Clinical Oncology News - March 2010 - Digital Edition

McMahon Publishing

Advances in Cancer Care CLINICALONCOLOGY.COM • March 2010 • Vol. 5, No. 3

SOLID TUMORS

9

Modified DCF regimen reduces toxicity in gastric cancers without compromising efficacy.

11 21

Y-90 improves survival in patients with unresectable HCC. Debate rages on over anthracycline use in breast cancer.

SUPPORTIVE CARE

25 31 33

New therapies on the horizon for venous thromboembolism.

Possible link suggested between opioids and cancer progression.

Alternative rasburicase dosing proposed for tumor lysis syndrome.

FDA NEWS

35

Rituxan approved for CLL. Generic morphine approved.

Lapatinib gets new indication.

PRN

43

Around the Water Cooler brings you news about people and places in oncology.

CLINICAL TRIALS

44

A list of Phase II and III trials initiated within the past 30 days.

WWW.CMEZONE.COM

In Breast Cancer ...

In Patients With CRC …

Radioactive Seed Localization: A New Gold Standard?

W

ill radioactive seeding replace wire placement for localization of nonpalpable breast cancer tumors?

There are a few obstacles for early adopters of this technique, but the radioactive seed appears to have many advantages and it may be only a matter of time before it catches on in a big way.

Wire localization is the gold standard for breast cancer tumors, but it has its drawbacks. The wire entry site can be far from the tumor, which has an impact on cosmesis. The wire can stray, making the tumor difficult to locate. The procedure can be uncomfortable for patients, and it must be done close to the time of surgery, which requires precise scheduling in the operating room (OR).

Radioactive seed localization may be a strong, if relatively unfamiliar, alternative. An unscientific survey in the lecture see STANDARD, page 8

Is Medical Publishing Due for an Exorcism?

S

everal recent studies, including an influential Journal of the American Medical Association analysis in 2008, and related findings published in the journal late last year, underscore the need for some journals to update their disclosure policies to help illuminate the ghosts lurking behind submitted manuscripts.

The first JAMA study (2008;299: 1800-1812, PMID: 18413874) was startling enough to cause a surge of effort to enforce more authorship transparency. The researchers sifted through the paper trail related to the Merck drug rofecoxib (Vioxx). Although nearly all see EXORCISM, page 24

BRAF Mutations Solidified as Prognostic Marker

Structure of the BRAF protein.

Orlando, Fla.—The BRAF tumor mutation is a marker for poor prognosis in patients with colon cancer, according to an updated analysis from a Phase III Belgian trial.

Presenting the results of the CRYSTAL

(Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial at the Gastrointestinal Cancers Symposium (GCS; abstract 281), Eric Van Cutsem, MD, PhD, professor see BRAF, page 12

POLICY & MANAGEMENT

Staying Ahead of the Curve A

re you worried about new rules and regulations? Have you already pared your expenses to the bone? Are you frustrated with demands by Medicare and insurers for lower reimbursement? Have you thought about leaving your practice or merging into a bigger group or partnering with a hospital? Would you embrace a paradigm shift if it offered you an alternative to this race to the bottom?

Clinicians who are successful today are the ones who have looked at what they do best and brought that piece forward in their practice. Just like the public reaction

when the poorly reported mammogram studies were made, oncologists can settle and support the status quo or they can embrace innovation and move forward to find a better test. They can buy into the current health care delivery paradigm that lowers costs at their expense or they can decide to make their practice about what made them choose oncology as a specialty in the first place.

Race to the Bottom Let’s look at the motivators driving see CURVE, page 36

McMahonMedicalBooks.com Atlas of Diagnostic Oncology: Expert Consult - Online and Print Arthur T. Skarin

EASTON, PA PERMIT #117

PAID For more information, see page 46

PRSRT STD U.S. POSTAGE

Help Deliver

in Chronic Phase Ph+ CML After Gleevec

®

(imatinib mesylate) tablets

WARNING: QT PROLONGATION AND SUDDEN DEATHS TASIGNA prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. TASIGNA should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to TASIGNA administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.

ADVERSE REACTIONS: Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. In CML-CP patients, the most commonly reported drug-related adverse reactions (>10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, and vomiting.

TASIGNA (nilotinib) capsules is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of TASIGNA is based on hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

Please see Important Safety Information, including Boxed WARNING, and brief summary of Prescribing Information on following pages.

TASIGNA delivers cytogenetic response in the chronic phase after Gleevec1 40% of patients achieved an unconfirmed major cytogenetic response (MCyR) (95% CI: 33-46)1 28% of patients achieved an unconfirmed complete cytogenetic response (CCyR) (95% CI: 22-34)1 12% of patients achieved an unconfirmed partial cytogenetic response (PCyR) (95% CI: 8-16)1 Rapid responses: 2.8 months median time to MCyR2

Important study design information1 A single, open-label, multicenter study was conducted to evaluate efficacy and safety in patients with Ph+ CML in the chronic phase with resistance or intolerance to Gleevec. At the time of data cutoff, 280 patients with a minimum follow-up of 6 months were enrolled Of the 280 patients, 232 were evaluable for efficacy. The efficacy end point was unconfirmed MCyR, which included CCyR and PCyR CyR criteria: CCyR (0% Ph+ metaphases) or PCyR (1%-35%). Cytogenetic responses were based on the percentage of Ph+ metaphases among ≥20 metaphase cells in each bone marrow sample

Prescribe TASIGNA for your patients in the chronic phase who are no longer responding or are intolerant to Gleevec1 Patients who are not meeting minimum treatment goals: Complete hematologic response (CHR) at 3 months, CyR at 6 months, or MCyR at 12 months Patients who lose HR or CyR at any time Patients who cannot tolerate Gleevec

References: 1. TASIGNA® (nilotinib) capsules prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; Aug 2009.

2. Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome–positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance.

Blood. 2007;110(10):3540-3546.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936

©2009 Novartis

10/09

C-AM7C-A M7 100 M70019

TASIGNA® (NILOTINIB) CAPSULES IMPORTANT SAFETY INFORMATION INDICATIONS AND USAGE TASIGNA (nilotinib) is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib.

The effectiveness of TASIGNA is based on hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

WARNING: QT PROLONGATION AND SUDDEN DEATHS TASIGNA prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. TASIGNA should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to TASIGNA administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment.

ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.

CONTRAINDICATIONS Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome.

WARNINGS AND PRECAUTIONS Myelosuppression Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Complete blood counts should be performed every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding TASIGNA temporarily or dose reduction.

QT Prolongation TASIGNA prolongs the QT interval. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated, and following dose adjustments. Correct hypokalemia or hypomagnesemia prior to administration and monitor periodically.

Significant prolongation of the QT interval may occur when TASIGNA is inappropriately taken with food, and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided. The presence of hypokalemia and hypomagnesemia may further enhance this effect.

Sudden Deaths There were sudden deaths reported in the safety population and in the expanded access program. Ventricular repolarization abnormalities may have contributed to their occurrence.

Elevated Serum Lipase Caution is recommended in patients with a history of pancreatitis.

Check serum lipase levels monthly or as clinically indicated.

Hepatotoxicity Serum bilirubin and hepatic transaminases The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated.

Electrolyte Abnormalities TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating TASIGNA and monitor periodically during therapy.

Hepatic Impairment Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment and QT interval should be monitored closely.

Drug Interactions The concomitant use of QT prolonging drugs and strong inhibitors or inducers of CYP3A4 should be avoided as they may affect serum concentration of TASIGNA. Concomitant strong CYP3A4 inhibitors The concomitant use of strong CYP3A4 inhibitors or antiarrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine, and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil, and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with TASIGNA be interrupted. If interruption of treatment with TASIGNA is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval, and a dose reduction to ½ the daily dose is recommended (400 mg once daily). If the strong inhibitor is discontinued, a washout period should be allowed before TASIGNA is adjusted upward to the indicated dose. Close monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors. Grapefruit products and other foods that are known to inhibit CYP3A4 should also be avoided.

Concomitant strong CYP3A4 inducers The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone,

phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital). Patients should also refrain from taking St John’s Wort. If patients must be co-administered a strong CYP3A4 inducer, the dose of TASIGNA may need to be increased, depending on patient tolerability. If the strong inducer is discontinued, the TASIGNA dose should be reduced to the indicated TASIGNA dose. TASIGNA is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and UGT1A1.

In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8, and CYP2C9, and decrease the concentrations of drugs which are eliminated by these enzymes. Single-dose administration of TASIGNA to healthy subjects did not change the pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9 substrate). The ability of TASIGNA to induce metabolism has not been determined in vivo. Caution should be exercised when co-administering TASIGNA with substrates for these enzymes that have a narrow therapeutic index. TASIGNA inhibits human P-glycoprotein. If TASIGNA is administered with drugs that are substrates of Pgp, increased concentrations of the substrate are likely and caution should be exercised.

Food Effects Food increases blood levels of TASIGNA. Patients should avoid food 2 hours before and at 1 hour after the dose is taken.

Lactose Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption.

Use in Pregnancy There are no adequate and well controlled studies of TASIGNA in pregnant women. However, TASIGNA may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should avoid becoming pregnant while taking TASIGNA and should be advised of the potential hazard to the fetus if they do.

ADVERSE REACTIONS In chronic phase patients, the most commonly reported adverse reactions (>10%) were rash (33%), pruritus (29%), nausea (31%), fatigue (28%), headache (31%), constipation (21%), diarrhea (22%), and vomiting (21%). The most common (>10%) Grade 3/4 adverse reactions were thrombocytopenia (28%), neutropenia (28%), elevated lipase (15%), and hyperglycemia (11%). In accelerated phase patients, the most commonly reported adverse reactions (>10%) were rash (28%), pruritus (20%), and constipation (18%). The most common (>10%) Grade 3/4 adverse reactions were thrombocytopenia (37%), neutropenia (37%), anemia (23%), and elevated lipase (17%). Other serious adverse reactions included pneumonia,

febrile neutropenia, leukopenia, intracranial hemorrhage, and pyrexia (Grade 3/4: 2%).

DOSE ADJUSTMENTS OR MODIFICATIONS TASIGNA may need to be temporarily withheld and/or dose reduced for QT prolongation, hematological toxicities that are not related to underlying leukemia, clinically significant moderate or severe nonhematologic toxicities, laboratory abnormalities, or concomitant use of strong CYP3A4 inhibitors. With concomitant use of strong CYP3A4 inducers, the dose of TASIGNA may need to be increased, depending on patient tolerability.

For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. For Grade 3 to 4 bilirubin elevations, dosing should be withheld, and may be resumed at 400 mg once daily.

Hepatic impairment If possible, consider alternative therapies. If TASIGNA must be administered to patients with hepatic impairment, a lower starting dose is recommended in patients with hepatic impairment and QT interval should be monitored. The following dose reduction should be considered: For patients with mild (Child-Pugh Class A) or moderate (ChildPugh Class B) hepatic impairment, an initial dosing regimen of 400 mg in the morning and 200 mg in the evening (12 hours apart) per day followed by dose escalation to 400 mg twice daily based on patient tolerability should be considered.

For patients with severe hepatic impairment (Child-Pugh Class C), a starting dose of 200 mg twice daily followed by a sequential dose escalation to 400 mg in the morning and 200 mg in the evening (12 hours apart) per day and then to 400 mg twice daily based on patient tolerability should be considered.

OTHER PATIENTS IN WHOM TASIGNA SHOULD BE USED WITH CAUTION TASIGNA should not be used during pregnancy. Sexually active female patients should use effective contraception during treatment. Women should not breast feed while taking TASIGNA. The safety and effectiveness of TASIGNA in pediatric patients have not been established.

Tasigna® (nilotinib) Capsules Initial U.S. Approval: 2007 BRIEF SUMMARY: Please see package insert for full prescribing information.

WARNING: QT PROLONGATION AND SUDDEN DEATHS Tasigna prolongs the QT interval (5.2). Sudden deaths have been reported in patients receiving nilotinib (5.3). Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome (4). Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored (5.2). Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided (5.7). Patients should avoid food 2 hours before and 1 hour after taking dose (5.8). A dose reduction is recommended in patients with hepatic impairment (5.9).

ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments. (5.2, 5.3, 5.6, 5.12) 1 INDICATIONS AND USAGE Tasigna (nilotinib) is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of Tasigna is based on hematologic and cytogenetic response rates. [See Clinical Studies (14) in the full prescribing information]. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing The recommended dose of Tasigna (nilotinib) is 400 mg orally twice daily. [See Clinical Pharmacology (12.3) in the full prescribing information]. Treatment should continue as long as the patient does not show evidence of progression or unacceptable toxicity.

Tasigna should be taken twice daily at approximately 12 hour intervals and must not be taken with food.

The capsules should be swallowed whole with water. No food should be consumed for at least 2 hours before the dose is taken and no food should be consumed for at least one hour after the dose is taken.

[See Boxed Warning, Warnings and Precautions (5.8), Clinical Pharmacology (12.3) and Clinical Studies (14) in the full prescribing information].

If a dose is missed, the patient should not take a make-up dose, but should resume taking the next prescribed daily dose.

Tasigna may be given in combination with hematopoietic growth factors such as erythropoietin or G-CSF if clinically indicated. Tasigna may be given with hydroxyurea or anagrelide if clinically indicated.

2.2 Dose Adjustments or Modifications QT interval prolongation: Table 1. Dose Adjustments for QT Prolongation ECGs with a QTc >480 msec 1. Withhold Tasigna, and perform an analysis of serum potassium and magnesium, and if below lower limit of normal, correct with supplements to within normal limits. Concomitant medication usage must be reviewed.

2. Resume within 2 weeks at prior dose if QTcF returns to <450 msec and to within 20 msec of baseline.

3. If QTcF is between 450 msec and 480 msec after 2 weeks reduce the dose to 400 mg once daily.

4. If, following dose-reduction to 400 mg once daily, QTcF returns to >480 msec, Tasigna should be discontinued.

5. An ECG should be repeated approximately 7 days after any dose adjustment.

Myelosuppression: Tasigna may need to be withheld and/or dose reduced for hematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 2).

Table 2. Dose Adjustments for Neutropenia and Thrombocytopenia 1. Stop Tasigna, and monitor blood counts Chronic Phase or ANC* <1.0 x 109/L Accelerated Phase and/or platelet counts 2.

Resume within 2 weeks at prior dose if ANC >1.0 x 109/L CML at 400 mg <50 x 109/L and platelets >50 x 109/L twice daily 3. If blood counts remain low for >2 weeks, reduce the dose to 400 mg once daily *ANC = absolute neutrophil count See Table 3 for dose adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases. [See Adverse Reactions (6.1)].

Table 3. Dose Adjustments for Selected Non-hematologic Laboratory Abnormalities Elevated serum lipase 1. Withhold Tasigna, and monitor serum lipase or amylase or amylase ≥Grade 3 2. Resume treatment at 400 mg once daily if serum lipase or amylase return to ≤Grade 1 Elevated bilirubin 1. Withhold Tasigna, and monitor bilirubin ≥Grade 3 2. Resume treatment at 400 mg once daily if bilirubin return to ≤Grade 1 Elevated hepatic transaminases ≥Grade 3

1. Withhold Tasigna, and monitor hepatic transaminases 2. Resume treatment at 400 mg once daily if hepatic transaminases return to ≤Grade 1

Other Non-hematologic Toxicities: If other clinically significant moderate or severe non-hematologic toxicity develops, dosing should be withheld, and may be resumed at 400 mg once daily when the toxicity has resolved. If clinically appropriate, escalation of the dose back to 400 mg twice daily should be considered. For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Serum lipase levels should be tested monthly or as clinically indicated. For Grade 3 to 4 bilirubin elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Bilirubin and hepatic transaminases levels should be tested monthly or as clinically indicated. [See Warnings and Precautions (5) and Use in Specific Populations (8) in the full prescribing information].

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 products may also increase serum concentrations of nilotinib and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, 400 mg once daily (a dose reduction to 1/2 of the original daily dose) is predicted to adjust the nilotinib AUC to the AUC observed without inhibitors.

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 should be allowed before the Tasigna dose is adjusted upward to the indicated dose. Close monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors. [See Boxed Warning, Warnings and Precautions (5.2 and 5.7) and Drug Interactions (7.2) in the full prescribing information].

Concomitant Strong CYP3A4 Inducers: The concomitant use of strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital).

Patients should also refrain from taking St. John’s Wort. If patients must be co-administered a strong CYP3A4 inducer, the dose of Tasigna may need to be increased, depending on patient tolerability. If the strong inducer is discontinued the nilotinib dose should be reduced to the indicated dose. [See Drug Interactions (7.2) in the full prescribing information].

Hepatic Impairment: If possible, consider alternative therapies. If Tasigna must be administered to patients with hepatic impairment, the following dose reduction should be considered: For patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an initial dosing regimen of 400 mg in the morning and 200 mg in the evening (12 hours apart) per day followed by dose escalation to 400 mg twice daily based on patient tolerability should be considered. For patients with severe hepatic impairment (Child-Pugh Class C), a starting dose of 200 mg twice daily followed by a sequential dose escalation to 400 mg in the morning and 200 mg in the evening (12 hours apart) per day and then to 400 mg twice daily based on patient tolerability should be considered. [See Boxed Warning, Warnings and Precautions (5.9) and Use in Specific Populations (8.7) in the full prescribing information].

3 DOSAGE FORMS AND STRENGTHS 200 mg light yellow opaque hard gelatin capsules with a red axial imprint “NVR/TKI.” 4 CONTRAINDICATIONS Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome. [See Boxed Warning].

5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Treatment with Tasigna (nilotinib) can cause Grade 3/4 thrombocytopenia, neutropenia and anemia.

Complete blood counts should be performed every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction. [See Dosage and Administration (2)].

5.2 QT Prolongation Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner. [See Clinical Pharmacology (12.4) in the full prescribing information]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated and following dose adjustments.

Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome.

Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy.

Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food, and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided. [See Drug Interactions (5.7) and Food Effects (5.8)]. The presence of hypokalaemia and hypomagnesaemia may further enhance this effect. [See Electrolyte Abnormalities (5.6), Monitoring Laboratory Tests (5.12), and Warnings and Precautions (5.8)].

5.3 Sudden Deaths There were five sudden deaths reported in patients receiving nilotinib in an on-going study (n=867; 0.6%).

A similar incidence was also reported in the expanded access program. The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.

5.4 Elevated Serum Lipase The use of Tasigna can cause increases in serum lipase. Caution is recommended in patients with a previous history of pancreatitis. Serum lipase levels should be tested monthly or as clinically indicated.

5.5 Hepatotoxicity The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated.

5.6 Electrolyte Abnormalities The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Electrolyte abnormalities must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy.

5.7 Drug Interactions The administration of Tasigna with agents that are strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted.

If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval. [See Boxed Warning, Dosage and Administration (2), and Drug Interactions (7.2) in the full prescribing information].

5.8 Food Effects The bioavailability of nilotinib is increased with food. Tasigna must not be taken with food. No food should be taken at least 2 hours before and at least one hour after the dose is taken. Grapefruit products and other foods that are known to inhibit CYP3A4 should be avoided. [See Boxed Warning, Drug Interactions (7.2) and Clinical Pharmacology (12.3) in the full prescribing information].

5.9 Hepatic Impairment Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment and QT interval should be monitored closely. [See Boxed Warning, Dosage and Administration (2) and Use in Specific Populations (8.7) in the full prescribing information].

5.10 Lactose Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactosecontaining products or of glucose-galactose malabsorption.

5.11 Use in Pregnancy There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Nilotinib caused embryo-fetal toxicities in laboratory animals at maternal exposures that were lower than the expected human exposure at the recommended dose of 400 mg BID. Women of child-bearing potential should avoid becoming pregnant while taking Tasigna and should be advised of the potential hazard to the fetus if they do. [See Use in Specific Populations (8.1) in the full prescribing information].

5.12 Monitoring Laboratory Tests Complete blood counts should be performed every two weeks for the first two months and then monthly thereafter. Chemistry panels should be checked periodically. ECGs should be obtained at baseline, seven days after initiation and periodically thereafter, as well as following dose adjustments. [See Warnings and Precautions (5.2)]. Laboratory monitoring for patients receiving Tasigna may need to be performed more or less frequently at the physician’s discretion.

6 ADVERSE REACTIONS The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in other sections of the package insert. [See Boxed Warning and Warnings and Precautions (5)].

QT prolongation and Sudden Deaths [See Boxed Warning, Warnings and Precautions (5.2, 5.3)] Myelosuppression [See Warnings and Precautions (5.1)] Elevated serum lipase [See Warnings and Precautions (5.4)] Hepatotoxicity [See Warnings and Precautions (5.5)] Electrolyte abnormalities [See Boxed Warning and Warnings and Precautions (5.6)]

6.1 Clinical Trials 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.

In the single open-label multicenter clinical trial, a total of 438 patients were treated (CML-CP=318; CML-AP=120).

The median duration of exposure in days for CML-CP and CML-AP patients is 245 (range 1-502) and 138 (range 2-503), respectively. The median dose intensity of 797 mg/day (range 145-1149) was similar for both the chronic and accelerated phase patients and corresponded to the planned 400 mg twice daily dosing.

The median cumulative duration in days of dose interruptions for the CML-CP patients was 18 (range 1-185), and the median duration in days of dose interruptions for the CML-AP patients was 22 (range 1-163).

In CML-CP patients, the most commonly reported drug-related adverse reactions (>10%) were rash, pruritis, nausea, fatigue, headache, constipation, diarrhea and vomiting. The common serious drugrelated adverse reactions were thrombocytopenia and neutropenia.

In CML-AP patients, the most commonly reported drug-related adverse reactions (>10%) were rash, pruritus and constipation. The common serious drug-related adverse reactions were thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia.

Sudden deaths and QT prolongation were reported. [See Boxed Warning and Warnings and Precautions (5.2 and 5.3)].

Discontinuation for drug-related adverse reactions was observed in 11% of CML-CP and 8% of CML-AP patients.

Table 4 shows the percentage of patients experiencing treatment-emergent adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in at least 10% of patients who received at least one dose of Tasigna are listed.

Table 4. Treatment-Emergent Adverse Reactions Reported in ≥10% of Patients in the Clinical Studya CML-CP CML-AP N=318 N=120 Body System and Preferred Term All Grades CTC Gradesb All Grades CTC Gradesb (%) 3/4 (%) (%) 3/4 (%) Skin and subcutaneous Rash 33 2 28 0 tissue disorders Pruritus 29 1 20 0 Gastrointestinal disorders Nausea 31 1 18 <1 Diarrhea 22 3 19 2 Constipation 21 <1 18 0 Vomiting 21 <1 10 0 Abdominal pain 11 1 13 3 Nervous system disorders Headache 31 3 21 2 General disorders and Fatigue 28 1 16 <1 administration site conditions Pyrexia 14 1 24 2 Asthenia 14 0 12 2 Edema, peripheral 11 0 11 0 Musculoskeletal and Arthralgia 18 2 16 0 connective tissue disorders Myalgia 14 2 14 <1 Pain in extremity 13 1 16 2 Bone pain 11 <1 13 <1 Muscle spasms 11 <1 14 0 Back pain 10 <1 12 <1 Respiratory, thoracic and Cough 17 <1 13 0 mediastinal disorders Dyspnea 11 1 8 3 Infections and infestations Nasopharyngitis 16 <1 11 0 a Excluding laboratory abnormalities b NCI Common Terminology Criteria for Adverse Events, Version 3.0 Table 5 shows the percentage of patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of Tasigna.

Table 5. Incidence of Clinically Relevant Grade 3/4 Laboratory Abnormalities CML-CP CML-AP N=318 N=120 Grades 3/4* Grades 3/4* Hematologic Parameters 37%2 Thrombocytopenia 28%1 Neutropenia2 28% 37%3 Anemia 8% 23% Biochemistry Parameters Elevated lipase 15% 17% Hyperglycemia 11% 4% Hypophosphatemia 10% 10% Elevated bilirubin (total) 9% 10% Elevated SGPT (ALT) 4% 2% Hyperkalemia 4% 3% Hyponatremia 3% 3% Hypokalemia 1% 5% Elevated SGOT (AST) 1% 1% Decreased albumin 1% 1% Hypocalcemia 1% 4% Elevated alkaline phosphatase 1% 3% Elevated creatinine <1% 0% *NCI Common Terminology Criteria for Adverse Events, version 3.0 1CML-CP: Thrombocytopenia: 11% were grade 3, 17% were grade 4 2CML-AP: Thrombocytopenia: 7% were grade 3, 30% were grade 4 3CML-AP: Neutropenia: 12% were grade 3, 25% were grade 4 6.2 Additional Data from Clinical Trials The following drug-related adverse reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (1%-10%), and uncommon (0.1%-1%) adverse reactions single events are captured as unknown frequency. For laboratory abnormalities, very common events (≥1/10) not included in Table 4 are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category.

Infections and Infestations: Uncommon: pneumonia, urinary tract infection, gastroenteritis, pharyngitis.

Unknown frequency: sepsis, bronchitis, herpes simplex, candidiasis.

Blood and Lymphatic System Disorders: Common: febrile neutropenia, pancytopenia.

Unknown frequency: thrombocytosis, leukocytosis.

Endocrine Disorders: Uncommon: hyperthyroidism.

Unknown frequency: hypothyroidism, thyroiditis.

Metabolism and Nutrition Disorders: Common: hypomagnesemia, hyperkalemia, hyperglycemia, anorexia.

Uncommon: hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, dehydration, decreased appetite, increased appetite.

Unknown frequency: diabetes mellitus, hypercalcemia, hyperphosphatemia.

Psychiatric Disorders: Common: Insomnia.

Uncommon: depression, anxiety.

Unknown frequency: disorientation, confusional state.

Nervous System Disorders: Common: dizziness, paresthesia.

Uncommon: intracranial hemorrhage, migraine, tremor, hypoesthesia, hyperesthesia.

Unknown frequency: brain edema, loss of consciousness, optic neuritis, peripheral neuropathy.

Eye Disorders: Uncommon: eye hemorrhage, visual acuity reduced, periorbital edema, conjunctivitis, eye irritation, dry eye.

Unknown frequency: papilloedema, diplopia, vision blurred, photophobia, eye swelling, blepharitis, eye pain.

Ear and Labyrinth Disorders: Common: vertigo.

Unknown frequency: hearing impaired, ear pain.

Cardiac Disorders: Common: palpitations, electrocardiogram QT prolonged.

Uncommon: cardiac failure, angina pectoris, atrial fibrillation, pericardial effusion, coronary artery disease, cardiomegaly, cardiac murmur, bradycardia.

Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, cardiac flutter, extrasysoles.

Vascular Disorders: Common: hypertension, flushing.

Uncommon: hypertensive crisis, hematoma.

Unknown frequency: shock hemorrhagic, hypotension, thrombosis.

Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea, dyspnea exertional, cough, dysphonia.

Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, epistaxis, pharyngolaryngeal pain, throat irritation.

Unknown frequency: pulmonary hypertension.

Gastrointestinal Disorders: Common: abdominal discomfort, dyspepsia, flatulence.

Uncommon: pancreatitis, gastrointestinal hemorrhage, melena, abdominal distension, mouth ulceration, gastroesophageal reflux, stomatitis, dry mouth.

Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus.

Hepatobiliary Disorders: Uncommon: hepatitis.

Unknown frequency: hepatotoxicity, hepatomegaly, jaundice.

Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema, urticaria, alopecia, erythema, hyperhidrosis, dry skin.

Uncommon: exfoliative rash, ecchymosis, swelling face.

Unknown frequency: erythema nodosum, skin ulcer, petechiae, photosensitivity.

Musculoskeletal and Connective Tissue Disorders: Common: musculoskeletal chest pain, musculoskeletal pain.

Uncommon: muscular weakness.

Unknown frequency: arthritis, joint swelling.

Renal and Urinary Disorders: Uncommon: dysuria, micturition urgency, nocturia, pollakiuria.

Unknown frequency: renal failure, hematuria, urinary incontinence.

Reproductive System and Breast Disorders: Uncommon: breast pain, gynecomastia, erectile dysfunction.

General Disorders and Administration Site Conditions: Common: pyrexia.

Uncommon: chest pain, face edema, gravitational edema, influenza-like illness, chills, malaise.

Investigations: Very common: lipase increased.

Common: blood amylase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood glucose increased, weight decreased, weight increased.

Uncommon: blood lactate dehydrogenase increased, blood glucose decreased, blood creatinine increased, blood urea increased.

Unknown frequency: troponin increased, blood potassium decreased, blood bilirubin unconjugated increased.

10 OVERDOSAGE No cases of overdose have been reported. In the event of overdose, the patient should be observed and appropriate supportive treatment given.

16 HOW SUPPLIED/STORAGE AND HANDLING Tasigna (nilotinib) capsules are light yellow opaque hard gelatin capsules, size 0 with the red axial imprint “NVR/TKI.” Tasigna capsules are supplied in blister packs.

Carton of 4 blister packs of (4x28)...............................................................................NDC 0078-0526-87 Blisters of 28 capsules .................................................................................................NDC 0078-0526-51 Each blister pack contains one folded blister card of 28 capsules each, for dosing two in the morning and two in the evening at 12 hour intervals over a 7 day period.

Tasigna (nilotinib) Capsules, 200 mg, should be stored at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

Rev: August 2009 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

T2009-95

8

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • MARCH 2010

Breast

STANDARD

‘Our surgeon stood by Dr. Gray’s side in the OR, and after the few cases he saw, he felt comfortable with the procedure.’

continued FROM PAGE 1

hall where Barbara Pockaj, MD, professor of surgery, chair, Section of Surgical Oncology, Mayo Clinic College of Medicine, in Scottsdale, Ariz., described the method at the 2008 American Society of Breast Surgeons conference showed that few surgeons use or know much about this method.

Radioactive seed localization is starting to gain some traction at various centers across the country. Dr. Pockaj predicted that it will become more popular as surgeons and institutions learn its advantages of more negative margins and greater patient convenience compared with wire localization. Beyond lack of familiarity, impediments to adopting the method include billing and nuclear regulatory issues, but Dr. Pockaj is confident these obstacles can be overcome with a little determination.

Radioactive seed placement is similar to wire placement and relatively simple.

Guided by either a mammogram or ultrasound, a radiologist places one 4.5×0.8mm titanium radioactive seed which contains 0.1 to 0.24 mCi of iodine, into a lesion using an 18-gauge spinal needle. If the clinical situation calls for it, the radiologist can bracket the lesion with more than one seed. Mammography confirms the position of the seed. At surgery, the surgeon uses a gamma probe to locate the seed, and then excises both the lesion and the seed, which is disposed of later following nuclear regulatory guidelines.

In the opinion of proponents of radioactive seed localization, this approach has many advantages over wire localization. “In the big picture, I think there are multiple reasons this is better—most importantly, there is a lower rate of positive margins, by 50% in our studies; this allows for better cosmesis and less trauma to the patient,” Dr. Pockaj said.

The concept of radioactive seeding evolved out of a scheduling mishap at the H. Lee Moffitt Cancer Center, in Tampa, Fla. A patient who was supposed to receive a wire did not, but she had received an intra-tumoral injection of technetium-99. “So the tumor site was radioactive. Between the mammogram and the site, that provided guidance,” said Richard J. Gray, MD, associate professor of surgery at Mayo Clinic College of Medicine, in Scottsdale, Ariz.

Dr. Gray and other surgeons at Moffitt, who were investigating alternatives to wire localization, took note of this case during a brainstorming session and hit on the idea of localizing tumors via the same radioactive seeds used for prostate brachytherapy. In the past decade, Dr. Gray and others conducted several studies to determine the safety and efficacy of radioactive seeding, and have found it an attractive

—Wayne W. Windham, MD

Publications on Radioactive Seed Localization* Cox CE, et al. Ann Surg Oncol. 2003;10:1039-1047, PMID: 14597442.

Gray RJ, et al. Ann Surg Oncol. 2001;8:711-715, PMID: 11597011.

Gray RJ, et al. Am J Surg. 2004;188:377-380, PMID: 15474429.

Jakub JW, et al. Current status of radioactive seed for localization of nonpalpable breast lesions. Am J Surg. 2009 Nov. 30 Epub ahead of print, PMID: 19954769.

Hughes JH, et al. Breast J. 2008;14:153-157, PMID: 18248562. *There will be a chapter on radioactive seed localization in the upcoming book, Master Techniques in Breast Surgery.

Using the gamma probe to re-orient to the position of the radioactive seed during dissection.

Images courtesy of Barbara Pockaj, MD.

Specimen radiograph with radioactive seed and gross specimen.

alternative to wire localization.

Others are concerned that, to date, there has not been a large, multicenter trial of this technique, but Dr. Pockaj does not think this is a problem. “This is really a modification of a known technique, which really does not change the original procedure dramatically; it is similar to using ultrasound guidance for breast lesion excision,” she said.

Patients who get radioactive seeds instead of wires have significantly fewer resections of additional margins and report greater convenience. The cosmetic results also tend to be better. “It has not been statistically significant, but there is a trend toward a decrease in the volume excised,” Dr. Pockaj said. “If you know exactly where you’re going, you can be much more accurate and center your incision so that you are able to take less tissue and get a better cosmetic result.”

Because radioactive seed localization can be done a day or two before surgery, it cuts down on potential scheduling problems. “A wire needs to be placed on the same day as surgery; sometimes this is done at a different site than where the surgery takes place,” requiring patient travel, Dr. Pockaj said. An early morning wire placement also can mean a very long day during a stressful time for the patient.

“This way we tell them there are two separate things they don’t have to worry about; they get their procedure and they’re ready for surgery the next day,” Dr. Pockaj said. “It’s like a pre-op visit.”

Tari A. King, MD, associate attending surgeon on the breast service at Memorial Sloan-Kettering, New York City, said the procedure potentially offers many advantages to both patients and physicians. “Wires are placed with the breast in compression and can become somewhat displaced when the breast is released or during transport from the radiology unit to the operating room,” she said. “As surgeons, we rely on proper placement of the wire and do not often know that this has happened until after the initial excision fails to retrieve the targeted lesion.” The placement of a radioactive seed could potentially give the surgeon more freedom in terms of planning the location of the incision as well as a more precise means of excising the targeted lesion. “If the latter

were to translate into an improved ability to obtain negative margins at the first lumpectomy, while maintaining or improving cosmesis, this would be a significant advance in breast-conserving surgery,” said Dr. King. “The increased efficiency may also translate into a cost savings as we frequently spend a lot of time waiting in the OR with the current procedure.”

So, what about risks? The risks are the same as those associated with wire localization, Dr. Pockaj said, citing a risk for infection, risks related to anesthesia and the possibility of seed migration.

“We’ve not had that problem, but it can happen, and then your ability to excise the lesion is not as good. But this can also happen with wire localization.”

Perhaps the biggest obstacle for surgeons who want to use radioactive seeding is that because the seeds are not FDAapproved for this procedure, there is no approved billing code for the radiologist.

To clarify billing issues: the same Current Procedural Terminology (CPT) code is used for the operative procedure, but the CPT code for the radiologic placement of the radioactive seed must be clarified with payers. Current CPT codes to be considered include 19499, 19290, A4641, 77032 and 76942.

In the past, insurers have covered the radiologic seed placement more frequently than does Medicare. Sometimes securing reimbursement simply requires a bit of persuasion. While Dr. Pockaj was gathering data for a lecture she was scheduled to give on billing issues, she investigated the status of reimbursement for radioactive seeding at the Mayo centers in Florida and Minnesota and discovered that they were successfully being compensated, while Arizona was not. “That didn’t make sense to me, so I went to the source.”

Dr. Pockaj called Medicare and see STANDARD, page 20

9

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • MARCH 2010

Gastric

Modified DCF Regimen Reduces Toxicity in Gastric Cancers Orlando, Fla.—Modifying the docetaxel, cisplatin and fluorouracil regimen (mDCF) given to patients with metastatic gastric and gastroesophageal junction cancers was found to significantly increase its tolerability without compromising its efficacy, during a study presented at the 2010 Gastrointestinal Cancers Symposium (GCS; abstract 46).

DCF is a standard first-line option for metastatic gastric cancer; however, 80% of patients experience grade 3/4 non-hematologic toxicity and 30% develop

The modified regimen was found to be more tolerable than traditional DCF, even when traditional DCF was given with growth factor support.

‘By fine-tuning the regimen, Dr. Shah and his colleagues from multiple centers appear to have maintained the regimen’s efficacy while easing the side-effect profile. This is a much better platform to which targeted agents can be added than the original DCF regimen.’

—Richard M. Goldberg, MD

Table. Comparison of DCF and mDCF Schedules Modified DCF q2wk Drug

Parent DCF q3wk (With G-CSF)

Dose, mg/m2

Drug

Dose, mg/m2

Docetaxel

40

Docetaxel

75

Cisplatin

40

Cisplatin

75

Leucovorin

400

Leucovorin

—

Fluorouracil

400 IV push

Fluorouracil

1,000 IV continuous infusion × 2 d

Fluorouracil

750 IV continuous infusion × 5 d

neutropenia, said Manish A. Shah, MD, an attending physician in gastrointestinal oncology at Memorial Sloan-Kettering Cancer Center, New York City, who presented the study at GCS. “Even though there is a survival advantage for DCF versus cisplatin/5-FU, the utility of DCF is limited by toxicity,” Dr. Shah said. “Our interest was in developing a regimen upon which we could add a targeted agent, and for gastric cancer, we do not have agreement on this. We knew we could not do this with parent DCF, so we modified the regimen. We thought if the toxicity is less and the efficacy good, then modified DCF could be a unifying regimen.”

Toxicity notwithstanding, DCF was approved for use in the metastatic first-line setting of gastric cancer. Because the toxicity was predictable, investigators gave the standard regimen with prophylactic growth factor support.

The Phase III multicenter study included 77 patients with metastatic or unresectable gastric cancer (n=51) or gastroesophageal junction (n=26) adenocarcinoma, previously untreated for metastatic disease. Patients were randomly assigned to standard DCF with prophylactic granulocyte macrophage colony-stimulating factor G-CSF or mDCF (Table).

“We reduced the doses of the drugs and gave them more frequently. Instead of five days of 5-FU, we gave it over 48 hours to reduce mucositis, and gave lower doses of docetaxel and cisplatin to reduce nausea and vomiting and myelosuppression,” said Dr. Shah.

Fifty-eight patients were evaluable for toxicity that occurred in the first three months. Grade 3/4 see MODIFIED DCF, page 10

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • MARCH 2010

Gastric

MODIFIED DCF continued from page 9

hematologic toxicity was seen in 11 of the 28 patients in the mDCF arm compared with 12 of the 30 patients treated with standard DCF. Grade 3/4 non-hematologic toxicity was observed in seven of the 28 patients in the mDCF arm compared with 17 of the 30 patients, respectively, Dr. Shah said. The non-hematologic toxicities were largely nausea and vomiting, fatigue, electrolyte imbalance, mucositis and thrombosis.

Although toxicity was reduced with mDCF, efficacy remained comparable or greater. Response rates were 50% with the modified regimen and 33% with standard DCF. Six-month progression-free survival was 90% compared with 78%; time to treatment failure was 8.6 months compared with 7.1 months; and

overall survival was 14.9 months compared with 12.5 months, respectively.

“We showed in a randomized multicenter study that the modified DCF regimen is indeed less toxic. In fact, the standard arm had to be closed for excessive toxicity, despite the use of prophylactic G-CSF. Of 22 people who developed significant toxicity in the first three months of treatment, we had to admit 16 to the hospital,” Dr. Shah said. “And [mDCF] is at least equally effective.”

According to Richard M. Goldberg, MD, professor and chief of hematology and oncology at the University of North Carolina at Chapel Hill, “Multi-agent

chemotherapy is the preferred standard of care for treating advanced gastric cancer. The modified DCF regimen used in this trial clearly is better tolerated than the original DCF program that has not been widely adopted due to patients’ difficulty tolerating it.

“By fine-tuning the regimen, Dr. Shah and his colleagues from multiple centers appear to have maintained the regimen’s efficacy while easing the side-effect profile,” he said. “This is a much better platform to which targeted agents can be added than the original DCF regimen and the investigators should be congratulated for this important work.”

—Caroline Helwick

Stomach

New Standard of Care Proposed for Gastric Cancer The addition of trastuzumab (Herceptin, Genentech) to standard chemotherapy in patients with human epidermal growth factor 2 (HER2)-positive gastric cancer improves overall survival (OS) without compromising quality of life (QoL), according to a recent study.

The study, which analyzed QoL data from the ToGA trial, was reported at the 2010 Gastrointestinal Cancers Symposium (GCS; abstract 7). “I think through the results of this trial, we have taken an important step forward to increase efficacy and improvement of quality of life during treatment of HER2-positive gastric cancer patients,” said lead investigator Taroh Satoh, MD, from the Kinki University School of Medicine in Osaka, Japan.

At the 2009 annual meeting of the American Society of Clinical Oncology, researchers involved with the ToGA trial reported that the addition of trastuzumab to standard chemotherapy in patients with HER2-positive gastric Percentage of gastric tumors that are HER2-positive

22.1%

‘Increasingly, quality of life is used by bodies such as the National Institute for Clinical Excellence in the United Kingdom to determine whether or not we should be applying treatment to patients.’

—David Cunningham, MD

cancer improves OS by two months (LBA4509). In a study of 3,807 gastric cancer patients, 22.1% had high amounts of HER2 in their tumors. Of these patients, 584 patients with locally advanced, recurrent or metastatic HER2-positive gastric cancer were randomized to receive either standard chemotherapy (5-fluorouracil or capecitabine and cisplatin) plus trastuzumab or standard chemotherapy alone. Trastuzumab was given until disease progression. Median OS was 13.8 months in patients who received trastuzumab compared with 11.1 months in patients who received standard chemotherapy (P=0.0046; Figure).

Safety profiles were similar with no unexpected adverse events in patients receiving trastuzumab. Asymptomatic left ventricular ejection fraction

decreases were reported in 4.6% of patients receiving trastuzumab and 1.1% of patients in the traditional chemotherapy arm. No difference in symptomatic congestive heart failure was identified between the two arms.

At the recent GCS meeting, researchers analyzed QoL data. A total of 563 (>95%) of the patients completed standard European Organisation for Research and Treatment of Cancer QoL questionnaires at baseline and every three weeks (on day 1 of each cycle prior to dosing) until disease progression. They used a standard QoL questionnaire and a disease-specific module for gastric cancer; the scoring range for both was based on a 100-point scale.

Global health status scores improved over time from 51 at baseline to 72 in the trastuzumab-containing arm and 71 in the chemotherapy-only arm. “We don’t see any difference between arms. Trastuzumab … was comparable if not better in the chemotherapy-alone arm,” Dr. Satoh said. “Disease-specific and symptom-specific scores improved over time in both treatment arms.” Pain intensity scores, calculated by the visual analog scale, and use of analgesic medicine were similar between treatment arms.

“For [patients with] advanced gastroesophageal cancer who are HER2positive, the combination of a fluoropyrimidine, a platinum and trastuzumab should become the new standard treatment,” said David Cunningham, MD,

Traditional chemotherapy plus trastuzumab Traditional chemotherapy

15

Overall survival, mo

10

13.8

11.1

10

5

0

Figure. Comparison of overall survival. professor and head of the gastrointestinal and lymphoma units at the Royal Marsden Hospital in London, who was not involved with the study.

He pointed out that QoL studies are becoming increasingly important. “Quality of life is very important to patients,” Dr. Cunningham said. “But increasingly, quality of life is used by bodies such as the National Institute for Clinical Excellence in the United Kingdom to determine whether or not we should be applying treatment to patients, factoring in health economics.”

Dr. Cunningham added that the trial was directed at both gastric and oesophagogastric (OG) junctional tumors. And although the incidence of gastric cancer is declining, the incidence of OG junction cancers is increasing, possibly because of rising rates of gastroesophageal reflux disease, Barrett’s esophagus and obesity.

—Kate O’Rourke

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • MARCH 2010

Liver

Y-90 Adds to the Armamentarium in Unresectable HCC Orlando, Fla.—In patients with unresectable hepatocellular carcinoma (HCC), radioembolization can improve survival, especially in certain subsets of patients, according to a study presented at the 2010 Gastrointestinal Cancers Symposium (GCS; abstract 130).

“Despite the limitations of its retrospective nature, this analysis provides a means for comparing radioembolization with other therapeutic procedures across different tumor stages,” said Bruno Sangro, MD, an investigator at the Clinica Universitaria, Pamplona, Spain, who presented the study.

‘For comparable patients in the intermediate stage, survival after radioembolization is within the range of that reported after [transarterial chemoembolization] and better than that reported after sorafenib.’

—Bruno Sangro, MD

The study, conducted by researchers from the European Network on Radioembolization, involved 250 patients from eight centers and assessed predictors of survival following radioembolization using 90Y-labeled resin microspheres (Y-90). Most patients had multinodular disease, more than 50% had disease invading both lobes, and 75% had cirrhosis. Most received a single administration of microspheres.

Median activity administered was 1.7 GBq, with predominantly whole-liver and right-lobe infusions.

At a median follow-up of 8.9 months, median overall survival was 14.1 months but varied significantly according to numerous parameters in a univariate model. In the multivariate Cox proportional hazards model, extra-hepatic

disease, total bilirubin higher than the median, number of nodules and Cancer of the Liver Italian Program (CLIP) score were the most consistent predictors of survival, Dr. Sangro reported.

Hazard ratios for death were 3.80 for extra-hepatic disease (P<0.001), 1.54 for high total bilirubin (P=0.025), 1.48

for high number of nodules (P=0.004), and 1.33 for high CLIP score (P=0.006).

Median survival was 7.4 months for patients with CLIP 3 compared with 24.4 months for CLIP 0 and 20.8 months for CLIP 1; 8.7 months for patients with more than five nodules compared with 24.4 months for those with one nodule;

and 7.5 months for extra-hepatic disease compared with 15.3 months without disease spread.

“For comparable patients in the intermediate stage, survival after radioembolization is within the range of that reported after TACE [transarterial chemoembolization] and better than that reported after sorafenib [Nexavar, Bayer Healthcare Pharmaceuticals]. And for comparable patients in advanced stage, survival is superior to see Y-90, page 15

11

12

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • MARCH 2010

Colon

BRAF continued from page 1

at the University Hospital Gasthuisberg, Leuven, Belgium, said, “This final analysis confirms KRAS tumor mutation status to be a predictive factor across all efficacy end points examined for cetuximab in combination with FOLFIRI [irinotecan, folinic acid and 5-fluorouracil]. It suggests that BRAF tumor mutations are a poor prognostic factor in first-line metastatic colorectal cancer.”

CRYSTAL At the joint meeting of the European CanCer Organisation and European Society for Medical Oncology (ECCO-ESMO) held this past fall, Dr. Van Cutsem presented the updated overall survival results of the CRYSTAL trial, in which 1,198 patients with metastatic colorectal cancer were randomized to FOLFIRI or FOLFIRI plus cetuximab (Erbitux, Bristol-Myers Squibb/ImClone Systems). The addition of cetuximab improved overall survival (OS) by 3.5 months in KRAS wild-type patients (hazard ratio ([HR], 0.796; 95% confidence interval [CI], 0.0670-0.946; P=0.0094). The response rate was 57.3% for the addition of cetuximab compared with 39.7% (P<0.0001). Treatment with cetuximab and FOLFIRI was associated with a 30% reduction in progression (P=0.0012) and a 20% reduction in mortality (P=0.0093), versus FOLFIRI alone, in the KRAS wild-type population.

“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 cytotoxic chemotherapy alone, specifically in patients with KRAS wild-type tumors,” said Cathy Eng, associate professor in the Department of Gastrointestinal Medical Oncology at the University of Texas M.D. Anderson Cancer Center, in Houston. Currently, cetuximab is FDA-approved in previously treated patients.

The updated analysis presented at the GCS included the effect of BRAF status, which was available for 83% of the study population. Of this population, 6% had mutations of the gene, as did 9% of the 666 patients with KRAS wild-type tumors.

Overall survival in the KRAS wild-type population was clearly longer in the patients treated with FOLFIRI plus cetuximab compared with FOLFIRI alone: 23.5 months compared with 20 months (HR, 0.796; P=0.0093). In these patients, BRAF status had a clear prognostic role, said Dr. Van Cutsem. Treated patients with a BRAF mutant tumor had a worse outcome

Structure of the BRAF protein.

(survival, progression-free survival [PFS] and response rate) regardless of the treatment (Table).

However, according to the investigators, BRAF mutation status does not appear to be a strong predictive biomarker for the addition of cetuximab to FOLFIRI in the first-line treatment of metastatic colorectal cancer; they acknowledged that the sample size may be too small to draw final conclusions on the predictive role of BRAF mutation status.

“The analysis suggests BRAF tumor mutation to be a poor prognostic factor in first-line mCRC [metastatic colorectal cancer],” Dr. Van Cutsem said. “Probably because BRAF is very rare, we could not show a predictive effect [for treatment with cetuximab], but for sure, BRAF is prognostic in these patients.”

According to Al Benson, MD, professor of medicine at Northwestern University School of Medicine, Chicago, the study could have future clinical implications but more analysis is needed. “At this time, interesting data are emerging about other markers beyond KRAS, including BRAF, that may improve patient selection for anti-EGFR [epidermal growth factor receptor] therapeutic approaches. Until more data are generated, however, the routine use of BRAF testing for patients cannot be recommended for a treatment decision,” he said.

“The hope is that prospective trials will give guidance as to which group of markers is most useful and to promote the development of other agents for patients who are unlikely to benefit from an anti-EGFR treatment using current drugs.”

Growing Evidence According to Dr. Eng, the study adds to the growing evidence of the importance of BRAF mutations. In a study presented at the ECCO-ESMO meeting (abstract

6114), investigators looked at BRAF as a prognostic marker in 213 surgically resected stage III colon cancer patients treated with surgery followed by 5-FUbased adjuvant therapy. They found that the presence of the BRAF V600E mutation was an independent prognostic factor for worse OS (P=0.006).

In another study presented at ECCO-ESMO, investigators evaluated the prognostic role of BRAF in the CAIRO2 study of patients with advanced colon cancer (abstract 6002). CAIRO2 was a randomized Phase III trial in which patients either received capecitabine (Xeloda, Roche) plus oxaliplatin (CAPOX) for six cycles, followed by capecitabine and bevacizumab (Avastin, Genentech) (control arm) or they received CAPOX for six cycles plus bevacizumab and cetuximab followed by capecitabine and bevacizumab and cetuximab. The investigators found that 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).

‘Probably because BRAF is very rare, we could not show a predictive effect [for treatment with cetuximab], but for sure, BRAF is prognostic in these patients.’

—Eric Van Cutsem, MD, PhD

Table. Clinical Efficacy in KRAS Wild-Type Tumors

By BRAF Mutation Status in CRYSTAL Trial KRAS wt/BRAF wt

Median OS, mo

FOLFIRI

Cetuximab Plus FOLFIRI

FOLFIRI

Cetuximab Plus FOLFIRI

21.6

25.1

10.3

14.1

P value Median PFS, mo

0.0549 8.8

P value OR, % P value wt, wild-type; mt, mutant tumor

KRAS wt/BRAF mt

10.9

0.74440 5.6

0.0016 42.6

61.0 <0.0001

8.0 0.8656

15.2

19.2 0.9136

In a small retrospective analysis reported in the Journal of Clinical Oncology (2008;26:5705-5712, PMID: 19001320), investigators found that the potential benefit of EGFR inhibitors in patients with colon cancer may be negated if patients have BRAF mutations despite having a KRAS wild-type tumor. Clinicians then thought that BRAF would also be a predictive marker for EGFR inhibition, said Dr. Eng. Unfortunately, the number of patients with the presence of the KRAS wild type/BRAF mutation may be too small to demonstrate a true difference in lack of benefit from EGFR inhibition. However, the current data strongly support that the presence of the BRAF mutation is a prognostic indicator rather than predictive.

—Caroline Helwick and Kate O’Rourke

In first-line metastatic NSCLC and first- and second-line MCRC

To reach beyond convention…

Indications 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.

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.

Boxed WARNINGS and additional important safety information Gastrointestinal (GI) perforation: Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies. Discontinue Avastin in patients with GI perforation Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. 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 Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention) Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal 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 In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls 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%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%) Please see following brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

©2010 Genentech USA, Inc.

All rights reserved.

9146401

(01/10)

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.

SOLID TUMORS Liver

Y-90 continued from page 11 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

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

®

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

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

sorafenib or placebo as reported in the SHARP (Sorafenib HCC Assessment Randomized Protocol) trial,” Dr. Sangro said. “Yet, prospective clinical trials are needed to understand the precise role of radioembolization in the treatment of HCC.” According to Anthony B. El-Khoueiry, MD, assistant professor of medicine at the University of Southern California Keck School of Medicine, Los Angeles, the characteristics of patients in the study are typical of the Western patient population treated with TACE; however, there was a significant number of patients with bilobar disease (53.4%), a significant number with portal vein involvement (9.9% branch and 8.3% complete) and a significant number with advanced disease (37.3% stage C). “[The new study’s] results are consistent with another large series reported recently by Dr. Salem from the United States,” said Dr. El-Khoueiry, referring to a study published in the journal Gastroenterology (2010;138:52-64, PMID: 19766639). “There has not been any randomized comparison of Y-90 to TACE, but a two-cohort study recently published by Dr. Carr suggests that Y-90 is at least equivalent to TACE. In regards to the treatment of patients overall with BCLC [Barcelona Clinic Liver Cancer] stage B and C, I think Y-90 is added to the armamentarium of options.” The two-cohort study was published in Cancer (2010 Jan 11. Epub ahead of print, PMID: 20066715).

He added that randomized trials are needed comparing TACE with Y-90 and with drug-eluting bead embolization, with special attention to the high-risk subgroups of Child-Pugh B and macrovascular invasion.

The GCS was co-sponsored by the American Gastroenterological Association, the American Society of Clinical Oncology, the Society for Radiation Oncology and the Society of Surgical Oncology.

—Caroline Helwick

Clinical Oncology News would like your feedback.

Please send opinions, criticism, ideas and suggestions to Kate O’Rourke, Editor, Clinical Oncology News, at korourke@mcmahonmed.com

15

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CLINICAL ONCOLOGY NEWS â&#x20AC;˘ MARCH 2010

Colon

Containing Costs Through Colon Cancer Screening With March being Colorectal Cancer Awareness Month, it is an appropriate time for cancer care providers to increase public awareness that colorectal cancer (CRC) is a truly preventable and curable disease through regular screening and early detection. Increasing CRC screening also is one way to help contain the skyrocketing costs of health care.

CRC continues to be a major health problem. In 2010, an estimated 148,000 new patients will be diagnosed and nearly 50,000 deaths will be attributed to this disease in the United States. Worldwide, approximately 800,000 new patients will be diagnosed with CRC, resulting in nearly 500,000 deaths.

Screening and early detection are absolutely critical in the fight to prevent and cure CRC. The American Cancer Society and the Centers for Disease Control and Prevention have approved several screening methods for CRC, including fecal occult blood tests (FOBTs), sigmoidoscopy, colonoscopy and barium enema. Prior to 2001, FOBT and sigmoidoscopy were the most widely used screening modalities for the general population. In July 2001, however, Medicare initiated coverage for screening colonoscopies, and since then, colonoscopy has become the most widely used diagnostic tool. The number of flexible sigmoidoscopies being performed has been dramatically reduced.

Another screening method increasingly being used is virtual colonoscopy, also known as computed tomography colonography. This noninvasive test does not require sedation, can be done relatively quickly (within 15-20 minutes) and allows patients to resume their normal activities as soon as the testing is completed.

Despite the many advantages of this screening method, it has not been uniformly embraced in the CRC screening guidelines, perhaps in large part because positive findings then require traditional colonoscopy to be performed. There also is great interest in incorporating stool DNA testing into the screening armamentarium. Without question, however, colonoscopy remains the gold standard screening method. It can directly visualize the presence of polyps, remove polyps when detected and potentially identify the presence of early-stage colon cancers.

So, why is CRC screening and early detection so important? In the large majority of sporadic cases, CRC arises from adenomatous polyps, which take eight to 12 years, on average, to transform into true malignancy.

Removal of these polyps essentially eliminates the root of many CRCs. When diagnosed in its earliest stages, nearly 90% of patients with colon cancer can be cured.

Once the disease presents in a more advanced stage with metastatic spread, however, the overall prognosis is poor and the vast majority of patients are incurable.

Although the median overall survival is now in the 24to 30-month range with the integration of cytotoxic chemotherapy and biologic agents, the overall fiveyear survival is less than 10%.

So, why is there a need for a big push in CRC screening? The most recent data on CRC screening modality trends from 2008 show that, at most, 55% of individuals in the United States over the age of 50 undergo any type of screening. Only approximately 50% of adults between the ages of 50 and 75 undergo a colonoscopy. Perhaps even more striking is the fact that women undergo screening less frequently than men. Although CRC screening for women has improved over the past five years, a misperception exists that women have a lesser risk for developing CRC than their male counterparts, despite the fact that colon cancer incidence is the same for males and females. Moreover, primary care physicians and health care professionals who take care of women do not appear to appreciate that CRC represents as significant a concern as breast and cervical cancers. Minority and underserved populations, such as blacks and Hispanics, also seek CRC screening at a much lower rate than the general population. Creative outreach and awareness programs that can lead to increased screening are needed to reach these populations.

As the health care debate continues in Congress, an important issue to consider is whether CRC screening is cost-effective. As noted above, screening can help reduce the number of life-years lost and several casecontrol studies suggest that CRC screening can lead to a 50% to 90% reduction in CRC incidence and mortality. Recent estimates show the average costs per lifeyear gained from screening colonoscopy to be in the range of $9,000 to $22,000 per life-year gained. This

ADVISORY BOARD EDITORIAL Ed Chu, MD Professor of Medicine and Pharmacology Chief, Section of Medical Oncology Deputy Director, Yale Cancer Center Yale University School of Medicine New Haven, Connecticut

In 2000, the cost for treating CRC in the United States was approximately $7.5 billion, and the expectation is that this figure will rise to more than $14 billion by 2020.

is well within the $50,000 per life-year gained figure that is frequently used as the threshold for cost-effectiveness of a medical intervention.

Over the past 10 years, significant advances have been made in the treatment of metastatic CRC; however, total costs for treating this disease have skyrocketed. In 2000, the cost for treating CRC in the United States was approximately $7.5 billion, and the expectation is that this figure will rise to more than $14 billion by 2020. Thus, effective CRC screening programs are critically important as they play a significant role in reducing CRC incidence and mortality as well as controlling the overall costs associated with CRC treatment.

For colon cancer survivors, March is certainly a time to celebrate. For individuals who are 50 and older, this month is an appropriate reminder to undergo screening. Individuals at increased risk for the disease because of family history should undergo screening at an earlier age and perhaps at more frequent intervals.

Finally, all health care professionals must continue to emphasize the importance of CRC screening and strive toward developing innovative outreach screening and education programs that serve their respective local communities. â&#x20AC;&#x201D;Edward Chu, MD

Courtesy of ACG

16

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CLINICAL ONCOLOGY NEWS • MARCH 2010

Breast

Bisphosphonates: A Dual-Edged Sword?

San Antonio–Oral bisphosphonates can prevent the development of breast cancer in healthy women, according to two recent studies.

The findings, presented at the 2009 San Antonio Breast Cancer Symposium (SABCS), add to the growing evidence that bisphosphonates have anti-cancer properties. Previously, studies have shown that bisphosphonates can reduce the risk for breast cancer recurrences.

“While these findings need confirmation, the idea that bisphosphonates can reduce breast cancer is very exciting, because about 30 million prescriptions are written for these agents each year in the United States targeting bone health.

More could easily be used to counteract both osteoporosis and breast cancer,” said Rowan Chlebowski, MD, medical oncologist at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center.

WHI Study Dr. Chlebowski led the study (SABCS abstract 21) that investigated the association between bisphosphonates and invasive breast cancer using data from more than 154,000 generally healthy, postmenopausal women enrolled in the Women’s Health Initiative (WHI). The analysis (P<0.01) showed that women who took bisphosphonates (90% alendronate; Fosamax, Merck) for osteopenia or osteoporosis had 31% fewer cases of invasive breast cancer than nonbisphosphonate users.

The analysis focused on 10,000 women in the WHI whose medical records included results of bone mineral density studies. Of these, 2,216 were using bisphosphonates at entry to the study and only 64 of these women developed breast cancer; 50 of the cancers were estrogen receptor-positive. An age-adjusted analysis showed that women taking an oral bisphosphonate had a breast cancer rate of 3.29 per 1,000 women-years of follow-up versus a corresponding rate of 4.38 among women not taking a bisphosphonate (Figure). There were 30% fewer estrogen receptor–positive cancers (P=0.01) and 34% fewer estrogen receptor– negative cancers in bisphosphonate users (not statistically different).

In contrast, the incidence of ductal carcinoma in situ (DCIS) was increased (P=0.002) in bisphosphonate users compared with non-users (1.53 vs. 0.92 per 1,000 patient-years, respectively). Dr. Chlebowski speculated that this phenomenon may occur because in situ lesions are arrested by bisphosphonates and prevented from becoming invasive lesions. Additional studies are

needed to clarify the findings related to DCIS. Dr. Chlebowski added that ongoing randomized trials of oral and intravenous bisphosphonates conducted in the adjuvant setting will help shed light on whether these agents can reduce the risk for new contralateral breast cancers.

Israeli Study In a second study presented at SABCS (abstract 27), a smaller case-control trial from Israel of 4,575 postmenopausal healthy women identified a 34% reduction in the relative risk for breast cancer in women taking bisphosphonates. The study matched 2,368 cases of newly diagnosed breast cancer with a control group for age, ethnic

‘I think the jury is still out on whether there are direct anti-tumor effects for bisphosphonates that are clinically meaningful.’

—Andrew Seidman, MD

Non-bisphosphonate users Bisphosphonate users

Rate per 1,000 Woman-years of Follow-up

18

5

P <0.01

4.38 38

4 3.29

3

2

1

0

Figure. Comparison of rate of invasive breast cancer in Women’s Health Initiative.

background and residential area.

Wo m e n we re interv i e we d ex t e n s i v e l y about medical and family history as well as medication use. The self-reported data were validated by pharmacy records, said lead author Gar Rennert, MD, from the Carmel Medical Center of Clalit Health Services and the Technion-Israel Institute of Technology, in Haifa.

Women who were long-term users of bisphosphonates had a 34% reduction in breast cancer incidence compared with non-users (2.5% vs. 3.7%, respectively). After adjusting for risk factors that included age, dietary consumption of fruits and vegetables, exercise, family history, ethnic group, body mass index, calcium supplementation, hormone replacement therapy use, number of pregnancies, months of breastfeeding and age at first pregnancy, the relative risk reduction in breast cancer between users and non-users was 29%. The effect on breast cancer was observed after patients took bisphosphonates for one year and remained stable over subsequent years.

Dr. Rennert said that most of the breast cancers that developed in bisphosphonate users were estrogen receptor– positive, were better differentiated and had a better prognosis than the cancers that developed in the non-bisphosphonate users. Additionally, there was no increase in DCIS incidence in bisphosphonate users in this study. “This study shows an association, not a proof. Randomized clinical trials are needed,” Dr. Rennert said.

Putting It in Perspective Theresa Guise, MD, a professor at the Indiana University School of Medicine in Indianapolis, noted that osteoporosis and breast cancer are both common problems in postmenopausal women.

Dr. Guise said it is encouraging that a second study in a different population found a similar protective effect against new breast cancers. “This needs to be confirmed by prospective, placebo-controlled clinical trials,” she said. “This cohort study indicates the possibility that a simple oral drug may prevent both of these common conditions.”

Researchers have put forth several possible explanations as to why bisphosphonates may have an antitumor effect; one involves angiogenesis. “Bisphosphonates reduce angiogenesis and stimulate immune cells responsible for tumor cell surveillance as potential mediators,” Dr. Chlebow-ski said. “This association needs to be studied further.” Alison Stopeck, MD, associate professor of medicine at the Arizona Cancer Center, University of Arizona Health Sciences Center, Tucson, offered another explanation.

“Bisphosphonates, and osteoclast-targeting agents in general—including denosumab [Prolia, Amgen]—may poison the soil [i.e., the bone microenvironment] by inhibiting osteoclast activity,” Dr. Stopeck said. “By resorbing bone, osteoclasts can release growth factors and cytokines from the bone matrix that foster tumor growth and adhesion to bone.”

‘Bisphosphonates reduce angiogenesis and stimulate immune cells responsible for tumor cell surveillance as potential mediators.’

—Rowan Chlebowski, MD

While the recent studies are intriguing, most researchers, including Andrew Seidman, MD, attending physician, Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, New York City, say more evidence is needed before any changes to practice are made. Despite the two SABCS trials as well as the ABCSG-12 and the ZO-FAST trials that showed a signal for reduction in breast cancer recurrence, Dr. Seidman awaits the results of larger, better-powered studies (e.g., AZURE, NSABP) to confirm whether indeed bisphosphonates confer an anti-tumor effect as opposed to a pure bone-strengthening effect. “I think the jury is still out,” he explained, “on whether there are direct anti-tumor effects for bisphosphonates that are clinically meaningful.”

—Alice Goodman

20

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CLINICAL ONCOLOGY NEWS • MARCH 2010

Breast

STANDARD continued from page 8

discussed this conundrum with the regional medical director. She sent him the studies published to date that demonstrated the significant reduction in positive margins and thereby second operations, along with the other advantages to the patient. “After he reviewed the studies he said that, yes, of course they would pay for this procedure,” she said. “Now that this is happening around the country, I think the ability to bill for it will get much easier.”

The other sticking point for adopting radioactive seed localization concerns nuclear regulatory issues, which vary from state to state. The seeds have a short half-life and present little risk to the patient, who has contact with them for only a short time. But they are radioactive and must be handled and disposed of properly.

Wayne W. Windham, MD, a radiologist at Florida Hospital, Florida Radiology Imaging and a member of Radiology Specialists of Florida brought radioactive seed localization into his practice in the past year, encouraged by a new chairman who had relocated from Mayo Clinic Florida, in Jacksonville, where the use of radioactive seeds had become routine.

“The statistics in terms of accuracy of the procedure and accuracy of the subsequent surgical precision seem to offer a significant advantage, so we put together

a committee of people interested in working with us to develop a pilot project,” Dr. Windham said.

The committee—including a surgeon, Dr. Windham, his radiation safety officer, a nuclear medicine director and an administrator from the radiology department—met with Dr. Gray’s team at Mayo Clinic in Arizona, for a day of discussion and training. “Our surgeon stood by Dr. Gray’s side in the OR, and after the few cases he saw, he felt comfortable with the procedure,” Dr. Windham said.

But first, Dr. Windham’s team had to clear some regulatory hurdles. The state initially informed them they

ERBITUX RBITUX E

® ®

would need approval from their institutional review board (IRB). “But we convinced them that this was an off-label use for a medical device for patient medical care, and they agreed to drop their requirement for IRB approval due to the fact that there was no research involved,” he said.

They also needed an amendment to their radioactive license adding their separate pathology building as a place of use. “That would have been a major hurdle except that we have a broad scope license that includes multiple sites,” Dr. Windham said. “But that would be an important thing for a new facility to

take into consideration.”

His team also needed to comply with regulatory issues on sterilizing the seeds and transporting radioactive material to, from and within their facility.

They have not abandoned wire yet, but the pilot project is progressing well and other surgeons have shown interest. “Once we have our 10 pilot project cases under our belt, we’ll put our heads together and figure out what fine-tuning we need to make to roll this out to other surgeons on staff,” Dr. Windham said.

“And then, hopefully, we’ll be off and running.”

—Monica J. Smith

(cetuximab): FOR PATIENTS WITH HEAD AND NECK C ANCER* (cetuximab): FOR PATIENTS WITH HEAD AND NECK C ANCER*

ERBITUX + RT: ERBITUX + RT: 26% reduction in 26% reduction in Risk of Death Risk of Death1,2 from SCCHN from SCCHN1,2

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Important Safety Information Including Boxed WARNINGS Important Safety Information Including Boxed WARNINGS Infusion Reactions

Infusion ■ GradeReactions 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX®® (cetuximab) in clinical trials, with fatal outcome reported in less ■ Grade infusion reactions occurred in approximately 3% of patients receiving ERBITUX (cetuximab) in clinical trials, with fatal outcome reported in less than 1 3/4 in 1000 than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway — Serious infusion reactions, requiring medical intervention and immediate, discontinuation of ERBITUX, rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, losspermanent of consciousness, myocardial infarction,included and/or cardiac arrest obstruction stridor, hoarseness), hypotension, shock, loss consciousness, myocardial infarction, and/or cardiac arrest — Immediately(bronchospasm, interrupt and permanently discontinue ERBITUX infusions for of serious infusion reactions Immediately interrupt permanently ERBITUX for serious infusion reactions ■— Most (90%) of the severeand infusion reactionsdiscontinue were associated withinfusions the first infusion of ERBITUX despite premedication with antihistamines ■ Most (90%)must of thebesevere infusion were associated with thewere first infusion ERBITUX despite premedication with antihistamines — Caution exercised withreactions every ERBITUX infusion, as there patients of who experienced their first severe infusion reaction during later infusions — be exercised everyERBITUX ERBITUXinfusions infusion, in asathere were patients who experienced infusion reaction during later infusions — Caution Monitormust patients for 1 hourwith following setting with resuscitation equipmenttheir and first othersevere agents necessary to treat anaphylaxis — Monitor patients for 1 hour following ERBITUXantihistamines, infusions in a setting with resuscitation equipment andobservation other agents necessary anaphylaxis (eg, epinephrine, corticosteroids, intravenous bronchodilators, and oxygen).

Longer periods may to betreat required in patients (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen).

Longer observation periods may be required in patients who require treatment for infusion reactions who require treatment for infusion reactions Cardiopulmonary Arrest Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation ■ Cardiopulmonary arrestasand/or sudden death in 4 (2%) of with 208 patients squamous carcinoma of the head and neck treated with therapy and ERBITUX, compared to none ofoccurred 212 patients treated radiationwith therapy alone. cell Fatal events occurred within 1 to 43 days after theradiation last therapy and ERBITUX, ERBITUX treatment as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the last ERBITUX treatment — Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, — Carefully consider the use ERBITUX inincombination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure orof arrhythmias light of these risks heartserum failureelectrolytes or arrhythmias in lightserum of these risks — congestive Closely monitor including magnesium, potassium, and calcium during and after ERBITUX therapy — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy Pulmonary Toxicity Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 ERBITUX of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms.

Permanently discontinue where ILD is confirmed onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed Dermatologic Toxicities Dermatologic Toxicities ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae ■ In clinical studies of ERBITUX, toxicities, includingconjunctivitis, acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscessdermatologic formation, cellulitis, blepharitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), hypertrichosis, occurred in patients ERBITUX therapy.

Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials.and Severe acneform rash occurred in 1-17%receiving of patients therapy.

Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical Severe rash occurred in 1-17% of patients — Acneform rash usually developed within the first two weeks of therapy and resolved intrials. a majority of acneform the patients after cessation of treatment, although — Acneform rashthe usually the28first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, eventdeveloped continuedwithin beyond days in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — patients receiving ERBITUX dermatologic toxicities and infectious sequelae — Monitor Sun exposure may exacerbate thesefor effects — Sun exposure may exacerbate these effects ERBITUX Plus Radiation Therapy and Cisplatin ERBITUX PlusofRadiation and Cisplatin ■ The safety ERBITUXTherapy in combination with radiation therapy and cisplatin has not been established ■ The safetyand of ERBITUX in combination withobserved radiationintherapy and cisplatin has not beenradiation established — Death serious cardiotoxicity were a single-arm trial with ERBITUX, therapy, and cisplatin (100 mg/m2) in patients with locally — Death andsquamous serious cardiotoxicity wereofobserved a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced cell carcinoma the headin and neck squamous cellone carcinoma of the head and neck — advanced Two of 21 patients died, as a result of pneumonia and one of an unknown cause — 21 patients died, onetreatment as a resultdue of pneumonia and oneTwo of an cause — Two Fourof patients discontinued to adverse events. of unknown these discontinuations were due to cardiac events — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

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CLINICAL ONCOLOGY NEWS • MARCH 2010

Breast

BCIRG Trial Results Fuels Debate on Anthracycline Use T

he third and final interim analysis of the Phase III BCIRG (Breast Cancer International Research Group) 006 study has fueled debate over whether anthracycline-based trastuzumab (Herceptin, Genentech) regimens should be continued in patients with human epidermal growth factor receptor 2 (HER2)positive breast cancer.

Triggering the concern are data showing up to a fivefold increase in congestive heart failure (CHF) seen in the anthracycline-based arm of the trial, according

to Dennis Slamon, MD, co-chair of the study, who presented the results at the 2009 San Antonio Breast Cancer Symposium (SABCS, abstract 62).

The new results dovetail with data presented at the 29th annual SABCS in 2006. When those data (abstract 52) were presented, Dr. Slamon, director of clinical and translational research at the University of California, Los Angeles Jonsson Comprehensive Cancer Center, questioned whether anthracyclinebased regimens should remain a viable

No. (%) of Patients No. (%) of Patients ERBITUX + RT RT Alone ERBITUX + RT RT Alone (n = 211) (n = 213) (n = 211) (n = 213) Delivery of planned RT dose Delivery of planned RT dose Adequate delivery per protocol Adequate delivery per protocol Inadequate delivery per protocol Inadequate delivery per protocol

184 (87.2) 184 (87.2) 27 (12.8) 27 (12.8)

Mucositis/stomatitis Mucositis/stomatitis Dysphagia Dysphagia Xerostomia Xerostomia Radiation dermatitis Radiation dermatitis

187 (87.8) 187 (87.8) 26 (12.2) 26 (12.2)

■ ■

† No difference in radiation dose delivered between the 2 treatment groups in a randomized trial comparing ERBITUX + RTdose versus RT alonebetween in patients locally orgroups regionally SCCHN. † No difference in radiation delivered thewith 2 treatment in aadvanced randomized trial 2 comparing ERBITUX + RT versus RT alone in patients with locally or regionally advanced SCCHN.2

treatment option for most patients with HER2-positive disease. “If we are now causing more problems than we are solving with [such] regimens, we have to rethink what we are doing,” he said.

At the 2009 SABCS, after presenting the latest BCIRG 006 results and reviewing the toxicity data, Dr. Slamon expressed similar concerns and concluded that the benefits of anthracyclines appear to be restricted to higher-risk patients—specifically, those with topoisomerase II amplification.

ERBITUX + RT (%) ERBITUX + RT (%) (n = 208) (n = 208) Grades Grade Grades Grade 1-4 3/4 1-4 3/4 93 56 93 56 65 26 65 26 72 5 72 5 86 23 86 23

RT Alone (%) RT(n Alone (%) = 212) (n = 212) Grades Grade Grades Grade 1-4 3/4 1-4 3/4 94 52 94 52 63 30 63 30 71 3 71 3 90 18 90 18

The incidences of grades 3/4 xerostomia, mucositis/stomatitis, The of gradeswere 3/4 xerostomia, mucositis/stomatitis, andincidences radiation dermatitis more frequent in the ERBITUX and plusradiation RT arm dermatitis were more frequent in the ERBITUX plus RT arm

*INDICATIONS *INDICATIONS ■ ERBITUX®® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced in combination withneck radiation therapy, is indicated for the initial treatment of locally or regionally advanced ■ ERBITUX squamous(cetuximab), cell carcinoma of the head and squamousas cell carcinoma of is the head and ■ERBITUX, a single agent, indicated forneck the treatment of patients with recurrent or metastatic squamous cell carcinoma of the ■ERBITUX, a single agent, is indicated for the therapy treatment offailed patients with recurrent or metastatic squamous cell carcinoma of the head and as neck for whom prior platinum-based has head and neck for whom prior platinum-based therapy has failed SCCHN = squamous cell carcinoma of the head and neck; RT = radiation therapy.

SCCHN = squamous cell carcinoma of the head and neck; RT = radiation therapy.

Electrolyte Depletion Electrolyte Depletionoccurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia ■ Hypomagnesemia ® ■ Hypomagnesemia in 55% (199/365) occurred of patientsdays receiving ERBITUX was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanyingoccurred electrolyte abnormalities to months after(cetuximab) initiation of and ERBITUX therapy and accompanying abnormalities occurred days to monthsand afterhypokalemia, initiation of ERBITUX therapy — Monitor patientselectrolyte periodically for hypomagnesemia, hypocalcemia during, and for at least 8 weeks following the completion of, ERBITUX therapy — patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Monitor Replete electrolytes as necessary — Replete electrolytes as necessary Late Radiation Toxicities Late Radiation Toxicitiesof late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone.

■ The overall incidence ■ The incidence of late radiation toxicities (any grade) waslarynx higher(52%/36%), with ERBITUX in combination with(49%/45%), radiation therapy compared with(48%/39%), radiation therapy alone.

The overall following sites were affected: salivary glands (65%/56%), subcutaneous tissue mucous membranes The following sites were affected: glands (65%/56%), larynx (52%/36%), tissue esophagus (44%/35%), and skin salivary (42%/33%) in the ERBITUX and radiation versussubcutaneous radiation alone arms,(49%/45%), respectivelymucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) the ERBITUX and radiation versus radiationtherapy alone arms, — The incidence of grade 3 or 4 late radiationin toxicities were similar between the radiation alonerespectively and the ERBITUX plus radiation therapy arms — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms Pregnancy Pregnancy ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ■ In women ERBITUX of childbearing potential, appropriate must beand usedhas during treatmenttowith ERBITUX andwhen for 6 months following the last dose of ERBITUX. may be transmitted from thecontraceptive mother to themeasures developing fetus, the potential cause fetal harm administered to pregnant women.

ERBITUX. ERBITUX may transmitted from the mother to the developing fetus,the and has therisk potential cause fetal harm when administered to pregnant women.

ERBITUX should only bebe used during pregnancy if the potential benefit justifies potential to theto fetus ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus Adverse Events Adverse Events ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation ■ The most serious reactions associated with ERBITUX across all embolus studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis,adverse renal failure, interstitial lung disease, and pulmonary sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ dermatitis, The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), ■ The most common reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea,adverse and infection diarrhea,adverse and infection ■ headache, The most frequent events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus ■ The most alone frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%).

The radiation alone (n=212) (incidence ≥50%)for were acneform rash (87%/10%), radiationtherapy dermatitis (86%/90%), lossdermatitis (84%/72%), andacneform asthenia (56%/49%).

The most common grade 3/4 adverse events ERBITUX in combination with radiation (≥10%) included:weight radiation (23%), rash (17%), and most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) weight loss (11%) For more information, please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

For more information, please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

References: 1. ERBITUX® (cetuximab) Package Insert. ImClone LLC, New York, NY 10014 References: 1. ERBITUX (cetuximab) Insert.

ImClone LLC, New York,PM, NY 10014 and Bristol-Myers Squibb,® Princeton, NJPackage 08543; July 2009.

2. Bonner JA, Harari Giralt J, et al. and Bristol-Myers Princeton, NJ 08543; July 2009. 2.ofBonner JA, Harari PM,NGiralt al.

Radiotherapy plusSquibb, cetuximab for squamous-cell carcinoma the head and neck.

EnglJ,J et Med. Radiotherapy plus cetuximab squamous-cell of the head and neck. N Engl J Med. 2006;354:567-578.

3. Data onfor file, Bristol-Myerscarcinoma Squibb, ERBI 001.

2006;354:567-578. 3. Data on file, Bristol-Myers Squibb, ERBI 001. © 2009, ImClone LLC, New York, New York 10014, U.S.A. and Bristol-Myers Squibb, Princeton, New Jersey 08543, U.S.A. © 2009, ImClone LLC, New York, New York 10014, U.S.A. and Bristol-Myers Squibb, All rights reserved.

ERBITUX a registered trademark of ImClone LLC. Princeton, New Jersey 08543,isU.S.A. All rights reserved. ERBITUX is a registered trademark of ImClone LLC.

693US09AB15316 693US09AB15316

7/09 7/09

Please see brief summary of Full Prescribing Information including Please see brief summaryregarding of Full Prescribing Information Boxed WARNINGS infusion reactionsincluding and Boxedcardiopulmonary WARNINGS regarding reactions arrestinfusion on adjacent page. and cardiopulmonary arrest on adjacent page.

But several breast cancer experts say they are not ready to completely abandon anthracyclines, including Debu Tripathy, MD, professor of medicine, Norris Comprehensive Cancer Center, University of Southern California. “I agree with Dr. Slamon to a certain extent—primarily that in many cases, we can omit anthracyclines.

However, I don’t think we fully understand in whom yet. The studies looking at topoisomerase are generally supportive that this is predictive of anthracycline see BCIRG, page 22

21

22

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CLINICAL ONCOLOGY NEWS • MARCH 2010

Breast

Study Detailed

BCIRG continued from page 21

response, but the association is not robust.

This is supported by a recent meta-analysis done by Angelo DiLeo and colleagues,” said Dr. Tripathy. “We need better markers before we can completely write off anthracycline use, and I am not sure that Topo II is the right one. We have not even defined ... a positive or negative test. So, I would not say that I am 180 degrees opposite of what Dr. Slamon is saying—I agree in principle, but not in the absolute terms that he states.”

BCIRG 006 randomized 3,222 patients with documented HER2-positive early breast cancer to one of three treatment arms: a control arm (AC-T) of anthracycline (doxorubicin) and cyclophosphamide therapy followed by docetaxel (Taxotere, Sanofi-aventis); an experimental arm of the anthracycline-based AC-T regimen followed by one year of trastuzumab (AC-TH); and another experimental arm of trastuzumab coupled with non-anthracycline (docetaxel/ carboplatin) chemotherapy (TCH).

Patients were enrolled from April 2001 to March 2004. Median age was

approximately 53 years; about 60% of the patients had a mastectomy, approximately 68% had radiotherapy, and about 51% had hormone therapy. Twenty-nine percent of all patients were node-negative; about 38% had one to three nodes involved; about 23% had four to 10 nodes involved; and approximately 10% had more than 10 nodes involved. The primary end point of the study was disease-free survival (DFS).

At the first planned analysis in 2005, DFS was 84% for AC-TH (P<0.0001 compared with the AC-T control arm), 80% for TCH (P=0.0002) and 73% for AC-T. In the updated five-year data reported at the

ERBITUX® (cetuximab) Solution for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.]

INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.]

Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.]

Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information].

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient.

Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines.

Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions.

Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.]

Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17% of patients.

Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.]

Use of Erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events.

Hypomagnesemia and Electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

2009 SABCS, DFS was 84% for AC-TH (P<0.001), 81% for TCH (P=0.04) and 75% for AC-T, Dr. Slamon said.

The 2009 final analysis also included the secondary end point of overall survival (OS). According to Dr. Slamon, 92%, 91% and 87% of patients were alive at five years in the AC-TH, TCH and AC-T arms, respectively. The number of deaths due to any cause was 94 in the AC-TH arm, 113 in the TCH arm, and 141 in the AC-T arm. Again, the difference in OS between the two experimental arms was not statistically significant, but favored the AC-TH arm.

For node-negative disease, five-year

Epidermal Growth Factor Receptor (EGFR) Expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry.

Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning and Warnings and Precautions.]

• Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.]

• Pulmonary toxicity [See Warnings and Precautions.]

• Dermatologic toxicity [See Warnings and Precautions.]

• Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.]

The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.

The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus.

Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions.

Clinical Trials 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 Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.]

Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.

Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients.

Renal: Renal failure occurred in 1% of patients with colorectal cancer.

Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11).

Table 1:

Incidence of Selected Adverse Events (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 29 1 13 1 Fever1 Headache 19 <1 8 <1 15 3 2 0 Infusion Reaction2 Infection 13 1 9 1 1 16 0 5 0 Chills Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 43 2 21 1 Alanine Transaminase, high3 Aspartate Transaminase, high3 38 1 24 1 33 <1 24 0 Alkaline Phosphatase, high3 Respiratory Pharyngitis 26 3 19 4 Skin/Appendages 4 87 17 10 1 Acneform Rash Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2

3 4

Includes cases also reported as infusion reaction.

Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”.

Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone.

Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

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CLINICAL ONCOLOGY NEWS • MARCH 2010

Breast

nodes, five-year DFS was 73%, 72% and 61%, respectively, which was highly significant for AC-TH and TCH arms versus AC-T (P=0.002 for AC-TH and TCH arms). OS in those patients with four or more positive nodes was 84%, 83% and 76%, respectively. Only the AC-TH arm was significantly superior to the AC-T group (P=0.02).

The non-anthracycline TCH regimen had a more favorable toxicity profile than AC-TH. Both nonhematologic and hematologic toxicities occurred significantly less frequently with TCH, including grade 3 and 4 arthralgia, myalgia, hand– foot syndrome, stomatitis, vomiting,

DFS was 93%, 90% and 85% in the ACTH, TCH and AC-T arms, respectively.

The difference was statistically significant favoring the AC-TH arm over the AC-T arm (P=0.02), with a trend favoring TCH compared with AC-T. Five-year OS in node-negative patients was 97%, 96% and 93% in the AC-TH, TCH and AC-T arms, respectively.

In patients with higher-risk, nodepositive disease, five-year DFS was 80%, 78% and 71%, respectively. Both experimental arms were significantly superior to control (P=0.0003 for AC-TH and P=0.013 for TCH). In highrisk patients with four or more positive

Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly).

Table 2:

Incidence of Selected Adverse Events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with Erbitux Monotherapy

Body System Preferred Term Dermatology Rash/Desquamation Dry Skin Pruritus Other-Dermatology Nail Changes Body as a Whole Fatigue Fever Infusion Reactions3 Rigors, Chills Pain Abdominal Pain Pain-Other Headache Bone Pain Pulmonary Dyspnea Cough Gastrointestinal Constipation Diarrhea Vomiting Stomatitis Other-Gastrointestinal Mouth Dryness Infection Infection without neutropenia Neurology Insomnia Confusion Anxiety Depression

Erbitux plus BSC (n=288) Any Grades Grades2 3 and 4 % of Patients

BSC alone (n=274) Grades 3 and 4

Any Grades

89 49 40 27 21

12 0 2 1 0

16 11 8 6 4

<1 0 0 1 0

89 30 20 13

33 1 5 <1

76 18

26 <1

4

0

59 51 33 15

14 16 4 3

52 34 11 7

16 7 0 2

48 29

16 2

43 19

12 1

46 39 37 25 23 11

4 2 6 1 10 0

38 20 29 10 18 4

5 2 6 <1 8 0

35

13

17

6

30 15 14 13

1 6 2 1

15 9 8 6

1 2 1 <1

1

Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls.

Adverse events were graded using the NCI CTC, V 2.0.

Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated.

BSC = best supportive care 2 3

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%).

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

neutropenia and leukopenia.

Cardiac toxicity was more frequent in the anthracycline arm, with a fourto fivefold increase in CHF in the ACTH arm compared with the TCH arm.

Although mean left ventricular ejection fraction (LVEF) declined at the beginning of treatment, patients treated with TCH recovered to normal at five years, whereas LVEF in patients randomized to the other two arms has not yet returned to normal.

Experts Divided “Our interpretation of the study data is that trastuzumab provides similar

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48).

Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area).

Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be 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 Erbitux, 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. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux.

Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab have not been studied in pediatric populations.

Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older.

OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area).

Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans.

Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment.

PATIENT COUNSELING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.

• Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy.

• That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy.

• To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux.

Erbitux® is a registered trademark of ImClone Systems Incorporated.

Manufactured by ImClone Systems Incorporated, Branchburg, NJ 08876 Distributed and Marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543

Copyright ©2009 by ImClone Systems Incorporated and Bristol-Myers Squibb Company. All rights reserved.

1236886A5 ER-B0001A-07-09

Rev July 2009

DFS and OS with an anthracycline and a non-anthracycline regimen in low- and high-risk patients,” Dr. Slamon said.

“Acute and chronic toxicity favors the non-anthracycline regimen. [But] the advantage of slightly fewer events with the anthracycline regimen plus trastuzumab comes at a cost of cardiotoxicity and leukemia.”

Clifford Hudis, MD, chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center in New York City, had a different view. “There were six AML/MDS events with AC-T, only one with AC-TH, and one with TCH. By lumping AC-T and AC-TH [together], one might be overstating the risk since both trastuzumab-containing arms had but one case each,” he said. Andrew Seidman, MD, an attending physician at the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, also said that Dr. Slamon’s fears over cardiac events and leukemias are overblown. “Numerically speaking many more women are dying of breast cancer on the TCH arm than are dying of heart failure or secondary leukemia with AC-TH,” Dr. Seidman said.

Laura Boehnke Michaud, PharmD, manager of clinical pharmacy services at the University of Texas M.D. Anderson Cancer Center in Houston, acknowledged that cardiac toxicity is higher with the chemotherapeutic agents. “In absolute terms, however, it is still extremely low [<2% in the anthracycline arm],” she said. “Those results have to be balanced with the added [survival] benefit seen in the trastuzumab-plus-anthracycline arm.”

Some experts agree that it is time to suggest an alternative regimen to women with HER2-positive breast cancer, but others expressed more reserve. Stephen Jones, MD, medical director at US Oncology, Baylor-Sammons Cancer Center in Houston, is in the former camp.

“This analysis of BCIRG 006 is mature and unlikely to change further,” Dr. Jones said. “There is no real difference between TCH and AC-TH, particularly in women at higher risk with positive nodes. The long-term risks for CHF and leukemia are real. We are at a point where patients deserve to know there are alternatives to standard anthracycline-based therapy.”

William J. Gradishar, MD, an oncologist at the Feinberg School of Medicine at Northwestern University in Chicago, was a bit more cautious. “Granted, I think we are moving in the direction of being able to avoid anthracyclines in HER2-positive breast cancer, and the most recent BCIRG 006 [data support] the efficacy and tolerability of TCH compared with AC-TH,” Dr. Gradishar said. But he stressed that the final data need to be published “before making a more definitive statement about the fate of anthracyclines in this setting.”

—Alice Goodman

23

24

PRN

CLINICAL ONCOLOGY NEWS • MARCH 2010

Medical Publishing

EXORCISM continued from page 1

of the 24 clinical trial articles included in their analysis disclosed Merck’s financial support, half of the 72 review articles contained such disclosures.

And it was not uncommon for external experts to be recruited as authors and to receive honoraria for manuscripts written on their behalf.

Increasing Transparency Rick Scheife, PharmD, editor-in-chief of Pharmacotherapy, admitted that he was “absolutely sideswiped” by the JAMA findings. For journal editors, they constituted a bit of an earthquake, he said. “What you basically saw was pretty much every major pharmacy, medical and science journal, all of a sudden took a very strong stance and came up with their own policy to make certain that things like this were not going to happen.” Soon after, the board at Pharmacotherapy (published by the American College of Clinical Pharmacy) created a revamped authorship policy, which went into effect in December 2008.

Most recently, The Oncologist started a new section to increase transparency.

In an editorial in the January 2010 issue of the journal, Bruce Chabner, MD, editor-in-chief of The Oncologist and clinical director of Massachusetts General Hospital Cancer Center, Boston, described the change in policy. “The new section will publish papers sponsored and supported by industry, but including academic contributors,” Dr. Chabner explained. “All authors must affirm responsibility for the content of their paper, and all authors, including professional medical writers hired by the company, will be identified in the byline. These industry-sponsored papers, which are expected to include information about the broader range of therapeutic options relevant to the discussion, will be peer reviewed and must meet standards of objectivity and fairness.” Dr. Chabner said that “in the discussion and debates about ghostwriting and pharmaceutical industry-sponsored manuscripts, at times the public, Congress and the academic community lose sight of the tangible contribution of the pharmaceutical industry to development of valuable new treatments, and the expansion of knowledge about why drugs work and why they fail.” The new section is aimed at offering an alternative for industry-sponsored or supported reviews.

The journal Blood also has made changes in recent years to ensure that any financial relationships are made clear. “We have made quite a few changes over the past couple of years, such as clarifying potential conflicts and specifically addressing ghostwriting,”

commented Virginia Ramsey, peer review manager of Blood.

“The journal has also added text to the descriptions of our ‘How I Treat and Review Articles.’” The new text reads, “Any involvement of medical writers/researchers, particularly those employed or supported by the pharmaceutical industry, in the writing of a review article must be clearly defined and disclosed in the Authorship section. For review articles, this type of involvement must be discussed with the editor-in-chief before the submission of the article. Generally, involvement of medical writers/researchers supported by the pharmaceutical industry is not acceptable for review articles published in Blood.” Blood requires that each author disclose all relevant financial and other interests, regardless of amount or value, that might be construed as resulting in an actual, potential or apparent conflict in one’s role as a contributor to Blood.

According to a study published in a November issue of JAMA (2009; 302:2230-2234, PMID: 19934424), variation exists among journals with respect to disclosure practices. The study, which scrutinized the policies posted online in 2008 for 256 medical journals, found that 89% included language requesting the disclosure of conflicts of interest and 54% required that each author involved sign a conflict-ofinterest statement. The questions asked in these statements were most likely to focus on direct financial relationships; more than 80% of the journals asked about related stock investments or consultancies. Fewer of the journals

asked about personal relationships (42%), paid expert testimony (42%) or travel grants (12%).

Revealing the Ghosts Underlying the recent discussion is a renewed focus on what constitutes authorship, along with strategies to better identify all of the hands and potential conflicts that touch a manuscript. “In 2008, 10% of The Oncologist’s papers acknowledged professional medical writers by name and medical communication company,” noted Ann Murphy, PhD, managing editor of The Oncologist. “In 2009, the total percentage of papers citing medical writers and communication companies decreased to 5%.” Now the journal is not accepting articles written by ghostwriters.

Daniel Haller, MD, editor-in-chief of the Journal of Clinical Oncology (JCO), said JCO updates their policies on disclosures and clinical publishing on an ongoing basis. “We do this on an ongoing basis, generally follow ICMJE [International Committee of Medical Journal Editors] guidelines, and believe we adhere to the strictest guidelines among medical journals,” commented Dr. Haller, professor of medicine and the Deenie Greitzer Professor of Gastrointestinal Oncology at the Abramson Cancer Center at the University of Pennsylvania. The ICMJE authorship standards include the disclosure of any ties—personal or financial—that might pose a conflict of interest. That includes the role of any company sponsors in designing, data collection or writing up the published results. According to JCO guidelines, “if someone other than the authors, such as a science writer

When a ghost author creates a manuscript and then invites a guest author to put his or her name on it with little to no input, ‘that can never be made right.’

—Rick Scheife, PharmD

or corporate employee, has participated in writing the paper, this participation must be disclosed. If a multicenter group conducted the research, the group should identify a writing committee that accepts direct responsibility for the manuscript.”

According to Cathy Rosenbaum, PharmD, MBA, RPh, a clinical effectiveness and safety officer at Bethesda North Hospital in Cincinnati, readers must practice due diligence when evaluating research studies, review articles and other types of journal articles, but there also should be inherent trust and transparency in the process itself. “I feel that there is, in research, a real need to eliminate as much variability as possible,” Dr. Rosenbaum said. “And I think accurate writing is a pivotal part of that element. It’s not just the design of the model that matters, but it’s all the collective hands and minds that touch the presentation of the results.”

Regardless of the policy involved, transparency ultimately relies on the author’s integrity. Arthur G. Lipman, PharmD, editor of the Journal of Pain & Palliative Care Pharmacotherapy, said he believes that “99.5 percent of people are honest and appropriate. But frankly, I have a couple of colleagues who are very good people who I know have allowed papers to be published under their names that were almost exclusively written by outside editors.”

At his own journal, authors are instructed to disclose any source of financial support along with the names of anyone involved with the manuscript’s preparation, Dr. Lipman noted. The review articles are among the easiest to take apart, he said. “We’ve received numerous review articles that had a clear bias, in which the conclusions were not supported by the [evidence provided]. We just rejected them based on the conclusions not being supported by the data.”

It was unknown, Dr. Lipman added, whether the authors of the review articles were working with a vested interest. Similarly, original studies can be scrutinized for inconsistencies in the data or conclusions that aren’t supported, he said. But it’s more difficult, he added, to ferret out problems. “You have to assume the data are legitimate. There is no way to go back and check the source documents.”

According to Dr. Scheife, having an outside medical writer involved in preparation is not, in and of itself, problematic. However, that individual should not be a ghost but rather should be listed as an author. That step not only reveals that writer’s involvement, he said, but also requires that, once the individual is identified as an author, they must disclose any related conflicts of interest. The line into the problematic guest authorship category is crossed when a ghost author creates the manuscript and then invites the guest author to put his or her name on it with little to no input,

SUPPORTIVE CARE

CLINICAL ONCOLOGY NEWS • MARCH 2010

VTE

Will New Therapies Replace Warfarin/Heparin for VTE? New Orleans—A series of Phase III studies suggest that the vitamin K antagonist warfarin will be largely or completely replaced by newer oral therapies that provide at least comparable protection against venous thromboembolism, but without the need for laboratory monitoring.

Both of the newer types of agents, a factor Xa inhibitor and a direct thrombin inhibitor (DTI), are administered orally in fixed doses. Neither is available to date in the United States, but both have been approved in other countries for other indications. Two of the most recent studies to predict the demise of warfarin were presented during the last annual meeting of the American Society of Hematology (ASH). The largest study was called RE-COVER (abstract 1).

Convenience “In the RE-COVER study, treatment with dabigatran [Pradaxa, Boehringer Ingelheim] was as effective as warfarin therapy, which achieved INR [international normalized ratio] values within the therapeutic INR range 60% of the time, a rate that is consistent with goodquality management of warfarin dosing,” said lead author Sam Schulman, MD, professor of medicine at McMaster University in Hamilton, Ontario, Canada,

and director of the Clinical Thromboembolism Program, Hamilton General Hospital. RE-COVER was a randomized, double-blind, noninferiority comparison of the DTI dabigatran and warfarin for treatment of acute venous thromboembolism (VTE). Dr. Schulman reported that dabigatran was well within the margin that defined noninferiority in this trial but, because it is delivered in a fixed dose, “is a far more convenient drug.”

In the outpatient setting, warfarin has been a mainstay of VTE treatment and prophylaxis, but it is notoriously difficult to maintain in the therapeutic range, even with frequent laboratory monitoring. Like the low-molecular-weight heparins (LMWHs), which are injectable, dabigatran can be administered in a fixed dose without a large interpatient variability in anticoagulant effect.

However, this agent, like the factor Xa inhibitor rivaroxaban (Xarelto, Bayer), is administered orally. After a series of studies suggesting these drugs are safe and

In the outpatient setting, warfarin has been a mainstay of VTE treatment and prophylaxis, but is notoriously difficult to maintain in the therapeutic range, even with frequent laboratory monitoring.

effective anticoagulants, there is an increasing sense that warfarin may soon be of historical interest only.

The senior author of a late-breaking study of rivaroxaban (abstract LBA2) also stressed that the issue is convenience rather than efficacy, but this is highly clinically relevant.

“An oral once-daily dose of rivaroxaban provides the clinician with a simple option for preventing recurrent symptomatic VTE,” said Harry Roger Buller, MD, PhD, Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands, who led the rivaroxaban study. Although the study compared this drug with placebo rather than warfarin or another active comparator in patients who had already completed six to 12 months of anticoagulant treatment for an acute episode of VTE, it also suggested a high degree of efficacy and safety for the prevention of recurrent VTE. Bleeding rates have been particularly low.

John Finnie, MD, a staff hematologist and medical oncologist at the David C. Pratt Cancer Center, see WARFARIN, page 32

Medical Publishing

Dr. Scheife said. If they do so, “that can never be made right,” he said.

For clinical practitioners, preserving the foundation of published research is of paramount importance, said Judi Jacobi, PharmD, president of the Society of Critical Care Medicine. It’s “appalling” when clinicians submit an industry-designed and written paper as their own, she said. “I can’t think of a time when it ever would have been an accepted practice, even before the standards became more stringent,” said Dr. Jacobi, the critical care pharmacy specialist at Methodist Hospital/Clarian Health, in Indianapolis. “We need unbiased information to make the best judgment for patient care, whether it’s for the patient in the bed in front of you or whether it is for a formulary decision for your organization.”

In some cases, such as when many people are involved in a paper, the line might become blurred in terms of who is doing the work and who is doing the writing, Dr. Jacobi said. But the stated author

‘If your reputation is tarnished and questioned, then the information you are presenting is damaged as well.’

—James O’Donnell, PharmD

must have been significantly involved throughout the process, she said. “I never would have participated in a paper where I wasn’t doing the writing and involved in selecting the content.”

Legal Implications Clinicians who misrepresent themselves, by claiming authorship when it isn’t warranted, may face potential legal risks, according to James O’Donnell, PharmD, associate professor of pharmacology at Chicago’s Rush University Medical Center, who has written several books about drug development and drug regulations. For example, what if the stated authorship of a prominent paper is sufficient to land a contract or a consultancy? That clinician could

be legally vulnerable for misrepresenting his or her expertise, Dr. O’Donnell said. “If your reputation is tarnished and questioned, then the information you are presenting is damaged as well,” he said.

Steps can be taken to prevent reliance on misleading papers and studies. Along with assessing the findings and searching for any inconsistencies, clinicians should pay attention to where the article was published, whether the journal was peer reviewed and any sponsorship connections or potential conflicts of interest, he said. In short, clinicians should be savvy enough “to smell a rat,” he said.

Dr. Lipman echoed the sentiment of several other clinicians interviewed, who said the problem was not industry-

sponsored research per se. “Some of the work that I’ve done that I’m very proud of and was published in first-tier journals were industry-sponsored projects,” he said. But the sponsor was clearly stated and the manuscript was his creation, Dr. Lipman said. “The bottom line is that whoever’s name is on the paper as the author is responsible for what’s there.

And the author can’t turn around and blame it on the ghostwriter.”

Because ghostwriting is by definition hidden, it’s difficult to know how much of a problem it truly was, according to clinicians interviewed. But the heightened scrutiny can only benefit research publishing, including the clinicians who rely on it to make formulary and other decisions, they said.

“I think there is more awareness and, in all candor, I think that the awareness is going up sky high,” Dr. Scheife said. “And because of that, the frequency of infractions is probably going down.”

—Charlotte Huff and Kate O’Rourke

25

Her struggle is fresh, but she can

move on with new confidence.

GLEEVEC® (imatinib mesylate) tablets are indicated for the adjuvant treatment of adult patients following complete gross resection of KIT (CD117)–positive GIST. Important Safety Information ■ GLEEVEC is often associated with edema and occasionally severe fluid retention. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention, which can be serious or life-threatening.

■ Cytopenias have been reported. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months).

■ Dose adjustments may be necessary due to hematologic adverse reactions, hepatotoxicity, and other nonhematologic adverse reactions.

■ In the adjuvant treatment of GIST trials (GLEEVEC; placebo) severe (NCI Grades 3 and above) lab abnormalities—increase in liver enzymes (ALT) (3%; 0%), (AST) (2%; 0%), and decrease in hemoglobin (1%; 0%)—and severe adverse reactions (NCI Grades 3 and above), including abdominal pain (3%; 1%), diarrhea (3%; 1%), rash (3%; 0%), fatigue (2% to 1%), nausea (2%; 1%), vomiting (2%; 1%), and periorbital edema (1%; 0%) were reported among patients receiving adjuvant treatment of GLEEVEC. ■ Severe congestive heart failure and left ventricular dysfunction have occasionally been reported. Most of the patients with reported cardiac events have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.

■ Hepatotoxicity, occasionally severe, may occur. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment.

■ Patients with moderate renal impairment (CrCL = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min). For patients with moderate renal impairment, doses greater than 400 mg are not recommended. Imatinib should be used with caution in patients with severe renal impairment.

■ There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, acute respiratory failure, and GI perforation.

■ Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of GLEEVEC at a lower dose with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction.

■ Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with GLEEVEC. TSH levels should be closely monitored in such patients.

■ Consider potential toxicities—specifically liver, kidney, and cardiac toxicity, and immunosuppression from long-term use.

■ Fetal harm can occur when administered to a pregnant woman; therefore, women of childbearing potential should be advised to not become pregnant while taking GLEEVEC tablets and to avoid breast-feeding while taking GLEEVEC tablets because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking GLEEVEC should use adequate contraception. If the patient does become pregnant while taking GLEEVEC, the patient should be advised of the potential hazard to the fetus.

1 in 2 patients experiences recurrent disease after surgery1

GLEEVEC for adjuvant therapy in KIT+ GIST

■

■

With a median follow-up of 14 months, more than double the number of patients in the placebo arm experienced disease recurrence compared with those in the GLEEVEC arm (P<0.0001): GLEEVEC 30/359 = 8.4%, placebo 70/354 = 19.8%.2

GLEEVEC Significantly Improves RFS vs Placebo2 100

Patients with RFS (%)

■

Some serious adverse reactions may occur, including severe congestive heart failure, left ventricular dysfunction, hepatotoxicity, edema, hemorrhage, GI perforation, and hypothyroidism.2 The most frequently reported common adverse reactions were gastrointestinal disturbances, fatigue, edema, decreased hemoglobin, and rash.2

80

60 TREATMENT PERIOD

FOLLOW-UP PERIOD

40 GLEEVEC (n=359)

20

Placebo (n=354)

0 0

6

12

18

24

30

36

42

48

54

Time to recurrence (months)

Patients at risk: GLEEVEC

359

258

207

166

105

60

33

23

5

Placebo

354

243

186

138

89

57

34

19

8

1

A Phase III, randomized, double-blind study of adjuvant GLEEVEC versus placebo was conducted in 713 patients following resection of primary KIT+ GIST. The efficacy end point of the study was recurrence-free survival (RFS), defined as the time from date of randomization to the date of recurrence, or death from any cause.2

■

■

GLEEVEC is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Dosage of GLEEVEC should increase by at least 50% and clinical response should be carefully monitored in patients receiving GLEEVEC with a potent CYP3A4 inducer such as rifampin or phenytoin. Examples of commonly used drugs that may significantly interact with GLEEVEC include ketoconazole, acetaminophen, warfarin, erythromycin, and phenytoin. (Please see full Prescribing Information for other potential drug interactions.)

For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron.

Common Side Effects of GLEEVEC Tablets ■ In the adjuvant treatment of GIST trials, the majority of both GLEEVEC- and placebo-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include (GLEEVEC; placebo) (all Grades) diarrhea (60%; 29%), fatigue (57%; 41%), nausea (53%; 28%), periorbital edema (47%; 15%), decreased hemoglobin (47%; 27%), peripheral edema (27%; 15%), rash (26%; 13%), vomiting (26%; 14%), and abdominal pain (21%; 22%).* ■ In the adjuvant GIST trial, drug was discontinued for adverse events in 17% of GLEEVEC- and 3% of placebo-treated patients. Edema, gastrointestinal disturbances (nausea, vomiting, abdominal distention, and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation.* ■ Supportive care may help management of some mild-to-moderate adverse reactions. However, in some cases, either a dose reduction or interruption of treatment with GLEEVEC may be necessary.

■ GLEEVEC tablets should be taken with food and a large glass of water to minimize GI irritation. GLEEVEC tablets should not be taken with grapefruit juice and other foods known to inhibit CYP3A4.

■ Patients should be informed to take GLEEVEC exactly as prescribed, not to change their dose or stop taking GLEEVEC unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose. *For more detailed study information, please see full Prescribing Information.

References: 1. National Comprehensive Cancer Network. Soft tissue sarcoma. Clinical Practice Guidelines in Oncology—V.1.2009. http://www.nccn.org. Accessed July 20, 2009. 2. GLEEVEC® (imatinib mesylate) tablets prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; May 2009.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2009 Novartis

Printed in USA

7/09

C-GLI-100051

GLEEVEC (imatinib mesylate) tablets for oral use Initial U.S. Approval: 2001 BRIEF SUMMARY: The following information refers to adult patients with Kit-positive GIST. Experience with other indications may differ. Please see package insert for full prescribing information.

1 INDICATIONS AND USAGE 1.9 Kit+ Gastrointestinal Stromal Tumors (GIST) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

1.10 Adjuvant Treatment of GIST Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Fluid Retention and Edema Gleevec is often associated with edema and occasionally serious fluid retention [see Adverse Reactions (6.1) in the full prescribing information]. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema was increased with higher Gleevec dose and age >65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. Severe fluid retention was reported in 9% to 13.1% of patients taking Gleevec for GIST [see Adverse Reactions (6.11)].

5.2 Hematologic Toxicity Treatment with Gleevec is associated with anemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months). In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias including neutropenia, thrombocytopenia and anemia. These generally occur within the first several months of therapy [see Dosage and Administration (2.11) in the full prescribing information].

5.3 Severe Congestive Heart Failure and Left Ventricular Dysfunction Severe congestive heart failure and left ventricular dysfunction have occasionally been reported in patients taking Gleevec. Most of the patients with reported cardiac reactions have had other co-morbidities and risk factors, including advanced age and previous medical history of cardiac disease. In an international randomized phase 3 study in 1,106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking Gleevec compared to 0.9% of patients taking IFN + Ara-C. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.

5.4 Hepatotoxicity Hepatotoxicity, occasionally severe, may occur with Gleevec [see Adverse Reactions (6.3)]. Liver function (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment and monthly, or as clinically indicated. Laboratory abnormalities should be managed with interruption and/or dose reduction of the treatment with Gleevec [see Dosage and Administration (2.10) in the full prescribing information].

When Gleevec is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended.

5.5 Hemorrhage In the newly diagnosed CML trial, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site.

In the Phase 2 unresectable or metastatic GIST study 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages.

5.6 Gastrointestinal Disorders Gleevec is sometimes associated with GI irritation. Gleevec should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of gastrointestinal perforation.

5.7 Hypereosinophilic Cardiac Toxicity In patients with hypereosinophilic syndrome and cardiac involvement, cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of Gleevec therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Gleevec. Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Gleevec should be considered at the initiation of therapy.

5.8 Dermatologic Toxicities Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of Gleevec.

5.9 Hypothyroidism Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Gleevec. TSH levels should be closely monitored in such patients.

5.10 Toxicities from Long-Term Use It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney and cardiac toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased BUN and creatinine were observed in several of these animals.

An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39-week monkey study, treatment with imatinib resulted in worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans).

Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died on study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Nonneoplastic lesions seen in this 2-year study which were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals.

5.11 Use in Pregnancy Pregnancy Category D Women of childbearing potential should be advised to avoid becoming pregnant while taking Gleevec.

Sexually active female patients taking Gleevec should use adequate contraception. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area. Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on body surface area [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice.

6.2 Hematologic Toxicity Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses ≥750 mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease.

In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients (see Tables 4 and 5 in the full prescribing information). The frequency of Grade 3 or 4 neutropenia and thrombocytopenia was between 2- and 3-fold higher in blast crisis and accelerated phase compared to chronic phase (see Tables 4 and 5 in the full prescribing information). The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3 weeks, and from 2 to 4 weeks, respectively.

These reactions can usually be managed with either a reduction of the dose or an interruption of treatment with Gleevec, but in rare cases require permanent discontinuation of treatment.

6.3 Hepatotoxicity Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 4 and 5 in the full prescribing information) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients. Bilirubin elevation was observed in 2.7% of patients.

6.5 Adverse Reactions in Other Subpopulations In older patients (≥65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade 1/2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen that were related to race but the subsets were too small for proper evaluation.

6.11 Gastrointestinal Stromal Tumors Unresectable and/or Malignant Metastatic GIST In the Phase 3 trials the majority of Gleevec-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were edema, fatigue, nausea, abdominal pain, diarrhea, rash, vomiting, myalgia, anemia and anorexia. Drug was discontinued for adverse reactions in a total of 89 patients (5.4%). Superficial edema, most frequently periorbital or lower extremity edema was managed with diuretics, other supportive measures, or by reducing the dose of Gleevec [see Dosage and Administration (2.10) in the full prescribing information]. Severe (CTC Grade 3/4) edema was observed in 182 patients (11.1%).

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Gleevec are shown in Table 9.

Overall the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema, which was reported more frequently in the 800 mg group.

Table 9: Number (%) of Patients with Adverse Reactions where Frequency is ≥10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials Imatinib 400 mg N=818 Reported or Specified Term

All Grades %

Edema Fatigue/lethargy, malaise, asthenia Nausea Abdominal pain/cramping Diarrhea Rash/desquamation Vomiting Myalgia Anemia Anorexia Other GI toxicity Headache Other pain (excluding tumor related pain) Other dermatology/skin toxicity Leukopenia Other constitutional symptoms Cough Infection (without neutropenia) Pruritus Other neurological toxicity Constipation Other renal/genitourinary toxicity Arthralgia (joint pain) Dyspnea (shortness of breath)

Imatinib 800 mg N=822

Grades 3/4/5 %

All Grades %

Grades 3/4/5 %

76.7 69.3 58.1 57.2 56.2 38.1 37.4 32.2 32.0 31.1 25.2 22.0

9.0 11.7 9.0 13.8 8.1 7.6 9.2 5.6 4.9 6.6 8.1 5.7

86.1 74.9 64.5 55.2 58.2 49.8 40.6 30.2 34.8 35.8 28.1 19.7

13.1 12.2 7.8 11.8 8.6 8.9 7.5 3.8 6.4 4.7 6.6 3.6

20.4 17.6 17.0 16.7 16.1 15.5 15.4 15.0 14.8 14.2 13.6 13.6

5.9 5.9 0.7 6.4 4.5 6.6 5.4 6.4 5.1 6.5 4.8 6.8

20.8 20.1 19.6 15.2 14.5 16.5 18.9 15.2 14.4 13.6 12.3 14.2

5.0 5.7 1.6 4.4 3.2 5.6 4.3 4.9 4.1 5.2 3.0 5.6 (continued)

Table 9: Number (%) of Patients with Adverse Reactions where Frequency is ≥10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials Imatinib 400 mg N=818 Reported or All Grades Specified Term % Fever in absence of neutropenia (ANC <1.0 x 109/L) 13.2 Sweating 12.7 Other hemorrhage 12.3 Weight gain 12.0 Alopecia 11.9 Dyspepsia/heartburn 11.5 Neutropenia/granulocytopenia 11.5 Rigors/chills 11.0 Dizziness/lightheadedness 11.0 Creatinine increase 10.8 Flatulence 10.0 Stomatitis/pharyngitis (oral/pharyngeal mucositis) 9.2 Lymphopenia 6.0

Grades 3/4/5 %

All Grades %

Grades 3/4/5 %

4.9 4.6 6.7 1.0 4.3 0.6 3.1 4.6 4.8 0.4 0.2

12.9 8.5 13.3 10.6 14.8 10.9 16.1 10.2 10.0 10.1 10.1

3.4 2.8 6.1 0.6 3.2 0.5 4.1 3.0 2.8 0.6 0.1

5.4 0.7

10.0 10.1

4.3 1.9

Table 10: Laboratory Abnormalities in the Phase 2 Unresectable and/or Malignant Metastatic GIST Trial 400 mg (n=73) %

600 mg (n=74) %

Grade 3

Grade 4

Grade 3

Grade 4

3 0 7

0 0 3

8 1 8

1 0 3

0 3 1

0 0 0

3 4 1

0 0 3

0 4 6

0 0 0

3 3 7

0 3 1

Grades: neutropenia (Grade 3 ≥0.5-1.0 x 109/L, Grade 4 <0.5 x 109/L), thrombocytopenia (Grade 3 ≥10-50 x 109/L, Grade 4 <10 x 109/L), anemia (Grade 3 ≥65-80 g/L, Grade 4 <65 g/L), elevated creatinine (Grade 3 >3-6 x upper limit normal range [ULN], Grade 4 >6 x ULN), elevated bilirubin (Grade 3 >3-10 x ULN, Grade 4 >10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN), albumin (Grade 3 <20 g/L)

1CTC

Adjuvant Treatment of GIST The majority of both Gleevec and placebo treated patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting and abdominal pain. No new adverse reactions were reported in the adjuvant GIST treatment setting that had not been previously reported in other patient populations including patients with unresectable and/or malignant metastatic GIST. Drug was discontinued for adverse reactions in 57 patients (17%) and 11 patients (3%) of the Gleevec and placebo treated patients respectively. Edema, gastrointestinal disturbances (nausea, vomiting, abdominal distention and diarrhea), fatigue, low hemoglobin and rash were the most frequently reported adverse reactions at the time of discontinuation.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Gleevec are shown in Table 11.

Table 11: Adverse Reactions Reported in the Adjuvant GIST Trial (≥5% of Gleevec Treated Patients)(1) All CTC Grades

Preferred Term Diarrhea Fatigue Nausea Periorbital Edema Hemoglobin Decreased Peripheral Edema Rash (Exfoliative) Vomiting Abdominal Pain Headache Dyspepsia Anorexia Weight Increased Liver Enzymes (ALT) Increased Muscle Spasms Neutrophil Count Decreased Arthralgia White Blood Cell Count Decreased Constipation Dizziness Liver Enzymes (AST) Increased Myalgia Blood Creatinine Increased Cough Pruritus

All CTC Grades

Imatinib 800 mg N=822

Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values were not reported or evaluated in the Phase 3 GIST trials. Severe abnormal laboratory values reported in the Phase 2 GIST trial are presented in Table 10.

CTC Grades1 Hematology Parameters – Anemia – Thrombocytopenia – Neutropenia Biochemistry Parameters – Elevated Creatinine – Reduced Albumin – Elevated Bilirubin – Elevated Alkaline Phosphatase – Elevated SGOT (AST) – Elevated SGPT (ALT)

Table 11: Adverse Reactions Reported in the Adjuvant GIST Trial (≥5% of Gleevec Treated Patients)(1)

Gleevec (n=337) %

Placebo (n=345) %

59.3 57.0 53.1 47.2 46.9 26.7 26.1 25.5 21.1 19.3 17.2 16.9 16.9 16.6 16.3 16.0 15.1 14.5 12.8 12.5 12.2 12.2 11.6 11.0 11.0

29.3 40.9 27.8 14.5 27.0 14.8 12.8 13.9 22.3 20.3 13.0 8.7 11.6 13.0 3.3 6.1 14.5 4.3 17.7 10.7 7.5 11.6 5.8 11.3 7.8

CTC Grade 3 and above Gleevec (n=337) % 3.0 2.1 2.4 1.2 0.6 0.3 2.7 2.4 3.0 0.6 0.9 0.3 0.3 2.7 0 3.3 0 0.6 0 0 2.1 0 0 0 0.9

Placebo (n=345) % 1.4 1.2 1.2 0 0 0 0 0.6 1.4 0 0 0 0 0 0 0.9 0.3 0.3 0.3 0.3 0 0.3 0.3 0 0 (continued)

Preferred Term Weight Decreased Hyperglycemia Insomnia Lacrimation Increased Alopecia Flatulence Rash Abdominal Distension Back Pain Pain in Extremity Hypokalemia Depression Facial Edema Blood Alkaline Phosphatase Increased Dry Skin Dysgeusia Abdominal Pain Upper Neuropathy Peripheral Hypocalcemia Leukopenia Platelet Count Decreased Stomatitis Upper Respiratory Tract Infection Vision Blurred

CTC Grade 3 and above

Gleevec (n=337) %

Placebo (n=345) %

Gleevec (n=337) %

Placebo (n=345) %

10.1 9.8 9.8 9.8 9.5 8.9 8.9 7.4 7.4 7.4 7.1 6.8 6.8

5.2 11.3 7.2 3.8 6.7 9.6 5.2 6.4 8.1 7.2 2.0 6.4 1.2

0 0.6 0.9 0 0 0 0.9 0.3 0.6 0.3 0.9 0.9 0.3

0 1.7 0 0 0 0 0 0.3 0 0 0.6 0.6 0

6.5 6.5 6.5 6.2 5.9 5.6 5.0 5.0 5.0 5.0 5.0

7.5 5.2 2.9 6.4 6.4 1.7 2.6 3.5 1.7 3.5 2.3

0 0 0 0.3 0 0.3 0.3 0 0.6 0 0

0 0 0 0 0 0 0 0 0 0 0

adverse reactions occurring in ≥5% of patients are listed regardless of suspected relationship to treatment. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category.

(1)All

6.12 Additional Data from Multiple Clinical Trials The following adverse reactions have been reported during clinical trials of Gleevec.

Cardiac Disorders: Estimated 0.1%-1%: congestive cardiac failure, tachycardia, palpitations, pulmonary edema Estimated 0.01%-0.1%: arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion Vascular Disorders: Estimated 1%-10%: flushing, hemorrhage Estimated 0.1%-1%: hypertension, hypotension, peripheral coldness, Raynauds phenomenon, hematoma Clinical Laboratory Tests: Estimated 0.1%-1%: blood CPK increased, blood LDH increased Estimated 0.01%-0.1%: blood amylase increased Dermatologic: Estimated 1%-10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction Estimated 0.1%-1%: exfoliative dermatitis, bullous eruption, nail disorder, purpura, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae Estimated 0.01%-0.1%: vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discoloration, angioneurotic edema, erythema multiforme, leucocytoclastic vasculitis Digestive: Estimated 1%-10%: abdominal distention, gastroesophageal reflux, dry mouth, gastritis Estimated 0.1%-1%: gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis Estimated 0.01%-0.1%: colitis, ileus, inflammatory bowel disease General Disorders and Administration Site Conditions: Estimated 1%-10%: weakness, anasarca, chills Estimated 0.1%-1%: malaise Hematologic: Estimated 1%-10%: pancytopenia, febrile neutropenia Estimated 0.1%-1%: thrombocythemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy Estimated 0.01%-0.1%: hemolytic anemia, aplastic anemia Hepatobiliary: Estimated 0.1%-1%: hepatitis, jaundice Estimated 0.01%-0.1%: hepatic failure and hepatic necrosis1 Hypersensitivity: Estimated 0.01%-0.1%: angioedema Infections: Estimated 0.1%-1%: sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis Estimated 0.01%-0.1%: fungal infection Metabolic and Nutritional: Estimated 1%-10%: weight decreased Estimated 0.1%-1%: hypophosphatemia, dehydration, gout, increased appetite, decreased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia Estimated 0.01%-0.1%: hyperkalemia, hypomagnesemia Musculoskeletal: Estimated 1%-10%: joint swelling Estimated 0.1%-1%: joint and muscle stiffness Estimated 0.01%-0.1%: muscular weakness, arthritis

Nervous System/Psychiatric: Estimated 1%-10%: paresthesia, hypesthesia Estimated 0.1%-1%: syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor Estimated 0.01%-0.1%: increased intracranial pressure1, confusional state, convulsions, optic neuritis Renal: Estimated 0.1%-1%: renal failure acute, urinary frequency increased, hematuria, renal pain Reproductive: Estimated 0.1%-1%: breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema Respiratory: Estimated 1%-10%: epistaxis Estimated 0.1%-1%: pleural effusion Estimated 0.01%-0.1%: interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage Special Senses: Estimated 1%-10%: conjunctivitis, vision blurred, eyelid edema, conjunctival hemorrhage, dry eye Estimated 0.1%-1%: vertigo, tinnitus, eye irritation, eye pain, orbital edema, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss Estimated 0.01%-0.1%: papilledema1, glaucoma, cataract 1Including

some fatalities

6.13 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of Gleevec.

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.

Nervous system disorders: cerebral edema1 Eye disorders: vitreous hemorrhage Cardiac disorders: pericarditis, cardiac tamponade1 Vascular disorders: thrombosis/embolism, anaphylactic shock Respiratory, thoracic and mediastinal disorders: acute respiratory failure1, interstitial lung disease Gastrointestinal disorders: ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, gastrointestinal perforation1 [see Warnings and Precautions (5.6)], diverticulitis Skin and subcutaneous tissue disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysaesthesia syndrome Musculoskeletal and connective tissue disorders: avascular necrosis/hip osteonecrosis, rhabdomyolysis/ myopathy Reproduction disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst 1Including

some fatalities

In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon rechallenge. Several foreign post-marketing reports have described cases in which patients tolerated the reintroduction of Gleevec therapy after resolution or improvement of the bullous reaction. In these instances, Gleevec was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines.

777DRUG INTERACTIONS 7.1 Agents Inducing CYP3A Metabolism Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of Gleevec, increased Gleevec oral-dose clearance by 3.8-fold, which significantly (p<0.05) decreased mean Cmax and AUC. Similar findings were observed in patients receiving 400-1200 mg/day Gleevec concomitantly with enzyme-inducing anti-epileptic drugs (EIAED) (e.g., carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone). The mean dose normalized AUC for imatinib in the patients receiving EIAEDs decreased by 73% compared to patients not receiving EIAED. Concomitant administration of Gleevec and St. John’s Wort led to a 30% reduction in the AUC of imatinib.

Consider alternative therapeutic agents with less enzyme induction potential in patients when rifampin or other CYP3A4 inducers are indicated. Gleevec doses up to 1200 mg/day (600 mg BID) have been given to patients receiving concomitant strong CYP3A4 inducers [see Dosage and Administration (2.9) in the full prescribing information].

7.2 Agents Inhibiting CYP3A Metabolism There was a significant increase in exposure to imatinib (mean Cmax and AUC increased by 26% and 40%, respectively) in healthy subjects when Gleevec was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is recommended when administering Gleevec with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of imatinib and should be avoided. Substances that inhibit the cytochrome P450 isoenzyme (CYP3A4) activity may decrease metabolism and increase imatinib concentrations.

7.3 Interactions with Drugs Metabolized by CYP3A4 Gleevec increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by Gleevec. Particular caution is recommended when administering Gleevec with CYP3A4 substrates that have a narrow therapeutic window (e.g., alfentanil, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus or tacrolimus).

Gleevec will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolobenzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.).

888USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.11)].

Gleevec can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses ≥100 mg/kg (approximately equal to the maximum human dose of 800 mg/day based on body surface area). Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. Female rats administered doses ≥45 mg/kg (approximately one-half the maximum human dose of 800 mg/day based on body surface area) also experienced significant post-implantation loss as evidenced by either early fetal resorption or stillbirths, nonviable pups and early pup mortality between postpartum Days 0 and 4. At doses higher than 100 mg/kg, total fetal loss was noted in all animals. Fetal loss was not seen at doses ≤30 mg/kg (one-third the maximum human dose of 800 mg).

There are no adequate and well-controlled studies with Gleevec in pregnant women. Women should be advised not to become pregnant when taking Gleevec. 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.

8.3 Nursing Mothers Imatinib and its active metabolite are excreted into human milk. Based on data from three breastfeeding women taking Gleevec, the milk:plasma ratio is about 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and active metabolite, a breast-fed infant could receive up to 10% of the maternal therapeutic dose based on body weight. Because of the potential for serious adverse reactions in nursing infants from Gleevec, 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 Pediatric Use Gleevec safety and efficacy have been demonstrated in children with newly diagnosed Ph+ chronic phase CML and in children with Ph+ chronic phase CML with recurrence after stem cell transplantation or resistance to interferon-alpha therapy. There are no data in children under 2 years of age. Follow-up in children with newly diagnosed Ph+ chronic phase CML is limited.

As in adult patients, imatinib was rapidly absorbed after oral administration in pediatric patients, with a Cmax of 2-4 hours. Apparent oral clearance was similar to adult values (11.0 L/hr/m2 in children vs.

10.0 L/hr/m2 in adults), as was the half-life (14.8 hours in children vs. 17.1 hours in adults). Dosing in children at both 260 mg/m2 and 340 mg/m2 achieved an AUC similar to the 400 mg dose in adults. The comparison of AUC on Day 8 vs. Day 1 at 260 mg/m2 and 340 mg/m2 dose levels revealed a 1.5- and 2.2-fold drug accumulation, respectively, after repeated once-daily dosing. Mean imatinib AUC did not increase proportionally with increasing dose.

8.5 Geriatric Use In the CML clinical studies, approximately 20% of patients were older than 65 years. In the study of patients with newly diagnosed CML, 6% of patients were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema [see Warnings and Precautions (5.1)]. The efficacy of Gleevec was similar in older and younger patients.

In the unresectable or metastatic GIST study, 16% of patients were older than 65 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis.

In the adjuvant GIST study, 221 patients (31%) were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema. The efficacy of Gleevec was similar in patients older than 65 years and younger patients.

8.6 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 cancer patients with varying degrees of hepatic impairment (Table 12) at imatinib doses ranging from 100-800 mg. Exposure to both imatinib and CGP74588 was comparable between each of the mildly and moderately hepatically-impaired groups and the normal group. Patients with severe hepatic impairment tend to have higher exposure to both imatinib and its metabolite than patients with normal hepatic function. At steady state, the mean Cmax/dose and AUC/dose for imatinib increased by about 63% and 45%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. The mean Cmax/dose and AUC/dose for CGP74588 increased by about 56% and 55%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function [see Dosage and Administration (2.10) in the full prescribing information].

Table 12: Liver Function Classification Liver Function Test

7.5 Interaction with Acetaminophen In vitro, Gleevec inhibits acetaminophen O-glucuronidation (Ki value of 58.5 μM) at therapeutic levels.

Systemic exposure to acetaminophen is expected to be increased when co-administered with Gleevec.

No specific studies in humans have been performed and caution is recommended.

Mild (n=30)

Moderate (n=20)

Severe (n=20)

Total Bilirubin

≤ULN

>1.0-1.5x ULN

>1.5-3x ULN

>3-10x ULN

SGOT

≤ULN

>ULN (can be normal if Total Bilirubin is >ULN)

Any

Any

ULN=upper limit of normal for the institution 8.7 Renal Impairment The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 cancer patients with varying degrees of renal impairment (Table 13) at single and steady state imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib (dose normalized AUC) in patients with mild and moderate renal impairment increased 1.5- to 2-fold compared to patients with normal renal function. The AUCs did not increase for doses greater than 600 mg in patients with mild renal impairment.

The AUCs did not increase for doses greater than 400 mg in patients with moderate renal impairment.

Two patients with severe renal impairment were dosed with 100 mg/day and their exposures were similar to those seen in patients with normal renal function receiving 400 mg/day. Dose reductions are necessary for patients with moderate and severe renal impairment [see Dose Modification Guidelines (2.9) in the full prescribing information].

Table 13: Renal Function Classification

Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin instead of warfarin.

7.4 Interactions with Drugs Metabolized by CYP2D6 Gleevec increased the mean Cmax and AUC of metoprolol by approximately 23% suggesting that Gleevec has a weak inhibitory effect on CYP2D6-mediated metabolism. No dose adjustment is necessary, however, caution is recommended when administering Gleevec with CYP2D6 substrates that have a narrow therapeutic window.

Normal (n=14)

Renal Dysfunction

Renal Function Tests

Mild Moderate Severe

CrCL = 40-59 mL/min CrCL = 20-39 mL/min CrCL = <20 mL/min

CrCL = Creatinine Clearance T2009-124 Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936 ©Novartis

SUPPORTIVE CARE

CLINICAL ONCOLOGY NEWS • MARCH 2010

Pain

Possible Link Between Opioids and Cancer Progression Two recent studies conducted by researchers at the University of Chicago add to a growing literature that suggest that opioid-based pain therapies may trigger the growth and migration of cancer cells.

The studies also suggest that modifying treatments may help patients avoid these deleterious peripheral effects. The new data were presented at the Molecular Targets and Cancer Therapeutics, a joint meeting of the American Association for Cancer Research, the National Cancer Institute, and the European Organisation for Research and Treatment of Cancer.

Experts caution that the findings are preliminary and should not impact clinical practice at this time. “This experimental evidence concurs with others, which suggests that opioids, the mainstay treatment of acute postoperative pain after cancer surgery, might inadvertently facilitate cancer cell survival and progression,” said Donal J. Buggy, MD, clinician investigator with the Mater-University College of Dublin Clinical Research Centre & Conway Institute for Biomedical Science at University College Dublin in Ireland. “Whether this translates into a realistic clinical factor only can be addressed by conducting a prospective, international clinical trial.”

New Evidence Each of the new studies focused on the µ-opioid receptor as a regulator of tumor growth and tested the effect of methylnaltrexone (Relistor, Wyeth), an opioid blocker that works on the µ-opioid receptor. In the first study, which looked at two models of nonsmall cell lung cancer, the researchers showed methylnaltrexone limited the tumor-promoting effects of the opioid (abstract C79). In the second study, researchers injected Lewis lung carcinoma cells into knockout mice without the µ-opioid receptor (abstract C78).

Those mice did not develop tumors.

Additionally, researchers showed that the opioid blocker prevented invasion in cell culture, tumor growth and metastasis in normal mice; methylnaltrexone reduced proliferation of cancer cells by 90% in normal mice.

“Our studies indicate morphine and other related µ-agonists can directly stimulate cancer cell proliferation and migration,” said Patrick A. Singleton, PhD, assistant professor of medicine at the University of Chicago Medical Center and principal author of both studies.

“In addition, we found that opiates promote angiogenesis, the growth of new blood vessels, and decrease endothelial barrier integrity, effects that may make

it potentially easier for tumors to invade tissue and spread to distant sites.”

Dr. Singleton explained that the question of whether methylnaltrexone could impact the spread of cancer in patients undergoing opioid pain therapy emerged

The new studies suggest the µ-opioid receptor may play a key role in tumor regulation and add to growing evidence that choices made in opioid therapies may influence survival in cancer patients, Dr. Singleton said. Recent work out of Ireland showed a difference in recurrence rates of prostate and breast cancers depending on whether patients received epidural or general anesthesia with opiates during surgery (Contemp Clin Trials 2008;29:517-526, and Anesthesiology 2008;109:180-187).

potential therapeutic target. “While our studies indicate opioids stimulate oncogenic signaling, they also show that the µ-opioid receptor can stimulate cancer growth even in the absence of exogenous opiates,” said Dr. Singleton. “Further, and most intriguing, µ-opioid receptor knockout mice have dramatically less Lewis lung carcinoma tumor formation than wild-type mice. Drugs that target the peripheral µ-opioid receptor may represent a novel strategy for cancer treatment.”

Preliminary Findings ‘Our studies indicate morphine and other related µ-agonists can directly stimulate cancer cell proliferation and migration.’

—Patrick A. Singleton, PhD

during clinical trials that were testing the drug as a treatment for constipation.

“During the approval process for methylnaltrexone, a peripheral opiate antagonist used to treat opioid-induced constipation in patients with advanced illness, we treated many patients in a compassionate use protocol,” Dr. Singleton explained. “Several of these patients treated by my colleague, Dr. Jonathan Moss, lived longer than expected, leading us to wonder whether this was the consequence of better gastrointestinal function or could there possibly be a direct effect on the tumors.” Jonathan Moss, MD, PhD, is a professor and vice-chairman of anesthesia and critical care at the University of Chicago Medical Center.

“If [our] laboratory studies are confirmed clinically, the selection of anesthetic technique used during the operative procedure and the possible use of peripheral opiate antagonists in the perioperative period could become potentially important therapeutic options in cancer surgery,” Dr. Singleton said.

The new studies provide an additional significant finding—the subtypes of non-small cell lung cancer expressing the highest levels of the µ-opioid receptor had the greatest oncogenic response to morphine and the greatest inhibition by opioid-receptor blockers. If confirmed clinically, this would indicate the peripheral µ-opioid receptor is a novel biomarker for cancer severity and a

According to Dr. Buggy, the recent findings are preliminary. “The µ-opioid receptor does not have any known or established role in cancer development or progression,” Dr. Buggy said.

“Conventional knowledge is that these receptors mediate the analgesic effect of opioids, and perhaps some of its mood-related side effects. That doing so might inadvertently alter processes and cellular behavior in a way that could affect cancer progression or outcome is novel indeed.” He said that it is too early to draw conclusions about the clinical implications of the work on µ-opioid receptors.

“I would advise caution in any interpretation of this work that suggests that the µ-opioid could be a potential predictive factor of cancer severity, and that in the future, treatments may be developed that target it as a cancer therapy,” Dr. Buggy said. “What this work and other international clinical scientists have shown, is that a number of factors occur in the perioperative period, which affect the balance of cancer cell progression metastases versus resistance to cancer spread.”

Dr. Buggy is leading a large, international, prospective trial that will attempt to answer some of the questions raised by recent research into the peripheral effects of pain therapy in cancer patients. The study is being done in collaboration with the Outcomes Research Consortium, directed by Daniel Sessler, MD, chair of the Department of Outcomes Research at the Cleveland Clinic in Ohio.

Dr. Singleton noted that Dr. Moss, a co-author on their studies, has a financial royalty interest in methylnaltrexone through the University of Chicago, and receives stock options and serves as a paid consultant to Progenics Pharmaceuticals, Inc., which has licensed methylnaltrexone from the University of Chicago. However, Progenics did not give financial support for these studies, he said.

—David Jakubiak

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CLINICAL ONCOLOGY NEWS • MARCH 2010

VTE

WARFARIN continued from page 25

St. John’s Mercy Medical Center in St. Louis, said alternatives to warfarin would be welcome since the drug is hard to use. “Warfarin is such a painful drug to use. Titrating the drug to the right degree of an INR [international normalized ratio], at goal 2-3, is a lot of work,” he said. “Some liver function abnormalities with the direct thrombin inhibitors have been an issue.”

Nitty-Gritty In the RE-COVER study, which was published in The New England Journal of Medicine (2009;361:23422352, PMID: 19966341) the same week the data were presented at the ASH meeting, 2,564 patients with acute symptomatic objectively verified deep vein thrombosis (DVT) of the legs or pulmonary embolism (PE) were randomly assigned to receive 150 mg of twice-daily dabigatran or warfarin that was doseadjusted to achieve an INR of 2.0 to 3.0. The primary outcome was recurrent, symptomatic, objectively confirmed VTE and related deaths. The drugs also were compared for safety, which included bleeding events and acute coronary events.

Although VTE rates were slightly greater in patients on dabigatran than in patients on warfarin (2.4% vs.

2.1%), the rate of major bleeding events was slightly lower on dabigatran (1.6% vs. 1.95%). Neither difference was statistically significant; the difference between the two agents was well within the prespecified noninferiority margin (P<0.001). The number of deaths, coronary events and abnormal liver function tests (LFTs) were similar in the two groups. This latter point is relevant

because another oral anticoagulant, ximelagatran, was withdrawn from clinical testing due to liver toxicity.

“We are dealing with a very safe compound,” said Dr. Schulman, who based his remark on the pooled data that included this study as well as the series of studies now completed for VTE prophylaxis after total hip and knee arthroplasty and in stroke prevention. Based on similar efficacy and safety, the practical advantages of dabigatran over warfarin are considered practicechanging. Monitoring INR is cumbersome, inconvenient and costly.

In the late-breaker study with rivaroxaban, 1,197 patients were randomized to 20 mg once daily of this DTI or to placebo after completing an initial six- to 12-month course of anticoagulation for acute VTE. The primary outcome was a composite of recurrent DVT or PE. Safety analyses were particularly focused on bleeding and liver enzyme function.

At the end of six to 12 months of follow-up, symptomatic VTE occurred in 1.3% of patients on rivaroxaban compared with 7.1% in those receiving placebo, producing an 82% risk reduction (hazard ratio, 0.18; 95% confidence interval, 0.09-0.39; P<0.0001).

The major bleeding rate was higher on rivaroxaban, but not significantly different from placebo (0.7% vs. 0%; P=0.106). Mortality rates of 0.2% and 0.3% in the rivaroxaban and placebo groups, respectively, did not differ significantly. No patient in either group had abnormal LFTs defined as three times the upper limit of normal.

The DTI dabigatran and the factor Xa inhibitor rivaroxaban have not been directly compared in any study, but both agents have been compared with the LMWH enoxaparin in noninferiority trials in VTE prophylaxis after total joint arthroplasty. The results of these studies reflect the delicate balance between

‘These newer agents may be a better alternative since they are oral, but the big unknown question in cancer patients is how much will the metabolism of these agents be affected by chemotherapy drugs, antifungal drugs, or patient symptoms such as nausea, vomiting, diarrhea, etc.’

—Jean Marie Connors, MD

‘An oral once-daily dose of rivaroxaban provides the clinician with a simple option for preventing recurrent symptomatic VTE.’ —Harry Roger Buller, MD, PhD

anticoagulant effect and risk for hemorrhage in that when one of these agents demonstrated greater protection against VTE than enoxaparin, they also produced a greater risk for bleeding. Conversely, less protection against VTE generally resulted in a lower relative risk for bleeding. The commercial doses of dabigatran and rivaroxaban are likely to be selected specifically to provide a similar risk–benefit ratio relative to warfarin for prevention or treatment of VTE. Even though they may not be any more effective or any safer, they will dramatically reduce the current inconvenience of VTE management.

Putting It in Perspective Jean Marie Connors, MD, medical director of the Anticoagulation Management Service at the DanaFarber Cancer Institute, Boston, agreed that the newer oral agents are not any better or safer than warfarin—they are just more convenient, but there are other issues involved.

“The convenience factor for very healthy stable patients with [atrial fibrillation] or no other medical problems and no risk for bleeding is a winner. It is less clear for medically complicated patients, and oncology patients fall into this category,” said Dr. Connors.

“Rivaroxaban has been used in Canada for a while and here is the yin-yang of a drug that is not being monitored: If the patient fails rivaroxaban or similar drug—they have progression of a clot or a new clot— is it because they were noncompliant or underdosed?

There is no good monitoring. Conversely, if someone starts bleeding, the only Rx is FFP [fresh frozen plasma], but there is no end point to titrate to. Warfarin is easily monitored, and in this setting anti-Xa for LMWH can be somewhat useful.”

According to Dr. Connors, the most recent studies show that cancer patients have a lower risk for blood clot recurrence if clinicians use LMWH rather than warfarin, because the metabolism of warfarin is so easily affected by many things, especially chemotherapy drugs. “The downside to LMWH is that they have to be given by daily subcutaneous injection,” she said.

“These newer agents may be a better alternative since they are oral, but the big unknown question in cancer patients is how much will the metabolism of these agents be affected by chemotherapy drugs, antifungal drugs, or patient symptoms such as nausea, vomiting, diarrhea, etc.”

For now, oncologists will just have to wait and see whether the drugs gain approval. Last May, while the FDA Advisory Committee recommended approval of rivaroxaban for the prevention of DVT and PE in patients undergoing hip or knee replacement surgery, the FDA put their decision on hold and asked for more information. “Rivaroxaban was under FDA review and we all thought it was going to be approved,” Dr. Connors said. “But it wasn’t.”

—Ted Bosworth

SUPPORTIVE CARE

CLINICAL ONCOLOGY NEWS • MARCH 2010

Tumor Lysis Syndrome

Alternative Rasburicase Dosing Proposed for TLS New Orleans—A single dose of rasburicase (Elitek, Sanofiaventis) may be sufficient to prevent tumor lysis syndrome in adults, according to results of a controlled trial.

Patients requiring second dose of rasburicase

for the administration of a repeat dose of this agent. The second dose was administered on day 3 in two patients, day 4 in one patient, and day 5 in two patients.

No patient received a third dose. In arm B, uric acid levels remained well controlled. All five of the patients in arm A who received a second dose of rasburicase were identified as high-risk patients prior to randomization.

Renal insufficiency, which was monitored as a secondary objective in this study, was not a clinical issue in either study arm. Overall, the electrolyte and the serum creatinine levels remained relatively stable before and after therapy. Although both regimens were relatively well tolerated, with no significant difference in the rate of serious adverse events, the single dose was associated with lower rates of several side effects,

14%

86%

Figure 1. Patients treated with a single dose of rasburicase given repeated doses if needed.

In addition to the shorter duration, the dose used in this study was 0.05 mg/kg lower than that currently approved for use.

oxidase that reduces the risk for TLS by rapidly converting uric acid, a key feature of TLS and a moiety largely responsible for the renal complications of TLS, into allantoin. Allantoin is five to 10 times more soluble than uric acid and is thus more easily excreted in urine. Allopurinol, which has

including nausea (11% vs. 33%), constipation (17% vs. 31%) and headache (9% vs. 22%) (Figure 2). There were significant reductions of serum interleukin-6 (IL-6) and tissue necrosis factor-alpha (TNF-α) after rasburicase was initiated in both treatment arms.

Rasburicase is a recombinant urate

Single 0.15 mg/kg infusion with repeated infusions as needed Fixed five-day dosing

40 35

33 31

% of Patients

Rasburicase has had a pediatric indication for tumor lysis syndrome (TLS) for more than seven years, but was only recently approved by the FDA for use in adults. The recommended regimen of rasburicase is 0.2 mg/kg in a 30-minute IV infusion for up to five days, but the new study evaluated a single oncedaily infusion of rasburicase in a dose of 0.15 mg/kg.

“In this study, all patients who were at intermediate risk for TLS and the majority of patients at high risk for TLS responded to a single dose of rasburicase. Only five patients at high TLS risk required a second dose,” said Saroj Vadhan-Raj, MD, chief of the Section of Cytokines & Supportive Oncology and professor of medicine in the Department of Sarcoma Medical Oncology, the University of Texas M.D. Anderson Cancer Center, Houston. Presenting results of this study at the annual meeting of the American Society of Hematology (ASH; abstract 105), Dr. VadhanRaj reported that although rasburicase is now approved for use in adults at a dose of 0.2 mg/kg for up to five days, the optimal dose and duration of its administration in adults was not previously well defined.

The majority of the 71 evaluable patients in the study had diffuse large B-cell lymphoma, but other hematologic malignancies associated with increased risk for TLS, such as mantle cell lymphoma, also were represented. Prior to randomization, patients were stratified into two groups: those at a potential risk, identified as intermediate risk, for TLS, and those at a high risk for TLS defined by hyperuricemia at baseline. After this stratification, patients were randomized on a one-to-one basis to a single 0.15 mg/ kg infusion with the opportunity for repeated infusions if needed, identified as arm A, or five infusions of 0.15 mg/kg (each one given over five consecutive days), identified as arm B. All doses were administered four or more hours before initiation of chemotherapy.

Investigators found that plasma uric acid levels fell rapidly to undetectable levels in the majority of patients in both arms after the initial dose of rasburicase.

Over the subsequent seven days of monitoring, uric acid levels were significantly lower in arm B than in arm A, but the arm A levels were still significantly below baseline. In arm A, five (14%) of the 35 patients required a second dose of rasburicase (Figure 1) when uric acid levels climbed above 7.5 mg/dL, the threshold

Patients receiving single dose

30 25

22

20

17

15 11 9

10 5 0 Nausea

Constipation

Figure 2. Comparison of side effects.

Headache

been used previously for the same purpose, provides a much slower protection against hyperuricemia, because it prevents formation of newly produced uric acid rather than rapidly diminishing existing uric acid elevations. Rasburicase was approved for pediatric use in 2002. The FDA conferred the indication for adults in October 2009. The study at M.D. Anderson Cancer Center is the first controlled study to suggest that an alternate dosing regimen is effective in adults at risk for TLS. In addition to the shorter duration, the dose used in this study was 0.05 mg/kg lower than that currently approved for use.

Although it offers potentially clinically meaningful information, there are some questions that remain in a study of relatively modest size. For example, Wyndham H. Wilson, MD, PhD, Lymphoma Therapeutics Section senior investigator, National Cancer Institute, Bethesda, Md., questions the potential significance of the reduction in IL-6 and TNF-α in a group of patients likely to be experiencing neutropenia. Specifically, he wonders whether rates of fever in the two study arms had been compared in an attempt to evaluate whether the sustained suppression of these cytokines had an impact on immune function. Dr. Vadhan-Raj, who also is a professor in the Department of Lymphoma/Myeloma, Division of Cancer Medicine at M.D. Anderson, acknowledged that this might be a valid clinical issue, but noted that there were no significant differences in febrile episodes between study arms. More data are needed to definitively address this and other potential clinical issues.

—Ted Bosworth

Publication Provides Advice for Oncology Fellows Oncology Fellow Advisor is a publication that provides support and information for the next generation of oncology practitioners.

For example, articles provide advice on finding a mentor, handling stress, managing finances, or deciding whether to pursue an academic position or a community-based career in a private or hospital-based practice.

For a free subscription to Oncology Fellow Advisor, please visit www.oncologyfellowadvisor.com.

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McMahon Awards Recently, the staff of McMahon Group celebrated the company’s 38th successful year, an especially welcome event given the challenging financial situation that pervaded the medical industry in 2009. McMahon Group, however, was fortunate to find itself in a better position in 2009 than in 2008, and the next 12 months look even better.

2010

The annual celebration recognizes the fact that some staff members truly excelled during the year and their exceptional efforts should be lauded. Here then are the winners of this year’s staff awards:

MANAGEMENT/SUPPORT PERSON OF THE YEAR:

ASSOCIATE/SENIOR EDITOR OF THE YEAR:

JEANNIE MOYER won for her ability to undertake a wide variety of both support, HR and insurance tasks, while always maintaining a smile and a pleasant demeanor.

SARAH TILYOU was recognized for her diverse skills, which include editing and writing for several of our publications. Her ability to move effortlessly from one publication to another, based on need, is much appreciated by the editorial staff.

GRAPHIC DESIGNER OF THE YEAR:

PRODUCTION PERSON OF THE YEAR:

DEANNA COSME won for her outstanding design work on General Surgery News, the best-read publication in surgery, as well as Infectious Disease Special Edition, our annual ID publication. She also was responsible for the designs of several special projects.

ACE PERSON OF THE YEAR: The company’s continuing medical education division, Applied Clinical Education (ACE), continues to negotiate the difficult terrain of CME, which would not be possible without the excellent skills of its manager of CME services, BARBARA JEAN WYNNE.

MANAGING EDITOR OF THE YEAR:

It’s fine to sell the ad space and to create the editorial, but then the newsmagazines and the special projects have to be printed and disseminated, and therein lies much detail.

MARK NEUFELD won the award for his innovative production ideas and accuracy.

In the crowded field of oncology publications, the one magazine that has risen faster in readership than any other is our own Clinical Oncology News. For her success in guiding the editorial direction of our newest publication, this award went to KATE O’ROURKE.

IT PERSON OF THE YEAR:

SALES ACHIEVEMENT AWARD:

SALESPERSON OF THE YEAR:

A gifted programmer, KWANGHEE CHUNG won the award only a few days after the birth of his son. Like his programs, everything went smoothly with that, too.

KATE CARMODY was the recipient of this award for her excellent work on General Surgery News, whose ad sales continue to advance, and her ability to sell custom projects while working diligently for her clients.

This award goes to the salesperson who sold the most, pure and simple. RICHARD TUORTO, group publication director of Anesthesiology News and Pain Medicine News, both of which are the best-read newsmagazines in their specialties, was by far the big winner—for the fourth year in a row.

MOST IMPROVED SALESPERSON OF THE YEAR:

FINANCE PERSON OF THE YEAR:

MCMAHON GROUP PERSON OF THE YEAR:

Because of her extensive work in refashioning the company’s financial systems, MARY LOU CAMPANELLA, director of finance, won this year’s award. After much hard work and many late nights, the financial tracking system has been successfully upgraded.

This award is granted to the single individual whose efforts have most significantly advanced the interests and success of the company. This year’s winner, JOE MALICHIO, director of medical education, has worked tirelessly with clients to create valuable editorial products that serve to further educate clinicians about important advancements in medical care.

This award went to JULIANNA DAWSON, the former associate publication director of Clinical Oncology News, our newest newsmagazine and one that has enjoyed dramatic success over the past year— which is why she is no longer the associate publication director, but the publication director.

FDA NEWS

CLINICAL ONCOLOGY NEWS • MARCH 2010

Rituxan Approved for CLL

T

he FDA has approved rituximab (Rituxan, Genentech) for people with previously untreated and previously treated CD20-positive chronic lymphocytic leukemia (CLL). Rituxan is administered with fludarabine (Fludara, Bayer HealthCare Pharmaceuticals) and cyclophosphamide (Cytoxan, BristolMyers Squibb).

Approval was based on two studies that measured progression-free survival (PFS). In one study of 817 patients who had not received any prior chemotherapy, PFS was eight months longer for those receiving rituximab plus chemotherapy than for those who received chemotherapy alone (39.8 vs. 31.5 months).

In another study of 522 individuals whose cancer had progressed following other chemotherapy drugs, PFS was five months longer for those who received rituximab plus chemotherapy (26.7 vs.

21.7 months). The drug did not benefit patients who were 70 years or older, but there also was no evidence that rituximab was harmful in the elderly.

Rituximab carries a boxed warning for infusion reactions, which can occur during infusion or within 24 hours afterward. Some 59% of patients treated with rituximab for CLL experienced an infusion reaction that resembled an allergic reaction (e.g., hives, low blood pressure, chills, fever and nausea). A decrease in infection-fighting, normal white blood cells also was commonly observed in patients enrolled in the rituximab clinical trials. Rituximab also can cause rashes and sores in the skin and mouth, progressive multifocal leukoencephalopathy and tumor lysis syndrome.

Morphine Approval Will Resolve Drug Shortage

T

he FDA has approved a generic formulation of 100 mg/5 mL (20 mg/mL) morphine sulfate oral solution from Roxane Laboratories, which will allow the agency to follow through on an initiative to pull unapproved opioid pain products from the market.

On March 31, 2009, as part of its ongoing Unapproved Drugs Initiative, the FDA sent warning letters to the makers of 14 unapproved opioid products, citing possible enforcement action if manufacturing and distribution of unapproved prescription pain products

was not halted within 60 and 90 days, respectively.

The FDA stated at the time of the initial letters that “removal of the unapproved narcotic products will not create a shortage for consumers,” but the move was met with immediate criticism from patients, physicians and health care organizations—particularly those in the palliative care community—over a potential shortage of 20 mg/mL morphine sulfate oral solution if the ban was put into effect. Concern centered on the potential for making pain control for patients receiving end-of-life care more difficult by removing the easyto-swallow 20 mg/mL morphine liquid

from the market.

Calling it an “enforcement discretion” on the part of the agency, manufacturing and distribution of high-concentrate morphine sulfate solutions was allowed under a temporary amendment to the FDA’s decision—but only until an FDAapproved version “or another acceptable alternative therapy” became available. Groups that initially had been critical of the FDA’s decision, such as the American Pain Foundation, praised the FDA’s reversal.

“This is the only FDA-approved morphine sulfate oral solution available at this concentration,” the FDA said on its Web site in announcing the new

approval. “The firm [Roxane Laboratories] has sufficient supply to meet the entire market demand and no shortage is anticipated.”

Morphine 20 mg/5 mL and 10 mg/5 mL remain available as approved products.

The FDA stated that the existing National Drug Code (NDC) numbers— NDC 0054-0352-44 for the morphine sulfate oral solution 30 mL bottle and NDC 0054-0352-50 for the morphine sulfate oral solution 120 mL bottle—will be in use for morphine 20 mg/mL until new packaging, labeling and NDC numbers become available.

FDA NEWS, continues on page 43

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POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • MARCH 2010

Planning

CURVE continued from page 1

practice today. During the 1970s and early 1980s, insurers moved to rein in their medical costs by limiting the number of providers in their plans through HMOs. This was largely unsuccessful because patients fought the efforts and employers didn’t buy the plans. The transformation that followed next wasn’t to find a different way to embrace new technology and reduce medical costs; instead, it was to hide limitations in technical language and force beneficiaries to limit their choices. Employers and their workforces, who now had to contribute money for their health insurance, allowed double-digit insurance increases to occur and, with nobody else stepping in to offer a solution, insurers offered reduced coverage options with lower premiums.

The losers in all of this were the physicians. Employers still were able to offer insurance and thus look like the good guys and attract workers. Physicians had to accept what insurers paid or look like the bad guys, only out to make money and maintain an indulgent lifestyle. Physicians bought into the game against their better interests. Some accepted positions at practices that were consumer-oriented and supported traditional medical values that included spending actual time with patients and getting to know them. Most couldn’t. As insurers reduced reimbursement to physicians, some doctors started asking patients to pay for services up front and then go directly to their insurance for out-of-network benefit reimbursement.

This happened in mostly urban and highincome areas.

Physicians felt the pinch of less money per procedure, payment grouping and new rules, such as only covering FDA labeled indications. In recent years, some physicians have been looking to improve their economic picture by forming large groups and networks so that they can monopolize the care in a given area by becoming the preferred

or in-network provider. Many of these physicians, however, are realizing that this is not the best solution because the focus is on making money by economies of scale and limiting patient choice, rather than maximizing quality care. An in-network provider refers patients to a provider in a network, rather than to the best-qualified provider. Many physicians are concerned that this will produce “cookbook” medicine and result in diminished patient outcomes.

These big entities or mega groups are exactly what insurers want—they guarantee volume to the insurers at lower prices and providers bear the brunt of the medical costs. Physicians traded volume for price and are now the driving force behind limited patient choice and, one could argue, reduced quality of care because of reduced competition among doctors.

Getting Out of This Mess So, how can physicians get out of this mess? They need to return to the principles that drive good medicine and good business.

If we look at the current practices of

Cornerstones of the New Paradigm 1. Develop meaningful results.

2. Let meaningful results be what drives you.

3. Demand that results be made available to the public.

4. Improve consumer communication.

5. Value the delivery of health care as part of a team rather than as an isolated player.

6. Become involved in rethinking medical education to foster improved results.

7. Support innovation as well as process.

leading institutions today, such as Mayo Clinic, the University of Texas M.D. Anderson Cancer Center and the Cleveland Clinic, to name just a few, we see that they are working not on process but rather on outcomes. The focus on process has been important in medicine. It brought improvements in patient safety, care minimums and cancer care guidelines, which are extremely useful for today’s practice. But it is outcomes data that really measure how doctors are doing in terms of caring for patients. Cancer care is founded on innovation, and innovation is not possible without sharing outcomes.

Times have changed since the 1950s, when American medicine needed to focus on creating local health care programs and institutions. Americans travel more, have better highway systems and are less isolated now than after World War II. The medical paradigm needs to shift. Today, we could lead America to reengage with physician-driven health care.

Physicians could lead the way away from insurance-driven care. Instead of spending time on detailed productivity and fulltime equivalency studies, start creating real outcome evidence.

Patient communication also is a key to success. Physicians need to help patients set realistic expectations of their medical care by sharing more information with patients about their own experiences, and not in an anecdotal way.

Physician practices should be teaching patients about what is realistic, rather than leaving that conversation to people marketing drugs and to insurers. As patients become better consumers, physicians with outcomes data will excel, instead of those with the biggest billing staff or the most process-driven protocols. Physician practices will benefit and because physicians are working

on the areas they love and enjoy, their personal lives will benefit, too.

So, what is the new paradigm? It is providers leading the charge to make patients better consumers of health care. I have mined ideas for this new paradigm from a 2006 book by Michael Porter called “Redefining Health Care” and from reports from the leaders in health care including Mayo Clinic, Cleveland Clinic, Dartmouth-Hitchcock Clinics, US Oncology, M.D. Anderson and the National Comprehensive Cancer Network. Clinicians can make patients better consumers of health care by following seven recommendations: 1. Develop meaningful results.

2. Let meaningful results be what drives you.

3. Demand that results be made available to the public.

4. Improve consumer communication.

5. Value the delivery of health care as part of a team rather than as an isolated player.

6. Become involved in rethinking medical education to foster improved results.

7. Support innovation as well as process.

Physicians have been on a downward slide and have driven themselves into a corner by focusing on economies of scale alone. Surviving the next few years is important, and it won’t happen unless practices change with the leaders driving medicine toward improved results and innovation. Doctors need to focus attention on the numbers that matter—numbers that illustrate outcomes.

—Mary Lou Bowers, MBA, President & CEO of The Pritchard Group, LLC, Rockville, Md. www.thepritchardgroup.net

Antifungal Prophylaxis Educational Review Available Exclusively Online Visit www.clinicaloncology.com and click on Educational Reviews on the left side of the page.

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • MARCH 2010

Communications

The Other Side of a Two-Way Street:

Active Listening Essential for Conversation Ever felt ignored in a conversation? Wondered if what you were saying had any impact on a staff member, or whether your medical findings were clearly received by a patient? Your confusion may have been created by a lack of communication on the part of your listener.

When we think about good communication, we often only consider how we deliver information verbally. Rarely do we consider the other side of communication—listening. Many individuals are surprised to discover that the quality of their interactions is determined by how others perceive them as listeners. When individuals are considered good listeners, they create a sense of connection, understanding and acceptance for the speaker. In turn, professional relationships with good listeners are desired, and these individuals are viewed as excellent resources for advice.

The best way to enhance your listening skills is to remember to employ the five key elements of active listening: focus your attention; maintain open body language; appear engaged; confirm what you have heard; then, clarify it.

Positive and Engaging Responses The first step in active listening is to give the speaker your undivided attention. This can be accomplished by

simply avoiding any suggestion of multitasking, which leaves the speaker feeling unimportant and dismissed. Providing the speaker your full attention will signal that your interest makes him or her feel respected and heard.

As you continue to listen to the speak-

er’s presentation, use open body language—keep your arms apart, direct your attention toward the speaker and use engaging facial expressions. This

stance shows you are receptive to the topic of discussion, encouraging the speaker to continue communicating openly.

When a listener is unresponsive in a conversation, it is difficult for a speaker to participate comfortably. The speaker might wonder if the listener is misunderstanding, maybe even ignoring, what is being said.

By engaging in direct eye contact, displaying slow affirming head nods and using encouraging phrases such as “I see …,” the listener shows the speaker that he or she is a participant in the conversation with a vested interest in continuing it.

Once the speaker has completed a thought, it is important for the listener to not respond too quickly. Asking a few openended questions can help you gain additional information and further clarify concepts shared by the speaker. At this point it is important to engage the speaker along the lines of, “Let me see if I understand, what you’re saying is,” to confirm your understanding.

Such inquiry should always end, “Is

that correct?” This will clarify for the speaker that you are simply confirming your understanding to avoid any misunderstanding or wrongful assumptions. When we take the time to clarify and confirm what we have heard as listeners, we ensure our conclusions are in alignment with the speaker’s intent, ultimately keeping the conversation on track.

When responding in a conversation, take special care to share your opinions candidly, openly and without judgment or criticism of what the speaker has shared. By avoiding a negative tone, you will prevent the speaker from becoming defensive or guarded, which can hinder communication.

Good listening skills are essential for several reasons: They build strong relationships, help avoid misunderstandings during communication and lead to more productive conversations. By engaging in active listening skills, we not only hear the words spoken; we also gain a full understanding of the messages being communicated by the speaker.

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

Dysfunction Identified in Physician-Scientist Pipeline

M

en and, more so, women who stand out early in their career for their potential as researchers appear to be falling off the academic ladder, say investigators.

Less than half of the men (46%) and even fewer of the women (36%) who won a coveted award recognizing their talents as young scientists were able to obtain a federal grant considered to be a milestone in a researcher’s career after a decade had passed, according to a report published in Annals of Internal Medicine (2009;151:804-811, PMID: 19949146).

“Our findings suggest dysfunction in the pipeline of physician-scientists,” said lead study author Reshma Jagsi, MD, DPhil, assistant professor of radiation oncology at the University of Michigan Medical School in Ann Arbor, in a news release. “This is not an easy career path for anyone, and it may be particularly hard for women. We need to figure out how to make this a more tenable career path, and right now both men and

women seem to need additional support.”

The investigators reviewed men and women who had been selected to receive one of two competitive awards, the K08 or K23 awards, meant to provide budding

significantly fewer K award recipients: Women made up 31.4% of the 1,919 who received the K08 award and 43.7% of the 865 who received the K23 award (P<0.001). Five years after receiving a

‘This is not an easy career path for anyone, and it may be particularly hard for women.’

—Reshma Jagsi, MD, DPhil

investigators who show great potential for a successful research career with the time, money and mentorship to pursue their goals. They set another prestigious award, a grant from the National Institutes of Health called an R01 grant, as an indicator of success, attempting to determine if recipients of the K awards went on to reach this milestone.

Between 1997 and 2003, 2,799 young researchers won a K award. The study investigators were able to determine the gender of 2,784 of the award recipients, finding that women represented

K award, 18.8% of women had obtained an R01 federal grant compared with 24.8% of men. After 10 years had passed, 36.2% of women and 45.6% of men had obtained an R01.

The study authors discussed several possible factors that may have contributed to the disparity, including differences in career and life goals and internalized expectations based on gender. Additionally, they called attention to the possible detrimental effect of the lower monetary amounts provided to women who win K awards compared with those awarded to

men, and the lack of mentors who understand the challenges women award winners face in developing their careers.

In an editorial on the topic, Amy C. Justice, MD, PhD, associate professor at Yale University School of Medicine and Public Health in New Haven, Conn., likened the difficulty of nurturing women scientists to the situation described by Virginia Woolf in her book, “A Room of One’s Own,” and called on the scientific community not to underestimate the cost to medical research in losing these talented scientists: “Like great writing, great science is difficult to accomplish in 15-minute slots between patients, or while worrying about personal responsibilities,” Dr. Justice wrote. “Excellence in research requires extended, undisturbed time and space in which to develop, evaluate, and fully test an idea. … The research enterprise must work with current junior clinical scientists to lay new, more flexible pipeline to scientific discovery and academic tenure.”

—Sandhya George

37

Indications and Important Safety Information for ALIMTA Indications ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

ALIMTA is indicated as a single agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

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

Contraindication: ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

Warnings and Precautions: Patients must be instructed to take folic acid and vitamin B12 with ALIMTA as a prophylaxis to reduce treatment-related hematologic and GI toxicities.

Pretreatment with dexamethasone or its equivalent has been reported to reduce the incidence and severity of skin rash.

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

ALIMTA® is a registered trademark of Eli Lilly and Company.

PM58001 0709 PRINTED IN USA © 2009, Lilly USA, LLC. ALL RIGHTS RESERVED.

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

Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicities.

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

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

Drug Interactions: Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. See Warnings and Precautions for specific information regarding ibuprofen administration.

Histology Matters with ALIMTA because

EXTENDED SURVIVAL MATTERS. Approved for the 1st-line treatment of advanced nonsquamous NSCLC and now approved for the maintenance treatment of advanced nonsquamous NSCLC. ALIMTA is not indicated for the treatment of patients with squamous cell NSCLC. Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Within the ALIMTA maintenance trial design, ALIMTA/cisplatin was not included as an induction therapy.

For more information, visit www.ALIMTA.com Use in SpeciďŹ c Patient Populations: It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother.

The safety and effectiveness of ALIMTA in pediatric patients have not been established.

Dose adjustments may be necessary in patients with hepatic insufďŹ ciency.

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

Abbreviated Adverse Reactions (% incidence) for NSCLC 1st-line: The most severe adverse reactions (Grades 3/4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (15 vs 27); leukopenia (5 vs 8); thrombocytopenia (4 vs 13); anemia (6 vs 10); fatigue (7 vs 5); nausea (7 vs 4); vomiting (6 vs 6); anorexia (2 vs 1); and creatinine elevation (1 vs 1).

Common adverse reactions (all Grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56 vs 53); fatigue (43 vs 45); vomiting (40 vs 36); anemia (33 vs 46); neutropenia (29 vs 38); anorexia (27 vs 24); constipation (21 vs 20); leukopenia (18 vs 21); stomatitis/pharyngitis (14 vs 12); alopecia (12 vs 21); diarrhea (12 vs 13); thrombocytopenia (10 vs 27); neuropathy/sensory (9 vs 12); taste disturbance (8 vs 9); rash/desquamation (7 vs 8); and dyspepsia/heartburn (5 vs 6).

Abbreviated Adverse Reactions (% incidence) for NSCLC Maintenance: The most severe adverse reactions (Grades 3/4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NSCLC) were anemia (3 vs 1); neutropenia (3 vs 0); leukopenia (2 vs 1); fatigue (5 vs 1); nausea (1 vs 1); anorexia (2 vs 0); mucositis/ stomatitis (1 vs 0); diarrhea (1 vs 0); infection (2 vs 0); neuropathy-sensory (1 vs 0). Common adverse reactions (all Grades) with ALIMTA as a single agent versus placebo, respectively, were anemia (15 vs 6); neutropenia (6 vs 0); leukopenia (6 vs 1); increased ALT (10 vs 4); increased AST (8 vs 4); fatigue (25 vs 11); nausea (19 vs 6); anorexia (19 vs 5); vomiting (9 vs 1); mucositis/stomatitis (7 vs 2); diarrhea (5 vs 3); infection (5 vs 2); neuropathy-sensory (9 vs 4); and rash/desquamation (10 vs 3).

Abbreviated Adverse Reactions (% incidence) for NSCLC 2nd-line: The most severe adverse reactions (Grades 3/4) with ALIMTA as a single agent versus docetaxel, respectively, for the 2nd-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (5 vs 40); leukopenia (4 vs 27); thrombocytopenia (2 vs 0); anemia (4 vs 4); fatigue (5 vs 5); nausea (3 vs 2); anorexia (2 vs 3); vomiting (2 vs 1); increased ALT (2 vs 0); increased AST (1 vs 0); and stomatitis/pharyngitis (1 vs 1). Common adverse reactions (all Grades) with ALIMTA as a single agent versus docetaxel, respectively, were fatigue (34 vs 36); nausea (31 vs 17); anorexia (22 vs 24); anemia (19 vs 22); vomiting (16 vs 12); stomatitis/pharyngitis (15 vs 17); rash (14 vs 6); diarrhea (13 vs 24); leukopenia (12 vs 34); and neutropenia (11 vs 45).

For additional safety and dosing guidelines, please see brief summary of Prescribing Information on adjacent page.

5 5.1

CONTRAINDICATIONS ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

WARNINGS AND PRECAUTIONS Premedication Regimen Need for Folate and Vitamin B12 Supplementation Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and GI toxicity [see Dosage and Administration (2.3)]. In clinical studies, less overall toxicity and reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B12 was administered.

Corticosteroid Supplementation Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction [see Dosage and Administration (2.3)].

5.2 Bone Marrow Suppression ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)].

5.3 Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)].

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

5.4 Use with Non-Steroidal Anti-Inflammatory Drugs with Mild to Moderate Renal Insufficiency Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Other NSAIDs should also be used with caution [see Drug Interactions (7.1)].

5.5 Required Laboratory Monitoring Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min [see Dosage and Administration (2.4)].

5.6 Pregnancy Category D Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA 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. Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. [see Use in Specific Populations (8.1)] 5.7 Third Space Fluid The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, the most common adverse reactions (incidence ≥20%) during therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

Non-Small Cell Lung Cancer (NSCLC)—Combination with Cisplatin Table 4 provides the frequency and severity of adverse reactions that have been reported in >5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.

Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa ALIMTA/cisplatin Gemcitabine/cisplatin Reaction b (N=839) (N=830) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) All Adverse Reactions 90 37 91 53 Laboratory Hematologic Anemia 33 6 46 10 Neutropenia 29 15 38 27 Leukopenia 18 5 21 8 Thrombocytopenia 10 4 27 13 Renal Creatinine elevation 10 1 7 1 Clinical Constitutional Symptoms Fatigue 43 7 45 5 Gastrointestinal Nausea 56 7 53 4 Vomiting 40 6 36 6 Anorexia 27 2 24 1 Constipation 21 1 20 0 Stomatitis/Pharyngitis 14 1 12 0 Diarrhea 12 1 13 2 Dyspepsia/Heartburn 5 0 6 0 Neurology Neuropathy-sensory 9 0 12 1 Taste disturbance 8 0c 9 0c Dermatology/Skin Alopecia 12 0c 21 1c Rash/Desquamation 7 0 8 1 a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity. c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

No clinically relevant differences in adverse reactions were seen in patients based on histology.

In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm.

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA plus cisplatin.

Incidence 1% to 5% Body as a Whole—febrile neutropenia, infection, pyrexia General Disorders—dehydration Metabolism and Nutrition—increased AST, increased ALT Renal—creatinine clearance decrease, renal failure Special Senses—conjunctivitis

ALIMTA姞 (pemetrexed for injection)

ALIMTA姞 (pemetrexed for injection)

ALIMTA姞 (pemetrexed for injection) BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information.

1

INDICATIONS AND USAGE

1.1

Nonsquamous Non-Small Cell Lung Cancer—Combination with Cisplatin ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

1.2

Nonsquamous Non-Small Cell Lung Cancer—Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

1.3

Nonsquamous Non-Small Cell Lung Cancer—After Prior Chemotherapy ALIMTA is indicated as a single agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy.

1.4

Mesothelioma ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

1.5

Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. [see Clinical Studies (14.1, 14.2, and 14.3)] 2

DOSAGE AND ADMINISTRATION

2.1

Combination Use with Cisplatin Nonsquamous Non-Small Cell Lung Cancer and Malignant Pleural Mesothelioma The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. Patients should receive appropriate hydration prior to and/or after receiving cisplatin.

See cisplatin package insert for more information.

2.2

Single-Agent Use Nonsquamous Non-Small Cell Lung Cancer The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.

2.3

Premedication Regimen Vitamin Supplementation To reduce toxicity, patients treated with ALIMTA must be instructed to take a low-dose oral folic acid preparation or multivitamin with folic acid on a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first dose of ALIMTA; and dosing should continue during the full course of therapy and for 21 days after the last dose of ALIMTA. Patients must also receive one (1) intramuscular injection of vitamin B12 during the week preceding the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as ALIMTA. In clinical trials, the dose of folic acid studied ranged from 350 to 1000 mcg, and the dose of vitamin B12 was 1000 mcg. The most commonly used dose of oral folic acid in clinical trials was 400 mcg [see Warnings and Precautions (5.1)].

Corticosteroid Skin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)].

2.4

Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/ mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)].

Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery.

Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin—Hematologic Toxicities Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3 75% of previous dose (pemetrexed and cisplatin) Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC 75% of previous dose (pemetrexed and cisplatin) Nadir platelets <50,000/mm3 with bleeding a, regardless of nadir ANC 50% of previous dose (pemetrexed and cisplatin) a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding.

If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2.

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin—Nonhematologic Toxicities a,b Dose of ALIMTA Dose of Cisplatin (mg/m 2) (mg/m 2) Any Grade 3 or 4 toxicities except mucositis 75% of previous dose 75% of previous dose Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea 75% of previous dose 75% of previous dose Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose a NCI Common Toxicity Criteria (CTC). b Excluding neurotoxicity (see Table 3).

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3.

Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin—Neurotoxicity Dose of ALIMTA Dose of Cisplatin CTC Grade (mg/m2) (mg/m2) 0-1 100% of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Renally Impaired Patients In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information].

3

DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.

4

PV 5206 AMP

PV 5206 AMP

Incidence Less than 1% Cardiovascular—arrhythmia General Disorders—chest pain Metabolism and Nutrition—increased GGT Neurology—motor neuropathy Non-Small Cell Lung Cancer (NSCLC) - Maintenance Table 5 provides the frequency and severity of adverse reactions that have been reported in >5% of 438 patients with NSCLC who received ALIMTA and 218 patients with NSCLC who received placebo. All patients received study therapy immediately following 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in both study arms were fully supplemented with folic acid and vitamin B12.

Table 5: Adverse Reactions in Patients Receiving ALIMTA versus Placebo in NSCLCa ALIMTA Placebo (N=438) (N=218) Reaction b All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) All Adverse Reactions 66 16 37 4 Laboratory Hematologic Anemia 15 3 6 1 Neutropenia 6 3 0 0 Leukopenia 6 2 1 1 Hepatic Increased ALT 10 0 4 0 Increased AST 8 0 4 0 Clinical Constitutional Symptoms Fatigue 25 5 11 1 Gastrointestinal Nausea 19 1 6 1 Anorexia 19 2 5 0 Vomiting 9 0 1 0 Mucositis/stomatitis 7 1 2 0 Diarrhea 5 1 3 0 Infection 5 2 2 0 Neurology Neuropathy-sensory 9 1 4 0 Dermatology/Skin Rash/Desquamation 10 0 3 0 a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTCAE Criteria version 3.0 for each Grade of toxicity.

No clinically relevant differences in Grade 3/4 adverse reactions were seen in patients based on age, gender, ethnic origin, or histology except a higher incidence of Grade 3/4 fatigue for Caucasian patients compared to non-Caucasian patients (6.5% versus 0.6%).

Safety was assessed by exposure for patients who received at least one dose of ALIMTA (N=438). The incidence of adverse reactions was evaluated for patients who received ≤6 cycles of ALIMTA, and compared to patients who received >6 cycles of ALIMTA. Increases in adverse reactions (all grades) were observed with longer exposure; however no clinically relevant differences in Grade 3/4 adverse reactions were seen.

Consistent with the higher incidence of anemia (all grades) on the ALIMTA arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the ALIMTA arm compared to the placebo arm (transfusions 9.5% versus 3.2%, ESAs 5.9% versus 1.8%).

The following additional adverse reactions were observed in patients with non-small cell lung cancer who received ALIMTA. Incidence 1% to 5% Dermatology/Skin—alopecia, pruritis/itching Gastrointestinal—constipation General Disorders—edema, fever (in the absence of neutropenia) Hematologic—thrombocytopenia Renal—decreased creatinine clearance, increased creatinine, decreased glomerular filtration rate Special Senses—ocular surface disease (including conjunctivitis), increased lacrimation Incidence Less than 1% Cardiovascular—supraventricular arrhythmia Dermatology/Skin—erythema multiforme General Disorders—febrile neutropenia, allergic reaction/hypersensitivity Neurology—motor neuropathy Renal—renal failure Non-Small Cell Lung Cancer (NSCLC)—After Prior Chemotherapy Table 6 provides the frequency and severity of adverse reactions that have been reported in >5% of 265 patients randomly assigned to receive single-agent ALIMTA with folic acid and vitamin B12 supplementation and 276 patients randomly assigned to receive single-agent docetaxel. All patients were diagnosed with locally advanced or metastatic NSCLC and received prior chemotherapy.

Table 6: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA versus Docetaxel in NSCLCa ALIMTA Docetaxel Reaction b (N=265) (N=276) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Laboratory Hematologic Anemia 19 4 22 4 Leukopenia 12 4 34 27 Neutropenia 11 5 45 40 Thrombocytopenia 8 2 1 0 Hepatic Increased ALT 8 2 1 0 Increased AST 7 1 1 0 Clinical Gastrointestinal Nausea 31 3 17 2 Anorexia 22 2 24 3 Vomiting 16 2 12 1 Stomatitis/Pharyngitis 15 1 17 1 Diarrhea 13 0 24 3 Constipation 6 0 4 0 Constitutional Symptoms Fatigue 34 5 36 5 Fever 8 0 8 0 Dermatology/Skin Rash/Desquamation 14 0 6 0 Pruritis 7 0 2 0 c 38 2c Alopecia 6 1 a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria for lab values for each Grade of toxicity (version 2.0). c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

ALIMTA姞 (pemetrexed for injection) PV 5206 AMP

No clinically relevant differences in adverse reactions were seen in patients based on histology.

Clinically relevant adverse reactions occurring in <5% of patients that received ALIMTA treatment but >5% of patients that received docetaxel include CTC Grade 3/4 febrile neutropenia (1.9% ALIMTA, 12.7% docetaxel).

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA. Incidence 1% to 5% Body as a Whole—abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection Dermatology/Skin—erythema multiforme Neurology—motor neuropathy, sensory neuropathy Renal—increased creatinine Incidence Less than 1% Cardiovascular—supraventricular arrhythmias Malignant Pleural Mesothelioma (MPM) Table 7 provides the frequency and severity of adverse reactions that have been reported in >5% of 168 patients with mesothelioma who were randomly assigned to receive cisplatin and ALIMTA and 163 patients with mesothelioma randomly assigned to receive single-agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid and vitamin B12.

Table 7: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in MPMa ALIMTA/cisplatin Cisplatin (N=168) (N=163) Reaction b All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Laboratory Hematologic Neutropenia 56 23 13 3 Leukopenia 53 15 17 1 Anemia 26 4 10 0 Thrombocytopenia 23 5 9 0 Renal Creatinine elevation 11 1 10 1 Creatinine clearance decreased 16 1 18 2 Clinical Eye Disorder Conjunctivitis 5 0 1 0 Gastrointestinal Nausea 82 12 77 6 Vomiting 57 11 50 4 Stomatitis/Pharyngitis 23 3 6 0 Anorexia 20 1 14 1 Diarrhea 17 4 8 0 Constipation 12 1 7 1 Dyspepsia 5 1 1 0 Constitutional Symptoms Fatigue 48 10 42 9 Metabolism and Nutrition Dehydration 7 4 1 1 Neurology Neuropathy-sensory 10 0 10 1 Taste Disturbance 8 0c 6 0c Dermatology/Skin Rash 16 1 5 0 Alopecia 11 0c 6 0c a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity except the term “creatinine clearance decreased” which is derived from the CTC term “renal/genitourinary-other”. c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned to receive ALIMTA plus cisplatin.

Incidence 1% to 5% Body as a Whole—febrile neutropenia, infection, pyrexia Dermatology/Skin—urticaria General Disorders—chest pain Metabolism and Nutrition—increased AST, increased ALT, increased GGT Renal—renal failure Incidence Less than 1% Cardiovascular—arrhythmia Neurology—motor neuropathy Effects of Vitamin Supplementations Table 8 compares the incidence (percentage of patients) of CTC Grade 3/4 toxicities in patients who received vitamin supplementation with daily folic acid and vitamin B12 from the time of enrollment in the study (fully supplemented) with the incidence in patients who never received vitamin supplementation (never supplemented) during the study in the ALIMTA plus cisplatin arm.

Table 8: Selected Grade 3/4 Adverse Events Comparing Fully Supplemented versus Never Supplemented Patients in the ALIMTA plus Cisplatin arm (% incidence) Fully Supplemented Never Supplemented Patients Patients a Adverse Event (%) (N=168) (N=32) Neutropenia/granulocytopenia 23 38 Thrombocytopenia 5 9 Vomiting 11 31 Febrile neutropenia 1 9 Infection with Grade 3/4 neutropenia 0 6 Diarrhea 4 9 a Refer to NCI CTC criteria for lab and non-laboratory values for each grade of toxicity (Version 2.0).

The following adverse events were greater in the fully supplemented group compared to the never supplemented group: hypertension (11%, 3%), chest pain (8%, 6%), and thrombosis/embolism (6%, 3%).

Subpopulations No relevant effect for ALIMTA safety due to gender or race was identified, except an increased incidence of rash in men (24%) compared to women (16%).

6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of ALIMTA. 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.

These reactions have occurred with ALIMTA when used as a single-agent and in combination therapies.

Gastrointestinal—colitis General Disorders and Administration Site Conditions—edema Injury, poisoning, and procedural complications—Radiation recall has been reported in patients who have previously received radiotherapy Respiratory—interstitial pneumonitis ALIMTA姞 (pemetrexed for injection)

PV 5206 AMP

7

DRUG INTERACTIONS

7.1

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ibuprofen Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥80 mL/min). Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Other NSAIDs Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration.

If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.

7.2

Nephrotoxic Drugs ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. 8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy Teratogenic Effects—Pregnancy Category D [see Warnings and Precautions (5.6)] Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA 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. Women of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA. 8.3

Nursing Mothers It is not known whether ALIMTA or its metabolites are 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 ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

8.4

In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.

The ability of ALIMTA to be dialyzed is unknown.

13

NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.

17

PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling.

Patients should be instructed to read the patient package insert carefully.

17.1 Need for Folic Acid and Vitamin B12 Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and gastrointestinal toxicity [see Dosage and Administration (2.3)].

17.2 Low Blood Cell Counts Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their physician should any sign of infection develop including fever. Patients should also contact their physician if bleeding or symptoms of anemia occur.

17.3 Gastrointestinal Effects Patients should be instructed to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear.

17.4 Concomitant Medications Patients should be instructed to inform the physician if they are taking any concomitant prescription or over-the-counter medications including those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)].

17.5 FDA-Approved Patient Labeling Patients should be instructed to read the patient package insert carefully.

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or www.fda.gov/medwatch.

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

8.5

Geriatric Use ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)].

In the initial treatment non-small cell lung cancer clinical trial, 37.7% of patients treated with ALIMTA plus cisplatin were ≥65 years and Grade 3/4 neutropenia was greater as compared to patients <65 years (19.9% versus 12.2%). For patients <65 years, the HR for overall survival was 0.96 (95% CI: 0.83, 1.10) and for patients ≥65 years the HR was 0.88 (95% CI: 0.74, 1.06) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 33.3% of patients treated with ALIMTA were ≥65 years and no differences were seen in Grade 3/4 adverse reactions as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.74 (95% CI: 0.58, 0.93) and for patients ≥65 years the HR was 0.88 (95% CI: 0.65, 1.21) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 29.7% patients treated with ALIMTA were ≥65 years and Grade 3/4 hypertension was greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.95 (95% CI: 0.76, 1.19), and for patients ≥65 years the HR was 1.15 (95% CI: 0.79, 1.68) in the intent-to-treat population.

The mesothelioma trial included 36.7% patients treated with ALIMTA plus cisplatin that were ≥65 years, and Grade 3/4 fatigue, leukopenia, neutropenia, and thrombocytopenia were greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.71 (95% CI: 0.53, 0.96) and for patients ≥65 years, the HR was 0.85 (95% CI: 0.59, 1.22) in the intent-to-treat population.

8.6

Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Dose adjustments based on hepatic impairment experienced during treatment with ALIMTA are provided in Table 2 [see Dosage and Administration (2.4)].

8.7

Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment.

8.8

Gender In the initial treatment non-small cell lung cancer trial, 70% of patients were males and 30% females. For males the HR for overall survival was 0.97 (95% CI: 0.85, 1.10) and for females the HR was 0.86 (95% CI: 0.70, 1.06) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 73% of patients were males and 27% females. For males the HR for overall survival was 0.78 (95% CI: 0.63, 0.96) and for females the HR was 0.83 (95% CI: 0.56, 1.21) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 72% of patients were males and 28% females. For males the HR for overall survival was 0.95 (95% CI: 0.76, 1.19) and for females the HR was 1.28 (95% CI: 0.86, 1.91) in the intent-totreat population.

In the mesothelioma trial, 82% of patients were males and 18% females. For males the HR for overall survival was 0.85 (95% CI: 0.66, 1.09) and for females the HR was 0.48 (95% CI: 0.27, 0.85) in the intent-to-treat population.

8.9

Race In the initial treatment non-small cell lung cancer trial, 78% of patients were Caucasians, 13% East/Southeast Asians, and 9% others. For Caucasians, the HR for overall survival was 0.92 (95% CI: 0.82, 1.04), for East/Southeast Asians the HR was 0.86 (95% CI: 0.61, 1.21), and for others the HR was 1.24 (95% CI: 0.84, 1.84) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 65% of patients were Caucasians, 23% East Asian, and 12% others.

For Caucasians the HR for overall survival was 0.77 (95% CI: 0.62, 0.97), for East Asians was 1.05 (95% CI: 0.70, 1.59) and for others the HR was 0.46 (95% CI: 0.26, 0.79) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 71% of patients were Caucasians and 29% others. For Caucasians the HR for overall survival was 0.91 (95% CI: 0.73, 1.15) and for others the HR was 1.27 (95% CI: 0.87, 1.87) in the intent-to-treat population.

In the mesothelioma trial, 92% of patients were Caucasians and 8% others. For Caucasians, the HR for overall survival was 0.77 (95% CI: 0.61, 0.97) and for others the HR was 0.86 (95% CI: 0.39, 1.90) in the intent-to-treat population.

Literature revised July 2, 2009

Eli Lilly and Company Indianapolis, IN 46285, USA

10

OVERDOSAGE There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.

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ALIMTA姞 (pemetrexed for injection)

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CLINICAL ONCOLOGY NEWS • MARCH 2010

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.

Around the Water Cooler Pediatric Cancer Pioneer Dies Teresa J. Vietti, MD, a pediatric oncologist who earned the nickname “the mother of pediatric cancer therapy,” died Jan. 25, 2010, of natural causes in St. Louis. She was 82.

Dr. Vietti, professor emeritus of pediTeresa J. atrics and of radiolVietti, MD ogy at Washington University School of Medicine, was an internationally renowned pioneer of pediatric cancer research and treatment for more than 40 years. She conceived the concept of multi-institution pediatric cooperative groups and founded the Pediatric Oncology Group (POG), now known as the Children’s Oncology Group (COG), which she chaired for its first 15 years. Under her leadership, POG grew to more than 100 institutions and 1,500 investigators. Today, COG has in excess of 200 institutions and more than 5,000 investigators. The success and growth of POG and COG is the impetus behind the participation of at least 60% of pediatric cancer patients

in clinical trials worldwide.

Dr. Vietti became an assistant professor of pediatrics at Washington University School of Medicine in 1961, and a full professor in 1972. She became chief of the Pediatric Hematology/Oncology Division in 1970 and remained in that role until 1986.

Throughout her career, Dr. Vietti played a critical role in the training of dozens of pediatric hematologists/ oncologists while also focusing her clinical work and research on soft tissue and bone sarcoma and acute lymphoblastic leukemia. Her scientific accomplishments include elucidating the genetic basis of leukemia, the pharmacology of new chemotherapy agents and the long-term effects of chemotherapy in survivors of childhood cancer. She designed and directed more than 200 clinical trials in the treatment of childhood cancer and published at least 200 research articles.

“Teresa Vietti was a dedicated teacher; compassionate physician; a most generous person, indeed self-effacing; and a model colleague,” said Alan Schwartz, PhD, MD, the Harriet B. Spoehrer Professor of Pediatrics, chair of the Department of Pediatrics and St. Louis Children’s Hospital pediatrician-in-chief.

“At a time when care for children with

cancer was only compassionate, Teresa Vietti almost single-handedly developed the approach of laboratory-based studies, translational research and clinical trials. She was truly the mother of multimodality cancer treatment.”

People on the Move Gerold Bepler, MD, PhD, has been named the new president and chief executive officer of the Barbara Ann Karmanos Cancer Institute. In addition to his chief administrative duties, Dr. Gerold Bepler, Bepler, a thoracMD, PhD ic oncologist, also will serve as principal investigator of Karmanos’ National Cancer Institute Comprehensive Cancer Center Support Grant; associate dean, Cancer Programs, Wayne State University School of Medicine (WSU SOM); director, Cancer Institute, WSU SOM; and chair of the soonto-be-created Department of Oncology of the WSU SOM. “Dr. Bepler is a rare triple-threat oncologist,” said Valerie Parisi, MD, interim dean of the WSU SOM. “He is a well-

funded investigator and an internationally recognized thoracic oncology clinician. His demonstrated leadership skills at Moffitt Cancer Center make him an ideal match for both the Wayne State University School of Medicine and the Karmanos Cancer Institute.”

Dr. Bepler most recently was director of the Comprehensive Lung Cancer Research Center, chair of the Department of Thoracic Oncology, and program leader of the Lung Cancer Program at the Moffitt Cancer Center in Tampa, Fla. He also served as a professor of medicine and oncology at the University of South Florida. Prior to his tenure at Moffitt, he was director of the Lung Cancer Program at Roswell Park Cancer Institute in Buffalo, N.Y. He has also held positions at Duke University Hospital and Durham VA Medical Center in Durham, N.C. Ariel Anguiano Jr., MD, has joined the medical staff of the DCH Cancer Center in Tuscaloosa, Ala., as a medical oncologist. Dr. Anguiano comes to Ariel Anguiano Oncology Associates Jr., MD of West Alabama see WATER COOLER, page 47

continued from page 35

FDA NEWS

Dose Adjustments With Bortezomib

C

linicians should be aware that prescribing information for bortezomib (Velcade, Millennium) pertaining to patients with hepatic impairment has been revised. The effect of hepatic impairment on the pharmacokinetics of bortezomib was assessed in 51 cancer patients at bortezomib doses ranging from 0.5 to 1.3 mg/m2. When compared with patients with normal hepatic function, mild hepatic impairment did not

alter dose-normalized bortezomib area under the curve (AUC). However, the dose-normalized mean AUC values were increased by approximately 60% in patients with moderate or severe hepatic impairment.

Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated per the recommended bortezomib dose. Patients with moderate or severe hepatic impairment should be started on bortezomib at a reduced dose of 0.7 mg/m2 per injection during the first cycle, and a subsequent

Table. Recommended Starting Dose Modification For Bortezomib in Patients With Hepatic Impairment Bilirubin Level

SGOT (AST) Levels

Modification of Starting Dose

≤1.0× ULN

>ULN

None

>1.0×-1.5× ULN

Any

None

Moderate

>1.5×-3× ULN

Any

Severe

>3× ULN

Any

Reduce bortezomib to 0.7 mg/ m2 in the first cycle. Consider dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability

Mild

AST, aspartate aminotransferase; SGOT, serum glutamic oxaloacetic transaminase; ULN, upper limit of normal

dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2 may be considered based on patient tolerance (Table). Bortezomib is indicated for patients with multiple myeloma and for patients with mantle cell lymphoma who have received at least one prior therapy.

Lapatinib Gets New Indication

T

he FDA has approved lapatinib (Tykerb, GlaxoSmithKline) in combination with letrozole (Femara, Novartis) to treat hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer in postmenopausal women for whom hormonal therapy is indicated.

Approval was based on results from a double-blind, placebo-controlled study that enrolled 219 women diagnosed with postmenopausal, hormone receptorand HER2-positive metastatic breast cancer and randomized them to receive lapatinib plus letrozole or letrozole alone. Women receiving the lapatinib plus letrozole combination experienced a 5.2 month increase in median progression-free survival compared with women treated with letrozole alone (35 vs. 13 weeks). GlaxoSmithKline sponsored the study.

Lapatinib was initially approved in

2007 in combination with capecitabine (Xeloda, Roche) 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 (Herceptin, Genentech).

Safety information from the new study was consistent with previous clinical studies of lapatinib in advanced breast cancer. The most commonly reported side effects of the combination were diarrhea, rash, nausea and fatigue. Treatment with lapatinib also has been associated with decreases in heart function, liver damage and lung tissue inflammation. Fetal harm may occur if used to treat advanced breast cancer in pregnant women. Patients should talk to their health care provider about the potential side effects, drug interactions and other medical conditions.

43

CLINICAL TRIALS

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ MARCH 2010

New Phase II and III Clinical Trials

Hematologic Malignancies

Solid Tumors

Trials added to the National Cancer Instituteâ&#x20AC;&#x2122;s list of clinical trials in the 30 days prior to Feb. 16, 2010. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials, click on the advanced link and enter the protocol ID.

Supportive

44

Protocol Type

Age

Protocol ID

Trial Sites

MRI (Including Spectroscopy and Fat-Saturations and Diffusion-Weighted Imaging) in Cervical Cancer, Phase I/II

18 and over

10-0033

MO

Study of Ad.p53 DC Vaccine and 1-MT in Metastatic Invasive Breast Cancer, Phase I/II

18 and over

MCC-16025

FL

Study of a HER2/Neu Vaccine for Stage IV HER2/Neu Positive Breast Cancer Patients on Herceptin, Phase II

18 and over

BC 030289

WA

Trial Comparing the Use of Fluoro-L-thymidine Positron Emission Tomography to Standard Computed Tomography to Assess Treatment Response of Neoadjuvant Docetaxel and Cisplatin in Stage IB-IIIA Resectable Non-Small Lung Cancer, Phase II

18 and over

J08134

MD

GW786034 in Patients With Non-Small Cell Lung Cancer 3rd Line, Phase II

18 and over

ILCC #2

IL

Evaluating Safety and Efficacy of Stereotactic Body Radiotherapy and Radiofrequency Ablation for Lung Tumors Near Central Airways, Phase II

18 and over

09-08-026

CA

Neoadjuvant GTX With Chemoradiation for Pancreatic Cancer (Stage II/III), Phase II

18 and over

AAAD6491

NY

Randomized Study of Gemcitabine Hydrochloride With Versus Without Hedgehog Antagonist GDC-0449 in Patients With Recurrent or Metastatic Pancreatic Cancer, Phase II

21 and over

UCCRC-8418

IL

Trial of Adjuvant Sutent for Patients With High-Risk Urothelial Carcinoma After Neoadjuvant Chemotherapy and Cystectomy, Phase II

18 and over

HUM00030127

MI

A Study of ABT-888 in Combination With Temozolomide for Colorectal Cancer, Phase II

18 and over

2009-170

DC

Panitumumab and Bevacizumab Maintenance After First-Line FOLFOX-Bevacizumab for Patients With Advanced Colorectal Cancer With Wild-Type Ras, Phase II

18 and over

BrUOG-CR-218

RI

Molecular Targeting of 15-Lipoxygenase-1 (15-LOX-1) for Apoptosis Induction in Human Colorectal Cancers, Phase II

Over 16

DM02-592

TX

Study of RAD001 in Soft Tissue Extremity and/or Retroperitoneal Sarcomas, Phase II

18 and over

MCC-15962

FL

Evaluation of Patients With Bulky GIST Using Sunitinib, Phase II

19 and over

F090910001

AL

ARQ 197 for Subjects With Relapsed or Refractory Germ Cell Tumors, Phase II

16 and over

ARQ 197-A-U251

NY

Pilot Study of Temsirolimus in Patients With Recurrent or Persistent Malignant Mixed Mesodermal and Mullerian Tumors (Carcinosarcoma) of the Uterus, Phase II

18 and over

AECM-8167

CA, NY

Hypo-fractionated Stereotactic Body Radiotherapy for Localized Prostate Cancer, Phase II

18 and over

09-10-081

CA

Docetaxel and Cisplatin With or Without Erlotinib for Metastatic or Recurrent Squamous Cell Carcinoma of Head and Neck, Phase II

18 and over

2009-0395

TX

Study of Tesetaxel in Metastatic Melanoma, Phase II

18 and over

2009-0624

TX

Nelfinavir in Recurrent Adenoid Cystic Cancer of the Head and Neck, Phase II

18 and over

200905704

IA

Study of Single Agent Lenalidomide in Older Adults With Newly Diagnosed Multiple Myeloma, Phase II

65 and over

MCC-16018

FL

Bone Effect of Bortezomib in Patients With Relapsed/Refractory Multiple Myeloma, Phase II

18 and over

HCI # 35813

UT

Trial of Activated Marrow Infiltrating Lymphocytes Alone or in Conjunction With an Allogeneic Granulocyte Macrophage Colony-stimulating Factor-Based Myeloma Cellular Vaccine in the Autologous Transplant Setting in Multiple Myeloma, Phase II

18 to 70

J0997

MD

CD34+ Selection for Partially Matched Family or Matched Unrelated Adult Donor Transplant, Phase II

0 to 26

CHNY 525

NY

Unrelated Donor Transplant for Malignant and Non-Malignant Disorders, Phase II

0 to 55

CHNY-02-516

NY

Hematopoietic Stem Cell Transplantation Using CD34 Selected Mismatched Related Donor and One Umbilical Cord Unit, Phase II

18 to 65

MCW 11491

WI

Randomized Trial of Rituximab With Either Pentostatin or Bendamustine for Multiply Relapsed or Refractory Hairy Cell Leukemia, Phase II

18 and over

100025

MD

Clinical Trial of Vitamin D3 to Reduce Cancer Risk in Postmenopausal Women, Phase III

55 and over

CAPS08-15024

NE

Systems of Support to Increase Colon Cancer Screening and Follow-up Supplement, Phase II

50 to 74

3 R01 CA121125-03S1

WA

Acupuncture in Treating Women With Stage I, Stage II, or Stage III Breast Cancer With Aromatase Inhibitor-Related Joint Pain, Phase II

18 and over

UPCC 07109

PA

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Robert Bristow; Deborah Armstrong

Each volume in the Early Detection and Treatment of Cancer Series is packed with practical, authoritative information designed to cover the full range of diagnostic procedures, including pathologic, radiologic, bronchoscopic, and surgical aspects. You’ll be able to determine the safest, shortest, least invasive way to reach an accurate diagnosis; stage the disease; and choose the best initial treatment for early stages.

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Early Diagnosis and Treatment of Cancer Series: Prostate Cancer: Expert Consult—Online and Print Li-Ming Su

Each volume in the Early Detection and Treatment of Cancer Series is packed with practical, authoritative information designed to cover the full range of diagnostic procedures, including pathologic, radiologic, bronchoscopic, and surgical aspects. You’ll be able to determine the safest, shortest, least invasive way to reach an accurate diagnosis; stage the disease; and choose the best initial treatment for early stages.

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For Doctors Only: A Guide to Working Less & Building More Christopher R. Jarvis, MBA; David B. Mandell, JD, MBA; Jason M. O’Dell, CWP; Claudio A. DeVellis, JD, CPA

For Doctors Only teaches doctors how to perform efficiently so they can get more out of a medical practice. More specifically, it will help doctors protect their personal and practice assets from lawsuits, taxes and bad investments while showing them the secrets to building wealth through the leverage of people, assets and effort.

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Hematology-Oncology Therapy

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Mastering Communication With Seriously Ill Patients

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Vertebral Tumors

Michael Boyiadzis; Peter Lebowitz; James Frame; Tito Fojo

This is the first manual to combine practical clinical information for both hematology and oncology. This resource provides a definitive focus on the often confusing combined practice of hematology and oncology. The manual covers all therapy-induced complications and disorders as well as chemotherapy and supportive care regimens and comprehensive coverage of all drugs used in treatment.

Anthony Back; Robert Arnold; James Tulsky

“Clear, concise, and brimming with useful advice, Mastering Communication with Seriously Ill Patients is one of those rare books that manages to be both eminently practical and thoroughly enjoyable. …This book is a must-read for clinicians who care not only for the seriously ill but for any patient.” —Pauline Chen, author of Final Exam (Knopf) and “Doctor and Patient” columnist for The New York Times

Robert Gunzburg; Marek Szpalski; Max Aebi

This volume is a comprehensive review of the state of the art in the management of spinal tumors. Leading experts from the United States, Europe and India present the latest concepts and findings on the epidemiology, classification, diagnosis, radiation therapy and surgical treatment of primary and metastatic tumors of the spine. A major portion of the book focuses on current strategies for surgical treatment.

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CLINICAL ONCOLOGY NEWS • MARCH 2010

WATER COOLER continued from page 43

from Regional Cancer Care in Durham, N.C. He previously served as an internal medicine physician, vice president of medical affairs at Maine General Medical Center, and as an oncology hospitalist in Winslow, Maine.

According to the Easton Courier, Robert Folman, MD, a practicing oncologist for more than 30 years, has been elected president of Bridgeport Hospital in Connecticut. Dr. Folman serves as chief of oncology and co-medical director of the Norma F. Pfriem Cancer Institute at Bridgeport Hospital. Additionally, he is an assistant professor at the Yale University School of Medicine, New Haven, Conn.

Debra Friedman, MD, has been named director of the Division of Pediatric Hematology/Oncology at Vanderbilt

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call Julianna Dawson at (212) 957-5300 x271.

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Please send opinions, criticism, ideas and suggestions to Kate O’Rourke, Editor, Clinical Oncology News, at korourke@mcmahonmed.com

University, Nashv i l l e, Te n n . D r.

Friedman, associate professor of pediatrics and the E. Bronson Ingram Chair in Pediatric Oncology at Vanderbilt, has served as interim director since July.

Dr. Friedman is Debra Friedman, the leader of the MD Cancer Control and Prevention Program at the VanderbiltIngram Cancer Center and director of the REACH for Survivorship Program,

a collaborative venture between the Department of Pediatrics, the Monroe Carell Jr. Children’s Hospital at Vanderbilt and the cancer center. She came to Vanderbilt in 2008 from Seattle, where she was director of the LiveStrong Survivorship Center of Excellence at the Fred Hutchinson Cancer Research Center and director of the Cancer Survivorship Program at Children’s Hospital and Regional Medical Center.

Cancer Center News According to an article in the Dallas Business Journal, Medical Edge Healthcare Group PA has acquired Arlington

Vectibix® (panitumumab) Injection for Intravenous Use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

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. [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions].

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. [see Warnings and Precautions and Adverse Reactions]. Although not reported with Vectibix, fatal infusion reactions have occurred with other monoclonal antibody products. [see Dosage and Administration].

INDICATIONS AND USAGE Vectibix is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens [see Clinical Studies (14) in Full Prescribing Information].

The effectiveness of Vectibix as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progression-free survival [see Clinical Studies (14) in Full Prescribing Information]. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix.

Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations.

DOSAGE AND ADMINISTRATION Recommended Dose and Dose Modifications: The recommended dose of Vectibix is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes [see Dosage and Administration].

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions.

Dose Modifications for Infusion Reactions [see Adverse Reactions] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion.

• Immediately and permanently discontinue Vectibix infusion in patients experiencing severe (grade 3 or 4) infusion reactions.

Dose Modifications for Dermatologic Toxicity [see Adverse Reactions] • 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.

• If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than two doses of Vectibix, treatment may be resumed at 50% of the original dose.

– If toxicities recur, permanently discontinue Vectibix.

– If toxicities do not recur, subsequent doses of Vectibix may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached.

Preparation and Administration: Do not administer Vectibix as an intravenous push or bolus.

Preparation Prepare the solution for infusion, using aseptic technique, as follows: • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Although Vectibix should be colorless, the solution may contain a small amount of visible translucent-to-white, amorphous, proteinaceous, panitumumab particulates (which will be removed by filtration; see below). Do not shake. Do not administer Vectibix if discoloration is observed.

• Withdraw the necessary amount of Vectibix for a dose of 6 mg/kg.

• Dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. Doses higher than 1000 mg should be diluted to 150 mL with 0.9% sodium chloride injection, USP. Do not exceed a final concentration of 10 mg/mL. • Mix diluted solution by gentle inversion. Do not shake.

Administration • Administer using a low-protein-binding 0.2 μm or 0.22 μm in-line filter.

• Vectibix must be administered via infusion pump.

– Flush line before and after Vectibix administration with 0.9% sodium chloride injection, USP, to avoid mixing with other drug products or intravenous solutions.

Do not mix Vectibix with, or administer as an infusion with, other medicinal products. Do not add other medications to solutions containing panitumumab.

– Infuse over 60 minutes through a peripheral intravenous line or indwelling intravenous catheter. Doses higher than 1000 mg should be infused over 90 minutes.

Use the diluted infusion solution of Vectibix within 6 hours of preparation if stored at room temperature, or within 24 hours of dilution if stored at 2° to 8°C (36° to 46°F). DO NOT FREEZE. Discard any unused portion remaining in the vial.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Dermatologic Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving 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. Withhold Vectibix for severe or life-threatening dermatologic toxicity. [see Boxed Warning, Adverse Reactions, and Dosage and Administration].

Infusion Reactions: In Study 1, 4% of patients experienced infusion reactions and in 1% of patients, these reactions were graded as severe (NCI-CTC grade 3–4).

Across all clinical studies, severe infusion reactions occurred with the administration of Vectibix in approximately 1% of patients. Severe infusion reactions included anaphylactic reactions, bronchospasm, and hypotension [see Boxed Warning and Adverse Reactions]. Although fatal infusion reactions have not been reported with Vectibix, fatalities 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 [see Dosage and Administration].

Increased Toxicity With Combination Chemotherapy: Vectibix is not indicated for use in combination with chemotherapy. In an interim analysis of Study 2, 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 [see Clinical Studies (14) in Full Prescribing Information]. NCI-CTC grade 3–4 adverse drug reactions occurring at a higher rate in Vectibix-treated patients included rash/dermatitis acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 4%) and included fatal events in three (< 1%) Vectibix-treated patients.

As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy.

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 one patient. In a single-arm study of 24 patients receiving Vectibix plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

Severe diarrhea and dehydration which may lead to acute renal failure and other complications have been observed in patients treated with Vectibix in combination with chemotherapy.

Pulmonary Fibrosis: Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. Following the initial fatality described below, 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 a general population that may include such patients is uncertain.

One case occurred in a patient with underlying idiopathic pulmonary fibrosis who received Vectibix in combination with chemotherapy and resulted in death from worsening pulmonary fibrosis after four doses of Vectibix. The second case was characterized by cough and wheezing 8 days following the initial dose, exertional dyspnea on the day of the seventh dose, and persistent symptoms and CT evidence of pulmonary fibrosis following the 11th dose of Vectibix as monotherapy. An additional patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia after 23 doses of Vectibix in combination with chemotherapy. Permanently discontinue Vectibix therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.

Electrolyte Depletion/Monitoring: In Study 1, median magnesium levels decreased by 0.1 mmol/L in the Vectibix arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or intravenous electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 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. Institute appropriate treatment, eg, oral or intravenous electrolyte repletion, as needed.

Photosensitivity: Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix.

EGF Receptor Testing: Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage and Clinical Studies (14) in Full Prescribing Information]. Patients with colorectal cancer enrolled in Study 1 were required to have immunohistochemical evidence of EGFR expression using the Dako EGFR pharmDx® test kit.

Assessment for EGFR expression should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specific reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Refer to the package insert for the Dako EGFR pharmDx® test kit, or other test kits approved by FDA, for identification of patients eligible for treatment with Vectibix and for full instructions on assay performance.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic Toxicity [see Boxed Warning, and Warnings and Precautions] • Infusion Reactions [see Boxed Warning, and Warnings and Precautions] • Increased Toxicity With Combination Chemotherapy [see Warnings and Precautions] • Pulmonary Fibrosis [see Warnings and Precautions] • Electrolyte Depletion/Monitoring [see Warnings and Precautions] • Photosensitivity [see Warnings and Precautions] 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, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. Adverse reactions requiring discontinuation of Vectibix were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis.

Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

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 [see Warnings and Precautions].

The data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix administered as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks) in 229 patients with mCRC enrolled in Study 1, a randomized, controlled trial. The median number of doses was five (range: one to 26 doses), and 71% of patients received eight or fewer doses. The population had a median age of 62 years (range: 27 to 82 years), 63% were male, and 99% were white with < 1% black, < 1% Hispanic, and 0% other.

Cancer Center, a free-standing cancer center with two additional clinics in North Texas. The acquisition is part of a push by Medical Edge, already one of the area’s largest primary care physician groups, to acquire additional small to midsize oncology practices throughout North Texas. In recent years, the growth of big oncology players such as US Oncology and Baylor Health Care System, and changes in Medicare reimbursements that have diminished profit margins, have made it difficult for smaller oncology practices to survive. Forming partnerships is one possible solution.

Table 1. Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients With a Between-Group Difference of ≥ 5% (Study 1) Patients Treated With Vectibix Plus BSC (n = 229) Best Supportive Care (BSC) Alone (n = 234) Grade* All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Fatigue 26 4 15 3 General Deterioration 11 8 4 3 Digestive Abdominal Pain 25 7 17 5 Nausea 23 1 16 <1 Diarrhea 21 2 11 0 Constipation 21 3 9 1 Vomiting 19 2 12 1 Stomatitis 7 0 1 0 Mucosal Inflammation 6 <1 1 0 Metabolic/Nutritional Hypomagnesemia (Lab) 38 4 2 0 Peripheral Edema 12 1 6 <1 Respiratory Cough 14 <1 7 0 Skin/Appendages All Skin/Integument Toxicity 90 16 9 0 Skin 90 14 6 0 Erythema 65 5 1 0 Dermatitis Acneiform 57 7 1 0 Pruritus 57 2 2 0 Nail 29 2 0 0 Paronychia 25 2 0 0 Skin Exfoliation 25 2 0 0 Rash 22 1 1 0 Skin Fissures 20 1 <1 0 Eye 15 <1 2 0 Acne 13 1 0 0 Dry Skin 10 0 0 0 Other Nail Disorder 9 0 0 0 Hair 9 0 1 0 Growth of Eyelashes 6 0 0 0 *Version 2.0 of the NCI-CTC was used for grading toxicities. Skin toxicity was coded based on a modification of the NCI-CTCAE, version 3.0.

Body System Body as a Whole

Dermatologic, Mucosal, and Ocular Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to, conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders occurred in 9% of patients [see Warnings and Precautions].

Median time to the development of dermatologic, nail, or ocular toxicity was 14 days after the first dose of Vectibix; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix; and the median time to resolution after the last dose of Vectibix was 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibix-treated patients [see Dosage and Administration].

Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported.

Infusion Reactions: Infusional toxicity was defined as any event within 24 hours of an infusion during the clinical study described as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across several clinical trials of Vectibix monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix was permanently discontinued for a serious infusion reaction [see Dosage and Administration].

Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix has been evaluated using two different screening immunoassays for the detection of anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) (detecting high-affinity antibodies) and a Biacore® biosensor immunoassay (detecting both high- and low-affinity antibodies). The incidence of binding antibodies to panitumumab (excluding predose and transient positive patients), as detected by the acid dissociation ELISA, was 3/613 (< 1%) and as detected by the Biacore® assay was 28/613 (4.6%).

For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Excluding predose and transient positive patients, 10/613 patients (1.6%) with postdose samples and 3/356 (0.8%) of the patients with follow-up samples tested positive for neutralizing antibodies.

No evidence of altered pharmacokinetic profile or toxicity profile was found between patients who developed antibodies to panitumumab as detected by screening immunoassays and those who did not.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading.

Postmarketing experience: The following adverse reaction has been identified during post-approval use of panitumumab. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Angioedema DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with Vectibix.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no studies of Vectibix in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring. [see Reproductive and Developmental Toxicology]. Vectibix should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

Women who become pregnant during Vectibix treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll.

Nursing Mothers: It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix, 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. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Pediatric Use: The safety and effectiveness of Vectibix have not been established in pediatric patients. The pharmacokinetic profile of Vectibix has not been studied in pediatric patients.

Geriatric Use: Of 229 patients with mCRC who received Vectibix in Study 1, 96 (42%) were ≥ age 65. Although the clinical study did not include a sufficient number of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differences in safety and effectiveness of Vectibix between these patients and younger patients.

OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenicity or mutagenicity studies of panitumumab have been conducted. It is not known if panitumumab can impair fertility in humans. Prolonged menstrual cycles and/or amenorrhea occurred in normally cycling, female cynomolgus monkeys treated weekly with 1.25 to 5 times the recommended human dose of panitumumab (based on body weight). Menstrual cycle irregularities in panitumumab-treated female monkeys were accompanied by both a decrease and delay in peak progesterone and 17␤-estradiol levels. Normal menstrual cycling resumed in most animals after discontinuation of panitumumab treatment. A no-effect level for menstrual cycle irregularities and serum hormone levels was not identified. The effects of panitumumab on male fertility have not been studied. However, no adverse effects were observed microscopically in reproductive organs from male cynomolgus monkeys treated for 26 weeks with panitumumab at doses of up to approximately 5-fold the recommended human dose (based on body weight).

Animal Toxicology and/or Pharmacology: Weekly administration of panitumumab to cynomolgus monkeys for 4 to 26 weeks resulted in dermatologic findings, including dermatitis, pustule formation and exfoliative rash, and deaths secondary to bacterial infection and sepsis at doses of 1.25 to 5-fold higher (based on body weight) than the recommended human dose.

Reproductive and Developmental Toxicology: Pregnant cynomolgus monkeys were treated weekly with panitumumab during the period of organogenesis (gestation day [GD] 20–50). While no panitumumab was detected in serum of neonates from panitumumab-treated dams, anti-panitumumab antibody titers were present in 14 of 27 offspring delivered at GD 100. There were no fetal malformations or other evidence of teratogenesis noted in the offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight).

PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions], • Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning and Warnings and Precautions], • Diarrhea and dehydration [see Warnings and Precautions], • Persistent or recurrent coughing, wheezing, dyspnea, or new onset facial swelling [see Warnings and Precautions, and Adverse Reactions], • Pregnancy or nursing [see Use in Specific Populations].

Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions], • Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix and for 2 months after the last dose of Vectibix therapy. [see Warnings and Precautions], • Adequate contraception in both males and females while receiving Vectibix and for 6 months after the last dose of Vectibix therapy [see Use in Specific Populations].

This brief summary is based on the Vectibix® prescribing information v8, 7/2009 Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent No. 6,235,883, as well as other patents or patents pending. © 2006-2009 Amgen Inc. All rights reserved.

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