Trials Of Novel Agents Research Articles

How far have we really come? Trends in survival and mortality for gliomas between 1973 to 2014 from SEER.

2038Background: Historical controls are often used as benchmarks for early stage, single arm trials of novel agents. We have investigated whether general or specific changes in the treatment of pat...

Survival by age in children and adolescents with Hodgkin lymphoma: A pooled analysis of Children’s Oncology Group (COG) trials.

7543 Background: The National Cancer Institute defines adolescent/young adult as 15-39y. Guidelines from ASCO and Friends of Cancer Research call for including children ≥12y on late phase trials spanning children and adults. We examined whether, in children and adolescents receiving response-based therapy for Hodgkin lymphoma (HL), age ≥12y would define a group with inferior outcomes compared to younger patients. Methods: This was a pooled analysis of individual patient-level data from three COG Phase 3 trials for intermediate, low, high-risk HL (AHOD0031, AHOD0431, AHOD0831). 5-yr event free survival (EFS) and overall survival (OS) by age were estimated via Kaplan Meier method. Cox regression models examined the influence of age on EFS and OS, adjusted for race/ethnicity, sex, insurance, histology, Ann Arbor stage, B symptoms, bulk, study, and radiation therapy (RT). Results: We included 2071 of 2155 patients, 1-21y enrolled from 2002 -2012. Mean age at diagnosis was 14.6y (±3.5) with 54% ≥15y (N = 1121) and 81% ≥12y (N = 1684). At median follow-up of 6.9 years, patients < 15y had statistically significantly better EFS ( < 15y: 85% vs. ≥15y: 80%, p = 0.02). A difference in EFS was noted in those < 12y vs. ≥12y (87% vs. 81%, p = 0.0503). OS was significantly better in patients < 15y vs. ≥15y (98% vs. 95%, p = 0.006), but did not differ in < 12y vs. ≥12y (99% vs. 97%, p = 0.136). Cumulative incidence of second malignant neoplasm did not differ by age category. In multivariable models, older age was an independent predictor of treatment failure in both age categories (Table). Conclusions: With contemporary, response-based therapy on COG trials, adolescents ≥12 and ≥15y had worse EFS than younger groups. This suggests that children ≥12y may benefit from therapy escalation and inclusion in late phase trials of novel agents incorporating antibody drug conjugates or checkpoint inhibitors. Multivariable cox model of 5-yr EFS and OS by age group. 5-yr EFS 5-yr OS HR 95% CI p-value HR 95% CI p-value < 12 years (R: ≥12) 0.71 (0.51, 0.98) 0.04 0.51 (0.2, 1.34) 0.17 < 15 years (R: ≥15) 0.74 (0.59, 0.93) 0.01 0.39 (0.2, 0.76) 0.006 HR: hazard ratio; 95%CI: 95% confidence interval; R: reference group

Abstract P6-03-05: Risk of needle-track seeding with serial ultrasound guided biopsies in triple negative breast cancer

Abstract Background: Image-guided percutaneous needle biopsy of the breast is a common procedure. In breast cancer patients (pts) undergoing core biopsies and surgical resection on the same day, the rate of tumor cell displacement along the needle track has been reported to be up to 50%. However, the clinical significance of this finding in triple negative breast cancer (TNBC) patients (pts) undergoing serial biopsies while receiving neoadjuvant chemotherapy (NACT) is unknown. Here we report the incidence of needle-track seeding (NTS) in a cohort of TNBC pts enrolled on a molecular triaging protocol involving serial biopsies of the index breast lesion. Methods: We reviewed the clinical records of 144 consecutive TNBC pts enrolled on a molecular triaging protocol at MD Anderson Cancer Center. Per protocol, all pts underwent a pre-treatment research biopsy and were initiated on anthracycline based NACT (AC). Pts with inadequate response to front-line NACT were encouraged to undergo additional biopsies of the index breast lesion prior to switching therapies. Serial breast ultrasound (US) was performed to monitor therapeutic response and incidental evidence of needle-track seeding noted on US was documented. Results: Clinicopathological characteristics of the pts are summarized in Table 1. 89% (128/144) of pts had a diagnostic breast biopsy done at another center prior to presenting at MDACC. To date, we have performed 209 US guided biopsies of index breast lesions in 144 pts. 92% (193/209) of these biopsies were done mainly for research purposes. 1.4% (2/144) of pts were found to have evidence of NTS on follow up US. The first pt had a T1N0 (1.9cm), grade 3, invasive ductal carcinoma (IDC) at diagnosis. She underwent a diagnostic biopsy followed by a research biopsy before initiating AC. She was found to have NTS as well as progression of disease (PD) on follow up US after 2 cycles of AC. The second pt had a T2N0 (3cm), grade 3 IDC at diagnosis. She underwent a diagnostic biopsy at another center, followed by a research biopsy before initiating AC. Like the first pt, she was found to have NTS and PD on follow up US after 2 cycles of AC. Both pts are currently on neoadjuvant clinical trials of novel agents. Conclusion: The rate of NTS detected on US in TNBC pts undergoing serial biopsies of index breast lesions while receiving NACT is low and further studies are needed to determine the impact of serial biopsies on long term outcomes in TNBC. Table 1: Patient CharacteristicsCharacteristicN=144Age - Median (years, interquartile range)55 (46-62)Tumor Size Mean (cm, standard deviation)3.4 (2.2)T1 – n(%)35 (24)T2 – n(%)89 (62)T3 – n(%)19 (13)T4 – n(%)1 (1)Clinical Nodal Status Negative – n(%)74 (51)Positive – n(%)70 (49)Grade 1 – n(%)1 (1)2 – n(%)17 (12)3 – n(%)124 (86)Unknown – n(%)2 (1)Histologic Subtype Invasive ductal carcinoma – n(%)121 (84)Invasive lobular carcinoma – n(%)2 (1)Mixed ductal and lobular carcinoma – n(%)3 (2)Metaplastic carcinoma – n(%)13 (9)Not specified – n(%)5 (3)Laterality Right – n(%)72 (50)Left – n(%)72 (50) Citation Format: Yam C, Santiago L, Candelaria RP, Adrada BE, Rauch GM, Hess KR, Litton JK, Piwnica-Worms H, Mittendorf EA, Ueno NT, Lim B, Murthy RK, Damodaran S, Helgason T, Huo L, Thompson AM, Gilcrease MZ, Symmans WF, Moulder SL, Yang W. Risk of needle-track seeding with serial ultrasound guided biopsies in triple negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-03-05.

Renal Medullary Carcinoma: Establishing Standards in Practice.

Although renal medullary carcinoma (RMC) is a rare subtype of kidney cancer, it is particularly devastating in that it is nearly uniformly lethal. No established guidelines exist for the diagnosis and management of RMC. In April 2016, a panel of experts developed clinical guidelines on the basis of a literature review and consensus statements. The goal was to propose recommendations for standardized diagnostic and management approaches and to establish an international clinical registry and biorepository for RMC. Published data are limited to case reports and small retrospective reviews. The RMC Working Group prepared recommendations to inform providers and patients faced with a low level of medical evidence. The diagnosis of RMC should be considered in all patients younger than 50 years with poorly differentiated carcinoma that arises from the renal medulla. These patients should be tested for sickle cell hemoglobinopathies, and if positive, SMARCB1/INI1 loss should be confirmed by immunohistochemistry. The majority of patients with RMC are diagnosed with metastatic disease. Upfront radical nephrectomy should be considered in patients with good performance status and low metastatic burden or after response to systemic therapy. Currently, cytotoxic, platinum-based chemotherapy provides the best, albeit brief, palliative clinical benefit. Vascular endothelial growth factor-directed therapies and mammalian target of rapamycin inhibitors are ineffective in RMC as monotherapy. Therapeutic trials of novel agents are now available for RMC, and every effort should be made to enroll patients in clinical studies.

Anthracycline, gemcitabine, and pazopanib in epithelioid sarcoma: Results of a retrospective multi-institutional case series.

11065 Background: To report on a multi-institution retrospective study on the activity of anthracycline-based (Ab) and gemcitabine-based (Gb) regimens as well as pazopanib (P) in patients with advanced epithelioid sarcoma (ES) treated within 16 sarcoma reference centres in Europe, US and Japan. Methods: Patients with a histologically confirmed diagnosis of locally advanced/metastatic ES were selected. Classic and distal subtypes were defined based on morphology (WHO 2014). INI1 expression is under evaluation.Response was evaluated by RECIST.Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. Results: Ninety ES patients were identified (Table 1). They were treated with Ab (72), Gb (30) and P (20); 25 pts received more than one treatment. The median follow-up for Ab, Gb and P groups was 32, 24 and 22 months, respectively. The response rate (RR) for Ab was 25% (95% CI 16%-37%), with a median PFS and OS of 6 and 17 months. The RR for Gb was 23% (95% CI 10% - 42%), with 1 complete response and a median PFS and OS of 5 and 20 months. In the P group, no objective responses were reported, and median PFS and OS were 3 and 9 months. A non-statistically significant trend towards a greater RR in proximal than classic subtype was seen in both Ab (27% vs 22%) and Gb (30% vs 13%) groups. Conclusions: This retrospective series, the largest currently available, confirms the activity of Ab and Gb in ES, with a similar RR and PFS in both groups. In this population, the value of P seems limited. These data may serve as a benchmark for trials of novel agents in ES. [Table: see text]

Characterization of patients (pts) with poor risk metastatic renal cell carcinoma (mRCC): Results from a pooled clinical trials database.

515 Background: Survival outcomes are heterogeneous across different subsets of mRCC pts. Poor risk pts have grim outcomes and are less likely to be enrolled in clinical trials, hence the lack of prospective data characterizing this pt population. We provide a comprehensive analysis of poor risk pts, as defined by three widely used prognostic models, in the era of targeted therapy. Methods: We conducted a pooled retrospective analysis of 4,736 mRCC pts treated on phase II and III clinical trials. Pts were defined as poor risk according to the Memorial Sloan Kettering Cancer Center (MSKCC), International Metastatic Database Consortium (IMDC), and Hudes prognostic risk models. We evaluated overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) in poor risk pts in each of the risk models in the total cohort and in a subset of pts who remained on treatment for &gt;12 months (mos). The models’ concordance (c-) index was used to assess their prognostic performance. Results: We identified 1145 (24.2%), 904 (19.1%), and 1901 (40.1%) poor risk pts by IMDC, MSKCC, and Hudes models, respectively. The majority were &lt;65 years of age (70-73%) with clear-cell histology (85-88%), prior nephrectomy (62-66%), and no prior systemic therapy (80-86%). The efficacy and toxicity outcomes as well as the c-indexes for each of the models are reported in the table below. Additionally, 9-14% of poor risk pts remained on therapy for &gt;12 mos and had higher OS (29.8-35.2 mos) and ORR (42-53%). Conclusions: In this large database of poor risk mRCC pts, we highlight that the models have similar predictive accuracy in the targeted therapy era. We also demonstrate that poor risk pts continue to have dismal outcomes and should be considered for trials of novel agents and combinations. A subset of these pts appears to derive prolonged clinical benefit and should be further explored.[Table: see text]

Characterization of Real World Survival Outcomes Among Older Adults with Chronic Lymphocytic Leukemia Receiving Second Line Treatment in the Pre Novel-Agents Era: An Analysis of the 2007-2013 SEER-Medicare Database

Characterization of Real World Survival Outcomes Among Older Adults with Chronic Lymphocytic Leukemia Receiving Second Line Treatment in the Pre Novel-Agents Era: An Analysis of the 2007-2013 SEER-Medicare Database

Clinical Trial Availability in Adolescent and Young Adult Patients with Non-Hodgkin Lymphoma

IntroductionIncidence of non-Hodgkin lymphoma (NHL) in adolescent and young adults (AYAs) has increased over the last 25 years. Diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, anaplastic large cell lymphoma, lymphoblastic lymphoma, and primary mediastinal B-cell lymphoma are the most common subtypes in patients between the ages of 15 and 19; follicular lymphoma has increased incidence in AYAs who are at least 20 years old.1 Additionally, AYAs with non-Hodgkin lymphoma have increased relapse rates and increased mortality compared to both their childhood and adult counterparts.2 Clinical trials of novel agents often exclude subjects under the age of 18. Because of this, we hypothesized that treatment in adult centers may be associated with increased availability of clinical trials studying novel agents in these at-risk patients.MethodsA keyword search of "Non-Hodgkin Lymphoma" in the database maintained by ClinicalTrials.govwas performed on May 1, 2016. Age groups, sample size, information on the studied agents, and lymphoma subtypes were collected, as well as whether study sites were members of the Children's Oncology Group. Seventeen categories of novel agents were identified; data was collected on any novel agent contained within a trial protocol.ResultsOf the 726 trials in the initial data set, 404 trials were included in our analysis; studies were excluded from the analysis if the study regimen did not contain a novel pharmacologic agent, or if they focused solely on a transplant conditioning regimen. Sixty-one studies (15%) of novel agents were open to enrollment for subjects under the age of 18 (Table 1). Twenty-five (25) of these trials of these utilized cellular therapy (CAR-T cells, donor lymphocytes, and cytotoxic T lymphocytes). Trials of tyrosine kinase inhibitors (7), novel small molecules (7), monoclonal antibodies (5) were the next-most common agents utilized in clinical trials with the remaining agent classes further detailed in Table 2.Of the 343 trials that were limited to patients who were at least 18 years old, 227 (66%) trials allowed the enrollment of subjects with DLBCL, Burkitt lymphoma, anaplastic large cell lymphoma, lymphoblastic lymphoma, follicular lymphoma, and primary mediastinal B cell lymphoma.All agent classes were represented in trials open to patients who were at least 18 years old; however, three agent classes were excluded from clinical trials in the under-18 subset: BiTE immunotherapy, PI3K inhibitors, and pleiomorphic pathway modifiers. Additionally, 178 of 343 trials (51%) included in the analysis that excluded patients under 18 years old had at least one study site which was a member of the Children's Oncology Group.ConclusionsAdolescent and young adult patients with non-Hodgkin lymphoma have higher relapse rates and lower survival rates than both their pediatric and older adult counterparts. The vast majority of trials study novel agents in the NHL subtypes that most commonly affect the adolescent and young adult population. Half of the trials that exclude patients under 18 years old take place at Children's Oncology Group member sites. While this suggests that adolescent and young adult patients treated at Children's Oncology Group member sites may have access to trials studying novel agents, the extent to which AYAs are being enrolled in these trials requires further study.[1]Hochberg, J., Waxman, I.M., Kelly, K.M., Morris, E. & Cairo, M.S. (2009) Adolescent NHL and Hodgkin lymphoma: state of the science. Br J Haematol, 144, 24-40.[2] Bleyer A, O'Leary M, Barr R, Ries LAG (eds): Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival: 1975-2000. National Cancer Institute, NIH Pub. No. 06-5767. Bethesda, MD 2006. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Characterization of Real World Treatment Patterns and Outcomes Among Older Adults with Chronic Lymphocytic Leukemia in the Pre Novel-Agents Era: An Analysis of the 2007-2013 SEER-Medicare Database

Background: Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in Western countries with a median age of 72 years at diagnosis. Data from recent randomized clinical trials of novel agents, such as ibrutinib, have shown significant improvements in overall survival (OS) among older CLL patients. Prior to the introduction of kinase inhibitor therapies, chemoimmunotherapy combinations were the mainstay treatment. However, older individuals and/or those with co-morbid conditions may be less likely to tolerate standard CLL chemoimmunotherapy. While we await real-world outcomes data on how novel agents have continued to change the CLL landscape, little is known about the management and survival among older CLL patients prior to the availability of novel agents in clinical practice. Our study uses comprehensive prescription and medical insurance claims linked with registry data to describe the time to treatment initiation, front line therapy, and survival outcomes in older adults with CLL between 2007-2013--an era that predates the approvals of ibrutinib, idelalisib and obinutuzumab.Methods: The study used the 2007 to 2013 SEER-Medicare linked database. The sample included patients with first primary tumor site as CLL or SLL (ICD-O histology codes 9670 and 9823) diagnosed between 2007 and 2011. This date of first diagnosis of CLL or SLL defines the index date. Patients aged > 65 years with Medicare fee-for-service coverage in the 12 months pre-index and Medicare fee-for-service and prescription drug coverage in the 6-months post-index period or until death were included. Study outcomes included time to first treatment since CLL/SLL diagnosis, type of treatment initiated, and OS since first treatment. The first treatment type was classified into 6 groups (rituximab monotherapy, chlorambucil monotherapy, rituximab + bendamustine, rituximab + fludarabine +/- other treatment, rituximab + other chemotherapy, and other chemotherapy without rituximab). Logistic regression examined factors associated with receiving any treatment within 1- and 2-years of diagnosis. Cox regression examined factors associated with OS. Covariates in both sets of models included age, gender, race, region, low-income subsidy status, anemia/thrombocytopenia at diagnosis, comorbidities, disability status, and year of diagnosis. Cox regressions also included covariates for time to treatment and type of first treatment.Results: We identified 3,214 newly diagnosed CLL/SLL patients. Our sample had a mean age of 78 years (SD: 8), 49% were male, and 30% had anemia and/or thrombocytopenia at diagnosis. Nearly 33% of the patients received at least one CLL treatment over a median follow-up of 1,099 days (IQR: 834-1735 days) from the date of diagnosis. The most common treatments were rituximab monotherapy (26%), fludarabine + rituximab +/- other treatment (23%), and chlorambucil monotherapy (16%). Among those who initiated treatment, the median time to initiation was 791 days (IQR: 127-1344 days) from diagnosis. Logistic regressions indicated that patients aged 75-79 years old (vs. 80+ year olds) and those with anemia and/or thrombocytopenia at diagnosis were significantly more likely to initiate treatment within 1- and 2-years of diagnosis.The median OS from treatment initiation among the 1,047 treated patients was 52.4 months (Figure 1). The estimated 1-year and 2-year OS since treatment initiation was 81% and 69%, respectively. The OS at 2 years was 68% for rituximab monotherapy, 73% for fludarabine + rituximab +/- other treatment, and 59% for chlorambucil monotherapy. Cox regressions showed older age, male gender, disability, higher comorbidity scores, and type of first treatment (chlorambucil monotherapy vs. rituximab as monotherapy or in combination with chemotherapies) to be significantly associated with lower OS.Discussion: About one-third of older individuals who were newly diagnosed with CLL initiated treatment over a median follow-up of 3 years. This real world study shows modest 2-year OS in older CLL patients after initiating treatment in the pre-novel therapy era. While available clinical trials suggest novel CLL agents offer significant improvements in survival for older adults with CLL, future studies should examine CLL outcomes in real world settings to correlate how results obtained in recent landmark clinical trials translate into clinical practice. [Display omitted] DisclosuresMato:Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding; Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy. Mehra:Janssen: Employment, Equity Ownership. Mahler:Janssen Research & Development: Employment. Huntington:Johnson & Johnson: Consultancy; Celgene: Consultancy, Honoraria; Oncosec Medical: Equity Ownership; Geron: Equity Ownership; Pharmacyclics: Honoraria; Exelixis: Equity Ownership. Doshi:Pfizer Inc.: Other: Spouse owns stock in company, Research Funding; Forest Labs: Membership on an entity’s Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Research Funding; Amgen: Research Funding; Janssen: Research Funding; PhRMA: Research Funding; National Pharmaceutical Council: Research Funding; Humana: Research Funding; Merck & Co., Inc.: Membership on an entity’s Board of Directors or advisory committees, Other: Spouse owns stock; Shire: Membership on an entity’s Board of Directors or advisory committees; Alkermes: Membership on an entity’s Board of Directors or advisory committees.

ADVANCING THERAPEUTICS FOR NEUROINFLAMMATION IN ALZHEIMER'S DISEASE: CLINICAL DEVELOPMENT CONSIDERATIONS

Substantial epidemiologic evidence associates chronic anti-inflammatory drug use with reduced AD risk; equally substantial biomarker and neuropathology evidence implicates neuroinflammation in AD pathophysiology. However, clinical trials of various anti-inflammatory drugs conducted from 1993-2008 were neutral or negative, reducing interest in inflammation-targeting therapeutics thereafter. Recently though, intriguing genetic findings of both risk and protective alleles associated with CNS innate immune system (IIS) components, particularly microglia, have dramatically galvanized interest in neuroinflammation as a therapeutic focus. Accordingly, the early trials were reviewed to appreciate reasons for lack of clinical benefit and to identify lessons that might promote success of forthcoming trials of novel agents. Relevant findings from recent molecular biology, genomic, and biomarker research, and data from clinical use of anti-inflammatory treatments for systemic disorders were also considered. Published reports of trials testing anti-inflammatory drugs or drug combinations were reviewed, supplemented by interactions with study leaders when possible. Factors investigated included drug class (steroid, NSAID, other), population (age, disease stage, APOE4 status), sample size, clinical entry criteria, concomitant medications, clinical/biomarker endpoints, and treatment duration. Performance characteristics of established neuroinflammatory biomarkers (cytokines, e.g., Ifn-γ, IL-6) and emerging measures (YKL-40, sCD40L, exosomes, PET tracers) were also reviewed to assess readout utility. The potential that systemic factors (inflammatory disorders and/or treatments) might influence outcome of brain IIS-targeting treatment trials was considered. Seventeen trials testing 13 drugs were identified; 16 were conducted in MCI or AD, 1 in at-risk elderly. Treatments included a glucocorticoid, several NSAIDs (both nonselective COX inhibitors and COX-2-selective antagonists), and a PPAR-γ agonist. Sample sizes ranged from 20-2981; treatment duration was 3 mos-3.5 y. Biomarkers use was fairly limited. Temporal variability of classical cytokines is high; properties of newer markers are incompletely established but show promise. Systemic inflammatory disorders and even non-BBB-penetrant treatments might influence CNS IIS biology. The reasons for failure of early trials remain uncertain, but evaluating their design can significantly inform trial strategies for novel agents targeting brain innate immunity. Future trials must address the potential influence of peripheral immune factors. Promising biomarkers need early, translational evaluation, and development plans should include robust bioinformatics/pharmacogenomic strategies.

Hepatitis B Reactivation with Novel Agents in Non-Hodgkin's Lymphoma and Prevention Strategies.

Hepatitis B virus (HBV) infection remains an endemic disease in most parts of the world despite available prophylactic vaccines. Non-Hodgkin’s lymphoma is the most common hematological malignancy, and certain patients undergoing therapy are at increased risk of HBV reactivation. Rituximab, a monoclonal antibody, is well studied in HBV reactivation, but newer agents have been implicated as well. Here, we review novel agents suspected in HBV reactivation and effective strategies to prevent HBV reactivation. Fifteen years of literature were reviewed in order to better understand the reactivation rates of hepatitis B in patients with non-Hodgkin’s lymphoma. Anti-CD20 antibodies continue to be the main medications that can lead to HBV reactivation, and HBV reactivation rates have decreased with increased awareness. HBV reactivation is uncommon when using other novel agents. Entecavir and lamivudine remain the agents of choice to prevent HBV reactivation in high risk patients. In conclusion, the immunosuppressive effect of NHL and its therapy provide a pathway for HBV reactivation, especially in patients treated with anti-CD20 antibody. Since many HBV positive patients are often excluded from clinical trials of novel agents in NHL, more aggressive post-market surveillance of new agents, well-designed best practice advisories, and timely case reports are needed to reduce the incidence of HBV reactivation. Lastly, large prospective investigations coupled with well-utilized best practice advisories need to be conducted to understand the impact of more potent novel NHL therapy on HBV reactivation.

Non-metastatic castrate-resistant prostate cancer: a call for improved guidance on clinical management.

Guidelines on the clinical management of non-metastatic castrate-resistant prostate cancer (nmCRPC) generally focus on the need to continue androgen deprivation therapy and enrol patients into clinical trials of investigational agents. This guidance reflects the lack of clinical trial data with established agents in the nmCRPC patient population and the need for trials of new agents. To review the evidence base and consider ways of improving the management of nmCRPC. Upon the development of castrate resistance, it is essential to rule out the presence of metastases or micrometastases by optimising the use of bone scans and possibly newer procedures and techniques. When nmCRPC is established, management decisions should be individualised according to risk, but risk stratification in this diverse population is poorly defined. Currently, prostate-specific antigen (PSA) levels and PSA doubling time remain the best method of assessing the risk of progression and response to treatment in nmCRPC. However, optimising imaging protocols can also help assess the changing metastatic burden in patients with CRPC. Clinical trials of novel agents in nmCRPC are limited and have problems with enrolment, and therefore, improved risk stratification and imaging may be crucial to the improved management. The statements presented in this paper, reflecting the views of the authors, provide a discussion of the most recent evidence in nmCRPC and provide some advice on how to ensure these patients receive the best management available. However, there is an urgent need for more data on the management of nmCRPC.

Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial

Non-clear cell renal cell carcinomas are histologically and genetically diverse kidney cancers with variable prognoses, and their optimum initial treatment is unknown. We aimed to compare the mTOR inhibitor everolimus and the VEGF receptor inhibitor sunitinib in patients with non-clear cell renal cell carcinoma. We enrolled patients with metastatic papillary, chromophobe, or unclassified non-clear cell renal cell carcinoma with no history of previous systemic treatment. Patients were randomly assigned (1:1) to receive everolimus (10 mg/day) or sunitinib (50 mg/day; 6-week cycles of 4 weeks with treatment followed by 2 weeks without treatment) administered orally until disease progression or unacceptable toxicity. Randomisation was stratified by Memorial Sloan Kettering Cancer Center risk group and papillary histology. The primary endpoint was progression-free survival in the intention-to-treat population using the RECIST 1.1 criteria. Safety was assessed in all patients who were randomly assigned to treatment. This study is registered with ClinicalTrials.gov, number NCT01108445. Between Sept 23, 2010, and Oct 28, 2013, 108 patients were randomly assigned to receive either sunitinib (n=51) or everolimus (n=57). As of December, 2014, 87 progression-free survival events had occurred with two remaining active patients, and the trial was closed for the primary analysis. Sunitinib significantly increased progression-free survival compared with everolimus (8·3 months [80% CI 5·8-11·4] vs 5·6 months [5·5-6·0]; hazard ratio 1·41 [80% CI 1·03-1·92]; p=0·16), although heterogeneity of the treatment effect was noted on the basis of histological subtypes and prognostic risk groups. No unexpected toxic effects were reported, and the most common grade 3-4 adverse events were hypertension (12 [24%] of 51 patients in the sunitinib group vs one [2%] of 57 patients in the everolimus group), infection (six [12%] vs four [7%]), diarrhoea (five [10%] vs one [2%]), pneumonitis (none vs five [9%]), stomatitis (none vs five [9%]), and hand-foot syndrome (four [8%] vs none). In patients with metastatic non-clear cell renal cell carcinoma, sunitinib improved progression-free survival compared with everolimus. Future trials of novel agents should account for heterogeneity in disease outcomes based on genetic, histological, and prognostic factors. Novartis and Pfizer.

Clinical Overview of Thyroid Cancer and Recent Advances in Treatment

Thyroid cancer represents a spectrum of biological and molecular activity. As such it can behave in a variety of ways. This makes metastatic thyroid cancer challenging to manage. In advanced rapidly progressive thyroid cancer new agents and multimodality care represent promising therapeutic options for patients. However, these agents are not without risk and clinicians must be judicious with their use, weighing toxicities, quality of life and likely benefits. We review the presentation, treatment and prognosis of thyroid cancer subtypes as well as the recent developments in targeted therapy for medullary thyroid cancer. We discuss the role of cytotoxic therapy in thyroid cancer and review recent trials of novel agents and currently recruiting trials.

Retrospective Analysis of Prognostic Factors for Waldenström Macroglobulinemia: A Multicenter Cooperative Study in Japan

Background: Analysis of prognostic factors and clinical trials of novel agents for Waldenstrӧm macroglobulinemia (WM) are ongoing in Western countries, but few studies of WM have been performed in Japan. As a step toward future investigations, we retrospectively analyzed clinical features and prognostic factors in Japanese patients with WM.Methods: We retrospectively analyzed clinical and laboratory characteristics, treatment and outcomes of 110 patients with WM, IgM-MGUS or lymphoplasmacytic lymphoma (LPL) diagnosed from January 2001 to March 2013 at 12 institutes. Overall survival (OS) was analyzed using Kaplan-Meier methods and survival was compared using log-rank testing. Several clinical characteristics at diagnosis were assessed by Cox regression for uni- and multivariate analysis for OS.Results: Median age at diagnosis was 69 (range, 41-96) years, 73.6% were male, 12.0% had an ECOG performance status 2-4 and 6.4% presented with B-symptoms. Hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia and cold agglutinin disease were shown in 9.1%, 4.5%, 1.8%, 4.5% and 2.7%, respectively. In 94 patients with available CT findings at diagnosis, lymphadenopathy, hepatosplenomegaly, pleural effusion, lung involvement, bone involvement and skin involvement were shown in 41.5%, 14.9%, 8.5%, 4.3%, 4.3% and 6.4%, respectively. Median serum monoclonal protein level was 2.62 g/dl (range, 0.70-9.35 g/dl). Symptomatic WM was present in 76 patients, asymptomatic WM in 23 and IgM-MGUS in 2 according to criteria of the Second International Workshop on WM. Seven patients showed IgG- or IgA-secreting LPL and 2 showed LPL without bone marrow infiltration. In patients with symptomatic WM, international prognostic scoring system for WM (ISSWM) was low in 9.2%, intermediate in 34.2%, high in 39.5% and unknown in 17.1%. Among patients with asymptomatic and symptomatic WM, watchful waiting was performed in 91.3% and 40.0%, respectively, with 61.9% and 36.7% remaining untreated, respectively. Median time to treatment from diagnosis of asymptomatic or symptomatic WM was 240 days (range, 3-1238 days) and 31 days (range, 0-2011 days), respectively. Oral alkylating agents were administered to 34.7% of patients with WM, 19.4% were treated with CHOP or CHOP-like regimen with or without rituximab, 8.2% received fludarabine mono- or combination therapy and 6.1% received rituximab monotherapy. Rituximab-containing therapy was administered as the initial treatment in 33.8% of patients who received treatment. Overall response rate (ORR) (complete + partial response rate) was 48.6%, and patients treated with rituximab-containing therapy displayed higher ORR (64.0%) compared to those with non-rituximab therapy (40.8%). Plasmapheresis was performed in 3.7% of patients. Three patients (2.7%) showed transformation to diffuse large B-cell lymphoma, and 7 (6.4%) developed second primary malignancies. Median follow-up was 38 months, 5-year OS rate for all patients was 74.9% (95% confidence interval (CI) 62.5-83.7) and rates for those with symptomatic WM, asymptomatic WM and other LPL were 66.0% (95%CI 50.6-77.6), 100% and 88.9% (95%CI 43.3-98.4), respectively. Significant differences in survival between risk groups of ISSWM in patients with symptomatic WM were not seen (5-year OS: high, 62.4%; intermediate, 64.3%; low, 75.0%; p=0.86). Although no significant difference in OS was observed compared to initial treatment (p=0.265), patients treated with rituximab during the observation period showed significantly prolonged OS compared to those treated without rituximab (5-year OS rates: 78.9% vs. 45.6%, p=0.036). In univariate analysis, age, pleural effusion, serum albumin, C-reactive protein and serum IgM levels were poor prognostic factors for OS. In multivariate analysis, age >65 years (hazard ratio (HR)=3.294; 95%CI 1.097-9.888, p=0.0336) and pleural effusion (HR=4.55; 95%CI 1.602-12.930, p=0.0045) were identified as significant prognostic factors for OS.Conclusion: Prognostic factors for WM in Western countries may not be applicable to Japanese patients. This study suggested presence of pleural effusion at diagnosis is associated with poor clinical outcomes. Further investigations including histopathological examinations and molecular analyses are required to elucidate prognostic factors in Japan. DisclosuresNo relevant conflicts of interest to declare.

Prognostic Factors for Hospitalization of Children with Sickle Cell Anemia Treated with Hydroxyurea at Maximum Tolerated Dose

Background: Hydroxyurea (HU) is recommended to be offered to children with sickle cell anemia (SCA; HbSS and HbSβ0 thalassemia) beginning at 9 months of age (Yawn, JAMA 2014). Intensifying HU to a maximum tolerated dose (MTD) provides fetal hemoglobin (HbF) levels of >20% (Ware, Blood 2010). Yet, children treated with HU at MTD still experience hospitalizations due to SCA-related complications (Nottage, PLoS One 2013). The ability to identify children at high risk of experiencing SCA-related complications while on HU would enhance clinical management and facilitate performance of clinical trials of novel agents. Our objective was to identify risk factors associated with hospitalization and to develop a prediction model for hospitalization of children treated with HU at MTD.Methods: The Hydroxyurea Study of Long-Term Effects (HUSTLE) is a prospective observational study (NCT00305175) designed to describe the clinical effects of HU in children with SCA. We have analyzed children who initiated HU per protocol and whose dose was escalated to MTD. Laboratory and clinical data were abstracted at baseline and at 9-12 months after enrollment. The first laboratory values of each interval were considered representative of the period. The primary outcome measure was hospitalization. After a multivariate regression logistic model identified risk factors for hospitalization based on a stepwise selection strategy, a smoothed receiver-operating-characteristic (ROC) curve was generated to predict hospitalization for the composite model and for each individual risk factor using the method of maximum-likelihood fitting of univariate distriubutions. Atlhough HbF was not identified in regression analysis among risk factors, because of its known effects as a disease modifier, it was inserted into the composite model. A prediction model was then generated for the identified risk factors utilizing optimal cutoff values defined by the maximum Youden method.Results: 151 children (mean [SD] age, 8.3 [5.0] years) were analyzed. HU resulted in higher HbF levels (22.6% [9.1] versus 10.1% [7.1]; p<0.0001), lower absolute neutrophil counts (4000/mm3 [2600] versus 7000/mm3 [3800]; p<0.0001), and fewer hospitalizations (7.8% [10/128] versus 28.9% [39/128]; p<0.0001) after 9-12 months compared to baseline.Children hospitalized after 9-12 months of therapy had similar HbF levels compared to those not hospitalized (OR 0.98 [95% CI: 0.9-1.1]; p=0.5), but higher total bilirubin (BiliT) (OR 1.3 [95% CI: 1.0-1.6]; p=0.03), blood urea nitrogen (BUN) (OR 1.3 [95% CI: 1.1-1.7]; p=0.19), and lactate dehydrogenase (LDH) (OR 1.01 [95% CI: 1.002-1.010]; p=0.006) levels. A ROC curve including insertion of HbF showed an area under the curve (AUC) of 0.90 (Figure 1). Optimal cutoffs for risk factors were: BiliT 1.05 mg/dL, BUN 8.5 mg/dL, and LDH 473 units/L. The probability of hospitalization varied in relation to identified risk factors (Table 1).Table 1Predicted probability of hospitalization after 9-12 months of HU at MTD# of risk factorsBiliTHbFBUNLDHProbability of≥1.05(mg/dL)≤20 (%)≥8.5(mg/dL)≥473(units/L)Hospitalization (%)0NoNoNoNo<11YesNoNoNo<1NoYesNoNo1.3NoNoYesNo5.8NoNoNoYes192YesYesNoNo<1YesNoYesNo<1YesNoNoYes2.2NoYesYesNo10NoYesNoYes29NoNoYesYes653YesYesYesNo1.1YesYesNoYes3.8YesNoYesYes15NoYesYesYes774YesYesYesYes25LDH, lactate dehydrogenase; BiliT, total bilirubin; BUN, blood urea nitrogenDiscussion: In this pediatric cohort, HU therapy at MTD produced a robust laboratory response with most children having HbF >20% after 9-12 months. At such high levels of HbF, few children experienced a hospitalization due to its protective effects; however, we identified three laboratory parameters (LDH, BiliT, and BUN) that were predictive risk factors for children who continued to be hospitalized despite high levels of HbF. After 9-12 months of HU therapy at MTD the probability of hospitalization ranged from <1% to 65% for children with HbF of less than <20% and <1% to 77% in children with HbF of >20%. This model may help identify children at risk for complications of SCA while being treated with HU at MTD. [Display omitted] DisclosuresEstepp:Eli Lilly and Company: Research Funding; Daiichi Sankyo: Research Funding. Off Label Use: Off label use of hydroxyurea in children with sickle cell anemia.

Targeted Therapies for Advanced Oesophagogastric Cancer: Recent Progress and Future Directions.

The genomic landscape of oesophagogastric (OG) cancer is highly complex. The recent elucidation of some of the pathways involved has suggested a number of novel targets for therapy. This therapy is urgently required as with conventional chemotherapy regimens patients with advanced OG cancer still have a median overall survival of under a year. This review outlines the rationale for the current treatment of OG cancer with chemotherapy and describes both previously conducted and ongoing clinical trials of novel agents in this area. The targets and associated treatments discussed include HER-2, EGFR, VEGF, c-Met, FGFR-2, PI3K, mTOR andIGF-1. To date only two targeted treatments, trastuzumab and ramucirumab, have become part of the treatment paradigm for OG cancer, partly due to difficulties in defining predictive biomarkers in this disease. However, there are a number of promising drugs in the pipeline and this article seeks to describe these and other potential novel approaches including targeting DNA repair deficiencies and the immune system.

Targeted therapy in cancer.

To describe the emergence of targeted therapies that have led to significant breakthroughs in cancer therapy and completed or ongoing clinical trials of novel agents for the treatment of patients with advanced cancer. The literature was systematically reviewed, based on clinical experience and the use of technologies that improved our understanding of carcinogenesis. Genomics and model systems have enabled the validation of novel therapeutic strategies. Tumor molecular profiling has enabled the reclassification of cancer and elucidated some mechanisms of disease progression or resistance to treatment, the heterogeneity between primary and metastatic tumors, and the dynamic changes of tumor molecular profiling over time. Despite the notable technologic advances, there is a gap between the plethora of preclinical data and the lack of effective therapies, which is attributed to suboptimal drug development for "driver" alterations of human cancer, the high cost of clinical trials and available drugs, and limited access of patients to clinical trials. Bioinformatic analyses of complex data to characterize tumor biology, function, and the dynamic tumor changes in time and space may improve cancer diagnosis. The application of discoveries in cancer biology in clinic holds the promise to improve the clinical outcomes in a large scale of patients with cancer. Increased harmonization between discoveries, policies, and practices will expedite the development of anticancer drugs and will accelerate the implementation of precision medicine. Combinations of targeted, immunomodulating, antiangiogenic, or chemotherapeutic agents are in clinical development. Innovative adaptive study design is used to expedite effective drug development.

Answering Pivotal Questions in the Diagnosis and Treatment of Primary Biliary Cirrhosis and Non-Alcoholic Steatohepatitis

Professor Trauner introduced the subject of liver disease and its burden within the European Union (EU) and across the globe. Professor Jones summarised the progress made in understanding the pathophysiology of primary biliary cirrhosis (PBC), current unmet needs in the ursodeoxycholic acid (UDCA) era, and novel therapeutic options for PBC treatment. Professor Ratziu discussed the emerging understanding of the complex multisystem pathophysiology of non-alcoholic steatohepatitis (NASH), summarised the available therapeutic targets, and detailed the trials of novel agents currently underway.

Novel Agents for Treatment of Multiple Myeloma

Multiple myeloma (MM) is a neoplasm of clonal plasma cells that closely interacts with the bone marrow (BM) microenvironment. The overall survival of patients with MM has improved dramatically in the last 20 years, due primarily to the development of autologous stem cell transplantation and novel drugs, including a proteasome inhibitor (bortezomib) and immunomodulatory agents (thalidomide and lenalidomide), as well as advances in supportive care. However, this disease remains classified as an incurable hematological malignancy. Understanding the intracellular mechanisms and the interactions between plasma cells and the BM microenvironment has accelerated development of second- and third-generations of “old novel” agents or new agents with novel targeted mechanisms of action, such as monoclonal antibodies, cell cycle-specific drugs, and deacetylase inhibitors. Among them, carfilzomib and pomalidomide have been approved for treating patients with relapsed/refractory MM. Results of ongoing preclinical and clinical trials of novel agents provide hope for continuous improvements and a cure for MM in the near future. (Korean J Med 2015;88:252-257)