Citations

Abstract Purpose: Polatuzumab vedotin (polatuzumab) was approved for up-front treatment of diffuse large B-cell lymphoma in combination with chemoimmunotherapy (Pola-R-CHP) based on the POLARIX trial. However, when stratified by cell of origin (COO), polatuzumab seems to have greater efficacy in activated B-cell than germinal center B-cell (GCB) subtype disease. Most studies of polatuzumab used RNA expression to assess COO, whereas in routine clinical practice, the immunohistochemistry-based Hans algorithm is used. Experimental Design: To assess the impact of COO by immunohistochemistry on polatuzumab efficacy, we conducted a multicenter real-world study of adults with large B-cell lymphoma (LBCL) receiving polatuzumab from 2015 to 2024, split by receipt of polatuzumab in first-line versus relapsed/refractory settings. The primary endpoint was overall response rate (ORR) to polatuzumab-based treatment in GCB versus non-GCB relapsed/refractory LBCL. Results: Of 740 patients, 305 received polatuzumab in the first-line setting and 435 in the relapsed/refractory setting. In the relapsed/refractory cohort, the ORR in non-GCB versus GCB LBCL was 59.7% versus 36.3% [OR, 2.6; 95% confidence interval (CI), 1.77–3.84; P < 0.0001], with a complete response rate of 35.7% versus 17.7% (OR, 2.6; 95% CI, 1.66–4.02; P < 0.0001). Progression-free survival was longer for patients with non-GCB versus GCB COO (HR, 0.64; 95% CI, 0.5–0.83; P = 0.0006). In the first-line cohort, ORR, complete response rate, and progression-free survival were similar in non-GCB versus GCB LBCL, as hypothesized based on outcomes in the Pola-R-CHP arm of POLARIX, suggesting that the addition of polatuzumab overcomes the adverse risk of non-GCB COO in patients receiving R-CHOP. Conclusions: Based on these data, COO classification by the Hans algorithm is a strong predictor of polatuzumab efficacy in LBCL, informing real-world treatment decisions.

465 Background: Molecular testing is crucial in advancing precision medicine, enabling oncologists to tailor targeted treatment strategies for cancer patients (pts). The National Comprehensive Cancer Network (NCCN) and ASCO guidelines recommend comprehensive biomarker testing for pts with mPC. However, compliance can vary considerably among institutions. This study aimed to assess current practices of molecular testing in diverse healthcare settings across the state of Florida and identify opportunities for improvement to optimize outcomes for pts diagnosed with mPC. Methods: We conducted a detailed 12-question survey, distributed both electronically and in-person to evaluate the molecular testing practices of healthcare providers throughout the state. The survey assessed multiple parameters including adherence to testing, reviewing test results to guide treatment decisions, and the availability of different supportive resources in biomarker testing. This initiative was executed in partnership with the Florida Society of Clinical Oncology and industry partners. Results: A total of 40 responses were collected from 11 institutions in Florida, including 5 academic centers and 6 community-based hospitals. Notably, 22.5% of respondents reported that their institutions either do not fully comply with NCCN guidelines or lack protocols to identify eligible pts and 67.5% stated they are responsible for their own biomarker education and updates. Only 56.4% consistently review molecular testing results during disease progression to guide treatment decisions. Nearly all institutions lack clinical decision support tools in the electronic medical records (EMR) to support testing, and 82.5% receive biomarker results outside the EMR. Additionally, 38.5% lack a standard process for obtaining prior authorization for testing. Furthermore, 38.5% lack a multidisciplinary review process for genetic test results, and 76.3% reported that their biomarker testing process does not involve geneticists or genetic counselors. Conclusions: Our study identified critical gaps in adherence to biomarker testing guidelines with many practices lacking decision support tools across healthcare institutions in Florida. Potential areas for improvement include better standardization of result integration into EMR, targeted educational initiatives, and stronger multidisciplinary collaborations. The implementation of these measures aims to improve the quality of care and outcomes for pts with mPC.

Abstract Epcoritamab and glofitamab are CD20-directed bispecific antibodies (BsAbs) approved in the United States for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Limited data exist for patients treated outside of trials. Patients with R/R DLBCL receiving commercial epcoritamab or glofitamab between 1 January 2023 and 15 October 2024 were collected from 21 United States institutions. Among 245 patients, 156 received epcoritamab and 89 received glofitamab, 113 were refractory to front-line therapy, 40 had MYC and BCL2 and/or BCL6 rearrangements, 147 received prior chimeric antigen receptor T-cell therapy, and 174 patients would have been ineligible for registrational trials. The overall response rate (ORR) for epcoritamab and glofitamab was 51% (23% complete response, [CR]) and 53% (30% CR), respectively. Median progression-free survival (PFS) was 2.6 months (95% confidence interval [CI], 2.0-3.8 months), and median overall survival (OS) was 7.8 months (95% CI, 6.2-11.0 months). The 6-month PFS was 36% (95% CI, 30-44) and the 6-month OS was 60% (95% CI, 54-67). Both trial ineligibility and undetectable CD20 pre-BsAbs portended shorter PFS and OS. Of 17 individuals with paired biopsies, 15 (88.2%) lost CD20 expression after BsAbs with a median time to progression of 3.7 months. This analysis including patients with R/R DLBCL shows the ORR to CD3/CD20 BsAbs was comparable to pivotal trials, although PFS and OS were lower. Baseline undetectable levels of CD20 were associated with poor outcomes. These results demonstrate the activity of BsAbs in R/R DLBCL, and underscore the importance of target antigen expression.

e16330 Background: Sarcomatoid hepatocellular carcinoma (SHC) is a rare and aggressive variant of hepatocellular carcinoma (HCC), accounting for less than 2% of all primary liver cancers. Characterized by the presence of both epithelial and mesenchymal components, SHC demonstrates a high degree of cellular plasticity, often associated with epithelial-mesenchymal transition. This phenotypic heterogeneity contributes to its aggressive clinical behavior, including rapid tumor progression, early metastasis, and poor response to conventional therapies. As a result, patients diagnosed with SHC typically have a median survival of less than 12 months, significantly lower than that observed in patients with conventional HCC. Methods: We conducted a retrospective study at the Mayo Clinic Comprehensive Cancer Center, focusing on patients diagnosed with SHC between April 2017 and December 2023. The data collected included demographics, performance status, underlying risk factors, alpha-fetoprotein (AFP) levels, next generation sequencing (NGS) testing, and the treatment received. Results: A total of ten patients with confirmed diagnoses of SHC were included, with median age at the time of diagnosis 63.5 years (37-77), predimonantly male (9 out of 10), and identifying white (8 out of 10). Alcoholic cirrhosis was identified as an underlying risk factor in three patients, NASH cirrhosis in two, and HCV in two patients. The majority (6 out of 10) of the patients had localized disease, with 4 patients having denovo metastatic disease with abdominal lymph node involvement. Five patients had NGS testing (Tempus, Guardant 360, and ProvsSeq523), with resultant pathogenic variants including TP53 in 3 patients, NTRK3 fusion, IDH2, EGFR, TERT, MLH1, ARIS1A, and PALB2. Four patients were treated with combined Yitrrium-90 and systemic therapy. Three patient started systemic therapy, and two patients underwent surgical resection. Systemic Therapy used included combined Atezolizumab/ Bevacizuamab, Pembrolizumab/ Lenvatinib, Gemcitabine/ Docetaxel, Gemcitabine/ Cisplatin, Cabozantinib, and pembrolizumab monotherapy. The median overall survival for this group was 11.5 months; 95% confidence interval (CI): 4.66-40.1 months. Seventy percent experienced progression, with a median progression-free survival after first line of treatment of 2.5 months; 95% CI: 1-15.3 months. Conclusions: Sarcomatoid HCC remains aggressive and difficult to treat cancer with limited overall survival. Immunotherapy based regimens have limited efficacy for this HCC variant.

e16265 Background: The pivotal TOPAZ-1 trial established durvalumab plus gemcitabine and cisplatin (GC) as a new first-line standard of care for advanced biliary tract cancer (ABTC). However, weekly administration of GC can lead to significant toxicity limiting its tolerability in clinical practice. Based on previous studies, we implemented biweekly regimen of GC on days 1 and 15 together with durvalumab on day 1 of each 28-day cycle to optimize the treatment delivery and improve tolerability. Here, we report the Mayo Clinic experience with biweekly GC with monthly durvalumab in patients with ABTC. Methods: At our three-site institution, we retrospectively identified patients with ABTC between January 2021 and August 2024, who received biweekly GC with monthly durvalumab. Patient demographics, tumor characteristics, treatment details - treatment related adverse events (trAEs) graded according to the NCTCAE V5.0 were collected. Outcomes included median progression-free survival (mPFS), median overall survival (mOS) and clinically assessed overall response rate (ORR) and disease control rate (DCR). Results: 57 patients were included in our analysis, median age was 68 years (range 35-90), and 57.9% were females. 91.2% of patients had ECOG performance status of 0-1. 71.9% had intrahepatic cholangiocarcinoma, 19.3% extrahepatic cholangiocarcinoma and 8.7% gallbladder carcinoma. 70.2% had metastatic disease, 21 % locally advanced unresectable disease and 8.7% recurrent metastatic disease. Patients were followed for a median of 9.1 months (2.3-28.5). 91.2% of the patients received biweekly GC plus monthly durvalumab while 8.8% switched from weekly to biweekly GC plus monthly durvalumab due to treatment toxicities. Median number of treatment cycles was 5. Maintenance regimens included durvalumab (19.3%), gemcitabine/durvalumab (8.8%) and GC/durvalumab (8.8%). Median duration of follow up was 9.1 months (range 2.3 – 28.5). ORR was 36.9% and DCR was 72% (complete response 5.3%, partial response 31.6% and stable disease 35.1%). mPFS was 7.2 months, while mOS was 16 months. Grade(G) 3 or 4 trAEs included abnormal liver function tests (15.7%), infections (11.5%), anemia (8.7%), thrombocytopenia (5.2%), peripheral neuropathy (1.7%), acute kidney injury (1.7%). Immune-related AEs were noted in 6 patients (10.5%) including colitis, gastritis, hepatitis, myocarditis and hypothyroidism. There was no patient with severe neutropenia or febrile neutropenia. Only 5 patients (8.8%) stopped treatment due to trAEs. Conclusions: Biweekly GC on days 1 and 15 plus durvalumab on day 1 of each 28-day cycle is associated with a more favorable toxicity profile while maintaining efficacy similar to that observed in the TOPAZ-1 trial indicating that a de-escalation strategy is feasible with improvement in patient centered outcomes.

9029 Background: Addressing guideline concordant FP and TPP with cancer is challenging, especially for OT. SIM, a well-known education tool, has not been traditionally used to teach these topics. As part of the hematology/oncology fellowship curriculum, we designed a SIM applying LSP to bridge this educational gap. Methods: Applying LSP of contrasting cases, elaboration, feedback, generation and just-in-time telling, chief OTs and faculty designed a SIM with 3 clinical scenarios (CS) and 3 standardized pts (SP): FP for a female pt hospitalized for acute lymphoblastic leukemia tx, FP for a male pt in clinic for germ cell tumor tx, and breast cancer tx for a pregnant pt in 2 nd trimester. OT received written educational materials (WEM) and attended a lecture 1 week and 1 day pre SIM, respectively. OT were split into 2 groups; 1 started in the FP CS and 1 in the TPP CS, and then they switched. To reduce cognitive overload, each OT participated in 1 of 2 FP CS: half in the female FP CS and half in the male. Faculty and chiefs led debriefing sessions after all CS. The FP debrief ended with a special “learner as a teacher” part, where OT who attended the female CS taught those from the male CS about their topic and vice versa. The SIM concluded with "take-home" points. Pre (after having WEM) and post SIM anonymous surveys and verbal feedback assessed OT comfort, perceptions, and knowledge. Results: A 3 hour SIM with 14 OT and 5 faculty was completed successfully. SIM ended with all OT verbally sharing a learning point and positive feedback. All OT filled pre and post SIM surveys. Pre SIM, 17% reported having prior FP education, and 42% had prior TPP education. However, only 8% and 25% felt adequately prepared for FP and TPP discussions, respectively. Post SIM survey showed major improvement in comfort and knowledge about FP and TPP (see table 1). 75% of OT favored a combination of SIM and learning by teaching over other SIM formats. 83% supported having a TPP lecture before SIM. 100% reported satisfaction with FP and TPP SIM’s quality and wanted similar activities in the future. 92% were satisfied with the learner as a teacher tool. 100% felt education about FP and TPP with cancer should be part of fellowship training. Moral/cultural concerns were discussed as possible challenges in FP education. Conclusions: The application of LSP through SIM significantly increased OTs’ comfort discussing FP and TPP with cancer, and objectively enhanced their knowledge on these topics compared to after reading WEM. The SIM was largely perceived as a successful activity to educate about challenging topics and should become part of fellowship curriculum. Pre SIM % Post SIM % Comfortable addressing FP 17 92 Comfortable addressing TPP 8 100 Correct answers about female FP 63 83 Correct answers about male FP 67 94 Correct answers about TPP with cancer 68 98

10587 Background: The American Society of Clinical Oncology (ASCO) and NCCN recommend germline testing for patients (pts) with biliary tract cancers (BTC), particularly those diagnosed at a young age. Prior studies estimate that approximately 15% of pts with BTC harbor pathogenic germline alterations. Germline testing can identify hereditary cancer syndromes, guide targeted therapy, and inform family counseling. This study aimed to further characterize and describe the prevalence of pathogenic germline variants (PGVs) in patients with young-onset BTC (YO-BTC). Methods: We conducted a retrospective review of medical records for pts diagnosed with YO-BTC (ages 18–55) across all Mayo Clinic tri-sites from January 2014 to October 2024. Data collected included results from germline DNA sequencing, tumor genetic testing, demographics, history of other malignancies, and family history of cancer. The primary outcome was the identification of pathogenic germline mutations associated with cancer predisposition. Results: Among 239 pts with YO-BTC, the median age at diagnosis was 43 years (range 19–55), with 62% female and 65.2% identifying as white. Clinical germline testing (e.g., Invitae, Ambry, Myriad) was performed in 123 pts (51.5%), revealing PGVs in 15 pts (12.1%), variants of uncertain significance (VUS) in 30 pts (24.3%), and likely benign variants in 4 pts (3.2%). Among those with PGVs, DNA repair mutations were the most common findings (10/15), including ATM (4), CHEK2 (2), BRCA2 (2), BAP1 (1), and PALB2 (1). One pt had a Lynch syndrome-associated mutation (MSH6), and four had mutations in other cancer-related genes (MUTYH, HOXB13, RMRP, and PIK3CA). Tumor genomic profiling (via CARIS, TEMPUS, or FoundationOne) was performed in 9 pts with PGVs, detecting the variant in 4 (44%), while liquid biopsy (Guardant) identified the PGV in 4 of 6 cases (66.6%).The majority of PGV carriers had advanced BTC (14/15), with intrahepatic cholangiocarcinoma being the most prevalent (11/15), while 4 had extrahepatic cholangiocarcinoma. Additionally, most PGV carriers had a first- or second-degree relative with a prior history of malignancy (14/15), and 3 pts had a second malignancy. Of the 15 pts with PGVs, 4 had BTC associated with primary sclerosing cholangitis. Conclusions: In this large institutional series of YO-BTC, PGVs were identified in 12.1% of pts, demonstrating a significant yield from germline testing in this population. Notably, tissue and liquid biopsies demonstrated different detection rates for PGVs, underscoring the variability in PGVs reporting across platforms. Germline testing through CLIA-approved methods should remain the standard of care. DNA repair pathway mutations, particularly ATM, CHEK2, and BRCA2, were the most frequently identified PGVs, highlighting their role in the pathogenesis of YO-BTC and their potential to guide treatment decisions.

163 Background: CRC with PM has a poor prognosis and limited treatment options. Immunotherapy has shown promise in improving outcomes for patients with microsatellite instability-high (MSI-H), mismatch repair-deficient (dMMR), and high tumor mutational burden (TMB-H) tumors. However the peritoneal niche has a unique microenvironment, which can influence the effectiveness of immune check point inhibitors (ICIs). We assessed the impact of ICI on progression-free survival (PFS) and overall survival (OS) in CRC patients (pts) and PM, considering key clinical and molecular characteristics. Methods: A retrospective review aiming to identify CRC pts with MSI-H/dMMR and PM treated with immunotherapy between 2015 and 2023 was performed. Data collected included pt demographics, tumor characteristics, and treatment details. Responses were evaluated using RECIST v1.1 criteria. Results: 37 pts were included, 9 (24%) had Lynch syndrome. The median age of diagnosis was 61 years and most pts were females (65%). Most pts had MSI-H/dMMR tumors, while one pt was treated based on ultra-hypermutated phenotype (TMB 202) and POLE mutation. Among those with available TMB data, the median TMB was 52 mutations/Mb (0-202). Common mutations were PMS2 (51%), MLH1 (38%), MSH6 (16.2%), and MSH2 (16.2%). Right-sided tumors were in 54%, mucinous histology in 62%, and ascites in 54%. Pts received a median of 11 cycles of ICI (2-52). Pembrolizumab was the most frequently used ICI (78%), while Nivolumab was used either alone (11%) or in combination with Ipilimumab (11%). Median PFS in our cohort was 7.8 months and median OS was 29.9 months. The disease control rate (DCR) was 81%, with an objective response rate (ORR) of 51.3% (9 complete responses, 12 partial responses). At the time of data collection, 30% of pts were off systemic therapy and 5-FU-based chemotherapy combined with a biologic agent was the most common subsequent treatment in 32% who had PD. Univariate analysis showed no significant differences in PFS or OS based on tumor sidedness, isolated PM, liver metastases, mucinous vs. non mucinous histology or BRAF / RAS status (WT vs mutant). Malignant ascites was associated with worse OS(HR 0.3; p= 0.03). Conclusions: Treatment with ICIs in pts with MSI-H/dMMR and/or TMB-H CRC and PM improved disease control in CRC pts with PM, however, as compared to historical controls for patients with MSI-H/d-MMR disease treated with ICI, this group showed less favorable outcomes. Malignant ascites was associated with poorer overall survival. Further research of the immune response and tumor microenvironment in the peritoneal cavity is warranted.

Introduction: The treatment of older patients with advanced stage classical Hodgkin lymphoma (cHL) is challenging and outcomes remain poor compared to younger patients (pts). A subgroup analysis of older pts (aged ≥ 60 years) enrolled in the SWOG S1826 study showed the Nivolumab-AVD regimen was better tolerated and improved progression free survival (PFS) compared to concurrent brentuximab vedotin-AVD (Bv-AVD). The sequential administration of Bv before and after AVD chemotherapy (seq Bv-AVD-Bv) is a commonly used approach to minimize the toxicity of Bv-AVD in older pts based on the tolerability and efficacy shown in a phase II study (Evens, et al. J Clin Oncol 2018). There is limited data on clinical outcomes with seq Bv-AVD-Bv in the real-world setting. We report our multicenter study of sequential Bv-AVD-Bv administration in older patients with cHL. Methods: This retrospective study included a total of 40 older pts with cHL treated with sequential Bv-AVD-Bv in 6 cancer centers. Descriptive statistics were used to depict patient demographics and disease characteristics prior to treatment initiation. Responses to therapy were assessed using the Lugano criteria. Response evaluable patients were those who received at least one cycle of chemotherapy with AVD. PFS and overall survival (OS) were estimated using log-rank testing with the Kaplan Meier curves. Results: The majority (n=23, 57.2%) of patients were male; median age was 72.5 years (range, 57-86 years); 10 (25%) pts were Hispanic, and 18 (45%) pts were Caucasian; performance status by ECOG was 0-2 in 33 (82.5%) pts. In terms of disease characteristics 19 (47.5%) pts had cHL NOS, 10 (25%) had nodular sclerosing subtype; stage III/IV in 35 (87.5%), stage II in 5 (12.5%) pts; B- symptoms in 21 (52.5%); extranodal disease in 19 (47.5%), with bone marrow involvement in 10 (25%) pts. Among the 38 response-evaluable patients the ORR and CR rates were 97.4% and 71.1%, respectively. Bv dose reductions or interruptions were reported in 14 (35.9%) pts. Treatment discontinuation (Td) occurred in 16 (40%) pts. The most common any grade adverse events were hematological toxicities (HT) in 28 (70%) pts and peripheral neuropathy in 24 (60%) pts. Forty-five percent of patients experienced grade 3 or higher HT. The overall incidence of grade 2 or higher peripheral neuropathy was 15%. The main reasons for treatment discontinuation were toxicity (n=9) and disease progression (n=4). During treatment, 1 (2.5%) pt reported loss of basic activities of daily living (ADLs) and 5 (12.5%) had loss of instrumental ADLs (iADLs). G-CSF prophylaxis was used in most (n=33, 82.5%) pts. At a median follow up of 25.7 months (range, 2.6 - 58.9) the 2 years PFS was 62.6% (95% CI: 46.1-79.1) and the 2 years OS was 83.3% (95% CI: 67-99.6). On univariate analysis, the median PFS correlated with the depth of response (CR: not reached; PR: 11.4 months; SD/PD: 3.9 months; P=0.0001); and with treatment discontinuation (No Td: not reached; Td: 21.6 months; P=0.007). There was no correlation between age, sex, institution, B- symptoms, bone marrow involvement, ADL/iADLs, or disease stage with treatment discontinuation. Conclusion: Sequential Bv-AVD-Bv in older patients with cHL can help minimize the toxicity associated with the concurrent administration of Bv-AVD. This sequential approach has shown comparable efficacy in real-word setting as seen in clinical trials. Our findings suggest seq Bv-AVD-Bv remains a feasible option for older fit patients with cHL outside clinical trials. Further randomized studies in older cHL pts are needed.