Ongoing Response Research Articles

Trends in drug use among nightclub and festival attendees in New York City, 2017-2022.

Drug use is prevalent among people who attend electronic dance music (EDM) parties at nightclubs or festivals. This population can serve as a sentinel population to monitor trends in use of party drugs and new psychoactive substances (NPS) that may diffuse through larger segments of the population. We surveyed adults entering randomly selected EDM parties at nightclubs and dance festivals in New York City about their drug use in 2017 (n=954), 2018 (n=1,029), 2019 (n=606), 2021 (n=229), and 2022 (n=419). We estimated trends in past-year and past-month use of 22 drugs or drug classes based on self-report from 2017-2022 and examined whether there were shifts pre- vs. post-COVID (2017-2019 vs. 2021-2022). Between 2017 and 2022, there were increases in past-year and past-month use of shrooms (psilocybin), ketamine, poppers (amyl/butyl nitrites), synthetic cathinones ("bath salts"), and novel psychedelics (lysergamides and DOx series), increases in past-year cannabis use, and increases in past-month use of 2C series drugs. Between 2017 and 2022, there were decreases in past-year heroin use and decreases in past-month cocaine use, novel stimulant use, and nonmedical benzodiazepine use. The odds of use of shrooms, poppers, and 2C series drugs significantly increased after COVID, and the odds of use of cocaine, ecstasy, heroin, methamphetamine, novel stimulants, and prescription opioids (nonmedical use) decreased post-COVID. We estimate shifts in prevalence of various drugs among this sentinel population, which can inform ongoing surveillance efforts and public health response in this and the general populations.

Health-related quality of life in survivors of advanced melanoma treated with anti-PD1-based immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have significantly improved survival in advanced melanoma but are associated with immune-related adverse events (irAEs). This single center, cross-sectional survey aimed to describe the long-term symptom burden and impact on health-related quality of life (HRQL) of advanced melanoma patients with sustained disease control following treatment with ICIs. Advanced melanoma patients (stage IIB, III or IV, AJCCv8), treated with anti-PD1-based ICIs, who were off-treatment and had at least 6 months follow-up from their last infusion with an ongoing response in the metastatic setting or no evidence of disease recurrence in the adjuvant setting. A paper-based questionnaire, consisting of the EORTC QLQ-C30, EORTC QLQ-FA12, and the PRO-CTCAE was administered. Of 90 participants, 61 (68%) completed the questionnaire; 40 received single-agent anti-PD1, and 21 anti-PD1/anti-CTLA4. Thirty-three (54%) were treated in the adjuvant setting. At the time of enrolment, 31 (51%) participants had active treatment for a previous irAE. Overall, 18/61 (30%) participants reported long-term symptoms and trouble in physical and emotional functioning. Physical fatigue was common and interfered with daily activities (n = 12, 20%). In the PRO-CTCAE questionnaire, muscle ache (n = 12, 20%) and joint ache (n = 9, 15%) were commonly reported. Despite this, participants reported overall good health (6.00, range 2.00-7.00) and reasonable level of HRQL (6.00, range 3.00-7.00). Melanoma survivors experience long-term symptoms in physical and psychosocial HRQL domains after ICI treatment. These results underline the importance to address existing gaps in survivorship care, implement these findings in clinical practice and increase awareness for long-term symptoms in these patients.

How Infectious Disease Experts Impacted the Coronavirus Disease 2019 Response: Lessons From the Front Lines.

In this article, we summarize findings from research conducted by the Johns Hopkins Center for Health Security and the Infectious Diseases Society of America to understand infectious disease (ID) workforce contributions to the coronavirus disease 2019 (COVID-19) response and their impacts. ID experts were found to have made diverse and unique contributions that went well beyond their usual responsibilities, with many spending several hours a week on these activities without additional compensation. These efforts were thought to not only build community resilience but also augment the ongoing public health response. Respondents also reported several hospital and clinical leadership roles taken on during the pandemic, such as developing protocols and leading clinical trials. We also make several policy recommendations, such as medical student debt relief and improved compensation, that will be needed to help fortify the ID workforce for future pandemics.

Individualized approach to elexacaftor/tezacaftor/ivacaftor dosing in cystic fibrosis, in response to self-reported anxiety and neurocognitive adverse events: A case series.

The prevalence of mental health disorders is high among people with Cystic Fibrosis. The psychological symptoms in CF are associated with poor adherence, worse treatment outcomes, and greater health utilization/cost. Mental health and neurocognitive Adverse Events (AEs) have been reported with all available Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators in small groups of patients. We report our experience with a dose reduction strategy in 10 of our patients on elexacaftor/tezacaftor/ivacaftor (7.9% of total number of patients) who self-reported developing intense anxiety, irritability, sleep disturbance and/or mental slowness after initiation of full dose treatment. Standard dose elexacaftor/tezacaftor/ivacaftor resulted in 14.3 points improvement in mean Percent Predicted Forced Expiratory Volume in 1s (ppFEV1), and a mean difference in sweat chloride of -39.3mmol/L. We initially discontinued and/or reduced therapy according to the AEs severity, with a subsequent planned dose escalation every 4-6weeks guided by sustainability of clinical effectiveness, absence of AEs recurrence, and patients' preferences. Clinical parameters including lung function and sweat chloride were monitored for up to 12weeks to assess ongoing clinical response to the reduced dose regimen. Dose reduction resulted in resolution of self-reported mental/psychological AEs, without loss of clinical effectiveness (ppFEV1 was 80.7% on standard dose, and 83.4% at 12weeks on reduced dose; sweat chloride was 33.4 and 34mmol/L on standard and reduced dose, respectively). Furthermore, in a subgroup of patients who completed 24weeks of the reduced dose regimen, repeat low dose Computed Tomography imaging showed a significant response when compared to pre-initiation of elexacaftor/tezacaftor/ivacaftor.

Prospective memory decision control: A computational model of context effects on prospective memory.

Prospective memory (PM) tasks require remembering to perform a deferred action and can be associated with predictable contexts. We present a theory and computational model, prospective memory decision control (PMDC), of the cognitive processes by which context supports PM. Under control conditions, participants completed lexical decisions. Under PM conditions, participants had the additional PM task of responding to letter strings containing certain syllables. Stimuli were presented in one of two colors, with color potentially changing after each set of four trials. A pretrial colored fixation was presented before each set. Under control and PM standard conditions, fixation color was meaningless. Under PM context conditions, fixation color indicated whether a PM target could occur within the next set. We replicated prior findings of higher PM accuracy for context compared to standard conditions, and the expected variation in PM costs (slowed lexical decisions) as a function of context relevance. PMDC, which formalizes PM as a process of evidence accumulation among ongoing and PM task responses, accounted for the impact of context on PM costs and accuracy via proactive and reactive cognitive control. Increased ongoing task thresholds and decreased PM thresholds in relevant contexts indicated proactive control. With context provision, PM accumulation rates on PM trials increased, as did inhibition of accumulation to competing responses, indicating reactive control. Although an observed capacity-sharing effect explained some portion of PM costs, we found no evidence that participants redirected more capacity from the ongoing to the PM task when contextually cued to relevant contexts. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Immune-related genetic prognostic index to predict prognosis and immune checkpoint inhibitor therapy efficiency in acute myeloid leukemia.

Immune-related genetic prognostic index to predict prognosis and immune checkpoint inhibitor therapy efficiency in acute myeloid leukemia.

Abstract CT162: A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the clear cell ovarian, endometrial, cervical cancer cohorts

Abstract Background: Dual checkpoint inhibition with anti-PD-1 and anti-CTLA4 checkpoint inhibitors have proven to be efficacious in numerous malignancies. This study presents the first results of ipilimumab and nivolumab in the clear cell gynecologic cancer cohorts of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg IV every 6wk) plus nivolumab (240mg IV every 2wk). The primary endpoint was objective response rate (ORR) (RECIST v1.1) (confirmed CR and PR); progression-free survival (PFS), overall survival (OS), stable disease (SD) >6 months, and toxicity are secondary endpoints. Results: Evaluable patients were as follows: clear cell ovarian cancer (N=19); clear cell endometrial cancer (N=8); clear cell cervical (N=5) (median ages, 53, 66, and 59 years; cohorts 46, 45, and 42, respectively) In the clear cell ovarian cancer cohort, ORR was 21.1% [CR, 15.8%, n=3; PR, 5.3%, n=1]; clinical benefit rate (CBR) (includes stable disease ≥6 months) was 31.6% (6/19 patients). Among three patients with confirmed CR, two patients showed 100% regression (with ongoing response at 36+ months and 37+ months respectively), and the other patient showed 67% regression (due to lymph node < 1.0cm), but eventually progressed after 722 days. One confirmed PR patient achieved 75% regression (ongoing response at 53+ months). Of note, three patients achieved unconfirmed PR; one showed 34% regression (5 months); another, 38% (51.5+ months); and another, 58% regression (5 months). The ORR when including unconfirmed PR is 36.8% (7/19). Median PFS was 3.7 months (95% confidence interval (CI); 1.7-∞). Median OS was 21.7 months (6.4-∞). In the clear cell endometrial cancer cohort, ORR was 0%; CBR, 25% (2/8 patients). Of note, one patient achieved unconfirmed PR with 69% regression (4 months). The ORR when including unconfirmed PR is 12.5% (1/8). Median PFS was 2.0 months (95% confidence interval; 1.8-na). Median OS was 4.3 months (4.2-na). In the clear cell cervical cancer cohort, ORR was 0%; CBR, 20.0% (1/5 patients). Median PFS was 2.2 months (95% CI; 1.9-na). Median OS was 23.6 months (95% CI; 15.3-na). The most common adverse events, in the three cohorts combined, were nausea (37.5%, n=12), fatigue (34.4%, n=11), anorexia (31.2%, n=10), hypothyroidism (31.2%, n=10), and pruritus (28.1%, n=9). Grade 3-4 adverse events were reported in 17 cases (53.1%) with no grade 5 adverse events. Conclusion: Ipilimumab plus nivolumab in 19 clear cell ovarian cancer patients resulted in an ORR of 21.1% and CBR of 31.6%, with two durable CRs ongoing at 3+ years; CBR was 25% and 20%, respectively, in clear cell endometrial and cervical cohorts, with no objective responses, albeit with only 8 and 5 patients per cohort. Correlative studies to determine response/resistance markers are ongoing. Further prospective studies in rare gynecologic malignancies are warranted. Citation Format: Young Kwang Chae, Christopher W. Ryan, Naing Aung, William R. Robinson, Megan Othus, Elad Sharon, David M. O'Malley, Floortje J. Backes, Charles D. Blanke, Ramez N. Eskander, Razelle Kurzrock. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the clear cell ovarian, endometrial, cervical cancer cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT162.

Abstract 3395: Clinical impact of FGFR inhibitors on FGFR2 positive pancreatic cancer

Abstract Objectives: Here we describe the durable clinical outcomes of four FGFR2 fusion positive pancreatic cancer patients treated with FGFR inhibitors as well as a pancreatic specific analysis of FGFR alterations through our collaboration with Foundation Medicine, Inc. (FMI). Methods: We identified four patients with FGFR2 fusion positive metastatic pancreatic cancer through tumor RNAseq (OSU-SpARKFuse) which identifies gene fusions from cell free DNA (cfDNA). We assessed two tumor markers (Ca19-9 and FGFRDx, an FGFR-focused cell free DNA liquid biopsy assay) and various clinical outcomes (Best overall response, duration, and side effects to their treatments). Additionally, 10,146 tumor-tissue clinical cases of pancreatic cancers were assayed by hybrid-capture based comprehensive genomic profiling (Foundation Medicine, Inc.) to identify genomic alterations in >300 cancer-associated genes, MSI, and tumor mutation burden (TMB). Results: All four patients demonstrated durable clinical responses to various FGFR inhibitors. Patient 1 harbored an FGFR2-USP33 fusion and exhibited a partial response to pemigatinib for 25 months following progression on gemcitabine/abraxane and FOLFIRI chemotherapy. Patient 2 harbored an FGFR2-INA fusion with 12 months of stable disease to pazopanib after experiencing progression from chemotherapy. Patient 3 harbored an FGFR2-INA fusion and exhibited a 12+ month on-going, partial response to pemigatinib. Patient 4 harbored an FGFR2-CEP55 fusion and demonstrated stable disease on ponatinib for 15 months, a 24-month response to gemcitabine/platinum chemotherapy, and a 7+ month on-going partial response to infigratinib. Through the genomic profiling of 10,146 tumor-tissue clinical cases of pancreatic cancer, we identified 108 FGFR fusions resulting in a prevalence of 1%. We are currently investigating co-occurring and mutually-exclusive genomic alterations, including TMB and MSI-H status, for pancreatic cancer patients harboring FGFR alterations. Conclusions: This retrospective analysis provides clinical evidence that there is a subpopulation of KRAS wild-type FGFR2 fusion positive pancreatic patients who can have beneficial and lasting responses to FGFR inhibitors further suggesting a need to investigate and expand the availability of FGFR inhibitors to more cancer types. Citation Format: Leah Stein, Julie W. Reeser, Michele R. Wing, Karthikeyan Murugesan, Anoosha Paruchuri, Zachary Risch, Eric Samorodnitsky, Emily L. Hoskins, Amy Smith, Thuy Dao, Melissa Babcook, Muhammad Imam, Aharon Freud, Sameek Roychowdhury. Clinical impact of FGFR inhibitors on FGFR2 positive pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3395.

Zanubrutinib, Alone and in Combination With Tislelizumab, for the Treatment of Richter Transformation of Chronic Lymphocytic Leukemia.

Zanubrutinib, Alone and in Combination With Tislelizumab, for the Treatment of Richter Transformation of Chronic Lymphocytic Leukemia.

LBA02-03 FIRST RESULTS FROM SunRISE-1 IN PATIENTS WITH BCG UNRESPONSIVE HIGH-RISK NON–MUSCLE-INVASIVE BLADDER CANCER RECEIVING TAR-200 IN COMBINATION WITH CETRELIMAB, TAR-200, OR CETRELIMAB ALONE

LBA02-03 FIRST RESULTS FROM SunRISE-1 IN PATIENTS WITH BCG UNRESPONSIVE HIGH-RISK NON–MUSCLE-INVASIVE BLADDER CANCER RECEIVING TAR-200 IN COMBINATION WITH CETRELIMAB, TAR-200, OR CETRELIMAB ALONE

A methodological approach to intra-action reviews - application and adaptation of existing global guidance during the COVID-19 pandemic response in Ireland, 2021.

Many countries were under-prepared for the arrival of an emergency such as the COVID-19 pandemic. An intra-action review allows countries, systems and services to reflect on their preparedness and response to date, and revise their policies and approaches as needed. We describe the approach to undertaking an intra-action review of Ireland's Health Protection COVID-19 response during 2021. A project team within National Health Protection developed a project plan, identified key stakeholders, trained facilitators and designed workshop programmes, employing integrated collaborative web tools. Multidisciplinary representatives participated in three half-day, independently facilitated workshops on challenges and solutions within specific response areas: communication, governance and cross-cutting themes such as staff well-being. An all-stakeholder survey sought further in-depth detail. Participants reviewed the ongoing pandemic response in terms of good practice and challenges and recommended implementable solutions. We customised our mixed-methods approach using existing ECDC/WHO guidance, producing consensus recommendations during Ireland's fourth wave of COVID-19, with particular focus on pathways to implementation. Our adaptations may help others in formulating and customising methodological approaches. During an emergency, identifying and reflecting on good practices to retain, and areas for strengthening, with a clear action plan of implementing recommendations, will enhance preparedness now, and for future emergencies.

Dynamic peripheral nerve stimulation can produce cortical activation similar to punctate mechanical stimuli.

During contact, phasic and tonic responses provide feedback that is used for task performance and perceptual processes. These disparate temporal dynamics are carried in peripheral nerves, and produce overlapping signals in cortex. Using longitudinal intrafascicular electrodes inserted into the median nerve of a nonhuman primate, we delivered composite stimulation consisting of onset and release bursts to capture rapidly adapting responses and sustained stochastic stimulation to capture the ongoing response of slowly adapting receptors. To measure the stimulation's effectiveness in producing natural responses, we monitored the local field potential in somatosensory cortex. We compared the cortical responses to peripheral nerve stimulation and vibrotactile/punctate stimulation of the fingertip, with particular focus on gamma band (30-65 Hz) responses. We found that vibrotactile stimulation produces consistently phase locked gamma throughout the duration of the stimulation. By contrast, punctate stimulation responses were phase locked at the onset and release of stimulation, but activity maintained through the stimulation was not phase locked. Using these responses as guideposts for assessing the response to the peripheral nerve stimulation, we found that constant frequency stimulation produced continual phase locking, whereas composite stimulation produced gamma enhancement throughout the stimulus, phase locked only at the onset and release of the stimulus. We describe this response as an "Appropriate Response in the gamma band" (ARγ), a trend seen in other sensory systems. Our demonstration is the first shown for intracortical somatosensory local field potentials. We argue that this stimulation paradigm produces a more biomimetic response in somatosensory cortex and is more likely to produce naturalistic sensations for readily usable neuroprosthetic feedback.

Identification of antigenic epitopes recognized by tumor infiltrating lymphocytes in high grade serous ovarian cancer by multi-omics profiling of the auto-antigen repertoire

Immunotherapeutic strategies aimed at enhancing tumor cell killing by tumor-specific T cells hold great potential for reducing tumor burden and prolonging survival of cancer patients. Although many potential tumor antigens have been described, identifying relevant targets when designing anti-cancer vaccines or targeted cell therapies remains a challenge. To identify novel, potentially immunogenic candidate tumor antigens, we performed integrated tumor transcriptomic, seromic, and proteomic analyses of high grade serous ovarian cancer (HGSC) patient tumor samples. We identified tumor neo-antigens and over-expressed antigens using whole exome and RNA sequencing and examined these in relation to patient-matched auto-antibody repertoires. Focusing on MHC class I epitopes recognized by CD8+ T cells, HLA-binding epitopes were identified or predicted from the highly expressed, mutated, or auto-antibody target antigen, or MHC-associated peptides (MAPs). Recognition of candidate antigenic peptides was assessed within the tumor-infiltrating T lymphocyte (TIL) population expanded from each patient. Known tumor-associated antigens (TAA) and cancer/testis antigens (CTA) were commonly found in the auto-antibody and MAP repertoires and CD8+ TILs recognizing epitopes from these antigens were detected, although neither expression level nor the presence of auto-antibodies correlated with TIL recognition. Auto-antibodies against tumor-mutated antigens were found in most patients, however, no TIL recognition of the highest predicted affinity neo-epitopes was detected. Using high expression level, auto-antibody recognition, and epitope prediction algorithms, we identified epitopes in 5 novel antigens (MOB1A, SOCS3, TUBB, PRKAR1A, CCDC6) recognized by HGSC patient TILs. Furthermore, selection of epitopes from the MAP repertoire identified 5 additional targets commonly recognized by multiple patient TILs. We find that the repertoire of TIL specificities includes recognition of highly expressed and immunogenic self-antigens that are processed and presented by tumors. These results indicate an ongoing autoimmune response against a range of self-antigens targeted by HGSC TILs.

Should We Stay or Should We Go? MNE Decisions to Withdraw or Remain during Geopolitical Crises

Geopolitical crises can create conflicting obligations for MNEs operating in now-hostile host countries, often requiring a strategic balance between home-country pressures to exit and the importance of continuing business in the present or retaining the option to re-enter business in the future. To identify such strategies and the country- and firm-specific characteristics informing such strategic decisions, I draw lessons from business history and an analysis of ongoing MNE responses to Russia’s invasion of Ukraine to provide insights into two specific options which managers can employ: namely, leveraging home country neutrality and relying on local partners to steward host-country operations. I also suggest steps managers can take to build resiliency for their MNEs in the event of future geopolitical crises.

Venetoclax in Relapse/Refractory AL Amyloidosis—A Multicenter International Retrospective Real-World Study

Therapeutic options in relapsed refractory (R/R) light-chain (AL) amyloidosis patients are limited. Given the encouraging results in t(11;14) multiple myeloma and the high prevalence of t(11;14) in AL amyloidosis, venetoclax is an attractive treatment option in this setting. We report here the results of a multi-center retrospective study on 26 R/R AL amyloidosis patients treated off-label with venetoclax. The median lines of therapy prior to venetoclax was 3.5 (range 1-7), and 88% of our cohort had t (11;14). Twenty-two patients (85%) were previously treated with daratumumab. The overall hematologic response rate was 88%, 35% achieved a CR, and 35% achieved VGPR. The median event-free survival was 25 months (m) (95% CI 9.7 m-not reached), and the median overall survival was 33 m (95% CI 25.9-39.2 m). Most of the patients in this cohort are in ongoing deep responses and continuing venetoclax therapy. The treatment was relatively safe. One patient died due to infection, and there were two grade 3 infections in our cohort. Tumor lysis syndrome (TLS) was not seen in any patient. Dose reductions were frequent but did not affect the efficacy. These promising results require confirmation in a randomized controlled trial.

Multi-omics studies in interpreting the evolving standard model for immune functions.

A standard model that is able to generalize data on myriad involvement of the immune system in organismal physio-pathology and to provide a unified evolutionary teleology for immune functions in multicellular organisms remains elusive. A number of such 'general theories of immunity' have been proposed based on contemporaneously available data, starting with the usual description of self-nonself discrimination, followed by the 'danger model' and the more recent 'discontinuity theory.' More recent data deluge on involvement of immune mechanisms in a wide variety of clinical contexts, a number of which fail to get readily accommodated into the available teleologic standard models, makes deriving a standard model of immunity more challenging. But technological advances enabling multi-omics investigations into an ongoing immune response, covering genome, epigenome, coding and regulatory transcriptome, proteome, metabolome and tissue-resident microbiome, bring newer opportunities for developing a more integrative insight into immunocellular mechanisms within different clinical contexts. The new ability to map the heterogeneity of composition, trajectory and endpoints of immune responses, in both health and disease, also necessitates incorporation into the potential standard model of immune functions, which again can only be achieved through multi-omics probing of immune responses and integrated analyses of the multi-dimensional data.

Effect of Non-pharmaceutical Interventions on COVID-19 in Rwanda: An Observational Study

BackgroundOn 11 March 2020, COVID-19 was declared as a pandemic by the World Health Organization (WHO). The first case was identified in Rwanda on 24 March 2020. Three waves of COVID-19 outbreak have been observed since the identification of the first case in Rwanda. During the COVID-19 epidemic, the country of Rwanda has implemented many Non-Pharmaceutical Interventions (NPIs) that appear to be effective. However, a study was needed to investigate the effect of non-pharmaceutical interventions applied in Rwanda to guide ongoing and future responses to epidemics of this emerging disease across the World.MethodsA quantitative observational study was conducted by conducting analysis of COVID-19 cases reported daily in Rwanda from 24 March 2020 to 21 November 2021. Data used were obtained from the official Twitter account of Ministry Health and the website of Rwanda Biomedical Center. Frequencies of COVID-19 cases and incidence rates were calculated, and to determine the effect of non-pharmaceutical interventions on changes in COVID-19 cases an interrupted time series analysis was used.ResultsRwanda has experienced three waves of COVID-19 outbreak from March 2020 to November 2021. The major NPIs applied in Rwanda included lockdowns, movement restriction among districts and Kigali City, and curfews. Of 100,217 COVID-19 confirmed cases as of 21 November 2021, the majority were female 51,671 (52%) and 25,713 (26%) were in the age group of 30–39, and 1866 (1%) were imported cases. The case fatality rate was high among men (n = 724/48,546; 1.5%), age > 80 (n = 309/1866; 17%) and local cases (n = 1340/98,846; 1.4%). The interrupted time series analysis revealed that during the first wave NPIs decreased the number of COVID-19 cases by 64 cases per week. NPIs applied in the second wave decreased COVID-19 cases by 103 per week after implementation, while in the third wave after NPIs implementation, a significant decrease of 459 cases per week was observed.ConclusionThe early implementation of lockdown, restriction of movements and putting in place curfews may reduce the transmission of COVID-19 across the country. The NPIs implemented in Rwanda appear to be effectively containing the COVID-19 outbreak. Additionally, setting up the NPIs early is important to prevent further spread of the virus.

Data pipelines in a public health emergency: The human in the machine

In an emergency epidemic response, data providers supply data on a best-faith effort to modellers and analysts who are typically the end user of data collected for other primary purposes such as to inform patient care. Thus, modellers who analyse secondary data have limited ability to influence what is captured. During an emergency response, models themselves are often under constant development and require both stability in their data inputs and flexibility to incorporate new inputs as novel data sources become available. This dynamic landscape is challenging to work with. Here we outline a data pipeline used in the ongoing COVID-19 response in the UK that aims to address these issues.A data pipeline is a sequence of steps to carry the raw data through to a processed and useable model input, along with the appropriate metadata and context. In ours, each data type had an individual processing report, designed to produce outputs that could be easily combined and used downstream. Automated checks were in-built and added as new pathologies emerged. These cleaned outputs were collated at different geographic levels to provide standardised datasets. Finally, a human validation step was an essential component of the analysis pathway and permitted more nuanced issues to be captured. This framework allowed the pipeline to grow in complexity and volume and facilitated the diverse range of modelling approaches employed by researchers. Additionally, every report or modelling output could be traced back to the specific data version that informed it ensuring reproducibility of results.Our approach has been used to facilitate fast-paced analysis and has evolved over time. Our framework and its aspirations are applicable to many settings beyond COVID-19 data, for example for other outbreaks such as Ebola, or where routine and regular analyses are required.

Abstract PD11-08: PD11-08 Trastuzumab deruxtecan (T-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic hormone receptor-negative (HR−), HER2-low breast cancer: updated results from BEGONIA, a phase 1b/2 study

Abstract Background: Patients with HR− advanced/metastatic breast cancer (a/mBC) with a low level of HER2 (immunohistochemistry [IHC] score 1+ or IHC 2+ and negative in situ hybridization [ISH]) have poor prognosis. Combining 1L chemotherapy with immune checkpoint inhibitors can modestly improve outcomes vs chemotherapy alone, but treatment benefit is largely seen in patients with PD-L1+ disease. BEGONIA (NCT03742102) is an ongoing 2-part, open-label platform study, evaluating safety and efficacy of D, an anti–PD-L1 antibody, combined with other novel therapies in 1L triple-negative a/mBC, including HR−, HER2-low disease. T-DXd is a trastuzumab-topoisomerase I inhibitor antibody-drug conjugate that improves survival in patients with previously treated HR−, HER2-low mBC (NCT03734029; Modi NEJM 2022). Here, we report updated results of the T-DXd + D combination from BEGONIA. Methods: Patients with unresectable HR−, HER2-low (per local testing, IHC 2+/ISH−, IHC 1+/ISH−, or IHC 1+/ISH untested) a/mBC were enrolled in the T-DXd + D arm. Patients eligible for 1L treatment, regardless of PD-L1 status, received intravenous T-DXd 5.4 mg/kg + D 1120 mg every 3 weeks until progression or unacceptable toxicity. PD-L1, assessed using the VENTANA PD-L1 (SP263) Assay, was defined as high if ≥ 5% of the tumor area was populated by PD-L1–expressing tumor or immune cells. Primary endpoints were safety and tolerability. Secondary endpoints included investigator-assessed objective response rate (ORR; RECIST v1.1); progression-free survival [PFS]; and response duration. Patients included in the efficacy analysis had ≥ 2 on-treatment disease assessments, progressed, died, or withdrew from the study. Results: As of April 8, 2022, 56 patients received T-DXd + D (34 ongoing) and 46 were included in the efficacy analysis. Median (range) follow-up was 10.1 (0–22) months. Median age was 53.5 years, 71% had received prior treatment for early stage BC, and 64% had visceral metastases at baseline. Confirmed ORR was 26/46 (57%; 95% CI, 41–71) and unconfirmed ORR was 33/54 (61%; 95% CI, 47–74); 1/46 patients (2%) had complete and 25/46 (54%) had partial responses. Confirmed response occurred irrespective of PD-L1 expression (PD-L1 high ORR, 5/7 [71%]; PD-L1 low, 13/21 [62%]; PD-L1 missing, 8/18 [44%]). Median duration of response was not reached; however, 64% of patients remained in response at 12 month follow-up and 73% had an ongoing response at data cutoff. Median PFS was 12.6 months (95% CI, 8–not reached). Adverse events (AEs) were consistent with the agents’ known safety, with treatment-related AEs occurring in 49 patients (88%), any Grade 3/4 AEs in 18 patients (32%), and any serious AEs in 10 patients (18%). The most common all-Grade AEs were nausea (41 [73%]), fatigue (26 [46%]), and vomiting (17 [30%]). Adjudicated treatment-related interstitial lung disease/pneumonitis occurred for 5 patients (9%), which were mostly Grade 1 or 2 and 1 case of Grade 5 associated with COVID pneumonia. Seven patients (13%) and 21 patients (38%) had T-DXd dose reduction and dose delay, respectively; 22 (39%) had D dose delay. Seven patients (13%) discontinued treatment due to AEs. Conclusions: For patients with HR−, HER2-low a/mBC, T-DXd in combination with D in the 1L setting shows manageable safety and promising efficacy including durable responses and an encouraging PFS. Although subgroups were small, responses were observed irrespective of PD-L1 expression. Analysis of additional translational data is ongoing. Funding: AstraZeneca/Daiichi Sankyo Citation Format: Peter Schmid, Piotr Wysocki, Yeon H. Park, Jacek Jassem, Kyung Hae Jung, Simon Lord, Robert Huisden, Ross Stewart, Petra Vuković, Ana T. Nunes, Zbigniew Nowecki. PD11-08 Trastuzumab deruxtecan (T-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic hormone receptor-negative (HR−), HER2-low breast cancer: updated results from BEGONIA, a phase 1b/2 study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-08.

Abstract PD11-09: PD11-09 Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): updated results from BEGONIA, a phase 1b/2 study

Abstract Background: Patients with a/mTNBC have limited treatment options and a poor prognosis (objective response rate [ORR] of 37%, median duration of response 6.5 months, median overall survival 15.5 months for 1L chemotherapy [Rugo, et al. Ann Oncol. 2021 LBA16]). Combining checkpoint inhibitors with 1L chemotherapy modestly improves outcomes but only in PD-L1–positive a/mTNBC, emphasizing a critical unmet need for patients with PD-L1–negative disease and for further improving outcomes in PD-L1–positive disease. BEGONIA (NCT03742102) is an ongoing 2-part, open-label platform study, evaluating safety and efficacy of D, an anti–PD-L1 antibody, combined with other novel therapies in 1L a/mTNBC, including Dato-DXd, an antibody-drug conjugate consisting of a humanized anti-TROP2 antibody covalently linked to a highly potent topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. Early data from BEGONIA of D in combination with Dato-DXd showed promising responses. Here, we report updated results of Dato-DXd + D. Methods: Patients with unresectable a/mTNBC eligible for 1L treatment were enrolled, regardless of PD-L1 or TROP2 status, and received intravenous Dato-DXd 6 mg/kg + D 1120 mg every 3 weeks until progression or unacceptable toxicity. PD-L1, assessed using the VENTANA PD-L1 (SP263) Assay, was defined as high if ≥ 5% of the tumor area was populated by PD-L1–expressing tumor or immune cells. Primary endpoints were safety and tolerability. Secondary endpoints included investigator-assessed ORR (RECIST v1.1) and duration of response. Patients included in the efficacy analysis had ≥ 2 on-treatment disease assessments, progressed, died, or withdrew from the study. Results: As of April 8, 2022, 47 patients received Dato-DXd + D (39 ongoing) and 33 of those were included in the efficacy analysis. Median (range) follow-up was 7.5 (0–11) months. Patient age was a median of 51 years, 57% received prior treatment for early stage TNBC, and 60% had visceral metastases at baseline. Confirmed ORR was 26/33 (79%; 95% CI, 61–91); 2/33 patients (6%) had a complete response and 24/33 (73%) had a partial response. Confirmed response was irrespective of PD-L1 expression (PD-L1 high ORR, 4/5 [80%]; PD-L1 low, 16/21 [76%]; PD-L1 missing, 6/7 [86%] patients). Median duration of response was not reached; 100% of patients with a complete or partial response remained in response at 6 month follow-up, and 96% had an ongoing response at data cutoff. Adverse events (AEs) were manageable and consistent with the known safety profiles of each agent, with treatment-related AEs occurring in 41 patients (87%), any Grade 3/4 AEs in 17 patients (36%), and any serious AEs in 7 patients (15%). The most common all-Grade AEs were gastrointestinal (nausea in 26 patients [55%] and stomatitis in 24 patients [51%]). A low rate of diarrhea was reported (6 patients [13%], all Grade 1 or 2); 4 patients had anemia and 1 had neutropenia. There were no cases of interstitial lung disease/pneumonitis or thrombocytopenia. Nine patients (19%) and 11 patients (23%) underwent Dato-DXd dose reduction and delay, respectively; 14 (30%) had D dose delay. Treatment was discontinued due to an AE for 3 patients (6%). There were no deaths due to treatment-related AEs. Conclusions: In this updated analysis with additional patients and longer follow-up, the combination of Dato-DXd + D in 1L a/mTNBC demonstrated a manageable safety profile and compelling high response rates with promising durability. Although subgroups were small, responses occurred irrespective of PD-L1 expression. Further investigation of this treatment combination is warranted. Analysis of translational data is ongoing. Funding: AstraZeneca/Daiichi Sankyo Citation Format: Peter Schmid, Piotr Wysocki, Cynthia Ma, Yeon H. Park, Ricardo Fernandes, Simon Lord, Richard D. Baird, Catherine Prady, Kyung Hae Jung, Jamil Asselah, Robert Huisden, Ross Stewart, Petra Vuković, Ana T. Nunes, Zbigniew Nowecki. PD11-09 Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): updated results from BEGONIA, a phase 1b/2 study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-09.