Pivotal Trial Data Research Articles

Dual pathway inhibition with faricimab for previously treated neovascular age-related macular degeneration and diabetic macular oedema: guidance from a UK panel of retina specialists

Background/objectivesSome eyes with neovascular age-related macular degeneration (nAMD) and centre-involving diabetic macular oedema (DMO) fail to respond sufficiently or lose response over time to standard of care intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy. This paper explores clinical scenarios for switching to dual action angiopoietin-2 (Ang-2)/VEGF-A inhibitor faricimab (Vabysmo, Roche Products Limited) in previously anti-VEGF-treated patients.MethodsA national steering group meeting of UK retina specialists was held in London on 27 October 2023. Clinician practice and experience were reviewed together with pivotal clinical trial data and early findings from real-world settings. Roche Products Limited facilitated and funded the meeting.ResultsWhile there is no standardised protocol for identifying suboptimal response, the authors review relevant clinical biomarkers of disease activity used in routine clinical practice to determine patient response and guide treatment decisions. Common reasons identified for considering a change of treatment were lack of efficacy demonstrated by suboptimal anatomic or visual improvement and insufficient durability of response. The panel outline strategies for switching to faricimab among eligible patients with a prior anti-VEGF treatment history, with initial monthly loading doses or maintaining the previous treatment interval before attempting to extend, that may be integrated into current treat-and-extend (T&E) clinical pathways for treating patients with nAMD and DMO. General considerations for switching between treatments are also reviewed.ConclusionClinicians may consider a treatment switch to faricimab in nAMD and DMO patients who have suboptimal disease control or insufficient durability of response on initial anti-VEGF therapy.

Targeting GPRC5D With Talquetamab: A New Frontier in Bispecific Antibody Therapy for Relapsed/Refractory Multiple Myeloma.

To evaluate the pharmacology, clinical efficacy, safety, dosing, administration, and clinical implications of talquetamab-tgvs, a novel bispecific antibody, in the treatment of relapsed or refractory (R/R) multiple myeloma (MM). A comprehensive English-language literature search of PubMed and Clinicaltrials.gov from January 2000 to May 2024 was conducted using the terms talquetamab, Talvey, JNJ-64407564, and "Multiple Myeloma." Relevant clinical trials, guidelines, and prescribing information were systematically reviewed and analyzed. Talquetamab-tgvs received accelerated approval from the United States Food and Drug Administration based on results from the pivotal phase I/II MonumenTAL-1 clinical trial, which demonstrated an overall response rate of nearly 74% in key cohorts. The median progression-free survival was 7.5 months in the 0.4 mg/kg weekly dosing cohort and 11.9 months in the 0.8 mg/kg biweekly dosing cohort. Treatment-related adverse events (AEs) included cytokine release syndrome, skin- and nail-related AEs, dysgeusia, infections, and immune effector cell-associated neurotoxicity syndrome. As a first-in-class anti-GPRC5D T-cell-redirecting bispecific antibody, talquetamab-tgvs represents a compelling treatment option for patients with R/R MM who have received at least 4 prior lines of therapy. No head-to-head clinical trials have been conducted comparing talquetamab-tgvs to other T-cell-redirecting therapies. While talquetamab-tgvs showed significant efficacy in the pivotal MonumenTAL-1 trial, long-term safety and efficacy data are needed. Additional clinical trials are necessary to establish the optimal timing, sequencing, patient population, and overall role of talquetamab-tgvs in the rapidly evolving treatment landscape of R/R MM.

Population health outcomes of blood-based screening for colorectal cancer in comparison to current screening modalities: insights from a discrete-event simulation model incorporating longitudinal adherence

Aim Insufficient adherence to colorectal cancer (CRC) screening impedes individual and population health benefits, with about one-third of individuals non-adherent to available screening options. The impact of poor adherence is inadequately considered in most health economics models, limiting the evaluation of real-world population-level screening outcomes. This study introduces the CAN-SCREEN (Colorectal cANcer SCReening Economics and adherENce) model, utilizing real-world adherence scenarios to assess the effectiveness of a blood-based test (BBT) compared to existing strategies. Materials and methods The CAN-SCREEN model evaluates various CRC screening strategies per 1,000 screened individuals for ages 45–75. Adherence is modeled in two ways: (1) full adherence and (2) longitudinally declining adherence. BBT performance is based on recent pivotal trial data while existing strategies are informed using literature. The full adherence model is calibrated using previously published Cancer Intervention and Surveillance Modeling Network (CISNET) models. Outcomes, including life-years gained (LYG), CRC cases averted, CRC deaths averted, and colonoscopies, are compared to no screening. Results Longitudinal adherence modeling reveals differences in the relative ordering of health outcomes and resource utilization, as measured by the number of colonoscopies performed per 1,000, between screening modalities. BBT outperforms the fecal immunochemical test (FIT) and the multitarget stool DNA (mtsDNA) test with more CRC deaths averted (13) compared to FIT and mtsDNA (7, 11), more CRC cases averted (27 vs. 16, 22) and higher LYG (214 vs. 157, 199). BBT yields fewer CRC deaths averted compared to colonoscopy (13, 15) but requires fewer colonoscopies (1,053 vs. 1,928). Limitations Due to limited data, the CAN-SCREEN model with longitudinal adherence leverages evidence-informed assumptions for the natural history and real-world longitudinal adherence to screening. Conclusions The CAN-SCREEN model demonstrates that amongst non-invasive CRC screening strategies, those with higher adherence yield more favorable health outcomes as measured by CRC deaths averted, CRC cases averted, and LYG.

Clinical Insights on Brexucabtagene Autoleucel for the Treatment of Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia.

Autologous chimeric antigen receptor-modified T-cell therapy (CAR-T) has revolutionized treatment paradigms across multiple lymphoid malignancies, including relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). The introduction of the CD19-directed CAR-T product brexucabtagene autoleucel (brexu-cel; Tecartus) in October 2021 made this treatment approach available for the first time for adults with R/R B-ALL, a historically challenging clinical entity to treat. In this review, we will discuss the pivotal clinical trial data from the ZUMA-3 study that led to the US Food and Drug Administration (FDA) approval of brexu-cel, including clinical outcomes and key toxicity data (most importantly, the incidence and severity of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome). Additionally, we will compare and contrast these data from the ZUMA-3 study with "real-world" data from examinations of patient outcomes with brexu-cel as an FDA-approved therapy in R/R B-ALL, and discuss practical considerations with brexu-cel use in the clinic, including the role of consolidative allografting for patients post-brexu-cel. We finish by discussing future directions for CAR-T use in R/R B-ALL with the anticipated introduction of a new CD19-directed CAR-T product - obecabtagene autoleucel - in the near future.

A Bayesian approach to pilot-pivotal trials for bioequivalence assessment

BackgroundTo demonstrate bioequivalence between two drug formulations, a pilot trial is often conducted prior to a pivotal trial to assess feasibility and gain preliminary information about the treatment effect. Due to the limited sample size, it is not recommended to perform significance tests at the conventional 5% level using pilot data to determine if a pivotal trial should take place. Whilst some authors suggest to relax the significance level, a Bayesian framework provides an alternative for informing the decision-making. Moreover, a Bayesian approach also readily permits possible incorporation of pilot data in priors for the parameters that underpin the pivotal trial.MethodsWe consider two-sequence, two-period crossover designs that compare test (T) and reference (R) treatments. We propose a robust Bayesian hierarchical model, embedded with a scaling factor, to elicit a Go/No-Go decision using predictive probabilities. Following a Go decision, the final analysis to formally establish bioequivalence can leverage both the pilot and pivotal trial data jointly. A simulation study is performed to evaluate trial operating characteristics.ResultsCompared with conventional procedures, our proposed method improves the decision-making to correctly allocate a Go decision in scenarios of bioequivalence. By choosing an appropriate threshold, the probability of correctly (incorrectly) making a No-Go (Go) decision can be ensured at a desired target level. Using both pilot and pivotal trial data in the final analysis can result in a higher chance of declaring bioequivalence. The false positive rate can be maintained in situations when T and R are not bioequivalent.ConclusionsThe proposed methodology is novel and effective in different stages of bioequivalence assessment. It can greatly enhance the decision-making process in bioequivalence trials, particularly in situations with a small sample size.

Differing Definitions of Vaso-Occlusion in Clinical Studies of Sickle Cell Disease Can Result in Differing Outcomes

Background: Frequent episodes of vaso-occlusion are the hallmark of sickle cell disease (SCD), but the definition of what constitutes a vaso-occlusive episode is not consistently applied across clinical trials, creating challenges in evaluating and comparing efficacy results among different therapies. Here, we compare vaso-occlusion endpoint definitions from clinical trials for various therapies, including genetic therapies, and use clinical trial data to demonstrate the potential for outcomes differences based on differing definitions of vaso-occlusive episodes. Methods: We reviewed completed and ongoing clinical trials and published articles using endpoints assessing the reduction or elimination of vaso-occlusive crisis/events, including trials of (i) exagamglogene autotemcel (exa-cel, CRISPR/Cas-9 based genome editing treatment), (ii) lovotibeglogene autotemcel (lovo-cel, gene addition therapy), (iii) L-glutamine, (iv) voxelotor, (v) hydroxyurea (HU) and (vi) crizanlizumab. Outcomes related to vaso-occlusion were compared across variables including care setting, care duration, treatments, and complications. Data from the CLIMB SCD-121 trial of exa-cel in patients aged 12 to 35 years with severe SCD (data cut as of 10 Feb 2023) were evaluated using different published definitions of vaso-occlusion. Results: The most substantial differences in vaso-occlusion endpoint definitions were associated with frequency and duration of visits to medical facilities for acute pain and inclusion of specific SCD specific complications. Definitions of vaso-occlusions for acute pain related events differed across studies. The definitions of severe vaso-occlusive crises for exa-cel (severe VOC; exa-cel), sickle cell pain-related crises (SCPC; crizanlizumab and L-glutamine), and VOC (VOC; voxelotor) include events with medical facility visits of any duration (severe VOC and SCPC) or medical records of a patient being seen or contacting a physician within 1 business day of an event (VOC), whereas the definition of severe vaso-occlusive events (severe VOE; lovo-cel) requires a ≥ 24-hour hospital or emergency room (ER) observation unit visit or ≥2 visits to a day unit or ER over 72 hours. Vaso-occlusion definition for HU (painful crisis) required a facility visit of ≥4 hours duration. All endpoints include acute chest syndrome and priapism; however, the definition of severe VOE requires ≥4 visits to a medical facility for priapism to meet criterion, while others require only a single visit. The exa-cel phase 3 trial in SCD employs a broad and inclusive definition for severe VOC which counts each individual medical facility visit, regardless of frequency or duration of hospitalization. Based on this, 19 out of 20 patients (95%) met the primary endpoint of freedom from severe VOCs for at least 12 consecutive months (95% CI, 75.1%, 99.9%; P<0.0001). However, when the primary endpoint was analyzed using the severe VOE definition, all patients (20/20; 100.0%) were free from severe VOEs for at least 12 consecutive months (95% CI: 83.2%, 100.0%; P<0.0001). Conclusions: Requirements for health care facility visits in the definitions of severe VOC (exa-cel), VOC, and SCPC were more broadly inclusive and include events that would not be counted in the definitions of severe VOE (lovo-cel) or painful crisis. Clinically, support for this observation comes from our analysis of exa-cel SCD pivotal clinical trial data using these different definitions, which showed the number of patients free from vaso-occlusive episodes changed depending on the definition of vaso-occlusion employed. These results show differences in vaso-occlusion definitions have the potential to impact assessments of treatment efficacy across different SCD therapies.

Three-Year Overall Survival of Advanced Stage ALK-Positive NSCLC at a Single Clinical Setting in Indonesia

Background: ALK-positive Non-Small Cell Lung Cancer (NSCLC) is a rare condition predominantly observed in much younger non-smokers with adenocarcinoma histology, often accompanied by brain metastases. Despite its unique features, there is a lack of data concerning the treatment of ALK-positive NSCLC in Indonesia. Therefore, this study represented the first attempt to document the treatment landscape for ALK-positive NSCLC in the country. The available ALK inhibitors included crizotinib, alectinib, brigatinib, and lorlatinib, and none of these were listed under the Indonesian Universal Health Coverage as of September 2022. This study aimed to characterize survival outcomes of ALK-positive NSCLC patients treated within a specialized thoracic oncology practice in Indonesia.Methods: The retrospective observational cohort study drew secondary data from medical records of ALK-positive NSCLC patients treated at a private thoracic oncology clinic. Data were collected retrospectively, spanning from December 2019 to December 31, 2022. Exclusion criteria included incomplete data, untreated ALK-positive NSCLC, cases at stage I-III, or diagnoses made after August 2021. The observation period extended up to 36 months, although several patients exceeded 48 months, with one individual currently boasting a 96-month survival.Results: A total of 15 patients with ALK-positive NSCLC were selected as the respondents in this study. The median age stood at 50.8 years, predominantly female, and diagnosed with adenocarcinoma. Predominant sites of metastasis included pleural effusion and brain metastases, and preliminary 36-month survival rates reached 73.3%. The 1-year survival rate was recorded at 100%, while the 2-year overall survival (OS) stood at 80%, aligning closely with global ALK inhibitors clinical trial data.Conclusions: This study provided the first-ever dataset indicating an ALK-positive profile within a singular thoracic oncology clinic in Indonesia. Despite the accessibility constraints of treatments, ALK-positive patients showed comparable total survival to pivotal clinical trial data. This preliminary dataset shed light on the profile and treatment of ALK-positive NSCLC in the country.

Clinical Outcomes of Tivozanib Monotherapy as First-Line Treatment for Metastatic Renal Cell Carcinoma: A Multicentric UK Real-World Analysis.

Tivozanib is a licensed as first-line treatment for metastatic renal cell carcinoma (mRCC). To evaluate the outcomes from tivozanib in a real-world mRCC population. Patients with mRCC commencing first-line tivozanib between March 2017 and May 2019 were identified across four specialist cancer centres in the UK. Data relating to response, overall survival (OS), progression-free survival (PFS) and adverse events (AEs) were collected retrospectively with censoring on 31 December 2020. A total of 113 patients were identified: median age was 69years; 78% had ECOG PS 0-1; 82% had clear cell histology; 66% had previous nephrectomy; International Metastatic RCC Database Consortium (IMDC) score was 22% favourable (F), 52% intermediate (I) and 26% poor (P). Twenty-six per cent were switched from another tyrosine kinase inhibitor (TKI) to tivozanib due to toxicity. Median follow-up was 26.6months with 18% remaining on treatment at data censoring. Median PFS was 8.75months. Median PFS by IMDC risk group was: F=23.0months; I=10.0months; P=3.0 months, p value < 0.0001. Median OS was 25.0months (F=not reached (NR) with 72% alive at data cut-off; I=26.0months; P=7.0months, p value < 0.0001). Seventy-seven per cent had an AE of any grade, and 13% had a grade ≥3 AE. Eighteen per cent of patients discontinued treatment due to toxicity. No patients who discontinued a prior TKI due to AEs stopped tivozanib due to AEs. These data suggest comparable activity of tivozanib with the pivotal trial data and other TKIs in a real-world population. Its tolerability positions tivozanib as an attractive first-line option for those unsuitable for combination therapies or unable to tolerate other TKIs.

Targeting Immune Checkpoint Pathways in Melanoma: Triumphs and Challenges

The immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced melanoma by significantly increasing survival rates, with the promise of durable disease remission in some patients. Herein we review the role of immune checkpoints in melanoma; the history of melanoma immunotherapy; pivotal clinical trial data for ipilimumab, pembrolizumab, nivolumab and relatlimab; and the current clinical role of each ICI. We discuss the challenges that accompany these triumphs in the treatment of melanoma, including: how to distinguish between responders and nonresponders; how to optimize ICI dosing and combinatorial approaches; and the best practices for monitoring response and managing immune-related toxicities. We offer our perspective on the financial toxicity of ICIs and new developments that could deliver answers to current challenges.

Tumor Growth Rate Informs Treatment Efficacy in Metastatic Pancreatic Adenocarcinoma: Application of a Growth and Regression Model to Pivotal Trial and Real-World Data.

Methods for screening agents earlier in development and strategies for conducting smaller randomized controlled trials (RCTs) are needed. We retrospectively applied a tumor growth model to estimate the rates of growth of pancreatic cancer using radiographic tumor measurements or serum CA 19-9 values from 3033 patients with stages III-IV PDAC who were enrolled in 8 clinical trials or were included in 2 large real-world data sets. g correlated inversely with OS and was consistently lower in the experimental arms than in the control arms of RCTs. At the individual patient level, g was significantly faster for lesions metastatic to the liver relative to those localized to the pancreas. Regardless of regimen, g increased toward the end of therapy, often by over 3-fold. Growth rates of PDAC can be determined using radiographic tumor measurement and CA 19-9 values. g is inversely associated with OS and can differentiate therapies within the same trial and across trials. g can also be used to characterize changes in the behavior of an individual's PDAC, such as differences in the growth rate of lesions based on metastatic site, and the emergence of chemoresistance. We provide examples of how g can be used to benchmark phase II and III clinical data to a virtual reference arm to inform go/no go decisions and consider novel trial designs to optimize and accelerate drug development.

Predictors of real-world utilisation of docetaxel combined with androgen deprivation therapy in metastatic hormone-sensitive prostate cancer.

Docetaxel has emerged as a standard-of-care for metastatic hormone-sensitive prostate cancer (mHSPC). Uptake of docetaxel for mHSPC in Australia has not previously been reported. To investigate the real-world uptake of docetaxel in mHSPC and to identify predictors of utilisation of docetaxel in mHSPC. Men diagnosed from June 2014 to December 2018 and enrolled in the Prostate Cancer Outcomes Registry-Victoria (PCOR-Vic) were included. Data collected include demographics, diagnosis method and institution, staging investigations and treatments within 12 months of diagnosis. Wilcoxon rank-sum, Chi-squared and trend tests were used to identify predictors of docetaxel utilisation. All predictors were entered as covariates simultaneously into a multivariable logistic regression model. Statistical significance was set at 0.05 (two sided). In all, 1014 men with mHSPC were analysed, 25% of whom received docetaxel with androgen deprivation therapy. Uptake of docetaxel increased from 20% in 2014 to 33% in 2018. Predictors of higher usage of docetaxel were younger age and treatment in a private hospital, with both remaining significant on multivariable analysis. Notably, the proportion of men aged <70 years receiving docetaxel increased from 54% in 2014-2015 to 64% in 2016-2018, while in men aged ≥70 years the comparative figures were 15% and 22% respectively. Although docetaxel was not used in the majority of cases, there was a clear increase in docetaxel uptake, especially in younger men following publication of the CHAARTED and STAMPEDE trials. Identifying barriers to real-world implementation of pivotal clinical trial data is critical to improving outcomes in mHSPC.

Selective Pharmacologic Therapies for Dry Eye Disease Treatment: Efficacy, Tolerability, and Safety Data Review from Preclinical Studies and Pivotal Trials.

Keratoconjunctivitis sicca, also known as dry eye disease (DED), is a prevalent, multifactorial disease associated with compromised ocular lubrication, ocular surface inflammation and damage, and ocular symptoms. Several anti-inflammatory, topical ophthalmic therapies are available to treat clinical signs and symptoms of DED in the USA and Europe. Cyclosporine A (CsA)-based formulations include an ophthalmic emulsion of 0.05% CsA (CsA 0.05%), a cationic emulsion (CE) of CsA 0.1% (CsA CE), and an aqueous nanomicellar formulation of 0.09% CsA (OTX-101). Lifitegrast is a 5% ophthalmic solution of a lymphocyte function-associated antigen 1 antagonist that is believed to target T cell activation and recruitment to inhibit ocular inflammation. Here we provide a comprehensive review summarising preclinical studies and pivotal trial data for these treatments to provide a complete understanding of their efficacy and safety profile. Overall, data in the evaluated studies show a favourable risk–benefit profile for the use of targeted topical anti-inflammatory pharmacologic treatments in patients with DED. Pivotal trials for CsA 0.05%, CsA CE, OTX-101, and lifitegrast clearly demonstrate treatment efficacy compared to vehicle across treatments with no serious ocular treatment-emergent adverse events (TEAEs). Patients using ophthalmic treatments reported ocular TEAEs more frequently than those treated with vehicle; however, relatively few TEAEs led to treatment discontinuation. The specific signs and symptoms of DED that improve with treatment vary with the treatment prescribed. Long-term and direct comparative studies between treatments are needed to further understand treatment differences in efficacy and safety profiles.

Use of Extrapolation in New Drug Approvals by the US Food and Drug Administration

The US Food and Drug Administration (FDA)-approved indications can be factors in prescribing practices and insurance coverage, yet the frequency with which the extrapolation of clinical characteristics from pivotal trial data to the final approved indication occurs is not well understood. To evaluate the frequency of extrapolation beyond pivotal trial data into approved indications in relation to disease severity, disease subtype, and concomitant medication use. In a cross-sectional study, the characteristics of patients in pivotal trials of 105 novel drug approvals from 2015 to 2017 were identified and compared with the FDA-approved indications for the drugs. Main sources analyzed included FDA reviews, published material describing the pivotal trials, and the original drug labeling. The study was conducted from July 4, 2019, to June 1, 2021. Clinical characteristics of pivotal trials used in FDA approval. Main outcomes included the nature and frequency of extrapolation from study populations to the final indications. Extrapolation was defined as the granting of an indication for use in a broader population than was included in the pivotal trials on the basis of disease severity, disease subtype, or concomitant medication use. Among the 105 novel FDA drug approvals studied, 23 extrapolations of trial population characteristics to the approved indication were identified in 21 drugs (20%): 12 times (29%) in 2015, 3 times (15%) in 2016, and 6 times (14%) in 2017. Extrapolation of trial findings to patients with greater disease severity was most common (n = 14 drugs), followed by differences in disease subtype (n = 6) and concomitant medication use (n = 3). The findings of this study suggest that extrapolation from pivotal trial data to FDA-approved indications is common. Although extrapolations may be grounded in reasonable clinical predictions, they can limit the generalizability of such indications to specific prescribing decisions; these findings suggest a greater need for close postapproval monitoring to determine whether new safety issues arise, or effectiveness differs from expectations when these medications are used in broader real-world populations.

Abstract P1-17-08: Abemaciclib and endocrine therapy for hormone receptor-positive, HER2-negative advanced breast cancer: A real-world UK multicentre experience

Abstract Background Abemaciclib is approved in 1st and 2nd line for hormone receptor (HR)-positive HER2-negative advanced breast cancer (ABC). However, outcomes on this agent are unclear in the real world.We determined the safety and efficacy profile of abemaciclib across 15 institutions in the United Kingdom. Methods We retrospectively identified HR-positive, HER2-negative ABC patients who received abemaciclib between July 2018 and June 2020. Demographics, disease characteristics, prior treatments, blood tests, toxicities, treatment delays and responses were recorded. Simple statistics, Fisher’s exact test, chi-squared method and Cox regression were used as appropriate. Results 228 patients identified had median age of 64 (31-93). 172 (75.4%) were postmenopausal and 209 (91.7%) had ECOG Performance Status 0-1. 145 (63.6%) had visceral involvement and 44 (19.3%) only bone disease. Patients received a median 1 (range 0-7) prior lines of treatment and 0 (range 0-5) prior chemotherapy lines.148 patients (64.9%) experienced diarrhoea (grade ≥3 in 16 [7.0%]). 146 patients (64.0%) developed neutropenia (grade ≥3 in 40 [17.5%]). 5 experienced febrile neutropenia (2.2%). 32 patients (14.0%) required hospitalisation due to toxicity (diarrhoea in 9 [3.95%]).Dose reductions were required in 107 patients (46.9%), mainly due to diarrhoea (55 [24.1%]) and to 50mg BD in 30 patients (13.2%). Dose delays were in median 14 (range 2-118). Abemaciclib was discontinued in 121 patients (53.1%) due to disease progression in 61 (26.7%) and toxicity in 48 (21.0%) (diarrhoea in 16 [7.0%]).Abemaciclib produced clinical benefit rate of 82.8% and overall response rate of 47.2% in 163 patients assessed. Overall, median progression-free survival (PFS) was 6.4 months (95% confidence interval [CI] 4.4-7.8) and median overall survival (OS) was 8.8 months (95% CI 7.6-10.6). Conclusions This a large real-world analysis of the safety and efficacy of abemaciclib in combination with endocrine therapy for advanced HR-positive breast cancer. In this analysis, the rates of diarrhoea were lower compared with the pivotal trial data, while neutropenia was more frequent. Although the PFS outcomes were similar to those previously reported, median OS was worse in this cohort which may reflect the different population of patients included, who were older and had more frequent visceral involvement. The selection of patients suitable for abemaciclib is crucial to ensure adequate efficacy and safety outcomes in this setting. Citation Format: Nicolò Matteo Luca Battisti, Laura Morrison, Tamsin Nash, Nishanti Senthivel, Samantha Kestenbaum, Parvin Begum, Mariam Obeid, William Hayhurst, Dorothy Yang, Shafiah Gafoor, Caroline Brown, Farah Rehman, Laura Kenny, Olivia Hatcher, Susan Susan, Jennet Williams, Anna Brown, Hamoun Rozati, Alexandros Alexandros, Elinor Sawyer, Charalampos Gousis, Eleni Karapanagiotou, Anna Rigg, Kleopatra Rapti, Rebecca Roylance, Mark Beresford, Abigail L Gee, Apostolos Konstantis, Judy King, Mark Nathan, Emma Spurrell, Mark Pearce, Dane Bradwell, Arshi Denton, Kate Swain, Sophie McGrath, Mark Allen, Alistair Ring, Stephen Johnston, Fharat Raja. Abemaciclib and endocrine therapy for hormone receptor-positive, HER2-negative advanced breast cancer: A real-world UK multicentre experience [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-08.

Impact of non-binding FDA guidances on primary endpoint selection in Alzheimer's disease trials.

IntroductionThe U.S. Food and Drug Administration (FDA)'s guidances help describe the agency's current thinking on regulatory issues and serve as a means of informal policymaking that is non‐binding. This study examines the impact of two guidance documents for Alzheimer's disease (AD) trials. The first guidance in 2013 encouraged the use of cognitive/functional endpoints, while the second in 2018 modified such recommendation.MethodsUsing pivotal trial data, we applied a regression discontinuity in time (RDiT) framework to examine trialist response to these guidance documents. Results were stratified by disease‐modifying therapy (DMT) status, and controlled for disease staging, FDA registration status, and trial phase.ResultsAmong AD DMT trials, annual use of cognitive/functional composite endpoints significantly increased after the 2013 guidance (+12.9%, P < .001), and significantly decreased after the 2018 guidance (–19.9%, P = .022).DiscussionAlthough guidance documents do not set new legal standards or impose binding requirements, our findings indicate they are broadly followed by AD trialists.

US COVID-19 Vaccines Proven to Cause More Harm than Good Based on Pivotal Clinical Trial Data Analyzed Using the Proper Scientific Endpoint, "All Cause Severe Morbidity"

Three COVID-19 vaccines in the US have been released for sale by the FDA under Emergency Use Authorization (EUA) based on a clinical trial design employing a surrogate primary endpoint for health, severe infections with COVID-19. This clinical trial design has been proven dangerously misleading. Many fields of medicine, oncology for example, have abandoned the use of disease specific endpoints for the primary endpoint of pivotal clinical trials (cancer deaths for example) and have adopted “all cause mortality or morbidity” as the proper scientific endpoint of a clinical trial. Pivotal clinical trial data from the 3 marketed COVID-19 vaccines was reanalyzed using “all cause severe morbidity", a scientific measure of health, as the primary endpoint. “All cause severe morbidity” in the treatment group and control group was calculated by adding all severe events reported in the clinical trials. Severe events included both severe infections with COVID-19 and all other severe adverse events in the treatment arm and control arm respectively. This analysis gives reduction in severe COVID-19 infections the same weight as adverse events of equivalent severity. Results prove that none of the vaccines provide a health benefit and all pivotal trials show a statically significant increase in “all cause severe morbidity" in the vaccinated group compared to the placebo group. The Moderna immunized group suffered 3,042 more severe events than the control group (p=0.00001). The Pfizer data was grossly incomplete but data provided showed the vaccination group suffered 90 more severe events than the control group (p=0.000014), when only including “unsolicited” adverse events. The Janssen immunized group suffered 264 more severe events than the control group (p=0.00001). These findings contrast the manufacturers’ inappropriate surrogate endpoints: Janssen claims that their vaccine prevents 6 cases of severe COVD-19 requiring medical attention out of 19,630 immunized; Pfizer claims their vaccine prevents 8 cases of severe COVID-19 out of 21,720 immunized; Moderna claims its vaccine prevents 30 cases of severe COVID-19 out of 15,210 immunized. Based on this data it is all but a certainty that mass COVID-19 immunization is hurting the health of the population in general. Scientific principles dictate that the mass immunization with COVID-19 vaccines must be halted immediately because we face a looming vaccine induced public health catastrophe.

Baseline Description of the Spanish Academy of Dermatology Infantile Haemangioma Nationwide Prospective Cohort. Comparison of Patients Treated with Propranolol in Routine Clinical Practice with Previous Pivotal Clinical Trial Data

BackgroundThere are several therapeutic options for infantile haemangiomas (IH). Propranolol is used according to a pivotal trial. We aimed to describe the characteristics of IH in clinical practice, including the therapies used, and to compare the characteristics of patients treated with propranolol with those of the trial to assess its external validity. MethodsConsecutive patients attending 12 Spanish hospitals from June 2016 to October 2019 were included (n = 601). ResultsThe mean age was 3.9 (SD: 1.9) months, with a 2:1 female-to-male ratio. Most IHs were localized (82%, 495), superficial (64%, 383) and located in the face (25%, 157) and trunk (31%, 188). Median size was 17 (IR: 10–30) × 12 (IR: 7–20) mm. Complications were found in 16 (3%) patients. Treatment was initiated for 52% (311). Most patients received timolol (76%, 237); propranolol was reserved for complications or high-risk IHs. Aesthetic impairment was the main reason for starting therapy (64%, 199). Several characteristics of the patients and IHs treated with propranolol are similar to those of the pivotal clinical trial, but 1/3 of IHs did not reach the minimum diameter to meet the inclusion criteria, and important prognostic information was not reported. ConclusionsAs most patients receive treatment for aesthetic impairment, there is a need to better understand the aesthetic results of therapies and to increase evidence on the use of timolol, which is currently the most common therapy. Propranolol is being used in a population generally similar to that of the trial; however, this statement cannot be definitely confirmed.

1234-P: Impact of Treatment Adherence to Observed Weight Loss in the GLOW Study

Adherence to weight management treatments is suboptimal. The Gelesis Loss Of Weight (GLOW; NCT02307279) pivotal trial data were used to assess treatment adherence impact on weight loss. The primary objectives of the GLOW study were to assess the effects of an oral superabsorbent hydrogel (OSH) on weight loss (targeted difference of ≥ 3%) and ≥ 5% weight loss responder status in subjects with a body mass index of 27-40 kg/m2. A total of 436 subjects were randomized to 3 capsules twice per day of OSH or placebo taken with 500 mL (16 oz) of water before lunch and dinner while on a hypocaloric diet (-300 kcal/day) for 24 weeks. There were 172 OSH- and 152 placebo-treated subjects who completed the study. Capsules counted at each study visit every 2-4 weeks were used to calculate overall percent treatment adherence (PTA) after the final visit. The PTA impact on weight loss was assessed using ANCOVA models with baseline BMI, fasting glucose and sex as covariates. A logit model with the same covariates was also used to assess the impact of PTA ≥ 95% or &amp;lt; 95% in subjects who achieved ≥ 10% or &amp;lt; 10% weight loss at 24 weeks. In the OSH group, mean PTA for was 97.61% ± 4.68% (SD) ranging from 70% to 111%, and all but 1 subject had PTA ≥ 80%. A significant interaction of ≥ 5% weight loss responder status and PTA was found (P=0.039); therefore, separate ANCOVA models were fit. PTA predicted weight loss at week 24 among the OSH group ≥ 5% responders, but not the ≥ 5% non-responders. Also, a PTA increase of 1 day/week predicted an additional 3.5% weight loss (β = 0.-25 ± 0.11 SE, P=0.024). PTA did not predict weight loss in the placebo group. OSH-treated subjects with ≥ 95% PTA were 4 times more likely to achieve ≥ 10% weight loss compared to those with &amp;lt; 95% PTA (P=0.027, odds ratio=4.27, 95%CI=1.18 to 15.41). These findings suggest that OSH has a binary impact on the treated subjects rather than a uniform effect. Increased PTA during OSH treatment predicted increased weight loss in patients responding to therapy with ≥ 5% weight loss, and not in non-responders or the placebo group. Disclosure L. E. Urban: Employee; Self; Gelesis. C. Apovian: Board Member; Self; Abbott, Allergan plc, Gelesis, Novo Nordisk, Nutrisystem, Tivity Health, Xeno Bioscience, Zafgen, Inc. L. Aronne: Other Relationship; Self; Allurion, Eisai &amp; Janssen Pharmaceuticals, ERX Pharmaceuticals, Gelesis, Jamieson Wellness, Myos Corp, Intellihealth Corp, Novo Nordisk, Pfizer Foundation, Real Appeal, Research Support; Self; Astrazeneca, Aspire Bariatrics. H. Leider: Employee; Self; Gelesis.

706-P: Robust Glycemic Outcomes after MiniMed Advanced Hybrid Closed-Loop (AHCL) System Use in the Pivotal Trial Regardless of Previous Therapy

Background: The Medtronic MiniMed™ AHCL system that autocorrects to 120mg/dL every five minutes and has an automated basal target of 100mg/dL or 120mg/dL has demonstrated improved A1C and time in range1,2 or improved time in closed-loop control,3 compared to open-loop run-in or control. Glycemic outcomes of study participants who used a different baseline therapy (HCL, SAP or CSII) during the MiniMed™ AHCL pivotal trial were analyzed. Methods: Across 16 sites, participants (N=157, 14-75 years) with T1D underwent a baseline run-in period (~2 weeks) of HCL, SAP or CSII followed by a 90-day study phase with AHCL automated basal and auto-correction. An exploratory analysis compared the mean sensor glucose and percentage of time spent across glucose ranges during the baseline run-in and AHCL-study phase for each cohort. Results: Glycemic outcomes for the overall group and each cohort are shown in the table. Significant changes were observed from run-in to study period for the overall group. The glycemic outcomes that were achieved were similar regardless of the baseline therapy. Conclusion: These MiniMed™ AHCL pivotal trial data demonstrate that the system achieves robust glycemic improvement regardless of baseline therapy. Disclosure J. Shin: Employee; Self; Medtronic. X. Chen: None. M. Liu: None. S. Huang: None. T. L. Cordero: Employee; Self; Medtronic. A. S. Rhinehart: Employee; Self; Medtronic, Stock/Shareholder; Self; AstraZeneca, Lexicon Pharmaceuticals, Inc., Medtronic. R. Vigersky: Employee; Self; Medtronic. Funding Medtronic

P290 Impact of concomitant 5-aminosalicylic acid therapy on vedolizumab efficacy and safety in Inflammatory Bowel Disease

Abstract Background Vedolizumab (VDZ), a gut-selective anti-lymphocyte trafficking monoclonal anti-a4β7-integrin antibody, has showed efficacy in multiple phase 3 clinical trials in patients (pts) with inflammatory bowel disease (IBD). Decreased likelihood of response to adalimumab was previously observed with concomitant 5-ASA.1 This post-hoc analysis assessed the impact of concomitant 5-ASA on efficacy and safety in VDZ-treated pts with IBD. Methods Pts with IBD treated with VDZ intravenous (IV) or subcutaneous (SC) in phase 3 trials who continued 5-ASA (at any dose) at the time of starting VDZ were compared with those who received no concomitant 5-ASA. Pts were also stratified by ulcerative colitis (UC) or Crohn’s disease (CD). Efficacy outcomes were the proportion of pts achieving clinical response, clinical remission and corticosteroid (CS)-free clinical remission at Wk 6 (end of induction phase) and Wk 52 (end of maintenance phase). Safety outcomes were the proportion of pts experiencing any infection and enteric infections. Studies included: GEMINI 1 and 2, and VISIBLE 1 and 2 in efficacy analyses; GEMINI 1, 2, 3 and long-term safety for VDZ IV, and VISIBLE 1, 2, and open-label extension (data cut-off 17 May 2019) for VDZ SC in safety analyses. Results At Wk 6, clinical response was achieved by 191 (70.0%) and 69 (61.6%) VDZ-treated pts with UC with and without 5-ASA, respectively, and by 139 (64.4%) and 161 (57.7%) pts with CD, respectively (Table 1). At week 52, clinical remission was achieved by 134 (46.0%) and 45 (38.8%) VDZ-treated pts with UC with or without 5-ASA, and by 116 (50.2%) and 132 (37.5%) pts with CD, respectively. CS-free clinical remission at Wk 52 was achieved by 55 (34.8%) and 19 (37.3%) VDZ-treated pts with UC with and without 5-ASA, respectively, and by 46 (41.4%) and 46 (31.5%) pts with CD, respectively. Multivariate analysis in general showed no differences in VDZ efficacy with or without 5-ASA. No new safety issues or signals were identified. A tendency towards lower incidence of all infections and enteric infections was observed in pts receiving VDZ (IV or SC) with versus without 5-ASA (Table 2). Conclusion In this post-hoc analysis of VDZ pivotal trial data, concomitant 5-ASA does not appear to significantly impact the efficacy of VDZ in pts with IBD. No new safety signals were identified. The safety profile of VDZ IV and SC, with and without 5-ASA was consistent with the known safety profile of VDZ. Although there was limited data in some subgroups, there was no evidence to suggest that concomitant 5-ASA usage was associated with higher infection rates. These data will be useful to inform risk-benefit assessments of continued 5-ASA in VDZ-treated pts. Reference