PracticeUpdate: Haematology & Oncology

VOL. 1 • No. 5 • 2016

RESEARCH NEWS AND VIEWS FROM ELSEVIER

FORMERLY HAEMATOLOGY & ONCOLOGY NEWS

OPINION

When you put me in a hospital gown, I ampowerless. Because a patient’s sitting there nodding their head doesn’t mean they understand a singleword. 27

Cabozantinib has potential to become first-line treatment for renal cell carcinoma

CONFERENCE ESMO 2016

Improvement in progression- free survival with ribociclib + letrozole may represent a paradigm shift in advanced breast cancer 5 HER2+ and ER+ breast cancer trials 9 Metastatic renal cell carcinoma review 12 Current concepts in managing rare histologies in bladder cancer 13 BREAST Current challenges in breast

Cabozantinib improved progression-free survival and the response rate versus sunitinib significantly in a phase 2 multicentre trial in patients with metastatic renal cell carcinoma. 5

cancer management in developing countries

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KIDNEY Adjuvant therapy in RCC was thought a dead question, thus this positive trial was a surprise for many 24

COLON & RECTUM Primary tumour location

predicts response to therapy for RAS WT

25

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to become a member of

Elsevier’s Medical Advisory Board? Scan this code or go to goo.gl/V4KLLq to have your say in this issue’s PracticeUpdate Haematology & Oncology Readers Poll.

Prognostic value of automated Ki67 scoring in breast cancer: a centralised evaluation of 8088 patients from 10 study groups Breast Cancer Research These findings support the prognostic value of automated Ki67 scoring in breast cancer.

Topotecan plus carboplatin vs standard platinum-based combinations in platinum-sensitive recurrent ovarian cancer Annals of Oncology The authors concluded that TC was well-tolerated and feasible in relapsed, platinum-sensitive ovarian cancer patients, but it did not reduce PFS or OS compared with standard platinum doublets in this population.

Prospective longitudinal analysis of 2-hydroxyglutarate magnetic resonance spectroscopy identifies broad clinical utility for the management of patients with IDH- mutant glioma Journal of Clinical Oncology The study results showed that measuring 2HG concentration by MRS is reproducible and that measuring 2HG concentration reliably reports on glioma disease state. 22

Long-term follow-up of the French Stop Imatinib (STIM1) Study in CML Journal of Clinical Oncology

Patients with CML who achieve undetectable MRD can safely discontinue imatinib with close molecular surveillance. Although most will relapse, some patients will have sustained molecular responses without therapy. 26

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NEWS

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Telehealth extension to provide remote cancer patients access to clinical trials Oncologists in Australia will soon be able to offer patients in rural and remote regions greater access to experimental and potentially lifesaving cancer treatments under a new national scheme that will extend access to clinical trials to patients outside major centres.

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

T ele-trial – an extension of the telehealth model – will offer rural patients the first opportunity to be enrolled, treated and monitored throughout a clinical trial without having to suffer the prohibitive costs and travel associated with participating in trials only offered in metropolitan areas. Sabe Sabesan, MBBS, FRACP, Chair of the Clinical Oncology Society of Australia’s Rural and Regional Oncology Group and Director of Medical Oncology at the Townsville Cancer Centre, has been the driving force behind the development and roll out of tele-trial. Speaking to Practice Update Haematology & Oncology , Professor Sabesan said the benefits of the new model would not be limited to regional, rural and remote areas. “This model has the potential to connect larger centres even within the same city and improve the rate of recruitment to highly specialised clinical trials, including rare cancer trials.” Professor Sabesan added that residents outside of major centres in Australia continue to struggle to gain access to promising experimental treatments offered in these trials. “These are people who are very sick, who are faced with having to travel long

will promote our capacity to support a wider range of trials,” said Professor Sabesan, who added that, without multi-site collaboration, Australia is less attractive to international trial sponsors, which limits the availability of experimental, lifesaving treatments clinicians are able to offer their patients. He has already received the backing of COSA and other medical professional bodies, big industry players such as Medicines Australia, pharmaceutical companies, hospitals, and research councils including the NHMRC. Professor Sabesan said he is now working with state governments in an effort to streamline the administrative and legal requirements that come with setting up a clinical trial and which currently varies from state to state. While he acknowledged that there is still a lot of work to be done before the model is up and running, Professor Sabesan said he has already made some progress. “If we can use these kinds of models to push for reforms in regulation and governance approval then it can only be a good thing for research as a whole in the country … South Australia, Victoria, New SouthWales and Queensland have already agreed to streamline their contracts and governance processes to support the model,” he said. But rural hospital sites will also have to play a part if the model is to work – and that may mean upgrading facilities and resources and seeking the appropriate trial accreditations. “Many of the rural sites do already have the facilities to be part of a big trial; we just haven’t had the numbers. But if other sites don’t have the resources then they need to create them … but we now have a model that allows for rural patients to be recruited into trials. If rural sites are serious about their patients, they will have to up the ante,” Professor Sabesan concluded. COSA have now released the national implementation guide for the tele-trial model.

distances, sometimes without family friends, and who may have to fork out a lot of money to get to major centres. So many rural and regional patients miss out on potentially lifesaving treatments.” Professor Sabesan has been instrumental in providing medical oncology and medical nursing services to patients with cancer in rural and remote Queensland for close to a decade through the Queensland Remote Chemotherapy Supervision (QReCS) model. QReCS, which Professor Sabesan and his team initially set up for patients in Townsville and which Queensland Health eventually adopted statewide, allows rural generalist nurses to administer chemotherapy at rural sites with the support of the rural generalist doctors and pharmacists, and under the supervision of medical oncologists and chemotherapy nurses from larger centres using telehealth. Under the tele-trial framework, patients from rural or regional sites can be recruited, consented, and even treated and monitored at follow-up visits using web-based systems and video capabilities to connect a primary trial site with smaller satellite sites, creating a trial cluster. “Developing these clinical trial networks through models like the tele-trial concept,

SALES Commercial Manager Fleur Gill fleur.gill@elsevier.com

Account Manager Linnea Mitchell-Taverner l.mitchell-taverner@elsevier.com

Sabe Sabesan

DISCLAIMER PracticeUpdate Haematology&Oncology provides highlights of key local and international conferences with timely and relevant news, 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. Please consult the full current Product Information before prescribing any medicationmentioned in this publication. For an annual print and/or digital subscription (6 issues) of PracticeUpdate Haematology & Oncology , please email news.au@elsevier. com or visit elseviermedcomms.com.au To share your feedback with us, please email news.au@elsevier.com Conference news, expert opinions and journal article reviews are sourced from PracticeUpdate.com PracticeUpdate provides professional research, expert insights, and education resources in a single online destination PracticeUpdate content is selected by medi- cal experts in haematology and oncology for its relevance, timeliness, and importance. It is guided by world-renowned editorial and advisory boards that represent community practitioners and academic specialists with cross-disciplinary expertise. For in-depth insights which matter, discover PracticeUpdate.com today. ISSN – 2206-463X (Print) ISSN – 2206-4648 (Online)

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New drugs and devices listing

THERAPEUTIC GOODS ADMINISTRATION (TGA) www.tga.gov.au Adalimumab (Humira) , Abbvie – uveitis Saxagliptin/dapagliflozin (Qtern 5/10) , AstraZeneca – type 2 diabetes mellitus PHARMACEUTICAL BENEFITS SCHEME www.pbs.gov.au Armodafinil (Nuvigil) , Teva Pharma – narcolepsy, improve wakefulness

Auranofin (Ridaura) , Amdipharma Mercury – rheumatoid arthritis Dexamethasone (Ozurdex) , Allergan – diabetic macular oedema Imatinib (Imatinib-DRLA) , Dr Reddy’s Laboratories – chronic myeloid leukaemia, Ph+ acute lymphoblastic leukaemia, myelodysplastic/myeloproliferative diseases, aggressive systemic mastocytosis, hypereosinophilic syndrome, chronic eosinophilic leukaemia, dermatofibrosarcoma protuberans Ruxolitinib (Jakavi) , Novartis – disease-related splenomegaly or symptoms in myelofibrosis, polycythemia vera Please consult the full Product Information before prescribing.

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EMON111601

VOL. 1 • No. 5 • 2016

CONFERENCE COVERAGE

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European Society of Medical Oncology 2016 Congress 7–11 OCTOBER 2016 • COPENHAGEN, DENMARK

Billed as the leading oncology event in Europe, the European Society of Medical Oncology 2016 Congress hosted 19,000 participants, including oncology professionals across varying fields and disciplines. In this issue of PracticeUpdate Haematology & Oncology , we bring you our picks from a very packed scientific programme, including the latest clinical investigations into targeted therapies in oncology.

Improvement in progression-free survival with ribociclib + letrozole may represent a paradigm shift in advanced breast cancer Adding the CDK4/6 inhibitor

A s reported by Gabriel Hor- tobagyi, MD, of the Univer- sity of Texas MD Anderson Cancer Center, the combination of ribociclib + letrozole Houston led to a 44% improvement in progression- free survival when used as a first-line treatment combination. He noted, “This was the definitive study to demonstrate the superiority of the combination of ribociclib + letrozole over letrozole alone.” A total of 668 postmenopausal women with hormone receptor- positive, HER2-negative advanced breast cancer, who had not under- gone prior systemic treatment, were randomised to ribociclib (600 mg daily, 3 weeks on/1 week off) + letrozole (2.5 mg daily, continuous), or letrozole + placebo. A 44% improvement was observed in the primary objective of progres- sion-free survival versus placebo in

hormone receptor-positive, HER2- negative advanced breast cancer who had received no prior therapy for advanced breast cancer. Giuseppe Curigliano, MD, of the European Institute of Oncology, Milan, Italy, commented, “I believe the results of this study are significant because now we have a newCDK4/6 inhibitor for patients with oestrogen receptor-positive metastatic breast cancer, in addition to palbociclib (already FDA approved) and abe- maciclib (under development).” He added, “The addition of riboci- clib to letrozole raises the rate of tox- icity, but overall, if we evaluate the magnitude of clinical benefit, adding ribociclib is clearly beneficial.” Dr Curigliano said, “Further stud- ies of ribociclib should examine bio- markers to better identify patients who would respond to the addition of the drug to letrozole.”

Serious adverse events were reported by fewer than 5% of patients in both groups. Other adverse events were significantly more common in patients taking ribociclib. Fifty-nine percent of patients in the ribociclib arm suffered fromneutropenia versus 1% in the placebo arm. Leukopenia occurred in 21% vs 1%, lymphopenia in 7% vs 1%, respectively. Patients who received ribociclib exhibited higher incidences of elevated ala- nine aminotransferase and aspartate aminotransferase. Too few patients in the study died to enable a reliable analysis of the impact of ribociclib therapy on overall survival. Dr Hortobagyi concluded that the combination of ribociclib and letrozole prolonged progression- free survival significantly and was well tolerated vs letrozole alone in postmenopausal women with

patients taking ribociclib (hazard ratio 0.556, P = 0.00000329). Median progression-free survival was 14.7 months in patients tak- ing placebo but was not reached in those taking ribociclib at data cutoff. “The results represent compelling proof of principle,” said Dr Horto- bagyi, “and suggest a paradigm shift in metastatic, hormone receptor-positive breast cancer. They also suggest that testing combinations of ribociclibwith other inhibitors of various signalling pathways might lead to additional progress in themanagement of several subtypes of breast cancer.” Patients who demonstrated measurable disease at baseline exhibited a significantly higher objective response rate to ribociclib + letrozole than to letrozole alone (53% vs 37%; P = 0.00028), as well as a better rate of clinical benefit rate (80% vs 72%, P = 0.02).

ribociclib to letrozole therapy significantly

improved progression-free survival in postmenopausal women with hormone receptor-positive advanced breast cancer, finds the first interim analysis of data from the randomised, placebo- controlled, double-blind MONALEESA2 reported at ESMO.

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY

ESMO 2016

5

In patients age 70 years and older, capecitabine monotherapy at a starting dose of 2000 mg/m 2 or lower is associated with a median time to progression of 8.2 months and a clinical benefit rate of 43–67%. >8

Changing the sunitinib schedule from 4/2 to 2/1, rather than reducing the dose, was safe and resulted in a longer median progression-free and overall survival in patients with metastatic renal cell carcinoma. >9

The way we’re thinking about bladder cancer is definitely changing. In the past, all of our trials would exclude patients with a predominant nonurothelial component. >13

Cabozantinib has potential to become first-line treatment for renal cell carcinoma

Cabozantinib improved progression-free survival and the response rate versus sunitinib significantly in a phase 2 multicentre trial in patients with metastatic renal cell carcinoma. T oni Choueiri, MD, of the Dana-Farber Cancer Institute, Boston, Massachusetts, explained, “Unlike sunitinib, which targets vascular endothe- Good-risk patients were not included. No biological or clinical rationale would preclude cabozantinib in good-risk patients, however.

Dr Choueiri concluded, “Cabozantinib is approved for second or later lines of therapies (in the US), after patients have progressed on a vascular endothelial growth factor/tyrosine kinase inhibitor, but this data shows that cabozantinib has the potential to become a first-line standard treatment.” Bernard Escudier, MD, of the Institut Gustave- Roussy, Paris, commented, “For many years, sunitinib has been the most commonly used first-line standard of care for metastatic renal cell carcinoma. Recently, cabozantinib was proven to be active second line, especially after sunitinib failure.” He added that results of the study raise numerous questions. Among them: • Are the results expandable to all metastatic renal cell carcinoma patients, including the good prognosis group? • Should cabozantinib become a new, first-line standard of care? • How do we interpret the several ongoing phase 3 first-line trials in which sunitinib is the control arm? Dr Escudier concluded, “While more mature data and additional studies using cabozantinib in the first- line setting will be required, this study has raised expectations in the treatment of metastatic renal cell carcinoma.”

lial growth factor receptors, cabozantinib targets tyrosine kinase enzymes. Cabozantinib also inhibits mesenchy- mal-epithelial transition (MET) factor andAXL kinase.” Dr Choueiri asserted, “BothMET andAXL seem to be associatedwith tumour progression. But more importantly, animal models showed that the development of resistance to vascular endothelial growth factor inhibitors like suni- tinib can be mediated by AXL kinase and MET factor.” A total of 157 patients with untreated clear cell metastatic renal cell carcinoma of intermediate or poor risk were randomised to oral cabozantinib (60 mg once daily) or sunitinib (50 mg once daily). Patients who received cabozantinib exhibited a 31% reduction in the median rate of progression or death versus those treated with sunitinib (8.2 vs 5.6 months, P = 0.012). These patients also demonstrated a signifi- cantly higher objective response rate than patients who received sunitinib (46% vs 18%). Dr Choueiri and colleagues observed a similar rate of adverse events in the two groups (70.5% grade 3 or higher adverse events for cabozantinib vs 72.2% for sunitinib). The most common adverse events for both drugs included diarrhoea, fatigue, hypertension, palmar-plantar erythrodysesthesia, and haematological events. Sixteen patients in each group discontinued early due to adverse events.

Palbociclib + letrozole maintains health-related quality of life vs letrozole alone in treatment-naive postmenopausal ER-positive, HER2-negative metastatic breast cancer The addition of palbociclib to

T his positive finding adds to the significant improvement in progression-free survival seen with palbociclib in PALOMA-2. Laura Esserman, MD, of the University of California, San Francisco, explained that palbociclib + letrozole significantly improved progression-free survival versus letrozole alone in the phase 3 PALOMA-2 trial. Quality of life is a critical consideration when adding tar- geted agents to hormone therapy in metastatic breast cancer. Dr Esserman and colleagues compared patient-reported health-related quality of life in treatment-naive postmenopausal patients with oestrogen receptor-positive, HER2-neg- ative metastatic breast cancer in PALOMA-2. PALOMA-2 randomised patients 2:1 to palbociclib + letrozole (n=444) or placebo + letrozole (n=222). Patient-reported outcomes were assessed at baseline, day 1 of cycles 2 and 3 and day 1 of every other cycle from cycle 5 until the end of treatment using the

Functional Assessment of Cancer Therapy – Breast (FACT-B) questionnaire. FACT- B includes FACT-General (FACT-G) and the breast cancer-specific subscale (BCS). FACT-B produces five subscale scores: 1. Physical well-being 2. Social/family well-being

between treatment groups in change from baseline scores for: • Physical well-being (–0.5 vs –0.3) • Social/family well-being (–0.6 vs –0.7)

letrozole maintains health-related quality of life in treatment-naive postmenopausal patients with oestrogen receptor-positive, HER2-negative metastatic breast cancer and showed no significant difference versus letrozole alone.

• Emotional well-being (0.7 vs 0.5) • Functional well-being (0.2 vs 0.3)

Overall change from baseline scores was comparable for the BCS (0.19 vs 0.83; P = 0.055), Trial Outcome Index (–0.1 vs 0.71; P = 0.325), FACT- G (–0.39 vs –0.53; P = 0.882), and FACT-B (–0.11 vs 0.22; P = 0.782) scores. Dr Esserman concluded that the addition of palbociclib to letrozole maintains health- related quality of life in treatment-naive postmenopausal patients with oestrogen receptor-positive HER2-negative metastatic breast cancer and showed no significant difference compared to letrozole alone. This data adds favourably to the significant improvement in progression-free survival seen in PALOMA-2.

3. Emotional well-being 4. Functional wellbeing 5. Breast Cancer Subscale (BCS).

The above are used to derive overall FACT- B, FACT-G, and Trial Outcome Index (TOI) scores. A higher score indicates a better qual- ity of life. Repeated measures mixed-effects analyses were performed to compare changes from baseline in each subscale and FACT-B scores, controlling for baseline. Baseline scores were comparable between the two treatment arms for FACT-B (102 vs 103), FACT- G, TOI, and each subscale score. No significant differences were observed

VOL. 1 • No. 5 • 2016

GET MORE PEOPLE WITH CML-CP WHERE THEY NEED TO BE 1-3†

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

Please review approved Product Information before prescribing. Approved Product Information can be accessed at http://www.novartis.com.au/products_healthcare.html. Please note change(s) in Product Information . Indications: Treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukaemia (Ph+CML) in chronic phase. Treatment of chronic or accelerated phase Ph+CML in adult patients resistant to or intolerant of at least one prior therapy including imatinib. Dosage: Patients with newly diagnosed Ph+CML-CP: 300 mg twice daily; patients with CP and AP Ph+CML resistant to or intolerant of at least one prior therapy including imatinib: 400 mg twice daily. Monitoring of response to therapy in Ph+ CML should guide appropriate CML management. Doses should be taken about 12 hours apart without food. No food should be consumed for at least two hours before and one hour after the dose. For patients who are unable to swallow capsules, the content of each capsule may be dispersed in one teaspoon of applesauce (pureed apple) and should be taken immediately. Not more than one teaspoon of applesauce and no food other than applesauce must be used. Contraindications: Hypersensitivity to nilotinib or excipients. Precautions: Thrombocytopenia, neutropenia and anaemia managed by temporary withdrawal or dose reduction; complete blood counts every two weeks for the first two months, monthly thereafter or as clinically indicated; patients at risk of QTc prolongation (e.g. patients with hypokalaemia, hypomagnesaemia, congenital long QT syndrome, with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia; patients taking anti-arrhythmic drugs or other drugs that may lead to QT prolongation); ECG is recommended prior to treatment, repeat after 7 days and as clinically indicated; correct hypokalaemia or hypomagnesaemia prior to treatment; uncommon cases (0.1 to 1%) of sudden death have been reported in patients with past medical history of cardiac disease or significant cardiac risk factors (not in the newly diagnosed Ph+ CML-CP study). Cardiovascular events were reported in 48 month extended follow-up trial in newly diagnosed CML patients and observed in the post-marketing reports. Grade 3/4 cases of cardiovascular events included peripheral arterial occlusive disease, ischemic heart disease and ischemic cerebrovascular events. If acute signs or symptoms of cardiovascular events occur, advise patients to seek immediate medical attention. The CV of patients should be evaluated and the CV risk factors should be monitored and actively managed during therapy according to standard guidelines. It is recommended that the lipid profiles be determined before initiating treatment with Tasigna, assessed at month 3 and 6 after initiating therapy, and at least yearly during chronic therapy. Blood glucose levels should be assessed prior to initiating Tasigna therapy and monitored during treatment. Test for hepatitis B infection before initiating treatment with Tasigna. In patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for hepatitis B infection during treatment, consult experts before initiating treatment. Closely monitor for signs and symptoms of active hepatitis B infection in carriers of hepatitis B virus throughout therapy and for several months following termination of therapy. Unexpected, rapid weight gain should be carefully investigated. If signs of severe fluid retention appear during treatment with nilotinib, the etiology should be evaluated and patients treated accordingly. Comorbidities in addition to the underlying malignancy were also frequently present as were concomitant medications; ventricular repolarization abnormalities may have been contributory factors. Hepatic impairment or previous history of pancreatitis; interrupt treatment in case of lipase elevations accompanied by abdominal symptoms; should not be used during pregnancy; sexually active males or females/women of child-bearing potential should be advised to use highly effective contraception while receiving Tasigna and for up to 2 weeks after ending treatment; not recommended in breast-feeding and in patients with rare hereditary problems of galactose intolerance, or severe lactase deficiency or of

† DEEP The only TKI to get >50% of patients to MR 4.5 by 5 years vs 31% with imatinib (p<0.0001) 1,2

† FAST Median time to first MR 4.5 reached 1.3 years faster than imatinib (p<0.0001) 1,4

† PROTECTIVE No patient who achieved MR 4.5 progressed to AP/BC (on core treatment; p-value not reported) 1,3

glucose-galactose malabsorption; the bioavailability of nilotinib might be reduced in patients with total gastrectomy. Interactions: numerous (see full Product Information) including concomitant use with drugs known to prolong the QT interval (e.g. chloroquine, methadone, halofantrine, clarithromycin, haloperidol, moxifloxacin, bepridil, pimozide); anti-arrhythmic medicines (e.g. amiodarone, disopyramide, procainamide, quinidine, sotalol); CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, itraconazole, voriconazole, telithromycin); CYP3A4 inducers (e.g. phenytoin, rifampicin, carbamazepine, phenobarbital or St. John’s wort); may be used concurrently with esomeprazole or other proton pump inhibitors and warfarin; exposure to midazolam; drugs affecting P-glycoprotein; avoid grapefruit juice and foods known to inhibit CYP3A4. In concurrent use: the H2 blocker (e.g. famotidine) may be administered approximately 10 hours before and approximately 2 hours after TASIGNA dose, antacids (e.g. aluminum hydroxide, magnesium hydroxide, simethicone) may be administered approximately 2 hours before or approximately 2 hours after TASIGNA dose. Nilotinib is a moderate CYP3A4 inhibitor. As a result, the systemic exposure of other drugs primarily metabolized by CYP3A4 (e.g. certain HMG-CoA reductase inhibitors) may be increased when co-administered with nilotinib. Appropriate monitoring and dose adjustment may be necessary for drugs that are CYP3A4 substrates and have a narrow therapeutic index (including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, astemizole, terfenadine, cisapride, quinidine, pimozide, sirolimus and tacrolimus) when co-administered with nilotinib. Due to possible occurrence of tumour lysis syndrome, correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to administration. Side effects: Very common: headache, nausea, constipation, diarrhoea, vomiting, rash, pruritus, alopecia, myalgia, arthralgia, fatigue, upper abdominal pain, myelosuppression (thrombocytopenia, neutropenia), hypophosphataemia (including blood phosphorus decreased), hyperbilirubinaemia (including blood bilirubin increased), alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased, lipoprotein cholesterol (including low density and high density) increased, total cholesterol increased, blood triglycerides increased. Common: decreased appetite, abdominal pain, muscle spasms, bone pain, pain in extremity, asthenia, oedema peripheral, folliculitis, upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis), skin papilloma, leukopenia, eosinophilia, febrile neutropenia, pancytopenia, lymphopenia, anaemia, electrolyte imbalance (including hyperkalaemia, hypokalaemia, hyponatraemia, hypocalcaemia, hypercalcaemia, hyperphosphataemia, hypomagnesaemia), hyperglycaemia, diabetes mellitus, hypercholesterolaemia, hyperlipidaemia, hypertriglyceridemia, insomnia, depression, anxiety, dizziness, peripheral neuropathy, hypoaesthenia, paraesthesia, eye haemorrhage, periorbital oedema, eye pruritus, conjunctivitis, dry eye (including xerophthalmia), vertigo, angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, tachycardia, bradycardia), palpitations, electrocardiogram QT prolonged, flushing, hypertension, dyspnoea, dyspnoea exertional, epistaxis, cough, dysphonia, abdominal discomfort, dyspepsia, dysgeusia, flatulence, abdominal distension, pancreatitis, hepatic function abnormal, night sweats, hyperhidrosis, dry skin, eczema, urticaria, erythema, dermatitis (including allergic, exfoliative and acneiform), contusion, acne, musculoskeletal chest pain, musculoskeletal pain, back pain, neck pain, flank pain, muscular weakness, blood creatine kinase (CK) increased, pollakiuria, pyrexia, chest pain (including non-cardiac chest pain), pain, chest discomfort, malaise, haemoglobin decreased, blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood alkaline phosphatase increased, blood insulin increased, weight decreased, weight increased, globulins decreased. (See full Product Information). Based on approved Tasigna Product Information dated 15 April 2016. For the most up to date Product Information go to http://www.novartis.com.au/products_healthcare.html Tas150416m.doc *Please note changes in Product Information. References: 1. Hochhaus A et al. Leukemia. 2016;30:1044–54. 2. Cortes J et al. J Clin Oncol 2016;34:2333–40. 3. Kantarjian HM et al. Lancet Oncol 2011;12:841–51. 4. Hughes TP et al. Efficacy and safety of nilotinib versus imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase: 6-year follow-up of ENESTnd. Poster presentation at the 20th Annual European Association Congress; June 11–14, 2015; Vienna, Austria. Novartis Pharmaceuticals Australia Pty Limited ABN 18 004 244 160. 54 Waterloo Road, Macquarie Park NSW 2113. Ph (02) 9805 3555. For medical enquiries please contact 1800 671 203 or medinfo.phauno@novartis.com. Tasigna ® is a Registered Trademark of Novartis Pharmaceuticals Pty Limited. TAS0846. NOT0011. Date of preparation: October 2016.

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If you’re going to not use a CDK4/6 inhibitor, then perhaps you want to start with fulvestrant. But if you are, the current data supports using letrozole and perhaps the combination, so I think we’re working it out. >9

If you don’t look at the subset analysis, you could make an argument that there is still room to treat low volume patients, but I think you’d select them very carefully to make sure that the benefit, which might be much smaller, is not outweighed by the risk. >15

Intensity-modulated radiotherapy + temozolomide improves quality of life in among grade III glioma with minimal toxicity Intensity-modulated radiotherapy + temozolomide has been shown to improve quality of life in grade III glioma, with minimal treatment-related toxicity and better quality of life, results of a prospective, single-centre comparative trial show. D eepa Gupta, MD, of the Medanta Cancer Institute, Medanta the Medicity, Gurgaon, India, explained that she and colleagues set out to evaluate grade III gliomas treated in the era of intensity-modulated radiotherapy and concurrent, adjuvant temozolomide in terms of early clinical outcome, prognostic factors, and quality of life. Fifty-three patients with anaplastic oligodendroglioma (n=25), anaplastic astrocytoma (n=18), or anaplastic oligoastrocytoma (n=10) were treated with intensity- modulated radiotherapy and concurrent (95%) and adjuvant temozolomide (90%). Data on 1p19q codeletion was available for 13 patients. Eighty percent had a Karnofsky performance score at least 90 with 30% experiencing seizures. Postoperative MRI was available in 65% cases and the intensity-modulated radiotherapy dose was 60 Gy in 30 fractions. Posttreatment imaging was performed 1, 3, and 6 months post intensity-modulated radiotherapy and then every 3 months. European Organisation for Research and Treatment of Cancer quality of life scales C35 and BN20 were administered before starting intensity-modulated radiotherapy, at completion, and then at each follow-up appointment. Kaplan-Meier analysis was used to estimate progression-free and overall survival. Median follow-up was 25 months, with 2 year disease- free and overall survival 75% and 88%, respectively. Patients tolerated treatment well with only 5% symp- tomatic central nervous system and 8% symptomatic haematological toxicities. Ninety-five percent completed the concurrent temozolomide schedule. At the first, 1-month evaluation, 30.4% exhibited a complete response; at 3 months, 40%; and at 6 months, 43%. At 6 months, only 4 % demonstrated

Capecitabine monotherapy extends life and benefits patients age 70 years and older with metastatic breast cancer

S tephen Johnston, MD, of the Royal Marsden Hospital National Health Service Foundation Trust, Lon- don, UK, explained that capecitabine monotherapy is associated with a clinical benefit rate of 60% and median time to progression of 4 months in patients 65 years of age and older with metastatic breast cancer. Thirty percent, however, require a dose reduction due to toxicity. The starting dose and schedule for capecitabine at Dr Johnston’s institution is 2000 mg/m 2 on days 1–14, every 3 weeks. Older patients with a poor performance status, comorbidities, and/or moderate to severe renal impairment may start with a further dose reduction. If early Common Terminology Criteria for Adverse Events grade ≥ 2 toxicity occurs, a switch from 3-weekly to a week on/week off schedule is used to improve tolerance. Dr Johnston and colleagues set out to evaluate toxicity and efficacy of capecit- abine monotherapy in patients 70 years of age and older diagnosed with metastatic breast cancer. The primary endpoint was toxicity. Secondary endpoints were clini- cal benefit rate, time to progression, and overall survival. From 2013 to 2015, 77 patients age 70 years and older were identified from the institution’s pharmacy data base. They had received capecitabine monotherapy for metastatic breast cancer. Capecit- abine was first-line therapy in 65 patients (84%). Forty-three and 34 patients received 2000 mg/m 2 and less than 2000 mg/m 2 , respectively (25 patients, 1500 mg/m 2 and nine patients, 1000 mg/m 2 ).

Patients starting at a lower dose were older (79 vs 73 years, P < 0.001); had more moderate to severe renal impairment (16% vs 44%, P = 0.016); Eastern Cooperative Oncology Group performance status ≥ 2 (11% vs 26 %, P = 0.156) and de novo metastatic disease (17% vs 35%, P = 0.09). With respect to toxicity, eight patients (19%) in the 2000 mg/m 2 group had grade 3–4 toxicities versus one patient (3%) in the <2000 mg/m 2 group. Nine versus 91% in the <2000 mg/m 2 and 2000 mg/m 2 group, respectively, required dose reduc- tion. Forty-two percent in the 2000 mg/ m 2 versus 32% in the <2000 mg/m 2 group switched to week on/week off due to early toxicity. No treatment-related deaths were observed. The clinical benefit rate for the 2000 mg/m 2 and <2000 mg/m 2 groups was 67% vs 43%, respectively (P = 0.05). After a median follow-up of 28.1 months, the combined time to pro- gression was 8.2 months. Overall survival was 18.6 months. Time to progression was 11.7 and 6.2 months in the 2000 mg/ m 2 and <2000 mg/m 2 groups, respectively (difference not significant). Dr Johnston concluded that, in patients age 70 years and older, capecit- abine monotherapy at a starting dose of 2000 mg/m 2 or lower is associated with a median time to progression of 8.2 months and a clinical benefit rate of 43–67%. Toxicity can be managed by dose reduc- tions and switching to a week on/week off schedule, which enables continued treat- ment in those deriving clinical benefit.

In patients age 70 years and older with metastatic breast cancer, capecitabine monotherapy at a starting dose of 2000 mg/m 2 or lower has been associated with a median time to progression of 8.2 months and a clinical benefit rate of 43–67%, results of a retrospective analysis show.

progressive disease. At last follow-up, 46/53 patients were evaluable. Eight had died and 55% experienced stable disease or a complete response. On univariate analysis for disease-free survival, Karnofsky performance scale score at presentation >90 (P = 0.001) and response at 6 months (P = 0.02) were significant and for overall survival, Karnofsky performance scale score at presentation alone (P = 0.004). Gross total resection, no residual at postoperativeMRI, up to six cycles of adjuvant temozolomide, and complete response at 6 months were favourable in terms of both disease-free and overall survival. Histopathological types were not significant for disease-free and overall survival. Only three patients exhibited the 1p19q codeletion. Quality-of-life scale scores suggested a decline in mood and cognition, as well as fatigue and toileting difficulty initially and an improvement beyond 3 months. Dr Gupta concluded that intensity-modu- lated radiotherapy + temozolomide improved quality of life in grade III glioma with minimal treatment-related toxicity. Proper case selection employing molecular prognostic markers yet to be developed will identify groups expected to respond most favourably.

© ESMO 2016

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY

ESMO 2016

9

Circulating tumour cells are an early predictor of disease progression in metastatic breast cancer Circulating tumour cells have been shown to be an early predictive biomarker of disease progression in metastatic breast cancer, conclude results of a 5-year, single-centre study of patients with stage 4 breast cancer. D ouaa M. Sayed, MD of South Egypt Cancer Institute SECI Assiut University, Assiut, Egypt, explained that circulating tumour cells are a prognostic marker in metastatic breast cancer, but their predictive value to monitor treatment efficacy needs further exploration. Eighty-five patients with stage 4 breast cancer met eligibility criteria. Before starting a new treatment, all patients underwent full imaging stud- ies and blood sampling for circulating tumour cell enumeration. Patients with fewer than five circulating tumour cells per 7.5 mL blood detected at baseline underwent no further count of circulating tumour cells. Patients with at least five circulating tumour cells per 7.5 mL blood underwent another blood sampling for estimation of circulating tumour cells before cycle 2. Disease status was assessed radiologically every 9 to 12 weeks. Disease response was assessed according to the Response Evaluation Criteria In Solid Tumors (RECIST). At baseline, 44 (51.8%) of the 85 eligible patients did not exhibit increased circulating tumour cell levels. Of the other 41 patients with at least five circulating tumour cells per 7.5 mL blood, only 38 underwent circulating tumour cell evaluation at first follow-up before cycle 2 that showed 25 (65.8 %) patients had fewer than five circulating tumour cells per 7.5 mL blood and 13 (34.2%) patients harboured at least five circulat- ing tumour cells per 7.5 mL blood. Seventy-five patients (75/85, 88.2 %) underwent radiological restaging. According to RECIST, 36 (48%) patients were scored as having expe- rienced a partial response, 19 (25.3%) stable disease, and 20 (26.7%) progressive disease. Radiologic response was concordant with follow-up circulating tumour cell levels in 76.5% of cases. Survival depended significantly results of both circulating tumour cell evaluation and radiological response. Median follow-up was 18.0 (1–60) months. Dr Sayed concluded that elevated circulating tumour cells before cycle 2 in patients with metastatic breast cancer starting a new line of chemotherapy can be considered an early predictive marker of disease progression, and of the benefit of treatment. The study confirmed that circulating tumour cells are an independent prognostic marker.

EXPERT OPINION ALISONK CONLIN HER2+ and ER+ breast cancer trials Interview by Sumanta Kumar Pal MD

Dr Sumanta Pal and Alison Conlin, MD, discuss HER2-positive and ER-positive breast cancer at ESMO 2016.

hormonal therapy for breast cancer, based on the data presented here, is it letrozole, is it fulvestrant? What’s your opinion there? Dr Conlin: I think that in the US we have a CDK4/6 inhibitor approved and available. It’s not ribociclib. It’s palbociclib. That’s an exciting first-line choice. It makes it a difficult decision because there is data, of course, com- bining it with fulvestrant. So if you’re going to not use a CDK4/6 inhibitor, then perhaps you want to start with fulvestrant, but if you are, the current data supports using letrozole and per- haps the combination, so I think we’re working it out. It’s not the same path for every wom- an depending on what her current pretreatment was, is she currently on an oestrogen-blocking therapy or is she oestrogen-naive.

Dr Pal: You have some really interest- ing data looking at a combination of HER2-directed therapy with a novel agent. Can you tell us a little bit about that? Dr Conlin: My presentation at this meeting is really a case series of eight women, who had cutaneous metastases or skin metastases with HER2-positive breast cancer. We find this to be a very morbid disease process for women with a lot of pain management, wound care. In my abstract, I’m looking at the results of a highly selective oral HER2 agent called tucatinib or ONT-380. We combined that with either Herceptin, Herceptin and capecitabine or T-DM1, and I found the eight women in the study in the phase I data who’d had skin disease and looked at their responses. We saw incredible responses. A woman with a complete response, partial responses, stable disease. And so clearly, this is an effective therapy in an area that’s another unmet need for women with HER2-positive metastatic breast cancer. Dr Pal: That’s fantastic. I mean skin metastases can be so cosmetically devastating. Dr Conlin: It’s really difficult for patients to manage, and so, we saw patients come down on their nar- cotics and have a better quality of life while being treated effectively for their HER2-positive disease. There is an abstract of a clinical

trial in progress of the phase 2 of this drug, so we’ll be looking at that with capecitabine and trastuzumab versus placebo, so more to come on this exciting tucatinib. Dr Pal: Now, I’m going to shift gears for just a second and ask you about another huge domain in breast cancer, which is ER-positive disease. There have been some really great abstracts highlighting that dataset here. Can you tell us a little bit about those? Dr Conlin: I think the two largest studies that were published at this meeting are the Mona Lisa study looking at a new oral CDK4/6 inhibitor ribociclib in combination with letrozole for women with first line metastatic disease that showed a great PFS benefit to that combination. That was published the same day as it was presented, so that’s always exciting to see it in print, as well as the FALCON study, which looked at whether first-line therapy for oestrogen- positive disease should be either fulvestrant or anastrozole showing, again, superiority with fulvestrant for those women. So I think we’re getting better at picking our first-line therapy for these women. Again, more to come when we look at later- line therapies. I think that will be exciting to see, as women need more therapies further down the line. Dr Pal: For the practicing oncologists out there, as you’re approaching

Dr Pal is an internationally recognised leader

in the area of genitourinary cancers. He is

the Co-Director of the City of Hope Kidney Cancer Program in California and is the head of the kidney and bladder cancer disease team at the institution.

Dr Conlin is a medical oncologist

at Providence Medical Group in Oregon.

Watch the full interview at PracticeUpdate.com

Sunitinib 2 weeks on/1 week off is superior to 4weeks on/2 weeks off in metastatic renal cell carcinoma Changing the sunitinib 4 weeks on/2 weeks off to 2 weeks on/1 week off schedule, rather than reducing the dose, was safe and resulted in a longer median progression-free and overall survival in patients with metastatic renal cell carcinoma, finds a comparative, single-centre trial. F ruzsina Gyergyay, MD, PhD, of the National Institute of Oncology, Budapest, Hungary, explained that the recom- mended schedule of sunitinib for metastatic renal cell carcinoma is 50 mg daily, orally for 4 weeks followed by 2 weeks of rest. Thirty-four (26%) had taken interferon and 21 (16%) patients had received interleukin-2 treatment. Patients received a total of 1617 cycles of sunitinib (median, eight cycles, range 1–68 cycles) were administered. • Diarrhoea 37% • Hand-foot syndrome 35% • Hypertension 30%. Though adverse events were frequent they were shorter. Dose reduction had to be performed in only 12% (n=16) during the 2/1 schedule.

A total of 344 (range 1–56) cycles were given according to the 4/2, and 1273 (1–18) according to the 2/1 schedule, respectively. On progression with sunitinib, the following therapies were given: • Sorafenib (n=10) • Axitinib (n=7) • Pazopanib (n=1) Median progression-free survival was 13.5 (95% CI 12–16.5) months. Median overall survival was 30 (24– 36) months. When the 2/1 schedule was given in more than 2/3 of total cycles (n=83), median progression-free survival was 18 (13.5–28.5) months and median overall survival was 38 (30–44) months. In those who received the 2/1 schedule for less than 2/3 of total cycles (n=47), median progression-free survival was 6 (4.5–9; P = 0.0002) months and median overall survival was 11 (7–21); P = 0.0001) months. Short-term adverse events were: • Cabozantinib (n=1) • Everolimus (n=16).

The half-life of sunitinib and its active metabolite is very long: 40–60 and 80–110 h, respectively. When given on several consecutive days, accumulations are 3–4-fold and 7–10-fold, respectively. Steady state concentration is achieved on days 7–10 and 10–14, respectively. Fifty milligrams daily is a high enough dose to achieve the target concentration ≥ 50 ng/mL. During the 14 days’ rest, the concentration decreases to the starting level. The correlation between the sunitinib area under the curve and time to progres- sion is well known. Based on the pharmacokinetics above, the 2 weeks on/1 week off schedule was applied rather than dose reduction, to reduce short-term adverse events. One hundred thirty patients with metastatic renal cell carcinoma (median age 61 years, male to female ratio 91/39) were enrolled. One hundred twenty-one (93%) patients were nephrectomised, 95% (n=123) had available renal cell carcinoma histology. Sixty-seven (30%); 49 (38%), and 42 (32%) patients were characterized as good, intermediate, and poor Memorial Sloan Kettering Cancer Center prognostic groups, respectively. Sunitinib was the first-line treatment in 75 cases (58%).

Dr Gyergyay concluded that changing the sunitinib schedule from 4/2 to 2/1, rather than reducing the dose, was safe and resulted in a longer median progression-free and overall survival in patients with metastatic renal cell carcinoma.

• Fatigue 41% • Anorexia 25% • Mucositis 35%

© ESMO 2016

VOL. 1 • No. 5 • 2016

MINIMUM PRODUCT INFORMATION: PALEXIA ® SR (tapentadol hydrochloride) INDICATION: Moderate to severe chronic pain unresponsive to non-narcotic analgesia. CONTRAINDICATIONS: Known hypersensitivity to tapentadol or any component of Palexia SR; conditions in which mu-opioid receptor agonist activity is contraindicated e.g. significant respiratory depression and acute or severe bronchial asthma or hypercapnia; confirmed or suspected paralytic ileus; acute intoxication with alcohol; hypnotics, centrally acting analgesics or psychotropic drugs; patients who are receiving MAO inhibitors or who have taken them within the last 14 days. PRECAUTIONS: Monitor for signs of abuse and addiction; repeated administration may lead to tolerance; withdrawal symptoms could occur after abrupt discontinuation; not recommended in patients with increased intracranial pressure, impaired consciousness, or coma and severe renal or severe hepatic impairment; caution in patients with impaired respiratory functions, patients with head injury, brain tumours, a history of seizures or any condition that increases risk of seizures, moderate hepatic impairment or biliary tract disease, including acute pancreatitis. Use in pregnancy (Category C). Should not be used during breastfeeding. Not recommended for children <18 years old. May impair ability to drive or operate machinery. INTERACTIONS: Care should be taken when combining with mixed opioid agonist/antagonists or partial mu-opioid agonists; additive CNS depression with concomitant administration of other mu-opioid receptor agonist PBS Information: Restricted benefit. Chronic severe disabling pain not responding to non-narcotic analgesics. Authority required for increased maximum quantities and/or repeats. Refer to PBS schedule for full restricted benefit and authority information. Before prescribing, please review the Product Information available at www.seqirus.com.au/PI.