Clinical Oncology News - November 2010 - Digital Edition

McMahon Publishing

Advances in Cancer Care CLINICALONCOLOGY.COM • November 2010 • Vol. 5, No. 11

SOLID TUMORS

4 6 7 8

Trials highlight benefits and risks of switching breast cancer patients to aromatase inhibitors.

Spotlight on BRCA mutations in triple-negative breast cancers.

Afatinib gets mixed review in non-small cell lung cancer LUX trial.

Identifying breast cancer patients who can avoid radiation therapy.

HEMATOLOGIC DISEASE

11

An expert discusses the need for disseminating advances in lymphoma treatment to practicing oncologists.

FDA NEWS

21

Trastuzumab is approved for use in patients with gastric cancer.

New Hormone Therapy Will Shake Up Treatment for mCRPC

T-DM1 Makes Big Splash at European Cancer Meeting Milan—A new type of drug that combines trastuzumab and chemotherapy, called trastuzumab-DM1 (T-DM1, ImmunoGen/Roche), may prove to be a “super Herceptin,” if preliminary results from a Phase II trial are any indication of the drug’s potential. The results showed the drug produces slightly higher response rates in patients with HER2-positive metastatic breast cancer than does trastuzumab with docetaxel treatment, but with significantly fewer side effects. The study was presented at the European Society for Medical Oncology (ESMO) Congress (abstract LBA3) held in October.

“T-DM1 appears to have a favorable overall safety profile compared to the older, more traditional trastuzumab [and] docetaxel regimen as first-line see T-DM1, page 18

Milan—The landscape for treating metastatic castration-resistant prostate cancer (mCRPC) is about to change again, according to experts in the field who have reviewed data from a recent Phase III trial. The study showed that adding abiraterone acetate (Cougar Biotechnology/Ortho Biotech) to prednisone improved overall survival (OS) by four months in patients with mCRPC who had progressed after treatment with docetaxel. It is the first hormone therapy that has been proven to increase survival in patients with prostate cancer after chemotherapy.

“This represents a new treatment option for patients with metastatic castrationresistant prostate cancer,” said Johann de Bono of the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust in London. He presented the results of the trial at the European Society for Medical Oncology (ESMO) congress (abstract LBA5) held in October. see THERAPY, Y page 24

A model of the abiraterone molecule, C24H31 NO.

CLINICAL TRIALS

26

A list of recently launched Phase II and Phase III clinical trials.

EDUCATIONAL REVIEW

Mycosis Fungoides and Sézary Syndrome: Updates From the First World Congress See page 9

WWW.CMEZONE.COM

Evidence Builds for Bevacizumab’s Role In Ovarian Cancer

POLICY & MANAGEMENT

Milan—A second Phase III study has shown that bevacizumab (Avastin, Genentech) can increase progressionfree survival (PFS) in patients with ovarian cancer. The study adds to the growing evidence that this drug may have a role in ovarian cancer, but some experts caution that the benefits in PFS may not improve overall survival (OS).

In an interim analysis of the ICON7 study presented at the recent European Society for Medical Oncology (ESMO) Congress (abstract LBA4), investigators found that providing bevacizumab concurrently with chemotherapy and then as maintenance for up to roughly one see BEVACIZUMAB, page 14

Oncology Drugs Lose Patent Protection: A Look Inside the Process

B

efore the generic version of the breast cancer drug, Arimidex, came out in the summer of 2010, a year’s supply of the branded drug could easily cost more than $5,000 out-of-pocket for uninsured patients or those with high co-pays. That amount has since dropped by about 25%, a considerable savings over the typical five-year course of drug therapy.

Arimidex (AstraZeneca; anastrozole)

is the first aromatase inhibitor to come off patent, and two more widely used oncology drugs are on the verge of losing their patent protection. The patent for Taxotere (Sanofi-aventis; docetaxel) covering treatment for patients with breast cancer is slated to end in midNovember, and the potential savings with generic forms for patients could be enormous. In see PATENT LOSS, page 25

McMahonMedicalBooks.com Williams Hematology: Eighth Edition Kenneth Kaushansky; Uri Seligsohn; Marshall Lichtman; Thomas Kipps; Josef Prchal

For more information, see page 23

New Product Herceptin approved for gastric cancer

See page 21.

Concerned about CYP2D6 in breast cancer?

Fareston may be the answer. ®

Fareston helps reduce the guess work

FARESTON (toremifene citrate) 60 mg Tablets: indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor positive or unknown tumors.

ALREADY ACTIVE

500,000 PATIENT YEARS

UNIQUE METABOLISM

PATIENT SAVINGS

Parent compound binds to and blocks estrogen receptors

Metabolized principally by CYP3A4 CYP2D6 does not play a signiÀcant role in the activity of FARESTON No known drug interactions with SSRI antidepressants

Proven clinical proÀle EfÀcacy comparable to tamoxifen in head to head trials Savings coupons offer up to $50 off each prescription for eligible patients Patient Assistance Program available for Medicare Part D and uninsured patients who qualify

Important safety information: FARESTON is contraindicated in patients with known hypersensitivity to the drug. FARESTON has been shown to prolong the QTc interval in a dose and concentration dependent manner. FARESTON should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice and others) increases the steady-state concentration in serum and should be avoided. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor flare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively.

References: FARESTON® Prescribing Information, 2004. Data on file, GTx, Inc.

Please see full prescribing information on the following page.

For more information about Fareston call 1-877-362-7595 or visit www.fareston.com

© 2010 GTx, Inc., Memphis, TN 38103. All rights reserved. FAR-071R0 June 2010

FARESTON® (toremifene citrate) tablets DESCRIPTION FARESTON (toremifene citrate) Tablets for oral administration each contain 88.5 mg of toremifene citrate, which is equivalent to 60 mg toremifene.

FARESTON is a nonsteroidal antiestrogen. The chemical name of toremifene is: 2-{p-[(Z)-4-chloro-1,2diphenyl-1-butenyl]phenoxy}-N,N-dimethylethylamine citrate (1:1). The structural formula is: OCH2CH2N

C C CH2 CH2Cl

CH3 CH3

CH2COOH HO

C

COOH

CH2COOH

and the molecular formula is C26H28 H O . The molecular weight of toremifene citrate is 598.10.

6 8 7 The pKa is 8.0. Water solubility at 37˚C is 0.63 mg/mL and in 0.02N HCI at 37˚C is 0.38 mg/mL. FARESTON is available only as tablets for oral administration. Inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and starch.

CLINICAL PHARMACOLOGY Mechanism of Action: Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mam-mary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, ie, its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor.

Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH).

Pharmacokinetics: The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (deaminohydroxy) toremifene were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5L/h.

Absorption and Distribution: Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady-state concentrations were reached in about 4-6 weeks. Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly to albumin.

Metabolism and Excretion: Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state.

Toremifene is eliminated as metabolites predominantly in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation.

Special Populations: Renal insufficiency: The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function.

Hepatic insufficiency: The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.

Geriatric patients: The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. Race: The pharmacokinetics of toremifene in patients of different races has not been studied.

Drug-drug interactions: No formal drug-drug interaction studies with toremifene have been performed.

CLINICAL STUDIES Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted to evaluate the efficacy of FARESTON for the treatment of breast cancer in postmenopausal women. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively. The studies included postmenopausal patients with estrogen-receptor (ER) positive or estrogen-receptor (ER) unknown metastatic breast cancer. The patients had at least one measurable or evaluable lesion. The primary efficacy variables were response rate (RR) and time to progression (TTP). Survival (S) was also determined. Ninety-five percent confidence intervals (95% CI) were calculated for the difference in RR between FAR60 and TAM groups and the hazard ratio (relative risk for an unfavorable event, such as disease progression or death) between TAM and FAR60 for TTP and S. Two of the 3 studies showed similar results for all effectiveness endpoints. However, the Nordic Study showed a longer time to progression for tamoxifen (see table).

Clinical Studies Study North American Eastern European Nordic Treatment Group FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 No. Patients 221 215 157 149 214 201 Responses 1 2 14+33 11+30 7+25 3+28 19+48 19+56 CR + PR RR3 (CR + PR)% 21.3 19.1 20.4 20.8 31.3 37.3 Difference in RR 2.2 -0.4 -6.0 95% CI4 for Difference in RR -5.8 to 10.2 -9.5 to 8.6 -15.1 to 3.1 Time to Progression (TTP) Median TTP (mo.)

5.6 5.8 4.9 5.0 7.3 10.2 Hazard Ratio (TAM/FAR) 1.01 1.02 0.80 95% CI4 for Hazard Ratio (%) 0.81 to 1.26 0.79 to 1.31 0.64 to 1.00 Survival (S) Median S (mo.)

33.6 34.0 25.4 23.4 33.0 38.7 Hazard Ratio (TAM/FAR) 0.94 0.96 0.94 95% CI4 for Hazard Ratio (%) 0.74 to 1.24 0.72 to 1.28 0.73 to 1.22 1 CR = complete response; 2PR = partial response; 3RR = response rate; 4CI = confidence interval The high-dose groups, toremifene 200 mg daily in the North American Study and 240 mg daily in the Eastern European Study, were not superior to the lower toremifene dose groups, with response rates of

22.6% AND 28.7%, median times to progression of 5.6 and 6.1 months, and median survivals of 30.1 and 23.8 months, respectively. The median treatment duration in the three pivotal studies was 5 months (range 4.2-6.3 months).

significant age-related differences in FARESTON effectiveness or safety were noted.

Race: Fourteen percent of patients in the North American Study were non-Caucasian. No significant race-related differences in FARESTON effectiveness or safety were noted.

INDICATION AND USAGE FARESTON is indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.

ADVERSE REACTIONS Adverse drug reactions are principally due to the antiestrogenic hormonal actions of FARESTON and typically occur at the beginning of treatment.

The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related.

North American Study FAR60 TAM20 n = 221 n = 215 Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4%

CONTRAINDICATIONS FARESTON is contraindicated in patients with known hypersensitivity to the drug.

WARNINGS Hypercalcemia and Tumor Flare: As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and if hypercalcemia is severe, FARESTON treatment should be discontinued.

Tumorigenicity: Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available. Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (about 1/4 and 1.4 times, respectively, the daily maximum recommended human dose on a mg/m2 basis).

Pregnancy: FARESTON may cause fetal harm when administered to pregnant women. Studies in rats at doses ≥1.0 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that toremifene is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, reduced fetal weight, and fetal anomalies; including malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Fetal anomalies may have been a consequence of maternal toxicity. Toremifene has been shown to cross the placenta and accumulate in the rodent fetus.

In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known.

Embryotoxicity and fetotoxicity were observed in rabbits at doses ≥1.25 mg/kg/day and 2.5 mg/kg/ day, respectively (about 1/3 and 2/3 the daily maximum recommended human dose on a mg/mt basis); fetal anomalies included incomplete ossification and anencephaly.

There are no studies in pregnant women. If FARESTON is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy.

PRECAUTIONS General: Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment (see Warnings). Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia.

Information for Patients: Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs.

Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur.

Laboratory Tests: Periodic complete blood counts, calcium levels, and liver function tests should be obtained.

Drug-drug Interactions: Drugs that decrease renal calcium excretion, eg, thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. There is a known interaction between antiestrogenic compounds of the triphenylethylene derivative class and coumarin-type anticoagulants (eg, warfarin), leading to an increased prothrombin time. When concomitant use of anticoagulants with FARESTON is necessary, careful monitoring of the prothrombin time is recommended.

Cytochrome P450 3A4 enzyme inducers, such as phenobarbital, phenytoin, and carbamazepine increase the rate of toremifene metabolism, lowering the steady-state concentration in serum.

Metabolism of toremifene may be inhibited by drugs known to inhibit the CYP3A4-6 enzymes. Examples of such drugs are ketoconazole and similar antimycotics as well as erythromycin and similar macrolides.

This interaction has not been studied and its clinical relevance is uncertain.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (about 1/100 to 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (about 1/15 to 2 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors, and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human antiestrogenic agents that have primarily estrogenic activity in mice.

Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests).

Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes). No significant adduct formation could be detected using 32P post-labeling in liver DNA from rats administered toremifene when compared to tamoxifen at similar doses. A study in cultured human lymphocytes indicated that adducting activity of toremifene, detected by 32P post-labeling, was about 1/6 that of tamoxifen at approximately equipotent concentrations. In addition, the DNA adducting activity of toremifene in salmon sperm, using 32P post-labeling, was 1/6 and 1/4 that observed with tamoxifen at equivalent concentrations following activation by rat and human microsomal systems, respectively.

However, toremifene exposure is fourfold the exposure of tamoxifen based on human AUC in serum at recommended clinical doses.

Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (about 3.5 times and 1/50 the daily maximum recommended human dose on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (about 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) for 52 weeks.

Pregnancy: Pregnancy Category D: (see WARNINGS).

Nursing mothers: Toremifene has been shown to be excreted in the milk of lactating rats. It is not known if this drug is excreted in human milk. (See WARNINGS and PRECAUTIONS).

Pediatric use: There is no indication for use of FARESTON in pediatric patients.

Geriatric use: The median ages in the three controlled studies ranged from 60 to 66 years. No

Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse events (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction).

Serious adverse events occurring in patients receiving FARESTON in the three major trials are listed in the table below.

Adverse Events North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) Cardiac Cardiac Failure 2 (1) 1 (<1) 1 (<1) 2 (1) 3 (1.5) Myocardial Infarction 2 (1) 3 (1.5) 1 (<1) 2 (1) 1 (<1) Arrhythmia 3 (1.5) 1 (<1) Angina Pectoris 1 (<1) 1 (<1) 2 (1) Ocular* Cataracts 22 (10) 16 (7.5) 5 (3) Dry Eyes 20 (9) 16 (7.5) Abnormal Visual Fields 8 (4) 10 (5) 1 (<1) Corneal Keratopathy 4 (2) 2 (1) Glaucoma 3 (1.5) 2 (1) 1 (<1) 1 (<1) Abnormal Vision/Diplopia 3 (1.5) Thromboembolic Pulmonary Embolism 4 (2) 2 (1) 1 (<1) 1 (<1) Thrombophlebitis 2 (1) 1 (<1) 1 (<1) 4 (2) 3 (1.5) Thrombosis 1 (<1) 1 (<1) 3 (1.5) 4 (2) CVA/TIA 1 (<1) 1 (<1) 4 (2) 4 (2) Elevated Liver Tests** SGOT 11 (5) 4 (2) 30 (19) 22 (15) 32 (15) 35 (17) Alkaline Phosphatase 41 (19) 24 (11) 16 (10) 13 (9) 18 (8) 31 (15) Bilirubin 3 (1.5) 4 (2) 2 (1) 1 (<1) 2 (1) 3 (1.5) Hypercalcemia 6 (3) 6 (3) 1 (<1) * Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual opthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated defined as follows: North American Study: SGOT >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: SGOT, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal).

Other adverse events of unclear causal relationship to FARESTON included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritis, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors.

In the 200 and 240 mg FARESTON dose arms, the incidence of SGOT elevation and nausea was higher.

Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms.

Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor.

OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/ dilatation leading to interference with digestion and adrenal enlargement.

Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient.

Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.

DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed.

HOW SUPPLIED FARESTON Tablets, containing toremifene citrate in an amount equivalent to 60 mg of toremifene, are round, convex, unscored, uncoated, and white, or almost white.

FARESTON Tablets are identified with TO 60 embossed on one side.

FARESTON Tablets are available as: NDC 11399-005-30 bottles of 30 NDC 11399-005-01 bottles of 100 Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Protect from heat and light.

Distributed by GTx, Inc. Memphis, TN 38163, USA Product covered by Orion Product Patents and related patent numbers. © 2004 GTx, Inc. All rights reserved.

1E Rev. 12/2004

4

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2010

Breast

Studies Highlight Benefits and Risks of Switching to AIs 10-Year Follow-up of ATAC Presented Washington—Women in their 40s who ceased to menstruate while on adjuvant chemotherapy followed by tamoxifen still have a substantial chance of recovering ovarian function, according to a study presented at the recent American Society of Clinical Oncology 2010 Breast Cancer Symposium (abstract 259).

The findings suggest that oncologists should exercise caution before switching patients in their 40s who appear to be menopausal to an aromatase inhibitor (AI).

“You’re not doing your patient any favors if you’re treating them with an aromatase inhibitor and they have ovarian function,” said Lea Krekow, MD, pointing out that AIs are ineffective in women with

ovarian function. Dr. Krekow, a medical oncologist at Texas Oncology-the Breast Care Center of North Texas in Bedford, was lead author of the study.

For the study, researchers at that

cancer center c aassessed serum ffollicle-stimullating hormone ((FSH) and E2 levels in patients aged 45 to 50 years who became amenorrheic after chemotherapy that included cyclophosphamide. Patients had been taking tamoxifen for a mean of 19 months before starting letrozole (Femara, Novartis). Of 142 patients

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2010

Breast

$

‘Clinical oncologists need to be aware that the incidence of ovarian function recovery is as high as it is, and regularly monitor FSH and E2 levels in amenorrheic patients in their 40s who have been placed on an aromatase inhibitor.’

—Lea Krekow, MD

Percentage of women aged 45-50 who became amenorrheic after chemotherapy and then regained ovarian function evaluable for ovarian function recovery, 27% had their ovarian function return.

The average time to ovarian function return on AI therapy was 6.9 months.

The findings are important given the mounting evidence that AIs provide a clinical advantage over tamoxifen, which has led doctors to switch their patients to AIs. The most recent evidence comes from a study also presented at the Breast Cancer Symposium (abstract 256), a 10-year analysis of the ATAC trial (Arimidex, Tamoxifen, Alone or in Combination). The 10-year follow-up of postmenopausal women with invasive breast cancer focused on the 3,125 women who had received anastrozole and 3,116 patients who had received tamoxifen. Investigators presented data for the women who were hormone receptor-positive, 84% of the study population.

The study, similar to other large trials, did not report an improvement in overall survival with the use of AIs, but other clinical markers were improved.

Disease-free survival rates (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.78-0.95; P=0.003) and time to recurrence (HR, 0.79; 95% CI, 0.70-0.89; P=0.002) were significantly improved in patients on anastrozole (Arimidex, AstraZeneca) compared with patients on tamoxifen.

“The data shows about a 21% reduction in risk of recurrence, which in absolute terms means that about 4.3% more women taking anastrozole are alive without recurrence, compared to those taking tamoxifen,” said Aman Buzdar, MD, professor of medicine in the Department of Breast Medical Oncology at M.D. Anderson Cancer Center, in Houston, and the lead investigator in the ATAC trial. “For postmenopausal women who want to remain free of cancer, an aromatase inhibitor gives them the best chance of that.” He pointed out that the absolute difference in recurrence rates increased after

treatment completion; at five years of follow-up, it was 2.7% and at 10 years of follow-up, it was 4.3%.

Time to distant recurrence (HR, 0.85; 95% CI, 0.73-0.98; P=0.02) and the risk for contralateral breast cancers (HR,

0.62; 95% CI, 0.45-0.85; P=0.003) were also improved in the anastrozole arm.

“Aromatase inhibitors compared to tamoxifen are more effective in reducing the risk of ipsilateral and contralateral new primary breast cancers, while

patients were on therapy and also after the completion of therapy,” Dr. Buzdar said. “There is about a 38% lower risk of developing ipsilateral/contralateral new primary breast cancers in this study population.”

Women in the anastrozole arm had higher fracture rates during treatment than women in the tamoxifen arm, but the rates were similar after treatment was discontinued. Some cancers continued to be higher with anastrozole such as colon cancer (66 vs. 44) and lung cancer (51 vs. 34), and other cancers were higher with tamoxifen including see AIs, page 22

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2010

Breast

BRCA Mutations Common in Triple-negative Cancers National Harbor, Md.—About one of every five patients with triple-negative breast cancer (TNBC) are carriers of mutations in either the BRCA1 or BRCA2 genes, according to new research presented at the American Society for Clinical Oncology’s 2010 Breast Cancer Symposium (abstract 160).

Researchers at the University of Texas M.D. Anderson Cancer Center, in Houston, performed genetic sequencing on 77 patients with TNBC (negative for estrogen and progesterone receptors and

HER2), who were diagnosed between 1987 and 2006. Of those patients, 15 (19.5%) were carriers of a BRCA1/2 mutation. Compared with those having wildtype (WT) cancers, TNBC patients with

BRCA1/2 mutations tended to be younger (P=0.005) and had a significantly better prognosis. Five-year recurrencefree survival estimates were 51.7% for WT patients and 86% for mutation carriers (P=0.031); five-year overall survival estimates were 52.8% for WT patients versus 73.3% for mutation carriers (P=0.225).

“In the past, most studies looking at the association between triple-negative

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CilENgitide in combination with Temozolomide and Radiotherapy In newly diagnosed glioblastoma phase III randomized Clinical trial A randomized multicenter, open-label, controlled phase III study to evaluate cilengitide in combination with standard treatment (TMZ with concomitant RT, followed by TMZ maintenance therapy) versus standard therapy alone in newly diagnosed glioblastoma patients with methylated MGMT gene promoter status.

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Cilengitide in subjects with newly diagnOsed glioblastoma multifoRme and unmethylated MGMT genE promoter A randomized multicenter, open-label phase II study, investigating two cilengitide regimens in combination with standard treatment (temozolomide with concomitant radiation therapy, followed by temozolomide maintenance therapy).

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tumors and BRCA mutations have assessed women who were BRCA-positive to determine the percentage that had triple-negative cancers,” said Jennifer Litton, MD, assistant professor of medical oncology at M.D. Anderson and a coauthor of the study. “This study, on the other hand, was trying to get at the real prevalence of the BRCA mutation among those with triple-negative tumors, so these women were unselected for anything other than TNBC status. We didn’t look for family history or genetic counseling.”

That finding makes biological sense, said Dr. Litton. “The way the BRCA mutation interacts with DNA may potentially make [these tumors] more susceptible to chemotherapy.” The finding may be important to the clinical oncologist considering who to refer for genetic counseling, she added. “We are still always refining our guidelines as to who to test and who not to. TNBC tumors may, in the future, be considered one of the factors put into the algorithm of who should get tested and who should not. Getting this finding further validated in a larger tumor set will also be very important.”

Commenting on the findings, Kostadinos Sideras, MD, assistant professor of medical oncology at Mayo Clinic, in Rochester, Minn., said, “This study confirms what we thought we knew: that patients with TNBC, which tends to be aggressive, have a high chance of carrying the BRCA mutation.” In addition, Dr. Sideras said, the study shows that although women with TNBC fare worse in general than the overall population of women with breast cancer, “women with TNBC who also have BRCA mutations tend to do better than those who do not have the mutation.”

It’s an interesting finding, said Dr. Sideras, but it needs to be replicated.

“This a small, retrospective study of 77 patients, and the overall survival difference was not statistically significant,” he said. At the moment, it does nothing to change practice. “I cannot tell my patient, ‘you have the BRCA mutation, your prognosis is better,’ until this is confirmed,” he said. “But if this is true, hopefully in the future we will be able to use this finding, not only as prognostic but also as predictive of treatment benefit. Perhaps, if you have the BRCA mutation, we will be able to tell you that you have a better response to chemotherapy or to certain drugs, such as the poly (ADP-ribose) polymerase (PARP) inhibitors, which have caused a lot of excitement in the oncology community. Undoubtedly, future research will answer these questions. ” —Gina Shaw

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2010

Lung

Active Drug in Lung Cancer Fails To Improve Overall Survival Milan—Patients with advanced non-small cell lung cancer (NSCLC) gained some delay in disease progression but no survival advantage from the epidermal growth factor receptor (EGFR) inhibitor afatinib, after progression on previous EGFR inhibitor therapy, according to a large randomized clinical trial.

Although afatinib (Boehringer Ingelheim) slowed disease progression by two months and increased the eightweek disease control rate threefold, the drug conferred no overall survival (OS) advantage, reported Vincent Miller, MD, medical oncologist at Memorial SloanKettering Cancer Center, in New York City. He presented the study at the recent European Society for Medical Oncology (ESMO) Congress (abstract LBA1).

The improvements in disease progression and control rate provide some positive news for NSCLC patients who have progressed on gefitinib (Iressa, AstraZeneca), which is used in Europe, or erlotinib (Tarceva, Genentech), noted Dr. Miller. “This drug clearly has activity in a subset of patients who currently have no proven treatment options,” Dr. Miller said. “The activity was associated with improvement in lung cancer symptoms, which should not be minimized.” Nonetheless, OS remains the gold standard for a therapy’s performance, he said.

unexpectedly healthy, which undoubtedly influenced survival, said Dr. Miller.

When the trial ended, the placebo group had a median OS of 12 months compared with 10.8 months in the afatinib arm, but this was not statistically significant.

The lack of difference in OS probably

reflected, in part, modest imbalances in subsequent treatment. Patients randomized to placebo received more lines of therapy after progression, according to Dr. Miller.

Analysis of secondary outcomes showed several statistically significant

advantages favoring afatinib. Median PFS was 3.3 months with the targeted therapy versus 1.1 months in the placebo group. The difference translated into a 62% reduction in the hazard for progression (HR, 0.38; P<0.0001).

At eight weeks, patients in the afatinib group had a confirmed overall response rate of 11% compared with 0.5% in the placebo group by investigator assessment and 7.4% versus 0.5% by independent review (P<0.01). The disease control see SURVIVAL, page 12

‘We have a negative Phase III trial with a very active agent.

How is this possible?’

—Jean-Charles Soria, MD

The findings came from the multicenter LUX-Lung 1 clinical trial, which involved 585 patients with stage IIIBIV adenocarcinoma of the lung that had progressed despite one or two prior regimens, including erlotinib or gefitinib. The ultimate goal of the study was to identify an alternative EGFR-targeted therapy to use after failure of platinum-based chemotherapy and one of the reversible EGFR inhibitors. The trial used a clinical enrichment strategy to target patients whose tumors would contain the EGFR T790M resistance mutation. Afatinib, an irreversible inhibitor of EGFR and HER2, had demonstrated preclinical activity against the mutation.

Investigators in North America, France, South Korea, China and Taiwan enrolled patients who received best supportive care and were randomized 2-to-1 to afatinib or placebo. The trial had 90% statistical power to detect a 30% reduction in the survival hazard (HR, 0.70).

Secondary end points were progressionfree survival (PFS), objective response rate, disease control rate (response plus stable disease), safety and quality of life.

The study population proved to be

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2010

Breast

Identifying Breast Cancer Patients Who Can Avoid XRT Washington—Compilation of data from two prospective, randomized clinical trials (RCTs) has provided evidence that neoadjuvant chemotherapy before lumpectomy or mastectomy can lessen the need for postoperative radiation therapy (XRT) in selected patients.

The trials did not include a randomization to XRT, so the findings are not considered definitive, but outcome data were collected from more than 2,600 patients, and the findings provide some guidance for clinicians attempting to identify the line between adequate and excessive treatment. The study was presented at the American Society of Clinical Oncology’s (ASCO) 2010 Breast Cancer Symposium (abstract 90).

The combined data from the NSABP (National Surgical Adjuvant Breast and Bowel Project)-18 and -27 trials provide the first large pool of data in which the impact of neoadjuvant chemotherapy was evaluated prospectively. According to Eleftherios P. Mamounas, MD, medical director of Aultman Hospital Cancer Center, Canton, Ohio, who presented the data, the factors affecting outcome were evaluated with multivariate analysis by type of surgery and pretreatment patient characteristics.

The analysis included study data from one arm of the B-18 study (the other did not employ neoadjuvant chemotherapy) and all three arms of the B-27 study. In the B-18 arm and one of the B-27 arms, surgery followed four courses of neoadjuvant chemotherapy with doxorubicin and cyclophosphamide (AC). In the other two arms of B-27, there was an additional sequence of treatment with docetaxel, which came before surgery in one arm and after surgery in the other, following four cycles of neoadjuvant AC chemotherapy. In B-18, all patients 50 years of age or older received five years of tamoxifen after completion of neoadjuvant chemotherapy. In the B-27 arm, tamoxifen was started concurrently with the neoadjuvant chemotherapy for all patients.

Patients who underwent lumpectomy received XRT confined to the breast after surgery. Patients undergoing mastectomy did not receive XRT. Overall, 2,691 patients from the four treatment arms in the two studies were included in the pooled analysis. In the combined set of data, the median follow-up is 12.1 years. The objective of this pooled-data analysis

was to identify the predictors of the 318 locoregional failures (LRF) recorded over the course of follow-up.

Although the cumulative incidence of LRF ranged between 10% and 12% for the treatment arms overall, multivariate analysis identified four significant independent predictors of outcome as defined by hazard ratio (HR).

These were older age (HR, 0.79 for women ≥50 years vs. younger; P=0.04), clinical tumor size before chemotherapy (HR, 1.52 for tumors >5.0 cm vs. smaller; P=0.005) clinical nodal status before chemotherapy (HR, 1.64 for positive vs. negative nodes; P<0.0001) and pathologic complete response (pCR), defined in this study as absence of invasive tumor

Take-Home Points From Eleftherios P. Mamounas, MD For lumpectomy patients with clinically node-negative disease before neoadjuvant chemotherapy and/or pathologically negative nodes after neoadjuvant chemotherapy, the rates of regional nodal failure are quite low (<2.5%) and the addition of regional nodal XRT to breast XRT is probably not needed.

For mastectomy patients with clinically node-negative disease prior to treatment and pCR after treatment, the nomograms suggest XRT can probably be avoided.

For patients who are clinically node-positive before and/or pathologically node-positive after neoadjuvant chemotherapy, XRT is probably appropriate.

in the breast (HR, 1.65 for node-negative but no pCR vs. node-negative with pCR; and HR, 2.77 for node-positive vs. nodenegative with pCR; both P<0.001).

When stratified by type of surgery, the size of the tumor lost independent predictive value for the 1,891 patients who underwent lumpectomy, but the other factors remained significant with comparable relative hazard ratios as those seen in the full data set. For the 1,070 patients who underwent mastectomy, age lost independent predictive value, but the others remained significant. In particular, tumors greater than 5 cm predicted a significantly greater risk for LRF than smaller tumors (HR, 1.60; P=0.008) as did pathologic node-positive status versus nodenegative with pCR (HR, 4.30; P=0.0004).

In patients aged 50 years or older who underwent lumpectomy, the LRF rates generally ranged between 6% and 9% for stratifications made by node status and pCR except for those who still had positive nodes after neoadjuvant therapy. In this group, LRF rates climbed to almost 15%. About half of these failures were from a regional recurrence.

Most recurrences in other lumpectomy patients were local. In mastectomy patients, LRFs occurred mostly in the chest wall, although about two-thirds of the 17% LRF in mastectomy patients with preoperative tumors less than 5 cm who still had positive nodes after neoadjuvant therapy were local. The LRF rate for the same group with preoperative tumors 5 cm or larger was 22.4%.

Based on these data, nomograms can be generated to combine prognostic factors in order to guide a rational plan for treatment. Dr. Mamounas singled out a few examples. For lumpectomy patients with clinically node-negative disease before neoadjuvant chemotherapy and/or pathologically negative nodes after neoadjuvant chemotherapy, the rates of regional nodal failure are quite low (<2.5%) and the addition of regional nodal XRT to breast XRT is probably not needed. For mastectomy patients with clinically node-negative disease prior to treatment and pCR after treatment, the nomograms suggest XRT “can probably be avoided but the number of patients in these subgroups was relatively small.” For patients who are clinically node-positive before and/or pathologically node-positive after neoadjuvant

‘Don’t go home thinking you now know how to do this, but this is a start.’

—Eric P. Winer, MD

chemotherapy, XRT “is probably appropriate.” For many other stratifications, Dr. Mamounas suggested that it may be necessary to individualize therapy based on a broader array of factors.

At the ASCO meeting, Eric P. Winer, MD, director of the Breast Oncology Center, Dana-Farber Cancer Institute, Boston, put the study in perspective for meeting attendees. He agreed that the pooled data from both NSABP studies will be useful for individualizing therapy, but he cautioned against overinterpretation. Although these may be the best available data for evaluating whether additional therapy is needed after neoadjuvant chemotherapy and surgery, he cautioned that the study, although based on prospective RCTs of neoadjuvant chemotherapy, was not a randomized comparison of radiation versus no radiation. As a result, he said, “It is uncertain to what extent radiation would have changed the recurrence risks.”

Dr. Winer said, however, that the study had some take-home points. In particular, he commented that these data provide support for the conclusion that lumpectomy and breast XRT after neoadjuvant chemotherapy produce an “acceptable risk of ipsilateral breast tumor recurrence.” He concluded that nodal XRT does not appear to be necessary in most patients who undergo lumpectomy unless there is a large tumor burden. He also suggested that these data indicate that pCR following neoadjuvant chemotherapy and mastectomy creates a low risk for LRF, but the data would support XRT in mastectomy patients with more than minimal disease.

In operable breast cancer, the data suggest that neoadjuvant chemotherapy might ultimately be useful “to tailor postoperative locoregional therapy with the potential to allow us to omit or limit irradiation in some patients and expand the use of radiation in others,” Dr. Winer acknowledged. He emphasized, however, that further work is needed, particularly in the current era that includes therapy choices directed by receptor status.

“Don’t go home thinking you now know how to do this, but this is a start,” Dr. Winer said.

—Ted Bosworth

EDUCATIONAL REVIEW

CLINICAL ONCOLOGY NEWS • NOVEMBER 2010

Mycosis Fungoides and Sézary Syndrome: Updates From the First World Congress of Cutaneous Lymphomas FREDERICK LANSIGAN, MD

FRANCINE FOSS, MD

Assistant Professor of Medicine Hematology and Oncology Norris Cotton Cancer Center Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire

Professor of Medicine Hematological Malignancies Medical Oncology Yale Cancer Center New Haven, Connecticut

M

ycosis fungoides (MF), the prototypical cutaneous T-cell lymphoma (CTCL) and the leukemic variant, Sézary syndrome (SS),

represent roughly 5% of all non-Hodgkin’s lymphomas.

Albert Sézary first described the condition in 1938, introducing this medical anomaly to the world.1

In September, almost 75 years later, the First World Congress of Cutaneous Lymphomas was held in Chicago.

Hosted by the United States Cutaneous Lymphoma Consortium (USCLC) and the International Society of Cutaneous Lymphomas (ISCL), and sponsored by Northwestern Feinberg School of Medicine and pharmaceutical educational grants, this conference, dedicated to skin lymphomas including MF and SS, revealed some exciting data on the epidemiology and basic science of CTCL, as well as updates on the clinical efficacy of active agents in CTCL. More importantly, perhaps, is that significant emphasis was placed on efforts to improve the quality of life (QoL) for patients with CTCL. CTCL is a devastating disease.

Clinically, patients with advanced disease (stages IIB-IV) do poorly with relapsing disease despite multiple therapies.2 They often are impacted emotionally by the chronicity of their disfigurement and the ultimate progression of their disease.

It is clear that the medical community needs to take a more comprehensive approach to the treatment of these patients, taking into account not only the disease but the patient as a whole. This World Congress elucidated how clinicians and researchers can work together to better understand this complex disease, share experiences regarding the clinical course of patients, help bring to light strategies to treat patients with

CTCL, and work to improve QoL for these patients. This review will highlight new insights into MF and SS.

Disease Associations It has long been realized that MF itself is associated with other comorbid conditions. In a presentation at the Congress, Hodak et al investigated the prevalence of comorbidities in 2 cohorts of 1,193 patients with MF taken from a comprehensive database in Israel that compared 1,700 gender- and age-matched controls.3 Hodak et al found that patients with MF had a significantly high overall risk (OR) for having Hodgkin’s lymphoma (OR, 7) and lung cancer (OR, 10). Using Surveillance, Epidemiology and End Results (SEER) data, Ai et al showed that in MF patients younger than age 30 years, the standard incidence ratio (SIR) for developing a secondary malignancy was 3.6.4 Significantly increased risks for lymphoma (SIR, 24.2) and melanoma (SIR, 10.6) were observed. One unique feature of MF is that the malignant T-cell clone expands at the expense of normal T cells, creating a deficiency in the number of functional T cells. The increased risk for secondary malignancy is likely the result of immune dysregulation leading to impaired immune surveillance.

Another interesting and profound association uncovered by the Hodak study was that patients with MF had a higher OR for psychiatric diagnosis such as anxiety (OR, 1.4) and

depression (OR, 1.4).3 Therefore, it not only is important for physicians to counsel these patients about increased risks for secondary malignancies but also to screen for manifestations of psychological distress, including depression and anxiety, and treat it accordingly.

Staging and Prognosis The National Comprehensive Cancer Network (NCCN) practice guidelines suggest that patient workup for CTCL should include flow cytometry analysis to screen for Sézary cells in all cases except for T1 disease.5 Perrin et al assessed the frequency of peripheral blood involvement with Sézary cells in patients with stage IA (T1, N0, M0) disease (ie, patients with <10% of skin involvement).6 Their evaluation of 143 patients with T1 disease showed that the incidence of peripheral blood involvement is only 1.3% in this population, supporting the conclusion that flow cytometry analysis is unnecessary in the standard evaluation of patients with stage IA disease, as indicated in the NCCN guidelines.

A new prognostic index for MF/ SS has been put forth by Benton et al7 using the proposed revised ISCL/ European Organization for Research and Treatment of Cancer (EORTC) staging system (Table).8 In early stage disease (IA-IIA), 6 variables were predictive of worse survival: age over 60 years, folliculotropic disease, male gender, presence of plaques, lymph

node stage N1/Nx, and blood stage B1 (>5% Sézary cells in the peripheral blood). Five variables were predictive of worse outcome in advanced-stage patients (IIB-IVB): age over 60 years, male gender, lymph node stage N2/ N3, blood stage B1/B2, and visceral involvement (M1). A prognostic scoring system coined CLPI (cutaneous lymphoma prognostic index) has emerged from this and will be a useful tool in determining outcome.

Skin-Directed Therapy Topical nitrogen mustard (mechlorethamine, Mustargen, Lundbeck), an alkylating agent, has been shown to produce responses in all stages of disease and can be very effective in palliating involved skin lesions in patients with MF, even when systemic treatment for CTCL is being administered. It was shown previously that aqueous nitrogen mustard can cause drug hypersensitivity in up to 45% of patients and that the ointment-based preparation is better tolerated. One limitation of topical nitrogen mustard therapy is that it is not widely available and must be prepared by a compounding pharmacy. Lessin et al conducted the first randomized trial of topical nitrogen mustard therapy using a gel-based formulation compared with an ointmentbased formulation.9 The combined overall response rate (ORR) to both treatments was 60% to 70%. The study suggested that the gel-based Text continues on page 10

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EDUCATIONAL REVIEW

CLINICAL ONCOLOGY NEWS • NOVEMBER 2010

Table. ISCL/EORTC Revision to the Classification of MF and SS TNMB Stages

Description of Disease

Skin T1

Limited patches, papules, and/or plaques covering <10% of the skin surface. May further stratify into T1a (patch only) versus T1b (plaque ± patch)

T2

Patches, papules, or plaques covering ≥10% of the skin surface. May further stratify into T2a (patch only) versus T2b (plaque ± patch)

T3

One or more tumors (≥1-cm diameter)

T4

Confluence of erythema covering ≥80% body surface area

Node N0

No clinically abnormal peripheral lymph nodes; biopsy not required

N1

Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 1 or NCI LN0-2

N1a

Clone negative

N1b

Clone positive

N2

Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 2 or NCI LN3

N2a

Clone negative

N2b

Clone positive

N3

Clinically abnormal peripheral lymph nodes; histopathology Dutch grades 3-4 or NCI LN4; clone positive or negative

Nx

Clinically abnormal peripheral lymph nodes; no histologic confirmation

Visceral M0

No visceral organ involvement

M1

Visceral involvement (must have pathology confirmation and organ involved should be specified)

Blood B0

Absence of significant blood involvement: ≤5% of peripheral blood lymphocytes are atypical (Sézary) cells

B0a

Clone negative

B0b

Clone positive

B1

Low tumor burden; >5% of peripheral blood lymphocytes are atypical (Sézary) cells, but does not meet the criteria of B2

B1a

Clone negative

B1b

Clone positive

B2

High blood tumor burden: ≥1,000/mcL Sézary cells with positive clone

EORTC, European Organization for Research and Treatment of Cancer; ISCL, International Society of Cutaneous Lymphomas; NCI, National Cancer Institute; TNMB, tumor-node-metastasis-blood Based on reference 8.

Text continued from page 9

preparation yielded higher response rates; however, it was slightly more toxic. A standardized preparation of topical nitrogen mustard would address an important unmet medical need for patients with MF.9 The standard dose of total skin electron beam radiation (TSEB) has been 36 Gy; however, this regimen is very time intensive and associated with skin toxicities. Harrison et al presented preliminary results from a small ongoing study of 11 patients using 12 Gy of TSEB (one-third of the standard dose) and showed an ORR of 90%, with one complete response (CR) in a stage IB patient.10 The median time to response was 8 weeks, and the median duration

of response was 24 weeks. There were fewer CRs than with standard dose TSEB, but toxicities (dermatitis, alopecia, nail loss, fatigue) were reduced. It is recommended that patients be treated with TSEB at centers that have experience with this complex radiation technique.

Systemic Therapy and Novel Agents Results of clinical trials exploring the use of chemotherapy and immunotherapy were presented at the Congress, and these may be useful strategies to consider when standard agents are no longer effective, become intolerable, or are contraindicated due to comorbid conditions.

Pralatrexate (Folotyn, Allos), a novel

targeted antifolate agent with a high affinity for the reduced folate carrier (RFC), is approved for use in peripheral T-cell lymphoma. Malignant cells overexpress the reduced folate carrier RFC-1 and, thus, selectively accumulate the drug. Once inside the cells, pralatrexate effectively interferes with the action of dihydrofolate reductase, a key enzyme involved in the synthesis of deoxythymidine and the purine DNA nucleotides, which leads to cell death. Horwitz et al reported the most recent results of their dose-finding trial.11 The optimal dose was identified to be 15 mg/m2 weekly, given 3 out of every 4 weeks. The ORR of patients treated at this dose or higher was 61%.

In the expansion cohort at this dose, the ORR was 45%. Vitamin B12 1,000

mcg injections given at least every 8 to 10 weeks and folic acid (1 mg daily) were part of this protocol to reduce the incidence of side effects. In this study, mucositis was the most common side effect, with 22% grade 1/2 toxicities and 17% grade 3 toxicities.

Lenalidomide (Revlimid, Celgene), is an oral immunomodulatory agent approved for the treatment of multiple myeloma. Querfeld et al demonstrated that lenalidomide has modest clinical activity in MF, with an objective response rate of 32% and 1 nearCR in heavily pretreated patients (median prior treatments, 6).12 The response duration was 4 months, and tumor flare occurred in 8 of 35 patients. The mechanism of action of Text continues on page 28

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • NOVEMBER 2010

Lymphoma

Advancing the Field of Lymphoma Treatment There is often a considerable lapse in time between the presentation of research findings that have important treatment implications and the implementation of the findings into clinical practice. Are you up to speed?

I

n October, Clinical Oncology News interviewed Owen A. O’Connor, MD, PhD, to find out what he thought community oncologists might be missing.

Dr. O’Connor is a professor of medicine and pharmacology, deputy director of clinical research and cancer treatment, and chief of the Division of Medical Oncology and Hematologic Malignancies at the New York University Langone Medical Center Cancer Institute, in New York City.

ClinOnc: What recent developments in lymphoma treatment would you like to see more effectively disseminated to practicing oncologists?

Owen O’Connor: There are many, but it might be that autologous stem cell transplants (SCTs) probably have much less efficacy and should have a much smaller role for patients with relapsed disease and that the role of SCTs is probably greatest for patients in their first complete remission. There are now several lines of data beginning to emerge supporting combination chemotherapy regimens that integrate high-dose Ara-C in the context of some other induction regimen, be it the Nordic Lymphoma Study Group maxiCHOP regimen [cytoxan, adriamycin, vincristine and prednisone/prednisolone] or the hyper-CVAD regimen [cyclophosphamide, vincristine, doxorubicin and dexamethasone] as reported by the M.D. Anderson Group followed by consolidation with an autologous SCT, with rituximab [Rituxan, Genentech]. While there is debate regarding the optimal induction therapy, it is clear that paradigms similar to what has been used in the treatment of ALL (acute lymphoblastic leukemia) using an induction, such as maxi-CHOP-R or hyperCVAD-R, followed by consolidation SCT and maintenance therapy with an agent such as rituximab may offer the best chance for prolonged survival and possibly cure.

ClinOnc: What difference does this make?

Dr. O’Connor: When I started out in the field, we used to often quote a median overall survival on the order of three months, with a median duration of benefit of about 18 months. Nowadays, we recognize that the median progressionfree survival (PFS) following hyperCVAD-R or dose-dense therapies followed by autologous SCT may be on the order of six to seven years. These data,

even from the Nordic Lymphoma Study Group, are beginning to demonstrate that monitoring and treating minimal residual disease can provide a survival advantage. We don’t know yet what the median survival or PFS is going to be with many of the new regimens, but I

believe that integrating autologous SCT into the up-front treatment of patients with mantle cell lymphoma (MCL) is going to have a very favorable impact on long-term survival.

I also think that the other major advance, at least in MCL, and possibly

in lymphoma in general, is that with the use of gene expression arrays and other sorts of sophisticated technologies, we are able to divide what we historically thought was one disease into multiple diseases. Diffuse large B-cell lymphoma (DLBCL) was the first example. Based on gene expression profiling, we can break that disease up into its cell of origin, that is, into germinal center or post-germinal center lymphoma. We know those see ADVANCES, page 31

ERBITUX Increased Overall Survival in Both: Squamous Cell Carcinoma of the Head and Neck (SCCHN)

EGFR-Expressing Metastatic Colorectal Cancer (mCRC)

in Combination With RT in Locoregionally Advanced Disease

after Irinotecan and Oxaliplatin Failure as a Single Agent

ERBITUX Indications Head and Neck Cancer ■ ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck

Metastatic Colorectal Cancer ■ ERBITUX, as a single agent, is indicated for the treatment of 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 ■ Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations

ERBITUX Boxed WARNINGS ■ 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. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions ■ 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 EGFR=epidermal growth factor receptor; RT=radiation therapy.

Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

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SURVIVAL continued from page 7

rate was 58% in the afatinib arm and 19% in the placebo arm (P<0.0001).

The most common side effects of afatinib therapy were an 87% incidence of diarrhea (17%, grade III) and a 78% incidence of acne rash (14%, grade III).

“The results of the LUX-Lung 1 trial clearly establish the biological activity of afatinib,” said Dr. Miller. “It induced tumor regression and disease stability, improved symptoms and was well tolerated.”

Following Dr. Miller’s presentation at the ESMO plenary session, discussant Jean-Charles Soria, MD, seconded the assessment of afatinib’s performance in the trial.

“The results provide a very clear and strong signal of activity,” said Dr. Soria, medical oncologist at Gustave Roussy Cancer Institute, in Villejuif, France. “Disease control is tripled. There is improvement in lung cancer–related symptoms:

cough, dyspnea and pain. PFS is improved by 2.2 months.

There is PFS improvement in almost all subgroups.

But there is no improvement in overall survival. We have a negative Phase III trial with a very active agent. How is this possible?”

A possible explanation relates to the study protocol, which required discontinuation of afatinib at the first sign of progressive disease, no matter how minimal, unlike the usual clinical

practice of continuing EGFR inhibition after minor progression. A previous study

by Dr. Miller has shown that in patients with lung cancer who develop resistance to EGFR inhibitors, stopping treatment results in a surge of cancer growth that involves increased tumor size and increased standardized uptake values.

Rechallenging patients with erlotinib or gefitinib, however, leads to an improvement in symptoms and a reduction in imaging-detected tumor activity (Clin Cancer Res 2007;13:5150-5155, PMID: 17785570). This suggests that some tumor cells remain sensitive to EGFR blockade after progression. Discontinuation of the

ERBITUX Significantly Increased SCCHN in Combination With RT in Locoregionally Advanced Disease Survival in Combination With RT (N=424)*1,2 ERBITUX (cetuximab) + RT (n=211)

Median overall survival 49.0 months

vs

RT alone (n=213)

vs

29.3 months

vs

45%

HR: 0.74; 95% CI: 0.57-0.97; P=0.03

3-year overall survival rate 55%

19.7 month improvement

P=0.05

*

RT=radiation therapy; HR=hazard ratio; CI=confidence interval.

A multicenter, randomized (1:1), controlled clinical trial was conducted with ERBITUX + RT vs RT alone. The primary endpoint of the trial was duration of locoregional control. Secondary endpoints included overall survival.1,2 Median follow-up=54 months.2

■ Primary endpoint: ERBITUX + RT (n=211) significantly improved median duration of locoregional control by 9.5 months (24.4 vs 14.9 months) vs RT alone (n=213) (log-rank P value=0.005; HR: 0.68 [95% CI: 0.52-0.89])1

ERBITUX Safety Information for SCCHN ■ The most serious adverse reactions associated with ERBITUX® (cetuximab) across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%).

The 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%) ■ ERBITUX Plus Radiation Therapy 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 squamous cell carcinoma of the head and neck. 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 ■ Late Radiation Toxicities: The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively. The incidence of grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

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Lung

EGFR inhibitor may have led to a surge in cancer growth.

However, according to Dr. Soria, a more likely explanation for the lack of OS benefit is the highly selected nature of the LUX-Lung 1 study population— patients who had characteristics favorable to EGFR inhibition: 100% had adenocarcinoma histology; 66% were Asian; 60% were female; 63% never smoked; and 25% had performance status 0 in the third- and fourth-line setting. “This is a population that was very sensitive to previous EGFR inhibition. The mean duration of previous EGFR blockade was close to a year. That is huge,” said Dr. Soria. “Of

the unreported EGFR mutation status, I am convinced [the mutation] is present in the vast majority of patients in this trial.”

EGFR mutations are prognostic for better OS, irrespective of treatment, he said.

“Unprecedented survival was observed for both arms in this trial,” said Dr. Soria.

“This is most probably related to the huge enrichment of EGFR mutation.

There is a considerable and unexpected use of further lines of chemotherapy that was the key consequence of this situation, and OS may have been confounded by subsequent lines of therapies.”

Educational & Commercial Reprints Reprints of Clinical Oncology News articles are available in minimum quantities of 500.

Reprints can be ordered in black & white or 4-color versions and printed on 80-lb. glossy stock.

Standard turnaround time is 4 weeks.

For specific price quotes,

call Julianna Dawson at (212) 957-5300 x271.

—Charles Bankhead

Overall Survival in Both: EGFR-Expressing mCRC after Irinotecan and Oxaliplatin Failure as a Single Agent Median Overall Survival, All Patients (N=572)†1 6.14 months ERBITUX + BSC (n=287)

vs

4.57 months BSC alone (n=285)

34% improvement

HR: 0.77; 95% CI: 0.64-0.92; P=0.0046

BSC=best supportive care.

CTG CO.17 was a multicenter, open-label, randomized (1:1) clinical trial conducted with ERBITUX plus BSC or BSC alone. The main outcome measure of the trial was overall survival.1

† NCIC

■ The data presented above include patients with K-ras mutations because K-ras mutational status was not assessed at the time the study was conducted ■ Use of ERBITUX is not recommended for the treatment of colorectal cancer with K-ras mutations in codon 12 or 13 because retrospective subset analyses have not shown a treatment benefit for ERBITUX in these patients1

ERBITUX Safety Information for EGFR-Expressing mCRC ■ The most serious adverse reactions associated with ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/ desquamation (12%), and other-gastrointestinal (10%) References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb; September 2010. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.

N Engl J Med. 2006;354(6):567-578.

Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

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BEVACIZUMAB continued from page 1

year increased PFS, the primary end point of the study, by 15% compared with chemotherapy alone at 12 months. The median PFS was 17.3 months in the control arm and 19 months in the bevacizumab arm (hazard ratio, 0.81; 95% confidence interval, 0.70-0.94; P=0.0041) (Figure). There were no unexpected safety signals.

Tim Perren, MD, consultant medical oncologist at the Leeds Teaching Hospitals NHS Trust in the United Kingdom, led the study. “We believe that

the results of ICON7, taken together with GOG (Gynecologic Oncology Group)-218, will influence treatment decisions and the design of the next

generation of clinical trials for patients with ovarian cancer,” he said.

GOG-218, presented at the American Society of Clinical Oncology’s (ASCO)

annual meeting in June (abstract LBA1), demonstrated that adding bevacizumab to initial chemotherapy and then providing maintenance bevacizumab improved median PFS by roughly four months compared with chemotherapy alone.

Although some clinicians may choose to use bevacizumab for patients with ovarian cancer, others urge clinicians not to jump the gun. “In the absence of an impact on overall survival and considering the cost of this agent, it is very hard to suggest that all patients should receive more than a year of bevacizumab,” said Maurie Markman, MD, vice president of

Important Safety Information Including Boxed WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — 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 — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — 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). Longer observation periods may be required in patients who require treatment for infusion reactions

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 therapy and ERBITUX, 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, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy

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 onset or worsening of pulmonary symptoms.

Permanently discontinue ERBITUX where ILD is confirmed

Dermatologic Toxicities ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, 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 — Sun exposure may exacerbate these effects

ERBITUX Plus Radiation Therapy 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 squamous cell carcinoma of the head and neck — 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

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CLINICAL ONCOLOGY NEWS • NOVEMBER 2010

Ovarian

patient oncology services and national director for medical oncology at the Cancer Treatment Centers of America. “Furthermore, maintenance paclitaxel results in a similar, if not superior, impact on PFS at a fraction of the cost of this drug.”

‘We believe that the results of ICON7, taken together with GOG-218, will influence treatment decisions and the design of the next generation of clinical trials for patients with ovarian cancer.’

—Tim Perren, MD

Two Similarly Designed Trials Both studies included women with newly diagnosed, previously untreated ovarian, primary peritoneal or fallopian tube cancer. Whereas the GOG-218 study included advanced stage III/IV disease, ICON7 included women with high-risk, early (International Feder-

ation of Gynecology and Obstetrics

stage I or IIa [grade 3 or clear cell] capped ≤10%) or advanced stage (stage IIb-IV) disease. In both studies, treatment was discontinued for disease progression, treatment toxicity or voluntary withdrawal, and disease progression was based on Response Evaluation

Criteria in Solid Tumors criteria and global clinical deterioration at any time after enrollment. In the ICON7 trial, unlike the GOG-218 study, patients who had asymptomatic, rising serum CA-125 as their only indication of potential progression continued on their specified

Electrolyte Depletion ■ Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary

Late Radiation Toxicities ■ The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — 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 and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. 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 only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. 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 ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX

Adverse Events ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The 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%) ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%)

Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

©2010, ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb, Princeton, NJ, 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company.

693US10AB08604

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medication until they had other evidence of progressive disease. The GOG218 trial utilized an intravenous placebo control in the reference arm, in place of bevacizumab, and also included a second experimental arm in which patients received bevacizumab concurrently with chemotherapy, but followed by placebo during the maintenance phase.

The studies were otherwise very similar, except for the doses of bevacizumab and number of cycles.

In the GOG-218 study, patients were randomized to six cycles of carboplatin and paclitaxel chemotherapy given see BEVACIZUMAB, page 16

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BEVACIZUMAB continued from page 15

once every three weeks or the same chemotherapy plus concurrent bevacizumab (15 mg/kg) for six cycles and then maintenance bevacizumab at the same dose for up to an additional 16 cycles. The first cycle of bevacizumab was omitted to reduce the risk for postsurgical wound complications.

The second experimental study arm testing the addition of bevacizumab to concurrent chemotherapy only, without maintenance, did not reveal an

improvement in outcome.

The ICON7 study involved 1,528 patients from 263 centers. Patients were randomized to either six cycles of car-

same chemotherapy plus concurrent bevacizumab (7.5 mg/kg) for six cycles and then maintenance bevacizumab at the same dose for up to a further 12

‘In the absence of an impact on overall survival and considering the cost of this agent, it is very hard to suggest that all patients should receive more than a year of bevacizumab.’

—Maurie Markman, MD

boplatin and paclitaxel chemotherapy given once every three weeks or the

cycles. The first cycle of bevacizumab could be omitted if clinicians were

ERBITUX® (cetuximab) injection, 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.

concerned about wound healing.

Patient characteristics were well balanced in the two arms. The median age was 57 years; 69% had serous histology; and 47% had Eastern Cooperative Oncology Group (ECOG) performance status of 0, 47% had ECOG PS 1, and 6% had ECOG PS 2.

In explaining the PFS improvement, Dr. Perren pointed out that the curves illustrating the two arms diverge during the treatment, but then start converging after treatment is finished. “We have demonstrated nonproportionality of the hazard ratios, and therefore the benefit is complicated,” Dr. Perren said.

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 Fever1 29 1 13 1 Headache 19 <1 8 <1 15 3 2 0 Infusion Reaction2 Infection 13 1 9 1 Chills1 16 0 5 0 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 3 43 2 21 1 Alanine Transaminase, high 3 38 1 24 1 Aspartate Transaminase, high 3 33 <1 24 0 Alkaline Phosphatase, high Respiratory Pharyngitis 26 3 19 4 Skin/Appendages Acneform Rash4 87 17 10 1 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.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ NOVEMBER 2010

Ovarian

At ESMO, Michael Bookman, MD, chief of the section of Hematology/ Oncology Arizona Cancer Center, Tucson, served as the discussant of the trial. He presented several informal analyses of the data from both studies and pointed out that the impact of bevacizumab was more pronounced in advanced disease. He also said other studies have shown that the drug has considerable activity in recurrent disease and that perhaps it will be more effective in this niche.

Dr. Bookman said clinicians should think about what â&#x20AC;&#x153;clinical benefitâ&#x20AC;?

actually means. Does delayed recurrence of progression in the absence of any change in disease-related symptoms mean there is clinical benefit?

With the increased accuracy and sensitivity of medical scans, doctors can detect very small changes in tumor size, but these are not clinically significant in many cases. And there is even some murkiness about what â&#x20AC;&#x153;functional tumor responseâ&#x20AC;? means. â&#x20AC;&#x153;I think we need to really focus on how to move this forward in terms of achieving benefit. We have to understand our goals and these could be different in the curative setting and

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 â&#x2030;Ľ10% of Patients with Advanced Colorectal Carcinoma1 Treated with Erbitux Monotherapy Erbitux plus BSC BSC alone (n=288) (n=274) Body System Any Grades Any Grades Preferred Term Grades2 3 and 4 Grades 3 and 4 % of Patients Dermatology Rash/Desquamation 89 12 16 <1 Dry Skin 49 0 11 0 Pruritus 40 2 8 0 Other-Dermatology 27 1 6 1 Nail Changes 21 0 4 0 Body as a Whole Fatigue 89 33 76 26 Fever 30 1 18 <1 3 Infusion Reactions 20 5 Rigors, Chills 13 <1 4 0 Pain Abdominal Pain 59 14 52 16 Pain-Other 51 16 34 7 Headache 33 4 11 0 Bone Pain 15 3 7 2 Pulmonary Dyspnea 48 16 43 12 Cough 29 2 19 1 Gastrointestinal Constipation 46 4 38 5 Diarrhea 39 2 20 2 Vomiting 37 6 29 6 Stomatitis 25 1 10 <1 Other-Gastrointestinal 23 10 18 8 Mouth Dryness 11 0 4 0 Infection Infection without neutropenia 35 13 17 6 Neurology Insomnia 30 1 15 1 Confusion 15 6 9 2 Anxiety 14 2 8 1 Depression 13 1 6 <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.

3 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

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 3â&#x20AC;&#x201C;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.

Postmarketing Experience The following adverse reaction has been identified during post-approval use of Erbitux. Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure. â&#x20AC;˘ Aseptic meningitis 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.

noncurative setting,â&#x20AC;? Dr. Bookman said.

He also pointed out that using a drug early in treatment could induce resistance, so that it is not effective later in the disease process when it is really needed.

Other clinicians have expressed similar thoughts about clinical benefit. At the ASCO meeting, Elizabeth Eisenhauer, MD, director of the Investigational New Drug Program with the NCIC Clinical Trials Group, said it was unclear whether increasing PFS improves the quality of life of patients with ovarian cancer.

Additionally, just because bevacizumab improves PFS doesnâ&#x20AC;&#x2122;t necessarily

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] 20â&#x20AC;&#x201C;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: â&#x20AC;˘ To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. â&#x20AC;˘ 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. â&#x20AC;˘ That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. â&#x20AC;˘ To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux.

ErbituxÂŽ is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company.

Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

Copyright Š 2004â&#x20AC;&#x201C;2010 ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company. All rights reserved.

1236886A7

ER-B0001A-09-10

Rev September 2010

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Defining Clinical Benefit

"

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Figure. Median progression-free survival in patients with ovarian cancer. mean the drug will improve OS. She pointed out that data from roughly 10 published trials of bevacizumab in colorectal, breast, pancreas, renal and lung cancers have shown that gains in PFS sometimes do not translate into robust gains in OS. This is not the case for most chemotherapy trials; in 13 first-line trials of chemotherapeutic agents in ovarian cancer, gains in PFS translated into even greater gains in OS. Dr. Eisenhauer is also professor in the Department of Oncology at Queenâ&#x20AC;&#x2122;s University, Kingston, Ontario, Canada. â&#x20AC;&#x153;Why are the PFS gains seen in these other bevacizumab trials not being carried forward into more striking overall survival improvements? Do tumors behave differently after angiogenesis inhibition?â&#x20AC;? Dr. Eisenhauer asked. â&#x20AC;&#x153;We cannot yet conclude that the delay in progression will translate into survival improvement.â&#x20AC;? Dr. Eisenhauer also pointed out that the 13 trials showing that PFS benefit translated into OS benefit were in first-line therapies, not maintenance therapies.

As far as impact on practice, only time will tell how the news will play out. In terms of clinical trials, however, the impact is already noticeableâ&#x20AC;&#x201D;two new Phase III trials initiated by the GOG now include bevacizumab in all arms, or permit the patient to elect to receive bevacizumab. â&#x20AC;&#x201D;Kate Oâ&#x20AC;&#x2122;Rourke

Correction An article in the October issue of Clinical Oncology News incorrectly stated that the FDA Oncologic Drugs Advisory Committee (ODAC) recommended removing bevacizumabâ&#x20AC;&#x2122;s indication for the first-line treatment of metastatic breast cancer (MBC) on the basis of several trials, including RIBBON-2. RIBBON-2 evaluated bevacizumab plus chemotherapy for the second-line treatment of MBC and was not reviewed by the ODAC panel.

17

SOLID TUMORS

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ NOVEMBER 2010

Breast

continued from page 1

therapy for HER2-positive metastatic breast cancer, with an incidence of grade 3 or greater adverse events in the T-DM1 arm which is half [of ] what is seen in the more traditional arm,â&#x20AC;? said Edith Perez, MD, deputy director of Mayo Clinic Cancer Center, Division of Hematology/Oncology, Mayo Clinic, in Jacksonville, Fla. Dr. Perez, the studyâ&#x20AC;&#x2122;s principle investigator, said data on the primary trial end point, progressionfree survival (PFS), were not yet mature.

T-DM1 is an antibody drug conjugate that combines the biological HER2-positive targeted properties of trastuzumab (Herceptin, Genentech) with a targeted delivery of a highly potent, anti-microtubule derivative of maytansine called DM1. The new drug selectively delivers DM1 to HER2-positive tumor cells.

The drug is then internalized within the cell, and because DM1 is delivered intracellularly, the chemotherapeutic agent does not damage healthy tissue. â&#x20AC;&#x153;From the standpoint of overall response, both T-DM1 and docetaxel [plus] trastuzumab appear to be remarkably similar: 48% response rate for T-DM1 and 41% response rate for docetaxel/trastuzumab,â&#x20AC;? said Eric P. Winer, MD, director of the Breast Oncology Center, Dana-Farber Cancer Institute, Boston, who critiqued the trial at the ESMO Congress. â&#x20AC;&#x153;The key difference relates to safety and tolerability. T-DM1 is highly effective and has very limited toxicity from the standpoint of the patient. In my view, T-DM1 is an agent that we need to bring to patients, particularly in the refractory setting, as soon as possible.â&#x20AC;?

The study included 137 patients with HER2-positive metastatic breast cancer who had not received previous chemotherapy for their disease. Patients were randomized in a 1-to-1 fashion to receive

The WAITING ROOM

â&#x20AC;&#x2DC;There was no incidence of grade 3/4 neutropenia with T-DM1 and there was a rate [any grade] of only 1.5% alopecia. These are side effects that are critically important to our patients.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Edith Perez, MD

T-DM1 3.6 mg/kg IV every three weeks until disease progression or trastuzumab 6 mg/kg IV (8 mg/kg in cycle 1) plus docetaxel 75 or 100 mg/m2 IV on day 1 every three weeks. Patients in the traditional therapy arm were allowed to cross over to the T-DM1 arm at disease progression.

Treatment was ongoing in 65.6% of the T-DM1 arm and 58.6% of the trastuzumab with docetaxel arm. Characteristics such as performance status were well balanced between arms, and 19.4% of the patients in the T-DM1 arm had received previous trastuzumab therapy compared with 25.7% in the trastuzumab with docetaxel arm. Tumor assessments were conducted every nine weeks, and responses were categorized using the Response Evaluation Criteria in Solid Tumors guidelines.

At the ESMO Congress, investigators highlighted data on two of the secondary end points, overall response rate (ORR) and clinical benefit rate (CBR). At a median follow-up of six months, the ORR in patients receiving T-DM1 was 47.8% (95% confidence interval [CI], 35.4-60.3) compared with 41.4% (95% CI, 30.2-53.8) in patients receiving trastuzumab and docetaxel. The CBR was 55.2% (95% CI, 43.167.2) in the T-DM1 arm and 57.1% (95% CI, 44.6-68.9) in the traditional therapy arm. Complete responses (4.5% vs. 1.4%) and partial responses (43.3% vs. 40%) were higher in the T-DM1 arm.

TDM-1 was far better tolerated by patients (Figures 1 and 2). The three most common AEs of any grade in the T-DM1 arm were nausea (47.8% vs. 39.7%), fatigue (46.3% vs. 46.2%) and pyrexia (35.8% vs. 20.6%). The three most common AEs of any grade in the traditional

therapy arm were alopecia (66.2% vs.

1.5%), neutropenia (57.4% vs. 7.5%) and diarrhea (45.6% vs. 10.4%). â&#x20AC;&#x153;There was no incidence of grade 3/4 neutropenia with T-DM1 and there was a rate [any grade] of only 1.5% alopecia,â&#x20AC;? Dr. Perez said. â&#x20AC;&#x153;These are side effects that are critically important to our patients.â&#x20AC;?

Grade 3 thrombocytopenia was more common in the T-DM1 arm (7.5% vs.

1.5%), as was hepatic dysfunction (13.4% vs. 1.5%), but neither arm had thrombocytopenia or hepatic dysfunction higher than grade 3. â&#x20AC;&#x153;T-DM1 was not associated with an increased risk of cardiac toxicity compared with trastuzumab and docetaxel,â&#x20AC;? Dr. Perez said.

Investigators say final PFS data are expected in the second quarter of 2011.

In July, Roche submitted a request for accelerated approval for T-DM1 based on the results of a single-arm Phase II study, which showed that T-DM1 shrank tumors in one-third of women with advanced HER2-positive breast cancer, who had received an average of seven previous medicines, including two HER2-targeted agents. The FDA issued a â&#x20AC;&#x153;Refuse to Fileâ&#x20AC;? letter, saying the drug did not meet the standards for accelerated approval because all available treatment choices approved for metastatic breast cancer had not been exhausted in the study population.

According to a press statement, Roche plans to submit data from the ongoing randomized Phase III EMILIA study to support a global regulatory submission in mid-2012. The EMILIA trial compares T-DM1 with lapatinib (Tykerb, GlaxoSmithKline) in combination

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with capecitabine, in patients with advanced HER2-positive breast cancer whose disease progressed after treatment. A Phase III first-line trial evaluating T-DM1 has been initiated called MARIANNE. â&#x20AC;&#x201D;Kate Oâ&#x20AC;&#x2122;Rourke

by Joan Chiverton

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.

FDA NEWS

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

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

Arm 1

Arm 2

(n = 396) 74%

(n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

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

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

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

Arm 2

Arm 3

(n = 98)

(n = 102)

(n = 109)

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

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

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

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

2% 1%

7% 6%

4% 1%

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

0%

5%

5%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

9%

14%

21%

24%

36%

36%

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

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

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

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

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

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

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

Trastuzumab Approved for Gastric Cancer

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

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

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

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

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

Capecitabine (n = 215)

Capecitabine + Avastin (n = 229)

47% 13% 25%

57% 33% 31%

2%

24%

19%

25%

8%

14%

18% 1%

27% 16%

75%

84%

7%

22%

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

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

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

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

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

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

α (n = 304) 16%

α + Avastin (n = 337)

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

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

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

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

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

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

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

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

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

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

21%

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

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

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

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

31%

36%

14% 6%

19% 12%

16%

24%

3%

20%

4% 0%

27% 5%

9%

28%

*Adverse events were encoded using MedDRA, Version 10.1.

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

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

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

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

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

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

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

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

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

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

Manufactured by: Genentech, Inc. 94080-4990

7453214 4835706 © 2009 Genentech, Inc

T

he FDA has approved trastuzumab (Herceptin, Genentech) in combination with chemotherapy (cisplatin plus either capecitabine or 5-fluorouracil [5-FU]) for HER2-positive metastatic cancer of the stomach or gastroesophageal junction, in men and women who have not previously received treatment for metastatic disease.

The approval is based on results from the Phase III ToGA oGA trial that showed the drug improved survivval. ToGA random-ized 594 people with locally advanced, recurrent or metastatic HER2-posi-tive gastric cancer err to receive trastuzumab plus chemotherapy (cisplatin plus either capecitabine or 5-FU) or chemotherapy alone. The final overall survival (OS) analysis revealed that trastuzumab plus chemotherapy improved OS by 37% compared with chemotherapy alone (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.600.91; P=0.0038; median OS, 13.5 vs. 11 months). An updated OS analysis based on an additional year of follow-up identified a 25% improvement in OS (HR, 0.80; 95% CI, 0.67-0.97; P=0.02; median OS, 13.1 vs. 11.7 months).

Dasatinib Gets First-line Indication for CML-CP

T

he FDA has approved dasatinib (Sprycel, Bristol-Myers Squibb) 100 mg once daily for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP).

Approval of dasatinib was based on the DASISION (Dasatinib versus Imatinib Study in Treatment-Naïve CPCML Patients) study, which showed dasatinib demonstrated superior efficacy in terms of complete cytogenetic response (CCyR) rate and major molecular response (MMR) by 12 months in newly diagnosed CML-CP patients.

The CCyR rate was 77% for 259 patients randomized to dasatinib compared with 66% for 260 patients randomized to imatinib (Gleevec, Novartis) (P=0.0067), after 12 months of followup. The MMR rates on dasatinib and imatinib were 46% and 28%, respectively (P<0.0001).

The most frequently reported serious adverse reactions included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%) and pyrexia (1%).

21

22

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2010

Breast

AIs continued from page 5

endometrial cancer (24 vs. 7), melanoma (19 vs. 8) and ovarian cancer (28 vs.

17). Overall, however, cancers were similar: 425 in the anastrozole arm and 431 in the tamoxifen arm.

Some clinicians worry that the advantage of AIs may be spurring some oncologists to switch their patients to an AI prematurely, while they still have residual ovarian function or the potential to develop it in the months ahead.

“The Texas Oncology Group study

‘The data shows about a 21% reduction in risk of recurrence, which in absolute terms means that about 4.3% more women taking anastrozole are alive without recurrence, compared to those taking tamoxifen.’

—Aman Buzdar, MD

demonstrates how hazardous this may be,” commented Harold Burstein, MD, PhD, associate professor of medicine at Harvard Medical School and a medical oncologist in the Breast Oncology Center at Dana-Farber Cancer Institute, both in Boston, who was not involved

with the study. “We know that aromatase inhibitors are not effective in women who have residual ovarian function, so you’re essentially not giving a woman a very important treatment.”

Previously, Dr. Krekow had assessed ovarian function in women aged 40 to

45 years who had ceased to menstruate while on adjuvant chemotherapy followed by at least one year of tamoxifen prior to switching to an AI. These women had an even higher rate of ovarian function recovery, ultimately reaching nearly 60%.

Oncologists prescribing AIs for women in their 40s should realize that the return of menstrual cycles is not the sole measure of ovarian function recovery. In Dr. Krekow’s study, ovarian function recovery in most patients was demonstrated by the return of premenopausal estradiol levels. “These women may have eventually started menstruating, but they were taken off the study at the time of ovarian function recovery as evidenced most often by premenopausal estradiol levels,” said Dr. Krekow. “Medical oncologists need to be aware that the incidence of ovarian function recovery is high following adjuvant chemotherapy. It is important to regularly monitor FSH and E2 levels in amenorrheic patients in their 40s who have been placed on an aromatase inhibitor.”

So what should clinicians do for patients? Dr. Buzdar monitors estradiol and FSH levels closely. “If [patients] stay in the postmenopausal range after assessing these levels three or four times, four to six months apart, then you have a little more assurance that the patient has really gone into menopause and it is safe to change to an aromatase inhibitor,” Dr. Buzdar said. “But if the levels are fluctuating up and down, it will be best for the patient to stay on tamoxifen.”

Dr. Krekow says that in her practice, she considers a patient’s risk for recurrence. For women diagnosed with an early-stage breast cancer, she initially places women on tamoxifen. “There’s no data that supports placing a premenopausal-aged woman immediately on an aromatase inhibitor,” she said.

In perimenopausal-aged women with a strongly hormone receptor-positive breast cancer with a higher risk for recurrence, Dr. Krekow prefers to provide goserelin (Zoladex, AstraZeneca) initially with tamoxifen, “to see how they tolerate further ovarian suppression if they need it,” she explains. “If they’re tolerating Zoladex with tamoxifen, then I consider switching to an aromatase inhibitor with bilateral oophorectomy, rather than relying on Zoladex to suppress ovarian function in these young women with high-risk breast cancer.”

—Gina Shaw

IN BRIEF

CLINICAL ONCOLOGY NEWS • NOVEMBER 2010

Art

Cancer Survivors Awarded Top Prizes in Oncology Art Competition “Wild Water” by Annette Zalewski, of Peoria, Ariz., won first place in the 2010 Oncology on Canvas Art Competition. Mrs. Zalewski sought to express her cancer journey on canvas by using a cut-up painting technique, which begins with painting the image once, then painting it a second time in a slightly altered shape. Both paintings are then cut up, and the two images are woven together. “My artwork represents my two lives—before and after my lung cancer diagnosis,” said Mrs. Zalewski.

Mrs. Zalewski designated the Lung Cancer Alliance as the recipient of her $10,000 first-place award. Lilly Oncology On Canvas awarded nearly $40,000 in prizes to cancer charities selected by the 20 winners in various categories.

“Wild Water” by Annette Zalewski

Second prize went to Victoria Kelly, an artist and cancer survivor from Baldwin, Mich., for her mixedmedia entry, “Breathing Room.”

“Following my lung cancer diagnosis, I needed to visualize what was happening inside my body through my art, so I created this collage of my lungs, surrounded by hope in the form of leaves and flowers,” Ms. Kelly said. She chose the LUNGevity Foundation as the recipient of her $5,000 prize.

(Stimulating Targeted Antigenic Responses To NSCLC)

“Breathing Room” by Victoria Kelly

Third place went to Juliana Carvatt, a teacher and cancer survivor from Clinton, N.J., for “No Words.” Her mixed-media entry features excerpts from a 150-page narrative she created about her cancer journey, which began with a diagnosis of melanoma at age 21. She converted a few of those stories into her artwork. First Descents will receive her $2,500 prize. It is an organization that helps young adults cope with cancer through adventure therapy.

“No Words” by Juliana Carvatt

23

SOLID TUMORS

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ NOVEMBER 2010

Prostate

THERAPY continued from page 1

Most prostate cancer experts expect the FDA to approve the drug in the near future, thus adding to the expanding options for mCRPC. This year, the FDA approved cabazitaxel (Jevtana, Sanofiaventis) for patients with mCRPC after progression on docetaxel therapy and sipuleucel-T (Provenge, Dendreon) for the treatment of asymptomatic or minimally symptomatic patients with mCRPC. According to Michael Carducci, MD, AEGON Professor in Prostate Cancer Research at the Johns Hopkins Kimmel Cancer Center, Baltimore, abiraterone may have a broader use than for patients with mCRPC who have failed docetaxel. â&#x20AC;&#x153;If you are a betting person, the big discussion is whether the label is going to be broad or narrow,â&#x20AC;? said Dr. Carducci, who was on the scientific advisory board of Cougar Biotechnology. â&#x20AC;&#x153;Based on where they did the study [the population], it is exactly the cabazitaxel patient, but because prostate cancer physicians and other providers think of this as a

countries and included 1,195 patients with mCRPC who previously had received docetaxel. Patients were randomized in a 2-to-1 fashion to receive prednisone (5 mg twice daily) and abiraterone (1,000 mg once daily) in a fasting state or prednisone and placebo.

During an interim analysis in August, the median OS was 14.8 months in the abiraterone arm and 10.9 months in the control arm (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.540.77; P<0.0001). The median number of months on therapy was eight months in the abiraterone arm and four months in the placebo arm. Treatment was ongoing in 28.1% of patients receiving abiraterone and 13.7% of patients receiving prednisone plus placebo.

Importantly, the drug was very well tolerated. Some adverse events were slightly more common in the abiraterone arm, including fluid retention (30.5% vs. 22.3%), hypokalemia (17.1% vs. 8.4%), liver function test abnormalities (10.4% vs. 8.1%), hypertension (9.7% vs. 7.9%) and cardiac disorders (13.3% vs.

10.4%). Grade 3/4 events, however, were infrequent (Figure).

â&#x20AC;&#x2DC;We now have unequivocal evidence that inhibition of persistent androgen synthesis and androgen receptor signaling remains key in targeting survival.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Cora N. Sternberg, MD

Howard Scher, MD, chief of the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center and coprincipal investigator of the trial, pointed out the drug was effective at a point in the illness where hormonal agents are rarely considered.

Cora N. Sternberg, MD, head of the Department of Medical Oncology, San Camillo, and Forlanini Hospital, Rome, Italy, agreed. â&#x20AC;&#x153;We now have unequivocal evidence that inhibition of persistent androgen synthesis and androgen receptor signaling remains key in targeting survival,â&#x20AC;? said Dr. Sternberg, who served as the study discussant at the ESMO Congress and was not involved with .OV_NaR_\[R =YNPRO\ the trial. â&#x20AC;&#x153;Abiraterone sets a new standard of therapy in the treatment of metastatic castration-resistant prostate cancer post docetaxel.â&#x20AC;?

While a Phase III trial

hormonal drugâ&#x20AC;&#x201D;and most hormonal drugs are used prior to chemotherapyâ&#x20AC;&#x201D; when this drug comes out, I think people are going to want to use this up front.â&#x20AC;?

Abiraterone acetate is a first-in-class intracrine androgen biosynthesis inhibitor that works by blocking CYP17 and inhibiting persistent androgen synthesis from adrenal and intratumoral sources.

The drug was first designed and synthesized at The Institute of Cancer Research, Sutton, United Kingdom, and the first clinical trials were conducted at the Royal Marsden Hospital. The trial presented at ESMO involved 147 centers in 13

%

=NaVR[a`

24

# !

testing abiraterone in patients pre-docetaxel is ongoing, many clinicians believe the drug will be used pre-docetaxel, regardless of what label is approved. â&#x20AC;&#x153;I would be hard-pressed to figure out why it wouldnâ&#x20AC;&#x2122;t work pre-chemo,â&#x20AC;? Dr. Carducci said. He projects that many clinicians will use abiraterone first and then move to sipuleucel-T, docetaxel and cabazitaxel, in that order. When asked why he thought clinicians would use abiraterone over sipuleucel-T, he said that sipuleucel-T doesnâ&#x20AC;&#x2122;t improve some clinical benefit measures, like prostate-specific antigen (PSA) levels, that physicians are used to monitoring, whereas abiraterone does and is orally administered.

All secondary end points in the COUAA-301 trial were improved in the abiraterone arm and achieved statistical significance, including median time to PSA progression (10.2 vs. 6.6 months; HR, 0.58; 95% CI, 0.46-0.73; P<0.0001), median radiographic progression-free survival (5.6 vs. 3.6 months; HR, 0.67; 95% CI, 0.58-0.78; P<0.0001) and PSA response (39% vs. 10.1%; P<0.0001).

Oliver Sartor, MD, LaBorde Professor for Cancer Research at Tulane Cancer Center, New Orleans, headed up the Phase III trial that led to cabazitaxelâ&#x20AC;&#x2122;s approval (Dr. de Bono also played a lead role in this trial). â&#x20AC;&#x153;I anticipate that both drugs [cabazitaxel and abiraterone] will have an important role,â&#x20AC;? Dr. Sartor said. â&#x20AC;&#x153;It would not surprise me to see abiraterone being used earlier in the mCRPC treatment paradigm, but issues of cost and insurance coverage will be potential issues to be addressed. Cabazitaxel is most likely to be used after docetaxel progression.â&#x20AC;? He said that a large trial comparing cabazitaxel with docetaxel therapy is starting soon and will address cabazitaxelâ&#x20AC;&#x2122;s potential in first-line chemotherapy.

According to William D. Figg, PharmD, MBA, â&#x20AC;&#x153;the real excitement comes with the combination of abiraterone plus cabazitaxel or docetaxel.â&#x20AC;? Dr. Figg is section head, molecular pharmacology section and clinical pharmacology program, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, in Bethesda. He said a Phase I trial he co-authored showed that an approach that combines androgen deprivation therapy with taxane-based chemotherapy has already been shown to be effective in patients with mCRPC. That study

â&#x20AC;&#x2DC;When this drug comes out, I think people are going to use this up front.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Michael Carducci, MD

showed the effectiveness of high-dose ketoconazole plus weekly docetaxel (J Urol 2010;183:2219-2226, PMID: 20399458). (In high doses, ketoconazole is an androgen blocker.)

Several clinicians said the proper dose of steroids needs to be worked out with abiraterone and questioned whether abiraterone can be tolerated without steroids.

Dr. Sternberg said that in three of four recent mCRPC Phase II trials, the majority of patients did not receive corticosteroids but had their toxicity managed with a mineralocorticoid antagonist or low-dose steroids if needed. â&#x20AC;&#x153;I think this really needs to be worked outâ&#x20AC;&#x201D;the exact dose of cortisone that is neededâ&#x20AC;&#x201D;especially if we are thinking about giving these drugs long- term,â&#x20AC;? she said. â&#x20AC;&#x153;The long-term effects of androgen deprivation therapy are loss of muscle mass, sarcopenia and obesity, and can include bone loss that can lead to osteoporosis and fractures.â&#x20AC;?

Dr. Sternberg pointed out that there hasnâ&#x20AC;&#x2122;t been a hormone therapy approved for prostate cancer since nilutamide, 11 years ago, whereas three hormone therapies have been approved for breast cancer in this time period. The tide, however, may have just started to turn; MDV3100 is an oral androgen receptor antagonist that is showing great promise in mCRPC. â&#x20AC;&#x153;[MDV3100] is in Phase III trials coming straight up behind abiraterone and there are several other novel anti-androgens on the scene with different mechanisms of action,â&#x20AC;? Dr. Sternberg said. â&#x20AC;&#x153;[This study] opens up the field, and there are other novel therapies that target the androgen receptor which are coming up quickly behind it.â&#x20AC;? â&#x20AC;&#x201D;Kate Oâ&#x20AC;&#x2122;Rourke

3YbVQ _RaR[aV\[

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Figure. Comparison of grade 3/4 adverse events by treatment.

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POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • NOVEMBER 2010

Drug Costs

PATENT LOSS continued from page 1

one possible treatment scenario, three courses of Taxotere for patients with breast cancer would run approximately $12,000 (based on a cost of $400 per 20 mg). Gemzar (Eli Lilly; gemcitabine), used for several types of cancer, will come off patent in November, despite the fact that the manufacturer waged— and lost—a strenuous legal battle to stave off competition from generic drug manufacturers.

The route taken by any drug from conception to the marketplace is long and expensive, lasting years and often costing hundreds of millions of dollars. Along the way, drugmakers are afforded two mechanisms to shield their intellectual property, and the income it earns, against competitors. The first mechanism, a patent, is granted by the U.S. Patent and Trademark Office. Patents protect not just a drug’s chemical formulation, but also different clinical applications of the drug. They expire 20 years from the date a drug manufacturer files its application, which may occur anywhere along the drug development timeline. Often, the patent is issued early in that process, so the effective protection typically does not last 20 years in the marketplace. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), new drugs reach the market and begin producing income, on average, about nine years after the patent takes effect. Patents can even expire before the FDA approves a drug, or can be issued afterward.

The second mechanism is exclusivity, which is accorded by the FDA and confers exclusive marketing rights after the agency approves a drug. Exclusivity exists independent of patents. The two may or may not run concurrently and encompass different claims.

According to the FDA, exclusivity was “designed to promote balance between new drug innovation and generic drug competition.”

Exclusivity durations vary depending on a drug’s category (Table); for example, an orphan drug is seven years and a new chemical is five years. The Waxman-Hatch Act of 1984 established these exclusivity rules. One of the law’s intents was to balance affordable medication with adequate incentives for drugmakers to innovate. But the law predated the surge in biologic agents, which were a rarity at that time. They fell into the “new chemical” category and thus received five years of exclusivity. But under the Patient Protection and Affordable Care Act signed into law earlier this year, biologic agents now get 12 years of exclusivity before any biosimilars can be developed. Many of the newer cancer drugs fall into this group.

“We fought very hard against the

‘Many people think the period of exclusivity is too long.

The reason this is important in oncology is because of these newer drugs that are priced at incredibly high levels.’

—Nancy Keating, MD, MPH

Table. Exclusivity Durations Vary by Drug Category Orphan drug: seven years New chemical: five years

12-year exclusivity for biosimilars,” said Gordon Johnston, vice president of regulatory sciences at the Generic Pharmaceutical Association (GPhA). For now, his industry has no plans to try to change other exclusivity or patent regulations. “Unfortunately, I don’t think there’s any appetite in Congress to open up that legislation in the near future,” he added.

“There’s a lot of controversy about what is the right length of time for exclusivity,” said Nancy Keating, MD, MPH, associate professor of health care policy and medicine, Harvard Medical School, in Boston. “Many people think the period of exclusivity is too long. The reason this is important in oncology is because of these newer drugs that are priced at incredibly high levels. No one really knows how to price them. The manufacturers seem to set the price at a point where they hope people will pay for it.”

Drugmakers defend the current exclusivity times, asserting that they serve to recover research and development costs—in many cases for chemicals that never reach the market. “Exclusivity protects the incentives for innovation for the pharmaceutical industry,” said Kate Michael, director, Communications and Public Affairs with PhRMA. “It can cost more than a billion dollars to develop a new drug. The whole concept is to determine when it is fair for somebody else to come on the market using the work of the innovator company.”

Branded drug manufacturers frequently try to delay competition from their generic drug counterparts. One tactic is to seek a patent extension through the courts, as Eli Lilly attempted for Gemzar.

Another is the so-called “pay-to-delay tactic,” in which brand name drug companies pay generic manufacturers large sums to postpone introducing a generic

‘If the trend line for the cost of cancer drugs continues, we’ll start to see treatment regimens costing $150,000 or $250,000.

We in oncology—and everybody in health care—must find the balance to make sure the system is sustainable and that innovation is not snuffed out.’

—Allen S. Lichter, MD

Biologic agents: 12 years Other drug: three years (e.g., a reformulation or new delivery method of the original drug) Pediatric drug: six months added to existing patents/exclusivity Patent Challenge drug: 80 days during which the first generic manufacturer is the only one allowed to market a generic version of the branded drug

version of the branded drug. Last March, the U.S. Senate dropped an amendment to the health care reform bill that would have banned this practice.

Competition from a generic drug can take an enormous bite out of revenues.

As an example, according to the Wall Street Journal (July 28, 2010), in the first half of 2010, worldwide sales of Gemzar dropped 19% to $581 million in large part because of the availability of generics in foreign markets. (A study commissioned by the GPhA concluded that generic drugs saved the U.S. health care system $842 billion over the past decade.)

High drug costs have been found to affect choices of therapy. In a national survey of 1,379 oncologists published in Health Affairs, 56% of respondents strongly or somewhat agreed that costs influence their decisions regarding which cancer treatments to recommend for their patients, and 84% of oncologists said that patients’ out-ofpocket spending influences treatment recommendations. Yet, only 43% said they always or frequently discuss costs with patients (Health Aff 2010;29:196202, PMID: 20048377).

Some cancer patients are forced to consider drug costs in their decisions.

“Certainly, there are situations where, because of cost considerations, patients will move toward one type of treatment rather than another,” said Allen S. Lichter, MD, chief executive officer of the American Society for Clinical Oncology.

“It’s a serious problem. If the trend line for the cost of cancer drugs continues, we’ll start to see treatment regimens costing $150,000 or $250,000. There’s a point at which one must ask whether we’ve crossed a threshold that’s completely unsupportable. We in oncology—and everybody in health care—must find the balance to make sure the system is sustainable and that innovation is not snuffed out.”

—Steve Frandzel

25

CLINICAL TRIALS

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ NOVEMBER 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 Oct. 20, 2010. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials, click on the advanced link and enter the protocol ID.

Supportive Care

26

Protocol Type

Age

Protocol ID

Trial Sites

A Safety and Efficacy Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer, Phase III

18 and over

MDV3100-03

NC, VA

Study of Atorvastatin Calcium and Celecoxib in Patients With Hormone-Dependent Prostate-Specific Antigen Progression After Local Therapy for Prostate Cancer, Phase II

18 and over

CINJ-080811

NJ

Study of Bafetinib (INNO-406) as Treatment for Patients With Hormone-Refractory Prostate Cancer, Phase II

18 and over

BAFETINIB-P2HRPC-01

CA

Randomized Study of Gamma-Secretase Inhibitor RO4929097 Combined With Whole-Brain Radiotherapy or Stereotactic Radiosurgery in Patients With Brain Metastases Secondary to Estrogen Receptor-Negative Breast Cancer, Phase I/II

18 and over

MDA-20090582

MA, OH, TX, WI

A Pharmacokinetic and Randomized Trial of Neoadjuvant Treatment With Anastrozole Plus AZDO530 in Postmenopausal Patients With Hormone Receptor Positive Breast Cancer, Phase I/II

18 and over

EPROST-20080325

FL

Partial Breast Irradiation Using 40 Gy for Select Patients With Early Invasive or Noninvasive Breast Cancer, Phase II

18 and over

10-114

NJ, NY

Endocrine Therapy Plus OSI-906 With or Without Erlotinib for Hormone-Sensitive Metastatic Breast Cancer, Phase II

18 and over

VICC BRE 09112

TN

Tesetaxel for Previously Treated Patients With Bladder Cancer, Phase II

18 and over

TOBL204

NY

Partially Randomized Study of Cediranib Maleate With Versus Without Lenalidomide in Patients With Iodine 131-Refractory Differentiated Thyroid Cancer, Phase I/II

18 and over

UCCRC-10182-B

IL, IN, MD, MI, MO, NC, SC, TN, TX, VA, WI

FOLFOX/Bevacizumab/Hydroxychloroquine (HCQ) in Colorectal Cancer, Phase I/II

18 and over

UPCC 07210

PA

Study of Erlotinib With or Without Investigational Drug (U3-1287) in Subjects With Advanced Non-small Cell Lung Cancer (NSCLC), Phase I/II

18 and over

U31287-A-U201

AZ

Trial of Adjuvant Combined Epigenetic Therapy With 5-Azacitidine and Entinostat in Resected Stage I, NSCLC Versus Standard Care, Phase II

18 and over

J1037 (NCI 8311)

MD

PD0332991 in Patients With Advanced or Metastatic Liposarcoma, Phase I

18 and over

10-094

NY

Study of RAD001 in Head and Neck Cancer, Phase II

18 to 80

08-032

PA

Trimodality Management of T1b Esophageal Cancers, Phase I/II

18 and over

2010-0333

TX

Pilot Study of Bisphosphonate Therapy (Zoledronic Acid) in Patients With Malignant Mesothelioma (UAB 0901), Phase II

18 and over

F090917002 (UAB 0901)

AL

Dendritic Cell Vaccine for Patients With Brain Tumors, Phase II

18 and over

10-000202

CA

Hypofractionated Intensity-Modulated Radiation Therapy With Temozolomide and Bevacizumab for Glioblastoma Multiforme, Phase II

18 and over

AVF4733s Dr. Chen

CO

ABT-888 and Temozolomide for Liver Cancer, Phase II

18 and over

2009-268

DC

Adjuvant Intraperitoneal Gemcitabine for Resectable Pancreatic Adenocarcinoma, Phase II

18 and over

WCI 2009-455

DC

STA-9090 in Metastatic Ocular Melanoma, Phase II

18 and over

10-137

MA

Study of Sapacitabine in Acute Myeloid Leukemia, Phase I/II

70 and over

CYC682-11

TX

Feasibility Study of a 60 Minute Rapid Infusion Rituximab Protocol in Patients With B-cell Malignancies, Phase II

18 to 89

OSU-10001

OH

Nilotinib in Patients With Relapsed or Metastatic Pigmented Villonodular Synovitis/Tenosynovial Giant Cell Tumor/ Diffuse-Type Giant Cell Tumor, Phase II

18 and over

10-179

MA

PACE Trial (PONATINIB Ph+ Acute Lymphoblastic Leukemia and Chronic Myeloid Leukemia Evaluation), Phase II

18 and over

AP24534-10-201

TX

Study on the Anti-tumor Activity, Safety and Pharmacology of IPH2101 Combined With Lenalidomide in Patients With Multiple Myeloma (MM) Experiencing a First Relapse, Phase I/II

18 to 80

IPH2101-202

MA

A Safety and Efficacy Study of Fixed Dose Radioimmunotherapy (Zevalin, Yttrium-90 Ibritumomab Tiuxetan) for Patients With Incomplete Response to Chemotherapy Prior to Autologous Stem Cell Transplant (SCT) for MM, Phase II

18 to 70

Zevalin

MA

Randomized Trial of Lenalidomide, Bortezomib, Dexamethasone vs High-Dose Treatment With SCT in MM Patients up to Age 65, Phase III

18 to 65

10-106

MA

Study of Metastatic Cancer Using Lymphodepleting Conditioning Followed by Infusion of Anti-VEGFR2 Gene Engineered CD8+ Lymphocytes, Phase I/II

18 and over

110013

MD

Multi-center Trial of Revlimid and Rituximab for Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL), Phase II

18 and over

CRC022

CA

A Study of CAL-101 and Rituximab in Elderly Patients With Untreated CLL or Small Lymphocytic Lymphoma, Phase II

65 and over

101-08

TN

Once Daily Targeted Intravenous (IV) Busulfex as Part of Reduced-toxicity Conditioning for Patients With Refractory Lymphomas Undergoing Allogeneic Transplantation, Phase II

18 to 65

WVU 11310

WV

Low Dose Tamoxifen in Hodgkin Lymphoma Survivors for Breast Cancer Risk Reduction, Phase II

25 and over

08218

CA

Study of Gabapentin to Reduce Duration of Postoperative Pain and Opioid Use, Phase III

18 to 75

SU-020320104882

CA

Immunogenicity of Fluzone HD, A High Dose Influenza Vaccine, In Children With Cancer or HIV, Phase II

3 to 21

FLUHD

TN

Trial of Combination Antifungal Therapy (Vori+Mica vs. Vori+Placebo) in Invasive Aspergillosis, Phase II

18 and over

UARK 2010-14

AR

Prophylactic White Cell Transfusions Versus Therapeutic White Cell Transfusions in Patients With Leukemia, Phase II

Not specified

2010-0468

TX

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CO1110

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EDUCATIONAL REVIEW

Continued from page 10

lenalidomide in patients with CTCL is unknown, and further studies need to be performed.

Alemtuzumab (Campath, Genzyme) is an antibody-based therapy that targets CD52 and is approved for use in relapsed chronic lymphocytic leukemia (CLL). Clinical activity has been demonstrated previously with response rates of 55%13 and 84%.14 Bernego et al presented efficacy data of alemtuzumab in patients with a high tumor burden of Sézary cells in the peripheral blood.15 The patients received alemtuzumab 10 mg subcutaneously on alternate days until the Sézary count was less than 1,000/mm3. The median Sézary counts decreased by 93.5%, and skin responses also were seen. An ORR of 83% was reported, with 5 CRs after the first alemtuzumab treatment course. The responses lasted a median of 24 months, with a median survival of 35 months. This agent is associated with high-incidence opportunistic infections, including cytomegalovirus (CMV) reactivation, bacterial infections, and hospitalizations. Appropriate prophylactic therapy as well as routine surveillance for detection of CMV DNA is recommended.

A new antibody-based treatment directed against CCR4 has been explored in patients with relapsed CTCL. CCR4 is a chemokine receptor protein overexpressed on malignant CTCL and peripheral T-cell lymphoma T-cells and also expressed on T-regulatory cells. Duvic et al reported the results of a Phase I/II dose-finding study of the humanized anti-CCR4 antibody KW-0761.16 The maximum tolerated dose (MTD) was not reached. The most frequent adverse events reported were lymphopenia, nausea, back pain, and headache. Preliminary efficacy data showed a CR or PR in 5 of 9 patients with CTCL. Further studies are underway to determine the immunomodulatory effects .

Extracorporeal Photopheresis: Mechanisms and Clinical Results The mechanism by which extracorporeal photopheresis (ECP)

CLINICAL ONCOLOGY NEWS • NOVEMBER 2010

exerts its clinical effects in patients with MF/SS has been elusive, but recent work by Berger et al has shown that ECP is capable of producing monocyte differentiation into functionally mature dendritic cells (DC).17 Further work by this group now shows that monocyte– platelet interactions are required for DC differentiation.18 A multicenter trial by Duvic et al demonstrated the efficacy of ECP in early-stage patients using the UVAR XTS photopheresis system (Therakos).19 Nineteen early-stage patients were treated and the ORR was 63% (10 partial response and 2 CR). These patients received a median of 12 ECP sessions every 4 weeks.

Seven patients were treated with combination therapy with bexarotene (Targretin, Eisai) with or without interferon-α during the study. ECP monotherapy was effective in earlystage patients with improvements in skin QoL indicators.

Formal QoL Studies Pruritus is the most prevalent bothersome symptom in patients in all stages of CTCL, but formal studies of pruritis have been lacking due to the lack of a validated QoL instrument or questionnaire. Chen et al used a new instrument called the ItchyQOL to assess the incidence of pruritus in a cohort of 30 patients.20 In total, 77% reported pruritis, and 100% of stage III-IV patients reported itching over greater than 24% of their body surface area. Chen et al also studied other instruments such as the Skindex-29 and Functional Assessment of Cancer Therapy General Scale (FACT-G) as well as the ItchyQOL (pruritis) and these were able to distinguish the different stages of CTCL among patients; however, the FACT-G (oncologic) was not predictive of symptomatology or overall QoL impact in these patients.21 As more clinical trials are done using existing or new agents, more robust QoL tools and indicators will be needed.

Conclusion The First World Congress of Cutaneous Lymphomas has raised much needed awareness of a less common but often very symptomatic

type of lymphoma. Although CTCL is considered an indolent lymphoma, many patients are physically and psychologically debilitated and require ongoing therapy for their disease. The international exchange of ideas and clinical expertise continues to facilitate advances to address this difficult disease and treat the patients who harbor it.

References 1.

Sézary A, Bouvrain Y, Erythrodermie avec presence de cellules monstreuses dons derma et sang circulant. Bull Soc Fr Dermatol Syph. 1938;45:254-260.

2. Sausville EA, Eddy JL, Makuch RW, et al.

Histopathologic staging at initial diagnosis of mycosis fungoides and the Sézary syndrome. Definition of three distinctive prognostic groups. Ann Intern Med. 1988;109 (5):372-382, PMID: 3408055.

3. Hodak E, Lessin S, Friedland R, David M, Cohen AD. Associated comorbidities in patients with mycosis fungoides. Presented at: First World Congress of Cutaneous Lymphomas; September 22-25, 2010; Chicago, IL. Abstract 15.

4. Ai WZ, Keegan T, Fish K, et al. Increased risk of second malignancies in patients with mycosis fungoides diagnosed before 30 years of age: a population-based study.

Presented at: First World Congress of Cutaneous Lymphomas; September 22-25, 2010; Chicago, IL. Abstract 13.

5. National Comprehensive Cancer Network.

NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin’s Lymphoma. V1.

2010. http://www.nccn.org/professionals/ physician_gls/PDF/nhl.pdf. Accessed October 25, 2010.

6. Perrin B, Morrissey K, Vittorio CC, Rook AH, Kim EJ. Predictors of blood involvement in Stage 1A mycosis fungoides patients.

Presented at: First World Congress of Cutaneous Lymphomas; September 22-25, 2010; Chicago, IL. Abstract 33.

7. Benton EC, Crichton S, Agar NS, et al.

Cutaneous lymphoma prognostic index (CLPI). Presented at: First World Congress of Cutaneous Lymphomas; September 2225, 2010; Chicago, IL. Abstract 50.

8. Olsen E, Vonderheid E, Pimpinelli N, et al.

Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization for Research and Treatment of Cancer (EORTC). Blood.

2007;110(6):1713-1722.

9. Lessin SR, Duvic M, Guitart J, et al. A randomized, pivotal trial to evaluate the safety and efficacy of 0.02% nitrogen mustard (NM) formulations in patients with stage I or IIa mycosis fungoides (MF).

Presented at: First World Congress of Cutaneous Lymphomas; September 22-25, 2010; Chicago, IL. Abstract 49.

10. Harrison C, Kim Y, Navi D, Armstrong R, Weng W, Hoppe R. A Phase II study of low-dose (12-Gy) total skin electron beam therapy in mycosis fungoides. Presented at: First World Congress of Cutaneous Lymphomas; September 22-25, 2010; Chicago, IL. Abstract 52.

11. Horwitz S, Duvic M, Kim Y, et al.

Pralatrexate in relapsed/refractory

cutaneous T-cell lymphoma (CTCL): results of the PDX-010 dose-finding trial.

Presented at: First World Congress of Cutaneous Lymphomas; September 22-25, 2010; Chicago, IL. Abstract 55.

12. Querfeld C, Rosen ST, Guitart J, Duvic M, Kim YH, Kuzel TM. Evaluation of a Phase II multicenter trial of lenalidomide in patients with relapsed cutaneous T-cell lymphoma.

Presented at: First World Congress of Cutaneous Lymphomas; September 22-25, 2010; Chicago, IL. Abstract 63.

13. Lundin J, Hagberg H, Repp R, et al. Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sézary syndrome. Blood. 2003;101(11):4267-4272, PMID: 12543862.

14. Querfeld C, Mehta N, Rosen ST, et al.

Alemtuzumab for relapsed and refractory erythrodermic cutaneous T-cell lymphoma: a single institution experience from the Robert H. Lurie Comprehensive Cancer Center. Leuk Lymphoma. 2009;50(12):19691976, PMID: 19860617.

15. Bernengo MG, Ouaglino P, Marenco F, et al. Treatment of Sézary syndrome by antiCD52 monoclonal antibody alemtuzumab: clinical and immunological findings in 24 patients. Presented at: First World Congress of Cutaneous Lymphomas; September 22-25, 2010; Chicago, IL. Abstract 60.

16. Duvic M, Jorgensen J, Ni X, et al. KW-0761, a monoclonal antibody directed against CC chemokine receptor type 4 (CCR4), in PTCL and CTCL patients: antigen expression may correspond to higher likelihood of clinical response. Presented at: First World Congress of Cutaneous Lymphomas; September 22-25, 2010; Chicago, IL. Abstract 77.

17. Berger C, Hoffmann K, Vasquez JG, et al. Rapid generation of maturationally synchronized human dendritic cells: contribution to the clinical efficacy of extracorporeal photochemotherapy. Blood.

2010 [epub ahead of print], PMID: 20720185.

18. Durazzo TS, Berger CL, Girardi M, Foss FM, Tigelaar RE, Edelson RL. Mechanism underlying extracorporeal photochemotherapy’s efficient and rapid induction of monocyte-to-dendritic cell maturation. Presented at: First World Congress of Cutaneous Lymphomas; September 22-25, 2010; Chicago, IL. Abstract 66.

19. Duvic M, Talpur R, Geskin L, et al.

Multicenter photopheresis intervention trial in early-stage mycosis fungoides.

Presented at: First World Congress of Cutaneous Lymphomas; September 22-25, 2010; Chicago, IL. Abstract 62.

20. Chen SC, Nguyen L, Pugliese S, et al.

Pruritus in cutaneous T-cell lymphoma patients: prevalence and quality of life impact. Presented at: First World Congress of Cutaneous Lymphomas; September 2225, 2010; Chicago, IL. Abstract 101.

21. Chen SC, Nguyen L, Pugliese S, et al.

Quality of life impact by cutaneous T-cell lymphoma: current instruments may not be sufficient. Presented at: First World Congress of Cutaneous Lymphomas; September 22-25, 2010; Chicago, IL. Abstract 102.

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Lymphoma

ADVANCES continued from page 11

patients with post-germinal center DLBCL tend to have an inferior prognosis compared to patients with the germinal center DLBCL. Similarly, with MCL, we now know that perhaps the most important prognostic factor in that disease is the proliferation rate. So, we know that with MCL that’s growing very rapidly and very aggressively, with a Ki-67 index of more than 30% or so, the disease is highly aggressive and needs to be treated in a very aggressive fashion. Likewise, we now recognize that there are subtypes of MCL where the proliferation rate is very low, more like the indolent lymphomas such as follicular and small lymphocytic lymphoma. Those patients actually have a very favorable long-term prognosis and may be observed for some period of time before starting chemotherapy.

Owen A. O’Connor, MD, PhD

The idea that we can now begin to tailor therapies, that we can personalize the treatment for some of the underlying biologies, is becoming a reality. You might imagine that in the future, we will treat patients that have aggressive MCL with very aggressive induction chemotherapy regimens followed by transplant, versus those patients with more favorable prognostic disease that can be “watched and waited” or given singleagent rituximab or bortezomib.

The idea that we can now begin to fractionate these diseases based on underlying molecular pathogenesis is going to open the door for personalizing treatment opportunities accordingly.

ClinOnc: What’s changed over the same period with regard to attitudes about side effects of treatment of lymphoma?

Dr. O’Connor: That’s a great question, and it’s really tied to our understanding of our treatment goals when we first see

I believe that integrating autologous SCT into the up-front treatment of patients with MCL is going to have a very favorable impact on long-term survival. a patient with lymphoma. Are we treating that patient with curative intent or as someone with a chronic disease? I think we’re getting much more sophisticated and less addicted to the idea that everybody needs to be cured. Follicular

lymphoma is a great example, because it’s a disease typically of older people. If we can use simple, well-tolerated therapies like rituximab and keep patients alive for 15 to 20 years or more, then they are likely to die of something other than their cancer. If your treatment goal is to cure this patient, like someone with Hodgkin’s or with DLBCL for example, then you’re willing to tolerate a little bit more toxicity and risk for that bigger gain.

But with indolent disease, excessive treatment or overuse of chemotherapy will, with time, only make the lymphoma more drug-resistant and the natural host cells more sensitive to future

Vectibix® (panitumumab) Injection for intravenous Infusion 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. Fatal infusion reactions occurred in postmarketing experience [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions].

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. [see Clinical Studies (14) in Full Prescribing Information].

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 Boxed Warning, Warnings and Precautions, and 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.

Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix.

Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions, and 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).

Infusion reactions, manifesting as anaphylactoid reactions, bronchospasm, and hypotension, can occur following Vectibix administration [see Boxed Warning, and Adverse Reactions]. In clinical studies, severe infusion reactions occurred with the administration of Vectibix in approximately 1% of patients.

Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions. [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, Dosage and Administration, and Warnings and Precautions] • Infusion Reactions [see Boxed Warning, Dosage and Administration, 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.

therapy. As a result of our improving understanding of the biology of these diseases, I believe, we are getting a lot wiser and smarter about titrating therapies for the aggressiveness of the disease. We’re really trying to manage the patients as if they have a chronic disease, much the way cardiologists manage heart disease or an endocrinologist manages diabetes. The idea is that we don’t need to cure everybody, and in many cases, we now have the pharmacologic tools to manage them.

—Interview conducted by Walter Alexander

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 (NCICTC 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 [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Anaphylaxis [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] 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.

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, Dosage and Administration, Warnings and Precautions and Adverse Reactions], • 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 v9, 5/2010 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.

MC46026-D © 2006-2009 Amgen Inc. All rights reserved.

31

The case for Vectibix® Q2W dosing schedule1 – The recommended dose of Vectibix® is 6 mg/kg every 14 days

60-minute infusion1 – Vectibix® is given by intravenous infusion over 60 minutes - Doses greater than 1000 mg should be administered over 90 minutes

Premedication not standardized1 – The use of premedication was not standardized in the clinical trials – The utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown

No loading dose1 – No loading dose is required

1% severe infusion reactions reported1 – 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) – 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 – Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions

INDICATION:

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.

The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®.

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.

Important Safety Information, including Boxed WARNINGS: WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 or higher) in 12% of patients receiving Vectibix® monotherapy. [See Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. [See Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Reactions (6.1, 6.3)].

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®.

Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage were reported. Withhold or discontinue Vectibix® for severe or lifethreatening dermatologic toxicity and monitor for inflammatory or infectious sequelae.

Terminate the infusion for severe infusion reactions.

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

Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. Of the 2 cases, 1 involved a patient with underlying idiopathic pulmonary fibrosis and resulted in death. The second patient had symptoms of pulmonary fibrosis, which was confirmed by CT. Additionally, a third patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia. Permanently discontinue Vectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.

In a randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or IV 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.

Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats, and limit sun exposure while receiving Vectibix® and for 2 months after the last dose.

Adequate contraception in both males and females must be used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus and has the potential to cause fetal harm when administered to pregnant women.

Discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®.

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.

Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of a randomized clinical trial, 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. NCICTC grade 3-4 adverse reactions occurring at a higher rate in patients treated with Please see brief summary of Prescribing Information on next page.

Vectibix® included rash/dermatitis/acneiform (26% vs 1%); diarrhea (23% vs 12%); Reference: 1. Vectibix® (panitumumab) dehydration (16% vs 5%), primarily occurring in patients with diarrhea; hypokalemia prescribing information, Amgen.

(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 patients treated with Vectibix® (7% vs 4%) and included fatal events in 3 (< 1%) patients treated with Vectibix®. ©2010 Amgen Inc. All rights reserved. 07-10 48257-A