Background Standard adjuvant chemotherapy for stage III colon cancer consists of a fluoropyrimidine-plus-oxaliplatin regimen. Whether the addition of atezolizumab (an anti-programmed death ligand 1 agent) to a modified FOLFOX6 regimen (fluorouracil, oxaliplatin, and leucovorin; called mFOLFOX6) would improve outcomes in patients with stage III colon cancer with mismatch repair-deficient (dMMR) status is unclear. Methods In a phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with resected stage III dMMR tumors to receive either adjuvant atezolizumab plus mFOLFOX6 for 6 months, with atezolizumab continued as monotherapy (for a total of 12 months of therapy), or mFOLFOX6 alone for 6 months. The primary end point was disease-free survival. Secondary end points were overall survival and the adverse-event profile. Results A total of 355 patients were assigned to receive atezolizumab plus mFOLFOX6 and 357 to receive mFOLFOX6 alone. The median age of the patients was 64 years, 55.1% were women, and 53.9% had tumors that were T4, N2, or both (indicating high risk). At a median follow-up of 40.9 months, the 3-year disease-free survival was 86.3% (95% confidence interval [CI], 81.8 to 89.8) in the atezolizumab-mFOLFOX6 group, as compared with 76.2% (95% CI, 70.9 to 80.6) in the mFOLFOX6 group (hazard ratio for disease recurrence or death, 0.50; 95% CI, 0.35 to 0.73; P<0.001). Adverse events of grade 3 or 4 occurred in 84.1% of the patients who received atezolizumab plus mFOLFOX6 and in 71.9% of those who received mFOLFOX6 alone. Conclusions The addition of atezolizumab to mFOLFOX6 significantly improved disease-free survival among patients with stage III dMMR colon cancer. (Funded by the National Cancer Institute of the National Institutes of Health and Genentech; ATOMIC ClinicalTrials.gov number, NCT02912559.)

LBA1 Background: Standard adjuvant chemotherapy of stage III colon cancer consists of a fluoropyrimidine plus oxaliplatin. In patients (pts) with stage III colon cancer and deficient mismatch repair (dMMR), the benefit of an immune checkpoint inhibitor combined with adjuvant chemotherapy is unknown. The phase III ATOMIC trial (NCT02912559) was conducted to determine whether atezolizumab (atezo), an anti-PD-L1 antibody, can improve pt outcomes when added to adjuvant 5-fluorouracil, leucovorin plus oxaliplatin (mFOLFOX6) in pts with stage III dMMR tumors. Methods: We conducted an NCI-sponsored, multicenter and randomized phase III trial in pts with surgically resected stage III dMMR colon adenocarcinoma (any T, N 1,2 M 0 ). Pts, age > 12 years (yr), were accrued at NCTN sites and the German AIO. Tumor dMMR was determined by local immunohistochemistry and centrally verified. Pts were randomized 1:1 to mFOLFOX6 plus atezo (840 mg IV q2 weeks) for 12 cycles (6 months)[mo] followed by atezo monotherapy for 13 cycles (12 mo total) versus mFOLFOX6 alone for 12 cycles. Randomization stratification factors were N-stage (N 1 /N 1c vs N 2 ), T-stage (T 1 -T 3 vs T 4 ) and site (proximal vs distal). The primary endpoint was disease-free survival (DFS); secondary endpoints were overall survival and adverse event (AE) profile (CTCAE, PRO-CTCAE). Primary efficacy analysis was done in the intent-to-treat population; DFS was compared by arm (stratified log-rank test). Hazard ratio (HR) and 95% confidence interval (CI) were calculated using a stratified Cox model; 3-yr DFS was determined by Kaplan-Meier method. Among 700 pts., 165 DFS events with two interim analyses (50% , 75% of events) yielded 90% power to detect HR 0.6 (3-yr DFS 75% vs. 84.2%) assuming exponential survival and 1-sided alpha (0.025). Results: From 9/2017 to 1/2023, 712 pts were randomized (1 pediatric) to either atezo plus mFOLFOX6 (n= 355; atezo arm) or mFOLFOX6 (n= 357). Median pt age was 64 yr. 55.1% were female. Among tumors, 83.8% were proximal, 46.1% were clinical low risk (T 1-3 N 1 ) and 53.9% high risk (T 4 and/or N 2 ). At the second interim analysis, median pt follow-up was 37.2 mo (interquartile range, 24.2 to 55.5) and 124 DFS events were observed. Three-year DFS was 86.4 % (95% CI, 81.8 to 89.9) in the atezo arm and 76.6 % (95% CI, 71.3 to 81.0) in the mFOLFOX6 arm (HR, 0.50; 95% CI, 0.35 to 0.72). Stratified log-rank p-value was <0.0001, crossing the pre-specified efficacy boundary of 0.009. Efficacy for the atezo arm was consistent across subgroups, including pts >70 yr and low- and high-risk groups. Treatment-related > grade 3 AEs occurred in 71.7 % of pts in the atezo arm vs 62.1 % in the mFOLFOX6 arm. Conclusion: The addition of atezolizumab to mFOLFOX6 significantly improved DFS and should be considered the new adjuvant standard of care for patients with dMMR stage III colon cancer. Support: U10CA180821, U10CA180882, U24CA196171; Genentech, a member of the Roche group; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02912559 .

TPS311 Background: Approximately 45% of dMMR/MSI-H metastatic colorectal cancer (mCRC) in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC patients (pts) may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF as well as between oxaliplatin/anti-PD-1 in murine CRC models, and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Within the AtezoTRIBE 8-pt dMMR CRC subgroup treated with FOLFOXIRI+bev+atezo, median PFS was not reached, with the first progression event at ~16 mos. Additionally, in other solid tumor malignancies, anti-PD-1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD-1 plus chemotherapy (i.e., gastroesophageal and lung cancers) combinations are standard first-line treatments. Methods: This two-arm prospective phase III open-label trial randomizes (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Key inclusion criteria have been simplified on recent amendments to better mirror clinical practice for pts receiving mFOLFOX6/bev+atezo: One cycle of FOLFOX or CAPOX, with or without bev (or biosimilar) prior to enrollment allowed, dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; pts with total bilirubin ≤4.0 x ULN; duration of therapy for up to two years for both arms; imaging frequency on post-treatment follow-up has been reduced; as has measurable disease per RECIST. Primary endpoint is PFS. Assuming the atezo monotherapy control arm has a 48% PFS at 24 mos as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include overall survival, objective response rate, safety profile, disease control rate, and duration of response. Archived tumor tissue and blood samples will be collected for correlative studies. Harmonization of translational analyses is planned between GI004 (COMMIT) and A021502 (ATOMIC). Sample size has been modified with the accrual goal of 120 pts randomized between the two immunotherapy arms needed for study completion. Enrollment actively continues at U.S. sites. Current accrual (as of 9-20-2024): 100/120. Clinical trial information: NCT02997228 .

4001 Background: LEAP-015 (NCT04662710), is a randomized, open-label, phase 3 study of pembrolizumab plus lenvatinib and chemotherapy as first-line treatment for advanced/ metastatic gastroesophageal adenocarcinoma. We report results from the interim and final analyses of LEAP-015. Methods: Eligible participants (pts) had untreated HER-2 negative locally advanced unresectable or metastatic gastroesophageal adenocarcinoma, measurable disease and ECOG PS 0-1. All pts were randomly assigned 1:1 to induction with pembrolizumab 400 mg IV Q6W (x2) plus oral lenvatinib 8 mg QD and investigators choice chemotherapy (CAPOX Q3W x4 or mFOLFOX6 Q2W x6) then consolidation with pembrolizumab 400 mg Q6W for ≤16 doses plus lenvatinib 20 mg QD (only if 8 mg tolerated for at least 3 weeks), or chemotherapy alone (CAPOX or FOLFOX). Randomization was stratified by region, ECOG PS, and chemotherapy choice. Dual primary endpoints were PFS (RECIST v1.1, BICR) and OS in pts with PD-L1 combined positive score (CPS) ≥1 and in all pts; secondary endpoints included ORR and DOR (RECIST v1.1, BICR) in pts with PD-L1 CPS ≥1 and in all pts, and safety and tolerability in all pts. The data cut-off date was Oct 29, 2024. Results: A total of 880 pts (78% PD-L1 CPS ≥1; 75% gastric primary) were randomized (443 pembrolizumab plus lenvatinib and chemotherapy; 437 chemotherapy alone).Median follow-up was 32.2 mo (range 19.0 – 41.7) in pts with PD-L1 CPS ≥1 and 31.8 mo (range, 19.0 – 41.7) in all pts. At interim analysis, PFS difference was statistically significant with pembrolizumab plus lenvatinib and chemotherapy vs chemotherapy in pts with PD-L1 CPS ≥1 (median 7.3 vs 6.9 mo; HR 0.75; 95% CI, 0.62-0.9; P = 0.0012), with 24-mo PFS of 20% vs 7%, and in all pts (median 7.2 vs 7.0 mo; HR 0.78; 95% CI, 0.66-0.92; P = 0.0019), with 24-mo PFS of 21% vs 8%. ORR was 59.5% vs 45.4% in pts with PD-L1 CPS ≥1 and 58.0% vs 43.9% in all pts; P < 0.0001 for both. At final analysis, OS in pts with PD-L1 CPS ≥1 was not statistically significant (median 12.6 vs 12.9 mo; HR 0.84; 95% CI, 0.71-1.00; P = 0.0244 (P-value boundary for significance of 0.0204), with 24-mo OS of 31% vs 23%. OS in all pts was not tested per multiplicity strategy (median 13.1 vs 13.0; HR 0.87; 95% CI 0.75-1.01). Drug-related adverse event (AE) rates were 98% vs 92% in pts receiving pembrolizumab plus lenvatinib and chemotherapy vs chemotherapy. Grade ≥3 drug-related AE rates were 65% vs 49% (grade 5 AEs 5% vs < 1%). Conclusions: Pembrolizumab plus lenvatinib and chemotherapy vs chemotherapy provided statistically significant improvement in PFS and ORR in pts with advanced unresectable or metastatic gastroesophageal carcinoma at interim analysis. However, there was no significant improvement in OS in pts with PD-L1 CPS ≥1 at final analysis. Safety profiles were consistent with known regimens, with higher AE rates seen in pts receiving the experimental treatment. Clinical trial information: NCT04662710 .

Background Pancreatic ductal adenocarcinoma is a clinically challenging malignancy largely because of its chemoresistance. Bacteria within the pancreatic ductal adenocarcinoma microbiome may mediate chemoresistance, suggesting that alteration of the microbiome with antibiotics could improve chemotherapy response.Methods We utilized the Surveillance, Epidemiology, and End Results Program-Medicare database to select patients with resected, early-stage pancreatic ductal adenocarcinoma diagnosed between 2007 and 2017. The primary outcome of this study was overall survival. Receipt of antibiotic treatment within 1 month after adjuvant chemotherapy initiation was determined from Medicare claims data. Propensity scores were used to match patients who received antibiotics with patients who did not receive antibiotics. The Kaplan-Meier method was used to calculate 5-year overall survival rates, and Cox regression analysis was used to assess the association between receiving antibiotics and overall survival. All hypotheses were 2 sided.Results Of the 712 patients with resected, early-stage pancreatic ductal adenocarcinoma, 629 (88.3%) were treated with adjuvant gemcitabine and 177 (24.9%) received antibiotics in the 1 month following chemotherapy initiation. The mean (SD) age at diagnosis was 73.7 (5.1) years, and patients were mostly women, White, and from metropolitan areas in the northeastern or western United States. A total of 143 propensity score-matched pairs were evaluated. Among patients treated with gemcitabine, antibiotic treatment was associated with a 37% improvement in overall survival and a 30% improvement in cancer-specific survival.Conclusions Antibiotic treatment in the 1 month following adjuvant gemcitabine initiation was associated with improved survival. These findings provide additional support for the hypothesis that antibiotic treatment may alter the pancreatic microbiome in a manner that reduces chemoresistance, potentially improving pancreatic ductal adenocarcinoma outcomes.

4175 Background: Patients (pts) with pancreatic adenocarcinoma (PDAC) who are candidates for surgery are anatomically segregated into two groups: those with resectable tumors (R-PDAC), and those with borderline resectable tumors (BR-PDAC). For each group, complete surgical resection with no visible or microscopic disease left behind (R0 resection) is generally accepted as the path to cure. Neoadjuvant therapy (NAT) has been used to improve the R0 resection rate. However, the optimal role and type of NAT that will improve R0 resection rate and overall survival (OS) remains controversial. The Academic Gastrointestinal Cancer Consortium (AGICC) evaluated a perioperative strategy with combination chemotherapy and preoperative stereotactic radiation therapy (SBRT) to improve the R0 resection rate. Methods: This prospective, multicenter open label, single arm phase 2 clinical trial conducted among 5 member AGICC institutions enrolled pts with R-PDAC and BR-PDAC. Treatment included 3 cycles of gemcitabine (1000mg/m2) and nab-paclitaxel (125 mg/m2) (GEM/NAB) on days 1, 8 and 15 of a 28-day cycle prior to SBRT (33Gy: 6.6Gy daily x 5) followed by surgery and 3 cycles of adjuvant GEM/NAB. Accrual goal was 20 R-PDAC and 30 BR-PDAC pts selected by central radiology review. Primary objective was to estimate the R0 resection rate for each cohort. Secondary objectives included safety and tolerability of neoadjuvant treatment and OS. Results: Eighty-six pts signed consent and after radiologic screening, 20 R-PDAC patients and 29 BR-PDAC patients were found eligible to begin treatment. One R-PDAC and two BR-PDAC pts did not initiate therapy. 14 (70%) and 19 (66%) R-PDAC and BR-PDAC pts, respectively, completed all neoadjuvant chemotherapy.14 R-PDAC (70%) and 17 BR-PDAC (59%) pts completed SBRT. 11 R-PDAC pts (55%) and 11 (38%) BR-PDAC, underwent surgery. 8 R-PDAC pts (40%) had an R0 resection. One R-PDAC pt had a complete pathologic response (pCR). 8 BR-PDAC pts (28%) had an R0 resection. 19% (3/16) pts undergoing an R0 resection are alive (47-73+ mos). 16 pts (32%) had at least one grade ≥ 3 non-hematologic adverse event (AE); 25 patients (51%) had at least one grade ≥ 3 hematologic AE. 8 pts, 4 R-PDAC and 4 BR-PDAC were hospitalized prior to surgery. One pt (2%) died during NAT. There were no deaths due to surgery. Conclusions: R0 resection rates and survival in R-PDAC and BR-PDAC were low despite a perioperative approach of systemic therapy and SBRT. The lack of survival benefit of GEM/NAB as an adjuvant regimen, as well as SBRT pre-operatively (both shown in studies subsequent to this one) may explain the disappointing results. While an R0 resection for localized PDAC is recognized as essential, our results demonstrate that an R0 resection is not sufficient to cure the majority of PDAC pts who receive NAT with GEM/NAB + SBRT. Future NAT therapy trials should aim to markedly improve the pCR rates associated with R0 resection. Clinical trial information: NCT02723331 .

e16309 Background: Despite substantial progress in cancer treatment, PDAC remains a highly lethal disease. CA19-9 plays a crucial role in PDAC diagnosis and therapeutic response assessment. We aimed to evaluate racial differences, tumor characteristics, and outcomes between CA19-9 non-producers and producers among advanced PDAC patients (pts) at an academic teaching hospital. Methods: A retrospective analysis was conducted in patients with unresectable or metastatic PDAC treated at Mount Sinai Health System between January 2012 and December 2021. Pts were categorized into two groups based on CA19-9 levels, using a threshold of 37 U/mL: CA19-9 non-producers (≤37 U/mL) and CA19-9 producers ( > 37 U/mL). Demographic and clinical data were compared between the two groups, and the association between CA19-9 levels and overall survival (OS) was assessed using Kaplan-Meier estimates and multivariable Cox proportional hazards regression models. Results: A total of 238 pts were included in the analysis, with a median age of 67 years and a balanced gender distribution (52% male). The cohort comprised locally advanced (29.8%) and metastatic (70.2%) cases, with a diverse ethnic composition including non-Hispanic whites (37%), non-Hispanic blacks (25%), and Hispanics (18%). Among the pts, 23.5% were CA19-9 non-producers, while 76.5% were CA19-9 producers. Significant racial differences were observed, with non-Hispanic blacks more likely to be CA19-9 non-producers compared to non-Hispanic whites ( P< 0.001). However, no statistically significant differences were found in age, smoking status, tumor location, size, or site of metastasis between the two groups. Median overall survival (OS) was 13m for CA19-9 producers and 16m for non-producers, but this difference was not statistically significant in both univariate and multivariate analyses (HR 1.09, 95% CI 0.74-1.58, P = 0.66; HR 1.06, 95% CI 0.72-1.58, P 0.8). Hispanic ethnicity was correlated with improved OS (HR 0.59, 95% CI 0.36-0.95, P = 0.029), while larger tumor size predicted worse OS (HR 1.17, P < 0.001). Conclusions: This study highlights racial disparities in CA19-9 production among locally advanced and metastatic PDAC patients. Despite observed differences, CA19-9 levels alone did not emerge as a statistically significant predictor of OS. Future research should delve deeper into the racial disparities observed in CA19-9 production, exploring underlying biological mechanisms and potential implications for diagnostic and therapeutic approaches as this could refine our understanding of PDAC, facilitating targeted interventions for improved patient outcomes.

TPS222 Background: ME-344 is a synthetic small molecule that inhibits oxidative phosphorylation, resulting in energy starvation and cell death via caspase-dependent and -independent mechanisms. The activity of mitochondrial inhibitors is enhanced when mitochondrial respiration is upregulated, a situation achieved in solid tumors by inducing vascular normalization and hypoxia correction with antiangiogenics. In a CT26 colon carcinoma syngeneic murine model, ME-344 in combination with regorafenib showed significantly reduced tumor growth compared to regorafenib alone (Navarro et al. Cell Reports. 2016;15:2705). A randomized phase 0/1 window of opportunity study in HER2-negative breast cancer showed significant decrease in the proliferation marker Ki67 in patients administered ME-344 plus bevacizumab vs. bevacizumab alone (Quintela-Fandino et al, Clin Cancer Res. 2020;26:35). The current study evaluates the safety and efficacy of ME-344 in combination with bevacizumab in refractory metastatic colorectal cancer, a clinical setting where continued antiangiogenic inhibition has established benefit. Prior phase 1-1b studies of ME-344 as a single agent and in combination have established the RP2D at 10 mg/kg when administered intravenously weekly. Methods: This is an open-label phase 1b study in patients ≥18 years old with metastatic colorectal cancer after failure of standard therapies, including fluoropyrimidine-, irinotecan-, and oxaliplatin-based regimens, anti-EGFR if RAS wild-type, PD/L-1-blocking antibody if MSI-H/dMMR, and BRAF-targeted therapy if BRAF V600E mutated. Other key eligibility criteria include measurable disease, ECOG performance status 0-1, adequate bone marrow, liver and renal function, no uncontrolled brain metastatic disease, no peripheral neuropathy grade ≥2, no uncontrolled hypertension or diabetes, and no increased hemorrhagic risk. Enrollment will proceed in 2 cohorts of 20 patients each. Cohort 1 will be administered ME-344 at 10 mg/kg on days 1, 8, and 15 of a 28-day cycle and bevacizumab 5 mg/kg on days 1 and 15. Cohort 2 will be administered ME-344 at 10 mg/kg and bevacizumab 5 mg/kg both on days 1 and 15 of a 28-day cycle. Treatment will continue until disease progression or intolerance. Tumor assessment is performed every 8 weeks for 6 months and then every 3 months using RECIST-1 criteria. The primary endpoint is 16-week PFS. Secondary endpoints are PFS, response rate, and safety. Correlative analysis will evaluate treatment-related metabolic response. The study is actively enrolling, funded by MEI Pharma, and registered under NCT02100007. Clinical trial information: NCT02100007 .

BACKGROUND:Early studies showed promise of combined anti-epidermal growth factor receptor (EGFR) plus anti-vascular endothelial growth factor (VEGF) antibodies for advanced colorectal cancer (CRC), yet this was later rejected as toxic and ineffective in studies not selected for RAS status. We studied advanced KRAS wild-type CRC, as second-line treatment, using irinotecan-cetuximab with or without the anti-VEGF receptor antibody ramucirumab. METHODS:Patients with 1 prior regimen including fluoropyrimidine, oxaliplatin, and bevacizumab, with KRAS wild-type tumors were stratified by Eastern Cooperative Oncology Group Performance Score, time since last chemotherapy, and progression on oxaliplatin to irinotecan-cetuximab (IC) (180 mg/m2 and 500 mg/m2 every 2 weeks) vs modified ICR (irinotecan-cetuximab with ramucirumab 150 mg/m2 and 400 mg/m2 plus 6 mg/kg, respectively). A total of 102 patients were compared for progression-free survival (PFS) as primary endpoint (85% power for 70% improvement in median PFS from 4.5 to 7.65 months). RESULTS:Of the 102 enrolled, 44 treated with irinotecan-cetuximab and 45 with modified ramucirumab were evaluable. Median PFS was 6.0 months vs 9.2 months, respectively (hazard ratio = 0.75, P = .07; statistically significant by study design for P < .128). Response rate was 23% vs 36% (P = .27), and disease-control rate was 52% vs 73% (P = .05). Grade 3 or higher toxicity was equivalent. Overall survival was not significantly different at approximately 19 months. CONCLUSION:Previous phase 3 trials without RAS genotyping rejected combining anti-epidermal growth factor receptor and anti-VEGF drugs. In this randomized multicenter phase 2 study for KRAS wild-type CRC (all previously bevacizumab treated), the addition of ramucirumab to irinotecan and cetuximab improved PFS and disease control rate, showing the combination is feasible and effective. Further, phase 3 trials with appropriate patient-selection are required. (NCT01079780).

Purpose/Objective(s) The use of atezolizumab and bevacizumab for advanced hepatocellular carcinoma (HCC) is a recently established standard of care. Addition of locoregional therapies (LRT) such as external beam radiotherapy (RT), radioembolization (Y90), transarterial chemoembolization (TACE), and/or radiofrequency ablation (RFA) may hold promise for further improving outcomes, but the safety of these approaches with atezolizumab/bevacizumab has not been established. This study assessed the safety of upfront LRT in conjunction with this immunotherapy regimen in HCC. Materials/Methods We reviewed all patients initiating atezolizumab with or without bevacizumab (IO) for HCC from July 2020 to January 2022 at a single institution. Patients receiving LRT (RT, Y90, TACE, and/or RFA) within 30 days of IO initiation (LRT+IO) were identified alongside a comparison arm of all patients initiating IO alone. Bevacizumab was typically held until after LRT. Treatment-related toxicities were recorded according to CTCAE definitions from the date of treatment initiation until discontinuation of IO or last follow up. Baseline, 1 month, and 3-month Child-Pugh (CP) score, ALBI score, transaminases, and total bilirubin were additionally recorded and analyzed using a repeated-measure mixed effects model. Results 50 HCC patients initiating atezolizumab were identified, 49 (98%) of these in combination with bevacizumab. Median follow up was 6.5 months (range 1.2-20), median age was 64 (34-79). 37 (74%) patients had BCLC stage C disease and 12 (34%) BCLC stage B. The majority of patients (86%) had CP class A liver function. Baseline characteristics were balanced between arms on univariate analysis (p>0.05). Of 27 (54%) patients in the LRT+IO arm, 9 received RT alone, 4 received RT combined with Y90 or TACE, 10 received Y90 alone, 3 received TACE alone, and 1 received RFA. The majority of the LRT+IO arm (63%) received LRT after the first infusion of atezolizumab. Grade 3 toxicities were observed in 2 (7.4%) patients in the LRT+IO arm, compared to 2 (8.6%) patients in the IO-only arm (p=0.87); grade 2 toxicity incidence was 63% in the LRT+IO arm versus 43% in the IO-only arm (p=0.17). The receipt of LRT+IO was associated with transient increase in CP and ALBI scores at 1 month relative to IO alone (median score increase 1 and 0.34, respectively, p<0.01); this association did not persist at 3 months. There was no treatment-related liver failure or grade 4/5 toxicity reported in either arm. LRT+IO was not associated with increased ALT, AST, or total bilirubin at 1 or 3 months. Conclusion In this single institution retrospective cohort study, upfront locoregional therapy with atezolizumab and bevacizumab for HCC was not associated with a significantly greater incidence of grade 2/3 toxicity or clinically significant liver dysfunction relative to the initiation of atezolizumab and bevacizumab alone. Further studies are needed to verify the safety of combination therapy and to assess clinical benefit.

4146 Background: Pancreatic cancer therapy remains a formidable challenge. Although chemotherapy offers tumor control and clinical stabilization, both standard regimens are limited in response durability and incur toxicity. YH003, a humanized agonistic anti-CD40 monoclonal antibody specifically recognizes and agonizes CD40 to enhance immune responses, has demonstrated good safety and promising antitumor activity in Phase I clinical studies in patients with solid tumors. Here, we report the results of the phase II study of YH003 plus Toripalimab with/without chemotherapy, as 1L or 2L treatment in patients with metastatic PDAC. Methods: Patients with unresectable/metastatic (u/m) PDAC were enrolled into two Cohorts. In the second and plus line (2L + ) Cohort, patients who had confirmed progressive disease during treatment with first line standard of therapy were enrolled and received 0.3 mg/kg YH003 plus 240 mg Toripalimab, iv, every 21 days. In the 1L Cohort, patients without any prior systemic treatment were enrolled and received 0.3 mg/kg YH003 plus 240 mg Toripalimab plus nab-paclitaxel + gemcitabine, iv, every 21 days. The treatment continued for 12 months if subject was deriving an ongoing clinic benefit. The primary endpoint was overall Response Rate (ORR) by investigator’s assessment per RECIST 1.1. The medium Progression-Free Survival (mPFS) and Overall Survival (mOS) were secondary endpoints. Results: A total of 92 patients were enrolled including 45 subjects for the 2L + Cohort and 47 subjects for the 1L Cohort. In the 2L + Cohort, 40 (including 14 Caucasians) of 45 patients had at least 1 evaluable post-treatment tumor assessment, the unconfirmed ORR was observed in 4 patients (10.0%) with 4 partial responses (PR). 10 patients (25.0%) had stable disease (SD), and the Disease Control Rate (DCR) was 35.0%. The mOS was 7.23 months. For the Caucasian subgroup (n = 14), the ORR was 7.1%, DCR was 50%, mPFS was 2.25 months and mOS 9.54 months. For the 1L Cohort, 43 (including 10 Caucasians) of 47 patients had at least 1 evaluable post-treatment tumor assessment, the unconfirmed ORR was observed in 12 patients (27.9%) with 1 CR and 11 PR. 23 patients (53.5%) had SD, and the DCR was 81.4%. The mOS time was 12.12 months. For the Caucasian subgroup (n = 10), the ORR was 50%, DCR was 100%, mPFS was 11.27 months and mOS 19.78 months. The grade 3 or above adverse events that occurred in the 92 patients were 57.8% (26/45) in 2L + Cohort and 74.5% (35/47) in 1L Cohort. There is no significant safety signal from the study. Conclusions: The results of the phase II study have shown that YH003 plus Toripalimab with/without chemotherapy, as 1L or 2L treatment in patients with u/m PDAC have promising antitumor activity and response durability, especially in the Caucasian subgroups. Both treatment regimens are well tolerated. Clinical trial information: NCT05031494 .

Background:Neoadjuvant chemotherapy (NACT) is increasingly being used in the management of locally advanced biliary tract cancer (BTC). The evidence suggests a contributing role of tumor infiltrating immune cells in the prognosis and response. We set out to characterize immune modulation of tumor immune microenvironment in BTC following NACT. Case Description:Patients with BTC who underwent diagnostic biopsy, then NACT then resection between 2014-2018 were identified. Multiplexed immunohistochemical consecutive staining on single slide (MICSSS) analysis was performed with a series of immune markers to characterize T-cells, immune checkpoints etc. on pre- & post-NACT tumor tissue. Density was calculated for each marker. The final analysis included five patients. Median age was 48 (range, 41-56) years, with 4 female, 4 intrahepatic cholangiocarcinoma and 1 gallbladder. All patients received gemcitabine/cisplatin as NACT (median of 5 cycles). Median time from diagnosis to surgery was 4.3 (range, 1.4-7.8) months. All patients were mismatch repair proficient (pMMR). NACT on average produced a depletion of all immune markers. Given small sample size, each patient was considered their own control and changes in mean cell densities post-NACT were calculated. Patient #2 with a 40-fold increase in PD-L1 expression & 5-fold decrease in CD8:FOXP3 ratio after NACT notably had the shortest disease-free interval (DFI). Patient #3 with the longest DFI had the largest increase in CD8:FOXP3 by about 8-fold with a decrease in PD-L1. Conclusions:Preliminary results suggest NACT may differentially modulate various compartments of the immune tumor contexture despite overall cell depletion. Future studies should focus on strategies to expand immune modulation of tumor microenvironment, including immune-oncology agents to augment the effects of chemotherapy.

Background Immune checkpoint inhibitors (ICIs) are standard therapy for unresectable HCC, but many patients do not respond. Non-viral HCC, particularly non-alcoholic steatohepatitis (NASH), have been implicated in ICI resistance. Methods We reviewed 288 patients with unresectable HCC who received ICI from 1/2017 to 12/2021. The overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) between patients with viral HCC and non-viral HCC were compared using the full and Child Pugh (CP) class A only cohorts. Results In total, 206 patients (71.5%) had viral HCC (most HCV), and 82 patients had non-viral HCC. Non-viral HCC was associated with worse OS (HR 1.6, 95% CI: 1.1–2.1, P = 0.006) and PFS (HR 1.5, 95% CI: 1.2–2, P = 0.002) in univariate but not multivariate analyses. For the CP class A cohort, non-viral HCC was independently associated with worse OS (HR 1.8, 95% CI: 1.2–2.7, P = 0.005) and PFS (HR 1.9, 95% CI: 1.3–2.7, P < 0.001). Viral HCC and CP class A liver disease was associated with better ORR than non-viral HCC (38% vs. 16%, P = 0.001). Conclusions Following ICI treatment, non-viral HCC correlated with worse OS, PFS, and ORR than viral HCC, particularly in patients with preserved liver function.

INTRODUCTION:National Comprehensive Cancer Network (NCCN) 2019 Guidelines recommend universal germline (GL) testing for patients (pts) with pancreatic cancer (PC), given germline mutations (gMut) can occur at a similar rate irrespective of an individual's family history of cancer. Molecular analysis of tumors in those with metastatic disease is also recommended. We aimed to determine rates of genetic testing at our institution, factors associated with testing, and outcomes of those tested.METHODS:Frequency of GL and somatic testing was examined in pts diagnosed with non-endocrine PC, with >2 visits between June 2019 and June 2021 at the Mount Sinai Health System. The clinicopathological variables and treatment outcomes were also recorded.RESULTS:A total of 149 pts met the inclusion criteria. Sixty-six pts (44%) underwent GL testing: 42 (28%) at time of diagnosis with the remainder later in treatment. The rate of GL testing increased every year: 33% (2019), 44% (2020), and 61% (2021). A family history of cancer was the only variable associated with the decision to perform GL testing. Eight pts (12% of pts tested) had pathological gMut: BRCA1 (1), BRCA2 (1), ATM (2), PALB2 (2), NTHL1 (1), both CHEK2 and APC (1). Neither gBRCA pt received a PARP inhibitor, all except one received first-line platinum. Ninety-eight pts (65.7%) had molecular tumor testing (66.7% of patients with metastases). Two pts with BRCA2 somatic mut did not have GL testing. Three pts received targeted therapies.CONCLUSION:Genetic testing based on provider discretion results in low rates of GL testing. Early results of genetic testing can have an impact on treatment decisions and trajectory of disease. Initiatives to increase testing are needed but must be feasible in real-world clinic settings.

Figure Legends for Figures S1-S8.

TPS232 Background: Despite the superiority in progression-free survival (PFS) of inhibition of programmed cell death-1 (PD-1) pathway in dMMR/MSI-H as compared to chemotherapy with either anti-vascular endothelial growth factor receptor (VEGFr) or anti-epithelial growth factor receptor (EGFr) antibodies in mCRC, more pts had progressive disease as the best response in the anti-PD1 monotherapy arm (29.4% vs. 12.3%) with mean PFS of 13.7 months ( N Engl J Med 2020; 383:2207). We hypothesize that the dMMR/MSI-H mCRC pts may be more effectively treated by the combination of PD-1 pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF and between oxaliplatin/anti-PD-1 in murine CRC models and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Additionally, in other solid tumor malignancies, anti-PD1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD1 plus chemotherapy (i.e., gastric and esophageal cancers) combinations are standard first-line treatments. Methods: The redesigned COMMIT study was reactivated on 1/29/2021 as a two-arm prospective phase III open-label trial randomizing (1:1) mCRC dMMR/MSI-H (211 pts) to atezo monotherapy versus mFOLFOX6/bev+atezo combination. Assuming our control arm, atezo monotherapy, 48% PFS at 24 months, as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 months) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include OS, objective response rate, safety profile, disease control rate, duration of response, and centrally-reviewed PFS. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; and measurable disease per RECIST. Enrollment actively continues to the target accrual of 211 patients randomized between the two immunotherapy arms. Support: U10CA180868, -180822, -180888, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228.

256 Background: Pancreatic Cancer is known to be associated with poor survival outcomes and high symptom burden. Integration of early palliative care has been associated with improved end of life care, including reduced hospitalizations and emergency room visits. We conducted a retrospective study to determine the utilization rates of specialist palliative care in patients diagnosed with metastatic pancreatic cancer at an academic teaching hospital and summarize the impact on end-of-life care. Methods: A database of patients diagnosed with metastatic pancreatic cancer on index presentation from 2011 and 2022 was analyzed for utilization of specialist palliative care. Patients who transitioned cancer care to other centers and those who were lost to follow-up were excluded. Data on patient demographics, treatment course, and end-of-life care were collected, and descriptive statistics were used to summarize the data. Results: In our study, 168 patients met the inclusion criteria. The average age of diagnosis was 66 years with a diverse ethnic composition, including White (35.7%), African American (26.8%), and Hispanic (15.5%) patients. Among the cohort, 126 out of 168 (75%) patients were seen by palliative care at least once, with 79 (62.7%) of them initially seen during one of the hospitalizations, and 47 (37.3%) were seen by palliative care outpatient for the first time. The median duration between pancreatic cancer diagnosis and first encounter with palliative care was 145 days (IQR 305 days). No significant differences were found in terms of age, race, sex, ethnicity or insurance type between patients who received palliative care and those who did not. The median time from consultation to death was 57 days and 36.5% patients received palliative care only within one month of their death. Patients who received palliative care were more likely to have a DNR/DNI code status (86.7% vs. 13.3%, p < 0.001) and were more likely to be enrolled in hospice care (86.3% vs. 13.7%, p < 0.001). Conclusions: Early involvement of specialist palliative care in management of patients with metastatic pancreatic cancer may lead to optimization of health care services with earlier hospice referrals and comfort directed care at the end of life. Further research is warranted to explore the impact of palliative care on patient outcomes, quality of life, and the potential benefits of aligning treatment decisions with patients' end-of-life preferences.