Complete Radiographic Response Research Articles

Voxel-Based Dosimetry Predicts Local Tumor Progression Post 90Y Radiation Segmentectomy of Colorectal Liver Metastases

Background Radiation segmentectomy (RS) is an alternative potential local curative treatment for selected colorectal liver metastases (CLMs) not amenable to ablation or limited resection. Purpose The aim of this study was to evaluate the dosimetric response of low volume CLMs to RS in heavily pretreated patients who are not candidates for resection or percutaneous ablation. Patients and Methods This single-center retrospective study evaluated CLMs patients treated with RS (prescribed tumor dose >190 Gy) from 2015 to 2023. RS doses to tumor(s) and margins were calculated from SPECT/CT and PET/CT images. Response and local tumor progression (LTP) were assessed using anatomic (RECIST 1.1) and metabolic (PERCIST) criteria. LTP-free survival (LTPFS) and overall survival were estimated with Kaplan-Meier methodology. Variables were assessed as predictors of LTPFS using the Cox proportional hazards model. Results Thirty-six patients underwent 38 RS procedures to treat 57 tumors. Median time from initial diagnosis to detection of liver metastases and RS were 16.4 (interquartile range: 6.5–32.2) and 26.8 (interquartile range: 12.5–40.0) months, respectively. Median overall survival after RS was 14.3 (95% confidence interval [CI]: 10.8–30.7) months. Predictors of LTPFS included tumor number(s), mean tumor dose (MTD), and margin mean absorbed dose (MMAD). Complete radiographic (hazards ratio [HR]: 1.29e-16, 95% CI: 4.06e–17-4.07e-16, P < 0.001) and metabolic response (HR: 0.38, 95% CI: 0.15–0.95, P = 0.038) correlated with prolonged LTPFS. One-year LTPFS rate was 83.3% for tumors receiving MTD ≥400 Gy and a 5-mm surrounding MMAD ≥350 Gy (P = 0.006). No instances of LTP were observed when tumors received stereotactic irradiation over 300 Gy (at least 95% of the tumor volume received ≥300 Gy). One-year LTPFS rate for tumors receiving MTD ≥400 Gy was 68.6% versus 14.3% for those that did not reach this threshold (P = 0.013). In multivariate analysis, MTD ≥400 Gy and 5-mm MMAD ≥350 Gy were independent predictors of LTPFS (HR: 0.11; 95% CI: 0.01–0.81; P = 0.03). Conclusions MTD ≥400 Gy, MMAD ≥350 Gy, and stereotactic tumor irradiation ≥300 Gy are associated with prolonged LTPFS after RS for CLMs.

Molecular Disease Monitoring in Patients With Relapsed/refractory B-Cell Lymphoma Receiving Anti-CD19 CAR T-Cell Therapy

BackgroundChimeric antigen receptor (CAR) T-cell therapy has improved the historically poor outcomes for relapsed and refractory (R/R) large B-cell non-Hodgkin's lymphoma (LBCL). However, nearly 60% of patients will either fail to respond or relapse after CAR T-cell therapy. Currently, PET/CT scans are used to assess response. Cell-free circulating tumor DNA (ctDNA) is released by tumor cells into the peripheral blood and can be measured for minimal residual disease (MRD) assessment. MethodsIn this retrospective, IRB approved pilot study, archived lymphoma tissue and ctDNA from peripheral blood samples on day 0, 14, 28, 56, 90, 180, and 365 after CAR T-cell infusion from 10 patients with R/R NHL were collected for next-generation sequencing (NGS) of clonal variable-diversity-joining (VDJ) rearrangements (Adaptive biotechnologies [Seattle, WA]). Response was assessed by PET/CT on days 90 and 365 and graded according to the Lugano 2014 criteria. The primary endpoint was to determine the feasibility of detecting ctDNA to monitor disease response after anti-CD19 CAR T-cell therapy. The secondary endpoint was to compare the sensitivity/specificity of MRD assessment from ctDNA to PET/CT imaging. ResultsNine out of 10 patients with a trackable sequence [median age 69 (range: 56-76); 55.6% male; median LDH 224], were included in this study. Each received tisagenlecleucel (tisa-cel) CAR T-cell therapy after median 2 prior treatments (range: 2-4). 7/9 patients had R/R diffuse large B-cell lymphoma (DLBCL), and 2/9 had transformed follicular lymphoma. At a median follow up of 12.7 months (range: 1.5-30 months), 4 patients were alive. By day 90, 3 patients (33.3%) achieved a radiographic complete response (CR) whilst 6 patients (66.6%) had progressive disease (PD). Detectable MRD on day 14 or day 28 had 83% sensitivity and 100% specificity for radiographic progression at any time before 1 year. For patients with PD, the median (interquartile range) MRD at day 0, 14, and 28 were 17.31 (1.01, 96.84), 9.12 (0.30, 18.8), and 23.77 (8.01, 137.53) copies per milliliter (mL), respectively. For patients with detectable MRD at day 28, mOS and mPFS were 6.7 and 1.3 months, respectively. ConclusionMonitoring MRD was a sensitive and specific method to detect poor response to tisa-cel. Additional studies evaluating MRD more frequently and with different products are warranted.

Paclitaxel and cisplatin/carboplatin plus tislelizumab in young patients with cervical cancer preserve fertility: Phase II prospective, single arm clinical study.

e17513 Background: Cervical function damage after fertility-sparing surgery has a lower pregnancy success rate. Chemotherapy (chemo) mainly plays an auxiliary role in the treatment of cervical cancer (CC), but its efficacy is limited. Recently, immunotherapy has shown remarkable progress in treatment of CC, potentially provide new treatment options for pts of childbearing age who require preservation of fertility. Herein, we conducted this study to evaluate the efficacy and safety of chemo plus tislelizumab (TIS) in young pts with CC who required fertility preservation. Methods: In this single arm, phase II trial, pts with histologically confirmed invasive, FIGO2018 stage IB1-IB3 or IIIC1r (localized cervical lesions) CC, and having fertility needs were enrolled. Eligible pts received 4 cycles chemo (175 mg/m2 paclitaxel + 70 mg/m2 cisplatin/AUC 5-6 carboplatin, Q3W) + TIS (200 mg, Q3W), followed by surgery-diagnostic cervical conization and sentinel lymph node (SLN) biopsy (IIIC1r stage with pelvic lymph node [PLN] systematic dissection)-upon achieving a radiographic complete response (CR). After surgery, pts will undergo 2-cycle chemo plus TIS therapy, if PLNs achieve a pathological complete response (pCR), regardless of the pCR status of localized cervical lesion. If the first cervical conization did not result in a pCR for localized cervical lesion only, a second conization was performed after 2-cycle chemo + TIS. Upon achieving pCR in both the cervical local disease and PLN, maintenance therapy (MT) with TIS will be continued for 1 year. Primary endpoint is pCR (SLN/PLNs + cervical conization) after surgery. The key secondary endpoints included clinical response to 4 cycles chemo + TIS, pregnancy rate, fertility rate, and treatment-emergent adverse events (TEAEs). Results: Between March 2022 and January 2024, 7 pts (mean age 31 years, range 27-38) were enrolled, with 2 pts (28.6%) having stage IIIC1r disease. All 7 pts received chemo plus TIS therapy; of these, 5 (71.4%) pts completed 4 cycles The objective response was achieved in 5 pts, with all complete response. Amenorrhea was observed in 3 of 5 pts (60%), with 2 recovering normal menstruation after chemo cessation, and 1 had finished the last chemo+TIS for 3 weeks and had not yet returned. During 4 cycles chemo + TIS therapy (n=7), the most common TEAEs of any grade were rash (71.4%), alanine aminotransferase increased (57.1%), neutrophil count decreased (57.1%), and white blood cell count decreased (57.1%). At data cutoff (median follow-up, 9 months, range 3.5-17), 1 pt experienced disease progression during MT, and 1 pt got pregnancy 3 months after completed MT. Conclusions: Chemo plus TIS could mediate tumor regression and eliminate micro-metastases with a tolerable safety profile, potentially allowing for fertility preservation in many pts for which this was not thought to be an option. Clinical trial information: ChiCTR2300067495.

Responses to immune checkpoint inhibitor therapy in NF1 mutated cutaneous melanoma.

e21535 Background: NF1 mutations occur in 14% of cutaneous melanoma. Less than 20% of advanced melanoma patients on Immune Checkpoint Inhibitor (ICI) therapy achieve radiographic Complete Response (CR). We present data on radiographic responses to ICI therapy in advanced melanoma patients with tumors harboring NF1 (Neurofibromatosis 1) mutations. Methods: Patients with metastatic or unresectable NF1 mutated melanoma were included in the analysis. Mutation status was identified via NGS and mutation pathogenic status was determined using Genome Oncology Software. All patients received ICI therapy. RECIST 1.1 was used to assess treatment responses with CT scans. CR on PET was defined as disappearance of all metabolically active lesions. Results: 26 metastatic or unresectable melanoma patients met criteria for inclusion. Of these, eight (30.8%) had CNS metastasis. ICI therapy included Ipilimumab-Nivolumab, Pembrolizumab, Nivolumab, or Relatlimab-Nivolumab (24/26 in front-line setting). The 12- and 24-month estimated cumulative incidence of CR were 43.9% and 60.6%, respectively. Altogether, 16 patients achieved CR as their best overall response. Four patients that achieved CR subsequently progressed. Four patients progressed without achieving CR. Six patients achieved a partial response by last follow-up without achieving CR or disease progression. Of the 8 patients with CNS metastasis, five (62.5%) had intra-cranial radiographic responses to ICI therapy, including 1 (12.5%) complete response. Five (62.5%) had multifocal ( > 2 sites of intracranial metastasis) intracranial disease. Five (62.5%) of these patients with intracranial disease received radiation, 2/8 (25.0%) received radiation and surgical resection, and one (12.5%) received neither radiation nor surgery. Three (37.5%) patients with CNS metastasis experienced disease progression while on ICI therapy. Conclusions: NF1 mutated melanoma appears to have high rates of radiographic responses to ICI therapy. Prospective validation of this finding, particularly in patients with CNS metastasis, is warranted.

A phase II multicenter study of abexinostat, an oral histone deacetylase inhibitor, in patients with relapsed/refractory follicular lymphoma.

7059 Background: Epigenetic alterations are major drivers of Follicular lymphoma (FL). Histone deacetylase (HDAC) inhibitors have potential to counteract the loss of histone acetylation that results from CREBBP or EP300 mutations. Abexinostat (Abx) is a novel potent oral pan-HDAC inhibitor with a pharmacokinetic profile that allows maintenance of sufficient drug concentrations for anti-tumor activity with twice daily (BID) dosing. Abx was shown to be well-tolerated with significant response in pts with relapsed/refractory (R/R) FL. Methods: This phase Ⅱ study evaluated Abx 80 mg administered orally BID 4 hours apart in a “one week on, one week off” schedule (days 1 to 7 & 15 to 21 of a 28-day cycle) in pts with R/R FL (grade 1-3a). Key inclusion criteria included age ≥18 years, ≥ 2 prior treatment regimens, ECOG of 0-2, and measurable disease per Lugano 2014 criteria. Pts undergo efficacy assessment by enhanced CT/MRI every 8 weeks for the first 24 weeks, and every 12 weeks thereafter, and PET-CT at weeks 12 and 24 and to confirm a complete response (CR), in accordance with the Lugano 2014 criteria. Bone marrow (BM) evaluation was mandated in pts with baseline BM involvement who achieved radiographic CR. The primary endpoint is independent review committee (IRC)-assessed overall response rate (ORR). Secondary endpoints include duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: At the data cut-off date of December 15, 2023, data were available for 90 pts. Median age was 55.0 (range 27-79), 57.8% of pts were male, and 22.2% had ≥ 3 FLIPI-2. Pts had a median of 3 prior lines of therapy (range 2-9), and 24.4% were refractory to the last prior regimen, 27.8% of pts had been treated with PI3K inhibitors before. With a median follow-up of 20.8 months, of 82 pts evaluable for efficacy, the IRC-assessed ORR was 67.1% (95% CI: 55.8%-77.1%), including 12.2% CR. The ORR for pts with > 3 lines of prior therapy was 69.0% (95% CI: 49.2%-84.7%). The median PFS and median DoR was 13.77 (95% CI: 9.69-not evaluable [NE]) months and 13.96 (95% CI: 8.34-NE) months, respectively. Median OS was not reached, and the 42-month OS rate was 74.3% (95% CI: 58.1%-85.0%). Of 90 pts evaluable for safety, the most common (≥ 40%) treatment-emergent adverse events (TEAEs) were thrombocytopenia (85.6%), neutropenia (58.9%), leukopenia (52.2%), nausea (50.0%), anemia (48.9%) and diarrhea (46.7%); ≥grade 3 TEAEs (≥ 5%) included thrombocytopenia (37.8%), neutropenia (23.3%), leukopenia (7.8%), and lymphopenia (5.6%). TEAEs led to dose reductions and discontinuations in 28.9% and 3.3% of all pts, respectively. Conclusions: Abx was well tolerated at dose of 80 mg BID as monotherapy, and demonstrated a significant response in pts with heavily pretreated R/R FL. Clinical trial information: NCT03934567 .

Abstract 5071: Minimal residual disease (MRD) status by peripheral blood mononuclear cells (PBMCs) and circulating tumor DNA (ctDNA) demonstrates rapid, deep, and sustained response in patients (Pts) with relapsed/refractory follicular lymphoma (R/R FL) treated with subcutaneous (SC) epcoritamab monotherapy in the pivotal phase 1/2 EPCORE™ NHL-1 trial

Abstract Introduction: Outcomes in high-risk R/R FL are poor. Epcoritamab SC, a CD3xCD20 bispecific antibody, demonstrated promising efficacy with a manageable safety profile in pts with R/R FL after ≥2 prior lines of therapy (phase 1/2 EPCORE NHL-1; NCT03625037). Here we evaluated MRD with PBMCs and ctDNA in pts with R/R FL and correlated the results with clinical findings. Methods: Adults with R/R FL 1-3A enrolled in EPCORE NHL-1 received epcoritamab SC in 28-day cycles. MRD analysis was performed on longitudinal plasma and PBMC samples collected at prespecified timepoints (clonoSEQ assay, Adaptive Biotechnologies). Screening tumor biopsies were used to identify trackable tumor clones; samples were quantified as tumor clones detected per mL plasma for ctDNA and per one million nucleated cells for PBMC. Overall response and progression-free survival (PFS) were assessed using Lugano criteria by independent review committee. Results: Of 128 pts in the R/R FL 1-3A cohort, 91 with PBMC data and 100 with ctDNA data were MRD evaluable. Overall MRD negativity was achieved in 67.0% [95% CI: 56.4-76.5] of pts per PBMC and 68.0% [95% CI: 57.9-77.0] of pts per ctDNA. Concordance of subject-level MRD status was high (79 of 89 with PBMC and ctDNA data; 88.8%). In most pts, MRD negativity was reached prior to radiographic complete response (PBMC, 76.4%; ctDNA 58.5%). MRD negativity by PBMC preceded ctDNA (median days to MRD negativity, 28 [PBMC] vs 57 [ctDNA]), suggesting a difference in methodology in detecting tumor DNA. Pts who became MRD negative had prolonged PFS (median not reached). Baseline MRD levels were not associated with clinical outcomes (PBMC; Wilcoxon P=0.59, ctDNA P=0.39). PFS was similar in pts achieving MRD negative status (median not reached, PBMC and ctDNA), independent of high-risk/difficult-to-treat disease (≥4 prior lines, Ann Arbor stage III-IV, bulky disease, double refractory, FLIPI 3-5, and POD24). The overall MRD negativity rate was also similar in high-risk pts, except those with ≥4 prior lines of therapy. Conclusions: Based on the EPCORE-NHL-1 study, one of the first pivotal studies to report MRD in pts with R/R FL, epcoritamab drives rapid, deep, and sustained responses as supported by MRD assessment by both PBMC and ctDNA. MRD results correlate with clinical outcome, and achieving MRD negativity is associated with longer PFS. PFS was similar among all pts who achieved MRD negativity, including those with high-risk disease. Citation Format: David Soong, Işıl Altıntaş, John Karavitis, Kim M. Linton, Wojciech Jurczak, Catherine Thieblemont, Kevin Zhao, Edith Szafer-Glusman, Daniela Hoehn, Elena Favaro, Mariana Sacchi, Maria Jure-Kunkel. Minimal residual disease (MRD) status by peripheral blood mononuclear cells (PBMCs) and circulating tumor DNA (ctDNA) demonstrates rapid, deep, and sustained response in patients (Pts) with relapsed/refractory follicular lymphoma (R/R FL) treated with subcutaneous (SC) epcoritamab monotherapy in the pivotal phase 1/2 EPCORE™ NHL-1 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5071.

177Lu]Lu-PSMA-617 as first-line systemic therapy in patients with metastatic castration-resistant prostate cancer: a real-world study.

The use of [177Lu]Lu-PSMA-617 radioligand therapy has become increasingly recognized as a viable therapeutic approach for patients in the advanced stages of metastatic castration-resistant prostate cancer (mCRPC). However, there is limited data regarding its effectiveness and safety in earlier lines. This study aims to present our institution's experience with [177Lu]Lu-PSMA-617 as a first-line systemic therapy for mCRPC. We collected and analyzed data from consecutive mCRPC patients who underwent first-line treatment with [177Lu]Lu-PSMA-617 at our center from 2015 to 2023. The various outcome measures included best prostate-specific antigen-response rate (PSA-RR) (proportion of patients achieving a ≥ 50% decline in PSA); objective radiographic response rate (ORR) (proportion of patients achieving complete or partial radiographic responses); radiographic progression-free survival (rPFS) (measured from treatment initiation until radiographic progression or death from any cause); overall survival (OS) (measured from treatment initiation until death from any cause); and adverse events. Forty treatment-naïve mCRPC patients with PSMA-positive disease on [68Ga]Ga-PSMA-11 PET/CT were included (median age: 68.5 years, range: 45-78; median PSA: 41 ng/mL, range: 1-3028). These patients received a median cumulative activity of 22.2 GBq (range: 5.55-44.4) [177Lu]Lu-PSMA-617 over 1-6 cycles at 8-12 week intervals. A ≥ 50% decline in PSA was observed in 25/40 (62.5%) patients (best PSA-RR). Radiographic responses were evaluated for thirty-eight patients, with thirteen showing partial responses (ORR 34.2%). Over a median follow-up of 36 months, the median rPFS was 12 months (95% confidence interval, CI: 9-15), and the median OS was 17 months (95% CI: 12-22). Treatment-emergent grade ≥ 3 anemia, leucopenia, and thrombocytopenia were noted in 4/40 (10%), 1/40 (2.5%), and 3/40 (7.5%) patients, respectively. The findings suggest that [177Lu]Lu-PSMA-617 is a safe and effective option as a first-line treatment in mCRPC. Further trials are needed to definitively establish its role as an upfront treatment modality in this setting.

Circulating tumor DNA in the surveillance of patients with oligometastatic renal cell carcinoma treated with stereotactic ablative radiation.

477 Background: Oligometastatic renal cell carcinoma (oRCC) patients receiving stereotactic ablative radiation (SAbR) are in need of effective biomarkers beyond imaging to identify those most likely to fail rapidly and therefore would benefit from systemic therapy. Detection of minimal residual disease (MRD) using circulating tumor (ctDNA) is a promising tool to guide decisions in the management of solid tumors. Herein, we investigate the utility of longitudinal ctDNA monitoring to identify high-risk patients. Methods: Patients with oRCC on surveillance after previous SAbR were enrolled in a prospective registry study and longitudinal quantitative ctDNA testing were performed using a tumor-informed commercial ctDNA assay (Signatera). Disease progression was assessed using standard-of-care clinical / radiographic exams and compared to the ctDNA levels that were obtained within the median 32.5 days (IQR 18.5-59) of radiographic exams. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) were calculated. Results: The cohort encompassed 17 patients with oRCC (16/17 metachronous >1 year after nephrectomy) who underwent 42 ctDNA measurements between September 2022 and August 2023 with a median of 3 (range 2-6) ctDNA time points per patient. Median follow up after start of ctDNA monitoring was 10.3 months. Seven patients developed radiographic progression at new sites including 6 who received additional SAbR and one who started systemic therapy with interleukin-2. At most recent follow up, 13/17 patients had no radiographic evidence of disease. Out of the 42 ctDNA time points, 11 had detectable ctDNA and 17 had clinical/radiographically detectable metastasis. The sensitivity, specificity, PPV, and NPV were calculated to be 64.7%, 100.0%, 100.0%, and 80.6% respectively. Out of 6 patients who underwent had ctDNA testing on SAbR, 5 had undetectable levels and the only patient that had detectable ctDNA levels showed a robust decline in ctDNA levels post SAbR. In the interleukin-2 treated patient, detectable levels of ctDNA became undetectable post treatment which also correlated with a complete radiographic response. Conclusions: This study highlights the utility of ctDNA as a prognostic biomarker in the surveillance of oRCC patients who were previously treated with SAbR. A high SPE and PPV suggests that rising ctDNA levels may harbinger radiographic progression requiring systemic therapy intervention. A larger study is warranted to further validate the findings of this study and to optimally integrate ctDNA kinetics to direct subsequent treatment choices for the oRCC patients.

Abstract B002: Phase I study of endoscopic ultrasound (EUS)-guided NBTXR3 delivery activated by radiotherapy (RT) for locally advanced or borderline resectable pancreatic cancer (LAPC or BRPC)

Abstract Patients with LAPC or BRPC often receive radiation therapy (RT) after chemotherapy (chemo) if no metastatic progression has occurred. Historically, CA19-9 normalizes in ~20 to 30% of patients after all therapy. While escalated dose radiotherapy (EDR) has shown promising survival in selected patients, extending use of EDR to all patients is challenging due to RT dose limitations of the bowel. To overcome this limitation, we are investigating NBTXR3, composed of functionalized hafnium oxide nanoparticles administered by a single intratumoral injection, locally amplifying the RT dose. In this phase 1 trial, the primary objective is to determine the NBTXR3 recommended phase 2 dose (RP2D). Secondary objectives are to measure anti-tumor effects. The study uses a Bayesian optimal interval design (BOIN) and has two parts: dose-finding (NBTXR3 at [level 1] 33% of gross tumor volume [GTV] or [level 2] at 42% of GTV) and cohort expansion at RP2D. In part 1, eligibility criteria included only LAPC patients with no evidence of metastatic disease after 2-6 months of chemo, part 2 allows BRPC. NBTXR3 was administered once prior to RT via an EUS-guided intratumoral injection. All patients received 45 Gy in 15 fractions with intensity modulated radiation therapy (IMRT). Patients were followed up to 1 year. Dose-limiting toxicities (DLTs) were defined as any grade ≥ 3 adverse events definitely or possibly related to NBTXR3 and/or RT. Target tumor response was per RECIST v1.1 criteria. CA19-9 was measured serially. We defined CA19-9 normalization as a value of 37 U/ml after finishing NBTXR3/RT. We compared rates of CA19-9 normalization in this phase 1 trial to a historical cohort of patients who received modern chemo/RT without NBTXR3. As of July 12, 2023, 15 LAPC patients have been treated with NBTXR3/RT. The median age was 63 years [range 43-81], 8 males, 7 females. The first patient (level 1) and subsequent 14 patients (level 2) had no injection complications. Level 2 had 1 non-serious DLT related to RT. At 4 weeks post RT, 13 had stable disease (SD) locally (2 had progressive disease [PD] overall), 1 had PD locally, and 1 had radiographic complete response (CR). At 3 months post RT, 11 had SD locally (1 PD overall), 1 PD locally, and 1 had surgery with negative margins and no residual viable tumor. 9 patients had elevated CA19-9 before NBTXR3/RT, 7 of these 9 (78%) had a decrease in CA19-9 subsequently, and 2 of these 9 (22%) had CA19-9 normalization eventually. 12 patients had elevated CA19-9 at diagnosis, and 5 out of 12 patients (42%) had normalization of CA19-9 after all therapy. We reviewed 455 patients with LAPC/BRPC between 2015-2019 who were treated at our institution as a comparison cohort for CA19-9 normalization rates. Out of 307 patients with elevated CA19-9 at diagnosis and normal bilirubin, 95 normalized (31%) and 212 did not normalize (69%) within 6 months of receiving cytotoxic therapy. The RP2D of NBTXR3 is 42% of GTV. The responses and CA19-9 results in comparison to historical data suggest promising anti-tumor efficacy of NBTXR3/RT. Citation Format: Gabriela Fuentes, Maria J. Rodriguez, Matthew H.G. Katz, Naruhiko Ikoma, Ching-Wei D. Tzeng, Michael Overman, Shubham Pant, Michael S. Lee, Robert A. Wolff, Milind Javle, Cullen M. Taniguchi, Emma B. Holliday, Ethan B. Ludmir, Prajnan Das, Albert C. Koong, Omar I. Vivar, Suyu Liu, Eric P. Tamm, Leonard A. Farber, Manoop S. Bhutani, Eugene J. Koay. Phase I study of endoscopic ultrasound (EUS)-guided NBTXR3 delivery activated by radiotherapy (RT) for locally advanced or borderline resectable pancreatic cancer (LAPC or BRPC) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B002.

Upfront Radiation Therapy (RT) for Post-Stem Cell Transplant Multiple Myeloma (MM) Patients with Oligo-Relapse/Progressive Disease: Factors Associated with Favorable Outcomes

Introduction: Relapsed or refractory disease post-stem cell transplant (SCT) for Multiple Myeloma (MM) can be clinically challenging. For localized relapses, radiation therapy (RT) can represent an attractive treatment modality. However, data on outcomes with RT remains scarce. We investigated the impact of RT as a treatment modality in the setting of oligo-relapse and oligo-progressive plasmacytomas after SCT and explored prognostic factors associated with favorable long-term outcome Methods: In this single-institution retrospective analysis, we identified 31 MM patients who underwent upfront RT for oligo-relapse or oligo-progressive MM after SCT between 2000 and 2021. Patients were excluded if they had received systemic therapy for evidence of concurrent biochemical relapse prior to RT start. The treatment responses to stem cell transplantation (SCT) and RT were assessed following the response criteria established by the International Myeloma Working Group (IMWG), which includes the categories: complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), stable disease (SD) and progressive disease (PD). Additionally, we utilized the R-ISS staging system to classify patients into Standard-Risk (R-ISS I), Intermediate-Risk (R-ISS II), and High-Risk (R-ISS III) groups, to allow for a comprehensive evaluation of treatment efficacy and outcomes. Results: Disease and treatment characteristics for the cohort are summarized inFigure 1. Of the 27 patients with imaging available prior to SCT, 67% (18) were assessed with PET, 22% (6) with skeletal survey, 3.7% (1) with MRI/CT, 3.7% with CT, and 3.7% (1) with x-ray. Following SCT, 48% (13) of patients were noted to have radiographic progression, 23% (7) had sCR, 23% (7) had a CR, 10% had a serologic CR, and 45% (14) had a VGPR. Among the 18 patients with radiographic evaluation (in addition to bone marrow biopsy and/or labs) post-SCT, 67% (12) were in radiographic CR at time of re-staging. Median times from SCT to new site of oligo-relapsed disease (20, 64.5%) and pre-existing but inactive sites of oligo-relapsed MM (4, 12.9%) were 31 months (3.2-117.5) and 9 months (3.4-15.9), respectively. Oligo-progressive MM, defined as active sites of disease both pre- and post-SCT were present in 22.6% (7) of patients. Prior to RT, 94% (29) had PET/CT imaging, with a median SUV of 4.4 (2.6-7.2) for target lesions. Solitary bone (77%) and extramedullary (23%) disease were treated to median dose of 30 Gy (8-49 Gy). At first disease response assessment post-RT, 77% (24) of which was done with PET/CT imaging , 42% (13) achieved CR. Among the 18 patients that did not achieve CR, 15 subsequently achieved CR at a median time of 7 months (1.7-44.5). A majority of patients (87%) received systemic therapy post-RT, with a median number of lines of therapy post-RT of 3 (1-17). The remaining 13% (4) of patients did not receive additional systemic therapy post-RT and did not experience progression. Median overall survival for the full cohort was 38 months (3.5-37.9). Conclusions: Utilizing modern systemic therapies in combination with post-transplant RT for patients with limited refractory or relapsed MM is a promising therapeutic approach. For those that remain refractory or relapse in a single site RT local control merits consideration supported by our report. Further investigation to identify patients at highest risk of progression and who may therefore benefit most from RT would be valuable. We plan to conduct additional analyses on the radiographic characteristics that may portend high risk disease, with the ultimate goal of developing well-defined criteria for giving RT earlier.

Minimal Residual Disease (MRD) Testing By Next Generation Sequencing (NGS) after Two Cycles (CY) of Non-Intensive Chemoimmunotherapy Is Predictive of Remission Duration and Need for Maintenance Therapy (MT) in Previously Untreated Mantle Cell Lymphoma (MCL): A Wisconsin Oncology Network Study

Introduction: Despite the variable course of MCL, limited prospective markers exist to identify more indolent disease. MCL is often diagnosed in older patients (pts) less able to tolerate intensive approaches. Bendamustine/rituximab (BR) is a standard non-intensive regimen for MCL, and use of MT remains controversial. Emerging data in MCL suggest a correlation between achieving MRD negativity (MRD-) and progression-free survival (PFS). The GALLIUM study (Marcus R, et al, N Engl J Med 2017) previously showed improved PFS with a bendamustine/obinutuzumab (BO) induction compared with BR in follicular lymphoma, and we postulated this benefit may be observed in MCL. Using MRD testing, we predicted that MT may be omitted in pts achieving MRD- status after induction BO chemoimmunotherapy for MCL. Methods: Adult pts ≥18 years (yrs) with previously untreated MCL who were ineligible for more intensive therapies (including transplant) were enrolled. Pts received 4-6 CY of BO induction intravenously (IV) every 28 days (D) with B 90 mg/m2 IV D1 & 2 every 28D for 6 CY concurrent with O IV (cycle 1 = 100 mg D1, 900 mg D2, and 1000 mg D8 & 15; then 1000 mg D1, CY 2-6). Peripheral blood (PB) MRD was obtained using NGS (ClonoSEQ®) after cycle 2 BO as an exploratory endpoint. Consolidation O (CO) 1000 mg IV weekly for 4 doses was initiated ≤12 weeks after the final dose of BO. Restaging and MRD testing of PB and bone marrow aspirate (BMA) was done ≤30 days after CO completion. For pts with complete response (CR) radiographically and MRD- in PB/BMA, maintenance O (MO) was omitted. For pts without CR or persistent MRD positivity (MRD+) in the PB or BMA, MO was given with 1000 mg IV D1 of a 56-day cycle for 8 CY. Pts were followed for ≥2 years from therapy completion. The primary endpoint is PFS from D1 of BO induction. Secondary endpoints are MRD status, concordance rate of PB/BMA in predicting MRD status, response rates and overall survival (OS). Results: Twenty-one pts (of planned 32) enrolled beginning 2/2018, with follow-up through 6/1/2023. The study closed prematurely due to slow enrollment. Median age is 70 yrs with 3 pts >80 yrs; majority were men (76%). Median MIPI score is 6.11 and median ECOG performance status 0. Twenty pts (95%) have stage IV disease. Twenty pts completed 4 (n=1) or 6 CY BO. Ten pts received MO; 10 did not receive MO per protocol due to radiographic CR and MRD- PB/BMA post-CO. Six pts did not complete MO for reasons of progressive disease (n=4), infection (n=1) and new carcinoma (n=1). After cycle 2 BO, PB analysis was MRD+ in 7 pts and MRD- in 13. Concordance rates between post-CO MRD testing in PB and BMA was 70% (14/20). Of non-concordant values, all had PB MRD- but BMA MRD+. Best responses in 20 assessable pts are: CR 75% (15/20), partial response 20% (4/20), and stable disease 5% (1/20). Most common grade 3/4 toxicities were: neutropenia (10/21), leukopenia (6/21), infections (5/21) and infusion reactions (2/21). One pt had grade 5 cardiac arrest with sepsis during BO. Most common grade 3 infections were abdominal/colitis (n=3) and pneumonia (n=2). Most common grade 1/2 toxicities were nausea (14/21), diarrhea (10/21), constipation (8/21), dysgeusia (6/21), fatigue (8/21) and dry skin/rash (12/21). After a median duration of follow-up of 43.9 months (mos) (95% confidence interval [CI] 28.3-60.1), PFS at 2-yrs and 3-yrs is 66.0% (95% CI 41.6-82.2) and 58.7% (95% CI 33.2-77.3), respectively; and median PFS is 46.5 mos (95% CI 16.4-∞). MRD- status after the exploratory endpoint post-C2 BO was predictive of 2-year PFS (Figure 1a), 83.3% (95% CI 48.2-95.6) for MRD- vs. 42.9% (95% CI 9.78-73.4) for MRD+, with hazard ratio [HR] 0.34 (95% CI 0.09-1.39), p value 0.133. Evaluation of PFS by MRD status post-CO showed similar outcomes regardless of receiving MO (Figure 1b): 2-year PFS is 77.8% (95% CI 36.5-93.9) in MRD- pts post-CO vs 60.0% (95% CI 25.3-82.7) in MRD+ pts; HR 0.45 (95% CI 0.10-1.91, p value 0.278. Median OS is 46.5 mos (95% CI 35.1-∞). Conclusion: Omission of MO in pts achieving MRD- status after induction/CO did not result in worsening PFS. Observed PFS and toxicities with BO induction and CO appears comparable with other data sets utilizing a BR-based induction +/- MT in older, less fit MCL pts. Correlation between PFS and PB MRD testing after C2 induction therapy represents a potential new prognostic marker of MCL behavior, and may be an important early disease indicator in development of risk-adapted therapies.

Subcutaneous (SC) Mosunetuzumab (mosun) As First-Line Therapy for Patients (pts) with High Tumor-Burden Follicular Lymphoma (FL): First Results of a Multicenter Phase 2 Study

Introduction: Cytotoxic chemotherapy plus anti-CD20 antibodies is the current standard of care for pts with newly diagnosed high-burden FL. While effective, this approach is burdened by toxicities, including infections and second cancers, and up to 20% of pts progress within 2 years and have poor outcomes. Intravenous (IV) mosun is a CD20xCD3 bispecific antibody recently approved for the treatment of pts with relapsed or refractory FL based on remarkable efficacy data, and its activity may be even greater in chemotherapy-naïve patients. Furthermore, SC mosun proved as effective as, and possibly better tolerated than, the IV formulation while increasing administration efficiency and convenience. Here, we present the first results of a phase 2 multicenter trial of SC mosun in patients with untreated high-burden FL. Methods: Key eligibility criteria included: Age ≥18 years, stage 2-4 FL in need of therapy per GELF criteria, being fit for chemoimmunotherapy, adequate bone marrow and organ function. SC mosun was administered at the dose of 5 mg on D1 and 45 mg on D8 and D15 of C1, and 45 mg on D1 of each subsequent 21-day cycle. Premedication consisted of dexamethasone, diphenhydramine, and acetaminophen before each mosun dose during C1 and on C2D1 if cytokine release syndrome (CRS) occurred in C1. Subjects with ≥3 CRS risk factors (stage 3-4, bulky disease, bone marrow (BM) involvement, elevated LDH) received dexamethasone 10 mg for 3 days with each mosun dose in C1 and C2. Prophylactic hospitalization was not required. Treatment lasted 8 cycles in pts who achieved complete response (CR), and up to 17 in those with partial response. Response was assessed per the Lugano 2014 and LYRIC 2016 criteria. BM evaluation was mandated in pts with baseline BM involvement who achieved radiographic CR. CRS and neurotoxicity were graded per the 2019 ASTCT criteria. Results: Between July 2022 and July 2023, 43 pts were enrolled. Median age was 55 years (range 26-77), 40% of pts had bulky disease (≥7 cm), 25% had grade 3A FL, and 27% had a FLIPI score ≥3. The median SUV max was 11.5 (range 3.7-41.1)(Table). At the cutoff date of 07/21/2023, 4 pts were in screening, 22 were on treatment, and 13 completed treatment. Four pts discontinued therapy early due to progressive disease (1), or adverse events (AE) (3, one related to study drug). Out of 230 patient-cycles administered, 9 (4%) were delayed due to AEs, by a median of 13 days (range 7-17). Among 39 safety-evaluable pts, the most common treatment-emergent AE were injection site reaction (72%, all G1), CRS (51%), fatigue (33%), dry skin (33%), skin rash (26%), ALT elevation (23%), and AST elevation (21%). G≥3 neutropenia occurred in 4 pts (10%), while infections occurred in 10 pts (26%), and were G1-2 in 8 cases and G3 in 2 cases. One pt died of cardiac arrhythmia in the setting of COVID19-associated pneumonia. CRS occurred most commonly after C1D1 and was G1 in 18 pts (90%) and G2 in 2 (10%). Median time to onset of the first CRS episode was 31h (2-91). Hospitalization and tocilizumab were only required in the two pts who experienced G2 CRS. Twenty-six pts were evaluable for response (1 had concurrent neoplasm at first response assessment, 1 had indeterminate response (IR)3 per LYRIC criteria, and 15 are yet to be evaluated). The best overall response rate was 96% and the CR rate was 81%. All 22 CR were seen at the first response assessment (Figure). Similar response rates were observed among higher-risk subgroups, including pts with high-risk FLIPI (figure), grade 3A FL (ORR 100%, CR 75%), bulky disease (ORR 100%, CR 82%), or SUVmax ≥13 (ORR 83%, CR 83%)). At a median follow-up for response-evaluable pts of 6.0 months, 2 pts have experienced progression, one with CD20-negative FL at the end of therapy, the other with DLBCL diagnosed 6 weeks after treatment initiation on a left axillary lymph node with baseline SUV 41 and not previously biopsied. Conclusion: SC mosun demonstrated a manageable safety profile and highly encouraging efficacy in pts with newly diagnosed high-burden FL, including those with higher-risk disease. Assessment of durability of responses will require additional follow-up. Enrollment continues and updated data will be presented.

Ibrutinib maintenance after frontline treatment in patients with mantle cell lymphoma

AbstractMaintenance rituximab in mantle cell lymphoma (MCL) has improved survival and supports exploration of maintenance with novel agents. We evaluated the safety and efficacy of ibrutinib maintenance (I-M) after induction in patients with treatment-naive MCL. Patients with MCL with complete response (CR) or partial response to frontline chemoimmunotherapy ± autologous stem cell transplantation (auto-SCT) received I-M 560 mg daily for up to 4 years. Primary objective was 3-year progression-free survival (PFS) rate from initiation of I-M. Minimal residual disease (MRD) assessments by next-generation sequencing (NGS) on peripheral blood were measured before I-M initiation and at 1, 6, and 18 to 24 months after initiation. Among 36 patients, the median age was 60 years (range, 46-90). For frontline treatment, 18 patients (50%) had consolidation with auto-SCT in CR1 before I-M. At median follow-up of 55.7 months, 17 patients (47%) completed full course I-M (median, 37.5 cycles; range, 2-52). The 3-year PFS and overall survival (OS) rates were 94% and 97%, respectively. With prior auto-SCT, 3-year PFS and OS rates were both 100%. The most common treatment–related adverse event with I-M was infection (n = 31; 86%), typically low grade; the most common grade 3/4 toxicities were hematologic. In 22 patients with MRD assessments, all were MRD negative after induction. Six became MRD positive on I-M, with 2 reverting to MRD-negative status with continued I-M, and all maintain radiographic CR with the exception of 1 with disease progression. I-M is feasible in MCL after frontline chemoimmunotherapy with manageable toxicities although significant. Changes in NGS-MRD were noted in limited patients during maintenance with few progression and survival events. This trial was registered at www.clinicaltrials.gov as #NCT02242097.

MDB-35. RECURRENT MEDULLOBLASTOMA A RARE COMPLETE RESPONSE IN EXTRA NEURAL DISEASE

Abstract Extra-neural metastasis in recurrent medulloblastoma, carries a potentially fatal outcome. No robust salvageable therapeutic strategy is present, for these clinical phenotypes. We present an 18-year male, who presented at the age of 8 years as a standard risk medulloblastoma and was treated with chemotherapy (as per ACNS0331) followed by craniospinal radiation. At first recurrence in the thoracic spine, he underwent a gross total resection of the tumor, followed by high-dose stem cell chemotherapy and focal radiation. The 2nd recurrence which occurred in the thecal sac 9 years later was treated with metronomic anti angiogenic chemotherapy with outcome a complete radiographic response. Third recurrence occurred in the liver, bone marrow, multiple bones of axial skeleton and sacrum. Molecular interrogation of the lesions showed a (non-WNT / non-SHH subtype) with absence of MYC or MYCN amplification or any other clinically significant biological aberration. He received local radiation to tumors, following which he developed severe myelosuppression. A bone marrow aspirate and biopsy showed greater than 95% involvement with medulloblastoma cells. He was treated with irinotecan and temozolomide. A dramatic response was noted after one cycle (with PET and MRI), with bone marrow involvement of less than 1%. He continues with that therapy. To-date no defined molecular profile is predictive of extra neural metastasis, and has been likened to a fatal outcome, most patients being declared for hospice care. Our patient with this unique clinical outcome, warrants extensive evaluation of these rare clinical phenotypes including methylation profiling and RNA sequencing, which might suggest, certain molecular aberrations which correlates with good response, even in these biologically aggressive variants.

EphrinB2 (B2) expression predicts poor response to PD1/L1 antibodies (Ab) in metastatic urothelial carcinoma (mUC).

4575 Background: B2 is a ligand for EphB4 which enhances tumor invasion, proliferation, survival and promotes angiogenesis. A prior analysis of TCGA data from 409 muscle invasive bladder cancer (MIBC) patients (pts) demonstrated that high (34%) B2 gene expression had poor survival vs. low (66%) expression (Hazard Ratio 0.7 p = 0.02). Our phase II trial of sEphB4-HSA (JCO PMID 35984996) which targets B2, in combination with pembrolizumab in previously treated mUC (N=70) demonstrated an objective response rate (ORR) of 37%. Among pts with high expression of B2, ORR was 52% with 24% complete response (CR). This retrospective study examined the ORR to PD1/L1 Ab in pts with mUC and its correlation with B2 mRNA expression. Methods: Pts with mUC who had received anti PD1/L1 Ab were eligible if they had radiographic response data and tumor tissue for B2 testing. Pts’ demographics and disease characteristics were abstracted. Radiographic images were reviewed using RECIST 1.1. Tumor specimens were analyzed for intensity of B2 expression using in-situ hybridization (ISH). Scores of 2-4 were considered High (Hi) and 0-1 were considered Low (Lo) expression. Standard descriptive statistics were used to summarize study results. Fisher’s exact test was used to test the association of ORR with B2 expression using SAS 9.4. Results: 120 (N) pts from University of Southern California (USC, n=49), Dana Farber (DFCI, n=55), and University of Colorado (UC, n=16) met were included. 88 pts were male (73%). Median age was 72. PD1/L1 Ab were administered in the post-platinum progressive disease (n=95, 79%) and first-line setting (n=25, 21%) and included pembrolizumab (n=88, 73%), atezolizumab (n=26, 22%) and nivolumab, avelumab, and durvalumab, 3%, 1%, and 1%, respectively. Objective response rate (ORR) defined as radiographic CR plus partial response (PR) were calculated and summarized. Among all pts (N=120), ORR was 20% (95% CI 13-28). 62% had B2 Hi expression with a response rate of 12%, and 38% had B2 Lo expression with a response rate of 33%, p=0.009). These proportions were similar for each institution. Conclusions: In addition to conferring poor prognosis in MIBC, B2 expression is associated with poor ORR to PD1/L1 Ab monotherapy in mUC. Given that the combination of B2 inhibition & pembrolizumab was more active in B2 expressing mUC, these data provide further rationale for investigating B2 as a mechanism of resistance to PD1/L1 ab, biomarker of response and a therapeutic target. [Table: see text]

Abstract LB200: Indoximod or ibrutinib/indoximod based clinical chemo-immunotherapy drives conversion of extra-tumoral circulating stem-like precursor CD8+ T cells into clonally expanded, rejuvenated effector cells

Abstract Increasing evidence suggests that many of the effector CD8+ T cells reactivated (‘rejuvenated”) by immunotherapy come from outside the tumor, derived from a circulating pool of “stem-like” memory or “precursor-exhausted” (TPEX) cells. These cells have been characterized in mice, but, despite their importance, circulating counterparts in humans have not yet been identified for study. We hypothesized that immunotherapy designed to enhance immunogenic antigen-presentation during chemotherapy might produce extensive reactivation of these precursor T cells. While the antigen-presentation step occurs in tissues, homing of the rejuvenated T cells to the tumor is via the circulation; thus, we hypothesized that they would be visible in blood. Informative patients were selected from two ongoing clinical trials of children with brain tumors treated with the IDO-inhibitor drug indoximod: a Phase 2 trial (NCT04049669) of indoximod plus chemotherapy; and a Phase 1 trial (NCT05106296) of indoximod, chemotherapy and the BTK-inhibitor ibrutinib, which synergistically destabilizes IDO (Immunity 54:2354-2371, 2021). Patient selection criteria included either (i) massive clonal expansion of activated CD8+ T cells on therapy (expanded clones reaching 16-25% of total CD8+ T cells); or (ii) complete radiographic tumor response (CR) on treatment; or (iii) both. Longitudinal blood samples (4-10 samples per patient) were obtained over a period of 6-24 months and analyzed by single-cell RNA-sequencing (scRNA-seq) with paired single-cell T cell receptor sequencing (scTCR-seq). TCR clonotypes of interest were identified based on robust clonal expansion on-treatment; then each clonotype was traced back through earlier samples to the pre-treatment baseline, or the earliest sample in which that clone could be detected. Clones were pooled, subjected to UMAP clustering, and differential gene-expression and trajectory analysis performed. At earliest appearance, each clonotype was enriched for a phenotype dominated by early transcription factors TCF7 and IKZF2 (Helios). These cells expressed little PDCD1 (PD-1) but showed a “hybrid” combination of genes associated with immaturity/arrest (BACH2, DUSP2, LTB, IL7R, CD160) and effector/memory (NKG7, GZMK, GZMA). Within each responding clone, this “precursor” phenotype could be observed to progressively transition into a mature cytotoxic/effector phenotype (PRF1, GZMB, GZMH, FGFBP2, KLRB1, IFNG). Trajectory analysis of this maturation sequence allowed us to analyze key gene-regulatory networks and transcription factor profiles at each stage. To our knowledge, this is the first study in humans to identify this key stem-like precursor population in circulation, allowing us to sequentially follow the molecular changes in these cells during rejuvenation. Citation Format: Theodore S. Johnson, Rafal Pacholczyk, Zuzana Berrong, Chenbin Huang, Eugene P. Kennedy, Eric Ring, Ramses F. Sadek, Sarthak Satpathy, Beena E. Thomas, Tobey J. MacDonald, Manoj Bhasin, David H. Munn. Indoximod or ibrutinib/indoximod based clinical chemo-immunotherapy drives conversion of extra-tumoral circulating stem-like precursor CD8+ T cells into clonally expanded, rejuvenated effector cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB200.

The Contemporary Presentation and Diagnosis of Endometrial Cancer Recurrence: When, Where, and How?

ABSTRACT Endometrial cancer (EC) is the most common gynecologic cancer in the United States. Despite a favorable prognosis in many, EC is one of the few cancers with rising mortality rates. This is in part due to recurrence rates, being as high as 50% in patients at high risk. Survival differences between locoregional and distant disease recurrence have prompted increased focus on multimodality adjuvant treatment. Disease surveillance using routine imaging for early detection of recurrence has not shown a survival benefit in those at low risk, and a more accurate profile of recurrence pattern and presentation may aid the screening current infrastructure. This retrospective review aimed to examine patterns of recurrence, presentation, and method of diagnosis of recurrent EC in a large contemporary cohort from a single, high-volume institution. Patients who underwent surgery for an EC diagnosis between June 2014 and December 2020 at Ohio State University Comprehensive Cancer Center were included. Disease recurrence was defined as evidence of disease after a 3-month disease-free interval following primary treatment. In the setting of metastatic disease, only those with a complete radiographic response after adjuvant therapy were eligible for recurrence. Locoregional recurrence was confined to the vaginal vault or pelvis. Multiple logistic regression analysis was used to assess the impact of covariates on the likelihood of receipt of treatment for recurrent disease, overall survival, and time from recurrence to death. A total of 1723 patients were included in the study cohort with a median follow-up time of 2.3 years. A total of 201 participants (11.6%) were included in the recurrence analysis. Of these patients, 120 (59.7%) were symptomatic, with abdominal and pelvic pain being the most common symptoms. Among asymptomatic recurrence cases, 15.4% were diagnosed by imaging at provider discretion, 13.4% were diagnosed by pelvic examination, and 7.5% were diagnosed by CA-125 at provider discretion. Patients diagnosed by pelvic examination were more likely to be at an early stage (66.7% vs 34.5%; P = 0.001), of endometrioid histology (66.7% vs 36.8%; P = 0.003), and without prior adjuvant therapy (48.2% vs 17.9%; P = 0.001). Patients who received adjuvant therapy experienced significantly more locoregional recurrences (60.5% vs 19.7%; P ≤ 0.001), but there was no difference in the median time to recurrence of 12.7 months. Patients with asymptomatic recurrence were more likely to be able to receive treatment than those with symptomatic presentations (91.3% vs 76.7%; P = 0.005). Age at initial diagnosis was associated with receipt of treatment for recurrence. Patients with symptomatic recurrence had a significantly shorter median time from recurrence to death (6.5 vs 11.1 months; P = 0.0053) than asymptomatic patients; however, this was driven by receipt of treatment. Overall survival did not differ significantly between mode of presentation or method of diagnosis. The results of this study find that recurrence for EC was observed in 12% of women, the majority of whom experienced symptoms, and symptomatic patients were less likely to receive treatment, which contributed to a shorter time from recurrence to death. These findings in the context of an increasing mortality for EC suggest improvements in providing timely treatment for recurrent disease are essential.

The High Incidence of Occult Carcinoma in Total Hepatectomy Specimens of Patients Treated for Unresectable Colorectal Liver Metastases With Liver Transplant.

To describe the rate of occult carcinoma deposits in total hepatectomy specimens from patients treated with liver transplant (LT) for colorectal liver metastases (CRLM). Previous studies have shown that patients with CRLM treated with systemic therapy demonstrate a high rate of complete radiographic response or may have disappearing liver metastases. However, this does not necessarily translate into a complete pathologic response, and residual invasive cancer may be found in up to 80% of the disappearing tumors after resection. Retrospective review of 14 patients who underwent LT for CRLM, at 2 centers. Radiographic and pathologic correlation of the number of tumors and their viability before and after LT was performed. The median (interquartile range) number of tumors at diagnosis was 11 (4-23). The median number of chemotherapy cycles was 24 (16-37). Hepatic artery infusion was used in 5 patients (35.7%); 6 (42.9%) underwent surgical resection, and 5 (35.7%) received locoregional therapy. The indication for LT was unresectability in 8 patients (57.1%) and liver failure secondary to oncologic treatment in the remaining 6 (42.9%). Before LT, 7 patients (50%) demonstrated fluorodeoxyglucose-avid tumors and 7 (50%) had a complete radiographic response. Histopathologically, 11 patients (78.6%) had a viable tumor. Nine (64.2%) of the 14 patients were found to have undiagnosed metastases on explant pathology, with at least 22 unaccounted viable tumors before LT. Furthermore, 4 (57.1%) of the 7 patients who demonstrated complete radiographic response harbored viable carcinoma on explant pathology. A complete radiographic response does not reliably predict a complete pathologic response. In patients with unresectable CRLM, total hepatectomy and LT represent a promising treatment options to prevent indolent disease progression from disappearing CRLM.

Strategies for the Treatment of Infantile Soft Tissue Sarcomas With BCOR Alterations.

BCOR alterations are described in ultra-rare infantile soft tissue sarcomas including primitive myxoid mesenchymal tumor of infancy and undifferentiated round cell sarcoma (URCS). Previous reports often describe dismal outcomes. Thus, we undertook a retrospective, multi-institutional study of infants with BCOR -rearranged soft tissue sarcomas. Nine patients aged 6 weeks to 15 months were identified. One tumor carried a BCOR :: CCNB3 fusion, whereas 7 tumors harbored internal tandem duplication of BCOR , including 4 cases classified as primitive myxoid mesenchymal tumor of infancy, 1 case as URCS, and 2 cases characterized by a "hybrid morphology" in our evaluation. Four patients underwent upfront surgery with residual disease that progressed locally after a median of 2.5 months. Locoregional recurrences were observed in hybrid patients, and the URCS case recurred with brain metastases. Complete radiographic responses after chemotherapy were achieved in patients treated with vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, vincristine/doxorubicin/cyclophosphamide alternating with cyclophosphamide/etoposide (regimen I), and ifosfamide/carboplatin/etoposide. Seven patients received radiotherapy. With a median of 23.5 months off therapy, 8 patients are with no evidence of disease. In our study, observation was inadequate for the management of untreated postsurgical residual disease. Tumors demonstrated chemosensitivity with anthracycline-based regimens and ifosfamide/carboplatin/etoposide. Radiotherapy was required to achieve durable response in most patients.

Ultrasensitive Circulating Tumor DNA (ctDNA) Dynamics after Autologous CD30.CAR-T Cell Therapy for Relapsed or Refractory (r/r) Classical Hodgkin Lymphoma (CHARIOT Trial)

Introduction Liquid biopsies leveraging circulating tumor DNA (ctDNA) are rapidly emerging as minimally invasive tools to detect, genotype, and monitor diverse tumors. ctDNA dynamics and early responses are well-characterized in non-Hodgkin Lymphomas, especially during frontline immunochemotherapy. However, ctDNA responses and minimal residual disease (MRD) are less well-defined in classical Hodgkin Lymphomas (cHL), especially in the relapsed/refractory setting and after cellular immunotherapy, where significant unmet needs remain. We hypothesized that ultrasensitive ctDNA-based MRD detection by Phased Variant Enrichment & Detection Sequencing (PhasED-Seq; Kurtz et al, 2021 Nat Biotech) can accurately track response and predict progression after investigational therapy of r/r cHL with autologous CD30.CAR-T cells. Method This Phase 2 single arm, multicenter study (NCT04268706) investigates safety and efficacy of CD30.CAR-T cells in cHL patients experiencing progression after at least 3 lines of therapy. In the Pilot part of the study, ctDNA was analyzed as an exploratory biomarker using PhasED-Seq at multiple time-points, including at baseline (pre-treatment), Day 42 post-CD30.CAR-T infusion (D42), and upon progressive disease (PD). Exploratory analyses were performed to assess the predictive role of ctDNA and to compare metabolic tumor response by positron emission tomography (PET) scan with ctDNA-based minimal residual disease (MRD). We profiled 55 serial blood specimens (41 plasma and 14 buffy coat samples) from 14 patients with available samples. Cell-free DNA was profiled by PhasED-Seq in the Foresight Diagnostics CLIA laboratory (Aurora, CO). Baseline plasma and D42 buffy coat specimens were used to genotype each patient's tumor to identify Phased Variants (PVs), and these were used to monitor MRD in subsequent blood specimens. Patients/samples were reported as MRD positive when ctDNA levels exceeded an analytical detection threshold (~1 part per million cfDNA molecules), corresponding to 98% clinical specificity. Result As of 22 July 2022, 17 patients have been screened and 15 patients enrolled in the Pilot segment (median age: 35 years [21-57], 66.7% male). Overall response rate (ORR) after CD30.CAR-T single infusion was 73.3% (n=11), with complete response (CR) rate of 60% (n=9). ORR in 5 patients after the 2nd infusion was 100% (n=5), with CR of 60% (n= 3). ctDNA was successfully genotyped directly from pre-treatment plasma in 12 out of 14 patients where samples were available. Both patients where PV genotyping failed had received bridging cytoreductive therapy before baseline plasma collection. Out of 12 profiled patients, 7 patients achieved CR with median baseline ctDNA concentration of 44.9 hGE/mL. 3 patients had PD with median baseline ctDNA level of 94.0 hGE/mL. One patient with PR and one patient with SD had baseline ctDNA levels of 38.9 hGE/mL and 231.1 hGE/mL, respectively. These results suggest that pre-treatment ctDNA levels could have predictive value on patient response to CAR-T therapy. ctDNA responses largely mirrored radiographic responses. Specifically, among 7 patients achieving radiographic CR, 4 also achieved undetectable ctDNA, and the other 3 had ctDNA responses with low MRD levels (median: 0.2 hGE/mL) at D42. One patient with PR also had low ctDNA concentration at D42 (0.7 hGE/mL). In comparison, 3 patients experiencing PD had relatively higher ctDNA levels (median: 131.4 hGE/mL). Furthermore, ctDNA levels at D42 were significantly correlated with PET Deauville score (p=8.7e-4), and patients with a response had significantly lower ctDNA than those without a response (p=0.004) (Fig B). These results suggest that ctDNA-MRD levels are strongly correlated with metabolic responses determined by PET imaging. Similar results were observed after 2nd infusions of the CAR-T. 3 out of 3 patients achieving CR had low ctDNA concentrations at Day 42 post-2nd infusion (median: 0.2 hGE/mL). Among 2 patients with PR, 1 patient with available sample had 31.9 hGE/mL ctDNA. Conclusion Minimally invasive ctDNA analysis is a viable method to monitor responses, rapidly risk stratify and predict outcomes of patients with r/r cHL treated with CD30.CAR-T therapy. A single infusion of CD30.CAR-T therapy rapidly induces MRD negativity in a significant subset of patients at Day 42. ctDNA as exploratory biomarker will be further evaluated in Pivotal part of the study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal