Citations

e17035 Background: 177 Lu-PSMA-617 was approved in March 2022 for patients with mCRPC pretreated with an androgen receptor pathway inhibitor (ARPI) and a taxane. There are limited data on the effectiveness of treatments post- 177 Lu-PSMA-617. The aim of this study was to describe prostate-specific antigen (PSA) responses among patients with mCRPC receiving a guideline-recommended therapy as the next therapy after 177 Lu-PSMA-617 treatment. Methods: This retrospective, observational study used real-world data from the PRECISION data platform, a proprietary dataset developed by Novartis, comprised of patient-level electronic health record and claims data that represent the US advanced prostate cancer population in the community, academic, urology, and medical oncology settings. Patients with mCRPC who received any guideline-recommended therapy at least 14 days after treatment with 177 Lu-PSMA-617 between March 23, 2022 and July 31, 2024 were included. Guideline-recommended therapies included abiraterone, enzalutamide, darolutamide, apalutamide, cabazitaxel, docetaxel, pembrolizumab, sipuleucel-T, niraparib, olaparib, talazoparib, rucaparib, and radium-223. Patients’ PSA values while on 177 Lu-PSMA-617 treatment were compared with their PSA values during the subsequent therapy course. Proportions of patients achieving reductions in PSA levels ≥50% (PSA50) and ≥80% (PSA80) were estimated. All analyses were descriptive. Results: A total of 152 patients receiving any subsequent guideline-recommended therapy after 177 Lu-PSMA-617 were identified. Mean age was 72.1 years. Most patients received an ARPI (n=93, 61.2%) – abiraterone (n=38), enzalutamide (n=37), darolutamide (n=10), or apalutamide (n=8) – as their subsequent therapy. Of patients who received a taxane (n=42, 27.6%), 24 received cabazitaxel and 18 received docetaxel. Median time to initiation of subsequent therapy was 206 days (interquartile range [IQR] 101–301 days) from 177 Lu-PSMA-617 initiation and 44 days (IQR 17–119 days) from 177 Lu-PSMA-617 discontinuation. Overall, among patients with sufficient information for PSA evaluation (n=30), 46.7% achieved PSA50 and 40.0% PSA80 post- 177 Lu-PSMA-617. Among patients receiving an ARPI, PSA50 was observed in 11/18 (61.1%) and PSA80 in 10/18 (55.6%). Among patients receiving a taxane, PSA50 and PSA80 were seen in 3/12 (25.0%) and 2/12 (16.7%), respectively. Conclusions: In this real-world analysis, the majority of patients who received guideline-recommended therapies after 177 Lu-PSMA-617 achieved at least a PSA50 response, suggesting that 177 Lu-PSMA-617 treatment does not preclude response to other subsequent therapies.

e17030 Background: The broad therapeutic arsenal for mCRPC, with overlapping indications, makes selecting the optimal treatment sequence challenging in clinical practice. The aim of this study was to evaluate the prostate-specific antigen (PSA) responses and overall survival (OS) among patients with mCRPC receiving 177 Lu-PSMA-617 based on prior ARPI and taxane treatment exposure. Methods: This retrospective, observational study used real-world data from the PRECISION data platform, a harmonized dataset of advanced prostate cancer patients in the US from diverse clinical settings. Patients with mCRPC who had received ≥1 dose of 177 Lu-PSMA-617 between March 23, 2022 and July 31, 2024, after prior treatment with ≥1 ARPI and ≥1 taxane, were included. To assess PSA response, the baseline PSA value obtained within 90 days before starting 177 Lu-PSMA-617 was compared with the on-treatment PSA value obtained ≥28 days after 177 Lu-PSMA-617 initiation. The number of patients achieving PSA reductions ≥50% (PSA50) and ≥80% (PSA80) were estimated, with patients classified into two cohorts based on prior ARPI and taxane exposure: (1) prompt cohort: after only 1 ARPI and 1 taxane, and (2) deferred cohort: >1 ARPI and/or >1 taxane. Patient characteristics and treatment patterns were evaluated descriptively. OS from 177 Lu-PSMA-617 initiation was estimated using Kaplan–Meier methodology. Results: A total of 431 patients were included: 177 patients in the prompt cohort and 254 patients in the deferred cohort. Of patients in the deferred cohort, 185 (72.8%) received ≥1 ARPI and 1 taxane, 32 (12.6%) received 1 ARPI and ≥1 taxane, and 37 (14.6%) received ≥1 ARPI and ≥1 taxane. Median (interquartile range) age was 73 (67–78) years and most demographic characteristics were balanced between groups. Patients in the deferred cohort had higher median PSA levels at baseline (63.1 ng/mL vs 25.2 ng/mL). PSA50 was observed in 18/33 (55%) patients in the prompt cohort vs 28/66 (42%) in the deferred cohort. PSA80 was observed in 13/33 (39%) patients in the prompt cohort vs 21/66 (31%) in the deferred cohort. Across both cohorts, median OS was 18.0 months (95% confidence interval [CI]: 15.1 months–not reached [NR]). Median OS was NR in patients in the prompt cohort vs 15.1 months in patients in the deferred cohort (95% CI: 11.6 months–NR). Conclusions: In this large real-world study, prompt initiation of 177 Lu-PSMA-617 (after only 1 ARPI and 1 taxane) showed superior clinical outcomes versus deferred initiation of 177 Lu-PSMA-617. Patients were more likely to achieve a PSA reduction ≥50% and ≥80% and had longer OS with prompt initiation of 177 Lu-PSMA-617. These results may help to guide treatment sequencing in clinical practice.

In the INTRIGUE phase III trial (ClinicalTrials.gov identifier: NCT03673501 ), adult patients with advanced gastrointestinal stromal tumor previously treated with imatinib were randomly assigned 1:1 to ripretinib 150 mg once daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off). In the primary analysis, overall survival (OS) was immature. In this study, we report the final planned analysis of OS (key secondary end point), progression-free survival (PFS) on third-line therapy (second PFS; prespecified exploratory end point), and long-term safety. Final OS analysis was prespecified to occur with approximately 200 and ≥145 events in the overall and KIT exon 11 intention-to-treat (ITT) populations, respectively. As of March 15, 2023, there were 211 and 151 OS events in the overall ITT and KIT exon 11 ITT populations, respectively. Median OS was similar between second-line ripretinib and sunitinib in both populations (overall, 35.5 v 31.5 months; KIT exon 11, 35.5 v 32.8 months). Median second PFS (on third-line therapy) for the overall ITT population was similar between the ripretinib and sunitinib arms (7.7 v 7.4 months). Safety was consistent with the primary analysis. OS from this analysis was similar between arms, and second PFS suggests that receiving ripretinib did not adversely affect the PFS of third-line therapy.

Abstract Arthrofibrosis of the knee is a difficult‐to‐manage complication after meniscoligamentous knee injuries, traumatic injuries with articular extension, and surgeries to treat these conditions. Treatment protocols for the management of postoperative arthrofibrosis exhaust nonoperative therapies before proceeding to the operating room for lysis of adhesions (LOA). Although LOA restores range of motion in most cases, a recurrence of arthrofibrosis is possible when postoperative therapy protocols are not strictly followed. Limited treatment options exist in the setting of recalcitrant arthrofibrosis. Revision arthroscopic LOA may be performed in this scenario. This revision procedure places neurovascular anatomy in the posterior compartment at risk. Performing a posterior capsule release in the arthroscopic management of recalcitrant arthrofibrosis is challenging but important to optimize recovery of range of motion. This Technical Note and accompanying video present a stepwise approach to LOA that demonstrates a safe method for performing an arthroscopic posterior capsule release in these challenging cases. Technique Video video See video under supplementary data.

AbstractStandard of care first‐line systemic treatment for advanced biliary tract cancer includes chemo‐immunotherapy with gemcitabine, cisplatin, and durvalumab, followed by maintenance durvalumab monotherapy. The present work aims to investigate the differences in baseline clinical and molecular characteristics between patients with early progression during chemo‐immunotherapy and those who reach durvalumab maintenance therapy. The study population included patients with unresectable, locally advanced, or metastatic BTC who received treatment at 38 clinical Institutions in 12 countries from July 2021 to December 2023. The primary objective of the study was to investigate whether baseline clinical and molecular characteristics differed between patients with early progression during chemo‐immunotherapy versus those reaching durvalumab maintenance therapy. Four hundred forty‐eight patients were included in this study. Two hundred twenty‐seven patients (50.7%) received maintenance with durvalumab monotherapy, whereas 221 (49.3%) did not receive maintenance therapy due to PD during first‐line chemo‐immunotherapy before completing 8 cycles. Results show that patients who received maintenance were more likely to be older (≥70 years), have an ECOG = 0, locally advanced disease, and a neutrophil‐to‐lymphocyte ratio (NLR) <3. A higher proportion of patients with BAP1 mutations received maintenance, while TP53 mutations were more common in those who progressed early. According to the present analysis, a substantial proportion of patients (50.7%) with advanced BTC who were treated with chemotherapy plus durvalumab proceeded to receive maintenance therapy with durvalumab monotherapy, with a median treatment duration of 4.4 cycles. Patients ≥70 years, with ECOG PS 0, with locally advanced disease, and with NLR <3 had a higher likelihood of receiving maintenance therapy.

Abstract Hip chondral defects often are encountered at the time of hip arthroscopy and can result in substantial pain and dysfunction. With the evolution of cell‐based techniques, there is growing interest in single‐stage, arthroscopic treatment of such chondral lesions. Arthroscopic orthobiologic delivery remains technically challenging, given the constrained and concave nature of the acetabulum and the need to perform instrumentation taking into account nearby structures such as the articular surface, hip capsule, and labrum. In this Technical Note, we describe our preferred method for arthroscopic delivery of orthobiologics at the time of single‐stage cartilage repair, which allows for needle‐based transcapsular, translabral access of hip chondral defects for both the acetabulum and femoral head. Technique Video video See video under supplementary data.

Background Secondary aortoenteric fistulas (SAEF) following endovascular aortic repair (EVAR) is an extremely rare event but life threatening. Our review offers comprehensive knowledge on pathophysiology, clinical presentation, diagnosis, and treatment options. Aim To summarize the current literature regarding pathophysiology, clinical, diagnostic and therapeutic approach of aortoenteric fistulas secondary to EVAR. Methods We performed a literature search in Pubmed/MEDLINE to identify the literature published about SAEF after EVAR. Cases were summarized in a table and prevalences. Other relevant literature was included in the results sections. Results A total of 35 reports (single cases and small series) with 45 patients were included. SAEF after EVAR can result from infection, inflammation, or mechanical factors. Clinical presentation is often non-specific, ranging from a gastrointestinal herald bleed to hemorrhagic shock, or malaise and general infection-related symptoms. Cross-sectional imaging plays a critical role in diagnosing SAEF. The treatment approach involves a multidisciplinary team approach and requires broad-spectrum intravenous antibiotics, endovascular intervention for urgent hemorrhage control, and open surgical intervention for definitive repair. Long-term antimicrobial therapy is essential to avoid reinfection. Conclusions SAEF following EVAR represents a complex, life-threatening condition with limited evidence-based management strategies. Given the growing prevalence of endovascular procedures, comprehensive knowledge of SAEF is crucial for all health care providers to improve early diagnosis and outcomes.

The NCCN Guidelines for Multiple Myeloma (MM) provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with MM. These NCCN Guidelines Insights highlight the important updates and changes specific to systemic therapy for patients with newly diagnosed as well as previously treated MM included in Version 1.2025 of the NCCN Guidelines for MM.

Abstract Purpose: Recent advances have seen the development of targeted therapeutics against the receptor tyrosine kinase (RTK)/RAS/MAPK pathway, which, when aberrantly activated, drives the malignant transformation of many cancer indications. However, the efficacy of inhibitors targeting single molecules is dampened by pathway feedback activation and acquired drug resistance. We seek to evaluate the application of JAB-3312 (sitneprotafib), a potent inhibitor of SHP2, in RTK/RAS/MAPK pathway–targeted combination therapies. Furthermore, SHP2 plays a vital role in PD-1–mediated immunosuppression. The rational combination of JAB-3312 with PD-1 blocking therapies is also explored. Experimental Design: Biochemical and cellular assays were applied to evaluate the potency of JAB-3312 in SHP2 inhibition. Tumor cell lines and cell line– and patient-derived xenografts were used to test different combinations of JAB-3312 with KRASG12C, MEK, EGFR, and PD-1 inhibitors. Results: JAB-3312 produced potent in vitro inhibition of SHP2 activity and downstream ERK phosphorylation, with IC50 values of 1.44 nmol/L and 0.68 to 4.84 nmol/L, respectively. When used in combination, JAB-3312 significantly increased the antitumor activity of the KRASG12C inhibitor glecirasib in naïve and resistant models. The combination of JAB-3312 with MEK inhibitors significantly delayed RTK signaling reactivation and enhanced tumor growth inhibition in KRAS-mutated cancer models. The JAB-3312–osimertinib combination exhibited great efficacy in osimertinib-resistant non–small cell lung cancer models. Additionally, JAB-3312 enhanced the efficacy of PD-1 blockade therapies by promoting an antitumor microenvironment. Representative cases of patients who responded to the combination therapies from two ongoing clinical trials (NCT05288205 and NCT04720976) were reported. Conclusions: JAB-3312 in combination with RTK/RAS/MAPK or PD-1 blockade therapies is a promising strategy that warrants further clinical investigation.

Abstract Glioblastoma Multiforme (GBM) is a highly aggressive malignant brain tumor. Despite decades of research, the tumor is essentially incurable, primarily due to the failure of small molecule drugs to pass the blood-brain barrier (BBB). This molecular "pump" within the brain's blood vessel linings restricts effective drug delivery to the tumor. To address this challenge, we have developed an antibody targeted nanoparticle therapeutic platform, NV103. NV103 employs liposomal nanoparticles with tumor antigen targeted antibodies specifically engineered to deliver otherwise ineffective drugs like irinotecan directly to tumor. GBMs are heterogeneous, characterized by diverse genomic profiles and tumor antigen expression patterns. EGFR is a well-known example. Here we identified a novel GBM tumor antigen, CD99. CD99 is not a commonly recognized GBM biomarker, but we find that GBMs consistently express CD99. We evaluated nearly 100 GBM PDXs in the Mayo Clinic repository and found that nearly all express CD99. We then evaluated NV103's efficacy across multiple GBM tumors with varying levels of CD99 cell surface expression. Importantly, NV103 demonstrated exceptional BBB penetration in an in vitro transwell system utilizing brain endothelial cells derived from human stem cells. NV103 also exhibits prolonged plasma persistence with detectable levels present at 24 hours, compared to free drug which is undetectable within hours. This prolonged drug availability combined with the ability to penetrate the BBB and preferentially bind to tumor cells results in dramatically enhanced anti-GBM activity. In GBM mouse studies, NV103 and its payload exhibited at least 5-fold enhanced delivery to tumor vs. brain. In preclinical animal studies, NV103 extended the survival of orthotopically implanted human PDX glioblastoma (GBMPDX43)-bearing mice by at least three-fold compared to free-drug treatments. We also showed that NV103 effectively induces cytotoxicity across a broad spectrum of CD99-expressing GBMs. NV103 showed significantly enhanced anti-tumor activity, even in low CD99-expressing tumors, such as GBMPDX43. Moreover, dose-response trends in GBM-bearing animals suggest that escalating doses of CD99-targeted nanoparticles could further improve survival outcomes. This targeted approach minimizes drug exposure to normal tissues, including brain. We found no dose limiting toxicity at 50mg/kg, five times higher than the 10mg/kg used for most of the tumor bearing animal studies. These findings underscore NV103's potential to effectively target heterogeneous GBMs, including those with variable CD99 expression levels, not unlike HER2-low tumors treated with HER2-directed ADCs. Further, preclinical data suggest that NV103 dose escalation will amplify its therapeutic impact, positioning this platform as a potential groundbreaking approach to overcome treatment resistant GBM. Citation Format: HyungGyoo Kang, Bryon Upton, Jon Nagy, Jann N. Sarkaria, Timothy J. Triche. Enhancing GBM therapy with tumor-targeted nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB183.