Citations

Abstract Background Magnetic Resonance‐guided Radiation Therapy (MRgRT) systems are increasingly used in clinical practice, necessitating a dedicated dosimetry protocol to address the challenges posed by the presence of strong magnetic fields. Purpose AAPM TG351 introduces a reference dosimetry protocol for external beam MRgRT systems, aligning with AAPM TG51 reports and incorporating elements from the IAEA TRS398 code of practice. Methods The protocol offers practical guidance on beam quality and dosimetry setup in the presence of strong magnetic fields. It reviews relevant literature to identify reference‐class chambers suitable for external beam MRgRT systems and determines their beam quality conversion and other relevant correction factors through a detailed analysis of available data and associated uncertainties. Results AAPM TG351 offers a comprehensive dosimetry protocol for external beam MRgRT systems, addressing the unique challenges posed by the presence of magnetic fields. It includes detailed guidance for measurement setups, a list of reference‐class chambers appropriate for reference dosimetry in MRgRT systems, and updated beam quality conversion and correction factors. Additionally, the protocol presents an in‐depth analysis of the uncertainty budget, identifying key contributors and providing strategies to minimize uncertainties, thereby enhancing clinical accuracy and reliability. Conclusions This protocol provides a practical, evidence‐based reference for medical physicists conducting reference dosimetry in external beam MRgRT systems.

TPS1143 Background: Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have revolutionized the treatment of patients (pts) with germline BRCA1/2 (gBRCA)-associated HER2-negative BC. However, resistance eventually occurs in almost all pts. Tumor-associated macrophages (TAMs), a key component of the BC tumor microenvironment, are highly immunosuppressive and associated with poor clinical outcomes. In preclinical immunocompetent models of BRCA-associated BC, PARP inhibition induces suppressive CSF-1R+ TAMs, contributing to resistance, so that combining anti-CSF-1R therapy with PARPi significantly enhances progression free survival (PFS) compared to PARPi monotherapy (190d vs 92d). Axatilimab (SNDX-6352; Ab969.g2), a humanized IgG4 monoclonal antibody targeting CSF-1R, reduces TAMs, potentially slowing tumor growth and enhancing anti-tumor immunity. In the Phase I SNDX-6352-0502 study for advanced solid tumors, axatilimab showed tolerability at the highest dose (6 mg/kg), with biomarker modulation observed at doses as low as 1 mg/kg. Axatilimab is FDA-approved for chronic graft-versus-host disease (cGVHD). Methods: AXALAP (NCT06488378) is a non-randomized open-label, proof-of-concept phase 1 study designed to evaluate axatilimab 1mg/kg or 3mg/kg every 2 weeks in combination with olaparib 300 mg twice daily in pts with somatic or germline BRCA1/2 - and PALB2 -associated HER2-negative metastatic BC. Patients must be PARPi naïve, or have not progressed on prior PARPi, and have received up to 2 prior lines of chemotherapy for metastatic disease. Pts will receive a two-week lead-in of olaparib monotherapy, followed by combined olaparib and axatilimab. Pts will undergo mandatory tumor biopsies pre-treatment, after the 2-week olaparib lead-in, and after 2 cycles of olaparib/axatilimab, with an optional biopsy at time-of-progression. Primary objectives are to establish the maximum tolerated dose (MTD) and recommended phase 2 dose and to assess the safety and tolerability of axatilimab and olaparib. Secondary objectives include assessment of changes in CSF-1R+ CD163+ macrophage levels after olaparib monotherapy and after 2 cycles of combination treatment at the MTD; to determine the objective response rate and the median PFS of the combination per RECIST 1.1 criteria. The MTD will be determined by Bayesian Optimal Interval (BOIN) design. Pts will be treated in cohorts of 3 with a maximum of 10 at each dose. If the MTD is identified as 3mg/kg, we will complete enrollment of 10 pts at 1 mg/kg to assess biological effectiveness and clinical efficacy of the lower dose. We expect to treat up to 20 pts, who will receive study treatment until development of unacceptable toxicity or disease progression. Enrollment began on 5/2024 at Dana-Farber Cancer Institute and the trial will also open at Beth Israel Deaconess Medical Center and Mayo Clinic-Rochester. Clinical trial information: NCT03604692 .

TPS5125 Background: Prostate cancer (PC) is common and despite recent advances in treatment options, patients with metastatic disease still have poor outcomes. The double PSMA binding moiety of SAR-bisPSMA in 64 Cu-SAR-bisPSMA (imaging) and 67 Cu-SAR-bisPSMA (therapy) may offer advantages compared to currently used single-target PSMA agents. Clinical evidence demonstrated 2-3 times higher uptake of 64 Cu-SAR-bisPSMA compared to the single-target PSMA agent, 68 Ga-PSMA-11. Pre-clinical efficacy data of 67 Cu-SAR-bisPSMA in mice showed statistically significant tumor growth inhibition and increased survival in a PC xenograft study. These results led to the development of the SECuRE trial, which aims to assess the safety and anti-tumor efficacy of 67 Cu-SAR-bisPSMA in patients with metastatic castrate resistant PC (mCRPC). Methods: SECuRE is a Phase I/IIa multi-center, open-label, non-randomized, dose-escalation and cohort expansion study of 64 Cu-SAR-bisPSMA and 67 Cu-SAR-bisPSMA in patients with mCRPC. The target population is patients who have progressed despite having at least one androgen receptor pathway inhibitor and demonstrate positivity on 64 Cu-SAR-bisPSMA PET. The study comprises 3 phases: Dosimetry (N=6), Dose Escalation (N~24) and Cohort Expansion (N=24). The 67 Cu-SAR-bisPSMA dose levels investigated in the Dose Escalation Phase are: 4 GBq (cohort 1, single dose), 8 GBq (cohort 2, single dose), 12 GBq (cohort 3, single dose) and 24 GBq across two doses (cohort 4, two doses at the maximum tolerated dose or maximum feasible dose [MTD/MFD] established in cohorts 1-3; two additional doses may be offered in case of radiological non-progression). In the Cohort Expansion phase, participants will receive 2 doses of 67 Cu-SAR-bisPSMA at the recommended dose determined in the Dose Escalation Phase (those with radiological non-progression may be offered up to 2 additional doses). A recent protocol amendment increased the number of participants from 14 to 24 in the Cohort Expansion phase, in which 8 will receive combination therapy of 67 Cu-SAR-bisPSMA with enzalutamide. The primary and key secondary objectives include assessment of 64 Cu- and 67 Cu-SAR-bisPSMA’s safety and dosimetry and determining the anti-tumor efficacy of 67 Cu-SAR-bisPSMA. Response to 67 Cu-SAR-bisPSMA will be assessed biochemically (≥50% decline in prostate-specific antigen) and radiographically (by RECIST V1.1 and PCWG3). Clinical trial information: NCT04868604 .

1510 Background: The National Comprehensive Cancer Network (NCCN) Harmonized Guidelines for Sub-Saharan Africa (SSA) have emerged as leading cancer treatment guidelines in SSA. The NCCN-SSA guidelines, derived by adapting NCCN guidelines for the SSA context, offer standardized recommendations to guide cancer care and shape policy in SSA. This study examines the evidence cited in support of the NCCN-SSA guidelines, with a focus on population characteristics and generalizability to SSA. Methods: Two reviewers independently examined the NCCN-SSA guidelines for the eight most common cancers in SSA to identify all studies cited in support of treatment/management recommendations. Study selection discrepancies were resolved by discussion. Full-text articles were reviewed and data on age, sex, race, and recruitment geography were abstracted. Descriptive analyses were performed using R statistical software. Results: Overall, 4,589 citations were reviewed, and 2,938 (64.0%) studies with individual-level data were included, representing >10.4 million study participants. Of the 2,061 studies reporting geographic information (70%), 50 (2.4%) recruited in SSA; of these, 39 (83.0%) recruited from South Africa. Three studies (0.2%) recruited exclusively in SSA. Most studies (95.3%) recruited exclusively from high or upper-middle income countries. Only 29.2% of studies with race data included >10% Black study participants. Conclusions: Most studies cited in the NCCN-SSA guidelines were conducted in high-income countries outside SSA. A small minority of all study participants were Black. Our findings underscore potential limitations in the generalizability of the NCCN-SSA guidelines to SSA and highlight a pressing need to generate and incorporate context-specific data to guide care and inform policy. WHO region of recruitment, race, and country-level income of studies included in NCCN-SSA guidelines. Cancer type # (%) studies reporting geography # (%) studies by recruitment region*: Americas # (%) studies by recruitment region*: Europe # (%) studies by recruitment region*: Sub-Sah. Africa % participants, White % participants, Black % participants, Other race # (%) studies representing only HMIC (per World Bank) Overall 2061(70%) 1177 (57%) 921 (45%) 50 (2%) 79% 9% 11% 1964(95%) B-cell 325(57%) 173 (53%) 178 (55%) 5(2%) 82% 7% 10% 307(94%) Breast 206(44%) 123 (60%) 124 (60%) 12 (6%) 80% 9% 11% 179(87%) Cervical 163(90%) 100 (61 %) 44(27%) 3(2%) 64% 14% 22% 158(97%) Colorectal 584(82%) 278 (48%) 292 (50%) 11 (2%) 80% 10% 10% 571 (98%) Hepato-cellular 183(74%) 80(44%) 68(37%) 0(0%) 69% 9% 22% 169(92 %) Kaposi sarcoma 51(80%) 25 (49%) 19(37%) 5(10%) 38% 51% 10% 44(86%) Ovarian 115(56%) 76 (66%) 35 (30%) 0(0%) 83% 4% 13% 115(100%) Prostate 434(88 %) 322 (74 %) 161 (37%) 14 (3%) 79% 9% 12% 421(97%) HMIC = high and upper-middle income countries. *Percent of studies includes as the denominator only the number of studies with reported geographies.

e15046 Background: BRAF V600 is the most common driver mutation in melanoma, seen in ≈50% of patients. Recently, the use of liquid biopsy assays that are based on circulating tumor DNA (ctDNA) has become widespread for diagnosis and residual disease monitoring. We have previously reported on our droplet digital PCR (ddPCR) test as a liquid biopsy for BRAF mutant (BRAFm) melanoma. Here we report the correlation between clinical and radiological parameters and ddPCR test results. Methods: Using the department of laboratory medicine archives, we have identified all biopsy proven BRAFm melanoma patients that were tested with the BRAF V600 ddPCR assay at our institution over the years 2018-2024. All patients had blood samples collected, and cell free DNA (cfDNA) was extracted from plasma using the Qiagen QIAamp Circulating Nucleic Acid Kit. cfDNA was evaluated with a BioRad QX200 droplet digital PCR platform assessing for BRAF V600E/K mutations. Clinical and demographic data were collected from medical records. Radiometabolic features including volumetric data and FDG PET SUV values were collected and analyzed using the MIM software (MIM Software Inc., Beachwood, OH, USA). Univariate and multivariate analyses were used to assess correlations between baseline variables and test results. Results: 71 patients were identified. The median age was 59 (26-85), 54% were males. 46 patients (65%) had a positive test result which was based on a cut-off of ≥4 mutant copies per ml. 65 patients (92%) had active disease on imaging studies, of which those with a positive test result were younger (p = 0.047), had a higher proportion of osseous metastases (p = 0.02) and had a higher number of lesions (p = 0.006). There was no difference in the median overall survival between the groups (11 months vs. 33 months for positive and negative result respectively, log-rank test; p = 0.15). Total tumor volume on PET-CT (in ml) was predictive of the quantitative ddPCR test result (in copies per ml), with every increase in 10 ml of tumor leading to an expected increase of 370 copies per ml (p < 0.001). Multivariate models have failed to show a correlation between baseline parameters and the quantitative ddPCR test result. When performing the analyses using logistic regression models with the binary ddPCR test result as the outcome, osseous metastases were predictive in a univariate model (OR = 4.3, 95% CI 1.4-15.4). The best fit multivariate model showed that higher burden of disease with ≥6 lesions (OR = 6.57, 95% CI 1.24-44.3) and elevated LDH (OR = 8.8, 95% CI 1.83-56.91) were associated with an increased risk for a positive result, while younger age was associated with decreased risk for a positive result (OR = 0.92, 95% CI 0.86-0.97). Conclusions: The results of ddPCR testing for BRAF mutation are correlated with the radiological and volumetric extent of the disease. This test could be useful in patients presenting with high-burden disease when a fast turnaround time is needed.

7049 Background: Odronextamab, an investigational off-the-shelf CD20×CD3 bispecific antibody, demonstrated compelling efficacy and a generally manageable safety profile in heavily pretreated pts with R/R FL in the primary analysis of the Phase 2 ELM-2 study (NCT03888105; Kim TM, et al. Ann Oncol 2024). We present updated efficacy and safety data for odronextamab in pts with R/R FL from ELM-2 after >2 yrs follow-up. Methods: Odronextamab was administered intravenously until disease progression/unacceptable toxicity, with Cycle (C) 1 step-up dosing to help mitigate cytokine release syndrome (CRS) risk, as reported previously. Pts with a complete response (CR) for ≥9 months (mo) switched from maintenance dosing Q2W to Q4W. Primary endpoint: objective response rate (ORR) per Lugano criteria by independent central review (ICR); secondary endpoints: CR rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS). Results: At the updated data cutoff (Aug 15, 2024), 157 pts with centrally confirmed R/R FL Grade (Gr) 1–3a were enrolled. Median no. of treatment cycles: 19.0 (range 0.1–117.3); 96.2% (n = 151) and 82.8% (n = 130) of pts completed C1 and C4, respectively. The global cohort comprised 128 pts evaluable for efficacy. At a median efficacy follow-up of 28.3 mo, ORR was 80.5% (n = 103) by ICR and CR rate was 74.2% (n = 95); 92.2% of responders achieved CR. Responses were durable (median DOR, 26.0 mo; median duration of CR, 32.2 mo). ORR was consistent across high-risk subgroups (Follicular Lymphoma International Prognostic Index score 3–5, 78.4%; progression of disease within 2 yrs of frontline therapy, 81.0%). Median PFS was 23.0 mo (estimated 36-mo PFS rate, 37.5%), and median OS was 54.2 mo (estimated 36-mo OS rate, 62.6%). Median PFS was longer in pts who were minimal residual disease (MRD) negative (42.4 mo) versus MRD positive (21.6 mo) at Week 12. Of 47/128 pts who switched to Q4W dosing, 32 remained in CR. The odronextamab long-term safety profile was consistent with the primary analysis. All 157 pts had TEAEs (Gr ≥3, 86.0%), and 15.3% discontinued treatment due to TEAEs (most common: COVID-19 infection, 2.5%). With 0.7/4/20 mg step-up dosing (n = 89), CRS events were mostly low grade (Gr 1, 46.1%; Gr 2, 13.5%; Gr 3, n = 1; Gr ≥4, n = 0), occurred mostly in C1, and resolved in a median of 8.4 hrs. Immune effector cell-associated neurotoxicity syndrome was reported in one pt (Gr 2). Infections were reported in 79.0% of pts (124/157; Gr ≥3, 42.0%). COVID-19-related infections were reported in 38.2% of pts (Gr 5, 5.7%). Conclusions: With longer follow-up, odronextamab demonstrated durable responses in heavily pretreated pts with R/R FL from ELM-2, with robust efficacy in those with high-risk features, and a generally manageable safety profile. Overall, these compelling results support odronextamab as a potential off-the-shelf treatment option for pts with R/R FL. Clinical trial information: NCT03888105 .

1015 Background: T-DXd is an antibody-drug conjugate approved for advanced HER2+/low/ultra-low breast cancer and multiple other solid tumors. T-DXd carries a rare but serious risk of ILD (incidence 12-15%), requiring frequent imaging and symptom evaluation. For > grade (G) 2 ILD, guidelines recommend permanent drug discontinuation. For asymptomatic G1 ILD, drug is held with the option for rechallenge (RC) if imaging findings resolve. Limited data exist on outcomes of RC after ILD in diverse real-world patients (pts). Methods: In this multi-center retrospective study, we analyzed pts with T-DXd related ILD treated from 2017-2024. Pts with ILD were identified via chart/ICD code review. Adjudication of T-DXd related ILD was based on treating providers’ assessment and graded via CTCAE v5. We collected pt demographics, T-DXd and steroid dosing, imaging results, and outcomes after RC. Statistical analysis was performed using Wilcoxon rank sum and Fisher’s exact tests. Results: Four centers treated 712 pts with T-DXd, with a 9.1% rate of any grade ILD (n=65). One other center reported only RC data in 18 pts with ILD. In total, 47 pts were RC; 38 after G1 ILD (81%), 9 after G2. Median (med) time to initial ILD was 145 days (d) after 1st dose (interquartile range [IQR] 78-205). Demographics for pts RC are shown in the table. Among 50 pts with G1 ILD, including pts not RC, 28/50 (56%) received steroids for a med of 36d (IQR 27-79). Radiographic improvement was seen at a med of 24d (IQR 19-63) for pts treated with steroids vs 82d (IQR 48-94) without (p<0.01); and a med of 35d (IQR 22-82) for pts RC vs 81d (IQR 68-105) for pts not RC (p=0.01). Among pts with G1 ILD, 38/50 (76%) were RC at a med of 42d (IQR 36-57) from last dose; 23/38 (61%) were dose reduced. After RC, pts remained on T-DXd for a med of 215d (IQR 60-334); 10/38 (26%) developed recurrent ILD (7-G1, 2-G2, 1-G3) at a med of 211d (IQR 47-273) from RC. No statistically significant differences were seen between ILD onset, time to RC, or demographics for pts with recurrent ILD vs not. Of the 9 pts RC after G2 ILD, T-DXd was continued for a med of 129d (IQR 49-171); 2/9 (22%) developed recurrent ILD (1-G2, 1-G3). No G5 toxicity was seen with RC. Conclusions: In this multi-center study, high RC rates were seen after G1 ILD with long duration of clinical benefit. Pts treated with steroids had faster radiographic ILD improvement, highlighting the importance of early steroid use. Among pts RC after G1 ILD, recurrent ILD rates were low, with the majority G1 and no G5 events. Notably, 9 pts with G2 ILD were RC, with a similar rate of recurrent ILD; this must be interpreted cautiously. Our large cohort data further supports the safety of T-DXd RC in diverse real-world settings. RC Pt Characteristics (n=47) n (%) or Median (IQR) Cancer typeBreastGIGyn 43 (91)3 (6)1 (2) Age (yrs) 57 (52-68) Prior # therapy lines in the advanced/metastatic setting 3 (1-5) Renal impairment (CrCl < 60 mL/min) 8 (17)

Background Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood. Methods We performed global untargeted metabolomics on plasma from 55 patients who underwent gold‐standard RV‐PA coupling measurements using multibeat pressure volume loop assessment in a single‐center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex‐adjusted linear regression was performed to identify associations between metabolites and coupling metrics. Additionally, we performed a metabolic flux analysis using gene expression data from RV tissue in an independent cohort of 32 patients. Partial least squares–discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. Results RV‐PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α‐ketoglutarate and fumarate were significantly associated with all coupling metrics in both cohorts. Metabolic flux analysis indicated that decompensated RVs exhibited aberrant TCA cycle activity, including reduced acetyl coenzyme A entry and increased lactate elimination, suggesting a shift from the TCA cycle toward glycolysis at the RV tissue level. Conclusions We identify an association between circulating TCA cycle intermediate levels and RV‐PA uncoupling in 2 independent cohorts, and dysregulated TCA cycle metabolism in decompensated PA hypertension RVs, suggesting that aberrant TCA cycle metabolism could represent a hallmark of RV maladaptation in PA hypertension. Further study of this pathway is warranted to develop novel biomarkers of RV function or RV‐targeted therapies.

SUMMARY Ewing sarcoma (EwS) is a group of bone and soft tissue cancers in children and young adults. Since EwS cells have pronounced sensitivity to radiation and chemotherapy-induced DNA damage, the role of the oncoprotein, EWS-FLI1, in DNA repair is likely. Here, we demonstrate that EWS-FLI1 causes a defect in microhomology-mediated end-joining (MMEJ) repair. EWSR1 is a splicing factor that promotes the faithful splicing of the POLQ pre-mRNA, required for the expression of POLΘ, a critical protein in the MMEJ pathway. Expression of EWS-FLI1, or loss of EWSR1, causes exon 25 skipping of the POLQ transcript, decreased POLΘ expression, impaired MMEJ, and cellular sensitivity to inhibitors of the Fanconi Anemia (FA), NHEJ, or HR pathways, through the mechanism of synthetic lethality. Knockdown of EWS-FLI1 expression restores POL0 mitotic foci and increases MMEJ activity. Inhibitors of the FA, NHEJ, or HR therefore may provide a targeted therapy for patients with EwS. Highlights - Ewing sarcoma tumors have a deficiency in POLθ expression and a corresponding loss of MMEJ activity - EWSR1 is a splicing factor that interacts with other splicing factors such as FUBP1 and KHSRP/FUBP2 to accurately splice the POLQ mRNA. - The EWS-FLI1 fusion oncoprotein, or loss of EWSR1, causes a splicing defect, leading to exon25 skipping of the POLQ pre-mRNA and loss of POLθ expression - The MMEJ deficiency of EwS cells results in cellular sensitivity to inhibitors of Fanconi Anemia, Homologous Recombination or Non-Homologous End-Joining - Exon 25 skipping of POLQ mRNA is a predictive biomarker for HR inhibitors in human cancers