Wolff, Robert A.

e16479 Background: Recent genomic data has demonstrated SBA to be a molecularly unique entity when compared to colon or gastric cancers. The ongoing SWOG 1922 randomized clinical trial is comparing FOLFIRI to ramucirumab/paclitaxel as the second-line treatment for metastatic SBA. We sought to further define the activity of taxane-based therapy in the largest collection of SBA patients treated with this therapy. Methods: A retrospective review of SBA patients treated with taxane-based chemotherapy from 1994 to 2024 at MD Anderson Cancer Center was performed. All patients had pathologic confirmation, received > 1 cycle of therapy, and had documented tumor response evaluation. Response was assessed by the treating physician based on the imaging studies and categorized as response, stable disease or progression. Patient demographics, clinical parameters, molecular data, and taxane treatment was reviewed. Kaplan-Meier survival analysis was performed to calculate time to progression (TTP) and overall survival (OS). Results: 70 SBA patients treated with taxane-based therapy were identified. The median age at diagnosis was 57 years (range 33-80 years), majority being male (59%) with primary tumor located at duodenum (44%), Jejunum (34%), Ileum (16%). The most common presenting metastatic site was peritoneum (39%), followed by liver (31%). The genomic status revealed mutations in the following genes: 62% TP53, 47% KRAS, 24% SMAD4, and 15% APC. Taxane treatment was single agent (nab-paclitaxel, paclitaxel, or docetaxel) in 29%, gemcitabine and taxane combination in 61% and other taxane-based combinations in 10%. Therapy was given in the metastatic setting as 2nd-line in 40%, 3rd-line in 33% and 4th-line or greater in 20%. Response status was response in 24%, stable disease in 26%, and progression in 50%. Median TTP was 3.1 months (95%CI: 2.0-4.2 months), and median OS was 8.7 months (95%CI: 7.4-10.1 months). Median TTP was similar between single agent (2.6 months) and gemcitabine-based combination (2.5 months) (p =0.75). Efficacy did not differ by line of therapy nor primary tumor site. Efficacy differed by TP53 mutation status: TP53 mutated vs wildtype (response 21% vs 43%, p = 0.02; median TTP 2.4m vs 4.9m, p = 0.013; median OS 7.3m vs 10.6m, p = 0.004). Conclusions: This retrospective study of 70 SBA patients confirms the activity of taxane-based therapy demonstrating a response rate of 24% and median TTP of 3.1 months. Though limited by sample size, TP53 mutations may represent a negative predictive marker for taxane-based therapy in SBA patients. These findings support the ongoing SWOG 1922 trial investigating taxane-based therapy as a second line for metastatic SBA.

Background and Aims: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). Approach and Results: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP, rs9842969, (0.51, [0.40–0.65]); 5p15.33, TERT, rs2242652, (0.70, (0.62–0.79]); 19q13.11, TM6SF2, rs58542926, (1.49, [1.29–1.72]); 19p13.11 MAU2, rs58489806, (1.53, (1.33–1.75]); and 22q13.31, PNPLA3, rs738409, (1.66, [1.51–1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74–0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. Conclusions: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.

4047 Background: BRAFV600E mutations occur in fewer than 10% of all patients (pts) with metastatic colorectal cancer (mCRC) and arise from sessile serrated adenomas. Despite efficacy with targeted therapies against MAPK signaling and with immunotherapies in this population, survival outcomes for pts with BRAFV600E mCRC in general are poor. Characteristics distinguishing pts with BRAFV600E mCRC with favorable versus unfavorable outcomes have not been well annotated. Methods: Records of 188 pts with BRAFV600E mCRC evaluated at MD Anderson Cancer Center between 3/2010-1/2020 were reviewed. Pts with the shortest and longest metastatic survival (N = 25 for each group) were compared. Associations between prognostic group and clinical/pathologic features were measured by odds ratio and for median survival by log-rank testing. Results: Median metastatic survival differed between the 2 BRAFV600E mCRC populations (8.6 vs 84 months, p < .0001). Pts with poor survival more commonly had primary tumors arising from the hepatic flexure/proximal transverse colon (44% vs 16%, p = .04) and more frequent hepatic involvement (75% vs 28%, p = .001). Pts with favorable survival were more likely to develop metachronous metastases (52% vs 16%, p = .01), have fewer distant organ involvement (median 1 vs 2, p = .02), and undergo definitive locoregional therapy to metastatic disease (44% vs 0%, p = .01). Microsatellite instability (36% vs 4%, p = .008) and a history of tobacco use (44% vs 16%, p = .04) were associated with a favorable prognosis. Durable responses to MAPK-targeted therapies (5/25) and immunotherapy (3/25) were noted in the favorable group. Conclusions: Pts with BRAFV600E mCRC can achieve excellent long-term survival which belies conventional context and is driven by locoregional and systemic treatment options alike. Anatomic localization of the primary tumor and prior exposures may highlight environmental influences on tumor biology which account for the clinical heterogeneity of pts with BRAFV600E mCRC.

4038 Background: GEM has served as the chemotherapy platform for most phase III clinical trials in APC, inc. CALGB 80303 (GEM +/- BEV). However, GEM-based combination regimens may confer superior outcomes in select pts and represent a preferred backbone in clinical trial design testing targeted agents. Methods: Data was pooled from 5 phase II trials evaluating GEM-based cytotoxic doublets plus BEV in APC. 1o endpoint was OS. 2o endpoints included ORR, CA19-9 response, and adverse events (AEs). Kaplan-Meier methods estimated time-to-event endpoints. The Cox proportional hazard model estimated univariate hazard ratios (HR) of death. Results: Of 261 pts, 90.7% were Caucasian, 95.4% had an ECOG PS 0-1, and 91.6% had metastatic disease. Median age = 60y. Pooled OS data (in mos), stratified for PS and stage, is shown in the table. ORR across all trials: CR 1.6%, PR 22.9%, SD 50.8%, PD 20.2%, NA 4.7%. HR for pts who achieved disease control (CR/PR/SD) was 0.35 vs. those with PD (95% CI 0.23-0.54, p<0.001). 76.5% of pts had elevated baseline CA19-9; of these, 62% achieved ≥50% reduction (HR 0.50; 95% CI 0.34-0.73, p<0.001). BEV-related AEs ≥grade 3: HTN (10.6%), hemorrhage (9.5%), VTE (10.1%), cardiac events (3.4%), and bowel perforation (2.2%). Median OS in pts with grade 3-4 HTN was 13.4 mos vs. 9.8 mos in those without (HR 0.77; 95% CI 0.48-1.24, p=0.29). Conclusions: Recognizing the limitations of single-arm phase II trial design and cross-study comparisons, these results compare favorably to those from CALGB 80303. The standard paradigm of GEM +/- drug X in clinical trial development for APC needs to be reconsidered. Based on our data as well as the recent phase III FOLFIRINOX study, building on more intensive combination chemo regimens in future trials may represent a better strategy, especially for pts with good PS. [Table: see text]

480 Background: Currently, there is a lack of imaging biomarkers of immunotherapy outcome in hepatocellular carcinoma (HCC). The study aim was to determine if HCC enhancement on MRI and stiffness change measured by magnetic resonance elastography (MRE) can predict immunotherapy response. Methods: This was a prospective, Institutional Review Board approved study of 38 patients with HCC treated with immune checkpoint blockade (ICB) therapy. All patients had liver MRI/MRE and HCC biopsy at baseline, and MRI/MRE with biopsy or resection after 6 weeks therapy. HCC stiffness (kPa) was measured on MRE elastograms (liver stiffness maps). HCC enhancement and change in stiffness were compared with treatment response to ICB in 1) non-surgical patients (pembrolizumab), and 2) surgical patients (nivolumab +/- ipilimumab). For non-surgical patients, treatment response was defined as overall survival >1 year. For surgical patients, treatment response was defined as <50% viable tumor at time of resection. Analysis was performed using descriptive statistics and Spearman correlation; p-value <0.05 was considered statistically significant. Results: Twenty-five patients were evaluable. Median age was 67 years (32, 78). Etiology of liver disease was NASH (n=8), HCV (n=8), HBV (n=2) and unknown (n=7). Treatment response occurred in 11/25 (44%) patients. Median HCC size and change in size were 4.7 cm (1.2, 14.0) and –0.32 cm, respectively. Median baseline HCC stiffness and change in stiffness were 5 kPa (2.2, 12.4) and –0.1 kPa (–2.2, 1.5), respectively. Median change in HCC size for responders and non-responders was –1.2 cm (–4.8, 0.4) and 0 cm (–1.5, 1.1), respectively (p = 0.02). Treatment response was associated with absence of portal venous phase capsular enhancement and increase in HCC stiffness, (p<0.001). Conclusions: Capsular enhancement and MRE stiffness change may be useful biomarkers of immune cell activated response to ICB therapy.

The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights discuss important updates to the 2019 version of the guidelines, focusing on postoperative adjuvant treatment of patients with pancreatic cancers.

350 Background: BTCs are often diagnosed at an advanced stage and have a poor prognosis. The standard therapy for aBTCs is the combination of GC. However, the median overall survival (mOS) is dismal at 11.7 months (mos) with a median progression free survival (mPFS) of 8 mos. Methods: A single arm, phase II study was conducted at MD Anderson and Mayo Clinic Arizona. Patients (pts) with aBTC were treated at initial dose level of G/C/N (in mg/m2) at 1000/25/125 (n = 30) which was reduced to lower doses due to grade 3/4 hematological (heme) toxicity (tox) - G/C/N: 800/25/100 (n = 30). Cycles were q21 days with restaging q3 cycles until progression. PFS was the primary endpoint (endpt). Using a Bayesian hypothesis test-based design, we assumed mPFS of 8 mos under the null hypothesis (H0), 10 mos under the alternative (H1). Secondary endpts included mOS, RECIST v1.1 response rate (RR), safety and CA19-9 response. Results: 60 pts were enrolled with 51 being response-evaluable having received more than 1 cycle of therapy (age: median 60 yrs [range 31-77], ECOG PS 0/1 (22/38), M/F (33/27), intrahepatic cholangiocarcinoma/extrahepatic/gallbladder (38/9/13). Median follow-up was 14 mos and median number of treatment (trmt) cycles = 5.24. Pts at initial dose level had significant grade 3/4 heme tox: neutropenia, febrile neutropenia, anemia, and thrombocytopenia leading to trmt discontinuation in 6/30 pts. After dose reduction to G/C/N (in mg/m2) at 800/25/100, trmt was better tolerated with only 3 pts experiencing grade 4 heme tox. Non-heme tox were grade 3 in 19 pts: nausea/vomiting, diarrhea, thromboembolic event/CVA, hypokalemia, constipation, cystitis, LFT elevations. The mPFS = 11.4 mos (95% CI: 6.1, 16.1) and mOS = 19.2 (95%CI: 13.6, NA), 1-year survival rate 67.6%. 51 pts evaluable for response: disease control rate (PR+CR+SD)-84.3% and RR-39%. 12 unresectable cases were operated post trmt with 1 pathologic CR. Conclusions: The combination of GCN was well tolerated at adjusted doses and demonstrates encouraging efficacy having met its mPFS endpt and an impressive mOS higher than historical control. These results merit evaluating GC +/-N in a randomized controlled study. Clinical trial information: NCT02392637.