clinical oncology news - November 2011, digital edition hematology edition

Independent News on Advances in Cancer Care

Hematology/Oncology Edition clinicaloncology.com • November 2011 • Vol. 6, No. 11

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Meeting the needs of adolescent and young adult cancer patients.

HematOlogic DISEASE

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S tudy provides first evidence linking gene mutations with MDS morphology.

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S tudy shows brentuximab also effective in kids.

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Investigating stem cells in CML.

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R -DHAP superior to R-ICE in relapsed/refractory diffuse large B-cell lymphoma.

Everolimus Touted As Game Changer In Breast Cancer Stockholm—Researchers have identified a drug that is expected to change the treatment landscape for patients with estrogen receptor (ER)-positive breast cancer that is resistant to nonsteroidal aromatase inhibitors. Adding everolimus (Afinitor, Novartis) to exemestane therapy improved progression-free survival (PFS) by four months compared with therapy with exemestane alone, according to an interim analysis of the Phase III trial BOLERO-2 (Breast Cancer Trials of Oral Everolimus). The study was presented at the recent European Multidisciplinary Cancer Congress (EMCC; abstract LBA9). see EVEROLIMUS, page 12 

SOLID TUMORS

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Tasquinimod shows promise in mCRPC.

Investigators discuss safety of immediate breast reconstruction.

Weekly nab-paclitaxel favored in older women with MBC.

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B RCA2 linked to improved ovarian cancer survival.

EDUCATIONAL REVIEW

Management of the Myelodysplastic Syndromes Between pages 16 and 17

Maximizing Fertility In Breast Cancer Patients: Part 1

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t is terrible for a young woman to have to go through surgery, radiation, chemotherapy and hormonal manipulation to prevent her dying of Steven Vogl, breast cancer.

MD Making her sacrifice her ability to reproduce and raise children as a condition of her survival makes it even worse. For many people, bearing and raising children remains one of the most fulfilling activities of life.

Until recently, the oncology research community has done relatively little to investigate ways to preserve fertility in these unfortunate women. see GONADAL, page 25 

In Newly Diagnosed Multiple Myeloma …

Italian Trial Bolsters Role Of Stem Cell Transplants Stockholm—Hematopoietic stem cell transplantation combined with high-dose chemotherapy produces a longer progression-free survival (PFS) than conventional chemotherapy combined with novel agents in patients with newly diagnosed multiple myeloma, according to results from a new trial.

The results—from the first prospective randomized trial to compare these two strategies— were reported at the 2011 European Multidisciplinary Cancer Congress (abstract 9200).

Investigators compared highdose melphalan (MEL200) followed by autologous stem cell transplantation (ASCT) with conventional melphalan-prednisone plus the novel immunomodulatory agent lenalidomide (MPR) in patients with newly diagnosed multiple myeloma (MM) see TRANSPLANT, page 26 

POLICY & MANAGEMENT

Drug Shortage Sparks Mayhem In Many Oncology Pharmacies

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n mid-September, Melissa Dinolfo, PharmD, director of pharmacy and clinical operations at Santa Monica, CA-based Premiere Oncology, had to tell a treating oncologist that she could not provide a patient with her next dose of chemotherapy. The patient, a 44-yearold woman with advanced breast cancer, had blown through the

available regimens, wasn’t well enough for a clinical trial, but still wanted to fight. So, she had been placed on a salvage regimen with liposomal doxorubicin (Doxil) every two weeks. This year, however, Doxil became the first brand-name chemotherapy drug to join an ever-growing list of generic chemotherapies see SHORTAGE, page 27 

McMahonMedicalBooks.com Year Book of Oncology 2011 Robert J. Arceci, MD, PhD

For more information, see page 19.

FDA News Denosumab (Prolia, Amgen) approved for two new indications.

See page 26.

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Clinical Oncology News • November 2011

Adolescent and Young Adult Oncology

Training Needed To Better Serve In-Between Population FILE SLUG

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Roughly a decade ago, doctors discovered that young adults with acute lymphoblastic Style chges fr. prev.

Copy Editor 1 leukemia had nearly twice the survival Revision rate# when Proof they were treatedSaleson a pediatric protocol Layout Date/Time November 7, 2011 11:44 AM Production rather than an adult protocol. But some young adults with this malignancy are still being Editorial Date/Time Creative treated with the adult protocol.

Trim Size TABLOID 63p X 78p COMMENTS: “It is a tragedy to me that 11 years after the first abstract was published at ASH [American Society of Hematology] that there are still young adult patients who are treated with a protocol for acute

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lymphoblastic leukemia the same as if they were 50 or 60 years of age, when we know that there is a big difference in outcomes,” said Leonard Sender, MD, director of the combined adolescent

and young adult cancer program at Children’s Hospital of Orange County and the University of California, Irvine.

The problem, he says, is that doctors are not educated about the unique

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TO: David This lackFROM: of Frank knowledge led Dr. Sender to found the Society for Adolescent and Young Adult Oncology Leonard (SAYAO) and the nonprofSender, MD it SeventyK. The international society, started in fall 2010, aims to improve AYA cancer care through the promotion of interdisciplinary

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Clinical Oncology News • November 2011

Adolescent and Young Adult Oncology

research, education, communication and collaboration among health professionals. Some cancers can behave more aggressively in AYAs, and individuals in this age group often have worse survival than children and older adults when it comes to several types of malignancies, including breast cancer, colorectal cancer, soft tissue sarcoma, non-Hodgkin’s lymphoma and leukemia.

The society hopes to raise awareness about AYA cancer patients and survivors through a variety of initiatives, including its official journal, the new quarterly Journal of Adolescent and Young

Stop A Doc

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he Stop A Doc campaign encourages doctors in training to stop a doctor who is working with a patient between the ages of 15 and 39 years and ask them five questions.

1. Do you know that there is an adolescent and young adult cancer segment called AYA (adolescent and young adult)?

2. Are you aware of the unique physical, psychological and social needs of AYAs? 3. Do you know if there are clinical trials for AYAs? 4. Can you refer AYA patients to specific resources?

5. Do you treat AYA patients, and if so, do you have academic and clinical experience treating 15- to 39-year-old cancer patients?

see AYA, page 19 

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Adult Oncology. SeventyK raises awareness through campaigns such as “Stop A Doc,” which encourages oncologists in training to stop a doctor who is working with a patient between the ages of 15 and 39 years and ask them five questions that gauge their knowledge of cancer in AYAs (sidebar).

Physicians need to be aware that AYAs often do better on more rigorous pediatric protocols than adult protocols. When treating an AYA, oncologists need to think about “sticking to the regimen, not dose-adjusting when

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HEMATOLOGIC DISEASE

Clinical Oncology News • November 2011

MDS

Study Links Gene Mutations With MDS Morphology Stockholm—Researchers have traced mutations in a single gene that could account for two-thirds of patients with a specific subtype of myelodysplastic syndromes (MDS), according to data from an ongoing clinical study.

Preliminary analysis showed that six of nine patients with MDS and ringed sideroblasts had somatically acquired mutations in SF3B1, which encodes a core component of RNA splicing machinery. Subsequent evaluation of

more than 2,000 tissue samples (from patients with and without MDS) showed that 20% of MDS patients had SF3B1 mutations, including 65% of patients with MDS and ringed sideroblasts.

The presence of SF3B1 mutations

conferred a more favorable prognosis, including fewer cytopenias and longer event-free survival compared with patients who did not have mutations, according to the study findings.

The study was presented at the European Multidisciplinary Cancer Congress (abstract 11LBA) and reported simultaneously online in The New England Journal of Medicine (NEJM; 2011;365:1384-1395, PMID: 21995386).

The findings are noteworthy because

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they constitute the first evidence of a gene’s direct association with morphologic features in MDS, said investigator Elli Papaemmanuil, PhD, of the Wellcome Trust Sanger Institute, in Hinxton, United Kingdom. Additionally, the findings implicate abnormalities in the mRNA splicing pathway, which had not previously been recognized as a mutation target.

SF3B1, which is mutated in 2% to 5% of several common cancers, including chronic lymphocytic leukemia (CLL), breast cancer, melanoma, kidney cancer and multiple myeloma, “is the most common gene to be mutated in MDS [and] the first gene to be associated with a specific MDS morphology, ringed sideroblasts,” noted Dr. Papaemmanuil.

During a press briefing at the congress, Dr. Papaemmanuil noted that the heterogeneity of MDS suggests that there are distinct molecular lesions that influence MDS morphology and clinical outcomes. To investigate the link between somatically acquired genetic mutations and MDS morphology, she and her colleagues from the International Cancer Genome Consortium used massively parallel sequencing technology to examine the genome of nine MDS patients for presence of point mutations across all protein-coding exons.

The initial nine patients had lowgrade MDS; eight of them had refractory anemia with ring sideroblasts (RARS). Sequencing identified 64 mutations, 0 to 20 per patient. Further study showed a predominance of transition mutations, similar to those associated with colorectal, pancreatic and brain cancers. The investigators identified recurrent somatic mutations in SF3B1 in six of the nine patients.

To expand on the findings, investigators performed targeted re-sequencing of SF3B1 in 2,087 samples, including specimens obtained from 354 patients with MDS. They found that 72 (20%) of see MUTATION, page 9 

CLINICAL ONCOLOGY NEWS

Clinical Oncology News • november 2011

EDITORIAL BOARD

Solid Tumors Bone Metastases Allan Lipton, MD Milton S. Hershey Medical Center, Penn State University Hershey, PA

Breast Cancer

Prostate Cancer Michael A. Carducci, MD AEGON Professor in Prostate Cancer Research, Co-Director, Prostate/GU Cancer and Chemical Therapeutics Programs, Johns Hopkins Kimmel Cancer Center Baltimore, MD

Hematologic Malignancies

Andrew Seidman, MD

Jennifer R. Brown, MD, PhD

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Maura N. Dickler, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Gastrointestinal Cancer Edward Chu, MD University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Cathy Eng, MD University of Texas, MD Anderson Cancer Center Houston, TX

Leonard Saltz, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Gastrointestinal Cancer and Sarcoma Ephraim Casper, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Harry Erba, MD, PhD University of Michigan Ann Arbor, MI

Shaji Kumar, MD Mayo Clinic Rochester, MN

Richard Stone, MD

Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic Cancer

Bioethics

Susan K. Seo, MD

Joseph P. DeMarco, PhD

Memorial Sloan-Kettering Cancer Center New York, NY

Cleveland State University Cleveland, OH

Oncology Nursing

Paul J. Ford, PhD

Betty Ferrell, RN, PhD City of Hope National Medical Center Duarte, CA

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

Policy and Management

Pharmacy

Mary Lou Bowers, MBA Cindy O’Bryant, PharmD University of Colorado Cancer Center Denver, CO

The Pritchard Group Rockville, MD

Rhonda M. Gold, RN, MSN Sara S. Kim, PharmD The Mount Sinai Medical Center New York, NY

The Pritchard Group Rockville, MD

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Community Oncology John W. Finnie, MD Mercy Medical Center St. Louis, MO

Editorial Philosophy Michael J. Fisch, MD, MPH University of Texas MD Anderson Cancer Center Houston, TX

Steven Vogl, MD Medical Oncologist New York, NY

Genitourinary Cancer Ronald M. Bukowski, MD

Infection Control

Symptom Control and Palliative Care William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY

The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the newsmagazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. They then review the articles before they are published. Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print.

Additionally, all news articles that appear in Clinical Oncology News are sent to the sources quoted in each article to review and verify the accuracy of the article’s content.

Educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA

Lung, and Head and Neck Cancers

Steven D. Passik, PhD Vanderbilt University Medical Center Nashville, TN

Edward S. Kim, MD

Joseph V. Pergolizzi Jr., MD

University of Texas, MD Anderson Cancer Center Houston, TX

Johns Hopkins University School of Medicine Baltimore, MD

Lung Cancer, Emesis Richard J. Gralla, MD Hofstra North Shore-Long Island Jewish School of Medicine, Monter Cancer Center North Shore University Hospital and Long Island Jewish Medical Center Lake Success, NY

Russell K. Portenoy, MD Beth Israel Medical Center New York, NY

McMahon Publishing is a 39-year-old, family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications.

Charles F. von Gunten, MD

Clinical Oncology News (ISSN 1933-0677) is published monthly by McMahon Publishing, 545 West 45th Street, New York, NY 10036. Copyright 2011 McMahon Publishing, New York, NY. All rights reserved.

University of California, San Diego, CA

POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036. www.mcmahonmed.com

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HEMATOLOGIC DISEASE

Clinical Oncology News • November 2011

Lymphoma

Study Shows Brentuximab Also Effective in Kids Stockholm—Brentuximab vedotin (Adcetris, Seattle Genetics), recently approved by the FDA for the treatment of adults with relapsed or refractory Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma (sALCL), is safe and effective in children with these diseases as well.

In a subset of nine pediatric patients aged 12 to 17 years who were treated in two Phase I and two Phase II clinical trials of brentuximab vedotin, the drug produced a complete remission (CR) in six patients (67%), four of whom had sALCL. Stable disease was achieved in the remaining three patients.

Additionally, the drug was well tolerated in this patient population.

These results were presented at the 2011 European Multidisciplinary Cancer Congress (abstract 9201).

“Usually when new drugs are evaluated in oncology, the focus is on adults aged 18 and older, but both of these diagnoses, particularly Hodgkin’s lymphoma, are present in children and adolescents,” said Michelle Fanale, MD, assistant professor in the Department of Lymphoma and Myeloma at University of Texas MD Anderson Cancer Center, Houston, who presented the study.

“Thus, we felt it was important that, while we’re initially evaluating brentuximab vedotin for approval in the adult population, to also gain some experience in the pediatric and adolescent patient population.”

About 80% of both pediatric and adult patients with Hodgkin’s lymphoma will go into CR after front-line treatment and their remission will be durable throughout their lifetime. But 20% will relapse, and go on to receive additional high-dose chemotherapy and autologous stem cell transplantation (ASCT). Unfortunately,

40% to 60% of these patients will again relapse. For patients with ALCL, the outcomes are even worse. From 40% to 60% will relapse after front-line treatment and will be considered for transplant.

“For both Hodgkin’s lymphoma and anaplastic large cell lymphoma, there is really no defined standard-of-care option if they relapse after stem cell transplant, and unfortunately,

adult population and also whether these younger patients were at higher risk for adverse side effects,” Dr. Fanale said.

Five patients had CD30-positive Hodgkin’s lymphoma, and four had sALCL. The baseline Karnofsky performance score was 0 in five patients and 1 in four patients. All had received at least one prior systemic chemotherapy regimen and four had undergone prior ASCT.

‘We felt it was important that, while we’re initially evaluating brentuximab vedotin for approval in the adult population, to also gain some experience in the pediatric and adolescent patient population.’

—Michelle Fanale, MD their median overall survival has been generally low, particularly if they relapse within six months of their stem cell transplant,” Dr. Fanale said. “So, there really is a very high unmet need to provide something for these patients that could potentially decrease their disease burden, and do that with minimal side effects.”

In the adults who were treated with brentuximab in the four clinical trials, the overall response rate (ORR) was 73% and the CR rate was 32% for those with relapsed or refractory Hodgkin’s lymphoma. For patients with relapsed or refractory sALCL, the ORR was 86% and the CR was 57%.

“In this abstract, we wanted to highlight just the pediatric outcomes to see if their responses mirrored those of the

Patients received IV brentuximab as a 30-minute outpatient infusion in weekly treatment cycles for three out of four weeks at doses of 0.8 mg/kg (n=1 patient) or 1.2 mg/kg (n=1 patient), or else every three weeks at doses of 1.2 mg/kg (n=1 patient) or 1.8 mg/kg (n=6 patients).

The duration of CR was 20.5 months for patients with Hodgkin’s lymphoma and 13.2 months for patients with sALCL. The FDA granted accelerated approval for brentuximab vedotin in August 2011, based on response rates, with no data available demonstrating improvement in patient-reported outcomes or survival. It is the first drug approved by the FDA for Hodgkin’s lymphoma in more than 30 years.

The drug is an anti-tubulin drug

monomethyl auristatin E (MMAE) conjugated with a monoclonal antibody. It targets the CD30-positive cells through linkage to the antibody, and it is this that has boosted response rates, Dr. Fanale said.

“This really opens up the door for continued research with a number of antibody drug conjugates that are currently being evaluated in lymphoma, particularly in the B-cell non-Hodgkin lymphoma area,” Dr. Fanale said. “I think this is the beginning of a significant further move toward really personalized treatment.”

According to Robert Hromas, MD, chairman of the Department of Medicine at the University of Florida, Gainesville, brentuximab vedotin represents a big step forward in the treatment of relapsed or refractory Hodgkin’s lymphoma and ALCL. “CD30 is a novel target. We don’t have anything else that targets that.

Hodgkin’s lymphoma and anaplastic large cell lymphoma are two very different lymphomas. Anaplastic large cell lymphoma is difficult to treat and most of the patients with ALCL eventually relapse, whereas a minority of patients with Hodgkin’s will relapse. But in both relapsed cases, this is the best thing going. It’s the best thing that we have available,” Dr. Hromas said. “I think it is going to be a remarkable addition to our treatment regimens for relapsed Hodgkin’s lymphoma and for anaplastic large cell lymphoma.”

In the United States, approximately 9,000 new cases of Hodgkin’s lymphoma and approximately 1,500 to 1,800 new cases of sALCL are anticipated in 2011.

—Fran Lowry Dr. Fanale reported that she receives research funding from Seattle Genetics.

She is also a consultant and is on the advisory board of the company. Dr. Hromas reported no conflicts of interest.

If you missed any recent issues of Clinical Oncology News, visit www.clinicaloncology.com.

HEMATOLOGIC DISEASE

Clinical Oncology News • November 2011

MDS

Research Institute in Cambridge, United

MUTATION continued from page 6 

the MDS patients had SF3B1 mutations. In particular, mutations in the gene were identified in 53 of 82 (65%) patients who had RARS. The analysis also revealed SF3B1 mutations in patients with several other myeloid cancers, including three of 57 patients with acute myeloid leukemia (5%), six of 136 patients with primary myelofibrosis (4%), six of 189 patients with essential thrombocythemia (3%) and five of 106 patients with chronic myelomonocytic leukemia (5%).

In multivariable analysis of patients with myeloid neoplasms, SF3B1 mutations were independently associated with better overall survival (hazard ratio [HR], 0.18; P=0.028) and lower risk for leukemic evolution (HR, 0.32; P=0.048).

cancer genes in all tumor types,” said Dr. Caldas. “We must look not only at point mutations, but amplifications also. I think we are in the face of a seminal discovery, and we have to broaden our understanding of cancer.” He concluded that the findings suggest potential opportunities for development of prognostic and therapeutic strategies.

—Charles Bankhead Drs. Papaemmanuill and Caldas reported no potential conflicts of interest.

‘We now have to look at all of these gene mutations as candidate cancer genes in all tumor types. We must look not only at point mutations, but amplifications also. I think we are in the face of a seminal discovery.’

What role may MUC1 play in NSCLC

—Carlos Caldas, MD

It’s well-known that mucins protect healthy cells, but did you know that aberrant overexpression of mucin 1 (MUC1) by tumor cells may play a role in tumor cell survival?1-3 At EMD Serono, we’re investigating the significance of MUC1 and its impact on your patients with NSCLC.

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SF3B1 mutations also occurred in patients with non-myeloid malignancies, including two of 172 patients (1%) with breast cancer, one of 30 with renal cancer (3%), two of 40 with CLL (5%), one of 32 with multiple myeloma (3%) and one of 27 with adenoid cystic carcinoma (4%).

Finally, the investigators examined 746 cancer cell lines, and identified SF3B1 mutations in eight (1%), including cell lines representing melanoma; lung, bladder, breast, and endometrial cancers; chronic myeloid leukemia; and teratoma.

Analysis of the types of mutations identified in SF3B1 revealed an absence of frameshift, nonsense, and splice-site mutations and a lack of key structural amino-acid residues as mutation sites.

Additionally, the mutations appeared less harmful than would have been expected by chance. Collectively, those observations suggest that SF3B1 protein retains structural integrity and at least some function, the investigators reported in the NEJM article.

Following Dr. Papaemmanuil’s presentation at the congress, invited discussant Carlos Caldas, MD, from the Cambridge

Kingdom, said the findings have major implications for investigations in cancer genetics. “We now have to look at all of these gene mutations as candidate

1. Ahmad R, Raina D, Joshi MD, et al. MUC1-C oncoprotein functions as a direct activator of the NF-κB p65 transcription factor. Cancer Res. 2009;69(17):7013-7021.

2. Behrens ME, Grandgenett PM, Bailey JM, et al. The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF. Oncogene. 2010;29(42): 5667-5677. 3. Raina D, Kosugi M, Ahmad R, et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther. 2011;10(5):806-816.

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HEMATOLOGIC DISEASE

Clinical Oncology News • November 2011

Lymphoma and Leukemia

Study Gives Slight Edge to R-DHAP for B-Cell Lymphoma Subtype From Journal of Clinical Oncology

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esults of an adjunct to CORAL (Collaborative Trial in Relapsed Aggressive Lymphoma) have confirmed that tumor biology is a predictive factor for response to therapy in patients with relapsed/refractory diffuse large B-cell lymphoma. The study also indicated that R-DHAP—rituximab (Rituxan, Genentech), dexamethasone, high-dose cytarabine and cisplatin may be superior to R-ICE—rituximab, ifosfamide, carboplatin and etoposide—in the germinal-center B-cell (GCB)-like subtype of this disease.

During the trial, a team of researchers EXPERT INSIGHT Peter Martin, MD Assistant Professor of Medicine Weill Cornell Medical College Assistant Attending Physician Center for Lymphoma and Myeloma Division of Hematology/ Oncology NewYork-Presbyterian/ Weill Cornell

from Paris analyzed the histologic data of 249 patients with diffuse large B-cell lymphoma at diagnosis (n=189) and/or relapse (n=147), or at both points (n=87) (Thieblemont C et al. J Clin Oncol 2011 Sep 26. [Epub ahead of print], PMID: 21947824). The histologic data were analyzed for CD10, BCL6, MUM1, FOXP1 and BCL2 expression via immunochemistry and for BCL2, BCL6 and c-MYC breakpoints via fluorescent in situ hybridization. The investigators used the log-rank test and the Cox model to assess for correlation with survival data.

The analysis revealed that, “characteristics of immunophenotype and chromosomal abnormalities were statistically

highly concordant in the matched biopsies.” After a median follow-up of 27 months, three-year progression-free survival (PFS) was not significantly different between the R-ICE and R-DHAP arms (28.7% and 40.9%, respectively; P=0.24). The investigators observed immunohistochemical expression of CD10, BCL6, MUM/IRF4, BCL2 and FOXP1 in 59%, 60%, 42%, 73% and 65% of the tumor cells, respectively.

Immunophenotype and chromosomal characteristics were statistically similar in the matched biopsies. Using univariate analysis, the c-MYC gene rearrangement was the sole parameter that indicated a worse PFS (P=0.02) and worse

overall survival (P=0.04). GCB-like diffuse large B-cell lymphoma was significantly associated with improved PFS in patients administered the R-DHAP regimen (three-year PFS rates of 52% vs. 32% in non-GCB patients; P=0.01).

Multivariate analysis showed an independent prognostic impact on PFS for GCB/non-GCB Hans phenotype interaction with treatment (P=0.04), previous rituximab exposure (P=0.0052), secondary age-adjusted International Prognostic Index (P=0.039), and FoxP1 expression (P=0.047).

The investigators concluded that their findings require further confirmation via a prospective study.

The optimal treatment of patients with relapsed/refractory diffuse large B-cell lymphoma remains unclear— many regimens exist, but there is no evidence that one is better than any other. When CORAL was first presented, not only were we disappointed that neither R-ICE nor R-DHAP proved superior, we were devastated to learn how poorly both regimens performed in patients who previously had been treated with rituximab.

The recent report published

by Thieblemont et al finally provides some encouraging news. In an

unplanned analysis involving a subset of patients treated in CORAL, the investigators found that R-DHAP may be superior to R-ICE in the GCBlike subtype of diffuse large B-cell lymphoma. Importantly, they stop short of proposing that R-DHAP be the new standard of care in patients with GCB-like diffuse large B-cell

lymphoma, recognizing the potential errors inherent in a study of this nature. Unfortunately (or fortunately, depending on one’s perspective), we may never learn the answer to this question. Although R-DHAP may be better, it is still not very good. Future trials are more likely to focus on more biologically based therapies.

imatinib therapy. Analysis showed that CD34+CD38-positive stem cells are a major reservoir of BCR-ABL-positive cells in patients with CML who are in remission following imatinib treatment.

Residual BCR-ABL-positive cells, when transplanted to immunodeficient mice, demonstrated the capacity to repopulate. Patients whose CMR is sustained after discontinuation of imatinib treatment nonetheless have BCR-ABL-positive cells that persist.

Beyond its core findings, the study demonstrates that residual leukemia

stem cells can be assessed for functional capacity, which will be important in the evaluation of various TKIs as potential leukemia therapy, as well as in the assessment of the effect of discontinuing the administration of these treatments. The investigators note that prolonging imatinib treatment also carries risks, including potential development of drug resistance, the threat of reduced compliance, long-term complications and considerable expense. Further study of BCR-ABLpositive stem cells and treatments in this population are warranted.

EXPERT INSIGHT

rarely is curative. The cancer stem cell hypothesis postulates that tumor growth is driven by a rare population of tumor cells with stem cell properties that are resistant to therapy. This hypothesis remains controversial for solid tumors, but has gained wider acceptance in both acute myelogenous leukemia (AML) and CML. A subfraction of AML cells that is able to form a transplantable leukemia in an immunodeficient mouse carries the same markers as normal hematopoietic stem cells (CD34+CD38). In CML, the existence of Philadelphia chromosome-positive hematopoietic stem cells is well established.

Study Sheds Light on Persisting CML From Blood

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CR-ABL-positive stem cells persist in patients with chronic myelogenous leukemia (CML) who are undergoing prolonged treatment with imatinib mesylate (Gleevec, Novartis), according to a new study published in the journal Blood (Chu S et al. 2011 Sep 19. [Epub ahead of print], PMID: 21931114).

Hematopoietic stem cell transformation by the BCR-ABL gene leads to CML. Treatment with imatinib, a BCRABL kinase inhibitor, can lead to significant reductions in BCR-ABL transcript levels and sustained clinical remissions in patients with CML. Despite remission, however, CML persists on a molecular level in most patients, and thus current guidelines recommend that patients continue imatinib therapy indefinitely.

Imatinib likely has heightened activity against progenitor and mature cells, but limited activity against stem cells.

BCR-ABL-expressing CML progenitors are eliminated within a year of imatinib therapy initiation, but BCR-ABL positivity persists at a reduced level in stem cells, declining slowly over time.

Similarly, the rate of disease relapse continues to decrease as treatment continues, raising the possibility that continued imatinib treatment forces the reduction or even elimination of CML stem cells. Nilotinib (Tasigna, Novartis) and dasatinib (Sprycel, Bristol-Myers Squibb), second-generation tyrosine kinase inhibitors (TKIs), demonstrate a similar lack of efficacy against CML stem cells.

In the present study, investigators from City of Hope National Medical Center, Duarte, Calif., evaluated stem cells from 20 patients with CML who had received imatinib treatment for at least four years.

All patients were in complete cytogenetic response and 19 were in complete molecular response (CMR); 12 of these were consistently negative on evaluation with polymerase chain reaction (PCR).

Bone marrow samples were analyzed for BCR-ABL gene expression in mononuclear cells, CD34+CD38-positive committed progenitors, and CD34+CD38primitive progenitors/stem cells.

Results found that BCR-ABL-positive stem and primitive progenitor cells persist in the bone marrow of patients with CML in remission, even after prolonged

Alex Morozov, MD, PhD Instructor of Medicine Weill Cornell Medical College Assistant Attending Physician NewYork-Presbyterian/ Weill Cornell Senior Medical Director ImClone Systems Bridgewater, NJ

The promise of targeted therapy is tempered by the sobering reality that it

see CML, page 30 

11

SOLID TUMORS

Clinical Oncology News • November 2011

Prostate

Tasquinimod Promising in mCRPC From Journal of Clinical Oncology

I

n patients with metastatic castrationresistant prostate cancer (mCRPC), tasquinimod (Active Biotech) significantly slows disease progression and improves progression-free survival (PFS) with an “acceptable” safety profile, according to findings of a recently published Phase II clinical trial (Pili R et al. J Clin Oncol 2011;29[30]:4022-4028, PMID: 21931019).

Tasquinimod, an oral quinoline-3-carboxamide derivative, has demonstrated antiangiogenic properties and tumor growth–inhibiting activity in prostate cancer. These actions may be mediated through induction of the endogenous angiogenesis inhibitor thrombospondin-1. Tasquinimod’s molecular target S100A9 is an immunomodulatory protein expressed on myeloid-derived suppressor cells.

In the double-blind, placebocontrolled study, 201 chemotherapynaive patients were randomized based on Karnofsky performance scores to receive either oral once-daily tasquinimod at an initial dose of 0.25 mg per day, which was escalated to 1.0 mg per day over four weeks, or placebo. The study assessed the proportion of patients without disease progression at six months (as defined by Response Evaluation Criteria in Solid Tumors Group, Prostate Cancer

Working Group or pain criteria).

Six-month PFS was 69% in the tasquinimod group and 37% in the placebo group (P<0.001), and median PFS was 7.6 months in the tasquinimod group and 3.3 months in the placebo group (P=0.0042). Adverse events (AEs) that occurred more frequently in the tasquinimod group included gastrointestinal disorders, fatigue, musculoskeletal pain, and elevations of pancreatic and inflammatory biomarkers. Grade 3/4 AEs, such as asymptomatic elevations in laboratory parameters (amylase, lipase, C-reactive protein and fibrinogen), were reported in 40% of

Op en En For rol lme n

EXPERT INSIGHT Scott Tagawa, MD Assistant Professor of Medicine and Urology Weill Cornell Medical College Medical Oncologist Medical Director Genitourinary Oncology Research Program NewYork-Presbyterian/ Weill Cornell

As in other tumor types, angiogenesis is of importance in prostate cancer, and anti-angiogenic therapy therefore has merit. Although one major Phase III study of an anti-angiogenic agent has been reported as negative for its primary end point of overall survival, it did demonstrate improved responses and PFS for docetaxel-prednisone plus bevacizumab (CALGB 90401, Kelly et al, ASCO 2010). Additional Phase III studies of docetaxel-prednisone plus afliberceptplacebo (NCT00519285) and lenalidomide-placebo (NCT00988208) are testing this concept and we await results.

Tasquinimod is an oral compound with several potential mechanisms of action, but it is thought to act by inhibiting angiogenesis. Pili et al report intriguing results of a randomized Phase II study demonstrating radiographic and symptomatic PFS in patients with mCRPC independent of significant PSA [prostate-specific antigen] effect. Drug therapy was relatively well tolerated, with a potential signal of cardiovascular toxicity. We await results of the Phase III tasquinimod versus placebo study being performed in men with minimally symptomatic mCRPC prior to chemotherapy (NCT01234311).

patients receiving tasquinimod compared with 10% among those receiving placebo. Four percent of patients treated with tasquinimod developed deep vein thrombosis, compared with none in the placebo group. AEs were of a slightly greater magnitude than those seen in a Phase I trial of the drug, perhaps due to the number of older men (aged ≥80 years) in this study. Tolerability of tasquinimod has been noted to decrease with age.

The authors noted that the PFS benefit was similar to or better than those seen with currently approved FDA treatments.

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Clinical Trial developed as a collaborative project by:

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SOLID TUMORS

Clinical Oncology News • November 2011

Breast

EVEROLIMUS continued from page 1 

“Everolimus is the first agent to enhance the clinical benefit of hormonal therapy in refractory ER-positive patients,” said José Baselga, MD, associate director of the Massachusetts General Hospital Cancer Center, in Boston. “Our results could represent a paradigm shift in the management of patients with hormone receptor–positive breast cancer.”

Novartis plans to ask the FDA to approve everolimus for this indication.

The standard of care for patients with HER2-negative/ER-positive metastatic breast cancer (MBC) is sequential use of several lines of endocrine therapy and chemotherapy. Patients who become resistant to endocrine therapy have a poor prognosis, and there is a need for a targeted agent in this population. Researchers thought everolimus might fit the bill, because the drug inhibits the P13K-mammalian target of rapamycin (mTOR) pathway.

Resistance to endocrine therapy has been associated with the activation of the P13KmTOR pathway, which, in turn, activates the estrogen receptor. Two randomized Phase II trials have already shown positive results for everolimus in patients with breast cancer (Table). Thus, investigators launched a Phase III trial to test whether they could use everolimus to reverse resistance to endocrine therapy and delay the start of chemotherapy.

They recruited postmenopausal ERpositive/HER2-negative women with MBC who were refractory to letrozole or anastrazole. Patients were randomized to receive exemestane plus everolimus (n=485) or exemestane and placebo (n=239). In both arms of the study, 84% of patients were sensitive to prior hormonal therapy and roughly 75% had bone disease. Crossover was not allowed.

In both arms, roughly 75% of patients were white and 20% were Asian. The median age was 62 years in the everolimus arm and 61 years in the placebo arm; other characteristics were well balanced

Table. Phase II Trials of Everolimus in HER2Negative/ER-Positive Breast Cancer Patients Drug Combination

Hazard Ratio

Number of Patients

Letrozole ± everolimus

0.61

270

J Clin Oncol 2009;27(16): 2630-2637, PMID: 19380449

Tamoxifen ± everolimus

0.53

111

SABCS 2010, abstract S16

Reference

SABCS, San Antonio Breast Cancer Symposium

in the two arms. A total of 528 events are required for the final analysis; an interim analysis was conducted after 60% of these events accrued.

At the interim analysis, the PFS by investigator assessment was 6.9 months in patients who received everolimus compared with 2.8 months in patients who received placebo (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.350.54; P<00001). The PFS by independent central assessment was 10.6 months in the everolimus arm compared with 4.1 months in the placebo arm (HR, 0.36; 95% CI, 0.27-0.47; P<0.0001). The overall response rate (9.5% vs. 0.4%; P<0.0001) and clinical benefit rate (33.4% vs. 18.0%; P<0.0001) by investigator assessment favored the everolimus arm. The benefit was observed in all patient subgroups.

Adverse events have been consistent with previous experience with everolimus including stomatitis, fatigue, non-infectious pneumonitis and hyperglycemia (Figure). Overall survival (OS) data are not yet mature. Importantly, treatment with everolimus did not affect quality of life according to results from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, which was administered during the study (time to ≥5% deterioration was comparable; HR, 0.91; P=0.217).

Fabrice Andre, MD, an oncologist from the Institut Gustave Roussy, Villejuif, France, served as the expert discussant for the abstract at the EMCC conference. He pointed out that clinical data from other studies supported the rationale for the study (Table), the trial

was well designed, and the results were “robust” and “clinically relevant.”

Dr. Andre said, however, that information regarding outcomes in patients with more aggressive ER-positive disease is needed, and he wondered about the distribution of luminal A/B in the current trial.

He also pointed out that inhibiting mTOR alone is not optimal because compensatory or parallel pathways can be activated. “The development of compensatory pathways will require sequential biopsies and use of kinome technologies to understand, reverse and personalize the mechanism of resistance,” said Dr. Andre.

Other compounds are candidates in this setting including P13K/mTOR dual inhibitors, P13K inhibitors, AKT inhibitors, and mTOR Complex1/Complex 2 inhibitors.

Nevertheless, he said, BOLERO-2 represents a major advance.

“Everolimus is the most important advance in breast cancer since trastuzumab,” Dr. Andre said. A flurry of excitement has certainly been building since the presentation at EMCC, but some oncologists are more cautious in interpreting the data.

It was not very long ago that the FDA granted accelerated approval for bevacizumab (Avastin, Genentech) for patients with MBC based on a 5.5-month PFS benefit, only to have subsequent trials show no improvement in OS, as well as smaller benefits in PFS for the drug. Are oncologists worried that everolimus might not show a benefit in OS? “It is a definite concern, as I suspect it will be more difficult to show a benefit in OS for a treatment that is added to endocrine therapy given the longer post-progression survival

100 Everolimus plus exemestane

80

Patients, %

12

60

Placebo plus exemestane 56

40

33 26

20 0

18

11

Stomatitis

16 8

Fatigue

Dyspnea

6

4

Anemia

Figure. Most common grade 3/4 adverse events.

AST, aspartate aminotransferase

13

12 0

AST

Pneumonitis

after endocrine therapy compared with patients treated with chemotherapy,” said Maura Dickler, MD, associate attending physician in the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, in New York City.

Responding to this comment, Dr. Baselga said comparing BOLERO with the Avastin trial is like comparing apples and oranges. “We are talking about very different disease entities,” he said, and most importantly, the study designs were very different. “The Avastin study was not a registration study and it was not placebo-controlled. This allows for very significant biases. As a reflection of this and other design issues, follow-up registration studies were requested,” Dr. Baselga said. “In addition, the hazard ratio was lower than in our study (0.6). This is quite different from our study, which was a double-blind registration study with both local and central review and a much more impressive hazard ratio.”

An expert on hormone therapy for breast cancer, Matthew J. Ellis, PhD, MB, director of the Breast Cancer Research Program at the Siteman Cancer Center, in St. Louis, said he was optimistic about everolimus but clinicians should be cautious until survival data are available. “I would be most comfortable with a new standard of care that involves improvement in overall survival, and I don’t think that is an unlikely scenario,” he said. Dr. Ellis also said studies provide evidence that other candidates that inhibit the P13K kinase pathway (as mentioned by Dr. Andre) might prove to be even more effective.

“In all the drugs that we have tested, everolimus is the weakest in inducing cell death in ER-positive cells that were deprived of estrogen,” said Dr. Ellis, referring to a study in Breast Cancer Research (2011;13:R21, PMID: 21362200). “This BOLERO study is a very exciting result in terms of a multitude of agents targeting the PI3 kinase pathway in ER–positive breast cancer.”

If the OS data pans out, researchers say the positive results of the BOLERO-2 trial could be just the tip of the iceberg in terms of using everolimus as a breast cancer therapy. The Phase III BOLERO-1 trial has just finalized accrual. This trial is testing the addition of everolimus to weekly paclitaxel and trastuzumab in patients with HER2-overexpressing MBC who are refractory to trastuzumab. And according to Dr. Baselga, future trials could test mTOR inhibitors in the early adjuvant setting in patients with ER-positive breast cancer.

—Kate O’Rourke The BOLERO-2 trial was funded by Novartis. Dr. Baselga has consulted for companies, including Novartis, Roche, Merck SA and Bayer. Drs. Dickler and Ellis consult for Novartis. Dr. Andre has received grants from Novartis and served as consultant and speaker.

SOLID TUMORS

Clinical Oncology News • November 2011

Prostate

Vitamin E and Prostate Cancer Risk From JAMA

T

he Selenium and Vitamin E Cancer Prevention Trial (SELECT), a large, long-term study designed to evaluate potential benefit of both vitamin E and selenium in prostate cancer prevention, actually showed that vitamin E supplementation significantly increases the risk for prostate cancer (Klein RA et al. JAMA 2011;306:1549-1556, PMID: 21990298).

From August 2001 to June 2004, investigators from 427 study sites in the United States, Canada and Puerto Rico, randomly assigned 34,887 men to one of four treatment groups: selenium 200 mcg per day plus placebo (n=8,752), vitamin E 400 IU per day plus placebo (n=8,737), selenium plus vitamin E (same dosages; n=8,702) or placebo (n=8,696). The men had average risk for prostate cancer based on baseline prostate-specific antigen levels of no greater than 4 ng/mL and normal digital rectal exams, started at age 50 for black men and 55 for other men. Patients were monitored every six months and with an annual physical examination. If a patient developed cancer, monitoring frequency

was reduced to an annual basis.

Initial results were reported in 2009, after a preplanned interim analysis showed a lack of efficacy for risk reduction and led to the discontinuation of the study supplements.

The final results, based on data collected through July 5, 2011, after planned followup for a minimum of seven and a maximum of 12 years, show that there were 17% more cancers in the group receiving vitamin E alone than in the placebo

group. There were 620 cancers among participants receiving vitamin E alone (hazard ratio [HR], 1.17; confidence interval [CI], 1.004-1.36; P=0.008), 575 among those receiving selenium alone (HR, 1.09; CI, 0.93-1.27; P=0.18), 555 among those receiving both vitamin E and selenium (HR, 1.05; CI, 0.89-1.22; P=0.46) and 529 in the placebo group. The increased risk associated with supplementation was evident for both low- and high-grade disease.

The findings contrast with those of earlier studies, particularly the ATBC (AlphaTocopherol, Beta-Carotene) trial, which reported a 35% reduction in prostate

cancer risk among men taking vitamin E (N Engl J Med 1994; 330:1029-1035, PMID: 8127329). SELECT investigators pointed out, however, that the study population in the ATBC trial was long-term smokers, that prostate cancer was a secondary end point in that trial and that cancers were diagnosed at later stages because there was no screening component, all of which may have contributed to the differences between the results.

The investigators concluded the study “demonstrates the potential for seemingly innocuous yet biologically active substances such as vitamins to cause harm.”

What role may MUC1 play in NSCLC

EXPERT INSIGHT Ketan K. Badani, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons Director, Division of Robotic and Minimally Invasive Surgery NewYork-Presbyterian/ Columbia

Select functions of MUC1 in normal cells • Lubricates epithelial surfaces3 • Acts as a physical barrier against microbes3 • Protects against proteolytic degradation3 • Involved in adaptive immunity against pathogens4 • Mediates normal T-lymphocyte responses and regulates T-lymphocyte proliferation5 • Involved in signal transduction, which regulates cell survival and proliferation2 • Can directly affect transcription within the nucleus1

110718-140032

This study evaluates the long-term follow up of the SELECT trial looking at the potential increased risk for prostate cancer with vitamin E supplementation. The authors conclude that daily supplement of vitamin E can increase the risk for prostate cancer in otherwise healthy men. It is relatively uncommon to see large, well-designed, randomized, placebo-controlled trials in the vitamin and supplement industry. This is the largest multicenter randomized study of its kind to look at this topic, and therefore, the results should be taken to heart. Even everyday vitamins (like vitamin E) taken in large amounts can be unhealthy.

As we see more well-controlled studies being conducted, we may continue to find that there are hidden dangers in taking anything in high doses without it first being properly studied.

Men considering taking supplements should discuss them with their doctor and treat supplements like their prescription medications.

MUC1 (mucin 1) is a transmembrane glycoprotein that is normally found on the apical surface of most simple secretory epithelial cells and is associated with a number of diverse cellular functions.1 The functions of the extracellular domain of MUC1 are largely dictated by the extent of its glycosylation.1,2 The cytoplasmic tail of MUC1 can serve as a scaffold for interactions with intracellular proteins that affect cell survival and proliferation and can have direct effects on transcription within the nucleus.1,2

Overexpression, altered distribution, and aberrant glycosylation of MUC1 have been observed in a variety of cancers, including non-small cell lung cancer (NSCLC).1,2,6 Aberrant overexpression of MUC1 by tumor cells is associated with several mechanisms of tumor cell survival.6-8 Overexpression of MUC1 may play a role in

abnormal cell signaling through interactions with regulatory proteins, such as with EGFR.2,7 In addition, the cytoplasmic tail of MUC1 can be targeted to the nucleus, where it interacts with transcription factors for genes related to invasion, angiogenesis, and metastasis.7,8 Furthermore, cells overexpressing tumor-associated MUC1 may escape the host immune response by suppression of the T-cell proliferation response and by failure to process and present MUC1 on class II major histocompatibility complexes.9,10 At EMD Serono, we’re investigating the significance of MUC1 and its impact on your patients with NSCLC. Visit www.emdserono.com to learn more about EMD Serono Oncology.

1. Hattrup CL, Gendler SJ. Structure and function of the cell surface (tethered) mucins. Annu Rev Physiol. 2008;70:431-457. 2. Bafna S, Kaur S, Batra SK. Membrane-bound mucins: the mechanistic basis for alterations in the growth and survival of cancer cells. Oncogene. 2010;29(20):2893-2904.

3. Carson DD. The cytoplasmic tail of MUC1: a very busy place. Sci Signaling. 2008;1(27):pe35.

4. McAuley JL, Linden SK, Png CW, et al. MUC1 cell surface mucin is a critical element of the mucosal barrier to infection. J Clin Invest. 2007;117(8):2313–2324. 5. Agrawal B, Longenecker BM. MUC1 mucin-mediated regulation of human T cells. Int Immunol. 2005;17(4):391-399.

6. Raina D, Kosugi M, Ahmad R, et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther. 2011;10(5):806-816. 7. Ahmad R, Raina D, Joshi MD, et al.

MUC1-C oncoprotein functions as a direct activator of the NF-κB p65 transcription factor.

Cancer Res. 2009;69(17):7013-7021. 8. Behrens ME, Grandgenett PM, Bailey JM, et al. The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF. Oncogene. 2010;29(42):5667-5677. 9. Agrawal B, Krantz MJ, Reddish MA, Longenecker BM. Cancer-associated MUC1 mucin inhibits human T-cell proliferation, which is reversible by IL-2.

Nat Med. 1998;4(1):43-49. 10. Hiltbold EM, Vlad AM, Ciborowski P, Watkins SC, Finn OJ. The mechanism of unresponsiveness to circulating tumor antigen MUC1 is a block in intracellular sorting and processing by dendritic cells. J Immunol. 2000;165:3730-3741.

EMD Serono Oncology | Combination is key™

EMD Serono, Inc. is an affiliate of Merck KGaA, Darmstadt, Germany

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SOLID TUMORS

Clinical Oncology News • November 2011

Breast

Commentaries on the Latest Studies C ontinuing in this issue is our monthly feature in which the oncologists and hematologist/

oncologists at NewYork-Presbyterian Hospital

provide insights about recent clinical studies of solid tumors, as well as hematologic malignancies. One area of expertise is indisputably breast cancer.

The National Accreditation Program for Breast Cancers (NAPBC), a consortium of professional organizations, has issued separate three-year accreditations to both NewYork-Presbyterian Hospital/Weill Cornell’s Breast Center, which is part of the Iris Cantor Women’s Health Center; and NewYork-Presbyterian Hospital/Columbia’s Clinical Breast Cancer Program, a section within the National Cancer Institute (NCI)-designated Herbert Irving Comprehensive Cancer Center.

These two breast centers are the only NAPBCaccredited centers in Manhattan.

The physician-scientists at NewYorkPresbyterian Hospital and its academic affiliates—Columbia University College of Physicians and Surgeons and Weill Cornell Medical College—have been instrumental in developing several innovations involving breast cancer care, including being among the first to use sentinel node biopsy; to perform total skin- and nipple-sparing mastectomy, as well as other oncoplastic procedures; to perform bone marrow examination during surgery to rule out micrometastatic disease; and to offer intraoperative radiofrequency ablation.

Currently, researchers are exploring an intraductal approach using a mini-endoscope to

access the milk ducts through the nipple; developing a balloon catheter, partial breast radiotherapy technique; exploring whether biomarkers in nipple fluid might be used as a screening test similar to a Pap exam; and, in an NCI-funded multicenter trial, studying the use of cryoablation as an alternative to mastectomy and lumpectomy.

—James Prudden, Group Editorial Director

Study Shows Immediate Breast Reconstruction Safe From Breast

I

mmediate breast reconstruction in conjunction with mastectomy carries no additional risk—with respect to survival, metastases or recurrence—compared with mastectomy alone, according to a recent study in the journal Breast (Nedumpara T et al. 2011;20:437-443, PMID: 21601458).

In the study, a team of researchers from the United Kingdom assessed the impact of immediate breast reconstruction following treatment for invasive breast cancer on disease progression and survival in 1,697 consecutive patients who received surgical treatment for operable primary breast cancer at the North Cumbria

EXPERT INSIGHT Sheldon Marc Feldman, MD Vivian L. Milstein Associate Professor of Clinical Surgery Columbia University College of Physicians and Surgeons Chief Division of Breast Surgery NewYork-Presbyterian/ Columbia

The study by Nedumpara et al is an important contribution. They describe oncologic outcomes of 691 patients who underwent mastectomy over an 11-year period (1996-2007) at a single institution. One hundred thirty-six of the patients (20%) underwent immediate breast reconstruction with latissimus flap (82) or subpectoral implant (54). Patients were reasonably well matched by disease severity

Breast Unit between January 1996 and December 2007. Among the study participants, 1,006 underwent breast conservation and 691 underwent mastectomy. Of the second group, 136 patients also underwent immediate breast reconstruction, using either the latissimus dorsi myocutaneous flap (82 patients) or subpectoral implant (54 patients). Postoperative radiotherapy and adjuvant systemic treatments were used according to local guidelines. Follow-up was conducted quarterly during the first year after surgery, and then twice annually thereafter.

Only patients younger than 75 years at the time of presentation were included in the final analysis, leaving 135 in the immediate breast reconstruction group and 452

in the mastectomy-alone group. Median age was 47 years in the immediate breast reconstruction group and 59 in the other group. Outcomes were analyzed in all study participants and also separately by subgroup as defined by Nottingham Prognostic Index (NPI) scores.

The median duration of follow-up of the study participants was 55 months.

The authors did not find a statistically significant difference in survival between the treatment groups (P=0.176). Of the patients who underwent immediate breast reconstruction, 9% developed local recurrence during the study period and 29% developed distant metastases. These rates were similar to the mastectomyalone group: 8% and 20%, respectively.

In the immediate breast reconstruction group, median time to local recurrence was 26 months, compared with 22 months in the mastectomy-alone group (P=0.505). Median time to distant metastases in the immediate breast reconstruction group was 36 months, compared with 24 months in the mastectomy-alone group (P=0.783).

The authors acknowledged the study’s limitations—the relatively small number of patients and the short minimum follow-up duration (16 months)—but concluded that the data show that immediate breast reconstruction after mastectomy for primary breast cancer is safe and is not associated with an increased risk for early local or distant recurrence or death.

using the NPI, as well as adjuvant systemic therapy and radiation received.

The strengths of the study are that it is a consecutive series of patients at a single institution with only 1.4% lost to follow-up. With a median followup of 55 months, local and systemic recurrence risks and deaths were comparable in patients with and without immediate breast reconstruction.

Quality-of-life comparison and surgical complications were not discussed in this study.

The paradigm in breast cancer treatment has changed. When I was going through surgical residency in the 1970s, there was trepidation about the safety of performing immediate breast reconstruction at the time of mastectomy. Over the ensuing decades, surgical techniques advanced allowing many patients to undergo skin-sparing, and more recently, nipple-sparing mastectomy with immediate implant or autologous tissue reconstruction. Numerous

prior studies have demonstrated comparable low recurrence risks in appropriately selected patients. Nedumpara et al’s important study adds to this literature.

There is a wide variation (15%-85%) in immediate breast reconstruction rates at hospitals nationally and internationally. The reasons for this are complex but include insurance coverage, patient education, and availability of plastic reconstructive expertise.

There are clear apparent advantages to immediate reconstruction including preservation of normal breast shape with skin-sparing and nipple-sparing techniques and maintenance of normal body appearance. This can have a profound impact on breast cancer patients regaining an excellent quality of life after breast cancer treatment.

A recently published study by Heneghan et al (Eur J Surg Oncol 2011;37:937-943, PMID: 21899982) demonstrated a comparable quality of life for patients who underwent

skin-sparing mastectomy with reconstruction compared with patients who had breast-conservation surgery. Measuring patient satisfaction is critical to understanding quality-oflife outcomes in addition to the usual oncologic end points. This has led to the development of the BREASTQ patient-reported outcome measure (Plast Reconstr Surg 2009;124:345353, PMID: 19644246).

The importance of the breast reconstruction issue resulted in the passage of a law (A10094B/S6993-B/Information and Access to Breast Reconstruction Surgery) in New York in August 2011. This law requires hospitals to inform breast cancer patients about the availability of and insurance coverage for reconstruction before they undergo mastectomy. Continued studies such as this one by Nedumpara et al will help to remove any concerns that oncology safety is a reason for a patient to not undergo immediate breast reconstruction.

SOLID TUMORS

Clinical Oncology News • November 2011

Breast

BCIRG-005: Sequential Adjuvant Rx Versus Combo Therapy From Journal of Clinical Oncology

S

equential administration of doxorubicin-cyclophosphamide therapy and then docetaxel is not superior to doxorubicin-cyclophosphamide-docetaxel combination therapy in the adjuvant breast cancer setting, according to results of a large, international trial (Eiermann W et al. J Clin Oncol 2011;29:3877-3884, PMID: 21911726).

Between August 2000 and February 2003, investigators at 335 centers in 37 countries enrolled 3,298 patients in the open-label, randomized Phase III BCIRG (Breast Cancer International Research Group)-005 trial. Investigators compared sequential therapy—four cycles of doxorubicin-cyclophosphamid followed by four cycles of docetaxel (AC-T)—with six cycles of all three

EXPERT INSIGHT Ellen Chuang, MD Associate Professor of Clinical Medicine Weill Cornell Medical College Associate Attending Physician Division of Hematology and Medical Oncology NewYork-Presbyterian/ Weill Cornell

agents given in combination (TAC) in patients with operable node-positive, HER2-nonamplified breast cancer.

Patients in the AC-T arm received doxorubicin (60 mg/m2 IV bolus over 15 minutes) and cyclophosphamide (600 mg/m2 IV over 5-60 minutes) on day 1, every three weeks for four cycles, followed by four cycles of docetaxel (100 mg/m2 IV over 60 minutes, every three weeks). Patients in the TAC arm received doxorubicin (50 mg/m2 IV), cyclophosphamide (500 mg/m2 IV) and docetaxel (75 mg/m2 IV) infused in this order every three weeks for six cycles.

All patients underwent mastectomy or a breast-conservation procedure with tumor-free margins and axillary-node dissection, with at least one involved axillary node. No prior systemic or radiation therapy for breast cancer

was permitted.

At a median follow-up of 65 months, 708 events were reported. There were no significant differences with respect to disease-free survival (DFS) and overall survival (OS). The five-year DFS rate was 78.6% in the sequential arm and 78.9% in the combination arm (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.86-1.16; P=0.98). The fiveyear OS rate was 88.9% in the sequential arm and 88.1% in the combination arm (HR, 0.91; CI, 0.75-1.11; P=0.37).

The efficacy also was equivalent across all subgroups, including by the number of involved axillary nodes and by hormone-receptor status.

There were some differences between the two arms with respect to toxicity. The incidence of grade 3/4 neutropenia was similar in the two arms, but the incidence

of febrile neutropenia was significantly higher in the TAC arm (17.4% vs 7.7%; P<0.001). Sensory neuropathy, myalgia and nail changes were more frequent in the AC-T arm, whereas thrombocytopenia was more frequent in the TAC arm.

Because the two regimens “have equivalent efficacy,” the investigators suggested that “the choice of regimen requires balancing the differences in toxicity and treatment duration.” They noted that when given with granulocyte-macrophage colony-stimulating factor support to lessen hematologic toxicities, the TAC combination regimen “provides an acceptable global safety profile and allows a substantially shorter duration of treatment, and it remains an appropriate standard adjuvant chemotherapy regimen for women with early-stage, HER2-nonamplified breast cancer.”

Taxanes have been shown to improve progression-free survival and OS when added to anthracyclines in the treatment of node-positive breast cancer and have become standard in this population. Whether the choice of taxane (ie, docetaxel vs paclitaxel) and the schedule of administration (in combination with or sequentially to anthracyclines; weekly; every two weeks; every three

weeks) affects efficacy has been the focus of several adjuvant studies, both published and ongoing.

Based on the BCIRG-005 study and others, it can be concluded that there are several effective adjuvant regimens for this patient population.

These include the two regimens tested in this study as well as dose-dense ACT (AC every two weeks for four cycles; paclitaxel 175 mg/m2 every

two weeks or AC for four cycles; paclitaxel 80 mg/m2 weekly for 12 cycles).

Until results of studies directly comparing TAC for six cycles and dosedense ACT (NSABP B-38) or weekly paclitaxel compared with dose-dense paclitaxel (SWOG 0221) are available, the choice of adjuvant therapy will continue to depend on factors such as tolerability, availability of growth factors, and duration of treatment.

Weekly nab-Paclitaxel Favored in Older Women With MBC From Breast

W

eekly administration of nab-paclitaxel (Abraxane, Abraxis) is safer and more effective than every-threeweek nab-paclitaxel and solvent-based paclitaxel and docetaxel in older women with metastatic breast cancer (MBC), according to a post-hoc analysis (Aapro M et al. Breast 2011;20:468-474, PMID: 21843943).

Paclitaxel and docetaxel often are used for MBC, despite the fact that serious hypersensitivity reactions may result.

To counteract this, prophylactic steroids are administered together with solvent-based paclitaxel and docetaxel. Solvents also reduce taxane bioavailability, potentially affecting efficacy. An albumin-bound formulation of paclitaxel, nab-paclitaxel, sidesteps these safety concerns and appears to have better bioavailability.

Swiss researchers conducted a posthoc analysis combining Phase II and Phase III studies. In the Phase II study (Gradishar WJ et al. J Clin Oncol 2009;​

27:3611-3619, PMID: 19470941), patients received nab-paclitaxel (300 mg/m2 every three weeks or 100 or 150 mg/m2 every week for three weeks) or docetaxel (100 mg/m2 every three weeks). In the Phase III study (Gradishar WJ et al.

J Clin Oncol 2005;23:7794-7803, PMID: 16172456), patients received nab-paclitaxel (260 mg/m2 every three weeks) or solvent-based paclitaxel (175 mg/m2 every three weeks). Of the total treatment population of the two studies, 114 women were 65 years old or older, and most had stage III or IV metastatic disease.

In the Phase II study (n=52), overall response rates (ORR) for nab-paclitaxel administered weekly were 60% to 64%, compared with 22% for the everythree-week nab-paclitaxel and 32% for docetaxel.

In the Phase III study (n=62), the ORR for the every-three-week nab-paclitaxel regimen was 27% compared with 19% for the solvent-based paclitaxel. Median progression-free survival (PFS) was 5.6 months for every-three-week nab-paclitaxel and 3.5 months for solvent-based

paclitaxel. Weekly nab-paclitaxel resulted in less serious adverse events EXPERT INSIGHT Matthew A. Maurer, MD Assistant Professor of Medicine Columbia University College of Physicians and Surgeons Oncologist NewYork-Presbyterian/ Columbia

Aapro et al performed a post-hoc analysis of patients 65 years or older from two studies comparing treatment with every-three-week nabpaclitaxel or solvent-based paclitaxel.

The conclusion was that these older patients were representative of the total treatment group with respect to both improved efficacy and improved tolerability. Although the study is

compared with all other regimens.

clearly underpowered to show statistically significant results, the study is important because it highlights an unmet need: to assess breast cancer treatments in older patients. As pointed out in the article, patients 65 years old and older represent at least 40% of all breast cancer patients and their number in both absolute and relative terms will continue to grow as the baby-boom generation ages. Yet, these older patients are underrepresented in trials, and this is the case (<20% of enrollment) with the two trials analyzed in this study. Although older patients may be more likely to be excluded based on performance status and comorbidities, it is not clear if this solely explains the discrepancy.

Regardless, judgments on how aggressively older patients should be treated in the palliative advanced see NAB-PACLITAXEL, page 18 

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Clinical Oncology News • November 2011

Ovarian

BRCA2 Linked to Improved Ovarian Cancer Survival From JAMA

I

n patients with ovarian cancer, the BRCA2 mutation is associated with better outcomes than the BRCA1 mutation and wild-type BRCA gene, according to a recent observational study (Yang D et al. JAMA 2011;306:1557-1565, PMID: 21990299).

Investigators used genomic and clinical data from The Cancer Genome Atlas (TCGA) to evaluate the relationships between BRCA1 and BRCA2 mutations and overall survival (OS), progression-free survival (PFS), chemotherapy response and mutation rate in patients with ovarian cancer. Of the 316 cases of

high-grade serous ovarian cancer in the TCGA database, 37 (11.7%) had BRCA1 mutations and 29 (9.2%) had BRCA2 mutations. Both mutations were seen in two of the cases.

BRCA2 mutation carriers had significantly higher OS and PFS than did wildtype BRCA carriers. The five-year survival rate of BRCA2 mutation carriers was 61% (95% confidence interval [CI], 43%87%), compared with 25% for wild-type carriers (hazard ratio [HR], 0.33; 95% CI, 0.16-0.69; P=0.003). The five-year survival of BRCA1 carriers did not significantly differ from that of wild-type carriers. BRCA2 carriers also had significantly longer PFS times than those with the

EXPERT INSIGHT Victor R. Grann, MD, MPH

Ramon E. Parsons, MD, PhD

Clinical Professor of Epidemiology Columbia University College of Physicians and Surgeons Oncologist NewYork-Presbyterian/ Columbia

Professor of Pathology and Medicine Columbia University College of Physicians and Surgeons Oncologist NewYork-Presbyterian/ Columbia

Since the 1990s, the central importance of mutations of the BRCA1 and BRCA2 genes to the lifetime risk for ovarian and breast cancers has emerged, and the extent of genetic

heterogeneity and penetrance of both the 17q and 13q tumor suppressor gene regions have been further defined.

In the present study, Yang et al have sought to assess the association of

wild-type gene (HR, 0.40; 95% CI, 0.220.74; P=0.004). Again, there was no significant difference between BRCA1 carriers and wild-type carriers. However, there was a significant PFS difference between BRCA1 and BRCA2 carriers: 44% of the cases with the BRCA2 mutation remained progression free three years after surgical resection compared with 22% of those with the BRCA1 mutation (P=0.05).

BRCA2 carriers also had improved chemotherapy response compared with BRCA1 carriers and wild-type carriers, both in terms of sensitivity to therapy and duration of response. All of the cases with BRCA2 exhibited complete or partial response to adjuvant chemotherapy

compared with 85% of cases with the wild-type gene (P=0.05) and 80% of cases with BRCA1 mutations (P=0.02). The BRCA2 cases also had a longer platinumfree duration (18 months) than cases with BRCA1 mutations (12.5 months; P=0.04) and wild-type cases (11.7 months; P=0.02).

Additionally, BRCA2 cases exhibited a “mutator phenotype” with significantly more mutations, which, according to the investigators, suggests “that the different associations between survival and BRCA1 and BRCA2 deficiencies likely result from patients’ distinct responses to platinumbased treatment, which may be caused by the differing nature of the dysfunction of these two genes.”

BRCA1 and BRCA2 mutations with survival of ovarian cancer, and go further by looking at variations in response to cancer chemotherapy.

The investigators noted significant differences in survival from ovarian cancer, finding that women with BRCA2 mutations had comparatively increased survival over those with BRCA1 mutations. The authors conclude that these results indicate that women with BRCA1 mutations were more resistant to platinum-based cancer chemotherapy.

The study had its limitations, including missing data from 15% of women that would have benefited inclusion into this epidemiologic study.

As noted in an editorial we wrote

(JAMA 2011;306:1597-1598, PMID: 21990304), these findings are important and should prompt further investigative attention into the differences between the deficits in DNA repair in BRCA1 and BRCA2 mutations, which may ultimately lead to more targeted clinical therapy. Patients deemed to be at higher risk for ovarian cancer may benefit from genetic testing, annual or semiannual diagnostic testing, prophylactic administration of tamoxifen or aromatase inhibitors, or even prophylactic surgery. The health care cost implications of these medical interventions must be weighed against the costs of treating patients who are terminally ill and increasing their OS.

Lung

Crizotinib Improves Survival in ALK-Positive NSCLC From The New England Journal of Medicine

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he anaplastic lymphoma kinase ALK tyrosine kinase inhibitor (TKI) crizotinib (Xalkori, Pfizer) improves survival in patients with advanced, ALK-positive non-small cell lung cancer (NSCLC), according to a retrospective analysis of Phase I clinical data published in the October issue of Lancet Oncology (Shaw AT et al. 2011;12:10041012, PMID: 21933749).

The international team of researchers focused on a cohort of 82 patients who had enrolled in the NCT00585195 Phase I clinical trial of crizotinib between December 2007 and February 2010. The study compared survival outcomes in crizotinib-treated patients in the trial to crizotinib-naive controls screened during the same period. The control group included 36 patients with advanced, ALK-positive NSCLC who did not receive crizotinib, either because they had died before crizotinib was clinically available or because

they had been screened solely for “non–trial-related research purposes.”

Additionally, 67 patients without ALK rearrangement (but positive for endothelial growth factor receptor [EGFR] gene mutation) and 253 wildtype patients lacking either ALK rearrangement or EGFR mutation also were included as comparators.

In the crizotinib-treated group, oneyear overall survival (OS) was 74%, and two-year OS was 54%; median OS had not been reached at the conclusion of the analysis. Additionally, one- and two-year OS were greater in 30 ALKpositive patients in whom crizotinib was administered as second- or thirdline therapy (70% and 55%, respectively) than in 23 ALK-positive controls given any second-line therapy (44% and 12%, respectively; P=0.004). In this latter group, median OS was six months.

Survival in 56 crizotinib-treated, ALKpositive patients was similar to that in 63 ALK-negative, EGFR-positive patients given EGFR TKI therapy. Survival in the 36 crizotinib-naive controls was similar to

that found in the 253 wild-type controls.

The authors concluded that their findings, along with those of the original Phase I study, “support the notion that crizotinib can fundamentally alter the natural history of ALK-positive

NSCLC.” The investigators note that clinicians should consider testing for ALK in NSCLC patients, particularly if it has already been determined that they are negative for EGFR and KRAS gene mutations.

EXPERT INSIGHT

fraction of NSCLC cases. Principally, these are found in patients with adenocarcinoma histology, limited smoking history and wild-type EGFR status. Positive in vitro and mouse data showing the efficacy of ALK kinase inhibition led rapidly to expanded Phase I/II studies of the readily available ALK/MET inhibitor crizotinib, demonstrating excellent response rates and good overall safety. This was followed by an exemplary biomarkerbased Phase II/III development program, ultimately leading to the accelerated approval of crizotinib by the FDA in August 2011 for the treatment of ALK-positive NSCLC. This was based on response rates without comparative survival or quality-of-life

Balazs Halmos, MD Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons Section Head Thoracic Oncology NewYork-Presbyterian/ Columbia

In recent years, we have witnessed one of the most spectacular examples of the power of molecular oncology through the discovery in 2007 of recurrent ALK translocations (most frequently EML4-ALK) in a small

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

Recent Advances in the Understanding and Management of

The Myelodysplastic Syndromes HARRY P. ERBA, MD, PHD Associate Professor of Internal Medicine University of Michigan Ann Arbor, Michigan

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he myelodysplastic syndromes (MDS) are a heterogeneous group of bone marrow failure disorders. A recent

claims-based algorithm estimated that there were 75 cases of MDS among individuals aged 65 or older in the United States in 2005,1

and the incidence increases with advancing age.

Indeed, patient age and comorbid conditions and performance status (PS) associated with increased age are arguably the most important factors influencing the choice of therapeutic goal—palliation alone, palliation with prolongation of survival, or curative intent— in patients with MDS. Based on the Adult Comorbidity Evaluation-27 (ACE-27) Scale, which can be used to predict outcomes of MDS patients, those with more severe comorbidities have a shorter median survival.2 The effect of the ACE-27 score is most pronounced in patients younger than 65 years.

Patients with MDS typically present with peripheral blood cytopenias in the setting of a (typically) hyperplastic bone marrow with dysplastic cellular elements.

They may present with signs or symptoms of cytopenias, such as fatigue, dyspnea, recurrent infections, and hemorrhage, or the disease may be discovered during routine blood counts. Patients with MDS are at risk for progressing to acute myeloid leukemia (AML), which is arbitrarily defined as the accumulation of myeloblasts to more than 20% of the nucleated cells of the bone marrow or peripheral blood. The etiology of ineffective hematopoiesis is complex and likely multifactorial.

This complexity has resulted in a fragmented knowledge base about MDS pathogenesis that has impeded rational selection of therapeutic interventions for individual patients.

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Factors Influencing Treatment and Survival At this time, clinical characteristics are the most important factors for the selection of available therapies, but, ultimately, a more thorough understanding of the molecular pathogenesis of MDS will direct therapeutic choices and influence survival. Some progress has been made in this area with respect to somatic mutations and other laboratory features associated with MDS.

GENES IDENTIFIED Recently, somatic mutations in 18 different genes have been identified in the marrow aspirates of 439 patients with MDS.3 At least one mutation was found in 51% of tested samples and in 52% of the samples with normal karyotype. These mutations could be correlated with other clinical features such as karyotype, blast count, and degree of thrombocytopenia. The 2 most commonly mutated genes, TET2 and ASXL1, were found in 20% and 14% of samples, respectively. The products of these 2 genes are involved in epigenetic regulation of gene expression by modification of chromatin structure. A set of 5 genes (TP53, EZH2, ETV6, RUNX1, and ASXL1) was independently associated with decreased overall survival (OS). The presence of mutation in any of these 5 genes in patients with low-, intermediate-1– and intermediate-2–risk disease was associated with an OS that was similar to that of patients in the next highest

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Figure 1. MDS-004: RBC-TI and cytogenetic response.

IWG, International Working Group; LEN, lenalidomide; RBC-TI, red blood cell transfusion independence a

Defined as absence of chromosome 5q31 abnormality Based on reference 26.

International Prognostic Scoring System (IPSS) risk group. It remains to be seen if these mutations can aid in the diagnosis of MDS in patients with normal karyotype and subtler morphologic dysplasia. These mutations also may prove to be predictive of response to various available drugs, such as DNA methyltransferase (DMT) inhibitors, immunomodulatory agents, and histone deacetylase (HDAC) inhibitors. Because these molecular studies were performed on DNA isolated from whole marrow aspirates, it remains to be determined if the mutations are present in myeloid cells or in other marrow elements, such as stromal cells.

During the 2011 European Multidisciplinary Cancer Congress, Papaemmanuil et al reported that they found a mutation of the SF3B1 gene in 20.3% of MDS patients overall and 64.6% of patients whose disease was defined by ringed sideroblasts.4 The team also found that patients with the mutation had better OS and leukemiafree survival compared with those without the mutation.

PROGNOSTIC MODELS A number of other laboratory features influence the survival and risk for progression to AML in patients with MDS, and there are several prognostic models in use. The International MDS Risk Assessment Workshop (IMRAW) developed the IPSS.5 The IPSS includes 3 clinical factors— percentage of bone marrow blasts, bone marrow karyotype, and number of cytopenias, and it divides patients into 4 prognostic groups, with median survival ranging from 5.7 years (low risk) to 0.4 years (high risk). This model is based on patients who had their MDS typed by the French-American-British (FAB) classification system and excludes patients with treatment-related MDS and patients who had received therapy other than supportive care. An alternative prognostic scheme for de novo MDS patients is based on the World Health Organization

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(WHO) classification of disease that relies on bone marrow karyotype and transfusion requirements to categorize the type of MDS.6 Kantarjian et al proposed a novel prognostic model that identifies 8 factors affecting prognosis—PS, age, platelet count, anemia, bone marrow blast percentage, leukocytosis, chromosome 7 abnormality or complex karyotype, and transfusion.7 The value of this new prognostic model was validated in patients with chronic myelomonocytic leukemia with leukocytosis and those with secondary MDS. This group also developed an IPSS-based prognostic model for patients with lowand intermediate-1–risk MDS that identifies patients at increased risk for mortality by incorporating age over 60 years, degree of thrombocytopenia, bone marrow blast percentage over 4%, degree of anemia, and any karyotype other than normal diploid and del(5q).8 However, it is not certain from this analysis that therapeutic intervention in this subset of patients will improve survival.

PROGNOSTIC ROLE OF RARE CYTOGENETIC ABNORMALITIES Rare karyotypic abnormalities in patients with MDS can help with prognosis and guiding therapeutic decisions. The cytogenetic changes that were most frequently identified in the IMRAW were del(5q), del(20q), loss of Y chromosome, trisomy 8, and abnormalities of chromosome 7. An analysis of patients included in the IMRAW, German-Austrian MDS Registry, and the Spanish and International Working Group on MDS Cytogenetics identified several single cytogenetic abnormalities associated with a more favorable prognosis, including –1/1p–, t(1;7), del(11q), del(12p), –13/13q–, del(16q), and +19.9

Hematopoietic Stem Cell Transplantation Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative therapeutic option for patients with MDS. IPSS has been shown to predict outcomes (survival and relapse) for patients who receive allo-HSCT. However, prospective clinical trials have not yet identified the optimal timing of allo-HSCT, and the procedure is associated with a significant risk for early treatment-related mortality.

Investigators addressed this problem by performing an analysis examining the optimal timing of bone marrow transplantation for patients younger than age 60 who received sibling donor allo-HSCT with myeloablative conditioning regimens, and comparing these patients with patients who received supportive care alone. For low- and intermediate-1–risk MDS, delayed allo-HSCT was associated with maximal life expectancy; immediate allo-HSCT for intermediate-2– and high-risk patients was associated with maximal life expectancy.

Risk was assessed using the IPSS.10 This retrospective analysis has several important limitations. For example, the median age of patients not receiving allo-HSCT was significantly higher than that of the patients who received allo-HSCT, and there were other clinical differences between patients in these 2 databases that could have affected survival, such as

comorbid illnesses and PS. Patients in the analysis underwent allo-HSCT between 1990 and 1999. Since that time, there have been improvements in supportive care offered to patients undergoing HSCT, thus resulting in improved outcomes. Likewise, patients with MDS can receive therapy that may affect their survival (see below). Finally, the analysis was limited to patients under the age of 60 and does not include patients receiving reduced-intensity conditioning regimens or alternative donors.

Over the past 2 decades, clinicians have witnessed important advances in the practice of allo-HSCT. Best supportive care (BSC) of patients receiving allo-HSCT has improved with the use of azole antifungal antibiotics, instead of the more toxic amphotericin preparations, and the use of antiviral prophylaxis to prevent recurrence of cytomegalovirus infection. The pool of donors has increased, and donor selection has improved with the use of molecular HLA typing using DNA-based technologies in place of serologic methods. Many different, reduced-intensity conditioning regimens have been developed, leading to a lower incidence of severe mucositis and less early mortality. Therefore, it is clear that the practice of restricting allo-HSCT to younger patients can no longer be accepted. It is possible for patients in their seventh and even eighth decade of life to undergo alloHSCT with acceptable morbidity and mortality.

Despite these advances, randomized trials comparing allo-HSCT with BSC or alternative therapies have not been performed for older patients with MDS. One retrospective analysis validated the use of allo-HSCT in older MDS patients and showed increased survival with HSCT over BSC,11 but such a retrospective analysis with case controls cannot determine which treatment strategy improves survival. Patients who receive BSC likely are very different from those selected for allo-HSCT. Case–control studies of patients with MDS should match participants based on PS, comorbid illnesses, and socioeconomic status, all of which can affect survival of older patients with highgrade hematologic malignancies. In the retrospective study, 60% of the 126 transplant patients underwent chemotherapy prior to allo-HSCT. This factor is important for several reasons. The implication is that these transplant patients had chemotherapy-sensitive disease and likely responded to the pretransplant chemotherapy. They also were shown to tolerate chemotherapy and comply with follow-up care. Finally, the contribution of the pretransplant chemotherapy to the survival benefit is difficult to discern. Several recent, prospectively validated clinical assessments of frailty in older patients may help clinicians in the future appropriately select patients for therapy.

Supportive Care: ESAs The erythropoietin-stimulating agents (ESAs) epoetin alfa (Epogen, Amgen; Procrit, Ortho Biotech) and darbepoetin (Aranesp, Amgen) have been recommended in the supportive care of selected MDS patients with anemia based on the results of several studies.12-17 However, recent randomized trials have demonstrated increased risk for thromboembolic complications and

inferior survival in patients with carcinoma receiving ESAs,18,19 raising concern about the use of these agents in oncology patients, including those with MDS. The Eastern Cooperative Oncology Group (ECOG) has published a prospective, randomized trial comparing daily erythropoietin (EPO) with or without granulyte colony-stimulating factor, to red blood cell (RBC) transfusion support alone in MDS patients and found no increased thrombotic risk among those treated with EPO.17 The data show that EPO is effective for the treatment of patients with MDS—especially those with lowgrade MDS, low- or intermediate-1–risk disease, and low endogenous EPO levels—and it is not associated with increased risks for mortality or leukemic transformation.

Immunosuppressive Therapy Laboratory investigation of bone marrow samples from patients with MDS suggests that immune dysregulation may contribute to the pathogenesis of the cytopenias, leading to investigations of several immunosuppressive approaches.

In a Phase II study, antithymocyte globulin (ATG) resulted in transfusion independence within 8 months of therapy for 34% of patients, with 76% of these responders remaining transfusion-independent at 5 years.20 Neutrophil and platelet responses also were observed.

The factors predictive of response were younger age, refractory anemia (RA) subtype, and lower platelet counts. Hypercellular marrow and abnormal karyotype were associated with lack of response. Subsequent analyses showed that expression of the HLA-DR15 (a serologic split of DR2) predicted for response to ATG in patients with MDS.21 Expression of HLA-DR15, younger age, and shorter duration of RBC transfusion requirement all predicted for response to ATG in multivariate analysis, resulting in the development of a predictive model of response based on these 3 factors.22 Another study reviewed long-term outcomes among patients with de novo MDS (N=129) who had been treated with immunosuppressive therapy (ATG, cyclosporine, or both) in 1 of 3 trials.23 The majority of patients (n=110) had low- and intermediate-1–risk MDS. Complete or partial responses were observed in 30% of patients: 24% with ATG alone, 45% with ATG plus cyclosporine, and 8% with cyclosporine alone. The response rate was significantly better in intermediate-1– risk patients treated with the combination versus ATG alone (54% vs 29%; P=0.004). In multivariate analysis, age and expression of HLA-DR15 were the most significant variables affecting response. The survival and risk for leukemic transformation of patients treated with immunosuppressive therapy were compared with the same long-term outcomes in patients in the IMRAW. OS in intermediate-1–risk MDS patients who were at least 60 years of age was superior for the immunosuppressive therapy cohort compared with the patients who received BSC alone in IMRAW (median survival >8.1 vs 5.2 years; P=0.001). Likewise, the proportion of patients developing AML was lower in the intermediate-1–risk

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Reprinted from reference 33, © 2011, with permission from Elsevier.

group treated with immunosuppressive therapy than in the IMRAW cohort. Because there was no difference in survival or risk for leukemic transformation between older patients in the 2 cohorts, lack of response to immunosuppressive therapy likely does not adversely affect the long-term outcome of patients with MDS. Alemtuzumab (Campath, Genzyme), an anti-CD52 humanized murine monoclonal antibody approved by the FDA for the treatment of relapsed chronic lymphocytic leukemia, has been associated with profound immunosuppression via T-cell depletion. Sloand et al reported the results of a Phase II study assessing the use of alemtuzumab (10 mg by IV infusion for 10 consecutive days) in 24 intermediate-1–risk MDS patients considered likely to respond to immunosuppressive therapy based on the criteria developed by Saunthararajah et al.22,24 HLA-DR15 expression was identified in 61% of patients; median age was 57 years. The overall response rate was 83%. The median time to response was 96 days. All responders were transfusion-independent; 12 of 16 patients became transfusion-independent. Five of 7 patients had complete cytogenetic remissions. Median follow-up was short (11 months), but responses were durable. The most common adverse events were infusion reactions. Subclinical viral reactivation was observed in 5 patients.

Lenalidomide Lenalidomide (Revlimid, Celgene) is approved by the FDA for the treatment of low- and intermediate-1–risk MDS patients with del(5q). In 4 different studies (including the pivotal trial MDS 003), 168 MDS patients with del(5q) were treated with lenalidomide.25 The median age of these patients was 71 years, and they were predominantly female. The majority had previously received

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EPO (74%); these patients were receiving 2 or more units of RBC every 4 weeks (71%). A minority of these patients had some neutropenia or thrombocytopenia. Sixty-eight percent of patients became RBC transfusion-independent, with a median time to RBC transfusion independence of 4.7 weeks. Response was not affected by IPSS classification or karyotype complexity. The median duration of response was 2.2 years, but responses were longer in patients with low-risk disease and the 5q– syndrome. Lenalidomide appears to be cytotoxic to the 5q– clone, with complete cytogenetic responses observed in 50% of the patients, likely explaining the early treatment-related myelosuppression in responders.

Lenalidomide dose interruptions/reductions due to myelosuppression are common early in therapy for patients with low- and intermediate-1-risk MDS with del(5q). Some have questioned the approved starting dose of lenalidomide in this population. MDS 004, a Phase III multicenter, randomized, double-blind, placebocontrolled trial conducted in Europe and Israel, assessed 5- and 10-mg lenalidomide doses as well as placebo.26 The trial included 205 patients with low- and intermediate-1–risk MDS with del(5q), RBC transfusion dependence, absolute neutrophil count (ANC) above 500 cells/mcL, and platelet count above 25,000 cells/mcL. Patients were randomized to receive lenalidomide 5 mg daily for 28 days, 10 mg daily for 21 of 28 days, or placebo; 67 patients were excluded for a variety of reasons including higherrisk disease and insufficient data, leaving 138 patients with centrally confirmed eligibility receiving more than one lenalidomide dose. The rate of RBC transfusion independence was significantly higher with lenalidomide than with placebo using both protocol-specific response criteria and International Working Group (IWG) criteria.

RBC transfusion-independence rate was not affected by age, gender, FAB classification, IPSS classification, time from diagnosis, cytogenetic complexity, baseline platelet counts, and number of cytopenias. Transfusion independence was achieved by a median of one cycle in both treatment groups, and the duration of transfusion independence was similar with both doses. Rates of complete and overall cytogenetic responses were significantly higher in the 10-mg daily group than in the 5-mg daily group (Figure 1), but there was no difference in grade 3/4 toxicities including hematologic toxicities, discontinuations, dose interruptions, and dose reductions between the 2 groups. The authors concluded that lenalidomide 10-mg daily is the appropriate starting dose for patients with low- and intermediate-1–risk MDS with del(5q). An analysis of the pooled results of MDS-003 and MDS-004 was presented at the 2011 American Society of Clinical Oncology annual meeting.27 The total first-cycle lenalidomide dose directly correlated with cytogenetic remission, and patients with complete or partial cytogenetic remissions had more durable RBC transfusion independence than nonresponders.

Lenalidomide also is active in patients with low- and intermediate-1–risk MDS without del(5q). However, the rate of RBC transfusion independence is 26%, and the median duration of RBC transfusion independence is 41 weeks.28 Again, the prognostic risk group and karyotype were not predictive of response. Myelosuppression was observed but was not associated with response. Identification of non-del(5q) MDS patients who are more likely to benefit from lenalidomide would avoid the potential toxicities of this agent in the majority of these patients who are unlikely to respond. Ebert et al identified a geneexpression signature predictive of response to lenalidomide in patients with MDS.29 Bone marrow samples of lenalidomide responders with or without del(5q) tend to underexpress a number of genes involved in normal erythroid differentiation. Patients with the 5q– syndrome often have bone marrow erythroid hypoplasia. Because the RNA was isolated from whole bone marrow aspirate samples without cell selection, it can be speculated that erythroid hypoplasia also may predict for response.

However, an association of erythroid response with marrow erythrogenesis has not been reported.

Major erythroid responses also were observed in a few patients with higher-risk MDS with del(5q) treated with lenalidomide in the MDS 003 study. Recently, Adès et al reported the results of a Phase II study of lenalidomide in patients with intermediate-2– and high-risk MDS.30 Forty-seven patients were treated with lenalidomide (10 mg daily for 21 days of a 28-day cycle).

Although this was a high-risk group of patients, 38% had an ANC below 1,000 cells/mcL and 57% had a platelet count less than 100,000 cells/mcL. The majority (81%) had either refractory anemia with excess blasts (RAEB)-2 or AML by WHO criteria; 40% had high-risk disease and 19% had del(5q) as an isolated cytogenetic abnormality. Of the 47 patients, 13 (28%) had a response, including 7 patients (15%) with a complete remission

(CR). Nine patients had a complete cytogenetic remission. However, CR only was seen in the patients with a baseline platelet count above 100,000 cells/mcL and del(5q) alone or with another single mutation. There was a trend for a higher CR rate in patients with marrow blast counts less than 20%. Myelosuppression was the major toxicity, with many patients requiring hospitalization for treatment of complications.

Although lenalidomide clearly exerts a cytotoxic effect on the del(5q) MDS clone, this agent should be used cautiously in del(5q) MDS patients with intermediate-2– and high-risk disease. The goal of therapy for patients with intermediate-2– and high-risk MDS is palliation of symptoms and improvement in expected survival.

DMT Inhibitors Azacitidine (Vidaza, Celgene) and decitabine (Dacogen, Eisai) are both FDA-approved for the treatment of MDS. The DMT inhibitors cause DNA hypomethylation, which alters global chromatin structure, resulting in reactivation of gene expression. However, it still is not known if responses are solely due to this mechanism of action.

Azacitidine was the first drug approved for the treatment of all FAB subtypes of MDS in 2004. Using IWG response criteria, CRs, partial remissions (PRs), and hematologic responses were observed in 10%, 1%, and 36%, respectively, of MDS patients treated in the CALGB 9221 study.31 Patients receiving azacitidine either at study entry or within 6 months of study entry had a superior OS compared with patients receiving BSC alone during this time.32 Azacitidine is the only agent that has been shown to improve the survival of MDS patients compared with other conventional care regimens, including BSC alone.33 In the AZA-001 study, patients were randomly assigned to receive azacitidine 75 mg/m2 per day for 7 consecutive days or a conventional care regimen (BSC, low-dose cytarabine, or anthracycline and cytarabine induction chemotherapy) selected by the physician prior to randomization. Patients assigned to intensive chemotherapy were more likely to be younger than age 65, to have highrisk disease, and to have AML by WHO criteria. Treatment with azacitidine continued as long as there was no evidence of progression or unacceptable toxicity; the median number of cycles was 9. Only patients with intermediate-2– and high-risk disease by IPSS and with RAEB and RAEB in transformation by FAB criteria were treated in this study. The median survival of patients was significantly longer with azacitidine than with the conventional care regimens (24.5 vs 15 months; P=0.0001; Figure 2). A survival benefit was observed even in patients over age 75, as well as in patients with high-risk disease, poor-risk cytogenetics including monosomy 7 or del(7q), and marrow blast counts between 21% and 30%. CRs and PRs were seen in 29% of azacitidine-treated patients; 49% of patients had hematologic improvement (HI). Patients achieving HI with azacitidine had superior survival compared with patients achieving the same response with the conventional care regimens.34 Treatment with 7 consecutive days of azacitidine is

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5

100 AZA 5-2-2

AZA 5-2-5

AZA 5

Patients, %

80 64

60

56

55 50

44

45 42

40

31 22

20

0

Any Hematologic Improvement

Red Blood Cell Transfusion Independence

Grade 3/4 Neutropenia

Figure 3. Comparison of 3 azacitidine (AZA) regimens.

Based on reference 35.

inconvenient, and several trials have explored alternative schedules. A randomized Phase II study investigated 3 doses and schedules of azacitidine: 75 mg/m2 per day for 7 days with a 2-day weekend break, 50 mg/m2 per day for 10 days with a 2-day break, and 75 mg/m2 per day for 5 days (Figure 3).35 The median age of patients in each treatment arm was 73, 76, and 76 years, respectively. The IPSS was not reported, but slightly more than 50% of patients in each arm had low-grade MDS by FAB criteria, and 4 of the 151 patients had RAEB in transformation. There was no obvious difference in rates of HI (44%-56%) or RBC transfusion independence (50%-64%) . Marrow CRs and PRs were not reported because followup bone marrow exams were not required in the protocol. However, patients receiving the 5-day schedule were less likely to have treatment-emergent hematologic toxicity. The majority of hematologic responses and transfusion independence occurred within 2 cycles of therapy.

It is not certain that this 5-day schedule also would lead to a survival advantage in intermediate-2– and high-risk patients. Data from AVIDA, a longitudinal, prospective, multicenter registry of azacitidine use in MDS patients, can shed further light on schedule.36 Of the 331 patients in the registry with MDS or oligoblastic leukemia, 57% received azacitidine by the IV route and 43% by subcutaneous injection. Only 17% of patients received the FDA-approved continuous 7-day dosing schedule; 51% received less than 7 days; 30% received 7 days with breaks; and 2% received more than 7 days. There was no difference in HI between IV and subcutaneous dosing (24% HI). Patients with higher-risk MDS were less likely to receive less than 7 days of azacitidine per cycle.

A Spanish registry of 144 MDS patients treated with

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azacitidine suggested that there is a lower rate of hematologic response in patients receiving less than 7 days of therapy per cycle, despite similar baseline patient characteristics.37 Decitabine also was approved for the treatment of MDS patients based on responses seen in a Phase III study.38 Both de novo and secondary MDS patients with intermediate-1–, intermediate-2–, and high-risk disease were treated with IV decitabine (15 mg/m2 over 3 hours every 8 hours for 3 consecutive days). The median number of cycles delivered was 3. The rates of CR, PR, and HI were 9%, 8%, and 13%, respectively. However, there was no difference in survival without leukemic transformation between decitabine-treated patients and those receiving BSC alone. The European Organisation for Research and Treatment of Cancer (EORTC) recently reported a Phase III study of the same dose and schedule of decitabine compared with BSC alone in 233 patients with MDS over the age of 60 with intermediate- and high-risk disease.39 The median number of cycles was 4, and no patient received more than 8 cycles by study design. Patients who achieved a CR only received 2 additional cycles of therapy. The rates of CR, PR, and HI were 13%, 6%, and 15%, respectively. Again, there was no difference in OS or survival without leukemic transformation between the 2 treatment arms. The discontinuation of decitabine after at most 8 cycles may have affected the ability to demonstrate a survival advantage over BSC alone.

A lower total dose of decitabine (100 mg/m2 per cycle) was evaluated in a randomized Phase II study conducted at the University of Texas MD Anderson Cancer Center in Houston.40 Among the 95 patients, median age was 65 years; 24% of patients had less than 5% blasts and 6% had 21% to 30% blasts. The patients received 1 of 3 schedules of decitabine. Those receiving IV decitabine (20 mg/m2 per day for 5 consecutive days) had a CR rate of 39%. The results of this study led to the multicenter ADOPT (Alternative Dosing for Outpatient Treatment) trial, in which 99 patients received decitabine (20 mg/m2 per day for 5 days) on an outpatient basis.41 The median number of cycles delivered was 5. The median age of the patients was 72 years; 37% had RA or RA with ringed sideroblasts; 53% had intermediate-1–risk, 46% had intermediate-2– and high-risk disease; 49% had good-risk karyotypes; 42% had less than 5% marrow blasts. The CR rate was 17%, marrow CR was 15%, PR was 0%, and HI was seen in 18%; 33% of RBC transfusion-dependent patients became transfusion-independent. Half of the patients experienced a cytogenetic remission. The response was not affected by IPSS or FAB subtypes.

Decitabine and azacitidine are both clearly effective therapies for MDS patients. The MD Anderson Cancer Center and ADOPT trials have demonstrated activity of decitabine in patients with treatment-related MDS. Decitabine 20 mg/m2 per day for 5 days is a more convenient outpatient dosing regimen than the higher total dose tested in the 2 Phase III studies. However, the patients treated in the MD Anderson Cancer Center and ADOPT trials appear to be different from the patients

treated in the EORTC study and the AZA-001 studies. The former studies include a higher proportion of patients with lower-grade and lower-risk disease. The studies also differ slightly in the response criteria. Although achievement of marrow CR does demonstrate activity, these patients may not have achieved HI.42 Therefore, it is difficult to determine the effect of marrow CR on the quality of life. Finally, the improvement in survival observed with azacitidine may well be due to maintenance therapy. The median number of cycles of therapy in the single-center and multicenter trials of the 5-day decitabine regimen was less than that in the AZA-001 study.

Combination Regimens Combinations of the DMT inhibitors with other agents that may have different mechanisms of action are being explored. HDACs are also hypothesized to alter chromatin conformation and affect DNA transcription. Combinations of azacitidine with HDAC inhibitors have shown synergism in vitro, with reactivation of gene transcription. The ECOG and Southwest Oncology Group (SWOG) completed a trial of azacitidine (50 mg/m2 per day for 10 days) with or without the oral HDAC entinostat (Syndax) in patients with MDS. Results were presented at the American Society of Hematology annual meeting in December 2010.43 Entinostat did not improve response to azacitidine, but the rate of trilineage HI appeared to be higher with this 10-day azacitidine regimen than that expected with the standard 7-day regimen.

Azacitidine (75 mg/m2 per day for 7 days) combined with the anti-CD33 immunoconjugate gemtuzumab ozogamicin (Mylotarg, Pfizer) (3 mg/m2 on day 8) in 20 older patients with high-risk MDS and AML resulted in a 70% CR rate. The majority of patients received therapy in the outpatient setting, with one death due to disease progression. A SWOG study of this combination in elderly patients with AML was temporarily closed to accrual due to the withdrawal of gemtuzumab ozogamicin from the commercial market, but the manufacturer is now supplying gemtuzumab, and the study is again actively accruing AML patients over age 70 years with a PS of 2.

Lenalidomide has a variety of actions that can affect the pathophysiology of MDS, including a direct cytotoxic effect on cells with del(5q) and multiple effects on the bone marrow microenvironment. A Phase I study of azacitidine and lenalidomide has been completed.45 Eighteen patients with high-grade MDS were treated in 6 dosage groups. Remarkably, a dose-limiting toxicity was not identified. The extent of myelosuppression was less than expected with this combination. Of 18 evaluable patients, 12 (67%) achieved a response including 8 patients with CR, 3 with HI, and 1 with marrow CR. Correlation with cytogenetic analysis and other molecular markers was performed; patients with normal karyotype and without mutation of Cbl and TET2 appeared to be more likely to respond to the combination therapy. The recommended Phase II dosing regimen (azacitidine 75 mg/m2 per day on days 1-5 and lenalidomide 10 mg per day on days 1-21) is being studied in multicenter clinical trials.

Conclusions The majority of patients with MDS are older and not candidates for curative therapies. There are now 3 FDAapproved drugs for the treatment of these patients.

Azacitidine in a dosage of 75 mg/m2 per day for 7 days is the only treatment that has been shown to improve the survival of intermediate-2â&#x20AC;&#x201C; and high-risk MDS patients.

Decitabine and azacitidine appear to be effective in the setting of high-risk clinical features, such as high-risk karyotype and treatment-related disease. Nonetheless, responses only are observed in at most half of the patients treated with the DMT inhibitors, and the responses are not durable even with maintenance therapy. Although maintenance therapy with azacitidine and decitabine is felt to be important, the value of maintenance has not yet been demonstrated in a randomized trial. The degree of cross-resistance between azacitidine and decitabine remains uncertain. These and many other unanswered questions remain in the treatment of MDS. It is appropriate to consider therapy on well-designed clinical trials for the majority of MDS patients. Combinations of the DMT inhibitors with other agents, such as the HDACs and lenalidomide, are actively being explored to continue to improve the outcome of MDS patients. Development of novel agents for MDS patients who are resistant or refractory to the DMT inhibitors is urgently needed.

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SOLID TUMORS

Clinical Oncology News • November 2011

Esophageal

Cancer Risk With Barrett’s Lower Than Previously Thought (LGD) from 1992 to 2009. They then determined the incidence in these patients of HGD, esophageal adenocarcinoma, and adenocarcinoma or HGD, the three end points of the study. Patients with a diagnosis of adenocarcinoma or HGD prior to or concurrent with the diagnosis of Barrett’s were excluded.

Patients were followed from the date of diagnosis until the occurrence of one of the three end points, emigration from Denmark, death or study completion.

Median follow-up was 5.2 years.

During that time, investigators identified 66 cases of adenocarcinoma that were diagnosed after at least one year of follow-up, for an annual risk of 0.12% (95% confidence interval [CI], 0.09%0.15%). In Denmark’s general population, 2,602 cases of adenocarcinoma

were diagnosed during the study period, for an annual incidence of 0.03% (95% CI, 0.09%-0.1%). Thus, compared with the general population, the relative risk among patients in the Barrett’s cohort was 11.3 (95% CI, 8.8-14.4).

A diagnosis of HGD was made in 106 patients after at least one year of followup, resulting in an incidence of 1.9 cases per 1,000 person-years, compared with an incidence of 0.008 in the general population. Thus, the relative risk among patients in the Barrett’s cohort was 65.3 (95% CI, 53.5-79.0).

The incidence of HGD or adenocarcinoma was 2.6 cases per 1,000 personyears compared with 0.035 in the general population, for a relative risk of 21.1 (95% CI, 17.8-24.7) among those in the Barrett’s cohort.

When they assessed the incidence of concurrent LGD in the cohort, they found that compared with patients with Barrett’s who were LGD-negative at baseline, those who were LGD-positive had a relative risk for esophageal adenocarcinoma of 4.8 (95% CI, 2.6-8.8) and a relative risk for esophageal adenocarcinoma or HGD of 5.1 (95% CI, 3.4-7.6).

The investigators concluded that their results, taken together with the results of a recent Irish study (J Natl Cancer Inst 2011;103:1049-1057, PMID: 21680910), as well as cost-effectiveness and quality-of-life data, “suggest that the risk of esophageal adenocarcinoma among patients with Barrett’s esophagus is so minor that in the absence of dysplasia, routine surveillance of such patients is of doubtful value.”

The results of this large population-based study demonstrate that

the annual risk for esophageal adenocarcinoma in patients with Barrett’s esophagus was much lower than the previously reported risk of 0.5% per year, thereby placing our current surveillance criteria for patients with Barrett’s in question.

The study also suggests that LGD, rather than metaplasia or other mucosal changes, was more significantly associated with risk for esophageal adenocarcinoma. The sensitivity of endoscopic techniques to detect LGD, however, must be reliable for the recommendations for surveillance to change to less frequent or no

further follow-up after a finding of Barrett’s.

Chronic reflux is the impetus for endoscopy and determines the population at risk. It is a relatively poor screening tool because a significant proportion of patients who develop esophageal adenocarcinoma do not exhibit this symptom. Compare this with fecal occult blood testing, which leads to colonoscopy and has been shown to decrease colorectal cancer mortality.

A combination of more refined screening based on biologic risk factors, more detailed symptom

histories, as suggested by a recent Veterans Affairs meta-analysis (Aliment Pharmacol Ther 2010;32:1222, PMID: 20955441), and more sensitive endoscopic techniques to detect dysplasia may improve the utility of upper endoscopy for esophageal cancer screening in the future.

Although it adds to knowledge about Barrett’s, this study does not provide sufficient grounds to change screening practices yet. Close monitoring of Barrett’s is still suggested because Barrett’s still increases the risk for developing esophageal adenocarcinoma by several-fold.

data. By now, our understanding of acquired resistance mechanisms to crizotinib is growing quickly, and both new ALK inhibitors and heatshock protein inhibitors hold promise to combat such resistance. This whirlwind success of crizotinib appears well deserved and adds a new, convenient and effective targeted agent to the growing armamentarium for the treatment of patients with advanced NSCLC and de facto establishes ALK testing along with EGFR gene mutation testing as a necessity for the best management of our patients with this devastating illness.

Hereby lies the conundrum: As much as crizotinib is undoubtedly an effective drug, its commercial availability will make it nearly impossible for solid survival data to be obtained to gauge more accurately its actual impact. Although key randomized studies comparing crizotinib with

first- or second-line chemotherapy are continuing and the results are eagerly awaited, these studies very ethically permit crossover to crizotinib for patients randomized to the chemotherapy arm, eroding their ability to identify a survival difference— just as studies comparing chemotherapy with EGFR TKI therapy for EGFR mutation-positive tumors consistently show dramatically improved response rates and progression-free survival with EGFR-targeted therapy, but OS differences so far have eluded detection—likely due to very high rates of crossover.

In this light, we have to applaud Shaw et al for their valiant effort to obtain very valuable although admittedly imperfect data to approximate the key question—whether crizotinib therapy actually affects OS or not—and more basically, whether the presence of ALK-positivity per se is a prognostic

factor besides its being a predictive factor for the efficacy of ALK-directed therapy. They approach these questions by very careful comparison of four distinct cohorts of patients: 1. ALK-positive patients treated in the original expanded Phase I study.

2. ALK-positive patients who were identified retrospectively from before the study was available and who could not receive crizotinib or patients who did not qualify for the study based on eligibility.

3. Control EGFR-mutant, EGFR TKItreated patients.

4. Control wild-type NSCLC patients.

After appropriate considerations for disparate populations, their analyses suggest a significant survival benefit gained through the use of crizotinib for ALK-positive patients.

The survival for this group matches the outstanding outcome of the EGFR TKI-treated EGFR-mutated

patient cohort, whereas the authors do not find an a priori differential survival for crizotinib-naive ALK-positive patients. Although the cohorts are relatively small and intrinsically quite disparate, and the efforts for appropriate matching might not have controlled for all differences as randomization would, still the results of this study add considerable weight to our understanding of the biology of ALK-positive lung carcinoma and the utility of ALK-directed therapy, and should further promote the widespread and routine use of ALK testing for all patients with advanced lung adenocarcinoma. It puts the onus on the medical oncology community to expeditiously conduct studies for patients with earlier stages of the illness, to be able to assess ALK-targeted therapy in a curative setting where its benefits might be expected to be even more impactful.

From The New England Journal of Medicine

T

he risk for esophageal adenocarcinoma in patients with Barrett’s esophagus is not as high as previously thought, according to results of a Danish population-based cohort study (Hvid-Jensen F et al. N Engl J Med 2011;365:1375-1383, PMID: 21995385).

The results have prompted some investigators to question the currently recommended screening guidelines.

To determine whether Barrett’s is a risk factor for adenocarcinoma or highgrade dysplasia (HGD), the team used data from Danish nationwide pathology and cancer registries to identify the 11,028 Danes diagnosed with Barrett’s with and without low-grade dysplasia

EXPERT INSIGHT Elizabeta C. Popa, MD Assistant Professor of Medicine Weill Cornell Medical College Department of Medicine Division of Hematology/ Oncology NewYork-Presbyterian/ Weill Cornell

17

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SOLID TUMORS

Clinical Oncology News • November 2011

Colon

Sequential Rx Not Inferior to Combo Rx in Colorectal Cancer From Lancet Oncology

F

or the treatment of advanced, nonresectable colorectal cancer, sequential administration of specific drugs was equally effective and less toxic than upfront combined administration of the same agents, according to a recent French study (Ducreux M et al. Lancet Oncol 2011;12:1032-1044, PMID: 21903473).

The open-label, Phase III FFCD (Fédération Francophone de Cancerologie Digestive) 2000-2005 trial involved investigators from 53 centers throughout France and 410 patients with measurable, but nonresectable metastatic colorectal cancer. The patients were randomized, in a 1-to-1 fashion, to receive

EXPERT INSIGHT Manish A. Shah, MD Assistant Professor of Medicine Weill Cornell Medical College Director, Gastrointestinal Oncology NewYork-Presbyterian/ Weill Cornell

Although performed within the last decade, the FFCD study is already of a different era because it did not include biologic therapy (ie, bevacizumab

NAB-Paclitaxel

first-line fluorouracil (5-FU) plus leucovorin followed by second-line FOLFOX followed by third-line FOLFIRI (sequential arm) or first-line FOLFOX6 followed by second-line FOLFIRI (combination arm). The two arms were well balanced in terms of performance status, previous chemotherapy, number of metastatic sites and treatment center. The primary end point was progression-free survival after second-line therapy (PFS2).

Similar proportions of patients in both arms received at least one cycle of firstline therapy (99% for both sequential and combination) and at least one cycle of second-line therapy (76% sequential, 73% combination). However, significantly more patients in the sequential therapy

arm received third-line (P=0.03) and fourth-line therapy (P=0.0001).

No significant difference between the two arms with respect to median PFS2 was identified (10.5 months in sequential arm compared with 10.3 months in combination arm; hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.771.16; P=0.61). At a median follow-up of 36 months, no significant overall survival (OS) difference was identified (HR, 1.02; CI, 0.82-1.27; P=0.85). During first-line treatment, however, patients in the combination arm had significantly longer PFS than did patients in the sequential arm (HR, 0.70; CI, 0.57-0.85; P=0.0004).

During first-line therapy, grade 3/4

neutropenia, nausea and vomiting and grade 2/4 neurologic toxicity were significantly more frequent in the combination arm than the sequential arm. Toxicityrelated discontinuation was higher for the combination arm during first-line therapy but higher for the sequential arm during second-line therapy.

The investigators concluded, “Frontline combination chemotherapy was not better than deferred combination chemotherapy for the treatment of patients with advanced colorectal cancer.” The investigators suggested that studies be conducted in which first-line therapy includes novel therapies added to 5-FU rather than combination therapy to “reduce the burden of toxic effects on patients.”

[Avastin, Genentech/Roche] or an epidermal growth factor receptor antibody). Also, the primary end point was PFS2, not OS. However, within the confines of a 400-patient study, the investigators demonstrate that sequential therapy was not inferior to combination therapy. Importantly, this study was consistent with other larger studies—FOCUS (Lancet 2007;370:143-152, PMID: 17630037) and CAIRO (Lancet 2007;370:135-142, PMID: 17630036)— that addressed the same question.

In each of these studies, sequential therapy was not inferior to the current standard combination approach in patients with noncurative disease.

Both the FFCD and FOCUS studies did, however, identify notable exceptions, for example, that patients with a worse performance status or greater disease burden perform worse with sequential therapy versus a strategy of using the best combination therapy first.

The challenge with these results lies in knowing when they may be applicable to the patient sitting in front of you. As with the other studies, the FFCD study was limited to “noncurable” patients. Patients who may be resectable at some time in the future should not receive single-agent therapy initially due to lower response rates. Instead, these

patients should be treated with combination chemotherapy to start, often with a biologic added. Knowing who will or will not be eligible for resection is sometimes difficult at the onset of treatment. The impact of biologic therapy on this paradigm also is an unanswered question.

Nevertheless, this series of Phase III studies raises the question that perhaps some patients with colorectal cancer can be managed as can patients with other solid tumor diseases characterized by longer survivals (ie, breast and ovarian cancers), for which initiation of therapy with the most aggressive strategy may not always be the best approach.

Can Celecoxib Reduce Hand-Foot Syndrome?

continued from page 15 

setting is a daily exercise among practicing oncologists. In this setting, we are a bit more concerned about harm because older patients may have more difficulty recovering from serious side effects, especially those that could predispose to injury (ie, increase risks for falls associated with neuropathy) and hospitalizations. The two studies that these older patients were drawn from showed improved time to tumor progression and PFS, respectively, when comparing nab-paclitaxel with solvent-based paclitaxel; we await results from CALGB 40502 for a direct comparison between the most widely used regimen, weekly solvent-based paclitaxel, with weekly nab-paclitaxel. However, in the interim, Aapro et al’s analysis has highlighted that nabpaclitaxel is a reasonable choice for first-line treatment of older patients with MBC, and that treatment of older patients should be specifically studied in future trials.

From Annals of Oncology

A

recent study has concluded that using celecoxib (Celebrex, Pfizer) with capecitabine-based therapy can reduce the incidence of hand-foot syndrome (HFS) (Ann Oncol 2011 Sept 22 Epub ahead of print, PMID: 21940785).

Described in three gradations, HFS is the most common potentially serious adverse event from capecitabine administration. In studies involving capecitabine, the overall incidence of any grade of HFS has ranged from about 15% to nearly 70%, with over 10% experiencing HFS grade 3.

In the present study, investigators from the People’s Republic of China designed a single-center, prospective, randomized, Phase III clinical trial to test the effect of the COX-2 inhibitor celecoxib on the incidence of HFS in patients with stage II and III colorectal cancer. Patients received celecoxib 200 mg twice daily for 14 days per cycle.

Seventy-one patients were administered capecitabine-based chemotherapy

without celecoxib, with 19 receiving capecitabine monotherapy and 52 receiving a regimen of capecitabine plus oxaliplatin. Sixty-eight patients were randomized to receive celecoxib with capecitabine-based therapy, with 18 receiving capecitabine and celecoxib and 50 receiving capecitabine plus oxaliplatin and celecoxib. All patients received at least four cycles of chemotherapy.

The incidence of HFS grade ≥1 was

higher in patients not receiving celecoxib (74.6% vs. 57.4%; P=0.034), and this held true for HFS grade ≥2 (29.6% and 14.7%; P=0.035). There was no statistically significant difference between these groups in the incidence of HFS grade 3. A multivariate Cox proportional hazards regression analysis pointed to celecoxib as the factor that influenced the incidence of HFS grade ≥1 (hazard ratio, 0.556; P=0.001).

EXPERT INSIGHT

Palmar-plantar erythrodysesthesia (PPE) or HFS is the most common side effect of capecitabine, an important chemotherapeutic agent in numerous solid tumors, especially colorectal and breast cancers. With the recent extension of the use of capecitabine in the adjuvant setting of colorectal cancer, the incidence of PPE is likely to increase (N Engl J Med 2005;352;26962704, PMID: 15987918).

Initial symptoms include dysesthesia and paresthesias in the palms,

Allyson Ocean, MD Assistant Professor of Medicine Weill Cornell Medical College Medical Oncologist Attending Physician in Gastrointestinal Oncology Jay Monahan Center for Gastrointestinal Health NewYork-Presbyterian/ Weill Cornell

PRN

Clinical Oncology News • November 2011

Adolescent and Young Adult Oncology

AYA continued from page 5 

you shouldn’t, not being kind by giving them the weekend off when they really need to get their chemo,” Dr. Sender said. AYAs also have unique psychosocial needs, may have fertility issues and will need long-term follow-up.

Future studies may tease out why differences in AYA oncology exist. “Why does a young woman in her 20s do worse than a woman who is 50 years of age with identical therapy? What is the difference? Is there a biological difference in the host or in the tumor?” Dr. Sender commented.

He said the next generation of practitioners needs to be trained to be aware fingers, and soles of the feet, and erythema, which may progress to burning pain with dryness, cracking, desquamation, ulceration, and edema. This condition greatly affects a patient’s quality of life, and in some cases results in patients not being able to work or perform normal daily activities. Treatment interruptions related to PPE may also impact the efficacy of the treatment regimen.

This single-institution study of 150 patients with adjuvant-treated stage II or III colorectal cancer, conducted in China, investigated celecoxib as a preventive agent for HFS. Prior studies have suggested inflammation as the potential causative factor of HFS, but this clearly remains to be determined (Oncology 2002;16:31-37, PMID: 12520638).

Although the present study showed a decrease in the incidence of grade ≥1 and grade ≥2 HFS in the celecoxib-treated group, the use of celecoxib, with its known potential cardiovascular toxicities, remains an investigational agent and not a standard of care in this setting. Therefore, a larger, US-based study needs to be conducted. Cancer and Leukemia Group B 80702, a large Phase III randomized trial soon to be open at Weill Cornell and accruing approximately 3,000 patients with stage III colon cancer, will investigate celecoxib’s role in polyp and tumor prevention. Possibly we will garner more information related to the effect of celecoxib on HFS toxicity in this large adjuvant population.

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

Clinicaloncology.com

of the issues surrounding AYAs, but they don’t necessarily need to know the details. “With Google and PubMed, you can bring yourself up to speed pretty quickly, if you know [how] to look for it.

You need to know that the word ‘young adult’ needs to be put into a search when you have a leukemia or a sarcoma,” said Dr. Sender.

mcmahonmedicalbooks.com

However, there is a need for specialists in AYA oncology. “There is a really rewarding career in doing young adult medicine,” Dr. Sender said.

For more information, visit www. seventyk.org and www.liebertpub.com/ JAYAO. —Kate O’Rourke

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Encyclopedia of Cancer, Third Edition

Manfred Schwab Springer, November 15, 2011

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The Encyclopedia of Cancer provides rapid access to focused information on all topics of cancer research for clinicians, research scientists and advanced students. Given the recent developments in the different fields of cancer research, the third edition is fully revised and expanded.

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Md Anderson Surgical Oncology Handbook

Barry Feig Lippincott Williams & Wilkins, November 15, 2011

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Care at the Close of Life: Evidence and Experience

Stephen McPhee; Margaret A. Winker; Michael W. Rabow; Steven Z. Pantilat; Amy J. Markowitz McGraw-Hill, October 4, 2010 This book offers evidence-based and clinical expert guidance on caring for patients with life-limiting illness, incorporating the words and perspectives of affected patients, their families and treating clinicians.

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Clinical Radiation Oncology: Expert Consult Online and Print: Third Edition

Leonard L. Gunderson Elsevier/Saunders, October 31, 2011 With thorough updates throughout, this edition provides the most comprehensive, authoritative and up-to-date information available for treating patients with cancer. From a multidisciplinary perspective, this book examines the therapeutic management of specific disease sites based on both singlemodality and combined-modality approaches—providing you with the well-rounded, cutting-edge guidance you need to offer the most effective treatments.

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Counseling About Cancer: Strategies for Genetic Counseling, Third Edition

Katherine Schneider John Wiley, December 6, 2011 Important scientific discoveries and ever-changing guidelines for how to identify and manage patients with hereditary cancer syndromes are constantly evolving. This edition features five new chapters on breast cancer, colon cancer, other solid tumors, clients and families and genetic test results and follow-up. This is the only reference for cancer genetics counselors who must quickly assimilate complex and everchanging data on the hereditary risk for cancer.

This portable handbook is a practical guide to established surgical oncology principles for each organ system. Maximize your surgical oncology skills with comprehensive coverage, multidisciplinary perspectives, proven therapeutic strategies, useful algorithms and recommended readings. Concise chapters illustrated with algorithms and line drawings outlining the essential elements of diagnosis, staging and clinical management of solid tumors treated in surgical practice.

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Md Anderson Manual of Medical Oncology, Second Edition

Hagop M. Kantarjian; Robert A. Wolff; Charles A. Koller McGraw-Hill, April 22, 2011 A hands-on desk reference for the practicing oncologist, this book details the personalized multidisciplinary approach to cancer management pioneered by The University of Texas MD Anderson Cancer Center. It is intended to bring a pragmatic approach to cancer management that can serve as a guide for oncologists around the world.

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Treatment Planning in Radiation Oncology

Faiz Khan Lippincott Williams & Wilkins, November 19, 2011 With the advent of computer technology and medical imaging, treatment planning in radiation oncology has evolved to a sophisticated process whereby imaging scanners are used to define target volume, simulators are used to outline treatment volume, and computers are used to select optimal beam arrangements for treatment. This book is designed to provide a comprehensive discussion of the clinical, physical and technical aspects of treatment planning.

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Year Book of Oncology 2011

Robert J. Arceci, MD, PhD Elsevier/Mosby, November 1, 2011 The Year Book of Oncology brings you abstracts of the articles that reported the year’s breakthrough developments in oncology, carefully selected from more than 500 journals worldwide. Expert commentaries evaluate the clinical importance of each article and discuss its application to your practice. There’s no faster or easier way to stay informed! co_onc1111

19

TASIGNA for adult patients with newly diagnosed Ph+ CML in chronic phase TASIGNA DOUBLED THE MAJOR MOLECULAR RESPONSE (MMR) RATE OF IMATINIB AT 12 MONTHS1

2 TASIGNA PATIENTS (<1%) PROGRESSED TO ACCELERATED PHASE OR BLAST CRISIS* (AP/BC) VS 17 IMATINIB PATIENTS (6%)1

MMR rates at 12 months1

Progression to AP/BC1 30

100

P<0.0001

60

25 20

44%

[95% CI, 38.4%-50.3%]

22%

40

[95% CI, 17.6%-27.6%]

Patients

Patients (%)

80

15 10

20

5

0

0

TASIGNA 300 mg bid (n=282)

n=17 (6%)

Imatinib 400 mg qd (n=283)

n=2 (0.7%) TASIGNA 300 mg bid (n=282)

Imatinib 400 mg qd (n=283)

ENESTnd study design: A randomized, controlled, open-label, multicenter Phase III trial of 846 patients with newly diagnosed Ph+ CML in chronic phase. Patients were randomized to receive either TASIGNA 400 mg bid (n=281), TASIGNA 300 mg bid (n=282), or imatinib 400 mg qd (n=283). The daily dose of imatinib could be escalated to 800 mg (400 mg bid), but no dose escalation was permitted with TASIGNA. A centralized laboratory was used for PCR testing.

The primary end point was MMR at 12 months. MMR was defined as ≤0.1% BCR-ABL/ABL by international scale measured by RQ-PCR, which corresponds to a ≥3-log reduction of BCR-ABL transcripts from standardized baseline.1,2

The distinct safety profile of TASIGNA supports its use in adult patients with newly diagnosed Ph+ CML in chronic phase1 ■ ■

Discontinuation for adverse events regardless of causality was observed in 7% of patients In ENESTnd, most side effects associated with TASIGNA did not lead to discontinuation in the first year

*Definition includes patients with clonal evolution and CML-related death. Time was censored at last assessment on treatment for patients without events.2,3

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

©2011 Novartis

Printed in USA

12/10

AM7-100030

Greater efficacy vs imatinib on every end point at 12 months TASIGNA (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of TASIGNA is based on major molecular response and cytogenetic response rates. The study is ongoing and further data will be required to determine long-term outcome.

Boxed WARNING and Additional Important Safety Information TASIGNA prolongs the QT interval. ECGs should be obtained to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter, as well as following any dose adjustments. Sudden deaths have been reported in patients receiving TASIGNA. TASIGNA should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to TASIGNA administration and should be periodically monitored. The concomitant use of strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine, and sotalol) and other drugs that may prolong the QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, and pimozide) should be avoided. The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, and phenobarbital). Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment as nilotinib exposure is increased in patients with impaired hepatic function.

■ ■ ■ ■

■ ■

■

■

■

Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia Caution is recommended in patients with a history of pancreatitis

The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia (see Boxed WARNING)

The exposure of nilotinib is reduced in patients with total gastrectomy Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption

Women of childbearing potential should avoid becoming pregnant while taking TASIGNA and should be advised of the potential hazard to the fetus if they do

In chronic phase patients, the most commonly reported nonhematologic adverse drug reactions (>10%) were rash, pruritus, nausea, fatigue, myalgia, headache, constipation, diarrhea, and vomiting

In accelerated phase patients, the most commonly reported nonhematologic adverse drug reactions (>10%) were rash, pruritus, and fatigue

References: 1. TASIGNA® (nilotinib) capsules prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; January 2011. 2. Saglio G, Kim D-W, Issaragrisil S, et al; for ENESTnd investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251-2259. 3. Data on file. Novartis Pharmaceuticals Corporation. East Hanover, NJ.

Please see brief summary of Prescribing Information on the following pages.

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

WARNING: QT PROLONGATION AND SUDDEN DEATHS Tasigna prolongs the QT interval (5.2). Sudden deaths have been reported in patients receiving nilotinib (5.3). Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome (4). Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored (5.2). Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided (5.7). Patients should avoid food 2 hours before and 1 hour after taking dose (5.8). A dose reduction is recommended in patients with hepatic impairment (5.9). ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments. (5.2, 5.3, 5.6, 5.12) 1 INDICATIONS AND USAGE 1.1 Newly Diagnosed Ph+ CML-CP Tasigna (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of Tasigna is based on major molecular response and cytogenetic response rates [see Clinical Studies (14.1) in the full prescribing information]. The study is ongoing and further data will be required to determine long-term outcome.

1.2 Resistant or Intolerant Ph+ CML-CP and CML-AP Tasigna is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of Tasigna is based on hematologic and cytogenetic response rates [see Clinical Studies (14.2) in the full prescribing information].

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing Tasigna should be taken twice daily at approximately 12 hour intervals and must not be taken with food. The capsules should be swallowed whole with water. No food should be consumed for at least 2 hours before the dose is taken and no food should be consumed for at least one hour after the dose is taken [see Boxed Warning, Warnings and Precautions (5.8), Clinical Pharmacology (12.3) in the full prescribing information].

For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in one teaspoon of applesauce (puréed apple). The mixture should be taken immediately (within 15 minutes) and should not be stored for future use [see Clinical Pharmacology (12.3) in the full prescribing information].

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

Newly Diagnosed Ph+ CML-CP The recommended dose of Tasigna is 300 mg orally twice daily [see Clinical Pharmacology (12.3) in the full prescribing information].

Resistant or Intolerant Ph+ CML-CP and CML-AP The recommended dose of Tasigna (nilotinib) is 400 mg orally twice daily [see Clinical Pharmacology (12.3) in the full prescribing information].

2.2 Dose Adjustments or Modifications QT interval prolongation: Table 1: Dose Adjustments for QT Prolongation ECGs with a QTc >480 msec

1. Withhold Tasigna, and perform an analysis of serum potassium and magnesium, and if below lower limit of normal, correct with supplements to within normal limits. Concomitant medication usage must be reviewed.

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

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

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

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

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

Table 2: Dose Adjustments for Neutropenia and Thrombocytopenia Newly diagnosed Ph+ CML in chronic phase at 300 mg twice daily Resistant or intolerant Ph+ CML in chronic phase or accelerated phase at 400 mg twice daily

ANC* <1.0 x 109/L and/or platelet counts <50 x 109/L

1. Stop Tasigna, and monitor blood counts 2. Resume within 2 weeks at prior dose if ANC >1.0 x 109/L and platelets >50 x 109/L 3. If blood counts remain low for >2 weeks, reduce the dose to 400 mg once daily

*ANC = absolute neutrophil count See Table 3 for dose adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases [see Adverse Reactions (6.1)].

Table 3: Dose Adjustments for Selected Non-hematologic Laboratory Abnormalities Elevated serum lipase or amylase ≥Grade 3

1. Withhold Tasigna, and monitor serum lipase or amylase 2. Resume treatment at 400 mg once daily if serum lipase or amylase return to ≤Grade 1

Elevated bilirubin ≥Grade 3

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

Elevated hepatic transaminases ≥Grade 3

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

Other Non-hematologic Toxicities If other clinically significant moderate or severe non-hematologic toxicity develops, withhold dosing, and resume at 400 mg once daily when the toxicity has resolved. If clinically appropriate, escalation of the dose back to 300 mg (newly diagnosed Ph+ CML-CP) or 400 mg (resistant or intolerant Ph+ CML-CP and CML-AP) twice daily should be considered. For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Test serum lipase levels monthly or as clinically indicated. For Grade 3 to 4 bilirubin or hepatic transaminase elevations, dosing should be withheld, and may be resumed at 400 mg once daily.

Test bilirubin and hepatic transaminases levels monthly or as clinically indicated [see Warnings and Precautions (5.4, 5.5), Use in Specific Populations (8.7) in the full prescribing information].

Hepatic Impairment If possible, consider alternative therapies. If Tasigna must be administered to patients with hepatic impairment, consider the following dose reduction: Table 4: Dose Adjustments for Hepatic Impairment (At Baseline) Newly diagnosed Ph+ CML in chronic phase at 300 mg twice daily

Mild, Moderate or Severe*

An initial dosing regimen of 200 mg twice daily followed by dose escalation to 300 mg twice daily based on tolerability

Resistant or intolerant Ph+ CML in chronic phase or accelerated phase at 400 mg twice daily

Mild or Moderate*

An initial dosing regimen of 300 mg twice daily followed by dose escalation to 400 mg twice daily based on tolerability

Severe*

A starting dose of 200 mg twice daily followed by a sequential dose escalation to 300 mg twice daily and then to 400 mg twice daily based on tolerability

*Mild = mild hepatic impairment (Child-Pugh Class A); Moderate = moderate hepatic impairment (Child-Pugh Class B); Severe = severe hepatic impairment (Child-Pugh Class C) [see Boxed Warning, Warnings and Precautions (5.9), Use in Specific Populations (8.7) in the full prescribing information].

Concomitant Strong CYP3A4 Inhibitors Avoid the concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit products may also increase serum concentrations of nilotinib and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, consider a dose reduction to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML-CP. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period should be allowed before the Tasigna dose is adjusted upward to the indicated dose. Close monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors [see Boxed Warning, Warnings and Precautions (5.2, 5.7), Drug Interactions (7.2) in the full prescribing information].

Concomitant Strong CYP3A4 Inducers Avoid the concomitant use of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). Patients should also refrain from taking St. John’s Wort. Based on the nonlinear pharmacokinetic profile of nilotinib, increasing the dose of Tasigna when co-administered with such agents is unlikely to compensate for the loss of exposure [see Drug Interactions (7.2) in the full prescribing information].

3 DOSAGE FORMS AND STRENGTHS 150 mg red opaque hard gelatin capsules with black axial imprint “NVR/BCR”.

200 mg light yellow opaque hard gelatin capsules with a red axial imprint “NVR/TKI”.

4 CONTRAINDICATIONS Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed Warning].

5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Treatment with Tasigna can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Perform complete blood counts every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated.

Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction [see Dosage and Administration (2.2)].

5.2 QT Prolongation Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner [see Adverse Reactions (6.1), Clinical Pharmacology (12.4) in the full prescribing information]. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated and following dose adjustments [see Warnings and Precautions (5.12)].

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

Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)].

Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided [see Warnings and Precautions (5.7, 5.8)]. The presence of hypokalemia and hypomagnesemia may further enhance this effect [see Warnings and Precautions (5.6, 5.12)].

5.3 Sudden Deaths Sudden deaths have been reported in patients with CML treated with nilotinib in clinical studies (n= 5,661; 0.3%). The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.

5.4 Elevated Serum Lipase The use of Tasigna can cause increases in serum lipase. Caution is recommended in patients with a previous history of pancreatitis. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically indicated.

5.5 Hepatotoxicity The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated [see Warnings and Precautions (5.12)].

5.6 Electrolyte Abnormalities The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia.

Electrolyte abnormalities must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)].

5.7 Drug Interactions The administration of Tasigna with agents that are strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning, Dosage and Administration (2.2), Drug Interactions (7.2) in the full prescribing information].

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

In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions (>10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting and myalgia. The common serious drug-related adverse reactions (>1%) were thrombocytopenia, neutropenia and anemia.

In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions (>10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (>1%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia.

Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steadystate was 10 msec. Increase in QTcF >60 msec from baseline was observed in 4.1% of the patients and QTcF of >500 msec was observed in 4 patients (<1%) [see Boxed Warning, Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.4) in the full prescribing information].

Discontinuation due to drug-related adverse reactions was observed in 16% of CML-CP and 10% of CML-AP patients.

Most Frequently Reported Adverse Reactions Tables 5 and 6 show the percentage of patients experiencing treatment-emergent adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of patients who received at least one dose of Tasigna are listed.

Table 5: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP (≥10% in Tasigna 300 mg twice daily or Gleevec 400 mg once daily groups)a

5.9 Hepatic Impairment Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment (at baseline) and QT interval should be monitored closely [see Boxed Warning, Dosage and Administration (2.2) and Use in Specific Populations (8.7) in the full prescribing information].

5.10 Total Gastrectomy The exposure of nilotinib is reduced in patients with total gastrectomy. More frequent follow-up of these patients should be considered. Dose increase or alternative therapy may be considered in patients with total gastrectomy [see Clinical Pharmacology 12.3) in the full prescribing information].

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

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

5.13 Use in Pregnancy There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Nilotinib caused embryo-fetal toxicities in animals at maternal exposures that were lower than the expected human exposure at the recommended doses of nilotinib.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should avoid becoming pregnant while taking Tasigna [see Use in Specific Populations (8.1) in the full prescribing information].

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

Patients with Newly Diagnosed Ph+ CML-CP

Sudden deaths [see Boxed Warning, Warnings and Precautions (5.3)] Elevated serum lipase [see Warnings and Precautions (5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Electrolyte abnormalities [see Boxed Warning, Warnings and Precautions (5.6)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Newly diagnosed Ph+ CML-CP The data below reflect exposure to Tasigna from a randomized trial in newly diagnosed patients with Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on treatment in the nilotinib 300 mg twice daily group was 18.6 months. The median actual dose intensity was 593 mg/day in the nilotinib 300 mg twice daily group.

The most common (>10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue and myalgia. Upper abdominal pain, alopecia, constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema and asthenia were observed less commonly (≤10% and >5%) and have been of mild to moderate severity, manageable and generally did not require dose reduction. Pleural and pericardial effusions occurred in 1% of patients. Gastrointestinal hemorrhage was reported in 0.4% of patients.

Increase in QTcF >60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of >500 msec.

The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (17%), neutropenia (15%) and anemia (7%) See Table 7 for Grade 3/4 laboratory abnormalities.

TASIGNA 300 mg twice daily

GLEEVEC 400 mg once daily

N=279

N=280

N=279

N=280

CTC Gradesb 3 / 4 (%)

All Grades

Skin and subcutaneous tissue disorders

Rash Pruritus Alopecia

36 19 10

16 7 5

<1 <1 0

1 0 0

Gastrointestinal disorders

Nausea Constipation Diarrhea Vomiting Abdominal pain upper Abdominal pain

19 15 14 9

38 4 37 22

1 0 <1 0

1 0 2 <1

15 12

10 9

<1 1

<1 <1

Nervous system disorders

Headache

28

16

3

<1

General disorders and administration site conditions

Fatigue Pyrexia Asthenia Edema, peripheral

19 10 11 8

14 12 9 17

<1 0 <1 0

1 0 0 0

Musculoskeletal and connective tissue disorders

Myalgia Arthralgia Muscle spasms Pain in extremity Back pain

14 15 10 9 12

16 13 29 13 10

<1 <1 0 0 <1

0 0 <1 <1 1

Respiratory, thoracic Cough and mediastinal disorders

12

9

0

0

Infections and infestations

Nasopharyngitis Upper respiratory tract infection

19

15

0

0

Eye disorders

Eyelid edema

13

9

0

0

1

14

0

<1

aExcluding bNCI

laboratory abnormalities Common Terminology Criteria for Adverse Events, Version 3.0 Table 6: Most Frequently Reported Non-hematologic Adverse Reactions in Patients with Resistant or Intolerant Ph+ CML Receiving Tasigna 400 mg Twice Daily (Regardless of Relationship to Study Drug) (≥10% in any Group)a CML-CP

CML-AP

N=321 Body System and Preferred Term

N=137

All Grades (%)

CTC Gradesb 3 / 4 (%)

All Grades (%)

CTC Gradesb 3 / 4 (%)

Skin and subcutaneous tissue disorders

Rash Pruritus Night sweat Alopecia

36 32 12 11

2 <1 <1 0

29 20 27 12

0 0 0 0

Gastrointestinal disorders

Nausea Constipation Diarrhea Vomiting Abdominal pain Abdominal pain upper Dyspepsia

37 26 28 29 15

1 <1 3 <1 2

22 19 24 13 16

<1 0 2 0 3

14 10

<1 <1

12 4

<1 0

Headache

35

2

20

1

Discontinuation due to adverse events regardless of causality was observed in 7% of patients.

Resistant or intolerant Ph+ CML-CP and CML-AP In the single open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=321; CML-AP=137) at the recommended dose of 400 mg twice daily.

The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range 1-1096) and 264 (range 2-1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range 151–1110) and 780 mg/day (range 150-1149), respectively and corresponded to the planned 400 mg twice daily dosing.

The median cumulative duration in days of dose interruptions for the CML-CP patients was 20 (range 1-345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range 1–234).

GLEEVEC 400 mg once daily

Body System and Preferred Term

Myelosuppression [see Warnings and Precautions (5.1)] QT prolongation [see Boxed Warning, Warnings and Precautions (5.2)]

TASIGNA 300 mg twice daily

Nervous system disorders

(continued)

Table 6: Most Frequently Reported Non-hematologic Adverse Reactions in Patients with Resistant or Intolerant Ph+ CML Receiving Tasigna 400 mg Twice Daily (Regardless of Relationship to Study Drug) (≥10% in any Group)a CML-CP

CML-AP

N=321 Body System and Preferred Term

Metabolism and Nutrition Disorders: Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia. Uncommon: dehydration, decreased appetite, increased appetite. Unknown frequency: hyperuricemia, gout, hypoglycemia, dyslipidemia.

N=137

All Grades (%)

CTC Gradesb 3 / 4 (%)

All Grades (%)

CTC Gradesb 3 / 4 (%)

General disorders and administration site

Fatigue Pyrexia Asthenia Edema, peripheral Myalgia

32 22 16 15 19

3 <1 0 <1 2

23 28 14 12 16

<1 2 1 0 <1

Musculoskeletal and connective tissue disorders

Arthralgia Muscle spasms Bone pain Pain in extremity Back pain Musculoskeletal pain

26 13 14 20 17

2 <1 <1 2 2

16 15 15 18 15

0 0 2 1 <1

11

<1

12

1

Respiratory, thoracic Cough and mediastinal Dyspnea disorders Oropharyngeal pain

27 15 11

<1 2 0

18 9 7

0 2 0

Infections and infestations

Nasopharyngitis Upper respiratory tract infection

24

<1

15

0

12

0

10

0

Metabolism and nutritional disorders

Anorexia

12

<1

15

<1

Psychiatric disorders Insomnia

12

1

7

0

Vascular disorders

10

2

11

<1

Hypertension

aExcluding

laboratory abnormalities bNCI Common Terminology Criteria for Adverse Events, Version 3.0 Laboratory Abnormalities Table 7 shows the percentage of patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of Tasigna.

Table 7: Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities Patient Population Resistant or Intolerant Ph+ Newly Diagnosed Ph+ CML-CP

CML-CP

CML-AP

TASIGNA 300 mg twice daily N=279 (%)

GLEEVEC 400 mg once daily N=280 (%)

TASIGNA 400 mg twice daily N=321 (%)

TASIGNA 400 mg twice daily N=137 (%)

Hematologic Parameters Thrombocytopenia Neutropenia Anemia Biochemistry Parameters Elevated lipase Hyperglycemia Hypophosphatemia Elevated bilirubin (total) Elevated SGPT (ALT) Hyperkalemia Hyponatremia Hypokalemia Elevated SGOT (AST) Decreased albumin

10 12 4

9 20 5

301 312 11

423 424 27

7 6 5 4 4 2 <1 <1 1 0

3 0 8 <1 3 1 <1 1 1 0

18 12 17 7 4 6 7 2 3 4

18 6 15 9 4 4 7 9 2 3

Biochemistry Parameters Hypocalcemia Elevated alkaline phosphatase Elevated creatinine

<1 0 0

0 <1 <1

2 <1 <1

5 1 <1

*NCI Common Terminology Criteria for Adverse Events, version 3.0 Thrombocytopenia: 12% were grade 3, 18% were grade 4 2CML-CP: Neutropenia: 16% were grade 3, 15% were grade 4 3CML-AP: Thrombocytopenia: 11% were grade 3, 32% were grade 4 4CML-AP: Neutropenia: 16% were grade 3, 26% were grade 4 1 CML-CP:

6.2 Additional Data from Clinical Trials The following adverse drug reactions were reported in patients in the Tasigna clinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (1%-10%), uncommon (0.1%-1%), and unknown frequency (single events). For adverse drug reactions listed under “Investigations”, very common events (≥10%), which were not included in Tables 5 and 6, are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category.

Infections and Infestations: Common: folliculitis. Uncommon: upper respiratory tract infection (including sinusitis, nasopharyngitis, pharyngitis), bronchitis, herpes virus infection, candidiasis pneumonia, urinary tract infection, gastroenteritis. Unknown frequency: sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis.

Neoplasms Benign, Malignant and Unspecified: Common: Skin papilloma. Unknown frequency: papilloma.

Blood and Lymphatic System Disorders: Common: febrile neutropenia, pancytopenia, lymphopenia. Unknown frequency: thrombocytosis, leukocytosis.

Immune System Disorders: Unknown frequency: hypersensitivity.

Endocrine Disorders: Uncommon: hyperthyroidism hypothyroidism. Unknown frequency: hyperparathyroidism secondary, thyroiditis.

Psychiatric Disorders: Common: depression, insomnia. Uncommon: anxiety. Unknown frequency: disorientation, confusional state, amnesia, dysphoria.

Nervous System Disorders: Common: dizziness, hypoesthesia, paresthesia. Uncommon: intracranial hemorrhage, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia.

Unknown frequency: brain edema, optic neuritis, peripheral neuropathy, lethargy, dysesthesia.

Eye Disorders: Common: eye hemorrhage, periorbital edema, eye pruritus, conjunctivitis, dry eye. Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, eye irritation. Unknown frequency: papilloedema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctival hemorrhage, conjunctivitis allergic, conjunctival hyperemia, ocular hyperemia, ocular surface disease, scleral hyperemia.

Ear and Labyrinth Disorders: Common: vertigo. Unknown frequency: hearing impaired, ear pain, tinnitus.

Cardiac Disorders: Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, pericardial effusion, coronary artery disease, cyanosis, cardiac murmur. Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, ejection fraction decrease.

Vascular Disorders: Common: hypertension, flushing. Uncommon: hypertensive crisis, hematoma. Unknown frequency: shock hemorrhagic, hypotension, thrombosis.

Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea, dyspnea exertional, epistaxis, cough, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing.

Gastrointestinal Disorders: Common: pancreatitis, abdominal discomfort, abdominal distension, dyspepsia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dysgeusia, dry mouth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, gastritis, hemorrhoids, hiatus hernia, rectal hemorrhage, sensitivity of teeth, gingivitis.

Hepatobiliary Disorders: Common: hepatic function abnormal. Uncommon: hepatitis, jaundice. Unknown frequency: cholestasis, hepatotoxicity, hepatomegaly.

Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis, dry skin. Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis, swelling of face. Unknown frequency: erythema nodosum, skin ulcer, palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy.

Musculoskeletal and Connective Tissue Disorders: Common: bone pain, musculoskeletal chest pain, musculoskeletal pain, flank pain. Uncommon: musculoskeletal stiffness, muscular weakness, joint swelling. Unknown frequency: arthritis.

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

Unknown frequency: renal failure, hematuria, urinary incontinence, chromaturia.

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

Unknown frequency: breast induration, menorrhagia, nipple swelling.

General Disorders and Administration Site Conditions: Common: pyrexia, chest pain, pain (including neck pain and back pain), chest discomfort, malaise. Uncommon: face edema, gravitational edema, influenza-like illness, chills. Unknown frequency: feeling hot, localized edema.

Investigations: Common: blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, weight decreased, weight increased. Uncommon: hemoglobin decreased, blood lactate dehydrogenase increased, blood urea increased. Unknown frequency: blood insulin increased, very low density lipoprotein increased, blood parathyroid hormone increased, blood pressure increased.

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

Cases of tumor lysis syndrome have been reported in Tasigna treated patients with resistant or intolerant CML. Malignant disease progression, high WBC counts and/or dehydration were present in the majority of these cases.

10 OVERDOSAGE Overdose with nilotinib has been reported, where an unspecified number of Tasigna capsules were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting, and drowsiness. In the event of overdose, the patient should be observed and appropriate supportive treatment given.

16 HOW SUPPLIED/STORAGE AND HANDLING Tasigna (nilotinib) 150 mg capsules are red opaque hard gelatin capsules, size 1 with black axial imprint “NVR/BCR”. Tasigna (nilotinib) 200 mg capsules are light yellow opaque hard gelatin capsules, size 0 with the red axial imprint “NVR/TKI.” Tasigna capsules are supplied in blister packs.

150 mg Carton of 4 blister packs of (4x28) ........................................................................................NDC 0078-0592-87 Blisters of 28 capsules............................................................................................................NDC 0078-0592-51 200 mg Carton of 4 blister packs of (4x28) ........................................................................................NDC 0078-0526-87 Blisters of 28 capsules............................................................................................................NDC 0078-0526-51 Each blister pack contains one folded blister card of 28 capsules each, for dosing two in the morning and two in the evening at 12 hour intervals over a 7 day period.

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

T2010-104 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland © Novartis

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936

SOLID TUMORS

Clinical Oncology News • November 2011

Breast

GONADAL continued from page 1 

The point of this editorial and the one to appear in the December issue is to suggest to the research community 2 simple manipulations of our adjuvant treatment programs that may help these women maintain fertility. One, which will be discussed in Part 2, is the substitution of other drugs for cyclophosphamide, because alkylating agents are the chemotherapy drugs known to be most toxic to the ovaries. The other, discussed here, focuses on gonadal protection and the delay or interruption of the 5 years of adjuvant tamoxifen that follow chemotherapy for women with hormone receptor (HR)-positive premenopausal breast cancer. Many women who are fertile at the start of those 5 years will be sterile when the 5 years are complete as a result of the natural aging processes that are likely accelerated by disease and chemotherapy.

Gonadal Protection Two contradictory studies of attempted gonadal protection published in 2011 were the springboard that led to this editorial. A 281-patient Italian randomized study published in July indicated that the gonadotropin-releasing hormone (GnRH) agonist triptorelin (Trelstar, Watson) affords some ovarian protection during modern chemotherapy.1 Alas, 4 months earlier, the 60-patient German ZORO (Zoladex Rescue of Ovarian Function) trial, which entered only women with HR-negative tumors, demonstrated no protection at all of menstrual function using a similar GnRH agonist, goserelin (Zoladex, AstraZeneca).2 The suggestions I have for further research in fertility preservation for adjuvant breast cancer patients will seem more attractive after a careful discussion of the Italian study.

Called PROMISE-GIM6, this prospective randomized trial had an unusual, even bizarre, end point: either a single menstrual period in the 12 months after chemotherapy or “premenopausal” levels of follicle-stimulating hormone (FSH) or estradiol measured once that year. Once the menstrual period occurred (or premenopausal hormone levels were recorded), HR-positive women (about 81%) resumed triptorelin for an additional 2 years, on the assumption that this would further reduce rates of recurrence, even though no data directly support this approach. In fairness, higher rates of relapse have been reported in women with estrogen receptor [ER]-positive tumors who resume menses after chemotherapy, even if they were given tamoxifen.3 Additionally, 2 to 3 years of ovarian suppression has been shown to delay or prevent breast cancer metastases as well as 6 months of CMF

Table 1. Likelihood of Chemotherapy-induced Ovarian Failure by Regimen Regimen

Chemotherapy-induced Ovarian Failure, %a,b

CMF x 6

30-80 (<40 y) 60-96 (≥40 y)

AC x 4

13-30 (<40 y) 57-63 (≥40 y)

FEC/FAC x 6-8

10-25 (<40 y) 80-90 (≥40 y)

AC x 4 followed by P x 4

35 (<40 y) 77 (≥40 y)

AC x 4 followed by T x 4

29-42 (<40 y) 66-75 (≥40 y)

TAC x 6

61.7

a b

The definition of ovarian failure might differ across studies.

Based on data from 14 trials.

A, doxorubicin; C, cyclophosphamide; E, epirubicin; F, 5-fluorouracil; M, methotrexate; P, paclitaxel; T, docetaxel Based on reference 8.

(cyclophosphamide, methotrexate, and 5-fluorouracil [5-FU]) chemotherapy, also supporting the assumption underlying this policy.

The end point of PROMISE-GIM6 is that single menstrual period within the year after chemotherapy year. The triptorelin given during chemotherapy increased the incidence of that first period within a year after cessation chemotherapy by 14%, and the primary end point is muddied by adding to that first period a “premenopausal” serum measurement of estradiol or FSH drawn at some point in the year in some of the patients, when we really do not know if these measurements are stable within a single patient, reproducible among the laboratories used, or predictive of subsequent ovarian function.

The effect of triptorelin on reducing amenorrhea was small compared with the effect of tamoxifen on increasing amenorrhea in this trial. Resumption of menses occurred in 93% of HR-negative patients who received triptorelin and 74% of those who did not. By contrast, among the HR-positive women who later received tamoxifen, menses resumed in 55% of those who were given immediate triptorelin and in 44% of those who did not receive immediate triptorelin. So tamoxifen prevented that first menstrual period in 30% of the no-triptorelin group, about twice the gain observed with concurrent triptorelin during chemotherapy.

The strange end point (one period), strange study design (induced amenorrhea for at least 2 years after that first period in HR-positive patients), and short follow-up lead me to conclude that the Del Mastro study provides no convincing evidence in favor of triptorelin ovarian protection during chemotherapy. The rest of the literature shows inconsistent benefits in terms of amenorrhea and is almost devoid of data to evaluate fertility.

The most encouraging paper on GnRH agonist ovarian protection is a 78-patient report from Egypt, in which patients were very young (median age 30 years) and were treated with unusual chemotherapy—IV FAC (cyclophosphamide, doxorubicin and 5-FU) (all IV) every 6 to 8 weeks for 6 cycles.4 Amenorrhea decreased from 67% to 10% by adding the GnRH agonist for seven 29-day doses. This is a huge reduction in what was a surprisingly high rate of amenorrhea in a very young population (one would have expected 30%40%). For the moment, I prefer to consider this report an outlier, but would love to see this studied again in similar young women with more conventional scheduling of CAF (cyclophosphamide, doxorubicin, and 5-FU). It would be of great interest if Dr. Badawy could tell us when the 35 women who did not have amenorrhea (because they got the GnRH agonist) eventually stopped menstruating.

A recent American Society of Clinical Oncology review of this subject5 and 2 editorials6,7 conclude that evidence is insufficient at present to recommend GnRH agonist therapy for ovarian protection during chemotherapy outside of controlled studies.

Complicating Factors These and other studies evaluating ovarian protection during adjuvant chemotherapy for breast cancer are complicated by a number of obvious issues that lead to small effects and inconsistent results: 1. Modern adjuvant chemotherapy for breast cancer uses shorter courses and lower doses of cyclophosphamide, the drug that is best established to compromise ovarian function and fertility. As more women escape sterility from cyclophosphamide, larger numbers are needed in each arm of comparative trials to demonstrate a benefit for the

minority that is still rendered sterile. In the Del Maestro study, for example, very few women (~2%-3%) received 6 months of classical CMF with oral cyclophosphamide. Most were given 3 to 6 doses of 600 mg/m2 of cyclophosphamide together with epirubicin and/or 5-FU followed by a taxane. These regimens produce much less amenorrhea than “classical CMF,” especially among younger patients (Table).8 Their relative effects on fertility (compared with amenorrhea) are still unclear.

2. Breast cancer is relatively rare in women who still want to get pregnant. Only 12% of the estimated 207,000 cases of breast cancer in the United States in 2010 were in women under the age of 45 years, and only 2% were in women under age 35. Fertility decreases substantially without chemotherapy by age 40.9 Breast cancer therapy itself takes about 12 months (counting surgery, radiation, and chemotherapy), and recovery of the “shocked” ovaries also takes some months. For a breast cancer patient undergoing chemotherapy, fertility beyond age 39 is unlikely unless assisted by in vitro techniques.

By my calculation (interpolated from Surveillance, Epidemiology, and End Results program), fewer than 12,500 American women with breast cancer are younger than 39 years old at diagnosis each year.10 Many of these women will have completed childbearing, some will have no interest in it, many will be socially disadvantaged and have other priorities they consider more pressing than fertility preservation, and it is likely that many will value their own survival above considerations of possible later fertility. This leaves relatively few women in whom to test methods of preserving fertility.

3. Until recently, fertility issues and quality of life for cancer survivors have failed to attract the attention, funding, recognition, and prestige attached to advances in patient survival and even to advances in the prevention of relapse.

4. Women with newly diagnosed breast cancers who are vitally concerned with fertility issues may be reluctant to allow randomization to treatments perceived as more likely to leave them sterile (ie, they will shun randomization to the control group).

5. Return of menstrual function and ovulation after chemotherapy is easy to study (although the thresholds for deciding when menses are regular are inherently arbitrary and variable between studies), but even regular menses do not mean that pregnancy is imminent or even possible.11 Because of social issues and see GONADAL, page 28 

25

HEMATOLOGIC DISEASE

Clinical Oncology News • November 2011

Multiple Myeloma

TRANSPLANT continued from page 1 

who had received induction treatment with lenalidomide and low-dose dexamethasone.

Investigators from the Italian Multiple Myeloma Network wanted to assess the role of ASCT in an era when successful therapy with agents such as the immunomodulatory agents thalidomide and lenalidomide (Revlimid, Celgene) and the proteasome inhibitor bortezomib (Velcade, Millennium) has significantly changed the treatment paradigm of MM and considerably improved patient outcomes.

In the study, 402 patients who had received four 28-day cycles of lenalidomide (25 mg on days 1-21) and lowdose dexamethasone (40 mg on days 1, 8, 15 and 22) as induction were randomized to receive either MPR (six 28-day cycles of melphalan 0.18 mg/kg on days

‘If you believe that PFS will give you longterm overall survival, obviously stay with transplanting.’

—Hani Hassoun, MD MPR group and patients in the MEL200 group. Sixty percent of those in the MPR group and 58% of those in the MEL200 group achieved at least a very good partial response (VGPR) (P=0.24); 20% of the patients in the MPR group and 25% of those in the MEL200 group achieved complete responses (P=0.55).

PFS after 26 months was 54% in the MPR group and 73% in MEL200 group (P=0.0002). The 18-month overall survival (OS) rate was similar between the two groups (91% MPR, 95% MEL200; P=0.073).

“A PFS advantage usually translates into overall survival with adequate fol-

low-up, if toxicity is not a problem, as in this case,” said Dr. Palumbo. He said that longer follow-up is needed to assess OS. Grade 3/4 toxicity—both hematologic (neutropenia and thrombocytopenia) and nonhematologic (mucositis, infections and gastrointestinal infections)—was significantly higher in the MEL200 group than in the MPR group.

The incidence of second tumors was 0.005% in both arms.

The available literature on melphalan-prednisone plus novel agents suggests that regimens containing novel agents might have the same impact on response rate as hematopoietic stem cell transplantation, noted Dr. Palumbo, but these findings indicate that “ASCT is still needed in multiple myeloma, despite novel agents.”

Although Dr. Palumbo acknowledges that the study showed that the toxicities of the MEL200 regimen were significantly higher, he said it “also confirmed that in the era of novel agents, high-dose chemotherapy followed by hematopoietic stem cell transplantation remains the essential strategy in younger patients with multiple myeloma.”

Only time will tell whether the improvement in PFS will translate into an improvement in OS, according to Hani Hassoun, MD, associate professor of medicine at Weill Cornell Medical College in New York City, who was not involved with the study. “There was a statistically significant difference in PFS in this trial, but it will take years to show a difference in overall survival.” He considered the similarity in the response rates “more surprising. … This means that either treatment would lead to similar response rates, and probably shows you that either way is acceptable.”

For a practicing oncologist, Dr. Hassoun said, “If you believe that PFS will give you long-term overall survival, obviously stay with transplanting. But transplant is just one modality among others.

In 10 years’ time, there will probably be

agency also has approved the drug to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy (ADT) for non-metastatic prostate cancer. The drug is the first therapy approved by the FDA for cancer treatment–induced bone loss in patients undergoing hormone ablation therapy.

Approval was based on two Phase III clinical trials. The first was a randomized, double-blind, placebo-controlled, multinational study involving 1,468 men with non-metastatic prostate cancer undergoing ADT. The second was a double-blind, placebo-controlled, multinational study involving 252 postmenopausal women with breast cancer

receiving AI therapy.

In men, bone mineral density (BMD) was significantly higher at the lumbar spine in patients treated with denosumab for two years than with placebo (5.6% vs. –1%; 95% confidence interval [CI], 6.2%-7.1%; P<0.0001). Additionally, after three years of treatment with denosumab, differences in BMD were 7.9% at the lumbar spine, 5.7% at the (total) hip and 4.9% at the femoral neck.

The incidence of new vertebral fractures was 3.9% in the placebo-treated men and 1.5% in the denosumab-treated men, representing a relative risk reduction of 62% (P=0.0125).

In women, BMD was higher at 12 months at the lumbar spine in patients

‘In the era of novel agents, high-dose chemotherapy followed by hematopoietic stem cell transplantation remains the essential strategy in younger patients with multiple myeloma.’

—Antonio Palumbo, MD 1-4, prednisone 2 mg/kg on days 1-4 and lenalidomide 10 mg on days 1-21) or MEL200 (tandem melphalan 200 mg/ m2 with stem cell support). The primary end point was PFS. Patient characteristics were well balanced between the two groups.

According to lead investigator Antonio Palumbo, MD, from the Division of Hematology of the University of Torino, the response rates were not significantly different between patients in the

100

Melphalan-prednisone plus lenalidomide High-dose melphalan followed by autologous stem cell transplant

80

Patients, %

26

60

73 54

40 20 0

Figure. PFS after 26 months in newly diagnosed patients with multiple myeloma after induction therapy.a a

i nduction therapy with lenalidomide and low-dose dexamethasone

PFS, progression-free survival

enough anti-myeloma medications that transplant will be used less often and may be regarded as an antiquated therapy.” There is no question that transplantation is currently an efficient and effective treatment, he said. But in the long run, new medications are the future of myeloma. “Ten years ago, the median survival for myeloma patients was three years. With novel therapies, median survival is now probably around nine or more years,” said Dr. Hassoun. “In the next 10 years, we will hopefully have a drug to cure the disease, or at least to sustain patients even longer than we now can.”

—Mark Fuerst Dr. Palumbo reports receiving honoraria from Amgen, Celgene, Janssen-Cilag and Merck, and is on the scientific advisory boards of Celgene and Janssen-Cilag.

FDA NEWS

Denosumab Receives Two New Indications

T

he FDA has approved denosumab (Prolia, Amgen) to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor (AI) therapy for breast cancer. The

treated with denosumab than placebo (+4.8% vs. –0.7%; 95% CI, 4.8-6.3; P<0.0001). Additionally, after two years of treatment with denosumab, differences in BMD were 7.6% at the lumbar spine, 4.7% at the (total) hip and 3.6% at the femoral neck.

The most common (per-patient incidence >10%) adverse reactions reported with denosumab in these two clinical trials were arthralgia and back pain.

In the prostate cancer trial, men treated with denosumab had a greater incidence of cataract adverse events. Pain in the extremities, musculoskeletal pain and hypocalcemia also have been reported as side effects of treatment with denosumab.

POLICY & MANAGEMENT

Clinical Oncology News • November 2011

Pharmacy

SHORTAGE continued from page 1 

that are in chronically short supply in the United States.

On Aug. 18, Dr. Dinolfo enrolled the patient in Doxil C.A.R.E.S. Physician Access Program, a rationing program established by Janssen Products. “They started putting people on a waiting list on Aug. 9. I have no idea how many people are ahead of her. There’s no drug available right now and they have no idea when they will have any,” Dr. Dinolfo said. On Sept. 7, the patient received the last dose of Doxil that Premiere Oncology had in its pharmacy. She has not been treated with the drug since then.

This is increasingly a common scenario.

The nationwide chemotherapy drug shortage crisis, which Clinical Oncology News reported in detail in January, has grown worse throughout the year. In an FDA public workshop held on Sept.

26, Erin Fox, PharmD, director of the Drug Information Service at the University of Utah, in Salt Lake City, reported 204 new drug shortages encompassing a wide variety of drug classes in 2011.

As of Sept. 30, that number had hit 213— surpassing 2010’s total of 211, with more than one-fourth of the year remaining.

In 2010, 23 of those shortages were cancer drugs. As of September, 22 new cancer drug shortages have been reported so far this year, and one-fourth of the year still remains.

In addition to Doxil, two other drugs that are causing particular distress as they run short are paclitaxel and 5-fluorouracil (5-FU), largely because of the prevalence of the diseases that they are used to treat, including breast, colon, testicular and small cell lung cancers. “It’s really getting to the point where standard of care or first-line therapies and even second-line cancer drugs are extremely scarce,” said Bona Benjamin, RPh, director of medication use quality improvement with the American Society of Health-System Pharmacists. “We’re hearing daily about the seriousness of cancer drug shortages from both patients and the providers who care for them.”

Ali McBride, PharmD, clinical pharmacy specialist at Barnes-Jewish Hospital in St. Louis, is constantly checking in with his suppliers to determine the availability of common chemotherapy and supportive care drugs, which fluctuates on a daily basis. “What used to be really bad has now turned into mayhem,” he said. “As a large institution we’re doing better, but a lot of the smaller infusion centers and hospitals literally can’t get anything.”

Skipping doses is becoming more and more frequent. “I’ve heard that other sites that have had ovarian cancer patients on Doxil with carboplatin are omitting the Doxil,” Dr. McBride said.

“Or they’ve changed over to the generic

doxorubicin, which is also on shortage, and it’s not liposomal. Busulfan and even carmustine, which we use for transplant patients, are on shortage. Ontak [denileukin diftitox], used to treat peripheral T-cell lymphoma, is on back order and we don’t know when we’ll get any.”

Earlier this year, Dr. McBride and other pharmacists discussed the tough decisions that had to be made in rationing chemotherapy drugs—putting patients with curable disease at the top of the waiting list. Now, it’s even worse. “In some cases,

effects are also problems. “If you’ve run out of 5-FU, the main drug used in combination therapy for colorectal cancer, you might go to capecitabine, but there are increased side-effect profiles and also payment issues with an oral drug,” said Dr. McBride.

Some practices are switching from paclitaxel to docetaxel because the first taxane is entirely unavailable—at a big increase in cost. “I know a practice in Orange County [California] that treats ovarian cancer almost exclusively, and

‘We could benefit from guidelines from the National Comprehensive Cancer Network or American Society for Clinical Oncology as to how to handle drug shortages.’

—Ali McBride, PharmD we have lost the ability to treat patients who have a curable disease state,” he said.

For example, all-trans retinoic acid (Vesanoid, Roche) is a chemotherapy drug that’s used in combination with other therapies to treat acute promyelocytic leukemia in patients who have not responded to other treatments. “It has an 85% to 90% cure rate,” said Dr. McBride.

“But last week we ran out of that.”

In addition to chemotherapy drugs, supportive medications and supplies like antibiotics and electrolytes are almost completely out at many smaller centers. “It’s a new shortage every day,” said Michael Neuss, MD, past chair of the American Society of Clinical Oncology’s Clinical Practice Committee. “Yesterday, it was Mesna, a chemoprotectant.”

Unsatisfactory Substitutions Substitutions are sometimes possible, of course, but as Clinical Oncology News pointed out in previous coverage of this issue, they raise the risk for medical errors due to issues such as dosage conversion—and cost and new side

has had to switch 100% of its patients [to docetaxel],” said Dr. Dinolfo. “That makes the docetaxel people happy, but it’s much more expensive.”

The University of Texas MD Anderson Cancer Center in Houston has managed to keep an adequate supply of 5-FU and paclitaxel, but like other centers, has its patients on a waiting list for Doxil. MD Anderson maintains a pharmacy alert system: Green means there is a reasonable supply of the drug, yellow means the drug is in limited supply and usage should be restricted and red means they can get no more of the drug. At press time, MD Anderson was at level green on some drugs that other centers are short on, like paclitaxel, but had limited supplies of daunorubicin and was completely out of Doxil.

“It’s very stressful for the patients, particularly the ones who’ve had a response to therapy,” said JoAnn Lim, PharmD, clinical pharmacy specialist in the Department of Investigational Cancer Therapeutics at MD Anderson. “To then take a drug away from them—they

think, ‘oh my god, is that going to change the outcome of my disease?’ The physicians have had to work very hard to reassure patients that they are doing everything they can and that they have found the best substitute.”

But it’s often not the best substitute— just the only other option. On Sept. 27, the Kansas City Star told the story of Bryan Schearer, a 20-year-old man with Hodgkin’s lymphoma who had been responding well to a four-drug chemotherapy cocktail that included bleomycin—until that drug vanished from the pharmacy shelves. Instead of the chemotherapy, which offered a 90% cure rate, he has been forced to undergo a grueling and risky stem cell transplant.

Sara S. Kim, PharmD, oncology pharmacy clinical coordinator at Mount Sinai Medical Center, New York City, says that her institution is in the process of developing a contingency protocol in case of a shortage, regarding what needs to be done, who needs to be contacted and how the decision will be made to impose restrictions. “After much discussion, there was even a suggestion to have our Ethics Committee involved in the decision-making process,” she said. “The problem is we don’t usually get informed of the drug shortage until we are down to a less than seven-day supply, which does not give us enough time to come up with a contingency plan at that point.”

It’s not just current patients who are threatened. The shortage has called a halt to literally hundreds of clinical trials, potentially slowing the pipeline for future therapies. In written testimony submitted to a Sept. 23 hearing on the crisis before the House Energy and Commerce Committee, Howard Koh, MD, MPH, assistant secretary of health for the Department of Health and Human Services, said that more than 300 studies funded by the National Cancer Institute involve a drug that is in short supply.

“The inability to obtain adequate supplies of these cancer drugs for research has resulted in promising clinical trials being suspended indefinitely and patient enrollment being abruptly halted,” Dr. Koh wrote in his testimony.

A Web of Confusion “It’s easy to see how the vicious cycle happens: You hear there’s going to be a shortage, people start overbuying because they want to protect themselves, then there really is a shortage, and then a gray market pops up,” said Dr. Neuss.

More than half of the 549 U.S. hospitals responding to a survey this summer by the Institute for Safe Medication Practices, reported buying one or more drugs from gray market vendors; 7% of those doing so reported side effects or other problems.

“It would be best for our practice if all manufacturers had a two-year supply on hand, but smart manufacturing practice see SHORTAGE, page 30 

27

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SOLID TUMORS

Clinical Oncology News • November 2011

Breast

GONADAL

node-positive breast cancer: International Breast Cancer Study Group Trial 13-93.

J Clin Oncol. 2006;24(9):1332-1341, PMID: 16505417.

continued from page 25 

age-related declines in fertility, most women will not be able to get pregnant after breast cancer treatment even if ovarian function is not impaired. Furthermore, women who resume menses after chemotherapy suffer an early menopause compared with women not exposed to chemotherapy. Among women younger than age 40 years who resumed menses after 6 or 7 months of classical CMF (none of whom received tamoxifen in the IBCSG [International Breast Cancer Study Group] trial) median age of menopause was 41 years, compared with 44 years for those with no CMF.12 I can find no data on the age of menopause after chemotherapy among younger women who resume menstruating after treatment with more modern chemotherapy regimens (AC [cyclophosphamide, doxorubicin], AC followed by a taxane, TAC [taxotere, adriamycin, and cyclophosphamide], FAC, or FEC [5-FU, epirubicin, and cyclophosphamide], alone or followed by a taxane). I would guess that the lower cumulative cyclophosphamide used in some of these regimens would be less damaging to ovarian function over the long term, but it would be preferable to know the data.

6. The pharmaceutical industry, to my knowledge, has no candidate drugs for fertility preservation (a small market in any case), so this source of funding for research is not available.

Tamoxifen and Pregnancy The literature on tamoxifen’s effects on fertility, ovarian function, implantation, and the embryo and fetus is limited and very difficult to interpret. The confusion has led most experts to recommend that patients avoid getting pregnant while tamoxifen or its metabolites are present.

With respect to fertility, I could find no data on direct effects of tamoxifen, although it does substantially reduce menstrual function. High estradiol and low FSH levels have been observed in over a third of amenorrheic women under age 55 on tamoxifen.1,13,14 Some amenorrheic women on tamoxifen have very high estrogen levels, probably from a direct effect on the ovaries.11,15 Data on the effects on the fetus also are conflicting. The data on tamoxifen inducing abortions are inconsistent. It clearly induces some abortions, and is as effective as methotrexate when given with misoprostol.16-18 With respect to fetal abnormalities, Barthelmes reviewed the published and unpublished literature in 2004, and found 6 reported cases of tamoxifen administration at conception and in the first trimester, with 4 healthy babies and 1 with abnormalities likely related to tamoxifen.19 At the

4. Badawy A, Einashar A, El-Ashry M, Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapyinduced ovarian damage: prospective randomized study. Fertil Steril. 2009;91(3):694697, PMID: 18675959.

5. Griggs JJ, Somerfield MR, Anderson H, et al. American Society of Clinical Oncology endorsement of the cancer care Ontario practice guideline on adjuvant ovarian ablation in the treatment of premenopausal women with early-stage invasive breast cancer. J Clin Oncol. 2011;29(29):3939-3942, PMID: 21900112.

6. Rugo H, Rosen MP. Reducing the long-term effects of chemotherapy in young women with early-stage breast cancer. JAMA. 2011;306(3):312-314, PMID: 21771995.

7. Partridge A. J Clin Oncol. 2011. In press.

Dr. Vogl with 3-1/2 year-old Luke, who was conceived while his mother was on a hiatus from tamoxifen. After being diagnosed at age 34, she received dose-dense AC (doxorubicin plus cyclophosphamide) followed by dose-dense paclitaxel, followed by tamoxifen and trastuzumab (Herceptin, Genentech) for one year.

time, AstraZeneca (which then marketed tamoxifen) had data on 37 pregnancies associated with tamoxifen—19 healthy babies, 10 with fetal or neonatal disorders, and 8 elective terminations.

Barthelmes et al suggest that tamoxifen administration may be relatively safe during pregnancy, and should be studied.19 Until such studies are done, it seems prudent to avoid using tamoxifen in women trying to get pregnant both because it probably reduces fertility and likely produces some excess rate of deformity in the offspring, and could produce late onset of cancer in the offspring, such as was seen in females exposed to diethylstilbestrol during gestation.

Altering Tamoxifen Schedule To Allow Conception Approximately 75% of breast cancers in women under age 39 are HR-positive, and 5 years of tamoxifen therapy is the mainstay of adjuvant therapy for these women. To maximize the fertility of women undergoing tamoxifen treatment, we should consider delaying, shortening, or interrupting the standard 5 years of tamoxifen therapy. Given the advanced age (for conception) of most women with breast cancer, adding 5 years before they are allowed to attempt conception will leave most unable to conceive.

To that end, the Breast International Group and North American Breast Cancer Group are about to launch a collaborative trial in which conception is attempted after a 2-year course of tamoxifen has “washed out.”20 This seems a good plan for women younger than age 36 at diagnosis, but probably will result in few pregnancies among those aged 36 or older because their fertility will probably be very low by the time they complete their 2-year tamoxifen regimen, even if they had not received chemotherapy.11,19

Alternatively, a woman older than age 36 who is at relatively low risk for breast cancer metastasis, who very much wants a biological child, and cannot afford or arrange oocyte harvesting and freezing of oocyte or embryo (with success rates of up to 60% reported for each), could discuss with her oncologist deferring tamoxifen for 18 months to allow her to bring a pregnancy to term before starting the tamoxifen. However, this patient must recognize that there is some increased risk for breast cancer relapse or metastasis as a result. A prospective trial looking at the rates of term pregnancy and distant relapse of breast cancer would help doctors and patients better weigh these competing concerns.

Several of my colleagues are afraid that delaying or interrupting tamoxifen will reverse some of the progress we have made against breast cancer deaths. It probably will, but we know that delayed endocrine therapy is clearly of value, so that all the benefit is not lost by delay. The patient should be allowed to decide after appropriate warnings by her physicians.

Occasionally, the results are gratifying (see picture).

References 1. Del Mastro L, Boni L, Michelotti A, et al.

Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial. JAMA. 2011;306(3):269-276, PMID:21771987.

2. Gerber B, von Minckwitz G, Stehle H, et al. Effect of luteinizing hormone-releasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: the GBG 37 ZORO study. J Clin Oncol.

2011;29:2334-2341, PMID: 21537042.

3. International Breast Cancer Study Group, Colleoni M, Gelber S, Goldhirsch A, et al.

Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph

8. Stearns V, Schneider B, Henry NL, Hayes DF, Flockhart DA. Breast cancer treatment and ovarian failure: risk factors and emerging genetic determinants. Nat Rev Cancer.

2006;6(11):886-893, PMID: 17036039.

9. teVelde, ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update. 2002;8(2):141-154, PMID: 12099629.

10. National Cancer Institute. SEER Stat Fact Sheets: Breast. http://seer.cancer.gov/ statfacts/html/breast.html. Accessed October 19, 2011.

11. Oktay K, Oktem O, Reh A, Vahdat L. Measuring the impact of chemotherapy on fertility in women with breast cancer. J Clin Oncol.

2006;24(24):4044-4046, PMID: 16921067.

12. Partridge A, Gelber S, Gelber RD, Castiglione-Gertsch M, Goldhirsch A, Winer E. Age of menopause among women who remain premenopausal following treatment for early breast cancer: long-term results from International Breast Cancer Study Group Trials V and VI. Eur J Cancer. 2007 Jul;43(11):1646-1653, PMID: 17512721.

13. Buijs C, Willemse PH, de Vries EG, et al.

Effect of tamoxifen on the endometrium and the menstrual cycle of premenopausal breast cancer patients. Int J Gynecol Cancer.

2009;19(4):677-681, PMID: 19509569.

14. Ganz PA, Land SR, Geyer CE Jr, et al.

Menstrual history and quality-of-life outcomes in women with node-positive breast cancer treated with adjuvant therapy on the NSABP B-30 trial. J Clin Oncol.

2011;29(9):1110-1116, PMID: 21300930.

15. Mourits MJ, de Vries EG, ten Hoor KA, van der Zee AG, Willemse PH. Beware of amenorrhea during tamoxifen: it may be a wolf in sheep’s clothing. J Clin Oncol.

2007;25(24):3787-3788, PMID: 17704431.

16. Wiebe, ER. Tamoxifen compared to methotrexate when used with misoprostol for abortion. Contraception. 1999; 59(4):265270, PMID: 10457872.

17. Jain JK, Meckstroth KR, Park M, Mishell DR Jr. A comparison of tamoxifen and misoprostol to misoprostol alone for early pregnancy termination. Contraception.

1999;60(6):353-356, PMID: 10715370.

18. Mishell DR Jr, Jain JK, Byrne JD, Lacarra MD. A medical method of early pregnancy termination using tamoxifen and misoprostol. Contraception. 1998;58(1):1-6, PMID: 9743889.

19. Barthelmes L, Gateley CA. Tamoxifen and pregnancy. Breast. 2004;13(6):446-451, PMID: 15563850.

20. Pagani O, Partridge A, Korde L, et al. Pregnancy after breast cancer: if you wish, ma’am. 2011;129(2):309-317, PMID: 21698406.

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POLICY & MANAGEMENT

Clinical Oncology News • November 2011

Pharmacy

SHORTAGE continued from page 27 

has you decrease your total inventory.”

With many centers starting to hoard product—perhaps understandably—it is taking longer and longer to resolve shortages. In the meantime, whether you get your chemotherapy or not has a lot to do with where you live and where you’re treated. “Each company can choose how they distribute a product that’s short,” said Dr. Fox. “They may have an allocation plan, something in place to prevent people from ordering large amounts—and that may be better overall for patients and clinicians [because] then everyone will be able to get at least some. But if a company has nothing like that in place, supply will be spotty. Some places will get huge amounts and hang on tightly, and others won’t get anything at all.”

That’s because although the FDA has authority over drug safety, it has no control over drug distribution. “There’s no standard method in this country for how drugs are distributed,” Dr. Fox said.

Another part of the problem with crafting a solution to the drug shortage problem lies in the complex web of drug company relationships. As a brand-name drug, Doxil would not have been expected to suffer from the short supply issues that many generic drugs have. But Janssen Products contracted with generic supplier Bedford to make the drug.

“Bedford is a company that has had a tremendous amount of problems, so this isn’t surprising,” said Dr. Fox. “It’s actually

very difficult to figure out which products are contract-manufactured or not. I ask all suppliers what measures they have to prevent shortages, such as manufacturing redundancy and business continuity, and now I’ve started asking if they use contract manufacturers or not. Of course, they often decline to tell me and say it’s proprietary.” (Janssen Products has found a potential alternative supplier.)

At two recent forums on the issue— the Sept. 23 Congressional hearing and a meeting at the FDA on Sept. 27—fierce debate continued about these factors and other contributing causes behind the shortage. Some (mostly manufacturers) blamed over-regulation by the federal government, whereas others pointed to profit margins. “The profit margins on generic drugs are quite small compared with brand-name drugs, and over time, some companies may choose to discontinue production of generic drugs due to lack of profitability,” Dr. Koh said in his testimony.

A Prescription There’s no one single culprit, said Dr. Fox, and there will be no single solution.

Instead, the experts Clinical Oncology News spoke with offer several possible strategies to help ease the pain: • Pass the Klobuchar-DeGette bill (Senate Bill 296/House Resolution 2245), which would require drug manufacturers anticipating a shortage to immediately notify the FDA. “The FDA has told us directly that, when notified of an impending shortage in advance, they’ve been able to prevent shortages,” said Ms. Benjamin. On Oct.

31, President Barack Obama signed an executive order similar to this proposed law. The order instructs the FDA to broaden reporting of manufacturing discontinuations, speed up the review process of applications to change production of drugs that face shortages and give the Department of Justice any information on shortages that have led market participants to stockpile the affected drugs or sell them at exorbitant prices. Because this order lacks the authority of law, however, its impact is uncertain.

• Establish a federal stockpile of “medically necessary” drugs. Dr. McBride suggested a list of perhaps 100 to 200 critical medications. “It will be expensive for the government to do, but if we continue on this route, what’s the alternative?”

• Establish practice guidelines. Currently, Dr. McBride said, oncologists and oncology pharmacists are flying blind and making up substitution practices as they go. “We could benefit from guidelines from the National Comprehensive Cancer Network or American Society for Clinical Oncology as to how to handle drug shortages,” he noted. “For example, there are no guidelines for how and what to substitute for Doxil in the face of a shortage. It would help out a lot of institutions, particularly smaller ones that may not have the manpower or facilities to appropriately determine what to do instead. People are implementing practices based on journal articles, but there are no existing guidelines as

Clinical Oncology News highlights key studies from the journals to help you stay up to date.

We hope you find this a useful tool.

—Gina Shaw

This group, as well as others, have demonstrated that these cells are resistant to imatinib, nilotinib and dasatinib, and can be detected in patients on continued from page 10  imatinib therapy. These studies, although only looking at patients who had been on imatinib for up to two years, were consistent with early clinical experience that discontinuation of imatinib leads to relapse, suggesting that treatment should continue indefinitely. However, the recently reported STIM (Stop Imatinib) trial demonstrated that in patients who have been on therapy for at least three years, and in complete molecular remission for at least two years, discontinuation of imatinib did not lead to relapse in approximately 40% within a median followup of 17 months (Lancet Oncol 2010;11:1029-1035, PMID: 20965785).

This observation led this group to examine bone marrow samples from patients at their center who had been on imatinib therapy for at least four years and had cryopreserved bone marrow. Of the 20 patients studied, all were in complete cytogenetic remission, and 19 were in complete molecular remission. However, all patients were found to have detectable levels of the BCR-ABL transcript in mononuclear cells by a sensitive PCR technique. By careful flow sorting followed by serial dilution and fluorescence in situ hybridization experiments, the authors demonstrate that the CD34+CD38-positive fraction is enriched for BCR-ABL-positive cells (approximately 0.6% vs 0.2% in the differentiated CD34+CD38-positive cells), supporting the notion that these cells are more resistant to imatinib. When these CD34+CD38-positive cells were implanted into immunodeficient mice, they gave rise to BCR-ABL-positive leukemia.

The authors conclude that using sensitive techniques, the majority of patients, even those on long-term imatinib therapy, can be demonstrated to retain the BCR-ABL-positive clone, preferentially within the stem cell compartment. They caution that a direct comparison to the STIM study is difficult because the patient populations may have been different; for example, the length of CMR is not provided in the current study.

Therefore, the clinical significance of these findings remains unclear, but the study underscores the need, both in leukemia as well as in other malignancies, for new therapies aimed at eradicating, rather than suppressing, the malignant clone.

CML

Having trouble keeping up with all of the oncology and medical journals that cross your desk?

to how to make substitutions or dose reductions in a drug shortage situation.” According to Cindy O’Bryant, PharmD, clinical oncology specialist, University of Colorado Cancer Center, in Denver, this is a good idea, but it may not be realistic. “In some cases, this may be possible, but if the trials to support such substitution are not done, then these types of decisions cannot definitively be made,” Dr. O’Bryant said. “In such a case, these organizations can provide guidance for how to set up rationing but not provide guidelines for substitutions.”

• Allow emergency extended dating. “I have a drug that in the bottle, in the box, in the fridge, is good until 2013,” said Dr. Dinolfo. “It comes in a 40-mg vial. I am going to use 32 mg today, so there’s 8 mg hanging out there that we might not be able to use. If I were the manufacturer, I’d put out an emergency email granting extended dating—say, 30 days—providing that the sites are accessing and storing the bottle in a sterile fashion, refrigerating it and protecting it from light.

It would at least make it easier for us to roll over supplies.”

• Provide tax incentives for the production of certain medically necessary drugs that are difficult to substitute— such as chemotherapy drugs. The Prescription Drug User Fee Act is up for review in 2012, and the FDA meeting included some discussion of the possibility of pushing through such incentives as a part of that review.

BRIEF SUMMARY OF PRESCRIBING INFORMATION WARNING: QT PROLONGATION FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided [see Warnings and Precautions].

INDICATIONS AND USAGE FARESTON® is an estrogen agonist/antagonist indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.

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

DOSAGE FORMS AND STRENGTHS Tablet is 60 mg, round, convex, unscored, uncoated, and white, or almost white, identified with TO 60 embossed on one side.

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

QT Prolongation, Hypokalemia, Hypomagnesemia Toremifene should not be prescribed to patients with congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia.

WARNINGS AND PRECAUTIONS Prolongation of the QT Interval Toremifene has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death.

Toremifene should be avoided in patients with long QT syndrome. Caution should be exercised in patients with congestive heart failure, hepatic impairment and electrolyte abnormalities. Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. Drugs that prolong the QT interval should be avoided. In patients at increased risk, electrocardiograms (ECGs) should be obtained at baseline and as clinically indicated [see Drug Interactions and Clinical Pharmacology].

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

Tumorigenicity Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available.

Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in animals treated with toremifene [see Nonclinical Toxicology].

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

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

Use in Pregnancy Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

Women of Childbearing Potential FARESTON is indicated only in postmenopausal women. However, premenopausal women prescribed FARESTON should use effective non-hormonal contraception and should be apprised of the potential hazard to the fetus should pregnancy occur.

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

Clinical Trials Experience Adverse drug reactions are principally due to the antiestrogenic actions of FARESTON and typically occur at the beginning of treatment.

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

North American Study FAR60 n = 221

TAM20 n = 215

Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4% Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse reactions (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction).

Serious adverse reactions occurring in at least 1% of patients receiving FARESTON in the three major trials are listed in the table below.

Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively [see Clinical Studies].

Adverse Reactions Cardiac Cardiac Failure Myocardial Infarction Arrhythmia Angina Pectoris Ocular* Cataracts Dry Eyes Abnormal Visual Fields Corneal Keratopathy Glaucoma Abnormal Vision/Diplopia Thromboembolic Pulmonary Embolism Thrombophlebitis Thrombosis CVA/TIA Elevated Liver Tests** AST Alkaline Phosphatase Bilirubin Hypercalcemia

North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) 1 (<1) 3 (1.5) -

1 1

(10) (9) (4) (2) (1.5)

16 (7.5) 16 (7.5) 10 (5) 2 (1) 2 (1) -

1 -

(2)

2 (1) 2 (1) 1 (<1) -

1 1 1 -

(<1) (<1) (<1)

4 24 4 6

30 16 2 1

(19) (10) (1) (<1)

2 2 -

(1) (1)

22 20 8 4 3 4 1

(<1)

11 (5) 41 (19) 3 (1.5) 6 (3)

(2) (11) (2) (3)

(<1) (<1)

(<1)

1 (<1) 2 (1) -

2 (1) 3 (1.5) 1 (<1)

3 (1.5) 1 (<1) 1 (<1) 2 (1)

-

3 (1.5)

5 (3) 1 (<1) 1 (<1) -

(<1)

4 (2) 3 (1.5) 4 (2)

1 (<1) 3 (1.5) 4 (2) 4 (2)

22 (15) 13 (9) 1 (<1) -

32 (15) 18 (8) 2 (1) -

35 (17) 31 (15) 3 (1.5) -

1 1

(<1)

* Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual ophthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated defined as follows: North American Study: AST >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: AST, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal).

Other adverse reactions included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritus, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors.

The incidence of AST elevations was greater in the 200 and 240 mg FARESTON dose arms than in the tamoxifen arms. Higher doses of FARESTON were also associated with an increase in nausea.

Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor.

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

Adverse reactions reported during post approval use of FARESTON have been consistent with clinical trial experience. The most frequently reported adverse reactions related to FARESTON use since market introduction include hot flash, sweating, nausea, and vaginal discharge.

DRUG INTERACTIONS Drugs that Decrease Renal Calcium Excretion Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. Agents that Prolong QT The administration of FARESTON with agents that have demonstrated QT prolongation as one of their pharmacodynamic effects should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that prolongs QT should be closely monitored for prolongation of the QT interval. Agents generally accepted to prolong QT interval include Class 1A (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol, ibutilide, dofetilide) antiarrhythmics; certain antipsychotics (e.g., thioridazine, haloperidol); certain antidepressants (e.g., venlafaxine, amitriptyline); certain antibiotics (e.g., erythromycin, clarithromycin, levofloxacin, ofloxacin); and certain anti-emetics (e.g., ondansetron, granisetron). In patients at increased risk, electrocardiograms (ECGs) should be obtained and patients monitored as clinically indicated [see Boxed Warning and Warnings and Precautions].

Effect of Strong CYP3A4 Inducers on Toremifene Strong CYP3A4 enzyme inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s Wort, lower the steady-state concentration of toremifene in serum.

Effect of Strong CYP3A4 Inhibitors on Toremifene In a study of 18 healthy subjects, 80 mg toremifene once daily coadministered with 200 mg of ketoconazole twice daily increased the toremifene Cmax and AUC by 1.4- and 2.9-fold, respectively.

N-demethyltoremifene Cmax and AUC were reduced by 56% and 20%, respectively.

The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) increase the steady-state concentration in serum and should be avoided. Grapefruit juice may also increase plasma concentrations of toremifene and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning and Warnings and Precautions].

Effect of Toremifene on CYP3A4 Substrates In a study of 20 healthy subjects, 2 mg midazolam once daily (days 6 and 18) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 6 and 18 relevant increases in midazolam and -hydroxymidazolam Cmax and AUC were not observed. Following coadministration on day 18 midazolam and -hydroxymidazolam Cmax and AUC were reduced by less than 20%.

Clinically relevant exposure changes in sensitive substrates due to inhibition or induction of CYP3A4 by toremifene appear unlikely.

Effect of Toremifene on CYP2C9 Substrates In a study of 20 healthy subjects, 500 mg tolbutamide once daily (days 7 and 19) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 7 and 19 plasma tolbutamide Cmax and AUC were increased by less than 30%. A reduction of similar magnitude was observed for hydroxytolbutamide and carboxytolbutamide Cmax and AUC. Toremifene is a weak inhibitor of CYP2C9. Concomitant use of CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with FARESTON should be done with caution and requires careful monitoring (e.g., substrate concentrations (if possible), appropriate laboratory markers, and signs and symptoms of increased exposure).

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

In animal studies, toremifene crossed the placenta and accumulated in the rodent fetus. Administration of toremifene to pregnant rats during organogenesis at doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m2 basis) resulted in signs of maternal toxicity and increased preimplantation loss, increased resorptions, reduced fetal weight, and fetal anomalies.

Fetal anomalies include malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Maternal toxicity may have contributed to these adverse embryo-fetal effects. Similar embryo-fetal toxicities occurred in rabbits that received toremifene at doses approximately 40% the daily recommended human dose of 60 mg (on a mg/m2 basis). Findings in rabbits included increased preimplantation loss, increased resorptions, and fetal anomalies, including incomplete ossification and anencephaly.

Animal doses resulting in embryo-fetal toxicities were ≥1.0 mg/kg/day in rats and ≥1.25 mg/kg/day in rabbits.

In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to effects seen with diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Neonatal rodent studies have not been conducted to assess the potential for toremifene to cause other DES-like effects in offspring (i.e., vaginal adenosis).

Vaginal adenosis in animals occurred following treatment with other drugs of this class and has been observed in women exposed to diethylstilbestrol in utero.

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

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

Geriatric Use The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.

Renal Impairment The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function.

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

Race The pharmacokinetics of toremifene in patients of different races has not been studied.

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

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

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

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

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

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

Effects on Cardiac Electrophysiology The effect of 20 mg, 80 mg, and 300 mg of toremifene on QT interval was evaluated in a double-blind, randomized study in healthy male subjects aged 18 to 45 years. The QT interval was measured at steady state of toremifene (Day 5 of dosing), including the time of peak plasma concentration (Tmax), at 13 time points (4 ECGs/time point) over 24 hours post dose in a time matched analysis. The 300 mg dose of toremifene (approximately five times the highest recommended dose 60 mg) was chosen because this dose produces exposure to toremifene that will cover the expected exposures that may result from potential drug interactions and hepatic impairment [see Drug Interactions].

Dose and concentration-related increases in the QTc interval and T wave changes were observed (see Table 1). These effects are believed to be caused by toremifene and N-demethyltoremifene. Toremifene had no effects on heart rate, PR and QRS interval duration [see Boxed Warning and Warnings and Precautions].

Table 1: QTc Prolongation in Healthy Male Volunteers Treatment Arm Toremifene 20 mg (N = 47) Toremifene 80 mg (N = 47) Toremifene 300 mg (N = 48)

Mean (90% CI) ΔΔQTc, ms 7 (0.9, 13.6) 26 (21.1, 31.2) 65 (60.1, 69.2)

ΔQTc > 60 ms (n, %) 0 2 (4.3%) 43 (89.6%)

QTc > 500 ms (n, %) 0 0 5 (10.4%)

Pharmacokinetics Absorption – Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady state concentrations were reached in about 4-6 weeks.

Distribution – Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly albumin.

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

Following multiple dosing with toremifene in 20 healthy volunteers, plasma toremifene exposure was lower on Day 17 compared to Day 5 by approximately 14%. N-demethyltoremifene exposure was higher on Day 17 compared to Day 5 by approximately 80%. Based on these data and an in vitro induction study in human hepatocytes, auto- induction of CYP3A4 by toremifene is likely. The effect of auto-induction on efficacy was likely captured following prolonged dosing in the clinical studies.

Elimination – The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days.

Elimination half-lives of major metabolites, N-demethyltoremifene and (Deaminohydroxy) toremifene, were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5 L/h. Toremifene is eliminated as metabolites primarily in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation.

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

Hepatic insufficiency – The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients.

Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.

Geriatric patients – The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.

Food – The rate and extent of absorption of FARESTON are not influenced by food; thus FARESTON may be taken with or without food.

Race – The pharmacokinetics of toremifene in patients of different races has not been studied.

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

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (approximately 1/50 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (approximately 1/15 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human estrogen agonists/antagonists that have primarily estrogenic activity in mice. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (approximately 1/3 and 1.4 times, respectively, the daily maximum recommended human dose of 60 mg, on a mg/m2 basis).

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

Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes).

Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (approximately 4 times and 1/50 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (approximately 1.5 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/3 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 52 weeks.

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

FARESTON may harm the fetus and increase the risk for pregnancy loss [see Warnings and Precautions and Use in Specific Populations].

Premenopausal women using FARESTON should use nonhormonal contraception during treatment and should be apprised of the potential hazard to the fetus should pregnancy occur [see Warnings and Precautions].

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

Patients who must take medications known to prolong the QT interval, or potent CYP3A4 inhibitors, should be informed of the effect of toremifene on QT interval. Toremifene has been shown to prolong the QTc interval in a dose-related manner [see Boxed Warning, Warnings and Precautions, and Clinical Pharmacology].

Specific interactions with foods that inhibit CYP3A4, including grapefruit juice, have not been studied but may increase toremifene concentrations. Patients should avoid grapefruit products and other foods that are known to inhibit CYP3A4 during FARESTON treatment.

Certain other medicines, including over-the-counter medications or herbal supplements (such as St. John’s Wort) and toremifene, can reduce concentrations of coadministered drugs [see Drug Interactions].

Distributed by GTx, Inc. Memphis, TN 38103, USA Product covered by Orion Product Patents and related patent numbers. © 2011 GTx, Inc. All rights reserved.

2E Rev. 03/2011

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Important safety information: FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia.

Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. FARESTON is contraindicated in patients with known hypersensitivity to the drug. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor flare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively.

References: FARESTON® Prescribing Information, 2011. Data on file, GTx, Inc.

Please see brief summary of prescribing information including boxed warning on the following page.

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