June 2011 - Special Edition - Digital Edition by McMahon Group

Independent News for the Oncologist and Hematologist/Oncologist clinicaloncology.com • June 2011

SPECIAL EDITION Evolving Treatment Paradigms In Non-Small Cell Lung Cancer

Update on Approaches to the Treatment of Follicular Lymphoma

Caleb T. Chu, MD, MPH

Andrew M. Evens, Do, Ms

Postdoctoral Fellow Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas

Associate Professor of Medicine The University of Massachusetts Medical School UMass Memorial Cancer Center Worcester, Massachusetts

Margaret E. M. Van Meter, Md

Jane N. Winter, Md

Medical Oncology Fellow Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, Texas

Professor of Medicine Northwestern University Feinberg School of Medicine Robert H. Lurie Comprehensive Cancer Center Chicago, Illinois

Edward S. Kim, Md Associate Professor of Medicine Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas

Updates in the Treatment Of Advanced Breast Cancer

Overview of Frontline Therapy For Metastatic Colorectal Cancer

Christina I. Herold, Md

Mebea Aklilu, Md

Division of Hematology/Oncology Department of Medicine Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts

Assistant Professor Hematology & Oncology Comprehensive Cancer Center Wake Forest Baptist Health Wake Forest University Health Sciences Winston-Salem, North Carolina

Cathy Eng, Md, Facp Associate Professor Department of Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

From the publisher of

TABLE of CONTENTS Evolving Treatment Paradigms In Non-Small Cell Lung Cancer Caleb T. Chu, MD, MPH

Postdoctoral Fellow Department of Thoracic/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Margaret E. M. Van Meter, MD Medical Oncology Fellow Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, Texas

Edward S. Kim, MD Associate Professor of Medicine Department of Thoracic/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Update on Approaches to the Treatment of Follicular Lymphoma

Andrew M. Evens, DO, MS Associate Professor of Medicine The University of Massachusetts Medical School UMass Memorial Cancer Center Worcester, Massachusetts

Jane N. Winter, MD Professor of Medicine Northwestern University Feinberg School of Medicine Robert H. Lurie Comprehensive Cancer Center Chicago, Illinois

Updates in the Treatment Of Advanced Breast Cancer Christina I. Herold, MD Division of Hematology/Oncology Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical School Boston, Massachusetts

Overview of Frontline Therapy For Metastatic Colorectal Cancer

Mebea Aklilu, MD Assistant Professor, Hematology & Oncology Comprehensive Cancer Center Wake Forest Baptist Health Wake Forest University Health Sciences Winston-Salem, North Carolina

Cathy Eng, MD, FACP Associate Professor Department of Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

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C L I N I C A L O N C O L O GY N E W S S P E C I A L E D I T I O N 2 0 1 1

EDITORIAL BOARD Solid Tumors

Gynecologic Cancer

Bone Metastases

Maurie Markman, MD

Allan Lipton, MD Milton S. Hershey Medical Center Penn State University, Hershey, PA

Breast Cancer Andrew Seidman, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Maura N. Dickler, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Gastrointestinal Cancer Edward Chu, MD University of Pittsburgh Cancer Institute University of Pittsburgh Pittsburgh, PA

Cathy Eng, MD The University of Texas MD Anderson Cancer Center Houston, TX

Cancer Treatment Centers of America Philadelphia, PA

Lung, and Head and Neck Cancers Edward S. Kim, MD The University of Texas MD Anderson Cancer Center Houston, TX

Lung Cancer, Emesis Richard J. Gralla, MD Hofstra North Shore-Long Island Jewish School of Medicine Monter Cancer Center North Shore University Hospital Long Island Jewish Medical Center Lake Success, NY

Prostate Cancer Michael Carducci, MD Johns Hopkins Kimmel Cancer Center Baltimore, MD

Hematologic Malignancies

Leonard Saltz, MD

Jennifer R. Brown, MD, PhD

Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Harry Erba, MD, PhD

Gastrointestinal Cancer and Sarcoma Ephraim Casper, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

Editorial Philosophy The Editorial Advisory Board of Clinical Oncology News is instrumental in guiding the content that appears in the newsmagazine. A significant proportion of the news coverage comes from studies presented at cancer-related meetings. Prior to these meetings, such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. They then review the articles before they are published. In their areas of specialty, board members also are consulted about review article topics, coverage of specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and they review articles before they go to print. Additionally, all news articles that appear in Clinical Oncology News are sent to the sources quoted in each article to review and verify the accuracy of the article’s content. Educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

John W. Finnie, MD

Oncology Nursing

David C. Pratt Cancer Center St. John’s Mercy Medical Center St. Louis, MO

Betty Ferrell, RN, PhD

Symptom Control and Palliative Care

Pharmacy

William S. Breitbart, MD

University of Colorado Cancer Center Denver, CO

Memorial Sloan-Kettering Cancer Center New York, NY

Steven D. Passik, PhD Vanderbilt University Medical Center Nashville, TN

Joseph V. Pergolizzi Jr., MD

Shaji, Kumar, MD

Johns Hopkins University School of Medicine Baltimore, MD

Mayo Clinic, Rochester, MN

Russell K. Portenoy, MD

Richard Stone, MD

Beth Israel Medical Center New York, NY

University of Michigan, Ann Arbor, MI

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

City of Hope National Medical Center Duarte, CA

Cindy O’Bryant, PharmD

Sara S. Kim, PharmD The Mount Sinai Medical Center New York, NY

Bioethics Joseph P. DeMarco, PhD Cleveland State University Cleveland, OH

Paul J. Ford, PhD

Charles F. von Gunten, MD

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

University of California,San Diego, CA

Policy and Management Mary Lou Bowers, MBA

Genitourinary Cancer

Community Oncology

Ronald M. Bukowski, MD

Michael J. Fisch, MD, MPH

Infection Control

Taussig Cancer Center Cleveland Clinic Foundation Cleveland, OH

The University of Texas MD Anderson Cancer Center Houston, TX

Susan K. Seo, MD

The Pritchard Group, Rockville, MD

Memorial Sloan-Kettering Cancer Center Center, New York, NY

Rhonda M. Gold, RN, MSN

McMahon Publishing is a 38-year-old, familyowned medical publishing and medical education company. McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications.

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An Investigational Therapeutic Cancer Vaccine for Unresectable Stage III NSCLC START (Stimulating Targeted Antigenic Responses To NSCLC) is a multi-center, Phase III clinical trial assessing the efficacy and safety of BLP25 liposome vaccine, an investigational therapeutic cancer vaccine, in patients with unresectable stage III non-small cell lung cancer (NSCLC), after chemoradiation. Based on experimental models, L-BLP25 may induce an immune response to MUC1, a tumor-associated antigen widely expressed on common cancers, that could potentially harness the bodyâ&#x20AC;&#x2122;s natural immune system to target cancer cells directly.1 MAIN INCLUSION CRITERIA Documented stable disease or response within 4 weeks after primary chemoradiotherapy for unresectable stage III disease Receipt of concomitant or sequential chemoradiotherapy: at least two cycles of platinum-based chemotherapy and 50 Gy radiation therapy Completed primary thoracic chemoradiotherapy between 4 and 12 weeks before randomization ECOG PS 0-1 Platelet count 140 x 109/L, WBC 2.5 x 109/L, and hemoglobin 90 g/L

MAIN EXCLUSION CRITERIA Any other lung cancer therapy including surgery Any history of metastatic cancer, malignant pleural effusion, another neoplasm, autoimmune disease, hepatitis B or C, immunodeficiency, or conditions requiring steroid therapy Received investigational systemic drugs (including off-label use of approved products) within 4 weeks prior to randomization

1. Butts C, Anderson H, Maksymiuk A, et al. Long-term safety of BLP25 liposome vaccine (L-BLP25) in patients with stage III/IV non-small cell lung cancer (NSCLC). ASCO Congress 2009; Abstract No. 3055. BLP25 liposome vaccine is currently under clinical investigation and has not been approved for use in the United States, Canada, Europe, or elsewhere. The product has not been proven to be safe or effective and any claims of safety and effectiveness can be made only after regulatory review of the data and approval of the labeled claims.

Learn More About the START Trial

Please call 1-800-507-5284 or refer to www.nsclcstudy.com or www.clinicaltrials.gov (NCT00409188)

101108 - 115622

RUIT

ING

BUILD A TREATMENT STRATEGY WITH EXTENDED SURVIVAL ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Important Safety Information for Contraindication: ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation. Warnings and Precautions: Patients must be instructed to take folic acid and vitamin B12 with ALIMTA as a prophylaxis to reduce treatment-related hematologic and GI toxicities. Pretreatment with dexamethasone or its equivalent has been reported to reduce the incidence and severity of skin rash.

with mild to moderate renal insufﬁciency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicities.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

Patients should not begin a new cycle of treatment unless the ANC is 1500 cells/mm3, the platelet count is 100,000 cells/mm3, and creatinine clearance is 45 mL/min.

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufﬁciency (creatinine clearance from 45 to 79 mL/min). Patients

The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

ALIMTA (pemetrexed for injection) Drug Interactions: Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA.

therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Reactions (% incidence): The most severe adverse reactions (grades 3/4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced Use in Speciﬁc Patient Populations: It is recommended that non-small cell lung cancer (NSCLC) were neutropenia (15 vs 27); nursing be discontinued if the mother is being treated with ALIMTA leukopenia (5 vs 8); thrombocytopenia (4 vs 13); anemia (6 vs 10); or discontinue the drug, taking into account the importance of the fatigue (7 vs 5); nausea (7 vs 4); vomiting (6 vs 6); anorexia (2 vs drug for the mother. 1); and creatinine elevation (1 vs 1). The safety and effectiveness of ALIMTA in pediatric patients have Common adverse reactions (all grades) with ALIMTA in not been established. combination with cisplatin versus gemcitabine in combination with See Warnings and Precautions for speciﬁc information regarding ibuprofen administration.

Dose adjustments may be necessary in patients with hepatic insufﬁciency. Dosage and Administration Guidelines: Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend

cisplatin, respectively, were nausea (56 vs 53); fatigue (43 vs 45); vomiting (40 vs 36); anemia (33 vs 46); neutropenia (29 vs 38); anorexia (27 vs 24); constipation (21 vs 20); leukopenia (18 vs 21); stomatitis/pharyngitis (14 vs 12); alopecia (12 vs 21); diarrhea (12 vs 13); thrombocytopenia (10 vs 27); neuropathy/sensory (9 vs 12); taste disturbance (8 vs 9); rash/desquamation (7 vs 8); and dyspepsia/heartburn (5 vs 6). For additional safety and dosing guidelines, please see brief

summary of Prescribing Information on adjacent page.

insideALIMTA.com

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Evolving Treatment Paradigms in

Non-Small Cell Lung Cancer Caleb T. Chu, MD, MPH Postdoctoral Fellow Department of Thoracic/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Margaret E. M. Van Meter, MD Medical Oncology Fellow Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, Texas

Edward S. Kim, MD Associate Professor of Medicine Department of Thoracic/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

ung cancer is the leading cause of cancer-related death in

the United States, accounting for 30% and 26% of all cancer deaths in men and women, respectively, and exceeding the

predicted death rates for breast and colorectal cancers combined.1

Non-small cell lung cancer (NSCLC) is the most common histologic subtype and accounts for more than 80% of lung cancers.

Although locally resectable NSCLC can be cured with surgical intervention, very few patients present with early-stage disease. Unfortunately, the majority present with advanced (stages IIIB and IV) disease; surgery and radiotherapy are not routinely part of care for these patients. Overall survival (OS) for these groups of patients has improved only modestly over the past few decades through advances in chemotherapy; median

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OS has improved by approximately 2 months, providing 1-year survival rates of about 30% for patients receiving chemotherapy compared with 10% for those receiving supportive care. More recently, the advent of newer chemotherapy regimens has increased median survival times in patients treated with standard doublet chemotherapy regimens from 8 to 11 months.2 The addition of biologic agents and efforts to focus their use

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in specific patient populations have further increased efficacy, with median survival times in some studies exceeding 12 months.3 Although previous studies of cytotoxic chemotherapy demonstrated no improvement in outcome when regimens were administered for more than 4 to 6 cycles, recent studies in the maintenance setting indicate that more prolonged therapy may be desirable.4 As treatment strategies evolve and chemotherapies and biologic therapies are being increasingly integrated, a more personalized approach should be used to provide the most effective and least toxic treatments to patients with advanced NSCLC.

Conventional Chemotherapy Platinum-based doublet regimens are the mainstay of chemotherapy in patients with advanced NSCLC and a good performance status (PS). The survival benefit of cisplatin in the treatment of NSCLC was established in 1995, based on a meta-analysis that included 52 clinical trials with more than 9,000 patients; in the trials involving patients with advanced disease, cisplatinbased chemotherapy showed a 27% reduction in the risk for death at 1 year.5 Thus, in 1997, the American Society of Clinical Oncology (ASCO) issued guidelines recommending the use of cisplatin-based chemotherapy for patients with advanced NSCLC and a good PS. Given the toxicity of cisplatin-based regimens, much effort over the past decade has been directed toward developing better-tolerated, equally efficacious treatments. To this end, trials have evaluated the use of newer agents, either as monotherapy or in combination regimens, as well as the use of carboplatin in lieu of cisplatin in doublet regimens. In comparisons of platinum-based doublets, 2 variables must be considered: the platinum agent used (cisplatin or carboplatin) and the agent combined with the platinum agent. The principal drugs combined with a platinum agent in the third-generation doublets are gemcitabine (Gemzar, Lilly), vinorelbine, docetaxel (Taxotere, Sanofi-aventis), paclitaxel, and pemetrexed (Alimta, Lilly). A large trial comparing cisplatin-paclitaxel with 3 other regimensâ&#x20AC;&#x201D;carboplatin-paclitaxel, cisplatin-docetaxel, and cisplatin-gemcitabineâ&#x20AC;&#x201D;in 1,155 patients with advanced NSCLC showed no significant difference in OS (median 7.9 months) among the 4 regimens.6 It is notable, however, that patients in the carboplatin-paclitaxel arm had a slightly lower rate of serious toxicities and that the study was limited to patients with an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1; initial analysis showed a higher rate of adverse events in patients with a PS of 2. The largest Phase III study ever performed in the first-line treatment of advanced NSCLC (N=1,725) compared cisplatin-pemetrexed with cisplatin-gemcitabine.7 A statistically significant survival advantage was demonstrated for patients with adenocarcinoma or large-cell carcinoma histology treated with cisplatin-pemetrexed compared with cisplatin-gemcitabine

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(median OS, 11.8 and 10.4 months, respectively; hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.700.94; P=0.005). In contrast, patients with squamous cell histology had a shorter median survival when treated with cisplatin-pemetrexed (OS, 9.4 vs 10.8 months; HR, 1.23; 95% CI, 1.00-1.51; P=0.05). This was the first Phase III trial to prospectively show a survival difference based on NSCLC histology.

Newer Targeted Therapies With the advent of new targeted therapies, first-line chemotherapy for advanced NSCLC is changing. Given the limited ability of current chemotherapy regimens to prolong OS, new drug development has focused on improving tolerance, quality of life, and ease of administration while maintaining at least comparable efficacy to standard first-line therapy. The Phase III ECOG 4599 trial evaluated firstline platinum doublet therapy (carboplatin-paclitaxel) with and without the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab (Avastin, Genentech) in patients with advanced nonsquamous NSCLC.3 Treatment in the experimental arm included bevacizumab combined with chemotherapy every 3 weeks for 6 cycles, followed by maintenance bevacizumab every 3 weeks until progressive disease or intolerable side effects occurred. Median OS, the primary end point, increased by 2 months (12.3 vs 10.3 months; HR, 0.79; 95% CI, 0.67-0.92; P=0.003) with the addition of bevacizumab. Statistically significant improvements in response rate (35% vs 15%) and progression-free survival (PFS; 6.2 vs 4.5 months) also were observed. The pivotal FLEX (First-Line Erbitux in Lung Cancer) trial compared the cisplatin-vinorelbine doublet plus the anti-epidermal growth factor receptor (EGFR) antibody cetuximab (Erbitux, Bristol-Myers Squibb) with cisplatin-vinorelbine alone in patients with EGFRexpressing advanced NSCLC.8 Cetuximab was given together with doublet chemotherapy for 6 cycles and continued as maintenance therapy until progressive disease or intolerable side effects developed. For the entire intention-to-treat population, median OS was 11.3 months in the cisplatin-vinorelbine-cetuximab arm and 10.1 months in those treated with cisplatin-vinorelbine alone (HR, 0.871; 95% CI, 0.762-0.996; P=0.044). Prespecified subgroup analysis showed that the survival benefit of treatment that included cetuximab persisted across most subgroups. However, gender, PS, histology, smoking status, and geographic region all had prognostic significance. Specifically, women had longer survival times than men (12.7 vs 9.3 months), Asians had a longer survival than whites (19.5 vs 9.6 months), and patients with a higher PS and those who had never smoked had better prognoses than patients with lower PS and smokers. Data presented at the ASCO meeting in 2009 expanded on prognostic factors and molecular predictors of OS from the FLEX trial. In one analysis,

KRAS mutational status was found not to be predictive for cetuximab efficacy, but patients taking cetuximab who developed an acne-like rash had a longer median OS than those without the rash (15.0 vs 8.8 months; HR, 0.63; 95% CI, 0.52-0.77; P<0.001).9 Improvements in OS seen with molecular-targeted therapies against VEGF and EGFR in combination with platinum doublets in patients with advanced NSCLC3,8 have led to further investigation of the combined effects. The SWOG (Southwest Oncology Group) 0536 Phase II study combined 4 drugsâ&#x20AC;&#x201D;cetuximab, bevacizumab, carboplatin, and paclitaxelâ&#x20AC;&#x201D;for up to 6 cycles, followed by maintenance bevacizumab weekly until disease progression.10 The primary end point was the frequency and severity of hemorrhagic toxicities that were grade 4 or higher in patients with advanced-stage nonsquamous NSCLC. Combining carboplatin, paclitaxel, cetuximab, and bevacizumab resulted in a tolerable safety profile, with a 2% incidence of hemorrhage that was grade 4 or higher (95% CI, 0%-7%). An ongoing Phase III trial (SWOG 0819) is comparing the 4-drug regimen used in SWOG 0536 with the 3-drug regimen used in ECOG 4599 (carboplatin-paclitaxel-bevacizumab). The studies described above have evaluated biologic targeted agents in combination with cytotoxic chemotherapy. Two additional Phase III studies, INTEREST (Iressa NSCLC Trial Evaluating Response and Survival against Taxotere) and IPASS (First-line Iressa versus Carboplatin/ Paclitaxel in Asia), compared single-agent biologic therapy using the oral EGFR tyrosine kinase inhibitor (TKI) gefitinib (Iressa, AstraZeneca) with traditional chemotherapeutic agents, with favorable outcomes. INTEREST is a randomized Phase III trial comparing gefitinib with docetaxel in patients with advanced NSCLC who had previously received at least 1 platinumbased chemotherapy regimen.11 Patients received either gefitinib daily or docetaxel every 3 weeks until disease progression or unacceptable toxicity. The primary end point was OS, analyzed via noninferiority in the overall population and superiority in patients with a high EGFR copy number. Results for all 1,433 patients confirmed noninferiority of gefitinib compared with docetaxel for OS (7.6 vs 8 months; HR, 1.020; 95% CI, 0.9051.150). However, in the 174 patients with a high number of EGFR gene copies, gefitinib did not show superiority for OS (8.4 vs 7.5 months; HR, 1.09; 95% CI, 0.781.51; P=0.62). Subsequent biomarker analysis of EGFR and KRAS in tumor biopsies from the INTEREST trial showed similar OS in patients treated with gefitinib and docetaxel, regardless of biomarker subgroup. However, patients with EGFR mutations had longer PFS and higher objective response rate (ORR), and patients with high EGFR copy number had higher ORR when treated with gefitinib compared with docetaxel.12 Recent data from the IPASS trial have shown that gefitinib is also a valid first-line therapy for a subset of patients.13 This study included patients in East Asia with advanced NSCLC of adenocarcinoma histology

who had a World Health Organization PS of 0 to 2 and were never smokers or former light smokers. The primary end point was PFS; median PFS was similar in those treated with gefitinib and those treated with carboplatin-paclitaxel (5.7 vs 5.8 months), but the KaplanMeier curves crossed at this point, and patients treated with gefitinib had a significantly higher rate of PFS at 12 months (24.9% vs 6.7%), with an overall HR of 0.74 (95% CI, 0.65-0.85; P<0.0001). Preliminary OS (28% maturity with follow-up ongoing) was similar for gefitinib and carboplatin-paclitaxel, but gefitinib demonstrated improved quality-of-life ratings and a more favorable tolerability profile. In the IPASS trial, EGFR mutational status appeared to be a strong biomarker for gefitinib efficacy.13 Similar analysis has shown that EGFR mutations also are associated with responsiveness to erlotinib (Tarceva, OSI Pharmaceuticals).14 These findings indicate that genetic screening of patients prior to therapy may be warranted to allow clinicians to tailor therapy to individual patients. The study results also highlight a need for a paradigm shift toward molecular profiling in the treatment of advanced NSCLC to improve tolerability of therapy.

Maintenance Therapy Debate continues about delayed (second- or thirdline) versus immediate (maintenance) chemotherapy in patients who already have received first-line therapy. Multiple trials have examined the role of maintenance chemotherapy after completion of initial chemotherapy in advanced NSCLC (Table).4,15-21 Maintenance chemotherapy could be either continuation of 1 or more of the initial chemotherapy agents or the addition of a new chemotherapeutic or targeted agent. In one multicenter Phase III trial, patients with advanced NSCLC who did not have evidence of disease progression after first-line treatment with 4 cycles of carboplatin-gemcitabine were randomized to receive docetaxel either immediately or at disease progression.19 Maintenance docetaxel was associated with a statistically significant improvement in PFS (5.7 vs 2.7 months; P=0.0001) and a trend toward improvement in OS (median 12.3 vs 9.7 months; P=0.0853). Several large Phase III trials of maintenance therapy reported at the 2009 ASCO annual meeting used erlotinib, erlotinib plus bevacizumab, or pemetrexed as maintenance therapy. The large Phase III SATURN trial tested erlotinib maintenance versus placebo after platinum-based doublet chemotherapy in 1,949 patients with advanced NSCLC. The SATURN trial met its primary end point of PFS, with results showing significantly increased PFS with erlotinib in all patients (HR, 0.71; 95% CI, 0.62-0.82; P<0.0001), and improved OS (12 vs 11 months).20 In exploratory analysis, an even greater benefit was seen in a subset of patients who had EGFR mutations. Based on this information, in April 2010, the FDA approved erlotinib for maintenance treatment of patients with advanced or metastatic NSCLC whose

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Table. Selected Trials of Maintenance Therapy in Advanced NSCLC Clinical Trial

Treatment Arms

Fidias et al19

Capuzzo et al20 (SATURN)

PFS, mo

Median OS, mo

309 GC, then immediate docetaxel GC, then delayed docetaxel

5.7 (P=0.001) 2.7

12.3 (P=0.0853) 9.7

CT, then E CT, then P

438 451

PFS was significantly prolonged with E versus P in all patients (HR, 0.71; 95% CI, 0.62-0.82; P<0.0001)

12 11

Pemetrexed + BSC P + BSC

441 222

Overall/NSQ/SQ 4.3/4.5/2.8 2.6/2.6/2.6

Overall/NSQ/SQ 13.4/15.5/9.9 10.6/10.3/10.8

CT + B, then B + P CT + B, then B + E

768

3.7 (P=0.0012) 4.8

Ciuleanu et al4

Miller et al21 (ATLAS)

B, bevacizumab; BSC, best supportive care; CI, confidence interval; CT, first-line platinum-based chemotherapy; E, erlotinib; GC, gemcitabine-carboplatin; HR, hazard ratio; NA, not available; NSQ, nonsquamous histology; OS, overall survival; P, placebo; PFS, progression-free survival; SQ, squamous histology

disease has not progressed after 4 cycles of platinumbased first-line chemotherapy.. Another Phase III trial evaluated pemetrexed as maintenance therapy. This trial included 663 patients with advanced NSCLC who did not progress on an initial platinum-based doublet and showed that pemetrexed maintenance resulted in significantly better OS (13.4 vs 10.6 months; HR, 0.79; 95% CI, 0.65-0.95; P=0.012) and PFS (4.3 vs 2.6 months; HR, 0.50; 95% CI, 0.42-0.61; P<0.0001) than placebo.4 Pemetrexedâ&#x20AC;&#x2122;s efficacy, favorable tolerability profile, ease of administration, and OS benefit make it appealing as a maintenance drug in advanced NSCLC. In July 2009, the FDA approved pemetrexed for maintenance treatment of patients with locally advanced or metastatic nonsquamous NSCLC whose disease has not progressed after 4 cycles of platinum-based firstline chemotherapy. Although most studies discussing maintenance options at the ASCO 2009 annual meeting tested nonâ&#x20AC;&#x201C; cross-resistant regimens, the ATLAS Phase III trial evaluated bevacizumab with or without erlotinib after completion of chemotherapy with bevacizumab for firstline treatment of advanced NSCLC.21 This study, the first to evaluate combination versus single-agent maintenance therapy options, showed significant improvement in PFS in the group receiving combination therapy (4.8 vs 3.7 months; HR, 0.722; 95% CI, 0.592-0.881; P=0.0012).

Biomarkers and Therapy As discussed above, many of the recent advances in the treatment of NSCLC have involved the integration of targeted therapeutics and more accurately defining the subset of patients who are most likely to benefit from a given treatment. Thus, it is more important now than ever before to explore predictors of efficacy to help direct the best therapy for each patient. In

I ndependently de v eloped b y M c M a h on P ublis h in g

clinical practice, factors such as smoking history, histology, gender, or ethnicity may help determine the choice of therapy. Genotypic correlates to response are being actively pursued.

Histology The importance of histology has been highlighted clearly for the use of pemetrexed in the treatment of advanced NSCLC in multiple settings. The large study by Scagliotti et al described above found that patients with nonsquamous tumors had a survival advantage when treated first-line with cisplatin-pemetrexed compared with those treated with cisplatin-gemcitabine, whereas those with squamous cell histology had a shorter median survival when treated with cisplatinpemetrexed.7 This was the first prospective study to show survival differences based on histology. A study by Hanna et al comparing pemetrexed and docetaxel in the second-line setting22 was subsequently analyzed retrospectively using subset histology data23; patients with nonsquamous NSCLC had a significant improvement in OS when treated with pemetrexed compared with those treated with docetaxel (9.3 vs 8.0 months; HR, 0.778; P=0.048). When pemetrexed was used as maintenance therapy by Ciuleanu et al, the improvements in PFS and OS were documented primarily in patients with nonsquamous histology.4 One possible explanation for the observed differential efficacy of pemetrexed is that baseline thymidylate synthase (TS) levels are higher in squamous cell carcinoma than in adenocarcinoma.24 Data on TS expression recently have been broadened to include undifferentiated large cell carcinoma. In a study presented at the ASCO meeting in 2009, significantly higher median mRNA and protein TS levels were detected in large cell and squamous cell carcinoma

Adenocarcinoma or nonsquamous

EGFR mutationpositive

Gefitinib Erlotinib

Squamous

EGFR mutationnegative or unknown

Bevacizumab + chemotherapy doublet a

Chemotherapy doublet with or without cetuximab a

Non-bevacizumab chemotherapy doublet (pemetrexed-based) a

Maintenance therapy • Pemetrexed a • Erlotinib with or without bevacizumab • Docetaxel

Disease progression

• Salvage therapy • Consider clinical trial

Figure. Proposed algorithm for treatment of NSCLC. a

FDA-approved regimens

EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer

samples compared with adenocarcinoma samples (large cell carcinoma: P<0.001 for both mRNA and protein values; squamous cell carcinoma: P=0.002 for mRNA, P<0.001 for protein).25

EGFR, VEGF,

and

KRAS

Somatic mutations in the tyrosine kinase domains of two erbB genes—the EGFR and HER-2 (human epidermal growth factor receptor 2) genes—have been found in lung adenocarcinomas. EGFR mutations are associated with sensitivity to the TKIs gefitinib26-28 and erlotinib, particularly those in exon 19.29 However, markers of resistance to EGFR inhibitors also have been identified, including the T790M mutation in exon 20.30,31 Approximately 15% to 30% of lung adenocarcinomas contain activating mutations in the KRAS gene and may be associated with unfavorable outcomes.32 Unlike in colon cancer, mutations in KRAS in lung cancer are not associated with a lack of sensitivity to either of the EGFR TKIs.33 Thus, although patients with EGFR mutations had improved PFS when treated with maintenance erlotinib in the SATURN trial, KRAS mutations had no predictive value.20

Broader Genotype Testing As EGFR mutations have emerged as an important target for therapy, strategies for treating patients harboring other mutations that make them refractory to treatment are being tested. EML4-ALK is a novel fusion oncogene in NSCLC.34 The fusion results from a small inversion within chromosome 2p, leading to expression of a constitutively activated, chimeric tyrosine kinase. Shaw et al have shown that the presence of EML4ALK results in a similar clinical profile to that seen in patients with EGFR mutations and is particularly frequent in light or never smokers; however, unlike EGFR mutations, EML4-ALK is found more often in men.35 Patients with EML4-ALK tumors did not benefit from EGFR TKIs; there were no responses in the EML4-ALK cohort. A promising Phase I trial testing the ALK inhibitor PF-02341066 showed an ORR of 57% (47 of 82 patients; 46 partial responses and 1 complete response) and 33% stable disease in patients with ALK rearrangements, with mainly grade 1 or 2 gastrointestinal side effects.36 This has allowed for the early development of several Phase III trials of ALK inhibitors as single agents, as well as with chemotherapy as second-line therapy.

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Another active area of research centers on mechanisms of resistance to EGFR TKIs, including amplification of the MET oncogene and secondary mutations in EGFR, such as the T790M mutation. Molecular testing for these abnormalities may eventually play a role in treatment selection. A recent Phase II study comparing the effects of the MET inhibitor METMAb plus erlotinib with placebo plus erlotinib showed nearly a 50% increase in OS and PFS in patients with high MET expression who received the MET combination therapy.37 However, patients with a low expression of MET fared worse on combination MET-erlotinib vs erlotinib alone, leading to future investigations into the possible interference of METMAb with erlotinibâ&#x20AC;&#x2122;s effectiveness. ARQ 197 is another MET-inhibiting targeted therapy that has showed promise in patients with nonsquamous histology, EGFR wild-type, and KRAS mutations.38 Preliminary results from a Phase II study comparing erlotinib plus ARQ 197 to erlotinib plus placebo indicated a greater median PFS in the experimental arm (16.1 vs 9.7 weeks), with similar adverse effects between the 2 arms. On another molecular front, there has been increasing interest involving irreversible EGFR inhibitors, mainly through the discovery of the small-molecule EGFR TKI BIBW 2992. Differing from its predecessors, BIBW 2992 binds irreversibly to both EGFR and HER-2 and is active against both wild-type and multiple mutant forms of EGFR. Preliminary results from an ongoing Phase II study of patients with NSCLC who had tumors with EGFR-activating mutations and progressive or recurrent disease following chemotherapy showed a 78% to 94% disease control rate, depending on the mutation subset, when BIBW 2992 alone was used.39 Additional Phase II/ III studies are under way investigating use of BIBW 2992 in NSCLC patients in other treatment settings.

Conclusion Paradigms in first-line and maintenance settings of advanced NSCLC are evolving toward targeted molecular therapies with better tolerability profiles. Based on recent studies, new standards of management in advanced NSCLC must be considered, evaluating the roles of histology, maintenance therapy, and testing for mutations in EGFR (Figure). Each patient with NSCLC presents a unique challenge, and therapy should be directed by more than simply PS. Agents targeting EGFR, VEGF, and ALK pathways in NSCLC have

I ndependently de v eloped b y M c M a h on P ublis h in g

demonstrated that different lung cancers respond differently to therapy. Efforts must continue to be made to understand the biology of individual tumors by emphasizing tissue-based clinical trials to create patient-specific therapy.40

References 1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90, PMID: 21296855. 2. Breathnach OS, Freidlin B, Conley B, et al. Twenty-two years of Phase III trials for patients with advanced non-small-cell lung cancer; sobering results. J Clin Oncol. 2001;19(6):1734-1742, PMID: 11251004. 3. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542-2550, PMID: 17167137. 4. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009;374:1432-1440, PMID: 19767093. 5. Non-small Cell Lung Cancer Collaborative Group (NSCL-CG). Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ. 1995;311(7010):899-909, PMID: 7580546. 6. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346(2):92-98, PMID: 11784875. 7. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26(21):3543-3551, PMID: 18506025. 8. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009;373(9674):1525-1531, PMID: 19410716. 9. Pirker R, Rodrigues-Pereira J, Szczesna A, et al. Prognostic factors in advanced NSCLC: experience from the FLEX trial. J Clin Oncol. 2009;27(15 suppl): Abstract 8083. 10. Kim ES, Herbst RS, Moon J, et al. S0536: Carboplatin, paclitaxel, cetuximab and bevacizumab followed by cetuximab and bevacizumab maintenance in advanced non-small cell lung cancer (NSCLC), a SWOG phase II study. PD3.5.5. Presented at: 2009 IASLC World Congress on Lung Cancer; July 31-August 4, 2009; San Francisco, CA. 11. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small cell lung cancer (INTEREST): a randomized Phase III trial. Lancet. 2008;372(9652):1809-1818, PMID: 19027483. 12. Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized Phase III INTEREST trial. J Clin Oncol. 2009;28(5):744-752, PMID 20038723.

13. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957, PMID: 19692680. 14. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10):958-967, PMID: 19692684. 15. Socinski MA, Schell MJ, Peterman A, et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non–small-cell lung cancer. J Clin Oncol. 2002;20(5):1335-1343, PMID: 11870177. 16. Park JO, Kim SW, Ahn JS, et al. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007;25(33):5233-5239, PMID: 18024869. 17. Westeel V, Quoix E, Moro-Sibilot D, et al. Randomized study of maintenance vinorelbine in responders with advanced non-small cell lung cancer. J Natl Cancer Inst. 2005;97(7):499-506, PMID: 15812075. 18. Sculier JP, Lafitte JJ, Lecomte J, et al. A phase III randomised trial comparing sequential chemotherapy using cisplatin-based regimen and paclitaxel to cisplatin-based chemotherapy alone in advanced non-small-cell lung cancer. Ann Oncol. 2007;18(6):10371042, PMID: 17404152. 19. Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27(4):591-598, PMID: 19075278. 20. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. SATURN: A doubleblind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. J Clin Oncol. 2009;27:(15 suppl): Abstract 8001. 21. Miller VA, O’Connor P, Soh C, et al. A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2009;27:(18 suppl): Abstract LBA8002.

cancer. J Clin Oncol. 2009;27:(15 suppl): Abstract 7521. 26. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129-2139, PMID: 15118073. 27. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497-1500, PMID: 15118125. 28. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101(36):13306-13311, PMID: 15329413. 29. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer— molecular and clinical predictors of outcome. N Engl J Med. 2005;353(2):133-144, PMID: 16014883. 30. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small cell lung cancer to gefitinib. N Engl J Med. 2005;352(8):786-792, PMID: 15728811. 31. Morgillo F, Kim WY, Kim ES, Ciardello F, Waun KH, Lee HY. Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res. 2007;13(9):2795-2803, PMID: 17473213. 32. Rodenhuis S, Slebos RJ. The ras oncogenes in human lung cancer. Am Rev Respir Dis. 1990;142(6 pt 2):S27-S30, PMID: 2252272. 33. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005;2(1):e17, PMID: 15696205. 34. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small cell lung cancer. Nature. 2007;448(7153):561-566, PMID: 17625570. 35. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247-4253, PMID: 19667264. 36. Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693-1703, PMID: 20979469.

22. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non–smallcell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22(9):1589-1597, PMID: 15117980.

37. Spigel D, Ervin T, Ramlau R, et al. MetMAb added to erlotinib improves survival in a subset of patients with lung cancer. Presented at: the ESMO 35th Congress; October 8-12, 2010; Milan, Italy; Abstract LBA15.

23. Peterson P, Park K, Fossella F, et al. Is pemetrexed more effective in adenocarcinoma and large cell carcinoma than in squamous cell carcinoma? A retrospective analysis of a phase III trial of pemetrexed vs docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC): P2-328. J Thorac Oncol. 2007;2(8):S851: Abstract P2-328.

38. Schiller JH, Akerley WL, Brugger W, et al. Results from ARQ 197209: a global randomized placebo-controlled phase II clinical trial of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated EGFR inhibitor-naïve patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2010;28:(18 suppl): Abstract LBA7502.

24. Ceppi P, Volante M, Saviozzi S, et al. Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer. 2006;107(7):1589-1596, PMID: 16955506.

39. Yang CH, Shih JY, Su WC, et al. A phase II study of BIBW 2992 in patients with adenocarcinoma of the lung and activating EGFR mutations (LUX-Lung 2). J Clin Oncol. 2010;28:(15 suppl): Abstract 7521.

25. Scagliotti G, Monica V, Ceppi P, et al. Baseline thymidylate synthase expression according to histological subtypes of non-small cell lung

40. Kim ES, Herbst RS, Wistuba II, et al. The BATTLE Trial: Personalizing Therapy for Lung Cancer. Cancer Discovery 2011;1:OF42-OF51.

I ndependently de v eloped b y M c M a h on P ublis h in g

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Docetaxel Injection safely and effectively. See full prescribing information for Docetaxel.

Docetaxel Injection, For intravenous infusion only. Initial U.S. Approval: 1996

• • • •

• •

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION See full prescribing information for complete boxed warning Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinumbased therapy receiving docetaxel at 100 mg/m2 (5.1) Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (8.6) Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4) Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy (5.4) Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 (4) Severe fluid retention may occur despite dexamethasone (5.5)

––––––––––––––––––––––––––––––––––––––––––––– CONTRAINDICATIONS –––––––––––––––––––––––––––––––––––––– • Hypersensitivity to docetaxel or polysorbate 80 (4) • Neutrophil counts of <1500 cells/mm3 (4) ––––––––––––––––––––––––––––––––––––––––– WARNINGS PRECAUTIONS ––––––––––––––––––––––––––––––––––––––– • Acute myeloid leukemia: In patients who received docetaxel doxorubicin and cyclophosphamide, monitor for delayed myelodysplasia or myeloid leukemia (5.6) • Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe skin toxicity may require dose adjustment (5.7) • Neurologic reactions: Reactions including. paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. (5.8) • Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.9) • Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant when receiving Docetaxel Injection (5.10, 8.1) ––––––––––––––––––––––––––––––––––––––––––––– ADVERSE REACTIONS ––––––––––––––––––––––––––––––––––––––– Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia (6) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

Manufactured by: Hospira Australia Pty., Ltd., Mulgrave, Australia Manufactured by: Zydus Hospira Oncology Private Ltd., Gujarat, India Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA

Reference EN-2761

Single Vial

Docetaxel Injection (10 mg/mL concentration)

Clarity of glass

Barrier sheath

Exclusive Onco-Tain™ packaging for safe handling1

PVC reinforced bottom

WARNING: Toxic Deaths, Hepatotoxicity, Neutropenia, Hypersensitivity Reactions, and Fluid Retention See full prescribing information for complete boxed warning • Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2 • Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle

• Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy • Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 • Severe ﬂuid retention may occur despite dexamethasone

• Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia

Indications and Usage

Safety Information

Docetaxel Injection is a microtubule inhibitor indicated for: Breast Cancer (BC): single agent for locally advanced metastatic BC after chemotherapy failure; and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC.

1. Data on ﬁle at Hospira P11-3232B-8.375x10.75-Mar., 11

only

Non-Small Cell Lung Cancer (NSCLC): single agent for locally advanced or metastatic NSCLC after platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC Hormone Refractory Prostate Cancer (HRPC): with prednisone in androgen independent (hormone refractory) metastatic prostate cancer

Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, ﬂuid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch See brief Prescribing Information on reverse side.

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Update on Approaches to the Treatment of

Follicular Lymphoma Andrew M. Evens, DO, MS Associate Professor of Medicine The University of Massachusetts Medical School UMass Memorial Cancer Center Worcester, Massachusetts

Jane N. Winter, MD Professor of Medicine Northwestern University Feinberg School of Medicine Robert H. Lurie Comprehensive Cancer Center Chicago, Illinois

ollicular lymphoma (FL) comprises more than 70% of all

“low-grade” histologies and 22% of all cases of non-Hodgkin’s lymphoma (NHL), second only to diffuse large B-cell lymphoma.1,2

Survival rates for patients with FL remained unchanged from the 1950s through the early 1990s, but recent evidence indicates that outcomes are improving.3-5 FL remains a challenge to treat, partly because it is generally an incurable disease requiring multiple treatments. Furthermore, it is a disease in which relatively long survival times elevate the importance of quality of life when treatments are considered.

Prognosis and Tumor Burden The Follicular Lymphoma International Prognostic Index (FLIPI) is a clinical prognostic model developed initially for newly diagnosed advanced-stage FL,6,7 but it also has been validated in early-stage disease8 and at first relapse.9 An updated report by Federico et al examined the importance of the FLIPI prognostic score among patients given rituximab (Rituxan, Genentech/ Biogen Idec)-based treatment (Table 1).10 They showed

C L I N I C A L O N C O L O GY N E W S S P E C I A L E D I T I O N 2 0 1 1

that the FLIPI-2 (Follicular Lymphoma International Prognostic Index-2) yielded 3 distinct risk groups with different outcomes. High tumor burden also is associated with shorter progression-free survival (PFS) and overall survival (OS), even in the rituximab era.11 There is no gold standard to define tumor burden, although a number of methods are in clinical use, including the Groupe D’Etude des Lymphomes Folliculaires (GELF) criteria (Table 2).12,13 Entry criteria for clinical trials of untreated FL often separate patient groups based on the GELF and/or FLIPI criteria.

Treatment Approaches Traditional treatment options for low-grade NHL include expectant observation for asymptomatic, low tumor burden disease and multiagent cytotoxic chemotherapy for patients who are symptomatic and/or have

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Table 1. Survival by Risk Group as Defined by the FLIPI-2 Risk Group

No. of Factorsa

Distribution of Patients, %

3-Year PFS, %

5-Year PFS, %

Low

Intermediate

1-2

High

3-5

FLIPI, Follicular Lymphoma International Prognostic Index; PFS, progression-free survival a Factors adversely affecting outcome include 1) age (>60 vs ≤60 y); 2) hemoglobin level (<120 vs ≥120 g/L); 3) β2-microglobulin (above normal vs normal or below); 4) largest involved lymph node (>6 vs ≤6 cm); 5) bone marrow (involved vs not involved).

Based on reference 10.

a high tumor burden. Biologic therapy has become an integral part of therapy and includes agents that specifically target B lymphocytes, such as monoclonal antiCD20 antibodies and radiolabeled anti-CD20 antibodies. Treatment response to cytotoxic and biologic therapies is high initially; however, with subsequent treatments, response rate and remission duration decline, whereas cumulative toxicities increase and relapse is inevitable. New combinations of novel targeted agents provide the opportunity to improve outcomes for patients with FL.

Initial Treatment of Advanced-Stage Disease Therapeutic Options For patients with symptoms or other reasons to undergo treatment, several treatment options are available, including single- or multiple-agent chemotherapy with concurrent CD20 antibody therapy; CD20 antibody therapy alone in selected cases; radioimmunoconjugates; and therapy with new agents, such as bortezomib (Velcade, Millennium) and lenalidomide (Revlimid, Celgene). Autologous and allogeneic hematopoietic stem cell transplantations (HSCTs) traditionally are reserved for patients with recurrent or refractory disease, but they may be used earlier in the disease course for patients with a poorer prognosis. Additionally, many clinical trials are available for patients with FL, and all patients should be encouraged to participate in such trials.

Rituximab: Single-Agent Induction Post-Induction Therapy

and

In previously untreated FL patients with low tumor burden, the overall response rate (ORR) with rituximab

is 47% to 74%,14-16 with a median PFS of approximately 2 years without maintenance therapy14,16,17 or 3 years with abbreviated post-induction rituximab.15 Very little data exist regarding use of single-agent rituximab for patients with newly diagnosed, high tumor burden FL. The Eastern Cooperative Oncology Group (ECOG) 1496 study randomized responding indolent lymphoma patients induced with CVP (cyclophosphamide, vincristine, and prednisone) chemotherapy to either maintenance rituximab or observation.11 The median PFS time and OS for patients receiving rituximab maintenance was significantly improved compared with those receiving no maintenance (Table 3). Patients with follicular histology, high tumor burden, and minimal residual disease appeared to gain the greatest benefit from maintenance rituximab. The 1,000-mg/m2 dose of cyclophosphamide used in ECOG 1496 may be important and may explain the somewhat lower responses and outcomes seen in other CVP-based trials.18,19 The results of 2 completed randomized trials in previously untreated patients have been eagerly awaited. The RESORT (Rituximab Extended Schedule or Retreatment Trial), which has not been reported yet, was conducted by ECOG. The study enrolled asymptomatic, low tumor burden patients; induction consisted of 4 weekly treatments with rituximab. Maintenance rituximab was compared with retreatment at the time of recurrence. The PRIMA (Primary Rituximab and Maintenance) trial compared maintenance rituximab with observation in high tumor burden FL patients treated with rituximab plus chemotherapy.20 With a median follow-up of 36 months, the PFS was 75% in the rituximab maintenance group versus 58% in the observation group (P<0.0001). The most common

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Table 2. Definition of Tumor Burden in FL by GELF Original GELF criteriaa • Any nodal or extranodal tumor mass >7 cm diameter • Involvement of at least 3 nodal sites, each with a diameter of >3 cm • Presence of any systemic or B symptoms • Splenic enlargement with inferior margin below the umbilical line • Compression syndrome (ureteral, orbital, gastrointestinal) • Pleural or peritoneal serous effusion (irrespective of cell content) • Leukemic phase (>5.0 x 109/L circulating malignant cells) • Cytopenia (granulocyte count <1.0 x 109/L and/or platelets <100 x 109/L) FL, follicular lymphoma; GELF, Groupe d’Etude des Lymphomes Folliculaires a

atients must meet only one criterion to be considered “high” P tumor burden.

Based on references 12 and 13.

adverse event (grades 2-4) was infection, which occurred in 39% of those in the maintenance rituximab group and 24% of controls (P<0.0001). Whether OS will be impacted by maintenance rituximab remains to be determined.

Chemotherapy

and

Rituximab Induction Therapy

Past clinical trials comparing multiple- and singleagent chemotherapy in patients with advanced-stage FL did not show improvements in the natural course of the disease.21,22 Fludarabine, identified in the 1980s as having activity in FL, has been incorporated into combination regimens that achieved high response rates; however, meaningful differences in outcome relative to other multiple-agent regimens have not been observed.23,24 Furthermore, there is concern that fludarabine-based treatment may impair stem cell collection25,26 and also may increase the risks for transformation27 and myelodysplastic syndrome. Several randomized Phase III trials evaluating various chemotherapy combinations plus rituximab versus chemotherapy alone have been reported and updated (Table 3).7,11,18,19,28-33 The response rates and either median time-to-treatment failure (TTF) or median event-free survival (EFS) were superior in the chemoimmunotherapy arm for chemotherapy-naïve patients and for those who were previously treated. Moreover, OS improvements for the chemoimmunotherapy arms (vs chemotherapy without immunotherapy) were present. Rummel et al reported in abstract form results of a

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randomized Phase III trial that compared induction chemotherapy using the chemotherapeutic agent bendamustine (Treanda, Cephalon) in combination with rituximab (BR) versus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) for untreated patients with high tumor burden indolent NHL or mantle cell lymphoma.34,35 ORR was similar in the 2 groups at 93% for BR and 91% for R-CHOP; however, the complete remission (CR) rate was improved with BR (40%) compared with R-CHOP (31%). Furthermore, BR was associated with a superior PFS compared with R-CHOP (median, 55 vs 35 mo; P=0.00012), as was time to next treatment (median, not reached vs 38 mo; P=0.00002). No difference in OS was noted. Of 513 evaluable patients, 179 had high tumor burden FL; BR was associated with significantly improved PFS in this group (not reached vs 47 mo; P=0.0281). More toxicity was seen with R-CHOP, with grade 3/4 neutropenia occurring in 47% of patients versus 11% with BR (P<0.0001), despite use of more granulocyte colony-stimulating factor in patients treated with R-CHOP (20% vs 4%). Other toxicities seen at higher rates in those treated with R-CHOP included alopecia (universal vs <2% patients; P<0.0001), paresthesias, stomatitis, infectious complications, and sepsis. Side effects more frequent with BR compared with R-CHOP were skin/erythema and allergic reaction (skin). Overall, the combination of BR improved PFS and CR rates, with a better tolerability profile. These results suggest that BR ultimately may become the new standard first-line treatment for patients with advanced-stage, high tumor burden FL.

Radioimmunotherapy The anti-CD20 radioimmunoconjugates 131I-tositumomab (Bexxar, GlaxoSmithKline) and 90Y-ibritumomab tiuxetan (Zevalin, Biogen Idec) deliver ionizing radiation to target cells and their neighbors. They are relatively easy to administer, safe, and effective in relapsed/ refractory FL,36,37 including rituximab-refractory disease.38 Radioimmunotherapy (RIT) also has been incorporated into the frontline management of patients with untreated indolent lymphoma through the paradigm of sequential therapy (RIT after multiagent induction chemotherapy). Morschhauser et al reported results of Phase III FIT (First-line Indolent Trial) examining consolidative RIT versus no consolidation in patients who achieved CR or partial remission (PR) following chemotherapy induction.32,39 Patients were randomized to one dose of 90Y-ibritumomab tiuxetan or no consolidation. RIT significantly improved median PFS in all patients (36.5 vs 13.3 mo with no RIT; P<0.0001). This gain was observed regardless of the degree of initial response to

Table 3. Selected Randomized Studies Of Chemoimmunotherapy for Patients With FL Series/Author

Year

Arms

Conclusions

Hiddeman30 and Buske7

2005 and 2006

428

CHOP vs R-CHOP (all patients randomized to IFN vs autologous HSCT)

4-y PFS: CHOP 28% vs R-CHOP 62% (P<0.0001) 4-y OS: CHOP 81% vs R-CHOP 90% (P=0.039)

Forstpointner28

2006

125 (relapsed)

FCM vs R-FCM with second randomization R maintenance vs observation

Response duration significantly prolonged by R maintenance after R-FCM

Marcus18,19

2006

321

CVP vs R-CVP

Median TTF: CVP 15 mo vs R-CVP 34 mo; OS improved for R-CVP (P=0.029)

Van Oers33

2006

465 (relapsed)

CHOP vs R-CHOP induction followed by second randomization to R maintenance vs observation

Improved PFS with R maintenance after CHOP (HR, 0.30; P<0.001) and R-CHOP (P=0.004) induction

Herold29

2007

358

MCP vs R-MCP (followed by IFN)

Median EFS (P=0.001) and median OS (P=0.0096) improved with R-MCP

Salles31

2008

358

CHVP x 12 cycles vs 6 cycles R-CHVP (both arms concurrent IFN x 18 mo)

EFS: CHVP 37% vs R-CHVP 53% (P<0.0001) Median OS: CHVP 79% vs R-CHVP 84% (P=ns)

Hochster11

2009

401

CVP vs CVP with R post-induction maintenance

3-y PFS: 64% with R vs 63% without maintenance (P=4.4 x 10-10) 3-y OS: 92% with R vs 86% without maintenance (P=0.05)

CHVP, cyclophosphamide, adriamycin, etoposide, prednisone; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CI, confidence interval; CVP, cyclophosphamide, vincristine, prednisone; EFS, event-free survival; FCM, fludarabine, cyclophosphamide, mitoxantrone; FL, follicular lymphoma; HR, hazard ratio; HSCT, hematopoietic stem cell transplantation; IFN, interferon; MCP, mitoxantrone, chlorambucil, prednisone; ns, not significant; OS, overall survival; PFS, progression-free survival; pts, patients; R, rituximab; TTF, time to treatment failure; TTP, time to disease progression

induction chemotherapy, although the benefit appeared to be greater for patients in PR versus CR. A limitation of the FIT trial was that the majority of patients did not receive rituximab-based induction chemotherapy. The extent of benefit of consolidation RIT after combined rituximab/chemotherapy therapy is not known. 131 I-tositumomab also has been incorporated sequentially following chemotherapy.16,40 Further information regarding the role of up-front, sequential RIT in indolent NHL should be available soon from the large US intergroup study led by the Southwest Oncology Group (S0016). In that Phase III trial, untreated FL patients were randomly assigned to 6 cycles of R-CHOP versus 6 cycles of CHOP followed by 131I-tositumomab. Several novel RIT-based therapeutic approaches—including concurrent use of radiation-enhancing agents, fractionation of RIT, pretargeting, and use

of new humanized antibodies—are being explored to increase efficacy and mitigate toxicity.41 Novel combinations include potentially synergistic radiation-sensitizing agents—eg, bortezomib,42 the synthetic 24-mer oligodeoxynucleotide CpG 7909,43 and the expanded porphyrin agent motexafin gadolinium (MGd; Xcytrin, Pharmacyclics),44 which targets redox-dependent pathways and enhances the sensitivity of tumor cells to ionizing radiation.45 In a Phase I clinical trial in which MGd was given concurrently with 90Y-ibritumomab tiuxetan, the ORR was 57% (CR 43%), with median TTF of 10 months and median duration of 17 months.44 Moreover, in rituximab-refractory FL, the ORR was 86% (CR 64%), with a median TTF of 14 months, which compares favorably to previous data.38 These results are encouraging, but randomized trials will be needed to prove the superiority of this combination over conventional RIT.

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Induction a

High-risk FL (FLIPI score 3-5 or GELF high tumor burden)

R A N D O M I Z E

Continuation

Rituximab 375 mg/m2 + bendamustine 90 mg/m2 q28d x 6 cycles

Rituximab 375 mg/m2 1 infusion q2mo x 2 y

Rituximab 375 mg/m2 + bortezomib (1.3 mg/m2, days 1, 4, 8, 11) + bendamustine 90 mg/m2 q28d x 6 cycles

Rituximab 375 mg/m2 1 infusion q2mo x 2 y

Rituximab 375 mg/m2 + bendamustine 90 mg/m2 q28d x 6 cycles

Rituximab 375 mg/m2 1 infusion q2mo x 2 y + lenalidomide 20 mg, days 1-21 q28d x 1 y

Figure. Untreated high tumor burden FL: E2408 study schema. FL, follicular lymphoma; FLIPI, Follicular Lymphoma International Prognostic Index; GELF, Groupe d’Etude des Lymphomes Folliculaires a

1:2:2 randomization; accrual: 250 patients

Stem Cell Transplantation Autologous An expert panel convened by the American Society for Blood and Marrow Transplantation published an evidence-based review and a more recent position paper on the role of HSCT in the treatment of FL.46.47 Although high-dose therapy with autologous HSCT as a component of up-front therapy in FL consistently improves PFS/EFS, this approach is not recommended because of the high incidence of secondary myelodysplastic syndrome/acute myeloid leukemia and the lack of improvement in OS. In the salvage setting, there are no large prospective studies addressing the question of autologous HSCT in patients with FL treated with rituximab as part of induction and/or salvage therapy, making it difficult to make a recommendation in this setting. Nonetheless, many patients benefit from this strategy.48,49

Allogeneic The potentially curative allogeneic HSCT is an alternative for an increasing number of patients, given the option of reduced-intensity conditioning and the greater availability of matched unrelated donors. Choosing between autologous and allogeneic HSCT is a difficult decision and depends on many factors, including donor availability, donor age, patient age, and comorbidities. Because of the high treatment-related morbidity and mortality associated with allogeneic HSCT, many centers will perform an autologous HSCT first, reserving an allogeneic transplant from either a matched sibling donor or matched unrelated donor with reduced-intensity conditioning for patients who later relapse. Today, the vast majority of allogeneic HSCTs are based on reduced-intensity conditioning, which is applicable to a wider range of patients and appears to result in PFS/OS that is similar to that of myeloablative transplantation.50

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The addition of rituximab to conditioning for both allogeneic and autologous HSCT has been associated with excellent outcomes in some series, but its role in transplantation for FL needs to be better defined.46,51

Novel Agents for Relapsed And Refractory Disease Vaccination Strategies FL occasionally undergoes spontaneous regression, leading some investigators to speculate that it might be responsive to immune regulation. All cells in a lymphoid clone express the same idiotype (Id)—the variable region of the immunoglobulin (Ig) molecule—making it a “tumor-specific antigen” and an ideal target for immunotherapy. Custom-made Id-specific monoclonal antibodies produced by Stanford investigators led to durable CRs in a subset of patients with FL.52 To provide a more long-lasting immune response to the lymphoma-associated Id, patients were vaccinated with Id specific to their own lymphomas.53 Patients who generated an immune response to vaccination were found to have a better survival than those who did not.53 A Phase III multi-institutional randomized trial compared vaccination with a nonspecific control vaccine in patients who achieved a CR with combination chemotherapy.54 Analysis showed that vaccination only marginally prolonged disease-free survival (DFS) among patients who received at least one immunization and were in complete remission for 6 months after intensive chemotherapy. However, DFS was prolonged significantly for patients receiving IgM-Id but not IgG-Id vaccines compared with isotype-matched control patients. In contrast to these positive results, 2 other large Phase III randomized trials of anti-Id vaccine have shown no benefit from vaccination. In a large Phase III trial of anti-Id vaccination following response

Table 4. Monoclonal Antibodies for Lymphoid Malignancies Antigen Antibody

Type

Status

CD20

Chimeric

FDA-approved

Y-ibritumomab tiuxetan (Zevalin, Biogen Idec)

Yttrium-90 murine

FDA-approved

131

I-tositumomab (Bexxar, GlaxoSmithKline)

Iodine-131 murine

FDA-approved

CD52

Alemtuzumab (Campath, Berlex)

Humanized

FDA-approved

CD20

Ofatumumab (HuMay-CD20, Genmab.com)

Humanized

Phase III

CD22

Epratuzumab (LymphoCide, Immunomedics/Amgen)

Humanized

Phase II/III

CD80

Galiximab (IDEC-114, Biogen Idec)

Primatized

Phase III

CD23

Lumiliximab (IDEC-152, Biogen Idec)

Primatized

Phase II

Rituximab (Rituxan, Biogen Idec/Genentech) 90

to cyclophosphamide, vincristine, and prednisone, immune response to Id but not to control vaccine correlated strongly with a favorable clinical outcome.55 These findings raise the possibility that the capacity to generate an immune response to Id is a marker of a favorable prognosis. A second anti-Id vaccine was studied after cytoreduction with rituximab, and again no significant difference in time to progression was observed in the entire group or any subgroup compared with patients receiving placebo and granulocyte macrophage colony-stimulating factor.56 Analysis according to isotype may have revealed a benefit from vaccination with IgM-Id in these 2 studies. New directions in vaccination include Id-pulsed dendritic cell and membrane proteolipsomal vaccines. Alternative immunologically based approaches also are in development.

Monoclonal Antibodies Some malignant B cells are resistant to rituximab straightaway, whereas others develop resistance over time after exposure to the antibody. There are many mechanisms of resistance, and thus there are innumerable potential strategies for the development of new targeted antibodies (Table 4). GA101 (GlycArt/Genentech) is a novel anti-CD20 that is the first humanized and “glyco-engineered” antiCD20 to be investigated clinically.57 “Glyco-engineering” enhances antibody-dependent cellular cytotoxicity (ADCC) by increasing affinity to the ADCC receptor FCgRIIIA. GA101 binds a type II epitope on CD20 with high affinity and has greater direct cell cytotoxicity compared with type I antibodies. Complementdependent cytotoxicity, however, is reduced. Toxicities mostly are related to the infusion, and response rates have been high among patients with FL.58,59 Veltuzumab (Immunomedics/Nycomed) is a second-generation

humanized anti-CD20 that differs from rituximab by 1 amino acid in 1 complementarity-determining region, but it has completely different framework regions. Veltuzumab has been shown to have slower “off rates” than rituximab in some lymphoma cell line studies, and it may be administered subcutaneously.60 Among patients with FL, ORRs have been high (44%), with 27% achieving CR/CRu (CR undefined).61 Other anti-CD20s under development include ocrelizumab (Roche), a humanized antibody with fewer infusion-related side effects and increased binding affinity to the low-affinity Fcγ RIIIa receptor.62 Some studies have shown that patients who are homozygous for high-affinity variants have superior disease outcome when treated with rituximab compared with those carrying low-affinity variants. In a Phase I/II trial of ocrelizumab in patients with relapsed/refractory FL, an ORR of 38% was observed, with similar response rates in patients with low-affinity and high-affinity variants.63 PRO13192 (Genentech), a third-generation, humanized anti-CD20 with enhanced ADCC and complementdependent cytotoxicity in in vitro models, also is under investigation.64 Ofatumumab (Arzerra, GlaxoSmithKline), a fully human antibody that targets a novel epitope of the CD20 molecule that was approved in October 2009 for the treatment of chronic lymphocytic leukemia (CLL), is reported to have stronger complementdependent cytotoxicity than rituximab.65 Although this antibody is very effective in CLL, the ORR in rituximabresistant FL was 11%, limiting enthusiasm for this agent in this patient population.66 CD22 is a B cell–associated antigen expressed on the surface of mature B cells. The humanized anti-CD22 epratuzumab (Immunomedics) acts predominantly by ADCC, but some studies suggest that it acts, at least partly, by mechanisms different from rituximab. Whereas epratuzumab and rituximab target different antigens and

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Table 5. Novel Agents for the Treatment of FL Target

Type

Agents

Proteasome

Proteasome inhibitors

Bortezomib, carfilzomib, NPI-0052

CD20

mAbs

Ofatumumab, IMMU-06, ocrelizumab, GA101

CD22 and CD74

mAbs

Epratuzumab and milatuzumab

CD19 and CD22

mAb-drug conjugates

Inotuzumab ozogamicin, SAR3419

HDAC

HDAC inhibitors

Vorinostat, PCI-24781

mTOR

Small molecule

Everolimus, temsirolimus

Bcl-2 family

Small molecule

ABT-263

B-cell receptor

Small molecule

Fostamatinib disodium, PCI-32765

JAK-2

Small molecule

SB1518

Multiple

Immunomodulatory drugs

Lenalidomide, thalidomide

FL, follicular lymphoma; HDAC, histone deacetylase; JAK-2, Janus kinase 2; mAb, monoclonal antibody; mTOR, mammalian target of rapamycin

likely effect cell kill through different signaling pathways, the combination has been studied in relapsed or refractory low-grade, CD20-positive NHL.67 A high ORR (85%) was reported for FL patients with low-risk FLIPI scores, whereas those with intermediate- or high-risk scores had an ORR of 39%. This combination with extended dosing recently has been evaluated, and results are undergoing analysis. CD74, the invariant chain of the major histocompatibility complex class II molecule, is another attractive target for the treatment of FL. Milatuzumab (Immunomedics), a humanized anti-CD74 monoclonal antibody, is rapidly internalized, and, consequently, has very limited capacity for ADCC or CDC, but it may prove to be an

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ideal agent for conjugation with radioisotopes or cytotoxic agents.68 Mapatumumab, a fully human agonistic monoclonal antibody to the tumor necrosis factorâ&#x20AC;&#x201C;related apoptosis-inducing ligand receptor 1 (TRAIL-R1), has also shown activity in FL.69

Conjugates Like the anti-leukemia agent gemtuzumab ozogamicin (Mylotarg, Wyeth), inotuzumab ozogamicin (CMC544; Pfizer) is composed of a humanized antibody conjugated to calicheamicin, a potent cytotoxic antitumor agent. This chemoimmunoconjugate targets the B-cell antigen CD22. Responses have been seen in both FL and

diffuse large B-cell lymphoma.70,71 Toxicity primarily has been self-limited thrombocytopenia. Dang et al recently reported the results of a study of patients with relapsed/ refractory FL treated with inotuzumab ozogamicin in combination with rituximab; they found an ORR of 87%, with a median PFS of 23.6 months.72 A new immunoconjugate, SAR3419 (ImmunoGen), consisting of the humanized anti-CD19 antibody huB4 conjugated to a potent tubulin inhibitor, resulted in tumor shrinkage in 68% of patients studied.73 Corneal changes resulting in blurred vision were the dose-limiting toxicity.

Other Novel Targeted Agents Additional agents aimed at specific molecular targets have shown promise in the treatment of FL (Table 5). The ubiquitinâ&#x20AC;&#x201C;proteasome pathway plays a critical role in regulating cell cycle progression, transcription-factor activation, apoptosis, and cell trafficking. Bortezomib has shown encouraging activity in relapsed or refractory lymphoma, with ORR ranging from 13% to 50%.74,75 Immunomodulatory drugs (IMiDs) such as thalidomide (Thalomid, Celgene) and lenalidomide (Revlimid, Celgene) have been investigated in a number of tumor types. IMiDs directly induce cell cycle arrest and also possess potent anti-angiogenic activity in vitro. Elegant preclinical studies by Gribben and colleagues showed that lenalidomide repaired several T-cell defects in FL cells, significantly enhancing the immune synapse function between tumor and T cells.76 Clinically, Witzig et al reported an ORR of 26% in relapsed/ refractory indolent lymphoma, with a 32% ORR in FL.77 Bortezomib may be safely combined with bendamustine and rituximab resulting in high response rates in patients with relapsed/refractory FL.78 Both bortezomib and lenalidomide are being incorporated into frontline FL studies, such as the BIONIC (Bortezomibbased Induction Or Novel IMID-based Continuation), or E2408, trial (Figure). Other novel agents being studied in FL include histone deacetylase (HDAC) inhibitors, mammalian target

of rapamycin (mTOR) inhibitors, and B-cell receptor (BCR)-modulating agents. HDACs have been shown to regulate cellular functions such as cell cycle progression, proliferation, survival, transcription factors, and signal transduction, and are a target of interest in lymphoma.79 Preclinical data support the use of these agents in the treatment of lymphoma,80 and data from early-phase clinical trials have shown encouraging activity in FL.81,82 A downstream target of the PI3K/ AKT pathway is the kinase, mTOR. The mTOR pathway also is important for cellular functions such as initiation of transplant, protein stability, and transcription of ribosome and stress response genes. Smith et al showed that the rapamycin ester derivative, temsirolimus (Torisel, Wyeth) resulted in an ORR of 54% in patients with FL histology.83

Conclusion Treatment options for patients with FL have significantly improved over the past several years, partly because of the development of antibody-based and other innovative, targeted approaches and the refinement of HSCT. These therapies have translated into alterations in the natural history of FL and increases in OS. Despite this optimism, FL remains an incurable disease for most patients. It is critical for oncologists and patients to be involved in clinical trials for advancements in the field to allow for continued improvements in the outcomes of patients with FL.

For reference list, go to clinicaloncology.com

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Updates in the Treatment of

Advanced Breast Cancer Christina I. Herold, MD Division of Hematology/Oncology Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical School Boston, Massachusetts

dvanced breast cancer remains challenging, with the major goals of treatment being prolongation

of life and preservation of patient-defined quality of life. The treatment of advanced breast cancer has become increasingly guided by molecular tumor markers, including the presence or absence of hormone receptors (HRs) and amplification or over-expression of human epidermal growth factor receptor (ErbB2 or HER2/neu).

The past few years have brought significant improvements in the treatment of subtypes of breast cancer, including HR-positive disease, HER2-positive disease, disease associated with BRCA mutations, triple-negative (estrogen receptor [ER]-, progesterone receptor [PR]-, and HER2-negative) disease, and treatment of patients with bony metastases. This review explores the recent data on treatment of various breast cancer subtypes, the role of metastatic tumor biopsies, and prevention of skeletal-related complications in patients with advanced breast disease.

Evolving Role for Metastatic Tumor Biopsies In the past year, multiple studies have sought to evaluate the frequency with which metastatic tumor biopsies

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display transitions in tumor markers when compared with the characteristics of the original primary tumor. Of these, perhaps Amir et al presented the most informative study at the American Society of Clinical Oncology (ASCO) 2010 annual meeting. In a combined analysis of the DESTINY and BRITS studies involving 271 patients, the investigators prospectively analyzed changes in marker status.1 The primary objective of this study was to ascertain the frequency with which medical oncologists changed their treatment plan based on the results of the metastatic biopsy. To this end, oncologists were asked to record their treatment plan both before and after the result of the metastatic biopsy was known. Analysis of these plans revealed that, based on the results of the metastatic biopsy, 15.1% of patients received a

C L I N I C A L O N C O L O GY N E W S S P E C I A L E D I T I O N 2 0 1 1

different treatment than originally had been planned. As secondary objectives, the researchers investigated the frequency of discordant results and reported an overall discordance of 39%, including 5.4% for HER2 status, 12.6% for ER status, and 34% for PR status. These results highlight the frequency with which tumor markers may change during the evolution of disease and suggest that metastatic tumor biopsies likely have an important role in targeting therapies to the most current profile of a patient’s disease.

Endocrine Therapy for HR-Positive Disease At the 2010 San Antonio Breast Cancer Symposium, several important studies were presented on the management of HR-positive disease. One of these studies, FIRST (Fulvestrant First-Line Study Comparing Endocrine Treatments), examined the first-line treatment of advanced breast cancer, whereas the other 2 studies used novel therapeutics—the mammalian target of rapamycin (mTOR) inhibitor everolimus (Afinitor, Novartis) and AMG 479 (Amgen)—to overcome endocrine resistance.

FIRST During the randomized Phase II FIRST study, investigators compared “high-dose” (500 mg intramuscularly on days 0, 14, and 28, and monthly thereafter) fulvestrant (Faslodex, AstraZeneca) with anastrozole (1 mg per day) as first-line therapy for advanced breast cancer.2 The primary outcome was time to progression (TTP); median TTP was significantly improved for the fulvestrant group (23.4 months) compared with the anastrozole group (13.1 months); this corresponds to a 35% reduced risk for progression for the fulvestrant group (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.47-0.92; P=0.01). Additionally, fulvestrant was well tolerated, and there were no new safety concerns. Although FIRST is a Phase II study, these results have the potential to influence clinical care, given the significant improvement in TTP associated with this treatment. Of note, the results from FIRST differ from those reported from EFECT (Evaluation of Fulvestrant versus Exemestane Clinical Trial), a Phase III randomized, double-blind, placebo-controlled study enrolling women with HR-positive advanced breast cancer who had demonstrated disease progression while taking a nonsteroidal aromatase inhibitor (AI).3 EFECT randomized women to receive “loading-dose” intramuscular fulvestrant (500 mg on day 0, followed by 250 mg intramuscular fulvestrant on days 14 and 28, and monthly thereafter) or the steroidal AI exemestane (Aromasin, Pfizer). EFECT essentially documented equivalence between the study arms; for example, median TTP was 3.7 months in both treatment groups. It is worth noting that FIRST was conducted using endocrine therapy first-line, whereas EFECT employed it as second-line therapy. Finally, the optimal dosing of fulvestrant has been controversial; the results from FIRST

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add weight to the recommendation that fulvestrant should be given intramuscularly at 500 mg (“highdose” schedule).

Everolimus

Based on the hypothesis that endocrine resistance may be associated with activation of the PI3K/AKT pathway, the Phase II TAMRAD (tamoxifen and RAD001everolimus) study investigated everolimus in postmenopausal women who had demonstrated progression while using an AI.4 Prior AI use was considered in the adjuvant setting (31% of patients), the metastatic setting (60%), and both settings (9%). However, all patients were deemed poorly hormone-sensitive in that 91% demonstrated progression either during AI use in the metastatic setting or within 6 months of adjuvant AI use. Patients were stratified by TTP after AI therapy and randomized to receive either tamoxifen or the combination of tamoxifen and everolimus. The combination arm demonstrated a statistically significant superior clinical benefit ratio (CBR), the primary study objective: 42.1% in the tamoxifen arm versus 61.1% in the tamoxifen-everolimus arm. Regarding TTP, a secondary study objective, an exploratory analysis showed improved TTP in the combination arm: 4.5 months in the tamoxifen arm versus 8.5 months in the tamoxifen-everolimus arm. Regarding safety, both treatment arms were well tolerated; grade 3/4 stomatitis was more common in the combination arm (11% vs 0%) and grade 3/4 pain was more common in the tamoxifen arm (19% vs 7%). The results from TAMRAD suggest that everolimus can play a therapeutic role in overcoming endocrine resistance, warranting further investigation in a larger Phase III study.

AMG 479 Based on the hypothesis that combined inhibition of both ER and type 1 insulin-like growth factor receptor (IGF1R) will impede cell proliferation more than targeting either pathway alone, Kaufman et al conducted a randomized Phase II study involving AMG 479, a fully human monoclonal antibody (mAb) that targets IGF1R by inhibiting binding of both IGF-1 and IGF-2.5 This study included postmenopausal woman with advanced breast cancer who had either progressed during prior endocrine therapy or had experienced disease recurrence within 12 months of completing adjuvant endocrine therapy. Study participants were randomized in a 2-to-1 manner to receive either endocrine therapy (exemestane or fulvestrant per investigator’s discretion) with AMG 479 or placebo. The primary study objective was assessment of progression-free survival (PFS). Of the 156 patients enrolled, PFS was 3.9 months in the AMG 479-endocrine therapy arm versus 5.7 months in the placebo-endocrine therapy arm (HR, 1.17; 95% CI, 0.91-1.50; P=0.435), demonstrating statistically equivalent results for PFS. Regarding safety, grade 3/4 adverse events (AEs) were more common in the AMG 479-endocrine therapy arm: hyperglycemia (6% vs 0%), neutropenia (6% vs 2%), thrombocytopenia (4% vs 0%), and increased aspartate

aminotransferase (4% vs 0%). In summary, patients who received AMG 479 with endocrine therapy did not seem to experience clinical benefit beyond that of endocrine therapy alone.

Novel Therapies and Combinations For HER2-Positive Disease Over the past several years, many promising new treatments have been developed to treat HER2-positive advanced breast cancer. Many of the research efforts have focused on developing new therapeutics to overcome resistance to trastuzumab (Herceptin, Genentech).

Pertuzumab In a recent Phase II single-arm study, Baselga et al investigated the combination of trastuzumab, a mAb directed against HER2, and pertuzumab (Genentech), a mAb that binds to the HER2 dimerization domain and prevents binding of HER2 with associated receptors in the HER family (HER1, HER3, and HER4).6 During the study, 66 patients who had received 3 or fewer prior chemotherapy regimens and who had progressed through prior trastuzumab-based therapy were enrolled to receive standard dosing of trastuzumab either weekly (4 mg/kg loading dose, followed by 2 mg/kg) or every 3 weeks (8 mg/kg loading dose, followed by 6 mg/kg) combined with pertuzumab (840 mg loading dose, followed by 420 mg every 3 weeks). In this single-arm study, the overall response rate (ORR) was 24.2%; of the responders, 7.6% experienced complete response and 16.7% had a partial response. An additional 25.8% had stable disease for at least 6 months, corresponding to a CBR of 50%. This combination was generally well tolerated. Cardiac function was monitored rigorously with minimal changes noted; no patients withdrew as a result of cardiac AEs. Further investigation of this combination is under way in the Phase III CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) trial.

Neratinib Neratinib (Pfizer), an orally available irreversible panErbB inhibitor (ErbB 1, 2, and 4), has emerged as another strategy to treat patients whose disease has progressed through prior trastuzumab therapy. In a Phase II trial with a primary objective of 16-week PFS, 2 cohorts of patients, 66 of whom had received prior trastuzumab and 70 of whom had not, were treated with oral neratinib 240 mg daily (Table 1).7 Gastrointestinal AEs were observed, with diarrhea, the most common grade 3/4 AE, occurring in 30% of patients who had received prior trastuzumab and 13% of patients who were trastuzumab-na誰ve. Due to the concern for potential cardiac toxicity, serial monitoring was done to assess left ventricular ejection fraction (LVEF). At baseline, the median LVEFs for patients with and without prior trastuzumab were 62% and 60%, respectively, with median LVEF remaining unchanged at the final study visit. No grade 3/4 cardiac toxicities were reported.

Table 1. Phase II Neratinib Results Prior Trastuzumab (n=66)

No Prior Trastuzumab (n=70)

16-wk PFS, %

Median PFS, wk

22.3

39.6

ORR, %

ORR, overall response rate; PFS, progression-free survival Based on reference 7.

T-DM1 Trastuzumab-DM1 (T-DM1) is an antibody-drug conjugate that targets delivery of the cytotoxic antimicrotubule agent DM1 (maytansine) to HER2-positive cells. During the 2010 European Society for Medical Oncology (ESMO) Congress, Perez et al reported preliminary results of a Phase II trial that randomized 137 patients with HER2-positive advanced breast cancer to firstline treatment with either T-DM1 (3.6 mg/kg IV every 3 weeks) or trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) with docetaxel (75 or 100 mg/m2 IV every 3 weeks) (TD).8 Of note, crossover from the TD arm to the T-DM1 arm was allowed at the time of disease progression. In this preliminary analysis, the authors reported ORR and safety results. Regarding ORR, comparable results were reported, with an ORR of 48% in the T-DM1 arm and 41% in the TD arm. T-DM1 was better tolerated than TD, with rates of grade 3/4 toxicities of 37.3% and 75%, respectively. More complete results, including PFS, CBR, and 1-year overall survival (OS), are expected in the coming year.

Lapatinib With Trastuzumab One common clinical scenario occurs in patients with HER2-positive advanced breast cancer who have progressed through multiple lines of therapy. In a Phase III trial, Blackwell et al randomized 296 patients who had received a median of 3 prior trastuzumab-based therapies to receive lapatinib (Tykerb, GlaxoSmithKline), an oral tyrosine kinase inhibitor (TKI) with activity against ErbB1 (EGFR) and ErbB2 (HER2), with or without trastuzumab.9 For the lapatinib monotherapy arm, the daily dose was 1,500 mg. For the combination arm, the lapatinib dose was 1,000 mg daily and the trastuzumab dose was a 4 mg/kg loading dose, followed by 2 mg/kg weekly. Patients who progressed on the lapatinib-only arm were allowed to cross over to the lapatinib-trastuzumab combination arm. Results were reported based on intention to treat. For the primary objective of this study, PFS, the combination arm was superior; compared with lapatinib alone, there was a 23% relative reduced risk for progression for patients who received combination therapy (HR, 0.75; P=0.008). CBR also was improved in

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Alkylating agents, oxygen radicals, spontaneous reactions, x-rays ➞ DNA damage Single-strand break

Normal cell

BRCA mutation

PARP deficient

BRCA mutation, PARP deficient

DNA repair

Viable cell

Cell death

Figure 1. The effects of BRCA dysfunction and PARP inhibition of cellular repair. BER, base excision repair; HRR, homologous recombination repair; PARP, poly(ADP)-ribose polymerase Adapted from reference 14 with permission. ©2011 UBM Medica. All rights reserved.

the combination arm, at 24.7% versus 12.4% (P=0.01). A nonstatistically significant trend for improved OS was observed in the combination arm (HR, 0.75; 95% CI, 0.53-1.07; P=0.106). There were no differences in ORR. Analyses of tolerability and safety showed that diarrhea was more common in the combination arm, 60% versus 48% (P=0.03). Common AEs for both arms included diarrhea, nausea, fatigue, and rash. Regarding cardiac safety, the incidence of both symptomatic and asymptomatic cardiac events was low. In summary, the combination of lapatinib and trastuzumab has emerged as a treatment option for patients who have experienced disease progression through multiple lines of prior trastuzumab-based therapies. The combination is generally well tolerated and represents a viable non–chemotherapy-based option.

PARP Inhibitors for BRCA-Associated And Triple-Negative Disease Poly(ADP)-ribose polymerase (PARP) inhibition recently emerged as a powerful treatment strategy in both BRCA-deficient advanced breast cancer and is being investigated in triple-negative metastatic breast cancer (TNMBC).10-12 PARP1 is a critical enzyme in DNA repair. Both BRCA deficiency and PARP inhibition impair the cancer cell’s ability to repair DNA; BRCA deficiency impairs homologous recombination, whereas PARP inhibition prevents base excision repair.13 Exposing BRCA-deficient cells to a PARP inhibitor results in synthetic lethality; the combined losses of homologous recombination and base excision repair leads to cell death because the cell cannot repair DNA damage (Figure 1).14

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In 2009, Tutt et al reported results from a Phase II single-arm study investigating the oral PARP inhibitor olaparib (AstraZeneca) in confirmed BRCA1 or BRCA2 carriers with advanced breast cancer who had progressed through a median of 3 prior lines of chemotherapy.10 In this heavily pretreated group of patients, the ORR was 38% and the toxicity of olaparib was limited, with grade 3/4 toxicities consisting of fatigue, nausea, and anemia being reported in a minority of patients. As a proof-of-concept study, these results support the premise that PARP inhibitors may have dramatic impact on the treatment of BRCA-associated breast cancer. BRCA-associated breast cancer shares many molecular features with TNMBC: Both typically are classified in the basal-like intrinsic subtype by genomic analysis, and BRCA-associated breast cancers are typically triple-negative.15 Given these molecular similarities, there has been considerable interest in determining whether the therapeutic benefit of PARP inhibitors in BRCAassociated breast cancer can be translated to TNMBC. In a Phase II trial to test this hypothesis, O’Shaughnessy et al enrolled 123 patients with TNMBC who had previously received 2 or fewer prior lines of chemotherapy in the metastatic setting.11,12 Patients were randomized to receive either gemcitabine 1,000 mg/m2 and carboplatin (GC) to an area under the curve of 2 on days 1 and 8 of a 21-day cycle, or GC with the IV PARP inhibitor iniparib (BSI-201; Sanofi-aventis) at a dose of 5.6 mg/kg on days 1, 4, 8, and 11, of a 21-day cycle (GCI). End points were ORR, CBR, PFS, and OS. Preliminary results of this trial (86 of planned 120 patients) were presented at ASCO 2009,11 and final

results (123 patients) were presented at ESMO 2010.12 Overall, comparing the preliminary results with the final results, the magnitude of difference in the results between the GC and GCI arms is reduced, as reflected by higher but still statistically significant P values. The addition of iniparib to chemotherapy was well tolerated; safety profiles were comparable between the 2 arms. Although these Phase II results were promising, Sanofi-aventis reported in late January that the Phase III randomized trial further investigating this treatment strategy in the same treatment arms failed to meet the prespecified criteria for significance for the primary end points of OS and PFS.16 The company noted, however, that the results of a prespecified analysis in patients treated in the second- and third-line setting did show improvement in OS and PFS that was consistent with the results of the Phase II study. The full Phase III results are expected to be presented at the 2011 ASCO meeting.

Eribulin: A Novel Microtubule Inhibitor Targeting microtubule dynamics of cancer cells is an approach that has been used with many existing cancer therapies, including vinca alkaloids, taxanes, and epothilone B analogs such as ixabepilone (Ixempra, Bristol-Myers Squibb). The newest addition to this general group is eribulin (E7389; Halaven, Eisai), a synthetic analog of the marine sponge halichondrin B (Figure 2). Eribulin inhibits microtubule growth by binding to tubulin and inhibiting microtubule polymerization; this results in cell cycle G2-M arrest.17 In EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus Eribulin E7389), a Phase III open-label study, women with advanced breast cancer who had received 2 to 5 prior chemotherapy regimens (including an anthracycline and a taxane unless contraindicated), with at least 2 of these prior lines of chemotherapy being in the setting of advanced disease, were randomized in a 2-to-1 fashion to receive either eribulin (1.4 mg/m2 IV on days 1 and 8 of a 21-day cycle) or treatment of physician’s

Halichondrin B

choice (TPC).18 The primary objective of this study was analysis of OS with secondary objectives including ORR, PFS, and safety. Median OS was 13.1 months for patients treated with eribulin versus 10.7 months for patients in the TPC group; this corresponds to an overall improvement in OS of 2.5 months (HR, 0.81; 95% CI, 0.66-0.99; P=0.04). Regarding PFS by independent review, the eribulin group had improved PFS, 3.7 months versus 2.3 months, but this difference was not statistically significant (HR, 0.85; 95% CI, 0.70-1.03; P=0.09). Grade 3/4 toxicities associated with eribulin use included fatigue (7.6%), neutropenia (44%), and peripheral neuropathy (8.4%). In summary, this study met the primary objective by demonstrating improved OS with eribulin compared with TPC. One caveat to interpretation of EMBRACE is the nonstandard design using TPC as the control arm. An advantage of this design is that there is no customary accepted sequence of chemotherapy agents to use in the advanced setting. Additionally, this design enabled enrollment of variably but heavily pretreated women with advanced breast cancer. A disadvantage of this design is that it is impossible to compare eribulin with one chemotherapy agent or regimen. The only conclusion to be made is that eribulin outperformed TPC; it is unclear how appropriate TPC was on a patient-by-patient basis.

Antiangiogenic Therapies Sunitinib Sunitinib (Sutent, Pfizer), an orally available multitargeted receptor TKI with activity that inhibits vascular endothelial growth factors (VEGFR1, VEGFR2, VEGFR3) and platelet-derived growth factors (PDGFRα, PDGFRβ), was recently investigated as combination therapy for advanced breast cancer in combination with capecitabine (Xeloda, Genentech) in SUN 1099 and with docetaxel (Taxotere, Sanofi-aventis) in SUN 1064.19,20 SUN 1099 was a multicenter, randomized Phase III

E7389

Figure 2. Structures of marine sponge halichondrin B and eribulin (E7389).

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trial that enrolled 422 women with heavily pretreated advanced breast cancer (2 or more lines of therapy in the advanced setting), who had received prior therapy with both an anthracycline and a taxane in any setting ,to receive either oral capecitabine alone (2,500 mg/ m2 per day, days 1-14 of a 21-day cycle) or combination therapy consisting of oral capecitabine (2,000 mg/m2 per day, days 1-14 of a 21-day cycle) plus oral sunitinib (37.5 mg daily).19 The primary end point of SUN 1099 was PFS, with secondary outcomes of OS and ORR. For all outcomes of interest, the study arms were statistically equivalent; for the capecitabine-alone arm versus the combination therapy arm, the results were as follows: PFS, 5.9 versus 5.5 months; OS, 16.5 versus 16.4 months; ORR, 16.3% versus 18.6%. Regarding safety and tolerability, grade 3/4 AEs (including neutropenia, thrombocytopenia, asthenia, and fatigue) and discontinuation of therapy also were more common in the combination arm. In summary, results from SUN 1099 do not support combined use of capecitabine and sunitinib in the treatment of advanced breast cancer. Whereas SUN 1099 studied women with heavily pretreated advanced breast cancer, SUN 1064 investigated the efficacy of chemotherapy (docetaxel), with or without sunitinib, as first-line therapy for advanced breast cancer.20 SUN 1064 was a Phase III open-label study that randomized 593 patients to either IV docetaxel alone (100 mg/m2 every 3 weeks) or combination therapy with IV docetaxel (75 mg/m2 every 3 weeks) and oral sunitinib (37.5 mg daily on days 2-15 of a 21-day treatment cycle). Of note, if docetaxel was discontinued for any reason other than progressive disease among those in the combination arm, sunitinib could be continued as monotherapy until disease progression. The primary end point, PFS, was not met, with comparable median PFS results of 8.3 months in the docetaxel arm versus 8.6 months in the combination arm. As a secondary end point, OS also was equivalent: 25.5 months in the docetaxel arm versus 24.8 months in the combination arm. However, ORR was significantly improved in the combination arm: 51% versus 39% (P=0.0018). Based on these findings, with superior results seen only for ORR, the authors did not endorse the regimen of docetaxel and sunitinib as a viable option for the first-line treatment of advanced breast cancer.

Avastin E2100 was a Phase III open-label trial that randomized 722 patients to first-line therapy consisting of either weekly paclitaxel alone (90 mg/m2 on days 1, 8, and 15 of a 28-day treatment cycle) or paclitaxel plus bevacizumab (Avastin, Genentech; 10 mg/kg on days 1 and 15).21 E2100 reported significantly improved PFS and ORR in the combination arm: 11.8 versus 5.9 months and 36.9% versus 21.2%, respectively. However, OS was similar between the 2 groups: 26.7 months for the combination and 25.2 months for paclitaxel alone. Based on the results from E2100, specifically a doubling of PFS, bevacizumab was granted accelerated approval in February 2008 for combination use with

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paclitaxel in the treatment of patients with advanced breast cancer. At the time, this original decision had been controversial, with opponents of the approval stating that no improvement in OS was seen with the addition of the drug. Later trials using bevacizumab with chemotherapy in the treatment of advanced breast cancer, including AVADO (AVastin plus Docetaxel) and RIBBON-1 (Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Chemotherapy With or Without Bevacizumab for First-Line Treatment of HER2-Negative Locally Recurrent or Metastatic Breast Cancer), did not replicate the impressive improvement in PFS seen in E2100 and also did not show any improvement in OS.22,23 Based on analysis of these trials, suggesting limited benefit of bevacizumab as well as significant risks associated with its use, such as hypertension, bleeding, perforations, and heart disease, in December 2010 the FDA recommended removing the drugâ&#x20AC;&#x2122;s breast cancer indication. Of note, the FDA does endorse ongoing research to attempt to identify a possible subset of breast cancer patients who may derive more significant benefit from bevacizumab. Ongoing trials examining the use of bevacizumab for breast cancer patients in the neoadjuvant and adjuvant settings will continue.

Treatment for Bony Metastases The most common site of metastasis in advanced breast cancer is bone, with the most serious complications being skeletal-related events (SREs). SREs are defined to include pathologic fracture, the need for radiation or surgery to bone, and spinal cord compression. The most common treatment to prevent complications of bone metastases, including SREs, pain, and hypercalcemia, consists of either oral or IV bisphosphonates, a class of drugs that function by inhibiting osteoclast activity, thereby slowing bone loss. Denosumab (Xgeva, Amgen), a fully human mAb against the receptor activator of nuclear factor-ÎşB ligand (RANKL), uses a completely separate mechanism of action. Tumor cells in the bone release growth factors that activate osteoblasts to release RANKL. Meanwhile, RANKL stimulates osteoclasts to break down bone, and in this destructive process more growth factors are released that promote tumor cell growth. By inhibiting RANKL, denosumab breaks this vicious cycle of bone destruction and tumor cell proliferation (Figure 3).24 In a recent Phase III double-blind, double-dummy trial, Stopeck et al randomized 2,046 patients to either denosumab at a dose of 120 mg subcutaneously every 4 weeks (with IV placebo) or zoledronic acid (Zometa, Novartis) at a dose of 4 mg IV every 4 weeks (with subcutaneous placebo).25 The primary study objective was the time to first on-study SRE, with additional study objectives being time to first and subsequent (multiple) on-study SREs, OS, disease progression, and safety. Denosumab significantly increased the time to first on-study SRE (HR, 0.82; 95% CI, 0.71-0.95; P=0.01), corresponding to an 18% reduced risk compared with zoledronic acid. The median time to first on-study SRE was 26.4 months in the zoledronic acid

Tumor cell

Tumor cell Preosteoclast

PTHrP IL-1, IL-6, IL-8 PGE2 TNF M-CSF

RANK

PTHrP BMP PDGF FGFs IGFs TGF-β

Denosumab RANKL

Differentiation

Tumor cell Osteoclast in apoptosis

Osteoblast RANK

Osteoclast

Denosumab: • Binds to RANKL and neutralizes its activity • Reduces osteoclast activity and bone resorption

Bisphosphonates:

Bone

• Inhibit tumor cell adhesion to bone • Inhibit osteoclast activity • Induce osteoclast apoptosis

Figure 3. Mechanisms of action for denosumab and the bisphosphonates. Tumor cells secrete a number of cytokines and factors that stimulate osteoblast production of RANKL, which binds to RANK on the suface of osteoclasts. This leads to osteoclast differentiation, activation, and survival, creating osteolytic lesions. Bone resorption releases factors such as BMP, PDGF, FGF, IGF, and TGF-β, which, in turn, stimulate production of PTHrP from tumor cells. Agents such as denosumab and bisphosphonates can interrupt this cycle and reduce osteoclast activity. BMP, bone morphogenic protein; FGF, fibroblast growth factors; IGF, insulin-like growth factors; IL, interleukin; M-CSF, macrophage colony-stimulating factor; PGE2, prostaglandin E2; PTHrP, parathyroid hormone-related peptide; RANK, receptor activator of nuclear factor-κB; RANK-L, receptor activator of nuclear factor κB ligand; TGF, transforming growth factor; TNF, tumor necrosis factor Adapted from reference 24 with permission. ©2010 American Society of Clinical Oncology. All rights reserved.

arm, whereas the median time to first on-study SRE has not yet been reached in the denosumab arm. The time to multiple SREs also was superior in the denosumab arm (HR, 0.77; 95% CI, 0.66-0.89; P=0.001), corresponding to a 23% risk reduction. There were no differences noted between the arms with respect to OS or disease progression. Regarding safety, renal AEs and acute-phase reactions were more common with zoledronic acid (8.5% vs 4.9% and 27.3% vs 10.4%, respectively), whereas hypocalcemia was more common with denosumab (5.5% vs 3.4%). Of note, the rates of osteonecrosis of the jaw were comparable between the groups (2% for denosumab and 1.4% for zoledronic acid). The authors conclude that improved time to SREs, comparable tolerance, and the ease of subcutaneous injections with no need for renal monitoring makes denosumab another viable option for treatment of women with advanced breast cancer metastatic to bone.

Conclusions Treatment of advanced breast cancer increasingly is based on defining subgroups of patients who are more likely to respond to a given therapy. In the clinic,

classical markers such as ER, PR, and HER2 status commonly define these subgroups. In the research setting, more advanced genomic techniques, such as intrinsic subtyping, are used to characterize and treat populations of breast cancer patients.15 In the past few years, advances in clinical research have yielded several significant improvements in the care of patients with advanced breast cancer, including new treatment targets and new therapies. Mature results from several of the Phase II trials reviewed above, as well as follow-up Phase III trials, will help define these benefits in larger populations in more detail.

References 1. Amir E, Clemons M, Freedman OC, et al. Tissue confirmation of disease recurrence in patients with breast cancer: pooled analysis of two large prospective studies. J Clin Oncol. 2010:28(15 suppl): Abstract 1007. 2. Robertson JFR, Lindemann JPO, Llombart-Cussac A, et al. A comparison of fulvestrant 500 mg with anastrozole as first-line treatment for advanced breast cancer: follow-up analysis from the “FIRST” study. Presented at: 33rd Annual San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX. Abstract S1-3.

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3. Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor–positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008:26(10):1664-1670, PMID: 18316794. 4. Bachelot T, Bourgier C, Cropet C, et al. TAMRAD: a GINECO randomized phase II trial of everolimus in combination with tamoxifen versus tamoxifen alone in patients (pts) with hormonereceptor positive, HER2 negative metastatic breast cancer (MBC) with prior exposure to aromatase inhibitors (AI). Presented at: 33rd Annual San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX. Abstract S1-6. 5. Kaufman PA, Ferrero JM, Bourgeois H, et al. A randomized, double-blind, placebo-controlled, phase 2 study of AMG 479 with exemestane (E) or fulvestrant (F) in postmenopausal women with hormone-receptor positive (HR+) metastatic (M) or locally advanced (LA) breast cancer (BC). Presented at: 33rd Annual San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX. Abstract S1-4. 6. Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 2010:28(7): 1138-1144, PMID: 20124182. 7. Burstein HJ, Sun Y, Dirix LY, et al. Neratinib, an irreversible erbB receptor tyrosine kinase inhibitor, in patients with advanced erbB2-positive breast cancer. J Clin Oncol. 2010:28(8):1301-1307, PMID: 20142587. 8. Perez EA, Dirix L, Kocsis J, et al. Efficacy and safety of trastuzumabDM1 versus trastuzumab plus docetaxel in HER2-positive metastatic breast cancer patients with no prior chemotherapy for metastatic disease: preliminary results of a randomized, multicenter, open-label phase 2 study (TDM4450G). Ann Oncol. 2010:21(8 suppl): Abstract LBA3. 9. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with erbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010:28(7):1124-1130, PMID: 20124187. 10. Tutt A, Robson M, Garber JE, et al. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer. J Clin Oncol. 2009:27(18 suppl): Abstract CRA501. 11. O’Shaughnessy J, Osborne C, Pippen J, et al. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): results of a randomized phase II trial. J Clin Oncol. 2009:27(18 suppl): Abstract 3. 12. O’Shaughnessy J, Osborne C, Pippen J, et al. Final efficacy and safety results of a randomized phase II study of the parp inhibitor iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple negative breast cancer (TNBC). Ann Oncol. 2010:21(8 suppl): Abstract LBA11.

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13. Carey LA. Directed therapy of subtypes of triple-negative breast cancer. Oncologist. 2010:15(5 suppl):49-56. 14. Comen EA. Inhibition of poly(ADP)-ribose polymerase as a therapeutic strategy for breast cancer. Oncology. 2010;24(1); http://www. searchmedica.com/resource.html?rurl=http%3A%2F%2Fwww.cancernetwork.com%2Fbreast-cancer%2Fcontent%2Farticle%2F10165% 2F1514491&q=comen&c=on&ss=cancerNetworkLink&p=Convera&fr= true&ds=0&srid=3. Accessed January 11, 2011. 15. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000:406(6797):747-752, PMID: 10963602. 16. Sanofi-aventis reports top-line results from Phase III study with BSI-201 in metastatic triple-negative breast cancer. http://en.sanofiaventis.com/binaries/20110127_BSI_en_tcm28-30168.pdf. Accessed February 1, 2011. 17. Jordan MA, Kamath K, Manna T, et al. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther. 2005:4(7):1086-1095, PMID: 16020666. 18. Twelves C, Loesch D, Blum JL, et al. A phase III study (EMBRACE) of eribulin mesylate versus treatment of physician’s choice in patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010;28(15 suppl): Abstract CRA1004. 19. Crown J, Dieras V, Staroslawska E, et al. Phase III trial of sunitinib (SU) in combination with capecitabine (C) versus C in previously treated advanced breast cancer (ABC). J Clin Oncol. 2010;28 (15 suppl): Abstract LBA1011. 20. Bergh J, Greil R, Voytko N, et al. Sunitinib (SU) in combination with docetaxel (D) versus D alone for the first-line treatment of advanced breast cancer (ABC). J Clin Oncol. 2010;28(15 suppl): Abstract LBA1010. 21. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007:357(26):2666-2676, PMID: 18160686. 22. Miles D, Chan A, Romieu G, et al. Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO. J Clin Oncol. 2008;26(15 suppl): Abstract LBA1011. 23. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, doubleblind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). J Clin Oncol. 2009;27(15 suppl): Abstract 1005. 24. Fornier MN. Denosumab: Second chapter in controlling bone metastases or a new book? J Clin Oncol. 2010:28(35):5127-5131, PMID: 21060038. 25. Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010:28(35):5132-5139, PMID: 21060033.

Celebrating Another Successful Year As 2010 came to a close, the McMahon Group took time out to recognize the best of an outstanding group of employees. During 2010, McMahon’s readership scores solidified the best-read status of many of its medical newsmagazines, and sales revenues increased despite a challenging economy. All of which proves yet again that a company powered by talented people will necessarily generate success. In 2010, McMahon’s publishing success was on display in the pages and on the Web sites of its publications and medical education platforms.

2010

Here then is a look at the winners of the 2010 employee awards.

SUPPORT/PRODUCTION/IT/FINANCE PERSONS OF THE YEAR:

GRAPHIC DESIGNER OF THE YEAR:

Employees were asked to pick the two most outstanding members from these four departments. The winners were MARTIN BARBIERI, production manager, for his dedication to his publications; and MARIELLA SINDONI, financial accounts receivable, for her ability to round up stray dollars.

GABRIEL BERLIN won the award in recognition for his creative approach as art director for Gastroenterology & Endoscopy News, as well as his design work on several medical education and custom media projects.

ACE PERSON OF THE YEAR: There is a strict firewall separating those who work in our CME division, Applied Clinical Education—but not for voting. The 2010 winner was GEORGE OCHOA, whose ability to research, write and edit sometimes dense medical information, and do it by tomorrow, is legendary.

NEWSMAGAZINE EDITOR OF THE YEAR: The 2010 winner was ADAM MARCUS, managing editor of Anesthesiology News. Adam’s pursuit of important stories led him to break several well before the competition, including a few of national importance.

PERSON OF THE YEAR

MOST IMPROVED SALESPERSON OF THE YEAR:

SPECIAL PROJECTS EDITOR OF THE YEAR:

In a crowded field of sales excellence, it can be difficult to stand out, but MATT SPOTO managed to do just that, honing his skills while working as account manager on Gastroenterology & Endoscopy News.

Despite first-rate competition, MEGAN BLOCK, managing editor, won the award for her superb work creating custom media of various kinds, including custom newsletters and podcasts.

SALES ACHIEVEMENT AWARD:

SALESPERSON OF THE YEAR:

JULIANNA DAWSON, publication director of Clinical Oncology News, was the 2010 winner in this category. Julianna sets herself up for success by working long hours for her clients.

Whereas their peers vote for the other award winners, this award is never subject to a vote. It’s a fact, not an opinion: The salesperson who brings in the most revenue receives this award. For a record-breaking fifth year in a row, the winner was RICHARD TUORTO, senior group publication director for Anesthesiology News and Pain Medicine News.

PARTNERS AWARD

PERSON OF THE YEAR 2010:

PARTNERS SPECIAL RECOGNITION AWARD 2010:

Representing the very best of the best, the 2010 Person of the Year was KEVIN HORTY, editor of General Surgery News. With Kevin at the helm of GSN, readership scores have enjoyed a steady climb skyward, and with these advancing numbers has inevitably come increased revenue. Kevin has concentrated on making the editorial he oversees fully relevant to the complicated world of today’s general surgeon, and the reward has been a publication that is, by far, better than ever.

The partners of McMahon Publishing occasionally present an award to someone who has contributed to the success of the company over many years of service. This year’s winner was GARY SMITH, CEO of Fairfield (Conn.) County Bank (FCB), for his decades-long financial service. FCB financed all of the company’s expansions over the years. “Gary has been a great partner in helping the family and staff grow this company from a start-up to a major medical publisher,” said Ray McMahon, CEO. “Gary will retire from FCB in June; we wish him the best and have appreciated his wise counsel over many years.”

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Overview of Frontline Therapy for

Metastatic Colorectal Cancer Mebea Aklilu, MD Assistant Professor, Hematology & Oncology Comprehensive Cancer Center Wake Forest Baptist Health Wake Forest University Health Sciences Winston-Salem, North Carolina

Cathy Eng, MD, FACP Associate Professor Department of Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

olorectal cancer (CRC) is the third most common cancer in the

United States and remains the second most common cause of cancer-related death, with 142,570 new cases of CRC and

51,370 CRC-related deaths estimated for 2010.1 In the past decade, the introduction of several new drugs and the results of pivotal clinical trials have transformed the management paradigm of metastatic CRC.

Traditionally, the treatment of metastatic CRC consisted of 5-fluorouracil (5-FU) monotherapy, which yielded a 10% to 15% response rate and a 10-month median overall survival (OS).2,3 The addition of cytotoxic chemotherapy (irinotecan and oxaliplatin) to the 5-FU backbone led to encouraging tumor responses and OS results, providing additional treatment options. The addition of molecular-targeted agents to combination cytotoxic agents has further altered the treatment landscape of metastatic CRC. The increasing therapeutic effectiveness has led to more patients with incurable disease being able to achieve palliation with therapy and more patients previously considered to have incurable

C L I N I C A L O N C O L O GY N E W S S P E C I A L E D I T I O N 2 0 1 1

disease being able to receive therapy with a curative intent. This review describes the pivotal trials that have established our present standards for frontline treatment of metastatic CRC.

Combination Cytotoxic Chemotherapy Initial explorations in combination cytotoxic chemotherapy evaluated the addition of irinotecan to the 5-FU backbone. The results of 3 Phase III trials established the superiority of this combination over 5-FU alone (Table 1).4-6 The trials differed in the way the 5-FU was given (bolus vs bolus plus 24-hour infusion vs bolus plus two 22-hour infusions), but they all demonstrated

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an 18% to 19% improvement in response rate (RR) and a 2- to 3-month improvement in OS with the addition of irinotecan. The use of irinotecan with bolus 5-FU (IFL) was associated with a greater 60-day mortality, mainly because of a syndrome characterized by diarrhea, neutropenia, and sepsis.7 The use of infusional 5-FU with irinotecan (FOLFIRI) avoided this risk and became accepted as the preferred regimen of the combination. The oxaliplatin and 5-FU combination was explored in 2 published Phase III trials (Table 1).8,9 One looked at the addition of oxaliplatin to chronomodulated 5-FU, while the other trial looked at the addition of oxaliplatin to infusional 5-FU (FOLFOX). These trials demonstrated 28% and 37% improvements in RR and approximately 3-month improvements in progression-free survival (PFS; P=0.048 and P=0.0003 for oxaliplatin/infusional 5-FU and oxaliplatin/chronomodulated 5-FU, respectively), but no statistically significant improvement in median OS was seen (P=not significant and P=0.12, respectively). Although diarrhea was more frequent in the oxaliplatin-treated arms, the most common dose-limiting toxicity was neuropathy, which increased in frequency when cumulative doses above 540 mg/m2 were given.10 The Phase III GI Intergroup N9741 trial compared IFL with FOLFOX and IROX (every 3 weeks combination of irinotecan and oxaliplatin).11 When FOLFOX was compared with IFL, RR (45% vs 31%; P=0.002), time to progression (TTP; 8.7 vs 6.9 months; P=0.0014), and OS (19.5 vs 15 months; P=0.0001) all favored FOLFOX. However, some argued that the comparison was flawed because FOLFOX was compared with IFL rather than FOLFIRI. Tournigand et al reported the results of a Phase III trial of FOLFOX followed by FOLFIRI at progression versus FOLFIRI followed by FOLFOX at progression (Table 1).12 There was no statistical difference in terms of RR (54% vs 56%; P=not significant), PFS (8 vs 8.5 months; P=0.26) or OS (20.6 vs 21.5 months; P=0.99). There were differences in toxicity, with more frequent grade 3/4 mucositis, nausea and vomiting, and grade 2 alopecia with FOLFIRI, and more frequent grade 3/4 neutropenia and neurotoxicity with FOLFOX. Thus, at present both sequences are deemed equally efficacious for frontline therapy, but they have differing toxicity profiles.

Choice of Fluoropyrimidine For Combination Therapy In the single-agent setting, infusional 5-FU provides a small (1-month) but real survival advantage over bolus 5-FU,13 and when combined with irinotecan, infusional 5-FU consistently has demonstrated improved OS and toxicity compared with bolus 5-FU.5,6 This has led to the uniform adoption of infusional 5-FU as the fluorouracil backbone of combinational therapy. The oral fluoropyrimidine capecitabine (Xeloda, Roche) was compared with bolus 5-FU in 2 large Phase III trials and resulted in improved RR, tolerability, and ease of administration but no OS benefit.14,15 This led to trials that tried to substitute capecitabine for fluorouracil in combinational therapy.

Table 1. Cytotoxic Combinational Chemotherapy Trials RR, %

PFS/ TTP, mo

OS, mo

Infusional 5-FU

4.4a

14.1

FOLFIRI

6.7

17.4

Infusional 5-FU

6.0

14.7

FOLFOX

9.0

16.2

Chronomodulated 5-FU

6.1

19.9

Chronomodulated 5-FU/oxaliplatin

8.7

19.4

IFL

6.9a

15.0

FOLFOX

8.7

19.5

AIO 5-FU

6.1

16.9

AIO/5-FU/irinotecan

8.5

20.1

Bolus 5-FU

4.3

12.6

IFL

7.0

14.8

FOLFIRI

8.5

21.5

FOLFOX

8.0

20.6

Author/Regimen Douillard et al

DeGramont et al9

Giacchetti et al8

Goldberg et al11

Kohne et al

Saltz et al6

Tournigand et al

Trial reported TTP not PFS.

AIO, weekly 24-h infusion of 5-FU; FOLFIRI, leucovorin/5-FU/irinotecan; FOLFOX, leucovorin/5-FU/oxaliplatin; 5-FU, 5-fluorouracil; OS, overall survival; PFS, progression-free survival; TTP, time to progression

Several Phase II trials have explored the capecitabine and irinotecan combination (CAPIRI/XELIRI). They reported RRs ranging from 35% to 61%, TTP of 6.6 to 9.2 months, and median OS of 17 to 25 months, but the toxicity of this combination was significant, with grade 3/4 diarrhea reported in 19% to 28% of patients and grade 3/4 neutropenia in 5% to 25%.16-18 The Phase III BICC-C trial studied the safety and efficacy of 3 irinotecan-containing regimens窶認OLFIRI, modified IFL, and CAPIRI (Table 2). Patients also were randomized to celecoxib or placebo. FOLFIRI showed statistically significant improvement in PFS over modified IFL and CAPIRI (7.6 vs 5.9 vs 5.8 months; P=0.004 and P=0.015, respectively), translating into a numerical, but not statistically significant, improvement in OS (23.1 vs 17.6 vs 18.9 months; P=0.09 and P=0.27, respectively). CAPIRI was associated with significantly higher rates of severe diarrhea, vomiting, and dehydration. This led to a protocol amendment that discontinued the CAPIRI arm.19 Capecitabine also has been explored in combination

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Table 2. Trials Evaluating Different Fluoropyrimidines Trial/Regimen

RR, %

PFS/TTP, mo

OS, mo

FOLFIRI

—

7.6

23.1

mIFL

—

5.9 (P=0.004)

16.6 (P=0.09)

CAPIRI

—

5.8 (P=0.015)

18.9 (P=0.27)

CAPOX

—

8.0

19.8

FOLFOX

—

8.5 (HR, 1.04; 92.5% CI, 0.93-1.16)

19.6 (HR, 0.99; 92.5% CI, 0.88-1.12)

BICC-C (period 1)19

N01696625

TREE (Phase II study)24 FOLFOX

—

19.2

Bolus 5-FU/ oxaliplatin

—

17.9

CAPOX

—

17.2

CAPIRI, capecitabine/irinotecan; CAPOX, capecitabine/oxaliplatin; HR, hazard ratio; FOLFIRI, leucovorin/5-FU/irinotecan; FOLFOX, leucovorin/5-FU/oxaliplatin; 5-FU, 5-fluorouracil; mIFL, irinotecan/bolus 5-FU/leucovorin; OS, overall survival; PFS, progression-free survival; RR, response rate; TTP, time to progression

with oxaliplatin (CAPOX/XELOX) and found to have similar results to FOLFOX. The results of several Phase II trials that explored different capecitabine schedules reported response rates of 42% to 55% and median OS of 19.5 to 20 months, confirming the activity of the regimen.20-23 TREE-1 (Three Regimens of Eloxatin Evaluation) was a randomized Phase II study exploring the safety and efficacy of 3 oxaliplatin combinations—FOLFOX, bolus 5-FU and oxaliplatin, and CAPOX.24 Following the approval of bevacizumab, the study later was amended to include bevacizumab (TREE-2). The results of the TREE-1 cohort showed RRs of 41%, 20%, and 27%, respectively. OS for the TREE-1 cohort was 19.2, 17.9, and 17.2 months for FOLFOX, bolus 5-FU and oxaliplatin, and CAPOX, respectively. Of those in the CAPOX arm, 31% had grade 3/4 diarrhea and 27% had grade 3/4 dehydration, which led to the reduction of the dose of the capecitabine (from 1,000 to 850 mg/m2 twice daily, days 1-14, repeated every 21 days) in the TREE-2 cohort, resulting in improved tolerance in that study. N016966 was an international Phase III trial initially designed to explore the noninferiority of CAPOX to FOLFOX. It was later amended to be a 2 × 2 analysis of patients assigned to either CAPOX or FOLFOX, and then to bevacizumab or placebo.25 In the pooled CAPOX-alone arms, the median PFS was 8, versus 8.5 months in the pooled FOLFOX-alone arms (hazard ratio [HR], 1.04; 97.5% confidence interval [CI], 0.93-1.16), and the median OS was 19.8 vs 19.6 months, respectively

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(HR, 0.99; 97.5% CI, 0.88-1.12). FOLFOX was associated with more grade 3/4 neutropenia and febrile neutropenia and CAPOX had more grade 3 diarrhea and hand– foot syndrome. What appears clear is that the tolerance of capecitabine is different in the United States than in Asia and Europe. It is uncertain if the differences are based on dietary variables or are the result of underlying differences in genetic polymorphisms that alter the pharmacokinetics of the drug in varying populations. Based on these tolerance issues, routine use of CAPIRI in the United States should be discouraged. CAPOX is a reasonable alternative to FOLFOX, but has differing toxicity profiles that warrant attention when selecting patients.

Antiangiogenic Therapy Vascular endothelial growth factor (VEGF) has been shown to be an important proangiogenic protein and a viable target for drug development. Bevacizumab is a monoclonal antibody that targets VEGF, and its role in the treatment of metastatic CRC has been refined through a series of randomized clinical trials (RCTs) (Table 3).24,26-28 The initial 3-arm Phase II study by Kabbinavar et al compared bolus 5-FU with 2 different doses of bevacizumab (5 and 10 mg/kg every 2 weeks) in combination with bolus 5-FU.28 The arm containing 5 mg/kg of bevacizumab produced a doubling of the RR (P=0.029) and an approximately 4-month improvement in PFS (P=0.005). This result led to the pivotal AVF 2107 Phase III trial, conducted by Hurwitz et al.27 This initially was a 3-arm trial, comparing the efficacy of IFL with or without bevacizumab. The third arm of bolus 5-FU plus bevacizumab was closed early after planned interim analysis showed no increase in toxicity of IFL plus bevacizumab. The addition of bevacizumab increased RRs from 34.8% to 44.8% and increased TTP from 6.3 to 10.6 months (P=<0.001). The median survival also improved from 15.6 with IFL alone to 20.3 months with the combination (P<0.001). Of note, this is likely the last metastatic CRC frontline randomized trial in which OS can serve as a surrogate marker of efficacy. The commercial availability of several drugs and use of subsequent lines of therapy make PFS a more reliable surrogate of efficacy. After data from the Hurwitz trial became available, the BICC-C trial (discussed earlier) had a second phase; it became a 2-arm trial of FOLFIRI/bevacizumab and modified IFL/bevacizumab after the CAPIRI arm was discontinued because of toxicity. Analysis of these data revealed that the FOLFIRI/bevacizumab arm had a median survival of 28 months, versus 19.2 months in the modified IFL/bevacizumab arm (P=0.007).26 The addition of bevacizumab to oxaliplatin-based chemotherapy was explored in the TREE and N016966 trials. The TREE study (discussed earlier) had a protocol amendment that accrued a sequential cohort of patients (TREE-2) with the 3 oxaliplatin-containing

Table 3. Selected Studies Evaluating Angiogenesis Inhibitors Trial/Regimen

RR, %

PFS/TTP, mo

OS, mo

34.8

6.2

15.6

AVF 2107

IFL IFL/bevacizumab

44.8 (P=0.004)

10.6 (P<0.001)

20.3

Bolus 5-FU/bevacizumab

40.0 (P=0.66)

8.8 (P=0.4192)

18.3 (P=0.2521)

BICC-C (period 2)26 FOLFIRI/bevacizumab

—

28.0

CAPIRI/bevacizumab

—

19.2 (P=0.037)

5.2

13.8

Kabbonavar et al28 Bolus 5-FU Bolus 5-FU/bevacizumab 5 mg/kg

40 (P=0.029)

9.0 (P=0.005)

21.5

Bolus 5-FU/bevacizumab 10 mg/kg

24 (P=0.434)

7.2 (P=0.217)

16.1

FOLFOX or CAPOX

19.9

FOLVOX/CAPOX + Bev

38 (P=0.99)

9.4 (P=0.0023)

21.3 (P=0.077)

N01696629

TREE-2 (Phase II study)24 FOLFOX/Bev

—

26.1

Bolus 5-FU/oxaliplatin/bevacizumab

—

20.4

CAPOX/bevacizumab

—

24.6

CAPIRI, capecitabine/irinotecan; CAPOX, capecitabine/oxaliplatin; FOLFIRI, leucovorin/5-FU/irinotecan; FOLFOX, leucovorin/5-FU/oxaliplatin; 5-FU, 5-fluorouracil; IFL, irinotecan/5-FU/leucovorin; OS, overall survival; PFS, progression-free survival; RR, response rate; TTP, time to progression

regimens—FOLFOX, bolus 5-FU/oxaliplatin, and CAPOX—plus bevacizumab.24 The addition of bevacizumab to any of the 3 arms generally resulted in a 10% improvement in RR and increased TTP by 2 months. The median OS for FOLFOX, bolus 5-FU/oxaliplatin, and CAPOX in TREE-2 were 26.1, 20.4, and 24.6 months, respectively. In comparison, during the TREE-1 period, median OS was 19.2, 17.9, and 17.2 months, respectively. Saltz et al conducted the analysis of the second portion of the N016966 trial (discussed earlier).29 They looked at the addition of bevacizumab or placebo to the oxaliplatin-containing regimens (FOLFOX or CAPOX) and found that bevacizumab led to similar RRs (38%), an increase in PFS from 8 to 9.4 months (P=0.0023), and a nonsignificant increase in median OS (21.3 vs 19.9 months; P=0.077). One possible explanation for the less-than-impressive survival benefit was that a majority of patients (71%) stopped all treatment for nonprogressive events, which were primarily oxaliplatin-related neurotoxicity.

Epidermal Growth Factor Receptor Epidermal growth factor receptor (EGFR) and its associated downstream signaling pathways are important in the maintenance of several characteristics displayed by neoplastic cells and are felt to be an important therapeutic target.30 Cetuximab (chimeric immunoglobulin G1 [IgG1] antibody) and panitumumab (fully humanized IgG2 antibody) both target EGFR with high

affinity. The results of a pivotal randomized Phase II study (BOND [Bowel Oncology and Cetuximab Antibody]) demonstrating the ability of cetuximab to overcome chemotherapy resistance led to a series of Phase II/III studies exploring the role of EGFR inhibitors in the frontline treatment of metastatic CRC (Table 4).31 The Phase III CRYSTAL (Cetuximab combined with iRinotecan in first line therapY for metaSTatic colorectAL cancer), Phase II OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer), and Phase II SAKK (Swiss Group for Clinical Cancer Research) trials were randomized studies that examined the addition of cetuximab to frontline treatment with FOLFIRI and FOLFOX. In the CRYSTAL trial, the addition of cetuximab increased RR (38.7% vs 46.9%; P=0.004) and PFS (8 vs 8.9 months; P=0.048) but resulted in no statistically significant improvement in OS (18.6 vs 19.9 months; P=0.31).32 In the OPUS trial, the addition of cetuximab to FOLFOX improved the RR (36% vs 46%; P=0.064) but had no impact on PFS (7.2 vs 7.2 months; P=0.62).33 The SAKK trial was a small study looking at the addition of cetuximab to CAPOX. This trial noted an improvement in RRs (14% vs 41%), PFS (5.8 vs 7.2 months), and median OS (16.5 vs 20.5 months).34 These trials supported the clinical activity of cetuximab, but the clinical benefit appeared modest at best. Data indicating that KRAS-mutant (MT) tumors are resistant to cetuximab therapy35 led to a retrospective analysis of the outcomes in CRYSTAL and OPUS with

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Table 4. Selected Studies Evaluating EGFR Inhibitors Trial/Regimen

RR, %

PFS/TTP, mo

OS, mo

FOLFIRI

38.7

8.0

18.6

FOLFIRI/cetuximab WT

46.9 (P=0.004)

8.9 (P=0.048)

19.9 (P=0.31)

FOLFOX

7.2

—

FOLFOX/cetuximab

46 (P=0.064)

7.2 (P=0.62)

—

FOLFIRI KRAS

43.2

8.7

21.0

FOLFIRI/cetuximab WT

59.3 (P=0.0025)

9.9 (P=0.02)

24.9 (HR 0.84; 95% CI, 0.64-1.1)

FOLFIRI KRAS

40.2

8.1

17.7

FOLFIRI/cetuximab MT

36.2 (p=0.46)

7.6 (P=0.75)

17.5 (HR 1.03; 95% CI, 0.74-1.44)

FOLFOX KRAS

7.2

—

FOLFOX/cetuximab WT

61 (P=0.011)

7.7 (P=0.0163)

—

FOLFOX KRAS

8.6

—

FOLFOX/cetuximab MT

33 (P=0.106)

5.5 (P=0.0192)

—

FOLFOX/CAPOX KRAS

8.6

17.9

FOLFOX/CAPOX + cetuximab WT

64 (P=0.049)

8.6

17.0 (P=0.68)

FOLFOX KRAS

8.0

19.7

FOLFOX/panitumumab WT

9.6 (P=0.02)

23.9

FOLFOX KRAS

—

8l8

—

FOLFOX/panitumumab MT

—

2.3 (P=0.02)

—

CRYSTAL (unselected)

OPUS (Phase II study, unselected)33

CRYSTAL32

OPUS (Phase II study)

MRC COIN37

PRIME

CI, confidence interval; FOLFIRI, leucovorin/5-FU/irinotecan; FOLFOX, leucovorin/5-FU/oxaliplatin; HR, hazard ratio; MT, mutant type; OS, overall survival; PFS, progression-free survival; RR, response rate; TTP, time to progression; WT, wild-type

respect to KRAS mutation status. In the CRYSTAL study, for those who were KRAS wild-type (WT), the addition of cetuximab to FOLFIRI led to an improvement in RR (43.2% vs 59.3%; P=0.0025) and PFS (8.7 vs 9.9 months; P=0.02) but no statistical difference in the median OS (21 vs 24.9 months; HR, 0.84; 95% CI, 0.64-1.11).32 The investigators subsequently released an update of their data showing that with longer follow-up, the addition of cetuximab led to an improvement in OS that was statistically significant (20 vs 23.5 months; P=0.0094).36 For patients who had KRAS-MT tumors, the addition of cetuximab had no impact on RR, PFS, or OS. Similarly, in the OPUS study, the addition of cetuximab to FOLFOX in patients with KRAS-WT tumors resulted in an improvement in RR (37% vs 61%; P=0.011) and PFS (7.2 vs 7.7 months; P=0.0163).33 For the KRAS-MT tumors, the addition of cetuximab led to a decrease in RR (49% vs 33%; P=0.106) and a worsening in PFS (8.6 vs 5.5 months; P=0.0192). The UK Medical Research Council (MRC)/COIN (Combination Chemotherapy With or Without Cetuximab as First-Line Therapy in Treating Patients With Metastatic

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Colorectal Cancer) study explored the addition of cetuximab to CAPOX or FOLFOX (investigator’s choice) in patients with untreated metastatic CRC.37 For the KRAS-WT group, the addition of cetuximab resulted in an improvement in RR (50% vs 59%; P=0.049) but no improvement in PFS (8.6 vs 8.6 months; P=0.60) or OS (17.9 vs 17 months; P=0.68). There were no differences seen in RR, PFS, or OS with the addition of cetuximab to the KRAS-MT population. Panitumumab also has been explored in frontline therapy of metastatic CRC. PRIME (Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) was a randomized Phase III trial of FOLFOX with or without panitumumab.38 The findings were similar to those of cetuximab-based frontline trials with FOLFOX. In the KRAS-WT population, the addition of panitumumab led to an improvement in RR (48% vs 55%; P=0.068) and PFS (8 vs 9.6 months; P=0.02), as well as a numeric difference in OS that was not statistically significant (19.7 vs 23.9 months; P=0.072). For the KRAS-MT population,

Table 5. Studies Evaluating Dual VEGF and EGFR Inhibitors Trial/Regimen

RR, %

PFS/TTP, mo

OS, mo

Irinotecan/cetuximab/bevacizumab

7.3a

14.5

Cetuximab/bevacizumab

4.9

11.4

FOLFOX/bevacizumab unselected

11.4

24.5

FOLFOX/bevacizumab + panitumumabw

10.0 (HR, 1.27; 95% CI, 1.06-1.52)

19.4 (HR, 1.43; 95% CI, 1.11-1.83)

FOLFIRI/bevacizumab unselected

11.7

20.5

FOLFIRI/ bevacizumab + panitumumab

10.1 (HR, 1.19; 95% CI, 0.29-1.29)

20.7 (HR, 1.42; 95% CI, 0.77-2.62)

BOND-2 (Phase II study)

PACCE41

FOLFOX/bevacizumab KRAS

11.5

24.5

FOLFOX/bevacizumab + panitumumab WT

9.8 (HR, 1.36; 95% CI, 1.04-1.77)

20.7 (P=0.45)

FOLFIRI/ bevacizumab KRAS

12.5

19.8

FOLFIRI/bevacizumab + panitumumab WT

10.0

FOLFOX/bevacizumab KRAS

19.3

FOLFOX/bevacizumab + panitumumab MT

10.4

19.3

FOLFIRI/bevacizumab KRAS

11.9

20.5

FOLFIRI/bevacizumab + panitumumab MT

8.3

12.8

CAIRO-242

CAPOX/ bevacizumab unselected

10.7

20.3

CAPOX/ bevacizumab + panitumumab

52.7 (P=0.49)

9.4 (P=0.01)

19.4 (P=0.16)

CAPOX/ bevacizumab KRAS

50.0

10.6

22.4

CAPOX/ bevacizumab + panitumumab WT

61.4 (P=.06)

10.5 (P=0.030)

21.8 (P=0.64)

CAPOX/ bevacizumab KRAS

59.2

10.5

24.9

CAPOX/ bevacizumab + panitumumab MT

45.9

8.1 (P=0.003)

17.2 (P=0.03)

TTP reported

CAPOX, capecitabine/oxaliplatin; EGFR, endothelial growth factor receptor; FOLFIRI, leucovorin/5-FU/irinotecan; FOLFOX, leucovorin/5-FU/oxaliplatin; HR, hazard ratio; MT, mutant type; OS, overall survival; PFS, progression-free survival; RR, response rate; TTP, time to progression; VEGF, vascular endothelial growth factor; WT, wild-type

the addition of panitumumab produced no difference in RR (40% vs 40%; P=0.98), but there appeared to have been a worsening in PFS (8.8 vs 7.3 months; P=0.02) and OS (19.3 vs 15.5 months; P=0.068). KRAS has demonstrated its ability to serve as a predictive biomarker of response for EGFR-targeted agents. Generally, anti-EGFR antibodies only are offered to patients with KRAS-WT tumors. The results of RCTs suggest that there may be a negative interaction between oxaliplatin and anti-EGFR antibodies and that irinotecan may be a better partner. Recent provocative data from De Roock et al question the validity of treating all KRAS-mutated tumors in a similar fashion.39 The KRAS mutation is found in 30% to 50% of CRC, commonly in codons 12, 13, and 61 (in decreasing order of incidence). De Roock et al conducted a retrospective pooled analysis of 579 patients with chemotherapy-refractory metastatic CRC treated with cetuximab and found that

patients with a mutation in codon 13 (p.G13d, n=32) had a longer PFS (4 vs 1.9 months; P=0.004) and OS (7.6 vs 5.7 months; P=0.005) compared with patients with other KRAS-mutated tumors. There was no difference in PFS or OS between KRAS-WT tumors and those that had the p.G13d mutation. The study was limited by the small sample size of the p.G13d group and the retrospective nature of the analysis. It will require further validation in an adequately powered trial before routine implementation of EGFR inhibitors in this population can be recommended.

Dual Therapy With Targeted Agents The activity of VEGF and EGFR inhibitors naturally led to exploration of regimens incorporating dual VEGF and EGFR blockade in metastatic CRC (Table 5). The results of the randomized Phase II BOND-2 trial in irinotecan-refractory metastatic CRC demonstrated that

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dual biologic inhibition improved the RR, PFS, and OS in the irinotecan/cetuximab plus bevacizumab arm as well as the cetuximab and bevacizumab arm.40 Patients had received a median of 3 lines of prior therapy. This trial was unique because the investigational arm of combined biologic therapy without cytotoxic therapy resulted in an impressive RR of 20%. The preliminary results of BOND-2 served as the impetus for the creation of 2 large Phase III trials exploring the benefit of dual inhibition for patients with metastatic CRC. The PACCE (Panitumumab Advanced Colorectal Cancer Evaluation) trial explored the addition of panitumumab to FOLFOX or FOLFIRI plus bevacizumab in KRAS-unselected metastatic CRC, with the end point limited to patients treated with FOLFOX.41 The addition of panitumumab to FOLFOX resulted in statistically significant worsening of PFS and OS. When the results were analyzed based on KRAS status, similar results were seen. Similar, but less pronounced, findings were seen in the FOLFIRI-based population. CAIRO2 also explored the role of dual inhibition. 42 Patients with unselected metastatic CRC were treated with CAPOX/ bevacizumab with or without the addition of cetuximab. This trial also reported a significantly worse PFS in the arm treated with cetuximab and no benefit with respect to RR or OS. Surprisingly, unlike in BOND-2, in the PACCE and CAIRO2 trials, combined biologic therapy added to the cytotoxic chemotherapy backbone appeared to result in a detrimental outcome. As a result, the CALGB (Cancer and Leukemia Group B) 80405 study was amended to exclude KRAS-MT tumors as well as dual biologic inhibition with bevacizumab and cetuximab (Figure).43 At present, there are no data to support the routine use of dual VEGF and EGFR inhibition in metastatic CRC, but as investigators identify more predictive biomarkers, a subset of patients with metastatic CRC who would benefit from dual inhibition with other biologic agents might be uncovered.

Alternative Treatment Schedules Pooled analysis from several clinical trials suggested that there was an association with improved outcome with exposure to all active agents in metastatic CRC.44 Investigators began to explore alternative treatment schedules that questioned sequential versus combination therapy, as well as duration of exposure to key chemotherapy agents. The MRC FOCUS (Fluorouracil, Oxaliplatin and Irinotecan: Use and Sequencing) trial explored different sequential and combination chemotherapy regimens for patients with untreated metastatic CRC (N=2,135).45 Patients on strategy A were treated with 5-FU monotherapy, followed by single-agent irinotecan at progression (control arm). Strategy B patients were treated with 5-FU monotherapy, followed by FOLFOX or FOLFIRI at progression. Strategy C patients were treated with FOLFOX or FOLFIRI. The median OS for strategy A patients was 13.9 months; the median OS for strategy B patients were

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15.2 and 15 months for FOLFOX and FOLFIRI, respectively; the median OS for strategy C patients were 15.4 and 16.7 months for FOLFOX and FOLFIRI, respectively. Logrank comparison of each group demonstrated superiority only for patients treated on strategy C with FOLFIRI (P=0.01). Comparison of strategies B and C demonstrated noninferiority (HR, 1.06; 95% CI, 0.97-1.17). Quality-of-life analysis revealed no significant differences between the 3 approaches. The original CAIRO study explored a similar question.46 Patients were assigned to either capecitabine followed by irinotecan followed by CAPOX, or CAPIRI followed by CAPOX. Despite improvements in RR or PFS in favor of up-front combinational therapy, there was no difference in median OS, which was 16.3 months for sequential treatment and 17.4 months for combination treatment (P=0.3281). Quality-of-life analysis suggested a decrease in all functional domains in the combination arm. Results from FOCUS and CAIRO challenged the paradigm of combination therapy for all patients and suggested that an alternative option is warranted for some patients. However, neither trial included biologic agents, and in the FOCUS trial, only 23% of patients received all available cytotoxic agents. Sequential therapy is not accepted as a routine standard option for all patients, but it is a viable alternative. The criteria to select patients who would benefit from sequential treatment is not defined. Generally, those patients who present with potentially resectable disease, are symptomatic, or have a heavy tumor burden appear more appropriate for up-front combination therapy. A review conducted by Folprecht et al demonstrated an association between RR to neoadjuvant chemotherapy and the rate of liver resection with curative intent.47 Furthermore, there is consistent evidence that exposure to all 3 active cytotoxic drugs can result in a greater fraction of patients undergoing secondary surgery on metastasis. But, with less-intense chemotherapy schedules, fewer patients are receiving subsequent lines of therapy. The Gruppo Oncologico Nord Ovest conducted a Phase III trial comparing infusional 5-FU, oxaliplatin, and irinotecan (FOLFOXIRI) with FOLFIRI.48 FOLFOXIRI resulted in an improved RR (60% vs 34%; P=0.0002). The clear resection margin (R0 stage) rate was greater in the FOLFOXIRI arm overall (15% vs 6%; P=0.033) and in those with only liver disease (36% vs 12%; P=0.017). Treatment with FOLFOXIRI improved PFS (9.8 vs 6.9 months; P=0.0006) and OS (22.9 vs 16.7 months; P=0.032) when compared with FOLFIRI alone. This trial highlights the concept of dose intensification as a treatment option for select patients. With increased use of oxaliplatin-based frontline chemotherapy, the development of cumulative neuropathy associated with prolonged exposure to oxaliplatin is a concern. One strategy that addresses this problem is the stop-and-go approach that has gained popularity as a result of the OPTIMOX (Optimized LV-5FU-Oxaliplatin Strategy in Metastatic Colorectal Cancer) studies. The

OPTIMOX1 study randomized patents to FOLFOX until progression or FOLFOX for 6 cycles, 5-FU/leucovorin maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX.49 There was no difference between the 2 arms with respect to RR (58.5% vs 58.2%), PFS (9 vs 8.7 month; P=0.47), and OS (19.3 vs 21.2 months; P=0.49 for the continuous and intermittent arms, respectively). Grade 3 neuropathy was observed in 17.9% of those treated continuously versus 13.3% of those in the intermittent arm. Of note, only 40.1% of patients in the intermittent arm were able to have oxaliplatin reintroduced. OPTIMOX2 was a follow-up randomized Phase II study that evaluated planned complete chemotherapy discontinuation.50 Patients were randomized to receive 6 cycles of FOLFOX followed by 5-FU monotherapy until progression, or 6 cycles of FOLFOX before a complete discontinuation of all chemotherapy, with reintroduction of FOLFOX after tumor progression in both arms. The primary end point was duration of disease control, which was 13.1 months in those assigned to the maintenance arm versus 9.2 months (P=0.046) for those who took a planned chemotherapy holiday. Similarly, both PFS (8.6 vs 6.6 months) and OS (23.8 vs 19.5 months) were worse for those who discontinued all chemotherapy. There was no difference in RR between the 2 arms (59.2% vs 59.6%). Based on these results, prolonged chemotherapy breaks with no treatment cannot be recommended.

Conclusion The past decade has significantly altered the treatment paradigm of metastatic CRC. The proliferation of active agents and the emergence of predictive biomarkers has made the management of CRC quite complex. 5-FU remains the backbone of cytotoxic chemotherapy, and infusional 5-FU or capecitabine are the preferred agents. Irinotecan and oxaliplatin are equally efficacious agents in combination with 5-FU in the frontline therapy of metastatic CRC. The addition of bevacizumab to cytotoxic chemotherapy has improved outcomes compared with chemotherapy alone. However, the magnitude of benefit appears modest at best in modern clinical trials using optimal chemotherapy platforms. Similarly, EGFR inhibition appears to have a modest benefit in the frontline setting. More importantly, the development in predictive biomarkers such as KRAS has helped identify those who would potentially not benefit from EGFR inhibition. There are still a large number of patients with KRASWT tumors who do not respond to EGFR inhibition, and identification of additional predictive markers is greatly needed to minimize exposure to ineffective chemotherapy. There are no reliable predictive markers to help select those who may benefit from VEGF-targeted agents. The progress in the treatment of metastatic CRC is encouraging, but challenges remain for patients with surgically incurable disease. Trials with novel approaches and agents that attempt to minimize toxicity and improve efficacy are urgently needed. Additional

biologic markers will continue to be identified and used to aid in treatment decisions. However, the underlying biology of CRC is complex and heterogenous, making it one of the most interesting malignancies for clinical research at this time.

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38. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28(31):4697-4705, PMID: 20921465. 39. De Roock W, Jonker DJ, Di NF, et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA. 2010;304(16):1812-1820, PMID: 20978259. 40. Saltz LB, Lenz HJ, Kindler HL, et al. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol. 2007;25(29):4557-4561, PMID: 17876013. 41. Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009;27(5):672-680, PMID: 19114685. 42. Tols J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360(6):563-572, PMID: 191966731. 43. NCT00265850. Cetuximab and/or bevacizumab combined with combination chemotherapy in treating patients with metastatic colorectal cancer. http://www.clinicaltrials.gov/ct2/show/NCT0026 5850?term=NCT00265850&rank=1. Accessed April 14, 2011. 44. Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line. J Clin Oncol. 2005;23(36):9441-9442, PMID: 16361649. 45. Seymour MT, Maughan TS, Ledermann JA, et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007;370(9582):143-152, PMID: 17630037. 46. Koopman M, Antonini NF, Douma J, et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007;370(9582):135-142, PMID: 17630036. 47. Folprecht G, Grothey A, Alberts S, Raab HR, Kohne CH. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol. 2005;16(8):1311-1319, PMID: 15870084. 48. Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007;25(13):1670-1676, PMID: 17470860. 49. Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 2006;24( 3):394-400, PMID: 16421419. 50. Chibaudel B, Maindrault-Goebel F, Lledo G, et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol. 2009;27(34):57275733, PMID: 19786657.

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