Introduction Of Novel Treatments Research Articles

The UK consensus supporting effective introduction of novel treatments for multiple myeloma in the National Health Service

AbstractIntroductionMultiple myeloma (MM) is a relapsing, debilitating blood cancer which remains incurable despite advances in treatments. Patients typically receive multiple lines of treatment, to which they become refractory, thereby limiting treatment options. B‐cell maturation antigen (BCMA) bispecific antibodies (BsAbs) represent a novel modality of treatment that has significant efficacy for relapsed or refractory patients.The objective was to develop consensus statements for the effective implementation of BCMA BsAbs for relapsed or refractory MM patients within the National Health Service (NHS).MethodsThe process employed a modified Delphi methodology. In March 2023, a literature review on the topic of novel treatments for MM was performed using the PubMed database.The process employed a modified Delphi methodology. Following a literature review, a steering group of eight expert clinicians identified and agreed on five main topics of focus and 44 statements. These were then developed into an online survey which was distributed to healthcare professionals working in Levels 1, 2 and 3 haematology centres in the United Kingdom. Results were then shared with the expert panel to determine conclusions. The threshold for consensus agreement was set at 75%.ResultsA total of 60 responses were received from all three centre levels. There was representation from all targeted centres. Consensus was achieved in 42 statements (95%) across three broad areas: the patient profile, initiation and step‐up dosing, monitoring and ongoing care, the role of multidisciplinary team and service designs for optimal management, consensus was not achieved for two statements. Given the level of agreement and that the stopping criteria were met, it was decided not to undertake further Delphi rounds.ConclusionThis consensus provides a framework to support the effective introduction of novel treatments for MM in the NHS. The results were used to inform a checklist for use within haematology services when considering the provision of MM care specific to BCMA BsAbs.

Biologics and targeted synthetic medicines for ulcerative colitis and Crohn's disease

Ulcerative colitis and Crohn's disease are chronic inflammatory bowel diseases. Recent pivotal phase 3 trials involving treatments like interleukin-23-, sphingosin-1-phosphate- and Janus kinase inhibitors have demonstrated notable effectiveness. However, they have also unveiled significant side effects such as herpes zoster, lymphopenia and bradycardia. The introduction of novel treatments raises valid concerns necessitating increased collaboration with diverse medical specialities to address potentially severe side effects, and this is vital for enhancing the future care of individuals with inflammatory bowel diseases, as argued in this review.

Abstract 1233: Novel inhibitor targeting triple integrated stress response kinase HRI, PERK, and GCN2 provides new insights into overcoming resistance to proteasome inhibitors in multiple myeloma

Abstract The introduction of novel treatments for Multiple myeloma (MM), particularly proteasome inhibitors (PI) such as bortezomib (BTZ), has greatly improved outcomes. However, many patients eventually experience relapse. Therefore, new approaches for managing patients with resistance to PI should be explored. The integrated stress response (ISR) is an evolutionarily conserved intracellular signaling network that is activated in response to both intrinsic and extrinsic stresses. Stresses are sensed by four specialized kinases: HRI, PERK, PKR, and GCN2, which converge on the phosphorylation of eIF2α. This phosphorylation triggers the translation of ATF4, thus promoting cell survival and homeostasis. Recent studies investigating the contribution of the four ISR kinases in overcoming resistance to PI treatment, have revealed the potential of a selective GCN2 inhibitor to overcome this resistance. Here, we observed that PI simultaneously induced mitochondrial stress, ER stress, and amino acid starvation, leading to the activation of HRI, PERK, and GCN2, respectively. However, the contribution of crosstalk among ISR kinases has not been considered thus far. To gain a comprehensive understanding of ISR kinases in BTZ resistance, we generated single or combination patterns of double and triple KO of the four ISR kinases and reevaluated their contribution to BTZ treatment. Sensitivity screening using the HAP1 single, double, and triple KO cell library showed that HRI primarily, and to a lesser extent, PERK and GCN2, contribute to BTZ resistance. Consistent with the HAP1 KO screening, MM cell line-derived KO cells revealed a similar dependency on these three kinases. Building upon our observation of the significance of the HRI/PERK/GCN2 triple kinase, we developed a novel and orally available small molecule, CRD-1367799, which inhibits these triple kinases in cells. CRD-1367799 effectively dampened the activity of these ISR kinases, leading to a complete inhibition of eIF2α phosphorylation and ATF4 activation. Additionally, we observed a distinct anti-growth effect when combined with BTZ in vitro and in vivo, which was not replicated by the GCN2 or PERK-selective inhibitor. Furthermore, we uncovered the mechanism of cell death induction in combination with proteasome inhibitors. Notably, the apoptosis inducers NOXA and CHOP were upregulated, but the mechanism did not seem to rely on previously known processes such as ATF4-mediated transcriptional induction. In summary, our novel findings on the contribution of the triple ISR kinase provides us with new insights for overcoming resistance to proteasome inhibitors with HRI/PERK/GCN2 inhibitor. To the best of our knowledge, the use of a triple kinase inhibitor in this context has not been reported thus far, making CRD-1367799 a new therapeutic strategy for MM with PI. Citation Format: Yasumichi Inoue, Koki Hikami, Shunsuke Ebara, Midori Sugiyama, Robert Oda, Akio Mizutani, Misaki Yoshida, Hiroko Yamakawa, Shigehiro Yagishita, Akinobu Hamada, Hidetoshi Hayashi, Masaki Ri, Shinsuke Iida, Daisuke Morishita. Novel inhibitor targeting triple integrated stress response kinase HRI, PERK, and GCN2 provides new insights into overcoming resistance to proteasome inhibitors in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1233.

Real-Life Use of [68Ga]Ga-DOTANOC PET/CT in Confirmed and Suspected NETs from a Prospective 5-Year Electronic Archive at an ENETS Center of Excellence: More Than 2000 Scans in More Than 1500 Patients.

The recent introduction of novel treatments for advanced neuroendocrine tumors (NETs) and the well-established impact of clinical case discussion within dedicated multidisciplinary teams indicates the need to promote the centralization of rare diseases, such as NENs (neuroendocrine neoplasms). Data on the real-life use of and indications for [68Ga]Ga-DOTANOC PET/CT were collected from a prospective monocentric 5-year electronic archive including consecutive patients with confirmed and suspected NETs (September 2017 to May 2022). Overall, 2082 [68Ga]Ga-DOTANOC PET/CT scans (1685 confirmed NETs, 397 suspected NETs) were performed in 1537 patients. A high positivity rate was observed across different clinical settings (approximately 70%). Approximately 910/2082 scans were requested by the local oncology ward (851 confirmed NETs, 59 suspected NETs). The following observations were found: (i) the detection rate across all indications was 73.2% (higher for staging, peptide receptor radioligand therapy (PRRT) selection, and treatment response assessment); (ii) in suspected NETs, PET was more often positive when based on radiological findings. This systematic data collection in a high-volume diagnostic center represents a reliable cohort reflecting the global trends in the use of [68Ga]Ga-DOTANOC PET/CT for different clinical indications and primary tumor sites, but prompts the need for further multicenter data sharing in such a rare and slowly progressive disease setting.

Trends in Survival Outcomes for Mantle Cell Lymphoma in the Era of Novel Therapies

Introduction Mantle Cell Lymphoma (MCL) is a rare malignancy, associated with aggressive features and poor outcomes. Previous treatment paradigms for MCL involved chemoimmunotherapy and stem cell transplant (SCT), though this has evolved in recent years with the introduction of novel treatments, including bruton's tyrosine kinase (BTK) inhibitors, chimeric antigen receptor T-cells (CAR-T) and immunomodulatory agents such as lenalidomide. Additionally, the incorporation of rituximab maintenance therapy following SCT has demonstrated improved progression-free (PFS) and overall survivals (OS) for MCL patients (pts). While the majority of these novel agents and treatments were FDA approved by demonstrating improved PFS, the benefits of these new treatments on OS trends for MCL pts are not well described. Therefore, to determine whether these advances have translated to OS improvement in the real-world setting, we performed a national analysis of OS trends through multiple treatment eras. Methods The National Cancer Database was used to identify pts diagnosed with MCL from 2004-2020. For pts receiving treatment, the use of front-line single or multiagent therapy, and upfront SCT was compared. Kaplan-Meier and Cox regression analysis was used to compare OS for all MCL pts. Survival was compared by year of diagnosis, with diagnosis in 2004-2013 considered to be managed in the era of chemoimmunotherapy, 2014 and later associated with the introduction of BTK inhibitors, and 2017 and later with the adoption of maintenance rituximab following SCT. Results A total of 31,284 pts with MCL were identified. The mean age at diagnosis was 67 years (yrs) [SD ±12], 93% of pts were White, and 70% had stage IV disease at diagnosis. Pts were increasingly more likely to have ≥2 comorbidities at MCL diagnosis (6.2% from 2004-2013, 8.6% from 2014-2016, and 10.8% from 2017-2020) and were increasingly managed at academic centers (40%, 44%, and 46%, respectively). Rates of pts managed with active surveillance significantly increased over time (4.7% from 2004-2013, 6.7% from 2014-2016, and 8.7% from 2017-2020). Regarding treatment, the rate of upfront multi-agent chemotherapy use decreased over time (67.7% from 2004-2013, 45.2% from 2014-2016, and 38.9% from 2017-2020), corresponding with an increase in single agent treatment (7.9%, 28.2%, and 32.4%, respectively). Notably, the rate of pts receiving SCT following front-line treatment remained similar in each time period (13.6%, 15.4%, and 14.1%, respectively). With a median follow-up of 3.5 yrs, the median OS for all pts with MCL from 2004-2020 was 5.9 yrs (95% CI 5.8-6.0 yrs). The median OS was significantly increased when comparing pts who were diagnosed between 2004-2013 (5.5 yrs) to those diagnosed 2014-2016 (6.8 yrs), and median was not reached for pts diagnosed 2017-2020 (all p<0.001). The median 1-, 3-, and 5-year OS significantly increased following the availability of novel agents after 2014 (2004-2013: 1-year 80%, 3-year 63%, 5-year 52% vs. 2014-2016: 1-year 82%, 3-year 67%, 5-year 58%, p<0.001). Whereas, pts diagnosed from 2017-2020 had similar OS trends as pts diagnosed from 2014-2016 with 1-year 82%, 3-year 66%, 5-year 51% OS, respectively. When adjusted for age and comorbidity burden, the most recent time periods were associated with decreased risk of death (2014-2016: HR 0.81 [95% CI 0.78-0.85], and 2017-2020: HR 0.82 [95% CI 0.78-0.86]) when compared to 2004-2013 (all p<0.001). Conclusions: To our knowledge, this is the largest retrospective review evaluating treatment trends and OS outcomes in pts with MCL in recent decades. These data show that OS has significantly improved for pts diagnosed in the most recent time periods. We hypothesize this is due to the introduction of novel agents such as BTK inhibitors, which is supported by the increased rate of single agent treatment over time, which may be related to BTK inhibitors supplanting chemoimmunotherapy in the front-line setting. We also found that no additional OS improvement was observed during the time period following the adoption of rituximab maintenance after transplant, which may be due to the limited number of pts receiving SCT through each time period. With more follow-up data, future studies may determine whether treatments such as CAR-T (FDA approved in 2020 with data not included in this cohort) have further improved OS outcomes for this incurable malignancy.

Identification of Potential Protein Targets in Extracellular Vesicles Isolated from Chemotherapy-Treated Ovarian Cancer Cells.

Despite the ongoing clinical trials and the introduction of novel treatments over the past few decades, ovarian cancer remains one of the most fatal malignancies in women worldwide. Platinum- and paclitaxel-based chemotherapy is effective in treating the majority of patients with ovarian cancer. However, more than 70% of patients experience recurrence and eventually develop chemoresistance. To improve clinical outcomes in patients with ovarian cancer, novel technologies must be developed for identifying molecular alterations following drug-based treatment of ovarian cancer. Recently, extracellular vesicles (EVs) have gained prominence as the mediators of tumor progression. In this study, we used mass spectrometry to identify the changes in EV protein signatures due to different chemotherapeutic agents used for treating ovarian cancer. By examining these alterations, we identified the specific protein induction patterns of cisplatin alone, paclitaxel alone, and a combination of cisplatin and paclitaxel. Specifically, we found that drug sensitivity was correlated with the expression levels of ANXA5, CD81, and RAB5C in patients receiving cisplatin with paclitaxel. Our findings suggest that chemotherapy-induced changes in EV protein signatures are crucial for the progression of ovarian cancer.

DAPA-HF applicability: the point of view of a cardiology setting

Randomised clinical trials, observational studies, and meta-analyses have shown that sodium–glucose cotransporter 2 inhibitors (SGLT2-i) reduce the risk of hospitalisation for heart failure (HF), chronic kidney disease (CKD) progression, and mortality in patients with HF, irrespective of the presence of type 2 diabetes mellitus. However, real-world epidemiology may differ from clinical trial populations, thereby limiting generalisability and delaying the introduction of novel treatments in clinical practice. The aim of the present study was to assess the prevalence of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) inclusion criteria in a population of HF with reduced ejection fraction (HFrEF) patients enrolled in the Italian Network on Heart Failure (IN-HF) registry. Overall, 3415 IN-HF patients matched the 4744 patients in DAPA-HF, overlapping for most baseline characteristics (e.g. similar average ejection fraction), with a slightly lower prevalence of type 2 diabetes and of HF ischaemic aetiology and a higher percentage of NYHA class II patients. The theoretical eligibility to DAPA-HF in a cardiology setting resulted to be 73%. The availability of an easily accessible database from a large nationwide prospective registry allows to provide insights to clinicians and policy makers on the applicability of the DAPA HF findings to a contemporary population of HFrEF patients followed by cardiologists. It is reasonable to assume that the results of this analysis can be applicable to the entire SGLT2-ir class of drugs.

Phosphodiesterase inhibitors in psychiatric disorders.

Challenges in drug development for psychiatric disorders have left much room for the introduction of novel treatments with better therapeutic efficacies and indices. As a result, intense research has focused on identifying new targets for developing such pharmacotherapies. One of these targets may be the phosphodiesterase (PDE) class of enzymes, which play important roles in intracellular signaling. Due to their critical roles in cellular pathways, these enzymes affect diverse neurobiological functions from learning and memory formation to neuroinflammation. In this paper, we reviewed studies on the use of PDE inhibitors (PDEIs) in preclinical models and clinical trials of psychiatric disorders including depression, anxiety, schizophrenia, post-traumatic stress disorder (PTSD), bipolar disorder (BP), sexual dysfunction, and feeding disorders. PDEIs are able to improve symptoms of psychiatric disorders in preclinical models through activating the cAMP-PKA-CREB and cGMP-PKG pathways, attenuating neuroinflammation and oxidative stress, and stimulating neural plasticity. The most promising therapeutic candidates to emerge from these preclinical studies are PDE2 and PDE4 inhibitors for depression and anxiety and PDE1 and PDE10 inhibitors for schizophrenia. Furthermore, PDE3 and 4 inhibitors have shown promising results in clinical trials in patients with depression and schizophrenia. Larger and better designed clinical studies of PDEIs in schizophrenia, depression, and anxiety are warranted to facilitate their translation into the clinic. Regarding the other conditions discussed in this review (most notably PTSD and BP), better characterization of the effects of PDEIs in preclinical models is required before clinical studies.

Complexity and clinical significance of drug-drug interactions (DDIs) in oncology: challenging issues in the care of patients regarding cancer-associated thrombosis (CAT).

Cancer patients have an increased risk of developing venous thromboembolic events. Anticoagulation management includes prophylactic or therapeutic doses of low molecular weight heparins (LMWHs) or direct oral anticoagulants (DOACs). However, the management of thrombosis in patients with cancer is complex due to various individual and disease-related factors, including drug–drug interactions (DDIs). Furthermore, DDIs may impact both, cancer and venous thrombosis, treatment effectiveness and safety; their relevance is highlighted by the advances in cancer therapeutics. Given that these new oncology drugs are extensively used, more attention should be given to monitoring potential DDIs to minimize risks. Recognition of DDIs is of utmost importance in an era of rapid developments in cancer treatments and introduction of novel treatments and protocols. When managing cancer-associated thrombosis (CAT), the concomitant use of a DOAC and a moderate or strong modulator (inhibitor or inducer) of CYP3A4 or a P-glycoprotein (P-gp) is most likely to be associated with significant DDIs. Therefore, LMWHs remain the first-line option for the long-term management of CAT under these circumstances and physicians must consider utilizing LMWHs as first line. This review describes the risk of DDIs and their potential impact and outcomes in patients with cancer associated thrombosis (CAT) receiving anticoagulation.

Early cardiac response is possible in stage IIIb cardiac AL amyloidosis and is associated with prolonged survival

AbstractPatients with immunoglobulin light chain (AL) amyloidosis and stage IIIb cardiac involvement have a dismal outcome despite the introduction of novel treatments. However, a rapid hematologic response translates in better survival. We evaluated the impact of early cardiac response and its depth on outcome in 249 patients with newly diagnosed stage IIIb cardiac AL amyloidosis. Hematologic and cardiac responses were evaluated by intent to treat. After a median follow-up of 52 months, 219 (84%) patients died, and median survival was 4.2 months. The 30- and 90-day hematologic response rates were 22% (at least very good partial response [VGPR] in 9%) and 24% (at least VGPR in 15%), respectively. Early hematologic response resulted in better survival. At 90 days, 21 (8%) patients achieved a cardiac response (cardiac very good partial response [cardiac VGPR] in 12 cases and cardiac partial response [cardiac PR] in 9). At the 90-day landmark analysis, cardiac response resulted in longer survival (median, 54 months), also in those patients who have achieved at least VGPR (median, 62 vs 26 months, P = .011). Patients with cardiac VGPR had a longer survival than those with cardiac PR (median, 92 vs 24 months; P = .027), whereas patients without cardiac response had a poor survival (median, 6 months). A baseline difference of involved/uninvolved free light chains > 50 mg/L (odds ratio [OR], 0.21, P = .024) and a bone marrow plasma cell infiltrate > 10% (OR, 0.23, P = .040) were negative predictors of 90-day cardiac response. Early cardiac responses are rare but possible in stage IIIb AL amyloidosis and translate to longer survival.

Precision Nephrology in Patients with Diabetes and Chronic Kidney Disease.

Diabetes is the leading cause of kidney failure and specifically, diabetic kidney disease (DKD) occurs in up to 30% of all diabetic patients. Kidney disease attributed to diabetes is a major contributor to the global burden of the disease in terms of clinical and socio-economic impact, not only because of the risk of progression to End-Stage Kidney Disease (ESKD), but also because of the associated increase in cardiovascular (CV) risk. Despite the introduction of novel treatments that allow us to reduce the risk of future outcomes, a striking residual cardiorenal risk has been reported. This risk is explained by both the heterogeneity of DKD and the individual variability in response to nephroprotective treatments. Strategies that have been proposed to improve DKD patient care are to develop novel biomarkers that classify with greater accuracy patients with respect to their future risk (prognostic) and biomarkers that are able to predict the response to nephroprotective treatment (predictive). In this review, we summarize the principal prognostic biomarkers of type 1 and type 2 diabetes and the novel markers that help clinicians to individualize treatments and the basis of the characteristics that predict an optimal response.

Characterizing Trends in Cancer Patients' Survival Using the JPSurv Software.

Improvements in cancer survival are usually assessed by comparing survival in grouped years of diagnosis. To enhance analyses of survival trends, we present the joinpoint survival model webtool (JPSurv) that analyzes survival data by single year of diagnosis and estimates changes in survival trends and year-over-year trend measures. We apply JPSurv to relative survival data for individuals diagnosed with female breast cancer, melanoma cancer, non-Hodgkin lymphoma (NHL), and chronic myeloid leukemia (CML) between 1975 and 2015 in the Surveillance, Epidemiology, and End Results Program. We estimate the number and location of joinpoints and the trend measures and provide interpretation. In general, relative survival has substantially improved at least since the mid-1990s for all cancer sites. The largest improvements in 5-year relative survival were observed for distant-stage melanoma after 2009, which increased by almost 3 survival percentage points for each subsequent year of diagnosis, followed by CML in 1995-2010, and NHL in 1995-2003. The modeling also showed that for patients diagnosed with CML after 1995 (compared with before), there was a greater decrease in the probability of dying of the disease in the 4th and 5th years after diagnosis compared with the initial years since diagnosis. The greatest increases in trends for distant melanoma, NHL, and CML coincided with the introduction of novel treatments, demonstrating the value of JPSurv for estimating and interpreting cancer survival trends. The JPSurv webtool provides a suite of estimates for analyzing trends in cancer survival that complement traditional descriptive survival analyses.

A systematic approach for introduction of novel treatments to a chronic patient group: sacubitril-valsartan as a case study

PurposeTo develop a model for systematic introduction and to test the feasibility in a chronic disease population. We also investigated how the approach was received by the patients.Methods and resultsThe systematic introduction approach is a seven-step procedure: step 1, define a few main criteria; step 2, primary scan patients with the one or two main criteria using computerized medical records/databases/clinical registries; step 3, identify patients applying the other predefined criteria; step 4, evaluate if any examinations/laboratory test updates are required; step 5, summon identified patients to the clinic with an information letter; step 6, discuss treatment with the patient and prescribe if appropriate; and step 7, follow up on initiated therapy and evaluate the applied process. The model was tested in a case study during introduction of the new drug sacubitril-valsartan in a heart failure population. In total, 76 out of 1924 patients were identified to be eligible for sacubitril-valsartan and summoned to the clinic to discuss treatment. Patient experiences with the approach were investigated in an interview study with general inductive approach using qualitative content analysis. This resulted in three final categories: a good approach, role of the information letter, and trust in care.ConclusionsThe systematic introduction approach ensures that strict criteria are used in the selection process and that a treatment can be implemented in eligible patients within a specified population with limited resources and time. The model was effective in our case study and maintained the patient’s confidence in healthcare.

Using Implementation Science to Better Integrate Novel Long-Acting Injectable Therapy Into Routine HIV Care.

The key to maximizing the value of implementation science data is to get the learnings early. A critical contributor to early clinical research data is the biopharmaceutical industry. In partnership with the implementation research community, industry has an opportunity to play a major role to increase the value of implementation research data through earlier integration of implementation questions in the development continuum. This article suggests that by using more hybrid implementation-effectiveness study designs in phase III trials, researchers can accelerate the availability of implementation data closer to the initial introduction of novel treatments into community settings. The biopharmaceutical industry is uniquely poised to lead or collaborate on these trials. The first LAI HIV medications are being studied for both HIV prevention and treatment. This paradigm shift in the provision of HIV care is an opportunity to blend implementation research into clinical trials earlier so that the public health community is armed with tested implementation strategies to maximize access and impact when these new medications become available. CUSTOMIZE, a novel phase IIIB-hybrid III implementation-effectiveness trial-is the first-of-its-kind study to examine different implementation strategies to overcome challenges of delivering a LAI antiretroviral medication in various types of HIV clinical settings the US health care system. Industry can play a complimentary and additive role by partnering with implementation science researchers to understand the implementation strategies sooner in the development pipeline. These collaborations may allow for earlier, more informed, and strategic HIV public health programs in the future.

The Relationship between Minimal Residual Disease and Patient Reported Outcomes in Relapsed/Refractory Multiple Myeloma

ObjectiveWith the introduction of novel treatments for multiple myeloma, patients are now achieving deeper and sustainable clinical responses. Recent studies have demonstrated that achieving Minimal Residual Disease (MRD) negativity leads to better progression-free survival and overall survival outcomes (Lahuerta JJ, et al. J Clin Oncol 2017. 35[25]:2900-10; Munshi NC, et al. JAMA Oncol 2016. 3[1]:28-35; Landgren O, et al. Bone Marrow Transplant 2016. 51[12]:1565-1568). However, the relationship between MRD status and patient reported outcomes (PRO) has not been reported. The objective of this analysis is to evaluate whether PRO endpoints change by MRD status using data from two randomized clinical trials of daratumumab containing treatment regimens, POLLUX (Dimopoulos MA, et al. N Engl J Med 2016. 375[14]:1319-1331) and CASTOR (Palumbo A, et al. N Engl J Med 2016. 375[8]:754-766), for patients with relapsed or refractory multiple myeloma.MethodsMRD status was assessed in POLLUX at the time of suspected CR, and at 3 and 6 months post-suspected CR for responders. Similarly, in CASTOR, MRD status was assessed for patients at the time of suspected CR and at 6 months and 12 months after first dose. MRD was assessed via next generation sequencing using the clonoSEQ® assay V2.0 (Adaptive Biotechnologies, Seattle, WA) at sensitivities of 0.001%. The PRO instruments (EORTC-QLQ-C30 and EQ-5D-5L) were collected in both POLLUX and CASTOR study prior to treatment, during the treatment phase, and post-progression. EQ-5D-5L assessed general health status and included an index value and visual analog scale (VAS) score. EORTC QLQ C30 assessed health related quality of life and included five functional scales (physical, role, emotional, social and cognitive), three symptom scales (fatigue, nausea & vomiting and pain) and a global health status (GHS) scale as well as six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Summary statistics (mean, standard deviation, median, min and max) by MRD status (baseline, prior to MRD negativity, MRD negativity prior to progression) were reported and for subjects who did not achieve MRD negativity (baseline, post baseline prior to progression) on a pooled sample of subjects from the two clinical trials. To interpret a meaningful change, a 5-point threshold was defined based on the EORTC guidelines for assessing quality of life in clinical trials.ResultsOverall 137 subjects in both CASTOR and POLLUX achieved MRD negativity and had PRO data available for analysis. At baseline, GHS, EQ-5D-5L VAS and index value were 62.1, 66.7, and 0.72 respectively (GHS and VAS scores closer to 100, and index value closer to 1.0 represent better health state). Mean values increased to 67.2, 70.9, and 0.75 after achieving MRD negativity. Pain scale (symptom scores closer to 0 represent less symptoms) reduced from 30.4 to 23.5 and fatigue was similar (33.8 at baseline to 31.2) when patients achieved MRD negativity. However, when we compared the five functional scales prior to and post MRD negativity, no evident differences were identified. The mean change from baseline to post-MRD-negativity in the EORTC QLQ-C30 GHS and Pain scores exceeded a 5-point threshold, reflecting a meaningful change in subject's health-related quality of life.A total of 893 subjects in the pooled data set did not achieve MRD negativity and had PRO data available for analysis (EQ-5D-5L data were not available for 3 subjects). Baseline values for these MRD positive subjects were 60.0, 65.3, and 0.71 and the mean post-baseline (pre-progression) values remained similar at 61.1, 66.0, and 0.71 for GHS, VAS, and the index value, respectively. Pain reduced from mean 33.3 to 29.4 and fatigue was similar, changing from 36.2 to 37.6.ConclusionTo our knowledge, this is the first analysis exploring the relationship between MRD status and PRO endpoints. Results from this analysis demonstrate that patients who achieve MRD negativity status show a trend in better health-related quality of life, with meaningful improvement in EORTC QLQ-C30 GHS and pain scores. These preliminary findings indicate that overall health-related quality of life and symptom domains of EORTC-QLQ-C30 and EQ-5D-5L might be sensitive to changes in MRD status, with changes in GHS and Pain exceeding meaningful threshold for subjects. DisclosuresAvet-Loiseau:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. He:Janssen global services: Employment. Gries:Janssen Research & Development, LLC: Employment. Pei:Janssen Research & Development, LLC: Employment. Saha:Janssen Research & Development, LLC: Employment. Chiu:Janssen Research & Development, LLC: Employment. Cote:Janssen Research & Development, LLC: Employment. Lam:Janssen Global Services, LLC: Employment.

Preparing for the Future of Rare Diseases.

Members of the rare disease community have devoted significant financial and personnel resources to address the numerous issues surrounding rare diseases. The past has been devoted to developing an emphasis on rare diseases including an emphasis on research studies or locating information on rare diseases and the requirements and limitations of conducting clinical trials with small patient populations. The expanded role of patient advocacy organizations and patient engagement in all aspects of clinical research continues to gain acceptance within the research community. The future will require a greater understanding and interpretation of available information from multiple sources including electronic health records and big data sources. The pipeline of potential orphan products continues to grow significantly and holds great promise for novel interventions due to advances in clinical trial design and data analyses. Expanding diagnostic procedures with improved sequencing methods will speed up the diagnosis or rare diseases. Accepting agreed upon nomenclature and codification of rare diseases will assist in differentiating diseases and identifying selected sub-populations of rare diseases. Improvements in patient recruitment and increased flexibility in the product review and approval procedures by regulatory agencies will facilitate product approvals. Children particularly will need help and assistance dealing with feelings of isolation from their peers due to their rare disease. During the transition from childhood to adolescence to adult, difficulties of fitting in with peers and not wanting to be different are a major concern. In response to increasing costs of treatments, Value-Based Care is gaining greater acceptance by the reimbursement and the payer community as a basis for payment for interventions. Mobile Health (M-health) Technologies have the potential to revolutionize how clinical research is conducted in the future. Wearable devices, remote sensors, and the development of mobile device applications (apps) will all assist in constant monitoring of patients for safety and efficacy of approved and investigational compounds. Tele Health and Tele Medicine may provide the necessary access to expert clinicians with a better understanding of individual rare diseases. The future promises great advances and even greater personalized treatments with the introduction of novel treatments and approaches to care.

Improving our understanding of the in vivo modelling of psychotic disorders: A protocol for a systematic review and meta-analysis.

Psychosis represents a set of symptoms against which current available treatments are not universally effective and are often accompanied by adverse side effects. Clinical management could potentially be improved with a greater understanding of the underlying biology and subsequently with the introduction of novel treatments. Since many clinical drug candidates are identified through in vivo modelling, a deeper understanding of the pre‐clinical field, might help us understand why translation of results from animal models to inform mental health clinical practice has so far been weak. We set out to give a shallow, but broad unbiased overview of experiments looking at the in vivo modelling of psychotic disorders using a systematic review and meta‐analysis. This protocol describes the exact methodology we propose to follow in order to quantitatively review both studies characterizing a model and those experiments that investigate the effects of novel therapeutic options. We are interested in assessing the prevalence of the reporting of measures to reduce risk of bias, and the internal and external validity of the animal models and outcome measures used to validate these models. This generation of strong empirical evidence has the potential to identify areas for improvement, make suggestions for future research avenues, and ultimately inform what we think we know to improve the current attrition rate between bench and bedside in psychosis research. A review like this will also support the reduction of animal numbers used in research and the refinement of experiments to maximize their value in informing the field.

THU0469 Genetic Variants in IL-6, IL-10, C5-TRAF1 and FCRL3 and Progression of Joint Damage in Rheumatoid Arthritis; A Study on Six Cohorts

BackgroundThanks to the introduction of novel treatments and up-to-date treatment strategies, the severity of joint destruction in rheumatoid arthritis (RA) has decreased considerably. Nonetheless, in daily clinical practice radiographic progression...

Decision making and management of gliomas: practical considerations

Over the last decade, diagnostic options and introduction of novel treatments have expanded the armamentarium in the management of malignant glioma. Combined chemoradiotherapy has become the standard of care in glioblastoma up to the age of 70 years, while treatment in elderly patients or with lower grade glioma is less well defined. Molecular markers define different disease subtypes and allow for adapted treatment selection. This review focuses on simple questions arising in the daily management of patients.

829P - Tumour Vascular Endothelial Growth Factor (VEGF) and Vascular Endothelial Growth Factor Receptors (VEGFR) Polymorphisms and Clinical Outcome in Advanced Renal Cell Carcinoma Patients Receiving First Line Sunitinib

ABSTRACT Background The introduction of novel treatments has radically changed the approach to the treatment of metastatic renal cell carcinoma (mRCC). Currently TKIs directed against the VEGF pathway are the therapeutic strongholds. However, criteria for treatment selection are largely lacking. In this study we assessed the role of VEGF and VEGFR polymorphisms, in the prediction of the clinical outcome in mRCC patients. Methods Forty-one formalin-fixed paraffin-embedded tissue blocks from mRCC patients receiving first-line sunitinib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). SNPs results were correlated with progression free survival (PFS) and overall survival (OS). Results Forty-one patients with metastatic renal cell carcinoma were available for our analysis. All patients received sunitinib as fist-line treatment with standard schedule, dose reduction was applied in patients with grade 3 and 4 toxicities. Median PFS was of 8,22 months, while median OS was of 32,13 months. VEGF A rs833061 polymorphism resulted statistically significant in PFS (17 months for CC + CT vs 4 months for TT; p = 0,0001) and OS (36 months for CC + CT vs 8 months for TT; p = 0,0040). VEGF A rs699947 was statistically significant for PFS (17 months for AA + AC vs 4 months for CC; p = 0,0001) and OS (36 months for AA + AC vs 11 for CC; p = 0,0059). VEGF A rs2010963 was significant in PFS (17 months for GG vs 5 for GC vs 3 for CC; p = 0,0186). VEGR3 rs6877011 was significant in PFS (12 months for CC vs 4 for CG; p = 0,0221) and OS (36 months for CC vs 17 for CG; p = 0,0052). Conclusions in our analysis patients with TT polymorphism of rs833061, CC polymorphism rs699947 and CC polymorphism of rs2010963 seem to have a worse PFS and OS in first line. VEGF-A gene polimorphisms are probably connected with the control of the neoangiogenesis, maybe controlling vasculature normalization. Patients with CG polymorphism of rs6877011 seem equally to have a poor impact of first line therapy. VEGFR-3 seems to be involved in vessels sprouting and architecture. Disclosure All authors have declared no conflicts of interest.