Personalized Medicine in Oncology April 2015

A Peer-Reviewed Journal

April 2015 • Volume 4 • Number 2

PM O

BIOMARKERS • TARGETED THERAPIES • DIAGNOSTICS

Personalized Medicine in Oncology TM

INTERVIEW WITH THE INNOVATORS Confirming Diagnoses and Identifying Biomarkers Linked to Targeted Treatments with the bioT3 Platform: An Interview with Ralph V. Boccia, MD, FACP, of Georgetown University.........................Page 74

HEMATOLOGIC MALIGNANCIES Two Cases of Triple-Hit Lymphoma: A Call for Imperative MYC, BCL2, and BCL6 Testing by FISH in Aggressive Lymphomas..................... Page 84

BREAST CANCER Biomarkers of the mTOR Pathway in Breast Cancer..................................................................Page 89

WORLD CUTANEOUS MALIGNANCIES CONGRESS CME A Focus on Melanoma, Basal-Cell Carcinoma, Cutaneous T-Cell Lymphoma, Merkel-Cell Carcinoma, and Rare Cutaneous Malignancies: Highlights from the Third Annual PMO Live Congress................. Page 104

THE LAST WORD President Obama’s Bet on Personalized Medicine........................................................ Page 122

GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

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GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

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LENVIMATM (lenvatinib) is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).

Visit LENVIMAinfo.com Important Safety Information Warnings and Precautions Hypertension was reported in 73% of LENVIMA-treated patients (of which 44% were ≥ Grade 3) and 16% of patients in the placebo group. Control blood pressure prior to treatment and monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly during treatment. Withhold LENVIMA for Grade 3 hypertension; resume at a reduced dose when hypertension is controlled at ≤ Grade 2.

Discontinue LENVIMA for life-threatening hypertension.

Cardiac dysfunction was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater). Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold LENVIMA for development of Grade 3 cardiac dysfunction until improved to Grade 0 or 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction. Discontinue LENVIMA for Grade 4 cardiac dysfunction.

Arterial thromboembolic events were reported in 5% of LENVIMA-treated patients; events of Grade 3 or greater were 3%. Discontinue LENVIMA following an arterial thrombotic event. LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

4% of LENVIMA-treated patients experienced an increase in ALT and 5% experienced an increase in AST that was Grade 3 or greater. Monitor liver function before initiation and during treatment with LENVIMA. Withhold LENVIMA for the development of ≥ Grade 3 liver impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure.

Proteinuria was reported in 34% of LENVIMA-treated patients (of which 11% were Grade 3). Monitor for proteinuria before initiation of, and periodically during treatment. Obtain a 24 hour urine protein if urine dipstick proteinuria ≥2+ is detected. Withhold LENVIMA for ≥ 2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue LENVIMA for nephrotic syndrome.

Events of renal impairment were reported in 14% of LENVIMAtreated patients. Renal failure or impairment ≥ Grade 3 was 3% in LENVIMA-treated patients. Withhold LENVIMA for development of Grade 3 or 4 renal failure / impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of renal impairment.

Events of gastrointestinal perforation or fistula were reported in 2% of LENVIMAtreated patients. Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula.

QT/QTc interval prolongation was reported in 9% of LENVIMA-treated patients (2% Grade 3 or greater). Monitor ECG in patients with congenital long QT syndrome, CHF, bradyarrhythmias, or patients taking drugs known to prolong the QT interval. Monitor and correct electrolyte abnormalities in all patients. Withhold LENVIMA for the development of ≥ Grade 3 QT interval prolongation. Resume LENVIMA at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline.

Hypocalcemia ≥ Grade 3 was reported in 9% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia.

Reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 3 patients across clinical studies in which 1108 patients received LENVIMA. Confirm the diagnosis of RPLS with MRI. Withhold LENVIMA for RPLS until fully resolved. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms.

Hemorrhagic events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group.

The incidence of Grade 3-5 hemorrhage was similar between arms at 2% and 3%, respectively. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of LENVIMA-treated patients. There was one case of fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage.

LENVIMA impairs exogenous thyroid suppression. Elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. Monitor TSH levels monthly and adjust thyroid replacement medication as needed.

LENVIMA can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.

Advise women not to breastfeed during treatment with LENVIMA. Adverse Reactions The most common adverse reactions observed in LENVIMA-treated patients vs. placebo treated patients respectively were hypertension (73% vs 16%), fatigue (67% vs 35%), diarrhea (67% vs 17%), arthralgia/myalgia (62% vs 28%), decreased appetite (54% vs 18%), weight decreased (51% vs 15%), nausea (47% vs 25%), stomatitis (41% vs 8%), headache (38% vs 11%), vomiting (36% vs 15%), proteinuria (34% vs 3%), palmar-plantar erythrodysesthesia syndrome (32% vs 1%), abdominal pain (31% vs 11%), and dysphonia (31% vs 5%).

Please see Brief Summary of Prescribing Information on the following pages.

LENVIMATM is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2015 Eisai Inc. All rights reserved.

Printed in USA/February 2015 LENV0014

S:14.5”

5.5 Proteinuria5.5 Proteinuria LENVIMA™ (lenvatinib) BRIEF SUMMARY – See package–insert for full prescribing information.

LENVIMA™ (lenvatinib) BRIEF SUMMARY See package insert for full prescribing information.

In Study 1, proteinuria was1,reported in 34% LENVIMA-treated patients and 3% patients of patients theofplacebo 1 INDICATIONS AND USAGE AND USAGE In Study proteinuria was of reported in 34% of LENVIMA-treated andin3% patients in the placebo 1 INDICATIONS group. The incidence of The Grade 3 proteinuria in LENVIMA-treated patients was 11% compared nonecompared in the to none in the LENVIMA is indicated for the treatmentfor of the patients with locally recurrent metastatic, progressive, radioactive group. incidence of Grade 3 proteinuria in LENVIMA-treated patients wasto11% LENVIMA is indicated treatment of patients with or locally recurrent or metastatic, progressive, radioactive placebo group. placebo group. iodine-refractory iodine-refractory differentiated thyroid cancer (DTC). differentiated thyroid cancer (DTC).

Monitor for proteinuria before initiation of, and initiation periodically throughout treatment.

If urinetreatment. dipstick proteinuria 2 DOSAGE AND ADMINISTRATION Monitor for proteinuria before of, and periodically throughout If urine dipstick proteinuria 2 DOSAGE AND ADMINISTRATION greater than or equal to 2+ is detected, a 24 hour obtain urine protein.

Withhold LENVIMA for ≥2 LENVIMA grams of for ≥2 grams of greater than or equal toobtain 2+ is detected, a 24 hour urine protein.

Withhold 2.1 Recommended Dose 2.1 Recommended Dose proteinuria/24 hours and resumehours at a reduced doseatwhen proteinuria is <2 gm/24 hours.

Discontinue LENVIMA proteinuria/24 and resume a reduced dose when proteinuria is <2 gm/24 hours.

Discontinue LENVIMA The recommended dose of LENVIMA is 24ofmg (two 10 ismg24capsules onecapsules 4 mg capsule) orally onceorally taken for nephrotic syndrome.

Thedaily recommended daily dose LENVIMA mg (twoand 10 mg and one 4 mgtaken capsule) once for nephrotic syndrome. daily with or without until disease progression or until unacceptable toxicity occurs. toxicity occurs.

5.6 Renal Failure and Impairment dailyfood. with Continue or withoutLENVIMA food. Continue LENVIMA until disease progression or until unacceptable 5.6 Renal Failure and Impairment Take LENVIMA atTake the LENVIMA same timeateach day. Iftime a dose is missed cannot be taken within 12 skip that the same each day. If aand dose is missed and cannot be hours, taken within 12 hours, skip that 1, eventsInofStudy In Study renal1,impairment wereimpairment reported in were 14% of LENVIMA-treated patients compared to 2% compared to 2% events of renal reported in 14% of LENVIMA-treated patients dose and take the nextand dose at the the next usualdose timeatofthe administration. dose take usual time of administration. of patients in theofplacebo group. incidence of The Grade 3 or greater renal3failure or impairment was 3% in patients in theThe placebo group. incidence of Grade or greater renal failure or impairment was 3% in Severe Renal or Hepatic Impairment LENVIMA-treatedLENVIMA-treated patients and 1% patients in the placebo group.

The primary risk factor for severe renal impairment in impairment in Severe Renal or Hepatic Impairment and 1% in the placebo group. The primary risk factor for severe renal The recommended of LENVIMAdose is 14ofmg taken orally daily in patients renalwith impairment LENVIMA-treatedLENVIMA-treated patients was dehydration/hypovolemia due to diarrhea and Thedose recommended LENVIMA is 14once mg taken orally once with dailysevere in patients severe renal impairment patients was dehydration/hypovolemia duevomiting. to diarrhea and vomiting. (creatinine clearance [CLcr] less than 30[CLcr] mL/min by thecalculated Cockroft-Gault or severe hepaticor severe hepatic Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment until resolved to Grade 0 to 1 orto Grade 0 to 1 or (creatinine clearance lesscalculated than 30 mL/min by theequation) Cockroft-Gault equation) Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment until resolved impairment (Child-Pugh C). (Child-Pugh C). baseline. Either resume at Either a reduced doseatora discontinue LENVIMA depending on thedepending severity and impairment baseline. resume reduced dose or discontinue LENVIMA on persistence the severity and persistence of renal impairment.

2.2 Dose Modifications of renal impairment.

2.2 Dose Modifications 5.7 Gastrointestinal Perforation andPerforation Fistula Formation Hypertension Hypertension 5.7 Gastrointestinal and Fistula Formation • Assess blood•pressure to pressure and periodically treatment.during Initiate or adjust Initiate medicalormanagement to management In Study gastrointestinal or fistula were reported in were 2% ofreported LENVIMA-treated patients and patients and Assessprior blood prior to during and periodically treatment. adjust medical to 1, eventsInofStudy 1, events ofperforation gastrointestinal perforation or fistula in 2% of LENVIMA-treated control blood pressure prior to and during treatment.

0.8% of patients in the placebo group. control blood pressure prior to and during treatment.

0.8% of patients in the placebo group.

• Withhold LENVIMA for Grade 3 hypertension persists despite therapy; resume therapy; Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula.

• Withhold LENVIMA for Gradethat 3 hypertension that optimal persistsantihypertensive despite optimal antihypertensive resume Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula. at a reduced doseat(see Table 1)dose when hypertension is controlled at less than or equal to Grade a reduced (see Table 1) when hypertension is controlled at less than or2.equal to Grade 2. 5.8 QT Interval5.8 Prolongation QT Interval Prolongation • Discontinue • LENVIMA for life-threatening Discontinue LENVIMA forhypertension. life-threatening hypertension.

In Study 1, QT/QTc wasprolongation reported in 9% LENVIMA-treated patients and 2% patients of patients Cardiac dysfunction or hemorrhage In interval Study 1,prolongation QT/QTc interval wasofreported in 9% of LENVIMA-treated andin2% of patients in Cardiac dysfunction or hemorrhage the placebo group.

The incidence of The QT interval prolongation of Grade 3 or greater was 32% LENVIMA-treated the placebo group. incidence of QT interval prolongation of Grade or in greater was 2% in LENVIMA-treated • Discontinue • for aDiscontinue Grade 4 event. for a Grade 4 event. patients compared to no reports in the placebo group.

Monitor electrocardiograms in patients with congenital long patients compared to no reports in the placebo group.

Monitor electrocardiograms in patients with congenital long • Withhold LENVIMA for development of Grade 3 event until improved to Grade 0 or 1 or baseline.

• Withhold LENVIMA for development of Grade 3 event until improved to Grade 0 or 1 or baseline. QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT • Either resume a reduced doseat(see Table 1)dose or discontinue LENVIMA depending on thedepending severity and • at Either resume a reduced (see Table 1) or discontinue LENVIMA on the severity andinterval, includingQTClass Iaincluding and III antiarrhythmics. interval, Class Ia and III antiarrhythmics. persistence of thepersistence adverse event. of the adverse event.

Monitor and correct electrolyte abnormalities all patients. Withhold LENVIMA for theLENVIMA development of development of Arterial thrombotic eventthrombotic event Monitor and correct electrolyteinabnormalities in all patients.

Withhold for the Arterial Grade 3 or greater QT interval prolongation.

Resume LENVIMA at a reduced dose QT prolongation Grade 3 or greater QT interval prolongation.

Resume LENVIMA at when a reduced dose when QT prolongation • Discontinue • LENVIMA following an arterial thrombotic event.thrombotic event.

Discontinue LENVIMA following an arterial resolves to Grade 0 or 1 ortobaseline. resolves Grade 0 or 1 or baseline.

Renal failure andRenal impairment or hepatotoxicity failure and impairment or hepatotoxicity 5.9 Hypocalcemia 5.9 Hypocalcemia • Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment or hepatotoxicityor until resolved until resolved • Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment hepatotoxicity In Study 1, 9% ofInLENVIMA-treated patients experienced Grade 3 or greater hypocalcemia compared to 2%compared in to Grade 0 to 1 ortobaseline.

Study 1, 9% of LENVIMA-treated patients experienced Grade 3 or greater hypocalcemia to 2% in Grade 0 to 1 or baseline. the placebo group. most cases responded to replacement dose interruption/dose reduction.

• Either resume at a reduced dose (see Table 1) or discontinue LENVIMA depending on the severity and theInplacebo group.hypocalcemia In most cases hypocalcemia respondedand to replacement and dose interruption/dose reduction.

• Either resume at a reduced dose (see Table 1) or discontinue LENVIMA depending on the severity and Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. persistence of renal impairment or hepatotoxicity.

Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. persistence of renal impairment or hepatotoxicity.

Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and • Discontinue • LENVIMA for hepatic failure.

Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and Discontinue LENVIMA for hepatic failure. persistence of hypocalcemia.

Proteinuria persistence of hypocalcemia.

Proteinuria 5.10 Reversible5.10 Posterior Leukoencephalopathy Syndrome • Withhold LENVIMA for ≥2 LENVIMA grams of proteinuria/24 Reversible Posterior Leukoencephalopathy Syndrome • Withhold for ≥2 grams ofhours. proteinuria/24 hours.

• Resume at a•reduced doseat(see Table 1)dose when proteinuria is <2 gm/24 hours.

Across clinical studies which studies 1108 patients received LENVIMA, there LENVIMA, were 3 reported reversible Resume a reduced (see Table 1) when proteinuria is <2 gm/24 hours.

Acrossinclinical in which 1108 patients received there events were 3of reported events of reversible • Discontinue • LENVIMA for nephrotic syndrome. posterior leukoencephalopathy syndrome (RPLS).syndrome Confirm the diagnosis of RPLS with MRI.ofWithhold RPLS until for RPLS until Discontinue LENVIMA for nephrotic syndrome. posterior leukoencephalopathy (RPLS).

Confirm the diagnosis RPLS withforMRI. Withhold Gastrointestinal perforation or fistula formation fully resolved. Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and Gastrointestinal perforation or fistula formation fully resolved. Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and • Discontinue • LENVIMA in patients who develop gastrointestinal or life-threatening symptoms.

Discontinue LENVIMA in patients who developperforation gastrointestinal perforation orfistula. life-threatening fistula.persistence of neurologic persistence of neurologic symptoms.

QT prolongation QT prolongation 5.11 Hemorrhagic 5.11 Events Hemorrhagic Events • Withhold LENVIMA for theLENVIMA development of Grade 3 or greater QT interval prolongation.

In Study 1, hemorrhagic occurred in 35% occurred of LENVIMA-treated patients and in 18% of theand placebo • Withhold for the development of Grade 3 or greater QT interval prolongation.

In Studyevents 1, hemorrhagic events in 35% of LENVIMA-treated patients in 18%group. of the placebo group.

• Resume LENVIMA at a reduced doseat(see Table 1)dose when QTTable prolongation to Graderesolves 0 or 1 ortobaseline. of Grade 3-5 hemorrhage similar between 2% and 3%, Therespectively. The • Resume LENVIMA a reduced (see 1) when resolves QT prolongation Grade 0 or 1 or However, baseline. the incidence However, the incidence of Grade was 3-5 hemorrhage was arms similaratbetween armsrespectively. at 2% and 3%, Reversible posterior leukoencephalopathy syndrome (RPLS) syndrome (RPLS) most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2).

Discontinuation due to Reversible posterior leukoencephalopathy most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2).

Discontinuation due to • Withhold for•RPLS until fully hemorrhagic events occurred in 1% ofoccurred LENVIMA-treated patients.

Withhold forresolved.

RPLS until fully resolved. hemorrhagic events in 1% of LENVIMA-treated patients.

• Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and Across clinical studies in which 1108 patients received LENVIMA, Grade 3 or greater hemorrhage was reported • Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and Across clinical studies in which 1108 patients received LENVIMA, Grade 3 or greater hemorrhage was reported persistence of neurologic symptoms. in 2% of patients.inIn2% Study 1, there In was 1 case of fatal intracranial hemorrhage among 16 patients who received persistence of neurologic symptoms. of patients.

Study 1, there was 1 case of fatal intracranial hemorrhage among 16 patients who received lenvatinib and had CNS metastases at baseline.

Manage other adverse reactions according to the instructions Table 1. BasedinonTable the absence lenvatinib and had CNS metastases at baseline.

Manage other adverse reactions according tointhe instructions 1. Basedofonclinical the absence of clinical experience, thereexperience, are no recommendations on resumption of dosing in patients with Grade 4 clinical adverse Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1.

Either resume at Either resume at there are no recommendations on resumption of dosing in patients with Grade 4 clinical adverse Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. reactions that resolve. a reduced dose ora discontinue LENVIMA depending on thedepending severity and hemorrhage. reactions that resolve. reduced dose or discontinue LENVIMA on persistence the severity of and persistenceDiscontinue of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage.

LENVIMA in patients who experience Grade 4 hemorrhage.

Table 1 Recommended Dose Modifications Persistent and Intolerableand Grade 2 or Grade 3 2 or5.12 Impairment of Thyroid Stimulating Hormone Suppression Table 1 Recommended Dose for Modifications for Persistent Intolerable Grade Grade 3 5.12 Impairment of Thyroid Stimulating Hormone Suppression a Adverse Reactions or Grade 4 Laboratory LENVIMA impairsLENVIMA exogenous thyroid suppression.

In Study 1, 88% of patients hadofaallbaseline Adverse Reactions or GradeAbnormalities 4 Laboratory Abnormalitiesa impairs exogenous thyroid suppression.

In all Study 1, 88% patientsthyroid had a baseline thyroid stimulating hormone (TSH) level less than or equal to 0.5 In those a normal TSH at baseline, b stimulating hormone (TSH) level less thanmU/L. or equal to 0.5patients mU/L. Inwith those patients with a normal TSH at baseline, Adverse Reaction Modification Adjusted Dose b Adverse Reaction Modification Adjusted Dose elevation of TSH elevation level above observed post baseline in 57% LENVIMA-treated patients as of 0.5 TSHmU/L levelwas above 0.5 mU/L was observed post of baseline in 57% of LENVIMA-treated patients as compared with 14% of patients receiving placebo.

Interrupt until resolved to 20 mg (two 10 mg capsules) orally compared with 14% of patients receiving placebo.

Interrupt until resolved to 20 mg (two 10 mg capsules) orally TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC. First occurrence First occurrence Grade 0-1 or baseline Monitor once daily Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC. Grade 0-1 or baseline once daily 5.13 Embryofetal 5.13Toxicity Embryofetal Toxicity 14 mg (one 10 mg14capsule mg (one 10 mg capsule Based on its mechanism action and dataoffrom animal reproduction studies, LENVIMA can cause fetal harm Interrupt until resolved to until resolved c Based onofits mechanism action and data from animal reproduction studies, LENVIMA can cause fetal harm Interrupt to plus one 4 mg capsule) Second occurrence plus one 4 mg capsule) Second occurrencec Grade 0-1 or baseline when administered to aadministered pregnant woman.

In animalwoman. reproduction studies, oral administration lenvatinib of lenvatinib when to a pregnant In animal reproduction studies, oralofadministration Grade 0-1 or baseline orally once daily orally once daily during organogenesis doses below the recommended dose resulted in embryotoxicity, duringatorganogenesis at doses below thehuman recommended human dose resulted infetotoxicity, embryotoxicity, fetotoxicity, and teratogenicityand in rats and rabbits. womenpregnant of the potential to apotential fetus. Advise Interrupt until resolved to until resolved 10 mgto(one 10 mg10capsule) teratogenicity in Advise rats andpregnant rabbits. Advise womenrisk of the risk tofemales a fetus.ofAdvise females of Interrupt mg (oneorally 10 mg capsule)reproductive orally Third occurrencecThird occurrencec Grade 0-1 or baseline potential to use effective during treatmentduring with LENVIMA forLENVIMA at least 2and weeks once daily reproductive potentialcontraception to use effective contraception treatmentand with for at least 2 weeks Grade 0-1 or baseline once daily following completion of therapy. following completion of therapy. a Initiate medicala Initiate management formanagement nausea, vomiting, or diarrhea priorortodiarrhea interruption reduction 6 ADVERSE REACTIONS medical for nausea, vomiting, priorortodose interruption or dose reduction 6 ADVERSE REACTIONS of LENVIMA of LENVIMA The following adverse reactionsadverse are discussed elsewhere in theelsewhere label. Please seelabel. the Warnings andthe Precautions b The following reactions are discussed in the Please see Warnings and Precautions Reduce dose inb succession based on the previous (24 mg, 20 mg, 14mg, mg 20 permg, day)or 14 mg per day) sections in the full prescribing Reduce dose in succession based dose on thelevel previous dose levelor(24 c sections in theinformation. full prescribing information.

Refers to the same or a different adverse reaction that requires dose modification c • Hypertension• Hypertension Refers to the same or a different adverse reaction that requires dose modification • Cardiac Dysfunction 4 CONTRAINDICATIONS • Cardiac Dysfunction 4 CONTRAINDICATIONS • Arterial Thromboembolic Events None.

• Arterial Thromboembolic Events None.

• Hepatotoxicity • Hepatotoxicity 5 WARNINGS AND PRECAUTIONS 5 WARNINGS AND PRECAUTIONS • Proteinuria • Proteinuria 5.1 Hypertension 5.1 Hypertension • Renal Failure•andRenal Impairment Failure and Impairment In Study 1 hypertension reported in 73% LENVIMA-treated patients and 16%patients of patients theofplacebo • Gastrointestinal and Fistula Formation In Studywas 1 hypertension was of reported in 73% of LENVIMA-treated and in 16% patients in the placebo • Perforation Gastrointestinal Perforation and Fistula Formation group. The median timeThe to onset of new hypertension washypertension 16 days for LENVIMA-treated patients.

• QT Interval Prolongation group. median timeor toworsening onset of new or worsening was 16 days for LENVIMA-treated patients.

• QT Interval Prolongation The incidence of The Grade 3 hypertension was 44% as compared to 4% for placebo, and the incidence of Grade 4 • 4Hypocalcemia incidence of Grade 3 hypertension was 44% as compared to 4% for placebo, and the incidence of Grade • Hypocalcemia hypertension washypertension less than 1%was in LENVIMA-treated patients and nonepatients in the placebo group.

• Reversible Posterior Leukoencephalopathy Syndrome less than 1% in LENVIMA-treated and none in the placebo group.

• Reversible Posterior Leukoencephalopathy Syndrome Control blood pressure to pressure treatmentprior withtoLENVIMA. blood pressure 1 week, then every 2 weeks Hemorrhagic•Events Controlprior blood treatmentMonitor with LENVIMA. Monitorafter blood pressure after 1 week, then every•2 weeks Hemorrhagic Events for the first 2 months, and then at least monthly thereafter during treatment with LENVIMA. Withhold LENVIMA • Impairment of Thyroid Stimulating Hormone Suppression for the first 2 months, and then at least monthly thereafter during treatment with LENVIMA. Withhold LENVIMA • Impairment of Thyroid Stimulating Hormone Suppression for Grade 3 hypertension optimal antihypertensive therapy; resume at a reduced doseatwhen hypertension 6.1 Clinical Trials for Gradedespite 3 hypertension despite optimal antihypertensive therapy; resume a reduced dose when hypertension 6.1 Experience Clinical Trials Experience is controlled at less than or equal to Grade Discontinue for life-threatening is controlled at less than or2.equal to GradeLENVIMA 2. Discontinue LENVIMA forhypertension. life-threatening hypertension. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 5.2 Cardiac Dysfunction clinical trials of aclinical drug cannot beadirectly compared to ratescompared in the clinical trials of another may notdrug reflect 5.2 Cardiac Dysfunction trials of drug cannot be directly to rates in the clinical drug trialsand of another and may not reflect In Study 1, cardiac defined as decreased leftasordecreased right ventricular cardiac function, failure, orcardiac pulmonary the rates observed practice.

In dysfunction, Study 1, cardiac dysfunction, defined left orfunction, right ventricular failure, or pulmonary theinrates observed in practice. edema, was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater) and 2% (no Grade 3 or greater) in data 1108obtained patients with advanced solid tumors whosolid received LENVIMA as a single agentas across edema, was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater) and 2% (no Grade 3 orSafety greater)data obtained Safety in 1108 patients with advanced tumors who received LENVIMA a single agent across of patients in theofplacebo group. majority of these cases inofLENVIMA-treated patients (14 of 17patients cases) were multiple usedstudies to further riskscharacterize of serious adverse reactions. median age The median age patients in theThe placebo group.

The majority these cases in LENVIMA-treated (14 of 17 cases) were clinical studies multiplewas clinical wascharacterize used to further risks ofdrug serious adverseThe drug reactions. based on findingsbased of decreased ejection fraction as assessed by echocardiography.

Six of 261 (2%) LENVIMAwas 60 years (range 21-89 years).

The21-89 dose years). range was 0.2 mgrange to 32was mg.0.2 Themg median duration of exposure in theof exposure in the on findings of decreased ejection fraction as assessed by echocardiography.

Six of 261 (2%) LENVIMAwas 60 years (range The dose to 32 mg.

The median duration treated patients in Studypatients 1 had greater than 20%greater reduction ejection fraction measured by echocardiography entire populationentire was 5.5 months. was 5.5 months. treated in Study 1 had thanin20% reduction in as ejection fraction as measured by echocardiography population compared to no patients who placebo. compared to received no patients who received placebo.

The safety data described are derivedbelow from are Study 1 which randomized (2:1) randomized patients with(2:1) radioactive The safetybelow data described derived from Study 1 which patients iodinewith radioactive iodineMonitor patientsMonitor for clinical symptoms or signs of cardiac decompensation.

Withhold LENVIMA for development refractory differentiated thyroid cancer (RAI-refractory to LENVIMADTC) (n=261) or placebo (n=131).

The median patients for clinical symptoms or signs of cardiac decompensation. Withhold LENVIMA for development refractory differentiated thyroid cancerDTC) (RAI-refractory to LENVIMA (n=261) or placebo (n=131). The median of Grade 3 cardiac untildysfunction improved tountil Grade 0 or 1 ortobaseline. at Either a reduced doseatora reduced dose treatment duration was 16.1 months for LENVIMA and 3.9 months for placebo. of dysfunction Grade 3 cardiac improved Grade 0 Either or 1 orresume baseline. resume or treatment duration was 16.1 months for LENVIMA and 3.9 months for placebo. discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction.

Discontinue LENVIMA for Amongfor 261 patients who261 received LENVIMA in Study 1, median age was 64 years,age 52% were women, 80% were discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction. Discontinue LENVIMA Among patients who received LENVIMA in Study 1, median was 64 years, 52% were women, 80% were Grade 4 cardiac dysfunction.

White, 18% wereWhite, Asian,18% and were 2% were Black; themselves as having Hispanic LatinoHispanic ethnicity.

Grade 4 cardiac dysfunction.

Asian, and4% 2%identified were Black; 4% identified themselves as or having or Latino ethnicity.

5.3 Arterial Thromboembolic Events In Study 1, the most common reactionsadverse observed in LENVIMA-treated patients (greaterpatients than or (greater than or 5.3 Arterial Thromboembolic Events In Study 1, theadverse most common reactions observed in LENVIMA-treated In Study 1, arterial events were reported 5% ofreported LENVIMA-treated patients and 2% patients of patients to 30%) were, decreasing frequency, hypertension, fatigue, diarrhea,fatigue, arthralgia/myalgia, In thromboembolic Study 1, arterial thromboembolic eventsinwere in 5% of LENVIMA-treated and 2% ofequal patients equalintoorder 30%)ofwere, in order of decreasing frequency, hypertension, diarrhea, arthralgia/myalgia, in the placebo group. incidence of The arterial thromboembolic events of Grade 3events or greater was 33% LENVIMAdecreased appetite, weightappetite, decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar in theThe placebo group. incidence of arterial thromboembolic of Grade or in greater was 3% in LENVIMAdecreased weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar treated patients and 1% in the placebo group. erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia.

The most common adverse serious adverse treated patients and 1% in the placebo group. erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. Theserious most common reactions (at least 2%) were pneumonia (4%),pneumonia hypertension (3%), and dehydration (3%).dehydration (3%).

Discontinue LENVIMA following an arterial thrombotic event.

The safety of resuming LENVIMA after an arterial reactions (at least 2%) were (4%), hypertension (3%), and Discontinue LENVIMA following an arterial thrombotic event. The safety of resuming LENVIMA after an arterial thromboembolic thromboembolic event has not been established and LENVIMA has notLENVIMA been studied in patients who have had anwho haveAdverse led to dose reductions 68%reductions of patients LENVIMA and 5%LENVIMA of patients event has not been established and has not been studied in patients had an reactionsAdverse reactions led to in dose in receiving 68% of patients receiving andreceiving 5% of patients receiving arterial thromboembolic event within the event previous 6 months. placebo; 18% of placebo; patients discontinued LENVIMA and 5%LENVIMA discontinued placebo for adverse reactions.

The most arterial thromboembolic within the previous 6 months.

18% of patients discontinued and 5% discontinued placebo for adverse reactions. The most common adversecommon reactionsadverse (at leastreactions 10%) resulting dose resulting reductions LENVIMA wereofhypertension (13%), 5.4 Hepatotoxicity (at leastin10%) in of dose reductions LENVIMA were hypertension (13%), 5.4 Hepatotoxicity proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least In Study 1, 4% ofInLENVIMA-treated patients experienced an increase in alanine aminotransferase (ALT) and 5% (ALT) and 5% proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least Study 1, 4% of LENVIMA-treated patients experienced an increase in alanine aminotransferase resulting in discontinuation LENVIMA wereofhypertension (1%)hypertension and asthenia(1%) (1%). experienced an increase in aspartate aminotransferase (AST) that was Grade or greater.

No patients in theNo patients in1%) 1%) resulting inofdiscontinuation LENVIMA were and asthenia (1%). experienced an increase in aspartate aminotransferase (AST)3that was Grade 3 or greater. the placebo group experienced Grade 3 or greater increases in ALT or AST. Across which studies 1108 in which 1108 Table 2 presents Table the percentage patients in Study 1 experiencing reactionsadverse at a higher rate inatLENVIMAplacebo group experienced Grade 3 or greater increases in ALTclinical or AST.studies Acrossinclinical 2 presentsofthe percentage of patients in Studyadverse 1 experiencing reactions a higher rate in LENVIMApatients receivedpatients LENVIMA, hepatic failure (including fatal events) wasfatal reported in 3was patients andinacute patients receiving placeboreceiving in the double-blind phase of the DTCphase study.of the DTC study. received LENVIMA, hepatic failure (including events) reported 3 patients and acutetreated patients than treated patients than patients placebo in the double-blind hepatitis was reported in 1was patient. hepatitis reported in 1 patient.

Monitor liver function before initiation of LENVIMA, then every 2 weeks for the first 2 months, and at least monthly Monitor liver function before initiation of LENVIMA, then every 2 weeks for the first 2 months, and at least monthly thereafter duringthereafter treatment.during Withhold LENVIMA for theLENVIMA development of Grade 3 or greater liver 3impairment until impairment until treatment.

Withhold for the development of Grade or greater liver resolved to Graderesolved 0 to 1 ortobaseline. at Either a reduced doseatora discontinue LENVIMA depending on thedepending on the Grade 0 Either to 1 orresume baseline. resume reduced dose or discontinue LENVIMA severity and persistence hepatotoxicity.

LENVIMA for hepatic failure. severity of and persistence ofDiscontinue hepatotoxicity.

Discontinue LENVIMA for hepatic failure.

S:14.5”

Table 2

Adverse Reactions Occurring in Patients with a Between-Group Difference of Greater than or Equal to 5% All Grades or Greater than or Equal to 2% Grades 3 and 4 LENVIMA 24 mg N=261 All Grades Grades 3-4 (%) (%)

Adverse Reaction Vascular Disorders 73 Hypertensiona Hypotension 9 Gastrointestinal Disorders Diarrhea 67 Nausea 47 b 41 Stomatitis Vomiting 36 Abdominal painc 31 Constipation 29 d 25 Oral pain Dry mouth 17 Dyspepsia 13 General Disorders and Administration Site Conditions e Fatigue 67 Edema peripheral 21 Musculoskeletal and Connective Tissue Disorders Arthralgia/Myalgiaf 62 Metabolism and Nutrition Disorders Weight decreased 51 Decreased appetite 54 Dehydration 9 Nervous System Disorders Headache 38 Dysgeusia 18 Dizziness 15 Renal and Urinary Disorders Proteinuria 34 Skin and Subcutaneous Tissue Disorders Palmar-plantar erythrodysesthesia 32 21 Rashg Alopecia 12 Hyperkeratosis 7 Respiratory, Thoracic and Mediastinal Disorders Dysphonia 31 Cough 24 Epistaxis 12 Psychiatric Disorders Insomnia 12 Infections and Infestations h 10 Dental and oral infections Urinary tract infection 11 Cardiac Disorders Electrocardiogram QT prolonged

9

Placebo N=131 All Grades Grades 3-4 (%) (%)

44 2

16 2

4 0

9 2 5 2 2 0.4 1 0.4 0.4

17 25 8 15 11 15 2 8 4

0 1 0 0 1 1 0 0 0

11 0.4

35 8

4 0

5

28

3

13 7 2

15 18 2

1 1 1

3 0 0.4

11 3 9

1 0 0

11

3

0

3 0.4 0 0

1 3 5 2

0 0 0 0

1 0 0

5 18 1

0 0 0

0

3

0

1 1

1 5

0 0

2

2

0

Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure b Includes aphthous stomatitis, stomatitis, glossitis, mouth ulceration, and mucosal inflammation c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, and gastrointestinal pain d Includes oral pain, glossodynia, and oropharyngeal pain e Includes asthenia, fatigue, and malaise f Includes musculoskeletal pain, back pain, pain in extremity, arthralgia, and myalgia g Includes rash macular, rash maculo-papular, rash generalized, and rash h Includes gingivitis, oral infection, parotitis, pericoronitis, periodontitis, sialoadenitis, tooth abscess, and tooth infection A clinically important adverse reaction occurring more frequently in LENVIMA-treated patients than patients receiving placebo, but with an incidence of less than 5% was pulmonary embolism (3%, including fatal reports vs 2%, respectively). a

Table 3

Laboratory Abnormalities with a Difference of at Least ≥2% in Grade 3 - 4 Events and at a Higher Incidence in LENVIMA-Treated Patientsa

Laboratory Abnormality

Chemistry Creatinine increased Alanine aminotransferase (ALT) increased Aspartate aminotransferase (AST) increased Hypocalcemia Hypokalemia Lipase increased Hematology Platelet count decreased

LENVIMA 24 mg N=258b Grades 3-4 (%)

Placebo N=131b Grades 3-4 (%)

3 4 5 9 6 4

0 0 0 2 1 1

2

0

With at least 1 grade increase from baseline Subject with at least 1 post baseline laboratory value In addition the following laboratory abnormalities (all Grades) occurred in greater than 5% of LENVIMA-treated patients and at a rate that was two-fold or higher than in patients who received placebo: hypoalbuminemia, increased alkaline phosphatase, hypomagnesemia, hypoglycemia, hyperbilirubinemia, hypercalcemia, hypercholesterolemia, increased serum amylase, and hyperkalemia.

7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on Lenvatinib No dose adjustment of LENVIMA is recommended when co-administered with CYP3A, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) inhibitors and CYP3A and P-gp inducers.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. a b

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Data Animal Data In an embryofetal development study, daily oral administration of lenvatinib mesylate at doses greater than or equal to 0.3 mg/kg [approximately 0.14 times the recommended human dose based on body surface area (BSA)] to pregnant rats during organogenesis resulted in dose-related decreases in mean fetal body weight, delayed fetal ossifications, and dose-related increases in fetal external (parietal edema and tail abnormalities), visceral, and skeletal anomalies. Greater than 80% postimplantation loss was observed at 1.0 mg/kg/day (approximately 0.5 times the recommended human dose based on BSA).

Daily oral administration of lenvatinib mesylate to pregnant rabbits during organogenesis resulted in fetal external (short tail), visceral (retroesophageal subclavian artery), and skeletal anomalies at doses greater than or equal to 0.03 mg/kg (approximately 0.03 times the human dose of 24 mg based on body surface area). At the 0.03 mg/kg dose, increased post-implantation loss, including 1 fetal death, was also observed. Lenvatinib was abortifacient in rabbits, resulting in late abortions in approximately one-third of the rabbits treated at a dose level of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA).

8.2 Lactation Risk Summary It is not known whether LENVIMA is present in human milk. However, lenvatinib and its metabolites are excreted in rat milk at concentrations higher than in maternal plasma. Because of the potential for serious adverse reactions in nursing infants from LENVIMA, advise women to discontinue breastfeeding during treatment with LENVIMA. Data Animal Data Following administration of radiolabeled lenvatinib to lactating Sprague Dawley rats, lenvatinib-related radioactivity was approximately 2 times higher (based on AUC) in milk compared to maternal plasma.

8.3 Females and Males of Reproductive Potential Contraception Based on its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman.

Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.

Infertility Females LENVIMA may result in reduced fertility in females of reproductive potential.

Males LENVIMA may result in damage to male reproductive tissues leading to reduced fertility of unknown duration.

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

Juvenile Animal Data Daily oral administration of lenvatinib mesylate to juvenile rats for 8 weeks starting on postnatal day 21 (approximately equal to a human pediatric age of 2 years) resulted in growth retardation (decreased body weight gain, decreased food consumption, and decreases in the width and/or length of the femur and tibia) and secondary delays in physical development and reproductive organ immaturity at doses greater than or equal to 2 mg/kg (approximately 1.2 to 5 times the clinical exposure by AUC at the recommended human dose). Decreased length of the femur and tibia persisted following 4 weeks of recovery. In general, the toxicologic profile of lenvatinib was similar between juvenile and adult rats, though toxicities including broken teeth at all dose levels and mortality at the 10 mg/kg/day dose level (attributed to primary duodenal lesions) occurred at earlier treatment time-points in juvenile rats.

8.5 Geriatric Use Of 261 patients who received LENVIMA in Study 1, 118 (45.2%) were greater than or equal to 65 years of age and 29 (11.1%) were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

8.6 Renal Impairment No dose adjustment is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended dose is 14 mg taken once daily. Patients with end stage renal disease were not studied.

8.7 Hepatic Impairment No dose adjustment is recommended in patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the recommended dose is 14 mg taken once daily.

10 OVERDOSAGE There is no specific antidote for overdose with LENVIMA. Due to the high plasma protein binding, lenvatinib is not expected to be dialyzable. Adverse reactions in patients receiving single doses of LENVIMA as high as 40 mg were similar to the adverse events reported in the clinical studies at the recommended dose.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).

Hypertension: Advise patients to undergo regular blood pressure monitoring and to contact their health care provider if blood pressure is elevated.

Cardiac Dysfunction: Advise patients that LENVIMA can cause cardiac dysfunction and to immediately contact their healthcare provider if they experience any clinical symptoms of cardiac dysfunction such as shortness of breath or swelling of ankles.

Arterial Thrombotic Events Advise patients to seek immediate medical attention for new onset chest pain or acute neurologic symptoms consistent with myocardial infarction or stroke.

Hepatotoxicity: Advise patients that they will need to undergo lab tests to monitor for liver function and to report any new symptoms indicating hepatic toxicity or failure.

Proteinuria and Renal Failure/Impairment: Advise patients that they will need to undergo regular lab tests to monitor for kidney function and protein in the urine.

Gastrointestinal perforation or fistula formation: Advise patients that LENVIMA can increase the risk of gastrointestinal perforation or fistula and to seek immediate medical attention for severe abdominal pain.

Hemorrhagic Events: Advise patients that LENVIMA can increase the risk for bleeding and to contact their health care provider for bleeding or symptoms of severe bleeding.

Embryofetal Toxicity: Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.

Lactation: Advise nursing women to discontinue breastfeeding during treatment with LENVIMA.

LENVIMA™ is a trademark of Eisai R&D Management Co., Ltd. and is licensed to Eisai Inc. © 2015 Eisai Inc. All rights reserved. Printed in USA/February 2015 LENV0176

APRIL 2015

VOLUME 4, NUMBER 2

TABLE OF CONTENTS INTERVIEW WITH THE INNOVATORS

74

Confirming Diagnoses and Identifying Biomarkers Linked to Targeted Treatments with the bioT3 Platform: An Interview with Ralph V. Boccia, MD, FACP, of Georgetown University

PMO speaks with Dr Boccia about the importance of accurate diagnoses and

acquiring genetic and biomarker information to assist oncologists in selecting

appropriate treatments for patients with metastatic cancer.

HEMATOLOGIC MALIGNANCIES

84

Two Cases of Triple-Hit Lymphoma: A Call for Imperative MYC, BCL2, and BCL6 Testing by FISH in Aggressive Lymphomas

Daniel C. McFarland, DO; Joshua Brody, MD; Joseph Tripodi, MS; Issa Leonard, BS;

Vesna Najfeld, PhD

The authors propose that consensus use of FISH and/or immunohistochemical

analysis to detect MYC, BCL2, and BCL6 would lead to improved categorization, better

study designs, and ultimately improved treatments for patients with aggressive lymphomas.

BREAST CANCER

89

Biomarkers of the mTOR Pathway in Breast Cancer Elisavet Paplomata, MD; Amelia Zelnak, MD; Ruth O’Regan, MD The authors discuss the role of the mTOR pathway in breast cancer and potential biomarkers that could predict response and resistance.

PROSTATE CANCER

95

Cabozantinib in Prostate Cancer Patients with Bone Metastasis Leonel F. Hernandez-Aya, MD; David C. Smith, MD

The authors provide a review focusing on the rationale for targeting the MET and VEGF signaling pathway with cabozantinib in prostate cancer patients with bone metastasis.

OUR MISSION Personalized Medicine in Oncology provides the bridge between academic research and practicing clinicians by demonstrating the immediate implications of precision medicine – including advancements in molecular sequencing, targeted therapies, and new diagnostic modalities – to the management of patients with cancer, offering oncologists, oncology nurses, payers, researchers, drug developers, policymakers, and all oncology stakeholders the relevant practical information they need to improve cancer outcomes. This journal translates the new understanding of the biology of cancer into the day-to-day management of the individual patient with cancer, using a patient’s unique genetic makeup to select the best available therapy.

OUR VISION Our vision is to transform the current medical model into a new model of personalized care, where decisions and practices are tailored for the individual – beginning with an incremental integration of personalized techniques into the conventional practice paradigm currently in place.

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PUBLISHING STAFF Vice President/Group Publisher Russell Hennessy rhennessy@the-lynx-group.com Manager, Client Services Travis Sullivan tjsullivan@the-lynx-group.com Editorial Director Kristin Siyahian ksiyahian@the-lynx-group.com Strategic Editor Robert E. Henry Senior Copyeditor BJ Hansen Copyeditor Rosemary Hansen Production Manager Marie RS Borrelli The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Director, Strategy & Program Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Wayne Williams Jr Digital Media Specialist Charles Easton IV Web Content Manager Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Mezzacappa Project Managers Deanna Martinez Jeremy Shannon Project Coordinator Rachael Baranoski IT Manager Kashif Javaid Administrative Team Leader Allison Ingram Administrative Assistant Amanda Hedman Office Coordinator Robert Sorensen Green Hill Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-656-7935 • fax: 732-656-7938

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Immunotherapy in

oncology A 6-PART SERIES

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APRIL 2015

VOLUME 4, NUMBER 2

REGISTER

TODAY

TABLE OF CONTENTS

(Continued)

cWORLD CUTANEOUS MALIGNANCIES CONGRESS CME

104

A Focus on Melanoma, Basal-Cell Carcinoma, Cutaneous T-Cell Lymphoma, Merkel-Cell Carcinoma, and Rare Cutaneous Malignancies: Highlights from the Third Annual PMO Live Congress Sanjiv S. Agarwala, MD; Axel Hauschild, MD

The faculty highlights key topics and opinions from WCMC presentations, including updates on molecular biology, emerging therapies, prevention, and early detection.

NEWS FROM GENITOURINARY CANCERS SYMPOSIUM

117 118

AR-V7 Predicts Chemotherapy Sensitivity in Metastatic Prostate Cancer No Role for Adjuvant Sorafenib or Sunitinib in Locally Advanced Kidney Cancer

PATIENT NAVIGATION

120

What Is a Navigator?

Sharon S. Gentry, RN, MSN, AOCN, CBCN Ms Gentry provides an overview specifically for patients about a critical member of the oncology care team.

THE LAST WORD

122

President Obama’s Bet on Personalized Medicine

Edward Abrahams, PhD

Dr Abrahams takes a closer look at the president’s proposed Precision Medicine Initiative.

JULY 22-25, 2015 THE WESTIN SEATTLE SEATTLE, WASHINGTON

Personalized Medicine in Oncology is included in the following indexing and database services: Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO research databases

Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN applied for (online) is published 6 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copy­right ©2015 by Green Hill Health­care Com­muni­cations, LLC. All rights reserved. Personalized Medicine in Oncology logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

EDITORIAL CORRESPONDENCE should be ad­dressed to EDITORIAL DIRECTOR, Personalized Medicine in Oncology (PMO), 1249 South River Road, Suite 202A, Cranbury, NJ 08512. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $50.00; institutions, $90.00; single issues, $5.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPART­MENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in PMO do not necessarily reflect those of the editorial board, the editorial director, or the publishers. Publication of an advertisement or other product mention in PMO should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the editorial board nor the publishers assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the editorial director.

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Vol 4, No 2

THE bioT3 METASTATIC CANCER SOLUTION ACTIONABLE GENOMIC INFORMATION TO HELP WITH ACCURATE DIAGNOSIS AND TREATMENT OF METASTATIC CANCER PATIENTS

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FOR MORE INFORMATION VISIT WWW.METASTATICCANCERSOLUTION.COM bioTheranostics, Inc. | 9640 Towne Centre Drive | Suite 200 | San Diego, CA 92121 | bioTheranostics.com Client Services: +1 (877) 886-6739 Fax: +1 (858) 587-5874 © 2014 bioTheranostics, Inc. CancerTYPE ID is a registered trademark of bioTheranostics, Inc. Indications for use and limitations available at www.biotheranostics.com

EDITORIAL BOARD

EDITORS IN CHIEF Sanjiv S. Agarwala, MD St. Luke’s Hospital Bethlehem, Pennsylvania

Prostate Cancer Oliver Sartor, MD Tulane University New Orleans, Louisiana

Al B. Benson III, MD, FACP, FASCO Northwestern University Chicago, Illinois

EDITORIAL BOARD Gregory D. Ayers, MS Vanderbilt University School of Medicine Nashville, Tennessee

SECTION EDITORS Biomarkers Pranil K. Chandra, DO PathGroup Brentwood, Tennessee

Lyudmila Bazhenova, MD University of California, San Diego San Diego, California

Darren Sigal, MD Scripps Clinic Medical Group San Diego, California Breast Cancer Edith Perez, MD Mayo Clinic Jacksonville, Florida Hematologic Malignancies Gautam Borthakur, MD The University of Texas MD Anderson Cancer Center Houston, Texas Pathology David L. Rimm, MD, PhD Yale Pathology Tissue Services Yale University School of Medicine New Haven, Connecticut Drug Development Igor Puzanov, MD Vanderbilt University Vanderbilt-Ingram Cancer Center Nashville, Tennessee Lung Cancer Vincent A. Miller, MD Foundation Medicine Cambridge, Massachusetts Predictive Modeling Michael Kattan, PhD Case Western Reserve University Cleveland, Ohio Gastrointestinal Cancer Eunice Kwak, MD Massachusetts General Hospital Cancer Center Harvard Medical School Boston, Massachusetts Melanoma Doug Schwartzentruber, MD Indiana University Simon Cancer Center Indianapolis, Indiana

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Leif Bergsagel, MD Mayo Clinic Scottsdale, Arizona Mark S. Boguski, MD, PhD Harvard Medical School Boston, Massachusetts Gilberto Castro, MD Instituto do Câncer do Estado de São Paulo São Paulo, Brazil Madeleine Duvic, MD The University of Texas MD Anderson Cancer Center Houston, Texas Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio Steven D. Gore, MD The Johns Hopkins University School of Medicine Baltimore, Maryland Gregory Kalemkerian, MD University of Michigan Ann Arbor, Michigan Howard L. Kaufman, MD Cancer Institute of New Jersey New Brunswick, New Jersey Katie Kelley, MD UCSF School of Medicine San Francisco, California Minetta Liu, MD Mayo Clinic Cancer Center Rochester, Minnesota

Nikhil C. Munshi, MD Dana-Farber Cancer Institute Boston, Massachusetts Steven O’Day, MD John Wayne Cancer Institute Santa Monica, California Rafael Rosell, MD, PhD Catalan Institute of Oncology Barcelona, Spain Steven T. Rosen, MD, FACP Northwestern University Chicago, Illinois Hope S. Rugo, MD University of California, San Francisco San Francisco, California Lee Schwartzberg, MD The West Clinic Memphis, Tennessee John Shaughnessy, PhD University of Arkansas for Medical Sciences Little Rock, Arkansas Lillie D. Shockney, RN, BS, MAS Johns Hopkins University Baltimore, Maryland Lawrence N. Shulman, MD Dana-Farber Cancer Institute Boston, Massachusetts Jamie Shutter, MD South Beach Medical Consultants, LLC Miami Beach, Florida David Spigel, MD Sarah Cannon Research Institute Nashville, Tennessee Moshe Talpaz, MD University of Michigan Medical Center Ann Arbor, Michigan Sheila D. Walcoff, JD Goldbug Strategies, LLC Rockville, Maryland Anas Younes, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Kim Margolin, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington Gene Morse, PharmD University at Buffalo Buffalo, New York

Personalized Medicine in Oncology

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PMMP O

ersonalized edicine in Oncology

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BIOMARKERS • IMMUNOTHERAPY • TARGETED THERAPIES • DIAGNOSTICS

Providing Critical Insights for Clinical Application Customized Drugs/Biologics Pharmacogenomics Diagnostics & Assays Gene Sequencing Targeted Therapies Immunotherapy Biomarkers Prevention Pathology

www.PersonalizedMedOnc.com GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

The official publication of

www.PersonalizedMedOnc.com GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

WORLD CUTANEOUS MALIGNANCIES CONGRESS

In partnership with PMOElementsAsize30714

™

PMOelementsAsize 40414

LETTER TO OUR READERS

The Ultimate Target of Personalized Oncology Treatment: Improving the Lives of Our Patients Dear Colleague,

T Al B. Benson III, MD, FACP, FASCO

he landscape of cancer care has evolved tremendously over the past decade in every aspect: research targets, available treatments, management strategies, even the makeup of the oncology multidisciplinary team. The publishers of Personalized Medicine in Oncology (PMO) recognize the importance of providing information for the entire oncology team to strengthen their ability to deliver the best care to patients. PMO offers information to physicians about the precision medicine effort whereas our sister organization, the Academy of Oncology Nurse & Patient Navigators (AONN+) provides a forum for oncology nurses. Also included under our umbrella are The Oncology Pharmacist, The Oncology Nurse-APN/PA, Value-Based Cancer Care, and the associated meetings we host, including PMO Live, the World Cutaneous Malignancies Congress, and the AONN+ Annual Meeting round out our offerings to the oncology community. Or do they?

In an effort to complete this circle, we feel compelled to include the person upon whom all our attention is directed—the patient. To that end, we are pleased to introduce a new magazine, CONQUER: the patient voice, in the hope of providing valuable information for your patients as well as their families, friends, and caregivers. This magazine addresses, in an easy-to-read format, the issues that patients, their family members, and caregivers face every day. It is our pleasure to offer an article from CONQUER in this issue of PMO on page 120.

In CONQUER, patients will discover articles written by and for patients with cancer, survivors, nurse navigators, and other oncology team members that include: • Interviews with survivors • Information about access to care • Nutrition • Stress management • Personal finance • Legal and employment issues.

We hope this new magazine proves valuable to your patients, and we encourage you to pass the word along to your patients that this resource is available to them by visiting www.conquer-magazine.com.

And, as always, thank you for your loyal readership.

Sincerely,

Al B. Benson III, MD, FACP, FASCO Coeditor in Chief Personalized Medicine in Oncology

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AONNonline.org The professional home to more than 5,000 oncology navigators nationwide

Members’ Dashboard Features For Your Patients Access patient tools and resources such as Conquer: The Patient Voice, a premier patient magazine.

Community Connect with AONN+ members and chapters, find out what’s working for others in the field, and learn about the latest best practices in navigation.

Education Earn CE credits and expand your knowledge base through expert commentary, supplements, white papers, interactive learning and AONN+’s video library.

Events Network with your peers at AONN+’s regional and national events.

Publications Gather the latest industry news through several oncologyrelated journals – free to AONN+ members.

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INTERVIEW WITH THE INNOVATORS

Confirming Diagnoses and Identifying Biomarkers Linked to Targeted Treatments with the bioT3 Approach An Interview with Ralph V. Boccia, MD, FACP, of Georgetown University

T

he current generation of oncologists has witnessed great advances in our understanding of tumor biology and biomarkers linked to treatments. Those advances started with research, but disseminating this information can be difficult given the myriad of obstacles in adoption to practice. The science behind these advances is fascinating and excites Ralph V. Boccia, those in medicine with the possibility of providMD, FACP ing meaningful, life-altering care to patients.

But still there exists the reality of the vetting of each new discovery, starting with niche use among the early users, before it gets adopted more broadly.

With the advent of molecular medicine, we have novel options to detect and identify genetic mutations and other biomarkers to assist in selecting the appropriate therapy to target cancer cells. Combining this knowledge with guidelines of how to treat based on

tumor type can only serve to improve patient outcomes.

There are many options in selecting tests to gather pertinent information related to a patientâ&#x20AC;&#x2122;s genetic profile and the biology of their tumor. In this current installment of Interview with the Innovators, and with the intent to assist in the dissemination of impactful information, we focus on the bioT3 approach, which provides a molecular diagnosis for tumors with unclear diagnosis as well as comprehensive biomarker profiling, including mutational analysis and protein expression markers to assist oncologists in selecting site-specific and targeted therapy options for patients with metastatic cancer. The publishers of PMO had the pleasure of meeting with Dr Ralph V. Boccia from the Center for Cancer and Blood Disorders and Clinical Associate Professor at Georgetown University who participated in the research for these products and has first-hand experience with them in the clinic. To view the live interview, please visit www.PersonalizedMedOnc.com/videolibrary.

PMO Genomic tools such as next-generation sequencing are not widely adopted in community practices for metastatic patients. In your experience, what are the barriers to adoption?

Dr Boccia The low uptake in the community is primarily due to the fact that the first wave of tools was developed to meet the needs of academia and donâ&#x20AC;&#x2122;t adequately address the needs of community practices. More specifically, when it comes to next-gen sequencing, research-focused oncologists are interested in understanding all mutations associated with a given tumor type, even if no agents are currently available that can target

the related pathways. Increasingly, there is interest among these academics in obtaining information across the entire genome in the hope of future actionability, and often in the context of their collaborations with research divisions of pharmaceutical companies.

In sharp contrast, treatment-focused oncologists are primarily interested in current actionability and thus interested in biomarkers linked to Food and Drug Administration (FDA)-approved drugs and late-stage clinical trial candidates. Further, they are focused on getting the information fast in a simple and easy-to-understand tumor-specific report at a reasonable cost. Therefore, the use will increase when the needs of community practices are more directly addressed.

PMO Can you discuss the strengths and weaknesses of the various next-gen sequencing tests to detect actionable biomarkers?

Dr Boccia In terms of the first wave of tools developed for academia, there are 2 main approaches: 1) se-

Dr Boccia is a founder and the Medical Director of The Center for Cancer and Blood Disorders. He is also Clinical Associate Professor of Medicine at Georgetown University, consulting Medical Director of the International Oncology Network (ION) Clinical Research Program, and Chairman of IONâ&#x20AC;&#x2122;s Medical Advisory Panel.

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Different needs related to

quencing only, and 2) testing evmetasta/c disease management Different needs related to metastatic disease management erything independent of tumor type. The strength of the “seTreatment-focused oncologists Research-focused oncologists quencing-only” approach is that it consumes very little tissue but, • Research focused, and interested • Focused on patient care unfortunately, it is not a comprein clinical trial enrollment hensive platform. For some spe­ • Often specialize in specific • More often see all cancers, with cific biomarkers, IHC [immunocancers specialization in select cases histochemistry] and FISH [fluorescence in situ hybridization] • Interested in all targets, including • Interested in targets with FDA-approved those in the discovery stage drug or late-stage clinical trials are the more appropriate platcandidates forms versus sequencing. IHC probes protein expression levels in • Actionable now or in the future • Actionable now the tumor, which cannot be per• Cost not usually a limiting factor • Cost-focused (especially patient portion) formed with sequencing. This is relevant both for traditionally important biomarkers such as HER2, ER [estrogen receptor], and PR [progesterone receptor] expression, which are recognized to be important in breast cancer, as well as relatively new biomarkers such as programmed death-ligand 1 (PD-L1), which may have a growing clinical relevance all standard-of-care options. in melanoma, lung cancer, and other solid tumors.

PMO How common is the issue of unclear diagnosis Sequencing also probes genetic rearrangements and in metastatic cancer? amplifications in a manner that is inconsistent with Dr Boccia In clinical practice, patients can present approved targeted therapy labels and inclusion criteria with carcinomas for which we cannot identify their priof many clinical trials. Recent ASCO/CAP [American mary site—otherwise called carcinomas of unknown Society of Clinical Oncology/College of American Paprimary site. In addition, there are certain ambiguous thologists] guidelines for biomarker testing in lung presentations where patients appear to have a certain cancer clearly state that ALK rearrangement testing type of tumor; however, the overlap of the clinical preshould be done by FISH, in line with the pivotal studies sentation with potentially different types of cancer for crizotinib and the corresponding package insert. makes the initial diagnosis unclear.

Rearrangements, in principle, can also be probed by sequencing, but the cutoff criteria and the test specifics When you run such a large number of are not identical. Unlike academia, where the remaining tests can be done by in-house pathology, it is not biomarkers independent of the type of pragmatic for a community oncologist to work with cancer, you end up with slower turnaround multiple testing facilities to obtain comprehensive biomarker information. times, high costs, and significant tissue The “testing everything independent of tumor type” use, in conflict with the basic needs of approach employs a very large number of biomarker tests.

The strength of this approach is that it is extremely comtreatment-focused oncologists. prehensive. However, when you run such a large number of biomarkers independent of the type of cancer, you end up with slower turnaround times, high costs, and signifiData would suggest that the combination of carcinocant tissue use, in conflict with the basic needs for a mas of unknown primary site and the ambiguous presencommunity oncology practice. In addition, many biotations probably make up for around 100,000 patients markers are only relevant within specific tumor types, so newly diagnosed each year, which is ~15% of all newly this approach is not aligned with the clinical evidence diagnosed metastatic patients. So it’s no small number. behind many biomarkers. High-cost tests like this are It is important for clinicians to identify the primary better used as a last resort when a patient has exhausted site, because the treatment that we render is dictated by

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in the context of tumor type is important.

PMO We understand that you have used bioT3 from bioTheranostics in your clinical practice. Can you share with us the type of Clear Diagnosis? patient for whom you use this approach, and Yes how it compares to other offerings that you No are familiar with?

Dx + Rx Rx alone Dr Boccia I’ve had the opportunity to work with bioTheranostics for a number of Offering years, first in the research setting and now in clinical practice. bioT3 was not commercially available when I first started doing research • Biomarkers linked to targeted • Help achieve definitive with them as part of a consortium looking at Value treatments diagnosis of tumor type & proposition carcinomas of unknown primary site. I cursubtype • Concise actionable panel rently use bioT3 in my everyday practice for • Biomarkers linked to targeted • Lower cost treatments metastatic patients with clear as well as un• Lower rejection rates (QNS) • Reimbursement ease clear diagnoses, from initial treatment through • Tumor-specific reports • Logistical ease, minimal tissue resistance and recurrence.

• Time: 5-7 days use (low QNS) 4 The bioT3 offering combines tumor type • Time: 7-10 days diagnosis and comprehensive biomarker profiling for metastatic tumors. It is made up of 2 components, the first being CancerTYPE Treatment driven by CancerTYPE resulted a 37% increase in overall TreatmentIDdriven by in CancerTYPE ID resulted in a ID, a gene expression–based molecular 37% increase in overall survival tumor classifier. CancerTYPE ID is necessurvival sary when we’re looking to identify a primaMedian Survival, months ry tumor type, specifically if we’re confront1.0 ed with a carcinoma of unknown primary Assay directed

12.5 0.9 (n = 194) site or potentially one of those ambiguous 0.8 Empiric* (n = 396) 9.1 states where there is a differential diagnosis.

0.7 An example of that might be metastatic 0.6 0.5 squamous cell carcinoma in the lung that 0.4 could be a primary bronchogenic squamous 0.3 cell carcinoma in the lung, or it could be a 0.2 primary head and neck squamous cell carci0.1 noma metastatic to the lung. If unidentified 0.0 using regular tools, CancerTYPE ID can 0 6 12 18 24 30 36 42 help distinguish between these tumor types.

Time (months) Another example might be a patient who Identified primary site of tumor in 98% of cases presents with abdominal carcinomatosis, and we don’t know if it’s a GI [gastroin­ * Based on historical control.

Hainsworth et al. J Clin Oncol. 2013;31:217-223. testinal] or a GU [genitourinary] primary.

3 CancerTYPE ID can be useful for cases in which the tumor type is unknown, and also where the tumor started, not where the tumor ends up. in cases where there is diagnostic ambiguity and several Accurate diagnosis of tumor type/subtype is necessary for tumor type possibilities exist. selecting the proper site-specific chemotherapy and molecThe second component is CancerTREATMENT ularly targeted therapies. It is important to note that moNGS+, a comprehensive platform that includes lecularly targeted therapies are indicated for specific tumor next-generation sequencing, FISH, and IHC that lends types. For example, vemurafenib is FDA approved for us the opportunity to select therapies. The biomarkers metastatic melanoma patients harboring a BRAF V600E tested by CancerTREATMENT NGS+ are based on mutation, but it is not approved in metastatic colorectal National Comprehensive Cancer Network and ASCO cancer with the same mutation and may not be effective guidelines and major phase 2 and phase 3 clinical trials, in this case. So understanding the biomarker profile resulting in more concise panels and reports. This is in

bioT3 addresses needs for a broad group of metastatic patients

Overall Survival (probability)

bioT3 addresses needs for a broad group of metastatic patients

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Tumor specific panels designed to optimize cost, turn-around time, QNS Tumor-specific panels designed to optimize cost,and turnaround time, QNS rates, and rates, actionability actionability IHC/FISH tests

Next-Generation Sequencing panel (NGS) NSCLC

CRC

Breast

Melanoma

ALK (FISH)

PTEN (FISH)

HER2 (IHC)

PD-L1 (IHC)

Comprehensive panel

ABL1

EGFR

GNAS

KRAS

PTPN11

AKT

ERBB2

GNAQ

MET

RB1

ALK

ERBB4

HNF1A

MLH1

RET

APC

EZH2

HRAS

MPL

SMAD4

RET (FISH)

PTEN FISH)

ATM

FBXW7

IDH1

NOTCH1

SMARCB1

PDL1 (IHC)

ER (IHC)

EGFR (IHC)

BRAF

FGFR1

JAK2

NPM1

SMO

PR (IHC)

FGFR1 (FISH)

CDH1

FGFR2

JAK3

NRAS

SRC

CDKN2A

FGFR3

IDH2

PDGFRA

STK11

CSF1R

FLT3

KDR

PIK3CA

TP53

CTNNB1

GNA11

KIT

PTEN

ROS1 (FISH)

HER2 (FISH)

ALK (FISH) C-MET (IHC) C-MET (FISH)

HER2 (IHC) HER2 (FISH) RET (FISH) ROS1 (FISH)

PD-L1 (IHC)

VHL

PTEN (FISH)

• Concise list of FISH and IHC biomarkers for NSCLC, CRC, Breast, and Melanoma based on NCCN® recommended biomarkers and phase 2/3 clinical trials • In contrast, the comprehensive panel is designed to maximize “shots on goal”

contrast to the complicated reports you receive when you do extensive next-generation sequencing that leave a lot of physicians in a position where they don’t understand where to go next.

PMO How do you view the strength of the clinical validation evidence for the CancerTYPE ID, and how does it compare with other gene expression tests?

Dr Boccia In comparison to other gene expression tests, CancerTYPE ID covers a significantly larger number of tumor types, 50 tumor types compared with 15 and 42. In addition, several studies have validated its accuracy and clinical utility. Specifically, the Mayo Clinic, University of California Los Angeles, and Massachusetts General Hospital have done a blinded study and documented the accuracy of CancerTYPE ID (Clin Cancer Res. 2012;18:3952-3960). A head-to-head comparison of CancerTYPE ID versus IHC demonstrated that CancerTYPE ID was significantly better (J Mol Diagn. 2013;15:263-269). A prospective study in patients with carcinomas of unknown primary site that we published in the Journal of Clinical Oncology showed a 37% improvement in overall survival in those patients profiled with this assay and then treated based on the tumor type identified compared with empiric standardof-care chemotherapy (J Clin Oncol. 2013;31:217-223).

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PMO For what types of patients do you see a role for CancerTYPE ID in clinical practice?

Dr Boccia We’ve used CancerTYPE ID in our clinical practice in a number of situations. When we get a pathology report back, the first thing we do is to look to see how they document where the tumor that they’re describing appears to have originated from. Oftentimes there is a long account of immunohistochemical stains describing what they conclude. But sometimes pathology

I currently use bioT3 in my everyday practice for metastatic patients with clear as well as unclear diagnoses, from initial treatment through resistance and recurrence. reports have an inconclusive or ambiguous diagnosis from a histologic and immunohistochemical standpoint.

An example might be a patient with a suspected diagnosis of non–small cell lung cancer [NSCLC] based on clinical correlation, but the pathology report indicates that the tumor is TTF-1 [thyroid transcription factor-1] negative, whereas most lung cancers, but not all lung

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cancers, are TTF-1 positive. If we think it is NSCLC but can’t be absolutely certain, that would be a reason to use the CancerTYPE ID. Additionally, if the clinical presentation is atypical, or if there are multiple lesions at a distant point from any organ, and standard workup does not provide a definitive diagnosis, then CancerTYPE ID can be very helpful in these situations.

CancerTYPE ID can be useful for cases in which the tumor type is unknown, and also in cases where there is diagnostic ambiguity and several tumor type possibilities exist.

PMO Considering the second component of bioT3, for which patients do you see a role for CancerTREATMENT NGS+ in your clinical practice?

Dr Boccia We find CancerTREATMENT NGS+ to be helpful in several situations. The first would be at the time of diagnosis where we’re looking to profile that patient’s tumor and make sure that we have in fact identified actionable targets.

An example of that might be NSCLC, the nonsquamous variety, where we want to be sure that we have given the patient the best treatment options since there are several targeted therapies available based on the biomarker profile of the tumor. If, for instance, the tumor is EGFR, ALK-1, or ROS1 positive, that’s not a patient we want to be giving chemotherapy to at the outset, because

As a treatment-focused community physician, it is very important for me to obtain actionable information in a costeffective manner, and I think the bioT3 approach takes this into account. randomized trials have clearly shown that the tyrosine kinase inhibitors offer the patient better response rates, better progression-free survival, and better overall survival. On the other hand, if these biomarkers are negative, then this patient is best suited for chemotherapy. So patients with a known diagnosis of metastatic NSCLC are candidates for CancerTREATMENT NGS+ in the up-front setting. CancerTREATMENT NGS+ is a great platform because it combines next-gen sequencing with FISH and IHC testing, which is important for NSCLC if

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you are looking for ALK rearrangements because ASCO/ CAP guidelines recommend that ALK testing be performed by FISH. If you’re looking for PD-L1 expression, the best way to assess this is through IHC. CancerTREATMENT NGS+ is also very useful for those metastatic cases in which several lines of therapy have been implemented and the disease progresses. A good example of that would be a breast cancer patient with ER+/PR+ tumor type; we would offer several lines of endocrine therapy before moving on to chemotherapy. Once we’ve gotten beyond those first several lines of therapy and looking for additional actionable targets or clinical trial options, that would be a good time to use CancerTREATMENT NGS+ secondarily.

There are times when we would use the 2 components of bioT3 together. An example would be an unknown primary site, let’s say an ambiguous primary site or one that we thought might be lung. CancerTYPE ID would help us confirm this is an NSCLC, and that it is nonsquamous, to allow us to better understand whether there is an actionable target, specifically ALK, ROS1, RET, and EGFR. So combining them in this instance would be a perfect tool for us to set up a treatment program that we could carry through for many lines of therapy.

PMO An important theme at ASCO 2014 is the importance of managing costs of cancer care, particularly for metastatic patients. How important is it to lower cost from the perspective of community practices, and how does bioT3 address this critical need?

Dr Boccia We’re at a point in this society where healthcare costs are clearly out of control. The budget is unsustainable, and it’s important that all of us contribute to controlling costs the best we can. There is ongoing payment reform, and so the whole system is changing in the next several years. What this means is that we’re going to be sharing risks with the carriers, as well as showing value and quality with our treatment selection. Accountable care organizations are forming and will recruit members, and all will share risk. The upside potential here is enormous to begin to control the cost of some of these more expensive tests and provide actionable answers for more effective therapy. In looking at Explanation of Benefits coming in from my patients for the testing we have ordered, I’m sometimes appalled. I’ve seen bills for profiling as high as $30,000, certainly $5000, $6000, $7000, and $8000. As a treatment-focused community physician, it is very important for me to obtain actionable information in a cost-effective manner, and I think the bioT3 approach takes this into account.

PMO Thank you very much for your time today, and our best wishes to you for continued success.

Dr Boccia Thank you, it was my pleasure. u

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SAVE THE DATE JULY 22-25, 2015 THE WESTIN SEATTLE • SEATTLE, WASHINGTON

The Global Biomarkers Consortium (GBC) and World Cutaneous Malignancies Congress (WCMC) will be holding their fourth annual joint meeting focused on personalized and precision medicine in oncology (PMO) on July 22-25, 2015, in Seattle, Washington.

July 22-24 A Focus on the Application of Molecular Biomarkers in Clinical Practice Across Multiple Tumor Types

SCHEDULE OF EVENTS (subject to change)

July 24-25 Spotlight on Cutaneous Malignancies, Including Melanoma, Cutaneous T-Cell Lymphoma, and Basal Cell Carcinoma

CONFERENCE CO-CHAIRS

Sanjiv S. Agarwala, MD

Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke’s Cancer Center Bethlehem, PA

Jorge E. Cortes, MD

Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

Hope S. Rugo, MD

Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller Family Hope Comprehensive S. Rugo, M.D. Cancer Center San of Francisco, Professor MedicineCA Director, Breast Oncology and Clinical Trials Education University of California San Francisco Helen Diller Fami Cancer Center San Francisco, CA

www.pmo-live.com

PMOLive2015_112114

ISTODAX® (romidepsin) for injection is indicated for treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

ISTODAX FOR THE 2ND-LINE TREATMENT OF PTCL

Important Safety Information WARNINGS AND PRECAUTIONS • Myelosuppression: ISTODAX® (romidepsin) can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; monitor blood counts regularly during treatment with ISTODAX; interrupt and/or modify the dose as necessary • Infections: Fatal and serious infections, including pneumonia, sepsis, and viral reactivation, including Epstein Barr and hepatitis B viruses, have been reported during and within 30 days after treatment with ISTODAX in clinical trials. The risk of life threatening infections may be greater in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow. Reactivation of Epstein Barr viral infection led to liver failure.

Consider monitoring for reactivation and antiviral prophylaxis in patients with evidence of prior hepatitis B infection. Ganciclovir prophylaxis failed to prevent Epstein Barr viral reactivation in one case • Electrocardiographic (ECG) changes: ECG changes have been observed with ISTODAX. In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment. Confirm that potassium and magnesium levels are within the normal range before administration of ISTODAX • Tumor lysis syndrome: TLS (Tumor lysis syndrome) has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden are at greater risk and should be closely monitored and managed as appropriate • Embryo-fetal toxicity: ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women of potential hazard to the fetus and to avoid pregnancy while receiving ISTODAX

ADVERSE REACTIONS Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (N=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (N=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/ fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%).

ISTODAX® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation 10/14 US-IST140021

www.istodax.com

ISTODAX demonstrated efficacy in PTCL after at least one prior therapy1 Efficacy and safety evaluated in the largest prospective single-arm PTCL study (Study 3, N=131) in a pretreated, histologically diverse PTCL population. All patients received prior systemic therapy for PTCL. Patients could be treated until disease progression at their discretion and that of the investigator.

60% (12/20) of complete responses were known to exceed

26% ORR

11.6 Months

(34/130)

(CR + CRu + PR) [95% CI: 18.8, 34.6a]

15% CR/CRu

(20/130)

Primary End Point

(CR + CRu) [95% CI: 9.7, 22.8a] 0

2

4

6

8

10

12

14

16

Months

• Follow-up on the remaining 8 patients was

56 days

(1.8 months, n=34)

median time to objective disease response2

discontinued prior to 8.5 months

a95% confidence interval. Response rates above are rounded to the nearest whole number.

CR=complete response; CRu=complete response unconfirmed; ORR=overall disease response rate.

Infections were the most common type of serious adverse event reported in Study 3 (N=131) and Study 4 (N=47).

In Study 3, 26 patients (20%) experienced a serious infection, including 6 patients (5%) with serious treatmentrelated infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections.

The most common adverse reactions regardless of causality in Study 3 (N=131) were nausea (59%), asthenia/ fatigue (55%), thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (N=47) were asthenia/fatigue (77%), nausea (75%), thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).

DRUG INTERACTIONS • Monitor more frequently prothrombin time and International Normalized Ratio in patients concurrently administered ISTODAX and warfarin or coumarin derivatives • Romidepsin is metabolized by CYP3A4 —Monitor patients for toxicity related to increased romidepsin exposure and follow dose modifications for toxicity when ISTODAX is initially co-administered with strong CYP3A4 inhibitors —Avoid co-administration of ISTODAX (romidepsin) with rifampin and other potent inducers of CYP3A4 • Exercise caution with concomitant use of ISTODAX and P-glycoprotein (P-gp, ABCB1) inhibitors

USE IN SPECIFIC POPULATIONS • Pregnancy Category D: If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution Please see Brief Summary of Full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS, on the following pages.

References: 1. ISTODAX [package insert]. Summit, NJ: Celgene Corp; 2014.

2. Data on file, Celgene Corporation, Summit, NJ.

10-MG SINGLE-USE VIAL

T:7”

NK/T-cell lymphoma. In one case, ganciclovir prophylaxis failed to prevent Epstein Barr viral reactivation.

5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies.

The clinical significance of these changes is unknown [see Adverse Reactions (6)].

In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment.

Confirm that potassium and magnesium levels are within normal range before administration of ISTODAX [see Adverse Reactions (6)].

5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients with advanced stage disease and/or high tumor burden may be at greater risk, should be closely monitored, and managed as appropriate.

5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose of 14 mg/m2/week. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS The following adverse reactions are described in more detail in other sections of the prescribing information.

• Myelosuppression [see Warnings and Precautions (5.1)] • Infection [see Warnings and Precautions (5.2)] • Electrocardiographic Changes [see Warnings and Precautions (5.3)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2.

The mean duration of treatment and number of cycles were 5.6 months and 6 cycles in Study 3 and 9.6 months and 8 cycles in Study 4.

Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2.

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Adverse Reactions n (%) All grades Grade 3 or 4 All grades Grade 3 or 4 Any adverse reactions 128 (97) 88 (67) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 14 (11) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 8 (6) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 33 (25) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) (continued)

Cosmos Communications

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ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a Brief Summary only; see full Prescribing Information for complete product information.

1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle.

Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the drug.

2.2 Dose Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2.

• Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2.

• Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction.

Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2.

• Grade 4 febrile (≥38.5°C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤ Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2.

2.3 Instructions for Preparation and Intravenous Administration ISTODAX is a cytotoxic drug. Use appropriate handling procedures.

ISTODAX must be reconstituted with the supplied diluent and further diluted with 0.9% Sodium Chloride Injection, USP before intravenous infusion.

• Each 10 mg single-use vial of ISTODAX (romidepsin) must be reconstituted with 2 mL of the supplied diluent. With a suitable syringe, aseptically withdraw 2 mL from the supplied diluent vial, and slowly inject it into the ISTODAX (romidepsin) for injection vial. Swirl the contents of the vial until there are no visible particles in the resulting solution. The reconstituted solution will contain ISTODAX 5 mg/mL. The reconstituted ISTODAX solution is chemically stable for up to 8 hours at room temperature.

• Extract the appropriate amount of ISTODAX from the vials to deliver the desired dose, using proper aseptic technique. Before intravenous infusion, further dilute ISTODAX in 500 mL 0.9% Sodium Chloride Injection, USP. • Infuse over 4 hours.

The diluted solution is compatible with polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), polyethylene (PE) infusion bags as well as glass bottles, and is chemically stable for up to 24 hours when stored at room temperature.

However, it should be administered as soon after dilution as possible.

Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia. Monitor blood counts regularly during treatment with ISTODAX, and modify the dose as necessary [see Dosage and Administration (2.2) and Adverse Reactions (6)].

5.2 Infections Fatal and serious infections, including pneumonia, sepsis, and viral reactivation, including Epstein Barr and hepatitis B viruses have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment. The risk of life threatening infections may be greater in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow [see Adverse Reactions (6)].

Reactivation of hepatitis B virus infection has occurred in 1% of PTCL patients in clinical trials in Western populations [see Adverse Reactions (6)]. In patients with evidence of prior hepatitis B infection, consider monitoring for reactivation, and consider antiviral prophylaxis.

Reactivation of Epstein Barr viral infection leading to liver failure has occurred in a trial of patients with relapsed or refractory extranodal

T:7”

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Adverse Reactions n (%) All grades Grade 3 or 4 All grades Grade 3 or 4 Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 14 (11) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 or Baxter Oncology GmbH Halle/Westfalen, Germany ISTODAX® is a registered trademark of Celgene Corporation © 2010-2014 Celgene Corporation. All Rights Reserved.

Pat.www.celgene.com/therapies IST_PTCL_BSv006 10/2014

Cosmos Communications

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Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 26 patients (20%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia (8%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%).

Reactivation of hepatitis B virus infection has occurred in 1% of patients with PTCL patients in clinical trials in Western population enrolled in Study 3 and Study 4 [see Warnings and Precautions (5.2)].

Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause.

Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%).

6.2 Postmarketing Experience No additional safety signals have been observed from postmarketing experience.

7 DRUG INTERACTIONS 7.1 Warfarin or Coumarin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and warfarin has not been formally studied, monitor PT and INR more frequently in patients concurrently receiving ISTODAX and warfarin.

7.2 Drugs That Inhibit Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Strong CYP3A4 inhibitors increase concentrations of romidepsin. In a pharmacokinetic drug interaction trial the strong CYP3A4 inhibitor ketoconazole increased romidepsin (AUC0-∞) by approximately 25%.

Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity [see Dosage and Administration (2.2)] when romidepsin is initially co-administered with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole).

7.3 Drugs That Induce Cytochrome P450 3A4 Enzymes Avoid co-administration of ISTODAX with rifampin.

In a pharmacokinetic drug interaction trial with co-administered rifampin (a strong CYP3A4 inducer), romidepsin exposure was increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively. Typically, co-administration of CYP3A4 inducers decrease concentrations of

drugs metabolized by CYP3A4. The increase in exposure seen after co-administration with rifampin is likely due to rifampin’s inhibition of an undetermined hepatic uptake process that is predominantly responsible for the disposition of ISTODAX. It is unknown if other potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) would alter the exposure of ISTODAX. Therefore, the use of other potent CYP3A4 inducers should be avoided when possible.

7.4 Drugs That Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.5)].

There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus.

Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures (AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week.

Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification.

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

8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established.

8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were >65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted.

Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution.

8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted.

Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution.

10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heartbeat, staggering gait, tremor, and tonic convulsions.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required.

There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable.

HEMATOLOGIC MALIGNANCIES

Two Cases of Triple-Hit Lymphoma: A Call for Imperative MYC, BCL2, and BCL6 Testing by FISH in Aggressive Lymphomas Daniel C. McFarland, DO

Daniel C. McFarland, DO; Joshua Brody, MD Division of Hematology/Oncology, Tisch Cancer Institute Icahn School of Medicine at Mount Sinai Joseph Tripodi, MsS; Issa Leonard, BS; Vesna Najfeld, PhD Department of Pathology, Icahn School of Medicine at Mount Sinai

R

emission in aggressive B-cell lymphomas is increasingly linked to complex karyotypes and gene rearrangements that often portend aggressive behavior and resistance to standard therapy. An understandJoshua Brody, MD ing of lymphoma cytogenetics has lagged behind that of leukemia, in which pretreatment karyotype constitutes an independent prognostic determinant for attainment of complete remission. In 2008, the World Health Organization added the category B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (BCLu-DLBCL/BL), which incorporates aggressive lymphomas with variable morpholVesna Najfeld, ogy. However, this category is nonspecific and PhD does not elevate cytogenetic criteria to a diagnostic status based on chromosomal abnormalities as seen in acute leukemia. In part, this could be because cytogenetic analyses or fluorescence in situ hybridization (FISH) studies are not routinely performed in diagnosing lymphomas. Double-hit lymphoma (DHL) is Dr McFarland is a Clinical Fellow in the Division of Hematology/ Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York, NY. Dr Brody is an Assistant Professor of Medicine in hematology and medical oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York, NY. Joseph Tripodi is an NYSDOE- and ASCP-certified research staff member at the Tumor CytoGenomics Laboratory at the Icahn School of Medicine at Mount Sinai in New York, NY. Issa Leonard is an NYSDOE- and ASCP-certified Lab Coordinator at the Tumor CytoGenomics Laboratory at the Icahn School of Medicine at Mount Sinai in New York, NY. Dr Najfeld has been Director of the Tumor CytoGenomics Laboratory since 1980 and is internationally known in the field of cancer cytogenetics, specifically for chronic myeloproliferative disorders.

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traditionally defined as a dual gene rearrangement containing MYC and another gene, usually BCL2. Triplehit lymphoma (THL) involves an additional rearrangement, which is usually BCL6. DHL and THL always contain complex karyotypes and can be seen in diffuse large B-cell lymphoma (DLBCL) or the newly created BCLu-DLBCL/BL. They are not seen in Burkitt lymphomas, which, by definition, always have simple karyotypes.1 DHL and THL typically present at a median age of 69 years and have a higher prevalence of extranodal and bone marrow involvement as well as central nervous system involvement.2 These characteristic features are responsible for their significantly shortened disease-free survival and overall survival (OS) when compared with other lymphomas in the same category, and thus their detection may have significant therapeutic implication. We propose that consensus use of FISH and/or immunohistochemical (IHC) analysis to detect MYC, BCL2, and BCL6 would lead to improved categorization, better study designs, and, ultimately, improved treatments for patients with aggressive lymphomas.

Case 1: Transformed A 42-year-old female presented with inguinal adenopathy in October 2010. Excisional biopsy and staging demonstrated grade 2 follicular lymphoma, stage 3A. She received 6 cycles of rituximab, cyclophosphamide, vincristine, and prednisone from November 2010 through March 2011 and achieved a partial remission. Surveillance imaging in September 2011 demonstrated progression of axillary, periportal, retroperitoneal, and inguinal lymphadenopathy. Excisional biopsies in both January 2012 and November 2012 reconfirmed follicular lymphoma grade 2. In December 2012, she began treatment with the PI3 kinase δ inhibitor, idelalisib. Over the following 2 months she noted a slight reduction of supraclavicular and axillary lymphadenopathy. In early January 2013, she developed profound fatigue and petechiae. An initial evaluation was most significant for anemia and thrombocytopenia, with a hemoglobin reduction from 14 g/dL to

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Table Characteristics and Comparison of Case 1 and 2 Pathology, Proliferation Indices, Flow Cytometric Analyses, Karyotype, and Present and Retrospective FISH Analyses Case 1

Case 2

Pathology

BCLu-DLBCL/BL

BCLu-DLBCL/BL

Proliferation index

Ki67 70%-80%

Ki67 85%-90%

Flow cytometry (BM)

Positive CD19 (dim), CD10, and kappa light chain restriction

Positive CD19 (dim), CD20, CD22, CD10 (dim), CD38, and lambda light chain restriction

Karyotype (BM)

52, XX, +X, del(2)(q35q37), +4, t(3;16)(q27;p13.2), +4, del(6) (q22.2q25.3), dup(12)(q13q15)x2, der(8)t(14;18;8)(q32;q21;24), der(14)t(14;18;8)(q32;q21;q24), der(18)t(14;18)(q32;q21),+20,+21,+21, +21[12]/53,XX,idem,+21[3]/46,XX[6]

47,XX,t(3;22)(q27;q11.2), +der(7;8) (18qter→18q21.33::14q32.33→14q32.33 ::8q24.21→8p12::7p22→7qter), der(8) t(8;14)(q24.q21;qq32.33) t(14;18)(q32.33;q21.33), der(14)t(14;18)(q32.33;q24.1), der(18) t(18;14)(q21.33;q32.33[13]/47-50, XX, idem,+7,+10,+12[5]/46,XX[4]

FISH* (% cells) (BM)

MYC-IGH (83%), IGH-BCL2 (91%), BCL6 (94%), D12Z3x2 (100%), MDM2(12q15)x4 (91%)

MYC-IGH (96%), IGH-BCL2 (94%), BCL6 (97%)

Prior FISH* (% cells) (paraffinembedded lymph node biopsy)

Oct 2010: MYC-, BCL2+ (88%), BCL6+ (90%), +DDIT3(12q13) (88%), +MDM2(12q15) (89%), D12Z3x2 (100%) Nov 2012: MYC-, BCL2+ (85%), BCL6+ (80%), +DDIT3 (12q13) (90%), +MDM2(12q15) (92%) D12Z3x2 (100%)

N/A

BM indicates bone marrow; FISH, fluorescence in situ hybridization; N/A, not available. *All probes were from Abbott Molecular, Pleasantville, IL, 200-300 nuclei scored for each probe. Multicolor probe kit, 24XCyte was obtained from MetaSystems, Altlussheim, Germany.

7.5 g/dL and a platelet reduction from 140K to 9K. A bone marrow biopsy performed at that time is shown in the Table along with the laboratory results.

The cytogenetic analysis of Giemsa-banded bone marrow aspirate cells described in the Table is also illustrated in panel A of the Figure. Interphase FISH analysis revealed MYC, BCL2, and BCL6 rearrangements (Table; Figure, panel B). Metaphase FISH analysis confirmed MYC-IGH fusion with colocalization of MYC and IGH on derivative chromosomes 8 and 14, as well as 1 IGH signal on 18q21 (Figure, panel B). Moreover, FISH results also revealed IGH-BCL2 fusion on 2 copies of derivative chromosome 18 and an unexpected colocalization of IGH and BCL2 on the derivative chromosome 8.

As shown in panel D in the Figure, there was a remaining IGH signal on the derivative chromosome 14, indicating that IGH locus must have been broken at 2 lo­ cations. Additionally, metaphase FISH with BCL6

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confirmed that 3′ BCL6 remained on 3q27 whereas the 5′ BCL6 moved to the 16p31 region as a result of translocation between the long arm of chromosome 3 and the short arm of chromosome 16 (Figure, panel C).

DHL and THL typically present at a median age of 69 years and have a higher prevalence of extranodal and bone marrow involvement as well as CNS involvement.

Paraffin-embedded lymph node tissue was obtained from the patient’s prior lymph node biopsies from October 2010 and November 2012 to retroactively evaluate the order of gene rearrangement occurrences. MYC-IGH fusion was not detected in either pretransformation biop-

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Figure

A

B

C t(3;16)(q27;p13.2)/3’BCL6-5’BCL6

D

Panel A: A karyotype of patient 1 with arrows pointing to abnormal chromosomes. Note that both chromosome 12q are abnormal in cells showing pentasomy 21 and 2 copies of der(18)t(8;14;18).

Panel B: Bone marrow interphase nuclei after triple-color FISH study showing MYC-IGH-BCL2 colocalization (on derivative chromosome 8; see below), MYC-IGH colocalization, and 2 copies of IGH-BCL2 as well as MYC, IGH, and BCL2 present in 1 copy on the normal chromosome 8, 14, and 18, respectively.

Panel C: Chromosomes 3 and 16 after FISH study using 2-color, break-apart probe for BCL6 showing 3′ BCL6 (green) remaining at 3q27 and the 5′ BCL6 (red) that moved to 16p13.2 as a result of t(3;16).

Panel D: Partial karyotype of chromosomes 8, der(8), 14, der(14), 18, and 2 copies of der(18). G-banded chromosomes are shown on the left, and DAPI-stained chromosomes, after metaphase FISH studies, are shown on the right. Note a normal MYC (aqua) localization on 8q24 region and its colocalization with IGH (green) on der(8) together with BCL2 (red). In IGH-BCL2–positive patients, BCL2 is colocalized on der(14), whereas in this THL, BCL2 is colocalized on der(8). Note 2 copies of IGH-BCL2 fusion on 2 der(18) chromosomes as a result of t(14;18). The second copy of der(18) is the result of replication of the first copy without the translocation.

sy, but BCL2 and BCL6 rearrangements were detected in both pretransformation samples. Moreover, interphase FISH with 2 probes covering loci on the long arm of chromosome 12 demonstrated 3 copies of DDIT3 (12q15) and MDM2 (12q13), consistent with formation of 12q duplication already present in 2010. However, FISH studies of the bone marrow with these 2 probes confirmed 4 copies of MDM2 and DDIT3 and 2 copies of centromere 12, confirming that the 12q13-q15 chro-

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mosomal region was present in 4 copies in the bone marrow cells.

The patient received 1 cycle of rituximab plus cyclophosphamide, doxorubicin, vincristine, methotrexate, leucovorin, filgrastim, intrathecal cytarabine, intrathecal methotrexate, ifosfamide, etoposide, and cytarabine yielding a complete remission, and then successfully underwent allogeneic stem cell transplantation from a matched related donor. She is alive and without evi-

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E

F

G

H

Panel E: A karyotype of patient 2 with arrows pointing to abnormal chromosomes. Note a gain of der(7;8) resulting in 3 copies of 7q and 3 copies of rearranged 8q, the 3-way translocation between chromosomes 8, 14, and 18, as well as a translocation (3;22).

Panel F: A bone marrow nucleus showing normal MYC (aqua), IGH (green), and BCL2 (red), as well as 2 copies of MYC-IGHBCL2 fusion, MYC-IGH, and IGH-BCL2 fusion.

Panel G: A partial karyotype after multicolor metaphase FISH study, using chromosome painting probes, showing a t(3;22) resulting in BCL6 rearrangement.

Panel H: A partial karyotype of chromosomes 7, 8, 14, and 18. G-banded chromosomes are on the left; DAPI-stained chromosomes with MYC (aqua), IGH (green), and BCL2 are in the middle; and multicolor-stained chromosomes are on the right. Note der(7) is composed of 7q (brown), gain of 8q (dark green), and the third copy of MYC-IGH-BCL2 fusion is on the tip of the 8q. Both patients had 3 copies of IGH2-BCL2, although cytogenetically this was manifested either in duplication of der(18) (patient 1) or in a gain of 8q (patient 2).

FISH indicates fluorescence in situ hybridization; THL, triple-hit lymphoma.

dence of disease 3 months posttransplant and 7 months after diagnosis of THL.

Case 2: De Novo A 58-year-old Trinidadian female developed fatigue, malaise, and abdominal symptoms in April 2013 prior to seeking care in the United States. In June 2013, laboratory testing revealed pancytopenia and renal failure with elevated markers of tumor lysis syndrome.

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Whole-body CT imaging revealed conglomerate mesenteric lymph nodes, splenomegaly, and encasement of both renal hila, but without hydronephrosis. As shown in panel E of the Figure and in the Table, the karyotype was complex and involved a gain of 8q translocated to the deleted chromosome 7 resulting in trisomy 7q and trisomy 8q, including a third copy of BCL2-IGH fusion.

Interphase FISH results were consistent with an atypical MYC-IGH fusion as the result of a third fusion with

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an additional IGH signal as well as IGH-BCL2 and BCL6 rearrangements. She received rituximab plus cyclophosphamide, doxorubicin, vincristine, dexamethasone, and filgrastim after emergent intubation for altered mental status and respiratory failure but quickly succumbed to multiorgan failure.

Discussion These 2 cases of rapidly evolving THL were identified at our institution within 6 months of each other. The transformation event for case 1 was caught relatively early and had a favorable outcome. FISH analysis confirmed a suspicion that IGH-MYC was the ultimate rearrangement and was concomitant with histologic transformation suggesting its causality. MYC-IGH translocation is known to be more aggressive than MYC non-IGH translocations.3 Two breakpoints within the IGH gene indicate that this was a complex rearrangement enhanced by duplication of derivative chromosome 18 and of 12q. Duplication of derivative chromosome 18 as well as of IGH-BCL2 is similar to those seen in duplications of the Philadelphia chromosome in the blast crisis of chronic myelogenous leukemia (CML), which is known to confer a more aggressive phenotype.

The mechanism is through the replication of the derivative chromosome 18 and IGH-BCL2, without another translocation. BCL6 rearrangements have not been described in healthy individuals; therefore, BCL2 was presumably the first event. BCL6 has 28 known translocation partners, and t(3;16)(q27;p13) has been described previously.4 Therefore, in this patient, the initial events most likely involved rearrangements of BCL2 and BCL6 as well as duplication of 12q, all detected in the lymph node biopsy in 2010, whereas later events involved MYC and other abnormalities, particularly pentasomy 21 and tetrasomy of the 12q13-q15 region.

Case 2 was not diagnosed early enough to benefit from treatment intervention. The complex karyotype in this patient involved a gain of 8q translocated to chromosome 7 resulting also in 3 copies of IGHBCL2, reminiscent of duplicated BCR-ABL1 in the blast crisis of CML associated with a more aggressive phenotype. Previous reports illustrate dismal outcomes. Tomita et al published a case series of aggressive lymphomas that included 7 patients with THL whose median OS was 4 months.5 The National Comprehensive Cancer Network 2013 guideline recommends using FISH to identify DHL/THL for specific diagnostic scenarios, although this has not become standard practice.6 Recent publications regarding DHL have examined the methods of detection (FISH vs IHC). Two indepen-

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dent groups have validated the use of IHC to define DHLs (or THLs), and others have validated its use in prognostication.7-9 Whereas IHC identifies 21% of DLBCL as DHL with a 1-year mortality of 25% to 35%, FISH identifies 5% of DLBCL as DHL with a 1-year mortality of 55%.9 Horn et al found that a combined IHC/FISH score was predictive of outcome independent of the International Prognostic Index.10 Their analysis of 442 de novo DLBCL tumor samples for MYC, BCL2, and BCL6 protein expression (IHC) and gene rearrangements (FISH) found that inferior survival was associated with low BCL6 expression, elevated MYC and BCL2 expression, and MYC gene rearrangements. The authors suggested MYC staining as a screening tool followed by FISH testing for all cases with MYC protein IHC expression >20%. This is a reasonable and cost-effective approach to diagnosing multiple-hit lymphomas, although interinstitutional variability in MYC expression positivity is unclear.

Conclusion Our brief review highlights the crucial role FISH and IHC should play in the evaluation of aggressive lymphomas in both the transformed and de novo setting. Improved outcomes with aggressive lymphomas may be possible with early diagnosis by FISH screening.

A role for IHC in identification of aggressive lymphoma phenotypes has also emerged and should be used concomitantly with FISH. Lymphoma pathophysiology has evolved. As such, we know many of the molecular mechanisms that determine our patients’ chance for survival and now have an opportunity to exploit that knowledge for our patients’ benefit. u References

1. Hummel M, Bentink S, Berger H, et al. A biologic definition of Burkitt’s lymphoma from transcriptional and genomic profiling. N Engl J Med. 2006;354:2419-2430.

2. Friedberg JW. Double-hit diffuse large B-cell lymphoma. J Clin Oncol.

2012;30:3439-3443.

3. Lin P, Dickason T, Fayad LE, et al. Prognostic value of MYC rearrangement in cases of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. Cancer. 2012;118:1566-1573.

4. Huret JL. BCL6 (B-Cell Lymphoma 6). Atlas Genet Cytogenet Oncol Haematol.

2013;17(6)371-379.

5. Tomita N, Tokunaka M, Nakamura N, et al. Clinicopathological features of lymphoma/leukemia patients carrying both BCL2 and MYC translocations. Haematologica. 2009;94:935-943.

6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Non-Hodgkin’s Lymphoma. Version 1.2013. www. nccn.org/professionals/physician_gls/pdf/nhl.pdf. Accessed July 7, 2013.

7. Green TM, Young KH, Visco C, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

J Clin Oncol. 2012;30:3460-3467.

8. Johnson NA, Savage KJ, Ludkovski O, et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood.

2009;114:2273-2279.

9. Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30:3452-3459.

10. Horn H, Ziepert M, Becher C, et al. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood.

2013;121:2253-2263.

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BREAST CANCER

Biomarkers of the mTOR Pathway in Breast Cancer Elisavet Paplomata, MD; Amelia Zelnak, MD; Ruth O’Regan, MD Department of Hematology and Medical Oncology Emory University School of Medicine Atlanta, GA

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t is estimated that 232,670 women will have been diagnosed with breast cancer in 2014 and 40,000 women will have died of the disease. Approximately 89% of women with breast cancer of any stage will survive 5 years; when breast cancer is diagnosed at an early stage the prognosis is excellent, whereas the diagnosis of distant disease decreases the 5-year relative survival to about 25%.1 Currently, treatment of breast cancer is largely dictated by hormone receptor (HR) and HER2 status.

Reliable biomarkers are needed to better guide treatment decisions and increase benefit while limiting toxicity. Gene expression profiling has helped us classify breast cancer into subtypes such as basal-like (usually corresponding to triple negative), ERBB2 positive (HER2 positive), normal breast-like, and luminal A and luminal B (HR positive).2-4 The Cancer Genome Atlas Network has identified the most frequent mutations associated with the above subtypes. The most common abnormalities seen in breast cancer are the loss of PTEN and PIK3CA mutations, commonly involving exons 9 and 20. More importantly, luminal and ERBB2-positive tumors are associated with the highest rate of PIK3CA mutations.5 However, the significance of these mutations in clinical practice and their use in finding druggable targets remain to be elucidated.

The Role of the mTOR Pathway in Breast Cancer The PI3K/Akt/mTOR pathway is an intracellular network that plays a major role in cell growth and proliferation.6,7 PI3K is a heterodimer that belongs to the class IA of PI3Ks and consists of a catalytic (p110) and

a regulatory (p85) subunit8; in response to nutrient availability or growth factor stimulation, the regulatory subunit interacts with proteins or receptors, and the catalytic subunit activates phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,4-trisphosphate (PIP3), thus leading to the phosphorylation of Akt, which is upstream of Elisavet mTOR.9 PTEN acts as a tumor suppressor and Paplomata, MD 10 mediates the opposite action (PIP3 to PIP2). mTOR is a serine/threonine protein kinase consisting of 2 complexes: mTORC1 (complex 1) and mTORC2 (complex 2). mTORC1 is the target of rapamycin and rapamycin analogs and is formed by the combination of raptor, mLST8, and proline-rich Akt substrate 40.11,12 Akt activates mTORC1 by inhibiting tuberous sclerosis complex 1/2 (TSC1/2), a tumor supZelnak, pressor that acts as a GTP-ase activating pro- AmeliaMD tein for Rheb-GTP (Ras homolog enriched in brain-guanosine-5′-triphosphate).12,13 In turn, when activated, mTORC1 stimulates metabolism and inhibits apoptosis through S6K1 (40S ribosomal protein S6 kinase 1) and 4EBP1 (eukaryotic initiation factor 4E-binding protein)14-16 (Figure).

In HR-positive breast cancer, the mTOR pathway has been implicated in endocrine Ruth O’Regan, MD therapy resistance and both estrogen-dependent and estrogen-independent activation of estrogen receptor alpha.17 PTEN loss and constitutive activation of mTORC1 have been associated with in-

Dr Paplomata is Assistant Professor, Department of Hematology and Medical Oncology at Emory University School of Medicine. Her research focus is on mechanisms of resistance in breast cancer. She has participated in basic science research and translational research on mechanisms of resistance to HER2-directed therapies and chemotherapy.

Dr Zelnak is Assistant Professor, Department of Hematology and Medical Oncology at Emory University School of Medicine. She has published in the area of breast cancer research and has been an invited speaker at multiple national conferences on early-stage, triplenegative, and metastatic breast cancer.

Dr O’Regan is Professor and Vice Chair for Educational Affairs of Hematology and Medical Oncology at Emory University School of Medicine, Director of Translational Breast Cancer Research at Winship Cancer Institute of Emory University, Louisa and Rand Glenn Family Chair in Breast Cancer Research at Glenn Family Breast Center, and Chief of Service for Hematology and Medical Oncology at Georgia Cancer Center for Excellence at Grady Memorial Hospital.

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KEY POINTS Mutations of PIK3CA and loss of PTEN are among the most frequent aberrations in breast cancer ➤ Preclinical data have suggested that these alterations could predict response to therapeutic agents, however, correlative data from clinical studies have failed to verify this ➤ Newer biomarkers, such as LKB1 and 4EBP-1 expression, may warrant further study ➤ PIK3CA-GS, a recently described PI3K/mTOR gene signature, may be a more reliable indicator of pathway activation and may help identify patients who will benefit from everolimus and other inhibitors of the pathway ➤ It is possible that patients with multiple genetic aberrations could benefit from the combination of targeted agents ➤ The overall interpretation of the data is limited by the small sample sizes of clinical trials ➤ Correlative studies from large prospective studies will be needed to identify patients who will benefit from PI3K/Akt/mTOR inhibition. ➤

trinsic or acquired resistance to endocrine therapy, and the combination of endocrine agents with mTOR inhibitors can overcome this resistance in preclinical models.18,19

PIK3CA mutations have been reported to to be more common in lobular cancers, particularly exon 9 mutations, and HR-positive cancers.

The activation of the mTOR pathway has also been associated with resistance to trastuzumab in HER2-overexpressing breast cancer.20 Oncogenic PIK3CA mutations or loss of PTEN has been linked to resistance to trastuzumab-based therapy and poor outcomes.21-23 Preclinical data combining the mTOR inhibitor everolimus with trastuzumab indicate that the combination is more effective in blocking cell growth compared with either agent alone.24 In the clinical setting, the BOLERO-2 study was a phase 3 randomized trial that evaluated everolimus in combination with exemestane in postmenopausal women with HR-positive, HER2-negative breast can-

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cer.25 These patients had recurred or progressed on a nonsteroidal aromatase inhibitor. The study showed that the combination of mTOR inhibition with endocrine therapy significantly improved progression-free survival (PFS). The local assessment reported an improvement in PFS from 2.8 to 6.9 months (hazard ratio, 0.43; P <.001); the central assessment reported a PFS of 10.6 months in the combination arm versus 4.1 months in the exemestane-alone arm (hazard ratio, 0.36; P <.001). This study led to the FDA approval of everolimus for the treatment of metastatic, HR-positive breast cancer.

The TAMRAD trial was a phase 2, open-label trial that evaluated everolimus in combination with tamoxifen versus tamoxifen alone in patients with HR-positive breast cancer. The clinical benefit rate (CBR) and time to progression were significantly improved in the combination arm compared with tamoxifen (CBR, 61% vs 42%, respectively; P = .045).26 The BOLERO-3 trial evaluated everolimus in com­ bination with cytotoxic therapy in patients with HER2-overexpressing advanced breast cancer with resistance to trastuzumab. This study showed that the addition of everolimus improved the PFS from 5.78 to 7 months (hazard ratio, 0.78; P = .0067). A central review and an adjudicated review that were done retrospectively revealed a hazard ratio of 0.88 and 0.85, respectively.

The reported PFS improvement resulted mainly from the HR-negative subset of patients, patients who did not have visceral metastases, patients younger than 65 years, and patients who had received trastuzumab in the adjuvant or preoperative setting.27 These data indicate there might be a broader role for mTOR inhibitors in breast cancer, especially after the development of resistance to therapy. Multiple studies are ongoing, investigating the role of mTOR inhibitors in various settings.

Biomarkers Predicting Response PIK3CA/PTEN PIK3CA mutations and loss of PTEN are the most common aberrations found in breast cancer.5 It has been postulated that the presence of these abnormalities has prognostic value and can also predict response to therapeutics targeting the PI3K/Akt/mTOR pathway.

PIK3CA mutations are most frequently found in exons 9 and 20, which correspond to the helical (E542K and E545G) and kinase (H1047R) domains, respectively.28,29 PIK3CA mutations have been reported to be more common in lobular cancers, particularly exon 9 mutations, and HR-positive cancers.30 The impact of PIK3CA mutations on prognosis is unclear. In one study, the presence of PIK3CA mutations was not found to have correlation to clinical variables overall.

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However, when exon mutations were evaluated separately, exon 9 mutations were associated with worse overall survival (OS) and disease-free survival, whereas the opposite was observed in tissues with exon 20 mutations.31 Conversely, another analysis identified exon 20 mutations as an independent factor of poor survival in patients with breast cancer.32 One group also found an association between PIK3CA mutations and large tumor size (>2 cm) and positive node status; the presence of mutations was an independent predictor of worse survival in HER2negative breast cancer.33 In a study of 547 human breast cancers and 41 cell lines, PIK3CA mutations were found more commonly in patients with either HR-positive or HER2-overexpressing tumors. The presence of PIK3CA mutations was not associated with long-term outcome after adjuvant endocrine therapy. However, PTEN loss predicted sensitivity to PI3K inhibitors in vitro.34 Breast cancer xenograft models were more sensitive to the PI3K inhibitor GDC-0941 when harboring PIK3CA mutations and HER2 amplification.35 Triple-negative breast cancer cells with activated PI3K/Akt signaling due to PIK3CA mutations or PTEN loss were more sensitive to PI3K/mTOR inhibition.36 The impact of PTEN loss on response to PI3K/mTOR inhibition is less consistent.37 A phase 1 study of PX-866, an oral irreversible PI3K inhibitor, in patients with advanced solid tumors demonstrated that patients who had PIK3CA mutations remained in the study longer than wildtype patients, although this difference was not statistically significant.38 In addition, Janku et al reported that patients with PIK3CA H1047R mutations had higher response rates compared with other PIK3CA mutations when treated with inhibitors of the PI3K/Akt/mTOR pathway. This effect was even more pronounced when patients were treated with a combination of agents as opposed to monotherapy.39 Biomarkers were also evaluated in the neoadjuvant trial of everolimus plus letrozole in patients with operable breast cancer.40 Tumors were sequenced for PIK3CA mutations in exons 9 and 20; a small number of patients who harbored mutations in the exon 9 helical domain had significantly improved response to the combination of everolimus plus letrozole versus letrozole alone, which may indicate a lack of sensitivity to endocrine treatment alone.

Molecular data derived from the TAMRAD trial showed that PI3K mutation status and PTEN and pAkt status did not associate with sensitivity or resistance to everolimus. However, patients with low PI3K and liver

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Figure The PI3K/Akt/mTOR Pathway EGFR/HER2/HER3/IGFIR

RTKs/IRS PI3K PIP2

PTEN

PIP3

LKB1

Akt

AMPK

TSC1/2

GDP-­‐Rheb

mTORC2

Rheb-­‐GTP HIF-1

mTORC1

4EBP1 S6K1

The phosphorylation of Akt inhibits TSC1/2 (tuberin/hamartin), which is a tumor suppressor GTP-ase for Rheb-GTP. mTORC1 stimulates angiogenesis, protein synthesis, and antiapoptosis through HIF-1, 4EBP1, and S6K1. mTORC2 acts on Akt. PTEN, TSC, and LKB1 are significant tumor suppressors (shown in gray).

4EBP1 indicates eukaryotic initiation factor 4E binding protein 1; Akt, protein kinase B; AMPK, AMP activated protein kinase; HIF-1, hypoxia inducible factor-1; IRS, insulin receptor substrate; LKB1, liver kinase B1; mTORC1/2, mammalian (mechanistic) target of rapamycin complex 1/2; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,4-trisphosphate; PTEN, phosphatase and tensin homolog; Rheb-GTP (Ras homolog enriched in brain-guanosine-5′-triphosphate; RTK, receptor tyrosine kinase; S6K1, 40S ribosomal protein S6 kinase 1; TSC1/2, tuberous sclerosis complex 1/2.

kinase B1 (LKB1) expression and high phospho-4E binding protein 1 (p4EBP1) had a better response. From these data, Treilleux et al concluded that tumors in which mTOR is activated in a manner in­dependent of PI3K may benefit more from mTOR inhibition.41 Correlative studies of 227 tumor specimens from the BOLERO-2 study showed that the most common genet-

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ic alteration was a mutation in PIK3CA.25 The efficacy of everolimus was similar among PIK3CA wild-type and PIK3CA-mutated tumors.42 Similarly, genetic alterations of the PI3K pathway and amplification of cyclin D1 did not have any influence on the efficacy of everolimus; however, tumors with fibroblast growth factor receptor 1/2 alterations derived slightly less benefit from everolimus, although the number of patients was small. Additionally, tumors with zero to 1 genetic alteration derived greater benefit from everolimus than tumors with multiple aberrations. Twenty-four percent of the patients evaluated carried multiple genetic alterations, and these patients did not benefit from everolimus; thus, these patients can be considered for combination treatments as opposed to monotherapy.

Clinical trial data to date have not been conclusive regarding the prognostic and predictive value of biomarkers of the mTOR pathway.

Oliveira et al reported a retrospective analysis assessing the role of PI3K dysregulation as a predictor of treatment response in heavily pretreated patients with metastatic breast cancer. The study showed that while monotherapy with a PI3K/Akt/mTOR inhibitor had limited benefit, combination of an inhibitor with endocrine therapy, HER2-directed agent, or chemotherapy in patients with PIK3CA mutations led to an increased time to progression compared with wild-type tumors.43 In this study, PTEN status did not correlate with clinical outcome. pS6K (S6 Kinase), pAkt The activation of Akt has been associated with endocrine resistance and poor outcomes in breast cancer patients.44,45 High levels of pS6K and pAkt are associated with the constitutive activation of the mTOR pathway and predict a response to rapamycin analogs in breast cancer cell lines.46 This is independent of PTEN status.

Similarly, increased levels of pAkt, GSK3β, and TSC2 also correlated with sensitivity to everolimus.47 INPP4B INPP4B is a tumor suppressor that negatively regulates the PI3K/Akt pathway.48 Loss or knockdown of INPP4B activates the PI3K/Akt pathway and leads to tumor growth and increased cell motility.49 This loss can often be seen in PTEN-null tumors or basal-like breast

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cancer tumors, and it correlates with worse clinical outcomes.50 These tumors may be candidates for PI3K/Akt/ mTOR inhibition.

HER2 Several preclinical models have demonstrated that HER2 status also correlates with response to inhibitors of the mTOR pathway.37,51 This is probably due to the activation of pAkt, which is downstream of HER2.46,52,53 A phase 2 study by Ellard et al that evaluated various dosing regimens of everolimus in breast cancer patients failed to find a correlation between clinical response and biomarkers.54 It is possible that the small number of patients, the variability of the tumors, and the techniques used influenced these results. It is also possible that mutations within the helical versus kinase domain of PIK3CA impact function differently and may need to be evaluated separately among patients treated with inhibitors of the mTOR pathway.

Finally, a meta-analysis that included 17 clinical studies in various solid tumors showed that the activation of the PI3K/Akt/mTOR pathway was linked to worse 5-year survival (odds ratio [OR] 2.12; P <.001). Six studies assessing PIK3CA mutations showed no association with survival (OR 1.24; P = .46). However, studies evaluating activated mTOR/Akt and PTEN loss identified a significant connection with worse survival (P = .01 and P <.001, respectively).55 In summary, there are data, mainly derived from preclinical models, supporting that the activation of the PI3K/Akt/mTOR pathway, regardless of the inciting factor, can predict response to rapamycin analogs and other inhibitors of the pathway. However, clinical trial data to date have not been conclusive regarding the prognostic and predictive value of biomarkers of the mTOR pathway.

Biomarkers Predicting Resistance PIK3CA mutations frequently coexist with KRAS mutations, the presence of which has been associated with worse outcomes and shorter OS.56,57 In xenograft models, Ihle et al showed that the presence of oncogenic Ras mutations conferred resistance to PI3K inhibition regardless of PIK3CA and PTEN status.58 Di Nicolantonio et al also showed that cancer cells with PIK3CA mutations and PTEN loss were more sensitive to everolimus; however, this response was abrogated when these aberrations were combined with KRAS or BRAF mutations.59 These data suggest that the presence of KRAS mutations may require targeting of both pathways for optimal tumor suppression.

However, an evaluation of breast and gynecologic tumors for PIK3CA and KRAS/BRAF mutations failed to

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show an impact of KRAS/BRAF status on response to treatment, although the number of patients was small.60 In a retrospective study, the same group reported that among patients treated with PI3K/Akt/mTOR inhibitors, the coexistence of PIK3CA and KRAS mutations (in codons 12 and 13) was associated with lower response rates.39 The number of patients in both studies was small, and the results should be interpreted with caution.

Other biomarkers of resistance demonstrated in breast cancer cell lines include activation of NOTCH and induction of c-MYC.61 The clinical significance of these biomarkers is currently uncertain but warrants further investigation.

Conclusion Mutations of PIK3CA and loss of PTEN are among the most frequent aberrations in breast cancer. Even though preclinical data have suggested that these alterations could predict response to therapeutic agents, correlative data from clinical studies have failed to verify this association.

Newer biomarkers, such as LKB1 and 4EBP1 expression, may be worth exploring. Additionally, a recently described PI3K/mTOR gene signature (PIK3CA-GS) may be a more reliable indicator of pathway activation and may help identify patients who will benefit from everolimus and other inhibitors of the pathway.62,63 It is possible that patients with multiple genetic aberrations could benefit from the combination of targeted agents.

Finally, the overall interpretation of the data is limited by the small sample sizes of clinical trials. Correlative studies from large prospective studies will be needed to identify patients who will benefit from PI3K/Akt/mTOR inhibition. u References

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21. Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395-402.

22. Nagata Y, Lan KH, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients.

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23. Wang L, Zhang Q, Zhang J, et al. PI3K pathway activation results in low efficacy of both trastuzumab and lapatinib. BMC Cancer. 2011;11:248.

24. Zhu Y, Zhang X, Liu Y, et al. Antitumor effect of the mTOR inhibitor everolimus in combination with trastuzumab on human breast cancer stem cells in vitro and in vivo. Tumour Biol. 2012;33:1349-1362.

25. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520-529.

26. Bachelot T, Bourgier C, Cropet C, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012;30:2718-2724.

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29. Campbell IG, Russell SE, Choong DY, et al. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 2004;64:7678-7681.

30. Kalinsky K, Jacks LM, Heguy A, et al. PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res. 2009;15:5049-5059.

31. Barbareschi M, Buttitta F, Felicioni L, et al. Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas.

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32. Lai YL, Mau BL, Cheng WH, et al. PIK3CA exon 20 mutation is independently associated with a poor prognosis in breast cancer patients. Ann Surg Oncol.

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33. Li SY, Rong M, Grieu F, et al. PIK3CA mutations in breast cancer are associated with poor outcome. Breast Cancer Res Treat. 2006;96:91-95.

34. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer.

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35. O’Brien C, Wallin JJ, Sampath D, et al. Predictive biomarkers of sensitivity to the phosphatidylinositol 3′ kinase inhibitor GDC-0941 in breast cancer preclinical models. Clin Cancer Res. 2010;16:3670-3683.

36. Lehmann BD, Bauer JA, Chen X, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121:2750-2767.

37. Brachmann SM, Hofmann I, Schnell C, et al. Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc Natl Acad Sci U S A. 2009;106:22299-22304.

38. Hong DS, Bowles DW, Falchook GS, et al. A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2012;18:4173-4182.

39. Janku F, Wheler JJ, Naing A, et al. PIK3CA mutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials. Cancer Res. 2013;73:276-284.

40. Baselga J, Semiglazov V, van Dam P, et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2009;27:2630-2637.

41. Treilleux I, Arnedos M, Cropet C, et al. Predictive markers of everolimus effica-

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cy in hormone receptor positive (HR+) metastatic breast cancer (MBC): final results of the TAMRAD trial translational study. J Clin Oncol. 2013;31(suppl). Abstract 510.

42. Hortobagyi GN, Piccart-Gebhart MJ, Rugo HS, et al. Correlation of molecular alterations with efficacy of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer: results from BOLERO-2. J Clin Oncol. 2013;31(suppl). Abstract LBA509.

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47. Breuleux M, Klopfenstein M, Stephan C, et al. Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition. Mol Cancer Ther. 2009;8:742-753.

48. Norris FA, Auethavekiat V, Majerus PW. The isolation and characterization of cDNA encoding human and rat brain inositol polyphosphate 4-phosphatase. J Biol Chem. 1995;270:16128-16133.

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50. Fedele CG, Ooms LM, Ho M, et al. Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers. Proc Natl Acad Sci U S A. 2010;107:22231-22236.

51. Weigelt B, Warne PH, Downward J. PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs.

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signaling pathway in anchorage-independent growth. Oncogene. 2001;20:7551-7562.

53. She QB, Chandarlapaty S, Ye Q, et al. Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling. PLoS One. 2008;3:e3065.

54. Ellard SL, Clemons M, Gelmon KA, et al. Randomized phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical Trials Group IND.163. J Clin Oncol. 2009;27:4536-4541.

55. Ocana A, Vera-Badillo F, Al-Mubarak M, et al. Activation of the PI3K/mTOR/ AKT pathway and survival in solid tumors: systematic review and meta-analysis.

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56. Janku F, Tsimberidou AM, Garrido-Laguna I, et al. PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors. Mol Cancer Ther. 2011;10:558-565.

57. Garrido-Laguna I, Hong DS, Janku F, et al. KRASness and PIK3CAness in patients with advanced colorectal cancer: outcome after treatment with early-phase trials with targeted pathway inhibitors. PLoS One. 2012;7:e38033.

58. Ihle NT, Lemos R Jr, Wipf P, et al. Mutations in the phosphatidylinositol-3kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. Cancer Res. 2009;69:143-150.

59. Di Nicolantonio F, Arena S, Tabernero J, et al. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest. 2010;120:2858-2866.

60. Janku F, Wheler JJ, Westin SN, et al. PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol. 2012;30:777-782.

61. Muellner MK, Uras IZ, Gapp BV, et al. A chemical-genetic screen reveals a mechanism of resistance to PI3K inhibitors in cancer. Nat Chem Biol. 2011;7:787793.

62. Loi S, Haibe-Kains B, Majjaj S, et al. PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci U S A. 2010;107:10208-10213.

63. Loi S, Michiels S, Baselga J, et al. PIK3CA genotype and a PIK3CA mutationrelated gene signature and response to everolimus and letrozole in estrogen receptor positive breast cancer. PLoS One. 2013;8:e53292.

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Cabozantinib in Prostate Cancer Patients with Bone Metastasis Leonel F. Hernandez-Aya, MD; David C. Smith, MD University of Michigan Comprehensive Cancer Center Ann Arbor, MI

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rostate cancer is the most common nondermatologic cancer diagnosed among males in the United States with approximately 233,000 new cases annually. In addition, prostate cancer is the second leading cause of cancer death in men with over 29,000 estimated deaths in 2014.1 Once prostate cancer has metastasized and progressed to a castration-resistant state, it is considered a lethal disease. Most patients with advanced castration-resistant prostate cancer (CRPC) develop bone metastases, which frequently become a major source of disease-related morbidity and mortality.2 The bones with higher vascularization such as the vertebral column, ribs, skull, and proximal ends of long bones are the predilected sites for prostate cancer cells.3 Bone metastases are often symptomatic and frequently affect the quality of life of patients, causing debilitating pain, pathologic fractures, bone marrow suppression, nerve compression syndromes, or spinal cord compression.4 Recent advances in the understanding of the biology of prostate cancer have led to the approval of multiple drugs for CRPC, including the chemotherapeutics docetaxel and cabazitaxel, the immunotherapeutic sipuleucel-T, and the androgen signaling pathway inhibitors abiraterone and enzalutamide.5 Although these agents can prolong survival, the prognosis for CRPC remains poor, and the morbidity related to bone metastases remains a major clinical problem. New therapeutic options are needed for treating patients with castration-resistant disease, particularly in the presence of bone metastasis.

Cabozantinib (XL184) is an oral inhibitor of multiple receptor tyrosine kinases (RTKs), including MET and vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2). Cabozantinib is a promising agent for the treatment of patients with prostate cancer. This review will focus on the rationale for targeting the MET and VEGF signaling pathway with cabozantinib in prostate cancer patients with bone metastasis.

Dr Hernandez-Aya is a Hematology/Oncology Fellow at the University of Michigan Comprehensive Cancer Center.

Dr Smith is Professor of Medicine and Urology and Associate Chief for Clinical Services in the Division of Hematology/Oncology at the University of Michigan Comprehensive Cancer Center.

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MET and VEGF Signaling in CRPC and Bone Metastases Data from preclinical models and clinical biomarker studies suggest that the RTK MET and the VEGF signaling pathway are implicated in development and progression of CRPC.6,7 Expression of VEGF is upregulated in metastatic prostate cancer compared with Leonel F. normal prostate tissues,8 and elevated levels Hernandez-Aya, of VEGF in plasma or urine correlate with MD advanced stage, progression, and poor patient outcomes in prostate cancer.9-11 Despite promising results in early-phase clinical trials, multiple VEGF-only targeting agents failed to demonstrate an improvement in overall survival in patients with CRPC.12,13 The lack of survival benefit may reflect the development of adaptive mechanisms of resistance such as upregulation of alternative proangiogenic C. Smith, signaling pathways.14 Upregulation of the David MD MET signaling pathway has emerged as a potential mechanism for the development of resistance for VEGF-targeting therapies.15 MET is an RTK and the only known receptor for hepatocyte growth factor (HGF). MET signaling plays important roles in embryogenesis, cell proliferation, angiogenesis, survival, and tumor cell invasion.6 In cancer cells, inappropriate activation of MET occurs through overexpression of wild-type MET or its ligand HGF, or as a result of activating mutations in the gene encoding MET. Both HGF and MET levels are increased by hypoxia triggered by angiogenesis inhibitors contributing to resistance to VEGF-targeting therapies.16,17 MET signaling plays a role in the biology of CRPC independently of VEGF. Preclinical models suggest that HGF and MET expression is higher in CRPC cell lines and CRPC xenograft tumors growing in vivo.18-20 Furthermore, clinical data suggest that MET expression is significantly higher in tumors from CRPC patients compared with androgen-sensitive tumors.21 A potential explanation of this difference originates from molecular studies showing that the androgen receptor directly represses expression of the gene encoding MET via inhibition of its promoter.19 Interestingly, MET expression is higher in

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KEY POINTS Most patients with advanced castration-resistant prostate cancer (CRPC) develop bone metastases, which frequently become a major source of diseaserelated morbidity and mortality ➤ The receptor tyrosine kinase MET and the vascular endothelial growth factor (VEGF) signaling pathways are implicated in the development and progression of CRPC. VEGF and MET signaling pathways are implicated in bone formation, remodeling, and development of metastases ➤ Cabozantinib (XL184) is a potent inhibitor of receptor tyrosine kinases, including MET and VEGF receptor 2 (VEGFR2). Other targets inhibited by cabozantinib include AXL, FLT3, KIT, and RET. The simultaneous inhibition of MET and VEGFR2 by cabozantinib may enhance the antitumor effect suppressing the development of resistance through MET-driven escape pathways seen with agents targeting the VEGF pathway alone ➤ Phase 2 clinical trials support the beneficial effects of cabozantinib on a variety of disease-related outcomes in patients with metastatic CRPC, including improvement in bone scans, patientreported pain and analgesic use, measurable disease, and bone biomarkers ➤ Extensive preclinical and early clinical data suggest that cabozantinib is biologically active in metastatic CRPC, especially in patients with bone metastases.

The effect of cabozantinib on overall survival of patients with CRPC is under investigation in 2 phase 3 randomized clinical trials. ➤

bone metastases than in primary tumors or lymph node metastases.22,23 Overall, robust preclinical data indicate that increased MET expression and signaling contribute to the emergence of castration-resistant disease.

The development of bone metastasis in prostate cancer involves an intricate process of dynamic interactions between cancer cells and the bone microenvironment, mainly osteoblasts, osteoclasts, and endothelial cells.24 Invading cancer cells cause local disruption of normal bone remodeling, with lesions exhibiting osteoblastic (bone-forming) and osteolytic (bone-resorbing) activity.5 Osteoblastic lesions are typically visualized by bone scan, which detects the rapid incorporation of a radiotracer into newly forming or remodeling bone. VEGF and MET signaling pathways are implicated in bone formation, remodeling, and development of metastases. Osteoblasts and osteoclasts express VEGF, VEGF

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receptors, HGF, and MET, which mediate cell proliferation, migration, differentiation, and survival.25-31 VEGF signaling is involved in potential autocrine and/ or paracrine feedback mechanisms regulating osteoblast and osteoclast cellular function.32,33 Secretion of HGF by osteoblasts promotes the development of bone metastases by tumor cells that express MET.30 This body of evidence suggests that simultaneous inhibition of MET and VEGF signaling may offer significant benefit over targeting either pathway alone.

Cabozantinib in Prostate Cancer Cabozantinib (XL184) is a potent inhibitor of RTKs, including MET and VEGFR2. Other targets inhibited by cabozantinib include AXL, FLT3, KIT, and RET. Preclinical studies in multiple cancers, including glioma, breast, lung, and pancreatic cancers, show that cabozantinib exhibits a potent and reversible inhibition of its targets, affecting angiogenesis and tumorigenesis.15,34 Cabozantinib potently inhibits both wild-type MET and MET with activating mutations. In vitro studies demonstrated that cabozantinib strongly inhibits HGF-induced migration and proliferation in cell lines known to be dependent on MET. Likewise, the in vivo studies showed that cabozantinib inhibits phosphorylation of MET and VEGFR2 in a reversible manner and significantly increases tumor hypoxia and cell death not only in tumor cells but also in endothelial cells of tumor vasculature.34 These studies suggest that antitumor efficacy of cabozantinib is the result of mechanisms affecting tumor angiogenesis and the blockade of invasive tumor growth as well as direct cytotoxicity in sensitive cells. Therefore, this drug has the potential to affect the malignant tumor cells and the tumor microenvironment. Furthermore, the simultaneous inhibition of MET and VEGFR2 by cabozantinib may enhance the antitumor effect suppressing the development of resistance through MET-driven escape pathways seen with agents targeting the VEGF pathway alone.14,15,35,36 More recent preclinical investigations reinforce the potential effects of cabozantinib on bone metastasis.

Nguyen and colleagues37 found upregulated levels of MET, P-MET, and VEGFR2 in prostate cancer bone and soft tissue metastases compared with primary tumors. Because VEGFR2 and MET signaling are important in bone biology, cabozantinib treatment not only affects metastatic bones but potentially normal bone as well. In vivo studies with LuCaP 23.1 and castrationresistant C4-2B prostate cancer xenografts showed that cabozantinib treatment attenuates the bone response to the tumor and increases bone volume in intact as well as castrated animals.37 Interestingly, in vitro studies in a bone organ culture model show that cabozantinib

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Table Cabozantinib in Clinical Trials Determinants for Its Potential Use in Prostate Cancer Clinical Trial

Clinical Setting

Study Results

Effects on Bone Metastasis

Phase 1 dose-escalation trial41 N = 85

Multiple advanced solid tumors MTD: 175 mg daily Expansion cohort with MTC Acceptable toxicity profile PR: 29% in MTC SD: 41% in MTC

Not reported

Phase 2 randomized discontinuation trial43 N = 171

Patients with mCRPC –87% with bone metastases

PFS 23.9 weeks vs 5.9 weeks (HR, 0.12; P <.001) –12% with CR in bone scan –PR: 5% –SD: 75% –PD: 11% –Dose reductions in 51%

–68% with bone scan improvement (post hoc) –12% with CR in bone scan –67% with improvement in pain control (post hoc) –56% with reduction in narcotics

40-mg cohort (n = 25): –64% bone scan response; 3 CR, 16 PR –No dose reductions 20-mg cohort (n = 11): –1 PR, 5 SD, 4 PD

–64% posttreatment bone scan improvements

63% of patients with bone scan response –SD: 19% –PD: 10% –PR in soft tissue disease: 80%

–63% with significant bone scan response –57% with improvement in pain control –55% with reduction in narcotics

Cabozantinib dose: 100 mg daily

Primary end points: ORR PFS

Phase 1 adaptive response schema44 N = 36

Patients with mCRPC and bone metastases

Phase 2 nonrandomized45

Patients with mCRPC and bone metastases postdocetaxel

Primary end point: Dose levels of cabozantinib: 6-week bone scan response 60 mg daily 40 mg daily 20 mg daily

Cabozantinib dose: Cohort 1: 100 mg (n = 93) Cohort 2: 40 mg (n = 51) Phase 3 randomized (COMET-1) Cabozantinib dose: 60 mg daily –Cabozantinib vs prednisone Phase 3 randomized (COMET-2) Cabozantinib dose: 60 mg daily –Cabozantinib vs mitoxantrone + prednisone

Primary end point: bone scan response Patients with mCRPC postdocetaxel and either abiraterone or enzalutamide

Pending NCT01605227

Primary outcome: overall survival Patients with mCRPC postdocetaxel and either abiraterone or enzalutamide

Pending NCT01522443

Primary outcome: durable pain response

CR indicates complete response; HR, hazard ratio; mCRPC, metastatic castration-resistant prostate cancer; MTC, medullary thyroid cancer; MTD, maximum tolerated dose; ORR, overall response rate; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

inhibits bone resorption, blocking the effects of parathyroid hormone–related protein (PTHrP).38 PTHrP stimulates VEGF expression and bone resorption by cancer metastases.39 PTHrP is produced by tumor cells and binds to receptors on osteoblasts stimulating the production of the membrane-bound cytokine RANKL,

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which then promotes the fusion activity and survival of osteoclasts.40 In this in vitro study, cabozantinib inhibited the expression of RANKL by osteoblastic cells, affected TRAP in osteoclastic cells, alkaline phosphatase in osteoblastic cells, and decreased cell viability in both cell types. The activity profile of cabozantinib on bone

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differs from that of the standard antiresorptive agents, which largely target osteoclasts.40 In summary, accumulating evidence suggests an effect of cabozantinib on both tumor and tumor-induced bone matrix remodeling important in treating patients with prostate cancer and bone metastases.

Clinical Trials of Cabozantinib in Prostate Cancer The phase 1 dose-escalation trial of oral cabozantinib enrolled patients with multiple advanced solid tumors with an expansion cohort for patients with medullary thyroid cancer (MTC) added to the trial.41 Eighty-five patients were enrolled, including 37 with MTC. There were no patients with prostate cancer included in this trial. The maximum tolerated dose with an acceptable side effect profile was 175 mg daily. A total of 77 patients (90%) reported at least 1 treatment-related ad-

Accumulating evidence suggests an effect of cabozantinib on both tumor and tumorinduced bone matrix remodeling important in treating patients with prostate cancer and bone metastases. verse event (AE), 43% of which were reported as grade 1 or 2. The most frequent AEs related to treatment were diarrhea, fatigue, anorexia, nausea, rash, increased AST level, vomiting, and mucosal inflammation. One patient had a pulmonary embolism, a grade 4 event that was assessed as related to cabozantinib. Dose-limiting toxicities were hand-foot syndrome and liver enzyme elevations. Peak plasma concentrations were reached 5 hours following oral administration. The half-life was shown to be 91 Âą 33 hours. Ten (29%) of 35 patients with MTC with measurable disease had a confirmed partial response, and 18 patients had tumor shrinkage of 30% or more. Forty-one percent of patients with MTC had stable disease for at least 6 months.41 Interestingly, 3 patients with a confirmed response had previously been treated with vandetanib or sorafenib that also target RET and VEGFR, supporting the hypothesis of MET being an escape mechanism to VEGFR inhibition.42 On the basis of the broad activity and responses seen in the phase 1 study, a phase 2 randomized discontinuation trial (RDT) was conducted in 9 selected tumor types, including CRPC.43 The results of cabozantinib treatment in the subset of patients with CRPC were encouraging. A total of 171 patients with metastatic CRPC were enrolled, of whom 87% had bone metas-

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tases. The patients received open-label treatment with cabozantinib 100 mg daily during a 12-week lead-in stage. The original design of the study stated that patients with stable disease at 12 weeks were randomly assigned to cabozantinib or placebo. At progression, patients were taken off study if they were receiving cabozantinib or were allowed to restart cabozantinib if on placebo. After enrollment of 122 patients, the random assignment to placebo was suspended because of unexpected changes on bone scan and decrease in pain observed during the lead-in stage; at that time, 31 patients had been randomly assigned to receive either cabozantinib or placebo.

Substantial improvements in bone scans were observed in 79 (68%) of the 116 evaluable patients, including complete resolution of lesions in 12% of these patients. Furthermore, 72% exhibited regression in soft tissue lesions, and 67% reported an improvement in pain control.43 In the 31 patients with stable disease who were randomized to placebo or cabozantinib before suspension of random assignment, cabozantinib treatment resulted in a median progression-free survival (PFS) of 23.9 weeks (95% CI, 10.7-62.4 weeks) compared with 5.9 weeks (95% CI, 5.4-6.6 weeks; hazard ratio, 0.12; P <.001) with placebo. Nine patients (5%) had a confirmed partial response within the first 12 weeks, 127 (75%) had stable disease, and 18 (11%) had disease progression. Prostate-specific antigen (PSA) levels of the patients did not correlate with the clinical responses to cabozantinib.43 Despite the relatively low response rate by RECIST, the results were promising, with cabozantinib-treated patients showing consistent effects on markers of bone formation and resorption, improvement in bone pain, narcotic use on retrospective analysis, and better PFS compared with the placebo group. More than 60% of patients required dose reductions related to AEs, similar to what has been observed with other tyrosine kinase inhibitors (TKIs) that target VEGFR. A subsequent single-institution dose-ranging study of men with metastatic CRPC reported bone scan improvements in most patients treated with cabozantinib at a lower starting dose of 40 mg daily, with more modest effects at the lowest dose of 20 mg daily.44 As an attempt to confirm the results of the phase 2 RDT and to test lower doses of cabozantinib, a multicenter phase 2 nonrandomized expansion study of men with CRPC and bone metastases was recently conducted.45 This study used a prespecified bone scan response as the primary study outcome. Patients with CRPC and bone metastases were sequentially enrolled into 100-mg (n = 93) and 40-mg cohorts (n = 51). All patients had received a docetaxel-containing regimen, and some had also received abiraterone or cabazitaxel.

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The primary end point was bone scan response, defined as at least a 30% improvement in bone scan lesion area (BSLA). BSLA is a quantitative biomarker of osseous disease obtained with validated software that assesses prostate cancer treatment response on a technetium-99 bone scan.46 In this study, 63% of patients had significant bone scan response, 19% had stable disease, and 10% had progressive disease. The bone scan response rate in the 100-mg cohort was 73% compared with 45% in the 40-mg cohort. The bone scan improvements were mostly observed at the first 6-week evaluation. In patients with measurable soft tissue disease, 80% had a reduction in measurable disease that was similar for both cohorts (80% vs 79%). Furthermore, 68% of the patients reported a pain decrease of at least 30%, and 55% of patients had a reduction in the use of narcotics.

The AE profile was similar to that previously reported in the phase 2 RDT. Compared with patients treated at a starting dose of 100 mg, those who received 40 mg had lower rates of dose reduction or drug discontinuation because of AEs. It is important to note that the study was not randomized; therefore, the outcomes for the 100-mg and 40-mg cohorts are not directly comparable.45 Both phase 2 studies support the beneficial effects of cabozantinib on a variety of disease-related outcomes in patients with metastatic CRPC, including improvement in bone scans, patient-reported pain and analgesic use, measurable disease, and bone biomarkers.43,45 Moreover, in the most recent phase 2 study, the benefits of cabozantinib were seen in patients heavily pretreated with drugs including docetaxel, abiraterone, and cabazitaxel, suggesting that cabozantinib does not share mechanism(s) of resistance with other prostate cancer treatments. The apparent nonoverlapping resistance between cabozantinib and other agents may reflect targeting of tumor, stroma, and tumor-stroma interactions by cabozantinib.45 Phase 3 studies (Cabozantinib MET Inhibition CRPC Efficacy Trial [COMET] 1 and 2) have been initiated to evaluate the effect of cabozantinib on morbidity and mortality in patients with CRPC with bone metastases. These studies are using cabozantinib at 60 mg daily as the starting dose. The main clinical trials determinants for the potential use of cabozantinib in prostate cancer are summarized in the Table.

Biomarkers of Response to Cabozantinib in CRPC Serum PSA is the most widely used marker to assess disease response and progression in patients with prostate cancer. Serum PSA is easily measured, and decreased PSA in prostate cancer patients correlates with better overall survival during treatment with androgen deprivation and chemotherapy.47-49 Nevertheless,

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multiple clinical trials with antiangiogenic TKIs have demonstrated conflicting changes in serum PSA levels. In the cabozantinib phase 2 trials reviewed above, PSA changes did not correlate with other efficacy parameters. Other trials with antiangiogenic TKIs such as cediranib, sorafenib, and sunitinib showed a similar pattern, with few patients having a decline in PSA levels despite reductions in pain and lymph node, lung, liver, and/or bone lesions.50-54 Interestingly, in vitro experiments have shown that PSA secretion from prostate cancer cells can increase during incubation with sorafenib,50 and PSA expression in prostate cancer cells can decrease in the presence of osteoblasts.55 These results suggest that during treatment of CRPC patients with angiogenesis inhibitors, changes in serum PSA may reflect a pharmacodynamic effect of tyrosine kinase inhibition in tumor cells or changes in osteoblast-tumor cell interactions in bone lesions, rather than changes in tumor growth.5 These observations emphasize the importance of radiographic or symptomatic progression over PSA progression, especially in trials of antiangiogenic agents.

The apparent nonoverlapping resistance between cabozantinib and other agents may reflect targeting of tumor, stroma, and tumor-stroma interactions by cabozantinib.

Changes in bone scan measurements also have been correlated with survival.56,57 New techniques are being validated for computer-assisted detection and assessment of bone lesions to standardize the measure of treatment effects.46 The significant improvement in bone scans seen with cabozantinib in the phase 2 studies is promising; however, its significance in terms of survival needs evaluation in a phase 3 clinical trial.

Circulating tumor cells (CTCs) are another promising measure of angiogenesis inhibitor effects in prostate cancer. CTCs have been shown to have prognostic value for patients treated with cytotoxic chemotherapy or targeted therapies.58-60 In the phase 2 nonrandomized expansion study of cabozantinib in chemotherapy-pretreated CRPC, posttreatment changes in CTC counts were assessed in 103 patients with baseline unfavorable CTC counts (â&#x2030;Ľ5 per 7.5-mL blood) and at least 1 follow-up assessment at week 6 or 12. In this study, 82% of patients had a decrease of at least 30% in CTCs at week 6 and/or 12.45 Additional clinical trials are needed to validate the use of CTCs as a surrogate end point,

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and more robust technologies are needed to improve the detection of CTCs.

Conclusion Extensive preclinical and early clinical data suggest that cabozantinib is biologically active in metastatic CRPC especially in patients with bone metastases. The therapeutic effects of cabozantinib are mediated by the simultaneous inhibition of VEGFR2, MET, and other RTKs that are important in prostate cancer progression, metastasis, and development of drug resistance. Furthermore, cabozantinib not only has effects on cancer cells but also on the tumor microenvironment and normal bone. This broad anticancer effect provides a biologic explanation for the significant clinical benefits in a variety of disease-related outcomes observed in the phase 2 clinical trials. The effect of cabozantinib on overall survival of patients with CRPC is under investigation in 2 phase 3 randomized clinical trials. u References

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50. Steinbild S, Mross K, Frost A, et al. A clinical phase II study with sorafenib in patients with progressive hormone-refractory prostate cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV. Br J Cancer. 2007;97:1480-1485.

51. Dahut WL, Scripture C, Posadas E, et al. A phase II clinical trial of sorafenib in androgen independent prostate cancer. Clin Cancer Res. 2008;14:209-214.

52. Adelberg D, Karakunnel JJ, Gulley JL, et al. A phase II study of cediranib in post-docetaxel, castration-resistant prostate cancer (CRPC). Poster presented at: 2010 ASCO Genitourinary Cancer Symposium; March 5-7, 2010; San Francisco, CA. Abstract 63.

53. Dror Michaelson M, Regan MM, Oh WK, et al. Phase II study of sunitinib in

men with advanced prostate cancer. Ann Oncol. 2009;20:913-920.

54. Sonpavde G, Periman PO, Bernold D, et al. Sunitinib malate for metastatic castration-resistant prostate cancer following docetaxel-based chemotherapy. Ann Oncol. 2010;21:319-324.

55. Li Y, Sikes RA, Malaeb BS, et al. Osteoblasts can stimulate prostate cancer growth and transcriptionally down-regulate PSA expression in cell line models.

Urol Oncol. 2011;29:802-808.

56. Sabbatini P, Larson SM, Kremer A, et al. Prognostic significance of extent of disease in bone in patients with androgen-independent prostate cancer. J Clin Oncol. 1999;17:948-957.

57. Morris MJ, Jia X, Larson SM, et al. Post-treatment serial bone scan index (BSI) as an outcome measure predicting survival. Poster presented at: 2008 ASCO Genitourinary Symposium; February 14-16, 2008; San Francisco, CA. Abstract 189.

58. Scher HI, Jia X, de Bono JS, et al. Circulating tumor cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data. Lancet Oncol. 2009;10:233-239.

59. Scher HI, Heller G, Molina A, et al. Evaluation of circulating tumor cell (CTC) enumeration as an efficacy response biomarker of overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC): planned final analysis (FA) of COU-AA-301, a randomized double-blind, placebo-controlled phase III study of abiraterone acetate (AA) plus low-dose prednisone (P) post docetaxel.

J Clin Oncol. 2011;29(suppl). Abstract LBA4517.

60. Danila DC, Fleisher M, Scher HI. Circulating tumor cells as biomarkers in prostate cancer. Clin Cancer Res. 2011;17:3903-3912.

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Š 2014 Genentech USA, Inc. All rights reserved. COB/091614/0001 Printed in USA.

IN METASTATIC MELANOMA, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY? Research has found that abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis.1 Overactivation of MAPK signaling has been implicated as a key driver of metastatic melanoma.2 Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

REFERENCES: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119. 2. Wang AX, Qi XY. Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. IUBMB Life. 2013;65:748-758.

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To receive credit, complete the posttest at http://ce.lynxcme.com/CPS268-1.

A Focus on Melanoma, Basal-Cell Carcinoma, Cutaneous T-Cell Lymphoma, Merkel-Cell Carcinoma, and Rare Cutaneous Malignancies: Highlights from the Third Annual World Cutaneous Malignancies Congress Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke’s Cancer Center Bethlehem, PA

Release date: March 24, 2015 Expiration date: March 31, 2016 Estimated time to complete activity: 1.0 hour Providers This activity is jointly provided by Postgraduate Institute for Medicine and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Bristol-Myers Squibb, Merck, and Prometheus Laboratories Inc. Target Audience This activity is directed toward medical and surgical oncologists, dermatologists, and radiation oncologists involved in the treatment of patients with cutaneous malignancies. Fellows, nurse practitioners, nurses, physician assistants, pharmacists, researchers, and other healthcare professionals interested in the treatment of cutaneous malignancies are also invited to participate.

Educational Objectives After completing this activity, the participant should be better able to: • Review the molecular biology and pathogenesis of malignant melanoma, cutaneous T-cell lymphoma (CTCL), basal-cell carcinoma (BCC), and Merkel-cell carcinoma (MCC) as they relate to targeted therapy • Describe therapeutic options and optimal sequencing of existing agents for patients with metastatic melanoma, CTCL, BCC, and MCC and how to tailor therapy for individual patients • Discuss emerging data and recent advances with new molecular targets for the treatment of patients with metastatic melanoma, CTCL, BCC, and MCC and how to integrate key findings into clinical practice • Identify new technologies for the prevention and early detection of cutaneous malignancies Faculty Sanjiv S. Agarwala, MD Professor of Medicine, Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke’s Cancer Center, Bethlehem, PA Axel Hauschild, MD, PhD Professor of Dermatology, Department of Dermatology Skin Cancer Center, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany Physician Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Postgraduate Institute for Medicine and Center of Excellence Media, LLC. Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.

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Axel Hauschild, MD, PhD Professor of Dermatology Department of Dermatology Skin Cancer Center University Hospital Schleswig-Holstein Campus Kiel Kiel, Germany

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Sanjiv S. Agarwala, Nothing to disclose MD Axel Hauschild, Consulting and honoraria fees and MD, PhD clinical trial/research support from Amgen, Bristol-Myers Squibb, Celgene, Eisai, GlaxoSmithKline, MedImmune, MELA Sciences, Merck Serono, MSD/Merck, Novartis, OncoSec, and Roche Pharma The following PIM planners and managers—Laura Excell, ND, NP, MS, MA, LPC, NCC; Trace Hutchison, PharmD; Samantha Mattiucci, PharmD, CCMEP; Jan Schultz, MSN, RN, CCMEP, and Judi Smelker-Mitchek, RN, BSN—hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

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C

utaneous malignancies are a highly heterogeneous group of cancers. Major subtypes of cutaneous malignancies—melanoma, cutaneous T-cell lymphoma (CTCL), basal-cell carcinoma (BCC), and Merkel-cell carcinoma (MCC)—exhibit widely divergent pathobiologic and clinical features. Even within each subtype, course and prognosis vary greatly. In melanoma, for example, prognosis is very good in patients who present with localized disease and primary tumors ≤1.0 mm in thickness, but outcomes are far worse in patients with larger tumors, nodal involvement, and distant metastasis.1 CTCLs encompass indolent cancers, such as mycosis fungoides (MF), and aggressive disease, such as primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma.2 BCC, although often a localized, nonaggressive cancer, has low-risk and highrisk forms, and can also manifest as locally advanced and metastatic disease.3 The heterogeneity of cutaneous malignancies has always dictated a management approach tailored to the individual patient. Currently, an evolving understanding of genetic and molecular mechanisms allows for ever-increasing personalization of care with novel, targeted therapies.

At the third annual World Cutaneous Malignancies Congress, held October 31-November 1, 2014, in San Francisco, experts from around the world came together to discuss personalized strategies for the treatment of patients with cutaneous malignancies. Presentations included updates on molecular biology, emerging therapies, prevention, and early detection. This monograph will highlight key topics and opinions from that meeting.

Genetic and Molecular Pathobiology of Cutaneous Malignancies Melanoma There continues to be an urgent need for research on the pathobiology of melanoma, because the incidence of this malignancy has risen rapidly over the past 3 decades and the disease carries significant excess mortality.1,4 Melanoma accounts for <2% of skin cancers, but causes the vast majority of skin-cancer–related deaths.4 According to a presentation by Antoni Ribas, MD, Professor at the Department of Medicine, Hematology/ Oncology, University of California at Los Angeles (UCLA), and Director of the Tumor Immunology Program at the Jonsson Comprehensive Cancer Center, UCLA, our understanding of the molecular biology and genetics of melanoma is now well-integrated into its management. Central to this understanding is the role of BRAF mutation versus BRAF wild type in the malignant tumor.5 BRAF mutation has been shown to occur in up to two-thirds of melanomas.6 The expression of BRAF protein phosphorylates MEK, which in turn phosphory-

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lates ERK proteins (Figure 1).6 In other words, BRAF mutation activates the MAP-kinase (MAPK) pathway of tumor-cell proliferation. Elucidation of this pathway was the rationale for the development of BRAF inhibitors (eg, vemurafenib, dabrafenib) and MEK inhibitors (eg, trametinib, cobimetinib). These classes of agents are active at different points in the tumorigenic pathway initiated by BRAF mutation. BRAF inhibitors suppress the activity of BRAF kinase expressed in the presence of BRAF V600E, the most common BRAF mutation, which occurs in 90% of cases7; whereas MEK inhibitors suppress the BRAF-activated proteins MEK1 and MEK2.8 In phase 3 trials, the use of vemurafenib, dabrafenib, and trametinib have shown favorable rates of overall survival (OS) or progression-free survival (PFS) compared with chemotherapy.8,9,10 It is important to note that the relationship between BRAF mutation and its downstream MAPK activation can give rise to secondary resistance to BRAF inhibitors.

When BRAF kinase is inhibited, MAPK reactivation may be driven by the emergence of secondary mutations in NRAS and MEK1 in some patients.5,11-14 The development of BRAF-inhibitor resistance by this mechanism provides the rationale for a therapeutic strategy in which MEK inhibition is added to BRAF inhibition to ensure control of the MAPK pathway.5,11-14 Clinical trials provide evidence that the combination of a BRAF inhibitor plus an MEK inhibitor may optimize systemic therapy in Figure 1 BRAF-mediated pathway of tumor cell proliferation.6

BRAF indicates B-Raf proto-oncogene; ERK, extracellular signal-related kinase; MEK, mitogen-activated protein kinase kinase.

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BRAF-mutation–positive melanoma.15-17 Trials of the combination of BRAF/MEK inhibitors have demonstrated overall response rates (ORRs) of 67% to 68%, which were significantly higher than ORRs with a BRAF inhibitor alone.15,16 In another trial, BRAF inhibition with vemurafenib plus the MEK inhibitor trametinib resulted in an OS advantage over single-agent vemurafenib that was large enough to warrant early termination of the study.17 The pathobiology of melanoma extends beyond BRAF mutation. For instance, NRAS mutation is also relevant to melanoma, and carries a very poor prognosis.18 Melanoma of the NRAS-mutation profile may respond to therapy with binimetinib (an MEK inhibitor) plus LEE011 (a CDK4/6 inhibitor).18

“Dysfunction in T-cell immunity plays a role in melanoma. That is the rationale for immunotherapy in this malignancy.”

—Antoni Ribas, MD Dysfunction in T-cell immunity also plays a role in melanoma. T-cell dysfunction is the rationale for immunotherapy in metastatic melanoma, which includes: interleukin-2 (IL-2, a cytokine signaling molecule); the monoclonal antibody ipilimumab (which blocks the immune checkpoint molecule, CTLA-4, to reverse downregulation of cytotoxic T-cell function)19; and anti–PD-1/PD-L1 antibodies such as nivolumab and pembrolizumab. Inhibition of the interaction between PD-1 (an immune checkpoint) and PD-L1 can enhance effector-phase T-cell response and support the cytotoxic function of T-cells.20,21 CTLA-4 and PD-1 are called immune checkpoints because their function is to terminate T-cell–mediated immune response to tumor cells after antigen activation.20 In principle, inhibition of checkpoints should interfere with a tumor’s ability to evade immune destruction, thus supporting a more robust immune response to the malignancy.20 This principle has borne fruit in practice: anti–CTLA-4 and anti–PD-1 agents have improved OS significantly in metastatic melanoma.19,22,23 Recent clinical data on these agents were discussed in detail at the conference (see New Drugs, New Trials).

BCC James Macdonald, MD, a dermatologist at the Central Utah Clinic, Provo, emphasized that, despite the typically nonaggressive clinical behavior of BCC, the disease does exhibit significant genetic and molecular heterogeneity, even among cells within a single tumor.24

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BCC arises from aberrant Hedgehog (Hh)-pathway signaling.25 The discovery of this pivotal pathway has given rise to therapeutic approaches that target the Hh signaling pathway, such as vismodegib.26 This class of drugs blocks the signaling activity of the SMO protein— restoring an inhibitory activity that is suppressed when Hh aberrations cause a loss of function of PTCH1 protein.26 Although the Hh pathway is the single common driver of BCC,25 subsequent molecular progression produces a range of subtypes, varying in appearance, behavior, and aggressiveness. For example, metatypical BCC is characterized by significant immunohistochemical expression of CXCR4, MMP-13, and β-catenin—expression which does not occur to the same degree in superficial BCC.27 Aggressive forms of BCC, such as micronodular BCC, may also overexpress the proteins p53, D2-40, or β-SMA, which are potential biomarkers for aggressiveness in BCC.28

CTCL In a group of cancers as diverse as CTCL, it may be useful to identify common pathobiologies. Anjali Mishra, MD, Assistant Professor at the Ohio State University Comprehensive Cancer Center, Columbus, presented evidence on the role of the cytokine IL-15 in the pathogenesis of CTCL. IL-15 is overexpressed in patients with these types of malignancies, and data in MF suggest that CTCL expression increases with progression to more advanced stages of disease.29 This cytokine, binding to its receptor (IL-15R), mediates several pathways of CTCL development: multiple JAK/STAT pathways and activation of Grb2/MAPK/Akt activity.30 Dr Mishra’s team has shown that IL-15 transgenic mice progress to a severe stage of CTCL characterized by erythematous plaques/patches, erythroderma, and pruritus. The pathways of IL-15–induced CTCL suggest 3 therapeutic targets: antibody blockade of IL-15 binding to its receptor (eg, Mikβ1); JAK/STAT inhibition (eg, AG-490); and proteasome inhibition (eg, bortezomib) to block activation of NF-κB downstream from MAPK/Akt.30 In addition, CTCLs are responsive to histone deacetylase (HDAC) inhibitors, such as vorinostat, which work by epigenetic regulation of gene transcription to suppress tumor cell proliferation and increase tumor cell apoptosis.31 HDAC inhibitors suppress CTCLs by transcriptional reprogramming that affects multiple molecular pathways, including those mediated by IL-15. For example, stimulation of the MAPK pathway (an effect of IL-15) is associated with histone activity and transcriptional activation of genes.32 In Dr Mishra’s investigations, administration of HDAC inhibitors to IL-15 transgenic mice minimized development of CTCL lesions.

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Current Treatment Algorithms Melanoma Various approaches to the management of patients with melanoma were the subject of back-to-back presentations by Dr Ribas and Axel Hauschild, MD, PhD, Professor of Dermatology at the University Hospital Schleswig-Holstein, Kiel, Germany.

Dr Ribas emphasized that the US treatment algorithm for advanced melanoma is changing profoundly with the introduction of therapies that inhibit BRAF and MEK and immunotherapies against CTLA-4 and PD-1.1,5 Currently, the major bifurcation in treatment selection arises from BRAF mutation status; when the mutation is found, it opens the option to use a BRAF inhibitor plus an MEK inhibitor.1,5 It is important to note, however, that the use of immunotherapies such as IL-2, ipilimumab (anti–CTLA-4), and nivolumab or pembrolizumab (anti–PD-1) need not be limited to patients without the BRAF mutation.1,5 Another interesting aspect of current US practice is a continued role for high-dose IL-2, which has the potential to produce very durable responses and, in responders, long-term survival.5 IL-2 is currently recommended as a first-line treatment by the Society for Immunotherapy of Cancer in BRAF-positive and BRAF-negative patients with stage IV melanoma, provided they have a good performance status and treated central nervous system disease.5 It is also important to note that chemotherapy, once the mainstay of therapy for metastatic melanoma, is generally not utilized until after a patient achieved received >1 targeted therapies/immunotherapies.5 Novel forms of immunotherapy continue to improve outcomes in melanoma. Anti–CTLA-4 and anti–PD-1 agents have demonstrated excellent rates of durable clinical response.19-21 In the case of anti–PD-1 agents, a response of ≥1 year was reported in 50% of patients with melanoma who were treated with nivolumab; median follow-up was 11 months in patients who had achieved a response to pembrolizumab.20,21 Immunotherapy is not without drawbacks, including immune-related adverse effects. These can range from vitiligo to symptomatic cutaneous, gastrointestinal, hepatic, and endocrine toxicities, and particularly development of autoimmunity.5 Additionally, because immunotherapy can have somewhat delayed antitumor activity, it may be most appropriate for patients with good performance status and without rapidly progressive melanoma to maximize the time available to respond to therapy.5 The anti–PD-1 agents appear to have the advantage of a lower incidence of immune-related adverse events than anti–CTLA-4 agents, although this observation was based on cross-study comparisons and should be viewed cautiously.21

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Dr Ribas predicted that within a few years, there will be clinically useful biomarkers for best response to anti– PD-1 therapy.33 Biomarker profiles will include PD-1 expression, but will also need to quantitate tumor antigen-specific T-cell infiltration.33 In other words, biomarker assay will need to show that there is a T-cell that recognizes the cancer and initiates signaling that leads to the expression of PD-1/PD-L1. When a patient’s tumor exhibits relevant T-cells and PD-1 expression, anti– PD-1 therapy will likely be a first-line option in both BRAF-positive and BRAF-negative patients.

In comparison to the approach used in the United States, Europe’s melanoma treatment algorithm is more strongly influenced by governmental requirements for cost control. Dr Hauschild began his presentation by acknowledging the importance of cost in treatment planning across Europe, as mandated by groups such as the National Institute for Health and Care Excellence and Germany’s Gemeinsamer Bundesausschuss. The availability of new drugs is limited in many European countries. These drugs are approved, but not reimbursed, and are cost-prohibitive for most patients.

Currently, there is no accepted pan-European guideAbbreviation Key (Genetic and Molecular Terms) α-SMA: α−smooth muscle actin BRAF: B-Raf proto-oncogene CCND1: cyclin D1 gene CCR4: C-C chemokine receptor type 4 CDK4/6: cyclin-dependent kinase 4/6 CTLA-4: cytotoxic T-lymphocyte–associated antigen 4 CXCR4: C-X-C chemokine receptor type 4 D2-40: podoplanin ERK: extracellular signal-related kinase GLI: glioma family protein GLI2: glioma family zinc finger 2 protein JAK: Janus-associated kinase MAP-kinase (MAPK): mitogen-activated protein kinase MEK: mitogen-activated protein kinase kinase MMP-13: matrix metalloproteinase 13 NF-κβ: nuclear factor kappa-light-chain-enhancer of activated B-cells NRAS: neuroblastoma rat sarcoma viral oncogene homolog PD-1: programmed cell death protein 1 PD-L1: programmed cell death ligand 1 PI3K: phosphoinositide 3-kinase PTCH1: patched homologue 1 SMO: smoothened homologue STAT: signal transducer and activator of transcription

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line for melanoma, although a guideline was developed by the European Society for Medical Oncology (ESMO),34 and there are several national guidelines. For example, there is a more recent German guideline,35 based on a Cochrane review of the existing literature and multidisciplinary consensus from the German Cancer Society. For the treatment of patients with stage IV melanoma, this guideline considers BRAF status, tumor load, and speed of progression in the decision-making process. Ipilimumab and BRAF inhibitors are specifically included in the German guideline; anti–PD-1 agents are not specified, and chemotherapy is recommended sooner in the course of therapy (eg, multidrug chemotherapy is a first-line option in BRAF-negative patients with a high tumor load and rapid progression).35 This German guideline is fairly robust in terms of detail and clinical support.

“In advanced melanoma, combination systemic treatment produces very good outcomes in terms of response rate and time to best response…data are strong with the combination of anti–PD-1 plus anti–CTLA-4 immunotherapies.”

—Axel Hauschild, MD, PhD Current guidelines in Europe, however, do not fully recognize the importance of combining systemic therapies for advanced melanoma. In his presentation, Dr Hauschild stressed that a valuable trend in melanoma care is the use of combinations of novel agents—BRAF inhibitors plus MEK inhibitors15-17 or antibody combinations.36 Recent data from a phase 1 trial show that the combination of nivolumab plus ipilimumab, at several doses, produced a very high 1-year OS (see New Drugs, New Trials).36 Among doses tested in the phase 1 trial, nivolumab 1 mg/ kg plus ipilimumab 3 mg/kg q3wk × 4 doses (followed by nivolumab 3 mg/kg q2wk) is the selected regimen for phase 2/3 trials.35 As research and anecdotal evidence accrue, this will help to determine whether specific combinations have additive or synergistic effects, and whether sequencing of combinations affects the efficacy of therapy.

For example, a new clinical trial is examining sequenced combinations: BRAF and MEK inhibition followed by anti–PD-1 plus anti–CTLA-4 treatment, compared with the opposite sequence of antibody combination followed

by BRAF and MEK inhibition.37

BCC Karl D. Lewis, MD, Associate Professor of Medicine of the Cutaneous Oncology Program at University of

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Colorado, Denver, reported on the shifting paradigm of care in BCC, which has been prompted by the development of targeted Hh-pathway agents. In the classic algorithm, treatment of patients with regional or locally advanced BCC is surgical and topical rather than systemic, including cryotherapy, electrodesiccation, or topical 5-fluorouracil or imiquimod for low-risk lesions; and surgical excision, micrographic (Mohs) surgery, or radiation therapy for high-risk lesions.3 However, Hh inhibitors now provide an option for systemic therapy of patients with advanced BCC. In 33 patients with metastatic disease, treatment with vismodegib produced an ORR of 30% (P = .001 for the end point of >10% response in metastatic disease).26 In 63 patients with locally advanced BCC, ORR was 43% (P <.001 for the end point of >20% response in locally advanced disease); 13 (21%) of these patients achieved a complete response.26 The Hh-pathway inhibitor sonidegib has demonstrated clinically meaningful tumor shrinkage over time, sustained responses, and prolonged PFS in locally advanced and metastatic BCC.38 More than half (57.6%) of the patients with locally advanced disease responded to treatment with sonidegib.38

CTCL From the 1990s to the present, beginning with the use of the HDAC inhibitor vorinostat, CTCL therapy has incorporated targeted agents and advanced chemotherapy. New patterns of care were described by Pierluigi Porcu, MD, Associate Professor of Medicine at the Ohio State University Comprehensive Cancer Center, Columbus.

The management of CTCLs is highly individualized, even within disease subtypes, due to heterogeneity of presentation and course. Patients with MF/Sézary syndrome (SS), for example, have variable risks for disease progression depending on clinical stage and T (primary tumor) classification.39 As the disease manifests in different stages, it requires different multidisciplinary approaches: dermatology-led care for early-stage disease gives way to oncology-led care in advanced stages. Treatment follows this trajectory as well: topical, skin-directed therapy for stage IA disease, with an increasing emphasis on systemic therapy as stages advance.2 Systemic therapies include HDAC inhibitors (vorinostat, romidepsin) and the retinoid bexarotene, along with chemotherapy combinations and alemtuzumab.2 Vorinostat and romidepsin have yielded response rates in MF/SS of approximately 25% to 35%.40 However, there is a good deal of overlap in therapeutic choices by stage. For example, topical therapies and radiation may be used at both early and advanced stages, even as systemic therapies are added to the mix.2

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Emerging Therapeutic Approaches Melanoma From adjuvant therapy in melanoma to advanced chemotherapies in MCC, the management of cutaneous malignancies continues to evolve. Reinhard Dummer, MD, Professor and Vice Chairman in the Department of Dermatology at University Hospital, Zürich, presented data on current and novel approaches to adjuvant therapy for patients with melanoma. In melanomas that can be removed surgically, there are some clinical indications that warrant use of adjuvant treatment; namely, larger tumor thickness and positive nodes.2 From that point, however, it is not always clear which adjuvant measures to apply, and whether to offer the mainstays of interferon or nodal radiotherapy, neither of which is supported by the most robust evidence (2B in guidelines from the National Comprehensive Cancer Network [NCCN]).2 Patients who are candidates for adjuvant therapy have additional choices: chemotherapy, alternative medicine, therapeutic vaccines, kinase inhibitors, ipilimumab, and, probably soon, anti–PD-1 agents. Such choices may be especially good if patients are enrolled in a clinical trial—something Dr Dummer advocates so that patients may take advantage of up-and-coming modes of adjuvant therapy.

Results with ipilimumab as adjuvant therapy have been promising. The phase 3 study, EORTC 18071/ CA184-029, met its primary end point of a significant improvement in recurrence-free survival (RFS) with adjuvant ipilimumab versus placebo in postresection, stage III melanoma.41 Median RFS with ipilimumab was significantly longer than with placebo (P = .0013) (Figure 2); 3-year RFS rates were 46.5% versus 34.8%, respectively.41 The safety profile of ipilimumab in adjuvant use was consistent with that for the drug in the treatment of advanced disease; the most common grade 3/4 immune-related adverse events in the ipilimumab and placebo arms, respectively, were gastrointestinal (15.9% vs 0.8%), hepatic (10.6% vs 0.2%), and endocrine (8.5% vs 0%); most were managed and resolved using established practice.41 For example, grade 3/4 immune-related diarrhea can be managed with methylprednisone, and, if response is not adequate, with infliximab and cessation of ipilimumab.42 Another phase 3 trial in the adjuvant setting is under way; this trial will compare ipilimumab at 3 mg/kg or 10 mg/kg versus high-dose interferon.43 BCC Aleksandar Sekulic, MD, PhD, Assistant Professor of Dermatology at the Mayo Clinic, Scottsdale, AZ, addressed the expanding use of Hh-pathway inhibition in the treatment of patients with advanced BCC and in neoadjuvant care. Several Hh-pathway inhibitors are in

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after Figure 2 Median RFS with ipilimumab versus placebo resection of stage III melanoma (N = 951).41

umab Ipilim

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RFS indicates recurrence-free survival.

development (eg, LEQ506, BMS-833823, TAK-441, IPI926, PF-04449913), with research spurred by the favorable data on vismodegib and sonidegib.26,38,44 According to Dr Sekulic, there is no question that Hh inhibitors play a key role in advanced BCC. The questions, instead, concern best practices in the use of these agents: • Who to treat? Patient selection depends on multiple factors, such as inoperability of the cancer, location, size, residual disease, and histologic subtype. Certain patient profiles seem to lend themselves to the consideration of systemic therapy. For example, patients with very large affected areas, orbital/sinus involvement, or residual disease after other treatments may be good candidates for Hh-pathway inhibitor therapy.

Histologic subtype may also predict response to therapy, and a trial is now evaluating the efficacy of vismodegib in the BCC histologic subtypes of infiltrative/morpheaform, nodular, and superficial.45 • How long to treat? This question has not been fully answered for Hh-pathway targeted therapies. BCC tumors respond at different rates, and it has been Dr Sekulic’s experience that some patients attain full resolution quickly with Hh inhibition, whereas others do not. Moreover, some patients with BCC, such as those with Gorlin syndrome, continue to develop new cancers, further complicating the question of how long to treat.

• How to manage toxicity? The most commonly observed adverse events (any grade) associated with the Hh-pathway inhibitor vismodegib were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, decreased appetite, and diarrhea. All occurred in

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≥20% of patients.26 Muscle cramping is a troublesome class effect associated with these agents. Management of muscle spasm may include hydration, multielectrolyte supplementation, and muscle relaxants; interruption of therapy may also help, although this raises issues in maximizing efficacy. Supplementation with L-carnitine is also being studied for a potential favorable effect on vismodegib-related muscle spasms.46 • How to cope with resistance? Primary and secondary resistance has been reported with Hh-pathway inhibitor treatment.47-49 Several molecular mechanisms are involved in resistance to these agents. One putative mechanism of primary resistance may be the development of an SMO G497W gene mutation that obstructs binding of the agents to the cell surface activator of Hh signaling, the SMO receptor.47 Mechanisms of acquired resistance include SMO gene mutation, amplification of the downstream Hh-signaling molecule GLI2, amplification of the Hh target gene CCND1, and upregulation of the PI3K pathway.50

“It is not always clear which patients with BCC should receive an Hh-pathway inhibitor.

You have to consider the site—has the cancer advanced to a place that you may not want to resect? You have to look at histology and history of recurrence.”

—Aleksandar Sekulic, MD, PhD On the horizon for Hh-pathway inhibition therapy is the potential for neoadjuvant use to control large BCCs prior to excision,51,52 multimodal therapy,53,54 and chemoprevention.55 Understanding of the clinical role of systemic treatment in advanced BCC will be abetted by the 8-year, RegiSONIC disease registry study.56

CTCL Several new approaches are emerging for the treatment of patients with CTCL. According to Steven M. Horwitz, MD, Associate Attending Physician on the Lymphoma Service at Memorial Sloan Kettering Cancer Center, New York City, these therapies do not represent a radical shift in paradigm, but rather an opportunity for incremental improvement. Patients will still be treated with sequential, single agents based on ORR as a study end point; innovation comes in the form of good-quality data on the systemic use of novel targets.

Phase 3 trials in CTCL are evaluating the anti–CCR4 antibody, mogamulizumab, versus vorinostat plus the CD30-antibody/drug conjugate, brentuximab vedotin,

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versus methotrexate or bexarotene.57,58 Mogamulizumab has the property of enhanced, antibody-dependent, cell-mediated cytotoxicity due to the absence of fucose in the antibody backbone,59 and has been shown to produce good ORRs in a variety of CTCL subtypes.60 There is also evidence that IPI-145, an oral kinase inhibitor of both the PI3K-δ and PI3K-γ isoforms, has single-agent activity in CTCL.61 A novel, topically applied HDAC inhibitor, SHP-141, which selectively inhibits specific HDAC isoforms, has demonstrated favorable activity in CTCL.62 Dr Horwitz also noted that the PD-1 pathway may provide a meaningful target in this disease.

MCC Shailender Bhatia, MD, Assistant Professor in the Department of Medicine, Division of Oncology, at Fred Hutchinson Cancer Research Center, Seattle, WA, presented cytotoxic strategies for the management of MCC, an aggressive skin cancer with neuroendocrine features that is sensitive to chemotherapy. Current NCCN guidelines recommend specific platinum-based, topotecan-based, or anthracycline-based chemotherapies for disseminated MCC.63 Chemotherapy is certainly not a panacea; first-line response rates are high, but response is not durable and second-line chemotherapy works infrequently.64 Given that no clear molecular target has yet emerged in MCC, clinicians and researchers must still rely on and investigate chemotherapy and radiation therapy. Single faction, 8-Gy radiation therapy has been a useful option for metastatic MCC at Dr Bhatia’s institution, with good tolerability and feasibility at visceral sites of metastasis.

Radiotherapy may also offer these patients a potentially immunogenic effect.65 There may also be some sensitivity of MCC to PI3K-inhibition.66 The kinase inhibitors pazopanib and cabozantinib are being studied in MCC; a case study has reported good clinical outcomes in a patient with PDGFR-α mutation in codon 478 treated with pazopanib.67 Immunotherapy with pembrolizumab in MCC and other PD-1–targeted agents is being evaluated, as are therapies that can be injected locally into MCC lesions. Somatostatin-receptor–targeting chemotherapy with pasireotide is also under investigation.

Dr Bhatia suggested that at this time, multidisciplinary management of MCC is the most appropriate choice. This strategy will allow for the judicious selection of immunotherapy to produce a durable response in eligible patients, cytotoxic chemotherapy and radiation therapy for symptom control and reduction of tumor bulk, and targeted chemotherapy to support quality of life.

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Melanoma: Screening and Prevention Susan Swetter, MD, Professor of Dermatology at Stanford University, Palo Alto, CA, presented current issues in the early detection of melanoma. The consensus of the US Preventive Services Task Force is that evidence is not sufficient to determine the benefit of primary-care screening or self-examination for the disease.68 The prevailing view is that targeted screening of highrisk subsets of patients (eg, those with clinical atypical nevi) is more effective than mass screening.

However, a German project of mass screening and public awareness, the Skin Cancer Research to Provide Evidence for Effectiveness of Screening in Northern Germany (SCREEN), has produced reductions in mortality,69 and an Australian screening project decreased the risk of thicker melanomas at diagnosis.70 A study conducted by Dr Swetter’s team found that a physician skin exam in the year prior to a melanoma diagnosis was associated with a 2.5 times greater likelihood of being diagnosed with a thin (≤1 mm) and, therefore, treatable melanoma, with notable benefit in men older than 60 years of age, a high-risk group.71 Important new data will be accruing in an ongoing, 3-year screening and data registry project at the University of Pittsburgh Medical Center, which will run from 2014 to 2017. Over the long term, these studies may show the public health value of screening. Moreover, the possibility of melanoma chemoprevention may increase the value of screening. Although many topical and systemic agents have been considered for this use, chemoprevention remains an underexplored area of melanoma care that could benefit from more research.72 Expanding on Dr Swetter’s presentation, Dr Hauschild presented updated results on SCREEN. Germany has implemented national skin cancer screening, and, thus far, approximately 18 million people have been screened via this mandate. SCREEN evaluated the results of screening in the Schleswig-Holstein region, beginning in 2003 and involving 360,288 participants (of 1.88 million eligible citizens).69 During SCREEN, the incidence of invasive melanoma increased 34%, but 5 years after the project, there were substantial decreases in melanoma mortality for both men and women.69 However, additional factors, such as a simultaneous public awareness campaign on melanoma, may have confounded the findings somewhat. According to Dr Hauschild, SCREEN shows that population-wide melanoma screening is feasible and beneficial, but the value of the findings should not be overestimated.

New Drugs, New Trials Melanoma In the systemic treatment of patients with advanced melanoma, a key area of research is combination immu-

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notherapy with CTLA-4 and PD-1 targeted agents.

Caroline Robert, MD, PhD, Head of the Dermatology Unit at Institut Gustave-Roussy, Paris, noted that each class of agent alone demonstrates clinical benefit.

In a pivotal trial, ipilimumab monotherapy produced a 45.6% 1-year OS rate and a 23.5% 2-year OS rate in patients with stage III or IV unresectable melanoma whose disease had progressed on prior therapy.19 A separate trial showed that adding ipilimumab to dacarbazine chemotherapy for untreated metastatic disease significantly improved OS.73

“Data from SCREEN suggest some very strong evidence that population-wide melanoma screening could reduce mortality.

It raises the question as to whether the US Preventive Services Task Force should now re-evaluate its view that data are insufficient to support widespread screening.”

—Susan Swetter, MD The anti–PD-1 agents pembrolizumab and nivolumab have yielded promising outcomes in metastatic melanoma. The original phase 1 data for pembrolizumab showed an ORR of 38% as confirmed by Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1; response did not vary according to prior treatment with ipilimumab.21,74 Data updates presented in 2014 showed a 34% ORR by RECIST: 40% in ipilimumab-naïve and 28% in ipilimumab-treated patients.22 Responses were durable (88% ongoing at analysis), with a 12-month OS rate of 69%.22 Nivolumab has produced comparable results in metastatic melanoma. The ORR for single-agent therapy has been reported at 32%, with 1-, 2-, and 3-year OS rates of 62%, 48%, and 41%, respectively.23,75,76 Survival curves for both agents are shown in Figure 3.22,23,76 Data suggest that these agents are effective regardless of BRAF status.36 The efficacy of single-agent therapy with these agents, plus the fact that they are nonredundant checkpoint inhibitors, gave rise to the concept of anti–CTLA-4 plus anti–PD-1 combination therapy. Results of a phase 1 study of nivolumab plus ipilimumab in several dose combinations were presented at the 2014 Annual Meeting of the American Society of Clinical Oncology36 and the 2014 ESMO Congress.77 At the time of the ESMO presentation, the combination of nivolumab plus ipilimumab at mg/kg doses of 0.3/3, 1/3, 3/1, and 3/3 produced 1-year OS rates of 57%, 94%, 94%, and 100%, respectively.77 Across

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in metastatic melanoma treated with pembrolizumab (n = 411) or nivolumab (n = 107) in Figure 3 Overall survival22,23,76 phase 1 trials.

100 90 80 70 60 50 40 30 20 10 0

Nivolumab

12 months 69% 18 months 62%

0

2

4

6

Overall survival (%)

Overall survival (%)

Pembrolizumab 100 90 80 70 60 50 40 30 20 10 0

8 10 12 14 16 18 20 22 24 26 28 Months

cohorts, 1- and 2-year survival rates were 85% and 79%, respectively. Response was durable and observed regardless of BRAF mutation status. Median duration of response had not been reached at multiyear follow-up. Aggregate clinical activity rate, a composite of types of response, was 70% across cohorts.77 Grade 3/4 adverse events occurred in 62% of patients; these included elevations in lipase (15%) and the hepatic enzymes alanine transaminase (12%) and aspartate aminotransaminase (11%).77

BCC Jean Y. Tang, MD, PhD, Associate Professor of Dermatology at Stanford School of Medicine, presented data from the first 131 patients evaluated in the ongoing, longterm RegiSONIC study and registry of patients with BCC.56 The goals of RegiSONIC are to learn how clinicians determine and treat advanced BCC in the real world by evaluating the effectiveness, safety, and use of systemic and local treatments in 3 populations: (1) patients with advanced BCC who do not have BCC nevus syndrome and are naïve to Hh-pathway inhibitors; (2) patients with advanced BCC who do not have BCC nevus syndrome and who were previously enrolled in a vismodegib trial; and (3) BCC nevus syndrome patients who have advanced disease or who have multiple nonadvanced BCCs untreated with Hh-pathway inhibitors.56 Goal enrollment is 750 patients. On analysis of the first 131 patients, median size of locally advanced BCC was 20.5 mm at determination; the most frequent location was the nose (19.8%), and the most common histopathology was nodular (58.8%) (Tang J, personal communication, October 2014).

Dr Tang also discussed scientific developments in

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1 year 62% 2 year 48% 3 year 41%

0

3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 Months

targeting the Hh pathway in BCC. In addition to vismodegib and sonidegib, drugs approved for other uses appear to have some Hh inhibitory effect. A small-molecule library screen of US Food and Drug Administration–approved drugs revealed that the antifungal agent itraconazole and the leukemia treatment arsenic trioxide (ATO) have inhibitory activity at different points in the Hh pathway—itraconazole at SMO, ATO at the downstream level of GLI protein.78 Oral itraconazole has been shown to suppress the Hh pathway by 65% and to reduce tumor size by 24%.79 Improvements were limited to vismodegib-naïve patients; vismodegib-treated patients showed no significant changes in tumor size.79 A study of ATO for the treatment of patients with BCC is on the research horizon.80

MCC Isaac Brownell, MD, PhD, investigator in the Dermatology Branch of the Center for Cancer Research at the National Cancer Institute, Bethesda, MD, summarized the status of immune-targeted therapies for MCC. According to Dr Brownell, MCC should, in principle, respond to immunotherapy; the disease exhibits many features of immunotherapy-sensitive cancers, such as a higher incidence in immunocompromised populations, cases of spontaneous regression, and expression of nonself Merkel-cell polyomavirus (MCV) viral antigens. In fact, MCV is an immune target in MCC.81-83 A number of immunotherapy strategies in MCC are currently being studied. The investigational anti–PD-L1 agent, MSB0010718C, will be evaluated in a phase 2 trial as second-line therapy for MCC.84 Ipilimumab will also be assessed as adjuvant therapy for excised MCC.85

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Additional upcoming trials include the Cancer Immunotherapy Trials Network phase 2 trial of anti–PD-1 therapy used first-line in MCC and the 4-1BB agonist, PF05082566, which has already been used in a phase 1 trial that included 6 patients with MCC.86 Investigators are also seeking support from the Southwest Oncology Group for a study of an anti–PD-1 agent plus an anti– CTLA-4 agent in the treatment of patients with MCC. Other treatments under consideration are MCV-reactive autologous T-cell therapy, IL-12 gene and in vivo electroporation-mediated plasmid DNA vaccine therapy, IL-glucopyranosyl lipid adjuvant-stable emulsion, and F16-IL2 antibody-cytokine fusion with paclitaxel.

Conclusion Personalized management of cutaneous malignancies is an important goal, given the heterogeneity and diversity of these cancers. An understanding of the pathobiologic mechanisms of cutaneous malignancies has paved the way for development of novel therapies, including molecularly and genetically targeted drugs and immunotherapies. As our knowledge grows, so too will our options for advanced treatment. u Dana Delibovi contributed to the development of this article.

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68. US Preventive Services Task Force. Screening for skin cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;150:188-193.

69. Breitbart EW, Waldmann A, Nolte S, et al. Systematic skin cancer screening in Northern Germany. J Am Acad Dermatol. 2012;66:201-211.

70. Aitken JF, Elwood M, Baade PD, et al. Clinical whole-body skin examination reduces the incidence of thick melanomas. Int J Cancer. 2010;126:450-458.

71. Swetter SM, Pollitt RA, Johnson TM, et al. Behavioral determinants of successful early melanoma detection. Cancer. 2012;118:3725-3734.

72. Demierre MF, Nathanson L. Chemoprevention of melanoma: an unexplored strategy. J Clin Oncol. 2003;21:158-165.

73. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526.

74. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384:1109-1117.

75. Weber JS, Minor DR, D’Angelo S, et al. A phase 3 randomized, open-label study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus investigator’s choice chemotherapy (ICC) in patients with advanced melanoma after prior anti-CTLA-4 therapy. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25: Abstract LBA3_PR. 76. Hodi SF, Sznol M, Kluger HM, et al. Long-term survival of ipilimumab-naive patients (pts) with advanced melanoma (MEL) treated with nivolumab (anti-PD-1, BMS-936558, ONO-4538) in a phase I trial. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl 5):Abstract 9002.

77. Kluger H, Sznol M, Callahan M, et al. Survival, response duration, and activity

by BRAF mutation (MT) status in a phase 1 trial of nivolumab (anti-PD-1, BMS936558, ONO-4538) and ipilimumab. Ann Oncol (ESMO Annual Meeting Abstracts).

2014;25:Abstract 1085O. 78. Kim J, Aftab BT, Tang JY, et al. Itraconazole and arsenic trioxide inhibit hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell. 2013;23:23-34.

79. Kim DJ, Kim J, Spaunhurst K, et al. Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J Clin Oncol. 2014;32:745-751.

80. Arsenic trioxide in treating patients with basal cell carcinoma (NCT01791894). https://clinicaltrials.gov/ct2/show/NCT01791894?term=NCT01791894&rank=1.

Accessed January 16, 2015.

81. Paulson KG, Carter JJ, Johnson LG, et al. Antibodies to merkel cell polyomavirus T antigen oncoproteins reflect tumor burden in merkel cell carcinoma patients.

Cancer Res. 2010;70:8388-8397.

82. Touzé A, Le Bidre E, Laude H, et al. High levels of antibodies against merkel cell polyomavirus identify a subset of patients with merkel cell carcinoma with better clinical outcome. J Clin Oncol. 2011;29:1612-1619.

83. Iyer JG, Afanasiev OK, McClurkan C, et al. Merkel cell polyomavirus-specific CD8+ and CD4+ T-cell responses identified in Merkel cell carcinomas and blood.

Clin Cancer Res. 2011;17:6671-6680.

84. MSB0010718C in subjects with Merkel cell carcinoma (NCT02155647). https:// clinicaltrials.gov/ct2/show/NCT02155647?term=NCT02155647&rank=1. Accessed January 16, 2015.

85. Prospective randomized trial of an adjuvant therapy of completely resected Merkel cell carcinoma (MCC) with 3mg/kg BW ipilimumab (Yervoy®) every 3 weeks for 12 weeks versus observation. www.clinicaltrialsregister.eu/ctr-search/search?query= eudract_number:2013-000043-78. Accessed January 16, 2015.

86. Segal NH, Gopal AK, Bhatia S, et al. A phase 1 study of PF-05082566 (anti-41BB) in patients with advanced cancer. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl 5):Abstract 3007.

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VALCHLOR® (mechlorethamine) gel is an alkylating drug indicated for the topical treatment of Stage IA and IB mycosis fungoides–type cutaneous T-cell lymphoma (MF-CTCL) in patients who have received prior skin-directed therapy WHEN IT’S TIME TO MANAGE THE CHALLENGES OF STAGE IA AND IB MF-CTCL

VALCHLOR IS ON IT The first and only FDA-approved topical formulation of mechlorethamine (commonly known as nitrogen mustard) • Proven efficacy in a 12-month study 1 • Once-daily gel (special handling and disposal procedures should be followed)

• Dependable formulation manufactured with consistent quality and potency • Comprehensive resources provided by VALCHLOR Support ™

For more information, including how to prescribe, visit www.valchlor.com or call 1-855-4-VALCHLOR (1-855-482-5245).

DOSING AND APPLICATION VALCHLOR is for topical dermatologic use only. Apply a thin film of gel once daily to affected areas of the skin. VALCHLOR is a cytotoxic drug and special handling and disposal procedures should be followed during use. Caregivers must wear disposable nitrile gloves when applying VALCHLOR. Patients and caregivers must wash hands thoroughly after handling or applying VALCHLOR.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS VALCHLOR is contraindicated in patients with known severe hypersensitivity to mechlorethamine. Hypersensitivity reactions, including anaphylaxis, have occurred with topical formulations of mechlorethamine.

WARNINGS AND PRECAUTIONS • Mucosal or eye injury: Exposure of mucous membranes to mechlorethamine such as the oral mucosa or nasal mucosa causes pain, redness, and ulceration, which may be severe.

Exposure of the eyes causes pain, burns, inflammation, photophobia, and blurred vision. Blindness and severe irreversible anterior eye injury may occur. Should eye exposure or mucosal contact occur, immediately irrigate for at least 15 minutes with copious amounts of water, followed by immediate medical consultation • Secondary exposure: Avoid direct skin contact with VALCHLOR in individuals other than the patients due to risk of dermatitis, mucosal injury, and secondary cancers

• Dermatitis: Dermatitis may be moderately severe or severe.

Monitor patients for redness, swelling, inflammation, itchiness, blisters, ulceration, and secondary skin infections.

Stop treatment with VALCHLOR or reduce dose frequency • Non-melanoma skin cancer: Monitor patients during and after treatment with VALCHLOR • Embryo-fetal toxicity: Women should avoid becoming pregnant while using VALCHLOR due to the potential hazard to the fetus. For nursing mothers, discontinue use of VALCHLOR or nursing • Flammable gel: VALCHLOR is an alcohol-based gel. Avoid fire, flame, and smoking until the gel has dried

ADVERSE REACTIONS The most common adverse reactions (≥5%) were dermatitis (56%), pruritus (20%), bacterial skin infection (11%), skin ulceration or blistering (6%), and skin hyperpigmentation (5%). These reactions may be moderately severe or severe.

Elderly patients aged 65 and older may be more susceptible. Depending on severity, treatment reduction, suspension, or discontinuation may be required.

To report SUSPECTED ADVERSE REACTIONS, contact Actelion Pharmaceuticals US, Inc., at 1-855-4-VALCHLOR (1-855-482-5245) or FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch.

Please see Brief Summary of Prescribing Information on adjacent page.

REFERENCE: 1. VALCHLOR [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; 2013.

VALCHLOR®and VALCHLOR Support™ are trademarks of Actelion Pharmaceuticals Ltd. © 2014 Actelion Pharmaceuticals US, Inc. All rights reserved. VAL-00163 0814

A great idea finally gels

VALCHLOR® (mechlorethamine) gel, 0.016% For Topical Dermatological Use Only BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION This brief summary does not include all the information needed to use VALCHLOR safely and effectively. See Full Prescribing Information for VALCHLOR. • INDICATIONS AND USAGE VALCHLOR is an alkylating drug indicated for the topical treatment of Stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in patients who have received prior skin-directed therapy.

• CONTRAINDICATIONS The use of VALCHLOR is contraindicated in patients with known severe hypersensitivity to mechlorethamine. Hypersensitivity reactions, including anaphylaxis, have occurred with topical formulations of mechlorethamine.

• WARNINGS AND PRECAUTIONS >> Mucosal or Eye Injury Exposure of the eyes to mechlorethamine causes pain, burns, inflammation, photophobia, and blurred vision. Blindness and severe irreversible anterior eye injury may occur. Advise patients that if eye exposure occurs, (1) immediately irrigate for at least 15 minutes with copious amounts of water, normal saline, or a balanced salt ophthalmic irrigating solution and (2) obtain immediate medical care (including ophthalmologic consultation).

Exposure of mucous membranes such as the oral mucosa or nasal mucosa causes pain, redness, and ulceration, which may be severe. Should mucosal contact occur, immediately irrigate for at least 15 minutes with copious amounts of water, followed by immediate medical consultation. >> Secondary Exposure to VALCHLOR Avoid direct skin contact with VALCHLOR in individuals other than the patient. Risks of secondary exposure include dermatitis, mucosal injury, and secondary cancers. Follow recommended application instructions to prevent secondary exposure. >> Dermatitis The most common adverse reaction was dermatitis, which occurred in 56% of the patients. Dermatitis was moderately severe or severe in 23% of patients.

Monitor patients for redness, swelling, inflammation, itchiness, blisters, ulceration, and secondary skin infections. The face, genitalia, anus, and intertriginous skin are at increased risk of dermatitis. Follow dose modification instructions for dermatitis. >> Non-Melanoma Skin Cancer Four percent (4%, 11/255) of patients developed a non-melanoma skin cancer during the clinical trial or during one year of post-treatment follow-up: 2% (3/128) of patients receiving VALCHLOR and 6% (8/127) of patients receiving the mechlorethamine ointment comparator. Some of these non-melanoma skin cancers occurred in patients who had received prior therapies known to cause non-melanoma skin cancer. Monitor patients for non-melanoma skin cancers during and after treatment with VALCHLOR. Non-melanoma skin cancer may occur on any area of the skin, including untreated areas. >> Embryo-fetal Toxicity Based on its mechanism of action, case reports in humans, and findings in animals, VALCHLOR can cause fetal harm when administered to a pregnant woman. There are case reports of children born with malformations in pregnant women systemically administered mechlorethamine. Mechlorethamine was teratogenic and embryo-lethal after a single subcutaneous administration to animals. Advise women to avoid becoming pregnant while using VALCHLOR. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. >> Flammable Gel Alcohol-based products, including VALCHLOR, are flammable. Follow recommended application instructions.

• ADVERSE REACTIONS In a randomized, observer-blinded, controlled trial, VALCHLOR 0.016% (equivalent to 0.02% mechlorethamine HCl) was compared to an Aquaphor ®-based mechlorethamine HCl 0.02% ointment (Comparator). The maximum duration of treatment was 12 months. Sixty-three percent (63%) of patients in the VALCHLOR arm and 67% in the comparator arm completed 12 months of treatment.

The body system associated with the most frequent adverse reactions was skin and subcutaneous tissue disorders. The most common adverse reactions (occurring in at least 5% of the patients) are shown in Table 1.

Table 1. Most Commonly Reported (≥5%) Cutaneous Adverse Reactions Comparator VALCHLOR N=127 N=128 % of patients % of patients Any ModeratelyAny ModeratelyGrade Severe or Severe Grade Severe or Severe Dermatitis 56 23 58 17 Pruritus 20 4 16 2 Bacterial skin infection 11 2 9 2 Skin ulceration or blistering 6 3 5 2 Skin hyperpigmentation 5 0 7 0 In the clinical trial, moderately-severe to severe skin-related adverse events were managed with treatment reduction, suspension, or discontinuation.

Discontinuations due to adverse reactions occurred in 22% of patients treated with VALCHLOR and 18% of patients treated with the comparator. Sixty-seven percent (67%) of the discontinuations for adverse reactions occurred within the first 90 days of treatment. Temporary treatment suspension occurred in 34% of patients treated with VALCHLOR and 20% of patients treated with the comparator.

Reductions in dosing frequency occurred in 23% of patients treated with VALCHLOR and 12% of patients treated with the comparator.

Reductions in hemoglobin, neutrophil count, or platelet count occurred in 13% of patients treated with VALCHLOR and 17% treated with Comparator.

• DRUG INTERACTIONS No drug interaction studies have been performed with VALCHLOR. Systemic exposure has not been observed with topical administration of VALCHLOR; therefore, systemic drug interactions are not likely.

• USE IN SPECIFIC POPULATIONS >> Pregnancy Pregnancy Category D Risk Summary Mechlorethamine can cause fetal harm when administered to a pregnant woman. There are case reports of children born with malformations to pregnant women systemically administered mechlorethamine. Mechlorethamine was teratogenic in animals after a single subcutaneous administration. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Animal Data Mechlorethamine caused fetal malformations in the rat and ferret when given as single subcutaneous injections of 1 mg/kg. Other findings in animals included embryolethality and growth retardation when administered as a single subcutaneous injection. >> Nursing Mothers It is not known if mechlorethamine is excreted in human milk. Due to the potential for topical or systemic exposure to VALCHLOR through exposure to the mother’s skin, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother. >> Pediatric Use Safety and effectiveness in pediatric patients have not been established. >> Geriatric Use A total of 79 patients age 65 and older (31% of the clinical trial population) were treated with either VALCHLOR or the comparator in the clinical trial. Forty-four percent (44%) of patients age 65 or older treated with VALCHLOR achieved a Composite Assessment of Index Lesion Severity (CAILS) response compared to 66% of patients below the age of 65. Seventy percent (70%) of patients age 65 and older experienced cutaneous adverse reactions and 38% discontinued treatment due to adverse reactions, compared to 58% and 14% in patients below the age of 65, respectively. Similar differences in discontinuation rates between age subgroups were observed in the comparator group.

Manufactured for: Actelion Pharmaceuticals US, Inc. South San Francisco, CA 94080, USA © 2014 Actelion Pharmaceuticals US, Inc. All rights reserved.

VAL-00170 0814

2015 GENITOURINARY CANCERS SYMPOSIUM

AR-V7 Predicts Chemotherapy Sensitivity in Metastatic Prostate Cancer

New biomarker to guide treatment decisions on the horizon

E

xperts are hopeful that the field of prostate cancer will soon be catching up to breast cancer and some other tumor types with regard to genomic markers. A study featured at the 2015 Genitourinary Cancers Symposium suggests that the androgen receptor (AR) abnormality known as AR-V7 will turn out to be a predictive marker to help in treatment selection for patients with metastatic castration-resistant prostate cancer (CRPC).

The study showed that the presence of AR-V7 in circulating tumor cells was predictive of sensitivity to chemotherapy with the taxanes docetaxel and cabazitaxel in men with metastatic CRPC. A previous study by the same team of researchers published last year showed that patients whose circulating tumor cells harbored AR-V7 had primary resistance to AR-directed therapy with enzalutamide and abira­ terone (N Engl J Med. 2014;371:1028-1038).

In Search of Biomarkers Taken together, the studies suggest that patients who are AR-V7–positive should be offered chemotherapy with one of the taxanes instead of enzalutamide or abiraterone, whereas patients who are AR-V7–negative can be offered either type of therapy safely.

Lead investigator Emmanuel S. Antonarakis, MBBCh, assistant professor of oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, said, “We urgently need markers that predict which therapies are going to be effective, and which are not, in individual patients with prostate cancer. AR-V7 testing may be extremely valuable in guiding treatment decisions for men with hormoneresistant disease in the near future.”

Antonarakis noted that the findings related to AR-V7 need to be validated in a prospective multicenter trial.

No commercial test for AR-V7 is currently available. These researchers and other investigators are working on developing a CLIA (Clinical Laboratory Improvement Amendments)-approved test for AR-V7, Antonarakis said.

“Taxanes may be more efficacious than AR-directed therapy in AR-V7–positive men,” Antonarakis stated.

“We need to prospectively validate this marker for

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therapy selection. The utility of the test will be greater in positive patients, if confirmed, whereas the utility in AR-V7–negative patients is not so great.”

Study Details The present study included 37 men with metastatic CRPC who were initiating cheEmmanuel S. motherapy with docetaxel or enzalutamide; Antonarakis, 17 of 37 patients (46%) were found to be MBBCh AR-V7 positive. In general, at least 33% of patients with CRPC are AR-V7 positive.

The primary end point of the study was the association between AR-V7 status and prostate-specific antigen (PSA) response rates; a ≥50% reduction in PSA from baseline was considered to be a positive PSA response to therapy. Other end points were progression-free survival (PFS) as measured by PSA levels and by clinical or radiographic progression.

No commercial test for AR-V7 is currently available. These researchers and other investigators are working on developing a CLIA-approved test for AR-V7.

PSA responses were achieved in 41% of AR-V7– positive and 65% of AR-V7–negative patients. The median PSA-based PFS rates were comparable between these 2 groups: 4.5 months versus 6.2 months, respectively; the median PFS was also comparable: 5.1 months versus 6.9 months, respectively.

When the investigators incorporated data from their previous study of 62 men who received abiraterone or enzalutamide, clinical outcomes were superior in AR-V7–positive men who received taxanes versus abir­ aterone or enzalutamide, whereas outcomes were not significantly different for AR-V7–negative men who received either type of therapy.

A striking difference in PSA response was observed between the 2 types of therapy in AR-V7–positive men; 41% of patients showed positive response with the taxanes

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versus 0% (P <.001) with enzalutamide or abiraterone.

The median PSA-based PFS and the median PFS were significantly longer in AR-V7–positive men who received taxanes (P = .001 and P = .003, respectively).

“The AR-V7 biomarker is better at separating patients requiring AR-directed therapy versus chemotherapy. If a patient is AR-V7–positive, he has a greater chance of progression on enzalutamide or abiraterone compared with taxanes. In fact, he has a 79% lower

chance of progression on a taxane and a 4.8-fold greater increase in risk of progression on enzalutamide or abiraterone,” Antonarakis commented. “In AR-V7– negative patients, there is no difference in PFS between taxanes or AR-directed therapy.”

According to these results, the presence of AR-V7 in circulating tumor cells is not associated with primary resistance to the taxanes; it is, however, associated with primary resistance to AR-directed therapy. u

No Role for Adjuvant Sorafenib or Sunitinib in Locally Advanced Kidney Cancer

U

se of adjuvant sorafenib and sunitinib failed to extend disease-free survival (DFS) in patients with locally advanced kidney cancer at high risk of recurrence, according to initial results from the ASSURE study presented at the meeting.

ASSURE is the first and largest study of adjuvant vascular endothelial growth factor Naomi B. Haas, (VEGF) receptor tyrosine kinase inhibitors in MD kidney cancer.

Both sorafenib and sunitinib are widely effective in metastatic kidney cancer, and the investigators of ASSURE hoped that the drugs would also provide benefit in the adjuvant setting. However, the findings of this randomized trial suggest that close observation should remain the standard of care, they said.

Adjuvant sorafenib and sunitinib failed to extend disease-free survival in patients with locally advanced kidney cancer at high risk of recurrence.

“No one could be more disappointed in these results than me, except for patients with kidney cancer. Even though these drugs provide benefit in the metastatic setting, they did not reduce disease recurrence in the adjuvant setting, while they did increase side effects,” said lead author Naomi B. Haas, MD, Abramson Cancer

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Center of the University of Pennsylvania, Philadelphia.

Haas said analysis of tumor specimens collected during the trial may provide some clues to whether specific subsets of patients might derive a treatment benefit from adjuvant sorafenib or sunitinib.

Study Details ASSURE enrolled 1943 patients who underwent complete resection and were categorized as intermediate risk or high risk for recurrence according to tumor size and grade and lymph node involvement. Treatment arms were well balanced for type of kidney cancer, type of surgery, performance status, and risk of recurrence.

Patients were randomized in a 1:1:1 ratio to receive sorafenib (n = 649), sunitinib (n = 647), or placebo (n = 647) for 1 year. After 1322 patients were accrued, the starting doses of active drugs were lowered and titrated according to side effects, which reduced the rates of discontinuation in the experimental arms from about 26% for patients initiated at full doses to 14% for those started on reduced doses. Haas said that the dosing adjustments could have relevance for reducing discontinuation of these drugs in other settings.

Interim analysis revealed similar rates of recurrence in all 3 groups (around 40%) and of DFS (5.6-5.7 years), the primary end point of the trial. Five-year DFS rates were 53.8% for sunitinib and 52.8% for sorafenib, which were similar to the 55.8% seen in the placebo arm. Overall survival was not significantly different between treatment arms and ranged from 77% to 81%.

Based on these interim findings, the Data Safety

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and Monitoring Committee recommended release of the results.

Both active drugs had side effects. The most common grade ≥3 side effects were hypertension (16% for both sorafenib and sunitinib, and 4% for placebo), hand-foot reaction (sorafenib 33%, sunitinib 14%, and placebo 1%), rash (15%, 2%, and 1%, respectively), and fatigue (7%, 17%, and 3%, respectively).

Final analysis of recurrence and survival will be presented in the future.

“The findings suggest that patients with locally advanced kidney cancer treated with surgery should not receive adjuvant sorafenib or sunitinib,” Haas noted.

All patients in the trial exceeded the 4.6-year DFS projected in the null hypothesis when the trial was designed, she added.

Other adjuvant trials are ongoing in kidney cancer.

These include a study of axitinib (a VEGF receptor

inhibitor) and a study of everolimus (mTOR inhibitor), both of which are accruing patients. Adjuvant trials of immunotherapy and other targeted approaches are being considered.

During a question and answer session following Haas’ presentation at a premeeting presscast, moderator Charles Ryan, MD, professor, University of California San Francisco School of Medicine, noted that some oncologists are using adjuvant VEGF therapy with no supportive evidence. In his view, the interim results of ASSURE provide convincing evidence against this practice.

“The fact that this is a negative trial in no way diminishes its importance. Tyrosine kinase inhibitors may not be as effective as chemotherapy in the adjuvant treatment of solid tumors,” Ryan stated. “This study supports my current practice of not using these drugs in the adjuvant setting.” u

REGISTER TODAY JULY 22-25, 2015 THE WESTIN SEATTLE • SEATTLE, WASHINGTON

CONFERENCE CO-CHAIRS

Sanjiv S. Agarwala, MD

Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke’s Cancer Center Bethlehem, PA

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Jorge E. Cortes, MD

Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

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Hope S. Rugo, MD

Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller Family Hope Comprehensive S. Rugo, M.D. Cancer Center San of Francisco, Professor MedicineCA ll030415 Director, Breast OncologyPMOLive_fi and Clinical Trials Education University of California San Francisco Helen Diller Family Cancer Center San Francisco, CA

Hope S. Rugo, MD, is a Professor of Medicine in the Divisio

119Diller Fam Personalized Medicine in Oncology the University of California San Francisco, l Helen

where she directs Breast Cancer and Clinical Trial Educatio novel therapies for advanced breast cancer, immune modula

PATIENT NAVIGATION

What Is a Navigator?

Sharon S. Gentry, RN, MSN, AOCN, CBCN

The following article is reprinted from our sister publication CONQUER, the magazine written exclusively for patients with cancer. We offer it in the hope that it will provide an additional support resource for your patients. For more from CONQUER, visit www. conquer-magazine.com.

Y

ou have just been diagnosed with cancer, and one of the first people you meet on your healthcare team is introduced as a navigator. “A what?” you think. “I need doctors, not a GPS!” But over time, you will realize this person is a great guide.

Because they are positioned inside the healthcare system and know the ins and outs Sharon S. Gentry, of that world, as well as the community RN, MSN, AOCN, around the system, navigators can be a great CBCN resource. According to the dictionary, a navigator is a person who finds out how to get to a place: a person who navigates a ship, an airplane, or a device (such as a computer) that is used to plan or find the route to a place. This is also a concise description of the navigators who work in the oncology healthcare system today.

“Think of your navigator as a partner who is focused on your personalized, individual care. Be honest with your navigator, so he or she can make appropriate referrals to enhance your care.”

Navigators can get you to where you need to go, and can describe the route or journey you will be traveling as a patient. Your navigator may have a clinical back-

Patient Resources The following websites offer additional information on cancer navigators: www.aonnonline.org www.cancerpatientnavigation.org/resources.html www.hpfreemanpni.org/resources/ www.accc-cancer.org/resources/patientnavigation.asp

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ground, such as a nurse or social worker, or he or she may have health education training, such as a community health worker or lay navigator.

When you look at the tasks (see box on next page) that many navigators perform, you can realize what questions or concerns you may want to share with them that will help you better navigate your care.

Your navigator is knowledgeable about cancer care and the cancer care system. Navigators view the healthcare system through the eyes of the patient. They are aware of the treatment you expect to get throughout your care and the community resources that can support you and your family. Navigators communicate with your healthcare team and collaborate on your behalf to facilitate your best care.

Think of your navigator as a partner who is focused on your personalized, individual care. If navigators do not know an answer, they can direct you to another team member. They have a defined role and will transition you to other healthcare team members as needed.

Be honest with your navigator, so he or she can make appropriate referrals to enhance your care.

One of my favorite quotes comes from an article in Patient Education and Counseling that summed up what patients thought about their experience with navigators: “Having a navigator as someone with personal knowledge of the participant’s overall life situation, while also having direct linkages as an ‘insider’ to the health-care system, helping them through administrative challenges, offering security, comfort, or peace of mind by simply knowing that the navigator was there as a resource, ‘checking in’ with calls or informal visits, were all described by participants as examples of ‘being there’” [Patient Educ Couns. 2010;80:241-247].

I hope you will embrace the care of a navigator in your cancer journey. u

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PATIENT NAVIGATION

Task of a Navigator Questions for Your Navigator Orient patients to the care system

Who do I need to see for care now?

Where do I go for care?

What type of doctors will I be seeing in the system?

Can I stay in my community for care?

Who is the expert in this field?

What are the contact numbers for my healthcare team?

Who do I call in the evenings and on weekends?

Can I ask my questions to the healthcare team electronically?

Provide education on your cancer diagnosis

What type of cancer do I have?

Are there different types of my cancer?

What are good Internet resources?

What tests/scans will be performed?

What is the treatment for my cancer (surgery, radiation therapy, chemotherapy, immunotherapy, other)?

What can I expect after surgery?

What can I expect after my first chemotherapy treatment?

What is radiation like?

What can I expect at the surgeon/medical oncologist/radiation visit?

Why am I being sent to a high-risk clinic?

What is a survivorship care plan?

What did the doctor mean by palliative care?

Provide emotional support for patients

Who can talk to my spouse/partner?

What do I tell my children?

How can I tell my parents?

Is there someone to discuss financial concerns with?

Will I be able to work?

Is there a support group?

I do not feel comfortable in groups. Is there someone I can talk with?

I cannot grasp all that is happening to me; who can I talk with?

Assist patients with logistics, such as transportation, costs

Is there transportation assistance?

I live far away. Is there an affordable place to stay?

What are the directions to the appointment/test?

Is there an interpreter available for me/my family?

Can you help me with the copays?

I am overwhelmed with these insurance forms; can you help?

Who can stay with my elderly parents while I get care?

Who do I see about my short-term or long-term disability forms?

Is there child care available?

Can someone help me with a living will?

Advocate for the patient

I feel dissatisfied with my care; can you help me?

I did not have a good experience with a healthcare team member; can you help me?

I did not feel comfortable asking questions; what did the doctor mean?

Can you review my care plan with me?

My appointments conflict with my work schedule; can you help?

I am frustrated with this bill, because another one came from the same visit. Are they all bills?

Why do I have to wait so long for an appointment?

Utilize community resources

Is there free legal aid available?

Is there an agency to help with medications?

Can I get financial help in my community?

Are there people/groups that can help with transportation?

Can someone clean my house?

Are there other survivors I can talk with?

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THE LAST WORD

President Obama’s Bet on Personalized Medicine Edward Abrahams, PhD President Personalized Medicine Coalition

I

“

want the country that eliminated polio and mapped the human genome to lead a new era of medicine, one that delivers the right treatment at the right time.” So said the president of the United States in his State of the Union Address on January 20, 2015.

By calling attention to the promise of personalized medicine, the president underlined Edward what has been the central contention of the Abrahams, PhD Personalized Medicine Coalition for a decade: linking therapy to diagnostics and thereby targeting the right treatment to the right patient at the right time will lead to a paradigm shift in modern medicine, improving outcomes while lowering overall costs. To be sure, the road is long, opposition real, and the president’s proposed investment of $215 million in fiscal year 2016 relatively small, given the stakes and the opportunity.

The president is proposing that we embark on a new era of discovery and delivery that places the individual at the center of his or her healthcare. It proposes creating, over time, a healthcare system that eschews one-size-fits-all, trial-and-error medicine in favor of a targeted approach that will deliver better results at a lower overall cost.

But a closer look at the president’s Precision Medicine Initiative reveals its potentially transformative implications for the future of medicine. Even if small and only for 1 year, if Congress approves, the new program will transform the nature of the biomedical research enterprise, a fact not unnoted by the White House, which calls the initiative “a bold new research effort to revolutionize how we improve health and treat disease.”

In particular, the president wants to: • Add $70 million to the budget of the National Cancer Institute (NCI) to study the genetic factors that cause cancer

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• Add $10 million to the budget of the Food and Drug Administration (FDA) to develop new approaches for evaluating next-generation genetic tests • Add $5 million to the budget of the Office of the National Coordinator for Health Information Technology to support the development of interoperability standards and requirements that address privacy and enable secure exchange of data across systems • And, most importantly, add $130 million to the budget of the National Institutes of Health (NIH) to build a “voluntary national research cohort” of a million or more volunteers in order to better understand the etiology of health and disease.

According to the White House, “Most medical treatments,” as proponents of personalized medicine have argued for some time, “have been designed for the ‘average patient.’ As a result...treatments can be very successful for some patients but not for others.”

Advised by NIH Director Francis Collins, MD, PhD, and NCI Director Harold Varmus, MD, the president is proposing that we embark on a new era of discovery and delivery that places the individual at the center of his or her healthcare. It proposes creating, over time, a healthcare system that eschews one-size-fits-all, trial-and-error medicine in favor of a targeted approach that will deliver better results at a lower overall cost.

What makes this vision possible and, in 2015, realistic, as Drs Collins and Varmus wrote in The New England Journal of Medicine for February 26, have been the creation of new methods of distinguishing among patients that include proteomics, metabolomics, genomics, and other molecular assays as well as computational tools that facilitate the development of large-scale databases, which can be used for research.

As they note, significant progress has already been made in understanding and therefore treating cancer as a genetic disease. The proposed additional investment in cancer research builds on ongoing success in developing targeted treatments.

With the declining cost of sequencing and the increased ability to integrate multipanel arrays to produce clearer and more informed analyses, diagnostics are becoming more sophisticated and important in the practice of medicine. Increasing investment, therefore, in regula-

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tory science will help allow the FDA to keep up with a rapidly evolving field and thereby ensure that the new tests coming on the market are accurate and reliable.

Aggregating data from multiple sources provides a foundation for personalized medicine. Therefore, it also makes sense to invest in ensuring that those data can cross systems to inform treatment, as the president proposes.

But most importantly for the future of biomedical research is the proposed creation of, in Drs Collins and Varmus’ words, “a longitudinal ‘cohort’ of 1 million or more Americans who have volunteered to participate in research.” By collecting biological specimens, including DNA, combining them with environmental informa-

tion, and linking the data to electronic medical records, researchers will finally have the instrument they need to understand individual variation. They will be able to ask the right questions and derive sophisticated answers that will produce individualized, and therefore more effective, treatments in the future.

Together, these 4 integrated programs put the federal government’s research agenda squarely on the side of finding the right treatment for the right patient at the right time. As the president said, “Something called precision medicine (in some cases, people call it personalized medicine) gives us one of the greatest opportunities for new medical breakthroughs that we have ever seen.” u

WORLD CUTANEOUS MALIGNANCIES CONGRESS ™

A Special Session at the Fourth Annual PMO Live Conference

July 24-25, 2015 The Westin Seattle Seattle, Washington

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