Practice Update: Oncology

VOL. 1 • NO. 3 • 2017

OUR EXPERTS. YOUR PRACTICE.

ISSN 2207-869X

Effect of Interleukin-1 β InhibitionWith Canakinumab on Incident Lung Cancer in Patients With Atherosclerosis

The European Society for Medical Oncology 2017 Congress

JOURNAL SCAN Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW Trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial

Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple- negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Development and validation of a novel acute myeloid leukemia-composite model to estimate risks of mortality

GIVE YOUR PATIENTS A KEY FOR FIRST-LINE TREATMENT OF METASTATIC MELANOMA

KEYTRUDA is indicated as monotherapy for the treatment of unresectable or metastatic melanoma in adults. ¹

PBS Information: Authority required (STREAMLINED) for treatment of metastatic melanoma. Refer to PBS Schedule for full authority information.

Before prescribing, please review the Product Information. Product Information is available at www.msdinfo.com.au/keytrudapi

Copyright © 2017 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, U.S.A. All rights reserved. Merck Sharp & Dohme (Australia) Pty Limited. Level 1 – Building A, 26 Talavera Road, Macquarie Park NSW 2113. ONCO-1231266-0000. First issued September 2017. MSDONC1105.

Reference: 1. KEYTRUDA Approved Product Information. 01 September 2017.

KEYTRUDA Minimum Product Information (PI) Indications: KEYTRUDA ® (pembrolizumab) is indicated: As monotherapy for the treatment of unresectable or metastatic melanoma in adults. For first-line treatment of patients with metastatic NSCLC whose tumours express PD-L1 ≥50% tumour proportion score (TPS) on a validated test, with no EGFR or ALK genomic tumour aberrations. For the treatment of patients with advanced NSCLC with a PD-L1 TPS level ≥1% and who have received platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumour aberrations should have received prior therapy for these aberrations prior to receiving KEYTRUDA. For recurrent or metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) with disease progression on or after platinum- containing chemotherapy. For relapsed or refractory classical Hodgkin Lymphoma (cHL) following ASCT or at least two or more prior therapies when ASCT or multi-agent chemotherapy is not a treatment option. See full PI. Contraindications: None. Precautions: Immune-mediated adverse reactions, including pneumonitis, colitis (including gastrointestinal perforation), hepatitis, nephritis, hypophysitis, type1diabetesmellitus,hyperthyroidism,hypothyroidism,uveitis,myositis,Guillain-Barresyndrome,myasthenicsyndrome,pancreatitis,myocarditis,solidorgantransplantrejection,severeskinreactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis), severe infusion reactions (hypersensitivity, anaphylaxis), and complications of allogenic HSCT including graft-versus-host-disease and hepatic veno-occlusive disease. Immune-mediated adverse reactions affecting more than one body system can occur simultaneously. For management of immune-mediated adverse events, see full PI. Limited information in patients with active infection and patients with on-going adverse reaction to ipilimumab – use caution. See full PI for further information. Pregnancy: Category D. Interactions: None expected. Avoid corticosteroids or immunosuppressants prior to treatment. Adverse events: Clinical trials (treatment-related only): hypothyroidism, nausea, fatigue, hyperthyroidism, pneumonitis, colitis, hepatitis, hypophysitis, nephritis, type 1 diabetes mellitus, arthralgia, cough, back pain, vitiligo, abdominal pain, pruritus, rash, hyponatremia, anaemia, diarrhoea, pyrexia, adrenal insufficiency, autoimmune hepatitis, upper respiratory tract infection. Dosage: The recommended dose of KEYTRUDA is 200 mg for cHL, HNSCC and previously untreated NSCLC, and 2 mg/kg for melanoma or previously treated NSCLC (administered as an intravenous infusion over 30 minutes every 3 weeks). Treat with KEYTRUDA until disease progression or unacceptable toxicity, or up to two years for NSCLC if no disease progression. Atypical responses (i.e. an initial transient increase in tumour size or small new lesions followed by shrinkage) have been observed. Clinically stable patients (i.e. asymptomatic and not requiring urgent intervention) with initial evidence of progression can remain on treatment until confirmed. See full PI for further information. Based on PI approved 01 September 2017.

PRACTICE UPDATE ONCOLOGY BOARD PracticeUpdate is guided by a world-renowned Editorial and Advisory Board that represents community practitioners and academic specialists with cross-disciplinary expertise. Editor-in-Chief Lee Schwartzberg MD, FACP Executive Director of the West Cancer Center, a multispecialty oncology practice affiliated with the University of Tennessee; Professor of Medicine and Division Chief of Hematology/Oncology at The University of Tennessee Health Science Center

PracticeUpdate® is a registered trademark of Elsevier Inc.

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ABOUT For a complete listing of disclosures for each board member and editorial contributor, please refer to their profile on PracticeUpdate.com PracticeUpdate ’s mission is to help medical professionals navigate the vast array of available literature and focus on the most critical information for their patients and practice. All journal articles selected for PracticeUpdate receive a Take-Home Message designed to quickly summarize the key findings and explain the importance of that research within the specialty area. The most critical articles also receive Expert Commentaries from experts who are handpicked by the PracticeUpdate Editorial Board, providing additional context on that research for the reader. Expert Opinion pieces give special highlights to important topics and Conference Coverage captures relevant takeaways from a vast array of medical meetings throughout the year. PracticeUpdate Oncology provides coverage of key research from leading international conferences, and a collection of top journal articles and accompanying expert commentaries in a convenient print periodical. These and more are also available online at PracticeUpdate.com PracticeUpdate and PracticeUpdate Oncology are commercially supported by advertising, sponsorship, and educational grants. Individual access to PracticeUpdate.com is free. Premium content is available to any user who registers with the site. While PracticeUpdate is a commercially-sponsored product, it maintains the highest level of academic rigour, objectivity, and fair balance associated with all Elsevier products. No editorial content is influenced in any way by commercial sponsors or content contributors. DISCLAIMER PracticeUpdate Oncology has been developed for specialist medical professionals. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Because of rapid advances in the medical sciences, in particular, independent verificationofdiagnosesanddrugdosagesshouldbemade.Pleaseconsult the full current Product Information before prescribing any medication mentioned in this publication. Although all advertisingmaterial is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer. This content is published in accordance with the editorial policies of Elsevier’s PracticeUpdate.com. All content printed in this publication can be found on PracticeUpdate.com CONTENT Abstracts are available when the publisher grants permission from MEDLINE/PubMed, a database of the US National Library of Medicine. • NLM data are produced by a US Government agency and include works of the United States Government that are not protected by US copyright law but may be protected by non-US copyright law, as well as abstracts originating from publications that may be protected by US copyright law. • NLM assumes no responsibility or liability associated with use of copyrighted material, including transmitting, reproducing, redistributing, or making commercial use of the data. NLM does not provide legal advice regarding copyright, fair use, or other aspects of intellectual property rights. Persons contemplating any type of transmission or reproduction of copyrighted material such as abstracts are advised to consult legal counsel. SALES Fleur Gill fleur.gill@elsevier.com Linnea Mitchell-Taverner l.mitchell@elsevier.com PRODUCTION Content was originally published on PracticeUpdate.com Production of this issue was executed by: Editorial Manager A nne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng • Designer Jana Sokolovskaja Cover: Lung cancer cells – 3D illustration PracticeUpdate Oncology is published by Elsevier Australia ISSN 2207-869X (Print) ISSN 2207-8703 (Online)

Associate Editors

Isabel Cunningham MD Adjunct Associate Research Scientist, Division of Hematology Oncology, Columbia University College of Physicians and Surgeons

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 Clinic, Seattle Cancer Care Alliance, Seattle, Washington Kimberly Blackwell MD Professor of Medicine and Assistant Professor in Radiation Oncology, Duke Department of Medicine, Durham, North Carolina 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 Rafael Fonseca MD Chair, Department of Internal Medicine; Mayo Clinic, Phoenix/Scottsdale, Arizona; 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 at Hackensack University Medical Center Annette Hasenburg Prof. Dr. med Director of Obstetrics and Gynecology Mainz University Medical Center, Mainz, Germany Brandt Esplin MD, PhD Hematology/Oncology Fellow, Mayo Clinic Graduate School of Medical Education, Rochester, Minnesota Jeremy Jones MD Fellow, Hematology and Medical Oncology, Mayo Clinic, Rochester, Minnesota 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

David Henry MD Clinical Professor of Medicine, Pennsylvania Hospital

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 Chief, Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan- Kettering Cancer Center David Straus MD Attending Physician, Lymphoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York Roger Stupp MD Professor of Neurological Surgery, Oncology Program Howard Scher MD

Neurology, and Oncology, 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

Editorial Contributors

Moshe Ornstein MD Hematology/Oncology Fellow, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio Erin Schenk MD, PhD Hematology/Oncology Fellow, Clinician- Investigator Training Program, Mayo School of Graduate Education Jeffrey Wiisanen MD Hematology/Medical Oncology Fellow, Mayo Clinic School of Graduate Medical Education, Rochester, Minnesota

ABN 70 001 002 357 475 Victoria Avenue Chatswood NSW 2067 Australia Locked Bag 7500 Chatswood DC NSW 2067 EMON101701

CONTENTS 5

COVER

RESEARCH Editor’s picks 6 Noninferiority of Partial-Breast and Reduced-Dose Radiotherapy After Breast Conservation Surgery for Patients With Early Breast Cancer Comment by Noam VanderWalde MD 7 The BRCA1ness Signature is Associated Significantly With Response to PARP Inhibitors in the I-SPY 2 Randomized Neoadjuvant Setting 8 Improved Efficacy of Palbociclib vs Chemotherapy for the Treatment of Postmenopausal Women With HR+/HER2− Advanced/Metastatic Breast Cancer Comment by Lee S. Schwartzberg MD, FACP 9 Neratinib Efficacy and ctDNA Detection of HER2 Mutations in HER2 Non-Amplified Metastatic Breast Cancer Comment by Reshma L. Mahtani DO 10 Effect of Interleukin-1β Inhibition With Canakinumab on Incident Lung Cancer in Patients With Atherosclerosis Comment by Peter Libby MD 11 Lenalidomide Maintenance After First-Line Therapy for High-Risk Chronic Lymphocytic Leukemia General oncology 26 Direct Detection of Early-Stage Cancers Using Circulating Tumor DNA Comment by Erin Schenk MD, PhD 27 Use of Alternative Medicine for Cancer Associated With Increased Mortality Breast 28 Adjuvant Tamoxifen and Exemestane in Women With Postmenopausal Early Breast Cancer Comment by Annette Hasenburg Prof. Dr. med 29 Ipatasertib Plus Paclitaxel vs Placebo Plus Paclitaxel as First-Line Therapy for Metastatic Triple-Negative Breast Cancer Comment by Lee S. Schwartzberg MD, FACP Hematology 30 Lenalidomide vs Placebo Maintenance After Single ASCT for Multiple Myeloma Comment by Rafael D. Fonseca MD 31 Novel Composite Model to Estimate Risk of Mortality in AML 31 Long-Term Follow-Up of Chemoimmunotherapy With Rituximab, Oxaliplatin, Cytosine Arabinoside, Dexamethasone in Patients With Relapsed CD20+ B-Cell NHL

10 Effect of Interleukin-1β Inhibition With Canakinumab on Incident Lung Cancer in Patients With Atherosclerosis

CONFERENCE 14

ESMO 2017 Congress

FEATURES – Q & A 32 Emerging Science in Gliomas and Glioblastomas: A Review 33 Current Concepts in Stem Cell Transplantation for Multiple Myeloma 34 New Data on Immunotherapy for Bladder Cancer: Part 1 14 Nutritional Status and Treatment Response: An Update 15 Abiraterone Acetate Plus Prednisolone Comparable to Docetaxel in High-Risk Prostate Cancer 16 New Data on Anti-Emesis Agents 16 Updates in the Management of GBM 17 New Data on the Management of HCC 20 MONARCH 3: Abemaciclib Improves Progression-Free Survival in Endocrine- Sensitive Advanced Breast Cancer 21 Systemic Immune-Inflammation Index, Neutrophil-Lymphocyte Ratio, and Platelet-Lymphocyte Ratio are Robust Predictors of Outcome of Nivolumab Therapy for Metastatic Renal Cell Carcinoma

22 Three Months of Oxaliplatin-Based Chemotherapy Usually Suffices, With Less Neurotoxicity Than 6 Months, in Stage 3 Colon Cancer 23 Cabozantinib Is Safe and Effective for Metastatic Renal Cell Carcinoma in Real- World Practice 24 MicroRNAs Are Identified as Possible Biomarkers of Outcome With Bevacizumab in Metastatic Breast Cancer

VOL. 1 • NO. 3 • 2017

EDITOR’S PICKS 6

Noninferiority of Partial-Breast and Reduced-Dose Radiotherapy After Breast Conservation Surgery for Patients With Early Breast Cancer The Lancet

Abstract BACKGROUND Local cancer relapse risk after breast conservation surgery fol- lowed by radiotherapy has fallen sharply in many countries, and is influenced by patient age and clinicopathological fac- tors. We hypothesise that partial-breast radiotherapy restricted to the vicinity of the original tumour in women at lower than average risk of local relapse will improve the balance of beneficial versus adverse effects compared with whole-breast radiotherapy. METHODS IMPORT LOW is a multicentre, ran- domised, controlled, phase 3, non-inferiority trial done in 30 radiotherapy centres in the UK. Women aged 50 years or older who had under- gone breast-conserving surgery for unifocal invasive ductal adenocarcinoma of grade 1-3, with a tumour size of 3 cm or less (pT1-2), none to three positive axillary nodes (pN0-1), and min- imum microscopic margins of non-cancerous margins, mostly hormone-positive (receiv- ing endocrine therapy) and node-negative (although the protocol allowed for N1 dis- ease, very few patients were enrolled). Although this study alone, with only 5 years of follow-up, may not convince radiation oncologists to change their current practice away from treating the whole breast in this population, it does offer supportive evidence that it is safe to block the medial left breast (when the tumor bed is not in that location) to avoid the heart. Additionally, although not directly addressed in this study, the low recurrence rate may also lend evidence to avoid boosting the lumpectomy cavity (as is common practice in the US) in this patient population.

Take-home message • This phase III noninferiority trial enrolled 2016 women who had undergone breast-conserving surgery for grade 1–3 unifocal invasive ductal adenocarcinoma. They were randomized 1:1:1 to receive 40 Gy whole-breast radiotherapy (control; n = 674), 36 Gy whole-breast radiotherapy and 40 Gy restricted to the vicinity of the original tumor (reduced-dose group; n = 673), or 40 Gy restricted to the vicinity of the original tumor only (partial-breast group; n = 669) to evaluate the balance of beneficial versus adverse effects among treatment groups. Compared with the control group, estimated 5-year differences in local relapse were −0.73% and −0.38% in the reduced-dose and partial-breast groups, respectively. Both the reduced-dose group and the partial-breast group exhibited noninferiority. Similar adverse events were reported among treatment groups, with significantly fewer reports of change in breast appearance (partial-breast group) and breast harder or firmer (partial-breast and reduced-dose groups). • These data demonstrate the noninferiority of reduced-dose and partial-breast radiotherapy compared with standard radiotherapy, approaches that can be imple- mented globally.

COMMENT By Noam VanderWalde MD

I n their impressive, phase III noninferi- ority trial, Coles et al randomized very early-stage breast cancer patients to one of three different techniques for adjuvant radiotherapy: 1) whole-breast radiotherapy using a hypofractionated technique (40 Gy in 15 fractions); 2) reduced dose of 36 Gy to the whole breast and an additional 40 Gy to the lumpec- tomy cavity (reduced-dose group); 3) 40 Gy in 15 fractions to the lumpectomy cav- ity (partial-breast group). All three groups were treated with forward planning field- in-field tangents, which is standard in most radiotherapy clinics. With 5 years of median follow-up, there were very few local recurrences (1.1% in the whole-breast group, 0.2% in the reduced-dose group, and 0.5% in the partial-breast group), and noninferiority for local recurrence was demonstrated among the three groups. Additionally, the results showed a statis- tically significantly lower patient-reported firmness of the breast in the reduced- dose and partial-breast groups, but no difference among the groups in any of the other adverse events. Many of late

adverse events, including heart, lung, and secondary cancers, occur so rarely that differences cannot realistically be demon- strated in a single study. This study is the first in what will likely be a number of studies to publish results comparing partial-breast radiotherapy to whole-breast radiotherapy (NSABP/RTOG, RAPID, SHARE, IRMA, etc), and the com- pilation of evidence will hopefully allow clinicians to make evidence-based deci- sions. What is unique about this study is that, as opposed to other partial-breast techniques that entail acceleration of tim- ing and other techniques of delivering radiotherapy (from one-dose intraoper- ative radiotherapy [IORT] to accelerated partial-breast irradiation [APBI] given over 1–2 weeks), this study only compared a change in one variable (ie, the volume of tissue being irradiated). The extremely low recurrence rate in all three groups and noninferiority demonstrate that it is at least safe to reduce the volume of tis- sue irradiated in this patient population (specifically very low-risk patients with unifocal non-lobular histology, >2 mm

Dr. VanderWalde is Assistant Professor,

Department of Radiation Oncology, University of Tennessee West Cancer Clinic.

PRACTICEUPDATE ONCOLOGY

EDITOR’S PICKS 7

The BRCA1ness Signature is Associated Significantly With Response to PARP Inhibitors in the I-SPY 2 Randomized Neoadjuvant Setting Breast Cancer Research Take-home message • In this study, a diagnostic gene expression signature was created using 128 triple-negative breast cancer samples and tested in 116 HER2-negative patients to determine the association between pathologic com- plete response and BRCA1ness in patients receiving veliparib–carboplatin combined with standard chemo- therapy compared with patients receiving standard chemotherapy alone. BRCA1ness was significantly associated with response to veliparib–carboplatin but not to standard chemotherapy. • In the I-SPY 2 neoadjuvant setting, the BRCA1ness sig- nature predicted the benefit of veliparib–carboplatin combined with standard chemotherapy compared with standard chemotherapy alone. Abstract BACKGROUND Patients with BRCA1-like tumors correlate with improved response to DNA double-strand break-inducing therapy. A gene expression-based classifier was developed to distinguish between BRCA1-like and non-BRCA1-like tumors. We hypothesized that these tumors may also be more sensitive to PARP inhibitors than standard treatments. METHODS A diagnostic gene expression signature (BRCA1ness) was developed using a centroid model with 128 triple-negative breast cancer samples from the EU FP7 RATHER project. This BRCA1ness signature was then tested in HER2-negative patients (n= 116) from the I-SPY 2 TRIAL who received an oral PARP inhibitor veliparib in com- bination with carboplatin (V-C), or standard chemotherapy alone. We assessed the association between BRCA1ness and pathologic com- plete response in the V-C and control arms alone using Fisher’s exact test, and the relative performance between arms (biomarker × treat- ment interaction, likelihood ratio p<0.05) using a logistic model and adjusting for hormone receptor status (HR). RESULTS We developed a gene expression signature to identify BRCA1- like status. In the I-SPY 2 neoadjuvant setting the BRCA1ness signature associated significantly with response to V-C (p=0.03), but not in the control arm (p=0.45). We identified a significant interaction between BRCA1ness and V-C (p=0.023) after correcting for HR. CONCLUSIONS A genomic-based BRCA1-like signature was success- fully translated to an expression-based signature (BRC1Aness). In the I-SPY 2 neoadjuvant setting, we determined that the BRCA1ness signature is capable of predicting benefit of V-C added to standard chemotherapy compared to standard chemotherapy alone. The BRCA1ness signature is associated significantly with response to parp inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting. Breast Cancer Res 2017 Aug 25;[EPub Ahead of Print], TM Severson, DM Wolf, C Yau, et al. www.practiceupdate.com/c/57694

tissue of 2 mm or more, were recruited. Patients were randomly assigned (1:1:1) to receive 40 Gy whole-breast radiotherapy (control), 36 Gy whole- breast radiotherapy and 40 Gy to the partial breast (reduced-dose group), or 40 Gy to the partial breast only (partial-breast group) in 15 daily treatment fractions. Computer-generated random permuted blocks (mixed sizes of six and nine) were used to assign patients to groups, stratifying patients by radiotherapy treatment centre. Patients and clinicians were not masked to treatment allocation. Field-in-field intensity-modulated radiotherapy was delivered using standard tangential beams that were simply reduced in length for the partial-breast group. The primary endpoint was ipsilateral local relapse (80% power to exclude a 2•5% increase [non-inferiority mar- gin] at 5 years for each experimental group; non-inferiority was shown if the upper limit of the two-sided 95% CI for the local relapse hazard ratio [HR] was less than 2•03), analysed by intention to treat. Safety analyses were done in all patients for whom data was available (ie, a modified inten- tion-to-treat population). FINDINGS Between May 3, 2007, and Oct 5, 2010, 2018 women were recruited. Two women withdrew consent for use of their data in the anal- ysis. 674 patients were analysed in the whole-breast radiotherapy (control) group, 673 in the reduced-dose group, and 669 in the partial-breast group. Median follow-up was 72•2 months (IQR 61•7-83•2), and 5-year estimates of local relapse cumulative incidence were 1•1% (95% CI 0•5- 2•3) of patients in the control group, 0•2% (0•02-1•2) in the reduced-dose group, and 0•5% (0•2-1•4) in the partial-breast group. Estimated 5-year absolute differences in local relapse compared with the control group were -0•73% (-0•99 to 0•22) for the reduced-dose and -0•38% (-0•84 to 0•90) for the partial-breast groups. Non-inferiority can be claimed for both reduced-dose and partial-breast radiotherapy, and was confirmed by the test against the critical HR being more than 2•03 (p=0•003 for the reduced-dose group and p=0•016 for the partial-breast group, compared with the whole-breast radiotherapy group). Photographic, patient, and clinical assessments recorded similar adverse effects after reduced-dose or partial-breast radiotherapy, including two patient domains achieving statistically significantly lower adverse effects (change in breast appear- ance [p=0•007 for partial-breast] and breast harder or firmer [p=0•002 for reduced-dose and p<0•0001 for partial-breast]) compared with whole- breast radiotherapy. INTERPRETATION We showed non-inferiority of partial-breast and reduced- dose radiotherapy compared with the standard whole-breast radiotherapy in terms of local relapse in a cohort of patients with early breast cancer, and equivalent or fewer late normal-tissue adverse effects were seen. This simple radiotherapy technique is implementable in radiotherapy centres worldwide. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW Trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet 2017 Aug 02;[EPub Ahead of Print], CE Coles, CL Griffin, AM Kirby, et al. www.practiceupdate.com/c/56606

VOL. 1 • NO. 3 • 2017

EDITOR’S PICKS 8

Improved Efficacy of Palbociclib vs Chemotherapy for the Treatment of Postmenopausal WomenWith HR+/HER2− Advanced/Metastatic Breast Cancer Breast Cancer Research and Treatment Take-home message

was progression-free survival (PFS)/time to pro- gression (TTP). Bayesian network meta-analyses (NMAs) and pairwise meta-analyses were con- ducted. Heterogeneity and inconsistency were assessed. RESULTS Sixty RCTs met eligibility criteria and were stratified by line of therapy. In the first line, palbociclib + letrozole showed statistically significant improvements in PFS/TTP versus capecitabine [intermittent: HR 0.28 (95% CrI 0.11- 0.72)] and mitoxantrone [HR 0.28 (0.13-0.61)], and trended toward improvements versus paclitaxel [HR 0.59 (0.19-1.96)], docetaxel [HR 0.51 (0.14- 2.03)] and other monotherapy or combination agents (HRs ranging from 0.24 to 0.99). In the second line, palbociclib + fulvestrant showed statistically significant improvements in PFS/ TTP versus capecitabine [intermittent: HR 0.28 (0.13-0.65)], mitoxantrone [HR 0.26 (0.12-0.53)], and pegylated liposomal doxorubicin [HR 0.19 (0.07-0.50)], and trended toward improvements versus paclitaxel [HR 0.48 (0.16-1.44)], docetaxel [HR 0.71 (0.24-2.13)] and other monotherapy or combination agents (HRs ranging from 0.23- 0.89). NMA findings aligned with direct evidence and were robust to sensitivity analyses. CONCLUSIONS Palbociclib + letrozole and pal- bociclib + fulvestrant demonstrate trends in incremental efficacy compared with chemo- therapy agents for the first- and second-line treatment of HR +/HER2- ABC/MBC. Systematic review and network meta-analy- sis comparing palbociclib with chemotherapy agents for the treatment of postmenopausal women with HR-positive and HER2-negative advanced/metastatic breast cancer. Breast Cancer Res Treat 2017 Jul 27;[EPub Ahead of Print], FR Wilson, A Varu, D Mitra, et al. www.practiceupdate.com/c/56530

• This systematic review and meta-analysis included 60 randomized controlled trials to evaluate palbociclib plus letrozole and palbociclib plus fulvestrant vs chemotherapy agents in postmenopausal women with HR+/HER2− advanced/ metastatic breast cancer as both first- and second-line therapy. Compared with mitoxantrone and capecitabine, palbociclib plus letrozole was associated with significantly longer progression-free survival and time to progression in the first-line setting. Trends toward improvements over docetaxel, paclitaxel, and other agents were also observed. Palbociclib plus fulvestrant were associated with significantly longer progression-free survival and time to progression in the second-line setting compared with capecitabine, mitoxantrone, and pegylated liposomal doxorubicin, with trends toward improvements over docetaxel, paclitaxel, and other agents. • These data demonstrate greater efficacy of palbociclib plus letrozole and palbociclib plus fulvestrant in both first and second lines in patients with HR+/HER2− advanced/ metastatic breast cancer.

Abstract PURPOSE To compare palbociclib + letrozole and palbociclib + fulvestrant with chemother- apy agents in postmenopausal women with hormone receptor-positive (HR+)/human epider- mal growth factor receptor 2-negative (HER2-) advanced/metastatic breast cancer (ABC/ MBC) who had no prior systemic treatment for advanced disease (first line) or whose disease progressed after prior endocrine therapy or chemotherapy (second line). METHODS A systematic search identified rand- omized controlled trials (RCTs) published from January 2000 to January 2016 that compared endocrine-based therapies, chemotherapy agents, and/or chemotherapy agents + bio- logical therapies in the first- and second-line treatment of postmenopausal women with HR+/ HER2- ABC/MBC. The main outcome of interest

COMMENT By Lee S. Schwartzberg MD, FACP T he combination of palbociclib, a relatively new CDK4/6 inhib- itor, with endocrine therapy is a potent regimen against hormone receptor-positive metastatic breast can- cer. This study compared palbociclib combinations against chemotherapy agents and doublets across studies in a network meta-analysis in an attempt to determine which approach is more efficacious. According to the parame- ters utilized, palbociclib plus endocrine therapy (either letrozole in the first line or fulvestrant in the second line) is superior in terms of PFS/TTP to many single-agent chemotherapy drugs and combinations based on published clin- ical trial results. This analysis lends strength to the standard approach of using endocrine therapy first before switching to chemotherapy when faced with hormone receptor-positive meta- static breast cancer.

Dr. Schwartzberg is Executive Director, West Cancer Center, Memphis, Tennessee.

PRACTICEUPDATE ONCOLOGY

EDITOR’S PICKS 9

Neratinib Efficacy and ctDNA Detection of HER2 Mutations in HER2 Non-Amplified Metastatic Breast Cancer Clinical Cancer Research Take-home message • Patients with confirmed HER2-mutated non-amplified metastatic breast cancer were treated with neratinib to evaluate outcomes in this single-arm phase II trial. Of 381 tumors sequenced centrally, 9 demonstrated HER2 mutation. A further 13 cases were identified locally. Neratinib was administered to 16 patients. The clinical benefit rate was 31%, with 1 complete response, 1 partial response, and 3 patients with stable disease ≥24 weeks. The median progression-free survival was 16 weeks. Despite prophylactic administration of loperamide, the most prevalent grades 2 and 3 side effect was diarrhea, which affected 69% of patients. Baseline ctDNA sequencing had a sensitivity of 79% and a specificity of 100% for identifying the HER2 mutation. • Neratinib demonstrates activity in patients with HER2-mutated nonamplified metastatic breast cancer, and ctDNA sequencing is a noninvasive technique to effectively identify patients with HER2-mutated cancers who may be eligible to participate in clinical trials. T he availability of HER2-targeted therapies has dramatically improved outcomes for patients with HER2-positive breast cancer. Although ongoing studies such as NSABP B47 are addressing the role of trastuzumab in HER2-negative breast cancer, generally HER2-directed therapies are only administered to the roughly 20% of breast cancer patients who have HER2 amplification. However, in patients who are HER2-negative by immunohistochemistry (IHC) and fluorescence-in-situ-hybridization (FISH), breast cancer genome sequencing has identified HER2-activating mutations. Preclinical work has documented that the majority of these HER2 somatic mutations are activating mutations, which are likely driving tumorigenesis in a small percent- age of breast cancer patients overall (2%–4%). Furthermore, the presence of these mutations confers resistance to the reversible HER2 inhibitor lapatinib, but not to the irreversible HER2 inhibitor neratinib. In the current study, 22 patients of 381 were found to harbor HER2 mutations, and the authors report a CBR of 31% and PFS of 16 weeks when neratinib was administered as a single agent. Circulating tumor DNA (ctDNA) sequencing was found to be accurate in identifying the cases. These data add to data from other studies which have indicated that the identification of HER2 mutations may offer additional targeted approaches for a small subset of breast cancer patients. Ongoing basket-trial designs, such as the design of the SUMMIT trial, are investigating the clinical potential of neratinib in a broad spectrum of tumor types that harbor HER2 mutations. Data from these types of trials will hopefully lead to a more personalized approach to treatment in oncology. COMMENT By Reshma L. Mahtani DO

Abstract PURPOSE Markers of chemotherapy efficacy in metastatic colorectal cancer (mCRC) are essen- tial for optimization of treatment strategies. We evaluated the applicability of early changes in circulating tumor DNA (ctDNA) as a marker of therapeutic efficacy. EXPERIMENTAL DESIGN This prospective study enrolled consecutive patients with mCRC receiving a first- or second-line chemother- apy. CtDNA was assessed in plasma collected before the first (C0), second (C1) and/or third (C2) chemotherapy cycle, using picodroplet-dig- ital PCR assays based either on detection of gene mutation (KRAS, BRAF, TP53) or hyper- methylation (WIF1, NPY). CT scans were centrally assessed using RECIST v1.1 criteria. Multivariate analyses were adjusted on age, gender, ECOG performance status (PS), metastatic synchronic- ity, and treatment line. RESULTS Eighty-two patients with mCRC treated in first- (82.9%) or second- (17.1%) line chemo- therapy were included. Patients with a high (>10 ng/mL) versus low (≤0.1 ng/mL) ctDNA concen- tration at C0 had a shorter overall survival (OS; 6.8 vs. 33.4 months: adjusted HR, 5.64; 95% CI, 2.5-12.6; P < 0.0001). By analyzing the evolution of the ctDNA concentration between C0 and C2 or C1 (C2or1), we classified the patients in two groups (named “good” or “bad ctDNA respond- ers”). In multivariate analysis, patients belonging to the group called “good ctDNA responder” (n = 58) versus “bad ctDNA responder” (n = 15) had a better objective response rate (P < 0.001), and a longer median progression-free survival (8.5 vs. 2.4 months: HR, 0.19; 95% CI, 0.09-0.40; P < 0.0001) and OS (27.1 vs. 11.2 months: HR, 0.25; 95% CI, 0.11-0.57; P < 0.001). CONCLUSION This study suggests that early change in ctDNA concentration is a marker of therapeutic efficacy in patients with mCRC. Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 nonam- plified metastatic breast cancer, Clin Cancer Res 2017 Aug 15;[EPub Ahead of Print], CX Ma, R Bose, F Gao, et al. www.practiceupdate.com/c/57071

Dr. Mahtani is Assistant Professor, Division of Hematology/Oncology, Sylvester Comprehensive Cancer Center, University of Miami Health System.

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Effect of Interleukin-1 β InhibitionWith Canakinumab on Incident Lung Cancer in Patients With Atherosclerosis The Lancet Take-home message • This randomized, double-blind placebo-controlled trial was designed to evaluate the effect of inhibition of interleukin 1b via canakinumab on recurrent vascular events in 10,061 patients with established coronary artery disease and high levels of hsCRP, with incident lung cancer assessed as a secondary endpoint. Total cancer mortality was significantly lower in patients taking canakinumab vs those taking placebo. Significantly less frequent incident lung cancer and lung cancer mortality were also reported in patients receiving canakinumab compared with those receiving placebo. Patients receiving canakinumab experienced significantly more fatal infections and sepsis than patients receiving placebo. • No difference in all-cause mortality was reported between groups. COMMENT By Peter Libby MD T he Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CAN- TOS) enrolled over 10,000 survivors

cancers. The results on cancer incidence from CANTOS have immediate scientific implications, mandate prospective replica- tion in independent clinical studies, andmay point the way to novel therapies for manag- ing individuals with markers for risk of lung and other cancers in the future. Given the highly exploratory nature of the analyses of cancer in CANTOS, the cancer findings should not change practice today, but may open new doors for immune modulation and anti-inflammatory interventions in oncol- ogy going forward. References 1. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease [published online August 27, 2017]. N Engl J Med doi: 10.1056/ NEJMoa1707914. 2. Ridker PM, MacFadyen JG, Thuren T, et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo- controlled trial [published online August 27, 2017]. Lancet DOI: http://dx.doi.org/10.1016/ S0140-6736(17)32247-X. 3. Dinarello CA. Why not treat human cancer with interleukin-1 blockade? Cancer Metastasis Rev 2010;29(2):317-329. 4. Stetler-Stevenson WG, Aznavoorian S, Liotta LA. Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu Rev Cell Biol 1993;9:541-573. 5. Galis Z, Muszynski M, Sukhova G, et al. Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion. Circ Res 1994;75(1):181-189. 6. Li HJ, Reinhardt F, Herschman HR, Weinberg RA. Cancer-stimulated mesenchymal stem cells create a carcinoma stem cell niche via prostaglandin E2 signaling. Cancer Discov 2012;2(9):840-855. Dr. Libby is Mallinckrodt Professor of Medicine, Harvard Medical School, Boston, Massachusetts.

carcinoma). In addition to the reduction in cardiovascular endpoints, canakinumab reduced total cancer mortality, incident lung cancer, and fatalities due to lung cancer. At the highest dose tested, canakinumab (300 mg four times yearly) reduced lung cancer fatalities by a remarkable 77%. 2 The enrolled population, as they were selected for an elevated inflammatory status, likely had enriched risk for lung cancer, given that chronic lung disease and lung cancer associate with increased C-reactive protein concentrations. A large body of prior evidence provides bio- logical plausibility for an anti-cancer effect of blockade of IL-1. 3 During the 3.7 year mean follow-up period of CANTOS, the reduction in cancer fatality probably did not result from de novo oncogenesis inhibition. Rather, a reduction in the invasiveness and metas- tasis of tumors likely accounted for the reductions in death. Considerable evidence supports the role of the enzyme matrix metalloproteinase 2 (MMP-2), a type IV col- lagenase, in the ability of cells in cancers to breach basement membrane barriers and become invasive and give rise to metasta- ses. 4 IL-1 augments the activation of MMP-2, providing one possible mechanistic expla- nation for the results found. 5 In addition, IL-1 can promote epithelial to mesenchy- mal transition, another process considered important in cancer development. 6 These exploratory results, although pre- liminary and by no means ready for clinical application, have important implications for understanding tumor spread. The results indicate that in addition to the exciting novel checkpoint inhibitor approaches to cancer therapy that target adaptive, T-cell-medi- ated immunity, the innate immune response may also contribute to the evolution of

of myocardial infarction at least 30 days following the index event who were equil- ibrated on a full panel of standard-of-care medications including highly effective sta- tin, aspirin, and beta blocking agent and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, as appropriate and tolerated. The investi- gators also selected a population that had residual inflammation despite this back- ground therapy as gauged by an elevation in C-reactive proteinmeasuredwith a highly sensitive assay (hsCRP) above median for the general population, i.e. 2 mg/L. Indi- viduals who met these entrance criteria received randomly allocated placebo or canakinumab, a monoclonal antibody that selectively neutralizes the pro-inflammatory cytokine interleukin-1 beta (IL-1 beta) admin- istered by subcutaneous injection four times yearly. The trial met its primary endpoint of producing major adverse cardiovascular events at the middle dose tested (150 mg every three months). The major unwanted action of canakinumab was a slight but sig- nificant increase in fatal infection, an excess on the order of one per thousand patient years exposed in the canakinumab-treated groups. A paper published in the New Eng- land Journal of Medicine reports details of the cardiovascular endpoints. 1 As certain anti-inflammatory biological ther- apies associate with a risk for lymphoma (e.g. anti-tumor necrosis factor strategies), an expert panel carefullymonitored incident malignancies in the study participants, none of whom had no known cancer at the time of enrollment (save for cutaneous basal cell

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Abstract BACKGROUND Inflammation in the tumour microenvironment mediated by interleukin 1β is hypothesised to have a major role in cancer invasiveness, progression, and metastases. We did an additional analysis in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), a randomised trial of the role of inter- leukin-1β inhibition in atherosclerosis, with the aim of establishing whether inhibition of a major product of the Nod-like receptor protein 3 (NLRP3) inflammasome with canakinumab might alter can- cer incidence. METHODS We did a randomised, double-blind, pla- cebo-controlled trial of canakinumab in 10 061 patients with atherosclerosis who had had a myo- cardial infarction, were free of previously diagnosed cancer, and had concentrations of high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater. To assess dose-response effects, patients were ran- domly assigned by computer-generated codes to three canakinumab doses (50 mg, 150 mg, and 300 mg, subcutaneously every 3 months) or pla- cebo. Participants were followed up for incident cancer diagnoses, which were adjudicated by an oncology endpoint committee masked to drug or dose allocation. Analysis was by intention to treat. FINDINGS Baseline concentrations of hsCRP (median 6•0 mg/L vs 4•2 mg/L; p<0•0001) and interleukin 6 (3•2 vs 2•6 ng/L; p<0•0001) were significantly higher among participants subse- quently diagnosed with lung cancer than among those not diagnosed with cancer. During median follow-up of 3•7 years, compared with placebo, canakinumab was associated with dose-depend- ent reductions in concentrations of hsCRP of 26-41% and of interleukin 6 of 25-43% (p<0•0001 for all comparisons). Total cancer mortality (n=196) was significantly lower in the pooled canakinumab group than in the placebo group (p=0•0007 for trend across groups), but was significantly lower than placebo only in the 300 mg group individ- ually (hazard ratio [HR] 0•49 [95% CI 0•31-0•75]; p=0•0009). Incident lung cancer (n=129) was sig- nificantly less frequent in the 150 mg (HR 0•61 [95% CI 0•39-0•97]; p=0•034) and 300 mg groups (HR 0•33 [95% CI 0•18-0•59]; p<0•0001; p<0•0001 for trend across groups). Lung cancer mortality was significantly less common in the canakinumab 300 mg group than in the placebo group (HR 0•23 [95% CI 0•10-0•54]; p=0•0002) and in the pooled canakinumab population than in the pla- cebo group (p=0•0002 for trend across groups). Fatal infections or sepsis were significantly more common in the canakinumab groups than in the placebo group. All-cause mortality did not differ significantly between the canakinumab and pla- cebo groups (HR 0•94 [95% CI 0•83-1•06]; p=0•31). INTERPRETATION Our hypothesis-generating data suggest the possibility that anti-inflammatory therapy with canakinumab targeting the interleu- kin-1β innate immunity pathway could significantly reduce incident lung cancer and lung cancer mor- tality. Replication of these data in formal settings of cancer screening and treatment is required. Effect of interleukin-1 β inhibition with canaki- numab on incident lung cancer in patients with atherosclerosis: exploratory results from a ran- domised, double-blind, placebo-controlled trial. Lancet 2017 Aug 25;[EPub Ahead of Print], PM Ridker, JG MacFadyen, T Thuren, et al. www.practiceupdate.com/c/57597

LenalidomideMaintenance After First-Line Therapy for High-Risk Chronic Lymphocytic Leukemia The Lancet Haematology Take-home message • This phase III study was designed to evaluate use of lenalidomide mainte- nance vs placebo in 89 patients with CLL who achieved at least a partial response after first-line chemoimmunotherapy. Patients were randomized to receive lenalidomide (n = 60) or placebo (n = 29). Median progression-free survival was 13.3 months vs not-reached, favoring lenalidomide. Frequently reported adverse events included skin disorders, gastrointestinal disorders, hematological toxicity, and infections. • The efficacy of lenalidomide maintenance therapy was demonstrated, with acceptable toxicity, in patients with CLL following chemoimmunotherapy.

Abstract BACKGROUND The combined use of genetic markers and detectable minimal residual disease identifies patients with chronic lym- phocytic leukaemia with poor outcome after first-line chemoimmunotherapy. We aimed to assess lenalidomide maintenance therapy in these high-risk patients. METHODS In this randomised, double-blind, phase 3 study (CLLM1; CLL Maintenance 1 of the German CLL Study Group), patients older than 18 years and diagnosed with immunophenotypically confirmed chronic lymphocytic leukaemia with active disease, who responded to chemoimmunotherapy 2-5 months after completion of first-line therapy and who were assessed as having a high risk for an early progression with at least a partial response after four or more cycles of first-line chemoimmunotherapy, were eligible if they had high minimal residual disease lev- els or intermediate levels combined with an unmutated IGHV gene status or TP53 alter- ations. Patients were randomly assigned (2:1) to receive either lenalidomide (5 mg) or placebo. Randomisation was done with a fixed block size of three, and was stratified according to the minimal residual disease level achieved after first-line therapy. Main- tenance was started with 5 mg daily, and was escalated to the target dose of 15 mg. If tol- erated, medication was administered until disease progression. The primary endpoint was progression-free survival according to an independent review. The pre-planned interim analysis done by intention to treat was done after 20% of the calculated progression-free survival events. FINDINGS Between July 5, 2012, and March 15, 2016, 468 previously untreated patients with chronic lymphocytic leukaemia were screened for the study; 379 (81%) were not eligible. Recruitment was closed prematurely due to poor accrual after 89 of 200 planned patients were randomly assigned: 60 (67%) enrolled patients were assigned to the lena- lidomide group and 29 (33%) to the placebo

group, of whom 56 (63%) received lenalido- mide and 29 (33%) placebo, with a median of 11·0 (IQR 4·5-20·5) treatment cycles at data cutoff. After a median observation time of 17·9 months (IQR 9·1-28·1), the hazard ratio for progression-free survival assessed by an independent review was 0·168 (95% CI 0·074-0·379). Median progression-free sur- vival was 13·3 months (95% CI 9·9-19·7) in the placebo group and not reached (95% CI 32·3- not evaluable) in the lenalidomide group. The most frequent adverse events were skin dis- orders (35 patients [63%] in the lenalidomide group vs eight patients [28%] in the placebo group), gastrointestinal disorders (34 [61%] vs eight [28%]), infections (30 [54%] vs 19 [66%]), haematological toxicity (28 [50%] vs five [17%]), and general disorders (28 [50%] vs nine [31%]). One fatal adverse event was reported in each of the treatment groups (one [2%] patient with fatal acute lymphocytic leu- kaemia in the lenalidomide group and one patient (3%) with fatal multifocal leukoenceph- alopathy in the placebo group). INTERPRETATION Lenalidomide is an efficacious maintenance therapy reducing the relative risk of progression in first-line patients with chronic lymphocytic leukaemia who do not achieve minimal residual disease negative disease state following chemoimmunother- apy approaches. The toxicity seems to be acceptable considering the poor prognosis of the eligible patients. The trial independently confirms the clinical significance of a novel, minimal residual disease-based algorithm to predict short progression-free survival, which might be incorporated in future clinical trials to identify candidates for additional mainte- nance treatment. Lenalidomide maintenance after first-line therapy for high-risk chronic lymphocytic leukaemia (CLLM1): final results from a ran- domised, double-blind, phase 3 study. Lancet Haematol 2017 Sep 12;[EPub Ahead of Print], AM Fink, J Bahlo, S Robrecht, et al. www.practiceupdate.com/c/58261

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