Practice Update | Onology

Volume 1 | Number 2 | 2017

VOL. 1 • NO. 2 • 2017

OUR EXPERTS. YOUR PRACTICE.

ISSN 2207-869X

Expert consensus on de-escalating and escalating treatments for early-stage breast cancer

Opinion

People are going to be looking at abiraterone with a low-dose prednisone, only 5mg of prednisone, add it to ADT as being a new potential standard of care.

Dr Oliver Sartor on the STAMPEDE trial and prostate cancer

Conference ASCO 2017

JOURNAL SCAN Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB)

Risks of breast, ovarian, and contralateral breast cancer for BRCA1- and BRCA2-mutation carriers

Liquid biopsy analysis of FGFR3 and PIK3CA hotspot mutations for disease surveillance in bladder cancer

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-1130195-0277. First issued June 2017. MSDONC1065.

Reference: 1. KEYTRUDA Approved Product Information. 20 March 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 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. See full PI. Contraindications: Hypersensitivity to pembrolizumab or any of the inactive ingredients. Precautions: Immune-mediated adverse reactions, including pneumonitis, colitis (including gastrointestinal perforation), hepatitis, nephritis, hypophysitis, type 1 diabetes mellitus, hyperthyroidism, hypothyroidism, uveitis, myositis, Guillain-Barre syndrome, myasthenic syndrome, pancreatitis, myocarditis, solid organ transplant rejection and severe skin reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis). 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. Dosage: The recommended dose of KEYTRUDA is 200 mg for 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 20 March 2017.

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CONTENTS 5

RESEARCH Editor’s picks 6 Consensus conference on de-escalating and 7 Dabrafenib plus trametinib in patients with BRAF(V600)- mutant melanoma brain metastases (COMBI-MB) and trastuzumab in early HER2+ breast cancer 9 Surgical resection vs watchful waiting in low- grade glioma Breast 22 Risks of breast, ovarian, and contralateral breast cancer for BRCA1- and BRCA2-mutation carriers 8 Adjuvant pertuzumab escalating treatments for early-stage breast cancer

Cover 6 Consensus

PracticeUpdate Oncology is published by Elsevier Australia ISSN 2207-869X (Print) ISSN 2207-8703 (Online) Although all advertising material 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. SALES Fleur Gill fleur.gill@elsevier.com Linnea Mitchell-Taverner l.mitchell@elsevier.com PRODUCTION Editorial Manager Anne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng Designer Jana Sokolovskaja Cover: Dividing breast cancer cell. ABN 70 001 002 357 475 Victoria Avenue Chatswood NSW 2067 Australia Locked Bag 7500 Chatswood DC NSW 2067 EMON071701 PracticeUpdate® is a registered trademark of Elsevier Inc. © 2017 Elsevier Inc. All rights reserved. ABOUT 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 www. 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 verification of diagnoses and drug dosages should be made. Please consult the full current Product Information before prescribing any medication mentioned in this publication. 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 Associate Editors Isabel Cunningham MD Axel Grothey MD Advisory Board Kimberly Blackwell MD, Roxana Dronca MD, Wilfried Eberhardt MD, Rafael Fonseca MD, Andre Goy MD, Annette Hasenburg Prof Dr med, David Henry MD, Eric Jonasch MD, Jeffrey Kirshner MD, FACP, Ruben Niesvizky MD, Howard Scher MD, David Straus MD, Roger Stupp MD Editorial Contributors Brandt Esplin MD PhD, Jeremy Jones MD, Jarushka Naidoo MD, Moshe Ornstein MD, Erin Schenk MD PhD

Conference 10 American Society of Clinical conference on de-escalating and escalating treatments for early-stage breast cancer Oncology 2017 Annual Meeting

10 Practice changers in advanced prostate cancer: STAMPEDE, LATITUDE vis-à-vis CHAARTED 11 Practice changers in breast cancer 14 Ten practice changes I will make after attending ASCO 2017 16 New standard of care for low risk stage 3 colorectal cancer? 17 Extent of lymph node dissection in prostatectomy: an update 18 Significant updates in glioblastoma 20 Novel treatment options for RCC: a review 20 Practice changers in myeloma

Melanoma 23 Adoptive transfer of tumor-infiltrating

lymphocytes for metastatic uveal melanoma

Colon & Rectum 24 Clinical implications of monitoring circulating

Features 28 My Approach Medullary

tumor DNA in patients with colorectal cancer

24 First-line chemotherapy combined with cetuximab or bevacizumab for KRAS wild-type advanced or metastatic colorectal cancer Genitourinary 26 Liquid biopsy analysis of FGFR3 and PIK3CA hotspot mutations for disease surveillance in bladder cancer 27 Similar oncological outcomes with partial and radical nephrectomy in RCC ≥4 cm

thyroid cancer and its primary treatment 30 Q & A Critical issues in thoracic oncology

VOL. 1 • NO. 2 • 2017

EDITOR’S PICKS 6

Consensus conference on de-escalating and escalating treatments for early-stage breast cancer Take-home message • The St. Gallen International Breast Conference Panel discussed treatment options for early-stage breast cancer, seeking to escalate or de-escalate therapy based on likelihood of improvement in outcomes. • The Panel favored interventions that would result in reduced surgical morbidity. The Panel additionally favored neoadjuvant therapy in HER2-positive and triple-negative, stage 2 and 3 breast cancer patients. For high-risk patients, the Panel favored nodal irradiation and escalating recommendations for adjuvant endocrine treatment to include ovarian suppression in premenopausal women and extended therapy for postmenopausal women. Annals of Oncology

Abstract The 15th St. Gallen International Breast Cancer Conference 2017 in Vienna, Austria reviewed substantial new evidence on loco-regional and systemic therapies for early breast cancer. Treatments were assessed in light of their inten- sity, duration and side effects, seeking where appropriate to escalate or de-escalate therapies based on likely benefits as predicted by tumor stage and tumor biology. The Panel favored sev- eral interventions which may reduce surgical morbidity, including acceptance of 2mm mar- gins for DCIS, the resection of residual cancer (but not baseline extent of cancer) in women undergoing neoadjuvant therapy, acceptance of sentinel node biopsy following neoadjuvant treatment for many patients, and the preference for neoadjuvant therapy in HER2 positive and triple-negative, stage II and III breast cancer. The Panel favored escalating radiation therapy with regional nodal irradiation in high risk patients, while encouraging omission of boost in low risk patients. The Panel endorsed gene expression signatures that permit avoidance of chemother- apy in many patients with ER positive breast cancer. For women with higher risk tumors, the Panel escalated recommendations for adjuvant endocrine treatment to include ovarian suppres- sion in premenopausal women, and extended therapy for postmenopausal women. However, low risk patients can avoid these treatments. Finally, the Panel recommended bisphospho- nate use in postmenopausal women to prevent breast cancer recurrence. The Panel recog- nized that recommendations are not intended for all patients, but rather to address the clinical needs of the majority of common presentations. Individualization of adjuvant therapy means adjusting to the tumor characteristics, patient comorbidities and preferences, and manag- ing constraints of treatment cost and access that may affect care in both the developed and developing world. De-escalating and escalating treatments for early stage breast cancer: the St. Gallen Inter- national Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol 2017 Jun 21;[EPub Ahead of Print], G Curigliano, HJ Burstein, EP Winer, et al.

COMMENT By Lee S. Schwartzberg MD, FACP T he St. Gallen conference makes recommendations on the treatment of early-stage breast cancer based on international expert consensus opin- ion. This year’s conference focused on de-escalating surgical approaches such as accepting a 2-mm margin for DCIS and smaller resections based on residual tumor size after neoadjuvant treatment. Notably, they endorsed incorporating one of several genomic assays into the decision-making process for ER-positive cancers and the need for chemother- apy. They agreed on some escalation of therapy with a recommendation of bis- phosphonate use in postmenopausal women, which differs from the NCCN recommendations, and regional nodal

irradiation if patients had positive nodal disease removed at surgery. In general, more precise subtyping and risk assessment has allowed more personalized adjuvant care, leading to different treatment approaches based on a combination of patient factors, tumor size and stage, and tumor biology.

Dr Schwartzberg is the Executive Director of the West Cancer Center, and he serves as Professor of Medicine and Division Chief of Hematology/ Oncology at The University of Tennessee Health Science Center.

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EDITOR’S PICKS 7

Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB) The Lancet Oncology Take-home message

(five [4%]) for trametinib. The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (four [3%] of 125) and headache (three [2%]). INTERPRETATION Dabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with BRAF(V600)-mutant melanoma without brain metastases, but the median dura- tion of response was relatively short. These results provide evidence of clinical benefit with dabrafenib plus trametinib and support the need for additional research to further improve outcomes in patients with melanoma brain metastases. Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metas- tases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 2017 Jun 02;[EPub Ahead of Print], MA Davies, P Saiag, C Robert, et al. that group of patients who have sympto- matic brain metastases at presentation. We know that a number of patients with brain metastases have symptomatic dis- ease at presentation and most of these patients are treated with some form of radiation. Because melanoma is a radi- ation-resistant disease, a focus on techniques such as stereotactic radiosur- gery is often employed in themanagement of these patients. The next set of clinical trials may want to focus on the treat- ment of patients with symptomatic brain metastases using a combination of either stereotactic radiosurgery with some form of targeted therapy or immune checkpoint blockade in these patients.

• This multicenter, multicohort, open-label, phase 2 trial was designed to evaluate the activity and safety of the dabrafenib plus trametinib combination in patients with BRAF V600-mutant melanoma brain metastases. The primary analysis included 76 patients with asymptomatic brain metastases and no prior local therapy. After a median of 8.5 months of follow-up, 58% patients had experienced an intracranial response. The toxicity profile was acceptable. • The authors conclude that the results of this trial support the safety and efficacy profile of this treatment combination, which is consistent with prior studies con- ducted in patients without the presence of intracranial disease. Further data are needed to improve outcomes in this particular subpopulation. Abstract

95% CI 30–80) of 16 patients in cohort B, seven (44%; 20–70) of 16 patients in cohort C, and ten (59%; 33–82) of 17 patients in cohort D. The most common serious adverse events related to study treatment were pyrexia for dabrafenib (eight [6%] of 125 patients) and decreased ejection fraction COMMENT By Manmeet Ahluwalia MD, FACP T raditionally, the treatment for brain metastases mostly focused on radi- ation-based approaches, including stereotactic radiosurgery. Recently, we have seen a number of trials that have looked at treating patients with brain metastases either with targeted therapies or immune checkpoint blockade. This is a phase II trial of a combination of dabrafenib and trametinib in four different cohorts of patients with BRAF(V600)-mutant mela- noma brainmetastases. As expected, most of patients had the V600E BRAF mutation, which is the most common type of BRAF mutation seen in patients with melanoma. The outcomes are impressive, with response rates of 58% in patients who were radiation-naïve and who had asymptomatic brain metastases. This is in comparison with the previously reported response rates of around 30% seen with dabrafenib alone in patients with asymptomatic brain metastases as reported in the BREAK-MB study. This trial supports the use of targeted ther- apy for oncogene-driven tumors such as BRAF-mutated tumors in patients who have asymptotic brain metastases. How- ever, what this trial does not address is

BACKGROUND Dabrafenib plus trametinib improves clinical outcomes in BRAF(V600)-mu- tant metastatic melanoma without brain metastases; however, the activity of dabrafenib plus trametinib has not been studied in active melanoma brain metastases. Here, we report results from the phase 2 COMBI-MB trial. Our aimwas to build on the current body of evidence of targeted therapy in melanoma brain metas- tases through an evaluation of dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases. METHODS This ongoing, multicentre, multico- hort, open-label, phase 2 study evaluated oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in four patient cohorts with melanoma brain metasta- ses enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAF(V600E)-positive, asymptomatic mela- noma brain metastases, with no previous local brain therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (B) BRAF(V600E)-positive, asympto- matic melanoma brain metastases, with previous local brain therapy, and an ECOG performance status of 0 or 1; (C) BRAF(V600D/K/R)-positive, asymptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0 or 1; and (D) BRAF(V600D/E/K/R)-positive, symptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0, 1, or 2. The primary endpoint was investigator-assessed intracranial response in cohort A in the all-treated-patients population. Secondary endpoints included intracranial response in cohorts B, C, and D. FINDINGS Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. At the data cutoff (Nov 28, 2016) after a median follow-up of 8.5months (IQR 5.5–14.0), 44 (58%; 95%CI 46–69) of 76 patients in cohort A achieved an intracranial response. Intracranial response by investiga- tor assessment was also achieved in nine (56%;

Dr Ahluwalia is the Dean and Diane Miller Family Endowed Chair in Neuro- Oncology in the Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, where he subspecializes in treatment

of patients with brain tumors and brain metastases. He is also Associate Professor in the Department of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.

VOL. 1 • NO. 2 • 2017

EDITOR’S PICKS 8

Adjuvant pertuzumab and trastuzumab in early HER2+ breast cancer The New England Journal of Medicine Take-home message

COMMENT By Lee S. Schwartzberg MD, FACP D oes dual anti-HER2 blockade add enough benefit to justify its use in the adjuvant setting of HER2-positive early-stage breast can- cer (ESBC)? The APHINITY trial tested the addition of pertuzumab to standard chemotherapy and 1 year of adjuvant trastuzumab. A statistically significant but clinically small benefit was seen at 3 years of follow-up, with a 1% improve- ment in invasive disease-free survival from 1 year of pertuzumab. The dis- tant recurrence rate was also 1% better. In subgroup analysis, node-positive patients and ER-negative patients had more (~2%) benefit with pertuzumab added. On the negative side of the ledger, pertuzumab added more all grade and grade 3 diarrhea, and a small increase in cardiac events. It can be argued that, based on these results, the decision to add pertuzumab to a standard adjuvant regimen for HER2-positive ESBC should be made carefully and not indiscriminately. Cer- tain clinically high-risk groups, such as patients with stage III or lower node-positive ER-negative/HER2-pos- itive cancers appear to derive benefit from the dual HER2 blockade. On the other hand, smaller, stage I HER2-posi- tive breast cancers do very well with just 12 weeks of paclitaxel and 1 year of tras- tuzumab, as evidenced by the long-term follow-up of the APT trial presented at ASCO 2017; so, additional therapy is unlikely to show a benefit. Like in all of medicine, one size does not fit all in the adjuvant treatment of ESBC. Some HER2-positive patients require dual anti-HER2 therapy, but many do well without incremental therapy, and, considering the additional cost and life impact of more treatment, they should not receive it. Overall, pertuzumab is a small step for- ward in HER2-positive ESBC compared with a big jump in the first-line metastatic setting with this drug as evidenced by the CLEOPATRA results.

• This study investigated whether pertuzumab added to adjuvant trastuzumab and chemotherapy would improve clinical outcomes among patients with node-positive or high-risk node-negative HER2-positive operable breast cancer. Disease recurred among 7.1% of patients in the pertuzumab group and 8.7% of patients in the placebo group (HR, 0.81; P = 0.045). The 3-year rate of invasive disease-free survival in the node-positive cohort was 92.0% with pertuzumab compared with 90.2% with placebo (HR for an invasive-disease event, 0.77; P=0.02). The 3-year rate of invasive disease-free survival in the node-negative cohort was 97.5% with pertuzumab and 98.4% with placebo (HR for an invasive-disease event, 1.13; P=0.64). The treatment effect was more evident among patients at higher relapse risk because of nodal involvement or hormone receptor-negative status, although it was homogeneous statistically among all the subgroups. • The results demonstrate that pertuzumab added to trastuzumab and chemotherapy significantly improved invasive disease-free survival rates among patients with HER2-positive breast cancer.

Abstract BACKGROUND Pertuzumab increases the rate of pathological complete response in the preop- erative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemother- apy, improves outcomes among patients with HER2-positive early breast cancer. METHODS We randomly assigned patients with node-positive or high-risk node-nega- tive HER2-positive, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed

a 3-year invasive-disease-free survival rate of 91.8% with pertuzumab and 89.2% with placebo. RESULTS In the trial population, 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node-positive disease and 36% had hormone-receptor-negative disease. Dis- ease recurrence occurred in 171 patients (7.1%) in the pertuzumab group and 210 patients (8.7%) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The estimates of the 3-year rates of invasive-dis- ease-free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group. In the cohort of patients with node-positive disease, the 3-year rate of invasive-disease-free survival was 92.0% in the pertuzumab group, as com- pared with 90.2% in the placebo group (hazard ratio for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In the cohort of patients with node-negative disease, the 3-year rate of invasive-disease-free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive-disease event, 1.13; 95% CI, 0.68 to 1.86; P=0.64). Heart failure, cardiac death, and cardiac dysfunc- tion were infrequent in both treatment groups. Diarrhea of grade 3 or higher occurred almost exclusively during chemotherapy and was more frequent with pertuzumab than with placebo (9.8% vs. 3.7%). CONCLUSIONS Pertuzumab significantly improved the rates of invasive-disease-free survival among patients with HER2-positive, operable breast cancer when it was added to trastuzumab and chemotherapy. Diarrhea was more common with pertuzumab than with placebo. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med 2017 Jun 05;[EPub Ahead of Print], G von Minckwitz, M Procter, E de Azambuja, et al.

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EDITOR’S PICKS 9

Surgical resection vs watchful waiting in low-grade glioma Annals of Oncology Take-home message • The authors of this population-based parallel cohort study compared clinical outcomes in patients with infiltrating low-grade gliomas treated with resection and those undergoing watchful waiting. Region A favored watchful waiting; region B favored early resection. The primary endpoint was overall survival. In total, 153 patients were involved (66 from region A and 87 from region B); 94 underwent early resection (19 from region A and 75 from region B). Overall survival was 5.8 years in region A and 14.4 years in region B. • Overall survival was associated with early surgical resection, even after adjustment for molecular markers (P = 0.001).

Abstract BACKGROUND Infiltrating low-grade gliomas (LGG; WHO grade 2) typically present with seizures in young adults. LGGs grow continuously and usu- ally transform to higher grade of malignancy, eventually causing progressive disability and premature death. The effect of up-front surgery has been controversial and the impact of molec- ular biology on the effect of surgery is unknown. We now present long-term results of upfront sur- gical resection compared to watchful waiting in light of recently established molecular markers. This report provides reasonably compelling evidence, and additional evidence to other more conventional retrospective series, that early surgery results in a better prognosis in this population, perhaps by delaying malignant transformation. MATERIAL AND METHODS Population-based paral- lel cohorts were followed from two Norwegian university hospitals with different surgical treat- ment strategies and defined geographical catchment regions. In region A watchful waiting was favored while early resection was favored in region B. Thus, the treatment strategy in indi- vidual patients depended on their residential address. The inclusion criteria were histopatho- logical diagnosis of supratentorial LGG from 1998 through 2009 in patients 18 years or older. Follow-up ended 1st January 2016. Mak- ing regional comparisons, the primary end-point was overall survival. RESULTS 153 patients (66 from region A, 87 from region B) were included. Early resection was carried out in 19 (29%) patients in region A com- pared to 75 (86%) patients in region B. Overall survival was 5.8 years (95% CI 4.5–7.2) in region A compared to 14.4 years (95% CI 10.4–18.5) in region B (P<0.01). The effect of surgical strategy remained after adjustment for molecular mark- ers (P=0.001).

CONCLUSION In parallel population based cohorts of LGGs, early surgical resection resulted in a clinical relevant survival benefit. The effect on survival persisted after adjustment for molecu- lar markers. COMMENT By Gene H. Barnett MD, MBA,FAANS, FACS

Surgical resection versus watchful waiting in low-grade gliomas. Ann Oncol 2017 May 05;[EPub Ahead of Print], AS Jakola, AJ Skjuls- vik, KS Myrmel, et al.

I n this retrospective review from Norway, the authors compared the results of two different hospitals’ (widely separated geographically) strategies for management of newly diagnosed low-grade gliomas. In one, early surgery was favored; in the other, biopsy and watchful waiting was the preferred approach. The overall survival in the early-surgery group was about 8 years longer than in the observation group (14.4 vs 5.8 years), and this difference was not explained by histological, molecular, or other characteristics of the group. As a randomized trial addressing the question of which approach is best is unlikely to ever be done, this report provides reasonably compelling evidence, and additional evidence to other more conventional retrospec- tive series, that early surgery results in a better prognosis in this population, perhaps by delaying malignant transformation.

Dr Barnett is Professor and Director, Rose Ella Burkhardt Brain Tumor & Neuro-Oncology Center, Cleveland Clinic Neurological Institute, The Cleveland Clinic in Ohio.

VOL. 1 • NO. 2 • 2017

CONFERENCE COVERAGE 10

American Society of Clinical Oncology 2017 Annual Meeting 2–6 JUNE 2017 • CHICAGO, USA

At this year’s ASCO annual meeting, the PracticeUpdate Editorial team spoke to some of oncology’s most esteemed minds for their thoughts on key clinical trial data presented at the meeting, and those they considered practice changers.

Practice changers in advanced prostate cancer: STAMPEDE, LATITUDE vis-à-vis CHAARTED

Dr Farzanna Haffizulla speaks with Oliver A Sartor MD, Laborde Professor in Cancer Research in the Medicine and Urology Departments at Tulane School of Medicine in Louisiana, on the STAMPEDE, LATITUDE and CHAARTED trials and what they mean for men with prostate cancer.

with a low-dose prednisone, only 5 mg of prednisone, add it to ADT as being a new potential standard of care. Dr Haffizulla: How does this data differ from LATITUDE? Dr Sartor: Well, the LATITUDE is a little bit more restricted, so what I didn’t tell you about STAMPEDE is it also took the non- metastatic patients, and I personally feel as though the nonmetastatic patients don’t have adequate maturity to be con- clusive. Their failure-free survival is very strongly positive on the abiraterone, but their overall survival and then the hazard ratio was good at 0.75. Confidence level is still big and not a lot of maturity in that. So, STAMPEDE actually took in a lot of the nonmetastatic patients.

Dr Haffizulla: I wanted to talk about the most recent data from STAMPEDE. We’re here at ASCO 2017 and I know in STAMPEDE we’re assessing abiraterone in the context of hor- mone-sensitive prostate cancer. What does this data mean for clinical practice? Dr Sartor: I think it’s practice changing. The utilization of ADT has been ongo- ing since 1941 and it’s sort of the standard that we’ve become accustomed to. There was a clinical trial called CHAARTED that helped change that standard by adding

in chemotherapy and STAMPEDE had another arm that added in chemotherapy. But the new data is with abiraterone, and it’s being compared against conventional ADT. It’s really strikingly positive, and within the metastatic subset almost a reduction of 40%; it’s like a 39% reduction in mortality. It’s pretty reasonably well tolerated. The PFS and other components of the endpoints were all strikingly positive, and I think it’s a practice changer. I think peo- ple are going to be looking at abiraterone

PRACTICEUPDATE ONCOLOGY

ASCO 2017 11

Practice changers in breast cancer Interview with Lee S. Schwartzberg MD, FACP Dr Farzanna Haffizulla speaks with Dr Schwartzberg, Executive Director of the West Cancer Center in Memphis, Tennessee, on the OlympiAD trial and its implications for patients with metastatic breast cancer harboring germline BRCA mutations, as well as the CDK4/6 inhibitor abemaciclib for ER-positive metastatic breast cancer. Dr Haffizulla: I would love for you to highlight any key practice changing data that’s pre- sented in the breast cancer arena at this time. Dr Schwartzberg: I think this year in breast cancer there was one overriding story, which was the phase 3 data in OlympiAD, which compared patients to best standard treatment of the physician’s choice in late-line metastatic breast cancer, compared to a novel agent, olaparib, which is a PARP inhibitor. This was selected for patients that had germline BRCA mutations, so this is truly personalized medicine based on a genomic alteration, and the results were positive. The progression-free survival was substantially enhanced by using olaparib versus chemotherapy. This, to me, represents a new standard for patients who have this genetic abnormality, and I will be incorporating it into my practice. Dr Haffizulla: You have been such a grand supporter of precision medicine in all that you do, and we appreciate all of that information that you’re sharing. Anything else for us to look forward to? Any trials that might be ongoing now or any data that might be coming up in the near future that you wanted to draw our attention to? Dr Schwartzberg: I think that the other area of great interest is the CDK4/6 inhibitors. We heard data with abemaciclib at this year’s ASCO, which is also very important, and gives us another opportunity to use abemaciclib in combination with anti-endocrine therapy for metastatic breast cancer that’s ER-positive. So now we have a third agent in the CDK4/6 arena where we can choose, based on toxicities or mode of administration and so forth. So, now we have options for patients with CDK4/6, and I think most of us believe that combination therapy for ER-positive breast cancer, endocrine therapy plus a CDK4/6, for most patients at the diagnosis of metastatic breast cancer will be the way we go.

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LATITUDE did not, so LATITUDE was purely within the metastatic space and they had some restrictions. You had to have at least three lesions or you could end up with a high Gleason 8, a little bit different entry criteria. The bottom line is, I kind of look at LATITUDE in a way as confirmatory or STAMPEDE as confirmatory. The two really sync together, and together they make a really good story, and the bottom line is that they’re positive, positive, positive for our most important endpoint, overall survival for those with metastatic disease. Dr Haffizulla: Fantastic to hear that. Now, you’ve also reviewed the role of chemo- therapy in prostate cancer based on CHAARTED, as you mentioned, and a previous presentation of STAMPEDE but related to docetaxel. What do you think the role of docetaxel is in the face of the data from LATITUDE and STAMPEDE? Dr Sartor: Well, you know, I mentioned that we have a new standard. I didn’t say the

that that is clearly a benefit for the high vol- ume subset, and for the abiraterone, I think it presents another option. Are we going to compare the two? Well, we need to, or what about combine the two? We need to do that. So, there’s a lot of path forward here and it just really means that men have more options. Dr Haffizulla: So, further research is needed before you can decide. Dr Sartor: Further research is needed, as always.

new standard. So, I chose thosewords care- fully. When we looked at docetaxel, they had a strikingly positive, particularly in the high volume subset based on CHAARTED. There had to be four or more lesions, vis- ceral lesions, things that sort of made the disease bad, and it turns out that when you look at these data together I think it tells you that there are two options. I don’t think we have to go with the docetaxel. I don’t think we have to go with the abiraterone. I think it’s conceivable to say that we’re unsure about which one really might be better. I’ll say that from a side effect per- spective, you know, probably from a safety perspective, the abiraterone might, in fact, be very favourable. But at the same time you have to realize the docetaxel it’s 6 doses and 6 doses only, then you’re done. Whereas the abiraterone you continue the therapy for a much longer period of time. So, there might be some who choose to be treated with chemotherapy, and I think

Farzanna S Haffizulla MD, FACP, FAMWA practices general internal medicine in Davie, Florida, within her own internal medicine concierge practice.

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VOL. 1 • NO. 2 • 2017

Now PBS listed 1

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SERIOUS ADVERSE EVENTS The following severe adverse events have been seen. Monitor closely and consider early dose reduction. See referenced () sections for details and appropriate management. • QT interval prolongation (see Pharmacokinetics, Precautions, Adverse Effects, Dosage & Administration).

• Interstitial Lung Disease/Pneumonitis, including fatal cases (see Precautions, Adverse Effects, Dosage & Administration). • Hepatotoxicity, including drug-induced liver injury (Pharmacokinetics, Precautions, Adverse Effects, Dosage & Administration).

• Gastrointestinal toxicity (Precautions, Adverse Effects, Dosage & Administration). ZYKADIA has not been studied in patients with moderate and severe hepatic impairment. ZYKADIA must be taken while fasting — any food consumption within a 2 hour period before or after administration increases systemic exposure up to 2-fold increasing the risk of toxicities, and also potentially exceeds the maximum dose tested, and the risks are unknown (see Pharmacokinetics, Dosage and Administration). ZYKADIA should only be prescribed and supervised by a qualified physician experienced in the use of anticancer agents. Please review Zykadia ® (ceritinib) product information before prescribing.

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A PATH FORWARD FOR 2L ALK+ NSCLC 2 ZYKADIA ® (ceritinib) is indicated as monotherapy for the treatment of adult patients with ALK+ locally advanced or metastatic NSCLC whose disease has progressed on or who are intolerant of crizotinib. 2 Note to indication: This indication is approved based on tumour response rates and duration of response. An improvement in survival or disease-related symptoms has not been established. 2

Indication: ZYKADIA is indicated as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK) positive locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on or who are intolerant of crizotinib. Note to Indication: This indication is approved based on tumour response rates and duration of response. An improvement in survival or disease-related symptoms has not been established. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Precautions: Hepatotoxicity; Interstitial lung disease / Pneumonitis, QT interval prolongation Bradycardia, Gastrointestinal toxicity, Hyperglycemia, Pancreatic toxicity, Women of child-bearing potential, Pregnancy, Lactation. Fertility, Children (below 18 years) See full PI. Interactions: Strong inhibitors or inducers of CYP3A and P-gp. Gastric acid-reducing agents (proton pump inhibitors, H2-receptor antagonists, antacids) Avoid co-administration CYP3A & CYP2C9 substrates known to have narrow therapeutic indices Exercise caution with concomitant use of CYP2A6 and CYP2E1 substrates and carefully monitor adverse drug reactions. Risk for induction of other PXR regulated enzymes apart from CYP3A4 cannot be completely excluded. Effectiveness of concomitant administration of oral contraceptives may be reduced. ZYKADIA capsules must be taken on an empty stomach. No food should be eaten for at least two hours before and two hours after the dose of ZYKADIA is taken. Patients should be instructed to avoid grapefruit or grapefruit juice as they may inhibit CYP3A in the gut wall and increase the bioavailability of ZYKADIA. See full PI. Dosage and administration: Recommended dose is 750 mg taken orally once daily at the same time each day. Maximum recommended dose is 750 mg daily. ZYKADIA capsules must be taken on an empty stomach. No food should be eaten for at least two hours before and two hours after the dose of ZYKADIA is taken. The dose should be reduced by decrements of 150 mg daily. ZYKADIA should be discontinued in patients unable to tolerate 300 mg daily. See full PI for dose interruption, reduction, or discontinuation of ZYKADIA in the management of select adverse drug reactions. Use caution in patients with severe renal impairment. See full PI. Side effects: Very common (≥10%): Anemia, decreased appetite, diarrhea, nausea, vomiting, abdominal pain, constipation, esophageal disorder, rash, fatigue, liver laboratory test abnormalities and blood creatinine increased. Common (1 to 10%): Hyperglycemia, hypophosphatemia, vision disorder, pericarditis, bradycardia, pneumonitis, abnormal liver function tests, renal failure, renal impairment, electrocardiogram QT prolonged, lipase increased, and amylase increased. Uncommon (0.1 to 1%): Hepatotoxicity and pancreatitis. See full PI ( ldk010816i ).

2L: second line, ALK+: anaplastic lymphoma kinase positive, NSCLC: non-small cell lung cancer References: 1. Pharmaceutical Benefits Scheme (PBS) www.pbs.gov.au 2. ZYKADIA Product Information

Zykadia® is a registered trademark of Novartis Pharmaceuticals Australia Pty Limited. ABN 18 004 244 160. 54 Waterloo Road Macquarie Park NSW 2113. Ph (02) 9805 3555. AU-1518 April 2017

CONFERENCE COVERAGE 14

Ten practice changes I will make after attending ASCO 2017 By Jeffrey J. Kirshner MD, FACP

Dr Kirshner is a partner of Hematology Oncology Associates of Central New York (HOACNY), and Director of Research and serves as the Principal Investigator of the HOACNY Community Clinical Oncology Program, East Syracuse, New York.

1. I will treat selected stage III colon cancer patients with 6 rather than 12 courses of FOLFOX adjuvant chemotherapy. As presented by Shi et al in LBA1 at the Plenary Session, IDEA, the prospective pooled analysis of six phase 3 trials investigating the duration of adjuvant therapy, demonstrated noninferiority in “lower-risk” stage 3 patients (T1–3, N1). 1 There appears to be a slight improvement in DFS in patients with more advanced stage 3 disease. As expected, the longer duration was associated with more neurotoxicity and certain T4 and N2 patients (especially those at risk for neurotoxicity) might want to consider the 6 courses, after a discussion of the risks and benefits of the longer regimen. 2. I will add abiraterone/prednisone to androgen deprivation therapy in newly diagnosed high- risk hormone-naive patients with metastatic prostate cancer. As presented by Fizazi et al in LBA3 at the Ple- nary Session, LATITUDE, the phase III, double-blind randomized trial of close to 1200 patients, clearly demonstrated an improvement in overall survival with the early initiation of abiraterone in this group of patients. 2 Toxicity was manageable. Median relapse- free survival was doubled to 33 months, and median overall survival has not been reached yet (34.7 months in the control group). This approach may replace the addition of docetaxel in this group of patients, reserving chemotherapy for patients with progressive disease. 3. I will offer patients with refractory triple-negative metastatic breast cancer (TNBC) pembroli- zumab. As presented by Adams et al in abstract 1008, Keynote-086, a phase 2 study of 170 patients with previously treated TNBC, demonstrated only a 5% response rate; however, 21% of patients had sta- ble disease, averaging 6 months, with some patients without progression at over 10 months. 3 In the same study, another cohort of patients was treated with pem- brolizumab as first-line treatment for metastatic TNBC (Abstract 1088). 4 Early results of the first 52 patients demonstrate a response rate of 23%, with stable dis- ease in 17%. Follow-up is short, but the estimated 6-month PFS is 29%. Note that, currently, pembroli- zumab is not FDA-approved for this indication but can often be obtained on compassionate release, and I look forward to approval within the year. 4. I will discuss with very high-risk patients who have resected HER2-positive stage 2 and 3 breast cancer the addition of pertuzumab to tras- tuzumab in the adjuvant setting for up to 1 year. As presented by von Minckwitz et al in abstract LBA500, the randomized placebo-controlled APHINITY trial

of over 4800 patients demonstrated that the addi- tion of pertuzumab to trastuzumab improved invasive disease-free survival by a little over 1%, which was sta- tistically significant. 5 Patients with nodal involvement, particularly those with hormone receptor-negative dis- ease achieved the most benefit and merit a discussion of the risk/benefit and cost of adding pertuzumab to trastuzumab. 5. I will offer patients with refractory upper gastroin- testinal adenocarcinomas checkpoint inhibitors . Two abstracts were presented at the Oral Session which confirm the activity seen in earlier studies. Fuchs et al reported the results of KEYNOTE-059 (abstract 4003), a global study of 259 heavily pretreated patients with gastric and gastroesophageal junction cancer. 6 Overall response rate was 11.2%, with 17% stable dis- ease. Median duration of follow-up is only 5.4 months; but, so far, median duration of response is 8.1 months, with some patients still responding at over 15 months. Responses correlated with less prior treatment, with PDL-1 positivity, and, especially, with MSI status. Jan- jigian et al reported updated results of CheckMate 032 (abstract 4014), a global study of 160 similar patients who were treated with one of three nivolumab reg- imens (two in combination with ipilimumab). 7 Overall response rate was 12% with nivolumab alone but increased to 24% when combined with ipilimumab at 3 mg/kg every 3 weeks (nivolumab was decreased to 1 mg/kg every 3 weeks). Median survival has not

PRACTICEUPDATE ONCOLOGY

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been reached in this latter group of 49 patients, but 18-month survival is 50%. As expected grade3/4 toxicity exceeded 10% in the combination arm (mainly diarrhea). These agents are not yet approved for this disease, but often can be obtained for com- passionate use, and I anticipate approval within the next year. 6. I will suggest to my patients receiv- ing taxanes, especially docetaxel, to apply a polyphenol-rich nail balm to pre- vent onycholysis. Thomas et al presented a poster (abstract 10103) with the results of the UK PolyBalm study, a randomized trial of 60 patients receiving taxanes. 8 There was a very highly significant improvement in nail health and quality of life in the 30 patients who treated their nails with the “balm” three times daily, as opposed to the control group, who used a petroleum balm. Polybalmwill be available online in the near future. Kim et al presented data in a poster at the same session (abstract 10108). 9 In a randomized Korean study of 103 patients receiving neoadjuvant docetaxel, those patients who used a hydrating nail solu- tion had a statistically significant decrease in onycholysis. This is another option and may be more readily available. 7. I will continue to use checkpoint inhib- itors in melanoma patients, even if they present with asymptomatic brain metastases and not refer for radiation treatment as initial therapy. Tawbi et al presented the results of CheckMate 204 (abstract 9507). 10 Patients were treated with the standard metastatic melanoma regi- men of nivolumab/ipilimumab followed by nivolumab maintenance. The first 75 patients in the trial had an intracranial 56% response rate, including 19% complete

the treatments as compassionate use. BONUS: I will test selective patients with refractory malignancies for TRK fusion gene in addition to MSI. Hyman et al pre- sented a much-anticipated report of 55 patients treated with the pan-TRK inhibi- tor larotrectinib (abstract LBA2501). 16 Over 17 cancer types were represented in both pediatric and adult patients. Confirmed response rate is 76%, with 12% stable dis- ease (and may be even higher after review of 5 additional patients)! Responses are durable, and toxicity is minimal. The drug is available for compassionate use. Patients who progress often respond to another inhibitor, which is being studied (LOXO- 195). Although this mutation affects only approximately 1% of cancer patients, when combined with MSI testing, very effective treatment may be found in up to 5% of patients, regardless of tumor type. Com- mercial laboratories are now testing for both; I will definitely discuss sequencing with my patients. I anticipate the discovery of additional targeted agents as we enter the age of personalized medicine! References 1. Shi Q, Sobrero AF, Shields AF, et al. Paper presented at ASCO 2017. Abstract LBA1. 2. Fizazi K, Tran N, Fein LE, et al. Paper presented at ASCO 2017. Abstract LBA3. 3. Adams S, Schmid P, Rugo HS, et al. Paper presented at ASCO 2017. Abstract 1008. 4. Adams S, Loi S, Toppmeyer D, et al. Paper presented at ASCO 2017. Abstract 1088. 5. Von Minckwitz G, Procter MJ, De Azambuja E, et al. Paper presented at ASCO 2017. Abstract LBA500. 6. Fuchs CS, Doi T, Jang RW-J, et al. Paper presented at ASCO 2017. Abstract 4003. 7. Janjigian YY, Ott PA, Calvo E, et al. Paper presented at ASCO 2017. Abstract 4014. 8. Thomas RJ, Williams MMA, Mutilib M, et al. Paper presented at ASCO 2017. Abstract 10103. 9. Kim J-Y, Ok O-N, Seo JJ, et al. Paper presented at ASCO 2017. Abstract 10108. 10. Tawbi HA-H, Forsyth PAJ, Patrick A, et al. Paper presented at ASCO 2017. Abstract 9507. 11. Long GV, Atkinson V, Menzies AM, et al. Paper presented at ASCO 2017. Abstract 9508. 12. Hoskin P, Misra V, Hopkins K, et al. Paper presented at ASCO 2017. Abstract LBA10004. 13. Raut CP, Espat NJ, Maki RG, et al. Paper presented at ASCO 2017. Abstract 11009. 14. D’Angelo SP, Mahoney MR, Van Tine BA, et al. Paper presented at ASCO 2017. Abstract 11007. 15. Burgess MA, Bolejack V, Van Tine BA, et al. Paper presented at ASCO 2017. Abstract 11008. 16. Hyman DM, Laetsch TW, Kummar S, et al. Paper presented at ASCO 2017. Abstract LBA2501.

response, without any unexpected toxic- ity. Similar results were reported by Long et al in an Australian study (abstract 9508) of 66 patients.11 There were three cohorts of patients; the group receiving the aforemen- tioned combination had a 44% intracranial response rate, with a 50% 6-month PFS. 8. I will ask our radiation oncologists to consider single-dose radiation for spi- nal cord compression in patients with a poor prognosis. As presented by Hoskin et al (abstract LBA10004), the SCORAD trial in the UK and Australia randomized 688 patients to receive a single dose of 8 Gy versus 20 Gy in 5 fractions in a noninferior- ity trial. 12 The primary endpoint, ambulatory status at 8 weeks, was similar, as was over- all survival and other secondary endpoints. Toxicity was slightly better with the single dose, as was cost. As expected, overall survival was poor in both groups, but main- taining ambulation contributes highly to quality of life. 9. I will extend adjuvant treatment with imatinib to at least 5 years in high- risk GIST patients. Raut et al reported the results of the PERSIST-5 phase III trial of 91 high-risk patients with resected GIST (abstract 11009) .13 The overall survival rate at 8 years was 95%. Only 1 patient recurred while receiving treatment. Disease recurred in 6 additional patients after discontinu- ing the drug. There were no unexpected toxicities, but nearly half the patients dis- continued the drug early. The presenter and discussant really encouraged high- er-risk patients to maintain treatment. 10. I will offer selected patients with metastatic sarcoma immune check- point inhibitors. There were two abstracts in the Sarcoma Oral Presentations that demonstrated clinically meaningful activity. Deangelo et al reported the results of ALLI- ANCE in abstract 11007. 14 The combination of nivolumab and ipilimumab was relatively active, with 54% survival at 1 year. Another multi-institutional study was reported in abstract 11008. 15 Pembrolizumab had activ- ity in UPS, LPS, and bone chondrosarcoma, meriting further study. These drugs are not yet FDA-approved, but there are clinical tri- als in progress and opportunities to obtain

Upfront PD-1 inhibitor treatment for NSCLC: a new paradigm Watch an interview with Dr Kirshner, where he discusses some of the more impressive and

practice-changing advances in non-small cell lung cancer in the past year.

VOL. 1 • NO. 2 • 2017

© ASCO 2017/Alyssa Schukar

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