitabine and capecitabine plus continuation of trastuzumab, respectively (HR = 0.71).

Overall survival was 19.9 months, with 31 events for capecitabine and 20.3 months with 26 events for capecitabine plus continuation of trastuzumab (HR = 0.79). The crude response rates were 24.6% and 49.1% in the two groups, respectively. Primary progressions were observed in 26.3% and 16% of patients in the two groups, respectively.

Grade 3/4 toxicities in the capecitabine and capecitabine plus continuation of trastuzumab groups, respectively, were neutropenia (3.3 vs. 6.3), febrile neutropenia (0 vs. 0), vomiting (6.0 vs. 1.6), diarrhea (20.9 vs. 14.8), mucositis (3.0 vs. 1.6), hand-foot syndrome (23.9 vs. 31.1), nail changes (0 vs. 4.9), sensory neuropathy (4.5 vs. 3.3), fatigue (6.0 vs. 4.9), allergic-related (3.0 vs. 3.3), and cardiac (2.9 vs. 4.9). No treatment-related death occurred.

Preliminary results of the TBP study suggest a greater efficacy but similar toxicity for continuing trastuzumab beyond trastuzumab progression when second-line chemotherapy with capecitabine is initiated. A final efficacy analysis will be performed later in the year.

Combination of Capecitabine and Trastuzumab (Herceptin) Is Active and Well Tolerated in Patients With HER2-Overexpressing Breast Cancer After Failure of Both Anthracyclines and Taxanes

In a general poster session, Takanori Ishida, MD, PhD of the Japan Clinical Oncology Group presented the results of a phase II study evaluating the activity of capecitabine and trastuzumab in patients with HER2-overexpressing breast cancer after failure of both anthracyclines and taxanes. The primary endpoint of the study was overall survival (OS).

Patients were treated with weekly trastuzumab given at a dose of 2 mg/kg per day over 90 minutes (4 mg/kg per day on the first infusion) and capecitabine given at a dose 1657 mg/m2 per day during 21 days, with a subsequent pause of seven days. This cycle was repeated every 28 days up to six cycles.

A total of 39 patients were enrolled, of whom 37 were evaluable for efficacy and safety. A total of 153.5 cycles were delivered, with a median of four cycles (range, 1-6 cycles). Median age of enrollees was 53 years (range, 30—69 yr). Median follow-up was 23.5 months.

Median OS was 23.5 months. Median PFS was 4.2 months. One- and twoyear survival rates were 83.8% and 48.6%, respectively. The response rate was 21.6% and the clinical benefit rate was 24.3%.

Grade 3 toxicities included hand—foot syndrome (5.4%), neutropenia (2.7%), diarrhea (2.7%), and constipation (2.7%). There were no grade 4 toxicities or treatment-related deaths.

Dr. Ishida and colleagues concluded that the combination of capecitabine plus trastuzumab is active and well tolerated in patients with HER2-overexpressing breast cancer after failure of both anthracyclines and taxanes. The researchers said further investigations are warranted.

ASCO Highlight—Advances in Breast Cancer

Addition of Zoledronic Acid (Zometa/Reclast) to Adjuvant Endocrine Therapy Significantly Prolongs Disease-Free Survival and Relapse-Free Survival Compared With Adjuvant Endocrine Therapy Alone

In a plenary session attended by more than 20,000 participants, Michael Gnant, MD, Professor of Surgery, Medical University of Vienna, Vienna, Austria, presented the first efficacy results from the Austrian Breast & Colorectal Cancer Study Group Trial 12 (ABCSG-12).

ABCSG-12 is a multicenter, open-label, phase III study that evaluated the efficacy of ovarian suppression using the gonadotropin-releasing hormone analogue goserelin in combination with anastrozole or tamoxifen, with or without zoledronic acid, in premenopausal women with early-stage, hormone-responsive breast cancer. Zoledronic acid is a bisphosphonate used in the treatment of bone metastases and osteoporosis.

A total of 1,801 premenopausal women with endocrineresponsive breast cancer were randomized to receive goserelin (3.6 mg q28d SC) and tamoxifen (20 mg/day PO) plus or minus zoledronic acid (4 mg IV q6mo), or goserelin and anastrozole (1 mg/ day PO) plus or minus zoledronic acid for three years (Figure). Enrollees in the ABCSG-12 trial had all undergone surgery for the primary tumor, and about 5% had received preoperative chemotherapy. None of the women enrolled in the trial received chemotherapy afterward, Dr. Gnant emphasized. The primary endpoint was disease-free survival (DFS) for both the comparison of tamoxifen versus anastrozole and the comparison of zoledronic acid versus no zoledronic acid.

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The results were impressive. With a median followup of 60 months, 137 (7.6%) DFS events and 42 (2.3%) deaths have occurred. There was no significant difference in DFS between patients who received tamoxifen alone and those who received anastrozole alone (HR = 1.10 [95% CI = 0.79-1.54]; = 0.59). However, endocrine therapy plus zoledronic acid significantly reduced the risk of DFS events by 36% compared with endocrine therapy alone (H = 0.64 [0.46-0.91]; = 0.01). The addition of zoledronic acid significantly reduced the risk of recurrence-free survival events by 35% (HR = 0.65 [0.46-0.92]; = 0.015) compared with endocrine therapy alone. For OS, there was a nonsignificant trend favoring zoledronic acid treatment (HR = 0.60 [0.32-1.11]; = 0.10). Treatment was generally well tolerated among the four groups, and adverse-event profiles were consistent with known safety profiles of the drugs.

In this landmark trial, there was no significant difference in DFS between tamoxifen and anastrozole. However, the addition of zoledronic acid to adjuvant endocrine therapy significantly prolonged DFS and RFS compared with adjuvant endocrine therapy alone in premenopausal women with endocrineresponsive breast cancer. “Adjuvant treatment with zoledronic acid should be considered in order to improve the standard of care in premenopausal breast cancer patients,” Dr. Gnant concluded.

ABCSG-12 is the first large-scale clinical trial to demonstrate that the anticancer properties of zoledronic acid provide a significant benefit for patients with early-stage breast cancer beyond that achieved with endocrine therapy alone.

Although bisphosphonates have shown anticancer effects in preclinical models, clinical studies with older compounds have yielded inconsistent results. “This is the first study to translate these effects into a clinical benefit,” stated Dr. Gnant.

ASCO Highlight—Advances in Breast Cancer

Bevacizumab (Avastin) in Combination with Docetaxel Significantly Improves Progression-Free Survival and Response Rate Compared with Docetaxel Alone in Patients with Locally Recurrent or Metastatic Breast Cancer

In an oral presentation, David Miles, MD, FRCP, Mount Vernon Cancer Centre, Middlesex, UK reported the results of AVADO, a randomized, double-blind, placebo-controlled, phase III study that evaluated the combination of bevacizumab and docetaxel as first-line therapy in patients with locally recurrent or metastatic breast cancer.

In the AVADO trial, docetaxel 100 mg/m2 plus placebo with docetaxel plus either bevacizumab 7.5 mg/kg 15 mg/kg. Docetaxel was administered q3w for up to 9 cycles. BV/PL was administered q3w until disease progression or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included OS, time to treatment failure, overall response rate (ORR), duration of response, and safety.

Key eligibility criteria were HER2-negative, inoperable locally recurrent or metastatic breast cancer; no prior chemotherapy for advanced disease; ECOG PS 0-1; adequate left-ventricular ejection fraction, and no central nervous system metastases.

A total of 736 patients in 24 countries were randomized. With median follow-up of approximately 11 months, PFS was statistically significantly superior for both bevacizumab-containing arms compared with docetaxel alone. ORR was superior in both combination arms relative to docetaxel alone. OS data were immature at the time of the presentation due to short follow-up.

Key conclusions from the AVADO trial were as follows: Both doses of bevacizumab in combination with docetaxel significantly improved PFS and RR compared with docetaxel alone. Bevacizumab added limited incremental toxicity relative to control. The safety results were comparable between the two bevacizumab arms, and the overall findings did not reveal any new safety problems.

As Dr. Miles explained, the results of the AVADO trial mirror those of the E2100 study (n = 722), which formed the basis for the approval of bevacizumab in the treatment of metastatic breast cancer in both Europe and the US. Approval in the US was accelerated; at the time, the US Food and Drug Administration (FDA) said that it was awaiting data from the AVADO study and from a third company- sponsored trial (RIBBON-1). The accelerated approval was considered rather controversial because it was based on progression-free and not overall survival data, and because the Oncologic Drug Advisory Committee (ODAC) had narrowly voted not to recommend approval.

Now that the AVADO results are available, the controversy should be eliminated. The results of the AVADO trial confirm those of the E2100 study. As Dr. Miles explained, “Both studies added bevacizumab to a taxane, but E2100 used paclitaxel and AVADO used docetaxel and had a placebo group. The trial also used different bevacizumab doses. E2100 used 10 mg/kg; and AVADO compared a high dose of 15 mg/kg and a low dose of 7.5 mg/kg.”

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Dr. Miles added, “After a median follow-up of 11 months, the AVADO trial showed a statistically significant difference in progression-free survival between women taking either dose of bevacizumab plus docetaxel and those taking docetaxel alone—the stratified HR was 0.69 ( = 0.0035) for the low dose and 0.61 ( = 0.0001) for the high dose. In other words, the risk for disease progression was reduced by 21% with the low dose and by 28% with the high dose. The median time to disease progression was 8 months with docetaxel alone, compared with 8.7 months with docetaxel plus low-dose bevacizumab, and 8.8 months with docetaxel plus high-dose bevacizumab.”

Dr. Miles ended his presentation by stating, “But perhaps the biggest message from AVADO is safety. There is no new safety signal, and we can be very reassured that bevacizumab is adding little toxicity to the chemotherapy that we are already using.”

Advances in Multiple Myeloma

Bortezomib (Velcade) Combination Delivers Significant Complete Response and Survival in Patients With Newly Diagnosed Multiple Myeloma

Jean-Luc Harousseau, MD, University Hospital Hotel-Dieu, Nantes, France, presented updated results from a 482 patient, multicenter, randomized, phase III clinical trial, comparing bortezomib and dexamethasone (Decadron) (BD) with vincristine (Oncovin), doxorubicin (Adriamycin) and dexamethasone (VDD).

Patients in the BD arm received four cycles of bortezomib at 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle. Patients also received dexamethasone at 40 mg on days 1 through 4 during cycles 1 through 4 and on days 9 through 12 during cycles one and two only. The patients in the VDD arm were treated for four 28-day cycles with vincristine at 0.4 mg/m2 on days 1 through 4; doxorubicin at 9 mg/m2 on days 1 through 4; and dexamethasone at 40 mg on days 1 through 4, days 9 through 12 during cycles one through four and on days 17 through 20 during cycles one and two only. Half of the patients in each arm received dexamethasone, cyclophosphamide, etoposide, and cisplatinum (DCEP) consolidation pretransplant.

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Results showed high complete remission (CR) rates of 19% in the BD arm (compared with 8% in the VDD arm) ( = 0.0004) as induction therapy and 35% post-transplantation (compared with 23% in the VDD arm) ( = 0.0063). The high CR rates contributed to 141 patients (63%) not requiring a second transplant ( < 0.0001). In addition, data showed 95% of patients in the BD arm were alive at one year (compared with 92% in the VDD arm).

The BD regimen was well tolerated with the incidence of grade 3 and grade 4 adverse events similar in each arm. Serious adverse events were slightly lower with BD.

“These updated results clearly confirm that the high CR rates with induction therapy improved post-transplantation outcomes, including a decrease in the need for second transplantation,” said Dr. Harousseau.

Pegylated Liposomal Doxorubicin (Doxil) Plus Bortezomib (Velcade) Found to Improve Outcomes in Multiple Myeloma Patients With Renal Insufficiency.

Joan Blade, MD, on behalf of the DOXILMMY-3001 Study Investigators (a study being undertaken at 144 sites in 18 countries), presented the results of a phase III trial in which Dr. Blade and colleagues sought to determine the efficacy and feasibility of pegylated liposomal doxorubicin (PLD) + bortezomib (B) in relapsed/refractory multiple myeloma (MM) patients with renal insufficiency (RI) (creatinine clearance [CrCl] < 60 ml/min).

Eligible patients who were randomized received bolus IV B 1.3 mg/m2 on days 1, 4, 8 and 11 of each 3-week cycle (N = 322) or the same B regimen plus IV PLD 30 mg/m2 on day 4 (N = 324) of each cycle. 193 patients with RI from this trial were analyzed retrospectively to determine the effect of RI on the efficacy and safety of PLD + B, as well as the effect on renal function. Patients with severe RI (CrCl < 30 ml/min) were excluded.

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The mean number of PLD + B cycles administered was comparable between the two subgroups (5.1 in the RI subgroup vs. 5.0 in the non-RI subgroup). For the RI subgroup, median TTP was 10.9 (95% CI: 9.1, n/a) and 6.5 (95% CI: 5.3, 7.2) months in the PLD + B and B arms, respectively ( = 0.002). These results are consistent with the benefit of PLD + B demonstrated in the overall study population. There was a steady improvement in renal function over the course of treatment in both the PLD + B and B treatment arms. The incidence of grade 3/4 anemia, diarrhea, and pneumonia were more common than in the RI subgroup compared with the non-RI group.

Researchers concluded that RI does not compromise the efficacy or tolerability of PLD + B in relapsed/refractory MM patients. Treatment with PLD + B or B alone appears to improve renal function in relapsed/refractory MM patients with RI.

Lenalidomide (Revlimid) Plus Low-Dose Dexamethasone Yields Increased Overall Survival Compared With Lenalidomide Plus High-Dose Dexamethasone in Newly Diagnosed Multiple Myeloma

S.V. Rajkumar, MD, and colleagues, the Mayo Clinic, Rochester, Minnesota, compared lenalidomide (Len) (Revlimid) plus high (standard) dose dexamethasone (RD) versus Len plus low-dose dexamethasone (Rd) in newly diagnosed multiple myeloma (MM). Patients with untreated, symptomatic MM were eligible. Len dose was 25 mg/day PO d 1-21 every 28 days. Patients in the RD arm received high-dose Dex 40 mg d 1-4, 9-12, and 17-20 PO q 28 d; patients in the Rd arm received low-dose Dex 40 mg d 1, 8, 15, and 22 PO q 28 d.

The primary null hypothesis was that response rates at four months on the 2 arms are equivalent (difference >15% unacceptable). All analysis were intent to treat.

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Researchers randomized 445 patients (median age, 65 yr) into two well-balanced treatment arms: 223 (RD) and 222 (Rd). Of 383 evaluable patients, Grade >3 toxicities occurred within 1st 4 cycles in 50% (RD) versus 30% (Rd) respectively, < 0.001. 149 patients reported stem cell harvest attempt; 97% were successful. PR or higher within the first 4 cycles was seen in 82% (RD) vs. 70% (Rd), = 0.007 (excluding 14 patients with missing data). CR+VGPR rates were 52% vs. 42%, = 0.06 (excluding 9 patients missing data). Overall survival (OS) was significantly superior with Rd, = 0.006; one-year survival 96% (Rd) vs. 88% (RD); two-year OS rates 87% (Rd) vs. 75% (RD).

Researchers performed a landmark analysis after four months of treatment. Of 421 patients alive at the landmark analysis, 210 went off-study and 211 continued primary therapy with RD/Rd. Of patients who went off study at four months, 108 patients (51%) did not pursue SCT (median age 67); 1-yr OS and 2-yr OS rates were 85% and 70% respectively. The remaining 102 patients (49%) underwent SCT (median age, 57 years); the 1-yr OS and 2-yr OS rates were 99% and 94% respectively. There was no difference in the percentage of patients who went to SCT between the 2 arms, 29% (RD) and 31% (Rd). Corresponding 1 yr and 2 yr OS rates among 211 patients (median age, 67 yr) who continued who