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In the era of personalized medicine, paradigms for treating non-small cell lung cancer (NSCLC) are evolv-
ing. With the discovery of mutation drivers for NSCLC—including EGFR, KRAS, and EMLA 4-ALK—targeted therapies directed to those mutations are beginning to make a difference. While more work needs to be done to improve outcomes, advances thus far were discussed by Chandra P. Belani, MD, deputy director of the Penn State Hershey Cancer Institute in Pittsburgh, Pennsylvania.
Lung cancer is still the leading cause of death in 2011. NSCLC currently accounts for about 87% of all cases and small cell lung cancer (SCLC) for about 13%.
Adjuvant chemotherapy is now the standard of care for early resectable (<4 cm) NSCLC, Belani said. Adjuvant chemotherapy has improved overall survival (OS) from 4.1% to 15%.
Cisplatin/vinorelbine has been the most common doublet used in all clinical trials, but up to 50% of patients are not
Lung Cancer News
Biomarker Identifies Patients With Advanced Lung Cancer Who Will Gain Most From Add-On Cetuximab
Feature
Changing Paradigms for NSCLC in Personalized Therapy EraBy Alice Goodman
By Jill Stein
Investigators reported that high tumor epidermal growth factor receptor (EGFR) expression is a predic-tive biomarker that defines patients with advanced
non–small cell lung cancer (NSCLC) who are most likely to derive a survival benefit from the addition of cetuximab to platinum-based, first-line chemotherapy.
“To our knowledge, this is the first study to show that tumor EGFR expression level is associated with survival benefit for a targeted therapy given concurrently with first-line chemotherapy in patients with advanced NSCLC,” said Robert Pirker, MD, with the Medical University of Vienna in Austria, and associates.
For their study, the group examined the association of tumor
(continued on page 14) (continued on page 14)
(continued on page 12)
Robert Pirker, MD
Chandra P. Belani, MD Prostate Cancer Armamentarium ExpandingBy Alice Goodman
Men with prostate cancer now have an array of treatments, which was not the case a decade ago. The radiopharmaceutical radium-223 will probably be approved by the FDA for metastatic castration-resistant prostate can-
cer (CRPC). That likely approval is based on the overwhelmingly positive findings in the Alpharadin in the Treatment of Patients With Symptomatic Prostate Cancer (ALSYMPCA) trial. Another experimental agent, XL-184 (cabozantinib), has shown encouraging results in disease stabilization in men with metastatic CRPC and sig-nificant effects on bone scans. A third agent undergoing clinical trials is a neu-traceutical, pomegranate extract, which appears to slow prostate-specific antigen (PSA) doubling time in men with rising PSA levels, but it is not clear if that will translate to improved outcomes. These prostate cancer treatments were discussed by different speakers at the 2011 Chemotherapy Foundation Symposium.
“Radium-223 promises to become a new standard of treatment for men with CRPC who have bone metastasis,” said Oliver Sartor, MD, director of the Tulane Cancer Center in New Orleans, Louisianna. This radiopharmaceutical is not only effective in improving survival, but its safety profile is at least as benign as placebo, according to results of the phase III, multicenter, randomized, placebo-controlled ALSYMPCA trial. Results of this trial were reported at the September 2011 meeting of the European Multidisciplinary Cancer Congress in Stockholm, Sweden.
The study included 922 patients with CRPC and at least 2 bone metastases and no known visceral metastasis who were randomized to radium-223 or placebo. At a pre-planned interim analysis, radium-223 had a clear survival benefit. Median overall survival was 14 months for radium-223 versus 11.2 months for placebo. The study was
(continued on page 16)
For the Practicing Oncology Professional
The Hope and Challenges of Personalized Medicine Cancer treatment is moving from a one-size-fits-all approach to personalized medicine, which means matching the right drug with the right tumor characteristics.
Gordon B. Mills, MD
In this issue...Breast Cancer• Applications
of Emerging Biomarker Research
• PARP Inhibition in Triple-Negative Breast Cancer
• NKTR 102 Moves to a Phase III Trial in Pretreated Metastatic Breast Cancer
Prostate Cancer• Integrating Targeted Therapies
Into Patient Care• Denosumab Delays Development
of Bone Metastasis in Hormone-Resistant Prostate Cancer
Hematologic Malignancies• Molecular Markers for Prediction,
Treatment, and Monitoring in AML • New Diagnostic Assays for
Leukemia
Lung Cancer• Bevacizumab Combination
Effective as Maintenance Therapy
Renal Cell Carcinoma• Axitinib Approved
Head and Neck Cancers• New Options Emerge
10th International Congress on Targeted Therapies in Cancer
L’Enfant Plaza HotelWashington, DCAugust 10-12, 2012
02.12
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OncLive TV provides short, focused interviews with key oncology thought leaders. This unique platform allows oncology professionals to learn about important developments directly from their peers.
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Dr. Rugo
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Dr. Scagliotti
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www.OncLiveTV.comA Network of Your Peers
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Oncology Nurseswww.OncNurseLive.comReports and Insights for Nurses and Nurse Navigators
OncLive.com’s nurses page provides clinical coverage for oncology nurses and nurse navigators. The exclusive content includes articles, videos, peer-to-peer clinical advice columns, and expert insights from our oncology nurse editors.
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OncLive.com provides meeting highlights from many of the top national and international conferences in oncology and hematology. From Physicians’ Education Resource meetings to scientific conferences such as ASCO, ECCO/ESMO, ASH, and SABCS, rely on OncLive.com to bring the meeting to you.
Condition Centerswww.onclive.com/specialtyTargeted Coverage for the Oncology Specialist
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From the Publisher
Welcome to Targeted Therapy News
2
Targeted Therapy News • 02.12
Editorial BoardPhysician Editor-in-Chief Alex A. Adjei, MD, PhDProfessor and Chair, Department of MedicineKatherine Anne Gioia Chair in Cancer MedicineSenior Vice President, Clinical ResearchRoswell Park Cancer InstituteBuffalo, NY
Howard A. Burris, MD, FACP Chief Medical Officer Executive Director, Drug Development ProgramSarah Cannon Research InstituteNashville, TN
Edward Chu, MDChief, Division of Hematology-OncologyUniversity of Pittsburgh School of MedicineDeputy Director, University of Pittsburgh Cancer InstitutePittsburgh, PA
Robert L. Coleman, MD, FACOG, FACSProfessor of Gynecologic OncologyVice Chair, Clinical Research, Department of Gynecologic OncologyThe University of Texas MD Anderson Cancer CenterHouston, TX
Jorge Eduardo Cortes, MDChair, CML Section, Department of LeukemiaDivision of Cancer MedicineThe University of Texas MD Anderson Cancer CenterHouston, TX
Axel Grothey, MDProfessor of Oncology; Consultant, Medical OncologyMayo ClinicRochester, MN
F. Stephen Hodi, Jr., MDDirector, Melanoma Center Associate Professor of Medicine, Harvard Medical SchoolDana-Farber Cancer InstituteBoston, MA
John P. Leonard, MDProfessor of MedicineRichard T. Silver Distinguished Professor of Hematology and Medical OncologyWeill Cornell Medical CollegeNew York, NY
Sagar Lonial, MDProfessor, Emory School of MedicineVice Chair of Clinical Affairs, Department of Hematology and Medical OncologyDirector, Translational Research, B-cell Malignancy ProgramEmory University School of MedicineAtlanta, GA
Patricia LoRusso, DOPhase I Director; Professor of MedicineBarbara Ann Karmanos Cancer InstituteWayne State UniversityDetroit, MI
Joyce A. O’Shaughnessy, MDCo-Director, Breast Cancer ResearchBaylor Charles A. Sammons Cancer Center/Texas OncologyUS OncologyDallas, TX
Antoni Ribas, MD, PhDAssociate Professor, Hematology-Oncology and Surgical OncologyAssistant Director for Clinical Programs, UCLA Human Gene Medicine ProgramDirector, JCCC Cell and Gene Therapy Core FacilityDavid Geffen School of MedicineUniversity of California, Los AngelesLos Angeles, CA
Hope Rugo, MDClinical Professor, Department of Medicine (Hematology/Oncology)Director, Breast Oncology Clinical Trials ProgramUniversity of California, San FranciscoSan Francisco, CA
Oliver Sartor, MDPiltz Professor of Cancer ResearchDepartments of Medicine and Urology Tulane University School of MedicineNew Orleans, LA
Mark A. Socinski, MDAssociate Professor, Clinical ResearchHematology/OncologyLineberger Comprehensive Cancer Center University of North CarolinaChapel Hill, NC
Anthony W. Tolcher, MD, FRCP(C)Director of Clinical ResearchSTART - South Texas Accelerated Research Therapeutics San Antonio, TX
Welcome to Targeted Therapy News, a new print and online initiative focused on the use of targeted thera-pies and personalized medicine—one of the most rapidly growing and clinically challenging areas of oncology today.
As targeted therapy research makes its way from bench to bedside, community oncologists face increasingly complex information and challenging treatment decisions. The goal of this new initiative is to provide oncology healthcare professionals with leading edge research results and treatment strategies that are directly relevant and applicable to clinical practice.
Our lead cover story, “The Hope and Challenges of Personalized Medicine,” examines the advances that have been made in moving targeted therapy research into patient care, and the issues that still remain. “Colorectal Tumor Marker: Molecular Evaluation Sheds Light on Negative Lymph Node Status,” provides a physician’s perspective on research efforts to find novel tumor markers Other articles focus on emerging research on diagnostic testing, pathways, biomarkers, and therapeutics, with an emphasis on breaking news and cutting-edge information about the use of personalized medicine in clinical care.
Targeted therapies and personalized medicine are the most important developments in cancer care today, and we are strongly committed to providing oncology healthcare professionals the information and resources they need to deliver the best possible treatment to their patients. Targeted Therapy News is part of our many other oncology-focused publications and Web sites, including the International Congress on Targeted Therapies in Cancer, a new, peer-reviewed journal. This journal capitalizes on the decade-long experience of the International Congress on Targeted Therapy in Cancer, the leading symposium on this topic. Both Targeted Therapy News and the International Congress on Targeted Therapies in Cancer can be found at www.TargetedTherapyOncology.com.
We thank you for joining us as we launch both of these exciting and important initiatives, and look forward to continuing to provide you with the tools and resources you need to keep you on the leading edge of advances in oncology research and clinical care.
Mike Hennessy
Visit OncLive.com today and become part of our online community of oncology specialists.
Bringing the Oncology Community Together
The OncLive.com Website brings together clinical news of the latest developments in cancer research, exclusive interviews with leading oncology experts, breaking coverage from national and international scientific meetings, and more. Here’s a brief recap of the stories, videos, and interactive content that you’ll find online.
Most-Read Web Exclusive Articles • BOLERO-2 Halted After Positive Interim Analysis (http://goo.gl/YSIhr) • ODAC Unanimously Supports Axitinib for Renal Cell Carcinoma (http://goo.gl/c7GJs) • Changing Fate of Bone Related Therapies for Prostate Cancer (goo.gl/jJGlB) • Ruxolitinib Gains FDA Approval for Bone Marrow Disease (http://goo.gl/ErzZD)
Most-Viewed Videos on OncLiveTV • José Baselga, MD, PhD, discusses the CLEOPATRA pertuzumab trial (http://goo.gl/lcBGl) • Tatyana Feldman, MD, discusses the difficulties in treating rare lymphomas (http://goo.gl/iOebG) • James R. Berenson, MD, reviews the toxicity profile of carfilzomib (http://goo.gl/4KfBQ)
Register for Conferences • 16th Annual International Congress on Hematologic Malignancies (http://goo.gl/rcdII) • 29th Annual Miami Breast Cancer Conference (http://goo.gl/cwDvj) • 9th International Symposium on Ovarian Cancer and Other Gynecologic Malignancies (http://goo.gl/EFz9g)
PHYSIC IANS’EDUCAT IONRE SOURCE , LLC
March 14-17, 2012Fontainebleau Miami Beach Hotel
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Physicians’ Education Resource designates this live activity for a maximum of 27.25 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.
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Topics Include:• Screening and management of high-risk women
• The biology of malignancy and progression—therapeutic implications
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• Emerging cytotoxic and biologic systemic therapies
• Considerations in neoadjuvant therapy
• Using molecular profiling to personalize therapy
• Electronic record-keeping
• … and much more
Visit us online for more information and registration:MiamiBreast2012.CancerLearning.com
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In This Issue...4
Targeted Therapy News • 02.12
Office Center at Princeton Meadows, Bldg. 300 Plainsboro, NJ 08536 • (609) 716-7777
BReasT CanCeR6 PARP Inhibition Explored in Triple-Negative Breast CancerBy Alice Goodman
PROsTaTe CanCeR6 Clinicians Face Challenges Integrating New TherapeuticsBy Anita T. Shaffer
7 Trial Shows Denosumab Delays Development of Bone Metastasis in Hormone-Resistant Prostate CancerBy Bonnie Gillis
16 Emerging Biomarker Science Presents Practical QuestionsBy Anita T. Shaffer
HeMaTOlOgIC MalIgnanCIes7 Using Molecular Markers in AML for Predic-tion, Treatment, and MonitoringBy Bonnie Gillis
8 New Assays Open Window in Evaluating Leukemia TypesBy Ben Leach
lung CanCeR9 Predictive Markers Needed for Adjuvant ChemotherapyBy Ben Leach
10 Biomarker Indentifies Patients With Advance Lung Cancer Who Will Gain Most From Add-On CetuximabBy Jill Stein
9 Hospitals for Vulnerable Patients Less Likely to Provide Optimal Lung Cancer Care
Renal Cell CaRCInOMa12 FDA Approves Axitinib for Advanced Kidney Cancer PatientsBy Alice Goodman
HeaD anD neCk CanCeRs12 Two New Options Represent Breakthroughs
17 Trials in Progress
19 Value-Based OncologyNICE’s Reluctance to Back Yervoy Turns on Cost-Benefit PerceptionsBy Ben Leach
20 Researcher ProfilePierre Hainaut, PhDAwakening the “Guard-ian of the Genome”
21 Therapy WatchNew FDA-Approved Oncology Drugs and Indications, 2011
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Targeted Therapy News (ISSN 1535-7201) is published 12 times a year by Intellisphere, LLC, Office Center at Princeton Meadows, Suite 300, Plains boro, NJ 08536. Telephone (609) 716-7777, Fax (609) 716-4747. Sub scription $79.00 per year US, $95.00 foreign, $35.00 medical students; $10.00 single issues. Copyright© 2012 by Intelli sphere, LLC. All rights reserved. Postmaster: Send address changes to Targeted Therapy News, Office Center at Princeton Meadows, Building 300, Plainsboro, NJ 08536. Printed in USA.
Features 13 Personalized Medicine Offers
Great Hope, Great Challenges By Bonnie Gillis
14 Changing Paradigms for NSCLC in Personalized Therapy Era
By Alice Goodman
14 Prostate Cancer Armamentarium Expanding
By Alice Goodman
15 Better Communication of Complex Medical Information Needed
15 Some Follicular Lymphoma Patients May Benefit From Treatment Delay
By Bonnie Gillis
News
Departments
Targeted Therapy News • 02.12
5
Colorectal Tumor MarkerMolecular Evaluation Sheds Light on Negative Lymph Node Status
By Maurie Markman, MD
The presence or absence of lymph node involvement has long been recognized as a critically relevant
prognostic factor in solid tumor oncol-ogy. While local and regional lymph nodes are no longer viewed as serving a “barrier function,” the documented presence of cancer within these ana-tomical areas provides important data regarding the statistical likelihood that a particular malignancy has spread to distant sites.
At the same time, it is also wel l un-derstood that individual cancers may have metastasized at the time of diag-nosis, even without the documented presence of malignant cells within local nodes. This well-established observa-tion raises the provocative question of whether the disease involved nodes prior to further dissemination or, con-versely, whether the finding of “nega-tive nodes” is often simply an artifact of the inherent insensitivity of existing diagnostic tools.
The question is highly clinically rele-vant in colorectal cancer, since adjuvant chemotherapy is known to improve both progression-free and overall survival in patients with lymph node-positive nonmetastatic disease. Thus, patients labeled as having “node-negative” dis-ease, when the cancer is actually more advanced, will be denied the opportu-nity to receive systemic antineoplastic therapy at a point in the natural history of the malignancy where the ultimate survival outcome may be most favor-ably impacted by its use.
This issue was recently addressed in an interesting analysis involving a group of patients with “node-neg-ative” colorectal cancer. Hyslop et al
It is important to emphasize that the results in this analysis will need to be confirmed by other investigators evalu-ating independent data sets. However, assuming such studies reveal similar outcomes, it would be reasonable to suggest that this type of quantitative molecular analysis may play an im-portant role in routine management of colorectal cancer patients discovered on initial histopathology review to have no evidence of malignant involvement of local or regional lymph nodes.
In addition to providing refined prog-nostic data for a specific patient, the re-
sults of this study strongly support the conclusion that this type of molecular analysis of lymph node involvement is associated with a far more accurate as-sessment of the population of individu-als who would be predicted to benefit from adjuvant chemotherapy following definitive surgical staging and tumor re-moval.
Finally, it is also reasonable to specu-late that future research efforts will be successful in defining specific molecu-lar markers in other malignancies that may more definitively separate patient populations with and without local/re-gional nodal involvement, permitting both more meaningful prognostic data regarding the ultimate risk of recur-rence and—of greatest importance—predictive information that can be used by clinicians to select a management program to optimize outcome. TTN
Maurie Markman, MD, is senior vice presi-dent for Clinical Affairs and national director for Medical Oncology at Cancer Treatment Centers of America, Eastern Regional Medi-cal Center, Philadelphia, Pennsylvania.
noted that approximately one-fourth of patients with negative- node sta-tus experience a recurrence of disease and set out to explore the relation-ship between molecular tumor bur-den in lymph nodes and outcomes (Clin Cancer Res. 2011;17(10):3293-3303).
In this particular research effort, the “noncancer bearing” lymph nodes were examined for the presence of guanylyl cyclase 2C (GUCY2C), a family of pro-teins that synthesizes cyclic guanosine monophosphate. GUCY2C is a previous-ly documented sensitive marker of the presence of malignant colorectal can-
cer, established through the technique of reverse transcriptase polymerase chain reaction (PCR).
The study included 291 patients (55% male), with 84% having >12 nodes re-moved at the time of surgery. The tu-mor grade was well or moderately dif-ferentiated in 85% of cases, and 15% were classified either as poorly differ-entiated or the grade was unknown. Lymphovascular invasion was present in 20% of the population.
Based on the laboratory findings, the patients were divided into 3 groups with a predicted quantitative tumor burden. The low, intermediate, and high tumor burden populations com-prised 60%, 31%, and 9% of the total, re-spectively. Of considerable interest, the recurrence rates documented within these 3 groups (median follow-up of 2 years) was found to be 2.3%, 33.3%, and 68%, respectively. Not surprisingly, the 3 patient populations were also shown to experience different overall survival rates consistent with their relative ob-served risk of recurrence.
Finally, the investigators concluded that in this analysis the molecular tu-mor burden was an independent pre-dictor of outcome.
Approximately 25% of patients whose colorectal malignancies are assessed as node-negative experience a recurrence, raising provocative questions that a novel tumor marker may help answer.
Peers& Perspectives
News
Targeted Therapy News • 02.12
6
Targeted Therapies in Breast Cancer
Emerging Biomarker Science Presents Practical QuestionsBy Anita T. Shaffer
although the use of tumor markers to evaluate patients with breast cancer is well established, the nu-
ances involved in such testing are grow-ing along with the emergence of novel assays and fresh research findings.
Debu Tripathy, MD, has made novel therapeutics in breast cancer the focus of his clinical research. He is delving into biomarkers that predict sensitivity and resistance to therapeutics, as well as growth factor receptor pathways that might be promising candidates for tar-geted therapies.
In this interview, Tripathy discusses practical implications of biomarker re-search.
How do you use gene profiling in clini-cal practice?The primary area where gene profiling such as the Oncotype DX score helps is in patients who have estrogen receptor (ER)–positive or progesterone receptor
What role does tumor heterogeneity play?Tumor heterogeneity is becoming an increasingly recognized phenomenon, and it’s very difficult to incorporate that into decision making. As the tumors grow, different cells within the tumor may start to acquire or select for differ-ent genetic changes, and then a certain part of the tumor may grow, expressing a different set of proteins than another part of the tumor. If you’re giving the patient a drug that might select out one of these subclones, you end up getting differences in markers across the tumor due to selective pressures.
Now we’re seeing that when we per-form estrogen, progesterone receptor, or HER2 analysis, we may find that the whole tumor doesn’t behave uniformly.
It’s still a controversial notion, but we do know that tumor heterogene-ity exists, and now the problem is how do we deal with it, how do we use that information? Certainly, it is not some-
(PR)–positive and HER2/neu–negative early-stage cancers.
It is primarily used in patients with negative nodes because in those pa-tients the benefit of chemotherapy on the average is very small. Those with a high or intermediate-to-high recur-rence score—perhaps a little more than a quarter of the patients—derive almost all of the benefit of chemotherapy, and most of the other patients do not.
More recently, there have been some studies to suggest that maybe in pa-tients with positive nodes, even though the risk of recurrence is higher, the re-currence score may still tell us who is likely to benefit from chemotherapy. There may even be patients with posi-tive nodes who really don’t benefit much from chemotherapy. The studies supporting that are not as robust, so that area is a little more controversial.
In fact, there’s an ongoing prospec-tive study right now for patients with one to three nodes and hormone recep-tor–positive, HER2/neu–negative tumors to use the Oncotype assay and random-ize those who have a score of less than 25 to hormonal therapy alone versus chemotherapy followed by hormonal therapy. In that study, patients with a recurrence score greater than 25 auto-matically get chemotherapy.
How do you use biomarkers when tu-mors recur? When patients have a local or distant re-currence, the standard now is to do a bi-opsy if feasible and send these biomarker assays because the markers can change.
For estrogen and progesterone re-ceptors, they may change up to 10% to 20% of the time. For HER2, it’s probably less, maybe in the 5% to 10% range, but it is important in decision making. It may affect the therapy op-tions that you would have in recurrent disease.
Many times, biomarkers from the original tumor that may have been de-termined years earlier are used, and we now know that sometimes those can change and affect tumor biology.
thing we’re routinely using. If you look at all the guidelines for how a patholo-gist should score ER, PR, or HER2, it’s by counting a lot of cells and then averag-ing them. There really isn’t accounting for these sorts of patches over larger segments of tumor. What do you do if you have just a small patch of HER2–positive cells and the rest of the tumor is HER2–negative? Should those pa-tients get trastuzumab?
These are questions that we simply cannot answer at the moment. So tu-mor heterogeneity is an evolving area. We think it’s a very interesting window of opportunity to learn about mecha-nisms of resistance in the research set-ting. But for clinical decision making, it is really bedeviling us. TTN
Debu Tripathy, MD, is co-chair of the 29th An-nual Miami Breast Cancer Conference, which will be held March 14-17, 2012, in Florida. To register, visit www.cancerlearning.com.
Debu Tripathy, MDCo-Leader, Women’s Cancer ProgramProfessor of MedicinePriscilla and Art Ulene Chair In Women’s CancerUSC/Norris Comprehensive Cancer Center University of Southern CaliforniaLos Angeles, CA
It’s still a controversial notion, but we do know that tumor heterogeneity exists, and now the problem is how do we deal with it, how do we use that information?
Targeted Therapy News • 02.12
7
It appears that PARP inhibition may potentiate other chemotherapies.
PARP Inhibition Explored in Triple-Negative Breast CancerBy Alice Goodman
PARP inhibitors, which are a group of pharmacologic inhibitors of the enzyme poly ADP ribose poly-
merase (PARP), are gaining ground as a potential strategy for treating triple-negative breast cancer. The data are more promising in hereditary triple-negative breast cancer than for sporadic triple-negative breast cancer, but more research is needed, according to a pre-sentation at the Chemotherapy Founda-tion Symposium held in New York City.
“It is still in the early days [of studying PARP inhibitors]. We still need results of clinical trials with veliparib, MK4827, and AGO14699, but research thus far suggests that PARP inhibition is likely to be active in hereditary triple-negative breast cancer,” stated Daniel P. Silver, MD, PhD, medical oncologist at the Breast Cancer Treatment Center at the Dana-Farber Cancer Institute, Boston, Massachusetts. However, Silver said, PARP inhibition is “not likely to be active as monotherapy in a large percentage of heavily pretreated sporadic triple-negative breast cancer, although biomarkers may identify a small subset that can benefit.”
PARP inhibition targets DNA repair in breast cancer by acting on the base excision repair DNA pathway, which
triple-negative cancers appear to have a ‘BRCA-ness,’ meaning that something is wrong with the BRCA pathway,” Silver explained.
PARP inhibitors are also being studied in sporadic triple-negative breast cancer. A phase II trial of olaparib in advanced ovarian cancer and triple-negative breast cancer found no objective response in 16 sporadic cases, and that arm of the study was closed (Gelmon K et al. Lancet Oncology. 2011;12(9):852-861). Looking at a waterfall plot, which shows tumor shrinkage (not objective response rates), 63% of patients with BRCA1 or BRCA2 showed some tumor shrinkage and stable disease for more than 8 weeks, while only 13% of sporadic tumors had any degree of tumor shrinkage.
“Clearly, more large trials are needed, but it is unlikely that a proportion of metastatic, heavily pretreated sporadic triple-negative cancers will respond to PARP inhibitor monotherapy. It is entirely possible that there may be small subsets
acts in concert with the homologous recombination DNA repair pathway that requires BRCA1 and BRCA2, Silver explained. This provides the rationale for studying PARP inhibition in hereditary triple-negative breast cancer. BRCA1 and BRCA2 are human genes that belong to a class of genes known as tumor suppressors. Mutation of these genes has been linked to hereditary breast and ovarian cancer.
Early studies of PARP inhibitors in hereditary triple-negative breast cancer showed clinical benefit in carriers of BRCA1 and BRCA2. A recent phase II study of the PARP inhibitor olaparib in both sporadic and hereditary triple-negative metastatic breast cancer patients (Tutt A et al. Lancet. 2010;376(9737):235-244) showed the best responses in BRCA1 and BRCA2 carriers; 11 of 13 hereditary triple-negative patients had an overall response rate of 54%. “In this study, higher doses were better,” Silver commented.
“A number of investigators have found that sporadic and hereditary triple-negative breast cancer tumors share several characteristics, and they have posited that a deep relationship exists between these tumors. Sporadic
of patients identified by biomarkers that might respond,” Silver said.
Combinations of PARP inhibitors with chemotherapy are being studied as well. It appears that PARP inhibition may potentiate other chemotherapies, such as carboplatin, cisplatin, cyclophosphamide, and irinotecan, Silver commented.
Unexplored issues include the opti-mal rational combinations of therapy with PARP inhibitors, which are the best of these agents to combine with other therapies, timing, doses, and whether PARP inhibitors can act as radiosensi-tizers. Chemoprevention in carriers of BRCA1 and BRCA2 is an attractive option, but the safety of this approach needs to be established. PARP inhibitors in combi-nation with chemotherapy or as part of other approaches may be useful in post-neoadjuvant therapy for triple-negative breast cancer patients who failed to achieve good response and are other-wise destined for poor outcomes. TTN
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News
Targeted Therapy News • 02.12
8
Targeted Therapies in Prostate Cancer
Clinicians Face Challenges Integrating New TherapeuticsBy Anita T. Shaffer
Trial Shows Denosumab Delays Development of Bone Metastasis in Hormone-Resistant Prostate CancerBy Bonnie Gillis
Treatment with denosumab achieved delay in the onset of bone metastasis in men with hormone-
resistant prostate cancer compared to placebo in the first large-scale clinical trial to demonstrate this effect.
“Up to 90% of men with hormone-resistant prostate cancer will develop bone metastases, suggesting that the cancer is entering the terminal phase,” said Stéphane Oudard, MD, of Georges Pompidou Hospital in Paris, France. “Currently, there is a gap in the treat-ment plan for these patients who have not yet developed bone metastases. Be-ing able to delay this turning point is very significant. We have shown that the use of denosumab in patients with hormone-resistant prostate cancer can impede the onset of bone metastases by just over 4 months.”
versus 29.5 months for denosumab, which represents a 15% risk reduction (P = .028). The effect of denosumab in delaying bone metastasis was observed across all subgroups, including age, geo-graphical region, race, Gleason score, and prostate-specific antigen (PSA) stra-tum.
Denosumab also resulted in fewer skeletal-related events (SREs): 15% for placebo versus 10% for denosumab, rep-resenting a 33% reduction in risk of SREs (P = .01). Most adverse events were simi-lar in both groups, with the exception of osteonecrosis of the jaw, which oc-curred in 5% of denosumab-treated patients versus 0% of placebo-treat-ed patients. Oudard pointed out that patients received about 20 cycles of de-nosumab.
“We can conclude that no matter
Denosumab is a RANK ligand (RANKL) inhibitor, which prevents the formation of osteoclasts (ie, cells involved in bone destruction). The phase III international, randomized, double-blind, placebo-controlled trial randomized 1432 men with hormone-resistant prostate cancer in a 1:1 ratio to receive denosumab 120 mg via subcutaneous injection every 4 weeks or placebo injections. All patients took calcium and vitamin D supplements. As of July 2010, more than 660 patients developed bone metastases or died, and the trial was stopped and unblinded.
The primary endpoint was bone metastasis-free survival; secondary endpoints were time to development of first bone metastasis and overall sur-vival. The median bone metastasis-free survival was 25.2 months for placebo
what the patient characteristics are— either a high PSA level or a short PSA doubling time—denosumab can delay the appearance of bone metastasis,” said Oudard. “In a condition where there is currently no effective treatment, this is a highly significant finding.”
Joaquim Belmunt, MD, of Hospital del Mar in Barcelona, Spain, said, “Denosumab, being the first agent to delay the onset of bone metastasis in castrate-resistant prostate cancer, represents a paradigm shift in our beliefs about the limited efficacy of the presently available antimetastatic strategies. The way this activity will translate into survival benefit will require future investigation.” TTN
The options for treating patients with prostate cancer are mush-rooming, presenting fresh ques-
tions for clinicians seeking to select and combine therapies for the best possible outcomes.
In April, the FDA approved Zytiga (abiraterone acetate), an oral CYP17 inhibitor, for use in combination with prednisone in patients with metastatic castration-resistant prostate cancer who have received prior docetaxel therapy.
In recent months, positive trial data have been reported about Alpharadin (radium-223 chloride), which emits alpha radiation targeted to bone
metastases, and MDV3100, an androgen receptor signaling inhibitor.
These developments come on top of the 2010 approvals of Jevtana (cabazitaxel), an injectable microtubule inhibitor, and Provenge (sipuleucel-T), a vaccine custom-made for each patient.
In an interview with OncologyLive, Daniel P. Petrylak, MD, discussed key points in evaluating therapies.
What are the challenges facing clini-cians?It’s a very difficult issue. We have some drugs that are approved in very, very similar clinical niches. For example, there is cabazitaxel as well as
abiraterone, and now MDV3100, which will probably be approved as therapy post-docetaxel, so there are 3 drugs in the space. Then there is Alpharadin, which will probably be approved for patients ineligible for docetaxel, as well as those patients who have failed docetaxel. And, if you consider the fact that you can administer Provenge to patients who fail docetaxel, that’s 5 different agents.
How do we sequence them? We don’t understand the biology as well as we should. We need good tests to tell us which drug or treatment is the best one to use in a given situation. Right now, it’s a bit of guesswork. If a patient is rapidly progressive, one tends to go toward chemotherapy, although there’s really no evidence to use that at this particular point. That’s just basically what a lot of clinicians are accustomed to using. If you’ve had chemotherapy and you’ve tolerated it poorly, one would tend to go to some of the other hormonal agents such as abiraterone or MDV3100.
Daniel P. Petrylak, MDProfessor of MedicineCo-Leader, Prostate Cancer ProgramProgram Director, Genitourinary Oncology SectionHerbert Irving Comprehensive Cancer CenterColumbia University Medical CenterNew York, NY
Is it frustrating to have new tools but many questions?I’m happy that we have all these drugs. If you look back to a review that I wrote with Alan Yagoda in 1993, we were labeled as being nihilist because we said nothing worked at that point. We went from that to Taxotere [docetaxel] in 2004. Our study supported the approval of that drug for castration-resistant disease. So that’s a big leap at that point. In an 11-year period, the field changed. And then for seven years it’s been quiescent and now we’ve had this explosion of new drugs.
So I’m really happy for the patients. It’s up to us to figure out how to use these drugs properly, and I think I have good confidence that we’ll be able to do that. TTN
Targeted Therapy News • 02.12
9
Targeted Therapies in Hematologic Malignanceis
New Assays Open Window in Evaluating Leukemia TypesBy Ben Leach
genetic markers are becoming a more integral part of diagnosing cancer and determining which
patients will encounter more aggressive forms of their disease. For patients with leukemia, recently approved diagnos-tic tests may revolutionize the way their treating physicians evaluate their disease.
In October, the FDA approved the Vysis EGR1 fluorescence in situ hybridization (FISH) Probe Kit for detecting a chromo-
LSI D13S319 probe targets and gain of the D12Z3 sequence in peripheral blood specimens from untreated patients with B-cell CLL.
Abbott Molecular, which developed the tests, said the assays are intended to help clinicians determine disease prognosis.
“When patients are given these tests, there are things that we can do differ-ently in terms of treatment,” said William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
Wierda works most closely with pa-tients who have CLL. For these patients, Wierda said that performing a FISH anal-ysis allows him to detect deletions of the 17p, 11q, and 13q chromosomes and tri-somy of chromosome 12. All of these de-letions and mutations have been shown to predict poorer outcomes for patients
somal deletion in bone marrow that usu-ally is associated with a poor prognosis for patients with acute myeloid leukemia.
It was the second new in vitro diag-nostic test for leukemia that the FDA ap-proved this year. In August, the agency approved the Vysis FISH Probe Kit for patients with chronic lymphocytic leu-kemia (CLL). The kit includes a panel of 5 individual FISH probes intended to de-tect deletion of the LSI TP53, LSI ATM, and
William G. Wierda, MD, PhDAssociate Professor of Medicine and InternistDepartment of LeukemiaThe University of Texas MD Anderson Cancer CenterHouston, TX
Using Molecular Markers in AML for Prediction, Treatment, and MonitoringBy Bonnie Gillis
several molecular markers for acute myelocytic leukemia (AML) are now used at top-tier cancer
centers for prediction, treatment selec-tion, and monitoring response.
But there is room for progress and more research is needed to identify markers beyond simple cytogenetics, said Jerald P. Radich, MD, in the Divi-sion of Cancer Research at the Fred Hutchinson Cancer Research Center in Seattle, Washington. Radich spoke at the National Comprehensive Cancer Network’s 6th Annual Congress on He-matologic Malignancies in New York, New York, September 9-10.
Conventional prognostic factors in-clude age, performance status, and cy-togenetics. In AML, as people get older they accumulate more cytogenetic risk factors. In clinical practice, 3 different cytogenetic markers are used at Fred Hutchinson and other research cen-ters: Flt3-ITD, NPM1, and CEBPA muta-tions. The presence of Flt3-ITD predicts increased rates of relapse and lower overall survival rates (ie, poor progno-
fare the best, Radich said. “This drives them from intermediate risk to im-proved risk,” he commented. Poor-risk patients are those with deletions of 5q and 7. Patients with 2 or more mono-somy karyotypes have a poor prognosis.
The presence of minimal residual disease (MRD) predicts relapse, even in a patient with complete response (CR) to induction and/or consolidation chemotherapy. Quantification of MRD defines the level of risk, Radich said. Molecular assays for MRD allow selec-
sis), while NPM1 and CEBPA mutations predict improved prognosis. There can be overlap of these markers in a given AML patient, Radich explained.
In good-risk patients, the presence of C-kit mutations (occurring in 20% to 50% of AML) downgrades risk status to inter-mediate risk, with a 4-year survival of 40%, he said. In patients with interme-diate risk AML and normal karyotypes, about 84% will have mutations; about 50% will have NPM1, about 31% will have Flt3-ITD, and these can overlap. About 14% of patients will have CEBPA muta-tions. The presence of all 3 mutations predicts improved outcomes.
Radich said that a further refinement in predicting clinical course is quanti-fying the amount of Flt3-ITD present; patients with high amounts of this mu-tation will have worse outcomes. “We think it is important to identify the presence of Flt3-IDT and to measure the amount that is present,” he said.
Patients with NPM1 mutations have a better clinical course, and those with Flt3-ITD wild-type and NPM1 mutations
tion of therapy, he added. Flow cytom-etry should be used to measure MRD, because “it is exquisitely sensitive to phenotype,” he said.
MRD pretransplant also predicts out-come. Posttransplant, MRD-negative patients have a good prognosis, while those who are MRD-positive have a poor prognosis. “Just because you identify MRD early does not mean you can im-prove outcome,” Radich told attendees.
The field is moving toward use of cy-togenetics and molecular testing for risk stratification of patients enrolled in clini-cal trials. “Using this testing up front al-lows you to choose the appropriate regi-men 48 hours later,” he said. A major prob-lem is lack of funding for this research.
He cited the following areas for im-provement: the need for better prognos-tic and diagnostic markers; the ability to identify a priori the 15% of AML patients who will be nonresponders to conven-tional chemotherapy; and a method for figuring out how to change therapy ac-cording to development of new clones as the disease progresses. TTN
with CLL.For patients who have the 11q deletion,
Weirda said he might use combination therapies such as fludarabine, cyclophos-phamide, and rituximab (FCR) along with an alkylating agent.
In the case of patients with a chromo-some 17p deletion, Wierda said that ef-fective treatment options are very limited or nonexistent. For those patients, Wierda said the diagnostic tests can be good pre-dictors of who would be an appropriate candidate for clinical trials of new thera-pies.
While these diagnostic tests are help-ful to patients, Wierda said he hopes the detection of chromosomal abnormalities and other biomarkers eventually will be used to develop targeted therapies that help patients with these very specific mutations. TTN
“Just because you identify MRD early does not mean you can improve outcome.”
Targeted Therapy News • 02.12
10 NewsTargeted Therapies in Lung Cancer
Predictive Markers Needed for Adjuvant ChemotherapyBy Ben Leach
Hospitals for Vulnerable Patients Less Likely to Provide Optimal Lung Cancer Care
since the mid-1990s, researchers have studied whether adjuvant chemotherapy for patients with
non-small cell lung cancer (NSCLC) pro-vides any added survival benefit. Initial studies appeared to find that adjuvant therapy did not provide any significant benefit in lung cancer patients, yet fur-ther studies have seemed to confirm that additional therapy might be help-ful in certain patient populations.
Studies are underway to find pre-dictive markers that could determine
new data show that patients treated for lung cancer at high safety-net burden hospitals
undergo curative-intent surgery signifi-cantly less often than individuals treat-ed at low safety-net burden facilities.
The Institute of Medicine of the National Academies defines healthcare safety-net facilities as institutions that deliver a significant level of medical care and other services to vulnerable patients, such as those who lack health insurance or who are on Medicaid.
Katherine S. Virgo, PhD, with the American Cancer Society in Atlanta, Georgia, and colleagues examined the relationship between hospital safety-net burden and receipt of curative-intent surgery for both black and white adults with early- stage non–small cell lung cancer
to benefit from platinum treatment as much as patients whose protein levels are low. A retrospective trial showed that patients did benefit from this treatment, but Wakelee said she would like to see a prospective study before recommending this treatment for her patients.
Adjuvant therapy trials that have studied the delivery of 4 cycles of cisplat-in-based treatment after surgery showed a 5% to 10% improvement in survival among patients age 65 and older. How-ever, Wakelee has concerns about which patients within that older population would benefit from treatment.
“I think we need to be very aware of the toxicities of the chemotherapy,” Wakelee said. “We know from patients with metastatic disease that well-se-lected elderly patients do just as well as younger patients.
evaluable patients showed that 67.1% of patients treated at high safety-net burden facilities had curative-intent surgery versus 77.1% of those treated at low safety-net burden centers (odds ratio 0.69; 95% CI, 0.62-0.77).
The results were maintained even after the investigators adjusted for multiple factors that decreased the likelihood of curative-intent surgery, including race, insurance status, disease stage, female gender, and other hospital characteristics.
Virgo and associates pointed out that the lack of consensus on the definition of safety-net status may represent a possible shortcoming of their study. They defined safety-net burden as “the percentage of uninsured and Medicaid-insured patients that hospitals treat, categorized as low, medium, and high,” and maintain that their definition is the one that is closest to that proposed by the Institute of Medicine. A lack of information on individual surgeon characteristics, such as volume or specialty, may also be a limitation.
The authors said that more studies are needed to determine if the relationship between hospital safety-
which patients with NSCLC are best suited for adjuvant therapy.
“Most of [the markers] have to do with DNA repair enzymes,” said Heath-er Wakelee, MD, during a presentation at the 12th International Lung Cancer Congress in Carlsbad, California, in Au-gust. “If they’re high, the tumor is able to repair any DNA damage and is there-fore resistant to the chemotherapy.”
For example, Wakelee said that pa-tients with higher concentrations of ERCC1, a DNA repair protein, tend not
(NSCLC). All patients had been treated between 2003 and 2005 at institutions that were accredited by the American College of Surgeons’ Commission on Cancer.
Roughly 85% of incident lung cancers are categorized as NSCLC, and surgical resection can be curative provided that treatment starts at an early stage.
Research has shown that black patients diagnosed with early-stage NSCLC are less likely than white patients to undergo surgery and are more likely to undergo resection at low-volume hospitals and to die in the hospital or within 30 days of their operation. However, there is scant information on the impact of hospital safety-net status on patient receipt of appropriate treatment.
In the present study, results in 52,853 Virg
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net burden and curative-intent surgery is the same for other cancer sites besides lung cancer, and whether safety-net burden is associated with receipt of multimodality therapy for patients with advanced disease. It would also be helpful to explore the link between hospital safety-net burden and hospital characteristics, such as bed size, ownership type, revenue margins, availability of diagnostic equipment, case mix, referral patterns, and staffing patterns. TTN
Virgo KS, Little AG, Fedewa SA, et al. Safety-net burden hospitals and likelihood of curative-intent surgery for non-small cell lung cancer [published online ahead of print August 29, 2011]. J Am Coll Surg. 2011;213(5):633-643.
Heather Wakelee, MDAssistant ProfessorDepartment of MedicineDivision of OncologyStanford UniversityStanford Clinical Cancer CenterStanford, CA
Katherine S. Virgo, PhDAmerican Cancer SocietyAtlanta, GA
“However, that’s looking at 65 or 70 [years old] as the cut point,” she said. “When we get into the octogenarians, there are very few patients in their eight-ies who are fit for chemo. However, we do know that for those who are fit, giving combination chemotherapy can be done.”
When discussing adjuvant therapy with patients, Wakelee said that in most cases the surgery has already “cured” their case of lung cancer, depending on the stage of the malignancy that has been treated.
“I tell them that if we were to give them the adjuvant chemotherapy that their likelihood of being cured is going to be improved by five to 10%, meaning that there will still be patients who go through the chemotherapy and are not cured,” said Wakelee. “That number will vary by stage and other factors that we really don’t know how to look at yet.” TTN
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Targeted Therapies in Renal Cell Carcinoma
ment options,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a state-ment concerning the approval of axitinib.
In a statement released by the manu-facturer, Pfizer noted that the drug is also being investigated in treatment-naïve and previously treated advanced RCC patients. Additionally, a randomized phase II trial is being conducted to test its efficacy in hepatocellular carcinoma (HCC).
The National Cancer Institute esti-mates that 64,770 new cases of kidney cancer will be diagnosed in 2012, and 13,570 people will die from the disease. Between 40% and 65% of patients whose disease progresses after receiving first-line therapy will receive some form of second-line therapy. TTN
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FDA Approves Axitinib for Advanced Kidney Cancer PatientsBy Ben Leach
The Pfizer drug axitinib gains FDA approval for advanced RCC
The FDA has approved axitinib (Inlyta) for the treatment of patients with advanced renal cell carcinoma (RCC) who have failed to respond to another drug.
The FDA approved axitinib on Janu-ary 27, 2011, based on the strength of a clinical trial that demonstrated an improvement in progression-free sur-vival (PFS). The randomized, open-label, multicenter study involved 723 patients from 22 countries who had RCC and progressed despite receiving sunitinib, bevacizumab plus interferon-alfa, temsi-rolimus, or a cytokine as first-line thera-py. Patients were randomly assigned to receive either axitinib or sorafenib.
The axitinib arm demonstrated a me-dian PFS of 6.7 months (95% CI, 6.3-8.6) compared with 4.7 months (95% CI, 4.6-5.6) for those receiving sorafenib. The re-sults of the study, first published in The Lancet in December 2011, demonstrated a 33.5% improvement in PFS (hazard ratio [HR] = 0.665; 95% CI, 0.544-0.812; P <.0001).
Treatment was discontinued in 14 of 359 patients receiving axitinib and in 29 of 355 patients receiving sorafenib. The most common side effects reported were diarrhea, hypertension, and fa-tigue in the axitinib arm, and diarrhea, palmar-plantar erythrodysesthesia, and alopecia in the sorafenib arm. The FDA warned that patients with hypertension should have their blood pressure well-controlled before taking axitinib, and patients with untreated brain tumors or gastrointestinal bleeding should not take axitinib.
Axitinib is an oral kinase inhibitor de-signed to selectively inhibit vascular endo-thelial growth factor (VEGF) receptors 1, 2 and 3, which have been known to promote angiogenesis and tumor progression.
“Through studying this drug we have learned that a VEGFR-targeted therapy can be effective following prior treat-ment options, including another VEG-
FR-targeted agent. This is important in helping physicians understand where these medications fit in the treatment armamentarium,” said Brian I. Rini, MD, associate professor of Medicine in the Department of Solid Tumor Oncology at the Cleveland Clinic in Ohio, lead author of the axitinib study and a consultant to Pfizer Oncology. Pfizer Inc will release the drug under its brand name Inlyta.
The FDA noted that this is the sev-enth drug approved for metastatic or ad-vanced RCC since 2005. The other drugs that have been approved are sorafenib, sunitinib, temsirolimus, everolimus, bev-acizumab, and pazopanib.
“Collectively, this unprecedented level of drug development within this time period has significantly altered the treat-ment paradigm of metastatic kidney cancer, and offers patients multiple treat-
Targeted Therapies in Lung Cancer
EGFR expression level with clinical outcome in patients enrolled in the phase III First-Line Erbitux in Lung Cancer (FLEX) study.
They pointed out that attention has been increasingly focused on the identification of predictive tumor biomarkers in order to improve the benefit-risk ratio of anticancer treatments. Ultimately, these biomarkers can help refine the selection of patients who are likely to benefit most from treatment.
The FLEX study had already shown that patients with EGFR-expressing, advanced NSCLC who had been randomized to the EGFR inhibitor cetuximab on top of chemotherapy involving cisplatin and vinorelbine had a superior overall survival (OS) than patients assigned to chemotherapy alone (hazard ratio [HR], 0.871; 95% CI 0.762-0.996; P =.044).
In the present analysis, the researchers used an immunohistochemistry scoring system in which a score <200 indicated low EGFR expression while a score ≥200 denot-ed high EGFR expression.
High EGFR expression was scored for 345 (31%) of 1121 patients in whom tumor EGFR expression data were available and low EGFR expression for 776 (69%) patients.
Median OS was longer in the high EGFR expression group in the cetuximab-plus-chemotherapy arm compared with the chemotherapy-alone arm (median of 12.0 mo [95% CI, 10.2-15.2] vs 9.6 mo [CI, 7.6-10.6]; HR, 0.73; CI, 0.58-0.93; P =.011).
The improved OS in the cetuximab-plus-chemotherapy, high-EGFR group was achieved without an appreciable increase in side effects.
There was no OS benefit in the low-EGFR-expression group (a median of 9.8 mo [CI, 8.9-12.2] vs 10.3 mo [CI, 9.2-11.5]; HR, 0.99; CI, 0.84-1.16; P =.88).
Extended OS in the chemotherapy-plus-cetuximab group was observed for patients with high EGFR expression in all major NSCLC histological subgroups that were examined.
The authors said that the clinically meaningful improvements in survival and benefit-risk ratio in patients with high tumor EGFR expression in the diverse population of patients enrolled in the FLEX study provide a strong rationale for the use of EGFR expression in clinical practice to identify which patients with advanced NSCLC will benefit from the addition of cetuximab to first-line chemotherapy. TTN
Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non–small cell lung cancer: analysis of data from the phase 3 FLEX study [published online ahead of print November 3, 2011]. Lancet Oncol. 2011. doi:10.1016/S1470-2045(11)70318-7.
Biomarker Identifies Patients With Advanced Lung Cancer(continued from cover)
Targeted Therapy News • 02.12
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Brian I. Rini, MDAssociate Professor of MedicineDepartment of Solid Tumor OncologyCleveland ClinicCleveland, OH
“Through studying this drug we
have learned that a VEGFR-targeted
therapy can be effective following
prior treatment options, including
another VEGFR-targeted agent. This
is important in helping physicians
understand where these medications fit
in the treatment armamentarium.”
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Targeted Therapies in Head and Neck Cancers
2 New Options Represent BreakthroughsBy Anita T. Shaffer
Hair Professionals Often Check Customers for Worrisome Skin Lesions
Caprelsa (vandetanib) is the first ap-proved treatment for patients with metastatic medullary thyroid can-
cer (MTC) who are not candidates for sur-gery and have disease that is advancing and causing symptoms. It is a tyrosine kinase inhibitor with multiple targets.
The drug, which is administered orally, was approved on the basis of a single, ran-domized study among 331 participants that demonstrated a median progression-free survival of at least 22.6 months in the vandetanib arm versus 16.4 months for those on placebo (Epub ahead of print No-vember 21, 2011. J Clin Oncol).
To prescribe the drug, physicians must register with a Risk Evaluation and Mitigation Strategy program.
Eric J. Sherman, MD, a medical oncol-ogist at Memorial Sloan-Kettering Can-cer Center in New York City, discussed the drug during the 7th Annual Multi-disciplinary Symposium on Head and Neck Cancer, a Physicians’ Education Resource (PER) conference held in Phila-delphia on November 19.
new survey results suggest that some cosmetologists and barbers inspect their customers’ scalps,
necks, and faces for the presence of skin lesions that they think may be cancerous.
Elizabeth E. Bailey, MD, with Brigham and Women’s Hospital in Boston, Mas-sachusetts, and colleagues analyzed responses to questionnaires completed by 203 hair professionals from 17 salons in a single chain in the greater Houston area. The chain was selected because its clientele are both male and female and reside in economically and geographi-cally diverse areas. The questionnaire focused on skin cancer knowledge, at-titudes, and behaviors of hair profession-als working in a salon.
Melanoma of the scalp and skin were responsible for 6% of all melanomas
to start when there is a significant pro-gression (not minor) on the scans or when symptoms due to the disease develop.”
For late-stage head and neck cancers, a category that includes cancers of the nasal cavity, sinuses, lips, mouth, sali-vary glands, throat, or larynx, oncologists can now consider Erbitux (cetuximab) in combination with chemotherapy.
In 2006, Erbitux gained approval as a treatment for advanced squamous cell carcinoma of the head and neck in com-bination with radiation therapy, or as a single agent after prior platinum-based therapy. Studies showed prolonged sur-vival and delay in tumor growth com-pared with radiation therapy alone (N Engl J Med. 2006;354[6]:567-578).
The study that led to its latest approv-al demonstrated that patients treated with cetuximab and chemotherapy (cisplatin or carboplatin and 5-fluoro-uracil) had a median overall survival of 10.1 months compared with 7.4 months on chemotherapy alone (N Engl J Med. 2008;359[11]:1116-1127).
“One of the concerns the FDA had was an increase in QTc interval and whether that can lead to further cardiac events,” said Sherman in an interview. “Very few people actually had a cardiac event in the study, but it still was a major concern of the FDA. Because of that concern, the FDA mandated that in order to be able to prescribe vandetanib, physicians would need to undergo registration, which ba-sically involves a short online course.”
Sherman said dosing and timing are issues. “It is not completely clear that the starting dose used in the study of 300 mg daily is the best dose for the treatment of medullary thyroid cancer,” he said.
“It’s still not clear when it is the per-fect time to start [Caprelsa] because peo-ple with metastatic medullary thyroid carcinoma, even those who have some progression, can live quite a number of years before any event,” said Sherman. “It shouldn’t be started just because someone has metastatic disease, and it shouldn’t be started just because tumor markers are increasing. However, it is very reasonable
Targeted Therapy News • 02.12
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Eric J. Sherman, MDHead and Neck OncologyMemorial Sloan-Kettering Cancer CenterNew York, NY
Everett E. Vokes, MDJohn E. Ultmann Professor of Medicine and Radiation OncologyChair, Department of MedicinePhysician-in-ChiefUniversity of Chicago Medical CenterChicago, IL
Everett E. Vokes, MD, chairman of the Department of Medicine and physician-in-chief at the University of Chicago Med-ical Center in Illinois, said the study of cetuximab combined with chemotherapy represents “a major breakthrough” for that patient population because it was the first to show an increase in survival.
“That is really where there is measur-able impact directly derived from cetux-imab at this point,” said Vokes, who also spoke at the PER conference.
“When moving into the curative-in-tense setting, we want to use it as a ra-diation sensitizer or as a chemotherapy sensitizer, so we add it to what we know to be curative modalities at this point,” Vokes continued. “The landmark study that was done was a comparison of ra-diation versus radiation and cetuximab. And the survival with cetuximab was improved, statistically and clinically. But in terms of where that leaves us as clini-cians or the patient, it’s really in the mid-dle of nowhere because radiation alone is not something we use frequently.”
“I think if I’m a community oncologist and I stick to evidence-based medicine, then I will give it with first-line chemo-therapy for patients who have recur-rence,” he said. “That is the indication with chemotherapy. Every other use with chemotherapy or chemoradiation upfront would be on experimental tri-als.” TTN
and 10% of all melanoma deaths in the United States between 1973 and 2003, and had a 5-year survival probability of 83.1% for stage I melanoma of the scalp and neck compared with 92.1% for stage I melanoma of other sites. The relatively high mortality rate for melanoma of the scalp and neck is probably due to the difficulty in detecting suspicious lesions during self-examination by patients and during routine examination by doctors.
While nonmelanoma skin cancer has a fairly low mortality rate, it may cause significant cosmetic disfigurement and functional impairment when the scalp, neck, and face are affected.
According to Bailey and associates, hair professionals have a “natural view of diffi-cult-to-see areas,” and they also meet with their customers on a regular basis and
may discuss such subjects as health and illness, diet, and medical care, all of which make them well suited for identifying skin cancer “that is otherwise unseen by the customer and customer’s physician.”
The primary outcome measure was the frequency with which hair profes-sionals looked for lesions on their cus-tomers’ scalps, necks, and faces during the prior month.
Overall, 37.1% of survey respondents reported looking at more than 50% of their customers’ scalps, 28.8% main-tained that they looked at more than 50% of their customers’ necks, and 15.3% said that they looked at more than 50% of their customers’ faces. Fifty-eight per-cent of hair professionals claimed that they had recommended at least once that a customer see a health professional
for an abnormal mole.Bailey and colleagues warned that the
results may not be broadly generalizable given that the cohort was drawn from a single salon chain in a single city. Also, the study did not provide longitudinal data, which would have made it possible to determine causality.
The investigators are now conducting a prospective study examining the impact of a 20-minute education session about skin cancer and the role that hair profes-sionals can play in its early detection and prevention. Pamphlets and customer in-formation cards are used to facilitate the discussion of skin cancer. TTN
Bailey EE, Marghoob AA, Orengo IF, et al. Skin cancer knowledge, attitudes, and behaviors in the salon. Arch Dermatol. 2011;147(10)1159-1165.
halted, and men in the placebo group were allowed to cross over to radium-223. Radium-223 also reduced the risk of time to first skeletal-related event by 39%. All subgroups benefited from this approach, including those who received prior docetaxel treatment. Amazingly, the placebo-treated patients had more side effects and a higher number of patients who discontinued treatment.
“We now have a variety of agents [for CRPC] that prolong survival. In the future we will need to learn how to combine them and sequence them,” Sartor said.
XL-184 (cabozantinib) is a dual inhibitor of mesenchymal epithelial transition factor (MET), a proto-oncogenic receptor, and vascular endothelial growth factor receptor 2. Theoretically, cabozantinib may block osteolytic lesions, said David C. Smith, MD, professor of the Department of Urology at the University of Michigan, Ann Arbor.
A phase II, randomized, discontinuation trial of cabozantinib versus placebo was conducted in
171 men with metastatic CRPC with measurable disease and evidence of disease progression. Median age was 68 years; 54% had bone pain, and 42% were taking narcotics for their pain. About 40% were pretreated with docetaxel. Results were good, so randomization to placebo was discontinued.
After 12 weeks of treatment, 68% had disease control (complete response, partial response, and stable disease). “Almost every patient had some evidence of activity [of the drug] on bone scan,” Smith said.
The major toxicities were fatigue (63%), thrombocytopenia (8%), and gastrointestinal perforation (1%). Fifty percent of patients required dose reductions. No significant effect was observed in patients who received prior docetaxel.
The moderator of the session, William K. Oh, MD, chief of the Division of Hematology and Medical Oncology at the Mount Sinai School of Medicine in New York City, said that both
radium-223 and cabozantinib target the microenvironment. “Radium-223 will be transformative, because of its efficacy and favorable toxicity. Cabozantinib should also be transformative. It had a remarkable effect on bone scans, but we need to see more studies,” Oh stated.
A randomized, phase II study of 2 different dose levels of pomegranate extract showed that the extract, which is more potent than pomegranate juice,
increased the PSA doubling time by about 6.6 months, from 11.9 months at baseline to 18.5 months after 6 months of treatment (P < .001). No dose response was observed. The study included 104 patients with a rising PSA without evidence of metastasis; at baseline, median age was 72, median Gleason score was 6-7 (44% were <Gleason 6), and 75% had a PSA doubling time of 9 months or longer.
Three-quarters of patients with a
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Targeted Therapy News • 02.12
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tenance therapy,” he stated.Two strategies have been studied:
switch maintenance therapy and continu-ation maintenance therapy. Switch main-tenance with pemetrexed following ini-tial therapy with a platinum-containing regimen improves survival in all patients. Switch maintenance with erlotinib also improves overall survival. However, only patients with good performance status are candidates for maintenance therapy.
Continuation maintenance therapy was studied in the PARAMOUNT trial, in which patients with stage IV NSCLC who responded to front-line cisplatin/peme-trexed were randomized to continuation pemetrexed or placebo. Progression-free survival (PFS) was improved with peme-trexed continuation maintenance; OS data have not yet been presented.
“Pemetrexed continuous maintenance has had similar results to switch mainte-nance therapy, and we await the overall survival data,” Belani said.
ECOG 5508 is accruing 1282 patients
able to get the recommended 4 cycles, and there is a clear need to reduce toxicity, improve dose delivery, and improve compliance. An adjuvant therapy trial by Winton et al compared standard cisplatin/vinorelbine versus cisplatin/pemetrexed. The feasibility of cisplatin/pemetrexed compared favorably with that of cisplatin/vinorelbine, with fewer toxicities and fewer dose delays. This regimen has been incorporated into the ECOG1505 trial for nonsquamous NSCLC, which will compare 1 of 4 chemotherapy regimens with no bevacizumab versus chemotherapy plus bevacizumab in the adjuvant setting.
“Maintenance therapy for NSCLC has become the new paradigm for about 50% of physicians, based on available data,” Belani continued. The other 50% are skeptics, he added. “The criticism [of maintenance therapy] is that about 40% of patients are unable to receive it. If we are going to change the paradigm from acute disease to chronic disease in stage IV NSCLC, we need to give less toxic main-
Changing Paradigms for NSCLC in Personalized Therapy Era(continued from cover)
Prostate Cancer Armamentarium Expanding(continued from cover)
with stage IV nonsquamous NSCLC who respond to 4 cycles of carboplatin/paclitaxel/bevacizumab and randomizing them to pemetrexed, bevacizumab, or the combination of pemetrexed/bevacizumab, following carboplatin, paclitaxel, and bevacizumab therapy.
“The next step is to personalize main-tenance therapy using molecular selec-tion. Patients with EGFR mutations can get erlotinib,” Belani continued.
Research by the Lung Cancer Mutation Consortium looked at 10 driver muta-tions in patients with stage IV adenocar-cinoma. Fifty-four percent of patients had 1 or more of these mutations; the most common ones were KRAS (22%), EGFR (17%), and EMLA 4-ALK (7%).
“These mutations were almost all mu-tually exclusive, since 97% of patients had only one of them. This work just scratch-es the surface, because lung cancer is a heterogeneous disease,” Belani explained.
The European Randomized Trial of Tarceva vs Chemotherapy (EURTAC) trial compared front-line chemotherapy with a platinum-based doublet versus erlo-
tinib in 174 patients with EGFR mutations (EGFR+). Erlotinib was superior for PFS, and all subsets of patients with EGFR+ status benefited from erlotinib. There was no improvement in OS, but Belani said that this was attributable to the fact that patients in the chemotherapy arm received second-line erlotinib.
“The new treatment paradigm is to test patients with NSCLC adenocarcinoma for EGFR-mutated status and treat with erlotinib if EGFR mutations are present,” he said.
Newer targeted therapies are being studied. Crizotinib (an ALK and MET in-hibitor) is approved for ALK-positive NSCLC, representing a second targeted approach. Afatinib (HER-1 and -2 inhibi-tor) plus cetuximab shows promise in patients with EGFR+ status who develop resistance to EGFR tyrosine kinase inhibi-tors. This drug is not yet approved.
There is a long list of other novel per-sonalized agents in earlier phases of de-velopment, including MetMAb, ARQ 197, Hsp90 inhibitors, talactoferrin, farletu-zumab, and hedgehog inhibitors. TTN
Oliver Sartor, MD
“Almost every patient had some evidence of activity [of the drug] on bone scan.”
“We now have a variety of agents [for CRPC] that prolong survival. In the future we will need to learn how to combine them and sequence them.”
David C. Smith, MD
PSA doubling time <3 months moved to a higher doubling time after taking pomegranate extract.
“The study met its primary endpoint but we did not see a dose response. Pomegranate extract may play a role in the treatment of older men who are looking for alternative therapies. I don’t recommend it to my patients, but if a patient of mine wants to take it and defer hormonal therapy, I tell him that
the extract is safe,” stated lead author Michael A. Carducci, MD, professor of Urologic Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland. TTN
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The decision to initiate therapy in an asymptomatic patient basically falls to patient preference. “From the patient’s perspective, there are two camps: ‘I can’t live my life fully knowing I have active lymphoma,’ or, ‘I feel fine now. You will treat me when I need it,’” Zelenetz explained.
Although a number of clinical trials using different regimens have shown that maintenance therapy after chemotherapy with or without rituximab with either radioimmunotherapy or rituximab dramatically improves progression-free survival (PFS) in FL, no therapy has shown a significant improvement in OS, which would be the gold standard. These trials include EORTC, SAAK, PRIMA, RESORT, and FIT. “Delaying therapy is effective,” Zelenetz said.
Using the PFS endpoint in clinical trials is not as optimal as OS. Achieving improvement in PFS delays the time to initiating the next therapy, but treatment may increase resistance to further treatment, and the impact of PFS on quality of life has not been explored, Zelenetz told attendees. Achieving improvement in OS would preserve future treatment options and delay the potential toxicities of subsequent treatments.
“Treatment decisions are currently based on clinical trials using PFS as an endpoint, but PFS is not the ideal surrogate,” Zelenetz noted. “We need better surrogate markers to predict the depth and quality of remission,” he stated.
Newly diagnosed patients who require treatment are those with symptoms,
should be written so that they can be understood by people with an eighth grade or lower level of education, and the use of clinical and statistical jargon should be avoided. Instead, the authors propose the use of focused information presented in a logical order coupled with a graphic design or page design involving subheadings and the use of more white space intended to make the document more readable.
They also advise oncologists to present statistical information using absolute risk instead of relative risk or number-needed-to-treat formats. In support of this recommendation, they point to evidence showing that “both in the context of making psychological and medical decisions…changes in risk appear larger when presented using relative risk
to that of patients in remission. No maintenance therapy has been shown to have an effect on transformation of the disease or on overall survival [OS],” Zelenetz told attendees at the National Comprehensive Cancer Network 6th Annual Congress on Hematologic Malignancies.
Follicular lymphoma is an indolent B-cell lymphoma that accounts for about 25% of patients with lymphoma in the United States. “Consultations for FL are the longest ones in my practice,” Zelenetz said. “The disease has a long natural history, with a median survival of 12 to 16 years. Survival has been dramatically improved due to rituximab, but relapse is inevitable over time.”
to make difficult decisions about cancer screening, prevention, and treatment, they are frequently not able to understand the types of health information needed to make such decisions.
Patients may, for example, lack the “health literacy” required to understand what their physician is saying to them, and they may also be unable to understand the educational materials issued by their healthcare providers. Low numeracy skills may also be a problem, meaning that patients may not be able to use numerical information discussed in educational materials (eg, risk and benefit statistics) in order to make informed decisions.
Fagerlin and associates said that the use of plain language is a must for cancer education. In short, materials
massive disease (ie, tumor burden >3 cm), cytopenia, concurrent disease transformation, compromised end-organ function, and who are candidates for ongoing clinical trials.
“Please do not treat every newly diagnosed patient with FL,” Zelenetz told the audience during a question-and-answer session. “Four prospective randomized clinical trials that have compared treatment versus observation in newly diagnosed asymptomatic patients (ie, candidates for observation) failed to show improved OS with chemotherapy.”
Disease proliferation is currently being studied at MSKCC as a marker for when to initiate treatment of FL. The technique used is a quantitative assessment based on image analysis of MIB-1/Ki-67 staining [Kedmi et al. Blood. 2010;116(suppl abstr 4149)]. Studies showed that median time to need for treatment was 5 years in FL patients with disease proliferation <30%, while median time to treatment initiation was 18 months in those with disease proliferation >30%.
In the current healthcare environment, cost of therapy is an important consideration. Cost of single-agent rituximab, the mainstay of FL treatment, is about $36,000 per year.
“If this treatment has no impact on OS, then the cost of quality-adjusted life years will be tens of millions of dollars,” Zelenetz said. “Currently, we have the luxury of using therapy that doesn’t impact OS, but I can’t predict the future. It might be difficult to get paid for maintenance rituximab [in the future].” TTN
than when using an absolute risk and that the treatments were viewed more favorably when presented in terms of relative risk.” The use of relative risk information may convince patients that a treatment is more effective than has been empirically demonstrated.
Additional strategies include the use of an incremental risk format to highlight how treatment changes the risk from preexisting baseline levels, along with the use of summary tables that include all of the risks and benefits for each treatment option.
Clinicians should also be aware that the order in which risks and benefits are presented can affect perceptions. TTN
Fagerlin A, BJ Zikmund-Fisher, Ubel PA. Helping patients decide: ten steps to better risk commu-nication. J Natl Cancer Inst. 2011;103:1-8.
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Some Follicular Lymphoma Patients May Benefit From Treatment DelayBy Bonnie Gillis
Maintenance therapy for follicu-lar lymphoma (FL) remains an option but is not mandatory
for patients in remission. The decision for initiating postremission therapy in asymptomatic patients should be based on discussions with the patient, said Andrew D. Zelenetz, MD, chief of Lymphoma Service at Memorial Sloan-Kettering Cancer Center (MSKCC), New York City. In addition, newly diagnosed patients with low tumor burden can have their initial treatment delayed, since living with asymptomatic disease is similar to being in remission.
“Taking a bird’s-eye view, the quality of life for FL patients who are asymptomatic and living with their disease is similar
Researchers are urging oncologists to improve the communication of complex medical information to
their patients.Angela Fagerlin, PhD, with the
University of Michigan and the VA Ann Arbor Center for Clinical Management Research, and colleagues cited 10 recommendations “that have shown strong evidence for improved patient understanding and decision making.”
Their methods, they said, are tailored to patients who need to make a decision that involves trade-offs (eg, between quality and length of life or between dif-ferent aspects of quality of life), in which the right choice depends on how impor-tant the patient finds these trade-offs.
The team issued its recommendations because of concern that while patients are increasingly being required
Better Communication of Complex Medical Information Needed
Andrew D. Zelenetz, MDChief of Lymphoma ServiceMemorial Sloan-Kettering Cancer Center (MSKCC)New York, NY
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Although personalized medicine has seen some exciting advancements in identifying tumor targets through ge-nomic sequencing and developing treat-ments aimed at those targets, other suc-cesses, such as trastuzumab for HER2-positive breast cancer and imatinib for chronic myelogenous leukemia and gas-trointestinal stromal tumor (GIST), do not tell the whole story. The Holy Grail may be in sight, but it remains elusive.
“While there is incredible excitement about the potential implementation of personalized cancer therapy, it is easy to contend that the excitement is massively overblown by the press,” said Gordon B. Mills, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, at the recent European Multidisciplinary Cancer Congress in Stockholm, Sweden.
“The number of successes—and in most cases these are only found in small subpopulations of patients and are transient—are outnumbered by spectacular failures,” he continued. “The cost of targeted therapy has added a tremendous burden to healthcare for a minor improvement in outcomes in small subpopulations. We are far from overcoming the hurdles associated with the implementation of personalized cancer therapy.”
Mills added, “We are coming closer to having scientific underpinnings for personalized medicine, but integrating our discoveries is an art. We have to ask ourselves whether we are overpromising successful treatments for cancer. Is this hype? Is this fundraising? Will there be repercussions if we don’t deliver on our promises?”
For trials of personalized medicine, each patient represents an “n” of 1. The therapy has to work with the specific patient’s genomics. Just identifying mutations does not mean that they are actionable and druggable; even if a tumor has actionable mutations, many responses to targeted therapy are in small subpopulations of patients and are short-lived. Also, regulatory hurdles need to be overcome for approval of targeted therapies.
In lieu of an ability to treat individual patients based on the changes in the genomes, experts are moving toward stratified therapy and treating groups of patients with similarities in their tumors, but Mills acknowledged that this is fraught with challenges. “Breast cancer is leading the way [in tumor stratification],” he said. “Ductal carcinoma used to be considered one disease; now eight subclasses have been identified. Some of these subgroups are orphan diseases and too small for clinical trials.”
Only subpopulations of patients with a particular biomarker show a response to targeted therapy, and the response is
itself. Targeted therapies themselves are also quite expensive, and, as mentioned, responses are typically not durable. Further, genomic testing is not 100% accurate, Mills said. Only 70% of tests are true positive and 70% are true negative. “The best deep-sequencing technologies come with increased cost,” he said.
Ethical considerations also come into play. Patients may not want to know their germ-line aberrations. Regulatory issues are another challenge. Validated assays for tumor testing are not available, and genomic testing is not reimbursed by about 95% of carriers. “We need to make genomic testing billable and payable,” stated Mills.
Also, physicians and patients need to be educated about genomic testing. “Most physicians at MD Anderson don’t understand what all the sequencing tests mean,” he said.
There are many unknowns, including whether a mutation present in only 1
tumor cell has any significance. “Patients hear about ‘cures’ and ‘nontoxic therapy,’ and we need to be more realistic about what we present to patients,” said Mills.
Pilot Program at MD andersonMD Anderson Cancer Center has launched a personalized medicine pilot program that services about 30,000 patients per year. The goal is to identify targetable and druggable genetic aberrations versus no aberrations. “Then we go to ‘n’ of 1 clinical trials to determine if a patient will benefit from a targeted therapy,” said Mills.
In the pilot program, 996 patients underwent testing with a mass array of 44 genes to identify activating mutations. There are 457 cancer-associated genes; 122 of them occur at a significant frequency in epithelial tumors. Less than 25% of
typically not durable. “We need to convert these short-lived responses to durable ones,” he said. He gave the example of the targeted agent crizotinib, which achieved a remarkable response in a subpopulation of lung cancer patients with the ALK mutation, “but every patient has recurred.”
Challenges in Personalized MedicineThe success of any cancer therapy is partly determined by the patient’s nongenetic makeup, the tumor characteristics, and the drug’s therapeutic index and toxicity. Tumor heterogeneity represents a challenge because characteristics of the primary tumor often change at relapse and at metastasis, signaling the need for rebiopsy at stages of disease progression. In some cases, the primary tumor itself may be heterogeneous at different sites.
Therapy should be sequenced based on the shift in characteristics at disease progression, Mills told the attendees.
With improved ability to characterize tumors in greater depth, multi- ple mutations are being identified, posing another hurdle to targeted therapy. When a mutational target is identified and targeted treatment is initiated, compensatory pathways may be activated, causing the emergence of resistance.
One focus of research is to distinguish between “passenger” mutations and “driver” mutations. “Not all mutations are targetable,” said Mills.
The price of mutational testing is considerable. There is the cost of genomic sequencing, and then the costs of handling and storing data, which can be much more expensive than genomic sequencing
mutations identified were actionable, and most of them were quite rare.
“We were surprised and disappointed. P53 was the most common aberration, but there is no targeted treatment for this,” said Mills. “Fifteen percent were Ras mutations, which are markers of resistance. The percentage with actionable mutations was much lower than in the literature.”
“The patient’s underlying gene lineage is important to response,” Mills said. “You can have efficacy with a targeted therapy, but it is determined by the patient’s lineage and tumor cell aberration.”
Patients with low-grade disease and mutations are frequently cured by targeted therapy, but most patients with advanced disease tend to have p53 mutations. “So we promise all patients that we can treat them, but only a few have actionable mutations,” said Mills. The ultimate outcome of a given cancer is determined by metastatic lesions that may differ from the primary tumor, he added.
Breast cancer is “the poster child for stratified medicine.” In the pilot program, Mills and colleagues looked at 51 primary breast tumors and 56 metastases. Over 40% of the time, the
dominant clone was discordant.“Patients with concordance of PTEN,
estrogen receptors, progesterone receptors, and HER2 have a better outcome, while the outcome is dismal
for those who are discordant,” said Mills. “Potentially, we have to obtain
multiple biopsies to know what we are treating. In one study, the primary
tumor had heterogeneity at different sites.”Testing for genetic aberrations does
not always yield results that can be acted upon. “In 10 patients where we’ve
sequenced the majority of the genome, not one new actionable mutation was found,” said Mills. “Most mutations we
find are not drivers.” For example, out of the 16 mutations most common in acute myelogenous leukemia and the 237 most common mutations in lung cancer, less than 6 were targetable.
“Many mutations are only passengers, not drivers,” he emphasized. “The ‘noise’ in mutations is challenging.”
A new program has been initiated at MD Anderson to distinguish between passenger and driver mutations. Thus far, investigators have identified a set of PK13R1 driver mutations.
“The future of personalized medicine will entail biopsy, biopsy, biopsy,” said Mills. “Eventually we hope to be able to move from biopsy to imaging and use of blood and circulating tumor cells to identify mutations.”
Mills envisions the process as follows: characterize the primary tumor and metastases, identify subclones, move to a trial of therapy (“n” of 1), and then biopsy at recurrence. “Personalized medicine offers great hope and many challenges. It is indeed a team science,” he said. TTN
We are coming closer to having scientific underpinnings for personalized medicine, but integrating our discoveries is an art. We have to ask ourselves whether we are overpromising successful treatments for cancer. Is this hype? Is this fundraising? Will there be repercussions if we don’t deliver on our promises?
–gordon B. Mills, MD, PhD
Personalized Medicine Offers Great Hope, Great Challenges(continued from cover)
Trials in Progress
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Breast Cancerevaluating trastuzumab/capecitabine and pertuzumab in patients whose cancer has progressed Researchers are recruiting for the multicenter, randomized PHEREXA study. The phase II, 2-arm study will examine the safety and efficacy of giving pertuzumab and trastuzumab with capecitabine in women with HER2-positive metastatic breast cancer whose disease has progressed during or following trastuzumab therapy. As of January 2011, researchers have recruited 58 patients for this open-label trial, but they hope to recruit 450 patients from 19 countries. Patients in both arms will receive trastuzumab and capecitabine, while 1 arm will also receive pertuzumab. Progression-free survival (PFS) is the primary endpoint. Overall survival, PFS, safety, and tolerability are secondary endpoints. Researchers plan to analyze HER1, -2, and -3 receptor status and downstream markers. Sponsor: Hoffmann-LaRocheClinicalTrials.gov identifier: NCT01026142
Phase II study of iniparib in breast cancer that has metastasizedResearchers plan to recruit 40 patients with triple-negative breast cancer (TNBC), which has metasta-sized to the brain, to evaluate the safety and efficacy of iniparib plus irinotecan. TNBC patients with brain metastases experience poor survival rates. The researchers are accepting patients with brain metasta-ses that measure more than 0.5 cm, even if they have already received therapy with iniparib or steroids. However, those with leptomeningeal disease will be excluded. Cohort 1 will be those with new and/or progressive brain metastases following radiation of the central nervous system (CNS). Cohort 2 will be asymptomatic patients who have not received CNS radiotherapy. Patients will receive irinotecan before iniparib. Researchers will use MRI and CT scans to determine the presence of intra- and extracranial dis-ease. Time to progression is the primary endpoint. Secondary endpoints include CNS and non-CNS re-sponse rates, progression-free survival, overall survival, quality of life, and correlative science endpoints. Sponsor: sanofi-aventisClinicalTrials.gov identifier: NCT01173497
PaRP inhibition among patients with TnBCThe Hoosier Oncology Group is conducting a multicenter, randomized, phase II trial of cisplatin alone or cisplatin with the experimental compound PF 01367338 among patients with triple-negative breast cancer (TNBC) who have not achieved pathologic complete response (pCR) on anthracycline-and/or taxane-containing neoadjuvant chemotherapy. The 2-year disease-free survival (DFS) of TNBC patients with residual disease category II or III is poor,―only about 40%. There are no standard systemic therapies for this high-risk group. The researchers chose cisplatin because of its DNA-damaging properties. Cisplatin and PF 01367338 appear to affect the PARP breast cancer cells; they inhibit the replication of DNA and their growth. After completing standard radiation therapy, patients will be randomized to cisplatin alone or with PF 01367338. The primary endpoint is 2-year DFS. Secondary endpoints include safety, 1-year DFS, overall survival, and biomarkers of tumor recurrence, resistance to chemotherapy and/or PARP inhibition. The estimated enrollment is 135 patients. Sponsor: Hoosier Oncology Group and PfizerClinicalTrials.gov identifier: NCT01074970
Gastrointestinal CancerDetecting c-kIT and PDgFRa in gIsT patient plasma Researchers from Germany are actively recruiting for a biomarker study in patients with gastrointestinal stromal tumors (GISTs). In this phase III, open-label trial, patients will be placed in 2 groups. One group is an assigned intervention group (surgery or a tyrosine kinase inhibitor); the other is comprised of patients whose disease has progressed irrespective of treatment. Blood will be drawn every 3 months for 2 years to look for the biomarkers c-KIT and PDGFRA (platelet-derived growth factor receptor alpha). Activating mutations of the kinases c-KIT and PDGFRA can be detected in 90% of GIST tissue samples. The researchers want to know if these markers will correlate with the clinical course of disease either under therapy or in progressive disease irrespective of the current therapy. The primary outcome is to detect tumor specific DNA encoding for mutated c-KIT or PDGFA in the plasma of these patients at least once during the study. The estimated enrollment is 25 patients.Sponsor: Technische Universität MünchenClinicalTrials.gov Identifier: NCT01462994
Investigating relationship between plasma platinum levels and neurotoxicity in gI cancer patients receiving oxaliplatin therapyFrench researchers are recruiting for a phase IV toxicity study in patients with gastrointestinal (GI) cancer who are taking oxaliplatin. Patients who are receiving or plan to receive oxaliplatin will be eligible for enrollment in this multicenter, open-label trial. Patients must have no pre-existing neuropathy, central nervous system disease, or cerebral metastases when enrolled. During the study, the patient’s neurological function and plasma levels will be measured at baseline after each treatment with oxaliplatin (2-hr IV infusions every 2-3 wk), and at the end of study treatment. The primary endpoint is to determine the relationship between plasma levels of residual platinum with persistent neurotoxicity in the hope that this information will help clinicians plan treatment and improve the quality of life of these patients. The secondary endpoint is to determine the pharmacokinetics of oxaliplatin in patients with GI cancer. The estimated enrollment is 58 patients.Sponsor: Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR) ClinicalTrials.gov Identifier: NCT00274885
Phase II trial of FOlFOX with or without vismodegib in advanced gastrointestinal cancerResearchers are recruiting for a multicenter, phase II study of FOLFOX with or without GDC-0449 (vismodegib) in treatment-naïve patients with advanced gastric and gastroesophageal (GE) junction carcinoma. This randomized, double-blind study will review the efficacy and safety of vismodegib plus FOLFOX versus FOLFOX alone as first-line treatment for advanced GE cancers. The hedgehog (Hh) pathway is critical in the development of both normal and malignant gastroesophageal cell growth and survival, but Hh overexpression correlates with clinical and histological features of GE tumors. Vismodegib, an oral Hh antagonist, binds to and inhibits SMO (Smoothened), a key component of the Hh pathway. By inhibiting SMO, Hh signal transduction is blocked. Patients will receive FOLFOX (leucovorin calcium, fluorouracil, oxaliplatin) with either vismodegib or placebo. Progression free survival is the primary endpoint. Secondary endpoints are overall survival, relative risk, and toxicity rates. The estimated enrollment is 116 patients. As of June 2011, the researchers had enrolled 58 patients.Sponsor: New York Cancer Consortium and National Cancer InstituteClinicalTrials.gov identifier: NCT00982592
Genitourinary CancerPReDICT looking for predictive biomarkers in renal cell carcinomaThe PREDICT (Personalized RNA Interference to Enhance the Delivery of Individualized Cytotoxic and Targeted Therapeutics) Consortium is conducting multicenter, single-arm phase II trials of everolimus (E-PREDICT) or sunitinib (S-PREDICT) administered around the time of the nephrectomy in patients with untreated metastatic renal cell carcinoma (mRCC). Although inhibitors of the vascular endothelial growth factor receptor (VEGFR) and the mammalian target of rapamycin (mTOR) have transformed mRCC therapy, predictive biomarkers have not been identified. The researchers plan to analyze the molecular markers of paired biopsies before and after treatment and compare them to clinical data to find predictive biomarkers. Sunitinib and everolimus will be given before and after nephrectomy and will continue until disease progression at metastatic sites. The primary clinical endpoint is the safety of peri-nephrectomy everolimus and sunitinib. Secondary endpoints include efficacy and biomarker measurements. The researchers hope to recruit 60 patients per trial.Sponsor: The PREDICT Consortium
The Trials in Progress section is intended to stimulate discussion about ongoing clinical trials and to promote collaboration across the oncology community. Each month, Targeted Therapy News will present summaries of ongoing research in a broad range of cancer types.
Targeted Therapy
Trials in Progress
Targeted Therapy News • 02.12
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Hematologic CancerPhase II study of nilotinib in Ph+ CMl patientsResearchers are evaluating patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) with low imatinib plasma concentrations to see if nilotinib will improve patient outcomes. Patients with low plasma concentrations of imatinib are at risk for treatment failure. Nilotinib is a second-generation Bcr-Abl tyrosine kinase inhibitor and has a high-er affinity for Abl than imatinib. Researchers will enroll 50 patients with Ph+ CML-CP who have been diagnosed within the 12 months prior to recruitment and who meet other European Leu-kemiaNet (ELN) response milestones, but who still have a low plasma concentration of imatinib. The patients will be switched from imatinib to nilotinib and treated for up to 2 years. The primary endpoint is the number of ELN-defined failure events during the course of nilotinib therapy. Sec-ondary endpoints include cytogenetic and molecular response, and event-free, progression-free, and overall survival. Changes in quality of life will also be considered.Sponsor: Novartis OncologyClinicalTrials.gov identifier: NCT01131325
Phase II study of elacytarabine/idarubicin as second-course remission-induction therapy in aMlResearchers are studying elacytarabine with idarubicin in patients with acute myeloid leukemia (AML), who have more than 5% remaining blasts in the bone marrow after the first induction course of a regimen containing cytarabine. The decreased expression of hENT1 (human equilibrative nucleoside transporter 1) has been shown to contribute to cytarabine resistance. Elacytarabine, with or without idarubicin, has shown activity in refractory or relapsed patients with AML during phase I studies with a safety profile similar to the cytarabine/idarubicin regimen. In this phase II, multicenter study, researchers will biopsy bone marrow to determine the hENT1 expression level prior to beginning the new protocol. The primary objectives are to assess the biological activity of elacytarabine/idarubicin and to examine the correlation between hENT1 and overall survival. Sponsor: Clavis Pharma, Theradex, INC ResearchClinicalTrials.gov identifier: NCT01035502
Head and Neckusing lyophilized black raspberries to prevent oral cancerOhio State University researchers are trying to determine the best method to administer lyophilized black raspberries as prophylaxis to patients who are at high-risk for oral cancer. The use of lyophilized black raspberries may prevent oral cancer in those with previously diagnosed stage I-IV or in situ head and neck cancer. In this phase I/II trial, there will be 2 treatment arms and 2 placebo arms. Patients will be randomized to (1) placebo lozenge or lyophilized raspberry lozenge; or (2) saliva substitute placebo or lyophilized black raspberry saliva substitute. Treatment will continue for 6 months. Primary objectives are to define safety and tolerability of long-term black raspberry administration after surgery in patients with head and neck cancer, to determine the best dose and delivery vehicle, and to correlate gene expression changes within regulatory pathways and dose and delivery method. The estimated enrollment is 140 patients.Sponsors: Ohio State University Comprehensive Cancer Center, National Cancer InstituteClinicalTrials.gov Identifier: NCT01469429
Hematologic malignanciesFludarabine and busulfan with or without clofarabine for aMl and MDs patients that need stem cell transplantResearchers at MD Anderson Cancer Center are actively recruiting for a new phase III study of 2 combination therapies in patients aged 3 to 70 years with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who also must undergo stem cell transplantation. AML patients in any stage and cytogenetic risk group who have not achieved complete remission with 1 course of induction therapy, and MDS patients with intermediate or high-risk IPSS score or treatment-related MDS are eligible for the trial. Some other low-risk MDS patients might be eligible. In this open-labeled trial, patients will be randomized to 1 of 2 arms. Arm 1 will receive busulfan, fludarabine, and clofarabine before stem cell transplantation. Arm 2 will receive busulfan and fludarabine before stem cell transplantation. Patients in both arms will also receive treatment to prevent graft-versus-host disease. Patients will be followed quarterly for 5 years after treatment. The primary endpoint is progression-free survival, and the secondary endpoint is overall survival. The researchers will also review safety data of this combination therapy. The estimated enrollment is 250 patients.Sponsor: MD Anderson Cancer Center ClinicalTrials.gov Identifier: NCT01471444
Brentuximab vedotin and combination chemotherapy for treating older patients with Hodgkin lymphomaResearchers from Northwestern University are actively recruiting for a phase II, open-label trial of patients with previously untreated stage II-IV Hodgkin lymphoma. The researchers want to determine the effects of adding the monoclonal antibody brentuximab vedotin which targets the cell membrane protein CD30, to traditional combination chemotherapy. There will be only 1 treatment arm. In the study, all previously untreated patients with stage II-IV Hodgkin lymphoma, who are 60 years old or older, will receive sequential therapy with brentuximab vedotin, and then receive doxorubicin, vinblastine, and dacarbazine (AVD). Primary out- come is overall response rate after sequential brentuximab vedotin therapy with AVD chemo- therapy. Secondary outcomes are progression-free survival, time to treatment failure, freedom from progression, and overall survival. The estimated enrollment is 48 patients. Sponsors: Northwestern University, Robert H. Lurie Cancer CenterClinicalTrials.gov Identifier: NCT01476410
Lung CancerFinding most effective radiation therapy for sClC patients receiving cisplatin/etoposideA 2-part, phase III, multicenter trial is testing the most effective radiotherapy for patients with small cell lung cancer who are receiving cisplatin and etoposide. All patients will receive cisplatin/etoposide and will be randomized to 1 of 3 treatment groups. Patients in arm 1 will receive standard-dose (45 Gy) thoracic radiotherapy delivered twice daily, 5 days a week for 3 weeks. Patients in arm 2 will receive 70 Gy radiotherapy once daily, 5 days a week for 7 weeks; and patients in arm 3 will receive 61.2 Gy once daily, 5 days a week for 16 days, then twice daily, 5 days a week for 9 days. The interim results will be analyzed, and the experimental arm with the most side effects will be discontinued. In part 2, standard radiotherapy will be compared with the remaining higher-dose regimen. Primary outcome measures are overall survival times. Secondary outcome measures are toxicity, complete and partial response rates, failure-free survival, local tumor progression, and rates of distant and intracranial metastases.Sponsors: Cancer and Leukemia Group B, National Cancer Institute, Radiation Therapy Oncology GroupClinicalTrials.gov Identifier: NCT00632853
Women’s Cancer Treatment versus observation in women with stage III/IV gynecological cancersA phase III trial is studying how well paclitaxel performs compared with polyglutamate paclitaxel or observation only in women with stage III/IV fallopian tube, ovarian, or peritoneal cavity cancer, which is in clinical complete response (CR) after platinum and taxane-based chemotherapy. In this multicenter study, the women are being randomized to 1 of 3 interventions: paclitaxel poliglumex, paclitaxel, or clinical observation. Sometimes women who are experiencing CR do not necessarily need more treatment, but researchers do not know if observation is better than maintenance therapy in these cases. The primary outcome is overall survival. Secondary outcomes are progression-free survival (PFS), toxicity, particularly peripheral neuropathy, and quality of life issues. Researchers also want to correlate biomarkers with overall PFS. After treatment, women will be followed every 3 months for 2 years, and then every 6 months for 3 years. Estimated enrollment is 1110 women (555 patients per treatment arm). Sponsors: Gynecologic Oncology Group, National Cancer InstituteClinicalTrials.gov Identifier: NCT00108745
Targeted Therapy
value-based oncology
Targeted Therapy News • 02.12
19
Sanjiv S. Agarwala, MDProfessor of MedicineTemple University School of MedicineChief, Oncology/HematologySt. Luke’s Hospital and Health NetworkBethlehem, PA
NICE’s Reluctance to Back Yervoy Turns on Cost-Benefit PerceptionsBy Ben Leach
The US oncology community ap-plauded the FDA’s approval of ipi-limumab (Yervoy) in March, and
the European Commission supported the use of the drug for patients with previously treated advanced melanoma among European Union member na-tions in July.
In the United Kingdom, however, the National Institute for Health and Clini-cal Excellence (NICE) has issued a draft recommendation against its approval, stating that clinical trial results thus far do not demonstrate sufficient benefits to justify its costs, and that biomark-ers are needed to identify patients who would benefit. The agency is scheduled
to make a final decision in February.Sanjiv S. Agarwala, MD, chief of Oncol-
ogy/Hematology at St. Luke’s Hospital and Health Network in Bethlehem, Penn-sylvania, is enthusiastic about Yervoy but believes NICE’s points are well taken.
“It certainly is practice-changing,” said Agarwala of the drug, noting that increasing overall survival in patients with melanoma has been quite difficult.
Agarwala agrees that focusing more ef-forts on genome mapping and biomarker identification research is critically impor-tant in order to deliver a more personal-ized therapy for melanoma patients.
At the same time, he said, the costs of the drug are certainly worthwhile to
those who would benefit.“There are about 8000 metastatic mela-
noma patients in the United States,” said Agarwala. “That’s a relatively small num-ber of patients who can be helped by the drug, but if it increases their survival, then it will be worth the cost to them.”
Yervoy, which Bristol-Myers Squibb developed, is the first drug that has been shown to help patients with ad-vanced melanoma live longer. The FDA’s approval was based on a clinical trial in which patients were randomized to receive Yervoy in combination with the investigational peptide vaccine gp100, Yervoy alone, or gp100 alone.
Patients who received Yervoy either alone or in combination had a median overall survival (OS) of approximately 10 months, compared with a median OS of 6 months for those in the vaccine-on-ly arm. Participants had been previously treated with 1 or more of 5 drugs.
Sir Andrew Dillon, chief executive of NICE, said in announcing the draft guid-ance in October that “the results did show
the drug could potentially be very effec-tive for a small percentage of patients.”
He said, however, that the trial did not compare Yervoy with currently used therapeutics, and it likely would im-prove survival for only about 30% of pa-tients, with about 10% of those patients experiencing long-term benefits.
In its economic analysis, NICE said the incremental cost-effectiveness ra-tio (ICER) would be at least £54,000 to £70,000, and possibly significantly high-er, per quality-adjusted life year (QALY). In the United States, a complete course of treatment consisting of 4 infusions of 3 mg/kg doses during a 3-month period carries an estimated cost of $30,000 per infusion, or $120,000 for the series.
NICE makes recommendations to the National Health Service that apply in varying ways in England, Wales, North-ern Ireland, and Scotland. The type of guidance ultimately issued determines whether a drug or device will be covered under a mandatory funding require-ment. TTN
International Journal of Targeted Therapies in Cancer is dedicated to improving cancer patient care through the publication of peer-reviewed, clinical articles that analyze advances in targeted therapies and personalized medicine and their application to clinical practice. The journal strives to expand oncologists’ knowledge of biomarkers, pathways, diagnostics, therapeutics, and strategies for personalized medicine in both oncology and hematology. International Journal of Targeted Therapies in Cancer recognizes that targeted therapies and personalized medicine in cancer is a rapidly emerging and complex area. The journal’s emphasis is to keep community oncologists abreast of new scientific advances in targeted therapy and their ultimate utility to improving patient care.
HER2 SignalingBeyond Herceptin: How New HER2–Targeted Therapies Will Change the Way You Practice
PI3K/Akt PathwayAre You Ready for PI3K/Akt Inhibitors? After 20 Years of Research, These New Therapies Are Poised to Enter the Market
SCF/KIT PathwayGIST, Melanoma, and More: A Better Understanding of the SCK/KIT Pathway Will Allow for More Precisely Targeted Therapy
EGFR SignalingWhen Targeted Therapies Dont Work: What Are Your Options for Overcoming Resistence to Drugs That Target EGFR?
Hedgehog PathwayHedgehog Speeds Along: A New Drug For Basal Cell Carcinoma is on Fast-Track Review. Here’s What You Need to Know.
JAK-STAT SignalingThe Many Possibilities of JAK Inhibition: Though ruxolitinib is approved for a rare disorder, JAK inhibitors may also have a place in treating breast, pancreatic, and lung cancers.
Insight into oncology research.
A P E E R - R E V I E W E D P U B L I C A T I O N
TargetedTherapies
International Journal of
in Cancer
What Turns a Good Cell Bad?Why New Theories on the “Hallmarks of Cancer” Matter to the Community Oncologist
Volume 1, Number 1, January 2012
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TargetedTherapiesInternational Journal of
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Researcher Profile
Targeted Therapy News • 02.12
20
Pierre Hainaut, PhDAwakening the “Guardian of the Genome”
By Jane de Lartigue, PhD
As its moniker “guardian of the genome” suggests, p53 has become recognized as one of the most important cancer-related molecules in the cell. As yet, p53-based research has not had a significant impact on cancer management. However, researchers continue to uncover complexities of and roles for the p53 pathway in both normal and cancerous cells, and the future for p53-targeted therapies is looking brighter than ever.
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Molecular Carcinogenesis and Biomarkers GroupInternational Agency for Research on CancerLyon, France
5 Questions on the Development of p53Pierre Hainaut, PhD, conducts research that spans basic molecular biology and molecular epidemiological studies related to the tumor suppressor gene p53, with an emphasis on its role in a variety of human cancers. His lab consistently generates important contributions on the molecular epidemiology and pathology of esophageal, breast, liver, and lung cancers.
The IARC center, in Lyon, France, is part of the World Health Organization. In January, Hainaut will take over the post of director at the International Center for Research and Training, Hospital AC Camargo, Sao Paulo, Brazil.
Cell cycle arrest
Dna repair
Cell cycle restart
apoptosis
Death and elimination of damaged cells
Dna damageCell cycle abnormalities
Hypoxia
Cellular and genetic stability
MDM2 p53 p53
1 What role does p53 signaling play in normal cells?p53 coordinates a number of antiproliferative programs in response to multiple forms
of stress, including low oxygen, depletion of ribonucleotides, hyperactivation of growth signaling, and many forms of DNA damage. Among the antiproliferative programs induced by p53 are cell cycle arrest, cell differentiation, senescence, autophagy, increased DNA repair, and apoptosis. The type of program activated depends upon cell type, status (eg, stem, progenitor, or differentiated cell), and the type of stress. One interesting theory proposes that the TP53 gene may have evolved as an adaptation of cells to enable them to handle oxidative damage caused by mitochondria.
2 How important is it in the development of cancer?It could be said that cancer cannot develop if p53 function and activity is intact and, in
fact, all cancers may have altered p53 function. Many mechanisms of p53 inactivation have been identified. For example, inactivating mutations occur in around 50% of cancers, and loss of p53 alleles is detectable in 30%–60%. Functional inactivation through interaction with inhibitory viral or cellular proteins is common in some cancers, and may account for another 5% to10% overall.
Other mechanisms include p53 promoter repression, competition with p53 homologues or with “inactive” p53 isoforms, and suppression of p53 expression by microRNA. The effects of these alterations may be very tumor-specific. In breast cancer, loss of p53 function is perhaps the most significant prognostic marker to date (with worse prognosis than ER/PR-, HER2-, or triple-negative). In lung cancer, TP53 mutation has no prognostic effect, but it may alter tumor response to adjuvant therapy, thus exerting a form of gain-of-function.
Subjects who inherit a mutant TP53 allele suffer from a familial syndrome of predisposition to multiple cancers: Li-Fraumeni syndrome (childhood solid tumors, early breast cancer, sarcomas). Long considered a rare disease, there is now evidence that it might be a much more common form of cancer predisposition.
3 Are there any p53-targeted anticancer agents currently available or under development?
In fact, many conventional treatments (radiotherapy or chemotherapy) are at least partially p53-dependent. With respect to “targeted therapies,” several approaches are in clinical trials: small drugs activating wild-type p53, small drugs “resuscitating” mutant p53, TP53-based gene therapy using viral vectors, and immunotherapy-targeting cells expressing p53 antigenic determinants. None are currently considered superior to standard treatments but there is significant hope that they may improve the effects of conventional therapy.
4 What has been the key discovery relating to p53 signaling in cancer in recent years?
The field is a goldmine for discoveries in molecular biology. In my view, the biggest recent advance is the identification of p53 as a key factor controlling oxidative metabolism (decreasing glycolysis, increasing oxidative phosphorylation in the mitochondria). Thus, loss of p53 function in cancer cells is one of the bases of the famous Warburg effect, the metabolic adaptation that
allows cancer cells to thrive on glucose with no or little oxygen usage. There is now good evidence that p53 operates as a link between telomere shortening and changes in oxidative metabolism to control cellular senescence.
5 What is the future of research with regard to p53 signaling in helping our understanding of cancer or developing targeted treatments?
Firstly, monitoring p53 (mutations, loss of alleles, molecular signatures of expression of target genes) is already proving very important for prognosis and prediction (depending upon tumor type), and this type of application will become standard practice in the coming years. Secondly, although p53 might prove difficult to “repair” using small drugs, pathways upstream and downstream offer a huge number of potential targets. As these pathways have multiple entry and exit routes, combination therapy will be needed. This will take time but may well herald the next therapeutic revolution. TTN
under normal conditions, p53 is held in check by the protein murine double minute 2 (MDM2) and functions as a tumor suppressor.
Targeted Therapy Watch
Targeted Therapy News • 02.12
21
In 2011, the number of approved cancer medicines—in terms of therapeutics alone—was higher than it had been in more than a decade. More significantly, 2011 was the first year that diagnostic tests were approved along with new cancer drugs, bringing the promise of personalized medicine closer than ever. Below is a list of some of the more significant approvals.
New FDA-Approved Oncology Drugs and Indications, 2011*
Conditions/Drugs New Indications CompaniesFDA Approval
Head & Neck CancersCaprelsa a
(vandetanib)Metastatic medullary thyroid cancer in adults ineligible for surgery with disease that is growing or causing symptoms
AstraZeneca April 6
erbituxb
(cetuximab)Recurrent or advanced locoregional or metastatic squamous cell carcinoma, in combination with radiation therapy or platinum-based therapy
Bristol-Myers SquibbEli Lilly and Company
November 7
Hematologic Malignanciesadcetrisa
(brentuximab vedotin)Hodgkin lymphomaAnaplastic large cell lymphoma
Seattle Genetics August 19
erwinazea
(asparaginase Erwinia chrysanthemi)Acute lymphoblastic leukemia in patients with hypersensitivity to E coli-derived asparaginase EUSA Pharma (USA), Inc November 18
Jakafi a
(ruxolitinib)Intermediate or high-risk myelofibrosis (MF), including primary MF, postpolycythemia vera MF, and postessential thrombocythemia MF
Incyte Corporation November 16
Rituxanb
(rituximab)Single-agent maintenance therapy in patients with previously untreated follicular, CD20-positive, B-cell non-Hodgkin lymphoma
GenentechBiogen Idec
January 28
Lung CancerXalkori (crizotinib)a
Vysis alk Break apart FIsH Probe kit (companion genetic test)
Locally advanced or metastatic non-small cell lung cancer in patients who express the ALK gene Pfizer Inc (drug)
Abbott Molecular (kit)
August 26
Melanomasylatronb
(peginterferon alfa-2b)Adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection
Merck & Co, Inc March 29
Yervoy (ipilimumab)a Metastatic melanoma Bristol-Myers Squibb March 25
Zelboraf (vemurafenib)a
cobas 4800 BRaF V600 Mutation Test(companion diagnostic)
Metastatic or unresected melanoma in patients whose tumors express BRAF V600E gene mutation
Genentech (drug)
Roche Molecular Diagnostics(test)
August 17
Pancreatic Cancerafinitor b
(everolimus)Progressive neuroendocrine tumors of pancreatic origin (pNET) that are unresectable, locally advanced, or metastatic
Novartis Pharmaceuticals May 5
sutentb
(sunitinib malate)Progressive, well-differentiated pNET tumors in patients with unresectable, locally advanced, or metastatic disease
Pfizer Inc May 20
Prostate CancerZytigaa
(abiraterone acetate)Metastatic castration-resistant prostate cancer in combination with prednisone after docetaxel therapy
Janssen Biotech, Inc April 28
*As of December 1, 2011Sources: FDA news releases, Drugs@FDA Website, prescribing information for individual drugsa Drug approved for the first time b New indication or formulation for previously approved brand-name drug or agent
HEMATOLOGIC1 6 t h A n n u a l I n t e r n a t i o n a l C o n g r e s s o n
F O C U S O N L E U K E M I A S , LY M P H O M A S , A N D M Y E LO M A
Significant progress has been made in the treatment of hematologic malignancies over the past decade, with the introduction of several targeted and biologic agents. Translational research leading to new drug development and treatment strategies requires changes in clinical practice for the optimal treatment of patients with lymphoma, leukemia, and myeloma. The rapid pace of discovery has led to the approval of several new drugs and a significant number of new oncology/hematology drug indications by the US Food and Drug Administration over the last two years, including several new updates to the National Comprehensive Cancer Network guidelines.
The 16th Annual International Congress on Hematologic Malignancies—Focus on Leukemias, Lymphomas, and Myeloma has been developed to educate medical oncologists, hematologists, and other healthcare professions on the continually evolving standards of care in hematologic malignancies. This annual program is designed to facilitate the integration of emerging data from clinical trials, evidence-based contemporary treatment recommendations, and guidelines into clinical practice.
Physicians’ Education Resource is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
February 23-26, 2012The Cliff Lodge Conference CenterSnowbird, Utah
PROGRAM DIRECTOR:Andrew D. Zelenetz, MD, PhDChief, Lymphoma Service Department of MedicineMemorial Sloan-Kettering Cancer CenterAssociate Professor of MedicineWeill Cornell Medical CollegeNew York, NY
For more information and registration, visit HemMalig2012.cancerlearning.com
Winter Oncology has found a new mountain!
This February, join us in Snowbird, UT!
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