Tran, Nguyen

Abstract Background Optimal treatment following first-line immunotherapy for advanced hepatocellular carcinoma (HCC) remains uncertain. This study evaluated futibatinib, a pan-FGFR inhibitor, combined with pembrolizumab in previously treated patients with FGF19-expressing HCC. Methods Eligible patients were ≥18 years old with advanced HCC, prior systemic therapy, Child-Pugh A-B7 liver function, ECOG 0–2, and FGF19 overexpression. Patients received futibatinib 20 mg orally daily plus pembrolizumab 200 mg intravenously every 3 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints included overall survival (OS), objective response rate (ORR), quality of life, and safety. Results Between August 2021 and March 2024, 14 patients enrolled and 13 were evaluable. Median age was 72 years (range, 60–87), 53.8% were male, 92.3% had Child-Pugh A liver function, and all had received prior immunotherapy. Median progression-free survival was 15 weeks (95% CI, 9.0–NE), with a PFS6 rate of 23.1% (95% CI, 8.6–62.3%). ORR was 0% (95% CI, 0–24.7%), while stable disease was observed in 53.9% of patients. Median OS was 55.7 weeks (95% CI, 47.3–NE). Grade ≥3 adverse events occurred in 69.2% of patients, and grade ≥4 adverse events in 15.4%. One grade 5 event (acute-on-chronic kidney injury) was deemed unrelated to treatment. Common adverse events included hyperphosphatemia, fatigue, diarrhea, elevated transaminases, dry eye, nail changes, rash, and oral mucositis. Conclusions Futibatinib plus pembrolizumab demonstrated an acceptable safety profile but did not meet efficacy thresholds supporting further study in FGF19-expressing HCC. Effective post-immunotherapy treatment strategies remain an unmet need.

PURPOSE Deficient mismatch repair/microsatellite instability (dMMR, MSI-H) in biliary tract cancers (BTCs) is observed in 1%-5% of tumors. MSI-H across solid tumors has demonstrated durable response to immune checkpoint inhibitors (ICIs) regardless of the anatomic location. Here, we describe clinical outcomes and surgical conversion of MSI-H BTC treated with ICIs. Patients and Methods We conducted a multicenter, retrospective analysis of BTC patients with dMMR/MSI-H between 2017 and 2024 at Mayo Clinic, University of Michigan, and University Hospitals Seidman Cancer Center. Outcomes of interest were surgical resection rate, rate of pathologic response, 2-year overall survival (OS; time from initiation of treatment to death/last follow-up), and time to treatment discontinuation (TTD; time from initiation of treatment to cessation because of any cause). Analyses were descriptive. RESULTS Thirty patients with MSI-H BTC were identified: 19 with cholangiocarcinoma, three with gallbladder cancer, and 8 with BTC undefined. The median age at diagnosis was 61.5 years (range, 26-86). Twenty-six (86.7%) patients had advanced stage at diagnosis. Twenty-seven patients (90%) received first-line systemic therapy, and 13 (48.1%) continued onto second line. Six patients (23.1%) were restaged to resectable from advanced disease after ICI therapy and underwent resection; all remained recurrence-free at last follow-up. Of these six patients, 3 (50%) achieved a pathologic complete response. Among those receiving first-line therapy, the median TTD was 9.9 months (95% CI, 5.7 to 14.5 months) and the 2-year OS was 73% (95% CI, 56% to 94%). CONCLUSION ICI therapy in patients with MSI-H BTC demonstrated durable response and downstaged some BTC to a resectable stage. dMMR/MSI-H should be performed up-front to guide treatment decisions.

PURPOSE Cholangiocarcinoma is a rare cancer associated with poor prognosis. Pemigatinib was the first FGFR1-3 inhibitor approved for second-line therapy and beyond, on the basis of the phase II FIGHT-202 trial. Here, we assess efficacy and safety of first-line pemigatinib. METHODS FIGHT-302 is a phase III, randomized, global trial evaluating pemigatinib as first-line therapy (ClinicalTrials.gov identifier: NCT03656536 ). Adults with advanced cholangiocarcinoma with FGFR2 rearrangement were randomized 1:1 to receive pemigatinib (13.5 mg once daily) or chemotherapy (1,000 mg/m 2 gemcitabine plus 25 mg/m 2 cisplatin once per day on days 1 and 8 of every 3-week cycle for ≤8 cycles) and were stratified by prior receipt of chemotherapy, geographic region, and tumor burden. Pemigatinib crossover was allowed for patients progressing on chemotherapy. The primary end point was progression-free survival (PFS). Secondary efficacy, safety, and exploratory end points were also analyzed. RESULTS Overall, 4,563 patients were prescreened, 196 were screened, and 167 randomly assigned to receive pemigatinib (n = 83) or chemotherapy (n = 84) before early closure of the study because of a change in standard of care. The median PFS was 8.3 months in the pemigatinib group versus 6.8 months in the chemotherapy group (hazard ratio, 0.58 [95% CI, 0.39 to 0.87]; nominal P = .0078); objective response rate was 47% versus 15%, and the median duration of response was 14.2 versus 6.3 months. Median overall survival was similar (24.4 v 25.0 months, respectively). In the crossover group (n = 42, second-line pemigatinib), the median PFS was 8.1 months. Safety was consistent with the known profile of pemigatinib. CONCLUSION To our knowledge, this was the largest, first-line, randomized, phase III trial of a targeted therapy for advanced FGFR2- rearranged cholangiocarcinoma. Pemigatinib demonstrated prolonged median PFS compared with chemotherapy, with no new safety findings.

Background: Metastatic squamous cell carcinoma of the anus (SCCA) carries a poor prognosis, with systemic therapy remaining the standard of care. While metastasis-directed therapy improves outcomes in select gastrointestinal malignancies, the role of liver-directed intervention in metastatic SCCA remains undefined. We evaluated clinicopathologic features and oncologic outcomes of patients with liver-limited metastatic SCCA treated with curative-intent hepatic local therapy at a tertiary academic center. Methods: We conducted a retrospective cohort study of adults with histologically confirmed SCCA and liver-only metastatic disease who underwent curative-intent hepatic resection or ablation at Mayo Clinic between 1993 and 2023. Patients with extrahepatic disease or incomplete records were excluded. Demographic, tumor, treatment, and outcomes data were abstracted from electronic medical records. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan–Meier method. Prognostic factors were assessed using univariate Cox proportional hazards models. Results: Twenty-five patients met inclusion criteria. Median age was 56.7 years, and 92% were female. Most patients had metachronous metastases (76%), a single hepatic lesion (56%), and unilobar disease (76%). Pre-intervention systemic therapy was administered in 52% of patients, with radiographic complete or partial responses observed in all treated patients. Liver-directed therapy consisted of surgical resection in 80% and thermal ablation in 20%. Among surgical patients, 90% achieved microscopically negative margins. With a median follow-up of 22 months, disease recurrence occurred in 80% of patients, most commonly within the liver. Median DFS was 7.27 months. Median OS from the date of liver-directed therapy was 51.3 months. On univariate analysis, poorly differentiated tumor histology was associated with inferior OS (hazard ratio 4.67, p = 0.018). No other clinicopathologic variables were significantly associated with DFS or OS. Conclusions: In this single-institution experience, carefully selected patients with liver-limited metastatic SCCA undergoing curative-intent hepatic-directed therapy achieved prolonged overall survival, substantially exceeding historical outcomes with systemic therapy alone. Despite frequent recurrence, the observed median OS exceeding four years supports consideration of liver-directed therapy within a multidisciplinary framework for patients demonstrating favorable disease biology and response to systemic treatment. Prospective studies are needed to better define patient selection and optimal integration of local and systemic therapies in the modern treatment era.

PURPOSE Neoadjuvant immune checkpoint inhibitors (nICIs) have demonstrated high response rates in deficient mismatch repair/microsatellite instability–high (dMMR/MSI-H) gastroesophageal adenocarcinoma (GEA). The NEONIPIGA and INFINITY trials demonstrated high rates of pathologic complete response (pCR) in this patient population. Furthermore, the INFINITY trial explored the feasibility of managing these patients nonoperatively, demonstrating promising results. This study aimed to evaluate clinical outcomes of nICIs in resectable dMMR/MSI-H GEA, with a focus on the feasibility of nonoperative management (NOM). MATERIALS AND METHODS This retrospective cohort study included patients with resectable dMMR/MSI-H GEA and treated with nICIs ± surgery at the Mayo Clinic. Patients were identified from institutional records, and clinical data were retrospectively reviewed. Primary outcomes were clinical complete response (cCR) and pCR. Secondary outcomes included event-free survival (EFS), radiologic complete response (rCR), and immune-related adverse events (irAEs). RESULTS A total of 26 patients treated between April 1, 2017, and July 30, 2025, were identified. Nine patients (34.6%) underwent surgery, of whom six (66.7%) achieved pCR. Seventeen patients (65.4%) pursued NOM, with 10 (71.4%) of 14 evaluable patients achieving cCR and 14 (82.4%) of 17 evaluable achieving rCR. One patient who initially achieved cCR had a local recurrence on surveillance endoscopy and underwent salvage endoscopic resection. At a median follow-up of 19.3 months, 15 (88.2%) of 17 patients in the NOM cohort were alive and metastasis-free, with EFS rates of 87.3% at 12 and 24 months for all patients. irAEs occurred in nine patients (34.6%), with no grade ≥3 toxicities. CONCLUSION In this retrospective cohort study, nICIs led to high cCR and pCR rates in resectable dMMR/MSI-H GEA, supporting the use of immune checkpoint inhibitors in this setting and the feasibility of NOM in select patients.

Abstract Background Unresectable hepatocellular carcinoma (uHCC) is a leading cause of cancer death. FDA-approved first-line systemic therapies include atezolizumab/bevacizumab (atezo/bev) and durvalumab/tremelimumab (durva/treme); however, there is a lack of comparative data. Methods We reviewed outcomes of patients with uHCC who initiated atezo/bev or durva/treme between 2017 and 2024, across six institutions. Overall survival (OS) and time to treatment discontinuation (TTD) were analyzed using the Kaplan–Meier and Cox models, adjusting for baseline characteristics. Results Four hundred fifty-two uHCC pts were included. Median age: 68 years; 77% male; 81% white. Most common etiologies were viral hepatitis (38.9%) and metabolic dysfunction-associated steatohepatitis (19.5%). Disease progression was the primary reason for treatment discontinuation, atezo/bev (56%) and durva/treme (42%). Outcomes were not statistically significant (median OS [month, m]: 14.0 vs 14.6 [P = .66]; median TTD [m]: 4.9 vs 3.9 [P = .42] for atezo/bev vs durva/treme). Outcomes were significantly different between Child-Pugh classes (CP: A, B7, B8/9, C) respectively, median OS(m): 19.0, 6.1, 5.1, 2.0 (P < .001); median TTD(m): 6.1, 2.3, 3.0, 1.3 (P < .001). Conclusions In this real-world study of uHCC, no significant difference in clinical outcomes was observed between atezo/bev and durva/treme in the first-line setting. CP scores were a key prognostic variable with both regimens.

Importance The prognosis of advanced pancreaticobiliary tumors is poor. Next-generation sequencing (NGS) of tissue samples is utilized to identify actionable alterations, but there are occasional limitations due to inadequate tissue acquisition. Circulating tumor DNA (ctDNA) is an alternative method, but its correlation with tissue-based NGS remains unexplored. Objectives To assess the mutation concordance (mCR) rates between ctDNA and tissue testing for patients with pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CC) and to evaluate how ctDNA performs as a treatment response biomarker. Design, Setting, and Participants This retrospective cohort study was conducted among patients with PDAC and CC treated at academic institutions from January 2014 to January 2025. Patients underwent ctDNA testing using 1 platform and tissue NGS testing using 2 platforms. Main Outcomes and Measures mCR, which measures the shared gene alterations observed by both ctDNA and tissue-based NGS testing, was calculated using the Spearman correlation for PDAC and CC. The performance of ctDNA as a treatment response biomarker was assessed by comparing serial ctDNA data with restaging scans and cancer antigen 19-9 levels in patients with PDAC. Results Our cohort included 790 patients: 570 with advanced PDAC (265 [46.5%] female; median [IQR] age, 64 [33-84] years) and 220 with advanced CC (95 [43.2%] female; median [IQR] age, 66 [42-88] years). Overall, 461 patients with PDAC (80.9%) and 192 patients with CC (87.2%) underwent ctDNA testing, while 239 patients with PDAC (41.9%) and 70 patients with CC (31.8%) had tissue NGS testing. Among patients with PDAC, 85 of 130 patients (65.4%) showed shared specific gene alterations between ctDNA and tissue testing; there was a significant mCR, with a Spearman correlation of 0.47 (95% CI, 0.28-0.62; P < .001). For patients with CC, 32 of 48 (66.7%) had shared alterations between ctDNA and tissue testing; there was a significant mCR, with a Spearman correlation of 0.56 (95% CI, 0.35-0.70; P < .001). A subgroup analysis of patients with PDAC who underwent serial ctDNA testing suggested that new TP53 subclones and increased ctDNA variant allele frequency levels of TP53 and KRAS were associated with higher odds of progressive disease (eg, increased TP53 frequency: odds ratio, 7.28; 95% CI, 2.15-24.66; P = .001). Conclusions and Relevance In this cohort study of patients with pancreaticobiliary tumors, there was a significant mCR between ctDNA and tissue NGS testing. Additionally, results suggest that ctDNA might detect resistant clones and enable assessment of treatment response.

Our study examined healthy human MASH and MASH-associated hepatocellular carcinoma (MASH-HCC) livers using bulk and scRNA sequencing, spatial transcriptomics, and immunohistochemistry. We found that ACSLs displayed differential and spatially heterogeneous expression. ACSL4 was abundant in tumor tissues, whereas ACSL5 was elevated in noncancerous MASH tissues. ACSL4 was mainly found in immune cells like natural killer cells and natural killer T cells in murine MASH-HCC, suggesting its role in tumor immune microenvironment modulation.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have become the first-line treatment of unresectable hepatocellular carcinoma (HCC). The prognostic value of immune-related adverse events (irAEs) in these patients remains controversial. We aimed to investigate the association between irAEs and clinical outcomes in patients with HCC treated with ICIs. METHODS: We searched the PubMed, Scopus, Web of Science, and Central Register of Controlled Trials databases for articles published from inception to June 2024, using keywords including ICI, HCC, and irAEs. Statistical analysis was performed with a random effects model. RESULTS: Of 3,028 studies, 24 (4,127 patients) met the criteria for inclusion. Atezolizumab plus bevacizumab was the most common treatment regimen (n = 10 studies). IrAEs were associated with an increased objective response rate (pooled relative ratio: 1.73; 95% confidence interval [CI]: 1.36–2.21, I 2 = 41%), a higher disease control rate (pooled relative ratio: 1.45; 95% CI: 1.21–1.74, I 2 = 74%), and longer progression-free survival (pooled hazard ratio [HR]: 0.66; 95% CI: 0.52–0.84, I 2 = 71%). There was a trend toward longer overall survival for patients with irAEs compared with those without (pooled HR: 0.84; 95% CI: 0.63–1.12, I 2 = 73%). Subgroup analysis indicated a survival benefit for patients with grade 1–2 irAEs (pooled HR: 0.50; 95% CI: 0.36–0.67, I 2 = 0%) and for those with endocrine irAEs (pooled HR: 0.63; 95% CI: 0.48–0.83, I 2 = 12%). DISCUSSION: The development of irAEs is associated with favorable clinical outcomes in HCC, including improved progression-free survival and higher objective response rate. Overall survival benefit was noted in patients with mild irAEs but not those with severe irAEs.

Abstract Background Atezolizumab plus bevacizumab (A/B) received FDA approval as the first-line therapy for patients with advanced hepatocellular carcinoma (HCC) in 2020. However, optimal subsequent treatment options are unclear. Here, we describe clinical outcomes of advanced HCC patients following first-line treatment with A/B. Patients and Methods We conducted a multi-site analysis of patients with HCC treated with first-line A/B between January 2018 and December 2022 at Mayo Clinic. This study cohort included all patients receiving second-line systemic therapy after A/B. Median overall survival (OS) and time-to-treatment discontinuation (TTD) were estimated using the Kaplan-Meier method. Child Pugh (CP) scores are also described at diagnosis, prior to first line, and prior to second-line therapy. Results Of the 342 patients who received A/B, 107 (31.3%) received second-line treatments including anti-VEGF therapy or immune checkpoint inhibitor (ICI) and were included in the final analysis. Median OS for all patients was 11.1 months from initiation of second-line therapy. Median OS was 10.7 months (95% CI: 7.2-12.8) and 15.7 months (95%CI: 6.8-NE) for those receiving anti-VEGF inhibitors and ICI ( P = .50). Median TTD for second-line therapies was 2.4 months (95% CI: 1.7-3.3) and 2.6 months (95% CI: 1.5-5.1) for anti-VEGF inhibitors and ICI, respectively (P = .87). In multivariate analyses, CP was significantly associated with survival. Conclusion Following first-line A/B treatment, there is no statistically significant difference in survival between ICI and anti-VEGF therapy, nor in time to treatment discontinuation. CP score remains an important prognostic tool.