US drug approvals rise in 2020 over previous year

Several medicines were approved as first treatments, including Gilead Sciences' Veklury (remdesivir) for patients with COVID-19 who require hospitalization (4);Amivas' artesunate for injection for severe malaria (5);Horizon Therapeutics Ireland DAC's Tepezza (teprotumumab-trbw), an antibody drug conjugate (ADC) for treating thyroid eye disease (6);and Ultragenyx Pharmaceutical's Dojolvi (triheptanoin) and Alnylam Pharmaceuticals' Oxlumo (lumasiran), both first treatments for metabolic disorders-Dojolvi for treating paediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders (7) and Oxlumo (lumasiran) for treating the rare genetic disorder, primary hyperoxaluria type 1 (8). Blueprint Medicines Corporation) for treating unresectable or metastatic gastrointestinal stromal tumours harboring a platelet-derived growth factor receptor alpha exon 18 mutation (9);Koselugo (selumetinib, AstraZeneca Pharmaceuticals), for neurofibromatosis type 1 (10);Pemazyre (pemigatinib, Incyte Corporation), for certain types of previously treated, advanced bile duct cancer (cholangiocarcinoma) (11);Tabrecta (capmatinib, Novartis) for non-small cell lung cancer that has spread to other parts of the body and whose tumours have mutations that lead to MET exon 14 skipping (12);and Retevmo (selpercatinib, Loxo Oncology, a subsidiary of Eli Lilly and Company) for treating three types of tumours with alterations of the "rearranged during transfection" gene (13). Gilead, "U.S. FDA Approves Kite's Tecartus, the First and Only CAR T Treatment for Relapsed or Refractory Mantle Cell Lymphoma," Press Release, 24 July 2020.

IDDF2023-ABS-0156 Poor tolerance of bowel preparation for index colonoscopy decreases surveillance rate in high-risk adenoma removal patients

IDDF-2023-ABS-0156 Table 1Association between Tolerance of BP for index colonoscopy and surveillance rateTolerance of BP for index colonoscopy Surveillance rate% (n/N) Total 67% (127/186) 1. Very intolerable 47% (9/19) 2. Intolerable 48% (10/21) 3. Neither tolerable nor intolerable 76% (55/72) 4. Tolerable 71% (22/31) 5. Very tolerable 72% (31/43) P for trend test 0.04 IDDF2023-ABS-0156 Table 2Risk factors of non-compliance of surveillance colonoscopy by multivariate regression analysis Multivariate OR (95%CI) p value Age,/1-year increase 1.04 (1.03-1.05) 0.001 Male sex 1.13 (0.85-1.52) 0.40 BMI,/1-kg/m2 increase 1.05 (0.96-1.15) 0.28 Family history of CRC 0.93 (0.16-5.25) 0.92 Low education 0.92 (0.39-2.15) 0.90 Comorbidities 1.05 (0.51-2.13) 0.90 Low tolerance of BP for colonoscopy 2.45 (1.11-5.41) 0.006 Absence of primary care physician 4.63 (1.60-13.4) 0.001 BMI: body mass index, CRC: colorectal cancer, BP: bowel preparation IDDF2023-ABS-0156 Table 3The reasons of non-compliance surveillance colonoscopyReasons of non-compliance surveillance colonoscopy n, (%) Total 62 (100%) Not knowing about follow-up intervals 4 (6%) Having no symptoms 15 (24%) Fear of examination Pain during colonoscopy 1 (2%) Embarrassment during colonoscopy 0 (0%) Bowel preparation for colonoscopy 17 (28%) Over sedation during colonoscopy 2 (3%) Old age/severe illness for surveillance 10 (16%) Having no time 10 (16%) Having no money 1 (2%) Fear of Covid-19 infection 2 (3%) IDDF2023-ABS-0156 Figure 1ConclusionsOur findings highlight the need for improvement of the surveillance colonoscopy rate, especially for patients who had poor tolerance to BP on index colonoscopy and no gastroenterology visit. Providing a well-tolerated BP regimen may lead to an increase in surveillance colonoscopy compliance.

Type 1 diabetes and environment . . . and other stories

A linked ecological analysis of environmental and demographic variables identified several factors, including poor air quality, outdoor light at night, and higher population density that were negatively associated with the incidence of diabetes (Diabetologia doi:10.1007/s00125-020-05087-7). A case-control study using a database of people known to have autoimmune disease raises anxiety about central nervous system inflammatory events (JAMA Neurol doi:10.1001/jamaneurol.2020.1162). A history of exposure to TNF inhibitors carried a threefold increase in risk both of demyelinating diseases, such as multiple sclerosis and optic neuritis, and of non-demyelinating conditions, such as encephalitis, neurosarcoidosis, and vasculitis.

COVID-19-The Shift of Homeostasis into Oncopathology or Chronic Fibrosis in Terms of Female Reproductive System Involvement.

The COVID-19 pandemic caused by the SARS-CoV-2 coronavirus remains a global public health concern due to the systemic nature of the infection and its long-term consequences, many of which remain to be elucidated. SARS-CoV-2 targets endothelial cells and blood vessels, altering the tissue microenvironment, its secretion, immune-cell subpopulations, the extracellular matrix, and the molecular composition and mechanical properties. The female reproductive system has high regenerative potential, but can accumulate damage, including due to SARS-CoV-2. COVID-19 is profibrotic and can change the tissue microenvironment toward an oncogenic niche. This makes COVID-19 and its consequences one of the potential regulators of a homeostasis shift toward oncopathology and fibrosis in the tissues of the female reproductive system. We are looking at SARS-CoV-2-induced changes at all levels in the female reproductive system.

Effects of Antibody Response after Booster Vaccination on SARS-CoV-2 Breakthrough Infections and Disease Outcomes in Advanced Cancer Patients: A Prospective Analysis of the Vax-on-Third Study.

(1) Background: The clinical implications of COVID-19 outbreaks following SARS-CoV-2 vaccination in immunocompromised recipients are a worldwide concern. Cancer patients on active treatment remain at an increased risk of developing breakthrough infections because of waning immunity and the emergence of SARS-CoV-2 variants. There is a paucity of data on the effects of COVID-19 outbreaks on long-term survival outcomes in this population. (2) Methods: We enrolled 230 cancer patients who were on active treatment for advanced disease and had received booster dosing of an mRNA-BNT162b2 vaccine as part of the Vax-On-Third trial between September 2021 and October 2021. Four weeks after the third immunization, IgG antibodies against the spike receptor domain of SARS-CoV-2 were tested in all patients. We prospectively evaluated the incidence of breakthrough infections and disease outcomes. The coprimary endpoints were the effects of antibody titers on the development of breakthrough infections and the impact of COVID-19 outbreaks on cancer treatment failure. (3) Results: At a median follow-up of 16.3 months (95% CI 14.5-17.0), 85 (37%) patients developed SARS-CoV-2 infection. Hospitalization was required in 11 patients (12.9%) and only 2 (2.3%) deaths related to COVID-19 outbreaks were observed. Median antibody titers were significantly lower in breakthrough cases than in non-cases (291 BAU/mL (95% CI 210-505) vs. 2798 BAU/mL (95% CI 2323-3613), p < 0.001). A serological titer cut-off below 803 BAU/mL was predictive of breakthrough infection. In multivariate testing, antibody titers and cytotoxic chemotherapy were independently associated with an increased risk of outbreaks. Time-to-treatment failure after booster dosing was significantly shorter in patients who contracted SARS-CoV-2 infection (3.1 months (95% CI 2.3-3.6) vs. 16.2 months (95% CI 14.3-17.0), p < 0.001) and had an antibody level below the cut-off (3.6 months (95% CI 3.0-4.5) vs. 14.6 months (95% CI 11.9-16.3), p < 0.001). A multivariate Cox regression model confirmed that both covariates independently had a worsening effect on time-to-treatment failure. (4) Conclusions: These data support the role of vaccine boosters in preventing the incidence and severity of COVID-19 outbreaks. Enhanced humoral immunity after the third vaccination significantly correlates with protection against breakthrough infections. Strategies aimed at restraining SARS-CoV-2 transmission in advanced cancer patients undergoing active treatment should be prioritized to mitigate the impact on disease outcomes.

Application of Convolutional Neural Network techniques to the classification of lung illnesses

The heterotypic perspective of cancer depicts solid tumors as ecosystems composed of aberrant epithelium tumor cells and a multitude of cell types together referred to as stromal cells. Macrophages, which are innate immune cells, are overrepresented in certain environments. Tumor-associated macrophages (TAMs) are macrophages found in the tumor microenvironment;they are derived from the blood's monocytes and are essential for tumor progression. TAMs acquiring tumorigenic qualities is dependent on a complicated interaction between TAMs and tumor cells. Using co-culture studies, we showed that tumor-derived secretory signals promote Tams' tumor-promoting characteristics, shaping up Tams' features in ways that are advantageous to the tumor. When model human monocytes (THP-1) were co-cultured with A549 cells, the A549 cells exhibited increased proliferation, migration, and invasiveness due to the secretion of tumor-promoting cytokines from the THP-1 cells. We showed that EDA-containing Fibronectin secreted by A549 cells reliably mediates the pro-inflammatory response of THP-1 monocytes in a paracrine manner. Ablation of such responses by the treatment of THP-1 cells with TLR-4 blocking antibody implicated Fibronectin-TLR4 axis in tumor-associated inflammation and suggests a paradigm wherein lung carcinoma cell derived EDA-containing Fibronectin drives a pro-inflammatory and pro-metastatic tumor microenvironment. Interestingly, autocrine proliferation, migration, and invasion were all boosted by EDA-containing Fibronectin secreted by A549 cells. Lastly, we demonstrated that the EDA in Fibronectin activates the epithelial-mesenchymal transition pathway in A549 cells, hence granting these cells the ability to metastasize. © 2023 IEEE.

Braun-Falco's dermatology

The 4th edition of the "Braun-Falco Textbook", an international standard text of dermatology, allergy and sexually transmitted disorders has been thoroughly rewritten and reedited and offers a comprehensive state-of-the-art review of the entire field for clinicians in hospital and private practice. The editors assembled an expert team of authors with outstanding international reputation who present a concise overview of the complete spectrum of dermatology and its groundbreaking progress with particular emphasis on aspects of practical care within the specialty. The treatment recommendations are based on current international guidelines and standards of care, and pay special attention to latest therapeutic progress as well as recent pathophysiological concepts. A special emphasis has been put on a unique array of high quality figures and a clear, easily understandable structure of the respective chapters. Besides the printed version, the new edition is available as a digital version. New aspects of the 4th edition that reflect the tremendous and rapid progress of dermatology include an up to date clinical classification of dermatoses, current guidelines and therapeutic concepts in inflammatory and neoplastic diseases, and dermatological aspects of the new Covid-19 infection. "Braun-Falco's Dermatology" is a must for specialists and trainees in dermatology, and of great value for all physicians who encounter skin diseases in general. © Springer-Verlag GmbH Germany, part of Springer Nature 1991, 2000, 2009, 2022. All rights reserved.

Diagnosis and treatment plan for severe cases of novel coronavirus infection

Novel coronavirus infection most often involves the respiratory system, leading to pneumonia. In severe cases, multiple organs or systems such as the heart, kidneys, intestines, and nervous system may also be affected. Therefore, 2019-nCoV infection requires comprehensive prevention and treatment targeting multiple organs. 1. Applicable people (1) Severe and critical cases of novel coronavirus infection, collectively referred to as "severe cases". (2) For those who do not meet the diagnostic criteria for severe cases, but develop pneumonia caused by novel coronavirus infection and have one of the following conditions, they can also be managed as severe cases: age > 65 years old, full vaccination has not been completed, and severe chronic Diseases (including high blood pressure, diabetes, coronary heart disease, chronic lung disease, malignant tumors, and low immune function, etc.).

Eastern Regional Meeting 2021

The proceedings contain 63 papers. The topics discussed include: doxorubicin cardiotoxicity in human organotypic cardiac slices is modulated by P38 MAPK inhibition in a sex- and isoform-specific manner;validation of a modified response evaluation criteria in solid tumors after stereotactic ablative radiosurgery for lung cancer;safer use of aspirin in older adults, need for a consensus;efficacy of facemasks in prevention of COVID-19: a systematic review;practice patterns of rapid influenza diagnostic test;equity and inclusion in patient centered outcomes research: lessons from the adaptable study at Montefiore site;a solution to decrease potentially inappropriate medications (PIM) use during hospitalization;predictors of misperceptions, risk perceptions, and personal risk perceptions about COVID-19 by country, education and income;cognitive function and the consumption of probiotic foods in older adults: an NHANES study;and registered dietitian nutritionist care impacts nutrition-related outcomes for patients with cancer in the outpatient setting.

The Korean Society for Neuro-Oncology (KSNO) Guideline for the Management of Brain Tumor Patients During the Crisis Period: A Consensus Recommendation Using the Delphi Method (Version 2023.1).

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, the need for appropriate treatment guidelines for patients with brain tumors was indispensable due to the lack and limitations of medical resources. Thus, the Korean Society for Neuro-Oncology (KSNO), a multidisciplinary academic society, has undertaken efforts to develop a guideline that is tailored to the domestic situation and that can be used in similar crisis situations in the future. METHODS: The KSNO Guideline Working Group was composed of 22 multidisciplinary experts on neuro-oncology in Korea. In order to reach consensus among the experts, the Delphi method was used to build up the final recommendations. RESULTS: All participating experts completed the series of surveys, and the results of final survey were used to draft the current consensus recommendations. Priority levels of surgery and radiotherapy during crises were proposed using appropriate time window-based criteria for management outcome. The highest priority for surgery is assigned to patients who are life-threatening or have a risk of significant impact on a patient's prognosis unless immediate intervention is given within 24-48 hours. As for the radiotherapy, patients who are at risk of compromising their overall survival or neurological status within 4-6 weeks are assigned to the highest priority. Curative-intent chemotherapy has the highest priority, followed by neoadjuvant/adjuvant and palliative chemotherapy during a crisis period. Telemedicine should be actively considered as a management tool for brain tumor patients during the mass infection crises such as the COVID-19 pandemic. CONCLUSION: It is crucial that adequate medical care for patients with brain tumors is maintained and provided, even during times of crisis. This guideline will serve as a valuable resource, assisting in the delivery of treatment to brain tumor patients in the event of any future crisis.

Synchronous Diagnosis of Squamous Cell Carcinoma of the Lung and Mixed Cellularity Hodgkin Lymphoma of the Nasopharynx.

Hodgkin lymphoma (HL) is a highly curable B cell lymphoproliferative neoplasm with a bimodal age distribution. Lung cancer is the leading cause of cancer-related deaths in both sexes. We present a rare case of synchronous squamous cell carcinoma (SCC) of the lung and mixed cellularity HL of the nasopharynx. A gentleman in his 70s presented with right-sided chest pain and shortness of breath. CT of the chest showed a peripheral lung mass, and a biopsy confirmed SCC of the lung. The patient underwent a positron emission tomography/computed tomography (PET/CT) for staging that revealed an 18F-fluorodeoxyglucose (FDG)-avid mass in the nasopharynx. Flexible nasal endoscopy and biopsy of the nasopharyngeal mass revealed mixed cellularity classical HL. The patient was started on chemoimmunotherapy for lung cancer. Unfortunately, two months after initiation of treatment, the patient died from COVID-19 pneumonia and multiorgan failure.

An Efficient Deep Learning based Approach for the Detection of Brain Tumors

Deep learning has stretched out its roots even more in our daily lives. As a society, we are witnessing small changes in lifestyle such as self-driving cars, Google Assistant, Netflix recommendations, and spam email detection. Similarly, deep learning is also evolving in healthcare, and today many doctors often use it more comfortably. Using deep learning models we can detect severe brain tumors with the help of MRI scans, in fact in the Covid era, deep learning evolved majorly to detect the disease with the help of Lung X-Rays. Magnetic Resonance Imaging (MRI) is used when a person has a brain tumor to detect it. Brain tumors can fall into any category, and MRI scans of these millions of people are needed to determine if they have the disease and if so, which category they belong to. Determining the type of brain tumor can be a rigid task and deep learning models play an important role here. For the proposed deep learning model, we have implemented convolution neural networks (CNN) through which our model has achieved a testing accuracy of 96.5%. Also, along with this, the libraries of Keras and Tensorflow have been explored by the authors in this research. © 2022 IEEE.

Antioxidant and Anti-Breast Cancer Properties of Hyaluronidase from Marine Staphylococcus aureus (CASMTK1)

This work studied the antioxidant and anti-breast cancer properties of hyaluronidase, extracted from a potential marine strain, Staphylococcus aureus (CASMTK1), isolated from Parangipettai coastal waters in southeast coast of India. The Staphylococcal enzyme production was tested under different carbon and nitrogen sources;and recorded the maximum production when the microbial strain was cultured with starch as the carbon source and ammonium sulphate as the inorganic nitrogen source with the enzyme production of 92.5 U/mL and 95.0 U/mL, respectively. The hyaluronidase enzyme production was also tested in different pH and temperature;and recorded the maximum yield of 102.5 U/mL in pH 5 and that of 95.5 U/mL in 45 °C. The partially purified enzyme was subjected to FTIR and FT Raman technique and found the presence of the amide- I and II, Carboxyl, N-H bending, C-H stretching and α-helices and β-sheet proteins between wave number 1500–1700 cm−1. The partially purified enzyme also exhibited strong antioxidant and in-vitro breast cancer properties. The enzyme showed the highest hydroxyl radical scavenging activity of 79% at the 50 µg/mL concentration, and this activity increased in a dose-dependent manner. The enzyme inhibited proliferation of the breast cancer cell line of MCF-7, and it caused 100% cell death at the concentration of 80 µg/mL. The enzyme generated capacity of producing free radicles that damage the cancer cells, and this effect was very nearer to the standard drug, paclitaxel. The enzyme damaged the cancer cells and induced apoptosis in 78% of cancer cells as evident by condensed or fragmented chromatin at 40 µg/mL. Further purification of the enzyme, analysis of its molecular aspects, and elucidation of exact mechanisms of its biological activities will throw new light on the utility of staphylococcal hyaluronidase in anticancer chemotherapy.

Human Lung Non-Invasive Anomaly Detection through UWB Microwave Imaging and Diagnosis of COVID-19: A Possible Application

This study shows a prototype for detecting lung effects using microwave imaging. Continuous monitoring of pulmonary fluid levels is one of the most successful approaches for detecting fluid in the lung;early Chest X-rays, computational tomography (CT)-scans, and magnetic resonance imaging (MRI) are the most commonly used instruments for fluid detection. Nonetheless, they lack sensitivity to ionizing radiation and are inaccessible to the general public. This research focuses on the development of a low-cost, portable, and noninvasive device for detecting Covid-19 or lung damage. The simulation of the system involved the antenna design, a 3D model of the human lung, the building of a COMSOL model, and image processing to estimate the lung damage percentage. The simulation consisted of three components. The primary element requires mode switching for four array antennas (transmit and receive). In the paper, microwave tomography was used. Using microwave near-field imaging, the second component of the simulation analyses the lung's bioheat and electromagnetic waves as well as examines the image creation under various conditions;many electromagnetic factors seen at the receiving device are investigated. The final phase of the simulation shows the affected area of the lung phantom and the extent of the damage. © 2023 IEEE.

Inpatient hospitalization, mortality high among patients with cancer, COVID-19

Patients with cancer who contracted COVID-19 had high risk for inpatient hospital admission and death, according to study results. "COVID-19 in patients with solid tumors and hematologic malignancies undergoing active therapy is associated with poor outcomes, including a high risk [for] inpatient mortality," Alok A. Khorana, MD, professor of medicine at Cleveland Clinic Lerner College of Medicine, told HemOnc Today. The Leukemia b Lymphoma Society encourages all patients with blood cancer to get vaccinated because the side-effect profile of vaccination is no different for them than the general population.

Drug-Induced Hand-Foot Syndrome in Cancer Patients Receiving Capecitabine in A Tertiary Care Hospital

Objective: To determine the frequency of hand-foot syndrome and associated factors among patients receiving Capecitabine for the management of cancer in a tertiary care setting. Study Design: Cross-sectional study. Place and Duration of Study: Oncology Department Combined Military Hospital, Rawalpindi Pakistan from Dec 2020 to May 2021. Methodology: One hundred patients with malignant conditions taking Capecitabine for more than two weeks were included in the study. A detailed relevant dermatological examination was carried out on all the patients to diagno se hand-foot syndrome based on the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 Grading of Hand-Foot Syndrome. Results: Out of 100 cancer patients using Capecitabine for more than two weeks included in the study. Sixty-eight showed the presence of hand-foot syndrome, while 32 did not show any features of hand-foot syndrome. Combination treatment was statistically significantly associated with hand-foot syndrome among the patients included in our study (p-value<0.001). Conclusion: Hand-foot syndrome was a common side effect seen in patients managed with Capecitabine for their cancerous condition. Patients using other chemotherapeutic agents along with Capecitabine were more at risk of having hand-foot syndrome than those taking Capecitabine alone.

Women with breast cancer, listening to the unheard voices: A qualitative study

Objective: This is a descriptive qualitative study with the aim of examining experiences of women diagnosed with breast cancer. Methods: The semi-structured interviews were conducted in the oncology clinic in Al Basheer Hospital in Jordan and included 15 women. Results: Several themes were identified such as knowledge before and after diagnosis, side effects of treatment, social and economic problems, lockdown and financial challenges in corona pandemic, coping strategies, and disclosure issues. Appropriate knowledge concerning causes of breast cancer, and side effects of administered drugs were lacking. Additionally, women were not comfortable telling others about their breast cancer diagnosis and considered it a private issue. During the COVID-19 pandemic, they faced many difficulties reaching hospitals, financial struggles, and inability to meet with their loved ones during lockdown. Conclusion: This study revealed the diversity of personalities and unique disposition of women regarding all the topics covered in the interviews. These differences should be considered in the support provided to these patients. [ FROM AUTHOR] Copyright of Electronic Journal of General Medicine is the property of Modestum Publications and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

PD13-08 Phase 1 TROPION-PanTumor01 Study Evaluating Datopotamab Deruxtecan (Dato-DXd) in Unresectable or Metastatic Hormone Receptor-Positive/HER2-Negative Breast Cancer (BC)

Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I (Topo I) inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. Dato-DXd demonstrated compelling single-agent antitumor activity in heavily pretreated patients (pts) with metastatic triple-negative BC (Krop, SABCS 2021). This is the first report of results from the TROPION-PanTumor01 study in pts with unresectable or metastatic hormone receptor- positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-;including HER2-low and HER2-zero) BC. Method(s): TROPION-PanTumor01 (NCT03401385) is a phase 1, multicenter, open-label, 2-part doseescalation/expansion study evaluating Dato-DXd in previously treated pts with solid tumors. Based on previous clinical findings and exposure-response results from pts with NSCLC, Dato-DXd 6 mg/kg IV Q3W is being evaluated in pts with unresectable or metastatic HR+/HER2- BC that progressed on standard therapies. The primary objectives were safety and tolerability. Tumor responses, including ORR (complete response [CR] + partial response [PR]) and DCR (CR + PR + stable disease [SD]), were assessed per RECIST version 1.1 by blinded independent central review. Result(s): As of the April 29, 2022, data cutoff, 41 pts had received Dato-DXd (median follow-up, 10.9 mo [range, 7-13]);9 pts were ongoing. The primary cause of treatment discontinuation was disease progression (63% progressive disease [PD] or clinical progression). Median age was 57 y (range, 33- 75);54% had de novo metastatic disease. Pts were heavily pretreated (Table) with a median of 5 (range, 3-10) prior regimens in the advanced setting;95% had prior CDK4/6i (adjuvant/metastatic). Median time from initial treatment for metastatic disease to the first dose of Dato-DXd was 42.7 mo (range, 10.2-131.1). Treatment-emergent adverse events (TEAEs;all cause) were observed in 98% (any grade) and 41% (grade >=3) of pts. Most common TEAEs (any grade, grade >=3) were stomatitis (80%, 10%), nausea (56%, 0%), fatigue (46%, 2%), and alopecia (37%, 0%). Serious TEAEs were observed in 6 pts (15%);1 pt died due to dyspnea, which was not considered to be treatment related. Dose reductions occurred in 5 pts due to stomatitis (n=3), fatigue (n=2), keratitis (n=1), and decreased appetite (n=1) (>1 AE per pt);14 pts had treatment delayed due to stomatitis (n=8), retinopathy (n=1), dysphagia (n=1), fatigue (n=1), malaise (n=1), COVID-19 (n=1), cellulitis (n=1), urinary tract infection (n=1), decreased lymphocyte count (n=1), and nasal congestion (n=1;>1 AE per pt). Three pts discontinued treatment due to keratitis (n=1) and pneumonitis (n=2);1 case of pneumonitis was adjudicated as grade 2 drug-related interstitial lung disease. The ORR was 29% (11 confirmed PRs;1 pending confirmation), the DCR was 85% (35/41), and the clinical benefit rate (CR + PR + SD >=6 mo) was 41% (17/41). Conclusion(s): Dato-DXd demonstrated a manageable safety profile and encouraging antitumor activity, with high disease control in heavily pretreated pts, the majority having received prior CDK4/6i. Based on these findings, the TROPION-Breast01 (NCT05104866) randomized phase 3 study comparing 2L+ Dato-DXd vs investigator's choice chemotherapy is currently enrolling pts with HR+/HER2- BC.

Lorigerlimab, a bispecific PD-13CTLA-4 DART molecule in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): A phase 1 expansion (exp) cohort

Background: Lorigerlimab (MGD019) is an investigational, bispecific Fc-bearing (IgG4) DART molecule designed to enhance CTLA-4 blockade on dual expressing, tumor infiltrating lymphocytes, while maintaining maximal PD-1 blockade on PD-1 expressing cells. Lorigerlimab has approximate dose proportional PK across 1-10 mg/kg IV dosing Q3W, with sustained PD-1 receptor occupancy evident at doses >=1 mg/kg Q3W. MGD019-01 is a global first-in-human dose finding and activity estimating study of lorigerlimab in advanced solid tumors (AST). Method(s): The exp phase of MGD019-01 evaluates single agent safety, PK, and antitumor effects of lorigerlimab at the recommended dose for exp of 6 mg/ kg IV Q3W in 4 tumor specific cohorts. Confirmed responses were noted in each cohort. Preliminary results of the mCRPC cohort are reported here. Response evaluable pts received >=1 dose and had >=1 postbaseline imaging evaluation. Measurable lesions were evaluated per RECIST v1.1 and skeletal metastases assessed by bone scan. Prostate specific antigen (PSA) response was defined as a >=50% (PSA50) or>=90% (PSA90) PSA decline from baseline with confirmation>=3 weeks later. Expression of proliferation marker, Ki67, and inducible costimulator (ICOS) by peripheral T cells was assessed by flow cytometry. Result(s): At data cutoff (9/10/22), 127 pts with AST received >=1 dose of lorigerlimab 6 mg/ kg. Median exposure was 10 weeks (range, 0.1, 94.4) with median of 4 infusions. 6 pts remain on therapy;36 discontinued for PD (n=13), AEs (n=17), or patient/physician decision (n=6). Treatment related adverse events (TRAE) occurred in 109/127 (85.8%) pts. TRAEs occurring in>=15% of pts were fatigue, pruritus, hypothyroidism, pyrexia. Rates of grade >=3 TRAEs and immune-related AEs were 32.3% and 7.9%, respectively. AEs leading to drug discontinuation occurred in 22.8% of pts. There were no fatal AEs related to lorigerlimab. In the mCRPC exp cohort (n=42), pts had a median of 2 prior lines of therapy for CRPC, >80% received prior ART or taxanes;88% had visceral (liver, 26%;lung, 26%) or nodal disease and 95% had bone metastases. 42 pts were PSA response evaluable;35 were RECIST evaluable. ORR was 25.7% (9/35;9 confirmed PRs). Median duration of response was 16.1 weeks (range 6-25+ weeks). 5 responders remain on study, 4 discontinued for unrelated fatal AEs: COVID-19 (2) cardiac arrest (1) C. difficile infection (1). Confirmed PSA50 and PSA90 response rates were 28.6%(12/42) and 21.4% (9/42), respectively. Increased frequencies of Ki67+ and ICOS+ T cells were observed on day 8 posttreatment compared to pretherapy per the flow cytometry analyses from 35 pts. Conclusion(s): Lorigerlimab demonstrates a manageable safety profile with evidence of encouraging and durable antitumor activity in a chemotherapy refractory mCRPC population. Randomized evaluation of lorigerlimab in mCRPC is warranted.

Treatment of HER2-positive (HER2+) hormonereceptor positive (HR+) metastatic breast cancer (mBC) with the novel combination of zanidatamab, palbociclib, and fulvestrant

Background: HER2+ mBC remains incurable, with a need for new HER2-directed therapies and regimens, including chemotherapy-free options. Zanidatamab (zani) is a novel HER2-targeted bispecific antibody that binds HER2 in a unique trans configuration, driving multiple mechanisms of antitumor activity, including complement-dependent cytotoxicity. A CDK4/6 inhibitor combined with endocrine therapy is an approved treatment for HER2-negative/HR+ mBC and this combination has also demonstrated encouraging antitumor activity when paired with HER2-targeted therapy(ies) in HER2+/HR+ mBC. Here, we report results from ZWI-ZW25-202 (NCT04224272), an ongoing singlearm phase 2 study of zani combined with palbociclib (palbo) and fulvestrant (fulv) in pts with HER2+/HR+ mBC. Method(s): Eligibility requirements include: HER2+/HR+ unresectable, locally advanced BC or mBC;ECOG PS of 0 or 1;prior treatment with trastuzumab, pertuzumab and T DM1 (additional prior HER2-targeting agents are permitted);and no prior treatment with CDK4/6 inhibitors. Part 1 of the study evaluated the safety and tolerability of the zani/palbo/fulv combination and determined the recommended doses for use in Part 2, where the antitumor activity of the combination is being evaluated. Endpoints include safety outcomes, progression-free survival at 6 months (PFS6), confirmed objective response rate (cORR) per RECIST v1.1;disease control rate (DCR=complete response [CR] plus partial response [PR] plus stable disease [SD]);duration of response (DOR);PFS;and overall survival. Result(s): As of 24 Feb 2022, 34 pts (33 HER2+/HR+ per central analysis) with a median age of 52 (range 36-77) have been treated. In the metastatic setting, pts had received a median (range) of 4 (1-10) prior systemic regimens, including 3 (1-8) different prior HER2 targeted therapies, and 1 (0-4) endocrine therapy. Seven pts (20%) had prior T DXd treatment and 7 pts had prior fulv treatment. All pts received zani (20 mg/kg Q2W) and standard doses of palbo and fulv. Eighteen pts (53%) remained on treatment;median duration of zani treatment was 6.9 mo (range 0.5- 16.3). A dose-limiting toxicity (DLT) of neutropenia occurred in 1 of 7 DLT-evaluable pts in Part 1. Among all pts (n=34), the most common (>20%) treatment (zani, palbo and/or fulv)-related adverse events (TRAEs) were diarrhea (74%), neutrophil count decreased/neutropenia (62%), stomatitis (41%), asthenia (26%), nausea (24%), and anemia (21%). Grade (Gr) >=3 TRAEs in 2 or more pts included neutrophil count decreased/neutropenia (50%), anemia (6%), diarrhea (6%), and thrombocytopenia (6%). AEs of special interest were all Gr <=2 and included 4 pts with cardiac events (LVEF decrease of >=10% from baseline) and 1 pt with infusion-related reaction. There were no treatment-related serious AEs. Palbo was discontinued for 1 pt due to an AE (AST increase);no pt discontinued zani treatment as a result of AEs. Two deaths occurred: 1 due to disease progression and 1 due to an unrelated AE of pneumonia caused by COVID-19. In 29 pts with measurable disease, the cORR was 34.5% (95% CI: 17.9, 54.3), all responses were cPRs, of which 1 is pending CR confirmation. DOR ranged from 2.3 to 14.9+ mo, with 8 confirmed responses ongoing, and the DCR was 93.1% (95% CI: 77.2, 99.2). Interim median PFS was 11.3 mo (range 0.03-16.7;95% CI: 5.6, not estimable). PFS6 analysis is planned following the completion of enrollment. Conclusion(s): Zani in combination with palbo and fulv shows encouraging antitumor activity with durable responses in heavily pretreated pts and a manageable safety profile. This regimen has the potential to be a chemotherapy-free treatment option in pts with HER2+/HR+ mBC. Enrollment in the study is continuing.