TAP Vol 3 Issue 3 Supplement by Harborside Press LLC

HER2 Blockade 3

Bisphosphonates in Breast Cancer 9

Novel Hematologic Agents 17, 18, 20, 21

VOLUME 3, ISSUE 3

FEBRUARY 15, 2012

ASCOPost.com

Editor-in-Chief, James O. Armitage, MD

REPORTS from

San Antonio Breast Cancer Symposium COV ER AGE Treatment and management of breast cancer, including: ■■ HER2-positive Breast Cancer ■■ Metastatic Breast Cancer ■■ Tumor Molecular Profiling ■■ Bisphosphonates in Early Breast Cancer

34th SABCS, San Antonio

American Society of Hematology Annual Meeting COV ER AGE Treatment and management of hematologic disease, including: ■■ Lymphoma ■■ Leukemia ■■ Multiple Myeloma

53rd ASH, San Diego

A Supplement to The ASCO Post™

A Harborside Press® Publication

The ASCO Post | FEBRUARY 15, 2012 | SUPPLEMENT

PAGE 2

Introduction

Editorial Board James O. Armitage, MD Editor-in-Chief

Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

William T. McGivney, PhD Philadelphia, Pennsylvania

ASSOCIATE EDITORS Joseph S. Bailes, MD Texas Oncology Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center

James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System

Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia

Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center

Douglas W. Blayney, MD Stanford University Medical Center

Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center

Philip D. Bonomi, MD Rush University Medical Center

George W. Sledge, MD Indiana University

Richard Boxer, MD University of Miami Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD Stanford University Medical Center Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center

Thomas J. Smith, MD Virginia Commonwealth University Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine

Jay S. Cooper, MD Maimonides Medical Center

Stanley H. Winokur, MD Singer Island, Florida

John Cox, DO Texas Oncology

William C. Wood, MD Winship Cancer Institute, Emory University

E. David Crawford, MD University of Colorado

INTERNATIONAL EDITORS

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria

George D. Demetri, MD Dana-Farber Cancer Institute

Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina

Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins John A. Fracchia, MD New York Urological Associates Louis B. Harrison, MD Continuum Cancer Centers of New York Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

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he ASCO Post presents this special supplement with comprehensive coverage of important data from the 34th Annual San Antonio Breast Cancer Symposium and the 53rd American Society of Hematology Annual Meeting. In addition to news about the individual abstracts, experts offer their perspectives on how these reports impact clinical care. A full index of the abstracts cited in this supplement is provided below. Readers may view the original pre-

sentations and/or other resources by using the Quick Response codes found in this supplement. These bar codes can be read by any mobile device with a camera, QR code– reading software, and internet access. Additional and continuing coverage of these important oncology meetings is also available in the February 15, 2012 issue of The ASCO Post or online at ASCOPost.com.

■

Index: SABCS and ASH Abstracts Cited in this Supplement San Antonio Breast Cancer Symposium

■■ Abstract S1-2: Long-term follow-up in ABCSG-12: Significantly improved overall survival with adjuvant zoledronic acid in premenopausal patients with endocrine-receptor-positive early breast cancer. Gnant M, Mlineritsch B, Luschin-Ebengreuth G, et al. ■■ Abstract S1-3: Long-term survival outcomes among postmenopausal women with hormone receptor-positive early breast cancer receiving adjuvant letrozole and zoledronic acid: 5-year follow-up of ZO-FAST. De Boer RH, Bundred N, Eidtmann H, et al. ■■ Abstract S1-7: Molecular tumor characteristics influence adjuvant endocrine treatment outcome. Biachini G, Pusztai L, Iwamoto T, et al. ■■ Abstract S1-8. Molecular signaling distinguishes early ER-positive breast cancer recurrences despite adjuvant tamoxifen. Liu MC, Dixon JM, Xuan JJ, et al. ■■ Abstract S2-3: NSABP protocol B-34: a clinical trial comparing adjuvant clodronate vs placebo in early stage breast cancer patients receiving systemic chemotherapy and/or tamoxifen or no therapy—Final analysis. Paterson AHG, Anderson SJ, Lembersky BC, et al. ■■ Abstract S2-4. GAIN (German Adjuvant Intergroup Node Positive) Study: A phase III multicenter Trial to compare dose dense, dose intense ETC (iddETC)

vs EC-TX and ibandronate vs. observation in patients with node-positive primary breast cancer—1st interim efficacy analysis. Möbus V, Diel IJ, Harbeck N, et al. ■■ Abstract S3-7. Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial. Hortobagyi GN, Piccart M, Rugo H, et al. ■■ Abstract S4-8: First results of AVEREL, a randomized phase III trial to evaluate bevacizumab in combination with trastuzumab + docetaxel as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. Gianni L, Romieu G, Lichinitser M, et al. ■■ Abstract S5-5: A phase III, randomized, double-blind, placebo-controlled registration trial to evaluate the efficacy and safety of pertuzumab + trastuzumab + docetaxel vs placebo + trastuzumab + docetaxel in patients with previously untreated HER2-positive metastatic breast cancer (CLEOPATRA). Baselga J, KimSB, Im S-A, et al.

American Society of Hematology Lymphoma/Leukemia

■■ Abstract 6: Fractionated doses of gemtuzumab ozogamicin combined to standard chemotherapy improve event-free and overall survival in newly diagnosed de continued on page 12

Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press®, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

ASCOPost.com | FEBRUARY 15, 2012 | SUPPLEMENT

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HER2-positive Breast Cancer Dual HER2 Blockade Substantially Delays Disease Progression Remission prolonged by 6 months with pertuzumab. By Caroline Helwick

here is an emerging theme in HER2-positive breast cancer: The greater the pathway inhibition, the better the outcome. The latest evidence comes from the phase III Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) trial of 808 patients with previously untreated metastatic disease. The results were presented at the 34th San Antonio Breast Cancer Symposium by Jose Baselga, MD, PhD, of Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston.1

Pertuzumab in Metastatic Breast Cancer ■■ CLEOPATRA found that adding pertuzumab to trastuzumab/docetaxel extended progression-free survival by a median of 6.1 months, a 38% reduction in risk of disease progression.

■■ Pertuzumab/trastuzumab/docetaxel may be considered a new “practicechanging” regimen in the first-line metastatic setting.

Jose Baselga, MD, PhD

In CLEOPATRA, the addition of pertuzumab to the standard trastuzumab (Herceptin)/docetaxel regi-

men extended progression-free survival by a median of 6.1 months. “This is huge,” Dr. Baselga noted. “It is very uncommon to have a clinical trial show this level of improve-

ment in progression-free survival.” Like trastuzumab, pertuzumab is a monoclonal antibody that binds to the HER2 receptor protein but in continued on page 6

EXPERT POINT OF VIEW

C. Kent Osborne, MD

he availability of effective therapies for HER2-positive tumors has made breast cancer a better managed disease, but outcomes could be further enhanced through the targeting of other players in this pathway, emerging data suggest. C. Kent Osborne, MD, of Baylor College of Medicine, Houston, commented on the pivotal CLEOPATRA trial of dual HER2 blockade and described future approaches he believes will make treatment of HER2-positive patients even more effective. As background, Dr. Osborne emphasized the need to move beyond trastuzumab (Herceptin) alone in HER2-positive disease. Trastuzumab works predominantly by inhibiting signaling from HER2 homodimers, and it induces antibody-dependent cell-mediated cytotoxicity (ADCC), but has no effect against HER1 homodimerization or HER1/HER3 heterodimerization, he pointed out. “This raises the possibility that incomplete blockade of the HER receptor layer by trastuzumab is a common mechanism of resistance,” he said. Fortunately, other drugs can fill this

gap. Pertuzumab can inhibit heterodimerization of HER1/HER2 and of the most potent of the HER family members, HER2/HER3. Additional HER family signaling is inhibited variously by the epidermal growth factor receptor inhibitors and by dual or pan tyrosine kinase inhibitors. Trastuzumab must remain part of any regimen, however, for optimal activity.

What If ER Is Also Targeted? In CLEOPATRA, the combination of trastuzumab and pertuzumab led to “impressive” response rates, with “striking” improvements in progression-free and probably overall survival, Dr. Os-

trastuzumab) and NeoSphere (pertuzumab/trastuzumab), lower pathologic complete respones are seen in ER-positive patients (who were not treated with endocrine therapy). “We would not think of not targeting HER2 if it is overexpressed. So when ER is positive, we need to target that as well,” Dr. Osborne maintained. In CLEOPATRA, 49% of patients were ER-positive but did not receive endocrine therapy. “We actually know very little about combining estrogen deprivation with chemotherapy, and since the effects on the cell are so completely different, one could imagine that ER deprivation com-

We would not think of not targeting HER2 if it is overexpressed. So when ER is positive, we need to target that as well. borne noted. “For patients meeting the study’s eligibility criteria, this is clearly a new standard and should be practicechanging,” he told attendees. But in this and other studies in HER2-positive patients, the effects were less dramatic among estrogen receptor (ER)-positive patients. That could be because ER-positive patients are less sensitive to chemotherapy, or because ER was not simultaneously targeted therapeutically, he suggested. “Complete responses were rare, obviously because multiple survival pathways are functioning in metastatic HER2 tumors,” he said. He noted that in NeoALLTO (lapatinib [Tykerb]/

bined with chemotherapy might be better. This is something we need to study,” he said. In addition, in CLEOPATRA only 46% had received prior chemotherapy and 10% prior trastuzumab. “So a large number were treatment-naive, which raises some question as to whether this combination is applicable to more heavily pretreated patients,” he suggested (though the investigators said the outcomes were similar regardless of pretreatment). “Certainly,” Dr. Osborne acknowledged, “this is a very well done study with convincing data, and the results speak for themselves … though one has

to imagine what the effect would be of simultaneously targeting HER2 and ER.”

Evidence for More Inhibition Being Better Preclinical studies have suggested that the more inhibition—and more agents in the mix—the better the outcomes. Anti-HER2 monotherapy only partially and temporarily inhibits growth in xenograft models; multidrug combinations are superior, though resistance still emerges. But when pertuzumab, trastuzumab, and gefitinib (Iressa, which inhibits HER1) are joined by tamoxifen or estrogen deprivation similar to an aromatase inhibitor in patients, there is true and durable eradication of tumor, according to work performed in Dr. Osborne’s lab. Similar results were observed when lapatinib and trastuzumab were comSEE PAGE 2 bined with tamoxifen or estrogen deprivation. “If you don’t target ER, even this potent cocktail is ineffective,” he observed. “Estrogen deprivation plus the triple combination is the most potent we have ever studied. All these tumors regressed, and none has ever come back with this fourdrug regimen, suggesting you must target both drivers in patients whose tumors are both ER- and HER2-positive.”

■

Disclosure: Dr. Osborne has served on advisory boards for AstraZeneca, Novartis, GlaxoSmithKline, Boehringer Ingelheim, Genentech, and Pfizer.

For chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab

EXPAND YOUR OPTIONS A study population in need of additional treatment options1,2

median prior therapies

59%

of patients received prior rituximab

93%

of patients received prior alkylating agents

100%

of patients received prior fludarabine and alemtuzumab

The following serious adverse events (AEs) are discussed in greater detail below: Infusion reactions, cytopenias, progressive multifocal leukoencephalopathy, hepatitis B infection and reactivation, and intestinal obstruction.

To learn more, please visit www.ARZERRA.com. Indication ARZERRA (ofatumumab) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. The eﬀectiveness of ARZERRA is based on the demonstration of durable objective responses. No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA. Important Safety Information Infusion Reactions ARZERRA can cause serious infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion reactions occur more frequently with the first 2 infusions. Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Interrupt infusion for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina, or other signs and symptoms of myocardial ischemia. In a study of patients with moderate to severe chronic obstructive pulmonary disease, an indication for which ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm during infusion. Infusion reactions occurred in 44% of patients on the day of the first infusion

(300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Cytopenias Prolonged (≥1 week) severe neutropenia and thrombocytopenia can occur with ARZERRA. Monitor complete blood counts (CBC) and platelet counts at regular intervals during therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. Discontinue ARZERRA if PML is suspected and initiate evaluation for PML including consultation with a neurologist, brain MRI, and lumbar puncture. Hepatitis B Infection and Reactivation Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can occur in patients following treatment with ARZERRA. Screen patients at high risk of HBV infection before initiation of ARZERRA. Closely monitor carriers

When treated with ARZERRA monotherapy, 42% of patients with CLL refractory to fludarabine and alemtuzumab achieved a partial response1 Patients had received a median of 5 prior therapies

Overall response rate with ARZERRA 60 50 40

42%

The investigator-determined overall response rate in patients with CLL refractory to fludarabine and alemtuzumab was 42% (99% CI: 26, 60) There were no complete responses The eﬀectiveness of ARZERRA is based on the demonstration of durable objective responses

30 20 10

FLUDARABINE AND ALEMTUZUMAB REFRACTORY (n=59)

of hepatitis B for clinical and laboratory signs of active HBV infection during treatment with ARZERRA and for 6 to 12 months following the last infusion of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis or reactivation of viral hepatitis, and institute appropriate treatment. Insuﬃcient data exist regarding the safety of administration of ARZERRA in patients with active hepatitis. Intestinal Obstruction Obstruction of the small intestine can occur in patients receiving ARZERRA. Perform a diagnostic evaluation if obstruction is suspected. Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied. Most Common Adverse Reactions In the pivotal study (total population, n=154) the most common adverse reactions (≥10%, all grades) were neutropenia, followed by pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%).

No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA 6.5 months—median duration of response (95% CI: 5.8, 8.3)

Most Common Serious Adverse Reactions In the pivotal study (total population, n=154), where ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses, the most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine- and alemtuzumab-refractory group was 17%. Please see Brief Summary of Prescribing Information on adjacent pages. How Supplied: Available as 2 different single-use glass vials for dilution and intravenous administration. Each vial contains either 100 mg ofatumumab in 5 mL of solution or 1,000 mg ofatumumab in 50 mL of solution. References: 1. ARZERRA (ofatumumab) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2011. 2. Tam CS, O’Brien S, Lerner S, et al. Leuk Lymph. 2007;48(10):1931-1939.

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HER2-positive Breast Cancer Dual HER2 Blockade continued from page 3

a different region. Pertuzumab prevents the receptor from linking to HER3, which stops the formation of a dimer that will further enhance tumor growth. It is the first in a new class of agents called “dimerization inhibitors,” and in combination with

trastuzumab, helps to provide dual blockade of the HER2 growth factor. Progression-free survival was 18.5 months for patients receiving pertuzumab vs 12.4 months for trastuzumab/docetaxel alone—a 38% reduction in the risk of progression (P < .0001). Adding pertuzumab to the combina-

The ASCO Post | FEBRUARY 15, 2012 | SUPPLEMENT B:22.5” T:21” S:19”

tion also yielded responses in 80.2% of patients, compared with 69.3% with standard therapy.

May Be Practice-changing “CLEOPATRA met its primary endpoint and demonstrated a statistically significant and clinically meaningful improvement in pro-

gression-free survival. This new regimen may be practice-changing in HER2-positive first-line metastatic breast cancer,” Dr. Baselga suggested. Although survival outcomes are not mature, there were 69 deaths among the 402 patients treated with the threedrug regimen vs 96 among the 406

Table 1. Incidence of All Adverse Reactions Occurring in ≥5% of Patients BRIEF SUMMARY BRIEF SUMMARY Table 1. Incidence of All Adverse Reactions Occurring in ≥5% of Patients ® (ofatumumab) Study 1 and inInjection, the Fludarabineand Alemtuzumab-Refractory Subset ARZERRA® (ofatumumab) Injection, for intravenous infusion ARZERRAin in Study 1 and in the Fludarabine- and Alemtuzumab-Refractory Subset for intravenous infusion of Study 1 (MedDRA 9.0) of Study 1 (MedDRA 9.0) The following is a brief summary only; see full prescribing information for The following is a brief summary only; see full prescribing information for complete product information. complete product information. Fludarabine- and Fludarabine- and AlemtuzumabAlemtuzumabTotal Population Total Population 1 INDICATIONS AND USAGE 1 INDICATIONS AND USAGE Refractory (n = 154) ARZERRA® (ofatumumab) is indicated for the treatment of patients ARZERRA® (ofatumumab) is indicated for the(n = 154) treatment of patients Refractory (n = 59) with chronic lymphocytic leukemia (CLL) refractory to fludarabine and with chronic lymphocytic leukemia (CLL) refractory to fludarabine and (n = 59) Grade Grade All All Grade All is basedGrade All alemtuzumab. The effectiveness of ARZERRA is based on the demonstration alemtuzumab. The effectiveness of ARZERRA on the demonstration ≥3 Body System/ ≥3 Grades Grades ≥3of full prescribing ≥3 Grades Grades System/ of durable objective responses [see Clinical Studies (14) of full prescribing of durable Body objective responses [see Clinical Studies (14) information]. No data demonstrate an improvement in disease-related information]. No data demonstrate an improvement in disease-related % Adverse Event % % % % % % % Adverse Event symptoms or increased survival with ARZERRA. symptomsInfections or increased with ARZERRA. andsurvival infestations Infections and infestations Pneumoniaa Pneumoniaa 23 14 25 15 23 14 25 15 4 CONTRAINDICATIONS 4 CONTRAINDICATIONS Upper respiratory tract Upper respiratory tract None. None. 11 0 3 0 11 0 3 0 infection infection 5 WARNINGS AND PRECAUTIONS 5 WARNINGS AND PRECAUTIONS Bronchitis 11 <1 19 2 Bronchitis 11 <1 19 2 5.1 Infusion Reactions ARZERRA can cause serious infusion reactions 5.1 Infusion Reactions ARZERRA can cause serious infusion reactions b Sepsisb 8 8 pulmonary 10 edema, 10 8 8 10 10 manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, manifesting asSepsis bronchospasm, dyspnea, laryngeal edema, Nasopharyngitis 8 cardiac ischemia/infarction, 0 8 0 Nasopharyngitis 8 0 8 0 flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, flushing, hypertension, hypotension, syncope, Herpes zoster 6 Herpes zoster 6 1 7 2 back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion back pain, abdominal pain, pyrexia, rash, urticaria, and 1angioedema.7 Infusion 2 5 2 infusions2 [see Adverse 3 2 Sinusitis 5 2 3 2 reactions occur more frequently with the first 2 infusions [see Adverse reactions occurSinusitis more frequently with the first Blood Premedicate and lymphaticwith acetaminophen, an antihistamine, and a Blood and lymphatic Reactions (6.1)]. Premedicate with acetaminophen, an antihistamine, andReactions a (6.1)]. corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing corticosteroid [seedisorders Dosage and Administration (2.1, 2.4) of full prescribing system system disorders information]. Interrupt infusion for infusion reactions of any severity. Institute information]. Interrupt reactions of 5any severity.17Institute 8 Anemia infusion for infusion16 Anemia 16 5 17 8 medical management for severe infusion reactions including angina or other medical management for severe infusion reactions including angina or other Psychiatric disorders Psychiatric disorders signs and symptoms of myocardial ischemia [see Dosage and Administration signs and symptoms of myocardial ischemia Insomnia 7 [see Dosage 0 and Administration 10 0 Insomnia 7 0 10 0 (2.3) of full prescribing information]. In a study of patients with moderate(2.3) of full prescribing information]. In a study of patients with moderate Nervous system disorders Nervous system disorders to severe chronic obstructive pulmonary disease, an indication for whichto severe chronic obstructive pulmonary disease, an indication for which Headache 6 0 7 0 Headache 6 0 7 0 ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm Cardiovascular disorders Cardiovascular disorders during infusion. 5.2 Cytopenias Prolonged (≥1 week) severe neutropeniaduring and infusion. 5.2 Cytopenias Prolonged (≥1 week) severe neutropenia and Hypertension 0 Hypertension 5 0 8 0 thrombocytopenia can occur with ARZERRA. Monitor complete blood counts thrombocytopenia can occur with ARZERRA.5 Monitor complete blood8 counts 0 Hypotension 5 during therapy, 0 3 0 Hypotension 5 0 3 0 (CBC) and platelet counts at regular intervals during therapy, and increase (CBC) and platelet counts at regular intervals and increase <1 7 2 Tachycardia 5 <1 7 2 the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. the frequency Tachycardia of monitoring in patients who5 develop Grade 3 or 4 cytopenias. 5.3 Progressive Multifocal Leukoencephalopathy Progressive multifocal 5.3 Progressive Multifocal Leukoencephalopathy Progressive multifocal Respiratory, thoracic, and Respiratory, thoracic, and leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. leukoencephalopathy including fatal PML, can occur with ARZERRA. mediastinal(PML), disorders mediastinal disorders Consider PML in any patient with new onset of or changes in pre-existing Consider PML Cough in any patient with new onset 19of or changes 0 in pre-existing 19 0 Cough 19 0 19 0 neurological signs or symptoms. Discontinue ARZERRA if PML is suspected, neurological signs or symptoms. Discontinue Dyspnea 14 ARZERRA 2if PML is suspected, 19 5 Dyspnea 14 2 19 5 and initiate evaluation for PML including consultation with a neurologist,and initiateGastrointestinal evaluation for PML including consultation with a neurologist, disorders Gastrointestinal disorders brain MRI, and lumbar puncture. 5.4 Hepatitis B Infection and Reactivation brain MRI, and lumbar puncture. 5.4 Hepatitis B Infection and Reactivation Diarrhea 18 0 19 0 Diarrhea 18 0 19 0 Fulminant and fatal hepatitis B virus (HBV) infection and reactivation canFulminant and fatal hepatitis B virus (HBV) infection and reactivation can Nausea 0 12 at high 0 Nausea 11 0 12 0 occur in patients following treatment with ARZERRA. Screen patients at occur high in patients following treatment with 11 ARZERRA. Screen patients and subcutaneous Skin and subcutaneous risk of HBV infection before initiation of ARZERRA. Closely monitor carriers risk of HBVSkin infection before initiation of ARZERRA. Closely monitor carriers tissue tissue disorders of hepatitis B for clinical and laboratory signs of active HBV infection during of hepatitis B for disorders clinical and laboratory signs of active HBV infection during c Rashc 14 <1 the last 17 2 14 <1 17 2 treatment with ARZERRA and for 6 to 12 months following the last infusion treatment withRash ARZERRA and for 6 to 12 months following infusion Urticaria ARZERRA in patients 8 who develop 0 viral hepatitis 5 Urticaria 8 0 5 0 of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis of or ARZERRA. Discontinue or 0 reactivation of viral hepatitis, and institute appropriate treatment. Insufficient reactivation ofHyperhidrosis viral hepatitis, and institute appropriate treatment. Insufficient 5 0 5 0 Hyperhidrosis 5 0 5 0 data exist regarding the safety of administration of ARZERRA in patientsdata with exist regarding the safety Musculoskeletal and of administration of ARZERRA in patients with Musculoskeletal and active hepatitis. 5.5 Intestinal Obstruction Obstruction of the small intestine active hepatitis. 5.5 Intestinal Obstruction Obstruction of the small intestine connective tissue disorders connective tissue disorders can occur in patients receiving ARZERRA. Perform a diagnostic evaluation can occur in patients receiving ARZERRA. Perform a diagnostic evaluation Back pain 8 1 12 2 Back pain 8 1 12 2 if obstruction is suspected. 5.6 Immunizations The safety of immunization if obstruction is suspected. 5.6 Immunizations Muscle spasms 5 The safety 0 of immunization 3 0 Muscle spasms 5 0 3 0 with live viral vaccines during or following administration of ARZERRA has with live viral vaccines during or following administration of ARZERRA has General disorders and General disorders and not been studied. Do not administer live viral vaccines to patients who have not been studied. Do not administer live viral vaccines to patients who have administration site administration site recently received ARZERRA. The ability to generate an immune responserecently to received ARZERRA. The ability to generate an immune response to conditions conditions any vaccine following administration of ARZERRA has not been studied. any vaccine following administration of ARZERRA has not been studied. Pyrexia 20 3 25 5 Pyrexia 20 3 25 5 6 ADVERSE REACTIONS 6 ADVERSE REACTIONS Fatigue 15 0 15 0 Fatigue 15 0 15 0 The following serious adverse reactions are discussed in greater detail in The following Edema serious peripheral adverse reactions are9 discussed<1 in greater detail 8 in 2 Edema peripheral 9 <1 8 2 other sections of the labeling: other sectionsChills of the labeling: 8 0 10 0 Chills 8 0 10 0 • Infusion Reactions [see Warnings and Precautions (5.1)] • Infusiona Reactions [see Warnings and Precautions (5.1)] a Pneumonia includes pneumonia, lung infection, lobar pneumonia, and Pneumonia includes pneumonia, lung infection, lobar pneumonia, and • Cytopenias [see Warnings and Precautions (5.2)] • Cytopenias [see Warnings and Precautions (5.2)] bronchopneumonia. bronchopneumonia. • Progressive Multifocal Leukoencephalopathy [see Warnings and • Progressive Multifocal Leukoencephalopathy [see Warnings and b Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock.b Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock. Precautions (5.3)] Precautions (5.3)] c c includes rash, rash macular,and andPrecautions rash vesicular. Rash includes rash, rash macular, and rash vesicular. • Hepatitis B Reactivation [see Warnings and Precautions (5.4)] • HepatitisRash B Reactivation [see Warnings (5.4)] • Intestinal Obstruction [see Warnings and Precautions (5.5)] • Intestinal Obstruction [seeInfusion Warningsreactions and Precautions Infusion Reactions: occurred(5.5)] in 44% of patients on theInfusion Reactions: Infusion reactions occurred in 44% of patients on the The most common adverse reactions (≥10%) in Study 1 were neutropenia, The most day common reactions (≥10%) in Study 1 were of theadverse first infusion (300 mg), 29% on the day of neutropenia, the second infusionday of the first infusion (300 mg), 29% on the day of the second infusion pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, Infections:(2,000 mg), (2,000 mg), and less frequently during subsequent infusions. A and less frequently during subsequent infusions. Infections: A nausea, bronchitis, and upper respiratory tract infections. The most common nausea, bronchitis, and upper respiratory tract infections. The most total of 108 patients (70%) experienced bacterial, viral, or common fungal infections. total of 108 patients (70%) experienced bacterial, viral, or fungal infections. serious adverse reactions in Study 1 were infections (including pneumonia serious adverse in Study 1 infections (including pneumonia A total reactions of 45 patients (29%)were experienced ≥Grade 3 infections, of which 19 A total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 and sepsis), neutropenia, and pyrexia. Infections were the most commonand sepsis), neutropenia, Infections the most common (12%) were fatal.and Thepyrexia. proportion of fatalwere infections in the fludarabine- and (12%) were fatal. The proportion of fatal infections in the fludarabine- and adverse reactions leading to drug discontinuation in Study 1. 6.1 Clinical adverse reactions leading to drug discontinuation Study 1. 6.1 Of Clinical alemtuzumab-refractory group was 17%.inNeutropenia: 108 patients alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients Trials Experience Because clinical trials are conducted under widely varying Trials Experience Because clinical trialsatare conducted underdeveloped widely varying with normal neutrophil counts baseline, 45 (42%) ≥Grade 3 with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 conditions, adverse reaction rates observed in the clinical trials of a drugconditions,neutropenia. adverse reaction rates observed in theGrade 4 clinicalneutropenia. trials of a drug Nineteen (18%) developed Some patients neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients cannot be directly compared to rates in the clinical trials of another drugcannot and beexperienced directly compared to rates in theneutropenia clinical trials of another drug and new onset Grade 4 >2 weeks in duration. experienced new onset Grade 4 neutropenia >2 weeks in duration. may not reflect the rates observed in practice. The safety of monotherapy may not reflect the rates observed Theforsafety of monotherapy 6.2 Immunogenicity Thereinispractice. a potential immunogenicity with therapeutic 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic with ARZERRA was evaluated in 181 patients with relapsed or refractorywith ARZERRA wassuch evaluated in 181 patients relapsed refractory proteins as ofatumumab. Serumwith samples fromorpatients with CLL in proteins such as ofatumumab. Serum samples from patients with CLL in CLL in 2 open-label, non-randomized, single-arm studies. In these studies, CLL in 2 open-label, non-randomized, single-armimmunosorbent studies. In these studies, Study 1 were tested by enzyme-linked assay (ELISA) for Study 1 were tested by enzyme-linked immunosorbent assay (ELISA) for ARZERRA was administered at 2,000 mg beginning with the second doseARZERRA anti-ofatumumab was administeredantibodies at 2,000 mg beginning with secondtreatment dose during and after thethe 24-week period. anti-ofatumumab antibodies during and after the 24-week treatment period. th for 11 doses (Study 1 [n = 154]) or 3 doses (Study 2 [n = 27]). The datafor 11 doses (Study 1 3 doses (Study 2 Theand data Results were[n = 154]) negative inor46 patients after the[n = 27]). 8 infusion Results were negative in 46 patients after the 8th infusion and in 33 patients in 33 patients th described in Table 1 and other sections below are derived from 154 patients describedafter in Table 1 other sections below are derived from the 12and infusion. Immunogenicity assay results are154 patients highly dependentafter on the 12th infusion. Immunogenicity assay results are highly dependent on in Study 1. All patients received 2,000 mg weekly from the second dosein Study 1.several All patients weekly from the secondassay dosemethodology, factorsreceived including2,000 mg assay sensitivity and specificity, several factors including assay sensitivity and specificity, assay methodology, onward. Ninety percent of patients received at least 8 infusions of ARZERRA onward. Ninety of patients at least 8 infusions of medications, ARZERRA andsample handling, timing of sample collection, concomitant medications, and samplepercent handling, timing ofreceived sample collection, concomitant and 55% received all 12 infusions. The median age was 63 years (range:and 4155% underlying received alldisease. 12 infusions. Thereasons, median comparison age was 63 years (range:of41 underlying disease. For these reasons, comparison of incidence of antibodies to For these of incidence antibodies to to 86 years), 72% were male, and 97% were White. to 86 years), 72% were and 97% White.to other products may be misleading. ARZERRA with male, the incidence of were antibodies ARZERRA with the incidence of antibodies to other products may be misleading.

ASCOPost.com | FEBRUARY 15, 2012 | SUPPLEMENT

PAGE 7

HER2-positive Breast Cancer patients receiving pertuzumab. Pertuzumab added minimally to toxicity, and Dr. Baselga called the three-drug combination “remarkably safe and well tolerated.” Enrollment is underway for a double-blind, randomized clinical trial, APHINITY, to test pertuzumab as adjuvant treatment for early-stage HER2-

positive breast cancer—“the setting in which you can really cure patients,” Dr. Baselga said.

■

Disclosure: Dr. Baselga has served in a consultant or advisory role for Novartis.

Reference 1. Baselga J, Kim-SB, Im S-A, et al: A phase III, randomized, double-blind, pla-

7 DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with ARZERRA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: There are no adequate or well-controlled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the recommended human dose of ofatumumab did not demonstrate maternal toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. There are no human or animal data on the potential short- and long-term effects of perinatal B-cell depletion in offspring following in utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ARZERRA have not been established in children. 8.5 Geriatric Use Clinical studies of ARZERRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) of full prescribing information]. 8.6 Renal Impairment No formal studies of ARZERRA in patients with renal impairment have been conducted [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Hepatic Impairment No formal studies of ARZERRA in patients with hepatic impairment have been conducted. 10 OVERDOSAGE No data are available regarding overdosage with ARZERRA.

Fetuses from treated dams exhibiting anti-ofatumumab antibody responses had higher B cell counts and higher spleen weights compared to the fetuses from other treated dams, indicating partial recovery in those animals developing anti-ofatumumab antibodies. When compared to control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared to the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab. The biological significance of decreased placental and thymic weights is unknown. The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated dams have not been studied in animals. 17 PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Signs and symptoms of infusion reactions including fever, chills, rash, or breathing problems within 24 hours of infusion [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)] • Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue [see Warnings and Precautions (5.2)] • Signs of infections including fever and cough [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)] • New neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.3)] • Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.4)] • New or worsening abdominal pain or nausea [see Warnings and Precautions (5.5)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring for blood counts [see Warnings and Precautions (5.2)] • Avoiding vaccination with live viral vaccines [see Warnings and Precautions (5.6)] Manufactured by: GLAXO GROUP LIMITED Greenford, Middlesex, UB6 0NN, United Kingdom U.S. Lic. 1809 Distributed by:

GlaxoSmithKline Research Triangle Park, NC 27709 ©2011, GlaxoSmithKline. All rights reserved. September 2011 ARZ:6BRS ©2011 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. AZA295R0 September 2011

Lessons Learned from Other HER2 trials From studies presented at the San Antonio Breast Cancer Symposium and elsewhere, important observations have emerged that will eventually advance our understanding of HER2-positive disease. According to C. Kent Osborne, MD, of Baylor College of Medicine, Houston, key findings include the following:

■■ Combinations of trastuzumab

(Herceptin) plus pertuzumab or lapatinib (Tykerb) are more effective than individual single agents; long-term adjuvant data are needed.

■■ Higher rates of pathologic

complete responses are observed when pertuzumab/ trastuzumab or lapatinib/ trastuzumab are added to chemotherapy. Since pathologic complete responses appear to predict long-term outcomes, neoadjuvant studies might inform adjuvant trials.

■■ Studies should evaluate estrogen receptor (ER)-targeted therapy as integrated into HER2-targeted regimens, perhaps even with a chemotherapy component.

■■ Targeting of HER1 is probably

important. This is not accomplished by pertuzumab/ trastuzumab therapy but may be possible with more potent duel or pan HER inhibitors.

B:15.125” T:14” S:12”

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the human dose of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies. 13.3 Reproductive and Developmental Toxicology Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the human dose of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the final dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab-treated dams exhibited decreases in mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15 to 20% of control values), and spleen weights (decreased by 15% for the low-dose and by 30% for the high-dose group, compared to control values).

cebo-controlled registration trial to evaluate the efficacy and safety of pertuzumab + trastuzumab + docetaxel vs. placebo + trastuzumab + docetaxel in patients with previously untreated HER2-positive metastatic breast cancer (CLEOPATRA). 2011 San Antonio Breast Cancer Symposium. Abstract S5-5. Presented December 9, 2011.

■■ Some HER2-positive patients

may be sufficiently treated with targeted therapy alone; their identification should be a research priority.

■■ Downstream inhibitors combined with receptor inhibitors warrant study in particular subsets, such as patients with PTEN loss or PI3K mutations.

Disclosure: Dr. Osborne has served on advisory boards for AstraZeneca, Novartis, GlaxoSmithKline, Boehringer Ingelheim, Genentech, and Pfizer.

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HER2-positive Breast Cancer Bevacizumab Progression-free Survival Benefit Upheld in AVEREL Trial Especially in patients with high VEGF-A expression By Caroline Helwick

evacizumamb (Avastin) added to trastuzumab (Herceptin) and docetaxel as first-line therapy for HER2-positive advanced breast cancer moderately improved progressionfree survival in the phase III AVEREL trial, presented at the 2011 San Antonio Breast Cancer Symposium by Luca SEE PAGE 2 Gianni, MD, of the San Raffaele Cancer Center in Milan.1

In the study of 424 patients followed a median of 26 months, bevacizumab was associated with an 18% reduction in progression or death by investigator assessment (P = .0775) and a 28% reduction by independent review (P = .0162; see Fig. 1 on page 9). Median progressionfree survival increased by approximately 3 months by each analysis. Response rates were significantly higher—by 10.6% (P = .0265)— only by independent review assess-

Bevacizumab in AVEREL ■■ Bevacizumab added to trastuzumab/docetaxel for first-line treatment in patients with HER2-positive breast cancer reduced the risk of progression by 18% (investigator assessment) to 28% (independent review).

■■ Patients with high plasma VEGF-A levels derived the most benefit. ment. Overall survival data are not yet mature, Dr. Gianni reported. Dr. Gianni said AVEREL shows further proof of concept for antian-

giogenic therapy, and that the challenge moving forward is to discover biomarkers of benefit. continued on page 9

EXPERT POINT OF VIEW

Hope S. Rugo, MD

odest benefit reported from AVEREL1 triggered comments among trialists about the future of bevacizumab (Avastin) in breast cancer. “Although there’s controversy about the recent revoking of FDA approval of bevacizumab for metastatic breast cancer, I think there is a consensus in our disappointment about the inability to show a more profound impact of bevacizumab on the outcome of women with late-stage disease,” commented Hope S. Rugo, MD, of the UCSF Helen Diller Family Comprehensive Cancer Center, San Fransicsco. Looking specifically at the HER2positive subset, the AVEREL trial found a “quite modest” gain in progression-free survival with bevacizumab, although it is noteworthy that the control arm fared better than would be expected from previous studies, for reasons unknown, she said. Meanwhile, the CLEOPATRA trial2 of pertuzumab showed the longest progression-free survival of any trial previously reported for HER2positive, treatment-naive metastatic

breast cancer, she noted. “So I don’t think that there is a road forward for bevacizumab in the treatment—at least in the early setting—of metastatic HER2-positive disease. Many competitors are efficacious and less toxic,” Dr. Rugo asserted. However, “I don’t think this is dead yet,” she added, pointing to AVEREL’s suggestion that high plasma VEGF-A levels may be a predictive biomarker for benefit—a finding that has recently been documented in other metastatic cancers as well.3 “So can bevacizumab, like the phoenix, rise from the ashes and make a miraculous comeback? Maybe,” Dr. Rugo predicted.

completely different conclusions. I’m puzzled,” he commented. “I am a practicing clinician 99% of the time. I use this drug and I don’t really recognize the FDA’s perception of the toxicity.” He firmly believes that bevacizumab has a place in breast cancer management, but “we need to pin down the marker that will tell us which patients benefit more,” he said. “We have a targeted therapy, but we don’t really understand the target.” He viewed the AVEREL data “somewhat positively,” as it produced another separate dataset that points to a marker (VEGF-A) that may be worth pursuing. “You cannot look at bevacizumab and say there is nothing happening there, but do we need to understand more? Absolutely. We need to do a proper validation study of potential biomarkers, and this is what we have planned,” he told The ASCO Post.

David Miles, MD

‘Biggest Mystery’ David Miles, MD, of Mount Vernon Cancer Center in London, and principal investigator of the AVADO trial (bevacizumab/docetaxel), took the opportunity to express his dismay at the FDA’s withdrawal of the drug. “The biggest mystery is how two licensing authorities—the FDA and the European Medicines Agency— can look at the same data and reach

Gabriel Hortobagyi, MD

Call for Biomarkers Gabriel Hortobagyi, MD, of The University of Texas MD Anderson Cancer Center, Houston, echoed the call for biomarker studies, not just for

bevacizumab, but for all targeted agents in development. “We need to know which group will derive the lion’s share of the benefit of adding drug X. We really need to invest in this,” he said. Meanwhile, he said, “bevacizumab, in my book, is alive and well. I continue to treat with bevacizumab in my clinic and we continue to run trials that include it.”

■

Disclosure: Dr. Miles has received honoraria from Roche, GlaxoSmithKline, Genomic Health, and Eisai. Dr. Hortobagyi has served as a consultant to Genentech with compensation. Dr. Rugo has received research funding from Genentech, Novartis, Merck, and Pfizer.

References 1. Gianni L, Romieu G, Lichinitser M, et al: First results of AVEREL, a randomized phase III trial to evaluate bevacizumab in combination with trastuzumab + docetaxel as first-line therapy for HER2positive locally recurrent/metastatic breast cancer. 2011 San Antonio Breast Cancer Symposium. Abstract S4-8. Presented December 8, 2011. 2. Baselga J, Kim-SB, Im S-A, et al: A phase III, randomized, double-blind, placebo-controlled registration trial to evaluate the efficacy and safety of pertuzumab + trastuzumab + docetaxel vs. placebo + trastuzumab + docetaxel in patients with previously untreated HER2-positive metastatic breast cancer (CLEOPATRA). 2011 San Antonio Breast Cancer Symposium. Abstract S5-5. Presented December 9, 2011. 3. Jayson GC, de Haas S, Delmar P, et al: Evaluation of plasma VEGFA as a potential predictive pan-tumour biomarker for bevacizumab. 2011 European Multidisciplinary Cancer Congress. Abstract 804. Presented September 24, 2011.

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Bisphosphonates in Early Breast Cancer Benefits of Some Bisphosphonates Confirmed in Breast Cancer Outcomes, but Questions Remain By Caroline Helwick

he story of bisphosphonates, and their disease-modifying potential in breast cancer, is still evolving. While some studies presented at the 2011 San Antonio Breast Cancer Symposium failed to show gains, others found benefits. The theme that is emerging is that bisphosphonates may be most beneficial in patients with low estrogen levels (eg, due to ovarian suppression or being greater than 5 years postmenopause).

Bisphosphonates in Early Breast Cancer ■■ Emerging data suggest bisphosphonates might modify disease progression in a “low-estrogenic environment.”

■■ ABCSG-12 long-term follow-up found that adding zoledronic acid to a

regimen of goserelin plus endocrine therapy in premenopausal women reduced recurrences by 28% and increased overall survival by 37%.

■■ ZO-FAST long-term follow-up showed a 34% improvement in

acid significantly improved both disease-free survival (HR = 0.72; P = .01) and overall survival (HR = 0.63; P = .049). The effect was mostly driven by the subset of patients over 40 years old, which is consistent with data from the ZO-FAST trial (see below) as well as a subset analysis from the AZURE trial showing a diseasefree survival benefit in patients who

Zoledronic Acid in Premenopausal Women Premenopausal women with estrogen receptor (ER)-positive early breast cancer who are receiving goserelin (Zoladex) plus tamoxifen or anastrozole might benefit from the addition of SEE PAGE 2 zoledronic acid, according to long-term follow-up of the phase III Austrian Breast and Colorectal Cancer Study Group trial (ABCSG-12) of 1,803 patients.1 Anticancer benefits were confirmed after a median follow-up of 7 years, particularly in patients with a “low-estrogen environment,” reported Michael Gnant, MD, of the Medical University of Vienna. Patients were randomly assigned to goserelin/tamoxifen or goserelin/ anastrozole for 3 years with or without zoledronic acid (4 mg every 6 months). The addition of zoledronic

Estimated probability

1.0

0.8

disease-free survival with immediate zoledronic acid treatment, in an unplanned post hoc analysis.

Michael Gnant, MD

were postmenopausal for more than 5 years (HR = 0.75; P = .02).2 Zoledronic acid reduced recurrences at all sites, not just bone, and there were no reports of osteonecrosis of the jaw or renal failure. H + DOC (n=208)

H + DOC + BEV (n=216)

Events

114 (54.8%)

111 (51.4%)

Median PFS (95% CI)

13.9 mo (11.2-16.7)

16.8 mo (14.1-19.5)

“The disease-free survival benefits of adjuvant zoledronic acid, first observed at 48 months, are maintained

0.2 16.8 mo

149 173

75 101

39 58

24 32

14 15

7 10

2 7

1 2

0 0

Time (months)

at 84 months, up to 4 to 5 years posttreatment, and now extend to overall survival, which is increased by 37%, suggesting a sustained anticancer effect,” Dr. Gnant commented. “This is exciting news for our patients.”

continued from page 8

0.4

No. at risk: 208 216

for ibandronate.

Search for Subset

.0162

Log -rank P value

■■ The German GAIN trial found no significant disease-modifying benefits

Bevacizumab in AVEREL Trial

0.72 (0.54 -0.94)

HR, stratified (95% CI)

13.9 mo

significant benefits with clodronate for time to distant metastases in bone and nonbone sites in the over 50 age group. (Clodronate is available in Europe and Canada, but not in the United States.)

The disease-free survival benefits of adjuvant zoledronic acid, first observed at 48 months, are maintained at 84 months, up to 4 to 5 years post-treatment, and now extend to overall survival, which is increased by 37%, suggesting a sustained anticancer effect.

0.6

0.0

■■ While the primary endpoint of NSABP B-34 was not met, the trial found

Fig. 1: Independent review committee–assessed progression-free survival (stratified, censored for nonprotocol therapy) in AVEREL trial. BEV = bevacizumab; DOC = docetaxel; H = trastuzumab; PFS = progression-free survival. Courtesy of Luca Gianni, MD.

A subgroup analysis (n = 161) showed greater advantage for bevacizumab among patients with higherthan-median levels of plasma VEGF-A expression, who had a 30% reduction on risk of progression with bevacizumab. “Now, we have to search for the subset of women who have the characteristics associated with benefit from adding an antiangiogenic,” he said. A global biomarker study is planned that will evaluate bevacizumab plus paclitaxel, stratified by VEGF-A levels, “to confirm or dispute the concept that this marker

ZO-FAST Long-term Outcomes Mature results from the ZO-FAST trial in postmenopausal women with ER-positive early breast cancer confirmed a bone mineral density benefit with adjuvant letrozole plus zoledronic acid.3 The study randomly assigned 1,065 patients to zoledronic acid (4 mg every 6 months), either immediately or upon evidence of bone loss (T score ≤ 2.0), clinical fracture, or asymptomatic fracture at 36 months. The 60-month analysis of mean percent change in lumbar spine bone mineral density showed a highly significant advantage for immediate treatment with zoledronic acid (P < .0001). In addition, disease-free survival (a secondary endpoint) showed a 34% imcontinued on page 10

has anything to do with predicting benefits with the addition of bevacizumab.”

■

Disclosure: Dr. Gianni is a consultant to Roche, Genentech, GSK, Wyeth, Novartis, Eisai, Pfizer, Millennium Takeda, SanofiAventis, Boehringer Ingelheim, Biogen Idec, AstraZeneca, Genomic Health, and Celgene.

Reference 1. Gianni L, Romieu G, Lichinitser M, et al: First results of AVEREL, a randomized phase III trial to evaluate bevacizumab in combination with trastuzumab + docetaxel as first-line therapy for HER2positive locally recurrent/metastatic breast cancer. 2011 CTRC-AACR San Antonio Breast Cancer Symposium. Abstract S4-8. Presented December 8, 2011.

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Bisphosphonates in Early Breast Cancer Early Breast Cancer continued from page 9

provement at 5 years (HR = 0.66; P = .038) favoring immediate treatment, reported Richard de Boer, MD, of Royal Melbourne Hospital in Victoria, Australia.

Richard de Boer, MD

Other Bisphosphonates The primary endpoint of diseasefree survival was not met for the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-34 trial of 3,200 postmenopausal women with early breast cancer randomly assigned to 3 years of oral clodronate (1,600 mg/d) or placebo, plus adjuvant chemotherapy and/or tamoxifen,

reported Alexander Paterson, MD, of the University of Calgary, Alberta, Canada.4 He noted, however, that 40% of patients did not complete 3 years of clodronate. Although the study failed to show a disease-free survival benefit in the overall patient population (HR = 0.91; P = .27), a distinct benefit was demonstrated in the subset of those at least 50 years old (similar to the zoledronic acid trials), and clodronate improved the distant metastasis-free interval both in bone and extraskeletal sites. Clodronate is available in Europe and Canada but not in the United States. Ibandronate (Boniva) also failed to improve disease-free and overall survival when added to a dose-dense regimen of epirubicin, paclitaxel, and cyclophosphamide in the German GAIN trial presented by Volker Möbus, PhD, of Frankfurt, Germany.5 In accordance with the NSABP B-34 study, older patients tended to have better outcomes with ibandronate, though the difference was not statistically significant.

■

Alexander Paterson, MD

Disclosure: Dr. Gnant has received research support from GlaxoSmithKline, sanofiaventis, Novartis, and Roche; honoraria and travel support from Amgen, Pfizer, Novartis, GlaxoSmithKline, Bayer, Sandoz, AstraZeneca, and Genomic Health; and has served as a consultant to Merrion and Novartis. Dr. de Boer is a member of the Novartis Australian Advisory Board and has received speaker’s honoraria from Novartis.

References 1. Gnant M, Mlineritsch B, LuschinEbengreuth G, et al: Long-term follow-up in ABCSG-12: Significantly improved overall survival with adjuvant zoledronic acid in premenopausal patients with endocrine-receptor-positive early breast cancer. 2011 San Antonio Breast Cancer Symposium. Abstract S1-2. Presented December 7, 2011. 2. Coleman RE, Marshall H, Cameron

D, et al: Breast-cancer adjuvant treatment with zoledronic acid. N Engl J Med 365:1396-1405, 2011. 3. De Boer RH, Bundred N, Eidtmann H, et al: Long-term survival outcomes among postmenopausal women with hormone receptor-positive early breast cancer receiving adjuvant letrozole and zoledronic acid: 5-year follow-up of ZO-FAST. 2011 San Antonio Breast Cancer Symposium. Abstract S1-3. Presented December 8, 2011. 4. Paterson AHG, Anderson SJ, Lembersky BC, et al: NSABP protocol B-34: a clinical trial comparing adjuvant clodronate vs. placebo in early stage breast cancer patients receiving systemic chemotherapy and/or tamoxifen or no therapy—final analysis. 2011 San Antonio Breast Cancer Symposium. Abstract S2-3. Presented December 7, 2011. 5. Möbus V, Diel IJ, Harbeck N, et al: GAIN (German Adjuvant Intergroup Node Positive) Study: A phase III multicenter Trial to compare dose dense, dose intense ETC (iddETC) vs. EC-TX and ibandronate vs. observation in patients with node-positive primary breast cancer—1st interim efficacy analysis. 2011 San Antonio Breast Cancer Symposium. Abstract S2-4. Presented December 7, 2011.

EXPERT POINT OF VIEW

James Ingle, MD

ames Ingle, MD, of the Mayo Clinic, Rochester, Minnesota, formally discussed the ABCSG-12 and ZO-FAST bisphosphonate studies presented at the 2011 San Antonio Breast Cancer Symposium, noting, “There is a lot of interest in the effect of bisphosphonates on the tumor microenvironment and the impact of bisphosphonates on modifying the recruitment of bone marrow precursors that may be related to the spread of cancer.” In the previous AZURE trial, the overall effect of zoledronic acid was negative, but there was significant heterogeneity among subsets. Women who were peri- or premenopausal had no benefit, but postmenopausal patients had improvements in dis-

ease-free and overall survival with zoledronic acid. Now, the long-term results of Austrian Breast and Colorectal Cancer Study Group (ABCSG)-12 showed significant improvements in diseasefree and overall survival, and reductions in locoregional recurrence, distant recurrence, and contralateral breast cancers. “And this was the ideal study,” Dr. Ingle concluded. “It was prospectively designed with the appropriate endpoint, and it robustly established those endpoints,” he said.

Level 1 Evidence “My conclusion is that ABCSG-12 provides level 1 evidence for the value of zoledronic acid as adjuvant therapy in premenopausal women receiving goserelin plus tamoxifen or anastrozole, or, one might argue, any third-generation aromatase inhibitor. It was safe and effective, and it is a new standard of care,” he said. Dr. Ingle emphasized, however, that he would not give zoledronic acid to premenopausal women receiving tamoxifen alone. “Abso-

lutely not,” he said in a media briefing.

ZO-FAST: Not So Fast Regarding the ZO-FAST data, Dr. Ingle noted that these findings are “consistent with other recent studies of zoledronic acid” that suggest adjuvant bisphosphonates are of value in women with a low-estrogenic environment. “The magnitude of improvement in ZO-FAST has been accepted to be clinically important in other areas,” he noted. However, the value demonstrated in postmenopausal women was based on an unplanned analysis, he pointed out. “Thus, the data are insufficient to support zoledronic acid as the standard of care in postmenopausal women,” he maintained. Regarding the use of zoledronic acid based on the findings from these trials, Dr. Ingle posed a few questions. “Are premenopausal women treated with ovarian function suppression, as in ABCSG-12, the same as postmenopausal women?” he asked. “Perhaps, but not necessarily, and we cannot directly extrapolate

ABCSG-12 results to postmenopausal women.” As for clodronate and ibandronate, NSABP B-34 and the GAIN trial provided “clues” that uphold some consistency of value for bisphosphonates in the low-estrogenic environment. “At the 30-foot level, they are both negative studies, but with close examination, the findings with respect to an age effect are consistent with this theme,” he said. Other issues remain, he said, regarding the use of bisphosphonates in breast cancer: relative efficacy per type of bisphosphonate, impact of age (eg, < 40 years), degree of estrogen suppression, impact of adjuvant chemotherapy, and optimal schedule and duration of treatment. Ongoing studies will provide more data. Unanswered questions notwithstanding, Dr. Ingle concluded, “mounting evidence suggests that bisphosphonates will become established as efficacious in the adjuvant treatment of postmenopausal women with early breast cancer.”

■

Disclosure: Dr. Ingle reported no potential conflicts of interest.

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Tumor Molecular Profiling Can Molecular Profiling Identify ER-positive Patients Destined for Relapse? Researchers improve understanding of the biology for early, vs later, recurrence. By Caroline Helwick

strogen receptor (ER)-positive breast cancer often recurs years after the initial diagnosis, and understanding the patterns of timing regarding relapse could identify patients needing more aggressive treatment. At the 2011 San Antonio Breast Cancer Symposium, several investigative teams reported progress in defining these patterns and risk categories.

Robust Molecular Differences “Our work provides clear evidence that robust molecular differences exist between ER-positive breast cancers that recur early vs much later, despite adjuvant tamoxifen,” said Minetta C. Liu, MD, of the Georgetown Lombardi Comprehensive Cancer Center, Washington, DC. Dr. Liu and colleagues analyzed gene-expression data from breast tumor biopsies, and then correlated them with the development of SEE PAGE 2 distant metastases.1 What emerged was a 91-gene classifier that reliably separates early recurrences (distant relapse

Overcoming Endocrine Resistance Investigators have proposed several strategies that might help overcome resistance to endocrine agents in patients with breast cancer. According to Eric P. Winer, MD, of Dana-Farber Cancer Center, Boston, these include the following approaches:

■■ Exploit the interaction between estrogen receptor (ER) and other Minetta C. Liu, MD

≤ 3 years from diagnosis) from late recurrences (≥ 10 years). The gene classifier was derived from pretreatment tumor biopsies collected at the Edinburgh Breakthrough Research Unit between 1982 and 1990 from 111 patients with stage I to III ER-positive breast cancer who received adjuvant tamoxifen. The optimized classifier was validated on a large independent data set and found to have high levels of accuracy, specificity, sensitivity, positive predictive value, and negative predictive value, Dr. Liu noted. In addition, patients predicted to experience an early recurrence had a greater than threefold risk of dying in both the training dataset (P < .0001) and the validation dataset (P = .0004).

growth factor pathways. Growth factor activation leads to endocrine resistance, and ER signaling may diminish the benefit derived from inhibiting growth factor pathways.

■■ Target ER and the PI3 kinase pathways simultaneously, which may

abrogate prior resistance to endocrine therapy. A hyperactivated PI3 kinase pathway seems to predict for resistance to hormonal therapy, and inhibition of mammalian target of rapamycin (mTOR) and PI3 kinase has been shown to prevent the emergence of estrogen-independent cells in preclinical studies.

■■ Address the problem of lack of adherence to endocrine therapy, which is a major problem in daily practice.

■■ Develop approaches to deal with the problem of heterogeneity in ER-

sensitive tumors. Studies of new agents are needed in the neoadjuvant setting, with rebiopsy of metastases to assess the molecular profile of the tumor and correlate response with biomarkers.

A novel computational procedure was developed to integrate gene-expression data with protein–protein interaction data and thus create a statistical network model of signaling. The majority of genes identified through

network modeling were related to apoptosis and proliferation. For example, tumors from patients with an early recurrence had increased expression of CALM1, CALM2, CALM3, continued on page 12

EXPERT POINT OF VIEW rather than sooner, post-treatment.

High-risk Time Period

Eric P. Winer, MD

astern Cooperative Oncology Group (ECOG) trials have demonstrated that recurrence patterns are different for estrogen receptor (ER)positive vs ER-negative breast cancer. While ER-negative disease carries a high risk for early recurrence—peaking around year 1.5 from diagnosis—risk steadily declines thereafter. ER-positive tumors, on the other hand, actually carry a higher risk of recurrence on an annual basis, as recurrence risk steadily rises. This makes relapse risk for ERpositive patients more common later,

“The period of time beyond 5 years is one of relatively high risk for women with ER-positive breast cancer,” said Eric P. Winer, MD, of Dana-Farber Cancer Center, Boston. We all know that breast cancer can recur many, many years after diagnosis,” he said at an educational session at the 2011 San Antonio Breast Cancer Symposium. “It’s a sobering fact that at year 9 of the MA.17 study (evaluating letrozole after 5 years of tamoxifen), some 3% of women entered the year free of cancer and ended the year with a recurrence.” Several potential scenarios may explain recurrences among luminal breast tumors, according to Dr. Winer. Very early recurrences (within the first year or two) probably represent primary de novo endocrine resistance. Recurrences between 2 and 5 years may be due to secondary endocrine resistance. After 5

or more years, discontinuation of endocrine suppression, on which tumor quiescence depends, may be a function of “a switch being flipped after a period of tumor dormancy,” he proposed. “And for women with recurrences 15 to 20 years after diagnosis, I scratch my head and wonder where the tumor was all those years,” Dr. Winer added. Identification of individual risk is critical. “Our goal is not to treat every patient for 5, 10, or 20 years, but to identify those with the greatest risk for recurrence,” he pointed out.

Lack of Established Treatment Meanwhile, the best way to manage ER-positive patients after 5 years of endocrine therapy—possibly ameliorating risk for late recurrences—remains unclear. In postmenopausal women, the International Breast Cancer Study Group is evaluating extended aromatase inhibitor use on an intermittent vs continuous schedule. For premeno-

pausal women who finish 5 years of tamoxifen, the lack of an established treatment is even more problematic. “This is truly an unmet medical need. Most women in this situation simply don’t want to go on another treatment at year 5, and so it’s hard to do a study, in spite of the fact that these women remain at high risk,” Dr. Winer said. “We also must keep in mind that the toxicity of 5-plus years of endocrine therapy can be substantial. Even minor side effects can become deeply troubling over time and they increase nonadherence to treatment,” he added. “While we have many challenges ahead, I believe that laboratory and clinical advances have put us in a better position than ever before,” he concluded, “to improve the lives of the three-fourths of patients with breast cancer who have ERpositive tumors and who constitute the majority of deaths from breast cancer.”

■

Disclosure: Dr. Winer has been a consultant for Novartis.

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Tumor Molecular Profiling Molecular Profiling continued from page 11

SRC, CDK1, and MAPK1. For late recurrences, increased tumor expression of ESR1, ESR2, EGFR, BCL2, and AR was observed. “Reliable prediction of early treatment failure may identify patients who require agents beyond endocrine therapy to prevent the early onset of distant metastases,” Dr. Liu said. “Exploiting the molecular differences between early vs late recurrences may also guide the development of effective novel drug combinations in this group.” She added that her group’s goals extend beyond development of a score predictive of long-term outcomes. “We want to understand the underlying mechanisms for the development of early vs late breast cancer recurrences and develop ways to convert them to never recurrences,” she said.

International Investigation An international study asked similar questions and discovered that patients could be risk-stratified for recurrence through a measure of genes related to proliferation plus those related to estrogen receptor expression.2 The study used three public geneexpression datasets involving 606 ER-

Index continued from page 2

novo AML patients aged 50-70 years old: A prospective randomized phase 3 trial from the Acute Leukemia French Association (ALFA). Castaigne S, Pautas C, Terre C, et al. ■■ Abstract 98: A phase III randomized intergroup trial [SWOG S0016] of CHOP chemotherapy plus rituximab vs CHOP chemotherapy plus iodine-131-tositumomab for the treatment of newly diagnosed follicular non-Hodgkin’s lymphoma. Press O, Unger JM, Rimsza LM, et al. ■■ Abstract 109. Initial findings from the PACE Trial: A pivotal phase 2 study of ponatinib in patients with CML and Ph+ ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. ■■ Abstract 248: A novel anti-CD22 immunotoxin, moxetumomab pasudotox: A phase I study in pediatric acute lymphoblastic leukemia. Wayne AS, Bhojwani D, Silverman LB, et al. ■■ Abstract 252: Anti-CD19 BiTE blinatumumab induces high complete remission rate in adult patients with relapsed B-precursor ALL: Updated results of an

positive patients who received tamoxifen. A measure of proliferation was calculated as the average expression of 12 mitotic kinases, which investigators called a mitotic kinase score (MKS). A four-gene estrogen-related score (ERS) was adopted from the ER gene subset of the Oncotype DX tool. Four groups were evaluated: low MKS/high ERS; low MKS/low ERS;

Giampaolo Bianchini, MD, of the Fondazione Centro San Raffaele del Monte Tabor in Milan, Italy. Mitotic kinase score and estrogenrelated score were both prognostic— independently and as a combined marker. High proliferation/low estrogen-related expression was associated with the worst outcomes, and low proliferation/high estrogen-related ex-

Exploiting the molecular differences between early vs late recurrences may guide novel drug combinations in some ER-positive patients. —Minetta C. Liu, MD

high MKS/high ERS; and high MKS/ low ERS. Patterns of distant recurrences were assessed in three time intervals: upfront (0–2.5 years), after a switch to an aromatase inhibitor (2.5–5 years), and years after treatment (5–10 years). The majority of relapses observed within the first 2.5 years occurred in patients with high proliferation and low estrogen-related scores. “These cancers are enriched in tumors intrinsically resistant to tamoxifen, and possibly to aromatase inhibitors,” said

ongoing phase II trial. Topp MS, Goekbuget N, Zugmaier G, et al: ■■ Abstract 455: Bosutinib versus imatinib in newly diagnosed chronic phase chronic myeloid leukemia—BELA trial: 24-month follow-up. Cortes JE, Maru A, De Souza CAA, et al. ■■ Abstract 875: Inotuzumab ozogamycin (I0), a CD22 monoclonal antibody conjugated to calecheamicin, is active in refractory-relapse acute lymphocytic leukemia (R-R ALL). O’Brien S, Thomas DA, Ohanian M, et al. ■■ Abstract 983: The Bruton’s tyrosine kinase inhibitor PCI-32765 induces durable responses in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: Follow-up of a phase Ib/II study. O’Brien S, Burger JA, Blum KA, et al. ■■ Abstract 3102: Inotuzumab ozogamicin is an effective salvage therapy that allows for allogeneic hematopoietic stem cell transplantation in remission in patients with advanced acute lymphoblastic leukemia. Kebriaei P, Wilhelm K, Ravandi F, et al.

Multiple Myeloma

■■ Abstract 301: Investigational agent

pression had the best outcomes. “But importantly, the odds ratios were not constant over time,” Dr. Bianchini said.

Time Patterns Analysis of the time pattern of relapse by the biomarker groups at three time points showed unique risk profiles according to the MKS/ERS gene patterns. For example, compared with low MKS/high ERS tumors, those with high MKS/low ERS had an almost 11-fold increased risk for

MLN9708, an oral proteasome inhibitor, in patients with relapsed and/or refractory multiple myeloma: Results from the expansion cohorts of a phase I dose-escalation study. Richardson PG, Baz R, Wang L, et al. ■■ Abstract 302: Phase 1 clinical evaluation of twice-weekly marizomib (NPI-0052), a novel proteasome inhibitor, in patients with relapsed/refractory multiple myeloma. Richardson PG, Spencer A, Cannell P, et al. ■■ Abstract 303: A phase 2 study of elotuzumab in combination with lenalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma. Lonial S, Jakubowiak AJ, Jagannath S, et al: ■■ Abstract 479: Phase 1 / 2 study of oral MLN9708, a novel, investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma Berdeja JG, Richardson PG, Lonial S, et al. ■■ Abstract 631: Final results of a frontline phase 1/2 study of carfilzomib, lenalidomide, and low-dose dexamethasone in multiple myeloma. Jakubowiak AJ, Dytfeld D, Jagannath S, et al. ■■ Abstract 632: A phase I/II study of pomalidomide-cyclophosphamide-pred-

recurrence within 2.5 years, but no increased risk at 5 to 10 years. “Low proliferation/high ERS tumors had an excellent prognosis, even after stopping tamoxifen,” he reported. “But high risk of recurrences after 5 years of tamoxifen was present in tumors with high MKS/high ERS. These patients may be the best candidates for extended endocrine therapy after 5 years of tamoxifen. High risk of late relapse after 5 years was also present in the low MKS/low ERS group, so we wonder if there is a role for aromatase inhibitors in this group as well.”

■

Laura Esserman, MD, provides another expert point of view on page 13. Disclosure: Drs. Liu and Bianchini reported no potential conflicts of interest.

References 1. Liu MC, Dixon JM, Xuan JJ, et al: Molecular signaling distinguishes early ER-positive breast cancer recurrences despite adjuvant tamoxifen. 2011 San Antonio Breast Cancer Symposium. Abstract S1-8. Presented December 7, 2011. 2. Bianchini G, Pusztai L, Iwamoto T, et al: Molecular tumor characteristics influence adjuvant endocrine treatment outcome. 2011 San Antonio Breast Cancer Symposium Abstract S1-7. Presented December 7, 2011.

nisone in patients with multiple myeloma relapsed/refractory to lenalidomide. Palumbo A, Larocca A, Carella A, et al. ■■ Abstract 633: Carfilzomib combined with thalidomide and dexamethasone (CARTHADEX) as induction treatment prior to high-dose melphalan in newly diagnosed patients with multiple myeloma. A trial of the European Myeloma Network. Sonneveld P, Hacker E, Zweegman S, et al. ■■ Abstract 634: Randomized, open label phase I/2 study of pomalidomide alone or in combination with low-dose dexamethasone in patients with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide and bortezomib: Phase 2 results. Richardson PG, Siegel DS, Vij R, et al. ■■ Abstract 812: High response rates to pomalidomide and dexamethasone in patients with refractory myeloma. Final analysis of IFM 2009-02. Leleu X, Attal M, Arnulf B, et al. ■■ Abstract 813: Final results form the bortezomib-naïve group of PX-171-004, a phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory MM. Vij R, Kaufman JL, Jakubowiak AJ, et al.

■

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Tumor Molecular Profiling EXPERT POINT OF VIEW

nderstanding the different relapse patterns within estrogen receptor (ER)-positive breast cancer is important for guiding treatment decisions, said Laura Esserman, MD, of the University of California, San Francisco, Medical Center. Women who fall into the two separate categories may have different treatment needs, said Dr. Esserman, who has led many studies in risk assessment and molecular profiling of tumors. “We have good predictors of early relapse. Our markers for late relapse are not so good,” she noted. Tumor cell proliferation, however, may be a means of sorting this out, she said. Dr. Esserman and colleagues looked at timing of recurrence among 346 untreated patients from Guy’s Hospital, followed for at least 23 years.1 In ER-positive tumors of low grade, they found risk for early recurrence was very low. However, 10 years or more postdiagnosis about 20% of patients recurred. Higher-grade ER-positive, nodenegative cases had an increase risk of relapse that extended ≥ 20 years, unlike hormone-negative and HER2-positive tumors where risk was confined to 5 years. Among node-positive cases, only low grade conferred late risk. Pooling data from other datasets, the investigators found that tumor proliferative genes predicted early but not late metastatic risk in ER-positive patients. Immunerelated genes were predictive for early metastatic risk in triple-negative and HER2-positive cases.

For predicting sensitivity to endocrine therapy, at least four assays have emerged, all based on estrogen-related genes. “So there is a commonality” in this research theme, which “tells us that this

approach is robust,” she added. “We are starting to ask the right questions, and to develop the kinds of tools we need.”

Prognostic Signatures Breast cancer prognostic signatures need to inform both risk and timing of metastatic events and may best be applied within subsets, she said. “Current signatures predict for outcome risk within 5 years of diagnoses, but predictors of late risk for ER-positive disease are needed.” Ultimately, she said, the best treatment decisions will be made when clinicians can dissect out the patient’s baseline risk with and without therapy, and predict their sensitivity to hormonal treatment. “It’s not simply being hormone receptor–positive. That’s only the minimum,” she pointed out.

■

Disclosure: Dr. Esserman reported no potential conflicts of interest.

Locate the mutation. Stay one step ahead of CML resistance.

Reference 1. Esserman LJ, Moore DH, Tsing PJ, et al: Biologic markers determine both the risk and the timing of recurrence in breast cancer. Breast Cancer Res Treat 129:607-616, 2011.

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Metastatic Breast Cancer Everolimus plus Exemestane Significantly Prolongs Remission in BOLERO-2 But will mTOR inhibitors work only in endocrine-resistant patients? By Caroline Helwick

dding an inhibitor of mammalian target of rapamycin (mTOR) to an aromatase inhibitor more than doubled the time to disease progression in patients with advanced, treatment-refractory breast cancer in the phase III BOLERO-2 trial, whose updated results were presented at the San Antonio Breast Cancer Symposium by Gabriel Hortobagyi, MD, of The University of Texas MD Anderson Cancer Center, Houston.1 “We believe these results underline the fact that everolimus [Afinitor] is the first agent to significantly enhance the efficacy of hormonal therapy in patients with estrogen receptor (ER)-positive, HER2-negative adSEE PAGE 2 vanced breast cancer, and could represent a paradigm shift in the management of this patient population,” Dr. Hortobagyi predicted. Virtually all patients with ERpositive advanced disease develop resistance to hormonal therapies, and finding a means of overcoming

this resistance is the subject of strong research efforts. Resistance to hormonal therapy in breast cancer has been associated with overactivation of the mTOR pathway, and by targeting mTOR, everolimus interferes with tumor cell proliferation, angiogenesis, and cell metabolism. “Everolimus is the first treatment to significantly enhance the efficacy of hormonal therapy in this patient population, where this remains a significant unmet need,” Dr. Hortobagyi noted.

Details of Updated Analysis Treatment with everolimus plus hormonal therapy more than doubled progression-free survival, from 3.2 months with exemestane alone to 7.4 months, representing a highly statistically significant 56% reduction in the risk of progression (P < 1×10 -16). While this analysis was done with local tumor assessment, another assessment by central independent review found even greater benefit, with progression-free survival of 11.0 months vs 4.1 months, a 64% risk reduction (P < 1×10 -16),

Everolimus plus Exemestane in Metastatic Breast Cancer ■■ In BOLERO-2, everolimus plus exemestane more than doubled the time to disease progression, from 3.2 months with exemestane alone to 7.4 months—a highly significant 56% reduced risk

■■ mTOR inhibitors may be able to overcome endocrine resistance, especially in previously treated patients

Dr. Hortobagyi reported. In remarking on the robustness of the findings at a media briefing, Dr. Hortobagyi noted that the prolongation of progression far exceeded the investigators’ expectations. “The study demonstrated not a 26% reduction in progression, as we had expected, but a 56% reduction in events, with a P value for which I don’t have enough fingers to count.” Disease-free survival rates at 1 year were 31% with the combination vs 10% with exemestane alone. As of December 2011, deaths had occurred in 23.1% and 29.3%, respectively. Side effects were consistent with those previously reported with everolimus. The most common

grade 3 or 4 adverse events were stomatitis, anemia, hyperglycemia, dyspnea, fatigue, and pneumonitis, all occurring in < 10% of patients receiving the combination. The addition of everolimus did not negatively impact quality of life.

■

Disclosure: Dr. Hortobagyi serves as a compensated consultant to Novartis and receives funding as a participant in a clinical trial based on zoledronic acid, also a Novartis drug.

Reference 1. Hortobagyi GN, Piccart M, Rugo H, et al: Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial. 2011 San Antonio Breast Cancer Symposium. Abstract S3-7. Presented December 8, 2011.

EXPERT POINT OF VIEW

Photo Courtesy © SABCS/Todd Buchanan 2011

ignaling of mammalian target of rapamycin (mTOR) is required for estrogen-induced breast tumor cell proliferation, and hyperactivation of the mTOR pathway is observed in endocrine-resistant breast cancer cells. Clinically, this makes for a rational one-two punch in endocrine-resistant breast cancer, targeting the estrogen receptor (ER) and inhibiting mTOR with agents such as everolimus (Afinitor), according to Ian Smith, MD,

Ian Smith, MD

of the Royal Marsden Hospital, London. Dr. Smith noted, “mTOR is a rational target to enhance the efficacy of hormonal therapy, but mTOR inhibitors may work better in patients who develop acquired endocrine resistance with a hyperactiveated mTOR pathway. In BOLERO-2, we saw the effect of this. And in an equally impressive though smaller phase II study, TAMRAD, tamoxifen plus everolimus also significantly prolonged time to disease progression with a hazard ratio in the same ballpark as BOLERO-2 [HR = 0.53].”1

Usefulness Limited to Refractory Patients? In TAMRAD, progression was reduced by 26% in patients with primary hormone resistance but by 62% in those with secondary

hormone resistance. “The gains seemed to be in the acquired-resistance group, which fits the hypothesis,” Dr. Smith noted. If such is the case, then mTOR inhibitors may not work well in the first-line setting, agreed Eric P. Winer, MD, of Dana-Farber Cancer Center, Boston. Dr. Winer pointed out that in another study of a different mTOR inhibitor, temsirolimus (Torisel), little to no benefit was found for the combination vs letrozole alone in the first-line metastatic setting. “So you have two very similar drugs, given in different settings. One is very positive, and one is negative. This is hard to explain, but it seems unlikely that this difference arose by chance alone,” he told The ASCO Post. “Some have suggested that temsirolimus may have been un-

derdosed. The other difference was that it was not given to patients refractory to aromase inhibitors, which raises the question as to whether there is upregulation of the mTOR pathway in response to resistance, which in turn could lead to greater sensitivity to mTOR inhibitors,” Dr. Winer said.

■

Disclosure: Dr. Winer has been a consultant for Novartis. Dr. Smith reported no potential conflicts of interest.

Reference 1. Bachelot T, Bourgier C, Cropet C, et al: TAMRAD: A GINECO randomized phase II trial of everolimus in combination with tamoxifen versus tamoxifen alone in patients with hormone-receptor positive, HER2 negative metastatic breast cancer with prior exposure to aromatase inhibitors. 2010 San Antonio Breast Cancer Symposium. Abstract S1-6. Presented December 9, 2010.

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Lymphoma Post-CHOP Radioimmunotherapy Comparable to Rituximab Given along with CHOP in Previously Untreated Follicular Lymphoma By Caroline Helwick

n patients with previously untreated follicular lymphoma, similar outcomes were achieved with CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, plus six doses of rituximab [Rituxan]) and CHOP-RIT (CHOP plus one dose of tositumomab/iodine-131 tositumomab [Bexxar]) in a phase III Intergroup trial conducted by the Southwest Oncology Group (SWOG) and Cancer and Leukemia Group B (CALGB).1 SWOG S0016/CALGB 50102 compared the efficacy of two immunochemotherapy regimens for follicular lymphoma in 554 patients, over half of whom had stage IV disease. “We found the outcomes are excellent with either CHOP-R or CHOP-RIT. They produce similar overall response rates, complete response rates, progres-

Radioimmunotherapy vs Rituximab in Follicular Lymphoma ■■ In SWOG S0016/CAOGB 50102, radioimmunotherapy following CHOP produced similar outcomes to CHOP-R.

■■ At a median follow-up of 4.9 years, progression-free survival was 80%

with CHOP-RIT and 76% with CHOP-R, while overall survival was 93% and 97%, respectively.

Oliver W. Press, MD, PhD

sion-free survival, and overall survival, and there are no major differences in the toxicities,” said Oliver W. Press, MD, PhD, of the Seattle Cancer Care Alliance.

Key Data At a median follow-up of 4.9 years, overall and progression-free survival rates were similar between the treat-

ment approaches. Two-year overall survival rates were 97% with CHOP-R and 93% with CHOP-RIT (P = .08). Progression-free survival rates were 76% and 80%, respectively. Response rates were 85% in each arm, including complete responses in 41% with CHOP-R and 46% with CHOP-RIT. Dr. Press suggested the response rates were in reality higher,

EXPERT POINT OF VIEW

WOG S0016, which compared treatment with CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, plus rituximab [Rituxan]) and CHOP-RIT (CHOP plus tositumomab/iodine-131 tositumomab [Bexxar]) in patients with follicular lymphoma, was one of the most important studies at the 2011 ASH meeting, Andrew Zelenetz, MD, of Memorial Sloan-Kettering Cancer Center, New York, told The ASCO Post. “The finding that these two treatment approaches are similar tells us that a single course of radioimmunotherapy can replace multiple doses of rituximab,” he said. But the study failed to answer the questions that are most relevant for today’s population of follicular lymphoma patients, he said, and other specialists agreed. “What would the outcome be if we added radioimmunotherapy to CHOP-R? That’s the key question,” according to Dr. Zelenetz.

Other Concerns Mark S. Kaminski, MD, of the University of Michigan Health System, Ann Arbor, elaborated. “The presentations in this session illustrate something in the back of our minds,” he said. “We are adding more and more treatment to these patients as we go along—not just chemotherapy, but radioimmuno-

therapy and maintenance. This is despite data showing that radioimmunotherapy as a single agent that takes only 2 weeks to deliver results in very long remissions in the majority of patients. I am concerned that we have swung the pendulum so far in one direction that we can never conduct a trial that will compare this single approach with what has become the current standard.” In his presentation, lead investigator Oliver Press, MD, of the Seattle Cancer Care Alliance, agreed on the need to evaluate strategies such as as CHOP-R followed by rituximab maintenance, CHOP-R followed by radioimmunotherapy, or CHOP-R followed by radioimmunotherapy followed by rituximab maintenance. Some of these studies are underway, he noted. The First-Line Indolent (FIT) Trial reported at ASH in 2007 and subsequently published1 concluded patients could receive chemotherapy with rituximab (CHOP-R), followed by adjuvant radioimmunotherapy (90Y-ibritumomab tiuxetan [Zevalin]). This trial led to approval of ibritumomab tiuxetan in previously untreated follicular NHL patients who achieve a partial or complete response to first-line chemotherapy. “I think it is still valuable to think about radioimmunotherapy as a frontline treatment, even as monotherapy, and also in terms of the order in which

Mark S. Kaminski, MD

it may be given with chemotherapy,” Dr. Kaminski added. “Perhaps there is another question to ask: What is the optimal schedule for radioimmunotherapy? Should it come before or after chemotherapy? For instance, we could use a very powerful agent upfront, like radioimmunotherapy, and the ‘cleanup’ could be with minimal chemotherapy.”

■

Disclosure: Dr. Zelenetz was involved in the initial trials leading to the approval of tositumomab/I131-tositumomab and is a consultant to GlaxoSmithKline, the manufacturer of tositumomab/I131-tositumomab. Dr. Kaminski has patents on CD20 radioimmunotherapy and receives research funding from GlaxoSmithKline.

Reference 1. Morschhauser F, Radford J, Van Hoof A, et al: Phase III trial of consolidations therapy with Yttrium–90–ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol 26:5156-5164, 2008.

since nonassessable patients (10%) were counted in the denominator in the analysis but not counted as responders. Four prognostic factors were highly significant for progression-free and overall survival: Follicular Lymphoma International Prognostic Index (FLIPI) score, serum beta2microglobulin plus lactate dehydrogenase (LDH), serum beta2SEE PAGE 2 microglobulin alone, and LDH alone. Adverse events were similar except for more thrombocytopenia with CHOP-RIT (18% vs 2%; P < .0001). There was a trend toward more myelodysplasia and acute myeloid leukemia in the CHOP-RIT arm (7 cases [2.7%]) compared with the CHOP-R group (3 cases [1%]), but this difference was not statistically significant (P = .34). Human anti-mouse antibodies developed in 17% of evaluable patients treated with CHOP-RIT.

Outstanding Outcome “It is important to emphasize that this clinical trial produced outstanding outcomes for patients on both arms of the study, with more than 60% of patients estimated to be progression-free 5 to 10 years after treatment. The flat slope of the progression-free survival curves after 3 years makes it likely that many of these patients will not relapse during their lifetimes,” Dr. Press speculated.

■

Disclosure: Dr. Press has been a consultant for Genentech/Roche and Spectrum Pharmaceuticals.

Reference 1. Press O, Unger JM, Rimsza LM, et al: A phase III randomized intergroup trial [SWOG S0016] of CHOP chemotherapy plus rituximab vs CHOP chemotherapy plus iodine-131-tositumomab for the treatment of newly diagnosed follicular non-Hodgkin’s lymphoma. 53rd American Society of Hematology annual meeting. Abstract 98. Presented December 11, 2011.

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Leukemia BELA Trial Reborn: Bosutinib Produces Improved Results in Chronic Myeloid Leukemia By Neil Canavan

he initial reports of the BELA trial (Bosutinib Efficacy and safety in chronic myeloid LeukemiA), presented at ASH 2010, were deflating. At 12-month follow-up, bosutinib failed to meet BELA’s primary endpoint. Things have since turned around, however, and results from the 24-month analysis presented at ASH 2011 suggest that this next-generation tyrosine kinase inhibitor may soon be ready for regulatory approval in chronic myeloid leukemia (CML).1

reaching the first postbaseline cytogenetic analysis. But most who dropped out did so because several adverse events, mainly gastrointestinal, were not properly managed,” he said. “We paid the price of a relative unfamiliarity with bosutinib in the medical community and of a nonoptimal selection of centers. This factor was in my opinion the cause of 9% of patients dropping out of the protocol before the first post-treatment assessment could be performed at month 3.”

Trial Design and Data

Carlo Gambacorti-Passerini, MD

Carlo Gambacorti-Passerini, MD, of the University of Milano Bicocca, Monza, Italy, who led the earlier trial, was not surprised. “I was not so disappointed about the 12-month results because I knew the background of the data,” he said in an interview. “And I knew why the primary endpoint (complete cytogenetic response) was not different when comparing the two groups, bosutinib vs imatinib [Gleevec].” The problem was not with the efficacy of the drug, but the experience of the investigators. As Dr. Gambacorti-Passerini explained, the trial included an intent-totreat analysis. “Unfortunately, a number of patients discontinued treatment before

Bosutinib

P < .05

100%

87%

80% 65% Responders

BELA is an international, multicenter trial with 139 sites, and some investigators were unaccustomed to the proactive patient management required, he added. With this oversight corrected, data from the 24-month follow-up were redeeming. BELA randomly assigned 502 patients with newly diagnosed, chronic phase CML to the standard imatinib treatment or bosutinib. The primary endpoint was complete cytogenetic response at 12 months. BELA is slated to run through 8 years of follow-up At 24 months, the cumulative intent-to-treat complete cytogenetic response for both drugs was nearly identical. In a subanalysis that excluded patients who discontinued, a cumulative complete cytogenetic response of 87% for bosutinib vs 81% for imatinib was demonstrated (Fig. 1). This analysis also showed superior major molecular response and complete molecular response for bosutinib compared to imatinib. Median durations of event-free

81%

66%

P < .05 P < .05

60%

67%

54%

52% 44%

40%

MMR

20% 0%

Imatinib

CMR

MMR MMR

MMR CMR CMR

CMR

Bosutinib Imatinib

CCyR at 24 months

Cumulative CCyR by 24 months

MMR and CMR at 24 months

Cumulative MMR and CMR by 24 months

Fig. 1: Complete cytogenetic response and molecular response rates in the evaluable population of the BELA trial. CCyR = complete cytogenetic response; CMR = complete molecular response; MMR = major molecular response. Courtesy of Jorge Cortes, MD.

Bosutinib in Chronic Myeloid Leukemia ■■ In the 24-month intent-to-treat analysis of BELA, bosutinib treatment

produced complete cytogenetic response rates similar to those seen with imatinib, but in a subanalysis excluding patients who discontinued, bosutinib produced a higher rate of complete cytogenetic response.

■■ Bosutinib also produced superior major molecular responses and

complete molecular responses, and was associated with lower treatment failure rates.

■■ Data are better than were observed in a previous analysis, primarily because side effects were better managed.

and overall survival have not yet been reached. However, at 24 months, bosutinib was associated with lower rates of treatment failure (4% vs 13%) and progression to acceleratedphase/blast crisis (2% vs 5%) for imatinib, Dr. Gambacorti-Passerini summarized. As expected, subjects in the bosutinib arm experienced more grade 3/4 diarrhea, whereas imatinib recipients had more edema, muscle cramps, and myalgia. Hematologic events were more common in the imatinib treat-

ment arm, especially neutropenia (24% vs 10% for bosutinib).

■

Disclosure: Dr. Gambacorti-Passerini has received research support from Pfizer and is a board member for Pfizer, Bristol-Myers Squibb, Novartis, and Biodiversity.

References 1. Cortes JE, Maru A, De Souza CAA, et al: Bosutinib versus imatinib in newly diagnosed chronic phase chronic myeloid leukemia—BELA trial: 24-month followup. 53rd American Society of Hematology Annual Meeting. Abstract 455. Presented December 12, 2011.

EXPERT POINT OF VIEW

iven the results of the BELA trial, with the problems of treatment side-effect management realized and seemingly resolved, Elias Jabbour, MD, Assistant Professor of Medicine at The University of Texas MD Anderson Cancer Center, Houston, assumes bosutinib will be approved in chronic myeloid leukemia. In fact, he urges the manufacturer to seek approval earlier rather than later, to avoid the coming crowd of tyrosine kinase Elias Jabbour, MD inhibitors. He does have concerns, however, regarding future treatment choices. Bosutinib would be one of four possible options, he said. “In my book, having several options is always better. But what we need to do is find the molecular/genetic factors to help us predict response, and hopefully that will tell us who should receive what,” Dr. Jabbour said in an interview. For the moment, there are subtle differences in side-effect profiles on which to base treatment decisions. “Dasatinib [Sprycel] can cause pleural effusion, so giving it to a smoker, or a patient with chronic obstructive pulmonary disease would not be appropriate; nilotinib [Tasigna] carries a risk of pancreatitis and other issues, so would not be ideal for diabetics,” he said. Bosutinib seems to have a cleaner side-effect profile in comparison with these two agents, but the issue overshadowing all three of the newer tyrosine kinase inhibitors is price. “There’s going to be a real dilemma when imatinib [Gleevec] goes off patent—and that’s soon,” Dr. Jabbour predicted. “Unless we show clear advantage in safety and efficacy compared to imatinib,” payers may balk at the additional cost of novel treatments.

■

Disclosure: Dr. Jabbour has received honoraria from Novartis, Pfizer, and Bristol-Myers Squibb.

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Leukemia Ponatinib Continues to Impress in Patients with Leukemia By Neil Canavan

Cancer Center, Houston. “We saw this regardless of mutational status or disease stage.”

nitial results from the PACE (Ponatinib Ph+ ALL and CML Evaluation) trial added to accumulating evidence that the tyrosine kinase inhibitor ponatinib should soon be considered for front-line treatment of chronic myeloid leukemia (CML). “Robust responses were observed in all patient cohorts,” said PACE lead investigator, Jorge Cortes, MD, Professor of Medicine and Deputy Chair in the Department of Leukemia at The University of Texas MD Anderson

■■ In the PACE trial, treatment with ponatinib in CML patients refractory to prior treatment produced a major cytogenic response rate of 47%.

Phase II Trial

Jorge Cortes, MD

Ponatinib in Chronic Myeloid Leukemia

Dr. Cortes presented the first results of PACE, a phase II study of CML patients who were resistant to or intolerant of available tyrosine kinase inhibitors.1 Nearly half the patients (47%) treated with ponatinib experienced a major cytogenetic response. For patients with the difficult-to-treat T315I mutation—none of whom responded to the currently approved tyrosine kinase inhibitors— ponatinib induced a major cytogenetic response rate of 65%, he reported. The high rates of response seen in the T315I patients was described as “exciting” but “not surprising” by study investigators. Ponatinib is an oral, pan-BCRABL, third-generation tyrosine kinase inhibitor that was rationally designed to

EXPERT POINT OF VIEW

t the 2011 ASH Annual Meeting, Pierre Laneuville, MD, Director of Hematology at McGill University in Montreal, predicted that ponatinib may be “the drug that will replace them all” in the treatment of chronic myeloid leukemia. Dr. Laneuville explained his rationale, recalling that in the pivotal trial for imatinib (Gleevec), IRIS, a 20% resistance rate had emerged at 8 years. “Half of those patients had mutations, and ponatinib is effective in virtually all those mutations,” he noted. He further agued that when used in the first-line setting, ponatinib might eliminate 10% of eventual treatment failures now currently observed with standard treatment. These failures are also due to mutations. “So, that’s potentially quite interesting, and we’ll see if the manufacturer pursues that indication. I hope they will,” he commented.

■

Disclosure: Dr. Laneuville reported no potential conflicts of interest.

■■ Of patients with the T315I mutation, ponatinib produced major cytogenetic responses in 65% and major molecular responses in 33% of patients.

overcome the T315I mutation. jor hematologic response rate of 74% PACE enrolled 449 chronic-phase and major cytogenetic response rates CML patients and patients with Philaup to 53%; blast-phase CML and Phdelphia chromosome (Ph)-positive positive ALL patients achieved a major acute lymphoblastic leukemia (ALL) hematologic response rate of 37% and previously treated with approved or major cytogenetic response rates of investigational tyrosine kinase inhibi34% and 37%, respectively. tors. The majorThe most draity (53%) had been matic results from After a median treated with at least PACE were for follow-up of 5 months, three prior tyrosine patients with the kinase inhibitors; problematic T315I high levels of response 39% had been treatmutation, who were observed in all ed with imatinib achieved a 33% (Gleevec) plus damajor molecular patient types, even satinib (Sprycel) response rate. patients who were or nilotinib (TasigFew treatmentgravely ill. na); only 4% had related adverse received imatinib events were obalone. Response served. The most rates to prior treatments ranged from common serious events were neutro33% for major histologic response and penia and thrombocytopenia. Disclosure: Dr. Cortes receives research 25% for major cytogenetic response.

■

support and has been a consultant for Ariad.

Major Results The primary endpoints of PACE were major cytogenetic response for chronic-phase CML, and major histologic response for accelerated-phase CML or Ph-positive ALL. After a median follow-up of 5 months, high levels of response were observed in all patient types, even patients who were gravely ill. Accelerated-phase CML subjects achieved a ma-

Reference 1. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al: Initial findings from the PACE Trial: A pivotal phase 2 study of ponatinib in patients with CML and Ph+ ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. 53rd American Society of Hematology Annual Meeting. Abstract 109. Presented December 11, 2011.

Three Novel Agents Show Promise in Acute Lymphoblastic Leukemia By Neil Canavan

usan O’Brien, MD, Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston, has a special interest in novel developments in the treatment of acute lymphoblastic leukemia (ALL). At the 2011 ASH Annual Meeting, she discussed her picks of top newsmakers in this tumor type.

Susan O’Brien, MD

Moxetumomab “A number of monoclonal antibodies being reported here at ASH look very

interesting,” said Dr. O’Brien. She first mentioned moxetumomab, a CD22 an-

tibody conjugated with the Pseudomonas exotoxin. Moxetumomab is being investigated in a phase I study in pediatric patients with relapsed/refractory ALL.1 “They have not reached a maximum tolerated dose yet, but even without that they report about a 30% response rate in a very heavily pretreated population. And remember,” she emphasized, “ALL is not like [chronic lymphocytic leukemia], or a low-grade lymphoma, where we treat patients, and if they relapse we treat them again until we gain

a lasting response. With ALL, we use all of our effective agents upfront so that when patients relapse, we do not have several unused agents still to try.”

Inotuzumab Ozogamicin A second agent for ALL on Dr. O’Brien’s radar was inotuzumab ozogamicin, a CD22-targeting agent that is conjugated to the same toxin, ozogamicin, as the acute myeloid leukemia drug gemtuzumab ozogamicin (Mycontinued on page 18

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PAGE 18

Leukemia Novel Agents

for the whole population was 5 months.

continued from page 17

lotarg). “This is the same toxin with a different antibody,” she explained, “except in this case we are targeting CD22, a cell-surface molecule present in over 90% of patients with ALL.” As reported by Kebriaei et al, inotuzumab ozogamicin was used as salvage therapy in a small study of 19 heavily pretreated ALL patients prior to bone marrow transplant.2 With a follow-up of 3 months among surviving patients, both overall and progression-free survival rates were 59%. This response allowed for more patients to proceed to successful transplant than would have been historically expected with stanSEE PAGE 2 dard treatment. Of the 19 subjects, 10 had minimal residual disease at time of the procedure. Those 19 patients were actually a subset of a larger group reported by Dr. O’Brien at the ASH meeting.3 Among all 49 patients with refractory or relapsed CD22-positive ALL, the overall response rate was 57%—the highest response rate reported for single-agent therapy in adult ALL. Median survival

Blinatumomab Dr. O’Brien is also keenly interested in blinatumomab, an agent in the so-called BiTE [bispecific T-cell engager] antibody drug class. “It’s a dual antibody that first binds to CD19 on malignant B cells, and then binds to CD3 on nearby T cells, thereby activating the T cells and directing them to kill the B cells,” she explained. Success with this agent was recently reported in the Journal of Clinical Oncology.4 “That was a minimal residual disease study that showed the ability to convert 16 of 21 chemotherapy-refractory patients to [minimal residual disease] negativity, and it appeared to be very durable,” she recalled. The probability for relapse-free survival was 78% at a median follow-up of 405 days. At the ASH meeting, investigators reported on a cohort of 18 ALL patients in full-blown relapse who received single-agent blinatumomab, 12 of whom achieved a complete remission within two cycles, corresponding to a response rate of 67%.5 Of these 12 responding patients, 75% had complete hematologic recovery of peripheral blood counts. Dr. O’Brien was impressed with blinatummab specifically, and the new drug

Novel Agents in Acute Lymphoblastic Leukemia ■■ Moxetumomab is a CD22 antibody conjugated with Pseudomonas exotoxin that is being investigated in pediatric patients with relapsed/refractory ALL.

■■ Inotuzumab ozogamicin is a CD22-targeting agent being used as salvage

therapy in heavily pretreated ALL patients prior to bone marrow transplant.

■■ Blinatumomab is a bispecific T-cell engager—a dual antibody that

binds to CD19 on malignant B cells, and then to CD3 on T cells, thereby activating and directing the T cells to kill the B cells.

class in general, commenting that “these dual antibodies are very hot in ALL.”

■

Disclosure: Dr. O’Brien reported no potential conflicts of interest.

References 1. Wayne AS, Bhojwani D, Silverman LB, et al: A novel anti-CD22 immunotoxin, moxetumomab pasudotox: A phase I study in pediatric acute lymphoblastic leukemia. 53rd American Society of Hematology Annual Meeting. Abstract 248. Presented December 12, 2011. 2. Kebriaei P, Wilhelm K, Ravandi F, et al: Inotuzumab ozogamicin is an effective salvage therapy that allows for allogeneic hematopoietic stem cell transplantation in remission in patients with advanced acute lymphoblastic leukemia. 53rd American Society of Hematology Annual Meeting. Abstract 3102. Presented December 11, 2011. 3. O’Brien S, Thomas DA, Ohanian

M, et al: Inotuzumab ozogamycin (I0), a CD22 monoclonal antibody conjugated to calecheamicin, is active in refractoryrelapse acute lymphocytic leukemia (R-R ALL). 53rd American Society of Hematology Annual Meeting. Abstract 875. Presented December 12, 2011. 4. Topp MS, Kufer P, Goekbuget N, et al: Targeted therapy with the T-cell–engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol 29:2493-2498, 2011. 5. Topp MS, Goekbuget N, Zugmaier G, et al: Anti-CD19 BiTE blinatumumab induces high complete remission rate in adult patients with relapsed B-precursor ALL: Updated results of an ongoing phase II trial. 53rd American Society of Hematology Annual Meeting. Abstract 252. Presented December 12, 2011.

Novel Agent Efficacious in Chronic Lymphocytic Leukemia By Caroline Helwick

novel inhibitor of B-cell receptor signaling produced high rates of remission and was well tolerated in patients with chronic lymphocytic leukemia (CLL) who were refractory to at least two previous treatments, reported Susan O’Brien, MD, of The University of Texas MD Anderson Cancer Center, Houston.1 “To have agents that are this effective and are not myelosuppressive is very exciting,” Dr. O’Brien said. “These agents will really change the paradigm for the treatment of CLL.”

New Molecular Target PCI-32765 is the first drug designed to target Bruton’s tyrosine kinase, a protein that is essential for CLL cell survival and proliferation. It is administered orally. In the study, 61 patients with CLL or small lymphocytic lymphoma who were relapsed/refractory to standard treatments received PCI-32765 daily (420 or 840 mg) in 28-day cycles. Almost three-fourths of the patients had at least one poor-risk molecular feature. Median follow-up for the 420-mg cohort was 10.2 months and for the

Bruton’s Tyrosine Kinase Inhibitor ■■ The oral agent PCI-32765 is the first drug designed to target Bruton’s

tyrosine kinase, a protein essential for chronic lymphocytic leukemia cell survival and proliferation.

■■ In a phase Ib/II trial, PCI-32765 produced response rates of 67% in

patients receiving 420 mg and 68% in those receiving 840 mg of the drug. Progression-free survival rates at 6 months were 92% in the 420-mg group and 90% in the 840-mg cohort.

■■ Phase III trials are planned.

Jane Winter, MD

840-mg cohort was 6.5 months. Responses were observed in 67% of patients receiving 420 mg and in 68% of those receiving 840 mg, with nodal partial responses seen in 23% of patients. Responses appeared to be independent of molecular risk features.

Evolving Responses “At the ASCO Annual Meeting, we reported partial response rates of 48%. Now we report a response rate of about 67%. The responses have evolved over time,” Dr. O’Brien noted. Only 5% of patients have progressed; 6-month progression-free survival was

92% in the 420-mg cohort and 90% in the 840-mg cohort. Phase III trials of PCI-32765 are planned. Jane Winter, MD, of Northwestern University Feinberg School of Medicine, Chicago, who moderated the press briefing where the results were announced, commented, “PCI-32765 is a promising new agent that is based on a novel strategy: targeting the B-cell receptor. It has a very low toxicity profile and high response rates. This is just the beginning of many new agents for the treatment of CLL and other lymphoid malignancies.”

■

Disclosure: Dr. O’Brien receives research support from and is a consultant for Pharmacyclics. Dr. Winter reported no potential conflicts of interest.

Reference 1. O’Brien S, Burger JA, Blum KA, et al: The Bruton’s tyrosine kinase inhibitor PCI32765 induces durable responses in relapsed or refractory chronic lymphocytic leukemia/ small lymphocytic lymphoma: Follow-up of a phase Ib/II study. 53rd American Society of Hematology Annual Meeting. Abstract 983. Presented December 13, 2011.

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Leukemia A Second Chance for Gemtuzumab in Acute Myeloid Leukemia By Neil Canavan

emtuzumab ozogamicin (Mylotarg) may have a second chance for regulatory acceptance, as studies presented at ASH 2011 demonstrated that gemtuzumab can be safely and effectively given by adjusting the dosing and treatment schedule. Gemtuzumab ozogamicin was approved for the treatment of acute myeloid leukemia (AML) in 2000, but in 2010 the drug was voluntarily pulled from the U.S. market by the manufacturer due to postmarketing evidence of lack of efficacy, as well as unacceptable toxicity. In a study described by Sylvie Castaigne, MD, of the Hôpital de Versailles in France, for the Acute Leukemia French Association (ALFA), a fractionated dosing regimen of gemtuzumab overcame the unacceptable drug toxicity issues and allowed the drug to function in combination with chemotherapy, thereby boosting overall efficacy.1

ALFA Trial “By using the standard dose of 9 mg/m2, gemtuzumab could not be combined with chemotherapy,” said Dr. Castaigne. But in the ALFA trial, dosing proceeded with the drug in three increments of 3 mg/m2 over a week’s time, rather than the single treatment bolus. The lower event rate that resulted allowed for the addition of chemotherapy. In the ALFA trial, 278 patients were randomly assigned to one of two treatment arms of standard chemotherapy (60 mg/m2 of daunorubicin for 3 days and 200 mg/m2 of cytarabine for 7

days) with or without fractionated gemtuzumab, and followed for 3 years. Both event-free survival and overall survival were improved with this approach. Median event-free survival was 19.6 months for the gemtuzumab/chemotherapy combination vs just 11.9 months for chemotherapy alone, while median overall survival was 34 vs 19.2 months, respectively. The adverse events reported for the ALFA study population were substantially lower that those historically observed with the single-dose infusion of gemtuzumab at 9 mg/m2, the investigators noted.

Next Regulatory Steps Not Obvious The manufacturer of gemtuzumab, Pfizer, is now in an unusual position—it has a drug that works, but no clear guidance on how to regain regulatory approval in the United

Gemtuzumab Update ■■ Gemtuzumab ozogamicin was withdrawn from the U.S. market,

but new studies using a fractionated dosing regimen showed better tolerability and efficacy in patients 50 to 70 years with newly diagnosed acute myeloid leukemia.

■■ French investigators reported median event-free survival of 19.6 months with gemtuzumab/chemotherapy vs 11.9 months with chemotherapy alone.

■■ Median overall survival was 34 months vs 19.2 months, respectively. ■■ Adverse events were substantially lower than those observed with a single infusion of the drug.

one several years ago and one within the past few months.” Dr. Shapiro had to admit some excitement over the results presented at ASH, but he acknowledged that the regulatory way forward is not obvious. There is no precedent for a drug to be withdrawn, then successfully reintroduced.

In the ALFA trial, [gemtuzumab] dosing proceeded with the drug in three increments of 3 mg/m2 over a week’s time, rather than the single treatment bolus. States. Referring to the French investigations, Mark Shapiro, MD, Global Medical Affairs Lead – Hematology Programs, Oncology Business Unit, at Pfizer Oncology, said in an interview, “I’ve been aware of this work for quite some time. I’ve known Professor Castaigne for many years, and she has shared data from her other studies with me in the past. In fact, Dr. Castaigne has previously published two papers on fractionated dosing—

“Of course, we have to discuss that with the regulatory agencies,” said Dr. Shapiro. “But first we need to assess the quality of the data and determine if the results are truly robust.” Only then could there be what would likely be a very interesting conversation between Pfizer and FDA.

Elephant in the Room For now, however, there’s an elephant in the room. Susan O’Brien,

Visit The ASCO Post website at:

MD, Professor, Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston, commented to The ASCO Post, “I’m unaware of any drug that was pulled and then later on was brought back. I have no idea what the mechanism of going about that would be. But it’s going to be very hard to ignore these data.”

■

Disclosure: Dr. Castaigne received consultant fees from Wyeth from 2006 to 2008. Dr. Shapiro is a full-time employee of Pfizer, Inc, and owns Pfizer stock. Dr. O’Brien reported no potential conflicts of interest.

Reference 1. Castaigne S, Pautas C, Terre C, et al: Fractionated doses of gemtuzumab ozogamicin combined to standard chemotherapy improve event-free and overall survival in newly diagnosed de novo AML patients aged 50-70 years old: A prospective randomized phase 3 trial from the Acute Leukemia French Association (ALFA). 53rd American Society of Hematology annual meeting. Abstract 6. Presented December 11, 2011.

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Multiple Myeloma Monoclonal Antibody Promising in Multiple Myeloma By Caroline Helwick

lotuzumab, a humanized IgG1 monoclonal antibody targeting human CS1, a cell-surface glycoprotein expressed on 95% of myeloma cells, elicited responses in 82% of relapsed/refractory myeloma patients in a phase II study reported at the ASH Annual Meeting.1 Objective response rates exceeded 90% in patients who had SEE PAGE 2 received one prior therapy, and in those receiving the 10 mg/kg dose. The median progression-free survival rate was 65% to 75% with a median follow-up of 14 months. “Overall, we see an 80% to 90% response rate, and at 14 months we have not yet hit median progressionfree survival,” said Sagar Lonial, MD, Professor, Hematology and

Elotuzumab in Multiple Myeloma ■■ Elotuzumab is a humanized IgG1 monoclonal antibody targeting CS1, which is expressed on 95% of myeloma cells. ■■ Elotuzumabub in combination with lenalidomide and dexamethasone produced an 82% response rate in relapsed/refractory patients. ■■ Median progression-free survival of 65% to 75% with a median follow-up of 14 months has not been reached. Sagar Lonial, MD

Medical Oncology, at Emory University School of Medicine, Atlanta.

Durable Responses The study included 73 patients with relapsed/refractory disease, who were treated until progression with 10 or 20 mg/kg elotuzumab in combination with lenalidomide (Revlimid) and low-dose dexamethasone. The drug was well tolerated, and, with prophylaxis, only one grade 3 infu-

sion reaction was documented. Approximately 12% of patients had complete responses and 36% had very good partial responses— outcomes called “very encouraging” by Dr. Lonial. “And these are durable responses. Over half the patients are still on study,” he added. Phase III studies of 10 mg/kg elotuzumab are ongoing in previously untreated patients and in relapsed/refractory patients (the

ELOQUENT1 and ELOQUENT2 trials).

■

Disclosure: Dr. Lonial reported no potential conflicts of interest.

Reference 1. Lonial S, Jakubowiak AJ, Jagannath S, et al: A phase 2 study of elotuzumab in combination with lenalidomide and low-dose dexamethasone in patients with relapsed/ refractory multiple myeloma. 53rd American Society of Hematology Annual Meeting. Abstract 303. Presented December 12, 2011.

EXPERT POINT OF VIEW

ith a wealth of new agents of various classes in the pipeline, “myeloma is going to become a chronic illness, with sustained complete responses achieved in a significant fraction of patients,” according to Kenneth C. Anderson, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.

Elotuzumab Paul G. Richardson, MD, of Dana-Farber Cancer Institute, Boston, agreed. “As we all know, recognizing the complex biology of myeloma, we need more treatment options,” he said.

killing mechanism of elotuzumab is antibody-dependent cell-mediated cytotoxicity, lenalidomide boosts the immune system and increases antigen expression. “With the combination, response rates are very robust,” he observed. “With this proof of concept we hope to take the antibody into an earlier phase of disease—‘smoldering myeloma.’”

Antibody-based Treatments

Daratumumab and BT062

The ASCO Post asked several myeloma experts their views on the investigational agents that could make Dr. Anderson’s prediction a reality. Their thoughts on antibody-based treatments follow. (See page 21 for their perspectives on the new proteasome inhibitors in multiple myeloma.) “We eagerly await monoclonal antibody–based therapy in myeloma, as we have had for years in lymphoma. These agents attack the plasma cell in a different way, and, encouragingly, what we heard at ASH is that they are not only tolerable but effective. They will certainly be additive to our arsenal,” said Sonja Zweegman, MD, PhD, of VU University Medical Center in Amsterdam, The Netherlands, who moderated a session on new agents in myeloma.

Dr. Richardson also singled out the novel CD38 antibody, daratumumab, which showed singleagent activity in a small study. 2 “This is unique and very interesting, since no other monoclonal antibodies to date have shown this,” he noted. Dr. Jagannath said he is also excited about BT062, an antibody conjugated to the cytotoxic agent DM4, a tubulin toxin. At ASH, Dr. Jagannath presented the results of the first-in-human study of BT062 in 32 patients with relapsed/refractory multiple myeloma.3 “Even in this phase I population, evidence of clinical activity was observed, with a favorable toxicity profile,” he said. “This conjugate eliminates myeloma cells but also overcomes drug re-

Sonja Zweegman, MD, PhD

Echoing Dr. Zweegman’s excitement over monoclonal antibodies, he commented, “We saw great data showing enhancement of effect when elotuzumab was added to lenalidomide [Revlimid]/dexamethasone.1 This is probably the ‘new rituximab [Rituxan]’ for myeloma because it is showing such promise in combination.” Sundar Jagannath, MD, of Mount Sinai Medical Center, New York, explained why the elotuzu mab/lenalidomide/dexamethasone combination is effective. While the

sistance in the bone marrow milieu. To our amazement, toxicity is minimal.”

■

Disclosure: Drs. Zweegman and Jagannath reported no potential conflicts of interest. Dr. Richardson has served on advisory boards for Celgene, Millennium, Novartis, and Bristol-Myers Squibb.

References 1. Lonial S, Jakubowiak AJ, Jagannath S, et al: A phase 2 study of elotuzumab in combination with lenalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma. 53rd American Society of Hematology Annual Meeting. Abstract 303. Presented December 12, 2011. 2. Gimsin P, Plesner T, Nahi H, et al: A phase I/II dose-escalation study of daratumumab, a CD38 Mab in patients with multiple myeloma—preliminary safety data. 53rd American Society of Hematology Annual Meeting. Abstract 1873. Presented December 12, 2011. 3. Jagannath S, Chanan-Khan, Heffner LT, et al: BT062, an antibody-drug conjugate directed against CD138, shows clinical activity in patients with relapsed or relapsed/ refractory multiple myeloma. 53rd American Society of Hematology Annual Meeting. Abstract 305. Presented December 12, 2011.

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Multiple Myeloma Next-generation Proteasome Inhibitors Will Improve Outcomes in Bortezomib-refractory Myeloma Patients Early-stage trials of novel compounds yield impressive results. By Caroline Helwick

he next-generation proteasome inhibitor carfilzomib is expected to gain FDA approval in the near future, offering a treatment option that may be as effective as and less neurotoxic than bortezomib (Velcade). Studies presented at the ASH Annual Meeting upheld benefits of the drug observed in earlier trials.

Phase II Carfilzomib Study

SEE PAGE 2

Very promising response rates, and limited toxicity were observed when carfilzomib was combined with le-

nalidomide (Revlimid) and low-dose dexamethasone in a phase I/II study presented by Andrzej Jakubowiak, MD, of the University of Chicago Medical Center.1 “The carfilzomib/lenalidomide/ dexamethasone regimen (CRd) is well tolerated and highly active, demonstrating rapid and deep responses in newly diagnosed myeloma,” Dr. Jakubowiak announced. The study included 53 patients (median age 59) who received eight cycles of carfilzomib (at three different doses), lenalidomide, and dexamethasone, followed by at least nine additional cycles for mainte-

nance. Stem cells were collected from the 24 patients who were autologous stem cell transplant candidates after completion of a median of five cycles. Only a few proceeded to transplant, and the majority, per protocol recommendations, continued on the CRd regimen after stem cell collection. After one or more cycles of the triple regimen, 94% of patients experienced a partial response or greater, and 53% of these were complete or nearcomplete responses. After 12 treatment cycles, 79% achieved a complete or near-complete response. Responses were rapid, and patients continued to

Andrzej Jakubowiak, MD

improve with additional treatment cycles. The high response rates were not affected by stage or cytogenetics. “These response rates compare favorably to our best front-line continued on page 22

EXPERT POINT OF VIEW

Paul G. Richardson, MD

yeloma experts agree that the new proteosome inhibitors are particularly welcome because they are at least as effective as bortezomib (Velcade) but produce much less neuropathy.

Dramatic Results “The activity of MLN 9708 is very encouraging,” said Paul G. Richardson, MD, of Dana-Farber Cancer Institute, Boston. “Upfront we have seen 100% response rates in combination with lenalidomide and dexamethasone, including some very good partial and complete responses. In the relapsed setting we are also seeing single-agent activity, which is promising, as this setting is where we might expect to see much less [activity].1 This signal, in fact, is most promising with the twice-a-week dosing in the advanced disease setting. Also, the main side effect is not neuropathy, but some mild to moderate

based on the remission status of the skin rash, which has proven generally of responsiveness. We think the real patient, a second or perhaps third drug to be manageable. For example, my benefit will emerge in a combinawill be added to control disease, she relapsed patients who participated in tion strategy,” he said. “Marizomib is predicted. “We won’t stop with a partial the study and who were veterans of also exciting for the general oncolresponse but will continue treating, and neuropathy from exposure to prior ogy community because it crosses it will be helpful to have new classes of bortezomib did not find the skin issue the blood-brain barrier and thereagents. It will also help to have a biologic to be a significant problem.” fore may be effective in brain tumors. determination of the malignant plasma Meanwhile, carfilzomib is the nextHeretofore, no other proteasome incells, and a predictive model for selectgeneration proteasome inhibitor exhibitor has done that.” ing the most appropriate treatment for pected to gain FDA approval soon, and “MLN 9708, carfilzomib, and a given patient.” while “it’s a great drug and is associated marizomib should provide a tremenDisclosure: Dr. Richardson has served on with less neurotoxicity, its delivery is dous platform going forward,” Dr. advisory boards for Celgene, Millennium, inconvenient for patients,” Dr. RichardRichardson said. All the proteasome Novartis, and Bristol-Myers Squibb. son maintained. “You must give carfilinhibitors have distinctly different References zomib intravenously weekly, 2 days in properties, which means “they should 1. Richardson PG, Baz R, Wang L, et a row, on days 1 and 2, 8 and 9, and 15 all find their place in the treatment of al: Investigational and 16. MLN9708 agent MLN9708, has the advantage of The activity of MLN 9708 is very encouraging; an oral proteasome being an oral drug, inhibitor, in patients which is conveupfront we have seen 100% response rates with relapsed and/or nient, and one that refractory multiple in combination with lenalidomide and also produces very myeloma: Results little neuropathy,” dexamethasone, including some very good partial from the expansion he noted. cohorts of a phase and complete responses. Dr. Richardson I dose-escalation said he is also imstudy. 53rd American Society of Hematology Annual Meetmyeloma,” he predicted. pressed with marizomib, though it too 2 ing. Abstract 301. Presented December “We need many drugs to prolong is administered twice a week. Mar12, 2011. izomib is an irreversible proteasome the lives of these patients. What we 2. Richardson PG, Spencer A, Caninhibitor, which gives it more potency increasingly see is the use of bionell P, et al: Phase 1 clinical evaluation but perhaps more side effects, includlogically determined treatment,” Dr. of twice-weekly marizomib (NPI-0052), ing mild (reversible) cognitive dysZweegman added. a novel proteasome inhibitor, in patients function with the higher dose. with relapsed/refractory multiple myeloPostinduction Measures “In patients who have received ma. 53rd American Society of HematolClinicians will aim for a complete prior bortezomib, there is a consisogy Annual Meeting. Abstract 302. Preresponse with induction therapy. Then, tent signal. You don’t lose evidence sented December 12, 2011.

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Multiple Myeloma Proteasome Inhibitors continued from page 21

regimens, and we’re still early in the course of the study. Responses continue to improve with time,” he said. “I think it’s going to be one of those regimens that will potentially change the landscape of what we can do.” A total of 27 patients (55%) began maintenance therapy; 43 patients (88%) remain on treatment.

Other Carfilzomib Trials

Pieter Sonneveld, MD, PhD

In other phase II studies of carfilzomib presented at the ASH meeting, similar benefits were observed. A regimen of carfilzomib combined with thalidomide (Thalomid) and dexamethasone as induction therapy prior to stem cell transplantation and as consolidation therapy after transplant achieved responses in 84% of patients in the CARTHADEX study reported by Pieter Sonneveld, MD, PhD, of Erasmus Medical Center in Rotterdam, The Netherlands.2 After induction, 16% achieved a complete or stringent complete response, 29% a very good partial response, and 39% a partial response. “‘Carthadex’ induction is feasible and tolerable, and responses are rapid and equal to what is observed with bortezomib, thalidomide, and dexamethasone,” Dr. Sonneveld said, “but longer follow-up is needed for major conclusions.” He added that peripheral neuropathy occurred in only about one-fourth of patients. Ravi Vij, MD, of Washington University School of Medicine, St. Louis, and colleagues studied carfilzomib as a single agent in relapsed/ refractory patients not previously treated with bortezomib. They noted responses in 42% of patients who received 20 mg/m2 for all cycles and 52% of those receiving 20 mg/ m 2 during the first cycle followed by 27 mg/m2 for subsequent cycles. 3

Median time to progression was 8.3 months in the first cohort but has not been reached in the group receiving the larger dose of carfilzomib.

MLN9708 For several novel compounds still in early development for multiple myeloma, results were promising enough to be included in oral sessions at ASH. MLN9708 is an investigational proteasome inhibitor, the first oral drug in the class to enter clinical trials in myeloma. In early trials, it showed activity as a single agent and in combination regimens. “This compound has similar selectivity and potency, dissociates from the proteasome faster, and has greater tissue penetration compared with bortezomib,” said Paul G. Richardson, MD, of Dana-Farber Cancer Institute, Boston, who has led some of the trials. He reported the results of a phase I dose-escalation expansion cohort study that has enrolled 56 patients averaging 3.5 prior therapies, with 88% exposed to bortezomib.4 MLN9708 was given orally twice weekly in 21-day cycles. Of 46 patients evaluable for response, 6 achieved at least a partial response, including 1 complete response. One patient achieved a minimal response, and 28 patients experienced stable disease. Five responses occurred in patients previously exposed to bortezomib.

Ravi Vij, MD

“All seven responding patients remain in remission, with disease control of up to 15.9 months,” Dr. Richardson said. “Preliminary data suggest there is activity in heavily pretreated relapsed/refractory myeloma, including durable responses and disease control.” MLN9708 is also being evaluated on a weekly schedule, and in combination with lenalidomide and dexamethasone in previously untreated myeloma. A phase I/II study in this

Next-generation Proteasome Inhibitors in Multiple Myeloma ■■ Carfilzomib/lenalidomide/dexamethasone produced partial responses in 94% (53% CR or near CR) of newly diagnosed patients. ■■ Carfilzomib as a single agent produced responses in up to 52% of relapsed/refractory patients; median time to progression has not been reached in patients receiving 20 mg/m2. ■■ MLN9708, an oral drug, provided disease control for up to 16 months in relapsed/refractory patients, and produced responses in 90% of treatment-naive patients. ■■ The next-generation proteasome inhibitors produce much less neuropathy than is seen with bortezomib.

setting found that 9 of 10 treatmentnaive patients achieved at least a partial response, including one complete and three very good partial responses.5 In addition, all patients had a 50% or greater reduction in M-protein after the first cycle, and no patients have yet had disease progression. In the MLN9708 investigations, fatigue, thrombocytopenia, and nausea are the most common adverse events that have been reported. No peripheral neuropathy of grade 3 or higher has been reported, and dose reductions have not been necessary.

Marizomib Also showing promise in earlyphase development is marizomib (NPI-0052), a nonpeptide proteaseome inhibitor that is delivered via infusion. With a twice-weekly dosing schedule, a study in 20 relapsed/refractory patients receiving marizomib with or without dexamathasone demonstrated stable disease or better in 55%, and minimal or partial responses in 15%.6 In patients refractory to bortezo mib, stable disease was achieved in 67% and a minimal or partial response in 17%.

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Disclosure: Dr. Vij has served on the advisory board for Onyx. Dr. Richardson has served on advisory boards for Celgene, Millennium, Novartis, and Bristol-Myers Squibb. Dr. Sonneveld reported no potential conflicts of interest. Dr. Jakubowiak is a consultant, has received honoraria, and has served on an advisory board for BristolMyers Squibb, Millennium, and Onyx; he is a consultant for and has received honoraria from Celgene.

References 1. Jakubowiak AJ, Dytfeld D, Jagannath S, et al: Final results of a frontline phase 1/2 study of carfilzomib, lenalidomide, and low-dose dexamethasone in

multiple myeloma. 53rd American Society of Hematology Annual Meeting. Abstract 631. Presented December 12, 2011. 2. Sonneveld P, Hacker E, Zweegman S, et al: Carfilzomib combined with thalidomide and dexamethasone (CARTHADEX) as induction treatment prior to high-dose melphalan in newly diagnosed patients with multiple myeloma. A trial of the European Myeloma Network. 53rd American Society of Hematology Annual Meeting. Abstract 633. Presented December 12, 2011. 3. Vij R, Kaufman JL, Jakubowiak AJ, et al: Final results form the bortezomib-naïve group of PX-171-004, a phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory MM. 53rd American Society of Hematology Annual Meeting. Abstract 813. Presented December 12, 2011. 4. Richardson PG, Baz R, Wang L, et al: Investigational agent MLN9708, an oral proteasome inhibitor, in patients with relapsed and/or refractory multiple myeloma: Results from the expansion cohorts of a phase I dose-escalation study. 53rd American Society of Hematology Annual Meeting. Abstract 301. Presented December 12, 2011. 5. Berdeja JG, Richardson PG, Lonial S, et al: Phase 1 / 2 study of oral MLN9708, a novel, investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma. 53rd American Society of Hematology Annual Meeting. Abstract 479. Presented December 12, 2011. 6. Richardson PG, Spencer A, Cannell P, et al: Phase 1 clinical evaluation of twice-weekly marizomib (NPI-0052), a novel proteasome inhibitor, in patients with relapsed/refractory multiple myeloma. 53rd American Society of Hematology Annual Meeting. Abstract 302. Presented December 12, 2011.

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Multiple Myeloma New Immunomodulatory Drug Produces Impressive Phase II Results in Multiple Myeloma By Caroline Helwick

Kenneth D. Anderson, MD

ata on pomalidomide, the novel oral immunomodulatory drug for multiple myeloma, was a major highlight of the 2011 ASH Annual Meeting, according to Kenneth D. Anderson, MD, of Dana-Farber Cancer Institute, Boston, who called the drug “very, very exciting.” Paul Richardson, MD, also of Dana-Farber Cancer Institute, who has led trials of pomalidomide, agreed. He told The ASCO Post, “An over 40% clinical benefit rate and almost 17-month median survival in heavily pretreated patients is extremely encouraging.”

Two-drug Combination Therapy Dr. Richardson presented the results of a phase II study comparing pomalidomide alone vs pomalidomide plus low-dose dexamethasone in relapsed/refractory multiple myeloma.1 The 221 patients had a median of five prior lines of therapy and most had experienced disease progression on both bortezomib (Velcade) and lenalidomide (Revlimid). A partial response was achieved in 34% of those treated with pomalidomide/dexamethasone vs 13% with pomalidomide alone; another 11% of patients had minor responses to the combination. MeSEE PAGE 2 dian progression-free survival was 4.7 and 2.7 months, respectively, and median overall survival was 16.9 and 14 months. The most frequently reported

grade 3 or 4 toxicity was neutropenia. The results suggest that pomalidomide combined with dexamethasone is more active than pomalidomide as a single agent, with no increase in toxicity. Xavier Leleu, MD, PhD, of Hôpital Huriez, CHRU Lille, France, presented similar findings from the French phase II IFM 2009-02 study of pomalidomide plus low-dose dexamethasone in 84 patients refractory to both lenalidomide and bortezomib.2

Xavier Leleu, MD, PhD

The overall response rate was 34.5%, with another 48% of patients achieving stable disease. The median duration of response was 8 months, and 37.5% of responders were stable for over 1 year. Median time to progression was 9.1 months, and median overall survival was 13.4 months in these heavily pretreated patients.

Is a Three-drug Combination Even Better? Antonio Palumbo, MD, of the University of Torino in Italy, presented phase II results from a study by GIMEMA, the Italian Multiple Myeloma Network, which evaluated pomalidomide in combination with cyclophosphamide and prednisone.3 A total of 29 patients whose disease had relapsed or was refractory to lenalidomide received six 28-day cycles, followed by maintenance with pomalidomide and prednisone until progression. “We have experience from other drug treatments suggesting that a

Pomalidomide in Multiple Myeloma ■■ A phase II study in relapsed/refractory multiple myeloma showed that pomalidomide plus dexamethasone is more active than pomalidomide as a single agent, with no increase in toxicity; median overall survival was 16.9 months for pomalidomide/dexamethasone and 14 months for pomalidomide alone. ■■ Positive results have also been found in other phase II investigations, including a trial combining pomalidomide, cyclophosphamide, and prednisone. ■■ Phase III studies of the drug are underway.

three-drug combination may improve upon the efficacy of a twodrug regimen, and I believe this should be the case with this drug,” Dr. Palumbo commented. “And with maintenance we can extend the opportunity for patients to stay in remission.” After a median of four cycles, at least a partial response was observed in 81% of the refractory patients and in 55.5% of the relapsed patients. Very

Antonio Palumbo, MD

good partial response or better was seen in 27% and 28%, respectively, and complete responses were documented in 9% and 5.5%, respectively. Pomalidomide was generally well tolerated in all studies. The most common grade 3 or 4 toxicities were neutropenia, anemia, pneumonia, thrombocytopenia, and fatigue. Rash occurred in some patients but was easily manageable. Dr. Palumbo also suggested that using a combination with “a good risk/benefit ratio, where there is not much toxicity,” and continuing the

three drugs as maintenance therapy, “may help explain the higher proportion of responses” in the Italian study. Phase III trials are currently evaluating pomalidomide in various combinations.

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Disclosure: Dr. Palumbo has received honoraria from Celgene. Dr. Anderson is on the advisory board for Celgene. Dr. Leleu reported honoraria, advisory board, lecture fees, and research grants from Janssen, Celgene, LEO Pharma, Novartis, and Amgen. Dr. Richardson is on the advisory boards for Celgene, Millennium, Novartis, and BristolMyers Squibb.

References 1. Richardson PG, Siegel DS, Vij R, et al: Randomized, open label phase I/2 study of pomalidomide alone or in combination with low-dose dexamethasone in patients with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide and bortezomib: Phase 2 results. 53rd American Society of Hematology Annual Meeting. Abstract 634. Presented December 12, 2011. 2. Leleu X, Attal M, Arnulf B, et al: High response rates to pomalidomide and dexamethasone in patients with refractory myeloma, final analysis of IFM 2009-02. 53rd American Society of Hematology Annual Meeting. Abstract 812. Presented December 12, 2011. 3. Palumbo A, Larocca A, Carella A, et al: A phase I/II study of pomalidomidecyclophosphamide-prednisone in patients with multiple myeloma relapsed/refractory to lenalidomide. 53rd American Society of Hematology Annual Meeting. Abstract 632. Presented December 12, 2011.

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