PracticeUpdate Oncology May 2019

VOL. 3 • NO. 2 • 2019

OUR EXPERTS. YOUR PRACTICE.

ISSN 2207-869X

Breast Cancer During Pregnancy

Expert Opinion Chemotherapy for Oligometastatic Prostate Cancer Interviewwith Tanya B. DorffMD Stereotactic Radiosurgery vsWhole Brain Radiation for PatientsWith ≥4 Brain Metastases InterviewwithMichael LimMD Immunotherapy and TKIs in Stage III Lung Cancer InterviewwithWilfried Eberhardt MD

The Radiation Oncology Summit 50th Annual Meeting onWomen's Cancer

JOURNAL SCANS A Randomized Trial of Lymphadenectomy in Patients With Advanced Ovarian Neoplasms

Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With BRAF V600E-Mutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study

Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial

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

COVER 18 Breast Cancer During Pregnancy Interview with Jennifer Litton MD by Tyeese L. Gaines DO

RESEARCH Editor’s picks 6 Lymphadenectomy in Patients With Advanced Ovarian Neoplasms

Comment by Annette Hasenburg Prof., Dr, med 7 Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study Comment by Axel Grothey MD 8 Neratinib and Capecitabine for Patients With HER2+ Breast Cancer and Brain Metastases Comments by Manmeet Ahluwalia MD, FACP and Reshma L. Mahtani DO

EXPERT OPINION 19 Chemotherapy for Oligometastatic Prostate Cancer Interview with Tanya B. Dorff MD by Farzanna S. Haffizulla MD, FACP, FAMWA 20 Stereotactic Radiosurgery vs Whole Brain Radiation for Patients With Four or More Brain Metastases Interview with Michael Lim MD by Aman Shah MD

21 Immunotherapy and TKIs in Stage III Lung Cancer Interview with Wilfried Eberhardt MD by Tyeese L. Gaines DO

9 Capecitabine Compared With Observation in Resected Biliary Tract Cancer 12 Talazoparib After Platinum or Cytotoxic Nonplatinum Regimens in Patients With Advanced Breast Cancer and Germline BRCA1/2 Mutations Comment by Reshma L. Mahtani DO 13 Cabozantinib in Advanced Non-Clear Cell Renal Cell Carcinoma Comment by Sumanta Kumar Pal MD 14 Increasing the Dose Intensity of Chemotherapy by More Frequent Administration or Sequential Scheduling Comment by Lee S. Schwartzberg MD, FACP 16 Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma Comment by Ari VanderWalde MD, MPH, FACP

CONFERENCE 22 The Radiation Oncology Summit: ACRO 2019 By the PracticeUpdate Editorial Team 22 Drug Targeting p53 Sensitizes Cancer Cells to Radiotherapy in Head and Neck Cancer 23 Link Between Germline Mutations and Severe Radiation Toxicity Identified 24 Tumor Grade/Size, Lymphovascular Invasion Predict Lymph Node Involvement in Early Endometrial Cancer 25 Recurrence Outside Treatment Field A Challenge With SBRT for Recurrent Head and Neck Squamous Cell Carcinoma

26 Society of Gynecologic Oncology 50th Annual Meeting on Women’s Cancer® By the PracticeUpdate Editorial Team 26 Dendritic Cell-Based Immunotherapy Appears Promising for Recurrent Ovarian Cancer 27 Lenvatinib + Weekly Paclitaxel Looks Promising for Recurrent Endometrial, Ovarian, Fallopian Tube and Primary Peritoneal Cancer 28 Olaparib and Neratinib Prove Synergistic

29 Mushroom Extract Supplementation Linked to Over 60% Eradication of HPV 30 DKN-01 Antibody Appears Promising in Wnt-Activated Recurrent Gynecologic Malignancies

in Models of HER2-Positive Ovarian Cancer, and PARP Inhibitors May Be Used Repeatedly

VOL. 3 • NO. 2 • 2019

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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

Isabel Cunningham MD Adjunct Associate Research Scientist, Division of Hematology Oncology, Columbia University College of Physicians and Surgeons, New York Axel Grothey MD Director, GI Oncology Research, West Cancer Center, University of Tennessee, Memphis, Tennessee

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 Sarah B. Goldberg MD, MPH Assistant Professor of Internal Medicine (Medical Oncology), Yale School of Medicine/Yale Cancer Center, New Haven, Connecticut 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

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 Medicine Malnati Brain Tumor Institute, Chicago, Illinois Sara M. Tolaney MD, MPH Assistant Professor of Medicine, Harvard Medical School; Director, Clinical Research, Breast Oncology; Associate Director, Susan F. Smith Center for Women’s Cancers; Dana-Farber Cancer Institute, Boston, Massachusetts

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. 3 • NO. 2 • 2019

EDITOR’S PICKS 6

Lymphadenectomy in Patients With Advanced Ovarian Neoplasms The New England Journal of Medicine

COMMENT By Annette Hasenburg Prof., Dr, med U ntil recently, systemic pelvic and para-aortic lymphadenectomy had been the “gold standard” in the surgical management of patients with advanced ovarian cancer. The LION study now challenged this widely used surgical practice. Patients with ovarian cancer stage IIB through IV who had undergone mac- roscopically complete tumor debulking and had no evidence of overt lymph node involvement both before and during surgery were intraoperatively randomized to either systematic lym- phadenectomy or no lymphadenectomy. In the lymphadenectomy group, a median of 57 lymph nodes were resected (22 para-aortic and 35 pelvic nodes); of those, 55.7% revealed micro- scopic lymph node metastases. The median overall survival was 69.2 months in the no-lymphadenec- tomy group and 65.5 months in the lymphadenectomy group, a non- significant difference. The median progression-free survival reached 25.5 months in both groups. Serious postoperative complications occurred more frequently in the lymphadenec- tomy group, with a higher incidence of repeat laparotomy (12.4% vs 6.5%) and increased 60-day mortality after surgery (3.1% vs 0.9%). Overall, patients enrolled in the trial had a favorable outcome, with a median overall survival of more than 5 years, which could at least in part be due to the fact that high surgical quality was assured in the participating centers. Patients with macroscopically complete resection of advanced ovarian cancer and clinically negative lymph nodes did not benefit from systematic lymphad- enectomy, which was associated with higher morbidity and mortality. There- fore, this approach should be omitted in patients meeting the inclusion criteria of the LION trial. This study is of practice-changing value.

Take-home message • Patients with newly diagnosed advanced ovarian cancer (FIGO stage IIB–IV) who underwent macroscopically complete resection and had normal lymph nodes before and during surgery were randomized to undergo (n=323) or not undergo (n=324) systematic pelvic and para-aortic lymphadenectomy. There was no differ- ence in the median overall and progression-free survival between the two groups. Significantly more serious postoperative complications occurred in the women who underwent lymphadenectomy compared with those who did not. • Systematic pelvic and para-aortic lymphadenectomy was not associated with a survival benefit among patients with advanced ovarian cancer and normal lymph nodes. Lymphadenectomy did, however, increase the risk of postoperative complications. Jeffrey M. Wiisanen MD

in the analysis. Among patients who under- went lymphadenectomy, the median number of removed nodes was 57 (35 pelvic and 22 paraaortic nodes). The median overall survival was 69.2 months in the no-lymphadenectomy group and 65.5 months in the lymphadenec- tomy group (hazard ratio for death in the lymphadenectomy group, 1.06; 95% confidence interval [CI], 0.83 to 1.34; P=0.65), and median progression-free survival was 25.5 months in both groups (hazard ratio for progression or death in the lymphadenectomy group, 1.11; 95% CI, 0.92 to 1.34; P = 0.29). Serious postopera- tive complications occurred more frequently in the lymphadenectomy group (e.g., incidence of repeat laparotomy, 12.4% vs. 6.5% [P=0.01]; mortality within 60 days after surgery, 3.1% vs. 0.9% [P=0.049]). CONCLUSIONS Systematic pelvic and paraaortic lymphadenectomy in patients with advanced ovarian cancer who had undergone intraabdom- inal macroscopically complete resection and had normal lymph nodes both before and during surgery was not associated with longer overall or progression-free survival than no lymphad- enectomy and was associated with a higher incidence of postoperative complications. A Randomized Trial of Lymphadenectomy in Patients With Advanced Ovarian Neoplasms. N Engl J Med 2019 Feb 28;380(9)822-832, P Harter, J Sehouli, D Lorusso, et al. www.practiceupdate.com/c/80429 clinically negative lymph nodes did not benefit from systematic lymphadenectomy, which was associated with higher morbidity and mortality. " " Patients with macroscopically complete resection of advanced ovarian cancer and

Abstract BACKGROUND Systematic pelvic and paraaor- tic lymphadenectomy has been widely used in the surgical treatment of patients with advanced ovarian cancer, although supporting evidence from randomized clinical trials has been limited. METHODS We intraoperatively randomly assigned patients with newly diagnosed advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage IIB through IV) who had undergone macroscopically complete resec- tion and had normal lymph nodes both before and during surgery to either undergo or not undergo lymphadenectomy. All centers had to qualify with regard to surgical skills before par- ticipation in the trial. The primary end point was overall survival. RESULTS A total of 647 patients underwent ran- domization from December 2008 through January 2012, were assigned to undergo lym- phadenectomy (323 patients) or not undergo lymphadenectomy (324), and were included

PRACTICEUPDATE ONCOLOGY

EDITOR’S PICKS 7

Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study Journal of Clinical Oncology

Take-home message • The safety findings of the triplet combination regimen of binimetinib, encorafenib, and cetuximab from the safety lead-in phase of the phase III BEACON trial in BRAF V600E-mutated colorectal cancer trial are encouraging and lay the groundwork for initiation of the randomized portion of the study. • Efficacy results are encouraging as well. The overall response rate was 48%, with 43% rate of responses exceeding 6 months. Median progression-free and overall survival were 8 months and 15.3 months, respectively.

Abstract PURPOSE To determine the safety and prelimi- nary efficacy of selective combination targeted therapy for BRAF V600E-mutant metastatic colorectal cancer (mCRC) in the safety lead-in phase of the open-label, randomized, three- arm, phase III BEACON Colorectal Cancer trial (ClinicalTrials.gov identifier: NCT02928224; European Union Clinical Trials Register identi- fier: EudraCT2015-005805-35). PATIENTS AND METHODS Before initiation of the randomized portion of the BEACON Colorectal Cancer trial, 30 patients with BRAF V600E-mu- tant mCRC who had experienced treatment failure with one or two prior regimens were to be recruited to a safety lead-in of encorafenib 300 mg daily, binimetinib 45 mg twice daily, plus standard weekly cetuximab. The primary end point was safety, including the incidence of dose-limiting toxicities. Efficacy end points included overall response rate, progression-free survival, and overall survival. RESULTS Among the 30 treated patients, dose-lim- iting toxicities occurred in five patients and included serous retinopathy (n = 2), reversible decreased left ventricular ejection fraction (n = 1), and cetuximab-related infusion reactions (n = 2). The most common grade 3 or 4 adverse events were fatigue (13%), anemia (10%), increased cre- atine phosphokinase (10%), increased AST (10%), and urinary tract infections (10%). In 29 patients with BRAF V600E-mutant tumors (one patient had a non- BRAF V600E-mutant tumor and was not included in the efficacy analysis), the con- firmed overall response rate was 48% (95% CI, 29.4% to 67.5%), median progression-free sur- vival was 8.0 months (95% CI, 5.6 to 9.3 months), and median overall survival was 15.3 months (95% CI, 9.6 months to not reached), with median duration of follow-up of 18.2 months (range, 16.6 to 19.8 months). CONCLUSION In the safety lead-in, the safety and tolerability of the encorafenib, binimetinib, and cetuximab regimen is manageable and accept- able for initiation of the randomized portion of the study. The observed efficacy is promising compared with available therapies and, if con- firmed in the randomized portion of the trial, could establish this regimen as a new standard of care for previously treated BRAF V600E-mu- tant mCRC. Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With BRAF V600E-Mutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study. J Clin Oncol 2019 Mar 20;[EPub Ahead of Print], E Van Cutsem, S Huijberts, A Grothey, et al. www.practiceupdate.com/c/81369

COMMENT By Axel Grothey MD

T he presence of a BRAF V600E mutation has long known to be associated with very poor prognosis in metastatic colorectal cancer. In contrast to melanoma and thyroid cancer, BRAF V600E inhibitors have very limited activity in this sub- group of colorectal cancers when used as single agents. In preclinical experimental models and translational studies, this lack of activity was found to be related to a reac- tivation of the MAP kinase pathway through a feedback loop via the EGF receptor in colorectal cancer cells. Based on these observations, a treatment approach toward BRAF V600E-mutated cancers was developed by combining a dual inhibition of the MAP kinase signaling pathway (BRAF inhibition with encorafenib and MEK inhibition with binimetinib) with an antibody to the EGF receptor (cetuximab). This regimen was tested in the BEACON trial, a randomized phase III study in a second- and third-line setting in BRAF V600E-mutated colorectal cancer. While the actual data of the ran- domized part of the trial are still pending, results are now available for the first 30 patients treated with the targeted triplet in a safety lead-in phase. The activity observed in this limited patient population (RR, 48%; mPFS, 8.0 months; mOS, 15.3 months) far exceeds any outcomes data from historical controls. As a consequence, even with the limited number of patients included in this analysis, the BEACON regimen has already been integrated in NCCN guidelines as a treatment option for patients with BRAF V600E-mutated colorectal cancers after failure of first-line therapy. The results of the phase III trial are expected sometime later in 2019. In addition, a first-line single-arm phase II study using the BEACON regimen in this patient population is underway.

VOL. 3 • NO. 2 • 2019

EDITOR’S PICKS 8

Neratinib and Capecitabine for Patients With HER2+ Breast Cancer and Brain Metastases Journal of Clinical Oncology Take-home message • The authors of this study evaluated neratinib plus capecitabine for treatment of HER2-positive breast cancer brainmetastases. PatientswithHER2-positive brainmetas- tases received neratinib 240mg orally once per day plus capecitabine 750mg/m 2 twice per day for 14 days, then 7 days off. The lapatinib-naive patients (n=37) experienced a composite CNS objective response rate of 49%. Lapatinib-treated patients (n=12) experienced a composite CNS objective response rate of 33%. • The study authors conclude that neratinib plus capecitabine is active against refractory HER2-positive breast cancer brain metastases.

COMMENT By Manmeet Ahluwalia MD, FACP U p to 50% of patients with metastatic HER2-positive breast cancer will develop brain metastases, making it a common clinical challenge in this patient population. The authors report their experience with 49 patients treated with neratinib and capecitabine, 37 of whom had received prior CNS-directed therapy but were lapatinib naive and 12 of whom had failed prior lapatinib therapy. The primary endpoint was CNS objective response rate (ORR = complete response [CR] + partial response [PR]) according to composite criteria. PR was defined as 50% or greater reduction in the sum of CNS target-lesion volumes, without new lesions and without CNS progression, clearly wors- ening neurologic status, or increase in corticosteroid dose (for neurologic symptoms). A CR was defined as disappearance of all target lesions plus the other PR criteria. In the lapatinib-naive group, 18/37 patients had a composite CNS ORR (49%; 95% CI, 32–66%); in the lapatinib failure group, 4/12 patients achieved PR (ORR, 33%; 95% CI, 10–65%). By RANO-BM, 9/37 patients (ORR, 24%; 95% CI, 12–41%) reported PR in the lap- atinib-naive group and 2 additional patients had unconfirmed responses that did not persist for 4 weeks or longer. In the lap- atinib-refractory group, 2/12 patients had PR by RANO-BM (ORR, 17%; 95% CI, 21–48%). In the lapatinib-naive group, the median PFS was 5.5 months (range, 0.8–18.8 months), and median OS was 13.3 months (range, 2.2–27.6 months). The results are promising and compare favorably to lapatinib and capecitabine. The limitations of this combination are the relative short duration of response, albeit most of these patients were refractory (having seen CNS-directed therapy), and the toxicity due to diarrhea. Further trials evaluating SRS and neratinib with capecitabine in the first-line setting are being planned to poten- tially improve both response rates and duration of response. This study also highlights the need for standardization of the response criteria to help determine efficacy – RANO BM is an example of the efforts in this direction. A recently held FDA workshop sup- ported such an effort.

By Reshma L. Mahtani DO T he development of effective therapies for the treatment of HER2+ advanced breast cancer metastatic to the brain remains an area of unmet need. In the adjuvant HERA study, CNS relapse accounted for a larger proportion of the sites of initial relapse in the trastuzumab arm compared with control. These data suggest the CNS represents a “sanctuary site” while many patients experience extracranial disease control. The current study was a phase II trial of neratinib and capecit- abine in HER2+ advanced breast cancer, metastatic to the brain. Both lapatinib-naive patients and patients previously treated with were enrolled. In the lapatinib-naive cohort, an impressive CNS ORR of 49% was reported, with a lower RR of 33% reported in those previously exposed to lapatinib (although numbers were small). In December 2018 top-line positive results were announced from the phase III NALA trial, a randomized controlled trial of neratinib plus capecitabine versus lapatinib plus capecit- abine in patients with third-line HER2+ metastatic breast cancer. For the secondary endpoint of time to intervention for symp- tomatic CNS disease (brain metastases), the results of the trial showed that treatment with neratinib plus capecitabine led to an improvement over the combination of lapatinib plus capecitabine (P = .043). Full results from the study are expected later this year and may represent an important new standard treatment option for this subset of breast cancer patients. It is important to note that the combination of neratinib and capecitabine is already currently endorsed as a category 2A NCCN recommendation (CNS guidelines). " Full results from the study are expected later this year and may represent an important new standard treatment option for this subset of breast cancer patients. "

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EDITOR’S PICKS 9

Capecitabine ComparedWith Observation in Resected Biliary Tract Cancer

The Lancet Oncology Take-home message

• This phase III study investigated if adjuvant capecitabine is beneficial for patients with resected biliary tract cancer. In the intention-to-treat analysis, the median recurrence-free survival was 24.4 months in the capecitabine group and 17.5 months in the observation group. According to per-protocol analysis, the median recurrence-free survival was 25.9 months in the capecitabine group and 17.4 months in the observation group. • Although the study did not meet its primary endpoint, the data strongly suggest a survival benefit in the range of 14.7 months with adjuvant capecitabine. Neil Majithia MD Abstract

Abstract PURPOSE Evidence-based treatments for meta- static, human epidermal growth factor receptor 2 (HER2)–positive breast cancer to the CNS are limited. We previously reported modest activ- ity of neratinib monotherapy for HER2-positive breast cancer brain metastases. Here we report the results from additional study cohorts. PATIENTS ANDMETHODS Patients with measurable, progressive, HER2-positive brain metastases (92% after receiving CNS surgery and/or radio- therapy) received neratinib 240 mg orally once per day plus capecitabine 750 mg/m 2 twice per day for 14 days, then 7 days off. Lapatinib-naïve (cohort 3A) and lapatinib-treated (cohort 3B) patients were enrolled. If nine or more of 35 (cohort 3A) or three or more of 25 (cohort 3B) had CNS objective response rates (ORR), the drug combination would be deemed promising. The primary end point was composite CNS ORR in each cohort separately, requiring a reduc- tion of 50% or more in the sum of target CNS lesion volumes without progression of nontar- get lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression. RESULTS Forty-nine patients enrolled in cohorts 3A (n = 37) and 3B (n = 12; cohort closed for slow accrual). In cohort 3A, the composite CNS ORR = 49% (95% CI, 32% to 66%), and the CNS ORR in cohort 3B = 33% (95% CI, 10% to 65%). Median progression-free survival was 5.5 and 3.1 months in cohorts 3A and 3B, respectively; median sur- vival was 13.3 and 15.1 months. Diarrhea was the most common grade 3 toxicity (29% in cohorts 3A and 3B). CONCLUSION Neratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted. TBCRC 022: A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epider- mal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases. J Clin Oncol 2019 Mar 12;[EPub Ahead of Print], RA Freed- man, RS Gelman, CK Anders, et al. www.practiceupdate.com/c/81137

BACKGROUND Despite improvements in multi- disciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adju- vant therapy. We aimed to determine whether adjuvant capecitabine improved overall sur- vival compared with observation following surgery for biliary tract cancer. METHODS This randomised, controlled, multicen- tre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eli- gible patients were aged 18 years or older and had histologically confirmed cholangiocarci- noma or muscle-invasive gallbladder cancer who had undergone a macroscopically com- plete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooper- ative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for bil- iary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m 2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or obser- vation commencing within 16 weeks of surgery. Treatment was not masked, and allocation con- cealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. FINDINGS Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecit- abine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. Themedian follow-up for all patientswas 60 months (IQR 37-60). In the intention-to-treat analy- sis, median overall survival was 51·1 months (95% CI 34·6-59·1) in the capecitabine group compared with 36·4 months (29·7-44·5) in the observation

group (adjusted hazard ratio [HR] 0·81, 95% CI 0·63-1·04; p=0·097). In a protocol-specified sen- sitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HRwas 0·71 (95%CI 0·55-0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30-44) in the observation group (adjusted HR 0·75, 95% CI 0·58-0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6-35·9) in the capecit- abine group and 17·5 months (12·0-23·8) in the observation group. In the per-protocol analy- sis, median recurrence-free survival was 25·9 months (95% CI 19·8-46·3) in the capecitabine group and 17·4 months (12·0-23·7) in the obser- vation group. Adverse events were measured in the capecitabine group only, and of the 213 patientswho received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most fre- quent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (<1%) patient had grade 4 cardiac ischaemia or infarction. Serious adverse events were observed in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 patients in the observation group. No deaths were deemed to be treatment related. INTERPRETATION Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol anal- yses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemother- apy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting. Capecitabine Compared With Observation in Resected Biliary Tract Cancer (BILCAP): A Ran- domised, Controlled, Multicentre, Phase 3 Study. Lancet Oncol 2019Mar 25;[EPub Ahead of Print], JN Primrose, RP Fox, DH Palmer, et al. www.practiceupdate.com/c/81577

VOL. 3 • NO. 2 • 2019

BREAK THE CYCLE With the first PBS listed CDK4/6 inhibitor - from 1 st July 1,2 PROVEN EFFICACY THAT REDEFINES FIRST LINE 1,2 KISQALI is a CDK4/6 inhibitor used in combination with an aromatase inhibitor for FIRST-LINE HR+/HER2- advanced/metastatic breast cancer 1

THE FIRST PBS LISTED CDK4/6 INHIBITOR

PBS Information: Authority Required. Refer to the PBS Schedule for full Authority information.

PLEASEREVIEWPRODUCT INFORMATIONBEFOREPRESCRIBING. APPROVEDPRODUCT INFORMATION IS AVAILABLE ONLINE AT WWW.NOVARTIS.COM.AU/PRODUCTS/HEALTHCARE-PROFESSIONALS. SHTML OR WWW.EBS.TGA.GOV.AU Kisqali ® (ribociclib): Indication: In combination with an aromatase inhibitor, for the treatment of men and postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer, as an initial endocrine therapy. Contraindications: QTcF>450ms; hypersensitivity to active substance, ingredients, soy products. Precautions: ECG, CBC, serumelectrolytes, LFTs, and pregnancy statusmust be assessed prior to initiation of treatment. QT interval prolongation, hepatobiliary toxicity, neutropenia (including febrile). Monitoring during treatment – see full PI. Pregnancy (Category D), effective contraception, lactation, fertility. Interactions: Strong CYP3A inhibitors or inducers. Caution with narrow therapeutic index CYP3A substrates. Monitor for ADRs. Avoid co-administration with drugs that have a potential to prolong the QT interval. Avoid pomegranate, grapefruit. Adverse effects: Very common (≥10%):

PRESCRIBE KISQALI WITH CONFIDENCE FOR: Proven efficacy • Over 2 years median PFS 2 • 43.2% reduction in risk of progression or death 2 (vs. placebo + letrozole; HR=0.568, 95% CI: 0.457 to 0.704, p<0.0001) • Improvement in efficacy across all patient subgroups and independent of treatment-free interval 2,3 Rapid response • 3 out of 4 patients saw a reduction in tumour size at Week 8 *2 *Subgroup analysis of patients with measurable disease at baseline. • Clinically meaningful improvement in pain score was seen as early as Week 8 and maintained up to Cycle 15 4 Predictable safety profile • Adverse events typically appeared early and resolved with appropriate management 2

UTI, neutropenia, leukopenia, anaemia, lymphopenia, decreased appetite, headache, insomnia, dyspnoea, back pain, nausea, diarrhoea, vomiting, constipation, stomatitis, abdominal pain, alopecia, rash, pruritus, fatigue, peripheral oedema, asthenia, pyrexia, abnormal LFTs, leukocyte count decreased, neutrophil count decreased, haemoglobin decreased, lymphocyte count decreased, platelet count decreased, ALT increased, AST increased, creatinine increased, phosphorous decreased, potassiumdecreased. Common (1-10%): thrombocytopenia, febrile neutropenia, lacrimation increased, dry eye, hypocalcaemia, hypokalaemia, hypophosphataemia, syncope, epistaxis, dysgeusia, dyspepsia, hepatotoxicity, erythema, peripheral oedema, weight decreased, ECG QT prolonged, bilirubin increased. Dosage: Adults - Kisqali 600 mg taken orally, once daily for 21 consecutive days followed by 7 days off treatment, in repeating cycles of 28 days. Caution in severe renal impairment and/ or moderate or severe hepatic impairment. Kisqali may require dose interruption, reduction, or discontinuation. Safety and efficacy not established in paediatrics, adolescents. Refer to full Kisqali PI and aromatase inhibitor PI. (kis120218m) ABBREVIATIONS: CDK, cyclin dependent kinase; HR+, hormone receptor positive; HER-, human epidermal growth factor receptor negative. REFERENCES: 1. Kisqali Product Information. 2. Hortobagyi GN et al. Ann Oncol 2018;29:1541–7. 3. Janni W et al. Breast Cancer Res Treat 2018;169:469–79. 4. Verma S et al. Breast Cancer Res Treat 2018;170:535–45.

Novartis Pharmaceuticals Australia Pty Limited ABN 18 004 244 160. 54 Waterloo Road, Macquarie Park NSW 2113. Ph (02) 9805 3555. ® Registered Trademark. Item No: AU-8602. Date of preparation April 2019. 3291RC_PU_DPS.

EDITOR’S PICKS 12

Talazoparib After Platinum or Cytotoxic Nonplatinum Regimens in Patients With Advanced Breast Cancer and Germline BRCA1/2 Mutations Clinical Cancer Research

A Phase II Study of Talazoparib After Platinum or Cytotoxic Nonplatinum Regimens in Patients With Advanced Breast Cancer and Germline BRCA1/2 Mutations (ABRAZO). Clin Cancer Res 2019 Mar 18;[EPub Ahead of Print], NC Turner, ML Telli, HS Rugo, et al. www.practiceupdate.com/c/81449 The current study is an earlier phase II open-label study of talazoparib in patients whose cancer responded to prior platinum therapy (cohort 1) and patients who had received at least three prior non-platinum cytotoxic chemother- apy regimens for metastatic disease (cohort 2). Anti-tumor activity was demonstrated in both groups; however, exploratory analyses revealed response to talazoparib was less likely in patients progressing with a short platinum-free interval than in patients with a long plat- inum-free interval. Patients who are truly platinum-refractory have not been ade- quately evaluated. As platinum therapy is increasingly utilized in earlier-stage disease, this will remain an issue that requires further investigation. COMMENT By Reshma L. Mahtani DO H ereditary breast cancer accounts for a minority of all cases of breast cancer. BRCA-mutated tumors have deficiencies in DNA repair pathways. The poly(ADP-ribose) polymerases (PARPs) 1 and 2 are DNA- binding enzymes that play a critical role in the repair of DNA. The use of PARP inhibitors represents a targeted approach that exploits the concept of “synthetic lethality.” Currently, there are two approved PARP inhibitors (PARPi) for BRCA-mutated metastatic breast cancer, olaparib and talazoparib; approval was based on the OlympiaD and EMBRCA trials, respectively. Both of these agents were evaluated in phase III randomized studies that evaluated the efficacy of the PARPi versus standard-of-care chemotherapy (PFS was improved in both trials with PARPi vs chemo).

Take-home message • This phase II study was designed to evaluate talazoparib after platinum or non- platinum regimens among patients with advanced breast cancer associated with germline BRCA 1/2 mutations. Confirmed objective response rates were 23%, 33%, 26%, and 29% in BRCA1, BRCA2, TNBC, and hormone receptor-positive patients, respectively. • Talazoparib demonstrated promising activity in this setting. Neil Majithia MD

Abstract PURPOSE To assess talazoparib activity in germline BRCA1/2 mutation carriers with advanced breast cancer. PATIENTS ANDMETHODS ABRAZO (NCT02034916) was a two-cohort, two-stage, phase II study of talazoparib (1 mg/day) in germline BRCA muta- tion carriers with a response to prior platinum with no progression on or within 8 weeks of the last platinum dose (cohort 1) or ≥3 platinum-free cytotoxic regimens (cohort 2) for advanced breast cancer. Primary endpoint was confirmed objective response rate (ORR) by independent radiological assessment. RESULTS We enrolled 84 patients (cohort 1, n = 49; cohort 2, n = 35) from May 2014 to February 2016. Median age was 50 (range, 31-75) years. Tri- ple-negative breast cancer (TNBC) incidence was 59% (cohort 1) and 17% (cohort 2). Median number

of prior cytotoxic regimens for advanced breast cancer was two and four, respectively. Confirmed ORR was 21% [95% confidence interval (CI), 10-35; cohort 1] and 37% [95% CI, 22-55; cohort 2]. Median duration of response was 5.8 and 3.8 months, respectively. Confirmed ORR was 23% (BRCA1), 33% (BRCA2), 26% (TNBC), and 29% (hormone receptor-positive). The most common all-grade adverse events (AE) included anemia (52%), fatigue (45%), and nausea (42%). Talazo- parib-related AEs led to drug discontinuation in 3 (4%) patients. In an exploratory analysis, longer platinum-free interval was associated with higher response rate in cohort 1 (0%ORR with interval <8 weeks; 47% ORR with interval >6 months). CONCLUSIONS Talazoparib exhibited promising antitumor activity in patients with advanced breast cancer and germline BRCA mutation.

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