Citations

192 Background: Rectal cancer treatment paradigm has been evolving over time. Historically, for locally advanced rectal cancer, standard therapy (ST) consisted of neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy. Recently, total neoadjuvant treatment (TNT) approach that delivers both neoadjuvant chemotherapy (CAPOX or FOLFOX) and chemoradiation (or radiation only) prior to surgery is increasingly being utilized. The prognostic and predictive values of mismatch repair deficient (dMMR) in rectal cancer is not well characterized. Most dMMR patients receive the same treatment as MMR proficient (pMMR) patients although there is limited data that dMMR rectal cancer patients may not have the same level of benefits from neoadjuvant treatment. This retrospective study aims to evaluate the clinicopathological/molecular characteristics, disease response, and clinical outcomes in dMMR localized rectal cancer patients. Methods: A retrospective analysis was conducted on consecutive adult patients with a diagnosis of dMMR rectal cancer who were treated at Mayo Clinic between January 2000 to September 2021. Patients who presented with concurrent primary non-colorectal malignancies were excluded. The distributions of demographics, clinicopathological features, biomarkers, and outcome data were collected. Survival was assessed using Kaplan-Meier curves and Cox models were stratified by treatment arms to determine significance of treatment strategies. Results: Forty-one patients were identified with a median age of 45.3 years. Thirty (73.2%) pts were male. The most common MMR were loss of MSH2 and MSH6 (12/42; 29.3%) followed by loss of MLH1 and PMS2 (10/42; 24.4%) and solitary loss of MSH2 (4/42; 9.8%). The treatment, pathological response, and clinical outcomes are listed in table. With a median follow up of 101 months, only 6 patients (14.3%) died and median overall survival was not reached. Conclusions: Our findings showed dMMR localized rectal cancer responded to both ST and TNT with good clinical outcomes.[Table: see text]

Purpose Clinical-pathologic features and natural history of patients with isocitrate dehydrogenase ( IDH)-mutant intrahepatic cholangiocarcinoma (CCA) are not well characterized. Here, we sought to describe the natural history, clinical phenotype, and prognostic impact of advanced, IDH-mutated CCA. METHODS We conducted a multicentric, retrospective analysis of patients with IDH-mutated (IDH1 or IDH2) CCA between 2010 and 2020. Median overall survival (OS) and progression-free survival (PFS) analyses were performed using the Kaplan-Meier method. Chi-square test was used to analyze disease control rate (DCR) and overall response rate (ORR). Matched controls were used for comparing survival between patients with and without IDH mutations (mIDH). RESULTS Sixty-five patients with IDH-mutated CCA were included. All patients had intrahepatic CCA. On first-line chemotherapy, median OS and median PFS were 21.2 months and 8.3 months, respectively. Notably, median OS (32.4 v 19.5 months, P = .12) and PFS (18.0 v 8.0 months, P = .12) were not significantly affected by disease status at presentation (locally advanced v metastatic, respectively). Median OS was significantly longer in patients with mIDH (21.2 v 10.5 months; P < .01). First-line gemcitabine-containing regimens had a significantly higher DCR and ORR than non–gemcitabine-containing regimens (DCR: 75% v 33%, P = .01; ORR: 39% v 0%, P = .02). In patients receiving IDH inhibitor therapy, median PFS was 4.6 months with a DCR of 29%. CONCLUSION CCA with m IDH confers a unique subtype resulting in a better survival compared with that of counterparts. IDH inhibitors represent a promising therapeutic option in later lines of therapy in this subgroup.

Prostate‐specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with 68Ga‐PSMA‐11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, 68Ga‐PSMA‐11 PET was prospectively performed in patients with treatment‐naïve HCC on a digital PET scanner using cyclotron‐produced 68Ga. Uptake was graded qualitatively and semi‐quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA (P < 0.0001); 91% of HCCs (n = 134) expressed PSMA, which principally localized to tumor‐associated neovasculature. Higher tumor grade was associated with PSMA expression (P = 0.012) but there was no association with tumor size (P = 0.14), fibrosis (P = 0.35), cirrhosis (P = 0.74), hepatitis B virus (P = 0.31), or hepatitis C virus (P = 0.15). Overall survival tended to be longer in patients without versus with PSMA expression (median overall survival: 4.2 vs. 1.9 years; P = 0.273). FGF14 (fibroblast growth factor 14) mRNA expression correlated positively (rho = 0.70; P = 1.70 × 10‐5) and MAD1L1 (Mitotic spindle assembly checkpoint protein MAD1) correlated negatively with PSMA expression (rho = −0.753; P = 1.58 × 10‐6). Of the 190 patients who met the eligibility criteria, 31 patients with 39 HCC lesions completed PET; 64% (n = 25) lesions had pronounced 68Ga‐PSMA‐11 standardized uptake value: SUVmax (median [range] 9.2 [4.9‐28.4]), SUVmean 4.7 (2.4‐12.7), and tumor‐to‐liver background ratio 2 (1.1‐11). Conclusion: Ex vivo expression of PSMA in neovasculature of HCC translates to marked tumor avidity on 68Ga‐PSMA‐11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.

Abstract Background:Biliary tract cancers (BTC) are rare, chemo resistant and are associated with a poor prognosis. Preclinical and early clinical work had demonstrated interesting anti-tumor activity from targeting fibroblast growth factor receptor (FGFR) pathway. We hypothesized that ponatinib, a multi-targeted tyrosine kinase inhibitor with activity against FGFR, would be active in BTC patients with FGFR alterations.Methods:This was a multi-center, single institution pilot study of ponatinib in patients with advanced, refractory BTC with FGFR alterations. The primary end point was overall response rate, with secondary points of overall survival (OS), progression-free survival (PFS) and Health Related Quality of Life (HRQoL) assessment. Results:Twelve patients were enrolled prior to early termination of the trial. Clinical benefit (defined as complete/partial response + stable disease) of 45.5% was observed. All observed toxicities were manageable and reversible. Toxicities were mild, with lymphopenia (75%), rash (63%) and fatigue (50%) being the most frequent. No significant detriment in global QoL was observed.Conclusions:Ponatinib as a single agent in FGFR altered BTC is tolerable with very modest clinical activity. This is the first report of prospective assessment of FGFR inhibition in BTC using ponatinib, and the first study to report its effect on HRQoL. Further development of ponatinib will involve correlative studies to better refine patient selection, focus on combinations with other molecular targeted agents, conventional cytotoxic chemotherapy, and studies to better understand mechanisms of treatment resistance.

PURPOSECholangiocarcinomas (CCA) are a group of heterogeneous tumors arising from the biliary epithelia. Significant sequencing efforts have provided further insights into the molecular mechanisms of this disease including fibroblast growth factor receptor ( FGFR) alterations, which occurs in approximately 15%-20% of intrahepatic CCAs. Herein, we describe the FGFR inhibitor (FGFRi)-associated treatment toxicity and cancer-specific outcomes from a multicenter single-institution cohort.METHODSThis is a retrospective study of patients with CCA and known FGFR alterations treated with FGFRi. We describe the toxicity and efficacy in patients treated at Mayo Clinic between January 2010 and December 2020.RESULTSOur group identified 61 patients with advanced or metastatic CCA, 19 males (31%) and 42 females (69%), harboring FGFR alterations who received FGFRi. The most common grade 1 or higher adverse events for all patients included fatigue (92%), AST elevations (78%), anemia (80%), decreased platelet count (63%), and hyperphosphatemia (74%). Median progression-free survival on FGFRi was 5.8 months for all patients (95% CI, 4.9 to 9.0). Females had significantly longer progression-free survival at 6.9 months (95% CI, 5.2 to 11.8) on FGFRi compared with males at 4.9 months (95% CI, 2.8 to not estimable; P = .038).CONCLUSIONFGFRi are well tolerated with clinical efficacy. With the recent approval of FGFRi by the US Food and Drug Administration and ongoing clinical trials for new FGFRi, understanding outcomes and toxicity associated with these medications is important for precision oncology.

Objective Effective medical therapy and validated trial outcomes are lacking for small bowel Crohn’s disease (CD) strictures. Histopathology of surgically resected specimens is the gold standard for correlation with imaging techniques. However, no validated histopathological scoring systems are currently available for small bowel stricturing disease. We convened an expert panel to evaluate the appropriateness of histopathology scoring systems and items generated based on panel opinion. Design Modified RAND/University of California Los Angeles methodology was used to determine the appropriateness of 313 candidate items related to assessment of CD small bowel strictures. Results In this exercise, diagnosis of naïve and anastomotic strictures required increased bowel wall thickness, decreased luminal diameter or internal circumference, and fibrosis of the submucosa. Specific definitions for stricture features and technical sampling parameters were also identified. Histopathologically, a stricture was defined as increased thickness of all layers of the bowel wall, fibrosis of the submucosa and bowel wall, and muscularisation of the submucosa. Active mucosal inflammatory disease was defined as neutrophilic inflammation in the lamina propria and any crypt or intact surface epithelium, erosion, ulcer and fistula. Chronic mucosal inflammatory disease was defined as crypt architectural distortion and loss, pyloric gland metaplasia, Paneth cell hyperplasia, basal lymphoplasmacytosis, plasmacytosis and fibrosis, or prominent lymphoid aggregates at the mucosa/submucosa interface. None of the scoring systems used to assess CD strictures were considered appropriate for clinical trials. Conclusion Standardised assessment of gross pathology and histopathology of CD small bowel strictures will improve clinical trial efficiency and aid drug development.

Abstract Background: Sorafenib (Sor) remains a first-line option for hepatocellular carcinoma (HCC) or refractory renal cell carcinomas (RCC). PLC/PRF/5 HCC model showed upregulation of hypoxia with enhanced efficacy when Sor is combined with hypoxia-activated prodrug evofosfamide (Evo). Methods: This phase IB 3 + 3 design investigated 3 Evo dose levels (240, 340, 480 mg/m2 on days 8, 15, 22), combined with Sor 200 mg orally twice daily (po bid) on days 1-28 of a 28-day cycle. Primary objectives included determining maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Sor + Evo. Results: Eighteen patients were enrolled (median age 62.5 years; 17 male /1 female; 12 HCC/6 RCC) across three dose levels (DL0: Sor 200 mg bid/Evo 240 mg/m2 [n=6], DL1:Sor 200 mg bid/Evo 480 mg/m2 [n=5], DL1a: Sor 200 mg bid/Evo 340 mg/m2 [n=7]). Two dose-limiting toxicities (DLTs) were reported with Evo 480 mg/m2 (grade 3 mucositis, grade 4 hepatic failure). Grade 3 rash DLT was observed in one patient at Evo 240 mg/m2. No DLTs were observed at Evo 340 mg/m2. MTD and RP2D were established as Sor 200 mg/Evo 340 mg/m2 and Sor 200/Evo 240 mg/m2, respectively. The most common treatment-related adverse events included fatigue, hand-foot syndrome, hypertension, and nausea/vomiting. Two partial responses were observed, one each at DL0 and DL1a.; disease control rate was 55%.Conclusions: RP2D was established as sorafenib 200 mg bid + Evo 240 mg/m2. While preliminary anti-tumor activity was observed, future development must account for advances in immunotherapy in HCC/RCC. NCT01497444Date of registration December 20, 2011

TPS594 Background: Effective treatment options are very limited for patients with advanced refractory biliary tract cancer (BTC). Fluoropyrimidine-based chemotherapy regimen such as 5-fluorouracil and irinotecan are frequently utilized for these patients after first-line therapy despite lack of FDA approval. Trifluridine/tipiracil (FTD/TPI) is a novel oral nucleoside with antitumor activity in both fluoropyrimidine sensitive and resistant tumors due to its unique mechanisms of action. Given early toxicity and efficacy data from our previous study on single-agent trifluridine/tipiracil (FTD/TPI) in advanced BTC, the clinical evaluation of its combination with irinotecan represents a rational approach for the treatment of advanced refractory BTC. Methods: This is a single-arm phase II trial with a two-stage design to assess the efficacy of trifluridine/tipiracil (FTD/TPI) and irinotecan in advanced refractory BTC. Key eligibility criteria include histologically confirmed advanced, unresectable BTC who have progressed on at least one line of systemic therapy and have measurable disease per RECIST v1.1. Target accrual is 25. Treatment includes trifluridine/tipiracil (FTD/TPI) 25 mg/m2 on days 1-5 and irinotecan 180 mg/m2 on day 1 in 14-day cycles. Patients will be evaluated for response every 4 cycles and in the absence of disease progression, therapy may be given up to 2 years. The primary end point is the progression-free survival rate at 16 weeks. Secondary endpoints include overall response rate, disease control rate, progression-free survival, overall survival, and incidence of adverse events. Correlative biomarker studies include evaluations of circulating tumor DNA and circulating tumor cells at baseline, after 4 cycles and at progression; and development of patient-derived tumor organoids from pre-treatment biopsies for parallel treatments. This study was approved and funded in part by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Taiho Oncology, Inc. Clinical trial information: NCT 04072445.