PracticeUpdate: Haematology & Oncology

Best of 2016

DECEMBER 2016

RESEARCH NEWS AND VIEWS FROM ELSEVIER

TOP 2016 RESEARCH ASCO 2016

• • 10 years of AI for breast cancer • • Daratumumab combo for MM • • Adjuvant temozolomide in glioma • • Checkpoint inhibitors in refractory cancers EHA 2016 • • Novel gene variants in bleeding, platelet disorders • • IDH-1/2 mutation in AML • • Inotuzumab ozogamicin in ALL ESMO 2016 • • Cabozantinib in RCC • • Ribociclib + letrozole paradigm shift • • Pembrolizumab in prostate cancer HAA 2016 • • Daratumumab in MM • • Venetoclax in elderly AML • • Pregnant women and low platelets • • Hydroxyurea for sickle cell disease

PracticeUpdate Oncology Advisory Board member Jeffrey Kirshner MD, FACP, and breast cancer treatment expert and advocate for breast cancer patients, Lillie Shockney RN, BS, MAS, discuss their top stories in oncology for 2016, focusing on breast cancer – aromatase inhibitors and survival rates. Aromatase inhibitors in breast cancer By Jeffrey Kirshner MD, FACP A lthough the increasing indications and usage of checkpoint inhibitors for multiple malignancies 2016 Top Stories in Oncology

EDITORIAL Managing Editor Anne Neilson anne.neilson@elsevier.com Editor Carolyn Ng carolyn.ng@elsevier.com Designer Jana Sokolovskaja j.sokolovskaja@elsevier.com Medical Advisor Dr Barry M Dale Consultant Haematologist, Medical Oncologist

SALES Commercial Manager Fleur Gill fleur.gill@elsevier.com Account Manager Linnea Mitchell-Taverner l.mitchell-taverner@elsevier.com

DISCLAIMER PracticeUpdate Haematology & Oncology provides highlights of key local and international conferenceswith timelyandrelevantnews,expert opinions and journal article reviews for specialist medical professionals. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier Australia 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 verificationofdiagnosesanddrugdosagesshould be made. Please consult the full current Product Information before prescribing any medication mentioned in this publication. 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.

because of the number of patients that it affects. There are hundreds of thousands of women receivingAI therapy at the present time in the United States (and many more worldwide!). Most practicing general oncologists see these patients on a daily basis and need to present these data to their patients at some point. They will have to discuss the pros and cons of whether to extend AI therapy to 10 years. It is not always a straightforward decision. One must take into account individual prognostic factors, comorbidity, life expectancy, bone health, and, of course, each patient’s wishes. Even though extended therapy has not affected overall survival (yet!), decreasing recurrences and fewer new breast cancers are obviously important goals. Is 10 years ofAI therapy the new standard of care for postmenopausal women with early-stage breast cancer? I would argue that it should be considered, taking into account the aforementioned factors; but, ultimately, the decision should be made by the patient with advice from her oncologist. Of course, many questions remain, including: Do we consider restarting AI in patients who had completed their treatment several years earlier? Are there certain high-risk patients who should continue AI beyond 10 years? Do the patients who have had tamoxifen prior to their 5 years of AI benefit as much as those who did not receive tamoxifen? We all anxiously await results from the NSABP B-42 study, which had a very similar design. Further breakdown and follow-up of these two studies will enable us to make even better decisions regarding the use of extendedAI therapy.

continues to be a “top story,” I have chosen another “story,” which arguably may affect even more patients presently. Oncologists are now offering an additional 5 years of aromatase inhibitor (AI) therapy (for a total of 10 years) to patients receiving these drugs as adjuvant therapy for early-stage breast cancer. This recommendation is based on the initial results of the MA.17R study, which was the first presentation at the ASCO Annual Meeting Plenary Session in June 2016 (Goss PE et al, MA.17R, Abstract LBA1). Study results were immediately presented online in The New England Journal of Medicine and subsequently published as a lead article the following month ( N Engl J Med 2016;375:209-219). In this international, multi-institutional study, over 1900 women were randomised to an additional 5 years of letrozole versus placebo (after completing an initial 5 years of letrozole and remaining disease-free). At a median follow-up of over 6 years, letrozole-treated patients had 67 “events” as opposed to 98 in the placebo group. This translated to an improvement in 5-year disease- free survival from 91% to 95%. There were fewer local–regional and distant recurrences in the treatment group and fewer cancers in the contralateral breast. To date, there has been no difference in overall survival. As expected, the patients randomised to additional letrozole had a slightly higher incidence of bone pain, fractures, and new-onset osteoporosis. There were no unexpected adverse events in the treatment group. This story is particularly important

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Breast cancer survival rates By Lillie Shockney RN, BS, MAS B reast cancer death rates among women decreased be- tween 2010 and 2014, although racial disparities con- tinue to be an issue according to a study by the Centers

LAUNCHING SOON The year’s top research, all in one issue Welcome to our special issue, PracticeUpdate Haema- tology&Oncology: Best of 2016 , featuring a collection of the best research of the year from some of the top oncology and haematology conferences. Our PracticeUpdate Oncology Advisory and Editorial Board members discuss their top oncology story of 2016 (see left), and share their take on the best studies and presentations from the ASCO, EHA, ESMO and HAA meetings. On behalf of the Elsevier Australia PracticeUpdate Haematology & Oncology team, I thank you for your continued support and readership. We’ve made some big changes this year, with a new masthead and improved content, in our continuing efforts to be relevant and integral to your day-to-day clinical practice. Happy holidays and I wish you well for 2017! Anne Neilson Managing editor, PracticeUpdate Haematology & Oncology (Australian Edition) rarehaematology.elsevierresource.com News, expert opinion, journal articles, conference coverage dedicated to rare haematological diseases Selected by editorial board members from the Journal of Molecular Genetics & Metabolism Rare Haematology RESOURCE CENTRE

for Disease Control and Prevention (CDC) in the US published recently in the Morbidity and Mortality Weekly Report ( Cancer Res Treat 2016;160:145-152). The report shows changes in death rates from breast cancer by age group for black and white women, the groups with the highest death rates in the United States. Lisa Richardson, MD, Director of the CDC’s Division of Cancer Prevention and Control, said, “First, the decline in deaths suggests that white and black women under 50 are benefitting equally from cancer treatments. Second, we’re hopeful the lack of difference in death rates between black and white women under 50 will start to be seen in older women.” It has been particularly devastating for families with young children to lose the young mother to metastatic breast cancer. We are making headway with improvement in treatment options and more personalised medicine based on specific prognostic factors and genomics, however, thus lowering the mortality rate and giving more time to young women diagnosed with stage IV disease to spend with their families. It is worthy to note that there was a greater decrease in breast cancer death rates among white women (1.9% per year) than black women (1.5% per year) between 2010 and 2014. The largest difference by race was among women aged 60 to 69 years, in whom breast cancer death rates dropped 2.0% per year among white women, compared with 1.0% per year among black women. “The good news is that overall rates of breast cancer are decreasing among black women. However, when compared with white women, the likelihood that a black woman will die after a breast cancer diagnosis is still considerably higher,” said Jacqueline Miller, MD, Medical Director of the CDC’s National Breast and Cervical Cancer Early Detection Program. The CDC’s research was further supported by the study, “Ten-year survival in women with primary stage IV breast cancer,” published in the November issue of Breast Cancer Research and Treatment ( MMWR Morb Mortal Wkly Rep 2016;65:1093-1098).The research study evaluated 25,323 women with stage IV breast cancer from 1990 to 2012 to determine how survival varies with age at diagnosis. Results showed decreasing survival with advancing age: for women aged 40 years and younger, the 10-year survival rate was 15.7%; for ages 41 to 50 years, it was 14.9%; and for women aged 51 to 70 years, it was 11.7% (P < 0.0001). The adjusted risk of death from breast cancer at 10 years was lower for women aged 40 years and younger (HR, 0.78) and women aged 41 to 50 years (HR, 0.82) compared with women 51 to 60 years old. In comparing age groups, as the CDC publication did, women with stage IV breast cancer have a 10-year survival rate of about 13%. Those women diagnosed with stage IV breast cancer up to the age of 50 years have a lower risk of death in 10 years compared with women over 50 years. Providers, including nurses, need to be vigilant in reminding women about breast cancer screening and teaching the warning signs of a breast health problem, no matter what type of patient encounter they are having with the woman, or what her age or race is. Take the time to assess each patient and determine if she falls into a high-risk population that may require closer monitoring than the average female population. This information about improvements in mortality provides hope for future young women tragically diagnosed with metastatic disease. Until there is true prevention and cure, survival remains the primary goal, along with preservation of quality of life.

The Rare Haematology Resource Centre has been funded by Sanofi Genzyme.

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DECEMBER 2016

AMERICAN SOCIETY OF CLINICAL ONCOLOGY 2016 ANNUAL MEETING 4

Dr Isabel Cunningham discusses key trials on haematologic malignancies presented at ASCO 2016

ASCO 2016 3–7 JUNE 2016 • CHICAGO, ILLINOIS, USA The American Society of Clinical Oncology 2016 Annual Meeting saw the presentation of key studies in glioma, pancreatic cancer, lung cancer, haematologic cancers and much more. PracticeUpdate Oncology Associate Editor Dr Isabel Cunningham and Advisory Board member Dr Jeffrey Kirshner discuss their top abstracts from ASCO 2016.

Isabel Cunningham MD is Adjunct Associate Research Scientist, Division of Hematology Oncology, Columbia University College of Physicians and Surgeons in New York.

Leukaemia, myelodysplastic syndromes, and allotransplant Optimizing chimeric antigen receptor (CAR) T cell therapy for adult patients with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL). NV Frey, PA Shaw, EO Hexner, et al • Researchers evaluated 27 adults with relapsed or refractory acute lymphoblastic leukaemia (ALL) who received CTL019 in one of four dosing cohorts. Objective response rate (ORR) was greatest at 83% with CTL019 dosed at 5 x 10 8 with fractionated dosing. ORRwas 33%with 5 x 10 7 and 50% with a single dosing of 5 x 10 8 . A total of 9 of 12 patients receiving fractionated CTL019 had grade 3 or higher cytokine release syndrome, compared with 6 of 6 patients receiving a single dose of 5 x 10 8 CTL019 and 6 of the 9 patients receiving 5 x 10 7 . • Researchers concluded that split dosing may maintain efficacy while reducing the toxicity of CTL019 in adults with relapsed or refractory ALL. Impact of disease burden on long-term outcome of 19-28z CAR modified T cells in adult patients with relapsed B-ALL. JH Park, I Riviere, X Wang, et al • In this phase I trial, 46 adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (B-ALL) received lympho-depleting chemotherapy followed by 19–28z chimeric antigen receptor (CAR) T-cell infusion. Complete response was observed in 91% of patients with minimal disease burden (<5% blasts) at baseline and 75% of patients with morphologic disease burden ( ≥ 5% blasts). While 44% patients with morphologic disease burden experienced severe cytokine release syndrome, it did not occur in any of the patients with minimal disease burden. Grade 3 to 4 neurotoxicity also occurred more frequently with morphologic versus minimal disease burden (40% vs 14%, respectively),

and 6-month overall survival rate was 57% and 73%, respectively. • Researchers concluded that 19–28z CAR T-cell infusion is effective for adults with relapsed and refractory B-ALL. Minimal disease burden is associated with better outcomes. Inotuzumab ozogamicin (InO) for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) in the phase III INO-VATE trial: Efficacy and safety by prior therapy. DJ DeAngelo, E Jabbour, M Stelljes, et al • In this ongoing phase 3 INO-VATE trial, researchers evaluated 109 patients with relapsed or refractory acute lymphoblastic leukaemia (ALL) receiving inotuzumab ozogamicin (InO) to determine the impact of prior therapy on efficacy and safety. In patients who received InO as salvage (S) 1, response was numerically higher, remission duration was longer, and rates of hepatobiliary adverse events were significantly lower compared with patients who received InO as S2. Prior stem cell transplant (SCT) was associated with a numerically lower rate of complete remission with incomplete haematologic recovery and a numerically higher rate of hepatobiliary adverse events compared with no prior SCT. • Prior therapy and SCT increase the risk for hepatotoxicity in patients taking InO; however, patients with relapsed or refractory ALL receiving InO as S1 or S2 therapy may gain clinical benefit. Impact of complete molecular response (CMR) on survival in patients with Philadelphia chromosome- positive (Ph+) acute lymphoblastic leukemia (ALL). NJ Short, E Jabbour, JE Cortes, et al • In a single-institution study, outcomes of 202 adult patients with Philadelphia chromosome- positive (Ph+) acute lymphoblastic leukaemia (ALL) were assessed to determine the association of complete molecular response (CMR) with survival.

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY

ASCO 2016 5

• The conclusion drawn is that pacritinib had no cumulative toxicity and offered durable response in patients with myelofibrosis. Lymphoma and chronic lymphocytic leukaemia Rituximab maintenance after induction with abbreviated FCR in previously untreated elderly (≥ 65 years) CLL patients: Results of the randomized CLL 2007 SA trial from the French FILO Group (NCT00645606). C Dartigeas, E Van Den Neste, H Maisonneuve, et al • Researchers randomised 409 patients aged ≥ 65 years with B-cell chronic lymphocytic leukaemia (CLL) who received induction with four cycles of FCR to receive rituximab or observation. Median progression-free survival was 59.3 months with rituximab versus 49 months with observation (P = 0.0011), and 3-year progression-free survival and overall survival was also greater with rituximab than observation (83% vs 64.2% and 92.6% vs 87.2%, respectively). Improvement in progression-free survival with rituximab was similar between patients with or without del11q and unmutated IGHV. Rates of haematological and infectious toxicity were significantly greater in patients taking rituximab than those on observation (6.9% vs 1.9% and 18.8% vs 10.1%, respectively). • Progression-free survival in elderly patients with CLL was improved with 2-year rituximab maintenance therapy, although rituximab was also associated with higher toxicity. Acalabrutinib, a second-generation bruton tyrosine kinase (Btk) inhibitor, in previously untreated chronic lymphocytic leukemia (CLL). JC Byrd, JA Jones, RR Furman, et al • In this ongoing phase 1/2 study, outcomes have been assessed through December 2015 in 74 patients with previously untreated chronic lymphocytic leukaemia (CLL) receiving monotherapy acalabrutinib, a Btk inhibitor. Of the original 74 patients, 72 have continued on acalabrutinib, with most common adverse events being grade 1/2 headache, diarrhoea, arthralgia, contusion, nausea, and increased weight. Approximately half of patients experienced treatment-related lymphocytosis, which resolved in all but 1 patient. Partial response and stable disease were observed in 86% and 4% of patients, respectively. • Acalabrutinib was well-tolerated and has been associated with high response rates in patients with previously untreated CLL. A phase 3 study has been initiated.

© ASCO/Matt Herp 2016

• At 3 months, CMR was associated with better overall and relapse-free survival than lesser molecular responses. Updated results from the phase II study of hyper-CVAD in combination with ofatumumab as frontline therapy for adults with CD20 positive (CD20+) acute lymphoblastic leukemia (ALL). GC Issa, HM Kantarjian, F Ravandi, et al • In this update from a phase 2 study, 53 adults with CD20-positive (CD20+) acute lymphoblastic leukaemia (ALL) received the combination of ofatumumab with hyper-CVAD. Of the 50 patients evaluable for response, 49 had complete remission following one cycle, with 48 of 52 patients becoming negative for minimal residual disease. A majority of patients had febrile neutropaenia during induction and consolidation (67% and 89%, respectively). CR duration and overall survival rates at 2 years were 74% and 83%, respectively. • The researchers concluded that ofatumum- ab with hyper-CVAD is effective and safe in patients with CD20+ Ph− ALL. Long-term survival of patients with therapy- related MDS (tMDS) compared with de novo MDS following allogeneic hematopoietic cell transplantation (alloHCT). AT Pham, IT Aldoss, SM Li, et al • In a retrospective study, the outcomes were compared between 264 patients who had either therapy-induced myelodysplastic

syndrome (tMDS) or de novo MDS who received allogeneic haematopoietic cell transplantation (alloHCT). Patients with tMDS were more likely to have poor-risk karyotype than patients with de novo MDS (63% vs 31%, respectively; P < 0.01), but researchers did not find differences in 5-year overall survival, non-relapse mor- tality, and relapse rates between the groups. In patients with tMDS, more recent era of alloHCT and younger age were associated with improved overall survival (P < 0.01). • The outcomes associated with alloHCT in patients with tMDS are similar to those in patients with de novo MDS. Pacritinib (PAC) vs best available therapy (BAT) in myelofibrosis (MF): 60 week follow-up of the phase III PERSIST-1 trial. RA Mesa, M Egyed, A Szoke, et al • In the phase 3 PERSIST-1 trial, researchers randomised 327 patients with myelofibrosis naive to JAK inhibitor therapy to receive pacritinib or best available therapy. Spleen volume stable (SVR) ≥ 35% was reached in 24% of patients receiving pacritinib at 60 weeks, and 84% of patients receiving best available therapy crossed over to pacritinib. After crossover, SCR ≥ 35% was reached in 19%. Diarrhoea associated with pacritinib therapy was highest in the first 8 weeks (51%). Anaemia, thrombocytopenia, and neutropenia were also common adverse events.

DECEMBER 2016

AMERICAN SOCIETY OF CLINICAL ONCOLOGY 2016 ANNUAL MEETING 6

Dr Jeffrey Kirshner discusses the top abstracts fromASCO 2016 on patient and survivor care

Jeffrey J. Kirshner MD, FACP is partner of Hematology Oncology Associates of Central New York (HOACNY) in East Syracuse. He is the Director of Research and serves as the Principal Investigator of the HOACNY Community Clinical Oncology Program.

In recent years, there has been a trend to integrate palliative care earlier in the timeline of treatment for patients with advanced can- cer. A leader in this field will present another study which evaluated additional benefits of early integration of palliative care. Randomized trial of early integrated palliative and oncology care. JS Temel, A El-Jawahri, JA Greer, et al • In total, 350 patients with newly diagnosed incurable cancer were randomised to palliative care integrated with oncology care or usual oncology care. At 24 weeks, the palliative care group had a higher quality of life, less depression, and more discussion about end-of-life preferences than the usual oncology care group. At 12 weeks, these differences were not observed. • The researchers concluded that early palliative care offers significant benefit for patients newly diagnosed with incurable cancer. Pegfilgrastim-induced bone pain (PIBP) continues to be a major toxicity which may lead to early discontinuation of this important growth factor. The following study objectively examined the use of two commonly used over-the-counter agents to decrease the incidence of PIBP. Nolan: A randomized, phase II study to estimate the effect of prophylactic naproxen (N) or loratadine (L) vs no intervention on bone pain in 600 patients (pts) with early-stage breast cancer receiving chemotherapy (chemo) and pegfilgrastim (PEG). J Kirshner, AS Guinigundo, L Vanni, et al • In an open-label, phase 2 study, researchers randomised 600 patients with newly diagnosed stage I–III breast cancer treated with chemotherapy and pegfilgrastim to receive prophylactic naproxen, loratadine, or no prophylaxis for bone pain. There were no differences among the groups in regard to levels of all-grade bone pain. Loratadine was associated with fewer adverse events than naproxen. • Naproxen and loratadine are tolerable, although their effects on bone pain are comparable to those associated with no prophylaxis. A trend toward less bone pain was noted with naproxen and loratadine.

Chemotherapy-induced peripheral neuropa- thy (CIPN) continues to be a major compli- cation of treatment for cancer patients and is often debilitating and permanent. Successful treatment has been of limited efficacy and attempts to understand and prevent this toxicity have generally been unsuccessful as well. The following three studies add impor- tant information to the understanding and possible treatment of CIPN. A URCC NCORP nationwide randomized controlled trial investigating the effect of exercise on chemotherapy-induced peripheral neuropathy in 314 cancer patients. I Kleckner, CS Kamen, LJ Peppone, et al • In a secondary analysis of a phase 3 study, researchers evaluated the association of ex- ercise with CIPN. In the original study, 314 patients were randomised to chemotherapy or chemotherapy with exercise.

• CIPN was reduced with exercise (P = 0.04), with greater benefit in older patients (P = 0.06). Comorbidities and risk of chemotherapy-induced peripheral neuropathy among participants in SWOG clinical trials. DL Hershman, C Till, JD Wright, et al • Using the SWOG database, researchers evaluated the association of comorbid conditions with the development of peripheral neuropathy among patients treated with taxane chemotherapy. The odds of neuropathy increased by 4% with each 1-year increase in age (P = 0.006). While patients with autoimmune disease were about half as likely to have neuropathy (not statistically significant), patients with diabetes complications were two times more likely to develop neuropathy (P = 0.06 and P = 0.002, respectively). • Diabetes, age, and drug-related factors predicted the development of chemotherapy- induced peripheral neuropathy. Body mass index, lifestyle factors, and taxane- induced neuropathy in women with breast cancer: The Pathways Study. H Greenlee, DL Hershman, Z Shi, et al • The authors evaluated the association of BMI and lifestyle factors with CIPN using data from a prospective cohort of women diagnosed with breast cancer. Patients with high levels of physical activity versus low levels were less likely to have CIPNworsen. In addition, worsening of CIPN was more likely to occur in obese vs normal-weight patients and in patients who initiated or discontinued an antioxidant supplement during treatment versus patients who did not use antioxidant supplements. • More severe and sustained CIPN was associated with obesity, low levels of physical activity, and change in antioxidant supplement use among patients receiving taxane chemotherapy for breast cancer.

© ASCO/Todd Buchanan 2016

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY

ASCO 2016 7

10 practice changes I will make after attending ASCO 2016 By Jeffrey J. Kirshner MD, FACP

1. Avoid neurotoxic chemotherapy in diabetic and older patients, when other options exist. Dr Hershman et al examined the SWOG database linked to Medicare claims (in the United States) and determined that age and diabetes were predictors of the development of neuropathy (Abstract 10001). 2. Recommend an exercise program for patients starting potentially neurotoxic chemotherapy treatment such as taxanes and platinum drugs. Greenlee et al presented data from the Pathways Study (Abstract 10002) demonstrating a higher incidence of taxane-induced neuropathy in breast cancer patients who were obese and had a low level of physical activity. At the same session, Dr Kleckner presented an analysis of a subset of 314 patients in the URCC CCOP/NCORP EXCAP study (Abstract 10000). Those randomised to the exercise program had a lower incidence of early neuropathy, highly significant in older patients. Although the majority of patients were women with breast cancer, there were also men, and drugs included vinca alkaloids in addition to taxanes and platinum. 3. Consider the combination of daratumumab (D), bortezomib (V), and dexamethasone (d) [DVd] as a treatment for relapsed or refractory multiple myeloma. Dr Palumbo presented the results of the European CASTOR study at the Plenary Session, which demonstrated superiority of DVd over Vd even in patients previously treaded with V (Abstract LBA4). There was a significant improvement in response rate, progression-free survival, and time to progression, and responses were brisk, which is important in these patients, many of whom are quite symptomatic. Progression-free survival and time to progression were approximately 7 to 8 months in the Vd group but have not been reached in those who were treated with D as well. 4. Offer short-course radiotherapy with temozolomide (TMZ) in selected glioblastoma multiforme patients over the age of 65. Dr Perry presented the results of a joint EORTC/NCIC study at the Plenary Session (Abstract LBA2). The addition of TMZ to radiation therapy resulted in an improvement in overall and progression- free survival, most dramatic in patients with MGMT methylated tumours. The regimen was well-tolerated, and there was an impressive improvement in 2-year survival rates. Median survival was increased from 3.9 to 5.3 months and in MGMT methylated patients from 7.7 to 13.5 months. 5. Use intermittent rather than continuous docetaxel in the treatment of metastatic prostate cancer (Abstract 5005). Although this German study, presented by Dr Cash did not complete accrual, the intermittent regimen of docetaxel (12 weeks of the drug either weekly or every 3 weeks, followed by a drug holiday until progression) appears to be noninferior to the continuous regimen. Another approach to decrease toxicity in chemotherapy-treated patients in this population is to lower the dose of cabazitaxel in the second line setting. DeBono et al presented the results of their PROSELICA study (Abstract 5008), which demonstrated that the lower dose of 20 mg/m 2 was noninferior to the standard dose of 25 mg/m2, and there was an improved overall safety profile!

6. Add capecitabine (CAP) to gemcitabine for the adjuvant treatment of resected pancreatic cancer while we await the results from ongoing studies of even more aggressive combinations. The ESPAC-4 trial results were reported by Neoptolemos et al (Abstract LBA4006), which demonstrated an improvement in median survival from 25.5 to 28 months when CAP was added to gemcitabine, with added but manageable toxicity. These were very high-risk patients. Most impressively the 5-year survival rates were increased by the addition of CAP from 16% to 29%! 7. Not use exemestane as adjuvant treatment for invasive lobular breast cancer in favour of one of the two nonsteroidal AIs, anastrozole or letrozole (Abstract 521). There are increasing data that exemestane is less effective in patients with this histology, which was confirmed by this review of the MA.27 study by Strasser-Weippl et al. Patients with invasive lobular carcinoma had improved overall survival when treated with anastrozole as opposed to exemestane (HR, 1.8; P = 0.55), consistent with the findings in the BIG 1-98 trial. 8. Use more AC/T and less TC in patients with high-risk early breast cancer , based on the ABC analysis of three randomised trials presented by Blum et al (Abstract 1000). In this initial report, the non-anthracycline regimen did NOT demonstrate noninferiority to the anthracycline regimens. TC may be noninferior for ER- positive patients, however, but for receptor-negative patients, I will use anthracyclines in most cases. 9. Continue aromatase inhibitor (AI) therapy for at least an additional 5 years in high-risk postmenopausal women with early-stage breast cancer . Many of these women have been reluctant to stop their AI at 5 years; I have generally made recommendations case by case, but mentioned that we will have data to help guide our decisions, once we had the results from the MA.17R and B42 studies. The initial results from MA17.R were presented at the Plenary Session (Abstract LBA1) by Dr Goss. In patients treated with 5 years of AI, as initial therapy or preceded by up to 5 years of tamoxifen, extended AI treatment to 10 years (as opposed to placebo) significantly improved disease-free survival. The gains were modest, and there was an increased risk of osteoporosis; so, I don’t plan on this approach in all of these women, but I will have the discussion, considering the risks and benefits, and probably recommend continuation in women at high risk of late recurrence. Data presented in Abstract 505 by Pan et al was an analysis of predictive factors for late recurrences in ER-positive patients (over 46,000 British women followed for up to 14 years), and its findings will help in advising our patients. 10. Consider the use of checkpoint inhibitors for patients with refractory cancers as there is increasing evidence of efficacy in a number of diseases, including metastatic colorectal, with high microsatellite instability (Abstract 3501; Overman et al), squamous cell anal (Abstract 3503; Morris et al), and even metastatic bladder as first-line in cisplatin-ineligible patients (Abstract LBA4500; Balar et al). I predict that these treatments will become approved in the near future and may even be available in some circumstances under compassionate use programs.

DECEMBER 2016

Dr Roy Herbst on practical aspects of immunotherapy for thoracic cancers AMERICAN SOCIETY OF CLINICAL ONCOLOGY 2016 ANNUAL MEETING 8

Roy S. Herbst MD, Ensign Professor of Medicine and Chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, Connecticut, discusses the impact of immunotherapy on thoracic cancer with PracticeUpdate’s Dr Farzanna Haffizulla.

Dr Haffizulla: During the poster discussion session, Dr Naiyer Rizvi presented data on the use of immuno- therapy for many thoracic malignancies. What’s your opinion on these data? Dr Herbst: Immunotherapy has changed the way we look at thoracic cancer. I lead the thoracic oncology program at the Smilow Cancer Hospital at Yale; I used to lead the program at MDAnderson for many years. I can tell you that – aside from targeted therapy, in which you know there’s a genetic defect, you have a target, you give an EGFR inhibitor, an ALK inhibitor – I’ve never seen anything as impressive as immunotherapy for many of these diseases. Now, the caveat is, as well as it works, it still only works in about 1 in 5 people; but, if you look at immunotherapy in lung cancer, mes- othelioma, patients are coming in who have no genetic drivers, who would have gotten chemotherapy, and had a survival of 6 months to a year, and now we are seeing people live longer. That’s important, I think, for your audience. Everyone else who sees these patients – the pulmonologist, the cardiologist, the internist – now needs to realise that there’s a whole new breed of patients with lung cancer, who are, maybe not cured of their disease, because it’s too soon to say that immunotherapy is curative, but who are living with the cancer. But, as you activate the immune system against a cancer, you do activate it against the thyroid; so you’re going to see a great deal of thyroid issues. Against the colon, you might see colitis. Against the lung, pneumonitis. Something to really keep an eye on, skin rash, other issues. But it really is a huge advance. Dr Haffizulla: ASCO named immunotherapy as the clinical cancer advance of the year for 2016, and you said it perfectly when you mentioned that this is now a whole new arena. Not just for oncologists, for all healthcare providers involved in caring for that par- ticular patient. How do you propose we translate some of that information, and this new thought process, throughout the medical community? To increase the collaborative spirit, as it were, as we’re seeing immu- notherapy on the horizon with such success? Dr Herbst: I lead a SPORE, which stands for Special- ized Programs of Research Excellence. It’s a large grant for lung cancer; we’re one of four sites in the United States that has one, and through the grant we’re actual- ly studying this very carefully. In science, in medicine,

the fact that we’re seeing activity, proof of concept, is huge. Everyone is so excited about it at ASCO, and they should be, because 20% response in a disease that kills 200,000 Americans a year and 1.5 to 2 million people in the world a year is a huge advance; but we still have to figure out why it works in some and not others. One of the things we’re very focused on in our research, and we’re presenting some data here and at other meet- ings this year, is what is it about those patients who respond and then become resistant? So, we’re doing biopsies at our centre at the start of treatment and after the patients become resistant to ask what’s different, and if there is any way that we can then stimulate them to respond again. Or what is it about those patients who never benefit, those primary resistant patients? That’s where combinations of drugs are going to come in, and as I walk through the halls of ASCO, that’s what the posters are about. In fact, I’m presenting one myself on a combination of pembrolizumab and ramucirumab, an angiogenesis inhibitor, and, while the results are early, we’re showing a safe combination and potentially a combination that could be more active than one drug alone, and that now needs to go to further study. Dr Haffizulla: I think that you mentioned something extraordinarily vital, in studying the tumour and then the changes that happen in that particular tumour, not only after treatment, but as it metastasises. You know, understanding the proteins that are translated and expressed in those particular tumours and then using targeted therapy, individualising the treatment and maximising use of the immune system. Dr Herbst: Exactly. One of the biggest papers here at ASCO basically shows that, in profiling tumours and by knowing what’s going on, you are able to treat them better; and that makes sense. If a car comes in to your shop, and it’s not running, you wouldn’t just start throwing stuff at the car; you’d figure out what’s exactly wrong. It’s much more important in a human.

Farzanna Haffizulla MD, FACP, FAMWA, practices general internal medicine in Florida. She was the national president of the American Medical Women’s Association (AMWA) 2014–2015.

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY

I have high grade serous ovarian cancer TEST ME

for BRCAm If I am positive

TREAT ME

with Lynparza TM *

*as maintenance therapy for PSR disease, in response after platinum-based chemotherapy (must have ≥ 2 courses) 1

PBS Information: This product is not listed on the PBS

BEFORE PRESCRIBING, PLEASE REVIEW FULL PRODUCT INFORMATION AVAILABLE ON REQUEST FROM ASTRAZENECA ON 1800 805 342 OR www.astrazeneca.com.au/PI LYNPARZA ® (olaparib) Minimum Product Information: INDICATIONS: Monotherapy for the maintenance treatment of patients with platinum- sensitive relapsed BRCA -mutated (germline or somatic) high grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete response or partial response) after platinum- based chemotherapy. Prior treatment must have included at least 2 courses of platinum- based regimens. CONTRAINDICATIONS: Hypersensitivity to the active substance (olaparib) or to any of the excipients. PRECAUTIONS: Haematological toxicity is common in patients treated with olaparib and usually mild -moderate. Patients should not start treatment with LYNPARZA until they have recovered from haematological toxicity caused by previous anti - cancer therapy. A baseline complete blood count followed by monthly monitoring is recommended for the first 12 months of treatment and periodically after this. Myelodysplastic syndrome/Acute Myeloid Leukaemia (MDS/AML) have been reported in a small number of patients (<1%) and the majority of reports have been fatal. Pneumonitis has been reported in a small number of patients receiving olaparib, and some reports have been fatal. Use in pregnancy: Category D. LYNPARZA may cause foetal harm when administered to a pregnant woman. Women of child bearing potential must use effective contraception during treatment and for 1 month after receiving the last dose. Use during lactation: Breast feeding should be avoided in women receiving LYNPARZA and for 1 month after the last dose. Use in Men: Not indicated Children or adolescents: Not indicated. Interactions with other medicines. INTERACTIONS: LYNPARZA co administration with strong CYP3A inducers or inhibitors should be avoided. Addition of LYNPARZA and cytotoxic agents has been shown to potentiate and prolong myelosuppressive side effects. ADVERSE REACTIONS : Very common (≥10%): decreased appetite, headache, dysgeusia, dizziness, nausea, vomiting, diarrhoea, dyspepsia, fatigue, anaemia, neutropenia, lymphopenia, mean corpuscular volume elevation, increased creatinine; Common (≥1% to <10%): stomatitis, upper abdominal pain, thromboyctopenia; for other listed adverse reactions, see full PI. DOSAGE AND ADMINISTRATION: 400 mg (eight 50 mg capsules) taken twice daily, equivalent to a total daily dose of 800 mg. LYNPARZA should be taken on an empty stomach and patients should refrain from eating

for 2 hours. Date of first inclusion in the ARTG: 7th January 2016 Reference 1. Lynparza Approved Product Information 10 October 2016.

Lynparza TM is a trademark of the AstraZeneca group of companies. AstraZeneca Pty. Ltd. ABN 54 009 682 311. 66 Talavera Road, Macquarie Park, NSW 2113. AstraZeneca Medical Information: 1800 805 342. www.astrazeneca.com.au. WL293061. AU-1404. Date of preparation November 2016.

AMERICAN SOCIETY OF CLINICAL ONCOLOGY 2016 ANNUAL MEETING 10

Dr Annette Hasenburg discusses key trials presented at ASCO 2016 on gynaecological cancers

Annette Hasenburg, Prof. Dr. med, is the Director of Obstetrics and Gynecology at Mainz University Medical Center in Mainz, Germany. She is Head of the European Society of Gynaecologic Oncology Task Force Psycho-Oncology, and is on the board of directors of the Institute of Sexuality and Health of the University Freiburg in Freiburg, Germany.

function, global health status, and abdominal/ GI symptoms were shown to be independent predictors for overall survival (all P < 0.001). The same QOL domains were significantly associated with stopping chemotherapy within 8 weeks (all P < 0.007). • QOL evaluation can help identify patients with platinum-resistant/refractory ovarian cancer who are unlikely to benefit from palliative chemotherapy. Pembrolizumab in patients with advanced cervical squamous cell cancer: Preliminary results from the phase Ib KEYNOTE-028 study. J-S Frenel, C Le Tourneau, BH O’Neil, et al • In this phase IB trial, 24 patients with PD-L1- positive advanced cervical squamous cell cancer received pembrolizumab, an anti-PD-1 antibody. Partial responses were observed in 3 patients (12.5%), with a median duration of response of 19.3 weeks. Stable disease occurred in 3 patients (12.5%), with a median duration of 19.6 weeks. The 6-month progression-free survival rate was 13.0% and the 6-month overall survival rate was 66.7%. Treatment-related adverse events were experienced by 18 patients (75%), with the most common being pyrexia and rash. Grade 3 treatment-related adverse events were experienced by 5 patients (20.8%). • The investigators concluded that pembrolizumab shows promising antitumour activity and was well-tolerated in patients with PD-L1-positive advanced cervical cancer. Tumor-infiltrating lymphocytes (TILs) and PDL1 expression in ovarian cancer (OC): Evolution with neoadjuvant chemotherapy (NCT) and prognostic value. S Mesnage, C Genestie, A Auguste, et al • In a retrospective study, investigators evaluated the levels of tumour-infiltrating lymphocytes (TILs) and PD-L1 expression in ovarian cancer samples from 113 patients treated with neoadjuvant chemotherapy. They found that 22% of tumours had high levels of stromal TILs prior to neoadjuvant chemotherapy. In 52% of evaluable paired samples (n = 83), stromal TILs were elevated following neoadjuvant chemotherapy. In paired samples where PD-L1 was evaluable (n =  27), 30% of tumours were PD-L1-positive prior to neoadjuvant chemotherapy and 63% were PD-L1-positive following. High levels of stromal TILs were an independent positive prognostic factor (HR, 0.49; P = 0.02).

Hormonal maintenance therapy for women with low grade serous carcinoma of the ovary or peritoneum. DM Gershenson, DC Bodurka, RL Coleman, et al • In a retrospective study, investigators evaluated the effect of hormonal maintenance therapy (HMT) versus surveillance following primary treatment in 180 patients with stage II–IV low-grade serous carcinoma of the ovary or peritoneum. Compared with surveillance, HMT significantly increased progression-free survival (52.0 months vs 29.9 months; P = 0.001) and reduced the risk of recurrence (HR, 0.21; P < 0.001). • HMT may present an option in women with this subtype of relatively chemo-resistant tumours. Additional prospective studies are warranted. Overall survival in patients with platinum-sensitive relapsed serous ovarian cancer receiving olaparib maintenance monotherapy: An interim analysis. JA Ledermann, P Harter, C Gourley, et al • In this interim analysis (77% maturity) of a phase 2 study, investigators evaluated the effect of maintenance monotherapy with olaparib, a PARP inhibitor, in patients with platinum- sensitive relapsed serous ovarian cancer. Olaparib, compared with placebo, increased overall survival (29.8 vs 27.8 months; HR, 0.73); the benefit of was greater in patients with a BRCA1/2 mutation (34.9 vs 30.2 months; HR, 0.62). • Maintenance therapy with olaparib after a response to platinum therapy provides an overall survival advantage in patients with serous ovarian cancer. Phase II study of everolimus, letrozole, and metformin in women with advanced/recurrent endometrial cancer. PT Soliman, SN Westin, DA Iglesias, et al • In this phase 2 study, the efficacy of everolimus, letrozole, and metformin combination therapy was assessed in 48 evaluable patients with advanced/recurrent endometrial cancer. • The clinical benefit rate was 66.7%; this was not affected by KRAS mutation status. Baseline quality of life as a predictor of stopping chemotherapy early, and of overall survival, in platinum-resistant/refractory ovarian cancer: The GCIG symptombenefit study. F Roncolato, R O’Connell, L Buizen, et al • Investigators evaluated 545 patients with platinum-resistant/refractory ovarian cancer to identify baseline quality-of-life domains associated with premature termination of palliative chemotherapy. Physical function, role

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY

ASCO 2016 11

• The investigators concluded that stromal TILs have prognostic value for patients with ovarian cancer both pre- and post- neoadjuvant chemotherapy. Cohort profile: African Collaborative Center for Microbiome and Genomics Research (ACCME) study. SN Adebamowo, E Dareng, A Famooto, et al • This multicentre prospective cohort study has enrolled 10,300 women in Nigeria to examine associations between cervical cancer and several relevant parameters, including genomics, epigenomics, HPV genotype, cervical cytokines, vaginal pH, and the vaginal microenvironment. At baseline, the mean age of the study participants was 40 years, 76% of the participants were married, and 30% of the participants were HPV-positive. • The trial withmore than 10,000 participants offers new opportunities of translational research in biomarker discovery that addresses high-impact public health challenges affecting women’s health in third-world countries Phase II study of anastrozole in recurrent estrogen/progesterone-positive endometrial cancer: The PARAGON trial – ANZGOG 0903. LR Mileshkin, RJ Edmondson, R O’Connell, et al • In an open-label arm of the phase 2 PARAGON trial, investigators assessed the effect of anastrozole on quality of life (QOL) in patients with ER/PR-positive metastatic hormone-naive endometrial cancer. At 3 months, the clinical benefit rate in patients treated with anastrozole was 44% (95% CI, 34–55%). Compared with patients who progressed on therapy, those who achieved clinical benefit also had significant improvements in QOL domains, including emotional functioning (39 vs 6%; P = 0.002), cognitive functioning (45 vs 19%; P = 0.021), fatigue (47 vs 19%; P = 0.015) and global health status (42 vs 9%; P = 0.003). • Anastrozole provided a significant clinical benefit, which was associated with improved QoL, in patients with ER/PR- positive endometrial cancer. Less versus more radical surgery in stage IB1 cervical cancer: A population-based study of long-term survival. MM Leitao, Y Sonoda, GJ Gardner, et al • In this retrospective study, the 10-year disease-specific survival (DSS) rate was evaluated in 2838 young (< 45 years of age) women with stage IB1 cervical cancer who had been treated with less radical surgery or more radical surgery. Less radical surgery

© ASCO/Todd Buchanan 2016

was defined as conization, trachelectomy, or simple hysterectomy; more radical surgery was defined as modified radical or radical hysterectomy. The researchers found no significant difference in the 10-year DSS rate between less and more radical surgery (92.8 ± 0.1% vs 92.3 ± 0.7%; P = 0.80) for all tumours, or for tumours stratified according to size. Neither approach was independently associated with the10-year DSS rate. • The conclusions reached are that less radical surgery does not appear to compromise 10-year DSS in patients with stage IB1 cervical cancer. Use of next-generation sequencing panels to predict recurrence in low-grade, early-stage endometrioid endometrial carcinoma. K Kurnit, B Fellman, DL Urbauer, et al • In this retrospective study, next-generation sequencing was used to profile samples from patients with low-grade, early-stage endometrioid endometrial cancer to identify variables associated with recurrence-free survival (RFS). Mutations in CTNNB1 and TP53 were associated with reduced rates of RFS (HR ,4.65; 95% CI, 2.33–9.30; P <  0.001). • Mutations in CTNNB1 and TP53 are independent predictors of poor RFS in patients with low-grade, early-stage endometrioid endometrial cancer. Impact of body mass index on surgical costs and morbidity for women with endometrial carcinoma/hyperplasia. RS Suidan, W He, CC Sun, et al • Investigators assessed whether body mass index (BMI) affected surgical complications and costs in 1112 patients with endometrial cancer and endometrial hyperplasia. Patients with BMI ≥ 40 had a higher rate

of wound infection following laparotomy compared with patients with BMI 30–39 or BMI ≤ 29 (14% vs 5% vs 5%; P < 0.01). These patients also experienced a higher rate of thromboembolic complications (3% vs 0.2% vs 0.3%; P < 0.01). The rates of wound infections and thromboembolic complications were not increased in patients with BMI ≥ 40 who underwent minimally invasive surgery. Other complications and median 30-day costs were not significantly different among the three BMI groups. However, median costs were higher for patients with complications. • Minimally invasive surgery may reduce costs and minimise complications in patients with endometrial cancer and BMI ≥ 40. Prognosis after local recurrence in vulvar cancer: A subset analysis of the AGO-CaRE-1 study. LL Woelber, C Eulenburg, J Kosse, et al • In this subgroup analysis of the retrospective AGO CaRE-1 study, investigators evaluated the rate of cancer recurrence in 1249 patients with primary squamous cell vulvar cancer. Following a median of 39.4 months, disease had recurred in 28.8% of the patients. In the 53.6% of patients with recurrent disease who suffered vulvar recurrence, nodal involvement was a negative prognostic factor (HR, 2.47; 95% CI, 1.52–4.03) and complete tumour resection was a positive prognostic factor (HR, 0.33; 95% CI, 0.17–0.63). Over the course of the study, a second recurrence developed in 30.1% of patients with a vulvar recurrence. • The investigators concluded that the prognosis for patients with isolated vulvar recurrence is worse than previously appreciated.

DECEMBER 2016