Haematology+Oncology_News

Vol. 9 • No. 1 • 2016

The Leading Independent Newspaper from Elsevier

Taxanes retain efficacy against mCRPC resistant to AR-antagonists

IN THIS ISSUE

Cancer prevention field riding high into the new year

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BY NEIL OSTERWEIL Frontline Medical News

AR-V7 may potentially serve as a treatment

At the Genitourinary Cancers Symposium, San Francisco T he variant, labelledAR-47, is a truncated form of the androgen receptor that is missing the ligand- binding domain, to which both androgens and androgen receptor inhibitors such as abiraterone and enzalutamide normally bind. AR-V7 has been detected in about one-third of men with metastatic castration-resistant prostate cancer (mCRPC). But a study of circulating tumour cells (CTCs) from 37 men with mCRPC shows that patients whose tumour cells are positive for AR-V7 retain their sensitivity to taxanes. “In this particular study, there was a 41% re- sponse rate to taxanes if a man was AR-V7-positive, compared to a 0% response to abiraterone or en- zalutamide in this setting,” said Dr Emmanuel S. Antonarakis from the Johns Hopkins Sidney Kimmel Comprehensive Cancer Centre, Baltimore. Dr An- tonarakis presented the study in a briefing prior to its presentation in a poster session at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. Testing for the presence of AR-V7 could in the future help guide clinicians when choosing thera- pies for men with mCRPC, Dr Antonarakis said. The investigators used a quantitative

reverse-transcriptase polymerase chain reaction (qRT-PCR) assay selection marker for men with metastatic castration- resistant prostate cancer seeking therapy with either taxanes or enzalutamide/ abiraterone.

ACOG recommends against annual cervical cancer screening 4

had significantly better progression-free survival when treated with taxanes, compared with androgen receptor antagonists. The hazard ratio (HR) for PFS with taxanes was 0.21 (P = 0.003). In contrast, PFS was similar for AR-V7-negative men treated with either taxanes or abiraterone/enzalutamide. “AR-V7 may potentially serve as a treatment se- lection marker for men with metastatic castration- resistant prostate cancer seeking therapy with either taxanes or enzalutamide/abiraterone. However, be- fore the data become clinically actionable, we need to prospectively validate this finding in at least one multicentre clinical trial,” Dr Antonarakis said. He noted that there is currently no commercial assay for AR-V7.

to detect and quantify levels of AR-V7 in the CTCs of 37 men with mCRPC who were scheduled to start taxane-based chemotherapy with docetaxel or cabazitaxel. For the primary endpoint of a prostate specific antigen (PSA) response, they found that 7 of 17 men (41%) who were positive for AR-V7 had a response to taxane therapy, compared with 13 of 20 (65%) men with the wild type of the androgen receptor (that is, AR-V7 negative). The difference in response rates between AR-V7-positive and -nega- tive men was not significant. When they included data from an earlier study of 62 men treated with abiraterone or enzalutamide, the investigators found that AR-V7-positive men

ASCO Genitourinary Cancers Symposium 2016 BCG/sunitinib combo 6 Higher BMI linked to better metastatic RCC outcomes 7 San Antonio Breast Cancer Symposium 2015 BRCA mutation predicts neoadjuvant therapy benefit but is not strongly prognostic 8 Neratinib shows consistent breast cancer benefit at 3 years 10 Pembrolizumab shows promise in PD-L1–positive breast cancer 11 produces high complete response rate in NMIBC

Nonalcoholic fatty liver disease linked to liver cancer without cirrhosis

had cirrhosis, compared with 91% of patients with chronic HCV infection, 92% of HCV-infected pa- tients, and 88% of patients with an alcohol use disorder. Notably, the odds of HCC in the absence of cirrhosis were more than five times higher when patients had NAFLD (odds ratio [OR], 5.4; 95% confidence interval [CI], 3.4–8.5) or metabolic syndrome (OR, 5.0; 95% CI, 3.1–7.8) compared with HCV infection. Patients with cirrhosis often go unscreened for HCC even though they are at greatest risk of this can- cer. Therefore, trying to screen all patients with NAFLD for HCC would be “logistically impractical,” particu- larly when the absolute risk of HCC in noncirrhotic patients is unknown and no one has examined the best ways to screen this population, the investigators said. Instead, clinicians could prioritise screening and treating NAFLD patients for diabetes mellitus and obesity, both of which are associ- ated with HCC. “There is evidence to suggest that metformin reduces the

patients to this disease entity ( Arch Pathol Lab Med 2008;132:1761–6). But few studies have systematically examined risk factors for HCC with- out cirrhosis in the general population, the investigators said. Therefore, they randomly selected 1500 patients from the US. Veterans Affairs system who were diagnosed with HCC between 2005 and 2010 on the basis of histo- pathology or established imaging cri- teria ( Hepatology 2005;42:1208–36). They reviewed complete medical records for these patients, and classi- fied those who did not have cirrhosis according to the quality of supporting histology, laboratory, and imaging data ( Clin Gastroenterol Hepatol 2015. doi: 0.1016/j.cgh.2015.07.019). In all, 3% of the cohort had level 1 (“highest-quality”) evidence for not having cirrhosis, while another 10% had level 2 evidence for no cirrhosis, the investigators said. “Compared with HCC in the presence of cirrho- sis, these patients were more likely to have metabolic syndrome or NAFLD or no identifiable risk factor, and less likely to have alcohol abuse or HCV infection,” they added. Only two- thirds of NAFLD patients with HCC

BY AMY KARON Frontline Medical News From Clinical Gastroenterology and Hepatology A bout 13% of US veterans with hepatocellular carcinoma had no evidence of preexisting cirrhosis, according to a report published in the January issue of Clinical Gastroenter- ology and Hepatology. “The main risk factors for this entity were nonalcoholic fatty liver disease [NAFLD] or metabolic syndrome” – not hepatitis C virus infection [HCV], HBV [hepatitis B virus] infection, or al- cohol abuse, said Dr Sahil Mittal of the Michael E. DeBakey Veterans Affairs Medical Centre and Baylor College of Medicine in Houston. Screening all patients with NAFLD for hepatocel- lular carcinoma [HCC] is impractical, so studies should seek “actionable risk factors” or biomarkers that reliably identify NAFLD patients who are at particular risk of HCC, wrote Dr Mit- tal and his coinvestigators. Researchers have debated whether chronic HCV infection or alcohol abuse can lead to HCC in the absence of cirrhosis, while at least one study has shown that NAFLD can predispose

American Society of Haematology 2015 Heavily pretreated myeloma responds to pembrolizumab combo

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First shot across the bow for CAR T cells in multiple myeloma

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By Nephron via Wikimedia Commons, Creative Commons license.

risk of HCC among diabetics,” they added. “Studies of these and other risk factors of HCC among NAFLD patients with and without cirrhosis are needed.” Most patients in the study were male, potentially limiting the general- isability of the findings, the research- ers noted. The American National Cancer In- stitute, the Houston Veterans Affairs Health Services Research and Develop- ment Centre of Excellence, the Michael E. DeBakey Veterans Affairs Medical Centre, and the Dan Duncan Cancer Centre funded the study. The research- ers had no disclosures.

Genes tag increased risk for avascular necrosis in ALL patients under age 10 2015 practice changers in oncology: FDA-approved EGFR TKIs for acquired resistance to targeted therapy in lung cancer 15 14

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H aematology & O ncology N ews • Vol. 9 • No. 1 • 2016

Ovarian suppression during breast cancer chemotherapy helped preserve long-term function

disease free at 5 years (HR, 1.17; 95% CI, 0.72 to 1.92; P = 0.52). The increase in risk among triptorelin patients was generally limited to those with hormone receptor-negative disease (5-year DFS, 62% and 76%), the investigators said. When combined with recent findings from the POEMS study, the results show that tem- porary ovarian suppression before and during chemotherapy is an option for preserving ovar- ian function in premenopausal women with early-stage breast cancer, they concluded. Istituto Nazionale per la Ricerca sul Cancro and the Associazione Italiana per la Ricerca sul Cancro funded the study. Dr Lambertini reported no relevant disclosures. Two coauthors reported receiving research funding and honoraria from Amgen, GlaxoSmithKline, and Eisai. The sen- ior author reported financial relationships with Takeda and with Ipsen, which supplied the triptorelin used in the study. recommending low-dose aspirin for colorectal cancer prevention based on age and risk. Randomised trials have also suggested that a single dose of human papillomavirus vaccine can provide durable protection against HPV infection. Tumour biology studies established new chemoprevention for familial adenoma- tous polyposis syndrome and universal tumour screening guidelines based on DNA mismatch repair mutations and microsatellite instability for colorectal cancer in patients with Lynch syndrome. Further, remarkable advances have been made in liquid biopsy technology, high-through- put functional screening, and computational biology methods and algorithms that “provide unprecedented opportunities to interrogate the biology of premalignancy...” they noted. In an American Association for Cancer Re- search blog post, Dr Lippman acknowledges that not everyone is the same page when it comes to the underlying principles of cancer prevention. A “contentious” paper published at the start of 2015 suggested that variations in cancer risk are due to random mutations or what might otherwise be called bad luck. The new year was heralded in by a second paper, however, that came to roughly the opposite conclusion or that most cancers are preventable. In February, an AACR Cancer Prevention Summit will bring together various stake- holders to discuss the current state of cancer prevention and to identify top priorities and research directions for the field, he noted. The authors acknowledged grant support from the US National Institutes of Health/National Cancer Institute.

receptor-positive or hormone receptor-negative breast cancer to receive chemotherapy alone or with 3.75 mg triptorelin, given intramuscu- larly at least 1 week before and every 4 weeks during cancer treatment. The median age of patients was 39 years, the range was 24–45 years ( JAMA 2015;314:2632–40). Nearly 73% of the triptorelin group and 64% of controls resumed menstruating within 5 years of completing chemotherapy, for an age-adjusted hazard ratio of 1.48 (95% CI, 1.12 to 1.95; P = 0.006). Cumulative 5-year pregnancy rates were 2.1% for the triptorelin group and 1.6% for controls (aHR, 2.4; 95% CI, 0.62 to 9.22; P = 0.2). About 81% of trip- torelin patients and 84% of controls remained being translated to the clinic and showing great promise. We stand at the edge of a new frontier that will include comprehensively characteris- ing the molecular and cellular events that drive premalignant progression (eg, PCGA),” Dr Scott M. Lippman, director of the University of Cali- fornia SanDiegoMoores Cancer Centre, and his coauthors wrote ( Cancer Prev Res 2016;9:2–10). The report details some of the clinical firsts in 2015 including genomic studies suggesting that clonal haematopoiesis is a premalignant state for blood cancer, the first precision medicine trial in cancer prevention (EPOC) reporting that loss of heterozygosity can predict which patients with premalignant mouth lesions are most likely to develop oral cancer, and the United States Preventive Services Task Force

BY AMY KARON Frontline Medical News From JAMA O varian suppression with triptorelin during chemotherapy for early-stage breast cancer significantly increased the chances that women would recover their long-term ovarian function, according to a multicentre phase III open-label study published online Dec. 22 in JAMA . The treatment and control groups had simi- larly low pregnancy rates at 5 years, with no significant overall difference in disease-free survival, reported Dr Matteo Lambertini of Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy, and his associates.

Cryopreserving embryos or oocytes remains the main way to protect fertility in young women with breast cancer. Clinicians have debated whether to use luteinising hormone- releasing hormone analogues because of scarce data showing efficacy and concerns about compromising disease-free survival, the investigators noted. They randomised 281 pre- menopausal women with stage I–III hormone Nearly 73% of the triptorelin group and 64% of controls resumed menstruating within 5 years of completing chemotherapy.

Cancer prevention field riding high into the new year BY PATRICE WENDLING Frontline Medical News From Cancer Prevention Research

Managing Editor

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

T he new year has us all looking forward and the cancer prevention community is no exception. In a special report entitled “Transforming Cancer Prevention through PrecisionMedicine and Immune-Oncology,” a team of experts offer a brief look at what we can expect in the near future for cancer prevention research, includ- ing a Pre-Cancer Genome Atlas (PCGA), and highlight some of the recent advances shaping their optimism. “Just as precision therapy and immunotherapy are transforming cancer treatment, precision medicine and immunoprevention approaches are

Editor

Designer

Medical Advisor

Commercial Manager Fleur Gill

fleur.gill@elsevier.com Stephen Yue s.yue@elsevier.com

Account Manager

FRONTLINE MEDICAL NEWS International Editorial Editor in Chief Mary Jo M. Dales Executive Editors Denise Fulton, Kathy Scarbeck Managing Editor Laura Nikolaides Senior Editors Therese Borden, Jeff Evans, Catherine Hackett, Gina L. Henderson, Susan Hite, Sally Koch Kubetin, Mark S. Lesney, Renée Matthews, Lora T. McGlade, Associate Editors Felicia Rosenblatt Black, Mike Bock, Lucas Franki, Richard Franki, Gwendolyn B. Hall, Jane Locastro, Madhu Rajaraman Reporters Patrice Wendling, Bruce Jancin, Michele G. Sullivan, Alicia Gallegos, Mitchel L. Zoler, Doug Brunk, Sherry Boschert, M. Alexander Otto, Deepak Chitnis, Whitney McKnight, Elizabeth Mechcatie, Gregory Twachtman Contributing Writers Christine Kilgore, Mary Ann Moon, Jennie Smith H aematology & O ncology N ews is an independent newspaper that provides the practicing specialist with timely and relevant news and commentary about clinical developments in the field and about the impact of health care policy on the specialty and the physician’s practice. The ideas and opinions expressed in H aematology &O ncology N ews 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 medication mentioned in this publication. To subscribe to H aematology & O ncology N ews , or to share your feedback with us, email news.au@elsevier.com For a digital edition visit elseviermedcomms.com.au ISSN: 1836-0726 Catherine Cooper Nellist, Terry Rudd, Mary Ellen Schneider, Heidi Splete

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H aematology & O ncology N ews is published by Elsevier Australia ABN 70 001 002 357 475 Victoria Avenue Chatswood NSW 2067, Australia Locked Bag 7500 Chatswood DC NSW 2067 © 2016 Elsevier Inc.

Asfotase alfa STRENSIQ, Alexion

Perinatal, infantile and juvenile-onset hypophosphatasia.

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NEWS 3

Vol. 9 • No. 1 • 2016 • H aematology & O ncology N ews

US task force supports mammography start at age 50 BY SHARON WORCESTER Frontline Medical News From Annals of Internal Medicine

with a family history of breast cancer may benefit more than average-risk women by beginning screening before age 50. This is a C recommendation, indicating “moderate certainty that net benefit is small.” The recommendation for biennial screening of those aged 50–74 is a B recommendation indicating “high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial,” Dr Albert L. Siu, task force chair, reported on behalf of the USPSTF ( Ann Intern Med 2016;164:279-96. doi: 10.7326/M15-2886). The task force found inadequate evidence to recommend for or against screening those aged 75 and older. Final evidence documents, including a systematic review of data on the harms associated with breast cancer screening and a modeling study of the benefits and harms associated ACOG encourages women to discuss this with their doctor, including concerns such as family history of cancer, risk factors such as overweight, and their own personal experiences with breast cancer. It is essential that physicians counsel women about the potential consequences of mammography, including false positives.

recommendations for comment, it noted, ‘Women deserve to be aware of what the science says so they can make the best choice for themselves, together with their doctor.’ We could not agree more. Let’s douse the flames and clear the smoke so that we can clearly see what the evidence shows and where we need to focus efforts to fill gaps in our knowledge so that women, along with their health care providers, can make the best decision to reduce their risk for breast cancer-related morbidity and mortality,” they wrote ( Ann Intern Med 2016 Jan 11. doi:10.7326/M15-2978). ACOG supports screening at 40 The American College of Obstetricians and Gynecologists is standing by its recommendation of annual mammograms begin- ning at age 40 and continues to support use of clinical breast examinations. In a Jan. 11 statement, Dr Mark S. DeFrancesco, ACOG president, said that “evidence and experience have shown that early detection can lead to improved outcomes in women diagnosed with breast cancer.” The organisation similarly stood by its recommendation in October 2015, when the American Cancer Society released recommendations for annual screening mammography for asymptomatic women at average risk for breast cancer begin- ning at age 45 years, with a transition to biennial screening mammography beginning at age 55 ( JAMA 2015;314[15]:1599- 1614. doi: 10.1001/jama.2015.12783). ACOG also supports the omnibus legislation passed by Con- gress in December that provides 2 years of no-copay coverage of breast cancer screening after age 40 via a moratorium on new breast cancer screening recommendations to allow time for ad- ditional research, anACOG spokesperson said in an interview. “ACOG strongly supports shared decision-making between doctor and patient, and in the case of screening for breast cancer, it is essential,” Dr DeFrancesco said. “Given the dif- ferences among current organisational recommendations on breast cancer screening, we recognise that there may be confu- sion among women about when they should begin screening for breast cancer. ACOG encourages women to discuss this with their doctor, including concerns such as family history of cancer, risk factors such as overweight, and their own personal experiences with breast cancer. Moreover, it is essential that physicians counsel women about the potential consequences of mammography, including false positives.” ACOG will convene a consensus conference later in Janu- ary “with the intent to develop a consistent set of uniform guidelines for breast cancer screening that can be implemented nationwide” in an effort to “avoid the confusion that currently exists among the women we treat,” according to the statement. The issue of divergence – and convergence – among various guidelines was the topic of another editorial published in con- junction with the USPSTF recommendations. In that article, task force chair Dr Siu and his colleagues acknowledged that disagreements exist but stressed that “it would be a disservice to women and their clinicians if these disagreements obscured a strong emerging convergence among groups who have recently issued evidence-based guidelines” ( Ann Intern Med 2016 Jan 11. doi:10.7326/M15-3065). The operations of the USPSTF are supported by the Agency for Healthcare Research and Quality. One of the members of the USPSTF reported receiving past grants and contracts from the National Cancer Institute and the Centres for Disease Control and Prevention.

W omen aged 50–74 years should undergo biennial screening mammography, and the decision to screen before age 50 should be individualised, according to a final recommen- dation from the United States Preventive Services Task Force. The recommendation statement, published Jan. 11 in Annals of Internal Medicine , is based on a comprehensive review of data since 2009, when the USPSTF last released breast cancer screening recommendations, and follows a public comment period in early 2015. “The task force continues to find that the benefit of mammog- raphy increases with age, and recommends biennial screening in women ages 50 to 74. Mammography can also be effective for women in their 40s, but the benefits are less and the harms potentially greater. The decision by women to start screening in their 40s should be an individual one, made in partnership with a doctor,” according to a statement from the USPSTF. Recommendations by age The latest USPSTF recommendations by age state that women aged 40–49 years should base their screening decision on personal values, preferences, and health history; women

with different screening strategies, are published along with the recommen- dation statement. The USPSTF did not make a rec- ommendation about the use of digital breast tomosynthesis as a primary screening method for breast cancer, noting that the current evidence is insufficient. Evidence also was insuf- ficient to make a recommendation on the benefits and harms of adjunctive screening for breast cancer using breast ultrasonography, magnetic resonance imaging, digital breast tomosynthesis, or other methods in women with dense breasts who had a negative screening mammogram. Dousing the ‘firestorm’ In an editorial penned by Annals of Internal Medicine Editor-in-Chief and Senior Vice President of the Ameri- can College of Physicians Christine Laine and her colleagues, they urged a dousing of the “firestorm around breast cancer screening.” That firestorm was ignited with the 2009 USPSTF breast cancer screening recommendation and was rekindled when the current recommendation was presented in draft form in 2015. However, “the USPSTF did a diffi- cult job well” and based its recommen- dations on an important understanding of the updated evidence, as well as po- tential harms and tradeoffs of different screening strategies, the authors wrote. “When the USPSTF posted its draft

Health conditions/problems studied

Trial identification

Title

Recruitment

ACTRN12615000963527 The Australasian Malignant Pleural Effusion (AMPLE) trial – 2: a study to evaluate the effect of aggressive daily versus symptomatic IPC drainage on breathlessness and quality of life in patients with a malignant pleural effusion. ACTRN12615000624583 The construction and experience of fertility in the context of cancer: evaluation of the effect of a self-help booklet combined with a health professional consultation versus the self-help booklet alone on quality of life in cancer patients. ACTRN12615000564550 Examining the feasibility of a peer-delivered healthy lifestyle intervention to reduce cardiovascular and cancer disease risk for people living with a severe mental illness: a randomised pilot trial. ACTRN12614000399695 A randomised controlled study comparing the effectiveness and cost-effectiveness of integrated oncogeriatric care with standard oncology care in improving quality of life in adults aged 70 years and older with cancer receiving cytotoxic chemotherapy, targeted therapy or immunotherapy. VIC

NSW, QLD, SA, WA

Malignant pleural effusion

ACT, NSW, NT, QLD, SA, TAS, WA, VIC

Fertility, psychological wellbeing, quality of life, cancer Severe mental illness, cardiovascular disease, cancer

NSW, QLD, WA, VIC

Cancer in older adults

Source: Australian and New Zealand Clinical Trials Registry, www.anzctr.org.au

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H aematology & O ncology N ews • Vol. 9 • No. 1 • 2016

ACOG recommends against annual cervical cancer screening

A history of having had the HPV vaccine series doesn’t obviate the need for screening or change the basic recommendations for screen- ing type or interval, according to the ACOG document. Even the 9-valent vaccine doesn’t cover all cancer-associated HPV. And many women may have had the series after al- ready acquiring an HPV infection, which reduces the vaccine’s efficacy. Finally, the ACOG committee noted that, “long-term efficacy of the vaccine remains incompletely established. Al- though HPV vaccination is an important step toward cervical cancer prevention, it does not remove the need for routine cervical cancer screening.” After age 65 years, screening can be discontinued for women with who have had consecutive negative testing in the prior 10 years. For women who have had grade 2 or 3 cervical intraepithelial neo- plasia (CIN), or adenocarcinoma in situ, screening needs to continue for 20 years after spontaneous regression or treatment. “Women aged 65 years and older do get cervical cancer,” the ACOG committee members wrote. “Women in this age group represent 14% of the US female popula- tion but have 19.6% of the new cases of cervical cancer.” However, since most cases occur in inadequately or unscreened women, and because of the long latency of HPV-driven cancers, “screening women in this age group would prevent very few cases ... [and the slight gain] would come at significant cost, including an increase in required colposcopy procedures.” Changes in most risk factors, including new sexual partners, are not a reason to start screening again in older women because of the long disease latency, according to the ACOG recommendations. Dr Rabin added, “I recon- sider this in certain instances if their status changes, especially if there is immunosuppres- sion, being with a high-risk partner, or having multiple sexual partners.” The guidelines recommend more frequent screening for women previously treated for CIN 2, CIN 3, or cancer; those with HIV infection; those who are immunocompro- mised, including have received solid organ transplants; and those who were exposed to diethylstilbestrol in utero. Women who’ve had a total hysterectomy and no history of CIN 2 or greater don’t need screening, but those who have had a high- grade CIN should continue it, as there can be a recurrence in the vaginal cuff even years later.

BY MICHELE G. SULLIVAN Frontline Medical News From Obstetrics and Gynecology C ervical cancer screening should begin at age 21 years and continue even beyond a woman’s reproductive years, but yearly testing is neither necessary nor recommended for most women, according to new guidelines issued by the American College of Obstetri- cians and Gynecologists. Since cervical cancer is “a rather indolent disease,” more frequent testing is much more likely to result in anxiety and unnecessary treat- ment than in preventing cancers, according to the document, which was published online in Obstetrics and Gynecology (2016;127:e1–20). “Annual screening leads to a very small increase in cases of cancer prevented at the cost of a very large excess of procedures and treatments and should not be performed,” members of the ACOG Committee on Prac- tice Bulletins–Gynecology wrote. Excisional procedures can confer an increased risk of preterm birth – another serious consideration when determining the frequency of screening. And, wrote the committee, the psychosocial aspects of earlier screening must also be taken into account. “The emotional effect of labelling an ado- lescent with a sexually transmitted infection and potential precancer must be considered, because adolescence is a time of heightened concern for self-image and emerging sexuality,” they wrote. Recommendations in this set of guidelines dif- fer slightly from those published in 2015 by the Society of GynecologicOncology (SGO) and the American Society for Colposcopy and Cervical Pathology (ASCCP). Both the SGO andACOG documents take into account the recently ap- proved HPV DNA test, which is indicated as a primary cervical cancer screening tool. The test detects 14 high-risk HPV types, and specifically identifies HPV 16 and 18. A positive result for either of those types should prompt a colposcopy; women who test positive for any of the other 12 high-risk types should have a Pap test. The SGO guidelines say that primary HPV testing alone can be considered for women beginning at age 25 years. The ACOG docu- ment also notes that HPV testing alone can be considered an alternative for women older

21–29 years, cervical cytology alone is suffi- cient for these women, and primary HPV co- testing is not appropriate. The recommended screening interval is every 3 years. HPV testing is more sensitive than is cytol- ogy but less specific, the authors said. And because women in this age group often have noncarcinogenic, transient HPV infections, co-testing could drive more testing and inter- ventions without decreasing cancer incidence. For women aged 30–65 years, however, HPV testing combined with cervical cytology is the optimum choice and should be conducted every 5 years. If cytology alone is performed, however, the recommended interval is every 3 years. Any woman in this age group who has an HPV-positive co-test with negative cytology should be retested with both methods in 12 months. A colposcopy is recommended if the repeat cervical cytology test result is unspeci- fied atypical squamous cells or higher, or if the HPV test result is still positive. Otherwise, the next co-testing can occur 3 years later. As an alternative strategy, an immediate HPV genotyping can be performed; if high-risk strains are present, an immediate colposcopy is indicated.

than 25 years but stresses that cytology alone or co-testing remain the options specifically recommended in current major society guide- lines. If screening with the primary HPV test is used, it should be performed according to the SGO guidance, the ACOG document states. Dr Jill Rabin favours the ACOG recommen- dations over HPV-only testing. She is a profes- sor of obstetrics and gynaecology and cochief of the division of ambulatory care, Women’s Health Programs – Prenatal Care Assistance Program Services at Northwell Health, New Hyde Park, New York “I know certain groups – and not just SGO – go with just the HPV-only test, but I can’t bring myself to do that,” she said in an interview. “Most of the literature agrees that you need to look at both cytology and HPV testing to get the best results. And all cervical cancer is not driven by HPV infections.” The ACOG document stresses that sexual initiation – whatever the age – should not be the precipitating factor for the first cervical cancer screening. HPV infections are normally acquired very quickly after vaginal intercourse begins, although nearly all cases are naturally cleared within a couple of years. From ages

KIR2DL5B genotype predicts outcome in chronic phase CML BY JENNIFER SHEPPHIRD Frontline Medical News From Blood T he presence of KIR2DL5B was associated with lower rates of major molecular response KIR genotypes, KIR2DL2pos and KIR2DS3pos, were also associated with inferior achievement of MMR, probably because of their associa- tion with KIR2DL5B due to linkage disequilibrium among KIR genes, according to the investigators.

samples available for genotyping. KIR genotype frequencies ob- served in this study were similar to other white populations reported in the Allele Frequency Database. Early molecular response was also significantly associated with treat- ment outcomes, independent of KIR prognostic significance, and may add additional prognostic information, available 3 months after treatment commences. “In contrast, KIR2DL5B can iden- tify, at baseline, the 20% of patients with a transformation risk of [about] 10% over 2 years versus the 80% of patients with a transformation risk of less than 3%,” the authors wrote. They suggest that KIR2DL5B, com- bined with other predictive markers, may enable targeted early interven- tions to improve outcomes.

Even with the potent second-generation TKI [tyrosine kinase inhibitor] nilotinib, KIR genotypes, a predetermined genetic host factor, may still be one of the most discriminatory prognostic markers available at baseline.

(MMR), transformation-free sur- vival, and event-free survival (but not overall survival) in patients with chronic phase-chronic myeloid leukaemia (CP-CML) treated with sequential imatinib/nilotinib, ac- cording to researchers. Univariate analysis demonstrated a significant association between KIR2DL5B and achievement of a major molecular response, with hazard ratio 0.423 (95% CI, 0.262–0.682; P < 0.001). Other

inhibitory KIR receptor, the absence of which may increase efficiency of NK-mediated killing of leukaemic stem cells, researchers suggested. The Therapeutic Intensification in De Novo Leukaemia (TIDEL-II) study included 210 patients with CP-CML who were treated with imatinib initially, and nilotinib sub- sequently if predetermined molecu- lar targets were not met. The KIR substudy included 148 patients with

( Blood 2015 Dec 17. doi:10.1182/ blood-2015-07-655589). Killer immunoglobulin-like recep- tors (KIRs) contribute to natural killer (NK) cell-mediated killing of tumour cells, in both activating and inhibi- tory roles. Normal cells are spared through actions of inhibitory KIRs. Although the mechanism underlying the association between KIR2DL5B and CP-CML treatment outcomes is still unclear, the gene encodes an

“Our findings suggest that even with the potent second-generation TKI [tyrosine kinase inhibitor] nilo- tinib, KIR genotypes, a predeter- mined genetic host factor, may still be one of the most discriminatory prognostic markers available at base- line,” wrote Dr David T. Yeung of the department of genetics and molecu- lar pathology, Centre for Cancer Bi- ology and the University of Adelaide, South Australia, and colleagues

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Vol. 9 • No. 1 • 2016 • H aematology & O ncology N ews

EADV: Vismodegib treatment breaks don’t hurt efficacy

and partial response rates were 34% and 33%, respectively, in patients with locally advanced BCC, and 7% and 31% in those with meta- static disease (Lancet Oncol 2015 Jun;16[6]:729–36). Dr Hansson presented new data on efficacy outcomes broken down ac- cording to treatment breaks, as well as quality of life results, at the annual congress of the European Academy of Dermatology and Venereology. Twenty-six percent of patients had one or more treatment breaks. Seventy-six patients had one, 41 had two, and 14 had three or more. The median duration of the breaks was 22 days. The two most frequent reasons for treatment breaks were intolerable adverse events in 53% of cases, and lesser adverse events in 23%. Close to 100% of STEVIE par- ticipants had treatment-emergent adverse events. The most common were muscle spasms, alopecia, al- tered sense of smell, and weight loss. Although the number of pa- tients with treatment breaks was relatively small, the response rates were higher in patients with more treatment breaks. So was median treatment duration as well as the median number of capsules taken. Median progression-free survival was 19.8 months in patients with no treatment breaks, was 19.0 months

BY BRUCE JANCIN Frontline Medical News

BCC, with median improvements of 14.3 points after two cycles and 23.8 points after seven cycles and at the 12-month mark. Clinically meaning- ful improvement in symptom scores on the Skindex-16 were noted in pa- tients aged 65 and older, in women, and in those with BCCs in locations other than the head or neck. However, no clinically meaningful improvement in the domain of function was seen at any time in patients with locally advanced BCC. Patients with metastatic BCC didn’t show significant improvement in any of the three quality of life domains at any time point, added Dr Hansson. The STEVIE trial is sponsored by F. Hoffmann–La Roche/Genentech. Dr Hansson reported receiving re- search grants from and serving as a consultant to Bristol-Myers Squibb, GlaxoSmithKline, Merck, Novartis, and Roche. We have to remember that although intriguing, these are tentative results from an exploratory analysis of subgroups in an ongoing study and should be interpreted with caution.

Impact of vismodegib treatment breaks

At the EADV congress 2015, Copenhagen T reatment breaks due to adverse events in patients taking vismo- degib for advanced basal cell carcinoma do not appear to com- promise the oral hedgehog pathway inhibitor’s efficacy; in fact, they might even enhance it, according to a prespecified interim analysis of the STEVIE trial. STEVIE is an ongoing phase II, long-term, open-label international study designed primarily to assess the safety of vismodegib in a situa- tion similar to routine clinical prac- tice. Efficacy and impact on quality of life are secondary endpoints. Al- though STEVIE has enrolled 1227 patients, a prespecified interim analysis was conducted in the first 499 followed for at least 12 months, of whom 468 had locally advanced basal cell carcinoma (BCC) and 31 had metastatic BCC, explained Dr Johan Hansson, an oncolo- gist at the Karolinska Institute in Stockholm. The drug was dosed at 150 mg once daily continuously in 28-day cycles until disease progression, intolerable toxicity, or study with- drawal. Safety follow-up was con- ducted at 1, 3, 5, 9, and 12 months. In an earlier report, the complete

Number of treatment breaks

None

One

Two

Three or more

Median treatment duration, days

223.5

289

399

454

Median dose intensity

97% 89% 86% 81%

Median number of capsules taken

215

256

354

380

Occurrence of grade 3 or higher TEAEs*

39% 45% 66% 79%

Grade 5 events

5% 4%

0

7%

Complete response

30% 33% 51% 39%

Partial response

31% 32% 44% 46%

Stable disease

28% 32% 5% 15%

*treatment-emergent adverse event Note: The interim analysis included the first 499 patients followed for at least 12 months. Source: Dr Hansson

deliberate intermittent dosing of vismodegib. Quality of life was assessed using the Skindex-16 questionnaire at baseline, again after two and seven 28-day cycles of vismodegib, and at 12 months. Three domains were examined: emotion, function, and symptoms. A clinically meaningful improve- ment – defined as a 10-point or greater reduction from baseline – was seen in the emotion domain at all time points in patients with locally advanced

in those with one, and hasn’t yet been reached in patients with two or more breaks. In interpreting these findings, Dr Hansson said, “We have to re- member that although intriguing, these are tentative results from an exploratory analysis of subgroups in an ongoing study and should be interpreted with caution.” The oncologist added, however, based upon these promising results he and his coinvestigators plan to look further into the concept of

RETHINK WHAT'S POSSIBLE...

CLL ZYDELIG + rituximab delivers significant efficacy for a broad range of relapsed CLL patients vs. rituximab + placebo 1-3

FL ZYDELIG monotherapy delivers rapid and durable efficacy in refractory FL patients after ≥ 2 lines of therapy 4

ZYDELIG has a manageable safety profile across a broad range of relapsed CLL and FL patients with most AEs grade 1-2 1,4-6

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SEE APPROVED PRODUCT INFORMATION BEFORE PRESCRIBING. APPROVED PRODUCT INFORMATION AVAILABLE FROM HTTPS://WWW.EBS.TGA.GOV.AU/EBS/PICMI/PICMIREPOSITORY.NSF/PDF? OPENAGENT&ID=CP-2015-PI-01225-1 Minimum Product Information ZYDELIG ® (idelalisib) 100 mg and 150 mg Tablets. INDICATIONS: with rituximab for CLL/SLL where chemo-immunotherapy is unsuitable, either: upon relapse after at least one prior therapy, or first-line with 17p deletion or TP53 mutation. Monotherapy of refractory follicular lymphoma after at least two prior systemic therapies. DOSAGE AND ADMINISTRATION: 150 mg twice daily. Dose modification may be required. CONTRAINDICATIONS: hypersensitivity. PRECAUTIONS: Hepatotoxicity: monitoring required. Hepatitis Infection and Reactivation: prior screen for HBV and HCV. Diarrhoea/Colitis: assessment of hydration and dose interruption shouldbeconsidered inseverecases. Pneumonitis: Dose interruptionshouldbeconsideredwithanyseverityofsymptomaticpneumonitis. Immunisation: Vaccinationprior to treatmentofpatientsatsubstantialriskofan infection. Neutropenia, Anaemia, Lymphopenia and Thrombocytopenia. Severe Cutaneous Reactions: life-threatening (Grade ≥ 3) cutaneous reactions. Fatal cases of SJS-TEN have occurred when patients were treated with Zydelig when administered concomitantly with other medications associated with SJS-TEN. Treatment should be interrupted immediately if SJS or TEN is suspected and permanently discontinued where there is a case of severe cutaneous reaction. Intestinal Perforation: discontinue permanently. Progressive Multifocal Leukoencephalopathy (PML): diagnosis should be considered with new onset of, or changes in pre-existing neurologic signs and symptoms. Transient Lymphocytosis. Infections: patients with signs of infection should be promptly treated. Effects on Fertility: highly-effective contraception during and 1 month after. Pregnancy (Cat. D). Lactation. Children (<18 years). INTERACTIONS WITH OTHER MEDICINES: Effects of other drugs on Zydelig: CYP3A Inducers (rifampin, phenytoin, St. John’s Wort, or carbamazepine). CYP3A Inhibitors (ketoconazole). Effects of Zydelig on other drugs: CYP3A Substrates (alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, fentanyl, quinidine, ergotamine, dihydroergotamine, midazolam, certain antiarrhythmics, calcium channel blockers, benzodiazepines, HMG-CoA reductase inhibitors, phosphodiesterase-5 (PDE5) inhibitors,

and warfarin), refer to full PI. ADVERSE EFFECTS: Neutropenia, Pneumonitis, Diarrhoea/Colitis, Transaminases increased, Rash, Pyrexia. This is not the full Product Information. Please review the full Product Information before prescribing. Product Information is available on request from Gilead Sciences Pty Ltd. Date of preparation 16 December 2015. References: 1. Furman RR et al. N Engl J Med 2014;370:997–1007. 2. Sharman JP SE et al. Second Interim Analysis of a Phase 3 Study of Idelalisib (ZYDELIG ) Plus Rituximab (R) for Relapsed Chronic Lymphocytic Leukemia (CLL): Efficacy Analysis in Patient Subpopulations with Del(17p) and Other Adverse Prognostic Factors. The American Society of Hematology (ASH) 56th Annual Meeting, 6–9 December 2014, San Francisco, CA, USA: Abstract 330. 3. Coutre SE et al. Second interim analysis of a phase 3 study evaluating idelalisib and rituximab for relapsed CLL. J Clin Oncol 2014;32(Suppl): Abstract 7012. 4. Gopal AK et al. N Engl J Med 2014;370:1008–18 4. Salles G et al. Idelalisib efficacy and safety in follicular lymphoma patients from a phase 2 study. J Clin Oncol 2015;33(Suppl): Abstract 8529. 6. Zydelig Product Information, 16 December 2015.

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NEWS 6 CONFERENCE COVERAGE

H aematology & O ncology N ews • Vol. 9 • No. 1 • 2016

BCG/sunitinib combo produces high complete response rate in NMIBC

ASCO Genitourinary Cancers Symposium 2016 7–9 January 2016 • San Francisco, California The 2016 Genitourinary Cancers Symposium was a 3-day scientific and education meeting sponsored by the American Society of Clinical Oncology. On pages 6 and 7, we bring you selected reports from our coverage of the meeting, including on aspirin’s potential protective effect against fatal prostate cancer, BMI and its impact on the outcome of patients with metastatic kidney cancer, and trials that failed to boost survival of men with metastatic castration-resistant prostate cancer.

mortality rate of 4–25%, Dr Helfand noted. “Complete response to BCG at 3 months has been shown to predict future recurrence-free sta- tus. Consolidating the initial tumour response to BCG with adjunctive therapies may help improve outcomes,” he said. BCG downregulates vascular endothelial growth factor (VEGF) receptors, and sunitinib binds to VEGF receptors to prevent vascular growth. To see whether the combined therapies could act synergistically, investigators treated patients with 6-weeks of BCG induction beginning within 6 weeks of diagnostic or restaging biopsy, followed by a 2-week hiatus, then 28 days of oral sunitinib 50 mg/day. Patients with a complete response at 3 months went on to BCGmaintenance, while those with an incomplete response or recurrence at 3 months went on to a second cycle of BCG followed by sunitinib. Patients with disease progression after either treatment cycle were treated with alternative therapies at the treating clinician’s discretion. A total of 36 of 39 patients completed BCG induction and at least one dose of sunitinib, and these patients were included in the efficacy analy- sis. The safety analysis was by intention to treat, and therefore included all 39 patients. The complete response rate at 3 months after cycle one, the primary endpoint, was 73% (26 of 36 patients). Of the responders, 73% have started on BCG maintenance, 23% had no maintenance BCG and no evidence of disease at last follow-up, and the remaining 4% had cystectomies.

BY NEIL OSTERWEIL Frontline Medical News

A combination of intravesical bacillus Calmette- Guerin (BCG) followed by sunitinib produced high complete response rates in patients with high-risk, non-muscle invasive bladder cancer. In a phase II trial, 26 of 36 patients (72%) with non-muscle invasive bladder cancer (NMIBC) had a complete response following bladder installation of BCG and consolidation therapy with sunitinib (Sutent), reported Dr Alexander M. Helfand of the University of Michigan Com- prehensive Cancer Centre, Ann Arbor. “Adding sunitinib after BCG induction may result in increased rates of complete response at 3 months over those of BCG alone. The durability of response appears promising, given a 77% 2-year recurrence in high-risk patients with non-muscle invasive bladder cancer,” he said at the 2015 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. “Certainly, this study provides the rationale to consider antiangiogenic therapy in the non- muscle invasive setting,” said Dr Jonathan E. Rosenberg of Memorial Sloan Kettering Cancer Centre, New York, the invited discussant. Induction and maintenance therapy with BCG is the mainstay of initial treatment of high-risk NMIBC. It has been associated in clinical studies with 3-month complete response rates ranging from 28% to 85%, 5-year cumulative recurrence rates from 50% to 55%, 5-year cumulative progres- sion rates of 8–20%, and a 10-year disease-specific

The results look quite good. Toxicity and tolerability, though, do make me concerned.

Of the 28% (10 patients) with residual disease at 3 months, four underwent cystectomy, two had Ta low-grade recurrences which were managed with repeat resection, and two elected a second BCG induction/sunitinib cycle. There were a total of 127 adverse events deemed to be minor among 34 patients, and 6 major adverse events occurring in 5 patients. The major events included rash on hands and feet, hand and foot syndrome, thrombocytopenia, febrile diarrhoea, sores on hands and feet, and reactivation of herpes zoster. In all, 13 patients required some delay of suni- tinib therapy, primarily due to jaundice/elevated liver enzymes or thrombocytopenia. All adverse events disappeared at the end of therapy. Of the 31 patients with an intact bladder, 2 years recurrence-free survival was 77%, and 2-year progression-free survival was 100%. Dr Rosenberg, the discussant, noted that over- all “the results look quite good. Toxicity and toler- ability, though, do make me concerned, and future trials might consider dose reduction [of sunitinib] at the start to 37.5 mg to actually increase the number of patients and time on therapy.” arm: objective response rates were 30.5% and 31.9%, respectively; median time to prostate- specific antigen progression was 8 months vs 7.6 months; uNTx reduction was 66% vs 60.6%; pain reduction was 66.6% vs 71.5%; progression-free survival was 11.8 months vs 11.1 months. The one exception was median time to first skeletal event, which was not reached in the dasatinib group and was in 31.1 months for the placebo group. Dr William Oh, chief of haematology and medical oncology at Tisch Cancer Institute and the Mount Sinai School of Medicine, New York, commented that “about two-thirds of the patients were not on bisphosphonates, which may explain why there was a trend toward a benefit in terms of (skeletal-related events)” in the dasatinib arm. DrAraujo reported there were no unexpected safety findings and no unanticipated events. Patients came off the trial for similar reasons in both arms, including disease progression and maximum clinical benefit. Adverse events re- lated to treatment included diarrhoea, fatigue, alopecia, and nausea and occurred in 18% of patients in the dasatinib arm and in 9% in the placebo arm. Grade 3–4 adverse events of inter- est included anaemia (8% vs 5.9% in placebo), neutropenia (6.2% vs 5.5%), hypocalcaemia (3.5% vs 3.1%), gastrointestinal bleeding (2.6% vs 1.3%), and pleural effusion (1.3 vs 0.4%). Dr Araujo has received research funding from Bristol-Myers Squibb, the maker of Sprycel and sponsor of the trial. Dr Oh has been consultant or adviser for Amgen, Astellas Pharma, Bayer, Bellicum Pharmaceuticals, Dendreon, Janssen Biotech, Medivation, and Pfizer. He has received research funding from Millennium.

Dasatinib adds no survival benefit to docetaxel in mCRPC BY NASEEM S. MILLER Frontline Medical News

Texas MDAnderson Cancer Centre, Houston. In READY, 1522 patients were randomised to receive docetaxel (75 mg/m 2 , three times a week) plus prednisone and either 100 mg daily of dasatinib (762 patients), or placebo (760 patients). There were no meaningful differences in the demographics or disease characteristics of the two study arms. Patients were treated until disease progression or they had unac- ceptable toxicity. The primary endpoint of the study was overall survival. The secondary endpoints were objective response rates, time to first skeletal- related event, time to prostate-specific antigen progression, urinary N-telopeptide (uNTx) reduction, pain reduction, progression-free survival, and safety. Overall survival was 21.5 months in the dasatinib group and 21.2 months in the placebo group (hazard ratio, 0.99; P = 0.90). Comparably similar outcomes were seen in secondary endpoints for dasatinib vs placebo

A dding dasatinib to standard-of-care chem- otherapy led to a modest delay in skeletal- related events but did not improve overall survival for patients with metastatic castrate- resistant prostate cancer in the READY trial. Dasatinib, a tyrosine kinase inhibitor, showed promising results in phase I and II studies, but fell short in READY, a multina- tional randomised double-blinded, placebo- controlled study, sponsored by Bristol-Myers Squibb. With no difference in overall survival and no meaningful changes in the study’s secondary endpoints, the search continues for treat- ments for this group of patients whose cur- rent options are mostly palliative with modest improvements in survival. The observed delay in skeletal-related events with dasatinib is be- ing further investigated, said the study’s lead author, Dr  John C. Araujo of the University of

Dr Fred Saad, professor and chief of urology and director of G-U Oncology at the University of Montreal Hospital Centres, deliv- ers highlights of the past year’s prostate cancer research at the ASCO GU symposium. He point- ed out that “although there were no new drugs approved in 2015, we learned a lot about what we have available – some good and some not so good.” From a clinical perspective, and with a focus on topics that con- firm or change current practice, PracticeUpdate summarises five key topics from prostate cancer research published in 2015: screening and active sur- veillance (Part 1); local therapy (Part 2); and androgen deprivation therapy, chemotherapy in men with hormone-sensitive disease, and new options in metastatic prostate cancer (all in Part  3). This exclusive report is available on www.practiceupdate.com

PracticeUpdate is an Elsevier website.

© ASCO/Todd Buchanan 2016