Citations

4591 Background: EV-302 and CheckMate 901 demonstrated significant survival benefit with enfortumab vedotin-pembrolizumab (EVPembro) and gemcitabine-cisplatin-nivolumab (GemCisNivo) as 1L therapy, respectively, in patients (pts) with la/mUC. However, whether these treatments are cost-effective or not remains unclear. Methods: A three-state Markov model (progression-free, progression and death) was developed. State utilities were derived from published literature. State transition probabilities were informed from point-probabilities and hazard ratios for OS and PFS obtained from the latest follow-up of eligible trials. Average sales price (2024 USD) for individual treatments (excluding ancillary charges) were obtained from the center of medicare and medicaid services (US payer’s perspective). Treatment strategies were modeled in accordance with the dose/schedule reported in the eligible trials. Pts who received GemCis or Gem-carboplatin (GemCarbo) and did not progress were modeled to receive Avelumab maintenance. Half-cycle corrected costs and utilities were accrued over a 10-year lifetime horizon and were discounted at 3%. Monte Carlo simulation was used to estimate quality adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). A willingness-to-pay threshold (WTP) of 100,000$ per QALY was used. Results: In cisplatin-eligible pts, GemCisNivo demonstrated a 0.8 QALY gain over GemCis at an ICER of 21,127 ($/QALY). GemCisNivo was also associated with an incremental net monetary benefit (INMB) of 63,099$ relative to GemCis. EVPembro demonstrated a 2.4 QALY gain over GemCis at an ICER of 915,283 and a 1.6 QALY gain over GemCisNivo at an ICER of 1,406,308. In cisplatin-ineligible pts, EVPembro demonstrated a 2.4 QALY gain over Gem-carboplatin (GemCarbo) at an ICER of 934,761. Price threshold analyses demonstrated that EVPembro is likely to be cost-effective at a cost of 12,344$ for cisplatin-eligible and 13,374$ per cycle for cisplatin-ineligible pts (original cost: 35,665.60$ per cycle). Sensitivity analysis using a total of 12 cycles for EVPembro showed cost-effectiveness at an ICER of 69,594 relative to GemCisNivo in cisplatin-eligible pts, and at an ICER of 53,099 relative to GemCarbo in cisplatin-ineligible pts. Conclusions: In terms of US payer’s perspective, GemCisNivo is most likely to be cost-effective in cisplatin-eligible pts at the WTP of 100,000 $/QALY. Limiting the number of cycles for EVPembro may render it as a cost-effective 1L treatment in la/mUC pts regardless of cisplatin-eligibility status.

Objective Peripheral nerve stimulation (PNS) is an emerging neuromodulation modality, yet there remains limited data highlighting its long-term effectiveness. The objective of this study was to report real-world data on pain intensity and opioid consumption after temporary and permanent PNS for chronic pain up to 24 months postimplantation. Methods A retrospective study was conducted on all patients who received PNS implants at a multi-centered enterprise between January 1, 2014 and February 24, 2022. The two co-primary outcomes were: (1) change in pain intensity (11-point Numerical Rating Scale) from baseline to 12 months postimplant; and (2) comparison of the change in pain intensity between temporary and permanent PNS cohorts 12 months postimplant. Results 126 patients were included in this analysis. Pain intensity significantly decreased 12 months postimplant in the overall cohort (mean difference (MD) −3.0 (95% CI −3.5 to −2.4), p<0.0001). No significant difference in this reduction was identified between temporary and permanent PNS cohorts (MD 0.0 (95% CI −1.1 to 1.0), p=1.00) 12 months postimplantation. Pain intensity significantly decreased in the overall, temporary, and permanent cohorts at all secondary time points (3, 6, and 24 months). No change in daily opioid consumption was observed at 6 and 12 months postimplant in the overall cohort. Conclusion This study found that both temporary and permanent PNS may be effective for reducing pain intensity in patients with chronic pain up to 24 months postimplantation, although no changes in opioid consumption were observed. The decrease in pain intensity was comparable between patients receiving temporary versus permanent implants, highlighting that temporary PNS may achieve long-lasting clinical benefits. However, given the substantial loss to follow-up, further large-scale studies are needed to solidify conclusions about the efficacy of PNS.

4574 Background: Mutations of COMPASS-related proteins KMT2D, KMT2C, and KDM6A are observed in 66% of advanced urothelial carcinomas (UC). In vivo, the administration of tazemetostat, an enzymatic EZH2 inhibitor (EZH2i), reduced tumor burden and enhanced the immune response in animal models of UC. We hypothesized that tazemetostat might improve response to immunotherapy in advanced UC. Methods: ETCTN 10183 (NCT03854474) is a multicenter pilot study evaluating the safety and efficacy of tazemetostat 800 mg BID+ pembrolizumab 200 mg given every three weeks for up to two years in patients (pts) with platinum-refractory (Arm A) or cisplatin/chemo-ineligible advanced UC (Arm B). The primary objective was to identify the recommended phase two dose (RP2D) of tazemetostat in combination with pembrolizumab. Secondary objectives included safety, response rate, and progression-free survival. Translational objectives included determining tumor mutational burden in COMPASS-related genes, tumor subtyping, TCR clonality, T cell infiltration, and PDL-1 expression. Results: There were no dose-limiting toxicities in the safety lead-in phase (n=6 pts), and the RP2D for tazemetostat was established at 800 mg BID. Baseline characteristics for Arm A N=12, Arm B N=13: 72% males; 96% white, 4% Black; 88% ECOG PS 0-1; 88% had bladder primary, 20% Stage III, 72% stage IV; 80% had visceral or bone metastases. The median number of cycles was 5 in Arm A (range 1-35) and 4 in Arm B (range 2-12). Treatment related G3/4 adverse events (AEs) were observed in 8 patients, most common were anemia and lymphopenia (n=2 each). Treatment related G1/2 AEs included nausea (n=6); skin and subcutaneous tissue disorders (n=3); anemia, lymphopenia, and thrombocytopenia (n=2 each). Among evaluable patients (n=10 in each arm), partial response rate was: Arm A 30%, Arm B 20%; stable disease: Arm A 30%, Arm B 30%; and progressive disease: Arm A 30%, Arm B 20%. 8 pts were on study treatment for ≥ 9 cycles (5 in Arm A, 3 in Arm B). All pts are off protocol treatment. Median progression-free survival was 3.06 (95% CI: 1.38-7.75) months for Arm A and 3.02 (95%CI: 2.4-5.65) for Arm B. Conclusions: Tazemetostat 800 mg BID and pembrolizumab combination is feasible and well-tolerated in patients with advanced UC. In this pilot study, improvement in efficacy relative to historical controls of pembrolizumab alone appears to be modest. Response in tumors with COMPASS-related mutations and EZH2 activity will be evaluated. Clinical trial information: NCT03854474 .

Background The efficacy of spinal cord stimulation (SCS) in chronic pain studies is traditionally assessed by pain scores, which do not reflect the multidimensional nature of pain perception. Despite the evidence of SCS’s influence on emotional functioning comprehensive assessments of its effect remain lacking. Objective To assess changes in emotional and psychosocial functioning in patients who underwent SCS implantation for chronic pain. Evidence review Ovid MEDLINE, EMBASE, PsychINFO, Cochrane CENTRAL and Scopus databases were searched for original peer-reviewed publications reporting emotional functioning after SCS. The primary outcomes were a pooled mean difference (MD) in anxiety, depression, global functioning, mental well-being and pain catastrophizing at 12 months. The Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) was used to determine the quality of evidence. Findings Thirty-two studies were included in the primary analysis. Statistically significant improvements were observed in anxiety (MD −2.16; 95% CI −2.84 to −1.49; p<0.001), depression (MD −4.66; 95% CI −6.26 to −3.06; p<0.001), global functioning (MD 20.30; 95% CI 14.69 to 25.90; p<0.001), mental well-being (MD 4.95; 95% CI 3.60 to 6.31; p<0.001), and pain catastrophizing (MD −12.09; 95% CI −14.94 to −9.23; p<0.001). Subgroup analyses revealed differences in Global Assessment of Functioning and mental well-being based on study design and in depression based on waveform paradigm. Conclusion The results highlight the statistically and clinically significant improvements in emotional and psychosocial outcomes in patients with chronic pain undergoing SCS therapy. However, these results need to be interpreted with caution due to the very low certainty of evidence per the GRADE criteria. PROSPERO registration CRD42023446326.

Abstract Introduction An unusual association between thyroid dysfunction and autoimmune encephalitis (AE) was noticed when patients presented with low free triiodothyronine (fT3) levels and antithyroid antibodies. We conducted a meta‐analysis to investigate whether thyroid dysfunction, that is, lower fT3 levels are associated with worsening clinical manifestations and prognosis in patients with AE. Methods Literature search of five electronic databases was performed till April 5, 2023. Inclusion criteria were as follows: Observational studies reporting patients with all subtypes of AE and assessing thyroid dysfunction categorized as low fT3 and non‐low fT3. Primary endpoints included modified Rankin scale (mRS) at admission, abnormal magnetic resonance imaging, length of stay, seizures, and consciousness declination. Results Comprehensive literature search resulted in 5127 studies. After duplicate removal and full‐text screening, six observational studies were included in this analysis. Patients with low fT3 were 2.95 times more likely to experience consciousness declination ( p = .0003), had higher mRS at admission ( p < .00001), had 3.14 times increased chances of having a tumor ( p = .003), were 3.88 times more likely to experience central hypoventilation, and were 2.36 times more likely to have positivity for antithyroid antibodies ( p = .009) as compared to patients with non‐low fT3. Conclusion The findings of our study suggest that low fT3 levels might be related to a more severe disease state, implying the significance of thyroid hormones in AE pathogenesis. This finding is crucial in not only improving the early diagnosis of severe AE but also in the efficient management of the disease.

e18073 Background: Selpercatinib is a highly selective RET inhibitor that is used for the treatment of RET-mutant medullary thyroid cancers, but its efficacy and safety is not fully understood. Our objective is to summarize available literature on the safety and efficacy profile of Selpercatinib. Methods: A search was conducted on PubMed, Embase and Cochrane from foundation to 31st January 2024. Patients aged above 18 with Advanced RET-Altered Medullary Thyroid Cancers who received Selpercatinib were identified. Data abstraction was done based on objective response rate, complete response rate, any grade adverse effect (AE) and grade ≥3 AE. Analysis was done using R (v.4.3) and reported as proportions with respective 95% confidence intervals (CI) on forest plots. Results: Four studies were identified that reported the use of Selpercatinib in Advanced RET-Altered Medullary Thyroid Cancers. Our analysis showed that the pooled proportion of objective response rate and complete response rate was 74.8% (95% CI: 70.1% – 79%) and 4.9% (95% CI: 3.1% – 7.7%) respectively. Pooled proportion of patients experiencing any grade AE and grade ≥3 AE was 93.4% (95% CI: 90.4% – 95.6%) and 46.2% (95% CI: 41.1% – 51.3%) respectively. Conclusions: Selpercatinib is a novel RET inhibitor which has potential use against RET-Altered Thyroid Cancers. It has an overall acceptable safety and efficacy profile. However it requires further studies to establish its adverse effects and clinical application. [Table: see text]

TPS5125 Background: B7-H3 is a member of the B7 superfamily, which includes PD-L1 (B7-H1) and PD-L2 (B7-DC). Enoblituzumab is a humanized Fc-optimized B7-H3–targeting antibody that induces antibody-dependent cellular cytotoxicity (ADCC). A recent investigator-initiated trial demonstrated that enoblituzumab therapy, used in the neoadjuvant prostate cancer setting, is feasible, safe, may enhance short-term clinical outcomes, and appears to stimulate intratumoral immune activation including CD8+ T cell infiltration and peripheral expansion of tumor-infiltrating T-cell clones that correlated with undetectable PSA at 1-year post-prostatectomy. To assess the impact of enoblituzumab on recurrence-free survival following prostatectomy, a phase 2, randomized, neoadjuvant clinical trial in high-risk localized prostate cancer patients has been started. We hypothesize that targeting B7-H3 with enoblituzumab will delay or prevent recurrence following prostatectomy compared to standard of care (SOC) . Methods: The HEAT trial is an investigator-initiated, multi-center, randomized, phase 2 study that is presently enrolling (NCT06014255). Eligible patients will undergo a pre-treatment prostate biopsy and conventional imaging (CT and bone scan) as well as PSMA-PET. Patients who have clinical stage cT1c-T3b, cN0 cM0 disease by conventional imaging (N1 by PSMA allowed with up to 3 LNs each ≤1 cm) will be eligible as long as concurrent hormonal or radiation therapy is not given. Prostate biopsy, within 3 months of enrollment, needs to show at least 3 positive cores containing at least 1 core with at least 50% disease involvement with Gleason ≥4+3=7 disease (with at least 1 additional high-risk feature such as PSA>20 ng/ml or cT3) or a Gleason sum ≥8. Patients will receive enoblituzumab at a dose of 15mg/kg IV biweekly for 6 doses (12 weeks) on the treatment arm, followed by prostatectomy, or will be scheduled for prostatectomy directly within 4-8 weeks on the SOC arm. 219 patients will be randomized (2:1) to treatment versus SOC. Pre-treatment, on-treatment, and post-treatment biomarkers of response and resistance will be collected. Patients will be followed according to standard institutional practices, but will require PSA evaluations every 3 (±1) months during year 1 and every 6 (±2) months during years 2-5. In both arms, salvage or adjuvant therapy will occur after biochemical or radiographic progression. The primary endpoint is recurrence-free survival (RFS) defined as any metastasis events, local pelvic visceral or lymph node recurrence, detectable prostate-specific antigen (PSA), or start of subsequent local or systemic therapy (including salvage or adjuvant therapy), or death for any cause, whichever occurs first. Secondary endpoints include additional clinical and immunologic correlates. Clinical trial information: NCT06014255 .

e16619 Background: Should patients (pts) with MIBC receive aIO given the DFS benefit seen in AMBASSADOR and CheckMate 274 trials is an important clinical question. Thus, we aimed to quantify the magnitude of absolute benefit across different subgroups to aid clinicians in shared decision-making with their patients. Methods: Phase III trials evaluating aIO as compared to observation or placebo (obs/plac) in pts with MIBC were considered eligible. Outcomes of interest included DFS and OS. Pre-specified subgroups included disease location, PDL1 status, neoadjuvant chemotherapy (NAC) receipt, and tumor and nodal (TN) staging. Pairwise comparisons were made using a DerSimonian-Lairds (DL) random-effects meta-analysis. Stratified baseline risks (obtained from clinical trials) and relative effect estimates were used to estimate corresponding intervention risks (CIRs). The difference in CIRs and baseline risk was calculated to present absolute risk differences (ARDs) in each subgroup category. Results: Analysis included three trials with 2220 pts (pembrolizumab, nivolumab, and atezolizumab assessed in each). No significant difference was observed in OS with aIO compared to obs/plac (hazard ratio: 0.91; 0.76-1.09). However, aIO significantly improved DFS compared to obs/plac (0.76; 0.64-0.91) in the overall population. In pts with bladder/lower tract disease, aIO improved DFS compared to obs/plac (0.72; 0.56-0.92); however, no significant difference was observed in DFS in pts with upper tract disease. There was a statistically significant effect modification by disease location (p: 0.01). Adjuvant IO significantly improved DFS in PDL1- (0.78; 0.64-0.94) but not in PDL1+ pts (0.75; 0.52-1.08). Likewise, aIO significantly improved DFS in pts who received NAC (0.69; 0.53-0.90) but not in pts who did not receive NAC (0.89; 0.75-1.05). In terms of TN staging, aIO improved DFS in T2-3N0 (0.73; 0.57-0.94), T4N0 (0.76; 0.61-0.95), and in T2-4N1 patients (0.75; 0.59-0.95). No statistically significant modifications were observed among these subgroups. Stratified ARDs for DFS by each subgroup are outlined (Table). Conclusions: When delayed disease progression is a vital consideration, a risk-adapted strategy for the optimal patient selection to receive aIO should be considered. Disease location (lower tract/bladder), node positivity, and receipt of NAC emerged as groups likely to derive greater benefit with aIO. [Table: see text]

e16531 Background: Hypoxia-inducible Factor-2α (HIF-2α) is a transcription factor that accumulates in clear cell renal cell carcinoma (ccRCC) and is responsible for genes involved in oncogenesis. Belzutifan is a HIF-2α inhibitor that has shown promising anti-tumor effects in patients with ccRCC. Our objective is to summarize the available literature on the safety and efficacy profile of the drug. Methods: An electronic search was conducted on PubMed, Embase, and Cochrane from inception till January 31st, 2024. We identified patients aged ≥ 18 years with ccRCC who received Belzutifan. We extracted data on objective response rate, complete response rate, any grade adverse effect (AE) and grade ≥3 AE. Data was analyzed using R (v.4.3) and reported as proportions with respective 95% confidence intervals (CI) on forest plots. Results: Three studies (n=168 patients) were identified that reported the use of Belzutifan in ccRCC. Our analysis showed that pooled proportion of objective response rate and complete response rate was 35% (95% CI: 24% – 47%) and 1% (95% CI: 0% – 5%) respectively. Pooled proportion of patients experiencing any grade AE and grade ≥3 AE was 98% (95% CI: 95% – 99%) and 49% (95% CI: 29% – 69%) respectively. Conclusions: Belzutifan is a novel drug that inhibits HIF-2α which in turn results in anti-tumor effects of the drug against ccRCC. The drug has an acceptable safety and efficacy profile from limited data but more studies are needed to establish a complete picture of drug’s adverse effects and clinical benefits. Pooled proportion of patients developing (A) Objective Response, (B) Complete response (C) Any adverse effect and (D) Grade ≥3 adverse effects. [Table: see text]

Abstract Neuroblastoma is an embryonic cancer that contributes disproportionately to death in young children. Sequencing data have uncovered few recurrently mutated genes in this cancer, although epigenetic pathways have been implicated in disease pathogenesis. We used an expression-based computational screen that examined the impact of deubiquitinating enzymes on patient survival to identify potential new targets. We identified the histone H2B deubiquitinating enzyme USP44 as the enzyme with the greatest impact on survival in patients with neuroblastoma. High levels of USP44 significantly correlate with metastatic disease, unfavorable histology, advanced patient age, and MYCN amplification. The subset of patients with tumors expressing high levels of USP44 had significantly worse survival, including those with tumors lacking MYCN amplification. We showed experimentally that USP44 regulates neuroblastoma cell proliferation, migration, invasion, and neuronal development. Depletion of the histone H2B ubiquitin ligase subunit RNF20 resulted in similar findings, strongly implicating this histone mark as the target of USP44 activity in this disease. Integration of transcriptome and epigenome in analyses demonstrates a distinct set of genes that are regulated by USP44, including those in Hallmark MYC target genes in both murine embryonic fibroblasts and the SH-SY5Y neuroblastoma cell line. We conclude that USP44 is a novel epigenetic regulator that promotes aggressive features and may be a novel target in neuroblastoma. Implications: This study identifies a new genetic marker of aggressive neuroblastoma and identifies the mechanisms by which its overactivity contributes to the pathophysiology of this disease.