PracticeUpdate Oncology Best of 2018

Best of 2018

OUR EXPERTS. YOUR PRACTICE.

VOL. 2 • NO. 4 • 2018

ISSN 2207-869X

TOP STORIES 2018 Venetoclax for Multiple Myeloma Renal Cell Carcinoma: Ipilimumab + Nivolumab PD-1 BlockadeWith Cemiplimab for Advanced SCC of the Skin Hematologic Malignancies: Haploidentical Stem Cell Transplant ER-Positive,

Node-Negative Breast Cancer

JOURNAL SCANS Pathological Response and Survival in Triple-Negative Breast Cancer Following Neoadjuvant Carboplatin Plus Docetaxel

Hyperprogressive Disease in Patients With Advanced Non-Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy

Edoxaban for the Treatment of Cancer- Associated Venous Thromboembolism

CONTINUE THE FIGHT There are always things in life worth fighting for PROVEN SURVIVAL BENEFIT WITH POMALYST + Lo-Dex in rrMM PATIENTS who have failed both Revlimid ® (lenalidomide) and bortezomib vs. Hi-Dex (median OS 13.1 vs. 8.1 months, HR: 0.72; P=0.009) in the MM-003 Trial 1 With 17.2 months median OS in patients achieving a minimal response or better (n=163) 1 PBS Information: Authority Required. Please refer to PBS Schedule for full authority information. Before prescribing Pomalyst ® (pomalidomide) please refer to the Product Information which is available at www.guildlink.com.au/gc/ws/celgene/pi.cfm?product=cjppomal Teratogenic Effects: Pomalidomide (Pomalyst) is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If pomalidomide is taken during pregnancy, it may cause birth defects or death to an unborn baby. Women should be advised to avoid pregnancy whilst taking Pomalyst (pomalidomide), during dose interruptions, and for 4 weeks after stopping the medicine. Pomalyst (pomalidomide) Capsules Minimum Product Information. Indication: Pomalidomide, in combination with dexamethasone, is indicated for the treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy. Contraindications: Pregnancy (Pregnancy Risk Category X); females of childbearing potential and male patients unless all of the conditions of the i-access ® program are met; hypersensitivity to pomalidomide or excipients. Precautions: To avoid the risk of foetal exposure, Pomalyst is only available under a restricted distribution program ( i-access ). Lactation. Paediatric use. Elderly use. Thromboembolic events. Haematological events such as neutropenia, anaemia, thrombocytopenia. Allergic reactions and serious skin reactions (angioedema and severe dermatologic reactions including Stevens- Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported). Dizziness, confusion, fatigue, depressed level of consciousness. Second Primary Malignancies. Peripheral Neuropathy. Cardiac dysfunction. Tumour lysis syndrome. Hepatic disorders. Infection (including viral reactivation). Interactions: Pomalidomide is partly metabolised by CYP1A2 and CYP3A4/5, and is a substrate for P-glycoprotein but not organic anion transporting polypeptides OATP1B1 or OATP1B3. If coadministering with strong CYP1A2 inhibitor, reduce the dose of pomalidomide by 50%. Effect of pomalidomide on other medicinal products has not been evaluated clinically. Monitor warfarin concentration. Smoking may reduce efficacy of pomalidomide. Adverse effects: anaemia, neutropenia, thrombocytopenia, leukopenia, febrile neutropenia, vertigo, constipation, diarrhoea, nausea, vomiting, fatigue, pyrexia, peripheral oedema, pneumonia, upper respiratory tract infection, bronchitis, nasopharyngitis, respiratory tract infection, bronchopneumonia, neutropenic sepsis, neutrophil count decreased, white blood cell count decreased, platelet count decreased, alanine aminotransferase increased, decreased appetite, hyperkalaemia, hyponatraemia, bone pain, muscle spasms, dizziness, tremor, peripheral sensory neuropathy, depressed level of consciousness, confusional state, renal failure, urinary retention, pelvic pain, dyspnoea, cough, pulmonary embolism, pruritis, rash, deep vein thrombosis. Post-marketing adverse reactions: pancytopenia, interstitial lung disease, hepatitis, hepatitis ß virus reactivation, herpes zoster, gastrointestinal haemorrhage, basal cell carcinoma, squamous cell carcinoma, skin and subcutaneous tissue disorders (SJS, TEN, DRESS). Dosage and administration: Recommended starting dose is 4mg orally daily on days 1-21 of repeated 28-day cycles until disease progression. Dosing is continued or modified based upon clinical and laboratory findings, and to manage grade 3 or 4 toxicities. Monitor patients with hepatic impairment. See full PI for further dosing information. (Min PI V1.7.1.) ABBREVIATIONS: Hi-Dex: high-dose dexamethasone; HR: hazard ratio; Lo-Dex: low-dose dexamethasone; OS: overall survival; rrMM: relapsed and/or refractory multiple myeloma. REFERENCES: 1. San Miguel JF, et al. Haematologica 2015;100:1334–9. Celgene Pty Ltd ABN 42 118 998 771. Level 15, 60 City Rd, Southbank VIC 3006, Australia. Tel 1800 CELGENE (1800 235 4363) www.celgene.com.au ® Registered Trademark. AU-POM0095. BB-CEL2674. Date of preparation: July 2018.

CONTENTS 3

EDITOR’S PICKS 10 Pertuzumab and Trastuzumab With or Without Metronomic Chemotherapy for Older Patients With HER2-Positive Metastatic Breast Cancer Comments by Reshma L. Mahtani DO and Lillie D. Shockney RN, BS, MAS 11 Pathological Response and Survival in TNBC After Neoadjuvant Carboplatin + Docetaxel Comment by Lee S. Schwartzberg MD, FACP 21-Gene Expression Assay in Breast Cancer Comment by Lee S. Schwartzberg MD, FACP 13 Enzalutamide Decreases Risk of Metastasis and Death in Men With Nonmetastatic CRPC Comment by Emmanuel Antonarakis MD 14 Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer Comment by Annette Hasenburg Prof. Dr. med 15 Hyperprogressive Disease in Advanced NSCLC Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy Comment by Axel Grothey MD 16 Pembrolizumab vs Paclitaxel for Previously Treated Advanced Gastric or Gastroesophageal Junction Cancer Comment by Axel Grothey MD 19 Edoxaban for the Treatment of Cancer- Associated Venous Thromboembolism Comment by Rakhi Naik MD, MHS 12 Adjuvant Chemotherapy Guided by a

CONFERENCE 24 American Society of Clinical Oncology Annual Meeting 24 Lung Cancer Studies at ASCO 2018 By Annette Hasenburg Prof. Dr. med. 26 10 Practice Changes That I Will Make After Attending ASCO 2018 By Jeffrey J. Kirshner MD, FACP 28 23rd Congress of The European Hematology Association By the PracticeUpdate Editorial Team 28 Consider Obinutuzumab Plus Chlorambucil for First-Line Treatment for CLL 29 Rituximab Yields Durable Response in Adults With Persistent or Chronic Immune Thrombocytopenia 30 Response Rates Improve Significantly With Three-Drug Combination for DLBCL 31 European Society For Medical Oncology 2018 Congress 31 Pembrolizumab for Recurrent HNSCC Interview with Barbara Ann Burtness MD by Tyeese L. Gaines DO 32 T-VEC in Early Metastatic Melanoma Interview with Alexander van Akkooi MD, PhD by Tyeese L. Gaines DO 32 Overall Survival With Palbociclib Plus Fulvestrant Interview with Timothy J. Pluard MD by Bradley McGregor MD 33 American Society for Radiation Oncology 2018 Annual Meeting By the PracticeUpdate Editorial Team 33 In Patients With DCIS, Radiotherapy Cuts Low Recurrence Risk by Half 34 High-Dose Radiotherapy Improves Survival Substantially in Patients With Oligometastatic Cancer 35 Radiation + Cisplatin Established as Standard of Care for HPV-Related Head and Neck Cancer Interview with Wilfried Eberhardt MD by Farzanna S. Haffizulla MD, FACP, FAMWA 25 Best in Ovarian Cancer

TOP STORIES 2018 6 Venetoclax for Multiple Myeloma By Rafael D. Fonseca MD

EXPERT OPINION 20 Adjuvant Chemotherapy or Adjuvant Chemoradiotherapy for Gastric Cancer? – A West Cancer Center Perspective Interview with Bradley G. Somer MD by Erin Schenk MD, PhD 21 Dr. Sara Hurvitz on Management of HER2-Positive Breast Cancer With Brain Metastases Interview with Sara A. Hurvitz MD 6 Renal Cell Carcinoma: Ipilimumab + Nivolumab By Eric Jonasch MD 7 PD-1 Blockade With Cemiplimab for Advanced SCC of the Skin By Roxana S. Dronca MD 8 Hematologic Malignancies: Haploidentical Stem Cell Transplant By Isabel Cunningham MD 8 ER-Positive, Node-Negative Breast Cancer By Jeffrey J. Kirshner MD, FACP

22 Dr. Sara Hurvitz on

Management of HER2-Positive Metastatic Breast Cancer

Interview with Sara A. Hurvitz MD by Ana C. Sandoval Leon MD 22 An Overview of Chemotherapy- Induced Heart Failure Interview with Joerg Herrmann MD by Jennifer N. Caudle DO 23 Evidence-Based Chemotherapy for Oligometastatic Prostate Cancer Interview with Tanya B. Dorff MD by Farzanna S. Haffizulla MD, FACP, FAMWA

VOL. 2 • NO. 4 • 2018

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Editor-in-Chief

Associate Editors

Lee Schwartzberg MD, FACP Executive Director, West Cancer Center; Professor of Medicine and Division Chief of Hematology/Oncology, The University of Tennessee Health Science Center, Tennessee

David Henry MD Clinical Professor of Medicine, Pennsylvania Hospital, Philadelphia, Pennsylvania Eric Jonasch MD Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine; Director, VHL Clinical Center, The University of Texas MD Anderson Cancer Center, Houston, Texas Jeffrey Kirshner MD, FACP Partner of Hematology Oncology Assoc of Central New York, East Syracuse; Director of Research, HOACNY Community Clinical Oncology Program, New York Howard Scher MD Chief, Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan- Kettering Cancer Center, New York David Straus MD Attending Physician, Lymphoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York Roger Stupp MD Professor of Medicine, Neurology and Neurological Surgery, Northwestern University Feinberg School of Medicine; Co-Director, Northwestern Brain Tumor Institute; Associate Director for Strategic Initiatives, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois Sara M. Tolaney MD, MPH Assistant Professor of Medicine, Harvard Medical School; Associate Director of Clinical Research, Breast Oncology; Associate Director, Susan F. Smith Center for Women’s Cancers; Senior Physician, Dana-Farber Cancer Institute, Boston, Massachusetts Isabel Cunningham MD Adjunct Associate Research Scientist, Division of Hematology Oncology, Columbia University College of Physicians and Surgeons, New York Axel Grothey MD Consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic; Professor of Oncology, Clinical and Translational Science, Mayo Graduate School, Rochester, Minnesota

Advisory Board

Benjamin Anderson MD, FACS Professor of Surgery and Global Health-Medicine, University of Washington; Director, Breast Health Global Initiative, Fred Hutchinson Cancer Research Center, Seattle, Washington Barbara Ann Burtness MD Professor of Medicine (Medical Oncology); Disease Aligned Research Team Leader, Head and Neck Cancers Program; Co-Director, Developmental Therapeutics Research Program, Yale Cancer Center, New Haven, Connecticut Roxana Dronca MD Assistant Professor of Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota Wilfried Eberhardt MD Associate Director, Regional Outreach West German Cancer Centre, University Hospital of University of Duisburg-Essen, Germany Wafiq S. El-Deiry MD, PhD, FACP Deputy Cancer Center Director, Translational Research Program; Co-Leader, Molecular Therapeutics Program; Professor of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania Rafael Fonseca MD Chair, Department of Internal Medicine; Getz Family Professor of Cancer, Mayo Clinic School of Medicine, Phoenix/ Scottsdale, Arizona Andre Goy MD Chairman and Director, John Theurer Cancer Center; Chief of Lymphoma, John Theurer Cancer Center, Hackensack University Medical Center, New Jersey Annette Hasenburg Prof. Dr. med Director, Obstetrics and Gynecology, Mainz University Medical Center, Mainz, Germany

Editorial Contributors

Neil Majithia MD Fellow in Hematology/ Oncology, Mayo Clinic School of Graduate Medical Education, Rochester, Minnesota Jarushka Naidoo MD Assistant Professor of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins, Baltimore, Maryland

Moshe Ornstein MD Genitourinary Medical Oncologist, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio Erin Schenk MD, PhD Assistant Professor of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Denver, Colorado

Jeffrey Wiisanen MD Hematology/Medical Oncology Fellow, Mayo Clinic School of Graduate Medical Education, Rochester, Minnesota

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PRACTICEUPDATE BENIGN HEMATOLOGY BOARD Editor-in-Chief Michael H. Kroll MD

Associate Editors

Editorial Contributors

Rakhi Naik MD MHS Associate Director for Hematology,

Kelly N. Casteel MD Fellow in Hematology/Oncology, MD Anderson Cancer Center, Houston, Texas

Professor of Medicine, Chief of the Section of Benign Hematology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas

Hematology/Oncology Fellowship Program; Assistant Professor of Medicine, Hematology, Johns Hopkins Medicine, Baltimore, Maryland Cristhiam M. Rojas Hernandez MD Assistant Professor of Hematology, MD Anderson Cancer Center, Houston, Texas

Eric Fountain MD, MA Fellow in Hematology/Oncology, MD Anderson Cancer Center, Houston, Texas

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ADVANCED PROSTATE CANCER Editors-in-Chief Thomas J. Guzzo MD, MPH

Associate Editors

Brian E. Lewis MD, MPH Assistant Professor of Clinical Medicine, Department of Hematology and Medical Oncology, Tulane University School of Medicine, New Orleans, Louisiana

Jonathan Silberstein MD, MBA Candidate 2018 Assistant Professor of Urology; Chief, Section of Urologic Oncology, Department of Urology, Tulane University School of Medicine; Chief of Urology Service, Department of Surgery, Southeast Louisiana Veterans Health Care Center, New Orleans, Louisiana

Chief of Urology, Associate Program Director, University of Pennsylvania Perelman Center for Advanced Medicine, Philadelphia, Pennsylvania Oliver A. Sartor MD Laborde Professor, Cancer Research, Medicine and Urology Departments, Tulane School of Medicine, New Orleans, Louisiana

BRAIN CANCER Editors-in-Chief

Associate Editor

Minesh P. Mehta MD, FASTRO Deputy Director, Chief of Radiation Oncology, Miami Cancer Institute, Miami, Florida

Patrick Y. Wen MD Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute; Director, Division of Cancer Neurology, Department of Neurology, Brigham and Women’s Hospital; Professor of Neurology, Harvard Medical School, Boston, Massachusetts

Manmeet Ahluwalia MD, FACP Dean and Diane Miller Family Endowed Chair in Neuro-Oncology, Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Neurological Institute and Taussig Cancer Institute, Cleveland Clinic; Associate Professor, Department of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio

METASTATIC BREAST CANCER Editor-in-Chief

Associate Editors

Lee Schwartzberg MD, FACP Executive Director, West Cancer Center; Professor of Medicine and Division Chief of Hematology/Oncology, The University of Tennessee Health Science Center, Tennessee

Reshma L. Mahtani DO Associate Professor, Division of Hematology/Oncology, Sylvester

Lillie D. Shockney RN, BS, MAS University Distinguished Service Professor of Breast Cancer, Administrative Director, Johns Hopkins Breast Center and Cancer Survivorship Programs, Baltimore, Maryland

Comprehensive Cancer Center, University of Miami Health System, Miami, Florida

RENAL CELL CARCINOMA Editors-in-Chief Sumanta K. Pal MD

Associate Editor

Advisory Board

Eric Jonasch MD Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine; Director, VHL Clinical Center, The University of Texas MD Anderson Cancer Center, Houston, Texas Oliver A. Sartor MD Laborde Professor, Cancer Research, Medicine and Urology Departments, Tulane School of Medicine, New Orleans, Louisiana

Heather R. Greene MSN, FNP, AOCNP Nurse Practitioner, The West Clinic, Memphis, Tennessee

Associate Professor, Department of Medical Oncology & Therapeutics Research; Co-Director, Kidney Cancer Program, City of Hope, Duarte, California Bradley G. Somer MD Medical Oncologist; Associate Professor of Hematology/Oncology, University of Tennessee Health Science Center; and Senior Partner, West Cancer Center, Memphis, Tennessee

VOL. 2 • NO. 4 • 2018

TOP STORIES 2018 6

Venetoclax for Multiple Myeloma By Rafael D. Fonseca MD

F or me, the top story for multiple myeloma in 2018, is venetoclax. Venetoclax represents the culmination of efforts to develop a therapeutic agent tailored to work in certain genetic subtypes of the disease. How did we get here? How can this development be the most important one for 2018, when everyone is talking about CAR T-cell therapies and bispecific antibodies? How can this develop- ment be so important given that we have the results of phase III trials showing improvement in disease control with daratumumab-based combinations? How could this be the story of the year when we have the possible addition of new drugs such as selinexor? The answer is simple. This is the first time that a truly targeted therapeutic has been developed for multiple myeloma. Let me explain. Myeloma has been, for several years, one of the best understood tumors when it comes down to dis- ease biology and genetic changes. Description of the major subtypes of the disease and secondary genetic changes dates back now close to 15 years. Although we have had important refinements to this

knowledge framework, the basic genetic groups are the same. The addition of novel tools, such as gene-expression profiling and mutation analysis with next-generation sequencing, has increased the depth of our understanding of the genetic nature of the disease. Myeloma is divided into two broad subgroups, the hyperdiploid and the non-hyperdip- loid variants. One of the hallmarks of myeloma is that the non-hy- perdiploid variant is enriched for chromosome translocations involving the immunoglobulin heavy- chain locus. Although the translocation t(11;14) could be detected through cytogenetic analysis, it was not until molecular genetic studies performed by Berg- sagel, Kuehl, and Chesi identified the presence of the translocations t(4;14) and t(14;16). Despite having this detailed knowledge of the disease, genetics had been predominantly used to stratify patients into risk categories and to propose different treat- ment pathways. However, none of these treatments has directly targeted the consequence of genetic aberrations. Previous efforts to target the FGFR3 gene, associated with t(4;14), have failed. Genetic understanding did not provide to myeloma the opportunity that was fully realized in chronic mye- logenous leukemia. Nevertheless, genetics in myeloma did help with a better understanding of the prognostic catego- ries of disease. This has allowed for a more tailored conversation with patients regarding the likelihood of better outcomes. Furthermore, the knowledge about high-risk genetic features changed the par- adigm upon which we recommend maintenance therapy in the post–stem cell transplant setting. Knowing that patients with high-risk genetic features derive greater benefit from the use of proteasome inhibitors became important practical knowledge. Arguably, the natural history of patients with t(4;14) was changed because of the addition of bortezomib to treatment. At the same time, great strides were made in the fight against multiple myeloma by the

Renal Cell Carcinoma: Ipilimumab + Nivolumab By Eric Jonasch MD T he top story for renal cell carcinoma in 2018 is the approval of ipilimumab plus nivolumab for the upfront treatment of patients with intermediate- and poor-risk renal cell carcinoma. 1 The approval arises from a phase III trial that randomized nearly 1100 patients with untreated advanced and metastatic renal cell carcinoma between ipilimumab 1 mg/kg IV every 3 weeks times four plus nivolumab 3 mg/kg IV together with ipilimumab followed by nivolumab maintenance therapy every 2 weeks. 2 The co-primary endpoints of overall survival and objective response rate in intermediate- and poor-risk patients were met. Strikingly, in patients with intermediate-/poor-risk features who were PD-L1–positive, the complete response rate was 16%, a result never before seen in renal cell carcinoma and particularly impressive for this patient subgroup. This combination is beset with significant immune toxicities, and care needs to be taken to manage these if they arise. Nonetheless, the combination of ipilimumab plus nivolumab is a high-water mark in the treatment of metastatic RCC and should be consid- ered as standard therapy for the appropriate patients. References 1. U.S. Food and Drug Administration: FDA approves nivolu-mab plus ipilimumab combination for intermediate- or poor-risk advanced renal cell carcinoma. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm604685.htm. Accessed November 8, 2018. 2. Motzer RJ, Tannir NM, McDermott DF, et al: Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378(14):1277-1290. www.practiceupdate.com/c/75853

PRACTICEUPDATE ONCOLOGY

TOP STORIES 2018 7

PD-1 BlockadeWith Cemiplimab for Advanced SCC of the Skin By Roxana S. Dronca MD

I n the past, the treatment of locally advanced or metastatic squamous cell carcinoma (SCC) of the skin has relied mostly on platinum-based systemic chemo- therapy, agents targeting the epidermal growth factor receptor (EGFR) pathway, and/

or radiation therapy. However, none of these approaches has definitively been proven to be effective, nor has any been spe- cifically approved to treat this condition. On September 28, 2018, the FDA approved a new anti–PD-1 agent, cemiplimab-rwlc, for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or radiation. Cemiplimab-rwlc has received breakthrough therapy designa- tion for this indication. The approval was based on data from an international phase I expansion cohort study and a phase II cohort that included 85 patients with metastatic or unresecta- ble locally advanced disease. 1 Overall, cemiplimab induced a response in approximately half the patients treated (50% in the expansion cohorts of the phase I study and 47% in the metastatic disease cohort of the phase II study) and provided disease con- trol in another 10% to 15%. Although there are only limited data on the role of systemic chemotherapy or biological agents tar- geting EGFR in the treatment of advanced CSCC, the response rate for cemiplimab-rwlc seems significantly higher than that previously reported with these older agents. Moreover, as was the experience with other cancer types, the responses to immu- notherapy are seen fairly early after treatment initiation, usually within the first 2 to 3 months, and they seem to be more dura- ble, with most patients continuing to have a response beyond 6 months. In subgroup analyses, similar efficacy was observed in patients with regional advanced disease and in those with distant metastatic disease. Novel cancer immunotherapies targeting the immune suppres- sive PD-1/PD-L1 pathway have become a true paradigm shift in the treatment of patients with many advanced tumors. These results represent a significant practice change for the treat- ment of patients with advanced SCCs of the skin, and will likely change substantially the way this malignancy is being treated. At present, other immunotherapies are also being tested, such as the anti–PD-1 agent pembrolizumab and combinations of anti–PD-1 and talimogene laherparepvec (TVEC). An unresolved issue, however, is the treatment of patients with advanced CSCC who cannot receive immunotherapies, such as organ transplant recipients or severely immunocompromised patients. Reference 1. Migden MR, Rischin D, Schmults CD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med 2018;379(4):341-351. www.practiceupdate.com/c/75967

incorporation of medications that target “normal plasma cell differ- entiation” and protein metabolism. The introduction of proteasome inhibitors and IMIDs, followed by the introduction of monoclonal antibodies, greatly improved the survival for myeloma patients. Nevertheless, genetics have not augmented our treatment arma- mentarium. However, that will change with venetoclax! Although there is still significant room for a better understanding of the mechanism of action of venetoclax in multiple myeloma, it is now very clear that this drug seems particularly effective for patients with the translocation t(11;14). Even if better biomarkers are developed for the selection of the right patients, venetoclax pro- vides options for patients with this translocation and for whom no treatments have been available. We are all hoping that venetoclax will be approved by the FDA soon. Patients have been treated with venetoclax, often in combination with steroids or with proteasome inhibitors, off-label when no further treatment options were availa- ble to them. Several clinical trials have now demonstrated a very high rate of response to combination strategies that use veneto- clax, particularly in patients with t(11;14). We have seen patients who have been heavily pretreated and who have achieved a complete response with venetoclax and dexamethasone alone. The obvious corollary questions are as follows. Should venetoclax be used as maintenance therapy in patients who have the translo- cation t(11;14)? What is the role of venetoclax in patients who have light-chain amyloidosis (50% have this translocation) and in patients with primary plasma cell leukemia (50% also have this translocation)? Should venetoclax be used earlier in the course of the disease in patients with this genetic abnormality as a part of combination strat- egies? If venetoclax can treat effectively the 15% of patients with this genetic abnormality, what about MCL-1 inhibitors? Recent data from the Mayo Clinic has shown that, although sur- vival for most myeloma patients has improved over the past 15 years, these improvements have lagged among patients with the translocation t(11;14). Perhaps this has been because t(11;14) plasma tends to be more lymphoid and their cytoplasm contains fewer proteins. Accordingly, the protein stress associated with the use of proteasome inhibitors and IMIDs is lessened in patients with t(11;14). Fortunately, we now envision the addition of venetoclax to our toolbox! www.practiceupdate.com/c/75855

VOL. 2 • NO. 4 • 2018

TOP STORIES 2018 8

Hematologic Malignancies: Haploidentical Stem Cell Transplant By Isabel Cunningham MD

I n hematologic malignancies, I am choos- ing the wide acceptance of haploidentical stem cell transplant for acute leukemia as the top story of 2018. This is illustrated by two very large cooperative studies published at the end of this year that show haploidentical

transplants achieving similar results to unrelated donor transplants. The European Bone Marrow Transplant Group reported results of 199 haploidentical donor compared to 1494 unrelated donor transplants in adults with relapsed/refractory AML, 1 and an Italian study of children with AML and ALL in remission compared 98 alpha/beta T and B cell–depleted transplants to 245 from unre- lated donors. 2 Comparable CR rates over 77% and 2-year DFS of 23% to 28% were obtained in the 218-center EBMT report. In the pediatric report of patients transplanted in remission, 5-year DFS was 55% to 67% in the compared arms. It is a true advance for our field that we have finally arrived at acceptance of haploidentical donors that enlarges the availability of transplant to virtually every eligible patient, and decreases the cost and prolonged time often required to find a suitable unrelated donor. Delays increase the risk of relapse and transplant failure. It should not have taken 20 years after the NEJM publication of the success of T cell–depleted haploidentical transplant in adult leu- kemia by Aversa et al. 3 That work was the logical extension of the T-cell technique pioneered in the 1980s by Yair Reisner and the Memorial Sloan Kettering group, which enabled parental marrow transplant to children with severe combined immune deficiency. The advent of techniques to harvest “mega-doses” of peripheral

stem cells in the 1990s made it possible to overcome rejection of haploidentical grafts while decreasing the risk of GvHD by T-cell depleting the grafts. Ongoing improvements in conditioning reg- imens and GvHD prevention increase the age of patients whose leukemia may be cured after transplant. Together with continuing development of CAR T-cell therapies, immunologic approaches are major advances in leukemia in 2018. References 1. Brissot E, Labopin M, Ehninger G, et al. Haploidentical versus unrelated allogeneic stem cell transplantation for relapsed/refractory acutemyeloid leukemia: A report of 1578 patients from the Acute Leukemia Working Party of EBMT. Haematologica 2018 Oct 25. doi: 10.3324/haematol.2017.187450. [Epub ahead of print.] 2. Bertaina A, Zecca M, Buldini B, et al. Unrelated donor vs HLA-haploidentical alpha/beta T-cell and B-cell depleted HSCT in children with acute leukemia. Blood 2018 Oct 22. doi: 10.1182/blood-2018-07-861575. [Epub ahead of print.] 3. Aversa F, Tabilio A, Velardi A, et al. Treatment of High-Risk Acute Leukemia

with T-Cell–Depleted Stem Cells from Related Donors with One Fully Mismatched HLA Haplotype. N Engl J Med 1998; 339(17):1186-1193. www.practiceupdate.com/c/76013 ER-Positive, Node-Negative Breast Cancer By Jeffrey J. Kirshner MD, FACP T he ASCO presentation and simulta- neous publication of the results of the TAILORx trial have led to a major change therapy for the primary endpoint of invasive disease-free survival (83.3% vs 84.3%). Noninferiority was also demonstrated in a num- ber of secondary endpoints, including overall survival (93.9% vs 93.8% in the chemoendocrine group). However, in an exploratory analysis of women 50 years of age and younger, there was some benefit of chemotherapy, which needs to be discussed with these patients, particularly with those who have RS 20 to 25. in the adjuvant management of women with ER-positive, node-negative breast cancer. 1 The standard of care has been to treat such

The take-home message is that it is “safe” to omit adjuvant chemo- therapy for most women with ER-positive, node-negative breast cancer with intermediate RS, which is a major practice change affecting thousands of women in the US annually and many more worldwide. Reference: 1. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med 2018;379(2):111-121 www.practiceupdate.com/c/74293

patients who have low recurrence scores (RS) on the Oncotype DX assay with hormonal therapy alone and to add chemotherapy for patients with high RS. However, the majority of these patients have RS in the intermediate range, and it has been unknown how much chemotherapy adds to endocrine therapy in this setting. In this trial, 6711 women with intermediate RS (11–25) were ran- domized to endocrine therapy alone versus the addition of chemotherapy prior to starting the hormonal treatment. At 9 years, endocrine therapy alone was noninferior to chemoendocrine

PRACTICEUPDATE ONCOLOGY

Your aplastic anaemia (AA) patient could also be your PNH patient 1

• A diagnosis of AA may not be the full picture 1 • Up to 1 in 4 AA patients has a PNH clone detected 2 • PNH clone size can increase rapidly and unpredictably over time in patients with AA 2 • Regular PNH screening of AA patients is essential 3

PNH: Paroxysmal Nocturnal Haemoglobinuria References: 1. Schrezenmeier H, et al. Haematologica. 2014;99:922- 929. 2. Movalia M, et al. Poster 0886. Presented at the 17th Congress of the EHA, June 2012, Amsterdam, The Netherlands. 3. Killick SB, et al. BJH. 2016, 172, 187–207. © 2018 Alexion Pharmaceuticals Australasia Pty Limited. All rights reserved. Alexion Pharmaceuticals Australasia Pty Limited. ACN 132 343 036. Suite 401, Level 4, Building A, 20 Rodborough Rd, Frenchs Forest, NSW 2086 Australia. September 2018. AU/SOL-P/18/0033

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Pertuzumab and Trastuzumab With or Without Metronomic Chemotherapy for Older Patients With HER2-Positive Metastatic Breast Cancer The Lancet Oncology

COMMENT By Reshma L. Mahtani DO T he goal of treatment in metastatic breast cancer patients is palliation, and when considering treatments, we must balance risks of toxicity with benefit. This is especially true in elderly patients who often have comorbidities and poorer tolerance to treatment. For patients with HER2-positive disease, the availability of HER2-directed therapies has dramatically improved outcomes. Many of these thera- pies, such as trastuzumab and pertuzumab, are very well tolerated. In the neoadjuvant setting, these agents have demonstrated significant activity in combination, with- out the use of concomitant chemotherapy. Therefore, there is interest in examining approaches that include less toxic therapies in combination with HER2-directed treat- ments, especially in older patients. In the current analysis, the authors report improvements in PFS with the addition of metronomic oral cyclophosphamide to trastuzumab and pertuzumab in older and frail patients. The toxicity profile was acceptable and is improved when compared with docetaxel, which was used in the CLEOPATRA trial. This study is therefore helpful in supporting the use of a less toxic chemotherapy partner for some patients, as we move towards a more personalized approach to treatment. By Lillie D. Shockney RN, BS, MAS C learly, cardiac toxicity is of concern when taking care of patients with HER2-pos- itive metastatic disease, especially when treating elderly patients with poorer performance function. This study demonstrated that considerable additional time was gained with metronomic chemo along with biologic targeted agents. Given the physical condition of these patients, however, based on age and/or comorbid conditions, it is important to know how the patient's time was spent during the addi- tional months achieved by taking these drugs. Was she able to attend and enjoy her grandson's graduation or was she home, feeling too ill to go? Did she get to her granddaughter's wedding and reflect back on that event with a smile that she was able to participate in that special day? We must always look at quality of life and tol- erance of drug therapies through the eyes of the patient and no one else's. Although we may believe we can judge how the patient is feeling and how well she is physi- cally doing, when comparisons are made, usually the patient is not doing as well as we hoped. These are all important when measuring trial outcomes as well as in daily care, whether the patient is participating in a study or not. • Among older patients with HER2-positive metastatic breast cancer, the addition of metronomic oral cyclophosphamide to treatment with trastuzumab plus pertuzumab provided a significant survival benefit without any added safety concerns. The use of this regimen may delay or reduce the need for taxane chemotherapy. Neil Majithia MD Take-home message • In this phase II multicenter trial, older patients with HER2-positive metastatic breast cancer were randomized to receive the combination of pertuzumab and trastu- zumab alone (n=39) or in conjunction with metronomic chemotherapy with oral cyclophosphamide (n=41). After a median follow-up of 20.7 months, the addition of metronomic cyclophosphamide provided a progression-free survival benefit of around 7 months over placebo (12.7 months vs 5.6 months). The most common grade ≥3 adverse events were hypertension, diarrhea, dyspnea, and fatigue, and the rates of adverse events were similar in the two groups.

Abstract BACKGROUND Despite the high incidence of met- astatic breast cancer and its related mortality in the elderly population, our knowledge about optimal treatment for older patients with cancer is far from adequate. We aimed to evaluate the efficacy of dual anti-HER2 treatment with or with- out metronomic chemotherapy in older patients with HER2-positive metastatic breast cancer. METHODS We did a multicentre, open-label, ran- domised, phase 2 trial in 30 centres from eight countries in Europe, in patients with histologi- cally proven, HER2-positive metastatic breast cancer, without previous chemotherapy for met- astatic disease, who were 70 years or older, or 60 years or older with confirmed functional restrictions defined by protocol, and had a life expectancy of more than 12 weeks and a per- formance status according to WHO scale of 0-3. Eligible patients were randomly assigned (1:1) by an online randomisation system based on the minimisation method to receive metronomic oral cyclophosphamide 50 mg per day plus tras- tuzumab and pertuzumab, or trastuzumab and pertuzumab alone. Trastuzumab was given intravenously with a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. Pertuzumab was given intravenously with a loading dose of 840 mg, followed by 420 mg every 3 weeks. Patients were stratified by hormone receptor positivity, previous HER2 treatment, and base- line geriatric screening. The primary endpoint was investigator-assessed progression-free survival at 6 months as per Response Evalu- ation Criteria in Solid Tumors (RECIST) version 1.1. A difference of 10% or greater between the two groups was sought. Efficacy analyses were by intention to treat; safety was assessed in all patients who received at least one dose of study treatment. In case of progression, all patients were offered trastuzumab emtansine. FINDINGS Between July 2, 2013, and May 10, 2016, 80 patients, of whom 56 (70%) had a potential frailty profile according to the geriatric screen- ing G8 score (≤14), were randomly assigned to receive trastuzumab and pertuzumab (n=39) or trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (n=41). Estimated pro- gression-free survival at 6 months was 46·2% (95% CI 30·2-60·7) with trastuzumab and pertu- zumab versus 73·4% (56·6-84·6) with trastuzumab

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EDITOR’S PICKS 11

Pathological Response and Survival in TNBC After Neoadjuvant Carboplatin + Docetaxel Take-home message • This study looked at recurrence-free and overall survival according to the degree of pathologic response in patients with stage I–III triple-negative breast cancer treated with neoadjuvant carboplatin plus docetaxel. The rate of pathological complete response (pCR) was 55%. The rate of residual cancer burden class I was 13%. At 3 years, overall survival for patients with pCR was 94% vs 79% for those without pCR. • These results indicate that neoadjuvant carboplatin plus docetaxel shows promise in extending survival in patients with triple-negative breast cancer. Neil Majithia MD Clinical Cancer Research

and pertuzumab plus metronomic oral cyclo- phosphamide (hazard ratio [HR] 0·65 [95% CI 0·37-1·12], p=0·12). At a median follow-up of 20·7 months (IQR 12·5-30·4), the median progression-free survival was 5·6 months (95% CI 3·6-16·8) with trastuzumab and pertu- zumab versus 12·7 months (6·7-24·8) with the addition of metronomic oral cyclophospha- mide. The most frequent grade 3-4 adverse events were hypertension (in six [15%] of 39 patients in the trastuzumab and pertuzumab group vs five [12%] of 41 in the trastuzumab and pertuzumab plus metronomic oral cyclo- phosphamide group), diarrhoea (four [10%] vs five [12%]), dyspnoea (two [5%] vs four [10%]), fatigue (three [8%] vs two [5%]), pain (two [5%] vs two [5%]), and a thromboembolic event (0 [0%] vs four [10%]). Severe cardiac toxicities were occasionally observed in both groups. In the trastuzumab and pertuzumab group four patients died without progression, due to cardiac arrest during treatment (n=1), peri- toneal infection (n=1), respiratory failure (n=1), and sudden death without a specified cause (n=1). In the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group, one patient died from heart failure. INTERPRETATION Addition of metronomic oral cyclophosphamide to trastuzumab plus pertuzumab in older and frail patients with HER2-positive metastatic breast can- cer increased median progression-free survival by 7 months compared with dual HER2 blockade alone, with an acceptable safety profile. Trastuzumab and pertuzumab plus metronomic oral cyclophosphamide, followed by trastuzumab emtansine after disease progression, might delay or super- sede the need for taxane chemotherapy in this population. Pertuzumab and Trastuzumab With or Without Metronomic Chemotherapy for Older Patients With HER2-Positive Meta- static Breast Cancer (EORTC 75111-10114): An Open-Label, Randomised, Phase 2 Trial From the Elderly Task Force/Breast Can- cer Group. Lancet Oncol 2018 Feb 09;[EPub Ahead of Print], HWildiers, K Tryfonidis, L Dal Lago, et al. www.practiceupdate.com/c/64062

Abstract PURPOSE Prognostic value of pathologic com- plete response (pCR) and extent of pathologic response attained with anthracycline-free plat- inum plus taxane neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) is unknown. We report recurrence-free sur- vival (RFS) and overall survival (OS) according to degree of pathologic response in patients treated with carboplatin plus docetaxel NAC. EXPERIMENTAL DESIGN One-hundred and ninety patients with stage I-III TNBC were treated with neoadjuvant carboplatin (AUC6) plus docetaxel (75 mg/m 2 ) every 21 days × 6 cycles. pCR (no evidence of invasive tumor in breast and axilla) and Resid- ual cancer burden (RCB) were evaluated. Patients were followed for recurrence and survival. Extent of pathologic response was associated with RFS and OS using the Kaplan-Meier method. RESULTS Median age was 51 years, and 52% were node-positive. pCR and RCB I rates were 55% and 13%, respectively. Five percent of pCR patients, 0% of RCB I patients, and 58% of RCB II/III patients received adjuvant anthracy- clines. Three-year RFS and OS were 79% and 87%, respectively. Three-year RFS was 90% in patients with pCR and 66% in those without pCR [HR = 0.30; 95% confidence interval (CI), 0.14-0.62; P = 0.0001]. Three-year OS was 94% in patients with pCR and 79% in those without pCR (HR = 0.25; 95% CI, 0.10-0.63; P = 0.001). Patients with RCB I demonstrated 3-year RFS (93%) and OS (100%) similar to those with pCR. On multivariable analysis, higher tumor stage, node positivity, and RCB II/III were associated with worse RFS. CONCLUSIONS Neoadjuvant carboplatin plus docetaxel yields encouraging efficacy in TNBC. Patients achieving pCR or RCB I with this regi- men demonstrate excellent 3-year RFS and OS without adjuvant anthracycline. Pathological Response and Survival in Triple-Negative Breast Cancer Following Neo- adjuvant Carboplatin Plus Docetaxel. ClinCancer Res 2018 Sep 26;[EPub Ahead of Print], P Sharma, S López-Tarruella, JA García-Saenz, et al. www.practiceupdate.com/c/73994

COMMENT By Lee S. Schwartzberg MD, FACP T he pCR rate from neoadjuvant chemotherapy for triple-negative breast cancer (TNBC) is enhanced by adding a platinum agent like carbo- platin but at the cost of additional toxicity when added to the traditional backbone of anthracycline, cyclophosphamide, and taxane. The authors of this study have previously presented a phase II study of carboplatin and docetaxel in TNBC, and the results are updated in Clinical Cancer Research for 3-year DFS and OS. There was an impressive pCR rate of 55% with this combination, with low incidence of grade 3/4 toxicity. Note that all patients received prophylactic growth factor support. The 3-year DFS for patients who had a pCR or a resid- ual cancer burden (RCB) of I was 91%, and the 3-year OS was 95%. Although a two-institution clinical trial single-arm study has to be replicated in a phase III setting, the regimen is the backbone of the TCH regimen and is familiar to almost everyone. It offers a potentially higher pCR rate and, impor- tantly, an improved clinical outcome compared with docetaxel and cyclo- phosphamide with similar toxicity, and takes advantage of the DNA repair defi- ciency that is present in many TNBCs, not limited only to BRCA1/2 mutation carriers. For TNBC patients who are not candidates for anthracyclines but who are at a higher risk of relapse (node-positive, larger tumors), this is an attractive regimen.

VOL. 2 • NO. 4 • 2018