PracticeUpdate Oncology February 2019

VOL. 3 • NO. 1 • 2019

OUR EXPERTS. YOUR PRACTICE.

ISSN 2207-869X

Ibrutinib Regimens vs Chemoimmunotherapy in Older PatientsWith Untreated CLL

Expert Opinion BrainMetastases: A Brave NewWorld By Rupesh R. Kotecha MD First- vs Next-Generation TKIs for NSCLCWith Driver Mutations Interviewwith Benjamin Besse MD Conference Coverage San Antonio Breast Cancer Symposium 2018

JOURNAL SCANS Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients With Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial

Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer

Venetoclax Combined With Decitabine or Azacitidine in Treatment-Naive, Elderly Patients With Acute Myeloid Leukemia

in patients with Stage III unresectable NSCLC whose disease has not progressed post platinum-based CRT IMFINZI: UNPRECEDENTED OVERALL SURVIVAL BENEFIT (vs placebo: HR 0.68; 95% CI, 0.53-0.87; P =0.0025) 1-3

NOW TGA REGISTERED

BEFORE PRESCRIBING PLEASE REVIEW FULL PRODUCT INFORMATION AVAILABLE ON REQUEST FROM ASTRAZENECA ON 1800 805 342 OR www.astrazeneca.com.au/PI

PBS Information: This product is not listed on the PBS.

CI: confidence interval; CRT: chemoradiation therapy; HR: hazard ratio; NSCLC: non-small cell lung cancer; OS: overall survival; TGA: Therapeutic Goods Administration. Stage III NSCLC is defined as locoregionally advanced disease due to primary tumour extension into extrapulmonary structures (T3 or T4) or mediastinal lymph node involvement (N2 or N3) without evidence of distant metastases (M0), including tumours greater than 5 cm in size with hilar, intrapulmonary, or peribronchial lymph node involvement (T3N1) or tumours greater than 7 cm (T4), regardless of lymph node involvement. 4 References: 1. IMFINZI Approved Product Information. 2. Antonia SJ, et al . N Engl J Med 2018;DOI: 10.1056/NEJMoa1809697. 3. McCall NS, et al. Clin Cancer Res 2018;24:1271-6. 4. Schild SE, et al. Management of stage III non-small lung cancer. UpToDate. May 30 2018. Available at: https://www.uptodate.com/contents/ management-of-stage-iii-non-small-cell-lung-cancer (accessed 6 July 2018). IMFINZI™ (durvalumab) 120mg/2.4mL or 500mg/10mL, Concentrated Solution for Infusion in a single-dose vial. Therapeutic indications: Urothelial carcinoma: Treatment of patients with locally advanced or metastatic urothelial carcinoma who: have disease progression during or following platinum-containing chemotherapy; have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved based on objective response rate and duration of response in a single arm study. An improvement in survival or disease-related symptoms has not been established. *Locally advanced non-small cell lung cancer (NSCLC): Treatment of patients with locally advanced, unresectable NSCLC whose disease has not progressed following platinum-based chemoradiation therapy . Dose and method of administration: Urothelial carcinoma: 10 mg/kg as an intravenous (IV) infusion over 60 minutes every 2 weeks, as long as clinical benefit is observed or unacceptable toxicity. *Locally advanced NSCLC: 10 mg/kg administered as an IV infusion over 60 minutes every 2 weeks, for one year or until disease progression or unacceptable toxicity . IMFINZI should be diluted prior to infusion. See full PI for compatible diluents. Dose escalation or reduction is not recommended. Dose withholding or discontinuation may be required based on individual safety and tolerability. See full PI for guidelines for management of adverse reactions. See Warnings and Precautions section of full PI for monitoring and evaluation information. IMFINZI has not been studied in patients with severe renal impairment. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Special warnings and precautions for use: Immune-mediated adverse reactions: Immune checkpoint inhibitors, including durvalumab, can cause severe and fatal immune-mediated adverse reactions (imARs), which may involve any organ system. Patients should be monitored for signs and symptoms associated with imARs including: immune-mediated pneumonitis, hepatitis, colitis, nephritis and dermatological adverse reactions; immune-mediated endocrinopathies including hypothyroidism, hyperthyroidism, adrenal insufficiency, Type 1 diabetes mellitus, hypophysitis/hypopituitarism, and other immune-mediated adverse reactions. See full PI for further monitoring and evaluation information and for management recommendations for imARs. Monitor patients for signs and symptoms of infusion-related reactions: severe reactions have been reported. *Efficacy in patients with PD-L1 expression <1%: post-hoc analyses suggest efficacy may be different for patients with PD-L1<1% . Paediatric use: safety and efficacy not established in patients less than 18 years. Use in pregnancy: Category D. Durvalumab has the potential to impact maintenance of pregnancy and may cause foetal harm. Not recommended during pregnancy; women of childbearing potential must use effective contraception during treatment and for at least 3 months after the last dose. Use in lactation: lactating women should be advised not to breastfeed during treatment and for at least 3 months after the last dose. ADVERSE REACTIONS: Urothelial carcinoma: Very common (≥10%, any grade): fatigue, musculoskeletal pain, constipation, decreased appetite/hypophagia, nausea, anaemia, urinary tract infection, diarrhoea/colitis, liver injury, abdominal pain, acute kidney injury, rash, peripheral oedema, dyspnoea/exertional dyspnoea, cough/productive cough, pyrexia/tumour associated fever, vomiting, arthralgia, hypothyroidism, hyponatraemia, insomnia. *Locally advanced NSCLC: Very common (≥10%, any grade): cough/productive cough, pneumonitis/radiation pnemonitis, dyspnoea, diarrhoea, abdominal pain, hypothyroidism, rash, pruritus, fatigue, pyrexia, pneumonia, upper respiratory tract infections; Common (≥1% to <10%, any grade): dysphonia, dysuria, night sweats, peripheral oedema, increased susceptibility to infections. See full PI for other listed adverse reactions including immune-mediated adverse reactions. Date of first inclusion in the ARTG: 2nd October 2018. Date of most recent amendment: 23rd October 2018. *Please note changes in Product Information.

IMFINZI ™ is a trademark of the AstraZeneca group of companies. Registered user AstraZeneca Pty. Ltd. ABN 54 009 682 311. 66 Talavera Road, Macquarie Park, NSW 2113. www.astrazeneca.com.au. For Medical Information enquiries: 1800 805 342 or medinfo.australia@astrazeneca.com. To report an adverse event: 1800 805 342 or via https://aereporting.astrazeneca.com. Date of preparation: January 2019. WL301685. AU-5510.

CONTENTS 3

EXPERT OPINION 18 Brain Metastases: A Brave New World By Rupesh R. Kotecha MD COVER 6 Ibrutinib Regimens vs Chemoimmunotherapy in Older Patients With Untreated CLL Comments by Isabel Cunningham MD and Alessandra Ferrajoli MD

RESEARCH Editor’s picks 6 Ibrutinib Regimens vs

Chemoimmunotherapy in Older Patients With Untreated CLL Comments by Isabel Cunningham MD and Alessandra Ferrajoli MD 7 Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade 8 Immediate vs Deferred Cytoreductive Nephrectomy in Patients With Synchronous mRCC Receiving Sunitinib Comment by Sumanta Kumar Pal MD 9 FOLFIRINOX Adjuvant Therapy Increases

20 Combination of Immune Checkpoint Blockade and Tumor Vaccine for HPV+ Cancer Interview with Barbara Burtness MD by Tyeese L. Gaines DO 21 First- vs Next-Generation TKIs for NSCLC With Driver Mutations Interview with Benjamin Besse MD by Tyeese L. Gaines DO Interview with Lee S. Schwartzberg MD, FACP by Farzanna S. Haffizulla MD, FACP, FAMWA 24 Baseline Circulating ESR1 Mutation Analysis From the EFECT study Interview with William John Gradishar MD, FACP by Farzanna S. Haffizulla MD, FACP, FAMWA 26 Neoadjuvant Talazoparib for BRCA 1/2 Mutated Triple-Negative Breast Cancer Interview with Jennifer Litton MD by Farzanna S. Haffizulla MD, FACP, FAMWA 27 Regional Analysis of Talazoparib for Treatment of Advanced Breast Cancer With Germline BRCA 1/2 Mutation Interview with Jennifer Litton MD by Farzanna S. Haffizulla MD, FACP, FAMWA 28 Race, Ethnicity, and Clinical Outcomes From the TAILORx Trial Interview with Sunil S. Badve MD, FRCPath by Farzanna S. Haffizulla MD, FACP, FAMWA 30 Lasofoxifene vs Fulvestrant for HR-Positive Breast Cancer Interview with Lee S. Schwartzberg MD, FACP by Farzanna S. Haffizulla MD, FACP, FAMWA 24 Eflapegrastim for Reducing Severe Neutropenia

Survival in Pancreatic Cancer Comment by Axel Grothey MD

CONFERENCE 22 San Antonio Breast Cancer Symposium 2018

10 Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer Comment by Lee S. Schwartzberg MD, FACP 11 Assessment of a Watch-and-Wait Strategy for Rectal Cancer Following Complete Response After Neoadjuvant Therapy Comment by Axel Grothey MD 12 Men With Clinically Detected, Localized Prostate Cancer Benefit From Radical Prostatectomy Comment by H. Ballentine Carter MD 13 Neoadjuvant Chemotherapy With or Without Anthracyclines in the Presence of Dual HER2 Blockade for HER2-Positive Breast Cancer Comment by Lee S. Schwartzberg MD, FACP 14 Venetoclax Plus Decitabine or Azacitidine in Treatment-Naive, Elderly Patients With AML Comment by Isabel Cunningham MD 15 Underdiagnosis of Hereditary Breast Cancer Comment by Lee S. Schwartzberg MD, FACP 16 Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease 17 Association of Gender With Efficacy of Immune Checkpoint Inhibitors and Overall Survival in Advanced Cancers Comment by Sumanta Kumar Pal MD

22 Adjuvant T-DM1 for HER2+ Breast Cancer: Critical Data From The KATHERINE Study Interview with Jame Abraham MD, FACP by Farzanna S. Haffizulla MD, FACP, FAMWA 23 Subgroup Analysis of Combination Immunotherapy for Triple-Negative Breast Cancer Interview with Alison K. Conlin MD by Farzanna S. Haffizulla MD, FACP, FAMWA

VOL. 3 • NO. 1 • 2019

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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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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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BRAIN CANCER Editors-in-Chief

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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

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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. 3 • NO. 1 • 2019

EDITOR’S PICKS 6

Ibrutinib Regimens vs Chemoimmunotherapy in Older Patients With Untreated CLL The New England Journal of Medicine Take-home message • This phase III trial evaluated the efficacy of ibrutinib, either alone or in combina- tion with rituximab, compared with chemoimmunotherapy in patients aged ≥65 years with untreated chronic lymphocytic leukemia (CLL). Patients were randomly assigned to receive bendamustine plus rituximab (n=183), ibrutinib (n=182), or ibru- tinib plus rituximab (n=182). • Treatment with ibrutinib was superior to treatment with bendamustine plus rituximab with regard to progression-free survival (PFS). PFS was similar in the ibrutinib group and the ibrutinib plus rituximab group.

" The benefit of receiving treatment with ibrutinib or ibrutinib plus rituximab was particularly large in patients carrying a del17p abnormality. "

COMMENT By Isabel Cunningham MD T his study reports on 547 patients over 65 years old with de novo CLL requiring treatment, enrolled over 2.5 years in 219 North American sites. Patients were randomized among three arms: one of standard bendamustine/rituximab for 6 cycles, and the other two contained ibrutinib given until progression, with or without rituximab, for 6 cycles. The supe- rior PFS of the ibrutinib arms is elucidated in the Kaplan-Meier plot that shows that a remarkable divergence of both ibrutinib arms from the benda/ritux arm began very early and grew much larger after 2 years and larger still at years 3 and 4. This no doubt reflects the different durations of therapy: 6 cycles in the benda/ ritux arm and a median of 32 months of continuous ibrutinib in By Alessandra Ferrajoli MD D efining the best treatment for older patients with CLL is very relevant. As older people are an increasing propor- tion of the population, the number of individuals affected by CLL will increase in parallel. Older patients with cancer have historically been under-represented in clinical trials. Fortunately, this is not the case for patients with CLL, who, for many years, have been enrolled in clinical trials, some of which are specifi- cally designed for older patients. Woyach and colleagues reported the result of a large phase III trial evaluating three treatment options: bendamustine and ritux- imab (BR) given for six cycles, ibrutinib as monotherapy given indefinitely, and the combination of ibrutinib and rituximab (ibru- tinib given indefinitely and rituximab given for six cycles) as initial therapy for patients with CLL age 65 and older. The results of this trial are likely to be practice-changing because of a significantly longer progression-free survival (PFS) observed in the patients treated in both ibrutinib-containing arms (2-year estimated PFS was 74% in patients treated with BR vs 87% and 88% in patients treated with ibrutinib and ibrutinib plus rituximab). The benefit of receiving treatment with ibrutinib or ibrutinib plus rituximab was particularly large in patients carrying a del17p abnormality.

its two arms that maintains response. Despite the higher rate of overall response (determined by CT and physical exam) in the ibrutinib arms (93% vs 81%), it is noteworthy that complete remis- sion was achieved in only 7%, compared with 26% in the benda/ ritux arm. Only small numbers of patients achieved undetectable MRD: 1% in benda/ritux arm and 4% to 8% in the ibrutinib arms. This trial raises questions about whether rituximab adds anything to ibrutinib in untreated CLL, and whether and how a higher inci- dence of MRD can be achieved, with the potential that patients would not require ibrutinib to be taken indefinitely. Results from comparison with younger patients in a similar ongoing trial are anticipated. This is a subgroup of patients for whom treatment with ibrutinib has already been clearly shown in phase II studies to be asso- ciated with a superior outcome compared with treatment with chemotherapy. For patients without del17p (the majority of front-line patients), the findings of this study confirm the superiority of ibrutinib as initial treatment in older patients with CLL seen in the RESO- NATE-2 study. In the RESONATE-2 study, a superiority for the ibrutinib as monotherapy arm compared with chlorambucil was seen in terms of PFS, and, most importantly, in terms of overall survival. The study of Woyach and colleagues will likely need a longer observation time before a difference in survival can be detected. More treatment-related toxicities were observed in the BR arm, particularly myelosuppression; however, treating physicians should be familiar with the increased rate of atrial fibrillation and uncontrolled hypertension observed in patients undergoing treatment with ibrutinib. Dr. Ferrajoli is Professor in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas.

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EDITOR’S PICKS 7

Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade JAMA Oncology Take-home message • In this case series of 1346 patients with prostate cancer who underwent paired tumor and germline sequencing, 32 of 1033 (3.1%) had micro- satellite instability-high or mismatch repair-deficient disease, of whom 7 (21.9%) carried a germline mutation in a Lynch syndrome-associated gene. Of 11 patients who received an anti–PD-1/PD-L1 agent, 5 had durable clinical benefit. • The microsatellite instability-high/mismatch repair-deficient phenotype is uncommon but clinically important in prostate cancer and can be somatically acquired during disease evolution. Jeffrey Wiisanen MD Abstract IMPORTANCE The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab is approved by the US Food and Drug Administration for the treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors, but the prev- alence of MSI-H/dMMR prostate cancer and the clinical utility of immune checkpoint blockade in this disease subset are unknown. OBJECTIVE To define the prevalence of MSI-H/dMMR prostate cancer and the clinical benefit of anti-PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy in this molecularly defined population. DESIGN, SETTING, AND PARTICIPANTS In this case series, 1551 tumors from 1346 patients with prostate cancer undergoing treatment at Memorial Sloan Kettering Cancer Center were prospectively analyzed using a targeted sequencing assay from January 1, 2015, through January 31, 2018. Patients had a diagnosis of prostate cancer and consented to tumor molecular profiling when a tumor biopsy was planned or archival tissue was available. For each patient, clinical outcomes were reported, with follow-up until May 31, 2018. MAIN OUTCOMES AND MEASURES Tumor mutation burden and MSIsensor score, a quantitative measure of MSI, were calculated. Mutational signature analysis and immu- nohistochemistry for MMR protein expression were performed in select cases. RESULTS Among the 1033 patients who had adequate tumor quality for MSIsensor anal- ysis (mean [SD] age, 65.6 [9.3] years), 32 (3.1%) had MSI-H/dMMR prostate cancer. Twenty-three of 1033 patients (2.2%) had tumors with high MSIsensor scores, and an additional 9 had indeterminate scores with evidence of dMMR. Seven of the 32 MSI-H/ dMMR patients (21.9%) had a pathogenic germline mutation in a Lynch syndrome-as- sociated gene. Six patients had more than 1 tumor analyzed, 2 of whom displayed an acquired MSI-H phenotype later in their disease course. Eleven patients with MSI-H/ dMMR castration-resistant prostate cancer received anti-PD-1/PD-L1 therapy. Six of these (54.5%) had a greater than 50% decline in prostate-specific antigen levels, 4 of whom had radiographic responses. As of May 2018, 5 of the 6 responders (5 of 11 total [45.5%]) were still on therapy for as long as 89 weeks. CONCLUSIONS AND RELEVANCE The MSI-H/dMMR molecular phenotype is uncommon yet therapeutically meaningful in prostate cancer and can be somatically acquired during disease evolution. Given the potential for durable responses to anti-PD-1/PD-L1 therapy, these findings support the use of prospective tumor sequencing to screen all patients with advanced prostate cancer for MSI-H/dMMR. Because not all patients with the MSI-H/ dMMR phenotype respond, further studies should explore mechanisms of resistance. Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Oncol 2018 Dec 27;[EPub Ahead of Print], W Abida, ML Cheng, J Armenia, et al. www.practiceupdate.com/c/77948

Abstract BACKGROUND Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) since 2016 but has not been compared with chemoimmuno- therapy. We conducted a phase 3 trial to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy. METHODS Patients 65 years of age or older who had untreated CLL were randomly assigned to receive bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab. The primary end point was progression-free survival. The Alliance Data and Safety Monitoring Board made the decision to release the data after the proto- col-specified efficacy threshold had been met. RESULTS A total of 183 patients were assigned to receive bendamustine plus rituximab, 182 to receive ibrutinib, and 182 to receive ibrutinib plus rituximab. Median progression-free survival was reached only with ben- damustine plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74% with bendamustine plus rituximab and was higher with ibrutinib alone (87%; hazard ratio for disease pro- gression or death, 0.39; 95% confidence interval [CI], 0.26 to 0.58; P<0.001) and with ibrutinib plus rituximab (88%; hazard ratio, 0.38; 95% CI, 0.25 to 0.59; P<0.001). There was no significant difference between the ibru- tinib-plus-rituximab group and the ibrutinib group with regard to progression-free survival (hazard ratio, 1.00; 95% CI, 0.62 to 1.62; P=0.49). With a median follow-up of 38 months, there was no significant difference among the three treatment groups with regard to overall sur- vival. The rate of grade 3, 4, or 5 hematologic adverse events was higher with bendamustine plus rituximab (61%) than with ibrutinib or ibrutinib plus rituximab (41% and 39%, respectively), whereas the rate of grade 3, 4, or 5 nonhematologic adverse events was lower with bendamustine plus rituximab (63%) than with the ibruti- nib-containing regimens (74% with each regimen). CONCLUSIONS Among older patients with untreated CLL, treatment with ibrutinib was superior to treatment with bendamustine plus rituximab with regard to progres- sion-free survival. There was no significant difference between ibrutinib and ibrutinib plus rituximab with regard to progression-free survival. Ibrutinib Regimens Versus Chemoimmunotherapy in Older Patients With Untreated CLL. N Engl J Med 2018 Dec 01;[EPub Ahead of Print], JA Woyach, AS Ruppert, NA Heerema, et al. www.practiceupdate.com/c/77047

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EDITOR’S PICKS 8

Immediate vs Deferred Cytoreductive Nephrectomy in Patients With Synchronous mRCC Receiving Sunitinib JAMA Oncology Take-home message • In this randomized trial, the authors examined the optimal sequence of sunitinib therapy and surgery in 99 patients with metastatic renal cell carcinoma. The patients were randomized to immediate cytoreductive nephrectomy followed by sunitinib therapy (n=50) or to three cycles of sunitinib followed by surgery in the absence of progression followed by sunitinib (n=49). Of the 50 patients in the immediate surgery arm, 40 received sunitinib; 48 of the 49 patients in the deferred arm received sunitinib. Systemic progression prior to surgery in the deferred arm resulted in a per-protocol recommendation against surgery in 14 patients. • Progression-free survival at 28 weeks was not improved when patients began sunitinib therapy before planned cytoreductive nephrectomy versus after, although overall survival was higher. The results suggest that cytoreductive nephrectomy could be avoided in patients who progress since pretreatment with sunitinib may identify those who have inherent resistance to systemic therapy before planned cytoreductive nephrectomy without inferior outcome. Jeffrey Wiisanen MD

COMMENT By Sumanta Kumar Pal MD

Abstract IMPORTANCE In clinical practice, patients with primary metastatic renal cell carcinoma (mRCC) have been offered cytoreductive nephrectomy (CN) followed by targeted therapy, but the optimal sequence of surgery and systemic therapy is unknown. OBJECTIVE To examine whether a period of sunitinib therapy before CN improves outcome compared with immediate CN followed by sunitinib. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial began as a phase 3 trial on July 14, 2010, and continued until March 24, 2016, with a median follow-up of 3.3 years and a clinical cutoff date for this report of May 5, 2017. Patients with mRCC of clear cell subtype, resectable primary tumor, and 3 or fewer surgical risk factors were studied. INTERVENTIONS Immediate CN followed by sunitinib therapy vs treatment with 3 cycles of sunitinib followed by CN in the absence of progression followed by sunitinib therapy. MAIN OUTCOMES AND MEASURES Progression-free survival was the primary end point, which needed a sample size of 458 patients. Because of poor accrual, the independent data monitoring committee endorsed reporting the intention-to-treat 28-week progression-free rate (PFR) instead. Over- all survival (OS), adverse events, and postoperative progression were secondary end points. RESULTS The study closed after 5.7 years with 99 patients (80 men and 19 women; mean [SD] age, 60 [8.5] years). The 28-week PFR was 42% in the immediate CN arm (n=50) and 43% in the deferred CN arm (n=49) (P= .61). The intention-to-treat OS hazard ratio of deferred vs immediate CN was 0.57 (95% CI, 0.34-0.95; P= .03), with a median OS of 32.4 months (95% CI, 14.5-65.3 months) in the deferred CN arm and 15.0 months (95% CI, 9.3-29.5 months) in the immediate CN arm. In the deferred CN arm, 48 of 49 patients (98%; 95% CI, 89%-100%) received sunitinib vs 40 of 50 (80%; 95% CI, 67%-89%) in the immediate arm. Systemic progression before planned CN in the deferred CN arm resulted in a per-protocol rec- ommendation against nephrectomy in 14 patients (29%; 95% CI, 18%-43%). CONCLUSIONS AND RELEVANCE Deferred CN did not improve the 28-week PFR. With the deferred approach, more patients received sunitinib and OS results were higher. Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned CN. This evidence complements recent data from randomized clinical trials to inform treat- ment decisions in patients with primary clear cell mRCC requiring sunitinib. Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients With Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial. JAMA Oncol 2018 Dec 13;[EPub Ahead of Print], A Bex, P Mulders, M Jewett, et al. www.practiceupdate.com/c/77436

I n a recent issue of JAMA Oncology , Bex and colleagues published data from the long-awaited SURTIME trial, a randomized study comparing immediate with deferred cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma (mRCC) receiving sunitinib. Beginning in July 2010, patients with clear cell mRCC and resectable primary tumors were selected to receive either immediate CN followed by sunitinib therapy or treatment with three cycles of sunitinib therapy followed by CN and followed again by sunitinib therapy if there was no evidence of progression. Due to difficulties in accrual, the primary endpoint of the study was changed after 3 years of recruitment from progression-free survival to the 28-week progression-free rate (PFR). Ultimately, a total of 99 patients were enrolled and no differ- ence was seen in the 28-week PFR between the immediate CN arm and deferred CN arm (42% vs 43%, respectively). There was, however, an improvement in overall survival (OS) in the intention-to-treat population, where the median OS of deferred and immediate CN was 32.4 months and 15.0 months, respectively. The results of this study complement recent data from CAR- MENA showing that immediate CN may negatively impact patients with clear cell RCC requiring sunitinib. Deferred CN for patients with nonprogressing disease after systemic therapy may account for the improved OS seen in SURTIME; the rele- vance of this strategy needs to be considered in the context of novel immune strategies that constitute the current first-line standard for mRCC. Additionally, initial treatment with sunitinib may identify those who are resistant to VEGFR-targeted thera- pies and are, therefore, poor candidates for CN. In the ever-changing systemic landscape of mRCC, it is chal- lenging to ascertain where CN would be the most beneficial. Results of CARMENA and SURTIME, however, give us further insight into this treatment option and encourage a multidisci- plinary approach to the initial treatment of this disease.

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EDITOR’S PICKS 9

FOLFIRINOX Adjuvant Therapy Increases Survival in Pancreatic Cancer The New England Journal of Medicine Take-home message • This study compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in 493 patients with resected pancreatic cancer. • Adjuvant therapy with the FOLFIRINOX regimen led to significantly longer survival (DFS, 21.6 months; OS, 54.4 months) than gemcitabine (12.8 months; 35.0 months) among patients with resected pancreatic cancer, at the expense of a higher inci- dence of toxic effects. Jeffrey Wiisanen MD

COMMENT By Axel Grothey MD T he use of FOLFIRINOX as adju- vant treatment in pancreas cancer has rightfully been called practice-changing. The difference in disease-free and overall survival compared with gemcitabine is quite remarkable and has established a new standard of care (SOC) for patients who can tolerate this chemo triplet. The results of the adjuvant gemcit- abine/nab-paclitaxel trial are pending, but they will have a high bar to meet. Still, I believe that gem/nab-paclitaxel is somewhat better tolerated than FOLFIRINOX (even with the dose mod- ification – see below) and could open the door for more patients receiving active adjuvant therapy – if the data are as we expect them to be. The FOLFIRINOX regimen used in the adjuvant study for most of the patients had two modifications compared with the initial regimen used in the meta- static setting: no bolus 5-FU and a lower dose of irinotecan (150 vs 180 mg/m 2 every 2 weeks). In my practice, I have changed FOLFIRINOX to reflect these modifications and would like to use this modified regimen for the adjuvant and palliative setting. The rationale is that if a regimen is the SOC in a curative set- ting, it would make no real sense to use anything but the more tolerable version in a palliative setting. Even with the very remarkable adjuvant FOLFIRINOX data, the trend in resectable pancreas cancer rightfully goes toward using a neoad- juvant approach. The tolerability of an aggressive chemo regimen is likely better pre- than post-op, the tumor biology can be observed, and cancers can declare themselves beyond cura- tive surgery during the neoadjuvant phase, and the combination of chemo plus radiation therapy (SBRT vs chemo- rads) conceivably allows for a higher rate of R0 resections. " In my practice, I have changed FOLFIRINOX to reflect these modifications and would like to use this modified regimen for the adjuvant and palliative setting. "

Abstract BACKGROUND Among patients with metastatic pancreatic cancer, combination chemother- apy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival than gemcitabine therapy. We compared the efficacy and safety of a modi- fied FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pan- creatic cancer. METHODS We randomly assigned 493 patients with resected pancreatic ductal adenocarci- noma to receive amodified FOLFIRINOX regimen (oxaliplatin [85 mg per square meter of body-sur- face area], irinotecan [180 mg per square meter, reduced to 150 mg per square meter after a pro- tocol-specified safety analysis], leucovorin [400 mg per square meter], and fluorouracil [2400 mg per square meter] every 2 weeks) or gemcitabine (1000 mg per square meter on days 1, 8, and 15 every 4 weeks) for 24 weeks. The primary end point was disease-free survival. Secondary end points included overall survival and safety. RESULTS At a median follow-up of 33.6 months, themedian disease-free survival was 21.6months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified haz- ard ratio for cancer-related event, second cancer,

or death, 0.58; 95% confidence interval [CI], 0.46 to 0.73; P<0.001). The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the mod- ified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. One patient in the gem- citabine group died from toxic effects (interstitial pneumonitis). CONCLUSIONS Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects. FOLFIRINOX or Gemcitabine as Adjuvant Ther- apy for Pancreatic Cancer. N Engl J Med 2018 Dec 20;379(25)2417-2428, T Conroy, P Hammel, M Hebbar, et al. www.practiceupdate.com/c/77688

VOL. 3 • NO. 1 • 2019

EDITOR’S PICKS 10

Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer The New England Journal of Medicine Take-home message • This phase III, open-label trial evaluated 1486 patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 (n=743) or trastuzumab (n=743) for 14 cycles. • The risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone. Jeffrey Wiisanen MD

COMMENT By Lee S. Schwartzberg MD, FACP

T he consequences of HER2-positive breast cancer patients receiving neoadjuvant chemotherapy and anti-HER2 therapy without achieving a pathologic complete response (pCR) are potentially serious: a significant risk of developing recurrent disease over the next 5 years despite receiving adjuvant trastuzumab +/− pertuzumab. In the KATHERINE trial, patients were randomized to receive the antibody–drug conjugate T-DM1 or trastuzumab for close to 1 year of therapy after less than a pCR to neoadjuvant treatment. Many of the patients in this trial had locally advanced, “nonoperable” breast cancer, and about one-fifth received chemotherapy with both trastuzumab and pertuzumab as neoadjuvant treatment. The results were striking, with a 50% improvement in DFS and a 40% reduction in distant recurrence rate. At 3 years, the absolute invasive DFS was 88.3% for T-DM1 post surgery compared with 77.0% for trastuzumab. All subgroups benefited from this approach, including those with little residual tumor in the breast, those with node-negative disease at surgery, and those with hormone receptor-positive disease. These impressive results are practice-changing, with the large improvement in outcome balanced by little in the way of increased toxicity for patients except for decreases in platelet count, and slight increases in grade 3 hypertension and sensory neuropathy. Notably, compared with the commonly used adjuvant treatment of trastuzumab and pertuzumab in this setting, the substitution of T-DM1 should be comparably or less expensive. Therefore, this is one of those rare situations where tangible improvements in patient outcome are not associated with a rise in cost for the benefit. A win all around!

Abstract BACKGROUND Patients who have residual inva- sive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastu- zumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhib- itor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy. METHODS We conducted a phase 3, open-label trial involving patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned

interval, 0.39 to 0.64; P<0.001). Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group. The safety data were consistent with the known safety profile of T-DM1, with more adverse events associated with T-DM1 than with trastuzumab alone. CONCLUSIONS Among patients with HER2-pos- itive early breast cancer who had residual invasive disease after completion of neoadju- vant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adju- vant T-DM1 than with trastuzumab alone. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med 2018 Dec 05;[EPub Ahead of Print], G von Minck-

to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was invasive disease-free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause). RESULTS At the interim analysis, among 1486 ran- domly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive dis- ease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastu- zumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease-free sur- vival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence

witz, CS Huang, MS Mano, et al. www.practiceupdate.com/c/77143

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