Standard Of Care For Treatment Research Articles

MINT Registry: Rationale and Study Design

BACKGROUND Mechanical thrombectomy has become the standard of care for treatment of acute ischemic stroke secondary to large‐vessel occlusion up to 24 hours from last known normal time. Multiple different techniques for mechanical thrombectomy have been described, including a direct aspiration first‐pass technique and stent retriever thrombectomy. With a direct aspiration first‐pass technique, classically, a large‐bore aspiration catheter is delivered over a microcatheter and microwire to the clot. Recently, a novel macrowire has been introduced as a potential alternative to the use of microwire–microcatheter to allow the delivery of the aspiration catheter. The aim of this study is to develop a multicenter registry comparing delivery of an aspiration catheter for intracranial thrombectomy for acute ischemic stroke secondary to emergent large‐vessel occlusion over a macrowire in comparison with traditional use of microcatheter and microwire. METHODS MINT (Macrowire for Intracranial Thrombectomy) is a multicenter, observational study currently enrolling patients with large‐vessel occlusion who underwent mechanical thrombectomy using a macrowire to deliver the aspiration catheter to the intracranial occlusion. All the participating sites will screen and report cases on a monthly basis. The decision to use the macrowire and various aspiration catheters is at the discretion of the interventionalist. RESULTS We will collect patient's clinical, demographic, and radiographic data. In addition, we plan to collect procedure variables and postprocedure clinical and imaging data. Outcomes include successful delivery of the reperfusion catheter to the clot interface, time taken from groin access to first pass, and a bailout strategy for thrombectomy in cases where this is not feasible. CONCLUSION The MINT registry will add to our understanding of safety and efficacy of this novel macrowire in intracranial thrombectomy. This registry will also highlight and allow for understanding in workflow improvements from simplifying setup and possibly cost effectiveness of this technique.

Effect of High Dose Atorvastatin and Allopurinol Preloading on No-Reflow in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction

Abstract Background No reflow is linked to worse prognosis post revascularization, so preventing no reflow is better than treating it. Objective this study aims to evaluate the effect of adding high-dose allopurinol and atorvastatin in preventing NRP when given before undergoing primary PCI in patients presenting with STEMI. Patients and Methods This study recruited 300 patients who were classified into 3 groups (100 each), Group A: patients were preloaded with high dose Allopurinol and Atorvastatin on top of the standard of care treatment according to the European society of cardiology guidelines. Group B: patients were preloaded with high dose Atorvastatin only on top of the standard of care treatment, Group C: were only preloaded with the standard care treatment according to the European society of cardiology guidelines, each group was subjected to the same pre procedural laboratory tests, primary percutaneous coronary intervention was done by the most experienced operator available according to the European society of cardiology guidelines. Results Percentage of post procedural no reflow was significantly lower in patients who were preloaded with high dose Allopurinol and Atorvastatin compared to the other 2 groups (highest with group C) (Group A: 11%, Group B: 23%, Group C: 39%). Conclusion preloading patients before primary percutaneous coronary intervention in patients presenting with ST elevation myocardial infarction with high dose Allopurinol and Atorvastatin significantly decreases incidence of post procedural no reflow.

Tumor regression following autologous tumor lysate-loaded dendritic cell vaccination immunotherapy: illustrative case.

Despite years of research, the standard of care (SOC) treatment for grade 4 glioma has remained virtually unchanged for the last 2 decades. Autologous tumor lysate-loaded dendritic cell vaccination (DCVax-L), a novel immunotherapy, has demonstrated a significant survival benefit in a phase 3 trial. A 34-year-old male presented with episodes of lightheadedness and was subsequently diagnosed with a large fronto-insulo-temporal tumor, likely to be high grade. He underwent an asleep craniotomy for debulking, with a residual tumor noted in the frontal lobe and amygdala. Tumor histopathology was reported as isocitrate dehydrogenase (IDH) mutant methylated grade 4 astrocytoma. He received SOC treatment, alongside a course of DCVax-L. Surveillance imaging showed cystic transformation followed by a reduction in size of the residual tumor in the frontal lobe; the residual in the amygdala had regressed entirely. The patient remained clinically well and had returned to his preoperative functionality. The authors report a patient with grade 4 astrocytoma who received DCVax-L treatment in addition to SOC adjuvant therapy. The pattern and extent of tumor regression are highly unusual and atypical for what is seen or expected with adjuvant SOC treatment alone. The addition of DCVax-L to SOC opens new avenues in the management of this difficult disease. https://thejns.org/doi/10.3171/CASE24112.

The anti-aromatase and anti-estrogenic activity of plant products in the treatment of estrogen receptor-positive breast cancer

Despite being the focal point of decades of research, female breast cancer (BC) continues to be one of the most lethal cancers in the world. Given that 80% of all diagnosed BC cases are estrogen receptor-positive (ER+) with carcinogenesis driven by estrogen-ERα signalling, current standard of care (SOC) hormone therapies are geared towards modulating the function and expression levels of estrogen and its receptors, ERα and ERβ. Currently, aromatase inhibitors (AIs), selective ER modulators (SERMs) and selective ER degraders (SERDs) are clinically prescribed for the management and treatment of ER+ BC, with the anti-aromatase activity of AIs abrogating estrogen biosynthesis, while the anti-estrogenic SERMs and SERDs antagonise and degrade the ER, respectively. The use of SOC hormone therapies is, however, significantly hampered by the onset of severe side-effects and the development of resistance. Given that numerous studies have reported on the beneficial effects of plant compounds and/or extracts and the multiple pathways through which they target ER+ breast carcinogenesis, recent research has focused on the use of dietary chemopreventive agents for BC management. When combined with SOC treatments, several of these plant components and/or extracts have demonstrated improved efficacy and/or synergistic impact. Moreover, despite a lack of in vivo investigations, plant products are generally reported to have a lower side-effect profile than SOC therapies and are therefore thought to be a safer therapeutic choice. Thus, the current review summarizes the findings from the last five years regarding the anti-aromatase and anti-estrogenic activity of plant products, as well as their synergistic anti-ER+ BC effects in combination with SOC therapies.

Cost trends in standard-of-care cancer treatments, 2017-2021.

11073 Background: Financial burden of cancer care in the United States is substantial. Prior studies have explored price trends at the level of individual cancer drugs but not that of clinical indications, which can be impacted not only by changes in drug prices but also changes in standard-of-care. This study evaluates temporal trends in the cost of providing the contemporary best guideline-concordant therapy for each cancer indication. Methods: We analyzed trends in the cost of the standard-of-care treatments for the 20 most prevalent cancer types, using NCCN Guidelines to identify the standard-of-care (SOC) treatment for each indication. Our primary comparison of interest was the cost of providing the SOC treatment regimen for each indication in 2021 vs. 2017. All solid tumor treatment indications present in the NCCN Guidelines at both study time points, 7/1/2017 and 7/1/2021, were included. Indications that involved radiotherapy or stem cell transplant among the treatment options were excluded. Costs of all recommended treatment options for each included indication were calculated using Medicare reimbursement rates. We included costs of the antineoplastic agents themselves as well as necessary supportive medications. Costs were inflation-adjusted to 2021 USD. We identified the SOC treatment for every indication at both time points by referring to NCCN Evidence Blocks and identifying the regimen(s) with the highest scores (prioritizing Efficacy, then Safety, then Quality, then Consistency, in that order). If multiple SOC treatments for a single indication had identical scores, we chose the least-costly treatment. Results: 83 clinical indications across 16 solid tumor cancer types (bladder, brain, breast, colon, kidney, liver, lung, melanoma, oropharyngeal, ovary, pancreas, prostate, rectal, soft tissue, stomach, and uterus) were included. Median SOC cost was $8,364 (IQR = $3,838, $15,783) in 2017, compared to a median of $4,290 (IQR = $1,438, $14,947) in 2021. 57 indications (68.7%) had lower SOC costs in 2021 vs 2017, with median change of -$935 (IQR = -$4,432, +$452), representing a 31% decrease (IQR = -50%, 8%). Gastric cancer perioperative chemotherapy had the biggest absolute cost decrease at $65,612 (-90%), while extensive stage small cell lung cancer had the biggest absolute increase at $37,213 (706%). 45 indications (54.2%) had the same SOC regimen across this study period, of which 75.6% saw price drops. Of the 38 indications with new SOCs, 60.5% had lower costs. Conclusions: Majority of the best SOC treatments decreased in cost over a 4 year period. Although introduction of newly approved drugs can cause large price increases for some indications, more commonly the financial cost of delivering the standard-of-care treatment for a given cancer trended down due to slower-than-inflation price increases and new generic entrants.

A randomized, multicenter, open-label, phase 2 study of TRK-950 in combination with ramucirumab and paclitaxel as second-line therapy in patients with Caprin-1 positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.

TPS4181 Background: Caprin-1 is strongly expressed on the cell membrane of many cancer types including G/GEJ and on cancer stem cells. High expression is associated with enhanced in vitro colony-forming activity and in vivo tumorigenicity. TRK-950 is a first in class humanized antibody targeting CAPRIN-11). In the phase I study (NCT02990481), TRK-950 was well tolerated as monotherapy with no DLTs and MTD not reached at doses of 3-30mg/kg IV weekly. Subsequently the Phase 1b study demonstrated that TRK-950 was well tolerated with a high potential for synergistic anti-tumor activity when used in combination with standard of care treatment(s) in selected advanced solid tumors (NCT03872947). Specifically, Regimen D which evaluated TRK-950 in combination with Ramucirumab and Paclitaxel in G/GEJ showed a DCR of 100% in all nine patients receiving 10 mg/kg and partial responses were seen in 5/9 (55%) patients. Caprin-1 strong expression was observed in 4/9 patients and an ORR of 100% was seen in those patients2). A Phase II clinical trial in gastric/GEJ cancer patients with strong Caprin-1 expressions is now enrolling patients. Methods: The phase II study is a multi-national, open-label, randomized, multicenter study evaluating the efficacy of TRK-950 in combination with ramucirumab (Ram) + paclitaxel (PTX ) as compared with Ram + PTX treatment alone in patients with previously treated metastatic G/GEJ adenocarcinoma (NCT06038578). Patients enrolled across 10 sites in Japan, South Korea and the United States are randomized 1:1:1 by the permuted block method to (arm A) TRK-950 5mg/kg plus Ram + PTX, (arm B) TRK-950 10mg/kg plus Ram + PTX or (arm C) Ram + PTX alone. Inclusion criteria include patients with Caprin-1 positive (cutoff; 30% at ≥ 2+ staining) advanced/metastatic G/GEJ adenocarcinoma who have received first line therapy. Key exclusion criteria include HER2 positive disease. The primary endpoint is progression free survival (PFS) based on Independent Central Review (ICR) assessment per RECIST v1.1. Key secondary and exploratory endpoints include overall survival (OS), ORR, DoR, and biomarker evaluation. An interim analysis will be performed after 105 patients are randomized in stage 1 to determine the optimal dose of TRK-950 (5mg/kg or 10mg/kg) that will be evaluated in arm stage 2. In total 146 patients will be enrolled (40 patients in one arm and each 53 patients in two arms). This study opened in September 2023. 1. Okano F, et al. Cancer Res Commun. 2023 Apr 18;3(4):640-658. 2. Cassier P, et al. J Clin Oncol. 2023 Vol. 41, No. 4, suppl. Clinical trial information: NCT06038578 .

A phase II trial to assess the impact of β2 adrenergic blockade in immune checkpoint inhibitor (ICI)– refractory metastatic triple negative breast cancer (mTNBC).

TPS1141 Background: In PD-L1+ mTNBC patients (pts), the standard of care treatment is chemotherapy and pembrolizumab (P) in the first-line setting. It has been shown that acquired resistance to P occurs as a result of immune exhaustion. Further, our group and others have demonstrated that chronic β2-adrenergic receptor (β-AR) signaling suppresses CD8+ cytotoxic T lymphocytes (CTL) function, drives their exhaustion, and increases the numbers of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the tumor microenvironment (TME), thus supporting tumor proliferation. Consequently, abrogation of β-AR signaling using the pan β-blocker propranolol or β-AR-/- knockout mice increased the intratumoral frequency of CTLs and elevated the CTL:Treg ratio (Bucsek et al. Cancer Res. 2017; PMID: 28819022). Similarly, mouse tumor models also demonstrated decreased exhaustion markers (PD1, TIM3, LAG3) on CTLs when β-AR was blocked, via propranolol (Qiao G et al. Cancer Immunol Res. 2021, PMID: 33762351). Confirming this phenomenon, we have shown, in a prospective clinical trial in metastatic melanoma, that β-AR blockade with propranolol significantly increased response to P with an objective response rate (ORR) of 78%, as opposed to 30-40% with P monotherapy (Gandhi et al, Clin Cancer Res 2021, PMID: 33127652). Therefore, we hypothesize that using propranolol in an ICI refractory population should improve responses to ICIs. Methods: This is a phase II single-arm, non-randomized single-center study for mTNBC pts. Participants will bewomen >=18 yrs with PD-L1+ mTNBC, who have progressed on treatment with chemotherapy and P in the upfront setting. They will continue P every 3 weeks in addition to 30 mg propranolol twice a day, based on our ongoing clinical trial in metastatic melanoma (NCT03384836) which has demonstrated safety with this combination. Treatment will continue until disease progression per irRECIST. The primary endpoint is ORR, defined as complete or partial response to treatment. The secondary endpoint is safety, 6-month progression-free survival and overall survival. As an exploratory endpoint, changes in tumor and blood immune markers will be assessed. In stage 1, n1=12 evaluable pts will be enrolled. If ≥ 1/12 response is observed, then the study will continue to enroll another n2=9 pts for a total of n=21, otherwise it will be suspended for futility. If ≥ 3/21 responses are observed, then the proposed therapy will be considered promising. Pre- and post-treatment tumor biopsies and sequential blood samples will be analyzed for changes in stress-induced biomarkers (epinephrine, norepinephrine, and frequency of CTL, MDSC, Treg) and expression of exhaustion markers (PD1, TIM3, LAG3). The study is currently open. Clinical trial information: NCT05741164 .

Ulnar shaft diameter as it relates to plate osteosynthesis: A cadaveric study

BackgroundUlnar shaft fractures are common and the standard of care treatment is with 3.5 ​mm plating. The purpose of this study was to measure diameters along the length of the ulna to provide information on screw length and appropriateness of 3.5 ​mm screws and plate location. MethodsTen embalmed cadaveric ulnas were dissected free of all soft tissues. The length of the ulna was measured and then divided by four. Transverse osteotomies were performed along the length of the ulna at ¼, ½ and ¾ its full length. The diameter of the ulna at these locations was then measured in a radio-ulnar direction as well as a volar-dorsal direction. ResultsThere were five female and five male specimens with an average age of 83.6 and 78.8 respectively. The smallest diameter in both the female and male specimens was in the distal ¾ shaft measured in a volar-dorsal direction with an average of 9.1 ​mm and 12 ​mm. The average volar-dorsal measurement was less than radio-ulnar measurement at all locations. The diameters increased along the ulna heading proximally. ConclusionThis study provides information pertinent to screw width and length with respect to the ulnar shaft and calls in to question the use of 3.5 ​mm screws in the distal and midshaft ulnar diaphysis in females. Removal of 3.5 ​mm screws in the mid and distal ulnar shaft in females can leave a hole corresponding to 23% and 27% of the bone which can be concerning for a stress riser.

HOPE: Harnessing olaparib, palbociclib, and endocrine therapy for BRCA1/2-associated HR+, HER2- metastatic breast cancer.

10616 Background: Thepoly (ADP-ribose) polymerase inhibitor olaparib yields superior progression-free survival, response rates and patient-reported outcomes compared with chemotherapy in patients with BRCA1- or BRCA2- ( BRCA1/2) associated metastatic breast cancer (MBC). Fulvestrant and palbociclib improve outcomes in patients with hormone receptor-positive (HR+) MBC. HOPE (NCT03685331) is a phase I trial to evaluate combination olaparib (O), fulvestrant (F), and palbociclib (P) in patients with BRCA1/2-associated HR+, HER2 negative MBC. Methods: A 3+3 dose escalation was used to assess safety and preliminary efficacy of O, F and P. Eligible participants (pts) had HR+ MBC, a germline (g) or somatic (s) mutation in BRCA1/2, measurable/evaluable disease, any/no prior endocrine therapy, and 0-2 prior lines of chemotherapy for MBC. Prior PARPi and CDK4/6i were permitted but not in combination. Palbociclib was added after a 28-day safety run-in (Cycle 0) of O + F alone. Fulvestrant dose was 500mg IM on day 1 of each 28-day cycle. Dose level 0 (DL0, starting level) was F, O 300mg orally BID continuously, P 75mg orally daily on days 1-21; DL-1 was F, O 250mg orally BID, P 75mg orally daily on days 1-21. The primary endpoint was MTD (adverse events (AEs) based on CTCAE v5.0). Dose limiting toxicity (DLT) period included Cycles 0 and 1. A 30% DLT rate was acceptable; 6 pts had to be treated at a dose for it to be declared MTD. RECIST v1.1 was used to evaluate response. Results: Eight treated pts (s BRCA1:1 ;g BRCA2:6; s BRCA2:1 ) had median (M) age 47; M 0 (0-2) prior lines of endocrine therapy and 0 (0-1) prior chemotherapies for MBC. Three pts each had received O, F, and CDK4/6i as part of their standard of care treatment before study. At DL0, 2/2 pts had DLT with persistent grade(G) 3 neutropenia. Among 6 pts treated at DL-1, none experienced DLT, but 3 pts missed doses of study treatment due to cytopenias (G3 neutropenia, G3 leukopenia, G3 thrombocytopenia) during the DLT period. Following the DLT period, 1 pt reduced O to 200mg orally daily and 1 discontinued P based on provider discretion due to cytopenias (G3 neutropenia, G3 thrombocytopenia). Grade 3 AEs occurring in >1 pt related to study treatment were: neutrophil count decrease (G3/2, n=5/2); white blood cell decrease (G3/2/1, n=3/2/2); platelet count decrease (G3/2/1, n=2/0/1). Overall related AEs in >50% of pts were anemia (n=7), fatigue (n=6) and nausea (n=5). Best responses were CR/PR/SD/PD in 1/1/5/1 pts. Conclusions: MTDof O, F and P (DL-1) was reached and demonstrated antitumor activity. Although no AEs meeting protocol-specified DLT criteria were observed at MTD, hematologic toxicity at this dose complicated drug delivery and required close monitoring during and after the DLT period. Combinations utilizing PARP1 selective inhibitors, lower doses of therapy or sequential rather than combination therapy may improve feasibility. Clinical trial information: NCT03685331 .

Use of gene expression patterns to identify unique molecular subtypes in muscle invasive bladder cancer: GUSTO.

TPS4621 Background: Muscle invasive bladder cancer (MIBC) is an aggressive disease with poor survival rates that are not improving. Curative treatment includes systemic neoadjuvant chemotherapy prior to radical cystectomy and adjuvant immunotherapy. However, many patients do not respond to chemotherapy or immunotherapy. Histologically similar MIBCs can be classified using gene expression patterns into unique molecular subtypes. Retrospective studies have shown that molecular subtypes each have unique biology and consequently respond differently to treatment. The GUSTO trial tests the hypothesis that outcomes can be optimized through subtype-guided allocation. Methods: Eligible participants are those with confirmed non-metastatic MIBC, an ECOG performance status 0-1, being considered for cisplatin-based neoadjuvant chemotherapy and radical cystectomy. Formalin-fixed diagnostic (TURBT) tumor samples undergo gene expression microarray analysis and characterization using the GUSTO Classifier (consisting of the Veracyte Decipher assay and TCGA_2017 classification system) to determine the molecular subtype: basal, neuronal, luminal infiltrated, luminal or luminal papillary. A total of 320 eligible patients (T2-4a N0 M0 or T(any) N1 M0 MIBC) will be randomized 1:1 to either standard of care treatment (neoadjuvant cisplatin and gemcitabine) or subtype-guided treatment (basal and neuronal subtypes - neoadjuvant cisplatin, gemcitabine, durvalumab and tremelimumab and adjuvant durvalumab; luminal infiltrated - neoadjuvant durvalumab and tremelimumab and adjuvant durvalumab; luminal and luminal papillary - proceeding directly to radical cystectomy). Sites are notified when a patient has been assigned a molecular subtype. Patients and sites in the standard of care arm remain blind to the genomic subtype. The trial has three stages: Stage 1 (after 6 months of recruitment) will assess feasibility of recruitment and molecular subtyping in clinical timelines. Outcomes include recruitment rate, time to, and success of subtype allocation. Stage 2 (after 24 months of recruitment) will confirm recruitment feasibility and assess sample size assumptions. Outcomes are recruitment numbers, distributions of subtypes, and pathological complete response (pCR) in the standard of care arm. A re-estimation of the sample size for stage 3 will be considered. Stage 3 (after 12 months post-cystectomy for the last participant randomized) will assess treatment outcomes using this stratified approach. The primary outcome for Stage 3 is the rate of pCR in each molecular subtype within the experimental arm. Progression between trial stages will be dependent upon achieving pre-defined criteria. Recruitment began in September 2023. The study will open the first 20 sites ready to proceed and is accepting expressions of interest. Clinical trial information: 17378733.

Phase 1 study of BDTX-1535, an oral 4th generation covalent EGFR inhibitor, in patients with recurrent glioblastoma: Preliminary dose escalation results.

2068 Background: Epidermal growth factor receptor ( EGFR) gene is the most frequently altered oncogenic driver in glioblastoma (GBM). In-frame deletion alterations (e.g., EGFRvIII) and missense mutations co-occur in the setting of EGFR gene amplification and are characterized as a hallmark of disease pathogenesis in GBM. BDTX-1535 is an oral, highly potent, brain penetrant, selective, irreversible 4th generation tyrosine kinase inhibitor that targets EGFR alterations in GBM and NSCLC. Preliminary results of the Phase 1 dose escalation study (NCT05256290) of patients with recurrent GBM (rGBM) are presented here. Methods: BDTX-1535-101 is a first-in-human study that enrolled patients with either rGBM harboring EGFR alterations following standard of care or patients with locally advanced or metastatic EGFR mutated NSCLC that progressed on prior EGFR TKIs. Using an adaptive Bayesian optimal interval design in the Phase 1 part, patients were enrolled at increasing dose cohorts and were treated daily for 21-day cycles until treatment discontinuation. The primary objective was to determine the BDTX-1535 recommended Phase 2 dose based on the overall safety, PK, pharmacodynamics, and preliminary antitumor activity. Results: Twenty-seven patients with rGBM were enrolled in the Phase 1 cohort that consisted of 54 patients in total including 27 patients with NSCLC. Patients were treated across seven dose levels (15mg – 400mg QD). The mean age of patients with rGBM was 58.7 years (range 41-85) with 96% of patients with previous temozolomide (TMZ) treatment and a median of 2 lines of prior therapy (range 1-4). The most common all-grade treatment-related AEs across all cohorts were rash (78%), diarrhea (41%), fatigue (15%), stomatitis (11%), decreased appetite (11%), nausea (11%) and paronychia (11%). Gr 3 TRAEs ≥ 10% included rash (19%) reported at 300 or 400 mg QD doses. Plasma exposure of BDTX-1535 increased dose proportionally and had a half-life of ~15h, supporting once daily dosing. The maximum tolerated dose (MTD) is 300 mg QD. Among 19 evaluable patients for response based on RANO criteria, 1 confirmed partial response was observed and 8 patients achieved stable disease. Five patients remained on BDTX-1535 with stable disease for an extended period (>5 months) who previously performed poorly on TMZ with short treatment duration, and 1 patient continues on BDTX-1535 after 16 months of treatment. Conclusions: BDTX-1535 was well-tolerated up to 300mg daily, which is the MTD, and promising preliminary clinical activity was observed in patients with rGBM after relapse on standard of care treatment. Given the inability to reconfirm EGFR status at the time of treatment with BDTX-1535 in this Phase 1 trial, further exploration of BDTX-1535 in a “window of opportunity” study is ongoing (NCT06072586). Clinical trial information: NCT05256290 .

Neoadjuvant dynamic marker-adjusted personalized therapy comparing trastuzumab-deruxtecan versus pacli-/docetaxel + carboplatin + trastuzumab + pertuzumab in HER2+ early breast cancer: WSG-ADAPT-HER2-IV.

TPS631 Background: In HER2+ early breast cancer (EBC), combination of standard chemotherapy (CTx) with anti-HER2-antibodies has shown higher efficacy versus CTx alone and/or anti-HER2-antibodies alone. Next to a need for treatment escalation in high-risk disease, there is also a substantial subset of patients (pts) (e.g., elderly pts; those with low - intermediate clinical risk) who need de-escalated but still effective treatment. Based on results from WSG ADAPT HER2+ subtrials, antibody-drug-conjugates (e.g., trastuzumab-emtansine (T-DM1), trastuzumab-deruxtecan (T-DXd)) are excellent candidates for de-escalation approaches in HER2+ EBC due to their high efficacy and low toxicity. Methods: WSG-ADAPT-HER2-IV (NCT05704829) is a multicenter, interventional, prospective, two-arm, randomized, open-label, controlled (neo-)adj., phase-II trial evaluating the efficacy and safety of T-DXd vs. standard-of-care (SOC) PAC+T+P in low-intermediate-risk or DOC/PAC+CARBO+T+P in intermediate-high-risk HER2+ EBC in pre- and postmenopausal pts. Pts will be assigned to 2 treatment groups, depending on risk of recurrence: Cohort 1 (HER2+ EBC, low-intermediate risk of recurrence per Investigator´s decision, 12 wks treatment) and cohort 2 (HER2+ EBC, intermediate-high risk, 18 wks treatment) will be randomized 2:1 to either T-DXd or SOC neoadj. treatment. After 12/18-wks of neoadj. treatment, pathological response (pCR) assessment is performed. Pts with pCR will receive further SOC post-neoadj. treatment according to AGO guidelines. Those with non-pCR qualify for a cross-over treatment: Pts with neoadj. T-DXd will receive SOC CTx + anti-HER2-treatment. Pts. with neoadj. SOC treatment and non-pCR (≥ 5mm residual tumor) receive T-DXd until completion of 52 wks of treatment. After post-neoadj. Treatment, 2 – 5.5 years follow-up will be performed, during which pts may receive any SOC treatment according. Co-primary objectives are comparison of pCR-rates after 12/18 wks of neoadj. treatment with T-DXd vs. SOC (PAC+T+P or PAC/DOC+Carbo+T+P) in pooled risk cohorts and to evaluate whether 3-year dDFS equals or exceeds 92% in T-DXd-treated pts from both risk cohorts. It is planned to randomize 402 pts (269 pts to cohort 1; 133 to cohort 2). Study start was in January 2024 (45 sites, enrollment period 24 months). Estimated trial duration of is 5.5 years. Translational analyses:Potential resistance markers and molecular alterations will be assessed in tumor tissue from primary diagnosis, after 3 wks and after neoadj. treatment, and at recurrence. ctDNA/ctRNA from optional blood samples will be assessed for mutations and gene expression relevant in HER2+ EBC. Clinical trial information: NCT05704829 .

INAVO121: Phase III study of inavolisib (INAVO) + fulvestrant (FUL) vs. alpelisib (ALP) + FUL in patients (pts) with hormone receptor-positive, HER2-negative (HR+, HER2–), PIK3CA-mutated (mut) locally advanced or metastatic breast cancer (LA/mBC).

TPS1136 Background: Standard-of-care (SoC) endocrine therapy (ET) for pts with HR+, HER2–, PIK3CAmut LA/mBC was transformed by combinations with cyclin-dependent kinase 4/6 inhibitors (CDK4/6is); a CDK4/6i-based combination is approved in high-risk, early BC. However, in most pts, mechanisms of resistance that emerge during or after treatment with a CDK4/6i and ET combination lead to relapse/disease progression. Dysregulating mutations in PIK3CA, occurring in ~40% of HR+, HER2– BCs, represent a common mechanism of resistance to CDK4/6is and ET combinations. ALP, a selective PI3Kα inhibitor (PI3Kαi) + FUL is approved for pts with HR+, HER2–, PIK3CAmut LA/mBC, but its widespread implementation in clinical practice has been challenging. As such, there is a significant need to develop PI3Kαis with a better therapeutic index. INAVO is a highly potent and selective PI3Kαi that also facilitates the degradation of mutated PI3Kα isoform. INAVO has demonstrated manageable safety/tolerability, alone and in combination with SoC treatments in HR+, HER2–, PIK3CAmut LA/mBC. Moreover, an ongoing Phase I trial showed that INAVO + FUL elicited encouraging preliminary antitumor activity in heavily pretreated pts, including in pts pretreated with a CDK4/6i-based regimen. Methods: INAVO121 is a Phase III, randomized, open-label study. Pts are randomized 1:1 to receive INAVO (9 mg oral daily [PO QD]) + FUL (500 mg intramuscularly on Days [D] 1 and 15 of Cycle 1, then D1 of subsequent cycles) or ALP (300 mg PO QD) + FUL. Randomization is stratified by visceral disease (yes vs. no) and prior CDK4/6i therapy (adjuvant vs. metastatic setting). Pts will receive treatment until disease progression or unacceptable toxicity. Pts have HR+, HER2–, PIK3CAmut LA/mBC (confirmed by circulating tumor DNA or tumor tissue), adequate hematologic and organ function, and disease progression after or during treatment with a CDK4/6i-based regimen. Up to two prior lines of systemic therapy in LA/mBC, including one line of chemotherapy, are allowed. The primary endpoint is progression-free survival (PFS) by blinded independent central review (BICR). Secondary endpoints include overall survival, BICR-objective response rate, BICR-best overall response, BICR-duration of response, BICR-clinical benefit rate, safety, tolerability, pt-reported outcomes, and pharmacokinetics. A stratified log-rank test at an overall 0.05 significance level (two-sided) will be used for the primary endpoint analysis. Median PFS will be estimated using Kaplan–Meier methodology. An independent data monitoring committee will be in place for safety and efficacy. The study is open for enrollment and has randomized 159 pts; the study is targeting 400 pts at ~200 sites globally. Clinical trial information: NCT05646862 .

Is the addition of running retraining to best standard care beneficial in runners with medial tibial stress syndrome? Protocol for a randomised controlled trial.

Running retraining is commonly used in the management of medial tibial stress syndrome (MTSS) but evidence for its effectiveness is lacking. The primary aim of this study is to determine if the addition of running retraining to best standard care is beneficial in the management of runners with MTSS. This study is an assessor-blinded and participant-blinded, parallel-group, randomised controlled trial. The trial will recruit 64 participants aged between 18 and 45years, with a clinical diagnosis of MTSS that has affected their running participation for at least four weeks. Participants will be randomised to receive best standard care (control) or running retraining and best standard care (intervention group) over an 8-week period. Best standard care will consist of load management advice, symptom management advice, footwear advice and a strengthening program. Running retraining will consist of a cue to reduce running step length. Outcomes will be measured at weeks 1, 2, 4 and 8. The primary outcome measure will be the University of Wisconsin Running Injury and Recovery Index at week 4. Secondary outcome measures include: (i) Exercise Induced Leg Pain Questionnaire-British Version, (ii) global rating of change scale, (iii) worst pain experienced during a run, (iv) weekly run volume, (v) reactive strength index score, (vi) single leg hop test, (vii) soleus single leg maximum voluntary isometric contraction, (viii) gastrocnemius single leg maximum voluntary isometric contraction, (ix) single leg plantar flexor endurance test, (x) running step length, and (xi) running step rate. Data will be analysed using the intention-to-treat principle. This randomised controlled trial will evaluate if reducing running step length provides additional benefit to best standard care in the management of runners with MTSS over an 8-week period. Australian New Zealand Clinical Trials Registry: ACTRN12624000230550.

Hospitalization risk in multiple myeloma episodes of care.

e23101 Background: The Enhancing Oncology Model (EOM) is a total cost of care (TCOC) program that was initiated in July 2023. Participating groups are expected to reduce expenditures while delivering high-quality care. Hospitalization (IP) is an important quality metric and cost driver in TCOC programs such as EOM. Understanding how cancer treatment may impact IP is essential for success. Multiple Myeloma (MM) treatment has transformed with multi-agent treatment as the standard of care (SOC), routinely incorporating 3 or more drugs used concurrently to maximize response. We examined the impact multi-drug treatment had on IP rates in MM patients. Methods: Using Parts A, B and D Medicare claims data from EOM baseline period (January 2019 - June 2022) for 12 participating practices, we extracted a unique count of chemotherapy drugs and IP admissions attributed to 6-month episodes of care. Dexamethasone (dex) was included even if claims were not found. Planned and cancer-surgery related IP were excluded using the Clinical Classifications Software Planned Admission Procedure Categories and per EOM specifications. IPs were dichotomized as Yes/No. A logistic regression model was developed to evaluate the association between the number of unique drugs and the unplanned IP, adjusting for variables: prior chemo, age at episode start, race, and HCC count. A 3-drug regimen was established as the reference (including dex) based on SOC. Results: 11,613 episodes had a primary diagnosis of MM, with at least one IP occurring in 2,382 episodes. The number of episodes (% IP) per drug count group are 1-2: 6636(16.3%); 3: 3772 (23.6%); 4: 863 (30.8%); 5+: 342 (40.9%). Detailed statistics are provided in Table 1. Compared to a 3-drug regimen, 4+ drugs increased the risk of IP, while episodes with 1-2 drugs had a lower risk of IP after adjusting for age, race, HCC count and prior treatment. Conclusions: Our findings can guide the design of care transforming interventions aimed at avoiding unnecessary IP while using guideline concordant SOC treatments for MM, driving TCOC reduction. Identifying patients with a higher likelihood of IP helps practices target patient monitoring programs. To understand why patients with prior treatment had lower IP identifying maintenance following initial treatment and patients receiving 3 or more drugs after failure of prior therapy, are worth exploring further. CMMI Disclaimer: The statements contained in this document are solely those of the authors and do not necessarily reflect the views or policies of CMS. The authors assume responsibility for the accuracy and completeness of the information contained in this document. [Table: see text]

A phase II multicenter study of enfortumab vedotin with or without pembrolizumab in rare genitourinary tumors (E-VIRTUE).

TPS4628 Background: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) targeting nectin-4 with a monomethyl auristatin E (MMAE) payload, a potent microtubule inhibitor. It is standard of care (SOC) in metastatic urothelial carcinoma in combination with pembrolizumab in untreated patients and as monotherapy in post-chemotherapy, post-immune checkpoint blockade (ICB) patients. Nectin-4 expression has been retrospectively observed in 66.7-100% of urinary tract adenocarcinoma, 70-100% of urinary tract squamous cell carcinoma (SCC) (Case et al., 2022; Hoffman-Censits et al., 2021) and 36% of testicular germ cell tumors (GCTs) (The Human Protein Atlas). Metastatic urinary tract adenocarcinoma and SCC, and treatment refractory GCTs do not have an established SOC. Given the known nectin-4 expression, we hypothesize that EV with or without pembrolizumab will be active in these rare GU tumors. Methods: E-VIRTUE is an open-label, non-randomized, Phase 2 multicenter study. Eligible patients must have locally advanced or metastatic urinary tract pure adenocarcinoma, urinary tract pure SCC or refractory GCTs and have measurable disease by RECIST 1.1. Patients may have received any number of lines of prior systemic therapy except EV or other MMAE-based ADCs, and GCT patients must be refractory to all curative SOC treatments. Each histology will have an ICB-naïve and post anti-PD-1/PD-L1 ICB cohort: ICB-naïve patients will be given EV 1.25 mg/kg (maximum 125 mg) on Days 1 and 8 and pembrolizumab 200 mg on Day 1 of 21-day cycles, and post ICB patients will be given EV 1.25 mg/kg (maximum 125 mg) on Days 1, 8 and 15 of 28-day cycles. EV will be given for up to 5 years and pembrolizumab will be given for up to 2 years, or until progressive disease (PD) or unacceptable toxicity. Patients who stop pembrolizumab after achieving a complete response may resume it for 1 year after developing PD. The primary objective is to evaluate the objective response rate (ORR) in all cohorts. Secondary objectives include safety, progression-free survival (PFS) and overall survival (OS). The initial 6 cohorts will each be evaluated with exploratory intent. With 10 patients in each cohort, an exact binomial test with a 10% one-sided significance level will have 85.3% power to detect the difference between a very low (5%) ORR and a higher (30%) ORR. If there are ≥2/10 objective responses in any cohort, activity will be demonstrated. Additional histologies may be added after nectin-4 data emerges to justify their inclusion. Exploratory objectives include estimating the level of nectin-4 expression for each histology, performing DNA and RNA sequencing of tumor and blood samples, and observing changes in levels of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) with treatment and disease status. Clinical trial registration NCT06041503. Clinical trial information: NCT06041503 .

#368 Matching-Adjusted Indirect Comparisons of eGFR slopes in the PROTECT study with UK RaDaR IgA nephropathy population and the control arm of NefIgArd

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is a rare kidney disorder characterized by deposition of IgA in the glomeruli leading to an increased risk of kidney failure. The PROTECT clinical trial in IgAN was designed to determine the long-term (approximately 2 year) nephroprotective potential of treatment with sparsentan compared to a blinded active control angiotensin receptor blocker (ARB) irbesartan, titrated to the maximum labelled dose after randomization (achieved in 97% of patients). To understand PROTECT clinical trial results relative to delivery of standard of care (SoC) treatment for IgAN in other clinical settings, this study compared two-year eGFR total slope outcomes between the two arms of PROTECT and delivery of SoC in two populations applying similar eligibility criteria: Method Using individual patient data (IPD) from PROTECT, unanchored matching-adjusted indirect comparisons (MAICs) were performed. Patients in both arms of PROTECT were weighted to match key baseline characteristics of the two comparator populations. Matching was based on published clinical characteristics using the method of moments. After weighting, two-year eGFR total slopes were calculated using random coefficients models. Two-tailed z-tests with pooled standard errors were used for indirect comparison. Results Based on assessment of cross-data source characteristics, populations were found to be sufficiently comparable for unanchored MAIC. After weighting IPD from PROTECT, all matched baseline patient characteristics were well-balanced between data sources. Comparative results showed that patients treated with maximally titrated irbesartan or sparsentan in PROTECT exhibited a slower decline in kidney function compared to SoC delivered in a real-world setting (RaDaR), with differences of: Similar results were observed compared to SoC delivered in a clinical trial (NefIgArd), with differences of: Conclusion Both “maximally tolerated dose of ARB” (as recommended in the KDIGO guideline for IgAN) using irbesartan in PROTECT and sparsentan were associated with significantly slower decline in kidney function compared to real-world SoC treatment for IgAN (RaDaR) and delivery of physician defined, optimized SoC (& placebo) in the context of a clinical trial (NefIgArd). 2-year eGFR slope differences between clinical trials in IgAN need to be considered in the context of what is achieved in current clinical practice. With existing real-world and emerging clinical trial data in IgAN, MAIC is an approach that can be applied to compare outcomes between relevant, sufficiently aligned data sources.

#2244 Safety and efficacy of daratumumab monotherapy in lupus nephritis refractory to conventional and rescue therapies

Abstract Background and Aims Refractory lupus nephritis (LN) is defined as either no response to standard of care (SOC), i.e., failure to improve within 3–4 months or not achieving partial response within 12 months or complete response after 2 years of treatment. This condition is characterized by poor outcome, is often life-threatening, and represents a relatively unexplored clinical setting. A dysregulation of CD38 expression has been reported in Systemic lupus Erythematosus, and highly expressing CD38 plasma cells relegated in bone marrow niches inaccessible to conventional and biological agents could represent a source of repowering of the immune dysregulation. The efficacy and safety of daratumumab, a monoclonal antibody specifically directed at CD38, given without any other immunosuppressant or agents targeting B-cell-activating factor, were assessed in a discrete cohort of patients with refractory LN, in whom both SOC and rescue treatments had failed. Method Six patients (1 male and 5 females) aged 41.3 years (range 20 to 61 years) were treated with Daratumumab monotherapy. The treatment protocol consisted of 16 mg/kg daratumumab administered intravenously weekly for 8 weeks, then every two weeks 8 more times, and lastly monthly for 8 times. All patients had failed previous treatments with both SOC including either mycophenolate mofetil or cyclophosphamide-azathioprine, and rescue therapies including Rituximab, Ocrelizumab, Belimumab, and iv IgG. Results One out of six patients did not show clinical response after 6 months of therapy, and Daratumumab was discontinued. Five patients continued to be treated (total treatment maximum 22 infusions) and reached a 12-month observation. Renal biopsy performed before daratumumab administration revealed a class IV LN in 1 patient, class V LN in 1 patient, class III+V LN in 1 patient and class IV+V LN in the other 2. Three patients achieved a complete renal response and the other two a partial renal response. A significant decrease in proteinuria from 5.6 g per 24 h to 0.59 g per 24 h, 0.9 g per 24 h and 0.8 g per 24 h (P = 0.0010) at 3 months, 6 months and 12 months, respectively, was observed. The mean value of serum Creatinine (sCr) decreased from 2.3 to 1.5 mg/dl. The mean value of sCr decreased from 2.3 mg dl−1 to 1.5 mg/dl (P = 0.98) at 12 months. C3 and C4 levels increased from 72.8 (range, 0–99) to 101.6 (range, 78.0–135) mg/dl (P = 0.16) and from 9.4 (range, 5–14) to 20.4 (range, 13–30) mg/dl (P = 0.0182), respectively. A decrease in IgG mean levels from 971.7 mg dl−1 (range, 251–1546) to 512.3 mg/dl (range, 88–957), 481.7 (range, 84–878) mg/dl and 508.4 mg/dl (range, 192–685) at 3 months, 6 months and 12 months, respectively, was observed. Improvement of clinical symptoms was paralleled by seroconversion of anti-double-stranded DNA antibodies (p = 0.03), significant decrease in interferon-gamma values (p = 0.0006), BMCA-B-cell maturation antigen (p = 0.0005) and soluble CD163 levels (p = 0.045), and IL 10 levels (p = 0.0006). Clinical remission was substantiated by improvement of SLEDAI-2K score (p = 0.03). Daratumumab was generally well tolerated. Conclusion These data suggest that Daratumumab administered alone (i.e., without any other immunosuppressant or agents targeting B-cell activating factor) is highly effective in refractory LN. The multifaced effects of Daratumumab on the inflammatory burden and the interferon gamma profile could provide a restoration of the immune balance.

Evaluation of the Efficacy and Safety of Intravenous Immunoglobulin (IVIG) in Moderate-to-Severe Hospitalized COVID-19 Patients: A Randomized, Open-Label Parallel-Group Study.

Since February 2020, the world has been overwhelmed by the SARS-CoV-2 outbreak, and several patients suffered interstitial pneumonia and respiratory failure requiring mechanical ventilation, threatening the capability of healthcare systems to handle this amount of critical cases. Intravenous immunoglobulins (IVIG) possess potential immunomodulatory properties beneficial for COVID-19 patients, yet evidence supporting IVIG as adjunctive therapy remains sparse. This study evaluated the outcomes of adjunctive IVIG with the standard of care (SoC) in moderate-to-severe COVID-19 patients. This randomized study included 59 moderate-to-severe COVID-19 patients with known comorbidities. One arm (n = 33) received high-dose IVIG (400 mg/kg/day) within 48 hours for five days alongside SoC, while the other arm (n = 26) received SoC, comprising steroids, enoxaparin, and remdesivir. The primary endpoint was clinical improvement, as measured by the National Early Warning Score 2 (NEWS2) and discharged/death proportions. Secondary outcomes included IVIG safety, hospitalization duration, changes in oxygen saturation, inflammatory markers, IgG titer, CTSS (CT severity score), and radiological findings. There was an improvement in the NEWS2 at the end of treatment in the IVIG arm (5.67 vs. 5.96). A significant absolute effect improvement (Day 1 vs. Day 9) was seen in serum LDH, D-dimer, hs-CRP, IL-6, CTSS, procalcitonin, respiratory rate, and chest radiographic findings. SARS-CoV-2 IgG titer increased significantly in the IVIG arm. There was a statistically significant reduction in mortality in the IVIG group (5 vs. 10). IVIG was a safe and effective adjunctive therapy to SoC treatment in moderate-to-severe COVID-19 patients needing ventilatory support. Furthermore, studies are required to validate our findings. This trial is registered with CTRI/2021/05/033622.

Critical reappraisal of prognostic indicators for 949 mucinous appendiceal neoplasm patients.

The standard of care for treatment of an appendiceal mucinous neoplasm with peritoneal dissemination is cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC). These two treatments are combined in the operating room. A crucial requirement for benefit long-term is proper patient selection. Clinical and histopathologic prognostic indicators are used, along with the patient's fitness for surgery, to select patients to receive CRS and HIPEC. This study seeks to identify the reliable prognostic indicators for four different groups of patients. They are (1) the low-grade appendiceal mucinous neoplasms (LAMN) with a complete CRS, (2) the mucinous appendiceal adenocarcinomas (MACA) with complete CRS, (3) MACA with lymph node metastases (MACA-LN) with complete CRS, and (4) all histologic subtypes with incomplete cytoreduction. The prognostic indicators were evaluated for their impact on overall survival in these four groups of patients. The completeness of cytoreduction (CC) score statistically significantly showed survival differences in all three histologic subtypes. The peritoneal cancer index (PCI) showed significance with LAMN and MACA-LN but not with MACA and not with incomplete CRS. The prior surgical score (PSS) was a prognostic indicator that predicted the outcome with LAMN, MACA-LN, and incomplete CRS patients but not with the MACA group. Patients who were symptomatic or who had extensive systemic chemotherapy before CRS had a significantly reduced survival. The utility of prognostic indicators varied greatly within our four different groups of appendiceal mucinous neoplasms. CC score was always a reliable prognosticator. Surprisingly, PCI was not.