Radiographic Response Research Articles

Assessment of serum tumor markers CEA, CA-125, and CA19-9 as adjuncts in non-small cell lung cancer management.

Conventional tumor markers may serve as adjuncts in non-small cell lung cancer (NSCLC) management. This study analyzed whether three tumor markers (CEA, CA19-9, and CA-125) held associations with radiographic and clinical outcomes in NSCLC. It constituted a single-center study of NSCLC patients treated with systemic therapy at the London Regional Cancer Program. Serum tumor markers were analyzed for differences in radiographic responses (RECIST v1.1 or iRECIST), associations with clinical characteristics, and all-cause mortality. A total of 533 NSCLC patients were screened, of which 165 met inclusion criteria. A subset of 92 patients had paired tumor markers and radiographic scans. From the latter population, median (IQR) fold-change from nadir to progression was 2.13 (IQR 1.24-3.02; p < 0.001) for CEA, 1.46 (IQR 1.13-2.18; p < 0.001) for CA19-9, and 1.53 (IQR 0.96-2.12; p < 0.001) for CA-125. Median (IQR) fold-change from baseline to radiographic response was 0.50 (IQR 0.27, 0.95; p < 0.001) for CEA, 1.08 (IQR 0.74, 1.61; p = 0.99) for CA19-9, and 0.47 (IQR 0.18, 1.26; p = 0.008) for CA-125. In conclusion, tumor markers are positioned to be used as adjunct tools in clinical decision making, especially for their associations with radiographic response (CEA/CA-125) or progression (CEA/CA-125/CA-19-9).

Optimizing perioperative treatment for potentially resectable stage III squamous cell lung carcinoma: promising results of a condensed four-cycle regimen with tislelizumaband chemotherapy

BackgroundThe standard care for resectable non-small cell lung cancer (NSCLC) involves perioperative therapy combining chemotherapy and immune checkpoint inhibitors, typically lasting 6 to 12 months. However, the optimal treatment strategies for potentially resectable squamous cell lung carcinoma (SCC) remain unclear. This Phase 2 trial aimed to assess the efficacy and safety of a condensed four-cycle perioperative treatment regimen with tislelizumab combined with chemotherapy in patients with potentially resectable stage III SCC.MethodsPatients with potentially resectable stage IIIA-IIIB (N2) SCC received intravenous tislelizumab, albumin-bound paclitaxel, and carboplatin for up to four cycles. The primary endpoints were major pathologic response (MPR) and incidence of treatment-related adverse events. Safety and potential biomarkers for efficacy prediction were also assessed.ResultsAmong 35 enrolled patients, 32 underwent surgery with R0 resection achieved in all cases. MPR was achieved in 24 patients and pathological complete response (pCR) in 14 patients. Radiographic objective response was observed in 31 patients. The 12-month and 24-month event-free survival rate was 85.7 and 61.0%, respectively. Four patients experienced grade 3 or 4 adverse events. Tumor tissue based next-generation sequencing revealed the potential associations between several biomarkers and pathological response, including tumor neoantigen burden score, 18-gene expression profile score, CD8 + T cells, M1/M2 macrophages ratio and interferon‐gamma expression level. Besides, circulating tumor DNA (ctDNA) dynamics and concentration were also associated with pathological response and the presence of ctDNA at postoperative month 1 was a strong predictor for disease relapse. Furthermore, metagenomic sequencing in bronchoalveolar lavage fluid demonstrated Streptococcus was the most abundant genus in the pCR group.ConclusionsA condensed four-cycle perioperative treatment regimen of tislelizumab combined with chemotherapy demonstrated promising efficacy and manageable toxicities in potentially resectable stage III SCC. Specific biomarkers showed potential for predicting treatment efficacy and the mechanism of superior antitumor response of pCR patients was preliminarily and indirectly explored.Trial registrationClinicalTrials.gov, NCT05024266. Registered August 27, 2021.

Des-gamma-carboxy prothrombin (DCP) as a prognostic biomarker in patients with advanced hepatocellular carcinoma treated with atezolizumab/bevacizumab.

e16167 Background: Causes of variable disease response to first-line treatment with atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma (HCC) remain unclear. Identifying tumor markers that predict treatment response and provide prognostic information may help clinicians optimize treatment strategies and patient outcomes. The role of des-gamma-carboxy prothrombin (DCP) is not well established in Hepatitis B Virus non-endemic areas. This study aimed to investigate DCP as a predictive biomarker of treatment response as well as explore prognostic implications of DCP in patients with advanced HCC. Methods: This single-center retrospective analysis evaluated DCP and radiographic response in patients with advanced HCC who received atezolizumab/bevacizumab in the first-line setting. DCP was measured at the time of best response, determined by radiographic evaluation, and compared to day one of atezolizumab/bevacizumab initiation. Elevated DCP was defined as &gt; = 7.5 ng/mL. DCP response was defined as a decrease of &gt; = 50% at response assessment compared with baseline. Comparisons of treatment effects were performed using two-tailed Fisher Exact Probability Test. Overall survival (OS) was defined as the interval between the first treatment and either the date of death or the last follow-up visit. OS was analyzed using the Kaplan–Meier method and compared between groups using the log-rank test. Results: A total of 53 patients with advanced HCC treated with atezolizumab/bevacizumab were included. Radiographic treatment responses were complete response 3.8%, partial response 22.6%, stable disease 52.8% and progression of disease 20.8%, respectively. On day one of treatment 70% of patients had an elevated DCP. Patients with DCP response had ORR of 69% (odds ratio, 15.75; 95% CI, 3.50 – 70.9; p = 0.0002) and disease control rate of 100% (p = 0.047). Conversely, patients with &gt; = 50% increase in DCP at response evaluation compared to day one of treatment had ORR of 4.5% and no response rate of 95% (p = 0.0035). Furthermore, patients who had &gt; = 50% increase in DCP had median OS of 15.4 months compared to patients without &gt; = 50% increase in DCP who had median OS of 28.4 months (HR = 2.48; 95% CI, 1.035 – 5.93; p = 0.042). There was no difference in ORR, or OS, between patients who had elevated DCP on day one of treatment and those who did not. Conclusions: DCP response correlates with objective radiographic response in patients with advanced HCC treated with atezolizumab plus bevacizumab in the first-line setting. DCP increase of &gt; = 50% correlates with decreased median OS and may serve as a negative prognostic biomarker in such patients.

Liquid biopsy in patients with metastatic pancreatic cancer using an optimized targeted sequencing approach: Data from the pancreatic cancer registry PanDaDETECT.

e16303 Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) conveys a dismal prognosis, and biomarkers for clinical diagnostics and treatment monitoring are urgently needed. Detection of circulating tumor DNA (ctDNA) using liquid biopsy (LB) has been shown to correlate with treatment response in other tumor entities. Here, we evaluated the feasibility of LB by targeted next generation sequencing (NGS) in metastatic PDAC, using an NGS approach optimized for PDAC. Methods: Patients from our PanDaDETECT registry with metastatic PDAC were included. Plasma samples were collected at initial diagnosis and every three months during palliative treatment. Targeted NGS of plasma samples was performed using a small, custom-generated gene panel optimized for LB provided by Qiagen (QiaSeq Targeted DNA Panel), covering the four most frequently mutated genes in PDAC with full exon coverage (KRAS, TP53, SMAD4 and CDKN2A). Sequencing was performed on the Illumina NextSeq 550 platform. LB results were compared to matched tissue NGS data from tumor samples. Results were correlated with the serological biomarker Ca 19-9 and radiographic response data. All patients provided written informed consent. The responsible ethics committee approved the study. Results: From 2020 to 2022, 57 patients were included and underwent plasma NGS at least at initial diagnosis. For 52 of these patients a tissue NGS result was available, and in 49 patients (94,2%), at least one of the four genes covered by our LB panel was mutated in the tumor tissue. In 35 patients, our LB approach detected ctDNA in the plasma sample at initial diagnosis (61,4%). Comparing tissue and plasma sequencing data at initial diagnosis, our LB approach detected ctDNA in 32 out of 49 patients who had a known mutation in tissue NGS in at least one of the four genes covered by the LB panel (65,3%). For 22 patients with positive ctDNA detection in plasma NGS, follow-up plasma samples after three months of treatment were available. In this subgroup, detection of ctDNA showed a superior correlation with radiographic response assessed by RECIST criteria than the serological biomarker Ca 19-9. In patients with a partial response or stable disease as defined by RECIST, ctDNA levels decreased markedly, while remaining elevated in patients showing disease progression. For 11 patients, plasma NGS at 6 months of treatment or later was performed, the results at these later time points correlated well with clinical and radiographic response in 9 out of 11 patients. Conclusions: Our LB approach optimized for PDAC is feasible and shows a good correlation with serological and radiographic response. Our optimized NGS panel covering only four genes is able to detect ctDNA in a majority of PDAC patients. LB by targeted NGS has the potential to detect a broad spectrum of relevant mutations in PDAC in an automatable and cost-effective matter.

Phase I dose escalation trial of the first-in-class TNFR2 agonist monoclonal antibody, HFB200301, in monotherapy and in combination with tislelizumab, an anti-PD-1 monoclonal antibody, in adult patients with advanced solid tumors.

2526 Background: Tumor necrosis factor receptor-2 (TNFR2) is expressed on effector CD8+, CD4+, and regulatory T (Treg) cells, natural killer (NK) cells, and myeloid cells. Activation of TNFR2 is anticipated to yield effective anti-tumor immunity by stimulating T-cell and NK-cell activation and proliferation in the tumor microenvironment. HFB200301 is a first-in-class anti-TNFR2 agonistic monoclonal antibody that triggers both innate and adaptive immune stimulation by binding to a specific epitope on TNFR2. We report initial results of an ongoing Phase I dose escalation, multicenter study (NCT05238883) of HFB200301 in monotherapy and in combination with tislelizumab (TIS) in patients (pts) with advanced refractory solid tumors. Methods: A Phase I trial designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and initial efficacy of HFB200301 in monotherapy and in combination with TIS. Eligible pts, ≥18 years with an ECOG PS 0-1 and advanced solid tumors, will be enrolled in dose escalation at 5 different dose cohorts in monotherapy (Q4W), 3 different dose cohorts in combination with TIS (Q4W), or in dose expansion following determination of safety. Radiographic response is assessed every 8 weeks. Results: A total of 39 pts have been enrolled, 27 pts in monotherapy and 12 pts in combination. All pts received prior systemic therapy (median 2, range 1-4); 23 pts (59%) had prior checkpoint inhibitor treatment. No dose limiting toxicities were observed in either the monotherapy or combination arms. Treatment-related adverse events (TRAEs) occurred in 44% of monotherapy and in 50% of combination pts, with pruritis (11%), tremor (7%), fatigue (7%), asthenia (7%) and nausea (7%) being the most common TRAEs. No ≥ Grade 3 TRAEs were reported, and there were no drug discontinuations due to TRAEs. Preliminary HFB200301 PK analysis demonstrated non-linear clearance of HFB200301, with dose-proportional maximum concentration [Cmax], achieving sufficient exposures for peripheral target engagement in all tested doses. Emerging PD data demonstrates evidence of immune activation and expansion of CD8+ T cells, but not Tregs, in the tumor microenvironment and peripheral blood. Single cell RNAseq analysis of peripheral blood mononuclear cells demonstrated PD modulation in TNFR2 positive immune cell types post-HFB200301 treatment. Early response evaluation reveals ongoing durable clinical responses (&gt; 6 months) in a PD-L1+ pleural mesothelioma pt and an EBV+ gastric cancer pt from combination cohorts. Conclusions: HFB200301 demonstrates a favorable safety profile, dose-dependent PK, with PD and preliminary clinical activity in monotherapy and in combination with TIS in pts with heavily pre-treated refractory solid tumors. Clinical trial information: NCT05238883 .

Evaluating antitumor activity and response determinants to trastuzumab deruxtecan in pediatric solid tumors.

10049 Background: Trastuzumab deruxtecan (T-DXd) is an anti-HER2 antibody-drug conjugate (ADC) linked to a topoisomerase inhibitor FDA-approved for several indications, including the treatment of HER2+ breast and gastric cancer. Although HER2 amplification is uncommon in pediatric cancers, recent demonstration of T-DXd efficacy in HER2-low breast cancer patients prompted us to examine the potential clinical relevance of T-DXd in pediatrics by evaluating HER2 expression and activity of T-DXd in preclinical pediatric solid tumor models. Methods: Cell viability was assessed in a panel of histologically diverse pediatric solid tumor cell lines and 2 HER2-amplified adult cancer cell lines treated with T-DXd, payload (DXd), and a control IgG-ADC. HER2 protein expression in patient-derived xenograft (PDX) tumors was evaluated by immunohistochemistry (IHC) using 5 clinically validated anti-HER2 antibodies. RNAseq was performed on clinical (n=290) and PDX (n=184) tumors to determine relative expression of ERBB2. In vivo activity of T-DXd was evaluated in osteosarcoma (OS, n=10), Wilms tumor (WT, n=1) and malignant rhabdoid tumor (MRT, n=1) PDX models and a desmoplastic small round cell tumor (DSRCT) cell line xenograft model. Differences in tumor volume and time to disease progression was assessed and compared across treatments and models. Responses were correlated with HER2 expression by IHC. Results: In vitro, HER2-amplified control cell lines demonstrated a &gt;30-fold reduction of IC50 when comparing T-DXd to ADC control. In contrast, the ADC control IC50 was nearly identical to T-DXd across all pediatric cancer cell lines, consistent with the absence of HER2 amplification in these models. We observed focal and membranous staining of HER2 by IHC in PDXs but was quite variable across antibodies tested: WT 0-17% HER2+ cases (n=6), MRT 0-40% (n=5), DSRCT 0-33% (n=24), OS 0-7% (n=30). ERBB2 gene expression was highest in DSRCT followed by WT, OS and MRT. In vivo efficacy studies demonstrated complete and partial responses in OS, WT, and DSRCT and improved disease control rates (OS: 67%, p=0.006, Mann-Whitney; WT: 100%; DSRCT: 100%). However, T-DXd and ADC control demonstrated similar activity in all tumor types with no consistent correlation between in vivo response and HER2 expression. Consistent with these preclinical studies, 4 patients with progressive DSRCT were treated with T-DXd via compassionate/off-label access with signs of clinical and radiographic responses. Conclusions: T-DXd shows significant preclinical antitumor activity across multiple pediatric solid tumors but little correlation with HER2 expression suggesting a mechanism of action similar to the clinical activity observed in HER2-low breast cancer. Xenograft efficacy studies and preliminary clinical experience with T-DXd in DSRCT patients warrant formal clinical trial investigation in this largely incurable disease.

Retrospective study of ivosidenib for patients with recurrent IDH mutant gliomas.

2040 Background: IDH mutant gliomas are the most common primary malignant brain tumors in adults under the age of 50 and accounts for approximately 12% of all glioma diagnoses each year. While lower grade gliomas (LGG) encompassing WHO grades II and III are less aggressive than their higher-grade counterparts, treatment is not curative, and most patients develop tumor recurrence in which there are a paucity of effective treatment options. Mutations in IDH1/ 2 occur upwards of 80% of patients with LGG and drive specific epigenetic programs to dysregulate and impair differentiation leading to tumorigenesis. As such, pharmacologic blockage of IDH mutant enzymes is being actively investigated as potential treatment option. Ivosidenib (AG-120), a second-generation IDH inhibitor, is an FDA approved medication for treatment of IDH-mutated acute myeloid leukemia and has demonstrated safety and clinical activity in patients with progressive IDH mutant gliomas. We explored the efficacy of Ivosidenib in IDH mutant gliomas. Methods: We retrospectively analyzed patients with IDHm gliomas treated with ivosidenib in our institution. We included patients with an IDH1 mutation who received at least one cycle of ivosidenib. Data collected included patient demographics, tumor histology, tumor location, grade, 1p/19q co-deletion, MGMT, CDKN2A, TERT, EGFR, P53, PTEN mutational status, prior treatment history, duration of treatment, toxicities, radiographic response, PFS, and OS. Descriptive statistics were used to summarize patients' characteristics. The distribution of mPFS was estimated by the Kaplan-Meier method. Results: Between April 2010 and December 2023, we identified 33 patients that received ivosidenib. 7 patients received ivosidenib in combination with bevacizumab, 3 patients received ivosidenib in combination with radiation, and 1 patient received ivosidenib and nivolumab. The median age was 52 (range 31-81). 21 (63%) were male. The median lines of medical therapy and radiation/surgery prior to starting ivosidenib were 3.03(range 0-6) and 1.5(range 0-4), respectively. 27(81%) were grade 2, 5(15%) were grade 3, and 1(3%) were grade 4. 19(57%) had 1p/19q co-deletion. As of 12/31/2023, 48%(16) patients were alive. The median PFS was 7.52 months (1-26) and median OS 12.7 months (3-25). 11(33%) patients experienced partial response (PR), 20(60%) experienced stable disease (SD) and 2(6%) demonstrated progressive disease (PD) at 12-week assessment. Nine patients experienced adverse events: grade 1 fatigue (3), grade 1 diarrhea (1), grade 2 fever (1), grade 2 weakness (1), and grade 3 confusion (1). One patient experienced grade 4 lobar hemorrhage thought to be related to concurrent bevacizumab use. Conclusions: Treatment with Ivosidenib therapy was associated with a manageable safety profile. In a subset of patients, there was disease stabilization in heavily pre-treated recurrent IDH mutant gliomas.

Effect of indoximod-based chemo-immunotherapy in patients with pediatric brain tumors on activation and clonal proliferation of a circulating population of early non-exhausted stem-like CD8+ T cells whose on-treatment expansion is predictive of long-term outcome.

2566 Background: Combination chemo-immunotherapy is a promising strategy, but it is difficult to determine whether clinical responses are associated with on-target immune activation or just due to chemotherapy. The field lacks well-accepted readouts of on-treatment T cell activation/expansion to answer this question. Methods: We analyzed longitudinal blood samples from 30 patients with pediatric brain tumors treated with the IDO-inhibitor drug indoximod combined with either chemotherapy (n=27, NCT02502708, NCT04049669) or chemotherapy plus ibrutinib (n=3, NCT05106296). Patients in this “Training Set” were selected to include multiple trials, various histologies/molecular risk factors, and a range of outcomes (overall survival (OS) range 6-55 months). Longitudinal blood samples (2-11 samples/patient) were obtained over 4-36 months, depending on duration of treatment, and analyzed by single-cell RNA and TCR sequencing (scRNAseq/TCRseq). TCR clonotypes of interest were defined as having at least 2-fold expansion (or appearance de novo) during treatment compared to baseline. To calculate a “Clonal Expansion Index” (CEI), the total number of T cells belonging to treatment-expanded clonotypes was summed for each sample and expressed as a percentage of total T cells. The peak CEI value for each patient was used to stratify subjects into “Immune Responders” vs “Non-responders”, based on an optimized cutoff established by Receiver Operating Characteristic (ROC) analysis with Youden’s J statistic. Results: In these patients, CEI ranged from &lt;1% to &gt;60% of all circulating T cells. The optimized cut-point was found to be a CEI of 8.6%, producing a sensitivity of 91% and specificity of 77% for this dataset. Kaplan-Meier analysis showed a highly significant 3-fold difference in median OS for the CEI-High patients (26.5 months) compared to CEI-Low (8.9 months, p=0.0003). The CEI metric was far superior as a predictor of long-term outcome than radiographic response by RANO, RAPNO or iRANO criteria, which were not predictive. UMAP clustering and Monocle trajectory analysis of the treatment-expanded T cells revealed that the majority arose from a population of early stem-like cells (TCF7+ LEF1+ FOXP1+), progressing through a more activated stem-like population (HOBIT/ZNF683+) to attain proliferation and effector maturation states. Throughout this sequence, the T cells showed minimal markers of exhaustion (PDCD1, HAVCR2, TOX) and acquired a lytic effector phenotype. Conclusions: We hypothesize that clonal expansion of this population of non-exhausted stem-like T cells, as quantitated by the CEI assay, provides a mechanistically based pharmacodynamic readout of T cell response to indoximod-based (and perhaps other) chemo-immunotherapy.

Safety and clinical efficacy of IOA-289, a novel autotaxin inhibitor, plus gemcitabine and nab-paclitaxel (GnP) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC).

e15130 Background: Autotaxin (ATX) plays a critical role in inflammation and resistance mechanisms in a wide range of malignancies. IOA-289 is a novel inhibitor of ATX, with anti-fibrotic, immune-enhancing and anti-tumour activity. This first-in-human trial evaluated safety and tolerability, pharmacokinetic (PK)/pharmacodynamic (PD) profile of IOA-289 in combination with GnP. Methods: IOA-289 was investigated, in untreated mPDAC, in a dose escalation study evaluating the continuous twice daily dosing (BID). IOA-289 was initially administered for 7 days as a monotherapy (Cycle 0) before adding GnP at standard doses in 3 weekly schedule followed by 1 week pause (Cycle 1 onwards). Primary objective: Safety and tolerability. Secondary objectives: PK; PD (e.g., plasma LPA and serum CA19-9); radiographic responses (RECIST 1.1); PFS and OS. Results: Cohort 1 assessed the safety at 100 mg BID (n = 4), cohort 2 at 200 mg (n = 4), and cohort 3 at 400 mg (n = 5). Safety assessment shows no treatment-emergent adverse events led to study drug discontinuation, or a dose limiting toxicity. Most toxicities were consistent with the known toxicity profile of GnP. Median time on treatment for cohort 1 was 4.8 months, for cohort 2 and cohort 3 patients are still under treatment and clinical outcomes are not yet established but are projected to surpass the observation from cohort 1. Five patients are currently remain active on treatment No clinical responses were observed in cohort 1. In cohort 2, 2 out of 4 patients (50%) achieved a Partial Response (PR) at cycle 5 and 7 respectively, which was confirmed and durable. No mature data is available yet for later cohorts. Exposure to the compound resulted in reductions in multiple LPA species, with a protocol-defined inhibition of &gt; 50% for over 24 hrs. Consistent reductions in levels of CA19-9 have been observed since cohort 2 (200 mg BID), with &gt; 50% reduction already from cycle 2, with durable reductions lasting longer than 4 months. No mature data is available for later cohorts. Conclusions: IOA-289 is well tolerated at all dose levels in combination with standard GnP. Patients in the higher dose cohorts are experiencing robust CA19-9 reductions consistent with ORR. Occurrence of PRs occurred later than compared to historical controls and were durable, suggesting a differentiated mode of action. Clinical trial information: NCT05586516 .

A phase I/II study of intraperitoneal (IP) paclitaxel (PTX) in patients with metastatic appendiceal adenocarcinoma.

TPS4215 Background: Appendiceal cancer is a rare, orphan disease, that is unfortunately becoming more common. There is growing data from our lab and others that particular subtypes of AA do not respond to CRC chemotherapy. The use of CRC chemotherapy to treat patients with AA tragically results in many patients enduring side effects from chemotherapy that is ineffective; however, this practice will likely continue unless AA-specific treatments are developed. The Shen lab has recently tested IP paclitaxel (PTX) in orthotopic PDX models of AA. After allowing implanted tumors to grow for four weeks to simulate diffuse peritoneal metastases, baseline MRI was performed and mice were randomly assigned to treatment groups of four mice and intraperitoneally (IP) administered increasing doses of PTX. Marked response was seen in all three models at dose of 25 mg/kg IP weekly, with a near complete response in model AAPDX-10. This dose given IP was well tolerated by the mice, notably this dose exceeds the know lethal IV PTX dose. Methods: The Phase I component of this study will be a prospective single-arm intervention trial giving IP PTX every 2 weeks for a total of 5 doses with primary endpoint of safety and tolerability (MTD determination). Each patient will have an initial diagnostic laparoscopy where PCI score will be calculated and IP catheter placed, dx lap is repeated at the end of study after 5 biweekly doses. For the Phase 1 portion of the trial a Bayesian Optimal Interval (BOIN) approach will be used to determine recommended phase 2 dose (RP2D). All patients treated at that dose or higher will be included in Phase 2 component of the study where the primary objective is response, determined by change in PCI score. With 15 patients Based on historical data, we estimate that the proportion of patients who will demonstrate an objective response without going on trial is 0.05, i.e., the null hypothesis is a 0.05 ORR. Treatment is expected to raise this proportion to 30%. Using an exact binomial test with one-sided type I error of 0.05, we will reject the null if at least 3 patients achieve response. This test has power of 87%. Secondary end points include pathologic, biochemical and radiographic response, PFS, OS, and the influence of KRAS/GNAS/TP53 mutation on response. PK measurements will also be performed during the Phase 1 portion of the trial to determine the degree to which the IP injected PTX enters the blood stream. Patients will be followed for up to 1 year. Adverse events (AEs) will be captured and graded using the National Cancer Institute’s (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) v. 5.0 (or latest version) and will include the event term, grading, duration and attribution. Attribution to the study agent or intervention will be determined by the PI, Co-PI or treating physician. Clinical trial information: NCT06207305 . [Table: see text]

State of the Art in Low-Grade Glioma Management: Insights From Isocitrate Dehydrogenase and Beyond.

Low-grade gliomas present a formidable challenge in neuro-oncology because of the challenges imposed by the blood-brain barrier, predilection for the young adult population, and propensity for recurrence. In the past two decades, the systematic examination of genomic alterations in adults and children with primary brain tumors has uncovered profound new insights into the pathogenesis of these tumors, resulting in more accurate tumor classification and prognostication. It also identified several common recurrent genomic alterations that now define specific brain tumor subtypes and have provided a new opportunity for molecularly targeted therapeutic intervention. Adult-type diffuse low-grade gliomas are frequently associated with mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), resulting in production of 2-hydroxyglutarate, an oncometabolite important for tumorigenesis. Recent studies of IDH inhibitors have yielded promising results in patients at early stages of disease with prolonged progression-free survival (PFS) and delayed time to radiation and chemotherapy. Pediatric-type gliomas have high rates of alterations in BRAF, including BRAF V600E point mutations or BRAF-KIAA1549 rearrangements. BRAF inhibitors, often combined with MEK inhibitors, have resulted in radiographic response and improved PFS in these patients. This article reviews emerging approaches to the treatment of low-grade gliomas, including a discussion of targeted therapies and how they integrate with the current treatment modalities of surgical resection, chemotherapy, and radiation.

Responses to immune checkpoint inhibitor therapy in NF1 mutated cutaneous melanoma.

e21535 Background: NF1 mutations occur in 14% of cutaneous melanoma. Less than 20% of advanced melanoma patients on Immune Checkpoint Inhibitor (ICI) therapy achieve radiographic Complete Response (CR). We present data on radiographic responses to ICI therapy in advanced melanoma patients with tumors harboring NF1 (Neurofibromatosis 1) mutations. Methods: Patients with metastatic or unresectable NF1 mutated melanoma were included in the analysis. Mutation status was identified via NGS and mutation pathogenic status was determined using Genome Oncology Software. All patients received ICI therapy. RECIST 1.1 was used to assess treatment responses with CT scans. CR on PET was defined as disappearance of all metabolically active lesions. Results: 26 metastatic or unresectable melanoma patients met criteria for inclusion. Of these, eight (30.8%) had CNS metastasis. ICI therapy included Ipilimumab-Nivolumab, Pembrolizumab, Nivolumab, or Relatlimab-Nivolumab (24/26 in front-line setting). The 12- and 24-month estimated cumulative incidence of CR were 43.9% and 60.6%, respectively. Altogether, 16 patients achieved CR as their best overall response. Four patients that achieved CR subsequently progressed. Four patients progressed without achieving CR. Six patients achieved a partial response by last follow-up without achieving CR or disease progression. Of the 8 patients with CNS metastasis, five (62.5%) had intra-cranial radiographic responses to ICI therapy, including 1 (12.5%) complete response. Five (62.5%) had multifocal ( &gt; 2 sites of intracranial metastasis) intracranial disease. Five (62.5%) of these patients with intracranial disease received radiation, 2/8 (25.0%) received radiation and surgical resection, and one (12.5%) received neither radiation nor surgery. Three (37.5%) patients with CNS metastasis experienced disease progression while on ICI therapy. Conclusions: NF1 mutated melanoma appears to have high rates of radiographic responses to ICI therapy. Prospective validation of this finding, particularly in patients with CNS metastasis, is warranted.

A phase I/II open-label clinical trial of CPI-613 in combination with modified FOLFIRINOX in patients with locally advanced (LAPC) or borderline resectable pancreatic cancer (BRPC).

4172 Background: Pancreatic ductal adenocarcinoma (PDA) carries a poor prognosis with a 5-year relative survival rate of 13%. Surgical resection is the only curative treatment option, but less than 20% of patients are eligible at diagnosis. A subset of patients with locally advanced disease can become candidates for resection with neoadjuvant (NA) therapy. mFOLFIRINOX is the standard of care in the adjuvant setting, with extrapolated data supporting its use in the NA setting. CPI-613/Devimistat (D) is a small molecule that targets mitochondrial metabolism in tumor cells leading to ROS-mediated apoptosis. A phase III trial of mFOLFIRINOX + D at 500 mg/m2 in metastatic PDA did not meet primary endpoint of overall survival (OS). Here we present the results of the combination’s use at standard and escalated doses in LAPC and BRPC. Methods: In this investigator-initiated, single-center, phase I/II, open-label trial treatment-naïve patients with investigator assessed LAPC or BRPC were treated with mFOLFIRINOX in 14 day cycles + D. In the standard dosing (SD) cohort, patients received D at 500mg/m2 while in the dose escalation (DE) cohort; D at 750 mg/m2 or 1000 mg/m2 was used. Radiographic response was assessed every 8 weeks. Patients who remained unresectable after 12 cycles could receive additional standard treatments, including chemoradiotherapy. The primary endpoint was median overall survival (mOS), with the study powered to show a mOS improvement from the historical standard of 14 months to 28 months with mFOLFIRINOX + D. Secondary endpoints were median progression free survival (mPFS), percent resected, and safety outcomes. NCT03699319 Results: Between Dec 2018 and Mar 2022, 37 patients and 11 patients enrolled in the SD and DE cohorts. Median age 69 years (range 47-78), male/female (27/21), Caucasian (83%), LAPC/BRPC (34/14). One patient (2%) withdrew, 4 patients (8%) discontinued treatment due to toxicity, 9 patients (19%) had progressive disease prior to completion of 12 cycles. In all patients mOS was 16.3 months and mPFS was 10.7 months. By cohort: SD/DE mOS: 16.2/17.6 months (p=0.56). Fourteen patients (29%) had partial response by RECIST 1.1. Twenty patients (41.7%) had resection; mOS 29.7 months. In the SD cohort, 78% and 24% of patients had grade 3 and/or 4 AEs. There were no dose limiting toxicities (DLT) in the DE cohort, and eight patients received the maximum dose of 1000 mg/m2 of D. After the DLT period, 100% patients in DE cohort had grade 3 toxicity and 55% had grade 4 toxicity. For all the most common toxicities (gr3,4) were neutropenia (27%,25%), diarrhea (25%,0), anorexia wt. loss (23%,0), nausea/vomiting (23%,0). Conclusions: The combination of mFOLFIRINOX and D is feasible in the LAPC/BRPC population at increased dose levels of D; however, it did not meet the primary endpoint of doubling OS compared to historical controls. Clinical trial information: NCT03699319 .

A phase 2 study of amivantamab plus lazertinib in patients with EGFR-mutant lung cancer and active central nervous system disease.

8517 Background: Patients (pts) with EGFR-mutant lung cancer (EGFR+LC) with active brain metastases (BrM) or leptomeningeal disease (LM) are often excluded from clinical trials. Despite central nervous system (CNS) disease control with osimertinib, &gt; 50% of pts with EGFR-mutant lung cancer have involvement of the brain (BrM) or leptomeninges (LM). Amivantamab and lazertinib have demonstrated systemic activity in pts with EGFR-mutant lung cancer whose disease progressed after osimertinib and/or platinum-based chemotherapy. This trial evaluated amivantamab +lazertinib in the setting of progressive CNS metastases (NCT04965090). Methods: We evaluated amivantamab and lazertinib in 2 cohorts: pts with 1) progressive or new BrM or 2) LM. All pts with EGFR exon 19 del/L858R/atypical mutations had prior osimertinib. All pts with EGFRexon 20 insertions (ex20ins) had prior chemotherapy. Each cohort was to enroll 20 pts powered to differentiate overall response rate (ORR) of 0.05 vs 0.25. Positive CSF assessment (cytology or circulating tumor cells (CTC)) +/- BrM allocated a pt to the LM cohort. Pts received standard dosing of amivantamab and lazertinib 240 mg daily. Co-primary endpoints were systemic ORR by RECIST v1.1 and CNS ORR by RANO-BM or LM. Paired pre-treatment tumor, blood, and CSF samples had targeted DNA sequencing and cell-free RNA (cfRNA) sequencing. Results: Trial enrolled 20 pts in BrM cohort and 22 pts in LM cohort. Median age 55 (range 31-80), 69% women,. 40% had L858R (n = 17), 40% del19 (n = 17), 12% ex20 ins (n = 5), and 8% atypical EGFR mutations (n = 3). Median lines of prior therapy: 2 (1-7). Except patients with ex20ins, all patients had prior osimertinib, and 55% had chemo. Efficacy Data: . 14 LM pts (64%) had decrease in CSF CTCs and 7 (32%) had improvement in neurologic symptoms. Most frequent treatment-related adverse events (TRAEs) (≥30% in overall population) were rash (71%), infusion-related reaction (59%), paronychia (43%), fatigue (40%), edema (40%), mucositis (33%), and nausea (33%). Most frequent (≥5%) grade ≥3 TRAEs were infusion related reactions (7%), thromboembolic event (5%), elevated AST/ALT (5%), and rash (5%). Three pts (7%) discontinued treatment due to TRAEs. Genomic data comparing concurrent systemic tumor, plasma and CSF samples, and ctDNA and cfRNA dynamics will be presented. Conclusions: The combination of amivantamab+lazertinib is a promising treatment for pts with EGFR-mutant lung cancer and active CNS disease, with clinically meaningful time on treatment and radiographic response. This is the first clinical trial successfully completed in pts with EGFR-mutant lung cancer and progressive CNS metastases. Clinical trial information: NCT04965090 .[Table: see text]

A biomarker-directed, multi-center phase II/III study of ctDNA molecular response adaptive immuno-chemotherapy in patients with non-small cell lung cancer.

TPS8669 Background: Liquid biopsy analyses of circulating cell-free tumor DNA (ctDNA) have shown promise as an early endpoint of immunotherapy response, allowing patients with primary resistance to be rapidly and accurately identified. BR.36 is a ctDNA-directed, phase II/III trial of molecular response-adaptive immuno-chemotherapy; in the first of two independent stages, the BR.36 trial met its primary endpoint, with a sensitivity of ctDNA response for radiographic RECIST response of 82% and a specificity of 75%, while demonstrating a median time to ctDNA response of 2.1 months. Additionally, patients with ctDNA molecular response attained longer progression-free (PFS) and overall survival (OS). Methods: The second stage of BR.36 is a multi-center, biomarker-directed, phase II/III clinical trial of ctDNA molecular response adaptive immuno-chemotherapy in patients with immunotherapy and chemotherapy-naïve metastatic NSCLC. The main objective is to evaluate if adding chemotherapy to pembrolizumab for patients who have persistent ctDNA on liquid biopsy drawn after 6 weeks of treatment will result in better PFS and OS compared to patients who remain on pembrolizumab until clinical progression. Key eligibility criteria include: age ≥18 years, ECOG performance status 0-2, metastatic NSCLC, EGFR and ALK mutation negative and PD-L1 Tumor Proportion Score (TPS) ≥ 50%, at least and not more than 2 cycles of the 200 mg or 2 mg/kg IV Q3W of pembrolizumab as first line systemic immunotherapy at the time of screening and RECIST non-PD or clinically stable PD documented prior to enrolment that can continue on immunotherapy. The phase II primary endpoint is PFS and has secondary endpoints of feasibility, overall response rate and safety/tolerability. Sex, RECIST response and ECOG status represent stratification criteria. With 110 randomized patients evaluable for progression (55 patients per arm and 71 PFS events observed in this phase), we would be able to detect a hazard ratio difference of 0.67 with a 1-sided alpha of 0.2 and power of 0.80 using a phase II screening design. The trial will not stop accrual for the phase II analysis of PFS if feasibility endpoints are achieved. In the phase III portion, a total of 210 randomized patients recruited over 3 years and followed for an additional 24 months are required to detect an OS hazard ratio difference of 0.67 with 1-sided alpha of 0.05 and power of 0.8. The total number of events for the final analysis is 156, and assuming 10% of patients are lost to follow-up, we are targeting 230 patients to be included overall. The primary endpoint of the phase III portion is OS, with secondary endpoints of best overall response, response duration, PFS and safety/tolerability. Exploratory endpoints include longitudinal ctDNA analyses. The BR.36 clinical trial is open to enrollment (ClinicalTrials.gov ID: NCT04093167). Clinical trial information: NCT04093167 .

Paclitaxel and cisplatin/carboplatin plus tislelizumab in young patients with cervical cancer preserve fertility: Phase II prospective, single arm clinical study.

e17513 Background: Cervical function damage after fertility-sparing surgery has a lower pregnancy success rate. Chemotherapy (chemo) mainly plays an auxiliary role in the treatment of cervical cancer (CC), but its efficacy is limited. Recently, immunotherapy has shown remarkable progress in treatment of CC, potentially provide new treatment options for pts of childbearing age who require preservation of fertility. Herein, we conducted this study to evaluate the efficacy and safety of chemo plus tislelizumab (TIS) in young pts with CC who required fertility preservation. Methods: In this single arm, phase II trial, pts with histologically confirmed invasive, FIGO2018 stage IB1-IB3 or IIIC1r (localized cervical lesions) CC, and having fertility needs were enrolled. Eligible pts received 4 cycles chemo (175 mg/m2 paclitaxel + 70 mg/m2 cisplatin/AUC 5-6 carboplatin, Q3W) + TIS (200 mg, Q3W), followed by surgery-diagnostic cervical conization and sentinel lymph node (SLN) biopsy (IIIC1r stage with pelvic lymph node [PLN] systematic dissection)-upon achieving a radiographic complete response (CR). After surgery, pts will undergo 2-cycle chemo plus TIS therapy, if PLNs achieve a pathological complete response (pCR), regardless of the pCR status of localized cervical lesion. If the first cervical conization did not result in a pCR for localized cervical lesion only, a second conization was performed after 2-cycle chemo + TIS. Upon achieving pCR in both the cervical local disease and PLN, maintenance therapy (MT) with TIS will be continued for 1 year. Primary endpoint is pCR (SLN/PLNs + cervical conization) after surgery. The key secondary endpoints included clinical response to 4 cycles chemo + TIS, pregnancy rate, fertility rate, and treatment-emergent adverse events (TEAEs). Results: Between March 2022 and January 2024, 7 pts (mean age 31 years, range 27-38) were enrolled, with 2 pts (28.6%) having stage IIIC1r disease. All 7 pts received chemo plus TIS therapy; of these, 5 (71.4%) pts completed 4 cycles The objective response was achieved in 5 pts, with all complete response. Amenorrhea was observed in 3 of 5 pts (60%), with 2 recovering normal menstruation after chemo cessation, and 1 had finished the last chemo+TIS for 3 weeks and had not yet returned. During 4 cycles chemo + TIS therapy (n=7), the most common TEAEs of any grade were rash (71.4%), alanine aminotransferase increased (57.1%), neutrophil count decreased (57.1%), and white blood cell count decreased (57.1%). At data cutoff (median follow-up, 9 months, range 3.5-17), 1 pt experienced disease progression during MT, and 1 pt got pregnancy 3 months after completed MT. Conclusions: Chemo plus TIS could mediate tumor regression and eliminate micro-metastases with a tolerable safety profile, potentially allowing for fertility preservation in many pts for which this was not thought to be an option. Clinical trial information: ChiCTR2300067495.

Use of baseline and serial ctDNA dynamics to predict outcomes in patients treated with first-line tebentafusp, including those who were and were not treated beyond progression.

9536 Background: Tebentafusp (tebe), a bispecific soluble T cell receptor specific for a gp100 peptide, is licensed for the treatment of metastatic uveal melanoma (mUM) in HLA-A*02:01+ individuals. As part of the pivotal, Phase 3 IMCgp100-202 study, 378 mUM pts were randomized to receive tebe or investigators choice. Approximately 60% of patients (pts) with metastatic UM in the IMCgp100-202 study had detectable baseline ctDNA. We have reported the strong relationship between change in ctDNA at 9 weeks (wks) and overall survival (OS). Additionally, radiographic treatment response is a poor predictor of who is benefitting from therapy. We hypothesized that ctDNA dynamics would help identify those patients (pts) who benefit from treatment beyond progression (TBP). Methods: Sera (n=202 pts) collected at baseline and wk 9 on tebe were analyzed for ctDNA using a targeted mPCR-NGS assay for 15 genes including GNAQ, GNA11, SF3B1, PLBC4, EIF1AX, and CYSLTR2. RECISTv1.1 was assessed by investigators; TBP was allowed per protocol. OS was analyzed in subsets of pts who were not TBP, and those who were TBP and treated with tebe for &lt; or &gt; 16 wks; the approximate time point where TBP pts would have had confirmatory imaging, although confirmatory scan data is not available. At baseline, pts were determined to be ctDNA detectable or undetectable. At wk 9, pts were determined to have cleared ctDNA, &lt; or ≥ 68% (0.5 log-fold) reduction, &lt; or ≥ 50% reduction. Data cut-off was July 2023. Results: Of 202 pts randomized to tebe and with ctDNA at baseline and wk 9, 126 (62%) received TBP (80 &lt;16 wks, 46 ≥ 16 wks). Undetectable ctDNA at baseline was associated with improved OS regardless of TBP, while TBP was associated with improved OS in those with baseline detectable ctDNA (hazard ratio, HR, 0.59, 95% confidence interval, CI, 0.4-0.88). Subgroup analysis of those with baseline detectable ctDNA demonstrated improved OS in only those who received TBP for ≥ 16 wks (HR 0.33; 95% CI 0.21-0.51). Clearance of ctDNA at wk 9 was associated with better OS than in those who did not have clearance. TBP was associated with better OS in pts who did not have clearance (HR 0.48, 95% CI 0.30-0.79), but not in those with clearance (HR 0.87, 95% CI 0.43-1.78). Finally, TBP was associated with improved outcomes in pts with ≥50% and ≥68% reduction, compared to those without reduction, HR 0.63 (95% CI 0.4-0.97) and 0.62 (95% CI 0.39-0.99), respectively. Conclusions: Baseline and wk 9 ctDNA detection predicts OS in mUM pts treated with first line tebe. The utility of ctDNA predicting pts most likely to benefit from TBP is less clear, although TBP seems to be more beneficial in those with reduction of ctDNA at wk 9. Optimization of time points, assay, and integration of ctDNA data with radiomics are necessary to understand the true utility of ctDNA in helping select which pts should receive TBP. Clinical trial information: NCT03070392 .

The role of neoadjuvant clinical trials in patients with newly diagnosed glioblastoma.

e14022 Background: Novel cytotoxic drugs are commonly first studied in patients with solid tumors who have recurrent disease. If high response rates and durable remissions are observed, further studies are conducted in previously untreated cancers where the novel agent can be combined with radiation or administered as neoadjuvant therapy (NAT) to reduce tumor size before surgery or radiation and to limit systemic dissemination. While NAT can provide critical information on response rates and survival in previously untreated patients, it can add toxicities and delay the administration of standard therapies. Neoadjuvant chemotherapy is now standard-of-care in many systemic cancers but is rarely considered in patients with glioblastoma (GBM). This literature review was conducted to describe factors leading to NAT playing an increasingly important role in systemic cancers and a diminishing role in patients with GBM. Methods: Prospective trials published between 1980 and 2023 where patients with newly diagnosed systemic cancers and GBM received NAT prior to radiation were identified in PubMed. Results: During these 43 years, over 5,000 NAT trials in patients with systemic cancers were published. As a result of these studies, NAT is now considered standard therapy for 28 different cancers. In contrast, during the same years only 51 prospective studies were reported evaluating the efficacy of NAT in newly diagnosed GBM. These clinical trials accrued a total of 2,047 patients and evaluated the efficacy of nitrosoureas, temozolomide, platinum-based agents, and targeted therapies. These studies peaked before 2005, when combining temozolomide and radiation was shown to improve survival, and declined thereafter. NAT temozolomide was studied in 12 trials (641 patients) resulting in a median response rate of 35% (range 8.7-51%) and a median overall survival of 12.5 (range 6-22) months. NAT trials in patients with GBM were not associated with unexpected toxicities, major reductions in survival, or poor patient accrual. Conclusions: As in other solid tumors, NAT in patients with GBM is relatively safe and feasible. Enthusiasm for this approach has been limited by the paucity of active agents in recurrent glioblastoma that could be subsequently evaluated in newly diagnosed patients. However, the neoadjuvant setting is ideally suited to rapidly screening novel cytotoxic agents for efficacy as it allows: 1) radiographic response rates in previously untreated patients to be the primary endpoint, 2) small sample sizes, and 3) efficacy results in 2-3 months when patients are transitioned to standard care. Given the well documented safety and feasibility history of using NAT in patients with solid tumors and GBM, this approach has the ability to rapidly identify potentially active, novel cytotoxic agents, especially in patients with MGMT unmethylated, IDH wildtype GBM who are unlikely to benefit from temozolomide.

A phase 1/2 study to investigate the safety and efficacy of OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy in patients (pts) with advanced solid tumors.

TPS9599 Background: Immune checkpoint inhibitors (ICI) have improved outcomes for pts with solid tumor malignancies; however, most pts relapse and treatment options are limited. Unengineered TIL cell therapy has shown promising efficacy in pts with ICI-resistant melanoma (1,2) and non-small cell lung cancer ([NSCLC] 3,4), but requires co-administration of systemic high-dose IL2, which is associated with safety risks and limits pt eligibility. OBX-115 TIL are engineered to express membrane-bound IL15 (mbIL15) under dose-dependent regulation using acetazolamide (ACZ), an FDA-approved small-molecule diuretic, avoiding the need for high-dose IL2. A first-in-human single-institution study (NCT05470283) evaluating the safety of OBX-115 in metastatic melanoma is ongoing. The current study (NCT06060613) is enrolling pts with solid tumors at multiple US sites using centralized manufacturing. Methods: This phase 1/2, single-arm, open-label, nonrandomized, multicenter study will assess the safety, tolerability, and efficacy of the OBX-115 engineered autologous TIL cell therapy regimen in pts with histologically confirmed unresectable Stage IIIC, IIID, or Stage IV metastatic melanoma (excluding uveal) with documented radiographic progression after systemic therapy containing an anti–PD‐1/PD-L1 agent (if adjuvant, progression during or within 12 wks after the last dose) and received a BRAF inhibitor ± MEK inhibitor if BRAF V600 mutation-positive OR metastatic NSCLC previously treated with an approved systemic therapy for metastatic disease (including an ICI-based regimen and/or targeted therapy where applicable) and progressed, no longer deriving benefit, or unable to continue due to treatment intolerance. Pts must have ECOG PS of 0 or 1 and life expectancy &gt;~6 months. Pts must have ≥1 lesion suitable for OBX-115 manufacturing (≥1.5 cm) and ≥1 RECIST v1.1-measurable lesion remaining after tumor tissue procurement. Primary objectives of Phase 1 are to characterize safety and tolerability and identify a recommended Phase 2 dose of OBX-115 + ACZ; Phase 2 will evaluate efficacy of the regimen (ORR using RECIST v1.1 per investigator). Cryopreserved OBX-115 is generated from the pt’s own tumor tissue procured by surgical excision or core needle biopsy, and is infused after standard- (5 days) or low-dose (4 days) lymphodepletion (cyclophosphamide and fludarabine), based on clinical status. ACZ is administered at cohort-defined doses once daily for up to 10 days starting day of OBX-115 infusion, with optional ACZ redosing at Wk 6–8 for up to 10 days in pts with suboptimal radiographic response. No systemic high-dose IL2 is administered. Two sites are open and recruiting, with additional sites being activated. 1. Rohaan NEJM 2022. 2. Chesney JITC 2022. 3. Creelan Nat Med 2021; Schoenfeld SITC 2021. Clinical trial information: NCT06060613 .

Lutetium-177–PSMA-617 experience in Appalachian patients with advanced prostate cancer at West Virginia University Health Science Center.

e17045 Background: Lutetium Lu-177 vipivotide tetraxetan (Lu-177) allowed for improved biochemical and radiographic response rate with relatively low toxicity for metastatic castration-resistant prostate cancer (PC) after multiple lines of therapy. In the 2021 VISION study (DOI: 10.1056/NEJMoa2107322), Lu-177 was reported to have a median overall survival (OS) of 15.3 months in patients (pts) with advanced prostate cancer (PC). We reviewed the result with Lu-177 for the treatment of advanced PC at a rural tertiary academic center at West Virginia University Health Science Center (WVU-HSC). Methods: All PC pts receiving one or more doses of Lu-177 at WVU-HSC were retrospectively reviewed. Pts were followed until death or the last clinic visit. All pts were established patients at WVU-HSC for management of the advanced PC between July 2022 and February 2024. Data was tabulated with descriptive statistics and median survival was calculated from Kaplan-Meier method. Results: Over an eighteen months period 34 pts received 126 doses of Lu-177. 26 pts were referred from outside the WVU-HSC specifically for Lu-177. Demographics from data collection showed predominantly Caucasian pts (91% Caucasian). The time from the initial PC diagnosis to the first dose of Lu-177 was a median of 67 months (range: 10 months-367 months). The median age at the first dose of Lu-177 was 65 years (range: 45-80). 18 patients (53%) remain alive as of Feb 2024. 14 pts (41%) completed 6 cycles of Lu-177 and 11 pts (32%) remain alive. The Kaplan-Meier median OS for these 34 pts starting from the first cycle of Lu-177 was 10 months. Conclusions: A 2022 estimated cost for Lu-177 was $42,500 per dose (excludes administration) so “payors” may have been charged more than $5,000,000 for the Lu-177 for these patients. Lu-177 may be of more benefit earlier in the PC disease spectrum, or perhaps pre-treatment PSMA imaging can better target patients who will benefit from Lu-177. Our observed median OS of 10 months did not match the 15.3 reported in the VISION study (DOI: 10.1056/NEJMoa2107322). Further data evaluation and collection are warranted from different communities to investigate the differences observed in the survival data reported in the literature and observed in the clinic setting. [Table: see text]