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7546 Background: MRD assessment informs relapse risk in MM but is typically bone marrow-based and invasive. We therefore compared two minimally invasive MRD assays: BM-informed cfDNA whole-genome sequencing (cfWGS) and plasma proteomic MRD (EasyM). Methods: 71 longitudinal plasma samples (22 diagnosis, 49 follow-up) from 22 newly diagnosed MM patients across 8 Canadian sites (TFRIM4) had paired cfWGS and EasyM (Rapid Novor Inc). cfWGS MRD used patient-specific mutation lists from diagnostic BM WGS (Abelman et al., medRxiv 2025). EasyM used mass spectrometry to quantify residual M-protein from baseline. The primary endpoint was progression-free survival (PFS). Results: Among 22 MM patients (8 male, 14 female; median age at diagnosis 62 years), 8 progressed at a median follow-up of 52.6 months (range: 10-79 months). At 1-year maintenance (n = 18 available), cfWGS MRD+ (6/18) predicted inferior PFS (HR 20.12, 95% CI 2.23-181.60, p = 0.007). EasyM any-detect positivity was frequent (16/18, reflecting delayed clearance) and not prognostic (p = 0.99), with poor agreement vs cfWGS (44.4%, κ = 0.118). An exploratory EasyM clearance threshold of 0.93% (hypothesis-generating) classified 5/18 patients as MRD+ and stratified PFS (HR 8.78, 95% CI 1.55-49.82, p = 0.004), improving agreement with cfWGS (17/18, 94.4%, κ = 0.870). Progression clustered in cfWGS+/EasyM-high patients (EasyM >0.93%; 4/5; median 11.9 months post-collection [1.9–22.8]) and occurred once in cfWGS−/EasyM-low patients (1/12, 27.6 months). The only discordant case (cfWGS+/EasyM−) progressed 8.7 months after collection. Higher quantitative MRD burden was associated with inferior PFS (cfWGS: HR 2.92 per 1 SD, 95% CI 1.29-6.59, p = 0.01; EasyM: HR 5.48 per 1 SD, 95% CI 0.79-37.90, p = 0.085). At ~100 days post-autologous stem cell transplantation (ASCT; n = 16 available), EasyM was uniformly MRD+ (16/16) while cfWGS was MRD+ in 7/16 patients. Applying an EasyM clearance threshold (2.13%; 9 cleared vs 7 residual) improved agreement with cfWGS (14/16; 87.5%; κ = 0.746). Of two discordant cases, one cfWGS+/EasyM-cleared patient relapsed 38.6 months post-collection and one cfWGS−/EasyM-residual patient remained progression-free at last follow-up. At post-ASCT, both assays showed consistent but underpowered associations with PFS (cfWGS HR 6.32, 95% CI 0.70–56.76, p = 0.100; EasyM-clearance HR 2.36, 95% CI 0.39–14.18, p = 0.335). Across all post-treatment samples (n = 49), continuous cfWGS burden correlated with EasyM residual M-protein (rho = 0.535, p < 0.001). Conclusions: BM-informed cfWGS MRD strongly stratified PFS, whereas EasyM required a clearance definition due to near-universal early positivity. Concordant plasma burdens support complementary MRD information. Future work will validate these findings in larger cohorts and quantify the incremental value of combined cfWGS and proteomic MRD for early relapse prediction.

7028 Background: Axi-cel, autologous anti-CD19 CAR T-cell therapy, showed long-term survival and curative potential in R/R LBCL (ZUMA-1; Neelapu et al. Blood . 2023). Few studies have examined long-term outcomes beyond clinical trials. Here we report long-term real-world outcomes of axi-cel in R/R LBCL using large-sample CIBMTR data. Methods: A total of 1500 adults from 79 US centers receiving commercial axi-cel after ≥2 LOT for LBCL from Oct 2017-Aug 2020 were enrolled in a post-marketing requirement study. A protocol was developed prior to the study’s implementation, reviewed by Kite and CIBMTR. This is a secondary analysis of said study. Key outcomes were progression-free survival (PFS), overall survival (OS), time to next therapy (TTNT), disease-specific mortality (competing risks were non-relapse deaths), subsequent malignancies, and non-relapse mortality (NRM). Outcomes were analyzed descriptively. Cases with missing data were excluded separately for each endpoint. Results: As of Aug 2025, 1446 patients (pts) were included in the analysis. Median age at infusion was 62.2 y (range, 19.6-90.8: 38% of pts ≥65 y); 65% were male. Five percent of pts had ECOG PS ≥2 and 16% had high-grade lymphoma. Pts had a median of 3 (range, 2-4) prior LOT, 28% had prior autologous hematopoietic cell transplantation, and 50% received bridging therapy. At 59.7 mo median follow-up, median PFS (95% CI) was 7.9 mo (6.3-10.9) and 5-y PFS was 30% (27-32). The median OS was 25.7 mo (21.6-30.2); 5-y OS was 38% (35-41). The 5-y cumulative incidence of disease-specific mortality was 51%. Among pts who were progression-free at 2, 3, 4, or 5 y post-infusion, the OS at 6 y (95% CI) was 73% (68-78), 81% (76-86), 90% (84-94), and 94% (89-97), respectively. The median duration of response (DOR) was 25.3 mo (95% CI, 20.7-32.8) and 5-y DOR was 38% (35-41). The median TTNT was 12.2 mo and 30% did not need additional LOT at 5 y. Of pts who received subsequent salvage therapy, 12 (2%) received cell therapy, 39 (7%) received hematopoietic cell transplant, and 475 (90%) received other therapy. The 1, 2, 3, 4, and 5-y cumulative incidence of relapse (95% CI) was 49% (46-51), 52% (50-55), 54% (52-57), 55% (53-58), and 56% (53-59), respectively. No new safety signals were observed. The primary causes of death (n=864; 60%) were primary disease (540; 63%), infection (111; 13%), and organ failure (57; 7%). The 5-y cumulative incidence of NRM was 16% (95% CI, 14-18). At 5 y, 11% (95% CI, 10-13) had subsequent malignancies, mostly therapy-related myeloid neoplasms (6%) and non-melanoma skin cancer (3%); none were directly attributed to axi-cel. Conclusions: This real-world study showed sustained survival at 5 y among pts with R/R LBCL treated with axi-cel after ≥2 LOT, consistent with ZUMA-1. Infection and organ failure were common causes of NRM. These results continue to support the use of axi-cel with curative intent in R/R LBCL.

560 Background: Patients (pts) with early stage hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) remain at both short and long term risk of recurrence. While clinico-pathological and gene-based biomarkers provide insight into early and late recurrence risk, additional prognostic tools are needed. We previously developed (Saha et al. Clin Cancer Res , 2025) a new breast MRI image-based artificial intelligence prognostic tool (TumorSight Risk) composed of both radiographic and clinical information. Here we sought to validate this tool in an independent cohort. Methods: In this multi-center, blinded, prospective/retrospective validation study, we sought to validate the 5-year recurrence-free survival (RFS) according to pre-defined risk scores (0-100) and categories (“high” or “low”) via pre-specified cutoff (≥47) for pts with HR+/HER2- BC. Kaplan-Meier and Cox regression analyses were then used to assess the unadjusted and adjusted association between risk category/score and the 5-year RFS. Results: 2,129 pts with HR+/HER2- BC diagnosed between January 1, 2010, and December 31, 2024, who underwent breast MRI prior to surgery (no neoadjuvant therapy) were included from four institutions. Median age was 57 years, 16% were Black, 15% had grade 3 disease, 93% were clinical T1 or T2, and 85%/15% were clinical N0/N1. At a median follow up of 6.24 years, the unadjusted hazard ratio (HR) for RFS comparing low (n=1808) and high risk (n=321) pts was 2.71 (95% CI = 1.95 – 3.76, p = 3x10 -9 ). The estimated 5 year RFS rate according to risk score (low and high) was 95.5% (95% CI: 94.63 – 96.3%) and 89.6% (95% CI = 86.4 – 92.6%) while the 10 year RFS estimates were 88.9% (95% CI = 86.5 - 90.9%) and 69.6% (95% CI = 59.1 – 77.9%). Univariate subgroup analysis demonstrated that the risk score was prognostic by age (< 50 vs. ≥50 years), pathologic nodal status, grade, and surgery type, regardless of chemo-, endocrine, or radiation therapy administration. The observed continuous risk score was strongly associated with risk of recurrence, with a 22% increase in relative risk per 10-unit change in risk score (0-100), translating to a 2.4% (95% CI = 1.2 – 4.5%) and 25.5% (95% CI = 15.4 – 40.4%) risk of recurrence at 5-years for pts at the lowest (0-9) versus highest (90-100) risk score. The prognostic association between risk score and RFS remained after adjusting for pathologic T- and N-stage, grade, age, race, and treatment (p = 0.002). Conclusions: TumorSight Risk is a new image-based biomarker for HR+/HER2- BC that provides prognostic information independent of standard clinico-pathological parameters. Given the ready availability of breast MRI in most pts with BC, TumorSight Risk may be a convenient tool for estimating risk for recurrence.

536 Background: Folate receptor alpha (FRα) is overexpressed in ~80% of triple-negative breast cancers (TNBC). We previously demonstrated that patients (pts) with breast cancer naturally mount immune responses to FRα. In prior Phase I and II studies, a GM-CSF-adjuvanted FRα peptide vaccine (FRPV) was safe and induced durable FRα-specific T-cell immunity in 83–90% of pts with breast and ovarian cancer. Methods: Eligible pts were women ≥18 years with TNBC (ER/PR ≤10%) with 1+ of the following: stage ≥T1c disease, node-positivity, or residual disease after neoadjuvant chemotherapy. Pts were randomized 2:1 to receive FRPV or placebo (GM-CSF alone) every 28 days for cycles 2-7 and then every six months for 7 booster doses, with cycle 1 consisting of cyclophosphamide 50mg orally twice daily for days 1-7 and 15-21 (in both arms). Randomization was stratified by chemotherapy setting (adjuvant only vs neoadjuvant) and stage (I/II vs III). FRα expression was evaluated by immunohistochemistry. The study was designed to detect (at 30 months after the last pt enrolled) a disease-free survival (DFS) difference of 14% assuming a 3.5-year DFS rate of 70% in the control group and with 78% power. Results: 280 pts were enrolled (median age 52). The majority had stage I or II tumors (n = 219, 78%). There were numerically more node-positive tumors in the vaccine arm, 78 (41%) vs 27 (32%), p = 0.15. Median follow-up was 3.5 years, and 33 (FRPV: 25, placebo: 8) DFS events were observed; 3.5-year DFS rate was 88% with FRPV and 90% with placebo (HR 1.42, 95% CI 0.64–3.15; p = 0.39). Overall survival (OS) also did not differ by arm (HR 2.48, 95% CI 0.55–11.20; p = 0.22). Among node-positive pts (n = 105), DFS did not differ between arms (HR 0.95, 95% CI 0.34–2.66; p = 0.92). However, a numerical DFS event rate improvement (14% for vaccine vs. 26% for placebo) was observed in 61 patients with stage III disease (HR 0.51, 95% CI 0.16–1.68; p = 0.26). DFS did not differ by chemotherapy setting or by receipt of anthracycline, capecitabine, and/or an immune checkpoint inhibitor. FRPV was well tolerated, with predominantly grade 1–2 adverse events (AEs) and no vaccine-related grade ≥4 AEs. FRα expression was available from tumor in 230 pts, with 72% expressing > 0. Overall, DFS was not significantly associated with FRα expression (0 vs > 0; HR 0.55, 95% CI 0.21–1.44; p = 0.21), and no significant differences in DFS by FRα expression were observed between treatment arms. Conclusions: FRPV following oral cyclophosphamide was safe, with no vaccine-related high-grade AEs. While no significant improvement in DFS or OS was observed overall, a numeric trend toward improved DFS was observed in pts with stage III TNBC. This finding is hypothesis-generating and supports further evaluation of FRα-targeted vaccination in higher-risk TNBC. Immune correlative analyses are ongoing to better define vaccine immunogenicity and its relationship to clinical outcomes. Clinical trial information: W81XWH-15-1-0293.

5069 Background: Inhibition of androgen receptor (AR)-signaling results in increases in double-strand DNA breaks and genomic instability. PARP inhibitors (PARPi) are a standard treatment option for patients (pts) with homologous recombination repair mutations (HRRm). Combinations of PARPi and AR pathway inhibitors (ARPI) are associated with synthetic lethality in multiple pre-clinical studies. Clinical trials have suggested potential benefits with co-targeting PARPi and ARPI in pts with and without HRRm. Methods: Alliance A031902 compared radiographic progression-free survival (rPFS) and overall survival (OS) as co-primary endpoints with enzalutamide and rucaparib (Enz/Ruca) versus enzalutamide plus placebo (Enz/Plac) for pts with metastatic castration resistant prostate cancer (mCRPC) regardless of BRCA/HRRm status. This trial was conducted by the Alliance for Clinical Trials in Oncology in 36 centers in the US. Target sample size was 1,002 patients. Eligibility required mCRPC with or without measurable metastatic disease and was agnostic regarding HRRm status. The trial was discontinued in 10/2023 due to changes in the treatment landscape for this pt population. Results: Between 10/21 and 4/23, 61 pts were randomized to Enz/Ruca (n=30) or Enz/Plac (n=31). Known BRCA1/2 or PALB2 mutations were present in 1 pt (3.3%) in the Enz/Ruca arm and 1 pt (3.2%) in the Enz/Plac arm; wildtype in 14 (46.7%) vs 15 (48.4%), and unknown in 15 (50%) vs 15 (48.4%), respectively. Three patients (11.5%) in the Enz/Ruca arm discontinued due to an adverse event (AE) vs 0 in the Enz/Plac arm. Among response-evaluable pts, 7/26 (27%) in the Enz/Ruca arm discontinued due to disease progression vs 10/31 (33%) in the Enz/Plac arm. Most common grade 3+ AEs were anemia (33% vs 3%) and hypertension (17% vs 10%) in the Enz/Ruca arm and Enz/Plac arm, respectively. All 61 pts were evaluable for response assessment. PSA declines ≥50% and ≥90% were observed in 79% vs 45% and 60% vs 43% of pts receiving Enz/Ruca versus Enz/Plac, respectively. Median PFS in the Enz/Ruca vs Enz/Plac arms was 17.1 vs 14.2 mos, respectively (HR 1.13 [95% CI: 0.42-3.01], p=0.81), median rPFS (inclusive of unequivocal clinical progression) was 17.1 vs 11.7 mos ( HR 0.72; 95% CI: 0.31-1.67, p = 0.44), and median OS was not reached vs 27.0 mos (HR 0.65; 95% CI: 0.29-1.45, p=0.29). Conclusions: In this prematurely terminated phase III study, Enz/Ruca was generally well tolerated, with the safety profile consistent with prior PARPi/ARPI combinations. Efficacy outcomes for rPFS and OS are inconclusive due to limited sample size. Definitive conclusions regarding the clinical benefit of this combination cannot be determined from this study. Clinical trial information: NCT04455750 .

5004 Background: Patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) treated continuously with testosterone suppression (TS) plus an androgen receptor pathway inhibitor (ARPI) can experience cumulative toxicity. We conducted this single-arm phase 2 trial (NCT05241860) to test the hypothesis that pts who achieve favorable response to TS + ARPI can have prolonged treatment-free interval with testosterone recovery after treatment interruption (TI). Here we report on the primary endpoint. Methods: Eligible pts had mHSPC by conventional imaging with prostate-specific antigen (PSA) ≥ 5 ng/ml and testosterone ≥ 150 ng/dl prior to starting TS+ARPI, with PSA < 0.2 ng/ml and testosterone < 50 ng/dl at the time of enrollment after having received TS for 540-750 days and ARPI for ≥ 360 days. Prior local therapy, radiation to metastases and docetaxel were permitted. After enrollment, pts discontinued TS and ARPI and were followed with PSA and testosterone levels every 3 months (mo), CT/MRI and bone scan at least every 6 mo, and FACT-P questionnaire for patient-reported outcomes (PROs) every 6 mo. Treatment was resumed for PSA ≥ 5 ng/ml, radiographic change (progressive disease [PD] per RECIST 1.1 on CT/MRI or unconfirmed PD per PCWG3 on bone scan), or prostate cancer-related symptoms. The primary endpoint was proportion of men remaining treatment-free 18 mo after TI with eugonadal testosterone ( > 150 ng/dl). Target enrollment was 75 pts to differentiate 18-mo treatment-free rates of 0.30 (H 0 ) and 0.45 (H a ). Results: Of 79 pts enrolled between 07/2022 and 03/2024, 78 were eligible and underwent TI. Among these 78, median PSA prior to starting TS+ARPI was 19 (range 5-6759), 27 (35%) had high volume disease, 31 (40%) never received local therapy, and 55 (71%) did not receive radiation to metastases. By 18 mo after TI, 67% (52/78) recovered testosterone and 58% (45/78) remained treatment-free; 41% (32/78) remained treatment-free with testosterone recovery (80% CI 33.5-48.9%, one-sided p 0.0249). At median follow-up of 21.2 mo, 35% (27/78) resumed initial TS+ARPI after meeting re-initiation criteria (of whom 1 required treatment switch for PD 9 mo later); 5% (4/78) resumed prior to meeting criteria; 9% (7/78) pursued alternative therapy instead of resuming TS+ARPI per protocol; 5% (4/78) withdrew; 1 died of myocardial infarction prior to resuming treatment. 4 pts died, 1 of prostate cancer. Conclusions: The primary objective was achieved with 41% of favorable responders to TS+ARPI remaining treatment-free with testosterone recovery at 18 mo after TI. Analyses of biomarkers and PROs are in progress, and pts will be followed for long-term outcomes. Support: U10CA180821, U10CA180882, UG1CA189823, https://acknowledgments.alliancefound.org, Veracyte Inc. Clinical trial information: NCT05241860 .

4178 Background: In the CABINET trial, CABO significantly prolonged progression-free survival (PFS) compared to placebo (PB) in patients (pts) with advanced, previously treated extrapancreatic NET (epNET) or pancreatic NET (pNET) (Chan et al., NEJM, 2025). Here we report outcomes according to functional status based on NET hormone secretion. Methods: Pts with locally advanced or metastatic epNET or pNET were randomized 2:1 in separate cohorts to receive CABO 60 mg daily vs PB. Eligibility included progression by RECIST within 12 months (mo) before registration, ≥ 1 prior systemic therapy not including somatostatin analogs (SSA). Pts with functional NET due to hormone secretion and non-functional NET were included. In this post hoc subgroup analysis, we analyzed PFS by blinded independent central review and adverse events for pts receiving CABO vs PB based on functional status. Cox regression models were used with stratification on primary tumor site (epNET vs pNET). Subset analyses to evaluate treatment arm differences were conducted in pts with functional and non-functional tumors. Due to small numbers, separate results for those with unknown functional status are not included. Results: Of the total 298 pts enrolled in both cohorts, 74 had a functional NET (CABO, n = 47; PB, n = 27); 179 had a non-functional NET (CABO, n = 123; PB, n = 56); 45 had unknown functional status (CABO, n = 28; PB, n = 17). For functional NET, primary tumor sites were GI tract (n = 50; 68%), pancreas (n = 15; 20%), unknown (n = 4; 5%), lung (n = 3; 4%), and thymus (n = 2; 3%). Secreted hormones that were reported included serotonin (55%), somatostatin (18%), gastrin (16%), glucagon (4%), insulin (4%), ACTH (1%), and vasoactive intestinal peptide (1%). For non-functional NET, primary tumor sites were pancreas (n = 75; 42%), GI tract (n = 42; 23%), lung (n = 30; 17%), unknown (n = 17; 9%), thymus (n = 8; 4%), and other (n = 7; 4%). Concurrent SSA was received by 91% and 53% of pts with functional and non-functional NET, respectively. In both subgroups, CABO was associated with improved PFS compared to PB (for functional NET: stratified hazard ratio [sHR], 0.40; 95% confidence interval [CI]: 0.20-0.82, P = 0.012; for non-functional NET: sHR, 0.26; 95% CI: 0.17-0.41, P < 0.001). The most frequent grade 3/4 adverse events (AEs) attributed to CABO vs PB in pts with functional NET included hypertension (21% vs 11%), diarrhea (9% vs 11%), and fatigue (2% vs 15%); in pts with non-functional NET, grade 3/4 AEs included hypertension (21% vs 4%) and fatigue (18% vs 4%). Conclusions: Subset analyses of the CABINET trial suggest that CABO is an effective treatment option for pts with functional and non-functional epNET or pNET. Efficacy and safety results for pts with functional or non-functional NET treated with CABO are consistent with results for the entire trial. Clinical trial information: NCT03375320 .

3510 Background: Patients with RAS-mutated mCRC have limited treatment options. Chemotherapy in combination with bevacizumab (Bev) has been the standard first-line treatment for the past two decades, yet the prognosis for these patients remains poor. Onvansertib (Onv), a selective PLK1 inhibitor, has previously demonstrated synergy with chemotherapy in the second line setting. The Phase 2 randomized CRDF-004 trial evaluated onvansertib plus standard-of-care (SoC; FOLFIRI or FOLFOX with Bev) in as first-line RAS-mutated mCRC. Methods: Patients with first-line KRAS or NRAS mutant mCRC were randomized to SoC alone or SoC plus onvansertib (20 mg or 30 mg). The primary endpoint was objective response rate (ORR) as determined by a blinded-independent central review (BICR) using RECIST v1.1. Key secondary endpoints included progression-free survival (PFS), duration of response, and safety. PFS was assessed by BICR and investigator assessments combined. Results are presented in the intent-to-treat population (ITT). Results: At the data cutoff of 22 Jan 2026,110 patients were randomized with a median follow up of approximately 10 months. Baseline characteristics were relatively balanced across arms. Onv 30 mg + FOLFIRI + Bev demonstrated numerically higher ORR (n = 13/18, 72.2%, 95% CI: 46.5, 90.3) compared with the FOLFIRI + Bev control arm (n = 8/19, 42.1%, 95% CI: 20.3, 66.5), the FOLFOX + Bev control arm (n = 8/18, 44.4%, 95% CI: 21.5, 69.2) and the combined control arms (SoC: n = 16/37, 43.2%, 95% CI: 27.1-60.5). Onv 30mg + FOLFIRI + Bev demonstrated a p-value of 0.051 for confirmed ORR vs. SoC; and a p-value of 0.045 for the 6-month ORR compared to FOLFIRI + Bev (n = 10/18, 55.6%, 95% CI: 30.8-78.5 vs. n = 4/19, 21.1%, 95% CI: 6.1-45.6, respectively). The median PFS for the control arms was 10.97 months (95% CI: 7.52, NR) for FOLFIRI + Bev, 9.89 months (95% CI: 9.43, NR) for FOLFOX + Bev and 10.97 months (95% CI: 9.43-15.44) for the combined SoC arms. The median PFS in the Onv 30mg+ FOLFIRI + Bev arm was not reached (95% CI: 9.72-NR). The PFS HR of 30mg + Onv +FOLFIRI + Bev vs FOLFIRI + Bev was 0.38 (95% CI: 0.12-1.17) and vs SoC was 0.37 (95% CI: 0.13-1.02, p = 0.048). The clinical benefit from Onv treatment was further evidenced by the 12-month PFS rates, 61.9% (95% CI: 40.1, 95.8) in the Onv 30 mg + FOLFIRI + Bev arm vs. 28.4% (95% CI: 9.3, 86.9) in the FOLFIRI + Bev arm, and 30.1% (95% CI: 13.8-65.7) in the SoC. Onvansertib was well tolerated, with no unexpected toxicities observed; the most common grade ≥3 adverse event was neutropenia. PK data support moving forward with the onvansertib 30mg dose with FOLFIRI + Bev. Conclusions: Onvansertib plus FOLFIRI and bevacizumab demonstrated improved antitumor activity and manageable safety in first-line RAS-mutated mCRC. These results support further clinical and support planned confirmatory Phase 3 evaluation. Clinical trial information: NCT06106308 .

2646 Background: Immune checkpoint inhibitors (ICIs) have transformed the management of many advanced cancers but identifying patients who are likely or unlikely to benefit from ICI treatment remains a critical challenge. Biomarkers, such as PD-L1, mismatch repair deficiency, and tumor mutational burden, capture only static, unidimensional features of the complex tumor microenvironment, and therefore inadequately predict response to immunotherapy in patients. In contrast, live tumor fragments (LTFs) preserve the full complexity of the tumor microenvironment and enable functional ex vivo assessments of ICI activity. Previous efforts have had limited clinical applicability because they required larger resection specimens often collected at a single academic center. Here, the predictive capability of an ex vivo platform using core needle and forceps biopsies from multiple clinical sites was assessed and compared to approved biomarkers. Methods: Patients with eligible solid tumors (where ICI has an indication, including renal, non-small cell lung, bladder, colorectal, and triple-negative breast cancer, and others) were enrolled in ongoing, prospective observational trials (NCT05478538, NCT05520099, NCT06349642). Biopsies were cut into LTFs, encapsulated in hydrogel, and treated sequentially with IgG antibody followed by ICI (αPD-[L]1 with or without αCTLA-4). Cytokine production was assessed by a multiplexed bead-based immunoassay at multiple time points during ex vivo treatment. Using receiver operating characteristic and precision recall analyses, we identified 9 predictive cytokines (including IFN-γ, granzyme B, and CXCL9/10), which were used to develop the Elephas score (ELP-score) to assess cytokine response to ex vivo ICI treatment. Results: Of 167 eligible patient specimens, 85% (n = 142) passed quality control metrics and 130 were used for model development. Hierarchical clustering of cytokine production revealed that 27% (n = 35) of patient specimens exhibited a cytokine response to ICI. In a validation set of 20 tumors, collected from patients who were subsequently treated with ICI, ELP-score positivity correctly identified 9 of 11 patients (82%) who had an objective response (PR/CR) to ICI, including 2 patients who were negative for FDA-approved standard-of-care ICI biomarkers. Furthermore, 5 of 5 patients (100%) with clinical progressive disease were correctly characterized as ELP-score negative. Conclusions: Using routine biopsy specimens, the ex vivo live tumor platform accurately identifies patients with clinical response to ICI therapy, including those incorrectly identified by conventional biomarkers. Ongoing efforts will test these findings in an additional validation set. If confirmed, the ex vivo LTF platform could enable the identification of patients likely to benefit from ICI therapy. Clinical trial information: NCT05478538 , NCT05520099 , NCT06349642 .

2090 Background: A subset of meningiomas has an aggressive clinical course requiring multimodal therapies. Yet, treatment options beyond surgery and radiation are limited. Somatostatin receptor 2 (SSTR2) is uniformly expressed in meningiomas and can be targeted by the radiopharmaceutical agent [ 177 Lu]Lu-DOTA-TATE ( 177 Lu-Dotatate). [ 68 Ga]Ga-DOTA-TATE ( 68 Ga-Dotatate) PET is emerging as a promising imaging modality to assess treatment response in SSTR2-expressing tumors. However, prospective clinical data supporting the use of 177 Lu-Dotatate and 68 Ga-Dotatate in treatment-refractory meningiomas is limited. Methods: In this multicenter, open-label, phase 2 clinical study (NCT03971461), adult patients with progressive intracranial meningiomas received 177 Lu-Dotatate at 7.4 GBq (200 mCi) every 8 weeks for 4 doses. The primary endpoint was 6-month progression-free survival (PFS-6). Up to 5 meningioma lesions per patient were assessed by gadolinium-enhanced T1 MRI every 12 weeks. 68 Ga-Dotatate PET was obtained before/after 177 Lu-Dotatate treatments. Lesional 68 Ga-Dotatate PET activity was assessed relative to liver/spleen or superior sagittal sinus (SSS). Results: 32 patients (female = 21, male = 11) with progressive meningiomas (WHO grade 1 = 7, grade 2 = 24, grade 3 = 1) were enrolled. Median age was 65.5 (range 41-78) years. All patients had at least one prior tumor surgery and at least one course of radiation. Overall, 177 Lu-Dotatate was well tolerated and the most common grade 3/4 adverse events were transient cytopenia in 15 patients (47%). One patient (3%) discontinued treatment due to grade 4 thrombocytopenia. PFS-6 was reached in 22 patients (69%), which includes 5 of 7 (71%) with grade 1 and 17 of 24 (71%) with grade 2 meningiomas. Best radiographic response by MRI was partial response (PR) in 5 (16%) and stable disease (SD) in 20 (63%) patients. Eight patients (16 lesions) were evaluable by paired MRI and 68 Ga-Dotatate PET pre- and post-treatment. Referenced to SSS, 68 Ga-Dotatate avidity reduced by ≥50% in 2 lesions (PR), 25-49% (minor response, MR) in 3 lesions and remained stable ( < 25% reduction and < 25% increase) in 11 lesions. Using liver/spleen as a reference (6 patients, 14 lesions), 68 Ga-Dotatate uptake was reduced in 9 lesions and stable in 5 lesions. 68 Ga-Dotatate PET assessments were generally concordant with MRI-based treatment response assessments. Conclusions: The primary endpoint (PFS-6) was met in this phase 2 study with 69% of patients achieving PFS-6, thereby surpassing established historical benchmarks. 177 Lu-Dotatate was generally well tolerated and deserves further study in patients with advanced meningiomas. Exploratory 68 Ga-DOTATATE PET studies showed decreased uptake in a subset of lesions and bears promise as an imaging biomarker to assess treatment response. Clinical trial information: NCT03971461 .