Babiker, Hani

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.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is driven predominantly by oncogenic KRAS signaling and characterized by an immunosuppressive, fibrotic tumor microenvironment that limits therapeutic responses. RMC-6236, a pan-KRAS inhibitor, and ONIOYID, an investigational anti-tumor agent, each demonstrate partial activity in KRAS-mutant cancers. However, their combined therapeutic potential in PDAC remains unexplored. Here, we evaluated the anti-tumor efficacy, survival benefit, and immunomodulatory effects of RMC-6236, ONIOYID and irinotecan alone and dual combinations multiple in vitro and in vivo PDAC models. Methods: In vitro cytotoxicity assays were performed using KPC, PANC-1, AsPC-1, and PANC-02 cell lines. In vivo therapeutic studies were conducted in orthotopic KPC and PANC-1 tumor models. RMC-6236 was administered orally at 10 mg/kg; ONIOYID and irinotecan was administered intravenously at 5 mg/kg. Tumor growth inhibition, survival, collagen deposition, and immune cell infiltration were analyzed. Tumor microenvironment remodeling was quantified via immunohistochemistry for CD8, CD4, collagen I, and fibronectin. Results: The combination of RMC-6236 and ONIOYID elicited potent anti-tumor effects across all evaluated PDAC cell lines, achieving greater than 90% growth inhibition in vitro. In vivo, co-treatment resulted in more than 90% tumor regression in both KPC and PANC-1 xenograft models, markedly surpassing the efficacy of individual monotherapies and other dual-agent controls. Combination therapy significantly extended overall survival and produced sustained suppression of tumor progression. Mechanistic analyses revealed a substantial reduction in collagen and fibronectin deposition within the tumor microenvironment, consistent with attenuation of desmoplasia. Immune profiling demonstrated a robust enhancement of intratumoral CD8+ and CD4+ T-cell infiltration, along with a pronounced decrease in survivin expression. Importantly, no observable systemic toxicity was detected in treated animals. Conclusions: RMC-6236 combined with ONIOYID yields synergistic anti-tumor effects, remodels the fibrotic PDAC microenvironment, enhances T-cell infiltration, and significantly improves survival in aggressive pancreatic tumor models. These findings provide strong rationale for clinical evaluation of RMC-6236-based combination therapies for KRAS driven PDAC. Citation Format: Hari Krishnareddy Rachamala, Fang Wei, Debabrata Mukhopadhyay, Hani M. Babiker. Combined KRAS pathway inhibition and ONIOYID treatment enhances tumor regression, attenuates desmoplasia, and augments T cell infiltration in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5842.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to aggressive biology, stromal desmoplasia, and profound immunotherapy resistance. Tumor Treating Fields (TTFields) disrupt mitosis and induce immunogenic cell death (ICD), type I interferon signaling, and microenvironment remodeling, providing a rationale for combining TTFields with immune checkpoint inhibition. This is the first systematic review to comprehensively synthesize mechanistic and clinical evidence for TTFields immunotherapy combinations across solid tumors, with emphasis on their translation relevance to PDAC. Methods: A systematic search of PubMed, Scopus, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov was conducted through October 26, 2025, following PRISMA 2020 guidelines. Eligible studies evaluated TTFields combined with immunotherapy. Two reviewers independently screened and extracted data using Covidence. Evidence was summarized narratively by tumor type, study design, and immunotherapeutic approach. Results: Thirty-seven studies met criteria, including preclinical and clinical investigations across glioblastoma, NSCLC, mesothelioma, PDAC, and other tumors. Preclinical models consistently showed that TTFields trigger ICD hallmarks such as calreticulin exposure, HMGB1 and ATP release, and activate STING/type I interferon pathways, enhancing dendritic-cell maturation and T-cell and NK-cell function. Across in vivo models, TTFields combined with PD-1 or CTLA-4 blockade, vaccines, or other immunotherapies reduced tumor growth and increased lymphocyte infiltration. Clinical evidence, although early-phase and heterogeneous, indicates the combination is feasible, with toxicity dominated by low-grade skin reactions and no excess immune-related adverse events. In glioblastoma, adding TTFields to pembrolizumab and temozolomide showed numerically improved survival. The LUNAR phase 3 trial in metastatic NSCLC demonstrated an overall survival advantage when TTFields were added to systemic therapy, including immunotherapy. Evidence in PDAC remains preliminary, but the ongoing PANOVA-4 study combining TTFields with atezolizumab and chemotherapy highlights emerging translational relevance. Conclusions: TTFields enhance antitumor immunity when combined with immunotherapy across solid tumors. In PDAC, these mechanisms may help counteract the immunosuppressive microenvironment. Ongoing gastrointestinal trials will clarify optimal combinations, biomarkers of response, and the clinical role of TTFields-based immunomodulation. Citation Format: Douaa Albelal, Hari Krishnareddy Rachamala, Hani Babiker. Synergistic immunomodulation by Tumor Treating Fields combined with immunotherapy across solid tumors: A systematic review with translational relevance to pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3813.

Abstract RMC-6236 (daraxonrasib) is a novel multiselect RAS(ON) inhibitor under investigation for pancreatic ductal adenocarcinoma (PDAC) and other RAS-mutant cancers. This compound shares structural similarities with RMC-7977 and exhibits a conserved binding site and interaction pattern within the tri-complex formed between active RAS (RAS(ON)) proteins and cyclophilin A (CypA). Tumor Treating Fields (TTFields) are low-intensity, alternating electric fields that disrupt mitosis and have shown clinical benefit in solid tumors. The PANOVA-3 trial demonstrated that TTFields combined with gemcitabine plus nab-paclitaxel improved survival, pain control, and quality of life in locally advanced PDAC. Our previous work demonstrated that TTFields abrogate oncogenic KRAS pathway. We thus hypothesize a potential for increase in effectievness with the combination. In this study, the metastatic PDAC cell line AsPC-1 was treated with TTFields (150 kHz, 1.8 V/cm), RMC-6236 (15 nM; sub-IC50), or combination. A sub-IC50 concentration (15 nM) of RMC-6236 was selected based on MTS assay results, and subsequent experiments were performed at this dose. The MTS assay revealed that both TTFields and RMC-6236 independently reduced AsPC-1 cell viability, with a more pronounced reduction observed at 72 hours compared to 48 hours. RMC-6236 alone produced minimal effects at either 48 hours (85.82 ± 13.9%) or 72 hours (90.48 ± 15.4%) compared with control (100.0 ± 8.4%, 48 h; 100.0 ± 8.2%, 72 h). TTFields treatment significantly reduced viability to 74.42 ± 21.4% at 48 hours and 50.17 ± 26.5% at 72 hours. The combination treatment (TTFields + RMC-6236) further decreased viability to 63.8 ± 25.2% at 48 hours and 40.93 ± 18.1% at 72 hours, demonstrating synergistic cytotoxicity relative to monotherapy. Clonogenic assays were performed to evaluate cell survival fractions following treatment with RMC-6236, TTFields, and their combination. Cell migration was assessed using scratch assays, revealing that untreated cells exhibited a migration rate of 91.49 ± 0.85%, RMC-6236-treated cells showed 89.48 ± 1.3%, TTFields alone reduced migration to 61.33 ± 16.3%, and combination treatment markedly suppressed migration to 24.6 ± 22.13% . For every case we were compared with 72h cell migration rate with 0 h migration rate. These findings indicate that TTFields alone significantly impair cellular motility, while their combination with RMC-6236 results in a profound anti-migratory effect, substantially inhibiting wound closure. Additionally, western blot analysis was performed to assess changes in KRAS protein expression, a key PDAC biomarker. Overall, our results demonstrate that the combination of TTFields and RMC-6236 significantly inhibits PDAC cell growth, migration, and survival at sub-IC50 concentrations, suggesting a promising alternative therapeutic approach for PDAC management. Citation Format: Ishita Saha, Santanu Bhattacharya, Debabrata Mukhopadhyay, Hani M. Babiker. Synergistic antitumor activity of tumor-treating fields and multiselect-RAS (ON) inhibitor RMC-6236 in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4478.

PURPOSE Gastroesophageal carcinoma (GEC) is increasingly managed using biomarker-guided therapies. Although both tissue DNA (tDNA) and circulating tumor DNA (ctDNA) testing are used clinically, the concordance of genomic alterations between primary tumors, metastatic sites, and liquid biopsy remains incompletely understood. METHODS We retrospectively analyzed 345 patients with GEC who underwent ctDNA testing at Mayo Clinic. tDNA next-generation sequencing and immunohistochemistry (IHC) for human epidermal growth factor receptor 2 (HER2)/erb-b2 receptor tyrosine kinase 2 ( ERBB2 ) and mismatch repair (MMR) were collected. Concordance was evaluated between ctDNA and tDNA, ctDNA and IHC, and across all three modalities, using 60-day and 30-day intervals. RESULTS Among 345 patients with ctDNA testing, 186 had tDNA testing, and 310 underwent IHC. ctDNA testing showed a shorter turnaround time than tDNA (median 6 v 13 days). The most frequent alteration in ctDNA, primary tDNA, and metastatic tDNA was TP53. Concordance between ctDNA and primary tDNA was ≥78.8% for key genes; between ctDNA and metastatic tDNA, it was ≥84.8%. IHC-ctDNA concordance was higher in metastatic tumors, with 91.1% for HER2/ ERBB2 and 97.7% for mismatch repair (MMR)/microsatellite instability (MSI) compared with 81.1% and 95.8%, respectively, in primary tumors. Triplet concordance for MSI/MMR was 97.6% in primary tumors and 100% in metastatic tumors, while ERBB2 /HER2 showed 84.4% and 93.9% concordance, respectively. ctDNA temporal heterogeneity analysis revealed 14 patients with fluctuating ERBB2 status and 3 with fluctuating MSI-H status. CONCLUSION ctDNA testing demonstrates high concordance with tDNA and IHC and offers faster turnaround. Given its minimally invasive nature and strong concordance with tissue-based testing, ctDNA is a reliable tool for genomic profiling and longitudinal monitoring in GEC.

Liver transplantation has emerged as a curative treatment option for selected patients with unresectable hepatic malignancies beyond hepatocellular carcinoma, marking a paradigm shift in transplant oncology. For colorectal cancer liver metastases (CRLM), prospective trials have demonstrated that highly selected patients achieve 5-year OS rates of 60–83%, with the Oslo score identifying optimal candidates for transplantation. Perihilar cholangiocarcinoma (pCCA) has been successfully treated using strict patient selection criteria combined with neoadjuvant therapy, achieving 5-year OS rates of 50–68%, though emerging data suggests chemotherapy-based approaches may be preferable to radiation in selected cases. Intrahepatic cholangiocarcinoma (iCCA), previously considered a contraindication to transplantation, can now achieve excellent long-term outcomes (79.5% 5-year OS) in patients demonstrating sustained response to neoadjuvant chemotherapy and radioembolization, with metabolic tumor volume < 70 cm3 serving as an objective prognostic marker. Across these three emerging indications, successful outcomes depend on strict patient selection based on tumor biology, intensive multimodal neoadjuvant therapy, multidisciplinary evaluation in high-volume centers, and careful observation during treatment to exclude patients with aggressive disease. This evolution in transplant practice offers curative intent therapy to patients that previously only had palliative therapeutic options, fundamentally transforming hepatobiliary and oncologic surgery.

Abstract Purpose: Prostate-specific membrane antigen (PSMA)–directed therapies provide meaningful clinical benefit in metastatic castration-resistant prostate cancer (mCRPC), yet responses remain limited, underscoring the need for additional biomarkers of PSMA expression heterogeneity. In this study, we explored the relationship between PSMA imaging and PSMA expression on circulating tumor cells (CTC) in our early-phase trial using a PSMA-targeted small molecule. Experimental Design: This phase I study investigated EC1169, a small molecule conjugated to a tubulysin analog warhead, and 99mTc–EC0652, a PSMA imaging agent. Part A (dose escalation) identified the recommended phase II dose. Part B (dose expansion) assessed radiographic progression-free survival (rPFS) as its primary endpoint. We enrolled and treated 103 patients with mCRPC. Most part B patients underwent 99mTc–EC0652 PSMA imaging. A CTC assay assessed PSMA-positive CTCs and their association with response and PSMA imaging. Results: 99mTc–EC0652 single-photon emission computed tomography (SPECT) imaging demonstrated increased sensitivity for detecting bone lesions compared with standard scans (computed tomography/bone scans). Using an optimized CTC assay, we observed that patients with a decrease in PSMA+ CTCs at baseline versus C3D1 displayed a longer rPFS (8 vs. 2.9 months; P = 0.04). Importantly, patients with predominantly PSMA-positive disease on 99mTc–EC0652 imaging also harbored PSMA-negative CTCs, with a subset displaying neuroendocrine prostate cancer–like morphology. Conclusions: Although EC1169 showed limited activity, CTC and imaging analyses showed significant heterogeneity in PSMA expression on CTCs in patients with predominantly PSMA-positive lesions on SPECT. Our study highlights the importance of assessing both PSMA-based CTC and imaging assays in future validation trials.

INTRODUCTION: A deeper understanding of the factors influencing survival in patients with pancreatic ductal adenocarcinoma (PDAC) is essential for optimizing treatment strategies. This study investigates the independent association of body composition parameters with overall survival in patients with PDAC. METHODS: This retrospective multisite cohort study included patients diagnosed with PDAC. Diagnostic computed tomography scans were retrieved, and body composition was evaluated using a validated deep learning-based segmentation algorithm that measured tissue volume and density in a 20 cm vertical abdominal section. RESULTS: A total of 1,666 patients with PDAC were included, 938 male (56.3%) and median age 69 years (interquartile range 61–76). In the subgroup of patients who underwent surgical resection (n = 509), myosteatosis (intramuscular infiltration of adipose tissue; hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.16–2.11, P = 0.004), sarcopenic obesity (HR 1.75, 95% CI 1.06–2.91, P = 0.03), and less subcutaneous adipose tissue (HR 1.09, 95% CI 1.03–1.16, P = 0.002) were associated with higher mortality. In patients receiving palliative systemic therapy (n = 439), lower skeletal muscle density (HR 1.43, 95% CI 1.03–1.99, P = 0.03) was associated with higher mortality. In patients who did not undergo tumor-targeted treatment (n = 718), less visceral adipose tissue (HR 1.04, 95% CI 1.01–1.08, P = 0.02) was associated with higher mortality. DISCUSSION: Body composition parameters, derived from computed tomography scans at the time of PDAC diagnosis, particularly low skeletal muscle density, sarcopenic obesity, and low adipose tissue, are independently associated with overall survival in patients with PDAC. Evaluating body composition at diagnosis could enhance clinical decision-making and enable more personalized treatment strategies.