Practice-changing Clinical Trials Research Articles

Paradigm-shifting, Practice-changing Clinical Trials in Urology (P2)

Paradigm-shifting, Practice-changing Clinical Trials in Urology (P2)

Children's Oncology Group's 2023 blueprint for research: Central nervous system tumors.

Tumors of the central nervous system (CNS) are a leading cause of morbidity and mortality in the pediatric population. Molecular characterization in the last decade has redefined CNS tumor diagnoses and risk stratification; confirmed the unique biology of pediatric tumors as distinct entities from tumors that occur in adulthood; and led to the first novel targeted therapies receiving Food and Drug Administration (FDA) approval for children with CNS tumors. There remain significant challenges to overcome: children with unresectable low-grade glioma may require multiple prolonged courses of therapy affecting quality of life; children with high-grade glioma have a dismal long-term prognosis; children with medulloblastoma may suffer significant short- and long-term morbidity from multimodal cytotoxic therapy, and approaches to improve survival in ependymoma remain elusive. The Children's Oncology Group (COG) is uniquely positioned to conduct the next generation of practice-changing clinical trials through rapid prospective molecular characterization and therapy evaluation in well-defined clinical and molecular groups.

Radiotherapy and Immunotherapy in Lung Cancer.

The emergence of immune checkpoint inhibitors (ICIs) as a pillar of cancer treatment has emphasized the immune system's integral role in tumor control and progression through cancer immune surveillance. ICIs are being investigated and incorporated into the treatment paradigm for lung cancers across stages and histology. To date, definitive concurrent chemoradiotherapy followed by consolidative durvalumab is the only National Comprehensive Cancer Network's recommended treatment paradigm including radiotherapy with ICI in lung cancers, although there are other recommendations for ICI with chemotherapy and/or surgery. This narrative review provides an overall view of the evolving integration and synergistic role of immunotherapy and radiotherapy and outlines the use of immunotherapy with radiotherapy for the management of small cell lung cancer and non-small cell lung cancer. It also reviews selected, practice-changing clinical trials that led to the current standard of care for lung cancers.

Immunotherapy through the Lens of Non-Small Cell Lung Cancer.

Immunotherapy has revolutionised anti-cancer treatment in solid organ malignancies. Specifically, the discovery of CTLA-4 followed by PD-1 in the early 2000s led to the practice-changing clinical development of immune checkpoint inhibitors (ICI). Patients with lung cancer, including both small cell (SCLC) and non-small cell lung cancer (NSCLC), benefit from the most commonly used form of immunotherapy in immune checkpoint inhibitors (ICI), resulting in increased survival and quality of life. In NSCLC, the benefit of ICIs has now extended from advanced NSCLC to earlier stages of disease, resulting in durable benefits and the even the emergence of the word 'cure' in long term responders. However, not all patients respond to immunotherapy, and few patients achieve long-term survival. Patients may also develop immune-related toxicity, a small percentage of which is associated with significant mortality and morbidity. This review article highlights the various types of immunotherapeutic strategies, their modes of action, and the practice-changing clinical trials that have led to the widespread use of immunotherapy, with a focus on ICIs in NSCLC and the current challenges associated with advancing the field of immunotherapy.

Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Guideline Update

To conduct an update of the ASCO venous thromboembolism (VTE) guideline. After publication of potentially practice-changing clinical trials, identified through ASCO's signals approach to updating, an updated systematic review was performed for two guideline questions: perioperative thromboprophylaxis and treatment of VTE. PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) published between November 1, 2018, and June 6, 2022. Five RCTs provided information that contributed to changes to the 2019 recommendations. Two RCTs addressed direct factor Xa inhibitors (either rivaroxaban or apixaban) for extended thromboprophylaxis after surgery. Each of these postoperative trials had important limitations but suggested that these two oral anticoagulants are safe and effective in the settings studied. An additional three RCTs addressed apixaban in the setting of VTE treatment. Apixaban was effective in reducing the risk of recurrent VTE, with a low risk of major bleeding. Apixaban and rivaroxaban were added as options for extended pharmacologic thromboprophylaxis after cancer surgery, with a weak strength of recommendation. Apixaban was also added as an option for the treatment of VTE, with high quality of evidence and a strong recommendation.Additional information is available at www.asco.org/supportive-care-guidelines.

Recent Advances in the Systemic Treatment of Localized Gastroesophageal Cancer.

The overall survival expectancy of localized gastroesophageal cancer patients still remains under 5 years despite advances in neoadjuvant and adjuvant treatment strategies in recent years. For almost a decade, immunotherapy has been successfully implemented as a first-line treatment for various oncological diseases in advanced stages. In the case of advanced gastroesophageal cancer, 2021 witnessed several approvals of immune checkpoint inhibitor therapies by different authorities. Although it is still a debate whether this treatment should be restricted to a certain subgroup of patients based on biomarker selection, immunotherapy agents are making remarkable steps in resectable settings as well. The Checkmate-577 study demonstrated significant benefits of nivolumab as an adjuvant treatment for resectable esophageal and gastroesophageal junction tumors and thereby obtained approvals both from U.S. American and European authorities. First results of further potential practice-changing clinical trials are expected in 2023, which might change the treatment armamentarium for resectable gastroesophageal cancers significantly. This review aims to demonstrate the advances of immunotherapy and targeted therapies in treatment of localized gastric, gastroesophageal junction and esophageal tumors and gives a short summary on promising ongoing clinical trials.

The Evolution of the Sentinel Node Biopsy in Melanoma.

The growing repertoire of approved immune-checkpoint inhibitors and targeted therapy has revolutionized the adjuvant treatment of melanoma. While the treatment of primary cutaneous melanoma remains wide local excision (WLE), the management of regional lymph nodes continues to evolve in light of practice-changing clinical trials and dramatically improved adjuvant therapy. With large multicenter studies reporting no benefit in overall survival for completion lymph node dissection (CLND) after a positive sentinel node biopsy (SLNB), controversy remains regarding patient selection and clinical decision-making. This review explores the evolution of the SLNB in cutaneous melanoma in the context of a rapidly changing adjuvant treatment landscape, summarizing the key clinical trials which shaped current practice guidelines.

Clin-STAR corner: Recent practice-changing studies at the interface of pulmonary and critical care medicine and geriatrics.

Older adults suffering from chronic pulmonary diseases, such as chronic obstructive pulmonary disease and interstitial lung disease, and critical illnesses, such as sepsis and acute respiratory failure, are more vulnerable to adverse outcomes like disability and greater side effects from treatments. In this update, we discuss recent practice-changing clinical trials and observational studies in Pulmonary & Critical Care Medicine that have advanced our understanding of the diagnosis or management of older adults with chronic lung diseases or critical illnesses.

Clin-Star corner: What's new at the interface of geriatrics, infectious diseases, and antimicrobial stewardship.

Antibiotics are among the leading causes of adverse drug events in older adults. Short-course antibiotic therapy has been shown to work as well as the traditional longer durations for many types of infections. Antibiotic stewardship interventions including deprescribing strategies have shown a reduction in patient readmissions and mortality among older adults. We identified practice-changing clinical trials focusing on three major domains of overprescribing antibiotics in older adults - community-acquired pneumonia, urinary tract infections, and gram-negative bacteremia. The selected articles underscore the safety and effectiveness of shorter durations of antibiotic treatment for infections in older adults, thus highlighting an opportunity for deprescribing in the aging population. By optimizing antibiotic use, we stand to reduce adverse events and enhance overall health outcomes in older adults.

Survival outcomes of metastatic renal cell carcinoma (mRCC) with sarcomatoid differentiation (SD): A single-institutional experience and literature meta-analysis.

332 Background: Patients (pts) with mRCC with SD have unfavorable outcomes and poor prognosis due to aggressive tumor behavior. Chemotherapy and targeted treatment are often of little benefit. However, recent studies have shown a survival benefit of immunotherapy (IO). Here, we report survival outcomes of pts with mRCC with SD treated with first line IO or chemotherapy or targeted treatment. In addition we performed a meta-analysis of recent practice changing phase III, IO trials in mRCC. Methods: This retrospective survival analysis was performed in pts with mRCC with SD treated with IO or non-IO treatment at Princess Margaret Cancer Centre (PM), Toronto. Demographics, disease characteristics and survival outcomes were collected. Progression free survival (PFS), and overall survival (OS) were calculated using the Kaplan-Meier method (log-rank). PFS and OS hazard ratios (HR) were calculated using cox proportional hazards model. We identified the major, practice changing clinical trials that reported survival outcomes of mRCC with SD treated with IO and performed a random-effects meta-analysis of HR for PFS and OS. We compared these pooled results to our single institution experience. Results: We identified 474 pts diagnosed with mRCC at PM between 2002 and 2019. In total, 44 (9.3%) pts had mRCC with SD who were treated with IO or non-IO. Of these, 29 (65.9%) pts had pure SD and 15 (34.1%) pts had mixed rhabdoid and SD features. Median age was 59.6 years (36-78) and 33 (75%) were male. Overall, as per the IMDC score, 3(6.8%), 21(47.7%) and 20(45.5%) pts were categorized as good, intermediate, and poor risk, respectively. Eight (18.2%) pts were treated with IO as first line of treatment, and 36 (81.8%) pts received non-IO. With a median follow up of 64.8 months (range, 45.7-83.8 months), the median OS for the whole mRCC with SD cohort was 15.6 months (95% CI: 8.6-22.5). The median OS in all pts treated with IO vs non-IO was not reached vs 10.3 months (95%CI: 1.49-19.1 months; p = 0.005), respectively. The HR for OS was 0.1 (95%CI: 0.01-0.78; p = 0.023) favoring IO receipt. The median PFS in all pts treated with IO vs non-IO was 24 months (95%CI: non-estimable) vs 5.4 months (95%CI: 2.9-7.8 months; p = 0.021), respectively. The HR for PFS was 0.3 (95%CI: 0.11-0.89; p = 0.03) favoring IO receipt. We identified through meta-analysis five phase III clinical trials reporting PFS and OS in pts with mRCC with SD who received IO. The overall HR for OS and PFS for the total cohort were 0.55 (95%CI: 0.41-0.74), and 0.53 (95%CI: 0.42-0.67), respectively. Conclusions: Our meta-analysis has confirmed the benefit of IO agents in mRCC with SD. While the numbers included in this retrospective review were small, they have provided real world corroboration of the trial findings. Pts with mRCC and SD benefit from IO treatment, which should be considered the standard of care for these patients.

Representation and Outcomes of Older Adults in Practice-Changing Oncology Trials in the Era of Novel Therapies: A Guideline Appraisal.

Older adults account for 70% of cancer-related deaths, but previous studies have shown that they are underrepresented in cancer clinical trials. We sought to analyze the representation and outcomes of older adults in trials conducted in the era of novel targeted therapy and immunotherapy. We searched the 2020 NCCN Clinical Practice Guidelines in Oncology and retrieved trials from the past 10 years leading to category 1 recommendations in the first-line metastatic setting for the 5 most common causes of cancer death. We categorized trials by cancer type, single-agent versus multiagent approach, and therapeutic class. We described the percentage of older adults (according to each trial's definition) and used a Mantel-Haenszel random-effects meta-analysis model to compare overall and progression-free survival by age. We identified 30 trials consisting of 24,416 patients. Across all trials, 44% of enrolled patients were older adults. Representation of older adults by cancer type within trials was 49% prostate cancer, 38% pancreatic cancer, 37% breast cancer, and 34% non-small cell lung cancer. Representation of older adults also varied by therapeutic class: 20% received immunotherapy, 44% received cytotoxic chemotherapy, 54% received targeted/hormonal therapy, and 34% received combination therapy (P<.001 for all comparisons). For each year since 2010, the percentage of older adults enrolled in trials increased by 1.9%, although this difference was not significant. We observed no difference in overall or progression-free survival between older and younger adults. In our analysis of practice-changing clinical trials, we found that 44% of clinical trial participants were older adults. Trials that included immunotherapy or a combination of therapeutic classes had a lower representation of older adults (<40%). We found that >40% of patients in practice-changing trials are older adults. Although they remain underrepresented in clinical trials compared with the general population, older adults in practice-changing trials seem to be better represented than in previously reported analyses of cooperative group trials.

NAFLD-Related Hepatocarcinoma: The Malignant Side of Metabolic Syndrome.

Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide and the second leading cause of cancer-related mortality. HCC typically arises within a cirrhotic liver, but in about 20% of cases occurs in absence of cirrhosis. Among non-cirrhotic risk factors, non-alcoholic fatty liver disease (NAFLD) currently represents the most important emerging cause of HCC in developed countries. It has been estimated that annual incidence of HCC among patients with non-cirrhotic NAFLD is approximately 0.1–1.3 per 1000 patients/year and ranges from 0.5% to 2.6% among patients with non-alcoholic steatohepatitis (NASH) cirrhosis. However, only a few clinical trials enrolling HCC patients actually distinguished NAFLD/NASH-related cases from other non-cirrhotic causes and therefore evidence is still lacking in this subset of patients. This review aims to describe the biology underpinning NAFLD development, to investigate the main molecular pathways involved in its progression to NASH and HCC and to describe how different pathogenetic mechanisms underlying the onset of HCC can have an impact in clinical practice. We hereby also provide an overview of current HCC treatment options, with a particular focus on the available data on NAFLD-related cases in practice-changing clinical trials.

Implementation of the Australian Computer-Assisted Theragnostics (AusCAT) network for radiation oncology dataextraction, reporting and distributed learning.

There is significant potential to analyse and model routinely collected data for radiotherapy patients to provide evidence to support clinical decisions, particularly where clinical trials evidence is limited or non-existent. However, in practice there are administrative, ethical, technical, logistical and legislative barriers to having coordinated data analysis platforms across radiation oncology centres. A distributed learning network of computer systems is presented, with software tools to extract and report on oncology data and to enable statistical model development. A distributed or federated learning approach keeps data in the local centre, but models are developed from the entire cohort. The feasibility of this approach is demonstrated across six Australian oncology centres, using routinely collected lung cancer data from oncology information systems. The infrastructure was used to validate and develop machine learning for model-based clinical decision support and for one centre to assess patient eligibility criteria for two major lung cancer radiotherapy clinical trials (RTOG-9410, RTOG-0617). External validation of a 2-year overall survival model for non-small cell lung cancer (NSCLC) gave an AUC of 0.65 and C-index of 0.62 across the network. For one centre, 65% of Stage III NSCLC patients did not meet eligibility criteria for either of the two practice-changing clinical trials, and these patients had poorer survival than eligible patients (10.6m vs. 15.8m, P=0.024). Population-based studies on routine data are possible using a distributed learning approach. This has the potential for decision support models for patients for whom supporting clinical trial evidence is not applicable.

Precision oncology in metastatic colorectal cancer - from biology to medicine.

Remarkable progress has been made in the development of biomarker-driven targeted therapies for patients with multiple cancer types, including melanoma, breast and lung tumours, although precision oncology for patients with colorectal cancer (CRC) continues to lag behind. Nonetheless, the availability of patient-derived CRC models coupled with in vitro and in vivo pharmacological and functional analyses over the past decade has finally led to advances in the field. Gene-specific alterations are not the only determinants that can successfully direct the use of targeted therapy. Indeed, successful inhibition of BRAF or KRAS in metastatic CRCs driven by activating mutations in these genes requires combinations of drugs that inhibit the mutant protein while at the same time restraining adaptive resistance via CRC-specific EGFR-mediated feedback loops. The emerging paradigm is, therefore, that the intrinsic biology of CRC cells must be considered alongside the molecular profiles of individual tumours in order to successfully personalize treatment. In this Review, we outline how preclinical studies based on patient-derived models have informed the design of practice-changing clinical trials. The integration of these experiences into a common framework will reshape the future design of biology-informed clinical trials in this field.

Cancer, Clinical Trials, and Canada: Our Contribution to Worldwide Randomized Controlled Trials.

Canada has a long tradition of leading practice-changing clinical trials in oncology. Here, we describe methodology, results, and interpretation of oncology RCTs with Canadian involvement compared to RCTs from other high-income countries (HICs). A literature search identified all RCTs evaluating anti-cancer therapies published 2014–2017. RCTs were classified based on the country affiliation of first authors. The study cohort included 636 HIC-led RCTs; 155 (24%) had Canadian authors. Three-quarters (112/155, 72%) of Canadian RCTs were conducted in the palliative setting, compared to two thirds (299/481, 62%) of RCTs from other HICs (p = 0.022). Canadian RCTs were more likely than those from other HICs to be supported by industry (85% vs. 69%, p < 0.001). The proportion of positive Canadian trials that met the ESMO-MCBS threshold for substantial clinical benefit was comparable to RCTs without Canadian authors (29% vs. 32%, p = 0.137). Thirteen percent (20/155) of all Canadian trials were affiliated with the Canadian Cancer Trials Group (CCTG). Canada plays a meaningful role in the global cancer research ecosystem but is overly reliant on industry support. The very low proportion of trials that identify a new treatment with substantial clinical benefit is worrisome. A renewed investment in cancer clinical trials is needed in Canada.

High rates of advanced prostate cancer in the Middle East: Analysis from a tertiary care center.

Objectives:Prostate cancer incidence is increasing in the Middle East (ME); however, the data of stage at the diagnosis and treatment outcomes are lacking. In developed countries, the incidence of de novo metastatic prostate cancer ranges between 4% and 14%. We hypothesized that the rates of presentation with advanced disease are significantly higher in the ME based on clinical observation. This study aims to examine the stage at the presentation of patients with prostate cancer at a large tertiary center in the ME.Methods:After Institutional Review Board approval, we identified the patients diagnosed with prostate adenocarcinoma and presented to a tertiary care center between January 2010 and July 2015. Clinical, demographic, and pathological characteristics were abstracted. Patients with advanced disease were stratified according to tumor volume based on definitions from practice changing clinical trials. Descriptive and Kaplan–Meier survival analysis was used.Results:A total of 559 patients were identified, with a median age at the diagnosis of 65 years and an age range of 39–94 years. Median prostate-specific antigen (PSA) at the presentation was 10 ng/ml, and almost a quarter of the men (23%) presented with metastatic disease. The most common site of metastasis was the bone (34/89, 38%). High-volume metastasis was present in 30.3%, 9%, and 5.2% of the cohort based on STAMPEDE, CHAARTED, and LATITUDE trial criteria, respectively.Conclusion:This is the first report showing the high proportion of men from ME presenting with de novo metastasis. This could be due to many factors, including the highly variable access to specialist multidisciplinary management, lack of awareness, and lack of PSA screening in the region. There is a clear need to raise the awareness about prostate cancer screening and early detection and to address the rising burden of advanced prostate cancer affecting men in the ME region.

Abstract 13205: Underrepresentation of Women as Clinical Trialists in Heart Failure: A Systematic Review of Randomized Controlled Trials Published in High-impact Medical Journals

Introduction: Clinical trials change practice in cardiology but leading them typically requires advanced research training, mentorship, sponsorship, and networking. Women are underrepresented in cardiology and report challenges in obtaining mentorship and networking opportunities. Objective: To evaluate the gender distribution of first and senior authors in practice-changing clinical trials in heart failure (HF), and explore clinical trial characteristics associated with women as first authors. Methods: We searched MEDLINE, EMBASE and CINAHL databases for randomized controlled trials (RCTs) published January 2000 - May 2019. We included RCTs that recruited adults with HF with reduced ejection fraction that were published in medical journals with an impact factor of &gt; 10. Two reviewers screened and extracted data independently. We determined the gender distribution of the authors, assessed temporal trends in authorship, and used logistic regression to identify characteristics associated with women in first authorship positions. Results: The search identified 10,596 unique studies, of which 317 met eligibility criteria. We found that 15.8%, 11.7%, and 10.7% of first, senior, and corresponding authors, respectively, were women. Multivariable analysis revealed that the first author was more likely to be a woman if the senior author of a clinical trial was a woman (odds ratio [OR] 2.17, 95% confidence interval [CI] 1.04-4.66, p=0.039), and if the trial was conducted at a single rather than multiple centers (OR 1.40, 95% CI 1.09-6.48, p=0.035). Source of funding (public or industry), type of intervention (health service, drug, device, or surgery), and region of trial coordination (Europe, North America, Central and South America, Asia, and Australia) were not associated with gender of first authors. The proportion of trials that included women as authors has decreased from 2000 to present. Conclusion: Women are under-represented as clinical trialists in HF. Adjusting for other trial characteristics, the first author of a clinical trial was more likely to be a woman if the senior author was a woman. Mentoring women as clinical trialists in the present era may be a strategic way to increase the gender diversity of clinical trialists in years to come.

Validation and implementation of a mobile app decision support system for quality assurance of tumor boards: Analyzing the concordance rates for testis cancer at a multidisciplinary tumor board of a tertiary referral center.

399 Background: Guideline-compliance in the management of GCT is suboptimal concerning and it results in significantly impaired long-term survival. To facilitating guideline concordant decisions even in less experienced MTD, we developed an algorithm-driven and validated mobile App to provide evidence-based recommendations. This App contains latest guideline versions and it is continuously updated to include practice changing clinical trials. It is the purpose of this study to analyse treatment decision made by MTD compared to guideline recommended therapy. Methods: 302 patients with GCT and MTD decision were randomly selected from our database. Concordance rates of MTD recommendations were compared to query results of the digital APP “Easy Oncology” performed by 2 independent, blinded reviewers. Descriptive statistics and data analysis included IBM´s statistics software SPSS Version 25. Correlation analysis of cancer case characteristics was performed by Kendalls Tau, Gamma, Pearson and Spearman tests. Results: Median age was 35 (18-82) years. Clinical stages I, IIA-C, and III were identified in 32%, 37%, and 31%, resp. According to IGCCCG 56%, 18%, and 25% demonstrated good, intermediate, and poor prognosis, resp. 56% were non-seminomas and 44% were seminomas. 60%, 16%, and 7% of MTD decisions were related to 1st-line, 2nd, and 3rd line therapy and 18% dealt with follow up. Overall concordance rate was 99% (301/302). Concordance rates in CS I, IIA-C, and III were 100%, 98% and 99%, resp. Concordance rates with regard to 1st, 2nd and 3rd line therapy were 99% (135/136), 100%, and 88% (13/14). Conclusions: Our validated expert-created mobile decision support system demonstrates easy and reliable application in daily routine in an expert tertiary referral centre. The APP relies on guideline and trial based information and avoids MTD decisions by expert opinions. It might improve the MTD decision in less experienced MTDs which is currently evaluated in a prospective study.

Abstract P4-15-05: Participation of emerging regions in practice-changing breast cancer trials over the last three decades

Abstract Introduction: Conduction of clinical trials (CT) became increasingly globalized and has expanded beyond the established regions of North America and Western Europe. Although emerging regions are attractive due to easier access to a treatment-naïve population, faster recruitment and lower costs, some challenges are involved. Knowledge about the conduction of CT in emerging regions is relevant to better understand the implications of CT globalization. Objective: Assess the contribution of selected emerging regions to practice-changing breast cancer (BC) trials, contrasted to an established one. Methodology: We conducted a descriptive analysis of the contribution of 3 emerging regions to practice-changing BC trials: Latin America and the Caribbean (LATAM); East Asia (E. Asia) and Eastern Europe, Northern/Central Asia (Non-Western Europe); and an established one: US-Canada (US-Can). Practice-changing CT were defined as those that supported FDA approval of a new drug or indication. We identified all FDA-approved drugs for BC treatment from Jan-1992 to Dec-2018. For each drug we identified the applicable practice-changing CT through the latest package insert and analyzed the corresponding publications. The main variables evaluated were: participating countries, sites/country and authors/country. Participating sites data was obtained from ClinicalTrials.gov if it was not available in the publication. To better correlate each region´s contribution, we adjusted the number of CT to the average number of medical doctors (MD) and the average BC incidence in each region (obtained from the World Health Organization and GLOBOCAN, respectively). Results: 34 CT that led to the approval of 17 drugs were included. LATAM participated in 24 (70%), E. Asia and Non-Western Europe in 19 (54%), and US-Can in 32 (94%). 42% of LATAM countries participated in at least one trial, 63% in E. Asia and 30% in Non-Western Europe. Additional data is shown in Table 1. The number of CT in emerging regions was negligible until ~2001, when a progressive increase is observed (Table 2). In the last 2 years (2016-18) the number of CT in these regions more than doubled the one in the 2011-15 quinquennium. Number of practice-changing CT conducted in US-Can over the last decade is similar to the one in each of the emerging regions. Despite, contribution in terms of authorship is much lower in these regions (LATAM: 0.7 authors/CT, E. Asia: 2 authors/CT, Non-Western Europe: 0.6 authors/CT, US-Can 6.6 authors/CT). E. Asia has shown a steady increase in authorship contribution since 2011 (Table 2). Conclusion: Although the majority of CT are still being run in established regions, we showed that the number of practice-changing BC CT in emerging ones is currently equivalent to US-Can, what also led to more authorship opportunities. Number of sites per trial is higher in US-Can, what may reflect sponsor´s higher interest in this region and poorer enrollment rates compared to emerging ones. The ongoing globalization of clinical research is an opportunity for all stakeholders and efforts should be made to enhance it. Table 1 - Region´s data of interestTrialsLATAME. AsiaNon-Western EuropeUSA- CanNumber of CT (Total = 34)24191932Number of CT per 100.000 MD1.70.632.026.6Number of CT per 10.000 new BC cases/year1.20.41.71.2Percentage of region’s countries participating in at least one CT426330100Mean number of countries per CT3.22.91.51.7Mean number of sites per CT13.521.18.057.6 Table 2 - Number of practice-changing CT and authors per-5 year period1992-19951996-20002001-20052006-20102011-20152016-2018Total number of CT185749LATAM024747E. Asia001549Non-Western Europe002539US-Can165749Total number of authors239395342101LATAM022633E. Asia00051023Non-Western Europe000433US-Can23737382672 Citation Format: Andres Machado, Clara Rodriguez, Andrea Migliaro, Rodrigo Fresco. Participation of emerging regions in practice-changing breast cancer trials over the last three decades [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-15-05.

Recent Developments in HER2-Directed Therapy in Breast Cancer

This review will discuss recent important trials for the treatment of HER2-positive breast cancer, emphasize ongoing areas of development, and highlight areas of unmet need. Advances for early-stage treatment have been driven by key clinical trials with pertuzumab, neratinib, and TDM-1. In the adjuvant setting, dual HER2 targeting with trastuzumab and pertuzumab has demonstrated modest improvement in disease-free survival. Neratinib also showed modest benefit in the extended adjuvant setting after prior trastuzumab. Finally, for patients who did not achieve pathologic complete response to neoadjuvant therapy, adjuvant therapy with TDM-1 showed significant disease-free survival benefit over trastuzumab. In advanced disease, neratinib appears to have activity beyond standard second line treatment. Promising compounds with early-phase data reviewed are tucatinib, margetuximab, and antibody-drug complexes. Immunotherapy in HER2-positive disease also has early-phase data. Endocrine therapy in combination with CDK4/6 inhibition and HER2-targeted therapy is in evaluation. Two areas of unmet need include CNS disease and disease treatment in the elderly population. In the wake of recent practice changing clinical trials, HER2-directed therapy is rapidly evolving. Future advances in therapy are anticipated with ongoing studies.