Therapy Clinical Trials Research Articles

Adrenoleukodystrophy an Overview

Adrenoleukodystrophy (ALD) is a rare X-linked peroxisomal oxidation disease caused by mutations in ABCD1. It presents with various clinical manifestations, including cerebral ALD, myelopathy, and primary adrenal insufficiency. About 80% of ALD patients suffer from adrenal insufficiency, and cerebral ALD affects one-third of boys under twelve, progressing to total impairment and death without treatment. Hematopoietic stem cell transplantation (HSCT) is the only disease-modifying treatment for early-stage cerebral ALD, but it does not halt adrenal insufficiency progression and carries significant morbidity and mortality risks. A recent gene therapy clinical trial showed short-term MRI and neurological outcomes equivalent to past HSCT treatments without the adverse side effects. Additionally, over a dozen states have initiated newborn screening (NBS) for ALD, with the number expected to triple by 2020. Genetic testing of NBS-positive newborns has identified novel variations of unknown significance, raising questions about monitoring and treating preclinical or moderate adrenal insufficiency or cerebral involvement. This presents further opportunities for genetic characterization. The availability of matching donors, transplant centers, and specialists will impact prompt treatment for those diagnosed with ALD at birth. As NBS and gene therapy trials improve ALD's clinical management and prognosis, endocrine management of presymptomatic and subclinical adrenal insufficiency will become increasingly important.

A randomized phase II clinical trial of stereotactic body radiation therapy (SBRT) and systemic pembrolizumab with or without intratumoral avelumab/ipilimumab plus CD1c (BDCA-1)+/CD141 (BDCA-3)+ myeloid dendritic cells in solid tumors

BackgroundRadiotherapy (RT) synergizes with immune checkpoint blockade (ICB). CD1c(BDCA-1)+/CD141(BDCA-3)+ myeloid dendritic cells (myDC) in the tumor microenvironment are indispensable at initiating effector T-cell responses and response to ICB.MethodsIn this phase II clinical trial, anti-PD-1 ICB pretreated oligometastatic patients (tumor agnostic) underwent a leukapheresis followed by isolation of CD1c(BDCA-1)+/CD141(BDCA-3)+ myDC. Following hypofractionated stereotactic body RT (3 × 8 Gy), patients were randomized (3:1). Respectively, in arm A (immediate treatment), intratumoral (IT) ipilimumab (10 mg) and avelumab (40 mg) combined with intravenous (IV) pembrolizumab (200 mg) were administered followed by IT injection of myDC; subsequently, IV pembrolizumab and IT ipilimumab/avelumab were continued (q3W). In arm B (contemporary control arm), patients received IV pembrolizumab, with possibility to cross-over at progression. Primary endpoint was 1-year progression-free survival rate (PFS). Secondary endpoints were safety, feasibility, objective response rate, PFS, and overall survival (OS).ResultsThirteen patients (10 in arm A, eight non-small cell lung cancer, and five melanoma) were enrolled. Two patients crossed over. One-year PFS rate was 10% in arm A and 0% in arm B. Two patients in arm A obtained a partial response, and one patient obtained a stable disease as best response. In arm B, one patient obtained a SD. Median PFS and OS were 21.8 weeks (arm A) versus 24.9 (arm B), and 62.7 versus 57.9 weeks, respectively. An iatrogenic pneumothorax was the only grade 3 treatment-related adverse event.ConclusionSBRT and pembrolizumab with or without IT avelumab/ipilimumab and IT myDC in oligometastatic patients are safe and feasible with a clinically meaningful tumor response rate. However, the study failed to reach its primary endpoint.Trial registration number: Clinicaltrials.gov: NCT04571632 (09 AUG 2020). EUDRACT: 2019-003668-32. Date of registration: 17 DEC 2019, amendment 1: 6 MAR 2021, amendment 2: 4 FEB 2022.

Apolipoprotein B: Bridging the Gap Between Evidence and Clinical Practice.

Despite data suggesting that apolipoprotein B (apoB) measurement outperforms low-density lipoprotein cholesterol level measurement in predicting atherosclerotic cardiovascular disease risk, apoB measurement has not become widely adopted into routine clinical practice. One barrier for use of apoB measurement is lack of consistent guidance for clinicians on how to interpret and apply apoB results in clinical context. Whereas guidelines have often provided clear low-density lipoprotein cholesterol targets or triggers to initiate treatment change, consistent targets for apoB are lacking. In this review, we synthesize existing data regarding the epidemiology of apoB by comparing guideline recommendations regarding use of apoB measurement, describing population percentiles of apoB relative to low-density lipoprotein cholesterol levels, summarizing studies of discordance between low-density lipoprotein cholesterol and apoB levels, and evaluating apoB levels in clinical trials of lipid-lowering therapy to guide potential treatment targets. We propose evidence-guided apoB thresholds for use in cholesterol management and clinical care.

The Meaning in Loss protocol: A clinical trial of online grief therapy

For a minority of the bereaved, the loss of a significant other can trigger an overwhelming emotional reaction and impaired functioning across life domains, known as prolonged grief disorder (PGD). Hence, ongoing efforts have been made to refine existing treatments to increase their efficacy and to accommodate the idiosyncrasies of grief reactions. This study presents the results of an open clinical trial of the feasibility and effectiveness of the Meaning in Loss (MIL) protocol in an online format. The brief intervention of 12 to 16 sessions combines constructivist and narrative strategies to explore and work through impediments to meaning reconstruction in loss. The sample included 25 participants diagnosed with PGD who were treated by six therapists. Baseline and post-therapy comparisons showed a significant improvement in all clinical measures (grief symptomatology, depression and general distress) and an increase of meaning making regarding the loss. Meaning making was found to be a prospective mediator of symptomatic improvement in grief across the course of therapy. These findings suggest the effectiveness of the MIL protocol in decreasing grief specific and associated symptomatology and argue for the relevance of further controlled evaluations of its efficacy. Moreover, results confirm previous findings that meaning making is a relevant factor in the evolution of grief reactions, including in the context of psychotherapy.

Longitudinal biomarker evaluation in Fabry disease patients receiving lentivirus-mediated gene therapy

Aim: In 2016, a team of Canadian researchers initiated the world’s first gene therapy clinical trial for Fabry disease. The study, aiming to determine the safety and toxicity of lentivirus α-galactosidase A transduced autologous CD34+ cells in adult males with Fabry disease (n = 5), was conducted at three Canadian centers. The objective of the present work was to evaluate a profile of Fabry disease-related biomarkers in five participants during a 5-year surveillance period, as part of the evaluation of this novel therapy. Methods: Sixteen globotriaosylceramide (Gb3) isoforms and eight globotriaosylsphingosine (lyso-Gb3) analogues were measured by LC-MS/MS in plasma and urine at numerous time points before and after gene therapy. Plasma and peripheral blood leukocyte α-galactosidase A activity were also measured. Results: Levels of urine and plasma lyso-Gb3 and analogues, and urine Gb3 were lower after gene therapy and while treated with enzyme replacement therapy (ERT) compared to baseline (before gene therapy) in participants treated with ERT only. Three participants chose to cease ERT treatment at some point after gene therapy. Two of these patients had lower levels of urine and plasma lyso-Gb3 and analogues compared to baseline, whereas one participant had higher levels of these biomarkers compared to baseline. An increase in urine Gb3 was observed when ERT treatment ceased after gene therapy (P < 0.05) in all three participants. Conclusion: The evaluation of this complete glycosphingolipid biomarker profile was useful in monitoring the biochemical response to gene therapy in this cohort of five patients with Fabry disease.

Alcohol use prior to episodes of nonsuicidal self-injury in women with borderline personality disorder participating in a randomized clinical trial of dialectical behavior therapy.

Alcohol use is an important, but understudied, risk factor for nonsuicidal self-injury (NSSI), defined as deliberate physical harm to oneself without intent to die. Alcohol use may facilitate engagement in NSSI by increasing impulsivity and physical pain tolerance. Limited data also suggest that people engage in more medically severe NSSI under the influence of alcohol. This secondary analysis study examined the use of alcohol prior to NSSI in a sample of 79 female patients with borderline personality disorder who were enrolled in a randomized clinical trial of dialectical behavior therapy. We used multilevel modeling (MLM) to examine preregistered hypotheses that alcohol use prior to NSSI would be related to the impulsivity of NSSI, physical pain experienced during NSSI, and the medical severity of injuries from NSSI. Participants endorsed alcohol use prior to 21.96% (47/221) of NSSI episodes, and roughly one third of participants (n = 27) reported at least one episode of NSSI preceded by alcohol use. For NSSI episodes preceded by alcohol use, more than half (52.38%) of participants reported using alcohol up to the moment of initiating NSSI. Alcohol use was significantly associated with higher impulsivity of NSSI episodes (b = 1.16, p = .041), but not physical pain from NSSI or medical severity of NSSI. Findings need to be replicated but indicate that alcohol use occurs frequently prior to NSSI and could be a target for reducing impulsive episodes of NSSI. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A Way Forward for Phage Therapy in the United States

Phage therapy is a potentially life-saving treatment for antibiotic-resistant infections, but it is not commonly available in the United States as it is in other parts of the world. Phage therapy is a historical practice in the former Soviet Union and Russia to treat bacterial infections. Since phages are naturally present in the environment, only synthetic bacteriophage that has been genetically engineered can be patented by pharmaceutical companies which makes it a difficult practice to integrate into clinical care in the United States. However, the growing costs of antibiotic resistance and recent advances in biotechnology are prompting US government agencies to partner with industry to support the development synthetic phage to combat antibiotic resistance. Although very few phages therapy clinical trials have progressed past phase two, there is incredible potential for further development. This review evaluates the outlook of phage therapy in the U.S. by evaluating the risk of widespread phage resistance against its potential benefits as effective products that target bacterial resistance mechanisms and increase antibiotic susceptibility.

LGG-04. TRAMETINIB COMBINED WITH CHEMOTHERAPY FOR INFANT BRAF-FUSED CHIASMATIC GLIOMA

Abstract BACKGROUND Infant chiasmatic gliomas present a major therapeutic challenge due to large size, threat to vision and progressive nature. Infants <1 year respond poorly to Vincristine/Carboplatinum chemotherapy (SIOP-LGG2). BRAF fusion is common, so MEK inhibitors have been used second line in older children, but time to response is slow (median ~20 months). Data on the use of these drugs in infants is limited as is data on the safety and efficacy of combining chemotherapy with MEK inhibitors. METHODS We report two infants treated successfully for BRAF fused chiasmatic glioma - both presented age 5 months with nystagmus and diencephalic syndrome. Both had significant tumor progression within 6 weeks of starting Vincristine/ Carboplatin which responded rapidly to the addition of Trametinib. RESULTS Case 1 required tumor debulking at week 6 of chemotherapy due to progressive hyponatremia, hydrocephalus and brainstem compression. Surgery caused diabetes insipidus, hemianopia and hemiparesis. Tumor growth continued despite reinstating chemotherapy. Addition of trametinib caused tumor shrinkage by 75% within 12 weeks and 90% by 1 year. Minirin doses were reduced by 80% on Trametinib. After 1.3 years, chemotherapy was stopped & Trametinib continued alone. Case 2 - tumor growth and severe hyponatremia by week 6 of chemotherapy prompted addition of Trametinib without surgery. There was tumor reduction of 50% over 6 months and improvement of severe failure to thrive. Hyponatremia, requiring sodium and urea supplementation, stabilized. Bilateral vision and age-appropriate development are maintained. Hypertension developed early, but resolved completely after stopping and then gradually reintroducing Trametinib. Recurrent diarrhea required dose reduction. CONCLUSIONS We show the safety and efficacy of combined treatment with chemotherapy and MEK inhibition in infants and postulate that both the combination and the young age at initiation of therapy may have contributed to the excellent outcome. We urge for clinical trials of combination therapy in this age group.

Perimacular Atrophy Following Voretigene Neparvovec-Rzyl Treatment in the Setting of Previous Contralateral Eye Treatment With a Different Viral Vector.

To report on cases of unilateral perimacular atrophy after treatment with voretigene neparvovec-rzyl, in the setting of previous contralateral eye treatment with a different viral vector. Single-center, retrospective chart review. In this case series, four patients between the ages of six and 11years old with RPE65-related retinopathy were treated unilaterally with rAAV2-CB-hRPE65 as part of a gene augmentation clinical trial (NCT00749957). Six to 10 years later the contralateral eyes were treated with the Food and Drug Administration-approved drug, voretigene neparvovec-rzyl. Best-corrected visual acuity (BCVA), fundus photos, ocular coherence tomography, two-color dark-adapted perimetry, full field stimulus threshold testing (FST), and location of subretinal bleb and chorioretinal atrophy were evaluated. Three out of four patients showed unilateral perimacular atrophy after treatment with voretigene, ranging from five to 22months after treatment. Areas of robust visual field improvement were followed by areas of chorioretinal atrophy. Despite perimacular changes, BCVA, FST, and subjective improvements in vision and nyctalopia were maintained. Perimacular atrophy was not observed in the first eye treated with the previous viral vector. We observed areas of robust visual field improvement followed by perimacular atrophy in voretigene treated eyes, as compared to the initially treated contralateral eyes. Caution is advised when using two different viral vectors between eyes in gene therapy. This may become an important issue in the future with increasing gene therapy clinical trials for inherited retinal dystrophies.

Multicentric Longitudinal Prospective Study in a European Cohort of MYO7A Patients: Disease Course and Implications for Gene Therapy.

We investigated the natural history of retinal dystrophy owing to variants in the MYO7A gene. Fifty-three patients (mean age, 33.6 ± 16.7years) with Usher syndrome owing to biallelic, mostly pathogenic, variants in MYO7A underwent baseline and two annual follow-up visits. Best-corrected visual acuity (BCVA), semiautomatic kinetic visual field, full-field electroretinogram, color fundus imaging, microperimetry, spectral-domain optical coherence tomography, and fundus autofluorescence were assessed. At baseline, all patients presented with decreased BCVA (66.4 ± 17.9 Early Treatment Diabetic Retinopathy score and 59.5 ± 21.7 Early Treatment Diabetic Retinopathy score, in the better- and worse-seeing eyes, respectively), restricted semiautomatic kinetic visual field (III4e area, 3365.8 ± 4142.1°2; 4176.4 ± 4400.3°2) and decreased macular sensitivity (9.7 ± 9.9dB; 9.0 ± 10.2dB). Spectral-domain optical coherence tomography revealed reduced central macular thickness (259.6 ± 63.0µm; 250.7 ± 63.3µm) and narrowed ellipsoid zone band width (2807.5 ± 2374.6µm; 2615.5 ± 2370.4µm). Longitudinal analyses (50 patients) showed a significant decrease of BCVA in better-seeing eyes, whereas no changes were observed in worse-seeing eyes for any parameter. BCVA, semiautomatic kinetic visual field (III4e and V4e) and macular sensitivity were related significantly to age at baseline. Hyperautofluorescent foveal patch (16 eyes [31.4%]) and abnormal central hypoautofluorescence (9 eyes [17.6%]) were significantly associated with worse morphological and functional read-outs compared with the hyperautofluorescent ring pattern (22 eyes [43.1%]). Our European multicentric study offers the first prospective longitudinal analysis in one of the largest cohorts of MYO7A patients described to date, confirming the slow disease progression. More important, this study emphasizes the key role of fundus autofluorescence patterns in retinal impairment staging and advocates its adoption as an objective biomarker in patient selection for future gene therapy clinical trials.

Neurocognitive Test Performance in relation to symptom severity and age of onset of trichotillomania

Prior research has yielded inconsistent findings on neurocognitive deficits, particularly in response inhibition and set shifting, when comparing patients with trichotillomania (TTM) to healthy comparison groups. This study used baseline data (N = 36) from a clinical trial of behavior therapy for TTM to test two possible explanations for these mixed results: (a) neurocognitive deficits are only noted among more severely symptomatic patients with TTM; and (b) age of onset is differentially associated with deficits in response inhibition vs. set shifting. Results were inconsistent with these hypotheses. Age of onset was not significantly correlated with either neurocognitive assessment. Interviewer ratings of TTM symptom severity or impairment were not significantly related to neurocognitive test performance. Self-reported symptom severity correlated significantly with motor response inhibition, but in the direction opposite to our expectation, such that faster reaction times to inhibit a dominant response were associated with more severe symptoms. Discussion centered on several possible explanations, including the possibilities that either (a) measurement methods or (b) variation across samples in the prevalence of ADHD comorbidity, not measured in this study, could explain mixed findings on the neuropsychological profile of TTM.

Supplemental Material for Alcohol Use Prior to Episodes of Nonsuicidal Self-Injury in Women With Borderline Personality Disorder Participating in a Randomized Clinical Trial of Dialectical Behavior Therapy

Supplemental Material for Alcohol Use Prior to Episodes of Nonsuicidal Self-Injury in Women With Borderline Personality Disorder Participating in a Randomized Clinical Trial of Dialectical Behavior Therapy

Treatment for non-tuberculous mycobacteria: challenges and prospects.

Non-Tuberculous mycobacteria (NTM) are opportunistic environmental bacteria. Globally, NTM incidence is increasing and modeling suggests that, without new interventions, numbers will continue to rise. Effective treatments for NTM infections remain suboptimal. Standard therapy for Mycobacterium avium complex, the most commonly isolated NTM, requires a 3-drug regime taken for approximately 18 months, with rates of culture conversion reported between 45 and 70%, and high rates of relapse or reinfection at up to 60%. New therapeutic options for NTM treatment are urgently required. A survey of ongoing clinical trials for new NTM therapy listed on ClinicalTrials.Gov using the terms 'Mycobacterium avium', 'Mycobacterium abscessus', 'Mycobacterium intracellulare', 'Non tuberculous Mycobacteria' and 'Nontuberculous Mycobacteria' and a selection criterion of interventional studies using antibiotics demonstrates that most trials involve dose and combination therapy of the guideline based therapy or including one or more of; Amikacin, Clofazimine, Azithromycin and the anti-TB drugs Bedaquiline and Linezolid. The propensity of NTMs to form biofilms, their unique cell wall and expression of both acquired and intrinsic resistance, are all hampering the development of new anti-NTM therapy. Increased investment in developing targeted treatments, specifically for NTM infections is urgently required.

Nociceptors are functionally male or female: from mouse to monkey to man.

The prevalence of many pain conditions often differs between sexes. In addition to such quantitative distinctions, sexual dimorphism may also be qualitative reflecting differences in mechanisms that promote pain in men and women. A major factor that influences the likelihood of pain perception is the threshold for activation of nociceptors. Peripheral nociceptor sensitization has been demonstrated to be clinically relevant in many pain conditions. Whether peripheral nociceptor sensitization can occur in a sexually dimorphic fashion, however, has not been extensively studied. To address this fundamental knowledge gap, we used patch clamp electrophysiology to evaluate the excitability of dorsal root ganglion neurones from male or female rodents, non-human primates, and humans following exposure to putative sensitizing agents. Previous studies from our laboratory, and others, have shown that prolactin promotes female-selective pain responses in rodents. Consistent with these observations, dorsal root ganglion neurones from female, but not male, mice were selectively sensitized by exposure to prolactin. The sensitizing action of prolactin was also confirmed in dorsal root ganglion neurones from a female macaque monkey. Critically, neurones recovered from female, but not male, human donors were also selectively sensitized by prolactin. In the course of studies of sleep and pain, we unexpectedly observed that an orexin antagonist could normalize pain responses in male animals. We found that orexin B produced sensitization of male, but not female, mouse, macaque, and human dorsal root ganglion neurones. Consistent with functional responses, increased prolactin receptor and orexin receptor 2 expression was observed in female and male mouse dorsal root ganglia, respectively. Immunohistochemical interrogation of cultured human sensory neurones and whole dorsal root ganglia also suggested increased prolactin receptor expression in females and orexin receptor 2 expression in males. These data reveal a functional double dissociation of nociceptor sensitization by sex, which is conserved across species and is likely directly relevant to human pain conditions. To our knowledge, this is the first demonstration of functional sexual dimorphism in human sensory neurones. Patient sex is currently not a common consideration for the choice of pain therapy. Precision medicine, based on patient sex could improve therapeutic outcomes by selectively targeting mechanisms promoting pain in women or men. Additional implications of these findings are that the design of clinical trials for pain therapies should consider the proportions of male or female patients enrolled. Lastly, re-examination of selected past failed clinical trials with subgroup analysis by sex may be warranted.

FOXP3+ Regulatory T Cells Require TBET to Regulate Activated CD8+ T Cells During Recovery from Influenza Infection.

FOXP3+ regulatory T (Treg) cells are necessary to coordinate resolution of lung inflammation and a return to homeostasis after respiratory viral infections, but the specific molecular requirements for these functions and the cell types governed by Treg cells remain unclear. This question holds significance as clinical trials of Treg cell transfer therapy for respiratory viral infection are being planned and executed. Here, we report causal experiments in mice determining that Treg cells are necessary to control the numbers of activated CD8+ T cells during recovery from influenza infection. Using a genetic strategy paired with adoptive transfer techniques, we determined that Treg cells require the transcription factor TBET to regulate these potentially pro-inflammatory CD8+ T cells. Surprisingly, we found that Treg cells are dispensable for the generation of CD8+ lung tissue resident-memory T (Trm) cells yet similarly influence the transcriptional programming of CD8+ Trm and activated T cells. Our study highlights the role of Treg cells in regulating the CD8+ T cell response during recovery from influenza infection.

Nivolumab monotherapy and associations in the treatment of advanced unresectable biliary tract cancer (BTC): A systematic review and meta-analysis.

e16216 Background: Patients with advanced unresectable BTC have a poor prognosis, and treatment options are limited and with variable response rates. Nivolumab (NIVO), a PD-1 inhibitor, has shown its effectiveness against multiple cancer types and has been tested as a therapeutic option in diverse settings and associations. Methods: We performed a systematic review and single arm meta-analysis of clinical trials of NIVO monotherapy or combined therapy in advanced unresectable BTC. PubMed, Embase, and Cochrane database were searched for clinical trials published up to May 1, 2023. Data were extracted from published reports and quality assessment was performed per Cochrane recommendations. The primary endpoints of interest were objective response rate (ORR = CR+PR) and disease control (DC = SD or better response) per RECIST v1.1, at any period of the trial. Results: Out of 80 database results, 6 clinical trials and 358 patients were included, all were using some form of NIVO therapy. Overall, NIVO and associations present an ORR = 13% (95% CI 0.08-0.16, I² = 23%, p = 0.26) and DC = 39% (95% CI 0.27-0.51, I² = 69%, p < 0.05). NIVO monotherapy present an ORR = 6% (95% CI 0.02-0.10, I² = 36%, p = 0.19) and DC = 28% (95% CI 0.04-0.51, I² = 87%, p < 0.001) while NIVO + ipilimumab association show an ORR = 11% (95% CI 0.004-0.22, I² = 76%, p < 0.05) and DC = 37% (95% CI 0.24-0.49, I² = 28%, p = 0.23). NIVO + gencitabine + cisplatin association trials reported an ORR within 13-18% and DC around 32%. This data suggests that associations of NIVO present higher efficacy in the treatment of BTC and should be considered among the first choices of therapy, however drug adverse effects tolerability might play an important part in the individualized patient care. Conclusions: There are marked limitations to the applicability of these findings in clinical practice, therefore a cautionary approach to this data is recommended, given their overall low statistical power, heterogenous study design, and tolerability to adverse effects. New trials of NIVO + associations with better standardized outcomes and comparative arms for different associations and populations will help to better clarify the effects of NIVO in the treatment of advanced unresectable BTC. [Table: see text]

Quality of life (QoL) benefits following 177Lu-DOTATATE therapy in patients (pts) with 68Ga-DOTATATE PET positive primary site agnostic neuroendocrine tumors (NET).

e16291 Background: The QoL experience during the 1st year of follow up for 68Ga-DOTATATE PET positive primary site agnostic pts with progressive metastatic NET enrolled in a prospective single arm clinical trial of 177Lu-DOTATATE therapy (OZM 067) is described here. Methods: Pts with progressive NET, Ki67 Index < 30%, adequate organ function & ECOG £2 were eligible. Only pts demonstrating positive disease (Krenning score 3-4) on 68Ga-DOTATATE PET were eligible to proceed to 177Lu-DOTATATE therapy (4 cycles at 8- to 12- week intervals. Primary outcome was progression free survival (PFS) at 12 mths. QoL (EORTC QLQ 30 and GINET21) at baseline, 6, 12, 18, 24, 30 months were recorded. Summary scores at time point of interest, and their change from baseline were estimated using a mixed model repeated measure, with baseline assessment included in the model as covariate. Data were normalized with a range of 0-100. A positive change score for Global Summary Status, Functioning Domains, and a negative change score for Symptom Scales and Items represent improvement. A ≥5 point change score is used as a threshold for Minimal Clinically Important Difference (MCID). Results: 195 pts were enrolled. 13 pts were 68Ga-DOTATATE PET negative while 5 pts withdrew consent. 177 pts received at least one dose of 177Lu-DOTATATE. All pts enrolled were eligible for a minimum of 12 mths follow up at time of data lock. The primary site was GEPNET in 143 (81%) and non GEPNET in 34 (19%). At 12 mths, the median follow-up was 33 (range 3-71) mths. PFS and OS were 81 (95% CI: 75-86)% and 92 (87-95)% respectively. QoL data at the following timepoints baseline, 6 & 12 (±2) mths were available in 174,128 & 111 pts respectively. The top three symptoms captured in EORTC QLQ 30 was Fatigue (32.5 SD 23.8) , Insomnia (26.7 SD 28.1) and Diarrhea (22.1 SD 29.4). At 12 mths, an improvement in mean score of ≥MCID in Global Health status (GHS) (+5.4), Role Fc Scale (+7,1), Social Fc Scale (+8.7) and multiple symptoms (Fatigue, Pain, Appetite, Constipation, Diarrhea, Financial Difficulties), Sexual fc, Social, Body image (Table 1) were captured. Conclusions: Patients with primary site agnostic 68Ga-DOTATATE PET positive NET experienced improvement in multiple quality of life domains including multiple symptoms post 177Lu-DOTATATE at 12 mths. Sexual fc and body image had the largest improvement. Clinical trial information: NCT02743741 . [Table: see text]

Racial/ethnic representation and disparities in preclinical cancer models.

1601 Background: Patient-derived xenograft models (PDXs) recapitulate tumor characteristics credibly and have become a standard for preclinical inquiries that form the basis of clinical trials of novel therapies in oncology. While ample evidence reveals racial/ethnic disparities in cancer care delivery and clinical research, limited data exists regarding racial composition of available PDXs. We sought to define the extent of racial/ethnic representation and disparities among existing PDXs. Methods: Data regarding available PDXs was gathered from the publicly accessible CancerModels.org website ( https://www.cancermodels.org/overview ). Seven members of the research team were involved in data extraction. Information on race/ethnicity (White, Black, Hispanic, Asian), sex, age, and cancer type were recorded. The primary objective was to determine the racial/ethnic composition of PDX models and compare this to racial/ethnic demographics of cancer patients, for which we used US population-based cancer estimates calculated using National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER Incidence Data, 11/2022 Submission (1975 - 2020), SEER 22 registries). Descriptive statistics were used. Proportions were compared using Fischer’s exact test or Chi-squared tests with Yates' correction (odds-ratio [OR] and 95% confidence intervals [95%CI] or Woolf logit interval) were reported. Results: We reviewed 4597 unique PDXs across 33 SEER cancer sites spanning 11 oncology sub-specialties. Of these, 55% models were derived from males and age groups were (years): < 20: 6%; 20-70: 69% and ≥ 70: 25%. Most common cancer sites represented were colorectal (26%), lung (12%), breast (9%), melanoma (9%) and leukemia (7%). Race/ethnicity was not reported in 3395 (73.9%) cases. Racial/ethnic composition of the remaining models was Whites (80.9%), Blacks (7.3%), Hispanics (6.4%) and Asians (5.4%). Compared with their respective proportion of US cancer incidence (69.9%, 10.9%, 13.2% and 5.9%, respectively), these models were over-representative for Whites (OR: 1.82, 95%CI: 1.6-2.1, P < 0.001) and under-represented Blacks (OR: 0.64, 95%CI: 0.5-0.8, P < 0.001) and Hispanics (OR: 0.45, 95%CI: 0.4-0.6, P < 0.001) but not Asians (OR: 0.89, 95%CI: 0.7-1.2, P = 0.43). Similar trends were seen in subgroups focused by cancer site. Among colorectal (N = 1201) models, race/ethnicity was reported for 17.2% of cases and Blacks (OR: 0.52; 55.7% of expected; P = 0.014) and Hispanics (OR: 0.57; 60.8% of expected; P = 0.015) were underrepresented compared to Whites (OR: 1.82; 116% of expected; P < 0.001). Conclusions: Race/ethnicity are infrequently reported for PDX models. Minority races/ethnicities (Blacks and Hispanics) are underrepresented in preclinical models compared to their burden of cancer incidence. There is a need to develop a diverse repertoire of preclinical models to ensure inclusivity and guide equitable research.

Clinical-genomic characteristics in patients with EGFR-mutated non-small cell lung cancer harboring MET copy number gains after progression on EGFR-TKI: A report from LC-SCRUM-TRY.

8628 Background: MET amplification (amp) account for 10-15% of resistance mechanism in EGFR-mutated non-small cell lung cancer (NSCLC) to EGFR-tyrosine kinase inhibitor (TKI) treatment. MET copy number (CN) gains consists of MET focal amp and polysomy (poly), but the clinical characteristics and outcome of EGFR-TKI resistant NSCLC patients harboring MET amp, poly remains unclear. Methods: The clinical-genomic characteristics and treatment outcome ofEGFR-TKI resistant EGFR-mutated NSCLC registered in LC-SCRUM-TRY (UMIN000041957) were analyzed. Genetic resistant alterations were screened using next-generation sequencing (NGS) (Tissue; Oncomine Precision Assay [OPA] or Plasma; Guardant360 [G360]), and MET-fluorescence in-situ hybridization (FISH). MET amp was defined as MET CN ≥4 (OPA), MET CN ≥2.12 (G360) or MET/CEP7 ratio ≥2 (FISH). MET poly was defined as MET CN≥5 and MET/CEP7 ratio <2 by FISH. Results: A total of 1559 patients had been enrolled in LC-SCRUM-TRY between Sep 2020 and Jan 2024. Of 1537 analyzed samples, 666 (43%) were EGFR-TKI resistant samples. Of these, 92 (14%), 239 (36%) and 335 (50%) had MET amp, poly, and no CN gain (no CNG), respectively. Patient characteristics and treatment outcome with 1st line EGFR-TKI and platinum-based chemotherapy (PBC) post EGFR-TKI is summarized (Table 1). The overall response rate (ORR) of PBC post EGFR-TKI in the patients with MET amp, poly and no CNG was 41%, 29% and 31%, respectively (p=0.34), with median progression-free survival (mPFS) being 5.7 months, 6.8 months, and 6.7 months (p=0.02). In addition, 12 and 11 of patients with MET amp and poly were enrolled into clinical trial of MET-targeted therapy (MET-TKI, n=2; MET-antibody-drug conjugate [ADC], n=4; EGFR/MET-antibody, n=2), and MET non-targeted therapy (EGFR-TKI, n=5; other ADCs, n=10: immunotherapy; n=1). The ORR of MET-targeted therapy/MET non-targeted therapy were 60/0% for MET amp, and 0/33% for MET poly, respectively. Conclusions: Patients with shorter PFS with prior 1st line EGFR-TKI are more likely to have MET amp. The efficacy of standard PBC post EGFR-TKI in patients with MET CNG is limited. Current MET-targeted therapy may not be effective for EGFR-mutated NSCLC harboring MET poly after progression on EGFR-TKI. [Table: see text]

Impact of trial eligibility criteria on enrollment to KRASG12C inhibitor trials in patients with non-small cell lung cancer.

11012 Background: Clinical trials of novel therapies should enroll a population that reflects patients (pts) who might receive the drug upon FDA approval. In 2017 ASCO proposed modifications to common eligibility criteria (EC) to increase the generalizability of trial findings. Despite this, barriers to trial enrollment in the recent era of molecularly-targeted therapies are not well-characterized. We examined a cohort of non-small cell lung cancer (NSCLC) pts with KRAS G12C mutations to determine whether EC for trials of KRAS G12C inhibitors allowed enrollment of patients seen as part of routine care at an academic medical center. Methods: We extracted EC for Phase I-III trials among six KRAS G12C inhibitors: sotorasib, adagrasib, LY3537982 , divarasib, JDQ443 and RMC-6291. We retrospectively reviewed pts with NSCLC and G12C mutations detected on universal, NGS-based testing of NSCLCs at Columbia University Irving Medical Center (CUIMC) from 2020 to 2023. We defined dates of disease progression and evaluated pts for clinical trial eligibility for each line of treatment. Pts were deemed trial-eligible if they met all EC, borderline if they had 1 laboratory value < 20% from cutoff, or ineligible. The association between baseline factors including self-reported race, sex, and age with rates of eligibility were evaluated with chi-squared tests. Results: EC criteria for 14 trials were characterized. EC were similar across trials regardless of agent or phase and did not substantially change over time; 1 Phase III trial had expanded EC from the Phase I/II trials. Of 1172 patients with NSCLC, we identified 185 pts with G12C mutations (15%), including 69 pts with advanced or metastatic disease. Of these, 19% (13/69) would have been eligible for any G12C trial, 15% (10/69) were borderline, and 67% (46/69) were ineligible. 9% (6) would have qualified for only 1 of the trials. The most common reasons for ineligibility were poor performance status (54% [30/56]), excluded comorbidities (25% [14/56]), and renal dysfunction (27% [15/56]). Among patients who received therapy after FDA accelerated approval (N = 22), only 23% (5) would have been eligible for the related Phase III trial. Conclusions: Our findings suggest that most patients with KRAS G12C mutations would not have been eligible for relevant trials, including > 75% of patients who received KRAS G12C inhibitors off-trial after accelerated FDA approval. EC did not expand after early phase trials demonstrated evidence of safety. These data should guide sponsor and FDA considerations in the development of trial protocols for targeted therapies, as fewer barriers to trial participation would enable trials to be completed more quickly and would improve the generalizability of trial results.