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Independent News for the Oncologist and Hematologist/Oncologist CLINICALONCOLOGY.COM • May 2015 • Vol. 10, No. 5

HEMATOLOGIC DISEASE Vogl, NY Y Weighs in on new MM guidelines .............

Guillermo Garcia-Manero, MD: How I Manage Lower-Risk MDS ............................................. 6

SOLID TUMORS

TKIs strike out in nonmetastatic kidney cancer ......................................

CURRENT PRACTICE Report From ACCC: Proving you provide quality oncology care can be challenging ........... 22

by the

numbers EGFR mutation testing and treatment decisions for patients in the U.S. with advanced/metastatic NSCLC

Trends in the oncology workforce, practice environment are predicted to affect patient care and access

Immunotherapy is on the horizon for breast cancer .......................................

Patients tested; results ready before first-line therapy decided

ASCO Report Details Changing Shape Of Cancer Care

Patients not tested before first-line therapy Patients tested; results not ready before first-line therapy decided

17 Based on data from Kantar Health-Boehringer Ingelheim survey presented at 2015 European Lung Cancer Conference.

t started with what one oncologist called “happy occurrences” in recent cancer care: more early diagnoses, more treatments and more survivors of cancer. And it’s led to a period of “turbulent transformation” in the United States, with too few oncologists being trained to meet the future demands of a growing and diverse population of cancer patients, according to a new report by the American Society of Clinical see CANCER CARE, E page 18

Paying for Cancer Care, Part 3

Getting It Right: In Breast Pathology, And in Headlines “You keep using that word. I do not think it means what you think it means.” Inigo Montoya’s famous words to the criminal “mastermind” Vizzini in “The Princess Bride” could be applied to many of the headlines describing a recent study on diagnostic concordance in breast pathology, published in March in the Journal of the American Medical Association (2015;313[11]:1122-1132, PMID: 25781441). “Breast Biopsies Leave Room for Doubt” declared The New York Times. “JAMA Report Highlights Inaccuracies in Pathologists’ Breast Cancer Diagnoses,” reported the Dark Daily. “Pathologists Often Disagree on Breast see PATHOLOGY, Y page 13

PD-L1 expression in NSCLC tumor cells correlated with an increased likelihood of benefit from pembrolizumab; story on page 14.

Lofty Goals Being Set For Reimbursement Reform T

hose seeking to reform oncology reimbursement for physicians have set lofty goals: create an equitable method for reimbursing oncologists for the entire continuum of care of these complex patients, and provide better care for patients— reducing adverse events, emergency department (ED) visits and hospitalizations, while lowering the overall cost of cancer treatment in America. It is hard to argue in favor of the status quo of fee-for-service and average sales price (ASP)-based reimbursement; critics charge that the current payment model incentivizes the use of expensive treatments over other treatments that are just as effective and less expensive, which increases the costs of care and can lead to more toxicities. Cancer care certainly is expensive: Direct medical spending on cancer treatment in the United States was $124.6 billion in 2010, according to the National Cancer Institute, which projects that cancer care will cost upward of $207 billion by 2020. New payment models that are well constructed can not only reduce management costs, but likely will result in lower overall drug costs, too, according to Jeffrey Ward, MD, a medical oncologist/hematologist at Swedish Cancer Institute, in Edmonds, Wash. “One of the problems right now is if I use a cheaper drug, I get paid less,” Dr. Ward said. see PAYMENT MODELS, S page 20

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CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

EDITORIAL BOARD

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

Hematologic Malignancies Jennifer R. Brown, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

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

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

Gastrointestinal Cancer

Paul J. Ford, PhD

University of Texas, MD Anderson Cancer Center Houston, TX

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

Pharmacy Harry Erba, MD, PhD

Breast Cancer

Michele Neskey, MMSc, PA-C

University of Alabama Birmingham, AL

Shaji Kumar, MD Mayo Clinic Rochester, MN

Richard Stone, MD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

Policy and Management

Cindy O’Bryant, PharmD

Mary Lou Bowers, MBA

University of Colorado Cancer Center Denver, CO

Mitchell Cancer Institute Mobile, AL The Pritchard Group Rockville, MD

Sara S. Kim, PharmD The Mount Sinai Medical Center New York, NY

Matt Brow VP, Public Policy & Reimbursement Strategy McKesson Specialty Health The US Oncology Network Washington, DC

Bioethics Joseph P. DeMarco, PhD

Infection Control

Cleveland State University Cleveland, OH

Susan K. Seo, MD

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

Memorial Sloan-Kettering Cancer Center New York, NY

Syed A. Abutalib, MD Cancer Treatment Centers of America Zion, Illinois

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

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

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

Michael Enright, Publication Sales menright@mcmahonmed.com McMahon Publishing is a 43-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. Clinical Oncology News (ISSN 1933-0677) is published monthly by McMahon Publishing, 545 West 45th Street, New York, NY 10036. Corp. Office, 83 Peaceable Street, Redding CT 06896 Copyright© 2015 McMahon Publishing, New York, NY. All rights reserved. POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036. www.mcmahonmed.com

Ephraim Casper, MD

Steven Vogl, MD

EDITORIAL STAFF

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Cancer Treatment Centers of America Philadelphia, PA

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Lung g and Head and Neck Cancers Edward S. Kim, MD Levine Cancer Institute Carolinas HealthCare Charlotte, NC

Lung g Cancer,, Emesis

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HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

Vogl, NY

Diagnostic Expansion in MM: Elegant, Thoughtful, but Risky EDITORIAL BOARD COMMENTARY Steven Vogl, MD Medical Oncologist New York City

n a thoughtful and precise paper, the International Myeloma Working Group (IMWG) last fall expanded the definition of multiple myeloma (MM) to include 3 groups of asymptomatic individuals as patients with the disease, because of data that each group is highly likely to develop organ or bone damage within 2 years (Table 1).1 To my knowledge, there are no prospective trials indicating that immediate treatment of individuals meeting one of these 3 criteria who are asymptomatic and who do not meet the strict “CRAB” criteria for diagnosis of MM (Table 2) makes them live longer or better compared with waiting and watching carefully for an early sign that something is getting significantly worse. Treating these individuals, largely identified because routine blood tests showed a high globulin level, is not very different from giving multiagent chemotherapy to women with resected breast cancer with multiple involved axillary nodes. For the latter situation, we required multiple positive large clinical trials before adjuvant chemotherapy became standard practice. I recall bitter arguments among conscientious physicians in 1974 about adjuvant breast cancer chemotherapy. Many worried that women who would never relapse would be exposed to the ravages of multiagent chemotherapy. Similarly, I initially worried that these new disease definitions might lead to frequent overtreatment, especially when decisions to treat the patient as overt MM are left to busy physicians who mechanically apply guidelines. On reflection, these considerations are outweighed by the benefits to thoughtful and conscientious physicians and their patients of expanding the disease definitions to include these ominous situations. Before the expanded definition, it was possible that payment for effective treatment of these patients would have been denied even when both patient and physician thought the patient would be best served by treatment.

Payors May Insist Only Overt MM Deserves Expensive Drugs Although those of us who treat MM are delighted that we can do much

better than give minimally effective (but cheap) melphalan and prednisone as initial treatment, the newer more effective treatments come with annual price tags that start at more than $100,000, putting them out of reach of patients without excellent insurance. If the definition of MM that needs treatment did not include these high-risk scenarios of what before was termed smoldering MM (SMM), then insurance companies may quickly discover that they can divert funds toward profits, rather than paying for bortezomib (Velcade, Takeda/Millennium) and lenalidomide (Revlimid, Celgene) for these patients. Drug companies are bringing ever more effective drugs to market. Alas, none are competing on price. Insurance companies, ever looking to the bottom line, are aware that if they deny treatment and the patient’s life is shortened, their expenditures may be lower as a result.

hemoglobin as it falls from 12 toward 10, creatinine as it rises toward 2, and calcium as it rises between 10 and 10.9 mg/ dL. These ominous trends would trigger many of us to treat a patient short of the CRAB criteria. The absence of such trends with near-normal and stable levels of hemoglobin, calcium, and creatinine might identify the 20% of individuals with light-chain ratios greater than 100 and the 30% of patients with 2 or more bone lesions at least 5 mm in diameter on magnetic resonance imaging (MRI) who will be progression-free 2 years later. Little is likely to be lost by watchful waiting in such patients, the critics argue, provided that observation is frequent and keen. It would be very useful to know the initial clinical characteristics of those who did not worsen enough to satisfy CRAB criteria 2 years into their observation periods, so we could especially consider a period of observation without interven-

Table 1. Newly Added Criteria To Diagnose MM Clonal bone marrow plasma cells ≥10% or plasmacytoma plus one of these: 2-y Incidence of Organ Damage, % 95

≥60%

Ratio of involved to uninvolved serum free light chain ≥100

80a

≥2 focal bone lesions ≥5 mm on MRI

70-80

27% had acute renal failure as the myeloma-defining event.

MM,, multiple u t p e myeloma; ye o a; MRI,, magnetic ag et c resonance eso a ce imaging ag g

The expanded criteria may make it easier for clinicians to get drug coverage for patients with early MM who do not meet CRAB criteria. Opponents of the revisions point out that so far no prescription plan has denied treatment for MM, whether it is smoldering or not, based on a failure to strictly meet the “CRAB” criteria. Additionally, SMM and overt MM share a billing code, as well as essentially identical bone marrow biopsy reports. As annual costs for each of several drugs leap over the $100,000 barrier, however, the incentive for insurance plans to scrutinize precise diagnoses increases exponentially.

Critics Favor Treatment Based On Clinical Deterioration Critics of the expanded definitions also point out that they are static, and that they ignore the clinician’s ability to carefully follow not only immunoglobulin levels and light-chain levels, but also

tion for patients like them. These critics fear that some individuals (admittedly a minority) will become MM patients on lifelong therapy by application of rigid criteria based on data that show that a majority are likely to progress within 1 to 2 years. My reply to the critics is that smart doctors will watch their patients carefully before committing them to chemotherapy. I hope that the members of the IMWG, as they speak at meetings and educational forums, will emphasize that the new diagnostic expansions are not engraved in stone, and that the presence of two 6-mm lesions on bone MRI does not mean that every such patient needs immediate systemic antimyeloma therapy. Indeed, in the Lancet Oncology paper, the IMWG favors repeat MRI in 3 to 6 months in

questionable situations.1 What is not stated, but is assumed, is close follow-up of hemoglobin, creatinine, and calcium.

How To Treat Asymptomatic Patients? There is little doubt that the myeloma clone can be effectively suppressed by modern chemotherapy when “CRAB” criteria are not met. In a Spanish trial of initial lenalidomide plus dexamethasone in unconventionally defined “highrisk” SMM, the overall response rate was 90%, including many remissions in which the paraprotein was no longer identifiable.2 For these individuals without symptoms or significant abnormalities in blood counts, kidney function, bones, and calcium level, one would like a treatment that is tolerable, easy to give outside of the hospital, unlikely to lead to severe symptoms or hospitalizations, and without long-term toxicities. I would favor low-dose dexamethasone (40 mg/wk)3 plus weekly bortezomib subcutaneously plus lenalidomide. Other tolerable regimens using just 2 drugs or incorporating newer agents, such as carfilzomib (Kyprolis, Onyx) and pomalidomide (Pomalyst, Celgene), also come to mind. These choices should be compared specifically in these lower burden myeloma patients. Having made MM better in the asymptomatic patient with no bone pain, we have no data on how long to treat the patient, whether to give bisphosphonates that reportedly prolong survival in overt MM, whether to consolidate at some point with high-dose melphalan rescued by autologous stem cells, when to collect these stem cells (early in treatment or after relapse just before highdose melphalan), whether to administer expensive and somewhat toxic maintenance therapy with lenalidomide and/or bortezomib, and how long to give such maintenance therapy. Because these patients begin therapy with a largely lower disease burden and with disease that in many cases is less virulent (perhaps genetically or epigenetically), one cannot reasonably assume that data derived from treatment of overt MM will apply. These patients may have deeper or longer remissions and more drug-sensitive relapses than patients with overt MM at initiation of treatment, and so may derive less benefit from prolonged and toxic therapies.

How Reproducible Are MRI Interpretations? Are Experts Available Everywhere? The IMWG has just published its comprehensive analysis of the MRI

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

Table 2. CRAB Criteria For MM Hypercalcemia: serum calcium >11 mg/dL Renal insufficiency: serum creatinine >2 mg/dL or creatinine clearance <40 mL/min Anemia: Hgb <10 g/dL Lytic bone lesions Hgb, hemoglobin; MM, multiple myeloma

literature on which the MRI recommendation was based.4 The paper convinces the reader that in expert hands, multiple MRI lesions greater than 5 mm are a sign of imminent progression of disease in the majority of SMM patients. Nowhere in the paper is there a citation showing that MRI interpretations are reproducible from one radiologist to another, especially in the presence of hemangiomas, Schmorl’s nodes, or benign compression fractures. Breast pathologists routinely err about 15% of the time when interpreting estrogen

images from equivocal cases elsewhere or where MRI experts are not available. The IMWG stated that when doubt exists as to the interpretation of the MRI, when there is diffuse infiltration of uncertain significance, or when there is just one focal lesion, the study should be repeated in 3 to 6 months. Patients whose lesions do not worsen seem to do relatively well, they report. Repeat MRI is expensive but a bargain compared with immediate commitment to lifelong expensive therapy. The MRI study recommended by the IMWG is imaging of the total body, something not widely available in the United States. Whole-spine and pelvis MRI (which detects about 90% of the lesions found in the total-body study) is more widely available at the moment, and is likely the test that will be widely applied.

Can Relatively Favorable Groups Be Defined Within The New MM Population? MM is heterogeneous in prognosis by cytogenetics, levels of normal immunoglobulins, levels of circulating plasma cells, percentage of abnormal plasma cells in marrow by multicolor flow cytometry,

The decision to begin treatment always should be patient focused, not disease focused, and based on a patient’s particular situation. receptors using immunohistochemistry—I would be surprised if even expert MRI radiologists had a concordance of greater than 85% in interpreting small areas of marrow heterogeneity. In the United States, it often is general radiologists with limited MRI experience who interpret MRI exams. Their concordance with a panel of experts would be expected to be less than 85%. The IMWG should assemble a panel of MRI images—positives, negatives, and some likely false-positives culled from among people with SMM—and circulate them to a panel to check concordance. If a high level of concordance can be established, members of the panel should make themselves available for reasonable fees to review MRI

Rigid application of the expanded criteria may induce some clinicians to treat asymptomatic and stable patients with toxic therapies years before symptoms or organ damage would develop. without treatment, whether they meet the old CRAB criteria or the new expanded criteria. In my career, I have cared for 2 patients with overt MM, each with multiple lytic bone lesions and a big protein spike, who have been stable for decades off treatment—for reasons I cannot explain. Even though MM is a terrible disease for mostt people unless it is controlled long-term by effective therapy, we should continue to seek to identify those who do not need that therapy— close observation likely will be part of that process.

IMWG Accepts Plain English Definition of ‘Symptomatic’

plasma cell proliferative rate, rate of paraprotein increase, and presumably other tests yet to be devised or applied to MM. Some of these tests may allow the identification of people with 2 or more marrow lesions on MRI who will progress slowly or not at all. These groups should be sought and the relevance of these prognostic factors tested prospectively.

The Lancet Oncology paper finally makes clear that the serious disease that myeloma doctors treat is called MM. In the past, regardless of whether the patient was bothered by any symptoms or not, it was referred to as symptomatic MM, even if the patient had no complaints at all. For those of us who are not doctors specializing only in MM, the use of plain English removes a source of recurring confusion. In Philadelphia, they like to call myeloma needing treatment “active MM.” In this editorial, I have used the term “overt MM.”

Will Some Interpret the New Definition as Demanding Immediate Treatment?

Approach to ‘At-Risk’ Asymptomatic Plasma Cell Dyscrasia

Guidelines committees at the American Society of Hematology, the National Comprehensive Cancer Network, and elsewhere should support thoughtful, cautious clinicians who closely follow asymptomatic and stable patients

When dealing with a patient who feels well, the smart, concerned clinician will always pause and be certain of parameters before committing the patient to lifelong therapy with a series of progressively more unpleasant

therapies. Single laboratory findings should be confirmed, a disease trajectory should be established, and radiographic findings checked carefully by experienced interpreters before clinicians leap into therapy. On the other hand, a previously healthy patient who appears with 20% monoclonal plasma cells in the marrow, a creatinine of 1.9, a hemoglobin of 10.5, a calcium of 10.7, and 5 clear-cut bone lesions on MRI that clearly are not hemangiomas or Schmorl’s nodules can pretty safely be assumed to have a serious illness and be treated for overt MM, even though the patient denies symptoms and has no lytic lesions on bone films, especially if any of the abnormal lab findings are getting worse.

References 1. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014; 15(12):e538-e548, PMID: 25439696. 2. Mateos MV, Hernandez MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013;369(5):438-447, PMID: 23902483. 3. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11(1):29-37, PMID: 19853510. 4. Dimopoulos MA, Hillengass J, Usmani S, et al. J Clin Oncol. 2015;33(6):657-664, PMID: 25605835. For our news coverage of the new MM guidelines, go to http://bit.ly/1EdPaLR.

What are your thoughts? Clinical Oncology News welcomes letters to the editor. Do you have thoughts on Dr. Vogl’s commentary? Please send comments to smtilyou@mcmahonmed.com

LOOK AHEAD

Next month in Clinical Oncology News: On the Spot Q&A: Genomics in Clinical Oncology Practice with Robert J. Green, MD, Prudence Lam, MD, Matthew F. Kaladny, MD, Nadine Tung, MD, and Thomas Abraham Samuel, MD

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

How I Manage ...

Table 1. A Prognostic Score For Patients With Lower-Risk MDS Parameters and Assigned Scores

Lower-Risk MDS

Guillermo Garcia-Manero, MD Department of Leukemia University of Texas MD Anderson Cancer Center Houston, Texas

he myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid malignancies characterized, in general, by peripheral blood cytopenias, evidence of marrow dysplasia, and the potential for increased bone marrow blasts and cytogenetic and molecular alterations.1

Usually, MDS is divided into lowerand higher-risk categories. It is important, therefore, to explain how we define lower- versus higher-risk MDS. Until the development of the Revised International Prognostic Scoring System (IPSS-R) classification,2 risk was defined using the IPSS classification.3 Lower risk by IPSS includes low and intermediate-1 categories and higher risk includes intermediate-2 and high-risk. This is more complicated to define using IPSS-R because this group of patients may include those with very low and low risk as well as some patients with intermediate-risk disease. The problem is that this subset of patients with intermediate IPSS-R–risk disease and a more “benign” natural history are not well defined. Intermediate IPSS-R risk can include patients whose

risk is based on blasts (may exceed 10%) or poor-risk cytogenetics (in both cases assuming no significant cytopenias) as well as those whose risk is based on cytopenias without excess blasts or abnormal cytogenetics. The natural history of these 3 subsets of patients and expectations with therapy probably are quite distinct. Because of this issue and also because approved drugs for MDS were evaluated using IPSS or a threshold of bone marrow blasts of up to 30%, I will refer to lower-risk MDS as patients with low- or intermediate-risk disease as defined by IPSS. Among patients with lower-risk disease, it also is important to distinguish between patients who have not received any prior disease-modifying therapy and those who have received such therapy, particularly hypomethylating

AT A GLANCE • MD Anderson has developed a prognostic score specific for patients with lower-risk MDS. • Transfusion dependency is considered the main trigger to initiate therapy in a patient with lower-risk MDS. • In patients with 5q– MDS who are not transfusion-dependent, it is not clear if early use of lenalidomide is associated with any benefit. • There is a potential role for early use of HMAs in patients with abnormal cytogenetics or poor-risk molecular features. • At this point, for most patients with lower-risk MDS, molecular information should not affect therapeutic decisions. • Investigators at Dana-Farber Cancer Institute have presented data showing that the presence of p53 3 and DNMT3a mutations is associated with a very poor prognosis in the context of allo-HCT. • Patients with lower-risk MDS should be encouraged to enroll in clinical trials.

Adverse Factor

Coefficient

P Value

Assigned Score

Unfavorable cytogeneticsa

0.203

<0.0001

Age ≥60 y

0.348

<0.0001

Hgb <10 g/dL

0.216

<0.0001

Platelets <50 × 109/L

0.498

<0.0001

Platelets 50-200 × 109/L

0.277

0.0001

Bone marrow blasts ≥4%

0.195

0.0001

Score

Median, mo

4-y Survival, %

113

185

223

166

Estimated Survival by Score

Hgb, hemoglobin; MDS, myelodysplastic syndromes a

Diploid and 5q only were considered favorable cytogenetics; all others were considered to be unfavorable cytogenetics. Adapted dapted from o reference e e e ce 4.

agents (HMAs). Note that there are geographic differences regarding this issue. For instance, in Europe, HMAs are not approved for lower-risk MDS, whereas in the United States and other parts of the world, HMAs are used commonly. In this article, I will refer to lowerrisk MDS previously untreated and lower risk treated with HMAs. The main questions when assessing a patient with lower-risk MDS are the following: • What are the expected survival and progression time from initial diagnosis of a patient with lower-risk MDS? • When should I start therapy? • What is the optimal therapy for a patient with lower-risk MDS? • What is the optimal therapy for a patient not benefiting from either lenalidomide (Revlimid, Celgene) or growth factor? • What about therapy for patients with lower-risk MDS who already have received HMA therapy? • Is there a role for allogeneic hematopoietic cell transplantation (allo-HCT) in patients with lower-risk MDS? • What is the role of supportive care measures in MDS? I will try to answer these questions individually. For a schema summarizing this article, see the Figure.

How do you calculate survival and the risk for progression for patients with lower-risk MDS? Both IPSS3 and IPSS-R2 provide estimates of survival and progression to

acute myelogenous leukemia (AML). The problem with these estimates is that the categories are so heterogeneous that these numbers are difficult to apply with precision for individual patients. For this reason, we at the University of Texas MD Anderson Cancer Center developed a prognostic score specific for patients with lower-risk MDS (Table 1).4 This model has been validated by multiple groups5 and probably is the most powerful prognostic system. I recommend using this system to calculate the survival and risk for progression to AML for patients with lower-risk MDS. Patients with lower-risk MDS can vary, from those who are predicted to have very long-term survival without intervention (0 to 3 points) to a subset of patients who may succumb to the disease after a median of 16 months or less after diagnosis (5 to 7 points). I use these data in my practice to determine the need for and frequency of follow-up and the need for intervention (discussed below).

When should therapy be started in patients with lower-risk MDS? This is a complex issue and results in a second question: What constitutes therapy in lower-risk MDS? Are supportive care measures, such as growth factor support and iron chelation, considered therapy? This also is controversial because some clinicians consider growth factor support and chelation therapy to be disease-modifying agents, whereas others (including myself ) do not consider these

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

interventions to modify survival or affect AML transformation. In general, transfusion dependency is considered to be the main trigger to initiate therapy in a patient with lower-risk MDS. Significant cytopenias (hemoglobin 8-10 g/dL and platelets 10,000-50,000/mcL) likely are considered to be as significant as transfusion dependency, particularly in symptomatic patients. Therefore, the question is whether there is a role for therapy in patients who are not transfusion-dependent or do not have significant cytopenia. This is answered below.

Is there a role for initiation of HMA therapy or lenalidomide in asymptomatic patients with lower-risk MDS without significant cytopenia? At this point, this is a research question, but it is a fundamental one. Is there a role for initiation of therapy in patients with abnormal cytogenetics or molecular features that are not transfusion-dependent? The data in Table 1 argue that if a patient’s expected survival is poor, therapy can be considered. The problem is that this has not been tested in prospective clinical trials. Indeed, for instance, early allo-HCT in patients with lowerrisk MDS has been shown to be associated with a poorer survival.6 This also depends on the risk of the disease. In patients with 5q– MDS who are not dependent on transfusions and have no significant anemia, it is not clear that early use of lenalidomide is associated with any benefit. In contrast, there is a potential role for early use of HMAs in patients with abnormal cytogenetics or poor-risk molecular features. This is being tested in a large randomized trial by the North American MDS Consortium; patients with lower-risk MDS are randomized to therapy or observation if transfusionindependent and to low-dose decitabine, low-dose azacitidine, or standard 5-day azacitidine if they require therapy (ClinicalTrials.gov identifier: NCT01720225). The results of this trial are expected to have a significant effect on practice.

What is the optimal therapy for a patient with lower-risk MDS? At this time, there are only 2 non-transplant therapies for these patients: lenalidomide and HMAs. I do not consider growth factors, iron chelation, or antithymocyte globulin to be therapy. These are discussed in the supportive care section below. Lenalidomide has a very clear role in patients who have anemia and platelets greater than 50,000/mcL and an alteration of chromosome 5.7 In this context, lenalidomide is very active, and response has been associated with prolonged survival.8 Recently, Santini et al presented data at American Society of Hematology 2014 indicating that lenalidomide has activity (albeit short-lived) in close to 30% of patients without an alteration of

chromosome 5 and anemia.9 This is important for physicians in Europe, where HMAs are not approved for lower-risk disease. In the United States, a patient with these characteristics probably will be treated with an HMA instead of lenalidomide. For the rest of the patients in need of therapy, the main treatment used in the United States is an HMA. The HMAs are known to be safe and active in this context. The main issue is the dose. Previous trials with IV azacitidine10 and oral azacitidine11 have suggested that very low doses may be effective in this group of patients. We tested this in a trial of low-dose

decitabine that showed responses in 40% of patients and rates of transfusion independence in over 60% of patients. We also are studying lower doses of azacitidine, and a Phase III trial of oral azacitidine is ongoing worldwide (ClinicalTrials.gov identifier: NCT01566695).

What is the optimal therapy after failure of lenalidomide or growth factors? These patients are HMA-naive and, therefore, will be treated with an HMA or considered for an investigational clinical trial (Table 2). Although this is probably

the correct course for most patients treated with growth factors, it is unclear whether it is appropriate for patients who lose benefit from lenalidomide, because the natural history of disease in such patients is not understood. There is the potential for the presence of p53 mutations in these patients, and checking for this molecular alteration probably is indicated. That said, in the United States, a large majority of these patients will be treated with an HMA. Younger patients treated with lenalidomide also should be considered for allo-HCT. see HOW I MANAGE, E page 8

CTCA® FORUM 2015

Cancer Treatment Centers of America®

SYMPOSIUM

Advances & Controversies in Malignant Hematology & Oncology Saturday, July 25, 2015 8:00 AM to 5:30 PM Radisson Blu Aqua Hotel Chicago, Illinois REGISTER NOW AT ctcaforumhemonc.org This CME program will efficiently discuss the most recent clinical advances and trials in the rapidly evolving field of malignant hematology and oncology by addressing the questions and controversies that have emerged from the latest data presented at both the American Society of Hematology (ASH) and American Society of Clinical Oncology (ASCO) annual conferences.* Complimentary for hematology/oncology and oncology fellows. #CTCAForum Jointly provided by Dannemiller and Athena Education Group. Dannemiller and Athena Education Group gratefully acknowledge an educational grant from Cancer Treatment Centers of America® in support of this continuing medical education activity. *This educational program is not an offi fficial program of ASH or ASCO, nor is it endorsed by ASH or ASCO.

PROGRAM CHAIRS Syed A. Abutalib, MD Assistant Director, Stem Cell Transplant and Cell Therapy Program Cancer Treatment Centers of America Zion, Illinois Maurie Markman, MD President of Medicine and Science Cancer Treatment Centers of America Philadelphia, Pennsylvania Faculty Al B. Benson III, MD Jennifer Brown, MD, PhD Jan C. Buckner, MD Timothy Kuzel, MD Hillard Lazarus, MD Edith Perez, MD

Jerald Radich, MD Paul Richardson, MD Richard Riedel, MD Ravi Salgia, MD, PhD John Sweetenham, MD Everett Vokes, MD Anas Younes, MD

HEMATOLOGIC DISEASE

HOW I MANAGE continued from page 7

What therapy should be used for patients with lower-risk MDS who already have received HMAs? There is no approved therapy for this group of patients. Recently, the MD Anderson group described the natural history of disease in these patients, showing a median survival of less than 17 months.12 If such patients are still in lower-risk MDS, allo-HCT should be considered (particularly in younger patients). For the rest, it is unlikely that growth factors or lenalidomide will have benefit (although this has not been formally tested) and, therefore, the patient would be a candidate for clinical trials (Table 2).

Is there a role for allo-HCT in patients with lower-risk MDS? No prospective study has been performed to answer this question. The best data can be derived from the study by Koreth et al.6 In this multicenter analysis, it was clear that allo-HCT (at least a reduced-intensity approach in patients older than age 60 years) has no role in first-line therapy. I do not recommend this for younger patients either. Stem cell

CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

transplant probably should be considered in patients fit for transplant if they have “failed” HMA and in very young patients after failure with lenalidomide.

What is the role of supportive care in lower-risk MDS? Supportive care can be divided into transfusional support, prophylactic antibiotics, growth factors (erythroid and neutrophils), and iron chelation. Guidelines for transfusion may vary depending on region, but in the United States, patients are transfused based on hemoglobin less than 8 g/dL (or higher depending on symptoms) and platelets less than 10,000/mcL (unless bleeding). Some centers have advocated for more liberal transfusion parameters, but they run the risk of alloimmunization and iron accumulation/overload. There are few data on prophylactic antibiotics in lower-risk MDS; I only consider them during the initial course of HMA therapy and do not use them in patients with isolated neutropenia. Growth factor support is controversial. Platelet growth factors (thrombomimetic agents) are not approved for MDS and should not be used in these patients because of potential risk for AML transformation. Erythroid growth factors

Table 2. Selected Clinical Trials For Lower-Risk MDS at MDACC Low Risk/IPSS Intermediate-1 Phase I/II

OPN-305 (2014-0432)

Phase III

Oral AZA + BSC vs placebo + BSC (2012-0733)

Phase I/II

ASTX727 (2014-0089)

Phase II

DAC vs AZA (2014-0112)

Phase II

DAC vs AZA (2012-0507)

Phase II

AZA +/- birinapant (2014-0399)

Phase I

Ruxolitinib (2013-0012)

Phase II

Sotatercept (ACE-011) (2012-0428)

Phase II

Bortezomib (2012-0562)

Phase II

Ruxolitinib + AZA (CMML) (2012-0737)

Phase I/II

Rigosertib + AZA (CMML) (2013-0030)

Post-HMA (Lower Risk) Phase I/II

OPN-305 (2014-0432

Phase I

MEDI4736 (2013-1041)

Phase II

Bortezomib (2012-0562)

Phase I

Ruxolitinib (2013-0012)

Phase II

Eltrombopag +/- HMA after HMA failure (2013-0225)

Phase I/II

Rigosertib + AZA (2013-0030)

AZA, azacitidine; BSC, best supportive care; DAC, decitabine; HMA, hypomethylating agent; MDACC, CC, University U ve s ty of o Texas e as MD Anderson de so Cancer Ca ce Center Ce te

commonly are used, but, in my opinion, it is unclear if they really affect the natural history of the disease. I rarely use them (although they are recommended for patients with low erythropoietin levels) and would be more inclined to use lenalidomide or HMA.

What are the implications of molecular aberrations in patients with lower-risk MDS?

Figure. Schema for treatment of lower-risk MDS. HMA, hypomethylating agent; IPSS, International Prognostic Scoring System; IPSS-R, Revised International Prognostic Scoring System; MDS, myelodysplastic syndromes; allo-HCT, allogeneic hematopoietic cell transplant

The molecular study of MDS has resulted in the identification of multiple genetic mutations associated with this disease. Common mutations affect genes involved in splicing—TET2, ASXL1, DNMT3a, and NRAS—and others that, albeit at a lower frequency, may be associated with poor prognosis ((p53 and EZH2) or be a potential target for therapy ((NRAS, Flt-3, IDH1, IDH2).13 It also has been shown that TET2 mutations are associated with an increased rate of response to HMAs.14 A number of clinical assays are commercially available, but the utility of these assays is yet to be determined. Thus, it is not clear whether ordering them is standard of care. The information from these studies can be difficult to interpret in patients with lower-risk MDS based on recent new evidence showing clonal hematopoiesis in older individuals without MDS.15 This means that older individuals without MDS can carry mutations known to occur in MDS in their peripheral blood. Although these patients are at increased risk for developing myeloid malignancies, there are no data that indicate how to follow or treat these patients.

At this point, for most patients with lower-risk MDS, this molecular information should not affect their therapy. However, the presence of specific mutations has been associated with poor prognosis in the context of lower-risk MDS.16 Specific examples are mutations in EZH2 and p53. Identification of these alterations probably will result in closer follow-up and a potential for early initiation of therapy in the context of a clinical trial. The presence of specific mutations, particularly NRAS, IDH1, IDH2, and Flt-3, also may help select patients for clinical trials. Recently, Bejar et al from Dana-Farber Cancer Institute, in Boston, have shown that the presence of p53 and DNMT3a mutations is associated with very poor prognosis in the context of allo-HCT.17 Whether transplant should be performed or not in patients with these mutations is being investigated. Caution should be used when employing these assays in patients without a clear diagnosis of MDS because they are not diagnostic at this point. Unlike the relationship between the presence of an alteration of chromosome 5 and lenalidomide response, there is no such biomarker for HMAs. The presence of specific mutations is associated with poor prognosis, but there are no guidelines to guide how to use these data for follow-up or therapeutic decisions. The data in terms of mutations and poor outcome with transplant are very important and should be discussed with the individual patient. see HOW I MANAGE, E page 10

Take a bite out of G-CSF acquisition costs Based on whole esale acquissition cost (WAC C) of o alll sho ort rt-a -act -a c in ct i g GG-CS CSF F pr prod oduc od ucts uc t ts as of November 11, 201 0 3. 3 WAC AC rep pre ese sent ntss pu nt publ blis bl ishe is he ed ca cata talo log gue gu g e or lisst pr pric ices es and n may not represent acctual tra ansa a tion ac o al pri r ce es. s. Ple leas ase e co con ntac actt yo your urr sup uppl plie er fo forr ac actu tual al pri r ce c s. s

GRANIX® is an option in short-acting G-CSF therapy » A 71 7 % red ducttio ion n in dur urat a ion at ion off sev ever ere e ne neutrro openia a vs placebo (1.1 days vs 3.8 8 da d ys, p<0 0.0 000 001) 11 – Effica c cy cy was eva valu uat ae ed d in a m mult mu ltin nat ational, m multice enter, randomized, controlled, Phase III study of chem motherapy-naïve patients tss witth hi hig g -ris gh-r gh iskk br brea east stt cance er receivving do oxorubicin (60 mg/m2 IV bo olus)/docetaxel (75 mg/m2)1 » Th he sa safe fe etyy of GR GRA A IX was esta AN ablishe ed in 3 Phase III trials,, with 680 p patients receiving g chemotherapy py for either breast 1 ca anccer er,, lu lung ng g can nce er, or non-Ho odgkin lympho oma (N NHL) » No Now w of offe ferri fe ring ng a new e presentation for self-ad dministration

Indication » GR G AN ANIX IX is a le leukocyte ocyte growth factor indicat indicated ted forr reduction in the duration of severe ne neutropenia eutropenia in p patients atients w th non wi onm mye oid malig myel gnancies receiving myelosuppresssive anticancer drugs associated with a clinically significant i ci in cide denc nce e of febrile neu utropenia.

Important Safety Information » Sple Sp eni n c ru upture: Splen nic rupture, including fatal cases, can occur following the administrattion of human granulocyte colo co lony ny-stimulating facttors (hG-CSFs). Discontinue GRAN NIX and evaluate for an enlarged spleen or sp s le enic rupture in pati pa tien e ts who report up pper abdominal or shoulder pain after receiving GRANIX. » Ac Acut ute resspiratory disttress syndrome (ARDS): ARDS ca an occur in patients receiving hG-CSFs. Evaluate pa p tients t who wh o de d ve elop fever and d lung infiltrates or respirator o y disstress after receiving GRANIX, forr ARDS. Disco c ntinue GRANIX X in patients with ARDS. » Al A lergic reactions: Serrious allergic reactions, including anaphylaxis, can occur in patientts receiving hG G-CSF S s. Reactions n ca an occurr on initial exp exposure. posure Permanentlyy discontinue GRANIX GRA ANIX in patients with serious allergic reac actions. tions D Do o no n t not administe er GRANIX to patients with a histo ory of serious allergic reactions to o filgrastim or pe egfilgr g astim. » Use e in pa atients with sickle cell disease: Severe and sometimes fatal sickle e cell crises can occur in pa patients with sickkle cell diseasse receiving hG-CSFs. Consider the potential risks and benefits prrior to the administration of GRAN NIX X in patients with sickle cell disease. Discontinu ue GRANIX X in patients undergoin ng a sickle cell crisis. » Capillary leak syndrome (CLS): CLS can occur in patients receiving hG-CSFs and iss charac a teriize z d by hyp ypote ensiion o , hypoalbuminemia, edema and hemoconce entration. Episodes vary in freque ency, severity and may be life f -thre eatening if treatme ent is delayed. Patients who develop symptoms of CLS should be closelyy monitored and d re ece c ivve sttanda dard r symptoma atic treatment, which may include e a need for intensive care. » Potential for tumor growth stimulatory effects on malign g ant cells: The granulocyte colony-stimullating fa actor o (G-CSF) re eceptor, through which GRANIX acts, has been fo f und on tumor ce ell lines. The pos o sibility tha hat GRAN NIX X acts as a grow wth factor for any tumor type, inclu uding myelo oid malignancies and myelodysplasia, diseasses e for which GRA ANIX is not app proved, cannot be excluded. » Most com mmon treatment-emergent adve erse e reaction: The most common n treatment-eme ergent ad dvers r e re ea action that occurred in patients treated with GRANIX at the recommended do d se with an incidence of at leastt 1% or gre eat e a er and two ti t mess more frequent than in the placebo group wass bone pain. Please see brief summary of Full Prescribin ng Information on adjacent page.

For more information, visit GRANIXhcp.com. Refe Re fere renc nce: e 1. GRA ANI N X® (tbo-filgrastim) Injection Prescribing g Info orm r ation. North Wales, PA: Teva Pharmaceuticals; 2014.

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva a Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved.. GRX-40582 January 2015.

HEMATOLOGIC DISEASE

HOW I MANAGE continued from page 8

In summary, the treatment of patients with lower-risk MDS is complex and requires proper staging and cytogenetic classifications. Decisions need to be made regarding the timing of initiation of therapy, the choice of initial therapy versus supportive care measures, and the timing of stem cell transplantation. The identification of new molecular targets,13 molecular pathways and inflammatory signals18,19 will result in new therapies for this group of patients.

CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

References

2008;22(3):538-543, PMID: 18079733.

1. Tefferi A, Vardiman JW. Myelodysplastic syndromes. N Engl J Med. 2009;361(19): 1872-1885, PMID: 19890130. 2. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454-2465, PMID: 22740453. 3. Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079-2088, PMID: 9058730. 4. Garcia-Manero G, Shan J, Faderl S, et al. A prognostic score for patients with lower risk myelodysplastic syndrome. Leukemia.

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX® (tbo-filgrastim) injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. 5.6 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: UÊ -« i VÊ,Õ«ÌÕÀiÊQsee Warnings and Precautions (5.1)] UÊ VÕÌiÊ,iÃ« À>Ì ÀÞÊ ÃÌÀiÃÃÊ-Þ `À iÊQsee Warnings and Precautions (5.2)] UÊ -iÀ ÕÃÊ iÀ} VÊ,i>VÌ ÃÊQsee Warnings and Precautions (5.3)] UÊ 1ÃiÊ Ê*>Ì i ÌÃÊÜ Ì Ê- V iÊ i Ê Ãi>ÃiÊQsee Warnings and Precautions (5.4)] UÊ >« >ÀÞÊ i> Ê-Þ `À i [see Warnings and Precautions (5.5)] UÊ * Ìi Ì > Êv ÀÊ/Õ ÀÊ À ÜÌ Ê-Ì Õ >Ì ÀÞÊ vviVÌÃÊ Ê > } > ÌÊ i ÃÊQsee Warnings and Precautions (5.6)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 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 clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of *10,000 x 106/L after nadir was reached.

5. Bejar R, Stevenson KE, Caughey BA, et al. Validation of a prognostic model and the impact of mutations in patients with lowerrisk myelodysplastic syndromes. J Clin Oncol. 2012;30(27):3376-3382, PMID: 22869879. 6. Koreth J, Pidala J, Perez WS, et al. Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis. J Clin Oncol. 2013;31(21):2662-2670, PMID: 23797000. 7.

Fenaux P, Giagounidis A, Selleslag D, et al. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusiondependent patients with Low-/

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-USapproved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data In an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported.

Intermediate-1-risk myelodysplastic syndromes with del5q. Blood. 2011;118(14):37653776, PMID: 21753188. 8. Giagounidis A, Mufti GJ, Fenaux P, et al. Lenalidomide as a disease-modifying agent in patients with del(5q) myelodysplastic syndromes: linking mechanism of action to clinical outcomes. Ann Hematol. 2014;93(1):1-11, PMID: 24018623. 9. Santini V, Almeida A, Giagounidis A, et al. Efficacy and safety of lenalidomide (LEN) versus placebo (PBO) in RBC-transfusion dependent (TD) patients (Pts) with IPSS low/intermediate (Int-1)-risk myelodysplastic syndromes (MDS) without del(5q) and unresponsive or refractory to erythropoiesis-stimulating agents (ESAs): results from a randomized phase 3 study (CC5013-MDS-005). Blood. 2014;124(21): abstract 409. 10. Lyons RM, Cosgriff TM, Modi SS, et al. Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol. 2009;27(11):1850-1856, PMID: 19255328. 11. Garcia-Manero G, Gore SD, Cogle C, et al. Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. J Clin Oncol. 2011;29(18):2521-2527, PMID: 21576646. 12. Jabbour EJ, Garcia-Manero G, Strati P, et al. Outcome of patients with low-risk and intermediate-1-risk myelodysplastic syndrome after hypomethylating agent failure: a report on behalf of the MDS Clinical Research Consortium. Cancer. 2015;121(6):876-882, PMID: 25410759. 13. Papaemmanuil E, Gerstung M, Malcovati L, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122(22):3616-3627; quiz 3699, PMID: 24030381. 14. Bejar R, Lord A, Stevenson K, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood. 2014;124(17):2705-2712, PMID: 25224413. 15. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488-2498, PMID: 25426837. 16. Bejar R, Stevenson KE, Caughey BA, et al. Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes. J Clin Oncol. 2012;30:3376-3382, PMID: 22869879. 17. Bejar R, Stevenson KE, Caughey B, et al. Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation. J Clin Oncol. 2014;32(25):2691-2698, PMID: 25092778. 18. Wei Y, Chen R, Dimicoli S, et al. Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+ cells. Leukemia. 2013;27(11):2177-2186, PMID: 23538751. 19. Yang H, Bueso-Ramos C, DiNardo C, et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. 2014;28(6):1280-1288, PMID: 24270737.

Series Editor ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40581 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

Syed Abutalib, MD Assistant Director, Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

Clinical Conundrums Updates in Hematology from the FDA, NEJM, Lancet Oncology and d Blood Primum non nocere. (First, do no harm.) Prepared by

Syed A. Abutalib, MD Assistant Director Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

QUESTIONS

1. In a study published in The New England Journal of Medicine on the genetic evolution of Janus kinase 2/Teneleven translocation 2 ((JAK2+/TET2+) myeloproliferative neoplasms (MPNs),

ANSWERS

True. The order in which JAK2 and TET2 mutations were acquired influenced clinical features, response to targeted therapy, biology of stem and progenitor cells, and clonal evolution in patients with MPNs. Compared with patients in whom the TET2 mutation was acquired first, patients who acquired the JAK2 mutation first had a greater likelihood of presenting with PV than with ET, an increased risk for thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib (Jakafi, Incyte) in vitro. Ortmann CA, Kent DG, Nangalia J, et al. Effect of mutation order on myeloproliferative neoplasms. N Engl J Med. 2015;372(7):601-612, PMID: 25671252.

2. True. In all, 768 patients were

enrolled, of whom 387 were randomly assigned to panobinostat, bortezomib, and dexamethasone; 381 were assigned to placebo, bortezomib, and dexamethasone. Median progression-free survival (PFS) was significantly longer in the panobinostat group than in the placebo group (11.99 months; 95% confidence interval [CI], 10.33-12.94 vs 8.08 months; 95% CI, 7.56-9.23; hazard ratio [HR], 0.63; 95% CI, 0.52-0.76; P<0.0001). San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;11:11951206, PMID: 25242045.

True. The approval was based on safety and efficacy results from Phase III studies, including the FIRST (Frontline Investigation of Lenalidomide + Dexamethasone versus Standard Thalidomide) trial (MM-020/IFM 07-01),

patients who acquired the JAK2 mutation before the TET2 mutation were more likely to develop polycythemia vera (PV) than essential thrombocytosis (ET). True or false?

3. The FDA expanded the indication of

lenalidomide (Revlimid, Celgene) in combination with dexamethasone for patients with newly diagnosed MM. True or false?

Three-year follow-up of treatmentnaive and previously treated patients with chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia receiving single-agent ibrutinib (Imbruvica, Pharmacyclics) failed to show further improvement in response. True or false?

Lenalidomide has no activity in relapsed and refractory diffuse large B cell lymphoma (DLBCL). True or false?

Lenalidomide is effective in refrac2. Panobinostat (Farydak, Novartis) 6. tory advanced cutaneous T-cell lympho-

emission tomography scan before autologous hematopoietic stem cell transplantation (auto-HCT), have worse outcomes than patients with Deauville score 1 to 3. True or false?

8. The MYD88 L265P is recurrently

mutated in patients with Waldenström macroglobulinemia (WM) but not in those with immunoglobulin (Ig) M monoclonal gammopathy of undetermined significance (MGUS). True or false?

Entospletinib (GS-9973) is an investigational orally bioavailable, small-molecule, selective inhibitor of spleen tyrosine kinase with clinical activity in patients with relapsed and refractory CLL. True or false?

received accelerated approval from the FDA based on the results of the PANORAMA 1 trial in which patients with relapsed, or relapsed and refractory multiple myeloma (MM) were randomly assigned to placebo or panobinostat, both in combination with bortezomib (Velcade, Millennium) and dexamethasone. True or false?

ma, with an overall response rate (ORR) of 28%. However, transient flare reaction (TFR) remains a concern with its use. True or false?

7. In

tional humanized monoclonal antibody targeting the chemokine receptor CCR4, has demonstrated activity in patients with advanced and refractory cutaneous T-cell lymphoma. True or false?

which evaluated continuous lenalidomide in combination with dexamethasone (Rd continuous) until disease progression versus melphalan, prednisone, and thalidomide for 18 months as the primary analysis, and a fixed duration of 18 cycles of Rd (Rd18) as a secondary analysis, in 1,623 newly diagnosed patients who were not candidates for auto-HCT. This combination also is feasible for auto-HCT–eligible patients but the cycles should be limited to 4 to 6 to ease hematopoietic progenitor and stem cell collection.

28%, respectively. It appears to be more effective in nongerminal center DLBCL, (ORR 53%, vs 9% for the germinal center subtype).

Subsequent studies using sensitive allele specific oligonucleotide–polymerase chain reaction confirmed the high prevalence of MYD88 L265P in WM (87%100%); they also revealed that the MYD88 mutation is present in a much higher fraction (≥50%) of IgM MGUS patients.

Celgene. FDA Expands Indication for REVLIMID® (Lenalidomide) in Combination with Dexamethasone to Include Patients Newly Diagnosed with Multiple Myeloma. http://ir.celgene.com/ releasedetail.cfm?releaseid=896912. Accessed April 16, 2015. Engelhardt M, Terpos E, Kleber M, et al. European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma. Haematologica. 2014;99(2):232-242, PMID: 24497560.

4. False. In this study published in

a study published in Blood, patients with chemosensitive relapsed and refractory DLBCL but Deauville 4 score on fluorodeoxyglucose-positron

Witzig TE, Vose JM, Zinzani PL, et al. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma. Ann Oncol. 2011;22(7):1622-1627, PMID: 21228334. Wiernik PH, Lossos IS, Tuscano JM, et al. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26(30):4952-4957, PMID: 18606983.

6. True. Patients demonstrate a TFR

in skin, blood, and/or lymph nodes that may be associated with improvement in disease burden. The TFR was not seen at the 10-mg starting dose.

Querfeld C, Rosen ST, Guitart J, et al. Results of an open-label multicenter phase 2 trial of lenalidomide monotherapy in refractory mycosis fungoides and Sézary syndrome. Blood. 2014;123(8):1159-1166, PMID: 24335103.

7. True. At 3 years, patients achiev-

Blood, longer treatment with ibrutinib was associated with improvement in response quality over time and durable remissions. Additionally, toxicity with longer follow-up diminished with respect to occurrence of grade 3 or greater cytopenias, fatigue, and infections. Progression remained uncommon, occurring primarily in some patients with relapsed del(17) (p13.1) and/or del(11)(q22.3) disease.

ing a Deauville response of 1 to 3 to standard therapy experienced superior PFS and overall survival rates of 77% and 86%, respectively, compared with patients achieving Deauville 4 (49% and 54%, respectively; P<0.001). According to the investigators of this study, patients achieving remission with standard therapy but who had a Deauville score of 4 should be the focus of risk-adapted investigational therapies.

Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125(16):2497-2506, PMID: 25700432.

Sauter CS, Matasar MJ, Meikle J, et al. Prognostic value of FDG-PET prior to autologous stem cell transplantation for relapsed and refractory diffuse large B-cell lymphoma. Blood. 2015;125(16):25792581, PMID: 25758829.

5. False.

8. False. The study by Treon et al dem-

Lenalidomide has activity in relapsed and refractory DLBCL. In NHL-002 and NHL-003, the overall responses in DLBCL were 19% and

onstrated that MYD88 was recurrently mutated in patients with WM (91%) but less frequently in IgM MGUS (10%).

10. Mogamulizumab, an investiga-

Paiva B, Corchete LA, Vidriales MB, et al. The cellular origin and malignant transformation of Waldenström macroglobulinemia. Blood. 2015;125(15):2370-2380, PMID: 25655603. Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med. 2012;367(9):826-833, PMID: 22931316. Jiménez C, Sebastián E, Chillón MC, et al. MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenström’s macroglobulinemia. Leukemia. 2013;27(8):1722-1728, PMID: 23446312.

9. True. In this multicenter, Phase II

study, PFS at 24 weeks was 70.1% (95% CI, 51.3%-82.7%). Of note, patients with other B-cell non-Hodgkin lymphomas also were included.

Sharman J, Hawkins M, Kolibaba K, et al. An open-label phase 2 trial of entospletinib (GS9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2015;125(15):2336-2343, PMID: 25696919.

10. True. The results of a Phase I/II

study published in Blood d show encouraging clinical responses to mogamulizumab across all disease stages in patients with mycosis fungoides (MF) and Sézary syndrome (SS). A global ORR of 36.8% (95% CI, 21.8%-54%) was observed for all evaluable patients: 47.1% (95% CI, 23-72.2) for SS patients and 28.6% (95% CI, 11.352.2) for MF patients. Median PFS was 11.4 months and the median duration of response was 10.4 months. Duvic M, Pinter-Brown LC, Foss FM, et al. Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma. Blood. 2015;125(12):1883-1889, PMID: 25605368.

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CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

Immunotherapy Lies on the Horizon for Breast Cancer Philadelphia and San Antonio—In metastatic triple-negative breast cancer, checkpoint inhibitors are demonstrating impressive activity. Although the data are being generated in earlyphase studies, they are drawing attention because the activity is so striking in a population with few viable treatment options and a disease for which there are no approved targeted therapies. The most recent study was conducted with a novel agent known as MPDL3280A. Although objective response is achieved in a minority of patients, these have included complete responses (CRs) and durable progressionfree survival (PFS). The median duration of response has not been achieved in follow-up now exceeding 56 weeks, reported Leisha A. Emens, MD, PhD, an associate professor of oncology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, in Baltimore. MPDL3280A, being developed by Genentech, which funded the study, received a breakthrough designation from the FDA for advanced bladder cancer late in 2014 and, on Feb. 2, 2015, a breakthrough designation for non-small cell lung cancer (NSCLC) when it has progressed after cisplatin treatment. This study, presented at the 2015 annual meeting of the American Association for Cancer Research, had 54 patients evaluable for safety and 21 patients evaluable for efficacy. MPDL3280A was administered every three weeks in one of three doses: 15 or 20 mg/kg, or 1,200 mg without regard to patient weight. Patients were required to be in good performance status (Eastern Cooperative Oncology Group [ECOG] 0 or 1) and to have failed prior treatment. Almost all patients had received at least four prior lines of therapy, with taxanes and anthracyclines being the most common. PD-L1 was measured at baseline, but a positive value was not required for study enrollment. Even though it was only a Phase 1A study, the PFS rate at 24 weeks in a challenging population was 27%. Of the four patients with objective responses, two were CRs and three have been ongoing for more than a year after the response was achieved. Three additional patients initially recorded as having progressive disease subsequently were found to have pseudoprogression. These responses were achieved in the context of a high degree of safety and tolerability, according to Dr. Emens. She listed the most common adverse events (AEs) as fatigue, nausea, fever and decreased appetite, but most were observed at a low grade. There were grade 3 events in 11% of patients. These were skin rash, dyspnea, adrenal insufficiency, low blood potassium and low

white blood cell coun nt (Table). The durability of response in patients with an oth herwise poor prognosis is w what is drawing attention to checkpoint inhibitors for thee treatment of patients witth metastatic triple-negativve breast cancer. A similar raate of objective response waas reported for the checkpoint inhibitor pembrolizumab (Keytruda, Merck) in this population at the most receent San Antonio Breast Cancer Symposium (abstract S1-09).. Pembrolizumab induced durable response rates es in roughly 20% of patients with heavily pretreated, advanced triple-negative breast cancer during the Phase Ib study. “Responses were durable, and the median duration of response was not yet reached, with three of the five responders remaining on therapy for greater than 11 months,” said lead study investigator Rita Nanda, MD, an assistant professor of medicine and the associate director of the Breast Medical Oncology Program at the University of Chicago. Pembrolizumab is approved for treating certain patients with metastatic melanoma but also is being tested in various solid tumors. In skin, breast and lung cancers, pembrolizumab has behaved

Table. TreatmentRelated Grade 3 or Higher AEs in Patients With TNBC Receiving Checkpoint Inhibitors AE Pembrolizumab Anemia Aseptic meningitis Decreased fibrinogen Headache

ECOG performance status of 0 or 1, with roughly half falling into each group; 12.5% had a history of brain metastases. Patients were excluded if they required systemic steroid therapy, had a history of or active autoimmune disease or had active brain metastases. Study participants received 10 mg/kg of IV pembrolizumab every two weeks. With a median follow-up duration of 9.9 months in the 27 patients who were evaluable for response, the overall response (OR) rate was 18.5%, with a 3.7% CR rate and a 14.8% partial response rate. Stable disease was observed in 25.9% of patients. The median time to response was 18 weeks. The median duration of response had not been reached. PFS at six months was 23.3%.

These and other data with checkpoint inhibitors suggest that ‘we are in the middle of a revolution’ that is likely to change the approach to many cancer types, not just triple-negative breast cancer. —Louis A. Weiner, MD similarly, in that it has been effective in roughly 20% to 30% of patients, but responses have been durable (American Society of Clinical Oncology 2014 Annual Meeting abstracts 8020, 8021, 8024, LBA9000 and 9002). In the breast cancer study, which was supported by Merck, Dr. Nanda and her colleagues enrolled 32 patients with recurrent or metastatic triple-negative breast cancer whose tumors expressed PD-L1. “Of note, just under 60% of patients who were triple-negative and screened for this study had PD-L1–positive tumors,” said Dr. Nanda. Approximately 45% of the study cohort had received three or more prior therapies for metastatic disease. Patients were required to have an

Dr. Nanda noted that “four of the five responders had received three or [more] chemotherapy regimens for advanced breast cancer.” Treatment-related AEs were seen in 56.3% of the study cohort (Table). One patient each experienced grade 3 anemia, headache, aseptic meningitis and pyrexia. One patient experienced a grade 4 treatment-related AE—decreased fibrinogen—which resulted in the only drug discontinuation. The decreased fibrinogen was associated with disseminated intravascular coagulation and resulted in death. Treatment-related AEs of a potentially immune-mediated nature, regardless of attribution, included pruritis (n=3; all grade 1), hepatitis (n=1; grade 3) and

Hepatitis Pyrexia MPDL3280A Adrenal insufficiency Dyspnea Low potassium Low WBC count Skin rash AEs, adverse events; TNBC, triple-negative breast b east cancer; ca ce ; WBC W C,, w white te b blood ood ce cell

hypothyroidism (n=1; grade 2). An expanded clinical trials program is planned for both agents in this disease. Dr. Emens reported that a Phase III global randomized trial testing MPDL3280A in combination with membrane-bound paclitaxel (Abraxane, Celgene) as first-line therapy in patients with metastatic triple-negative breast cancer is being launched, and Dr. Nanda noted that a Phase II study of pembrolizumab for patients with advanced triple-negative breast cancer is due to begin later this year. In triple-negative breast cancer, checkpoint inhibitors are attractive because these cancers generally are more likely to express PD-L1 than other breast cancers, according to Dr. Emens. In addition, she noted that tumor-infiltrating lymphocytes, which are believed to be essential for the immune response generated by inhibiting the activity of checkpoint proteins, tend to be present in these cancers in substantial numbers. However, Dr. Emens said, patients with and without tumors expressing PD-L1 have been and are continuing to be included in the clinical trials. Each of the checkpoint inhibitors has unique features. MPDL3280A, for example, targets the PD-L1 ligand whereas pembrolizumab targets the PD-1 receptor. However, it is unclear whether these differ substantially by

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CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

PATHOLOGY continued from page 1

Biopsy Findings,” said CancerNetwork. But the focus on “doubt,” “inaccuracies” and “disagreement” misses the mark, said investigator Joann Elmore, MD, a professor of medicine and an adjunct professor of epidemiology at the University of Washington, in Seattle. “Sadly, many media outlets have been emphasizing the idea that one of every four breast biopsies is wrong. That conclusion is wrong if you are suggesting these results reflect outcomes at a population level.” The study, which asked 115 breast pathologists to review test sets of 60 breast biopsy slides and then compared their findings with a “reference diagnosis” determined by a panel of three expert pathologists, found that the pathologists agreed with the expert panel 75.3% of the time—which does suggest that they were wrong (or, alternatively, the experts were wrong) about 25% of the time. “But that’s an inaccurate interpretation of the study’s findings if you are suggesting that this is what you would find among the 1.6 million breast biopsies performed annually in the U.S., as the majority of biopsies are normal— benign without atypia,” Dr. Elmore said. “The diagnostic concordance differed in 25% of cases within this study design—many of those cases the most ambiguous of the set.” Drilling down from the overall finding, the study found that invasive cancer diagnoses were concordant a reassuring 96% of the time, and underdiagnosed 4% of the time. “There was near-perfect agreement in the diagnosis of invasive cancer,” Dr. Elmore pointed out. “Concordance among the experts and the test group was really quite good for invasive disease,” agreed Julie Gralow, MD, a professor of medical oncology and the Jill Bennett Endowed Professor of Breast Cancer at the University of Washington, in Seattle. “This reassures us that we are actually in pretty good agreement in defining the

either efficacy or safety in triple-negative breast cancer or in other cancers for which they are being evaluated. The unusual degree of optimism generated by Phase I trials is due to the unusual quality of these responses. “This activity signal is unequivocal,” reported Louis A. Weiner, MD, the director of Georgetown University’s Lombardi Comprehensive Cancer Center, in Washington, D.C. Asked to comment specifically why clinicians should be paying attention to Phase I data, he characterized these results as “very exciting” and unlike the more

cancers that rea lly need to be treat-ed due to risk of spread and recurr e n c e.” W h a t ’s more, according to study coinvestigator Donald Weavver, MD, a professor of pathology at the U University of Vermon nt, in Burlington, “most of the 4% disagreement was due to one challenging case with focal microinvasion.” Ductal carcinoma in situ (DCIS) diagnoses were concordant 84% of the time, underinterpreted in 13% of cases and overinterpreted in 3% of cases; and benign cases were concordant 87% of the time and overinterpreted 13% of the time. The primary driver of the one-infour discordance rate in diagnosis was atypical hyperplasia (atypia), which had a concordance rate of 48% and was overinterpreted 17% of the time and underinterpreted in 35% of cases. Because atypia and DCIS cases in the sample set represented a significantly higher proportion of the total cases used to generate the slides (72 and 73 of 240, respectively) than is generally seen in clinical practice, the overall findings were skewed.

test sets with atypia and DCIS cases to have adequate statistical power to make comparisons and see how well we are doing in diagnosing atypia versus DCIS, and ben nign versus atypia,” Dr. Elm more said. She aadded that the research team is now working on using their data to calculate diagnostic concordance in a set of cases that more accurately reflects the population level of these diagnoses. Stuart Schnitt, MD, a professor of pathology at Harvard Medical School, in Boston, and a co-author of the study, admitted that he found its limitations frustrating. “The study design provided the pathologist a single slide to review, without the opportunity to look at additional slides from the same case, to do immunostains, or consult a colleague. That’s just not the way we practice,” he said. “They were also forced to make a specific diagnosis, even if they were concerned about the lesion’s being borderline. We found a lower level of concordance in cases scored as having a high degree of difficulty, which tells us

‘Concordance among the experts and the test group was really quite good for invasive disease. This reassures us that we are actually in pretty good agreement in defining the cancers that really need to be treated due to risk of spread and recurrence.’ —Julie Gralow, MD Edi Brogi, the director of breast pathology at Memorial Sloan-Kettering Cancer Center, noted that, in the literature, atypia cases represent approximately 4% to 10% of core biopsies, and they are even rarer in surgical excision specimens. “The study is not reflective of what happens in real practice,” she said. That was a necessary tradeoff, Dr. Elmore said. “You have to augment

that the pathologists in the study recognized when there were diagnostic challenges. In the real world, no pathologist with a difficult slide would just look at it and say, ‘OK, it’s borderline, but I’ll make a diagnosis and have the patient treated anyway.’” Dr. Brogi agreed. “If there is any question about the diagnosis, we do ancillary studies, such as cutting deeper into the

modest and transient types of activity typically seen with a novel therapy in advanced disease. He said that these and other data with checkpoint inhibitors suggest that “we are in the middle of a revolution” that is likely to change the approach to many cancer types, not just triple-negative breast cancer. Speaking after Dr. Nanda’s presentation, Mary Disis, MD, a professor in the Department of Medicine at the University of Washington, in Seattle, also was enthusiastic about the promise of immunotherapy in breast cancer. “Let’s move immunotherapy forward in breast

cancer and really try to change the game in this disease,” she said, noting that recent studies demonstrated that pembrolizumab had activity in multiple cancers, with OR rates of 20% in kidney cancer, 30% in gastric cancer, 20% in head and neck cancer, 24% in lung cancer and 34% in melanoma. “With triple-negative breast cancer, we are right in the ballpark,” said Dr. Disis. “We are seeing 20% response rates with triple-negative breast cancer. It’s important to note that in melanoma, people are already moving toward combination therapy and seeing response

block or doing stains,” she said. “When we review cases of patients treated at Memorial who’ve had regional biopsies elsewhere, the rate of discordance that has significant impact is extremely rare.” Dr. Schnitt said that the study confirms two things: the high accuracy of diagnosis of most invasive breast cancers, and the fact that there are some cases about which very well-trained and experienced pathologists will disagree. “I was one of the three experts who helped to establish the consensus reference diagnosis, and there was also disagreement in these difficult cases among our group. That’s further evidence that these were really difficult and problematic cases.” There always will be gray areas in diagnostic breast pathology, as in all areas of clinical medicine, Dr. Schnitt said. “For example—and there’s published data to support this—if you ask a group of breast surgeons about the adequate negative margin width for a lumpectomy, there is no margin width about which 50% or more of them will agree is adequate or negative. Does that mean a 2-mm margin is right and a 1-mm margin is wrong? No, it just means that there are things about which there is no correct answer. One of the most positive things that could come out of this study is that pathologists, clinicians and patients realize that there are cases in which reasonable, informed people disagree.” Dr. Gralow stressed the importance of strong communication among pathologists, imaging specialists, and surgeons and other oncologists, as well as patients. “We need to make a bigger effort in the U.S. in better explaining the actual risk these proliferative lesions represent,” she said. “These are not cancer (and many argue DCIS should not be called cancer either) and they are rarely accidentally mislabeled as cancer per this study. And true invasive breast cancers were rarely missed in this study as well.” —Gina Shaw

rates of 50% to 60%. So, let’s not wait. Let’s move this forward so we can benefit our breast cancer patients. Onward to rational combinations, so we can drive that response rate up.” —Ted Bosworth and Kate O’Rourke Dr. Emens reported financial relationships with Aduro, Amplimmune, Aveo, BristolMyers Squibb, Celgene, EMD Serono, Genentech, MaxCyte, Merck, Roche and Vaccinex. Dr. Disis reported relationships with Celgene, EMD Serono, Emergent, EpiThany, Seattle Genetics and VentiRx. Drs. Nanda and Weiner reported no relevant financial relationships.

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CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

Report From AACR Annual Meeting:

Pembrolizumab Shows Promise in Treating NSCLC P

embrolizumab showed promise against non-small cell lung cancer (NSCLC), in both treatment-naive and previously treated patients, during an early-phase study presented at the 2015 annual meeting of the American Association for Cancer Research (AACR) and published in The New England Journal of Medicine. The investigators also identified a potentially relevant biomarker to identify patients for whom pembrolizumab, and other therapies that target the programmed death (PD)-1 receptor, might be particularly effective. The multinational study, a Phase I trial called KEYNOTE-001, (2015 Apr 19. [Epub ahead of print], PMID: 25891174), evaluated response to pembrolizumab (Keytruda, Merck) in 495 patients with advanced NSCLC. The investigators evaluated the safety and antitumor activity of pembrolizumab and sought to define and validate an expression level of PD-L1, a ligand of PD-1 that enables cancer to evade the body’s immune response, associated with an increased likelihood of benefit from pembrolizumab. “The data indicate that pembrolizumab is effective in a large population of nonsmall cell lung cancer patients,” said investigator Edward Garon, MD, MS, the director of the Thoracic Oncology Program at the University of California, Los Angeles

Jonsson Comprehensive Cancer Center. “The sideeffect profile looked quitee good overall,” Dr. Garon tolld Clinical Oncology News, no oting that less than 10% of thee patients in the study experienced a severe (grade III or greater) adverse event, “much less than what we would expect with chemotherapy,” he said. The investigators also employed a prototype immunohistochemical assay to assess PD-L1 levels, using tissue taken from all of the patients by contemporaneous biopsy on enrollment, before administration of pembrolizumab. Upon determining that higher PD-L1 levels on the surface of tumors correlated with a higher rate of response to pembrolizumab, the investigators designated 182 patients as a training group to determine a cutoff point, which they defined as membranous PD-L1 expression in at least 50% of tumor cells. The designated cutoff was validated in the remaining 313 patients, in whom PD-L1 staining levels of 50% or higher were associated with better outcomes using pembrolizumab. The overall response rate in patients with PD-L1 expression of 50% or higher was 45.2% (95% confidence interval [CI], 33.5%-57.3%) compared with 19.4% (95% CI, 16.0%-23.2%) in the total

study populaation. Of the patients who responded, 84.4% had no disease progresh sion. The median duration of response was 12.5 months in all patients, 10.4 months in patients who had m undergone p previous treatment and 23.3 months in paatients who had not received previous treatment. Dr. Garon noted that all of the patients who responded to pembrolizumab experienced similar results, regardless of their PD-L1 expression level. “High levels of staining predicted who was most likely to benefit, but everyone who responded did quite well, whether they had high levels of staining or not,” he said. The findings show “significant efficacy and relatively low toxicity in the treated and untreated groups,” according to Abraham Chachoua, MD, a professor of medical oncology at NYU Langone Medical Center’s Perlmutter Cancer Center, in New York City, who was not involved with the study. “Immunotherapy is one of the most exciting treatment modalities for patients with non-small cell lung cancer,” Dr. Chachoua said in an interview. “The data presented are from a relatively large patient cohort, and the findings support this conclusion.” Dr. Chachoua also noted that other

studies targeting PD-1 or PD-L1 have reached conclusions similar to those of the present study. Recent research suggests that PD-L1 may be a promising immunotherapy target for several cancers. A study conducted at the University of Texas MD Anderson Cancer Center, in Houston, and also presented at the AACR meeting (abstract 2875), identified a possible mechanism that regulates PD-L1 via the tumor suppressor gene p53. Another study, led by investigators at Memorial Sloan-Kettering Cancer Center, in New York City, examined a subset of data from the present study to determine why PD-1 inhibitors might be effective for some patients and not others. The results, published in Science (2015;348[6230]:124-128, PMID: 25765070), suggest that patients with genetic mutations caused by smoking are more likely to benefit from therapies targeting PD-1. Dr. Garon said that Merck has several trials ongoing to evaluate the performance of the drug relative to standardof-care therapy in patients with NSCLC. —Ajai Raj See related story about the use of pembrolizumab in patients with breast cancer on page 12.

Report From ASCO Genitourinary Symposium:

TKIs Strike Out in Nonmetastatic Kidney Canc Orlando, Fla.—Providing adjuvant sorafenib and sunitinib to patients with locally advanced, nonmetastatic, resected kidney cancer does not improve outcomes, according to preliminary results from the Phase III ASSURE (ECOG E2085) trial. The findings, presented at the 2015 Genitourinary Cancers Symposium (abstract 403), are disappointing, given that these two multitargeted vascular endothelial growth factor tyrosine kinase inhibitors (VEGF TKIs) have worked well for many patients with metastatic kidney cancer. “Nobody is more disappointed than me, except for the patients with kidney cancer who were participating in the trial,” said investigator Naomi Haas, MD, a medical oncologist at the University of Pennsylvania’s Abramson Cancer Center, in Philadelphia. Approximately one-third of patients with kidney cancer develops metastatic

disease and, ultimately, will die of their disease. Multitargeted VEGF TKIs, including sorafenib (Nexavar, Bayer) and sunitinib (Sutent, Pfizer), have controlled disease in thousands of patients with unresectable, metastatic kidney cancer ((BJU Intt 2011;108[10]:1556-1563, PMID: 21952069) In the ASSURE (Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma) trial, researchers set out to test whether adjuvant sorafenib or sunitinib could improve disease-free survival (DFS) in patients with non-metastatic, resected primary disease at a high risk for recurrence. The current standard of care for these patients is close observation with scans performed at regular intervals, Dr. Haas said. In the study, 1,943 patients with locally advanced renal cell carcinoma underwent surgery and then were randomly assigned to receive one year of sorafenib,

sunitinib or placebo. All the patients were at high risk for recurrence based on factors such as tumor size, tumor grade or cancer in the lymph nodes. “Patients had cancer that was at least 4 cm in size, with high-grade disease, but we also included patients with larger cancers or who were node-positive,” Dr. Haas said. “Patients had to have negative margins.” The trial arms were balanced in terms of type of kidney cancer, type of surgery (open or laparoscopic), patient performance status and risk for recurrence. The investigators found no difference in five-year DFS (5.8 years for sunitinib and sorafenib and six years for placebo). The median overall survival for the study has not yet been reached. Charles Ryan, MD, a professor of clinical medicine and urology at the University of California-San Francisco, who was not involved with the study, said that VEGF inhibitors have been

used anecdotally as adjuvant therapy in patients with non-metastatic kidney cancer. The new data, he said, provide strong evidence that this should not continue. “TKIs are not chemotherapy; they are a stromal-targeted therapy and, therefore, act in a different manner,” Dr. Ryan said. see TKIs Is, page 23

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CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

Do We Need More-Sensitive Lung Cancer Screening Criteria? F

ewer patients with lung cancer today meet the screening criteria necessary to qualify for sensitive screening with low-dose computed tomography (CT) than would have several decades ago, according to a recent study by investigators from Mayo Clinic in Rochester, Minn. They suggested that perhaps it is time to broaden the criteria. Ping Yang, MD, PhD, and her colleagues examined the trends in the proportion of patients with lung cancer meeting the U.S. Preventive Services Task Force (USPSTF) screening criteria. Studies show a significant 20% reduction in mortality with annual low-dose CT screening for individuals at high risk for lung cancer, and several guidelines, including those from the USPSTF, suggest screening for asymptomatic adults with a 30 pack-year smoking history, who still smoke or quit in the past 15 years. The investigators evaluated the roughly 140,000 residents of Olmstead County, Minn., who were older than 20 years during the evaluation period of 1984 through 2011. Of this cohort, 83% were non-Hispanic white and socioeconomically similar to the overall population of the Midwest. All pathologically confirmed cases of primary lung cancer were identified using the Rochester Epidemiology Project database. Trends in lung cancer incidence rates were determined based on census data adjusted for the age and sex distribution of the U.S. population in 2000, which enabled the investigators to identify the proportion of cases meeting the USPSTF screening criteria. Between 1984 and 2011, 1,351 patients received a new diagnosis of primary lung cancer. During that time, the proportion of patients with lung cancer who smoked more than 30 pack-years declined, and the proportion of former smokers, especially those who had quit smoking more than 15 years ago, increased (JAMA ( 2015;313[8]:853-855; PMID: 25710663). Over time, the investigators found a decline in the relative proportion of patients with lung cancer meeting the USPSTF criteria overall, from 57% in 1984-1990 to 43% in 2005-2011. The proportion of patients who would have been eligible under the criteria decreased from 52% to 37% among women and from 60% to 50% among men. The investigators said that this decline of patients means that fewer patients at risk for lung cancer would be screened with low-dose CT. They concluded that “more sensitive screening criteria may need to be identified while balancing the potential harm from computed tomography.” In an interview with Clinical Oncology News, James L Mulshine, MD, who did not participate in the study, said, “It

is reasonable to assume that eligibility criteria could evolve as we accrue experience from the success, harms and benefits analysis emerging from capturing the results of the national implementation screening.” However, he noted that Minnesota has a more favorable smoking cessation rate than some other states in the nation, where more people would qualify for low-dose CT under the current criteria. “Across the nation, there are still

many smokers and recent former smokers who may benefit from the new CMS NCD [Medicare coverage determinations] for lung cancer screening,” said Dr. Mulshine, a professor and the associate provost for research at Rush Medical College, Rush University, in Chicago, whose research involves translating basic science into meaningful tools for cancer management, especially lung cancer management. Dr. Mulshine called the data interesting. “I look forward to the day that we

have outcomes across the nation as good as in Olmstead County,” he said. In the meantime, he cautioned clinicians to “be knowledgeable about the best screening practices, so they can engage in informed discussions with high-risk individuals considering lung cancer screening.” —Marie Rosenthal None of the sources reported any relevant financial relationships.

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CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

Molecularly Guided Therapy for NSCLC Found Cost-Effective G

uidelines recommend the use of biomarker screening to guide treatment decisions in non-small cell lung cancer (NSCLC), and recent research suggests that, from a societal point of view, this approach is cost-effective compared with administering chemotherapy and not screening patients for mutations and gene rearrangements. “Both organizationally and nationally, we are having a big discussion about the future of precision medicine in oncology and the proper role for molecular, genetic and genomic assessment of cancers,” said Neal J. Lindeman, MD, the director of the Molecular Diagnostics Laboratory and an associate professor at Harvard Medical School, in Boston. “Based on the experience we’ve had at our institution testing lung cancer and the genomics of lung cancer, we thought we were in a position to go beyond what we’ve done scientifically and look at this issue practically, from a policy perspective.” To assess the cost-effectiveness, life expectancy and quality-adjusted lifeyears (QALY) between molecularly guided therapy and treatment with cisplatin-pemetrexed, Dr. Lindeman and his colleagues created a micro-simulation model comparing four scenarios in patients with metastatic NSCLC. In the first scenario, patients are

not tested for epidermal growth factor receptor ((EGFR) mutations or anaplastic lymphoma kinase ((ALK K) gene rearrangements. They receive standard chemotherapy. If they relapse, they receive molecular therapy as secondline treatment. In the other three scenarios, patients are tested and receive targeted therapy, if appropriate, in one of three ways: 1) Treatment is withheld until testing is complete, after which the patient is treated with an EGFR- or ALK-inhibitor if a mutation is found; 2) the patient is started on standard chemotherapy before being tested and, if testing reveals a mutation, he or she is switched over to targeted therapy immediately; and 3) the patient is started on standard chemotherapy before being tested and, if testing reveals a mutation, he or she is switched over to targeted therapy after a standard four-week course of chemotherapy. “We looked at two metrics to decide whether or not an approach is the right thing to do from a societal perspective. First, we considered the incremental differences in life expectancy and QALY,” Dr. Lindeman said. The second metric the researchers assessed is the incremental cost-effectiveness ratio—how much money is spent for one additional year of life or one QALY.

“What emerged is that the most efficient way to preserve life per dollar spent is to withhold treatment until the test result comes back, and to then proceed immediately to the definitive therapy,” Dr. Lindeman said. The analysis showed that this approach cost approximately $102,000 per year of life, and $136,000 per year of quality life. “Society has to determine if that’s the right amount of money to spend or not, and, by most standards, that is a bit of a bargain in the cancer field,” Dr. Lindeman said, noting that the World Health Organization suggests society should spend about $155,000 per QALY. In the cases in which a patient has an EGFR or ALK K mutation and receives targeted therapy, the gain in life expectancy is about nine months. “It’s a relatively modest increase [overall] because most lung cancer patients don’t have these mutations, so this benefits a subset of patients,” Dr. Lindeman said. “I think a lot more of this type of research needs to be done,” he added. “We’re just scratching the surface with lung cancer. ... But I’d like to see where large-scale genomic testing falls in terms of cost-effectiveness in all kinds of cancers.” After reviewing the study, Edward Kim, MD, FACP, the chair of Solid Tumor Oncology and Investigational

Therapeutics at the Carolinas HealthCare System’s Levine Cancer Institute, in Charlotte, N.C., noted that the research confirms a logical course of thought. “As therapies and testing, including biomarker testing and imaging, get more expensive, we have to find ways to be mindful of costs. Certainly, even without conducting a formal evaluation, one would assume that being more precise in treatment would reduce cost by helping us derive the best treatment,” he said. Dr. Kim supports biomarker testing for known markers that have associated treatments, “but one should not assume broad biomarker testing will drive down costs because we don’t have clear associations between the majority of these genetic markers we find in patients and therapies.” He also noted that the extension of survival is another component of costeffectiveness. “Obviously, when we keep people alive longer, it will cost the system more, but that is our goal: to keep people alive longer with a good quality of life, and, certainly, biomarker testing helps us accomplish that with appropriate treatments.” —Monica Smith Drs. Lindeman and Kim reported no relevant financial relationships.

Study Assesses Role of Proteomic Test To Guide NSCLC Rx A

serum-based, proteomic test may help improve overall survival in patients with advanced non-small cell lung cancer (NSCLC) while also helping to contain treatment-related costs, according to new research. The study used data from the PROSE study, a Phase III evaluation of the effectiveness of VeriStrat (Biodesix) in predicting which patients would benefit from second-line erlotinib (Tarceva, Genentech) versus chemotherapy. The aim of the study, which was funded by Biodesix, was to evaluate the outcomes and economic implications of using the proteomic test to guide treatment decisions. To conduct their analysis, the investigators used the proteomic test to guide treatment recommendations for patients with advanced NSCLC who had epidermal growth factor receptor ((EGFR)- and anaplastic lymphoma kinase (ALK ( K)-negative or unknown status, and who had progressed after at least one chemotherapy treatment. They compared outcomes between patients whose treatment was influenced by the results of the proteomic test and patients whose treatment went unchanged. They used

treatment utilization, adverse events, survival and the number of qualityadjusted life-years (QALY) as clinical end points, and gauged economic end points based on the cumulative lifetime cost of medical care and the cost per QALY gained. They found that 27.3% of the patients taking erlotinib for second- or third-line therapy were switched to chemotherapy after the proteomic test. Overall survival and QALYs increased, by 0.091 and 0.050 years, respectively, whereas medical costs decreased. The investigators concluded that the proteomic test modified treatment decisions in patients with NSCLC who failed prior chemotherapy regimens and, as a result, improved QALY and saved money. “The leading question in this type of analysis is, are you offsetting any cost in the health care system?,” said lead investigator John Hornberger, MD, MS, an adjunct professor of clinical medicine at Stanford University, in California, and the CEO of Cedar Associates, LLC, a Menlo Park, Calif.-based company that researches the comparative value of health care technologies. The test itself costs $3,260,

but given the difference in price between erlotinib and chemotherapy, the offset of switching from the former to the latter due to the test’s influence is more than $4,000. Surveillance costs were higher in those patients because they lived longer. Between the costs of the test, surveillance, drugs and administration and management of adverse events, use of the proteomic test ultimately resulted in cost savings of $135 per patient. “What sets this test apart from genomic tests is that you usually do not see survival benefits with genomic tests,” Dr. Hornberger said. “Take, for example, the Oncotype DX test. Too many women were getting chemotherapy who didn’t need it. There’s no survival advantage with [forgoing chemotherapy], but it helps to determine who can avoid the toxicity of chemotherapy.” Veracyte, which identifies the subgroup of patients with indeterminate nodules who should undergo thyroid surgery, is another test that benefits patients, by sparing those who don’t need it the morbidity and mortality of surgery, but it offers no true survival benefit, he said. The VeriStrat test, however, “translates into a month of survival, and that’s

actually quite remarkable,” Dr. Hornberger said. “There are a lot of drugs administered in cancer that do not do that. This has a survival benefit you rarely see.” Edward S. Kim, MD, FACP, the chair of solid Tumor Oncology and Investigational Therapeutics at the Carolinas HealthCare System’s Levine Cancer Institute, in Charlotte, N.C., said the availability of biomarker-directed, personalized therapy has the potential to drive down costs by optimizing which patients will benefit from a therapy, as opposed to treating everyone knowing that some will do a little better with the addition of a drug and some will get a little worse. “Although prior blood-based biomarker tests have had mixed results, this is definitely an area of high interest,” he said. “But I do think this test has a specific niche in an area that is becoming less and less relevant because people are using other therapies and are not using erlotinib in either second- or third-line treatment in patients without EGFR mutations.” —Monica J. Smith Dr. Hornberger reported a financial relationship with Biodesix. Dr. Kim reported no relevant financial relationships.

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CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

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The following is an excerpt from

Colorectal Cancer

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By Shahab U. Ahmed, MD and Cathy Eng, MD The University of Texas MD Anderson Cancer Center, Houston, Texas

Treatment of Metastatic Colorectal Cancer Studies have found that approximately 50% to 60% of patients with colorectal cancer (CRC) develop metastatic CRC (mCRC).1-3 The SEER database shows 5-year survival for stage IV CRC is only 12.9%. Several agents (cytotoxic and biologic) are available for use alone or in combination to treat advanced mCRC. The NCCN-recommended lines of therapies are illustrated in the Figure.

References 1. Van Cutsem E, Nordlinger B, Adam R, et al. Towards a pan-European consensus on the treatment of patients with colorectal liver metastases. Eur J Cancer. 2006;42(14):2212-2221, PMID: 16904315. 2. Lee WS, Yun SH, Chun HK, et al. Pulmonary resection for metastases from colorectal cancer: prognostic factors and survival. Int J Colorectal Dis. 2007;22(6): 699-704, PMID: 17109105. 3. Yoo PS, Lopez-Soler RI, Longo WE, et al. Liver resection for metastatic colorectal cancer in the age of neoadjuvant chemotherapy and bevacizumab. Clin Colorectal Cancer. 2006;6(3):202-207, PMID: 17026789.

First-line Therapy

Second-line Therapy

Third-line Therapy

Salvage Therapy

FOLFOX ± bevacizumab CAPOX ± bevacizumab FOLFOX ± cetuximab or panitumumab

FOLFIRI ± bevacizumab or aflibercept

Irinotecan ± cetuximab or panitumumab

Regorafenib or trial(s)

FOLFIRI ± cetuximab or panitumumab Irinotecan ± cetuximab or panitumumab

Regorafenib

Trials(s)

FOLFOX ± bevacizumab CAPOX ± bevacizumab

Irinotecan ± cetuximab or panitumumab

Regorafenib or trial(s)

Irinotecan ± cetuximab or panitumumab

FOLFOX or CAPOX

Irinotecan ± cetuximab or panitumumab

Regorafenib

Trials(s)

Oxaliplatin- or irinotecan-based therapy ± targeted therapy

Supportive care

FOLFIRI ± bevacizumab FOLFIRI ± cetuximab or panitumumab

FOLFOXIRI

Regorafenib 5-FU/leucovorin or cetuximab or panitumumab

Responded

Progressed

Treatment options for metastatic CRC according to NCCN guidelines.

CURRENT PRACTICE

CANCER CARE continued from page 1

Oncology (ASCO). “The State of Cancer Care in America: 2015,” published in the March issue of the Journal of Oncology Practice and presented at a Congressional briefing, chronicles the current realities of the cancer care system and outlines trends in the oncology workforce and practice environment that affect patient care and access (J ( Oncol Pract 2015;11[2]:79-113, PMID: 25784575). “This year’s report clarifies multiple stresses in our nation’s cancer care system, but there is reason to be hopeful,” said ASCO President Peter P. Yu, MD, in a statement. “With this knowledge and insight, we can identify ways to ensure that all patients with cancer receive high-quality care—and help oncology practices adapt, survive and succeed in today’s demanding health care environment.” The report’s findings come as no surprise to people who have been following trends in cancer care over the past decade. The Institute of Medicine’s (IOM) first report on cancer care delivery in 1999 warned about the growing need for care and the shrinking workforce. Since that time, updated reports from the IOM found the system to be “in crisis,” and recommended changes to make cancer care more patient-centered, coordinated and evidence-based. As part of these efforts, ASCO performs regular analyses to track demographics and other workforce trends in the medical oncology community. The organization’s latest report found that, in 2014, the United States made significant progress in cancer, demonstrated by an improvement in the five-year survival rate for many cancer types and a record 14.5 million survivors, as well as

CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

the availability of 10 new drugs and several new tests for the diagnosis or treatment of patients with cancer.

Demand Outpacing Supply At the same time, however, ASCO reported new challenges to high-quality cancer care delivery. Due largely to an aging population, a dramatic 45% increase in cancer incidence is expected by 2030, leading to an overwhelming demand for cancer care and posttreatment services in coming years. Barring any unexpected changes in current diet and exercise patterns, obesity will continue to increase, contributing to an additional 500,000 cancer

cases over the same period. Despite this forecast, the oncology workforce size remains unchanged and may soon be outpaced by demand. ASCO reports that nearly 20% of medical oncologists are aged 64 years or older, and their numbers are not matched by those of young oncologists entering the field. Oncologists younger than age 40 years represent only 16% of the workforce. Because training takes at least 10 years from the time medical school begins, these data suggest that the number of new physicians will not be adequate to replace those leaving. Moreover, professional burnout rates are rising, with one-third of oncology

ASCO Report Describes Continued Shifting of Oncology Practices

SCO’s “The State of Cancer Care in America: 2015,” warned that oncology practices continue to experience extreme volatility, “with changes occurring in virtually every facet of the cancer care delivery system.” Economic constraints, competition, growing administrative burdens and the proliferation of cost-containment programs are some of the pressures that contribute to practice uncertainty, according to the report. Among the findings: • In 2014, cost and payor pressures persisted as the most pressing oncology practice concern, especially among physician-owned and hospital-based practices. • Escalating drug prices remains a major concern. • Nearly three-quarters (72%) of practices report continuing to work in a feefor-service payment system; other payment models (including capitation and bundled payment) are being used to a lesser degree but are on the rise. • About 36% of oncology practices report either implementing or considering implementing a pathways program, and 30% were considering medical-home programs that emphasize care coordination. (Medicare recently announced plans to dramatically change 85% of its fee-for-service payment system to a value- or quality-based model by 2016 and 90% by 2018.) • One-quarter of community-based oncology practices report the likelihood of becoming affiliated with a hospital over the next year; smaller percentages of practices indicated the likelihood of affiliation with another practice (18%) or an academic medical center (17%). • Oncology practices report that the administrative burden imposed by insurance companies and time spent dealing with patient insurance issues are reducing the time available for patient care. —C.F.

fellows reporting burnout and saying they do not anticipate working as many hours as their older colleagues. ASCO cautioned that failure to address physician burnout and other quality-oflife issues could lead to serious workforce consequences, with oncologists reducing their patient volume or retiring at younger ages. “I think that we are going to be coming to a point where there simply will not be enough people who are formally trained and certified in oncology to take care of all the patients,” said Edward J. Benz, MD, the president of Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston. Dr. Benz said he wasn’t surprised by the report, noting that the “worrisome trends are continuing and, if anything, becoming more pronounced.” He added that effects of the insufficient oncology workforce are already being felt. “I think right now it is affecting cancer care in a geographically heterogeneous way. I think the areas that have major health centers, that have comprehensive cancer centers, the supply of oncologists is adequate. In some cases, there is probably an abundance of oncologists. But, if you start to look at the availability of oncologists in more rural regions or in underserved regions, you find that the shortage is already being felt.” The workforce issues go beyond the number and age of practicing oncologists, the report found. Diversity—rather, a lack of it—remains a problem in oncology care. Only 2.3% of practicing oncologists are black, although the U.S. Census estimates that approximately 13% of the population is black. Even in training programs, the numbers remain low, with only 4% of oncology fellows being black. ASCO notes that this figure, which lags about 2% behind the general population

9-12 13-14 15-17 18-43

Oncologists per 100,000 residents aged 55 years and older.

Rural sites Urban sites

Urban and rural oncology care sites.

Used with permission from American Society of Clinical Oncology; based on Centers for Medicare & Medicaid Services Physician Compare and Census Tiger Shapefiles. © ASCO 2015

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

of residents and fellows, has hovered at this level for a decade. Women are also underrepresented in medical oncology, the numbers show. Women account for just over 30% of oncologists in 2014, a figure approaching but still slightly below the 32.6% overall figure for women in medicine. “Usually, workforce development and diversity have not been on the forefront of the agenda, so I’m very pleased to see that ASCO has highlighted both workforce shortages and cancer disparity,” said Maureen Y. Lichtveld, MD, MPH, the chair and associate director of population sciences at Tulane University School of Public Health and Cancer Center, in New Orleans. Dr. Lichtveld led public health workforce efforts for more than a decade and is a board member of C-Change, a national multi-stakeholder group dedicated to “eliminating cancer as a major public health problem at the earliest time.” She and other experts who have been involved with cancer care policy argue that oncology must adopt a more “teamcare approach” to caring for cancer patients, to provide effective care to the growing numbers of patients. “The ASCO data demonstrate that turning out more specialists will not solve our problem in a sustainable fashion,” Dr. Lichtveld said. “It requires a system-driven, interdisciplinary approach to bolster the cancer workforce, and that means establishing a dream team of oncologists and nononcologists working seamlessly together across the cancer continuum from prevention to survivorship.” Payment reform is needed to support such new systems for care, experts say (see related article, page 1). “Things really just need to be reorganized; so, we may not have as much of a doomsday if we can think outside of the box and get ourselves organized to share care among various members of the oncology care team,” said Patricia Ganz, MD, a medical oncologist at the University of California, Los Angeles, who chaired the 2013 IOM panel that wrote a consensus report on delivery of highquality cancer care. “There are many people who could do important pieces of the care delivery, and many of those areas of the workforce are also going to be in short supply. Right now, what we have is the physician who is the one who can bill and be compensated for the visit. Other professionals, such as nurses, genetic counselors and pharmacists, have relevant skills and could provide essential components of care. Currently, they are not participants in care, either because they don’t have the ability to bill or are not part of the care team and, thus, aren’t available when the patient may be coming for an office visit,” she said. “I’m not saying that we all need to be institution-based, salaried and under

‘I think that we are going to be coming to a point where there simply will not be enough people who are formally trained and certified in oncology to take care of all the patients.’

—Edward J. Benz, MD

one roof. That’s not going to happen in America,” Dr. Ganz said. But, she added, “We need to have a better way of organizing care, so that the patient doesn’t need to be navigated and so that care is better coordinated with

all professionals contributing and providing the care they are trained and licensed to deliver. Patient navigation is a solution for a system that is broken and fragmented,” Dr. Ganz said. Asked about the role of practicing

oncologists in attracting more young colleagues to this career, Dr. Benz called on oncologists to be “great ambassadors for our field. We need to make sure people know that as challenging as the management of cancer patients can be, as challenging as some of the changing economics of practice are, this is still a wonderful way to practice medicine,” he said. “Our messaging of what’s it’s like to be in oncology is probably the most powerful thing we can do to make sure that more people decide to go into oncology.” —Christina Frangou

CTCA® FORUM 2015

Cancer Treatment Centers of America®

SYMPOSIUM

Advances & Controversies in Gynecologic Oncology Friday, July 24, 2015 8:00 AM to 5:15 PM Radisson Blu Aqua Hotel Chicago, Illinois REGISTER NOW AT ctcaforumgynonc.org Participants in this CME program will be invited to share their perspectives and clinical experience surrounding evolving management strategies to improve outcomes in patients with gynecologic cancer.

PROGRAM CHAIRS Giuseppe Del Priore, MD, MPH National Director, Gynecologic Oncology Cancer Treatment Centers of America Newnan, Georgia Maurie Markman, MD President of Medicine and Science Cancer Treatment Centers of America Philadelphia, Pennsylvania

CME Credits will be available. Complimentary for gynecologic and medical oncology fellows. #CTCAForum Jointly provided by Dannemiller and Athena Education Group. Dannemiller and Athena Education Group gratefully acknowledge an educational grant from Cancer Treatment Centers of America® in support of this continuing medical education activity.

Faculty Peter Argenta, MD William A. Cliby, MD Robert L. Coleman, MD David M. Gershenson, MD Maurie Markman, MD

Daniela Matei, MD Julian Clifford Schink, MD William Small, MD Jason D. Wright, MD

CURRENT PRACTICE

PAYMENT MODELS continued from page 1

“If I use an expensive drug, I get paid 6% of an expensive drug; if I use a cheap drug, I get 6% of a cheap drug. So, the financial incentive is to use more drugs and to use more expensive drugs. None of us believe that we respond to these incentives, but economists say we are kidding ourselves, and payors and policymakers certainly believe that incentives drive utilization.” In this final installment of a three-part series, Clinical Oncology News will discuss specific programs and proposals to reduce total costs and improve patient care while using the highest standards of care—lofty goals for all.

New Medicare Models This year, the Centers for Medicare & Medicaid Services (CMS) announced a new, voluntary, five-year pilot oncology care model that focuses on an episode of chemotherapy care. An episode is a six-month period. Oncologists will continue to receive their normal feefor-service payments, with an additional $160 per beneficiary per month (the one-sided model). A two-sided model is an option for practices after the second year of the program. If a practice chooses the two-sided risk model, the target price for savings is easier to achieve. However, if the practice spends more than the target price, CMS does not reimburse for the extra spending, essentially making the practice share the risk for the reduced savings. “CMS is using this amalgam of feefor-service, global payments and extra monetary incentives for quality, but when one looks at the quality metrics, they are nonspecific,” said Sam Silver, MD, PhD, MACP, a professor of hematology at the University of Michigan, Ann Arbor. The metrics concern issues such as how quickly a patient is placed into hospice and the number of ED visits or hospitalizations a patient needs. Requirements for qualification are provided in the Table. Dr. Silver said he could not see a downside to joining the one-sided model that provides the episode payment. “There’s no risk. You are going to collect $160 per patient per month—money you would not have otherwise gotten. After three years, you probably won’t be able to show that you are 4% under the predicted spend, and you probably won’t be invited back for year 4 or 5, but for the first three years, you will have had a bonus for every patient on IV or oral chemotherapy or hormonal therapy,” he said philosophically. Dr. Ward disagreed. “Medicare is going to pay me a management fee up front and ask me to collect a whole bunch of data, for which Medicare hasn’t given us any details. So my guess is that management fee really is not going to

CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

Table. Qualifications for the CMS Pilot Oncology Model To qualify, practices must: • Provide 24/7 patient access to a clinician who can immediately review the patient’s EMR • Have a certified EMR • Use data for continuous quality improvement • Provide core functions of patient navigation • Document a care plan for every patient that covers specific components • Use nationally recognized clinical treatment guidelines • Show a reduction in costs after the third year of the program CMS, Centers for Medicare & Medicaid Services; EMR, electronic medical record

be a management fee. It’s going to be a data collection fee, and it will get swallowed up entirely [and won’t be used for patient care].”

Insurance Programs: UnitedHealthcare and Anthem Although UnitedHealthcare offers Medicare Advantage plans, which CMS has encouraged to be part of the pilot, it will not be joining the CMS model right now because it is busy with other programs. This year, UnitedHealthcare is rolling out a national prior authorization program based on guidelines from the National Comprehensive Cancer Network (NCCN) that will be offered for its commercial insurance and some Medicaid plans. “We’ve always used the NCCN guidelines to determine what we will cover, and now it is online. As the physician goes online and gives us the clinical information we need, we can take him to the exact point in the guideline and show all the treatments that we will cover,” said Lee Newcomer, MD, senior vice president of oncology at UnitedHealthcare. If there is a compelling medical reason to deviate from the guideline, the physician also can request this online and receive an answer quickly. In Florida, where this program was piloted, UnitedHealthcare has received 2,600 requests, and only 40 of them were denied. UnitedHealthcare also is expanding its own cancer care payment model for its commercial insurance customers. Five medical oncology groups across the country participated in the threeyear pilot program, which covered 810 patients with the most prevalent cancers in the United States: breast, colon and lung cancers. The cancers were split into 19 different episodes of care. Each oncology group declared which regimen, based on NCCN guidelines, they would follow for these episodes. UnitedHealthcare calculated the payment based on

the regimen and the existing contract between the insurer and the oncology group, and that entire payment was given up front for each patient. “They continued to see patients fee-for-service, but that was all we paid. We paid for the cost of the drugs, but we did not pay the profit for the drugs a second time, and they, in turn, focused on reducing expenses,” Dr. Newcomer said. The new cancer care model resulted in a 34% reduction in medical costs ((J Oncol Pract 2014;10[5]:322-326; PMID: 25006221). As a result, UnitedHealthcare is expanding the program. Texas Oncology joined the program in January, and five more groups will join in September, according to Dr. Newcomer. Additionally, the University of Texas MD Anderson Cancer Center, in Houston, and UnitedHealthcare launched another pilot payment model for head and neck cancers. Under this new threeyear arrangement, MD Anderson will share the risk and “accept all responsibility for the care” of 150 patients with newly diagnosed head and neck cancers for a bundled payment, Dr. Newcomer said. Eight bundled payments based on clinical practices and protocols developed by MD Anderson are used. “When these patients come into the MD Anderson system, [the center’s clinicians] will evaluate them, and then they will go into one of the bundles based on the kinds of therapies they are getting. Once we decide that, the bundle covers everything: medicine, surgery, hospitalizations, other specialists such as speech pathologists—the entire care that the patient needs,” he added. “The way [oncologists] win in this scenario is you have fewer complications,” Dr. Newcomer said. MD Anderson “has done careful work mapping out how to care for these patients, and it has reduced its complication rate.” Noting the importance of oncology as an area to focus on for cost reduction, Dr. Newcomer said that cancer therapy

accounts for 11% of UnitedHealthcare’s commercial health plan spending. “We have between 25,000 and 30,000 patients on active therapy in any given year, and the cancer spend is second to cardiac care for us.” Anthem Inc., the largest Blue Cross Blue Shield Association licensee, also is looking to reduce its $37.1 billion cancer costs for its 3.7 million members receiving treatment for cancer in any given year. The Anthem Cancer Care Quality Program provides enhanced reimbursement for oncologists who follow certain clinical pathways. “Our cancer care quality program is built around cancer treatment pathways, which is a subset of the whole universe of treatment regimens that are the most effective, have the best side effect profiles and are the most efficient way to treat a particular cancer,” said Jennifer L. Malin, MD, PhD, the medical director for oncology at Anthem. Participating oncologists who follow the pathways can bill for an additional $350 a month for treatment planning and care coordination, she explained. She added that the pathways, which are developed by a team of oncologists, nurses and pharmacists, based on medical evidence, would be applicable to 80% to 90% of all patients with that particular cancer type. For the remaining patients, the treating oncologist may decide on another treatment regimen. “The main benefits are first and foremost that they are part of a program that is going to provide some framework for quality care and value-based care,” Dr. Malin said. Additionally, the practice will receive quarterly reports that will tell them recent ED use and hospitalizations, as well as a comparison of their quality performance against national measures so they can benchmark themselves. Dr. Malin said that the program “allows us to shift the reimbursement from being driven primarily on the margin on drugs and to have a way to support practices so that they can practice in a more value-conscious way while still achieving the best quality possible.” There is no doubt that clinical pathways can help an oncologist provide good, evidence-based care for his or her patients, explained Marcus Neubauer, MD, the medical director of oncology services for McKesson Specialty Health and The US Oncology Network. Many practices, including those in The US Oncology Network, have developed clinical pathways. However, Dr. Neubauer said, it could be difficult if a practice has to follow different clinical pathways for each third-party payor. “The problem is that a busy oncologist today could have four or five different pathways to follow, depending on the insurer, and I do not think this is the best model.”

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

Oncologists’ Initiatives Total in 2010

Projected increase in 2020

Breast

20.5 20

Colorectal Lung Lymphoma Prostate Leukemia

Cancer Site

Third-party payors are not the only ones trying to deliver better, more cost-effective care. Oncologists also are taking on the challenge. Several associations, including the American Society of Clinical Oncology (ASCO), have developed new payment models. ASCO’s model tries to develop a patient-centered payment structure, while better matching the services that oncologists and their teams provide. Additionally, ASCO wants to simplify billing, create a more predictable revenue stream and incentivize high-quality, high-value care, according to Dr. Ward, who headed the ASCO oncology payment reform committee that developed the program. Instead of a six-month or total payment up front, the ASCO model calls for a monthly payment based on phases of the patient’s care: new patient, treatment months, monitoring months and transition of treatment, because each phase requires a different effort from the oncologist and staff. Instead of tying the payment to a disease, ASCO ties the payment to the individual patient and his or her performance status, comorbidities and the complexity of the regimen they are receiving. It better reflects the circumstances of an individual patient, Dr. Ward explained. There also would be payments for hitting quality measures that adhere to clinical pathways, reduce resource utilization, such as ED visits and hospitalizations, and encourage patients to join clinical trials. “It limits the incentive to use expensive or unnecessary treatments, rewards oncologists for getting it right and offers coding simplicity, replacing more than 50 codes with less than 10,” Dr. Ward explained. The physician-led US Oncology Network, one of the nation’s largest networks of integrated, community oncology practices, with more than 1,000 physicians in 400 sites of care, instituted a pathways program (now called Value Pathways powered by NCCN) in 2005. “In the last 10 years, we’ve been able to show that if you adhere to clinical pathways, you preserve quality and outcomes and you decrease costs,” Dr. Neubauer said. The clinical pathways program is embedded into The US Oncology Network electronic health records system, so every physician at every practice site uses it. Network physicians can make an off-pathway choice for a particular patient, but most patients fit into the treatment pathway, he said. US Oncology also has an oncology medical home model, called Innovent Oncology, that uses the pathways program and a nurse call center to reduce ED visits and avoidable hospitalizations. Innovent Oncology supports patients before the first scheduled treatment and continues throughout

Ovary Brain Bladder Kidney Head/Neck Uterus Melanoma Pancreas Stomach 0

U.S. Billion Dollars

Figure. Trends in cancer costs. Source: National Cancer Institute (http://costprojections.cancer.gov/expenditures.html)

pain in her chest, the nurse will help her decide whether that pain is due to her cancer or she is having a heart attack. If she is having a heart attack, she will be directed to call 911 and go to the ED. “On the other hand, if she is having chest pains because she is a 40-year-old woman with breast cancer that has spread to her ribs, and her ribs hurt, I don’t want her going to the ED as a heart attack and having a bunch of cardiac testing done to her. I want her to come to the office,” Dr. McAneny said. Dr. McAneny’s cancer center sees about 3,000 new cancer patients a year and, although she and the other community cancer centers covered by the grant still are collecting outcomes data, she estimated that hospitalizations have dropped by between 30% to 50%, ED use has decreased and patient satisfaction is routinely in the 90th percentile. “And we are saving money,” she said, “about $4,000 per patient.” But an oncologist cannot just come into the office one day and declare his or her facility an OPCMH. Medical homes require an infrastructure that includes electronic medical records and the staffing to care for patients outside of normal business hours. Dr. McAneny and her team developed diagnostic, therapeutic and triage pathways that ensure that patients are managed appropriately. That infrastructure is an expensive investment, she said. “Right now, we are open until 8:00 at night, and we’re open on weekends, but that is an expensive thing to do because if only one person shows up, I’m still paying a doctor, two nurses, a laboratory technician and an x-ray technician to sit around and wait in case somebody gets sick,” said Dr. McAneny. “That’s a lot of expense with no revenue.”

Conclusion the course of therapy, striving to achieve consistency of care, cost control and a better patient experience. Results of an Innovent Oncology pilot, sponsored by Aetna and conducted by Texas Oncology, an affiliate of US Oncology, were published in 2014. The program decreased ED visits by 39.8%, hospital admissions by 16.5% and number of hospital days by 35.9% among the 184 enrolled members. The program resulted in approximately 12% cost savings for lung, breast and colorectal cancers alone, according to Dr. Neubauer, and there are plans to expand the program to other practices in the network. Barbara L. McAneny, MD, CEO of the New Mexico Cancer Center, in Gallup, set up an oncology patient-centered medical home (OPCMH), which uses a team approach to care for the patient, a growing trend to reduce the fragmented delivery of primary health care. Dr. McAneny received a CMS Innovation grant in early 2012 to duplicate her

ideas in six other community oncology practices. Another goal of the OPCMH is to provide a framework for better-coordinated, evidence-based care. Under such a framework, “the oncologist and everyone else on the team can work to the top of their license,” Dr. McAneny explained. “Oncologists can focus on what we do, which is discussing treatment options with patients, setting up treatment plans, overseeing patient care, making sure that treatment happens properly, and, if there are any side effects or complications, [making sure] they are taken care of, and then watching for any recurrence or new problem.” Triaging cancer patients is an important part of Dr. McAneny’s services. Anyone who calls the cancer center with a variation of “I’m sick” is sent to the triage nurse, who uses the electronic triage pathways to direct that patient’s care. For instance, if a woman with breast cancer calls because she is having

These and other pilot programs appear to provide the basis for lowering the cost of managing cancer patients, while improving outcomes and providing a fair reimbursement to oncologists. Which model eventually will cover all oncologists is impossible to predict. Quite possibly, it will remain a patchwork of ideas for some time. “We need to continue to sort through which programs are the best fit for oncology practices,” Dr. Neubauer added. “But there is no question in my mind—innovative payment models are not going away.” Regardless of which payment models are used, it is clear that there will be a dramatic shift in the way that America pays for cancer care. —Marie Rosenthal

For Parts 1 and 2 of this series, go to clinicaloncology.com.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

Report From ACCC Annual Meeting:

Proving You Provide Quality Oncology Care Can Be Challenging Arlington, Va.—Every cancer care provider is in favor of quality, but adhering to all quality measures and extracting data from patient medical records to demonstrate proof of quality care to insurance providers and accrediting organizations isn’t easy right now for any oncology practice, large or small, panelists said at the Association of Community Cancer Centers’ annual meeting. Implementing quality improvement (QI) processes also can be difficult for oncology practices, they said. Representatives from four organizations—American Society of Clinical Oncology (ASCO), the Commission on Cancer (CoC), Flatiron Health, Inc, and the National Quality Forum (NQF)— described initiatives they are working on to enable oncology programs to more easily adhere to quality measures and monitor performance. ASCO has a long history of promoting cancer care quality, said Robert Miller, MD, the organization’s senior director of quality and guidelines. ASCO has

developed a portfolio of quality programs, including the Quality Oncology Practice Initiative (QOPI), an oncologist-led practice-based quality assessment and QI program. Participating practices can sign up for patient data extraction twice a year, reported through a centralized system. Now in its 10th year, the program has 7,000 participants, representing half of U.S. oncology practices, Dr. Miller said. ASCO also has a QOPI Certification Program (QCP), in which the organization awards three-year certifications to outpatient hematology/oncology practices that demonstrate quality. Additionally, ASCO has about 50 evidencebased clinical practice guidelines. Later this year, the organization is expected to launch CancerLinQ, a health information technology platform that will aggregate and analyze cancer care data in real time, so practices can measure their performance against guidelines and peer performance. Information about all of these efforts can be found at the ASCO Institute for Quality’s website: http://

www.instituteforquality.org/. CoC, a program of the American College of Surgeons, is a consortium of 55 organizations aiming to improve quality of life and survival for cancer patients, said Daniel McKellar, MD, the organization’s chair. The CoC guides oncology practices during QI efforts, providing quality metrics and accrediting practices that adhere to the metrics. The organization also has launched a Rapid Quality Reporting System, a QI tool providing reports on hospital adherence to quality of care measures for breast and colorectal cancers. Hospitals submit data in real time, and receive monthly reports. Centers can see if there are patients for whom they haven’t met quality indicators “so that it’s not too late to impact those cancer patients that may fall through the cracks,” Dr. McKellar said. For more information, see https:// www.facs.org/quality-programs/cancer/ ncdb/qualitytools/rqrs. Flatiron Health, a health care technology company in New York City, is

developing software programs aimed at reducing the time and effort it takes to report on quality metrics, said Robert Green, MD, the company’s vice president of oncology. One program, OncoAnalytics, integrates electronic medical record (EMR), practice management and billing data to boost data analysis. Another, called OncoEMR, is a cloud-based system that integrates various oncology pathways, so clinicians “don’t have to log on to three different pieces of software to document that they’re adhering to NCCN [National Comprehensive Cancer Network] guidelines,” said Dr. Green, a community oncologist who practiced for 15 years in West Palm Beach, Fla., before joining the company last summer and now sees patients on a limited basis. For more information, see http://www.flatiron.com/. The NQF identifies QI priorities and endorses and recommends measures for use in payment and public reporting programs for all areas of health care, including cancer and palliative/ end-of-life care. Descriptions of the 72

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CLINICAL ONCOLOGY NEWS • MAY 2015 • CLINICALONCOLOGY.COM

NQF-endorsed cancer and palliative/ end-of-life care measures can be found through the organization’s Quality Positioning System (QPS) at http://qualityforum.org/QPS. NQF also identifies gaps in measures as a way to prompt developers and others to focus their efforts, said Ann Greiner, the organization’s vice president of external affairs. Examples include pain screening and monitoring, total cost of cancer care, and effectiveness of surgical, radiation and medical therapies. “We’re very focused on making sure that the performance measures we endorse are evidence-based and have the highest scientific rigor,” Ms. Greiner said. “But we can have the best quality measures and they can sit on a shelf unless everybody in health care agrees that these are the measures they will use and that they value.” NQF brings stakeholders together to try to forge consensus, she said.

electronic version of QOPI, called eQOPI that would make it easier by extracting data directly from the EMR; eQOPI could launch as soon as this year, Dr. Miller said. This electronic version of QOPI will have a manual supplement to enter data such as comorbidity adjustments or patient refusal of therapy, he said. Better understanding of QI also is needed, the panelists said. Many practices don’t understand what to study or how to improve, said Dr. McKellar, who lectures frequently on QI. The CoC offers educational tools to help make things more clear. Additionally, ASCO piloted a

Data Extraction Is A Major Challenge A major barrier to oncology practices improving quality lies in the difficulty of extracting data from medical records, the panelists said. The CoC started a pilot project for accreditation of oncology medical homes, in which oncology practices must submit patient data that document the care that is being delivered. “The data is there, but it has to be manually extracted” from EMRs for QOPI and for hospital cancer registries, Dr. McKellar said. Smaller hospitals struggle with getting data to his organization. “Every practice I talk to thinks QOPI is great,” Flatiron’s Dr. Green said, but the reason more hospitals don’t contribute to it is because of the work involved. ASCO is in the process of developing an SOLID TUMORS

TKIs continued from page 14

“This may be why they are not as effective against micrometastatic disease as chemotherapy is,” he added, pointing out that this has been shown in other solid tumors, such as colon and breast tumors. Dr. Haas said that ASSURE is the first trial to report on the efficacy of VEGF TKIs as adjuvant therapy for patients with locally advanced, resected kidney cancer at high risk for recurrence. Trials testing VEGF inhibitors and mammalian target of rapamycin inhibitors are underway in this same patient population, and some are evaluating longer treatment durations. —Kate O’Rourke Dr. Haas disclosed relevant relationships with Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Merck and Tetralogic. Dr. Ryan disclosed relationships with Astellas Pharma, Bayer, BIND, Janssen Oncology, Karyopharm, Millennium and Novartis.

quality training program through which practices are able to go to the organization’s headquarters to learn more about QI, Dr. Miller said. “You can’t improve quality unless you know what level of quality you’re delivering now,” Dr. Green said. Data programs that allow practices to assess how they are doing and see improvement over time help, he said. “There are different tools people can use to affect change, but the starting point has to be understanding your baseline and the direction you’re going.” Ms. Greiner said she would like to see more programs retrieve patient-reported

outcome measures directly from patients, through cell phones and other applications that are accessible and easy to use. But physicians and other front-line clinicians need to stay at the forefront of quality programs, Dr. Miller said. “You’re never going to have success unless the people in the trenches are the ones helping to design the systems to tackle some of these data questions.” —Karen Blum Dr. Green is an employee of Flatiron Health. None of the other sources reported any relevant financial relationships.

Cases in Hyponatremia

Minimizing Risks, Optimizing Outcomes To participate in this FREE CME activity, log on to

www.CMEZone.com/hyponatremia Release Date: November 11, 2014

Expiration Date: November 11, 2015

Faculty

Goal

Michael L. Moritz, MD

The goal of this educational activity is to provide clinicians with clinically relevant information and practice strategies concerning the assessment and management of hyponatremia.

Professor, Pediatrics Clinical Director, Pediatric Nephrology Medical Director, Pediatric Dialysis Children’s Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania

Denise H. Rhoney, PharmD Ron and Nancy McFarlane Distinguished Professor and Chair Division of Practice Advancement and Clinical Education UNC Eshelman School of Pharmacy Chapel Hill, North Carolina

Learning Objectives At the completion of this activity, participants will be better prepared to: 1 Distinguish the various subtypes of hyponatremia. 2 Describe the comorbidities and causes commonly associated with hyponatremia and their signiﬁcance in treatment. 3 Summarize current evidence and best practices in the management of hyponatremia. 4 Explain how to mitigate adverse events secondary to treatment of hyponatremia. 5 Apply strategies to improve the management of hospitalized patients with hyponatremia.

Intended Audience The intended audience for this educational activity includes physicians (cardiologists, critical care specialists, endocrinologists, hepatologists, hospitalists, intensivists, and nephrologists), nurses, pharmacists, and other clinicians who care for individuals with hyponatremia.

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies

This activity is jointly provided by Global Education Group and Applied Clinical Education.

of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group and Applied Clinical Education. Global Education Group is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Global Education Group designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Pharmacist Continuing Education Accreditation Statement Global Education Group is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Credit Designation Global Education Group designates this continuing education activity for 1.0 contact hour(s) (0.10 CEUs) of the Accreditation Council for Pharmacy Education. (Universal Activity Number - 0530-9999-14-061-H01-P) This is a knowledge-based activity

Accreditor Contact Information For information about the accreditation of this program, please contact Global Education Group at (303) 395-1782 or inquire@globaleducationgroup.com.

Supported by an educational grant from Otsuka America Pharmaceutical Inc.

Distributed via CMEZone

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