Clinical Oncology News - January 2010 - Digital Edition

McMahon Publishing

Advances in Cancer Care CLINICALONCOLOGY.COM • JANUARY 2010 • Vol. 5, No. 1

SUPPORTIVE CARE

5

ESA restrictions may be pushing up transfusion rates.

HEMATOLOGIC DISEASE

10

Jennifer Brown, MD, highlights news from the ASH meeting.

SOLID TUMORS

17

Cathy Eng, MD, discusses practice-changing colon cancer news from recent international meeting.

25 26

Adding sorafenib to chemotherapy improves PFS in metastatic breast cancer.

Bendamustine-R Is Potential New Standard New Orleans—A large, Phase III multicenter study has revealed that the combination of bendamustine (Treanda, Cephalon) and rituximab (Rituxan, Biogen Idec/Genentech) is better tolerated and more effective than the current standard of CHOP-R (cyclophosphamide, hydroxydaunorubicin, vincristine and prednisone plus rituximab) for the treatment of indolent lymphomas and mantle cell lymphoma. The greater efficacy was somewhat unexpected; the researchers had anticipated similar efficacy with greater tolerability.

“These promising results suggest that the combination of bendamustine and rituximab [bendamustine-R] has the potential to become the new standard, first-line treatment option for patients with these non-Hodgkin’s lymphoma see BENDAMUSTINE-RITUXAN, page 16

TS biomarker ready for routine clinical application in NSCLC. FDA NEWS

28

For Indolent Lymphomas\MCL:

FDA approves Arzerra for CLL, Istodax for CTCL and Elitek for plasma uric acid control.

EDUCATIONAL REVIEW

Gastrointestinal Stromal Tumors What Oncologists Need To Know About the Treatment of Localized and Advanced Disease After page 24.

WWW.CMEZONE.COM

Promising Homeopathy For Mucositis Fails Trial Alternative Medicine Trials Fraught With Challenges

San Antonio—The combination therapy of trastuzumab (Herceptin, Genentech) and lapatinib (Tykerb, GlaxoSmithKline) improves overall survival by 20 weeks compared with lapatinib alone in women with

reported at the recent San Antonio Breast Cancer Symposium (SABCS; abstract 61).

“This is the first time that someone has shown that continuing Herceptin through progression and adding a second type of anti-HER2 therapy

HER2-positive metastatic breast cancer (MBC) who have progressed on therapy with trastuzumab.

Survival was roughly 60 weeks in the combination arm and 40 weeks in the lapatinibonly arm. This news comes from a study

leads to a survival improvement compared with just moving to another drug and eliminating the trastuzumab, so it really validates the concept that trastuzumab is an important drug to see ONE-TWO PUNCH, page 24

POLICY & MANAGEMENT

New York—Despite a previously published pilot study that had positive outcomes, an alternative medicine for mucositis called traumeel was shown to be ineffective in children in a multicenter, double-blind trial conducted by the Children’s Oncology Group (COG). The study was a rare effort to subject alternative medicines, which are now widely used by cancer patients, to the same rigorous, evidence-based examination used for conventional treatments.

According to Edward Chu, MD, chief of medical oncology and director of clinical research at Yale Cancer see MUCOSITIS, page 6

Trastuzumab Plus Lapatinib Lands Strong One-Two Punch

Hospitals May Be Letting Crucial Drug Pricing Tool Rust Rosemont, Ill.—Results from a national survey indicate that many hospitals are not properly managing a drug pricing tool, which may lead to inadequate reimbursement. In a national survey, more than one-half of hospitals said they reviewed and changed line-item drug products on their pricing lists quarterly or less often. Nearly onethird (28%) reported reviewing the list only once annually. Lax updating of the

list, known as a hospital pharmacy charge master, can result in reduced reimbursement that not only hurts health-systems individually, but can also trigger artificially low national pay rates set by the Centers for Medicare & Medicaid Services (CMS), according to lead investigator Christine A. Pierce, a partner in The Resource Group, a reimbursement consulting firm based see DRUG PRICING, page 30

New Product Istodax approved for CTCL. See page 28.

EASTON, PA PERMIT #117

PAID PRSRT STD U.S. POSTAGE

IMPORTANT SAFETY INFORMATION BOXED WARNINGS

Additional Safety Information, Continued

Cardiotoxicity, infusion reaction, myelosuppression, liver impairment, substitution ◗ The use of DOXIL may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2 — Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose — Cardiac toxicity may also occur at lower cumulative doses (400 mg/m2) in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy ◗ Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/ or hypotension have occurred in up to 10% of patients treated with DOXIL. In most patients, these reactions have resolved within several hours to a day once the infusion is terminated. In some patients, reactions resolved with slowing of the infusion rate — Serious and sometimes life-threatening or fatal allergic/ anaphylactoid-like infusion reactions have occurred.

Medications to treat such reactions, as well as emergency equipment, should be available for immediate use — The initial rate of infusion should be 1 mg/min to minimize the risk of infusion reactions ◗ Severe myelosuppression may occur ◗ DOXIL dosage should be reduced in patients with impaired hepatic function ◗ Accidental substitution has resulted in severe side effects.

Do not substitute for doxorubicin HCl on a mg per mg basis

blood count (including platelet count), at least prior to each dose of DOXIL — In patients with multiple myeloma, hematologic toxicity (based on platelet count, absolute neutrophil count, hemoglobin level, or neutropenia with fever) may require dose reduction, delay in administration, or suspension of DOXIL and/or VELCADE — Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage — Sepsis occurring during neutropenia has resulted in discontinuation of treatment and in rare cases of death ◗ DOXIL may potentiate the toxicity of other anticancer therapies, especially hematologic toxicities, when used in combination with other therapies that suppress bone marrow ◗ Hand-foot syndrome (HFS) may occur during therapy with DOXIL — Based on HFS toxicity grade, dose reduction, delay in administration, or discontinuation of DOXIL may be required — HFS was generally observed after 2 to 3 cycles of treatment, but may occur earlier • The reaction was mild in most patients, resolving in 1 to 2 weeks • The reaction can be severe and debilitating in some patients, resulting in discontinuation of therapy ◗ DOXIL is an irritant, not a vesicant; use precautions to avoid extravasation ◗ DOXIL can cause fetal harm when used during pregnancy ◗ Recall reaction has occurred with DOXIL administration after radiotherapy ◗ DOXIL may interact with drugs known to interact with the conventional formulation of doxorubicin HCl ◗ In patients with multiple myeloma, the most common all-grade adverse reactions ≥20% (VELCADE plus DOXIL vs VELCADE, respectively) included: neutropenia (36% vs 22%), thrombocytopenia (33% vs 28%), anemia (25% vs 21%), fatigue (36% vs 28%), pyrexia (31% vs 22%), asthenia (22% vs 18%), nausea (48% vs 40%), diarrhea (46% vs 39%), vomiting (32% vs 22%), constipation (31% vs 31%), mucositis/stomatitis (20% vs 5%), peripheral neuropathy (42% vs 45%), neuralgia (17% vs 20%), and rash (22% vs 18%) — In addition, 19% vs <1% reported HFS

Contraindications ◗ Patients with a history of hypersensitivity reactions to a

conventional doxorubicin formulation or the components of DOXIL ◗ Nursing mothers

Additional Safety Information ◗ Cardiac function should be carefully monitored

— Congestive heart failure or cardiomyopathy may occur after discontinuation of anthracycline therapy — For patients with a history of cardiovascular disease, or if the results of cardiac monitoring indicate possible cardiac injury, the benefit of therapy must be weighed against the risk of myocardial injury — In the randomized multiple myeloma study, 25 patients (8%) in the VELCADE for Injection arm and 42 patients (13%) in the VELCADE plus DOXIL arm experienced left ventricular ejection fraction decrease (defined as absolute decrease ≥15% over baseline or a ≥5% decrease below institutional lower limit of normal)

◗ Myelosuppression may occur; frequently monitor complete

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, on adjacent pages.

Distributed by: Centocor Ortho Biotech Products, L.P., Horsham, Pennsylvania 19044-3607 © Centocor Ortho Biotech Products, L.P. 2009 Printed in U.S.A. 10/09 08DM09002 405041

In Multiple Myeloma*...

Turn to VELCADE With DOXIL For a Statistically Significant Increase in Time to Progression vs VELCADE Alone

VELCADE

VELCADE + DOXIL

6.5 Months Median TTP a

9.3 Months Median TTPa

(95% CI: 5.6, 7.1) (n=322)

(95% CI: 8.2, 11.1) (n=324)

*DOXIL in combination with VELCADE® (bortezomib) is indicated for the treatment of patients with multiple myeloma who have not previously received VELCADE and have received at least one prior therapy.

Study Design A 43% increase in median TTP when DOXIL was combined with VELCADE— a statistically significant increase (P<.0001)

Percentage of Patients Progression-Free

100 90

Randomized, open-label, international, multicenter study (N=646) of patients with multiple myeloma who had not previously received VELCADE and whose disease progressed during or after at least 1 prior therapy. The primary endpoint was time to progression (TTP). Patients were randomized (1:1 ratio) to receive either DOXIL (30 mg/m2 as a 1-hour IV infusion) administered on Day 4 following VELCADE (1.3 mg/m2 IV bolus on Days 1, 4, 8, and 11) or VELCADE alone (1.3 mg/m2 IV bolus on Days 1, 4, 8, and 11). Treatment was administered every 3 weeks. Patients were treated for up to 8 cycles until disease progression or the occurrence of unacceptable toxicity. Patients who maintained a response were allowed to receive further treatment. The median number of cycles in each treatment arm was 5 (range, 1–18).

80 70

VELCADE + DOXIL

VELCADE

60

(n=324)

(n=322)

50 40 30 N=646 P<.0001b HR=0.55 c 95% CI 0.43 to 0.71

20 10 0

6.5

0

8

a

12

15

TTP (Months)

Number of Subjects at Risk

VELCADE + DOXIL 324 VELCADE 322

9.3

4

301 290

269 253

201 189

170 150

127 112

97 84

70 56

56 35

38 25

19 14

13 9

6 2

4 1

2 1

0 0

Kaplan-Meier estimate.

Stratified log-rank test. c HR based on stratified Cox proportional-hazards regression. An HR <1 indicates an advantage for VELCADE + DOXIL. b

Please see Important Safety Information, including Boxed WARNINGS, on previous page.

SUPPORTIVE CARE

CLINICAL ONCOLOGY NEWS • JANUARY 2010

Anemia

ESA Restrictions May Be Pushing Up Transfusion Rates Rosemont, Ill.—Recent restrictions on erythropoietin-stimulating agents (ESAs) may be increasing blood transfusion rates, according to two recent studies.

According to the studies presented at the recent American Society of Health-System Pharmacists meeting, centers in Maryland and New Jersey have seen increases in the rates of blood transfusions in cancer patients with anemia ever since label changes and reimbursement cutbacks were implemented for ESAs. Investigators at these and other centers fear that the full effect of the 2007 ESA restrictions on transfusion rates has not yet been seen and that centers need to take a closer look at their own rates.

In Maryland, John DiBona, PharmD, corporate director of pharmacy at Lifebridge Health, Sinai Hospital of Baltimore, conducted a retrospective study of transfusion rates in cancer patients before and after implementation of the August 2007 Medicare National Coverage Determination (NCD) restricting coverage for ESAs. The study focused on inpatient and outpatient visit and billing data and laboratory results for all cancer patients treated from Aug. 1, 2005 through Aug. 31, 2008, at the hospital. The researchers assessed chemotherapy episodes for two pre-NCD periods as well as one post-NCD period. Outcome measures included ESA use and number of blood transfusions.

The results showed that ESA restrictions had a significant effect on the use of the growth factors: In the two time periods studied before the restrictions were put in place, ESAs were given to 75.4% and 80.9% of patients

TM

undergoing chemotherapy. After the restrictions took effect, only slightly more than half (50.4%) of patients were prescribed ESAs, the investigators reported (P<0.0001).

Additionally, with the decrease in ESA rates came a corresponding increase in the rate of transfusions (21% before the NCD vs. 31% afterward; P<0.05).

The increase from 21% to 31% “is not a huge jump, but if you look at it in relative terms, it is almost onethird,” Dr. DiBona said. He acknowledged that the data are limited to his center and he doesn’t know for sure “whether [the results are] externally valid.” But he expressed concern that if the data were in fact generalizable, “and you extrapolated the one-third increase across the country, that is a huge amount of blood use.”

Dr. DiBona further speculated that his study may underestimate the impact of the NCD on transfusion rates because, in the wake of the same adverse events related to increased hematocrits that led to the NCD, prescribers may have become “a little bit skittish about bringing hematocrits up.” That hesitation may have

Gastrointestinal Cancer Edward Chu, MD Cathy Eng, MD

ADVISORY BOARD Bioethics Joseph P. DeMarco, PhD Paul J. Ford, PhD

Michael J. Fisch, MD, MPH John W. Finnie, MD

Hematologic Malignancies Jennifer R. Brown, MD, PhD Agnes Y.Y. Lee, MSc, MD

Betty Ferrell, RN, PhD

Pharmacy Polly E. Kintzel, PharmD Melvin E. Liter, MS, PharmD

Policy and Management Mary Lou Bowers, MBA Barbara Constable, RN, MBA Rhonda M. Gold, RN, MSN

Solid Tumors Bone Metastases

Robin B. Weisberg, Manager, Copyediting Services Elizabeth Zhong, Associate Copy Chief

Gastrointestinal Cancer and Sarcoma

SALES STAFF

Ephraim Casper, MD

Thomas Ciriacks, Group Publication Director thomasc@mcmahonmed.com

Genitourinary Cancer Gynecologic Cancer Maurie Markman, MD

Lung, and Head and Neck Cancers Edward S. Kim, MD

Lung Cancer, Emesis Richard J. Gralla, MD

Richard Stone, MD

Oncology Nursing

see RESTRICTIONS, page 15

Leonard Saltz, MD

Ronald M. Bukowski, MD

Community Oncology

persisted even regarding patients undergoing transfusions instead of ESA therapy, he noted. If that is the case, Dr. DiBona said, the one-third increase in the rate of blood transfusions would be even more significant in light of the downward effect that a possible increased clinical threshold for transfusions would have exerted on the transfusion rate.

At the New Jersey center, investigators conducted a study focused on the NCD’s influence on the use of the ESA darbepoetin alfa (Aranesp, Amgen). Robert T. Adamson, PharmD, and his colleagues at Saint Barnabas Health Care System, in South Plainfield, retrospectively evaluated patients who were admitted as inpatients during Nov. 1, 2006 through Jan. 31, 2008, and had received a dose of darbepoetin for chemotherapy-induced anemia as outpatients four weeks or less before hospitalization. End points for the study included inpatient and outpatient darbepoetin utilization patterns. The investigators evaluated darbepoetin use before and after four darbepoetin-related events occurred between March and July 2007: Darbepoetin labeling was changed to include a black box warning; a medication reconciliation program was initiated at Saint Barnabas; the FDA’s Oncology Drug Advisory Committee reviewed the drug; and the NCD was implemented.

The investigators reviewed the hospital database and found 726 patients who fit the inclusion criteria and were included in the analysis. Whereas there was a

Infection Control Susan K. Seo, MD, Director

Symptom Control and Palliative Care William S. Breitbart, MD Steven D. Passik, PhD Joseph V. Pergolizzi Jr., MD Russell K. Portenoy, MD Charles F. von Gunten, MD

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Allan Lipton, MD

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Breast Cancer

James Prudden, Group Editorial Director

Andrew Seidman, MD Maura N. Dickler, MD

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SUPPORTIVE CARE

CLINICAL ONCOLOGY NEWS • JANUARY 2010

Mucositis

MUCOSITIS continued from page 1

Center, New Haven, Conn., research groups that want to test botanical herbal medicines in clinical trials face unique challenges because many of these medicines are complex agents. Generally, standard Western anticancer therapies consist of a single active agent that must be titrated into a therapeutic window in which the agent is both tolerable and active. In contrast, the large majority of therapies derived from botanicals are made up of multiple components for which the composition ratio may be critical.

“The agent in the study conducted by the COG has at least 14 different ingredients that may be important for the activity of the agent. In approaching these agents, ensuring the consistency of the source and preparation is challenging but essential for an adequate test of clinical efficacy,” said Dr. Chu, who was not involved with the study. He said one explanation for the highly positive pilot study and the negative multicenter study is that the second study used a version of traumeel that was in fact quite different from the original.

The trial had one of the most rapid accruals in the history of COG, presumably because of interest in alternative therapies for mucositis.

of benefit in mucositis, for which no therapy has been particularly effective, provided the justification for a large study of traumeel.

Rigorous Testing of Homeopathies Although the lack of benefit from traumeel was a disappointing first attempt by COG to validate complementary therapies in oncology, the fact that COG even conducted a clinical trial with the agent is a big thing in itself. “With lots of scientific soul searching, COG did agree that it should become involved in testing alternative medicines, not least because so many patients are taking them,” said Susan F. Sencer, MD, medical director of Hematology/Oncology at Children’s Hospitals and Clinics of Minnesota in Minneapolis, who led the study of traumeel. Presenting the results of the study at the recent annual meeting of the Society for Integrative Medicine in New York City, Dr. Sencer reported that traumeel was a reasonable candidate for study in a large multicenter trial because there was abundant evidence that the drug is safe; there was preliminary evidence of efficacy from a controlled pilot study; and current treatments of mucositis offer little benefit.

Traumeel is considered a complex homeopathic agent, because it is a combination of defined and measurable ingredients that are believed to act together to exert its effect. This therapy has been widely used by homeopathists to treat a variety of indications, particularly inflammatory diseases. A controlled trial demonstrating the efficacy of traumeel in mucositis was published in a peer-reviewed journal in 2001 (Cancer 2001;92:684-690, PMID: 11505416). Although this study randomized only 32 patients, it was double-blinded and used an objective scoring system to compare efficacy of the homeopathy with placebo. In the study, traumeel reduced the risk for mucositis by almost 30% (67% vs. 93%) and prevented the likelihood that those who had mucositis would develop a more severe case by roughly 50% (47% vs. 93%).

The interest in traumeel after this study was published led the National Cancer Institute (NCI) to fund the COG study to see if these results could be replicated. Although Dr. Sencer acknowledged that she was not initially receptive to the idea of conducting a study of an alternative medicine, she and others participating in COG have accepted that such therapies, now used in up to 90% of cancer patients, deserve to be studied when there is at least some existing support for efficacy and safety. The published evidence

Study Details In the COG study, 190 patients at 26 participating centers in several countries were randomized to receive either traumeel or placebo. Patients between the ages of 3 and 25 years receiving a myeloablative regimen for stem cell transplantation were eligible.

The primary outcome was the severity of mucositis as measured with the World Health Organization (WHO) scoring system, which was used in the previous trial, and with a scoring system developed by the COG. Secondary outcomes included narcotic use and need for total parenteral nutrition. On their assigned therapy, patients were required to rinse their mouth vigorously for 30 seconds before swallowing. This was repeated five times per day, and patients were told to avoid food or drink for 30 minutes after each dose.

One explanation for the highly positive pilot study and the negative multicenter study is that the second study used a version of traumeel that was in fact quite different from the original.

Although Dr. Sencer noted that the trial had one of the most rapid accruals in the history of COG, presumably because of interest in alternative therapies for mucositis, compliance with the regimen proved to be difficult; 66 patients dropped out before the study was completed. Dropouts occurred as frequently on

placebo as on active treatment. Although the patients remaining in the study provided adequate power to detect a difference, none was found. This was true of both the primary and secondary end points except for a small and nonsignificant trend for reduced narcotic use in the traumeel group. Post-hoc analyses in which patients were stratified by varying levels of compliance also failed to show any advantage of traumeel.

“We looked at the data at all angles and really did not find any difference,” Dr. Sencer said.

Trials Are Complicated According to Dr. Chu, testing homeopathies in clinical trials is more complicated than testing standard drugs. “The importance of the complexity of botanical and traditional medicines is not very well understood by those used to working with standard pharmaceuticals,” said Dr. Chu, who has been active in evaluating traditional Chinese medicines for cancer care. Ensuring the composition of a homeopathy is difficult. He emphasized that quality control is a major issue, but he and others have had success in establishing highly sophisticated chemical and biologic fingerprint profiling methodologies to ensure consistency across batches. With his colleagues at Yale Cancer Center, Dr. Chu has conducted a series of pilot studies with a particular Chinese herbal medicine called PHY906, and they have demonstrated promising efficacy as a modulator of chemotherapy-induced toxicities in several gastrointestinal cancers.

“I think the FDA feels uncomfortable with agents that have more than six active components. At our center, we are looking at a Chinese herbal medicine that is made up of four main herbs. However, using a very sensitive LC-MS [liquid chromatography-mass spectrometry] method, we have now identified at least 64 individual molecules contained within these four main herbs, which highlights the complexity of these herbal medicines,” Dr. Chu said. He believes the FDA may come to accept the complex composition of alternative agents, but he still expects the agency to insist on a rigorous analysis capable of providing characterization of the herbal formulation to ensure that it is reproducible. Dr. Chu believes these drugs should be subjected to the same types of rigorous clinical trials that have established the safety and efficacy of traditional Western therapies.

Because of the difficulties of compliance and inadequate information about appropriate dose, traumeel was not proven inactive in the COG study. Instead, the study conclusion was that it cannot be considered an evidence-based therapy for mucositis in children, according to Dr. Sencer. However, despite these disappointing results, Dr. Sencer said that COG will undertake clinical studies of other alternative agents if pilot studies provide an expectation of efficacy and safety.

“COG is committed to the study of any therapy that will improve management of pediatric cancer,” said Dr. Sencer, who characterized the large, controlled studies as “the final common pathway” for establishing the clinical viability of treatments in cancer. Dr. Chu did not disagree, but he suggested that lack of understanding of the nature of these therapies combined with baseline skepticism increases the likelihood of failed trials. He suggested that the study of these botanical medicines requires a different approach that places an emphasis on recognizing and preserving the active ingredients. He believes this field is highly promising, but consistent results across trials require that the quality and consistency of the study agent be initially established.

—Ted Bosworth

APPROVED for first-line metastatic NSCLC and first- and second-line MCRC

Raising the survival standard as observed in pivotal Phase III trials1-4 First-line

First-line

Second-line

NSCLC

MCRC

MCRC

Primary Endpoint: OS

Primary Endpoint: OS

Primary Endpoint: OS

10.3 12.3 months months

15.6 20.3 months months

10.8 13.0 months months

vs

Chemotherapy*

Avastin + chemotherapy*

19%

vs

Chemotherapy*

Avastin + chemotherapy*

30%

vs

Chemotherapy*

Avastin + chemotherapy*

20%

increase†

increase†

increase†

P=0.013 Study E4599

P<0.001 Study 2107

P=0.001 Study E3200

Avastin is recognized by the NCCN‡ as a standard of care for appropriate patient types in combination with first-line IV chemotherapy5,6

*Chemotherapy regimens with Avastin-based therapy: Study E4599, paclitaxel/carboplatin; Study 2107, IFL; Study E3200, FOLFOX4. † Difference statistically significant. Hazard ratios (HRs) for survival: Study E4599, HR=0.80; Study 2107, HR=0.66; Study E3200, HR=0.75. ‡ National Comprehensive Cancer Network.

Indications Avastin, in combination with carboplatin and paclitaxel, is indicated for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer.

Avastin, in combination with intravenous 5-fluorouracil–based chemotherapy, is indicated for first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum.

Boxed WARNINGS and additional important safety information Gastrointestinal (GI) perforation: Avastin administration can result in the development of GI perforation, in some cases resulting in fatality.

GI perforation, sometimes associated with intra-abdominal abscess, occurred throughout treatment with Avastin. Permanently discontinue Avastin therapy in patients with GI perforation.

Wound healing complication: Avastin administration can result in the development of wound dehiscence, in some instances resulting in fatality.

Permanently discontinue Avastin therapy in patients with wound dehiscence requiring medical intervention. The appropriate interval between termination of Avastin and subsequent elective surgery has not been determined.

Hemorrhage: Severe, and in some cases fatal, pulmonary hemorrhage can occur in patients with NSCLC treated with chemotherapy and Avastin.

Do not administer Avastin to patients with recent hemoptysis (≥1/2 tsp of red blood). Permanently discontinue Avastin in patients with serious hemorrhage and initiate aggressive medical management.

Additional serious adverse events included non-GI fistula formation, arterial thromboembolic events, hypertensive crisis, reversible posterior leukoencephalopathy syndrome, neutropenia and infection, nephrotic syndrome, and congestive heart failure.

The most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events that may have occurred in Avastin indications (first-line NSCLC, first- and second-line MCRC) included neutropenia, fatigue, hypertension, infection, hemorrhage, asthenia, abdominal pain, pain, deep vein thrombosis, intra-abdominal thrombosis, syncope, diarrhea, constipation, leukopenia, nausea, vomiting, dehydration, ileus, neuropathy–sensory, neurologic–other, and headache.

Please see following brief summary of Prescribing Information, including Boxed WARNINGS, for additional safety information.

References: 1. Avastin Prescribing Information. Genentech, Inc. March 2008. 2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550. 3. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342. 4. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544. 5. The NCCN Colon Cancer Clinical Practice Guidelines in Oncology (Version 1.2008). ©2007 National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org. Accessed February 8, 2008.

To view the most recent and complete version of the guideline, go online to www.nccn.org. 6. The NCCN Non-Small Cell Lung Cancer Clinical Practice Guidelines in Oncology (Version 2.2008). ©2008 National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org. Accessed February 8, 2008. To view the most recent and complete version of the guideline, go online to www.nccn.org.

©2008 Genentech, Inc.

All rights reserved.

9146400

Printed in USA.

www.avastin.com

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), and Adverse Reactions (6.1).]

Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), and Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

1.2 Non-Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

1.3 Metastatic Breast Cancer (MBC) Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel.

The effectiveness of Avastin in MBC is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).]

Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

1.4 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease following prior therapy as a single agent.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).]

1.5 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.

Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]

Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.

The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).]

Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%–5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

5.4 Non-Gastrointestinal Fistula Formation Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%.

Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuation of Avastin.

Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days,although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]

5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy.

Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection.

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57).

[See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]

5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

[See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

[See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to Avastin in 2661 patients with mCRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin.

[See Clinical Studies (14).] The population was aged 21-88 years (median 59), 46.0% male and 84.1% white.The population included 1089 first- and second-line mCRC patients who received a median of 11 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin.

Surgery and Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy.Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding In Study 7, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with and resolved without medical intervention. Grade 1 or 2 hemorrhagic gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic Events The incidence of Grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving chemotherapy following a venous thromboembolic event. Among these patients, an additional The overall incidence of Grade 3–4 venous thromboembolic events in following Grade 3–4 venous thromboembolic events was higher in intra-abdominal venous thrombosis (10 vs. 5 patients).

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%.

Proteinuria Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See Warnings and Precautions (5.8).]

Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.

All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving presented in Table 1.

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AVASTIN® (bevacizumab) Table 1 NCI-CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

NCI-CTC Grade 3-4 Events Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra-Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa a

Arm 1

Arm 2

(n = 396) 74%

(n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

Central laboratories were collected on Days 1 and 21 of each cycle.

Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who Table 2 NCI-CTC Grade 1-4 Adverse Events in Study 1 Arm 1

Arm 2

Arm 3

(n = 98)

(n = 102)

(n = 109)

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6%

52% 43% 40% 32% 24% 24%

47% 35% 29% 30% 17% 19%

2% 1%

7% 6%

4% 1%

Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

0%

5%

5%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

9%

14%

21%

24%

36%

36%

Avastin in Combination with FOLFOX4 in Second-line mCRC Only Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events) occurring at 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used in Study 2.

Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/ pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).

Metastatic Breast Cancer (MBC) Only Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events were collected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs.

3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs.

0.3%) and proteinuria (3% vs. 0%).

Sensory neuropathy,hypertension,and fatigue were reported at a ≥ 5% higher absolute incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm. plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/hypotension (2).

Avastin is not approved for use in combination with capecitabine or for use in second or third line treatment of MBC.The data below are presented to provide information on the overall safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, controlled study in which all adverse events were collected for all

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AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

patients. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease.Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3.

Table 3 NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)

may be influenced by several factors, including sample handling, timing of

Asthenia Headache Pain Cardiovascular Hypertension Digestive Stomatitis Metabolic/Nutrition Musculoskeletal Myalgia Respiratory Dyspnea Epistaxis Skin/Appendages Exfoliative dermatitis Urogenital Albuminuria

Capecitabine (n = 215)

Capecitabine + Avastin (n = 229)

47% 13% 25%

57% 33% 31%

2%

24%

19%

25%

8%

14%

18% 1%

27% 16%

75%

84%

7%

22%

Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan.Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.

In patients receiving Avastin alone (N=84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%).Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of Avastin-related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%).The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving α) plus Avastin compared to 304 patients receiving α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).

Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving α α plus placebo arm are presented in Table 4.

Table 4 NCI-CTC Grades 1−5 Adverse Events in Study 9 α α + Placebo) Preferred term* Gastrointestinal disorders Diarrhea General disorders and administration site conditions

α (n = 304) 16%

α + Avastin (n = 337)

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin.

However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

In Study 9, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]

Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Because of the observed teratogenic effects of known inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.

8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.

21%

Investigations Metabolism and nutrition disorders Anorexia Musculoskeletal and connective tissue disorders Myalgia Back pain Nervous system disorders Headache Renal and urinary disorders Proteinuria Respiratory, thoracic and mediastinal disorders Epistaxis Dysphonia Vascular disorders Hypertension

reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS Digestive: Intestinal necrosis, mesenteric venous occlusion, anastomotic ulceration Hemic and lymphatic: Pancytopenia Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia

31%

36%

14% 6%

19% 12%

16%

24%

3%

20%

4% 0%

27% 5%

9%

28%

*Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5-fold greater incidence in the α α alone and not represented in Table 4: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

6.2 Immunogenicity As with all therapeutic proteins,there is a potential for immunogenicity.The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected.

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay.Additionally, the observed incidence of antibody positivity in an assay

greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]

In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether the overall adverse events profile was different in the elderly as compared with younger patients.

Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.

In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age.The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs.

2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

Manufactured by: Genentech, Inc. 94080-4990

7453214 4835706 © 2009 Genentech, Inc

C

urious about how much the National Institutes of Health is spending this year on cancer research in Arkansas? Until now, finding out would have involved searching a litany of difficult-to-navigate databases scattered across the agency’s 27 institutes and centers.

No longer. The NIH has launched a new Web site, RePORTER (project reporter.nih.gov), that offers visitors a single access point for data on the agency’s spending. Users can search by keyword, institute, investigator name, dollar amount, Congressional district—handy for seeing which legislators are best able to bring home the biomedical bacon—and other categories. The site also links to PubMed, PubMed Central and the U.S. Patent & Trademark Office, so users can look up the published findings of particular projects they have searched for.

“With the addition of RePORTER, we have taken a big step toward providing NIH’s broad community of stakeholders—including biomedical researchers, research administrators, science policy makers and members of the general public—with richer information, accessible in a form designed to meet their diverse set of needs,” said Sally Rockey, PhD, acting deputy director of extramural research for NIH, in a statement.

The site is housed on the NIH’s RePORT Web site (www.report.nih.gov), which in September replaced the agency’s previous repository of grant information, CRISP.

Where do you go? ✪

If you recall seeing an in-depth review of a topic but no longer have a hard copy?

✪

If you heard about an interesting piece from a colleague?

✪

If you see an installment from a multipart series but wish to see the other parts?

Clinicaloncology.com

9

10

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CLINICAL ONCOLOGY NEWS • JANUARY 2010

Multiple Cancers

Expert Highlights Hematology News From ASH Meeting B

elow, Jennifer R. Brown, MD, PhD, highlights news from the recent annual meeting of the American Society of Hematology (ASH) regarding Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). Dr. Brown is an attending physician with the CLL & Lymphoma Program, Dana-Farber Cancer Institute, and an assistant professor of medicine at Harvard Medical School, both in Boston.

Hodgkin’s Lymphoma Combined Modality Versus Chemo Alone Results from the German Hodgkin Study Group HD10 trial demonstrated that two cycles of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) followed by 20 Gy involved-field radiation therapy (IFRT) is a highly effective therapy for patients with early-stage, favorable HL (abstract 716).

In recent years, clinicians continue to debate the best therapy for earlystage favorable HL, in particular the role of combined modality therapy compared with chemotherapy alone.

The HD10 trial, reported at this year’s ASH meeting, attempted to shed light on this matter. The study randomized 1,370 patients to two versus four cycles of ABVD followed by 20 versus 30 Gy IFRT. Disease features were well balanced between the arms.

Expected toxicities were greater with four cycles of ABVD compared with two cycles, and with 30 rather than 20 Gy radiation. With a median follow-up of 79 to 91 months, there was no significant difference between two and four cycles of ABVD in terms of overall survival (OS) at five years (four cycles, 97.1%; two cycles, 96.6%), freedom from treatment failure (FFTF; 93.0% vs. 91.1%) and progression-free survival (PFS; 93.5% vs.

91.2%). For the radiotherapy question, there also were no significant differences between patients receiving 30 and 20 Gy IFRT in terms of OS (97.6% vs. 97.5%), FFTF (93.4% vs. 92.9%) and PFS (93.7% vs. 93.2%).

Dose-Dense/Dose-Intense ABVD Examined Results of a Phase II study revealed that the activity of intensified ABVD is significantly higher than the activity of standard ABVD in patients with intermediate- or advanced-stage HL. Intensified ABVD increased rates of complete response (CR) and event-free survival (EFS) while maintaining a low-toxicity profile (abstract 715).

In the study, the intercycle period was shortened from 28 to 21 days, and for the dose-intense schedule, adriamycin was escalated to 70 mg/m2 for cycles 1 through 4. Early CR calculated by positron emission tomography occurred in 95% of patients; by the end of six cycles, the CR rate was 98.6%. The EFS rates

were 95.8% for intermediate-disease patients and 91.3% for advanced-disease patients, with a minimum follow-up of 12 months, which is significantly better than expected with standard ABVD.

Treatment for Relapsed HL Interim results from a trial showed that bendamustine (Treanda, Cephalon) is highly active in heavily pretreated patients with relapsed/refractory HL,

Interim results from a trial showed that bendamustine (Treanda, Cephalon) is highly active in heavily pretreated patients with relapsed/ refractory HL. and the use of the drug enables a significant portion of eligible patients to be

DOSE MODIFICATION GUIDELINES For dose modification guidelines, please see Brief Summary of Prescribing Information on following pages.

BOXED WARNING: HEPATOTOXICITY TYKERB has been associated with hepatotoxicity. Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >1.5 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated.

If changes in liver function are severe, therapy with TYKERB should be discontinued and patients should not be re-treated with TYKERB.

IMPORTANT SAFETY INFORMATION Decreased Left Ventricular Ejection Fraction—TYKERB has been reported to decrease LVEF. Caution should be taken if TYKERB is to be administered to patients with preexisting cardiac conditions, including uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure. Confirm normal LVEF before starting TYKERB, and continue evaluations during treatment.

Patients With Severe Hepatic Impairment—If TYKERB is to be administered to patients with severe hepatic impairment, dose reduction should be considered.

Diarrhea—Diarrhea, including severe diarrhea, has been reported during treatment with TYKERB and was the most common adverse reaction resulting in discontinuation of TYKERB therapy. Proactive management of diarrhea with antidiarrheal agents is important, and severe cases of diarrhea may require administration of oral or intravenous electrolytes and fluids and interruption or discontinuation of therapy with TYKERB. Interstitial Lung Disease/Pneumonitis—TYKERB has been associated with interstitial lung disease and pneumonitis. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis and if symptoms are ≥grade 3 (NCI CTCAE), TYKERB should be discontinued.

QT Prolongation—TYKERB prolongs the QT interval in some patients. TYKERB should be administered with caution to patients who have or may develop prolongation of QTc. Hypokalemia or hypomagnesemia should be corrected prior to TYKERB administration. Baseline and on-treatment electrocardiograms with QT measurement should be considered.

Pregnancy—Pregnancy Category D: TYKERB can cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant when taking TYKERB. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions—The most common adverse reactions (>20%) during therapy with TYKERB plus capecitabine compared to capecitabine alone were diarrhea (65%, 40%), nausea (44%, 43%), vomiting (26%, 21%), palmar-plantar erythrodysesthesia (53%, 51%), rash (28%, 14%), and fatigue (46%, 47%).

The most common grade 3 and 4 adverse reactions (NCI CTCAE v3) with TYKERB plus capecitabine compared to capecitabine alone were diarrhea (14%, 10%) and palmar-plantar erythrodysesthesia (12%, 14%).

References: 1. TYKERB Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; 2008.

2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V.1.2010. www.nccn.org. Accessed October 20, 2009.

www.TYKERB.com 1-866-4-TYKERB 1-866-489-5372

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Multiple Cancers

referred to nonmyeloablative allogeneic stem cell transplantation (abstract 720).

Therapeutic options for patients with HL who have relapsed after autologous stem cell transplantation (ASCT) can be limited. Early results of a Phase II study of bendamustine 120 mg/m2 on days 1 and 2 every 28 days with pegfilgrastim (Neulasta, Amgen) support suggest significant efficacy, albeit with myelotoxicity. The overall response rate (ORR) was 75% with six CRs (38%) and six partial responses (38%), in the first 18 patients of a planned 37 patients. Although the data are preliminary, this study suggests another active treatment for relapsed HL.

Non-Hodgkin’s Lymphoma Bendamustine-R for Indolent Lymphomas The German Indolent Lymphoma Study Group reported the final results of their randomized Phase III trial comparing initial therapy with bendamustine (Treanda, Cephalon; 90 mg/m2) plus rituximab (Rituxan, Biogen/Idec) to initial therapy with CHOP-R (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, plus rituximab) for follicular, indolent and mantle cell lymphomas (abstract 405).

In the trial, 549 patients were enrolled,

with 513 evaluable, and the arms were equally balanced for all patient characteristics, including histology and stage (with approximately 75% stage 4). The ORR for patients treated with bendamustine and rituximab (BR) was similar to that of the CHOP-R group (about 94%).

The CR rate was significantly higher at 40.1% for BR compared with 30.8% for CHOP-R (P=0.0323). The median PFS, EFS and time to next treatment (TTNT) were significantly longer after BR compared with CHOP-R: PFS at 54.8 months for BR compared with 34.8 months for CHOP-R (P=0.0002); EFS at 54 months for BR compared with 31 months for

IN HER2+ METASTATIC BREAST CANCER (MBC)

WHEN FIRST-LINE THERAPY FAILS*

TREAT HER DIFFERENTLY WITH TYKERB *TYKERB is indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.1

Proven After 1st-line MBC

Dosage & Administration

2010 NCCN CLINICAL PRACTICE GUIDELINES TYKERB + capecitabine is listed as a preferred regimen for second-line treatment of HER2+ MBC patients who have received prior therapy including an anthracycline, a taxane, and trastuzumab2

28% TO 43% REDUCTION IN RISK OF PROGRESSION TYKERB plus capecitabine reduced risk of progression 28% to 43% vs capecitabine alone†1 †

TYKERB was studied in a phase 3 trial of 399 women with HER2+ MBC; ≈95% of patients had prior treatment with an anthracycline, a taxane, and trastuzumab.

Patients were randomized to either: TYKERB 1250 mg orally daily throughout the trial + capecitabine 2000 mg/m2/day orally in 2 divided doses, days 1-14 every 21 days (n=198); or capecitabine 2500 mg/m2/day orally in 2 divided doses, days 1-14 every 21 days (n=201). Primary end point was time to progression (time from randomization until objective tumor progression or death due to breast cancer).1

Please see Brief Summary of Prescribing Information on adjacent pages.

CHOP-R (P=0.0002); and TTNT median not yet reached in the BR group compared with 40.7 months in the CHOP-R group (P=0.0002). The OS did not differ between the groups.

In addition to the improved CR rate and PFS, the BR regimen was also better tolerated, with less hematologic toxicity, less hair loss, less neuropathy and fewer infections. These data suggest that BR is a reasonable up-front therapy for indolent lymphomas.

Initial Therapy of MCL Initial therapy of mantle cell lymphoma see HIGHLIGHTS, page 12

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Multiple Cancers R-CHOP-14

HIGHLIGHTS continued from page 11

(MCL) remains controversial. The authors of the study described in abstract 403 used the National Comprehensive Cancer Network database to compare the outcomes of newly diagnosed patients treated with R-CHOP (rituximab plus cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone), R-CHOP with autologous SCT for consolidation, or R-hyperCVAD (rituximab with hyperfractionated cyclophosphamide, doxorubicin, vincristine and

dexamethasone). At the presentation at ASH, 156 patients were evaluable, with a median follow-up of 30 months.

R-CHOP alone showed inferior PFS and a trend toward inferior OS. However, R-CHOP followed by autologous SCT was equivalent to R-hyperCVAD for both PFS and OS, and had less toxicity and fewer days in the hospital. Unfortunately, the study revealed that with either treatment, the median PFS is only three years in this younger patient population, suggesting a need for novel therapeutic options.

R-CHOP-21 Remains Standard For Elderly DLBCL

R-CHOP-21

100

% of Patients

12

80

67

60 40 20 0

Figure. Comparison of response rate.

Results from a study reported at ASH suggest that R-CHOP-21 should remain the standard therapy for elderly patients

TYKERB® (lapatinib) tablets The following is a brief summary only; see full prescribing information for complete product information.

WARNING: HEPATOTOXICITY Hepatotoxicity has been observed in clinical trials and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. [See Warnings and Precautions (5.2).]

1

INDICATIONS AND USAGE TYKERB is indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.

2 2.1

DOSAGE AND ADMINISTRATION Recommended Dosing The recommended dose of TYKERB is 1,250 mg (5 tablets) given orally once daily on Days 1-21 continuously in combination with capecitabine 2,000 mg/m2/day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in a repeating 21 day cycle. TYKERB should be taken at least one hour before or one hour after a meal. The dose of TYKERB should be once daily; dividing the daily dose is not recommended [see Clinical Pharmacology (12.3) of full prescribing information]. Capecitabine should be taken with food or within 30 minutes after food. If a day’s dose is missed, the patient should not double the dose the next day. Treatment should be continued until disease progression or unacceptable toxicity occurs.

2.2

Dose Modification Guidelines Cardiac Events: TYKERB should be discontinued in patients with a decreased left ventricular ejection fraction (LVEF) that is Grade 2 or greater

by NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) and in patients with an LVEF that drops below the institution’s lower limit of normal [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. TYKERB may be restarted at a reduced dose (1,000 mg/day) after a minimum of 2 weeks if the LVEF recovers to normal and the patient is asymptomatic.

Hepatic Impairment: Patients with severe hepatic impairment (ChildPugh Class C) should have their dose of TYKERB reduced. A dose reduction to 750 mg/day in patients with severe hepatic impairment is predicted to adjust the area under the curve (AUC) to the normal range and should be considered.

However, there are no clinical data with this dose adjustment in patients with severe hepatic impairment.

Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit may also increase plasma concentrations of lapatinib and should be avoided. If patients must be coadministered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, a dose reduction to 500 mg/day of lapatinib is predicted to adjust the lapatinib AUC to the range observed without inhibitors and should be considered.

However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib dose is adjusted upward to the indicated dose. [See Drug Interactions (7.2).]

Concomitant Strong CYP3A4 Inducers: The concomitant use of strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John’s Wort). If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dose of lapatinib should be titrated gradually from 1,250 mg/day up to 4,500 mg/day based on tolerability. This dose of lapatinib is predicted to adjust the lapatinib AUC to the range observed without inducers and should be considered. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued the lapatinib dose should be reduced to the indicated dose.

[See Drug Interactions (7.2).]

Other Toxicities: Discontinuation or interruption of dosing with TYKERB may be considered when patients develop ≥Grade 2 NCI CTC toxicity and can be restarted at 1,250 mg/day when the toxicity improves to Grade 1 or less. If the toxicity recurs, then TYKERB should be restarted at a lower dose (1,000 mg/day).

See manufacturer’s prescribing information for capecitabine dosage adjustment guidelines in the event of toxicity.

4

CONTRAINDICATIONS None.

See manufacturer’s prescribing information for capecitabine contraindications.

5 5.1

75

WARNINGS AND PRECAUTIONS Decreased Left Ventricular Ejection Fraction TYKERB has been reported to decrease LVEF [see Adverse Reactions (6.1)]. In the randomized clinical trial, the majority (>60%) of LVEF decreases occurred within the first 9 weeks of treatment; however, data on long-term exposure are limited. Caution should be taken if TYKERB is to be administered to patients with conditions that could impair left ventricular function. LVEF

with diffuse large B-cell lymphoma (DLBCL).

Following the studies of the German lymphoma group that suggested that CHOP given every two weeks may be better than CHOP given every three weeks in DLBCL, the GELA (Groupe d’Étude des Lymphomes de l’Adulte) initiated LNH03-6B, a multicenter Phase III randomized trial comparing R-CHOP given every 14 days with R-CHOP given every 21 days, in elderly patients with DLBCL. At the ASH meeting, they reported a planned interim analysis of 202 patients, with a median follow-up of 24 months (abstract 406).

should be evaluated in all patients prior to initiation of treatment with TYKERB to ensure that the patient has a baseline LVEF that is within the institution’s normal limits. LVEF should continue to be evaluated during treatment with TYKERB to ensure that LVEF does not decline below the institution’s normal limits [see Dosage and Administration (2.2)].

5.2

Hepatotoxicity Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >1.5 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with TYKERB should be discontinued and patients should not be retreated with TYKERB [see Adverse Reactions (6.1)].

5.3

Patients with Severe Hepatic Impairment If TYKERB is to be administered to patients with severe pre-existing hepatic impairment, dose reduction should be considered [see Dosage and Administration (2.2) and Use in Specific Populations (8.7)]. In patients who develop severe hepatotoxicity while on therapy, TYKERB should be discontinued and patients should not be retreated with TYKERB [see Warnings and Precautions (5.2)].

5.4

Diarrhea Diarrhea, including severe diarrhea, has been reported during treatment with TYKERB [see Adverse Reactions (6.1)]. Proactive management of diarrhea with anti-diarrheal agents is important. Severe cases of diarrhea may require administration of oral or intravenous electrolytes and fluids, and interruption or discontinuation of therapy with TYKERB. 5.5

Interstitial Lung Disease/Pneumonitis Lapatinib has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies [see Adverse Reactions (6.1)]. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis. TYKERB should be discontinued in patients who experience pulmonary symptoms indicative of interstitial lung disease/pneumonitis which are ≥Grade 3 (NCI CTCAE).

5.6

QT Prolongation QT prolongation measured by automated machine-read evaluation of ECG was observed in an uncontrolled, open-label dose escalation study of lapatinib in advanced cancer patients [see Clinical Pharmacology (12.4) of full prescribing information]. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc. These conditions include patients with hypokalemia or hypomagnesemia, with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Hypokalemia or hypomagnesemia should be corrected prior to lapatinib administration. The prescriber should consider baseline and ontreatment electrocardiograms with QT measurement.

5.7

Pregnancy Pregnancy Category D TYKERB can cause fetal harm when administered to a pregnant woman.

In a study where pregnant rats were dosed with lapatinib during organogenesis and through lactation, at a dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC), 91% of the pups had died by the fourth day after birth, while 34% of the 60 mg/kg/day pups were dead. The highest no-effect dose for this study was 20 mg/kg/day (approximately equal to the human clinical exposure based on AUC).

Lapatinib was studied for effects on embryo-fetal development in pregnant rats and rabbits given oral doses of 30, 60, and 120 mg/kg/day.

There were no teratogenic effects; however, minor anomalies (left-sided umbilical artery, cervical rib, and precocious ossification) occurred in rats at the maternally toxic dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC). In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day (approximately 0.07 and 0.2 times the human clinical exposure, respectively, based on AUC) and abortions at 120 mg/kg/day. Maternal toxicity was associated with decreased fetal body weights and minor skeletal variations.

There are no adequate and well-controlled studies with TYKERB in pregnant women. Women should be advised not to become pregnant when taking TYKERB. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

6 6.1

ADVERSE REACTIONS Clinical Trials Experience The safety of TYKERB has been evaluated in more than 3,500 patients in clinical trials. The efficacy and safety of TYKERB in combination with capecitabine in breast cancer was evaluated in 198 patients in a randomized, Phase 3 trial. [See Clinical Studies (14) of full prescribing information.] Adverse reactions which occurred in at least 10% of patients in either treatment arm and were higher in the combination arm are shown in Table 1.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be

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Multiple Cancers

The response rate (CR+CRu) was 67% in the R-CHOP-14 arm and 75% in the R-CHOP-21 arm (P=NS). The twoyear EFS was 48% with R-CHOP-14 compared with 61% with R-CHOP-21 (P=NS). A similar trend was observed for two-year PFS (49% vs. 63%), twoyear disease-free survival (57% vs.

70%) and two-year OS (67% vs. 70%; P=NS for all). Hematologic toxicity was higher in the R-CHOP-14 group, but no difference was observed in other toxicities. These results suggest that R-CHOP-21 will remain the standard therapy for elderly patients with DLBCL.

Pooled Analysis of MCL Trials Results from a study suggest that both rituximab in induction and autologous SCT in first remission confer prolonged response duration and survival in MCL, although this response is still relatively short (abstract 880).

The German Low-Grade Lymphoma Study Group and European MCL Network carried out a pooled analysis of three previous randomized trials (involving CHOP or R-CHOP induction followed by randomization to autologous SCT or interferon-α for consolidation), in order to determine the relative contributions of rituximab and autologous

directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reactions (>20%) during therapy with TYKERB plus capecitabine were gastrointestinal (diarrhea, nausea, and vomiting), dermatologic (palmar-plantar erythrodysesthesia and rash), and fatigue. Diarrhea was the most common adverse reaction resulting in discontinuation of study medication.

The most common Grade 3 and 4 adverse reactions (NCI CTC v3) were diarrhea and palmar-plantar erythrodysesthesia. Selected laboratory abnormalities are shown in Table 2.

Table 1. Adverse Reactions Occurring in ≥10% of Patients

Reactions

TYKERB 1,250 mg/day Capecitabine + Capecitabine 2,500 mg/m2/day 2,000 mg/m2/day (N = 191) (N = 198) All Grade Grade All Grade Grade Gradesa 3 4 Gradesa 3 4 % % % % % %

Gastrointestinal disorders Diarrhea 65 13 1 40 10 0 Nausea 44 2 0 43 2 0 Vomiting 26 2 0 21 2 0 Stomatitis 14 0 0 11 <1 0 Dyspepsia 11 <1 0 3 0 0 Skin and subcutaneous tissue disorders Palmar-plantar 53 12 0 51 14 0 erythrodysesthesia Rashb 28 2 0 14 1 0 Dry skin 10 0 0 6 0 0 General disorders and administrative site conditions Mucosal inflammation 15 0 0 12 2 0 Musculoskeletal and connective tissue disorders Pain in extremity 12 1 0 7 <1 0 Back pain 11 1 0 6 <1 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 12 3 0 8 2 0 Psychiatric disorders Insomnia 10 <1 0 6 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. b Grade 3 dermatitis acneiform was reported in <1% of patients in TYKERB plus capecitabine group.

Table 2. Selected Laboratory Abnormalities

SCT to the up-front therapy of MCL. With a median follow-up of 63 months and 180 evaluable patients, median response duration was 16 months after CHOP without ASCT, 26 months after R-CHOP without ASCT, 39 months after CHOP with ASCT, and 41 months after R-CHOP with ASCT. In multivariate Cox regression analysis including R and ASCT, the hazard ratios of R (0.60; P=0.0056) and ASCT (0.50; P=0.0001) were both significant. Median OS was 54 months after CHOP without ASCT, 66 months after R-CHOP without ASCT, 90 months after CHOP with ASCT, and not reached after R-CHOP

signs or symptoms of deterioration in left ventricular cardiac function that are ≥Grade 3 (NCI CTCAE), or a ≥20% decrease in left ventricular cardiac ejection fraction relative to baseline which is below the institution's lower limit of normal. Among 198 patients who received lapatinib/capecitabine combination treatment, 3 experienced Grade 2 and one had Grade 3 LVEF adverse reactions (NCI CTC 3.0). [See Warnings and Precautions (5.1).]

Hepatotoxicity: Lapatinib has been associated with hepatotoxicity [see Boxed Warning and Warnings and Precautions (5.2)].

Interstitial Lung Disease/Pneumonitis: Lapatinib has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies [see Warnings and Precautions (5.5)].

7 DRUG INTERACTIONS 7.1 Effects of Lapatinib on Drug Metabolizing Enzymes and Drug Transport Systems Lapatinib inhibits CYP3A4 and CYP2C8 in vitro at clinically relevant concentrations. Caution should be exercised and dose reduction of the concomitant substrate drug should be considered when dosing lapatinib concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4 or CYP2C8. Lapatinib did not significantly inhibit the following enzymes in human liver microsomes: CYP1A2, CYP2C9, CYP2C19, and CYP2D6 or UGT enzymes in vitro, however, the clinical significance is unknown.

Lapatinib inhibits human P-glycoprotein. If TYKERB is administered with drugs that are substrates of Pgp, increased concentrations of the substrate drug are likely, and caution should be exercised.

7.2

Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Lapatinib undergoes extensive metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 alter lapatinib concentrations significantly (see Ketoconazole and Carbamazepine sections, below). Dose adjustment of lapatinib should be considered for patients who must receive concomitant strong inhibitors or concomitant strong inducers of CYP3A4 enzymes [see Dosage and Administration (2.2)].

Ketoconazole: In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 200 mg twice daily for 7 days, systemic exposure (AUC) to lapatinib was increased to approximately 3.6-fold of control and half-life increased to 1.7-fold of control.

Carbamazepine: In healthy subjects receiving the CYP3A4 inducer, carbamazepine, at 100 mg twice daily for 3 days and 200 mg twice daily for 17 days, systemic exposure (AUC) to lapatinib was decreased approximately 72%.

7.3

Drugs that Inhibit Drug Transport Systems Lapatinib is a substrate of the efflux transporter P-glycoprotein (Pgp, ABCB1). If TYKERB is administered with drugs that inhibit Pgp, increased concentrations of lapatinib are likely, and caution should be exercised.

7.4

Other Chemotherapy Agents In a separate study, concomitant administration of lapatinib with capecitabine did not meaningfully alter the pharmacokinetics of either agent (or the metabolites of capecitabine).

8 8.1

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions (5.7)].

8.3

Nursing Mothers It is not known whether lapatinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from TYKERB, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4

TYKERB 1,250 mg/day + Capecitabine 2,000 mg/m2/day Parameters

Capecitabine 2,500 mg/m2/day

Grade Grade All Grade Grade All 4 Gradesa 3 4 Gradesa 3 % % % % % %

Hematologic Hemoglobin 56 <1 0 53 1 0 Platelets 18 <1 0 17 <1 <1 Neutrophils 22 3 <1 31 2 1 Hepatic Total Bilirubin 45 4 0 30 3 0 AST 49 2 <1 43 2 0 ALT 37 2 0 33 1 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Decreases in Left Ventricular Ejection Fraction: Due to potential cardiac toxicity with HER2 (ErbB2) inhibitors, LVEF was monitored in clinical trials at approximately 8-week intervals. LVEF decreases were defined as

Pediatric Use The safety and effectiveness of TYKERB in pediatric patients have not been established.

8.5

Geriatric Use Of the total number of metastatic breast cancer patients in clinical studies of TYKERB in combination with capecitabine (N = 198), 17% were 65 years of age and older, and 1% were 75 years of age and older. No overall differences in safety or effectiveness of the combination of TYKERB and capecitabine were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6

Renal Impairment Lapatinib pharmacokinetics have not been specifically studied in patients with renal impairment or in patients undergoing hemodialysis. There is no experience with TYKERB in patients with severe renal impairment. However, renal impairment is unlikely to affect the pharmacokinetics of lapatinib given that less than 2% (lapatinib and metabolites) of an administered dose is eliminated by the kidneys.

8.7

Hepatic Impairment The pharmacokinetics of lapatinib were examined in subjects with preexisting moderate (n = 8) or severe (n = 4) hepatic impairment (Child-Pugh Class B/C, respectively) and in 8 healthy control subjects. Systemic exposure

with ASCT. The hazard ratios for OS were 0.70 (95% CI, 0.44-1.12; P=0.14) for R and 0.63 (95% CI, 0.41-0.97; P=0.0379) for ASCT.

Multiple Myeloma VMP Induction Followed by VT Maintenance Best The previously reported VISTA trial showed that adding bortezomib (Velcade, Millennium Pharmaceuticals) to melphalan and prednisone (MP) was better than MP alone in patients with MM. The question of whether an see BROWN HIGHLIGHTS, page 14

13

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JANUARY 2010

Multiple Cancers

HIGHLIGHTS continued from page 13

alkylating agent or immunomodulatory agent is the better partner with bortezomib, however, was not answered by the trial. The Spanish Myeloma Group therefore undertook a study to answer this question (abstract 3).

The group with the best PFS, therefore, had VMP induction followed by VT maintenance.

The trial randomized 260 patients to receive six cycles of VMP (bortezomib, melphalan [Alkeran, Celgene], prednisone) or VTP (bortezomib, thalidomide, prednisone) as induction therapy followed by maintenance with VT or VP for up to three years. Bortezomib was given on the usual schedule for the first six weeks, and then weekly thereafter during induction. The patient characteristics were well balanced between arms. The ORR was 80% in both arms with CR rates of 20% to 27%; maintenance improved the CR rate for both groups to 42%. A trend toward better PFS with VMP induction was observed. The main difference was observed during maintenance, where VT improved PFS and OS regardless of the induction therapy. The group with the best PFS, therefore, had VMP induction followed by VT maintenance.

Optimal Timing of ASCT The optimal timing of ASCT in the era of new therapies is not clear. Mayo Clinic therefore conducted a retrospective review of 292 patients with MM between 2000 and 2008 who were

treated initially with thalidomide–dexamethasone or lenalidomide–dexamethasone as their up-front therapy (abstract 956). The median estimated follow-up for the entire group was 54 months from diagnosis, 52 and 61 months respectively for the early and delayed SCT groups.

The investigators found that continuing initial therapy with delay of SCT until relapse proved similar to early consolidation transplantation, in terms of OS.

VDCR Appears Promising While lenalidomide–bortezomib–dexamethasone (RVD) regimens have been found to be safe and effective in myeloma, the role of cyclophosphamide in this regimen has not been established. The Phase I multicenter EVOLUTION study revealed that the VDCR regimen (bortezomib, dexamethasone, cyclophosphamide, lenalidomide [Revlimid, Celgene]) is a highly active and generally well-tolerated induction therapy in previously untreated MM patients.

This year, the results of the noncomparative Phase II trial including VDR, VDC and VDCR, were reported (abstract 127). Thus far, the VDCR arm may have a slightly higher rate of high-quality responses (CR or vgPR), albeit with greater toxicity. Longer follow-up will be required to see what cyclophosphamide will add to the regimen.

(abstract 535). The median PFS for FC is now 33 months, compared with 52 months for FCR. An OS benefit is now observed for FCR, with 82.5% of FC patients alive compared with 87.2% of FCR patients (P=0.012), with a median follow-up of 37.7 months. FCR appeared to overcome the adverse impact of 11q deletion, but did not overcome the adverse impact of 17p deletion, which was still associated with a significantly shorter PFS. In multivariate analysis, the only predictors of improved OS were receiving FCR, low β2-microglobulin and absence of 17p deletion.

FC FCR a

median follow-up of 37.7 months

100

Chronic Lymphocytic Leukemia German CLL Study Updates The German CLL Study Group (GCLLSG) updated the results of the CLL8 study, a randomized controlled trial comparing FCR (fludarabine, cyclophosphamide, rituximab) to FC (fludarabine, cyclophosphamide) in fit patients with CLL requiring initial therapy

% of Patients Alivea

14

82.5 80 60 40 20 0

Figure. Comparison of overall survival.

(AUC) to lapatinib after a single oral 100-mg dose increased approximately 14% and 63% in subjects with moderate and severe pre-existing hepatic impairment, respectively. Administration of TYKERB in patients with severe hepatic impairment should be undertaken with caution due to increased exposure to the drug. A dose reduction should be considered for patients with severe pre-existing hepatic impairment [see Dosage and Administration (2.2)]. In patients who develop severe hepatotoxicity while on therapy, TYKERB should be discontinued and patients should not be retreated with TYKERB [see Warnings and Precautions (5.2)].

clinical exposure based on AUC, respectively).

10

17.2 Diarrhea Patients should be informed that TYKERB often causes diarrhea which may be severe in some cases. Patients should be told how to manage and/or prevent diarrhea and to inform their physician if severe diarrhea occurs during treatment with TYKERB.

OVERDOSAGE There is no known antidote for overdoses of TYKERB. The maximum oral doses of lapatinib that have been administered in clinical trials are 1,800 mg once daily. More frequent ingestion of TYKERB could result in serum concentrations exceeding those observed in clinical trials and could result in increased toxicity. Therefore, missed doses should not be replaced and dosing should resume with the next scheduled daily dose.

There has been a report of one patient who took 3,000 mg of TYKERB for 10 days. This patient had Grade 3 diarrhea and vomiting on Day 10. The event resolved following IV hydration and interruption of treatment with TYKERB and letrozole.

Because lapatinib is not significantly renally excreted and is highly bound to plasma proteins, hemodialysis would not be expected to be an effective method to enhance the elimination of lapatinib.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies with lapatinib are ongoing.

Lapatinib was not clastogenic or mutagenic in the Chinese hamster ovary chromosome aberration assay, microbial mutagenesis (Ames) assay, human lymphocyte chromosome aberration assay or the in vivo rat bone marrow chromosome aberration assay at single doses up to 2,000 mg/kg.

However, an impurity in the drug product (up to 4 ppm or 8 mcg/day) was genotoxic when tested alone in both in vitro and in vivo assays.

There were no effects on male or female rat mating or fertility at doses up to 120 mg/kg/day in females and 180 mg/kg/day in males (approximately 6.4 times and 2.6 times the expected human clinical exposure based on AUC, respectively). The effect of lapatinib on human fertility is unknown. However, when female rats were given oral doses of lapatinib during breeding and through the first 6 days of gestation, a significant decrease in the number of live fetuses was seen at 120 mg/kg/day and in the fetal body weights at ≥60 mg/kg/day (approximately 6.4 times and 3.3 times the expected human

17

87.2

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (17.6) of full prescribing information.

17.1 Decreased Left Ventricular Ejection Fraction Patients should be informed that TYKERB has been reported to decrease left ventricular ejection fraction which may result in shortness of breath, palpitations, and/or fatigue. Patients should inform their physician if they develop these symptoms while taking TYKERB.

17.3 Drug Interactions TYKERB may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products.

17.4 Food Patients should be informed of the importance of taking TYKERB at least one hour before or one hour after a meal, in contrast to capecitabine which should be taken with food or within 30 minutes after food.

17.5 Divided Dosing The dose of TYKERB should not be divided. Patients should be advised of the importance of taking TYKERB once daily, in contrast to capecitabine which is taken twice daily.

TYKERB is a registered trademark of GlaxoSmithKline.

©2009, GlaxoSmithKline. All rights reserved.

Revised: August 2009 TKB:5BRS ©2009 The GlaxoSmithKline Group of Companies.

All rights reserved. Printed in USA. TKB834R0 October 2009

The GCLLSG also reported the results of their Phase II study of bendamustine (90 mg/m2)–rituximab (BR) as up-front therapy for CLL (abstract 205). The study enrolled 117 patients; 48% were Binet C patients. Although hematologic toxicity was low (20%-25% grade 3/4 neutropenia or thrombocytopenia), the treatmentrelated mortality was 3.4%, with two fatal septic events, one case of fatal pneumonia and one death due to liver failure associated with suicide. The ORR was 91%, with CR rate of 33%. Minimal residual disease was not detectable in 58% of patients in peripheral blood and 28% in bone marrow. With a median follow-up of 15 months, 85% of patients remain in remission. The GCLLSG has an ongoing randomized trial comparing BR to FCR in up-front CLL. Although these data for up-front BR are typical of many chemoimmunotherapy regimens, overall they are not as impressive as the up-front data for FCR.

Updates of CALGB Trials Kanti Rai, MD, updated the results of CALGB 9011, a randomized trial comparing initial therapy with chlorambucil, fludarabine, or chlorambucil plus fludarabine (abstract 536). He reported that the OS curves start to separate at six years, and that by eight years, 31% of fludarabine patients are alive compared with 19% of chlorambucil patients (P=0.04). The chlorambucil plus fludarabine arm was closed early due to excessive toxicity. The finding of improved overall survival in the fludarabine arm is intriguing, suggesting that initial therapy selection may have a delayed impact on survival. However, the result is a little hard to interpret given that no information about subsequent therapies was available for either patient group.

Investigators also presented long-term follow-up of CALGB 9712, which compared sequential and concurrent schedules of FR (fludarabine, rituximab; abstract 539). At a median follow-up of 117 months, the overall PFS is 42 months.

PFS remains shorter in patients with unmutated IgVH (33 months) and deletions 11q and 17p (25 months), suggesting that this regimen is best for low-risk CLL patients.

—Jennifer R. Brown, MD, PhD

SUPPORTIVE CARE

CLINICAL ONCOLOGY NEWS • JANUARY 2010

Anemia

RESTRICTIONS continued from page 5

decreasing trend for darbepoetin use after restrictions were in place (28% vs. 21%; not significantly different), transfusions showed an upward trend. After implementation of the NCD, more patients received transfusions than before implementation (29% vs. 21%; P=NS). Transfusions also increased after each of the other three darbepoetin-related events.

Dr. Adamson said that because Saint Barnabas was slow to adopt the NCD restrictions, only two to three months of data were generated after implementation. Thus, he speculated that if they looked further out, the transfusion rate would continue to increase.

Philip E. Johnson, MS, RPh, said that although transfusions have not increased at his center, it is not clear whether this is “because there’s not blood available or that there’s no clinical need.” The changes in ESA prescribing appear to be “affecting different places differently,” said Mr. Johnson, director of pharmacy at H. Lee Moffitt Cancer Center, in Tampa, Fla. “A lot has to do with the physician’s philosophy” and how conservatively they treat anemia.

Jerry Siegel, PharmD, senior director of pharmaceutical sciences at The Ohio State University Medical Center in Columbus, said that while “ESA use is way down, it’s harder to assess transfusion rates because transfusion tipping points vary by center.” Some centers, for example, wait until the hemoglobin is less than 7 g/dL or even lower, while some have higher thresholds; and some consider whether the patient is symptomatic, while others may not, he noted.

Dr. Siegel added that because the cost of blood is so high, if transfusions have gone up, the overall costs of therapy for chemotherapy-induced anemia may be higher now than before the restrictions were put in place. “The message here,” he said, “is if you haven’t already looked at your transfusion rates and cost of treating anemia post-NCD, maybe you should. Are you just transferring costs?”

While Saint Barnabas has an approach to reduce ESA waste and costs, Dr. Siegel also suggested that centers can try to reduce transfusion rates and costs in ways unrelated to ESA use. A simple example, he said, is to just “draw less blood.”

When Ohio State University Medical Center implemented a blood conservation program in 2005, “it really had a big impact on decreasing the need for transfusions,” Dr. Siegel said. The actions they took were “switching from adult to pediatric tubes for blood samples to reduce the volume of blood taken when blood is drawn” and putting “more clinical input into the decision of when they are going to do a transfusion.” They included

Dr. Siegel added that because the cost is so high, if transfusions have gone up, the overall costs of therapy for chemotherapyinduced anemia may be higher now than before the restrictions were put in place.

hemoglobin levels and clinical symptoms into the mix, eliminating a lot of transfusions that were done automatically but were not necessarily clinically appropriate.

At this point, Mr. Johnson said, “I don’t

think there’s conclusive data. There’s still a blood supply problem in this country.

We are still at war.” With the reductions in ESA use, “the call is out to look at whether transfusions are being used appropriately and how does it affect patient outcomes.

That’s what we need more data on.”

Dr. DiBona agreed that more information is needed. He said that the findings of the studies raise more questions than they answer, including the question of “whether any consideration was given to these issues when the NCD was made.”

—Sarah Tilyou Sejal Badre, MS, and Larry Green, PharmD, from Amgen Inc., were co-investigators involved with the Saint Barnabas study, and Dr. Green was also a co-investigator on the Sinai Hospital of Baltimore study, along with Leo Lichtig, PhD, of AON Consulting.

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CLINICAL ONCOLOGY NEWS • JANUARY 2010

Lymphoma Bendamustine plus rituximab

BENDAMUSTINE-R continued from page 1

entities,” said Dr. Mathias J. Rummel, MD, PhD, head of the Department of Hematology, University Hospital, Giessen, Germany. Presenting these results on behalf of Studiengruppe Indolente Lymphoma at the annual meeting of the American Society of Hematology (ASH; abstract 405), Dr. Rummel said the study did not just suggest comparable efficacy, but “clear, statistically significant superiority for a better-tolerated regimen.”

The study found that the overall response rates were similar in the two arms, but in patients who received bendamustine plus rituximab, there were a greater number of complete responses (CRs) and progressionfree survival (PFS) was extended.

Although the data are impressive, both Dr. Rummel and the co-chairman of the Scientific Program Committee for this year’s ASH meeting, Richard A. Van Etten, MD, PhD, were careful to describe the data not as practice changing but as “potentially” practice changing. This caution despite a Phase III study that clearly showed both an efficacy and a safety advantage was explained by Dr. Van Etten, chief of the Division of Hematology and Oncology at Tufts Medical Center, Boston. He clarified that both experts and regulating agencies are reluctant to declare any therapy as firstline on the basis of PFS alone.

“In oncology, what we ideally want to see is an [overall] survival advantage for a therapy that is identified as a new standard,” Dr. Van Etten commented. Although he agreed that the results were compelling, he indicated that there are a number of additional steps in the process, including longer follow-up and publication of the data, which would be necessary for changing the characterization of bendamustine-R from a potential to an established first-line therapy.

In the study, conducted at 82 centers in Germany, patients with a relapsed or refractory indolent

lymphoma (follicular, marginal zone, Waldenströms or small lymphocytic) or mantle cell lymphoma were randomized to the conventional CHOP-R regimen given on a 21-day schedule or to a regimen on a 28-day schedule that combined 90 mg/m2 bendamustine on days 1 and 2 with 375 mg/m2 rituximab on day 1. The median age of the study population was 65 years. Relevant characteristics, including age, stage, bone marrow infiltration and extranodal involvement, were comparable between the groups. The primary outcome was PFS, but safety and tolerability also were monitored closely.

Overall response rates over a median observation time of 32 months and a median of six treatment cycles in both groups were almost identical—92.7% for bendamustine-R and 91.3% for CHOP-R. However, the quality of the response was better with bendamustineR, including a greater number of CR (39.6% vs. 30%; P=0.03). More importantly, the PFS was two years longer in patients on bendamustine-R relative to CHOP-R (54.9 vs. 30 months; P=0.0002). The efficacy advantage was reinforced by other data showing that the bendamustine-R arm was superior including longer time to next treatment (not yet reached on bendamustine-R vs.

46 months on CHOP-R; P=0.0002) and event-free survival (54 vs. 31 months; P=0.0002). In the follow-up so far, there has been a similar number of deaths in each arm, so overall survival has not differed.

When efficacy was assessed separately in those with follicular lymphoma, which represented 54% of the study population, the relative advantage of bendamustine-R over CHOP-R was consistent with that observed for the whole population. For example, the median time to PFS has not yet been reached in those randomized to bendamustine-R versus 46 months in those who received CHOP-R. These efficacy advantages were achieved with a treatment that was much better tolerated from the perspective of laboratory analyses and side effects. Most grade 3 and 4 hematologic side effects, including neutropenia (10.7% vs. 46.5%; P<0.0001) and leukocytopenia (12.1%

CHOP-R

60

54.9

50

PFS, mo

16

40

30

30 20 10 0

Figure. Comparison of progression-free survival.

CHOP-R, cyclophosphamide, hydroxydaunorubicin, vincristine and prednisone plus rituximab; PFS, progression-free survival

vs. 38.2%; P<0.0001) were far less common on bendamustine-R. Those on bendamustine-R were also less likely to receive granulocyte colony-stimulating factor than those on CHOP-R. The lower rate of cytopenias is likely to explain the lower rate of infectious complications in the bendamustine-R arm (P=0.04).

Whereas almost all patients on the CHOP-R regimen had hair loss, there was no hair loss in patients on bendamustine-R more severe than grade 1. Peripheral neuropathy (P<0.0001) and stomatitis (P<0.0001) also were significantly less common with bendamustine-R. The only side effects more common with bendamustine-R were erythematous skin reactions (P=0.01).

Although CHOP-R remains the standard of care for aggressive lymphomas in which there is potential for cancer remission, a better-tolerated therapy for indolent lymphomas, which are considered incurable, has major clinical advantages. The authors emphasized that it is particularly important for noncurative treatments to extend survival with an acceptable quality of life.

—Ted Bosworth

PRN Eye on the Community Oncologist

Rapid Infusion of Rituximab Works in Community Setting

R

ituximab (Rituxan, Genentech/Biogen Idec) is generally well tolerated by patients with non-Hodgkin’s lymphoma (NHL), but the probability of infusionrelated toxicities still exists. Due to the risk of these toxicities, the manufacturer of rituximab recommends a slow standard administration schedule, requiring an average of five to six hours during the initial infusion and three to four hours during subsequent infusions. Rituximab’s long infusion times and expanding indications have increased nursing resource and time demands in community-based outpatient infusion clinics that could potentially lead to administration errors and increased patient stress. To help alleviate some of these concerns, we implemented a rapid rituximab infusion protocol in effort to decrease infusion times along with nursing and patient stress.

From September 2008 to June 2009, we initiated a 90-minute rapid rituximab infusion protocol at three communitybased outpatient infusion clinics located in Gainesville, Ga. Study participants were diagnosed with CD20-positive NHL and

were allowed to enter the trial at any point in their treatment cycle.

Patients received the standard rituximab dose of 375 mg/m2 over 90 minutes (20% of the dose during the first 30 minutes and 80% over the subsequent 60 minutes) in a total volume of 250-mL normal saline. Premedications were not standardized and could vary per facility protocol.

We used a strict safety monitoring algorithm, measuring blood pressure, heart rate and respiratory rate before the infusion and at 15, 30, 60 and 90 minutes to monitor respiratory or cardiac symptoms.

We also monitored temperature prior to the infusion and questioned patients about adverse reactions throughout the infusion and at each visit. Sixteen patients were enrolled and treated with a total of 51 rapid rituximab infusions. The median number of infusions each patient received was three (range, one to seven). Most of the patients were younger than 60 and male. Three patients experienced minor adverse reactions which were expected with rituximab administration. The total infusion time saved compared with

standard infusion rates was 2,925 minutes (49 hours; 57 minutes per infusion).

Patient and nursing satisfaction, assessed through surveys, was extremely high in all but one statement.

We report excellent safety and tolerability using a 90-minute rapid rituximab infusion in our community outpatient infusion clinics. The results of this study support other reports of success with decreased rituximab infusion time.

Patients and nurses preferred the rapid infusion to the standard infusion rate because of the time saved with this regimen. Nursing staff, however, did feel that the intense monitoring schedule in this trial required equal attention to that of the standard infusion. If medical oncologists at these practice sites adopted this regimen as standard practice, an easier monitoring schedule should be employed to

free up nursing time and resources.

We believe that most patients will tolerate the rapid rituximab infusion as long as no severe adverse reactions are seen on initial infusions. Other investigators have adopted this as the standard of care and have had excellent results.

Sehn et al reported the use of a 90-minute rapid rituximab infusion in more than 1,200 patients with only one grade III reaction (Blood 2007;109:41714173, PMID: 17244675). Furthermore, one study has assessed a 60-minute rapid rituximab infusion without severe adverse reactions (Ann Oncol 2006;17:1027-1028, PMID: 16322113).

—Chad J. Coulter, PharmD Assistant Professor of Clinical and Administrative Sciences Sullivan University College of Pharmacy Louisville, Ky.

Do you have something that you would like to share with community oncologists? Send submissions (300-600 words) that you would like considered for publication to korourke@mcmahonmed.com.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JANUARY 2010

Colon

Colon Cancer Highlights From International Meeting Which colon cancer news was all the rage at the recent joint meeting of the European CanCer Organisation and the European Society for Medical Oncology (ECCO-ESMO)?

C

athy Eng, MD, can provide you with what you need to know. Dr. Eng, an associate professor in the Department of Gastrointestinal Medical Oncology at the University of Texas M.D. Anderson Cancer Center, in Houston, recently gave the highlights to Clinical Oncology News.

ClinOnc: What were the most significant studies in colon cancer to come out of the ECCO-ESMO meeting?

Dr. Eng: I think the ESMO meeting had some very informative studies. We have now confirmed the role for adjuvant capecitabine (Xeloda, Roche) in combination with oxaliplatin (Eloxatin, SanofiAventis). XELOX-A was a Phase III trial that randomized patients to XELOX (capecitabine 1,000 mg/m2 bid, days 1-14; oxaliplatin 130 mg/m2, day 1, every 21 days) or a regimen of Roswell Park or Mayo Clinic bolus 5-fluorouracil (5-FU)/leucovorin (control arm). The investigators determined that XELOX was superior in terms of prolonging disease-free survival (DFS) when compared with the bolus 5-FU regimens (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.69–0.93; P=0.0045); the difference in three-year DFS was 4.5%.

From these results, it appears reasonable for clinicians to consider the XELOX combination in the adjuvant setting, but doctors must believe that the patient will be adherent and will properly communicate information about any potential toxicities.

In patients with metastatic colorectal cancer, Eric Van Cutsem, MD, reported that there was overall survival (OS) benefit to using cetuximab (Erbitux, Bristol-Myers Squibb) in the front-line setting. The addition of cetuximab improved OS by 3.5 months in KRAS wild-type patients [HR, 0.796; 95% CI, 0.06700.946; P=0.0094]. The response rate was 57.3% for the addition of cetuximab compared with 39.7% (P<0.0001).

You can infer from this trial that cetuximab plus FOLFIRI (5-FU, folinic acid and irinotecan) has a role in the front-line setting in comparison with standard

FOLFIRI FOLFIRI plus cetuximab

Overall Survival, mo

25 20

23.5 20

15 10 5 0

Figure. Comparison of regimens in metastatic colorectal cancer.

cytotoxic chemotherapy alone, specifically in patients with KRAS wild-type tumors. Currently, cetuximab is FDA-approved in previously treated patients. The results of this study open up another therapeutic possibility in the front-line setting. Rather than giving bevacizumab (Avastin, Genentech) to all front-line patients, this trial shows there might be another treatment option for patients with wild-type KRAS tumors.

It’s important to keep in mind that this study is not a direct head-to-head comparison of cetuximab and bevacizumab. Once completed, the trial that may potentially answer this question is CALGB 80405 [Cancer and Leukemia Group B], but the results may be difficult to interpret.

ADVISORY BOARD EDITORIAL Cathy Eng, MD Associate Professor Department of Gastrointestinal Medical Oncology University of Texas M.D. Anderson Cancer Center Houston, Texas

(LBA10) showed that panitumumab improved progression-free survival (PFS) by roughly 1.6 months and was well tolerated when added to FOLFOX4 as firstline chemotherapy in patients with metastatic colorectal cancer who have wild-type KRAS (abstract LBA10).

The study also found that patients with mutated KRAS had worse PFS if they received panitumumab than if they received chemotherapy alone (7.3 vs. 8.8 months; P=0.02). The second study (LBA14) showed that adding panitumumab to FOLFIRI prolongs PFS by two months compared with FOLFIRI alone when used as secondline therapy for metastatic colorectal cancer in patients with wild-type KRAS. I presume these two studies are likely to be updated at the 2010 ASCO Gastrointestinal Cancers Symposium.

ClinOnc: Were there important studies focusing on markers?

BRAF is a prognostic indicator for overall survival.

ClinOnc: Why will the results be difficult to interpret?

Dr. Eng: The CALGB 80405 trial was created and opened for patient accrual before the importance of KRAS status was known. The trial also included an arm of combined biologic therapy. In the original study design, patients received either FOLFOX (5-FU, leucovorin and oxaliplatin) or FOLFIRI and then were randomized either to bevacizumab or cetuximab or the combination of bevacizumab and cetuximab. After data regarding the significance of KRAS were reported at the American Society of Clinical Oncology (ASCO) 2008 meeting, the study was amended to only include KRAS wild-type patients.

Shortly after, data came from the PACCE trial (evaluating panitumumab) and the CAIRO 2 trial (examining capecitabine, irinotecan [Camptosar, Pfizer] and oxaliplatin) that demonstrated that combined biologic therapy was not beneficial to patients resulting in a recent amendment to remove the third arm of combined biologic therapy. The revised study design will be a direct head-to-head comparison of cetuximab and bevacizumab, but these recent amendments are likely to confound the final results.

ClinOnc: What other studies presented at ESMO were noteworthy?

Dr. Eng: There were two large Phase III studies reported that discussed data on panitumumab (Vectibix, Amgen) in combination with chemotherapy. The PRIME trial

Dr. Eng: There was a small study by Farina (abstract 6114) that looked at the role of BRAF as a prognostic marker in patients with stage III colon carcinoma.

Some investigators have focused specifically on BRAF as a predictive marker, other than KRAS, to predict response to EGFR (epidermal growth factor receptor) inhibition. In the Farina study of 213 surgically resected stage III patients, investigators looked at BRAF as a prognostic marker. They reported a higher than expected number of individuals with a presence of a BRAF mutation—19.5% of patients (the BRAF mutation is commonly reported to be in less than 10% of patients). The investigators concluded that the presence of the BRAF V600E mutation was an independent prognostic factor for worse OS (P=0.006).

Another study discussed was the CAIRO2 study that was originally reported at ASCO 2008. The investigators retrospectively evaluated the prognostic role of BRAF in those patients. CAIRO2 was a randomized Phase III trial in which patients either received capecitabine plus oxaliplatin (CAPOX) for six cycles, followed by capecitabine and bevacizumab (control arm) or they received CAPOX for six cycles plus bevacizumab and cetuximab followed by capecitabine and bevacizumab and cetuximab. Dr. [J.] Tol reported in abstract 6002 that the BRAF mutation was present in 8.7% of all patients and he noted that the presence of the BRAF mutation was a prognostic indicator, regardless of treatment arm or KRAS status. Patients with BRAF mutations had decreased median PFS compared with patients with wild-type tumor irrespective of the treatment arm—5.9 versus 12.2 months (P=0.003, control arm) compared with 6.6 versus 10.4 months (P=0.010) in the investigational arm. The same held true for OS—15 versus 24.6 months in the control arm (P=0.002), and 15.2 versus 21.5 months in the investigational arm (P=0.001).

These two reported studies are of interest because people have been looking at BRAF as a predictive see COLON HIGHLIGHTS, page 25

17

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JANUARY 2010

Breast

ONE-TWO PUNCH continued from page 1

maintain through progression in this setting,” said Edith Perez, MD, director of the Breast Cancer Program at Mayo Clinic in Jacksonville, Fla., who was not involved with the study.

Practice-Changing News

‘The survival data from the new study will set this approach apart from the other studies.

This is noteworthy and likely will impact clinical practice.’

—Andrew Seidman, MD

Early results from this trial, which were reported at the 2008 annual meeting of the American Society of Clinical Oncology, showed the combination studies. This is noteworthy and likely will impact improved progression-free survival by roughclinical practice,” Dr. Seidman said. “It will ly one month. The updated and planned also drive interest in beginning lapatinib event-driven survival analysis reportplus trastuzumab alone or in comed at SABCS, with 75% of the wombination with cytotoxic agents even en having died, revealed that patients earlier in the treatment of metastatwho received the combination ic breast cancer. Indeed, the combinatherapy had a 26% reduction in tion is already being studied in the postthe risk for dying compared with operative adjuvant setting in the ALTTO patients who received lapatinib alone, [Adjuvant Lapatinib and/or Trastuzumaccording to Kimberly Blackwell, MD, who led the study. ab Treatment Optimization] trial.”

“The survival benefit was seen in spite of the Study Details fact that over half of the patients crossed over to go on to receive dual HER2 blockade,” said Dr. BlackThe study reported at SABCS randomized 296 well, an associate professor of medicine and direcwomen with HER2-positive MBC who had protor of the Clinical Trials Program in Breast Cancer at gressed on trastuzumab-containing regimens to Duke University Medical Center, Durham, N.C. “As a receive either lapatinib 1,500 mg once daily or lapapracticing clinician, I think it is really amazing that tinib 1,000 mg once daily in combination with trasthere was not a significant safety signal considering tuzumab 2 mg/kg (after a 4-mg/kg loading dose). the heavily pretreated nature of If patients had objective disthese patients.” ease progression at or after four According to Andrew Seidman, weeks of lapatinib alone, they MD, an attending physician at the were allowed to cross over to the Trastuzumab Breast Cancer Medicine Service combination arm—52% ended at Memorial Sloan-Kettering Canup crossing over. “Half of these cer Center, New York City, there patients [crossed over] before or are three common approaches at week 8, and 46% [did so] after to treating patients with trastuweek 8,” Dr. Blackwell said. zumab-refractory MBC: disconThe two arms of the study were tinue trastuzumab and switch well matched. One-third of the HER1 HER2 to capecitabine (Xeloda, Roche) patients had received six or more plus lapatinib; continue trasturegimens and the median number zumab and add capecitabine, or of prior trastuzumab-containcontinue trastuzumab and add ing regimens was three. Half of lapatinib. The new data, he said, the patients were estrogen recepsupport the use of the trastuzumtor-negative. “Unlike many of ab-lapatinib option because it is the studies that were done with the only approach that has been HER2-targeted agents in the early demonstrated to improve overall days, we allowed for known brain survival. metastases and these were equally The study that spurred FDA matched between the two arms,” Lapatinib approval of lapatinib in combiDr. Blackwell said.

P13-K K SO SOS nation with capecitabine in this Median overall survival (FigRAS Akt kt patient population was based ure) following treatment with on data that showed improved lapatinib plus trastuzumab was RAF AF response rate and time to progres60.7 weeks compared with 41.4 Cell survival sion (N Engl J Med 2006;355:2733weeks in patients who received MEK EK 2744, PMID: 17192538). Results lapatinib alone (hazard ratio from the study testing the com[HR], 0.74; 95% confidence interCell MAPK bination of capecitabine with val [CI], 0.57-0.97; P=0.026). The proliferation or without trastuzumab, pubsurvival benefit was maintained lished in 2009 (J Clin Oncol after adjusting for baseline progThe HER2 receptor shown in its transmembrane position, with 2009;27:1999-2006, PMID: nostic factors (HR, 0.71; 95% CI, trastuzumab bound to the 19289619), also only showed an 0.54-0.93; P=0.012). extracellular domain, and lapatinib improvement in response rate Both regimens were well tolerto the intracelullar tyrosine kinase and time to progression. ated. One cardiac-related death domain, inhibiting downstream signalling through the PI3K/Akt and “The [overall] survival data occurred in the combination arm the Ras/Raf/Mek/MAPK pathways. from the new study will set this and was attributable to a fatal pulapproach apart from the other monary embolism. “There was

Patients receiving lapatinib plus trastuzumab

80

Patients receiving lapatinib

70 60.7

Survival, wk

24

60 50

41.4

40 30 20 10 0

Figure. Comparison of overall survival.

Patients had HER2-positive metastatic breast cancer and had progressed on trastuzumab-containing regimens.

only one significant grade 3/4 adverse event seen in greater than or equal to 5% of the patients enrolled in this heavily pretreated population and that was diarrhea, almost certainly attributable to lapatinib, at 8% in the combination arm and 7% in the lapatinib arm,” Dr. Blackwell said.

Perspective Lapatinib is the only small molecule inhibitor currently approved for the treatment of HER2-positive breast cancer; it is a dual-targeting agent aimed at HER1 and HER2. Trastuzumab is a monoclonal antibody that targets HER2.

“Because of the different mechanisms of attack on the HER2 receptor, it was very appealing to combine the two agents within the clinical arena without using a chemotherapy backbone,” Dr. Blackwell said.

“In addition, this study was really based on preclinical data that there was synergy between trastuzumab and lapatinib which included enhancement of apoptosis through the downregulation of survivin.” She added that lapatinib has a potential benefit of working against tumors that have become resistant to trastuzumab through a potential resistance mechanism of cleavage of the extracelluar domain, the known binding site for trastuzumab.

Dr. Seidman said the study was important in showing that there was benefit to continuing trastuzumab in patients who appeared to be resistant to the drug.

“These are patients who had Herceptin in combination with a number of different agents and had progressed, and now fairly far along in the course of their disease, lapatinib is being added and they had a 60-week survival at that juncture,” he said. “It’s pretty compelling.”

Dr. Perez pointed out that the results of the trial support the ALTTO study, which is testing four treatment options: trastuzumab alone for 52 weeks; lapatinib alone for 52 weeks; trastuzumab for 12 weeks, followed by a six-week break, then lapatinib for 34 weeks; or lapatinib in combination with trastuzumab for 52 weeks. The study also supports the neo-ALTTO trial, which will study the same regimens but before breast surgery. This latter trial is expected to report results in the next 18 months.

Dr. Blackwell disclosed that she has received honoraria from Genentech and GlaxoSmithKline and served as a consultant to Genentech.

—Kate O’Rourke

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Gastrointestinal Stromal Tumors What Oncologists Need to Know About the Treatment of Localized and Advanced Disease

CHANDRAJIT P. RAUT, MD, MSC Department of Surgery Brigham and Women’s Hospital and Dana-Farber Cancer Institute Assistant Professor of Surgery Harvard Medical School Boston, Massachusetts

G

astrointestinal stromal tumors Illustration by James A. Cooper, MD

(GISTs) are rare, representing only 0.1% to 3% of all

gastrointestinal (GI) malignancies,1-4

but they account for 80% of GI mesenchymal neoplasms. 5 Mazur and Clark coined the descriptive term in 1983 to define intra-abdominal noncarcinomatous neoplasms that lacked the ultrastructural features of smooth muscle cells and immunohistochemical characteristics of nerve cells.6

I N D E P E N D E N TLY DEVELOPED BY MCMAHON PUBLI SHING

C L INIC AL ONCOLOGY NE WS • JANUARY 2010

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Until the late 1990s, there were no objective criteria to classify GISTs. They were frequently misclassified as leiomyomas, leiomyoblastomas, leiomyosarcomas, Schwannomas, or GI autonomic nerve tumors.7 Consequently, the interpretation of clinical results for GISTs published before 2000 is challenging.

Receptor Tyrosine Kinase Mutations Since 1998, a series of major breakthroughs have drastically changed the management of primary and metastatic GIST in particular, and have served as a model for the targeted management of solid tumors in general. The first key development was the 1998 discovery of gain-of-function mutations in the c-kit protooncogene in GISTs.8 KIT encodes the transmembrane KIT receptor tyrosine kinase (TK), which is activated by binding its cytokine ligand, stem cell factor.9 Mutated KIT remains constitutively active even in the absence of ligand binding and results in both unregulated cell growth and malignant transformation.8 More than 85% of GISTs have activating KIT mutations.10 Some GISTs that stain strongly for KIT by immunohistochemistry (KIT-positive) lack KIT mutations,10 whereas KIT-negative GISTs harbor KIT mutations.11 Another 3% to 5% of KIT-negative neoplasms have activating mutations in the platelet-derived growth factor receptor-α (PDGFRA) gene encoding a related receptor TK.12-14

Epidemiology AGE GIST has been documented in individuals of all ages, but is generally a malignancy of adults, with a median age at diagnosis of 60 years (range, 40-80).2,15 No consistent gender predilection has been noted. Occasionally, GISTs may be observed in children, often as a familial syndrome or as part of Carney’s triad (a rare constellation of gastric GIST, extra-adrenal paraganglioma, and

pulmonary chondroma).16,17 Children more commonly present with multifocal gastric GISTs, harbor wild-type KIT/PDGFRA genes, and have a higher incidence of lymph node metastases.18

HEREDITARY GIST Most GISTs are sporadic. However, a growing number of kindreds with germline KIT mutations and at least one family member carrying a PDFGRA mutation have been characterized with a predilection for developing multiple GISTs.19-27 Individuals with GISTs secondary to germline KIT mutations are usually younger than those with sporadic GISTs, but metastases are uncommon.26 GISTs are found in approximately 7% of individuals with von Recklinghausen’s neurofibromatosis (NF1), most commonly in the small intestine.28-30 KIT and PDGFRA point mutations have been reported in 8% and 6% of GISTs, respectively, from patients with NF1.31 Conversely, NF1 gene mutations have not been identified in GISTs in non-NF1 individuals.32

INCIDENCE The true incidence of GIST remains uncertain. Epidemiologic data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program are difficult to interpret because many GISTs were previously misclassified as other GI mesenchymal neoplasms.33 The near doubling in the observed incidence of all GI mesenchymal tumors (more than 80% were GIST), from 0.17 per 100,000 in 1992 to 0.31 per 100,000 in 2002, in a contemporary SEER analysis is potentially the result of an increase in recognition, an increase in screening, and quite possibly a true increase in incidence of the tumor.33 The most recent National Comprehensive Cancer Network (NCCN) guidelines estimate an annual incidence of approximately 5,000 new cases in the United States.34 Population-based studies from Iceland and Sweden identified annual incidence rates of 11 and 14.5 cases per 1 million population, respectively.15,35

Clinical Presentation

Figure 1. Computed tomography image of primary jejunal gastrointestinal stromal tumor.

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GISTs demonstrate a broad spectrum of clinical behavior. In a population-based study, 69% of tumors were symptomatic, 21% were discovered incidentally at surgery, and 10% were discovered at autopsy.15 Small GISTs (<2 cm) may remain asymptomatic, only detected incidentally on radiographic studies, endoscopy, or laparotomy. Approximately 50% to 70% of primary GISTs are identified in the stomach, 25% to 35% in small intestine, 5% to 10% in colon and rectum, 7% in mesentery or omentum, and less than 5% in the esophagus.7,36 Between 15% and 47% of GISTs are metastatic at diagnosis.2,37 Common sites of metastasis include liver, peritoneum, and omentum; lymph node metastases are rare. Unlike other sarcomas, lung and brain metastases are uncommon and appear only late in the disease course, if ever.

Table 1. Risk Assessment for Primary Gastrointestinal Stromal Tumors45 % of Patients With Progressive Disease/Risk Classification, Based on Site of Origin Mitotic Rate

Tumor Size

Stomach

Duodenum

Jejunum/Ileum

Rectum

≤/50 hpf

≤2 cm

0

0

0

0

>2 to ≤5 cm

1.9/very low

8.3/low

4.3/low

8.5/low

>5 to ≤10 cm

3.6/low

insuff. data

24/moderate

insuff. data

>10 cm

12/moderate

34/high

52/high

57/high

≤2 cm

insuff. data

insuff. data

insuff. data

54/high

>2 to ≤5 cm

16/moderate

50/high

73/high

52/high

>5 to ≤10 cm

55/high

insuff. data

85/high

insuff. data

>10 cm

86/high

86/high

90/high

71/high

>5/50 hpf

hpf, high-power field; insuff., insufficient Risk for recurrence based on data from the pre-imatinib era.

Reprinted from Raut CP, Hornick JL, Bertagnolli MM. Advanced gastrointestinal stromal tumor: potential benefits of aggressive surgery combined with targeted tyrosine kinase inhibitor therapy. Am J Hematol/Oncol. 2006;5(12):707-712, with permission from Haymarket Media Inc.

Diagnosis RADIOGRAPHIC STUDIES Contrast-enhanced computed tomography (CT) of the abdomen and pelvis is the most common imaging modality for both initial evaluation and surveillance for recurrence.38 Primary GISTs appear as well-circumscribed, often highly vascular masses associated with hollow viscera (Figure 1). Magnetic resonance imaging (MRI) may be of value in characterizing disease in the liver or around the rectum. [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) is a functional imaging technique that is sensitive in identifying metabolic activity within these tumors. It complements CT for detecting GISTs, characterizing ambiguous masses, monitoring response to therapy, and identifying emergence of drug-resistant clones, but is not specific enough for the diagnosis of the disease.39-41 Routine use of PET for surveillance after complete resection is not recommended.39

ENDOSCOPY, FINE-NEEDLE ASPIRATION,

AND

BIOPSY

Endoscopic ultrasound (EUS) is not generally necessary to evaluate the extent of the disease. Because endoscopic biopsies and EUS-guided fine-needle aspiration (FNA) are not consistently diagnostic,42 diagnosis may require additional cytologic morphology, immunohistochemistry, and reverse transcriptase– polymerase chain reaction analysis for KIT mutations from an EUS-FNA specimen.43 A preoperative biopsy is not routinely necessary for a primary, resectable neoplasm that doctors suspect is GIST. In fact, preoperative biopsy may rupture

a suspected GIST and increase the risk for dissemination. However, if the differential diagnosis includes entities such as lymphoma, which would be treated differently, if neoadjuvant therapy is under consideration, or if there is metastatic disease, then biopsy is appropriate.

Prognostic Factors Most experts now consider all GISTs to have malignant potential. Although tumors less than 1 cm likely have a low risk for recurrence, no tumors can be definitively called benign. Tumor size, mitotic index, and tumor site of origin are the 3 most widely accepted indices predictive of outcomes (Table 1).44,45 The mitotic index may be the most important single variable.46 Individuals with small-bowel GISTs carry a higher risk for progression than those with gastric tumors of comparable size and mitotic count.

Additional independent adverse prognostic factors observed in some but not all studies include high cellular proliferation index,47 aneuploidy,47,48 and telomerase expression.49,50 Univariate analysis suggests that KIT exon 9 mutations and KIT exon 11 deletions involving amino acid W557 and/or K558 have a higher risk for recurrence, whereas point mutations and insertions of KIT exon 11 may have a favorable prognosis.46,51 A macroscopically complete resection with or without microscopically negative margins (R0 or R1 resection, respectively) is better than a macroscopically incomplete resection (R2 resection); there are no data to confirm that a microscopically positive margin (R1 resection) impacts survival.2

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Surgical Therapy The standard of care and only potentially curative therapy for patients with primary, resectable, localized GIST is surgery. The goal of the surgery should be a macroscopically complete resection with an intact pseudo-capsule and a negative microscopic margin (R0 resection). In general, primary GISTs do not invade surrounding organs despite CT appearance.

Wedge or segmental resection of the involved stomach or bowel is typically all that is required. Rarely, a more extensive resection (total gastrectomy for a large proximal gastric GIST, pancreaticoduodenectomy for a periampullary GIST, or abdominoperineal resection for a low rectal GIST) may be necessary. In a series of 140 patients with gastric GISTs, wedge resections were performed in 68%, partial gastrectomies in 28%, and total gastrectomies in only 4%.52 Lymphadenectomy is not required because lymph nodes are rarely involved.

All GISTs at least 2 cm in size should be resected when safely possible, as none of these are considered benign.45 Management of GISTs smaller than 2 cm is more debatable, as their natural history is unknown.

Any symptomatic small GISTs (eg, hemorrhage from erosion through the mucosa) or GISTs that increase in size on serial follow-up should be resected.

Historically, small lesions (<1 cm) have been followed rather than resected. However, with the understanding that all GISTs have malignant potential, the rationale for observation is called into question. Such subcentimeter gastric GISTs are relatively common, found in 22.5% of autopsies in German individuals over the age of 50 and in 35% of Japanese patients undergoing gastrectomy for gastric cancer.53,54 Yet few of these neoplasms ever become clinically relevant, and thus management remains undefined. Further data are required to determine the natural history of these

subcentimeter GISTs. Endoscopic resection of small gastric GISTs has been reported, but because of the inherent risks for positive margins (GISTs frequently involve the muscularis propria), its role remains controversial.55 GISTs 1 to 2 cm in size pose an even greater dilemma.

Again, the natural history of such tumors is not known.

The very low risk for recurrence in patients with GISTs less than 2 cm and a low mitotic index supports a more conservative, nonoperative approach. However, an accurate mitotic index cannot be determined on biopsy or FNA, and thus observation cannot be recommended based on size alone. Resection is preferred, particularly when laparoscopy is possible. The risks and benefits associated with surgery versus observation should be reviewed with the individual patient.

Given the higher risk for aggressive behavior in tumors originating in the small bowel and colon, any GIST in these locations should be resected irrespective of size.

Laparoscopic or laparoscopy-assisted resection of primary GISTs may be performed under appropriate circumstances using standard oncologic principles (Figure 2). Two studies confirmed the safety and feasibility of using a laparoscopic approach early on. Among 35 gastric GISTs resected laparoscopically, no local or distant recurrences were noted for tumors smaller than 4 cm with a median follow-up of 53 months.56 In another study of 50 gastric GISTs (1.0-8.5 cm) resected laparoscopically or using laparoscopy assistance, 92% of patients were diseasefree with a mean follow-up of 3 years.57 The management of surgical margins is not as well defined for GISTs as it is for epithelial tumors such as adenocarcinoma. There are no data supporting the need for the same wide margins of resection typically recommended for adenocarcinomas.58 There also are

A B

C

Figure 2. Endoscopic image of GIST along greater curvature of stomach (A) (arrow). Laparoscopic view of same tumor, with traction sutures placed proximally and distally (B). Stomach partially divided using stapling device (C).

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100 Recurrence-Free and Alive, %

A

90 80 70 60 50 40 30 Total 359 354

20 Imatinib Placebo

10

Events 30 70

0 0

6

12

18

HR, 0.35 (95% CI, 0.22-0.53); P<0.0001

24 30 Time (months)

36

42

48

Number at risk Placebo Imatinib

354 359

188 207

89 105

34 33

8 6

100

B

90 80

Alive, %

70 60 50 40 30 20

Total 359 354

Imatinib Placebo

10

Events 5 8

HR, 0.66 (95% CI, 0.22-2.03); P=0.47

0 0

6

12

18

24 30 Time (months)

36

42

48

Number at risk Placebo Imatinib

354 359

241 226

151 137

58 51

15 15

Figure 3. (A) Recurrence-free survival and (B) overall survival Kaplan-Meier curves from the ACOSOG Z9001 Phase III trial of 1 year of adjuvant imatinib versus placebo after complete macroscopic resection of primary gastrointestinal stromal tumor.76 Reprinted from Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373(9669):1097-1104, with permission from Elsevier.

no data indicating that patients who have an R1 resection require re-excision.34

OUTCOMES Even after a macroscopically complete resection,

disease may recur in as many as 50% of patients, with a median time to recurrence of 24 months.2,59 An R0 or R1 resection is associated with 5-year overall survival (OS) rates of 34% to 63%, whereas R2 resection is associated with 5-year OS as low as 8%.1,2,60-64

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5

A

B

Figure 4. Computed tomography image of large locally advanced gastric gastrointestinal stromal tumor (A) before and (B) after 9 months of neoadjuvant imatinib therapy. Note not only the change in size of the mass, but also the change in density.

Adjuvant Therapy for Primary Disease Another critical advancement in the management of GIST was identification of 2 effective, relatively welltolerated, orally available, targeted tyrosine kinase inhibitors (TKIs), imatinib mesylate (Gleevec, Novartis) and sunitinib malate (Sutent, Pfizer, Inc.). These agents initially were developed for the management of patients with metastatic disease in whom standard systemic chemotherapy and radiation therapy were largely ineffective.1,2,65 The first effective agent identified was

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imatinib, which selectively inhibits several TKIs, including KIT, PDGFRA, and ABL, among others.66-69 Its clinical potential was first demonstrated in a landmark case report of a Finnish patient with metastatic GIST who was treated with a daily dose of imatinib 400 mg and demonstrated a rapid and sustained partial response.70 Several clinical trials have subsequently confirmed that up to 80% of patients with metastatic GIST achieve a complete or partial response or demonstrated disease stability on imatinib.71,72 Because recurrence rates are so high and survival rates so low after an R0/R1 resection, investigators have explored the role of adjuvant therapy with imatinib after resection of primary disease. These trials tested durations of adjuvant imatinib of 12 months (American College of Surgeons Oncology Group73 Z9000, ASOSOG Z9001, China Cooperative Group), 24 months (European Organization for the Research and Treatment of Cancer [EORTC] 62024), or 12 versus 36 months (Scandinavian Sarcoma Group [SSG] XVIII).74-76 For the sake of brevity, only data from the recently published ACOSOG Z9001 trial are discussed in detail. In this Phase III trial, patients with completely resected primary GISTs at least 3 cm in size were randomized to receive either postoperative placebo or imatinib for 1 year. This trial was halted early when a planned interim analysis of 644 evaluable patients confirmed that the 1-year recurrence-free survival (RFS) was significantly better in the imatinib arm (97% vs 83%; P=0.0000014). However, the slope of the Kaplan-Meier curves representing the 2 treatment arms were similar (Figure 3A). This suggested that adjuvant imatinib delayed recurrence, but did not result in a cure.

Furthermore, there was no difference in OS between the 2 treatment arms (Figure 3B). Thus, the long-term impact of adjuvant imatinib currently is unknown. This issue will be explored further in EORTC 62024, which, like ACOSOG Z9001, compared placebo with 400 mg imatinib daily, but in contrast will examine OS as its primary end point. This study completed accrual in late 2008, but results are not yet available nor are they expected for quite some time. The SSG XVIII trial, which also completed accrual in late 2008, will in part address whether 3 years of imatinib results in improved RFS and OS compared with 1 year. However, the eligibility criteria for this trial also allowed enrollment of patients with tumor rupture or metastatic disease, so the data may not be directly applicable to the adjuvant setting. Thus, although adjuvant imatinib does seem to improve RFS, its long-term benefit in terms of OS and the optimal duration of treatment remain unknown. Perhaps most important is the question of whether administration of imatinib as an adjuvant agent following resection of primary disease is better than waiting until objective disease recurrence.

Optimal imatinib dosage in the metastatic setting appears to be related to the mutational status of the primary tumor. Although the adjuvant trials to date employed an imatinib dose of 400 mg daily, it is known that patients with advanced GIST whose

Table 2. Resection and Survival Rates for Cytoreductive Surgery For Advanced GIST After TKI Therapy Author

No. of RTK-I PR/SD on Patients Therapy RTK-I, % PD on RTK-I, %

R0/R1, %

Raut85

69

IM/SU

33

Limited, 47 Generalized, 20

83

Rutkowski89

24

IM

75

25

91

Bonvalot87

22

IM

95

5

68

Andtbacka86

46

IM

45

55

48

DeMatteo78

40

IM/SU

50

Limited, 33 Generalized, 17

Gronchi88

38

IM

71

Limited, 21 Generalized, 8

1-Yr PFS, %

1-Yr OS, %

PR/SD, 80 Limited PD, 33 Generalized PD, 0

PR/SD, 80 Limited PD, 33 Generalized PD, 0

80

PR/SD, 70 Limited PD, 48 Generalized PD, 14

PR/SD, 100 Limited PD, 90 Generalized PD, 36

82

PR/SD, 96 PD, 0

PR/SD, 100 PD, 60

IM, imatinib mesylate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; R0, macroscopically complete resection with negative microscopic margins; R1, macroscopically complete resection with positive microscopic margins; RTK-I, receptor tyrosine kinase inhibitor; SD, stable disease; SU, sunitinib malate Reprinted from Raut CP, Bertagnolli MM. Controversies in the surgical management of GIST in the era of imatinib. Oncology.

2009;23(1):69, 74-76, with permission from CMPMedica LLC.

tumors contain KIT exon 9 mutations have improved survival if treated with 800 mg daily.77 It is not known whether imatinib dosing in the adjuvant setting should be adjusted based on GIST mutational status, an issue further complicated by the fact that mutational status is not routinely determined.

course of preoperative therapy. Data from trials of advanced GIST have demonstrated that maximal radiographic response to imatinib generally required 6 to 9 months of treatment.1,2,64 Consequently, the optimal preoperative imatinib regimen may be upward of 6 months or more as long as continued radiographic response is observed (Figure 4).

Neoadjuvant Therapy for Primary Disease The Radiation Therapy Oncology Group (RTOG) 0312 trial is the only reported multicenter study thus far to evaluate the use of imatinib as a neoadjuvant agent.

In this Phase II trial, patients with resectable primary or recurrent GIST were treated with imatinib 600 mg per day for 8 to 12 weeks before surgery. Patients who did not progress were eligible for surgery followed by 2 years of adjuvant imatinib.78 Of patients with primary GIST, 90% demonstrated an objective response before surgery, and 92% underwent R0/R1 resections. The 2-year RFS was 83%, which compares favorably with the 2-year RFS of 73% reported from the Phase II ACOSOG Z9000 trial, which treated patients with 1 year of adjuvant imatinib (and no neoadjuvant imatinib) after resection of solitary GISTs at least 10 cm in size, ruptured/hemorrhaging GISTs, or multifocal GISTs (<5).

Although it is impossible to compare the results of RTOG 0132 and ACOSOG Z9000, the data raise 2 questions: Does neoadjuvant imatinib improve progression-free survival (PFS)? Is 2 years or more of adjuvant imatinib better than just 1 year?

RTOG 0132 confirmed the safety of neoadjuvant imatinib, but only treated patients with a relatively short

Advanced Disease The majority of patients experience tumor recurrence despite successful resection of their primary tumor. At the time of recurrence, 66% have liver disease and 50% have peritoneal disease.79,80 Imatinib (400 mg/d) is the first-line therapy for advanced (unresectable primary or metastatic) GIST. In patients who develop progressive disease on 400 mg, dose escalation is effective.81-84 If disease progresses on higher doses of imatinib, or if such doses are not tolerated, then second-line sunitinib is started. When sunitinib resistance develops, protocol-based therapies should be considered.

Surgery for metastatic disease or disease rendered resectable following neoadjuvant chemotherapy is a relatively common practice for some solid tumors, such as those from ovarian, testicular, and colonic primary sites. With the advent of imatinib and sunitinib therapy, the philosophy on the role of surgery in the management of advanced GIST is changing. Three observations support the consideration of a similar strategy of aggressive cytoreductive surgery in patients with metastatic GIST on TKI therapy. First, the majority of patients experience durable periods of partial response

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7

1.0

Probability

0.8

Stable disease

0.6

P=0.002

0.4

0.2

P<0.001

Limited disease progression

Generalized disease progression

0

5

10

15 20 25 Time, mo

30

35

40

Figure 5. Progression-free survival after cytoreductive surgery in patients with metastatic gastrointestinal stromal tumor corresponds to response to tyrosine kinase inhibitor therapy at the time of surgery.85 Reprinted from Raut CP, Posner M, Desai J, et al. Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol. 2006;24(15):2325-2331, with permission from the American Society of Clinical Oncology (ASCO). Copyright 2008 ASCO. All rights reserved.

or stable disease on imatinib, lasting months to years.

Second, pathologic complete responses are rare, noted in less than 5% of patients.83,84 Third, response to imatinib is not maintained indefinitely; the median time to progression due to the development of secondary resistance to imatinib is 18 to 24 months.71,72 When drug resistance develops, disease progression may be either limited (progression at one site of tumor, with other tumor deposits showing ongoing response to TKI) or generalized (progression at more than one site).78,85 If imatinib treatment does not cure the patient, but instead suppresses metastatic cells present at the time of resection for a finite period of time, then additional surgery may prolong the time until second-line sunitinib therapy is necessary.

Several single-institution retrospective studies have documented the first PFS and OS rates following extensive cytoreductive surgery in patients with advanced GIST treated with TKI therapy (Table 2).78,85-89 The goal of such operations is to perform an R0 or R1 resection when safely possible. However, the disease frequently may be too extensive to be removed completely,

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in which case progressing lesions are preferentially removed. Following surgery, these patients remain on imatinib indefinitely, as failure to resume imatinib results in rapid disease recurrence.

In the experience at Brigham and Womenâ&#x20AC;&#x2122;s Hospital/Dana-Farber Cancer Institute (BWH/DFCI), liver resections were required in approximately 40% of patients, and more than 60% included peritonectomy and/or omentectomy.85 More than 60% underwent multivisceral resections.85 Radiofrequency ablation may be considered for liver disease. Complication rates ranged from 40% to 60%, although the majority were minor.78 Perioperative deaths were rare, usually occurring in the setting of emergency procedures.87,89 In the BWH/DFCI series, the best results were generally seen in patients whose disease was still responsive to TKI therapy at the time of surgery. The ability to remove all macroscopic disease was greatest in patients demonstrating ongoing response to TKI therapy. After surgery, there was no evidence of any residual disease in 78%, 25%, and 7% of patients with responsive disease, limited progression, and generalized progression, respectively (P<0.0001).85 On the other hand, bulky residual disease remained after surgery in 4%, 16%, and 43% of patients with responsive disease, limited progression, and generalized progression, respectively.

Another critical finding in 3 of the series was that the highest rates of PFS and OS were observed when cytoreductive surgery occurred while the patients were still responding to TKI therapy. PFS rates for patients with ongoing response to TKI therapy (ie, partial response or stable disease at the time of surgery) were 70% to 96% at 1 year after surgery and 72% at 4 years from initiation of imatinib therapy (Figure 5).78,85,88 In contrast, the 1-year PFS for patients with generalized progression ranged from 0% to 14%. OS rates approached 100% at 1 year after surgery in patients responding to TKI therapy and only 0% to 60% at 1 year in the setting of generalized progression. Although patients with limited progression had lower rates of PFS than those with responsive disease, the rates of OS were not consistently different; the benefits of surgery in this population remain uncertain.

Based on these data from limited single-institution series, the patients who seemed to derive the most benefit from cytoreductive surgery were those still responding to TKI therapy at the time of surgery (partial response or stable disease). These patients should be considered for surgery on an individual basis. Patients with generalized progression do not appear to derive any benefit from surgery and are best treated with nonsurgical therapies, except for palliative or emergency purposes. Most importantly, although cytoreductive surgery is feasible, there is still no evidence that outcomes are superior or even equal to those for patients who continue on TKI therapy without surgery. This only can be answered in a randomized clinical trial; such trials are under development in the United States and

already have opened in Europe and China.

Surveillance The postoperative follow-up for patients who have successfully undergone surgical resection of a primary GIST recommended by the NCCN consensus panel includes history and physical examination every 3 to 6 months during the first 5 years and abdomen/pelvis CT scans with IV contrast every 3 to 6 months during the first 3 to 5 years, then annually thereafter.34

Conclusion

histogenesis. Am J Surg Pathol. 1983;7(6):507-519, PMID: 6625048.

7. Miettinen M, Majidi M, Lasota J. Pathology and diagnostic criteria of gastrointestinal stromal tumors (GISTs): a review. Eur J Cancer.

2002;38(suppl 5):S39-S51, PMID: 12528772.

8. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science.

1998;279(5350):577-580, PMID: 9438854.

9. Savage DG, Antman KH. Imatinib mesylate—a new oral targeted therapy. N Engl J Med. 2002;346(9):683-693, PMID: 11870247.

10. Rubin BP, Singer S, Tsao C, et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res. 2001;61(22):8118-8121, PMID: 11719439.

Prior to the development of imatinib, the principal treatment modality for GIST was surgery. Recurrence was common, and survival in the setting of recurrent or metastatic disease was poor. With the advent of therapy with TKIs—first imatinib, and then sunitinib—patient outcomes have improved considerably.

Ongoing studies will establish the role of TKIs as adjuvant and neoadjuvant agents. The type and dose of TKI administered soon may be guided by mutational analysis. Future studies will focus on the integration of surgery with targeted therapy and the development of new agents for drug-resistant GIST. Because of its relatively low toxicity and significant efficacy in treatment of GIST, TKI therapy has altered dramatically the natural history of this disease. Early studies have demonstrated the feasibility and safety of neoadjuvant imatinib for primary GIST and dramatic improvement in RFS with adjuvant imatinib after complete macroscopic resection of primary GIST. They have not adequately addressed the optimal length and dose of adjuvant and neoadjuvant imatinib therapy, defined the subset of candidates most likely to benefit from such therapy, or determined the long-term impact on OS. Studies also suggest that cytoreductive surgery should be considered in a certain subset of patients with advanced disease, but Phase III trial data are necessary to determine if surgery adds any benefit in terms of PFS/RFS and OS over continuing imatinib therapy alone.

11. Emile JF, Theou N, Tabone S, et al. Clinicopathologic, phenotypic, and genotypic characteristics of gastrointestinal mesenchymal tumors. Clin Gastroenterol Hepatol. 2004;2(7):597-605, PMID: 15224284.

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ACOSOG Z9000. ASCO Gastrointestinal Symposium; 2008.

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83. Scaife CL, Hunt KK, Patel SR, et al. Is there a role for surgery in patients with “unresectable” cKIT+ gastrointestinal stromal tumors treated with imatinib mesylate? Am J Surg. 2003;186(6):665-669, PMID: 14672776.

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2006;24(15):2325-2331, PMID: 16710031.

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87. Bonvalot S, Eldweny H, Pechoux CL, et al. Impact of surgery on advanced gastrointestinal stromal tumors (GIST) in the imatinib era. Ann Surg Oncol. 2006;13(12):1596-1603, PMID: 16957966.

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J Surg Oncol. 2006;93(4):304-311, PMID: 16496358.

Figure 2 will appear in a chapter by Dr. Raut in the Atlas of Minimally Invasive Surgical Techniques, edited by Ashley SW and Vernon AH, to be published by Elsevier in 2010.

AUTHOR DISCLOSURES—Dr. Raut discloses that he serves on the advisory board of Novartis.

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CLINICAL ONCOLOGY NEWS • JANUARY 2010

Breast

Sorafenib Potential Partner for Chemo in Metastatic Breast Ca San Antonio—Adding sorafenib to chemotherapy extends progression-free survival (PFS) in patients with locally advanced or metastatic breast cancer (MBC), according to two companion Phase IIb studies.

Presented at the recent San Antonio Breast Cancer Symposium (SABCS), the two studies are part of a series of four worldwide Phase IIb clinical trials testing the use of sorafenib (Nexavar, Bayer Healthcare Pharmaceuticals) in advanced HER2-negative breast cancer in a program called TIES (Trials to Investigate the Effects of Sorafenib in Breast Cancer). Sorafenib is an oral multikinase inhibitor approved for advanced renal cell carcinoma and hepatocellular carcinoma; it is investigational in breast cancer.

Sorafenib Plus Paclitaxel Combo The first study (abstract 44) was a double-blind, randomized placebocontrolled Phase IIb trial that included 237 patients from the United States, India and Brazil with HER2-negative, advanced or MBC. The study randomized 119 patients to paclitaxel (90 mg/ m2 weekly) plus sorafenib 400 mg twice daily and 118 patients to the same dose and schedule of paclitaxel plus placebo.

“The study showed activity for sorafenib. Sorafenib may provide added benefit when combined with paclitaxel compared with single-agent paclitaxel

in the first-line treatment of advanced breast cancer,” said lead investigator, William S. Gradishar, MD, a professor of medicine at Northwestern University Feinberg School of Medicine, in Chicago.

Median PFS was 6.9 months in patients in the sorafenib-containing arm compared with 5.6 months in patients receiving paclitaxel alone, representing a 21% reduced relative risk for death or progression, although this was not statistically significant (P=0.0857).

According to Dr. Gradishar, the failure for PFS to reach statistical significance may have been the result of excess deaths in the sorafenib arm (17 of 20) that were not drug-related. These deaths occurred mainly among 17 patients enrolled in India who died of causes not usually seen in the United States, including malaria and tuberculosis.

“These deaths [in India] appeared to skew the PFS,” Dr. Gradishar said. “Time to progression, which does not include deaths, showed a greater advantage for sorafenib plus paclitaxel spread that looks more impressive.”

The addition of sorafenib increased time to progression by 33%. Median duration of response was 5.6 months in

patients receiving sorafenib compared with 3.7 months in the paclitaxel-alone arm (P=0.0079), and objective response rates were 67% versus 54%, respectively (P=0.0234). Median duration of response was 5.6 months compared with 3.7 months, respectively (P=0.0079).

No unexpected toxicities were reported with the combination of sorafenib and paclitaxel. Hand–foot syndrome was the major toxicity seen in patients receiving sorafenib. Grade 3 hand– foot syndrome occurred in 30% of the sorafenib arm compared with 3% of the paclitaxel-alone arm.

“We are not suggesting that the incidence of hand–foot syndrome is acceptable. As we go forward [with sorafenib], we will have to modify the dose,” Dr. Gradishar said.

According to some researchers not involved in the study, further trials should consider whether the appropriate dose of sorafenib is being used. “It is not clear that the dose of sorafenib in this Phase IIb trial is the best dose. Targeted therapy may not require the maximal dose,” said C. Kent Osborne, MD, director of the Breast Center at Baylor College of Medicine in Houston. “We are learning as we go along, and it is possible that we can get away with a lower dose.”

Sorafenib Plus Capecitabine In a separate Phase IIb study presented at SABCS (abstract 45), investigators tested the combination of sorafenib plus

capecitabine (Xeloda, Roche). According to the lead author Jose Baselga, MD, a professor at Vall d’Hebron University Hospital, Barcelona, Spain, the combination of sorafenib plus capecitabine was tolerable, with no unexpected major toxicities, and the toxicities that did occur were clinically manageable. A significant benefit was found for PFS with the addition of sorafenib, and subgroup analyses confirmed the robust benefit in both first- and second-line therapy for MBC. The SOLTI-0701 trial had a similar design to the trial led by Dr. Gradishar; 220 patients with HER2-negative MBC from Spain, France and Brazil were randomized in a 1:1 fashion to receive capecitabine 1,000 mg/m2 for 14 of every 21 days and sorafenib 400 mg twice daily continuously or the same dose and schedule of capecitabine plus placebo.

The dose of capecitabine in this trial is lower than the approved dose of 1,250 mg/m2, Dr. Baselga said. Treatment was continued until progression or unacceptable toxicity.

Patients were over the age of 18 with confirmed HER2-positive, locally advanced unresectable or MBC. Seventy percent were hormone receptorpositive; 80% had one prior adjuvant or neoadjuvant chemotherapy. Prior bevacizumab was an exclusion criterion.

The investigators found that the regimen was well tolerated. Most adverse events were grade 1 or 2, with the see SORAFENIB, page 26

Colon

COLON HIGHLIGHTS continued from page 17

marker for EGFR inhibition based on a small analysis (N=113) by Di Nicolantonio (J Clin Oncol 2008;26:57055712, PMID: 19001320). This retrospective analysis indicated that in the presence of the BRAF mutation, the benefit of EGFR inhibition may be possibly negated despite having a KRAS wild-type tumor. These new data strongly indicate that BRAF may be more of a prognostic indicator than predictive.

ClinOnc: What does this potentially mean for clinicians down the road?

Dr. Eng: The presence of the BRAF mutation may serve as a poor prognostic indicator for patients and physicians and will aid in decision making, analogous to our concerns regarding histology, number of involved lymph nodes and/or dissected, and gastrointestinal perforation.

ClinOnc: Are there any other studies you would like to highlight?

Dr. Eng: Toxicity data were reported from the AVANT trial (abstract 6010) that is evaluating the role of bevacizumab (Bev; Avastin, Genentech) in combination with FOLFOX as adjuvant therapy in

stage II and III colon cancer patients. Clinicians are anxiously awaiting the final results of AVANT. At ASCO 2009, investigators reported that 12 months of bevacizumab did not improve the DFS of patients versus that of six months of adjuvant FOLFOX alone (NSABP C-08). In AVANT, of those individuals who received FOLFOX/Bev in the adjuvant setting, 8.3% of patients versus 5.5% developed a venous thrombotic event. The arterial thrombotic event rate was similar—1.6% for the investigational arm versus 1%.

The final results of the COIN trial also were reported (abstract 5733). COIN was a three-arm, Phase III trial of oxaliplatin therapy (continuous vs. intermittent oxaliplatin) with a third arm that included cetuximab. In the final results of this trial, a difference in OS or PFS was not identified, even in the KRAS wild-type patient. The results are a bit perplexing—they conflict with data from the Phase III CRYSTAL and the Phase II OPUS trials. It is important to note that a majority of patients received capecitabine (1,000 mg/m2 bid, days 1-14) in combination with oxaliplatin (Eloxatin, Sanofi-Aventis) resulting in approximately 50% of the patients requiring a dose reduction because of grade 3/4 toxicities. The question then is—did these patients not fare well due to the toxicity of the capecitabine combination or possibly because of the decreased efficacy of cetuximab in combination with oxaliplatinbased therapy? It will be very interesting to see how

the authors will account for these differences after they analyze their data further.

ClinOnc: Which trials are clinicians eagerly anticipating results from in 2010?

Dr. Eng: We await the final results from the AVANT trial. Its results may impact the ongoing ECOG 5202 stage II adjuvant trial. The other trial of interest includes NSABP R-04, which is examining the role of oxaliplatin versus fluoropyrimidine-based therapy for radiosensitization in patients with rectal carcinoma. The STAR trial and the ACCORD 12 were conducted with our European colleagues and showed that the addition of oxaliplatin for radiosensitization for rectal cancer resulted in increased toxicities with no additional benefit for pathologic complete response rate. NSABP R-04 is near accrual completion, so I presume toxicity results will be available in 2011. However, there are many interesting biologic agents in Phase I/II development, so I am eager to see the role of these various agents in advanced colorectal cancer (c-met, IGF-R, src-kinase, PARP, etc.) especially given the increased recognition of the significance of predictive and prognostic markers.

It is imperative that all investigators continue to encourage patients to provide blood and tissue for correlatives.

As you can see, our understanding of colorectal carcinogenesis is evolving daily.

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JANUARY 2010

Lung

In NSCLC ...

TS Biomarker Ready for Routine Clinical Application San Francisco—After EGFR mutation status, thymidylate synthase (TS) may be one of the most promising biomarkers for individualizing therapy in patients with advanced non-small cell lung cancer (NSCLC).

This news comes from presentations at the 13th World Conference on Lung Cancer (B2.6 and D7.1). Although high TS expression is correlated with squamous cell histology, it appears to be a much more specific predictor of response to folate antimetabolites such as pemetrexed (Alimta, Eli Lilly). The level of TS expression is likely the primary reason that squamous cell NSCLC responds poorly to chemotherapies such as pemetrexed. However, not all squamous cell NSCLCs have high TS levels and not all non-squamous cell NSCLCs have low TS levels.

In one of the studies presented at the 13th World Conference on Lung Cancer exploring the potential clinical value of measuring TS, median TS RNA expression was almost twice as great in squamous cell carcinomas as in adenocarcinomas (4.10 vs. 2.5 × 10(–3); P<0.001), but there was tremendous overlap of expression ranges in individual patient tumors, according to David R. Gandara, MD. Dr. Gandara, director of the Thoracic Oncology Program at the University of California, Davis Cancer Center, Sacramento, said that evaluation of TS levels might allow clinicians to individualize treatment irrespective of histology.

The ability of TS gene expression to predict response to pemetrexed on an experimental basis has been recognized for several years (J Clin Oncol 2006;24: abstract 13058). These studies have associated low numbers of TS gene copies with sensitivity to pemetrexed and high numbers with resistance. Clinically, differences in response to pemetrexed have been correlated with histology. Most recently, a maintenance study with pemetrexed after first-line chemotherapy found almost all benefit confined to nonsquamous NSCLC (J Clin Oncol 2009;27: abstract CRA8000). However, histology may be a surrogate for

Ribbon diagram of human thymidylate synthase in complex with deoxyuridine monophosphate (orange) and the antimetabolite chemotherapy drug raltitrexed (lime green).

TS expression and a much less sensitive discriminator for treatment choice.

“Our findings suggest that such molecular biomarkers as TS as well as others in development will supplant histology in decision making for personalizing pemetrexed therapy in patients with NSCLC,” Dr. Gandara said.

TS, an important enzyme in the pathway of DNA and RNA synthesis, is easily and reproducibly quantified with standard immunohistochemistry techniques, but it still requires tissue samples. The new studies indicate that an important shift is under way in the routine

management of patients with advanced NSCLC, independent of TS measurements specifically. The need to collect tissue samples to better characterize NSCLC and identify the best therapies was an often-repeated refrain during the course of the World Congress.

“While we are trying to better assess histology, biomarkers and gene profiles, what we are realizing is that the most important first step is getting adequate tissue,” said Sarita Dubey, MD, assistant clinical professor of medicine in the Division of Medical Oncology, University of California, San Francisco. Cautioning that the time is rapidly approaching when “it is no longer going to be acceptable to have just a FNA [fine needle aspiration] for advanced NSCLC,” Dr. Dubey predicted that biopsy “is going to be a standard of care.”

The list of therapies that might be guided by biomarker status is lengthening quickly. At the World Congress, data were presented associating positive EGFR mutation status with greater response to tyrosine kinase inhibitors (TKIs), low ERCC1 expression with greater response to platinum chemotherapy and low RRM1 expression with greater response to gemcitabine (Gemzar, Eli Lilly). George R. Simon, MD, director of the Thoracic Oncology Program at Fox Chase Cancer Center, Philadelphia, a member institution of the National Comprehensive Cancer Network, suggested that individualized chemotherapy may change the disease course.

“We postulate that the tumors low in ERCC1/RRM1 will upregulate their ERCC1/RRM1 after they are exposed to platinum/gemcitabine, thereby altering the intrinsic disease biology to a more indolent form, the benefit of which will persist well after the chemotherapy has been discontinued,” said Dr. Simon, who provided clinical data from prospective studies that led to the generation of this postulate. Although the survival benefit of individualized therapy relative to conventional chemotherapy (not guided by biomarkers) is still being confirmed in ongoing prospective randomized trials, the studies presented at the World Congress capture an important direction in NSCLC research and care.

—Ted Bosworth

Breast

SORAFENIB continued from page 25

exception of grade 3/4 hand–foot syndrome, which occurred in 45% of the experimental arm compared with 13% of patients receiving only capecitabine. Management of hand–foot syndrome was prespecified in the protocol. For grade 2, 3 and higher, sorafenib was withheld until the condition resolved; a reduced dose was initiated for grade 3 and higher. In the patients who received sorafenib, 65% discontinued treatment due to adverse events compared with 29% of patients in the

capecitabine plus placebo arm. Treatment discontinuations due to progressive disease also were higher in the patients who received sorafenib, 15% compared with 7%.

Sorafenib significantly increased median PFS: 6.4 compared with 4.1 months (P=0.006), representing an absolute improvement of 2.3 months and a 42% relative risk reduction in progressive disease or death. Response rates were 38% and 30.7%, respectively. In a prespecified subgroup analysis, median PFS in the first-line setting was 7.6 versus 4.1 months, representing a 50% relative risk reduction with the addition of sorafenib. In the second-line setting,

median PFS was 5.7 versus 4.1 months, for a 35% relative risk reduction.

More Study Needed “These are impressive results but the toxicity is worrying,” said Stephen R.D. Johnston, MA, PhD, of Royal Marsden NHS Foundation and Trust and Institute of Cancer in London, who was not involved with the study. At the SABCS, he asked Dr. Baselga what percentage of the prescribed dose of sorafenib patients were able to receive. Dr. Baselga said the majority had dose reductions of capecitabine and sorafenib for grade 3 toxicity and only 10% of the sample kept to the initial dose.

According to other clinicians not involved with the studies, the trials show sorafenib has promise in MBC, but larger studies are needed to confirm the preliminary suggestion of benefit and optimal dosing needs to be studied. “Although promise is demonstrated for sorafenib-based chemotherapy combinations based on these studies, additional study is needed to maximize efficacy and reduce toxicity,” said Maura Dickler, MD, attending physician in the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, New York City.

—Alice Goodman

PRN

CLINICAL ONCOLOGY NEWS • JANUARY 2010

Communication

Five Steps To Delivering an Effective Presentation Being asked to present at a medical conference or to a group of your peers can be challenging and, for some, even frightening.

T

oo often, one struggles to prepare and deliver a presentation while the audience struggles to maintain interest. Most presenters, even those who fail, begin with good intentions. But effective public speaking is a learned skill that can be honed by applying specific techniques. The fastest way to improve your presentation skills is to learn the five basic principles of communication: 1. Understand your audience; 2. Define your purpose; 3. Have a clear message; 4. Organize your content for optimal impact; and 5. Maintain a natural, relaxed state.

The ability to connect with the audience improves if your presentation is aligned with their needs. Begin by asking yourself some simple questions: Who is my audience? What are their medical backgrounds? What do they hope to gain from my presentation? How much knowledge do they have about this subject? Will they be receptive or hostile to the subject matter? Answering these questions will clarify the needs of the audience, and help you tailor your presentation to heighten its relevance.

Once you have completed the audience analysis, you need to determine the purpose of the presentation. Are you seeking support for your research? Are you trying to establish your credentials, further the quest for a cure, or promote a promising new drug? Presenting copious amounts of information with an ambiguous purpose may frustrate and confuse the audience.

By defining the objectives, you will make it less difficult to create the presentation and easier for your audience to understand its content.

Next, state your message in a clear and concise manner. Your presentation is an opportunity to deliver a message that can motivate and inspire the audience.

Remember that you are the expert on the subject and your audience may not have the same depth of understanding. Keeping the message brief, specific and repeatable will guide audience members in their interpretation of what you are saying. Ask yourself, “If they only remember one key concept about my talk, what is it I want them to remember?” Then state that concept clearly throughout the presentation.

Every major point of your talk should end with, “…and that’s why it is so important that we fund this research”; or “…drug X accomplishes this goal”; or “…and this will help us provide cost-effective care.”

After clarifying your message, it is

essential to develop a strategy for effectively delivering the content. Your format will affect the overall impression with which you leave the audience. There are five formats from which to choose when presenting

medical or clinical information; make sure you choose the one that best conveys your message. They are: 1. Timing—arrange information in sequential order; 2. Climax—deliver the main points in order of escalating importance; 3. Problem/Solution—present a problem followed by a solution and its benefits; 4. Classification—focus the presentation on important items that are not delivered in any particular order; and

5. Simple/Complex—arrange information from the simplest concepts to the most complex.

When delivering your content, remember that body language communicates a variety of information to the audience. It is important to recognize that the audience is not only listening to your presentation, but also is interpreting any nonverbal messages you may be sending. It is critical that you project confidence, while at the same time appearing relaxed during see PRESENTATION, page 29

In the treatment of patients with documented iron deficiency in whom oral administration is unsatisfactory or impossible

Making the Case for INFeD ®

Broad usage1 Allows FDA-approved treatment of a wide range of patients with documented iron deficiency anemia

Proven safety profile of iron dextran In a retrospective analysis of 841,252 doses, dyspnea, hypotension, and neurological symptoms were the most common major adverse drug events (ADEs)2 — The most common minor ADEs were nausea, vomiting, flushing, and pruritus2 Serious adverse events are rare — In a nonuremic population, 3 serious adverse events occurred in 481 patients (0.6%) receiving 2099 iron dextran injections (0.1%), with no fatalities reported3 — In a retrospective analysis of 61,950 hemodialysis patients, the incidence of reactions requiring resuscitative medications was 0.0016% (7 episodes in 440,406 exposures)4 Iron dextran products are not clinically interchangeable1 — Differ in chemical characteristics and may differ in clinical effects Important Safety Information1 Anaphylactic-type reactions, including fatalities, have followed the parenteral administration of iron dextran injection. A test dose should be administered prior to the first therapeutic dose, followed by the full therapeutic dose if no signs or symptoms of anaphylactic-type reactions are seen. Resuscitation equipment and personnel trained in the detection and treatment of anaphylactic-type reactions must be readily available during all INFeD® administrations. Patients should be observed for signs or symptoms of anaphylactic-type reactions during all INFeD® administrations. Fatal reactions have followed the test dose and have also occurred in situations where the test dose was tolerated. Use INFeD® only in patients in whom clinical and laboratory investigations have established an iron deficient state not amenable to oral iron therapy. Patients with a history of drug allergy or multiple drug allergies may be at increased risk of anaphylactictype reactions. INFeD® should be used with caution in individuals with histories of significant allergies and/or asthma, and is contraindicated in patients with hypersensitivity to the product and patients with all anemias not associated with iron deficiency. INFeD® should be used with extreme care in patients with serious impairment of liver function, and should not be used during the acute phase of infectious kidney disease.

Unwarranted therapy with parenteral iron will cause excess storage of iron with the consequent possibility of exogenous hemosiderosis, which is particularly apt to occur in patients with hemoglobinopathies and other refractory anemias.

Please see next page for references and brief summary of full Prescribing Information.

www.infed.com

© 2009, Watson Pharma, Inc., Morristown, NJ 07960. All rights reserved. 06107 11/09

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FDA NEWS

Arzerra Gets Accelerated Approval for CLL

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he FDA has granted accelerated approval to ofatumumab (Arzerra, GlaxoSmithKline) for the treatment of patients with chronic lymphocytic leukemia (CLL) that is refractory to fludarabine (Fludara, Berlex Laboratories) and alemtuzumab (Campath, Berlex).

The approval is based on results from a study of 59 patients with CLL who were refractory to both fludarabine and alemtuzumab. In this population, 42% responded to treatment with ofatumumab; median duration of response in patients who responded was 6.5 months.

CLINICAL ONCOLOGY NEWS • JANUARY 2010

The drug’s safety was evaluated in 181 patients in two studies of patients with cancer. Common side effects included a decrease in normal white blood cells, pneumonia, fever, cough, diarrhea, reduced red blood cell counts, fatigue, shortness of breath, rash, nausea, bronchitis and upper respiratory tract infections. The most serious side effects of ofatumumab are increased risks for infections, including progressive multifocal leukoencephalopathy. Patients at high risk for hepatitis B should be screened before being treated with ofatumumab. Patients with evidence of inactive hepatitis should be monitored for reactivation of the infection during

and after completing treatment.

Further studies are needed for the accelerated approval to be turned into full approval.

Istodax for Patients With Cutaneous T-cell Lymphoma

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he FDA has approved romidepsin (Istodax, Gloucester Pharmaceuticals) for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. Approval was based on overall response rate (ORR), defined as the proportion of patients with confirmed complete response (CR) or partial response (PR). The drug, a histone

References: 1. INFeD® full Prescribing Information. Watson Pharma, Inc. September 2009. 2. Fletes R, Lazarus JM, Gage J, Chertow GM. Suspected iron dextran-related adverse drug events in hemodialysis patients. Am J Kidney Dis. 2001;37:743-749. 3. Hamstra RD, Block MH, Schocket AL. Intravenous iron dextran in clinical medicine. JAMA. 1980;243:1726-1731. 4. Walters BAJ, Van Wyck DB. Benchmarking iron dextran sensitivity: reactions requiring resuscitative medication in incident and prevalent patients. Nephrol Dial Transplant. 2005;20:1438-1442.

Drug/Laboratory Test Interactions: Large doses of iron dextran (5 mL or more) have been reported to give a brown color to serum from a blood sample drawn 4 hours after administration.

The drug may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium.

Serum iron determinations (especially by colorimetric assays) may not be meaningful for 3 weeks following the administration of iron dextran.

Serum ferritin peaks approximately 7 to 9 days after an intravenous dose of INFeD and slowly returns to baseline after about 3 weeks.

BRIEF SUMMARY: For full Prescribing Information, see package insert.

WARNING: RISK FOR ANAPHYLACTIC-TYPE REACTIONS Anaphylactic-type reactions, including fatalities, have followed the parenteral administration of iron dextran injection. ß Have resuscitation equipment and personnel trained in the detection and treatment of anaphylactictype reactions readily available during INFeD administration.

Examination of the bone marrow for iron stores may not be meaningful for prolonged periods following iron dextran therapy because residual iron dextran may remain in the reticuloendothelial cells.

Bone scans involving 99m Tc-diphosphonate have been reported to show a dense, crescentic area of activity in the buttocks, following the contour of the iliac crest, 1 to 6 days after intramuscular injections of iron dextran.

Bone scans with 99m Tc-labeled bone seeking agents, in the presence of high serum ferritin levels or following iron dextran infusions, have been reported to show reduction of bony uptake, marked renal activity, and excessive blood pool and soft tissue accumulation.

Carcinogenesis, Mutagenesis, Impairment Of Fertility: See WARNINGS.

ß Administer a test INFeD dose prior to the first therapeutic dose. If no signs or symptoms of anaphylactic-type reactions follow the test dose, administer the full therapeutic INFeD dose.

Pregnancy: Pregnancy Category C: Iron dextran has been shown to be teratogenic and embryocidal in mice, rats, rabbits, dogs, and monkeys when given in doses of about 3 times the maximum human dose.

ß During all INFeD administrations, observe for signs or symptoms of anaphylactic-type reactions.

Fatal reactions have followed the test dose of iron dextran injection. Fatal reactions have also occurred in situations where the test dose was tolerated.

No consistent adverse fetal effects were observed in mice, rats, rabbits, dogs and monkeys at doses of 50 mg iron/kg or less. Fetal and maternal toxicity has been reported in monkeys at a total intravenous dose of 90 mg iron/kg over a 14 day period. Similar effects were observed in mice and rats on administration of a single dose of 125 mg iron/kg. Fetal abnormalities in rats and dogs were observed at doses of 250 mg iron/kg and higher. The animals used in these tests were not iron deficient. There are no adequate and well-controlled studies in pregnant women. INFeD should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

ß Use INFeD only in patients in whom clinical and laboratory investigations have established an iron deficient state not amenable to oral iron therapy. ß Patients with a history of drug allergy or multiple drug allergies may be at increased risk of anaphylactic-type reactions to INFeD. INDICATIONS AND USAGE: Intravenous or intramuscular injections of INFeD are indicated for treatment of patients with documented iron deficiency in whom oral administration is unsatisfactory or impossible.

CONTRAINDICATIONS: Hypersensitivity to the product. All anemias not associated with iron deficiency.

WARNINGS: Risk for Anaphylactic-type Reactions: Anaphylactic-type reactions, including fatalities have followed the parenteral administration of iron dextran. Always have resuscitation equipment and personnel trained in the detection and treatment of anaphylactic-type reactions readily available during INFeD administration. Prior to the first therapeutic dose, administer a test INFeD dose of 0.5 mL. (See DOSAGE AND ADMINISTRATION.) Although reactions are usually evident within a few minutes, observe patients for at least one hour before administering the therapeutic dose. During all INFeD administrations, observe patients for signs or symptoms of anaphylactic-type reactions. Fatal reactions have followed the test dose of iron dextran and have also occurred in situations where the test dose was tolerated. Use INFeD only in patients in whom clinical and laboratory investigations have established an iron deficient state not amenable to oral iron therapy.

The factors that affect the risk for anaphylactic-type reactions to iron dextran products are not fully known but limited clinical data suggest the risk may be increased among patients with a history of drug allergy or multiple drug allergies.

Additionally, concomitant use of angiotensin-converting enzyme inhibitor drugs may increase the risk for reactions to an iron dextran product. The extent of risk for anaphylactic-type reactions following exposure to any specific iron dextran product is unknown and may vary among the products.

Iron dextran products differ in chemical characteristics and may differ in clinical effects. Iron dextran products are not clinically interchangeable.

Delayed Reactions: Large intravenous doses, such as used with total dose infusions (TDI), have been associated with an increased incidence of adverse effects. The adverse effects frequently are delayed (1-2 days) reactions typified by one or more of the following symptoms: arthralgia, backache, chills, dizziness, moderate to high fever, headache, malaise, myalgia, nausea, and vomiting. The onset is usually 24-48 hours after administration and symptoms generally subside within 3-4 days. The etiology of these reactions is not known. The potential for a delayed reaction must be considered when estimating the risk/benefit of treatment.

Placental Transfer: Various animal studies and studies in pregnant humans have demonstrated inconclusive results with respect to the placental transfer of iron dextran as iron dextran. It appears that some iron does reach the fetus, but the form in which it crosses the placenta is not clear.

Nursing Mothers: Caution should be exercised when INFeD is administered to a nursing woman. Traces of unmetabolized iron dextran are excreted in human milk.

Pediatric Use: Not recommended for use in infants under 4 months of age. (See DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS: Severe/Fatal: Anaphylactic reactions have been reported with the use of iron dextran injection; on occasions these reactions have been fatal. Such reactions, which occur most often within the first several minutes of administration, have been generally characterized by sudden onset of respiratory difficulty and/or cardiovascular collapse.

Because fatal anaphylactic reactions have been reported after administration of iron dextran injection, the drug should be given only when resuscitation techniques and treatment of anaphylactic and anaphylactoid shock are readily available.

(See BOXED WARNING and PRECAUTIONS: General, pertaining to immediate availability of epinephrine.)

Cardiovascular: Chest pain, chest tightness, shock, cardiac arrest, hypotension, hypertension, tachycardia, bradycardia, flushing, arrhythmias. (Flushing and hypotension may occur from too rapid injections by the intravenous route.)

Dermatologic: Urticaria, pruritus, purpura, rash, cyanosis.

Gastrointestinal: Abdominal pain, nausea, vomiting, diarrhea.

Hematologic/lymphatic: Leucocytosis, lymphadenopathy.

Musculoskeletal/soft tissue: Arthralgia, arthritis (may represent reactivation in patients with quiescent rheumatoid arthritis – See PRECAUTIONS: General), myalgia; backache; sterile abscess, atrophy/fibrosis (intramuscular injection site); brown skin and/or underlying tissue discoloration (staining), soreness or pain at or near intramuscular injection sites; cellulitis; swelling; inflammation; local phlebitis at or near intravenous injection site.

Neurologic: Convulsions, seizures, syncope, headache, weakness, unresponsiveness, paresthesia, febrile episodes, chills, dizziness, disorientation, numbness, unconsciousness.

Respiratory: Respiratory arrest, dyspnea, bronchospasm, wheezing.

Urologic: Hematuria.

Delayed reactions: Arthralgia, backache, chills, dizziness, fever, headache, malaise, myalgia, nausea, vomiting. (See WARNINGS.)

The maximum daily dose should not exceed 2 mL undiluted iron dextran.

Miscellaneous: Febrile episodes, sweating, shivering, chills, malaise, altered taste.

Risk in Patients with Underlying Conditions: INFeD should be used with extreme care in patients with serious impairment of liver function. It should not be used during the acute phase of infectious kidney disease.

OVERDOSAGE: Overdosage with iron dextran is unlikely to be associated with any acute manifestations. Dosages of iron dextran in excess of the requirements for restoration of hemoglobin and replenishment of iron stores may lead to hemosiderosis. Periodic monitoring of serum ferritin levels may be helpful in recognizing a deleterious progressive accumulation of iron resulting from impaired uptake of iron from the reticuloendothelial system in concurrent medical conditions such as chronic renal failure, Hodgkins disease, and rheumatoid arthritis. The LD50 of iron dextran is not less than 500 mg/kg in the mouse.

Adverse reactions experienced following administration of INFeD may exacerbate cardiovascular complications in patients with pre-existing cardiovascular disease.

Carcinogenesis: A risk of carcinogenesis may attend the intramuscular injection of iron-carbohydrate complexes. Such complexes have been found under experimental conditions to produce sarcoma when large doses or small doses injected repeatedly at the same site were given to rats, mice, and rabbits, and possibly in hamsters.

The long latent period between the injection of a potential carcinogen and the appearance of a tumor makes it impossible to measure accurately the risk in man. There have, however, been several reports in the literature describing tumors at the injection site in humans who had previously received intramuscular injections of ironcarbohydrate complexes.

PRECAUTIONS: General: Unwarranted therapy with parenteral iron will cause excess storage of iron with the consequent possibility of exogenous hemosiderosis. Such iron overload is particularly apt to occur in patients with hemoglobinopathies and other refractory anemias that might be erroneously diagnosed as iron deficiency anemias.

INFeD should be used with caution in individuals with histories of significant allergies and/or asthma.

Rx Only Revised: September 2009 Address medical inquiries to: WATSON Medical Communications P.O. Box 1953 Morristown, NJ 07962-1953 800-272-5525

Patients with rheumatoid arthritis may have an acute exacerbation of joint pain and swelling following the administration of INFeD. Reports in the literature from countries outside the United States (in particular, New Zealand) have suggested that the use of intramuscular iron dextran in neonates has been associated with an increased incidence of gramnegative sepsis, primarily due to E. Coli.

Information For Patients: Patients should be advised of the potential adverse reactions associated with the use of INFeD.

The FDA granted approval based on results from two prospective, multicenter, single-arm clinical studies in patients with CTCL. In one study, sponsored by Gloucester Pharmaceuticals, 96 patients with confirmed CTCL after failure of at least one prior systemic therapy were enrolled. The second study, sponsored by the National Cancer Institute, included 71 patients with a primary diagnosis of CTCL who received at least two prior skin-directed therapies or one or more systemic therapies. Patients were treated with romidepsin at a starting dose of 14 mg/ m2 infused over four hours on days 1, 8 and 15 every 28 days.

In both studies, patients could be treated until disease progression at the discretion of the investigator and local regulators. Objective disease response was evaluated according to a composite end point that included assessments of skin involvement, lymph node and visceral involvement, and abnormal circulating T-cells (Sézary cells).

The ORRs in these two trials were similar (34% in the first study and 35% in the second study, respectively) and CR rates were the same (6%). Median response duration was 15 months (range, one to more than 20 months) in the first study and 11 months (range, one to more than 66 months) in the second study. Median time to first response was two months (range, one to six months) in both studies. Median time to CR was six months in the first study and four months in the second study (range, two to nine months). The most common adverse reactions were nausea, fatigue, anemia, infections, electrocardiographic T-wave changes, neutropenia, lymphopenia, thrombocytopenia, vomiting and anorexia.

In the first study, the median number of prior skin-directed therapies and of prior systemic therapies was two for both. In the second study, the median number of prior skin-directed therapies was one and of prior systemic therapies was two. In the first study, 71% of the patients had stage IIB or greater disease and 87% of the patients in the second study had stage IIB or greater disease.

Elitek Effective in Managing Plasma Uric Acid

Anaphylaxis and other hypersensitivity reactions have been reported after uneventful test doses as well as therapeutic doses of iron dextran injection. Therefore, administer a test dose prior to the first therapeutic dose of INFeD. (See BOXED WARNING and DOSAGE AND ADMINISTRATION: Administration.)

Epinephrine should be immediately available in the event of acute hypersensitivity reactions. (Usual adult dose: 0.5 mL of a 1:1000 solution, by subcutaneous or intramuscular injection.) Note: Patients using beta-blocking agents may not respond adequately to epinephrine. Isoproterenol or similar beta-agonist agents may be required in these patients.

deacetylase inhibitor, is expected to be commercially available in January 2010.

Distributed by: Watson Pharma, Inc. Morristown, NJ 07962 Manufactured by: Patheon Italia S.p.A. Ferentino, Italy 03013 251279 S0909

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he FDA has approved rasburicase (Elitek, Sanofi-Aventis) at a daily dose of 0.20 mg/kg intravenously for up to five days for the initial management of plasma uric acid (PUA) levels in

PRN

CLINICAL ONCOLOGY NEWS • JANUARY 2010

Communication

PRESENTATION continued from page 27

your presentation. Speakers who express nervousness through actions transmit discomfort to their audiences. To counter this effect, apply key presentation skills, such as maintaining good eye contact, using purposeful gestures, and speaking in an expressive manner. These skills will enhance your credibility and keep the audience engaged.

The most important of these skills is eye contact. Rather than scanning the audience, focus on one person at a time FDA UPDATE

adults with leukemia, lymphoma and solid tumors receiving anticancer therapy expected to result in tumor lysis syndrome (TLS) and subsequent elevation of plasma uric acid.

Approval was based on data from a Phase III trial that demonstrated the drug significantly reduced PUA levels compared with the current standard of care (oral allopurinol) in adults with hematologic cancers at risk for TLS, a potentially life-threatening complication.

The multicenter, open-label, randomized Phase III trial compared the safety and effectiveness of three treatments for achieving uric acid response: intravenous rasburicase alone daily for five days, intravenous rasburicase daily for day 1 to day 3 followed by oral allopurinol daily for day 3 to day 5, and oral allopurinol alone daily for five days.

The PUA response rate was defined as the proportion of patients with PUA levels of 7.5 mg/dL or lower from day 3 to day 7 after initiation of treatment.

Results showed that among patients treated with rasburicase alone or followed by oral allopurinol, uric acid levels were 2.0 mg/dL or lower in 96% of patients (at four hours of dosing on day 1). There were no failures to control PUA in patients in either rasburicase treatment group. In patients treated with rasburicase alone (n=92), the PUA response rate was 87%, which was higher than that seen in patients treated with oral allopurinol alone (n=91) at 66% (P=0.0009), a statistically significant difference, or in those treated with combined rasburicase and oral allopurinol(n=92) at 78%. The difference in PUA response rate between rasburicase treatment versus rasburicase and oral allopurinol treatment was not statistically significant.

while relaying a full thought. Remaining focused on one person for a complete sentence creates the impression that you are simply having a conversation with the audience rather than delivering a formal presentation. Additionally, this skill helps reduce your nervousness and increases your ability to remain calm.

As you prepare your next presentation for a medical conference or peer group discussion, remember that presenting is a learned skill and not an innate talent. Delivering a powerful and effective presentation requires learning and practicing and, finally, using these

techniques successfully.

— Dalli Simmons Dalli Simmons, certified school psychologist, is a consultant at Exec|Comm LLC, a New York Citybased communications consulting firm, where she coaches medical professionals, scientists and senior-level executives in a wide variety of communication skills. She can be reached at dsimmons@ exec-comm.com.

Part 1 of a 3-Part Series Be sure to watch for more articles on effective communication skills in future issues: PART 2: “Open Body Language: Optimizing Your Nonverbal Communication” PART 3: “The Other Side of a Two-Way Street: Active Listening is Essential for Conversation”

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POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • JANUARY 2010

Reimbursement

DRUG PRICING continued from page 1

in Richfield, Ohio.

The CMS, Ms. Pierce explained, collects charge data from hospitals and then aggregates them to use in a formula for establishing national levels of payment. “If the payment rates are set artificially low—which they may be if too many hospitals fail to maintain their charge master—everyone suffers,” Ms. Pierce said. “So there are compelling reasons why hospitals should scrutinize and update their hospital pharmacy charge masters at frequent intervals—especially when you consider the growth of high-cost drug products such as biologics.”

The study was based on a self-reporting questionnaire that was sent to the directors of pharmacy and chief financial officers at 4,000 U.S. hospitals. A total of 48 states were included in the survey (rural 72%, urban 28%; beds: <100 52%, 100-300 30%, >300 18%). Participation was voluntary and no payments were offered for completing the survey.

Wide Variation Seen The frequency of reviewing and changing line-item drug products varied considerably, said Ms. Pierce. Some of the respondents reported updating the products continually, in “real time,” when manufacturers and distributors announce drug price changes. In contrast, “some of the respondents said they only looked at pricing information in their hospital charge master data once a year,” she said. “And in more than 15% of cases, the respondents said the methodology used to develop the charge master had not been reviewed or changed in more than five years.”

Ms. Pierce acknowledged several limitations to the study, which was discussed at a meeting of the American Society of Health-System Pharmacists.

The findings, for example, were based on only 356 returned surveys. “So from a power calculation standpoint, the sample size is too low for these results to be generalizable,” she said. Additionally, the survey is a self-reporting instrument, “so there’s always the potential for bias—that people’s perceptions come through, rather than objective data.”

Ms. Pierce stressed, however, that the results “do provide a snapshot of what’s happening in hospitals of varying sizes across the United States, and what it suggests is that many facilities may not be paying enough attention to keeping their charge masters up to date.”

Understanding the Problem Asked to explain the lax updating, Ms. Pierce replied, “I don’t think it’s a lack of awareness.” Instead, she cited several factors, particularly the challenge of

managing today’s business while balancing the long-term implications of untimely pricing updates. “Hospitals are scampering to deal with what’s immediately in front of them, especially in this ongoing economic downturn,” she said. As a result, “it just may be too much” to expect hospitals to constantly be thinking about what they do today impacting their reimbursement in the future. Under CMS ratesetting methodology, Ms. Pierce noted, cost reports from today will be used to determine reimbursement rates two years later.

“In hospital-think,” she said, “that two-year time frame is infinity—it’s too far away from what they have to deal with today to survive, whether it be crushing loads of charity care, lost endowments, regulatory and accreditation reviews, a tough new technology rollout and so on.”

Ms. Pierce listed several steps hospitals can take to ensure that their pharmacy charge master is updated consistently.

The first step is to have all stakeholders understand why that process is such an important undertaking for maintaining fiscal health.

“Hospital finance, pharmacy and clinical departments must work synergistically so that updates are not missed,” she said. “If your charges are understated on the charge master, that flows to your cost report into a category called drugs charged to patients, which provides an aggregate snapshot of hospital drug charges. So when Medicare goes to set [national] reimbursement rates and it looks at your data, it is starting with a flawed baseline. Coupled with other hospitals that don’t update regularly, over time, that is going to give Medicare the impression that the products and services you rendered cost you less

than they actually did.”

Hospitals already are under intense financial pressure, she added, “but you don’t need to add to that with flawed charging practices.”

Fixing the Problem Hospitals that want to improve their charge master updating should follow the lead of facilities that excel at the process, Ms. Pierce noted; one common strategy “is the wisdom to get someone at a very senior level to take ownership of this [process].”

Increasingly, Ms. Pierce said, positions such as vice president or senior vice president of the revenue cycle are being created to tackle the hospital charge master as an essential aspect of reimbursement accuracy. Such an approach is important, she added, because the charge master “is just one cog in the wheel of the entire revenue cycle. So appointing someone in

‘The charge master is where the rubber meets the road. I can get a great contract price for a drug, but if I’m not tracking price updates and entering them into the charge master on a regular basis, those savings can go out the window.’

—Rob Adamson, PharmD

a leadership position in finance is crucial to pulling this off.”

The next step is to team up the finance person with a colleague in pharmacy who can take ownership of the pharmacy-specific aspects of the charge master. This commonly, she said, is the pharmacy director, who typically has both the clinical and business acumen to understand the spectrum of drug costs, handling and what needs to be done to ensure adequate payment rates.

“When new drug payment rates and coding are released,” Ms. Pierce explained, “the pharmacy director is usually in an ideal position to bring that new information to the attention of the vice president of revenue cycle or a similar position within finance, and then have the team determine how the information will impact charging strategy going forward.”

A Not Uncommon Failing Rob Adamson, PharmD, corporate vice president of clinical services, Saint Barnabas Health Care System, West Orange, N.J., said he was not surprised that 15% of respondents to Ms. Pierce’s survey failed to upgrade their hospital charge masters. “Most pharmacy departments do a great job negotiating contracts with manufacturers and insurers and in general holding drug costs down as much as possible,” Dr. Adamson said. “But the charge master is where the rubber meets the road. I can get a great contract price for a drug, but if I’m not tracking price updates and entering them into the charge master on a regular basis, those savings can go out the window.”

Saint Barnabas is certainly not immune to the oversight. After more than a year of not tracking its hospital charge master on a regular basis, Dr. Adamson said, the institution found several problems, including wrong reimbursement codes for drugs, out-of-date drug prices and a lack of dose “multipliers” that result in underbilling. “The lesson we learned,” he said, “is that it’s not just about the charge master—there are other pieces to the reimbursement puzzle that have to be in place.”

Accurate charging is all the more important because of the growth of high-ticket pharmaceuticals. “Very few drugs come to market at anywhere near the pricing structure of five to eight years ago,” Dr. Adamson said. “Biologics are a case in point; these treatments can cost hundreds of thousands of dollars per patient per year, and they’re the fastest growing line of the business. You can’t afford to not get this right.”

—David Bronstein

IN BRIEF

CLINICAL ONCOLOGY NEWS • JANUARY 2010

Around the Water Cooler Pediatric Oncologist Leads COG Peter C. Adamson, MD, a pediatric oncologist and leading scientist at the Children’s Hospital of Philadelphia Research Institute, has been selected to lead the Children’s Oncology Group (COG). Dr. Adamson is the director of clinical and translational research and chief of the Division of Clinical Pharma- Peter C. cology and Thera- Adamson, MD peutics at Children’s Hospital. He is also a professor of pediatrics and pharmacology at the University of Pennsylvania School of Medicine, in Philadelphia. He will remain on the staff of Children’s Hospital and on the UPenn faculty while serving as COG chair.

Dr. Adamson came to the Children’s Hospital of Philadelphia in 1999 from the National Cancer Institute.

Dr. Adamson’s previous roles at COG included leading a 21-site Phase I consortium that conducted initial evaluations of drugs being developed to treat cancer in children. During the eight years that Dr. Adamson led this effort, the collaborating sites conducted more than 25 studies designed to test the safety of novel anticancer drugs.

Doctor Wins Lawsuit A radiation oncologist who formerly worked for the University of Pittsburgh Cancer Institute (UPCI) has won a potential $3 million verdict in federal court based on a jury conclusion that the institute retaliated against her for raising discrimination concerns.

The lawsuit by Kristina Gerszten, MD, alleged that she had been discriminated against because of her gender and retaliated against for making a complaint to hospital officials. The jury did not find evidence of sex discrimination, but concluded that she was retaliated against when the UPCI did not hire her as medical director at both University of Pittsburgh Medical Center (UPMC) St. Margaret and at its facility in Natrona Heights, Pa. According to an article in the Pittsburgh Post-Gazette, after leaving her position as medical director of radiation oncology at Magee-Womens Hospital in February 2004, Dr. Gerszten signed a two-year contract under which she traveled to various UPMC cancer centers and provided coverage.

This section brings you news about people and places in the field of oncology. If you have news to share (a new job, an award, a cancer center closure or expansion, etc.), please send information to korourke@mcmahonmed.com.

Dr. Gerszten negotiated her schedule so that she would work only 180 to 200 days each year but would still be considered a full-time employee. According to the Post-Gazette, Dr. Gerszten was given a new, one-year contract at the UPCI in 2006, but in January 2007, the institute chose not to renew. As part of that contract, Dr. Gerszten said, she had an 18-month non-compete clause and was left without work until January 2009.

The jury recommended that Dr. Gerszten be awarded $1.5 million in back pay

and $827,292 in front pay from the UPCI, $200,000 in compensatory damages and $300,000 in punitive damages. A judge will determine the actual amount.

Durden on the Move Donald L. Durden, MD, PhD, has been named professor and vice chair for research in the Department of Pediatrics and research director, Division of Hematology/Oncology at the Rebecca and John Moores Cancer Center of the University of California, San Diego (UCSD).

Dr. Durden was formerly the Aflac Endowed Chair and professor of pediatrics at Emory University School of Medicine and scientific director of basic and translational research at Emory’s Aflac Center for Cancer and Donald L. Durden, MD, PhD Blood Disorders, in Atlanta.

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Based on independent review of disease progression, a statistically significant prolongation in PFS was observed in patients receiving Vectibix® plus BSC vs those patients receiving BSC alone1,2 100% 90%

Kaplan-Meier Plot of PFS Time as Determined by the Independent Review Committee1,2

80%

Proportion Event Free

The first fully human* anti-EGFR monoclonal antibody

70%

Treatment Group Vectibix® + BSC (n=231) BSC Alone (n=232)

P < 0.0001

60% 50% 40% 30% 20% 10% 0% 0

Safety data are available from 15 clinical trials in which 1467 patients received Vectibix®; of these, 1293 received Vectibix® monotherapy and 174 received Vectibix® in combination with chemotherapy.

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy. Withhold Vectibix® for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix®. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage were reported.

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Severe infusion reactions included anaphylactic reactions, bronchospasm, and hypotension. Although not reported with Vectibix®, fatal infusion reactions have occurred with other monoclonal antibody products. Stop infusion if a severe infusion reaction occurs. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®.

Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of a randomized (1:1) clinical trial of patients with previously untreated metastatic colorectal cancer, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions.

In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

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10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 8

8

5

2

2

1

1

1

2

1

1

1

1

1

1

0

Infusion reactions

Important Safety Information including Boxed WARNINGS:

6

232 209 175 149 75 41 31 20 17 11

Q2W dosing

INDICATION: Vectibix® is indicated as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival.

Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®.

4

231 217 209 197 118 85 76 65 49 41 40 40 31 22 19 19 13 8

Prolonged PFS

*Correlation with safety and efficacy is unknown

2

7

7

7

4

4

3

3

3

Weeks Subjects at risk: Vectibix® + BSC BSC Alone

Statistically significant prolongation in PFS time vs BSC alone1,2 The recommended dose of Vectibix® is 6 mg/kg administered over 60 minutes (for doses over 1000 mg infuse over 90 minutes) as an intravenous infusion every 14 days1 The use of premedication was not standardized in clinical trials (the utility of premedication in preventing infusional toxicity is unknown)1 ~1% incidence of severe infusion reactions reported1 - See Important Safety Information including Boxed WARNINGS for infusion reactions

Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. Following the initial fatality, patients with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in such patients is uncertain. Permanently discontinue Vectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.

In the randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm. Additionally, hypomagnesemia (NCI-CTC grade 3 or 4) requiring electrolyte repletion occurred in 2% of patients 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy, and appropriate treatment instituted, as needed.

Exposure to sunlight can exacerbate dermatologic toxicity. It is recommended that patients wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

Dermatologic, mucosal, and ocular toxicities were also reported.

Adequate contraception in both males and females must be used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy.

The most common adverse events of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events of Vectibix® are pulmonary fibrosis, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

Please see brief summary of Prescribing Information on next page.

References: 1. Vectibix® (panitumumab) prescribing information, Amgen.

2. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol.

2007;13:1658-1664.

©2009 Amgen. All rights reserved.

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