Back to Authors

O’Donnell, Conor

Mayo Clinic

Mayo Clinic in Florida

Citations 16

Long-Term Outcomes and Surgical Conversion After Immunotherapy in Microsatellite Instability-H Biliary Tract Cancers
Shah, Priyanshi , Peersen, Anina, Sahai, Vaibhav , Mahipal, Amit , Naleid, Nikolas , Borad, Mitesh J. , Bekaii‐Saab, Tanios , Sonbol, Mohamad Bassam , Majeed, Umair , Babiker, Hani M. , O’Donnell, Conor, Malla, Midhun , Conboy, Caitlin B. , Fonkoua, Lionel Kankeu, Washburn, L. , Peterson, Nicole , Carr, Ryan M., Starlinger, P, Smoot, Rory, Warner, Susanne, Ilyas, Sumera L., Heimbach, Julie, Borad, Mitesh J , O'Donnell, Conor D J , Conboy, Caitlin B , Washburn, Leslie A , Halfdanarson, Thorvardur R , Peterson, Nicole , McWilliams, Robert R , Graham, Rondell P , Gores, Gregory J. , Roberts, Lewis R , Ou, Fang-Shu , Tran, Nguyen , Mahipal, Amit , Sonbol, Mohamad B , Bekaii-Saab, Tanios S , Babiker, Hani , Majeed, Umair , Sahai, Vaibhav , Peersen, Anina, Gupta, Garima , Fonkoua, Lionel Aurelien Kankeu , Hálfdánarson, Þorvarður R. , McWilliams, Robert R. , Carr, Ryan M , Graham, Rondell P. , Starlinger, Patrick, Warner, Susanne, Ilyas, Sumera I. , Gores, Gregory J. , Roberts, Lewis R. , Heimbach, Julie K. , Ou, Fang‐Shu , Tran, Nguyen H.

JCO Precision Oncology | July 10, 2026 | Volume: 10 | Issue: 7 | Pages: No page available

10.1200/po-25-01156 Get It

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.
Anal Squamous Cell Carcinoma with Bilateral Renal Metastases: A Rare Presentation with Literature Review
Gul, Khujasta , Kamatham, Saivaishnavi , Chiriboga, Guido , Nassar, Aziza , O’Donnell, Conor, Majeed, Umair , O'Donnell, C. , Nassar, Aziza , O'Donnell, Conor D J , Majeed, Umair , Abdelhakeem, Ahmed

Current Oncology | January 26, 2026 | Volume: 33 | Issue: 1 | Pages: 64

10.3390/curroncol33010064 Get It

Anal squamous cell carcinoma (ASCC) is a rare malignancy of the lower gastrointestinal tract, with distant metastases typically involving the liver and lungs. Metastasis to the kidneys is uncommon, and only one prior case has been reported in the literature. Herein, we report a rare presentation of a patient with biopsy-confirmed metastatic ASCC presenting as bilateral renal lesions. We then provide a review of the literature for rare metastatic presentations of ASCC, highlighting all the cases described in the literature. Clinicians should maintain a high index of suspicion for unusual metastatic sites, perform targeted imaging and biopsy when indicated, and consider systemic therapies to optimize outcomes in rare metastatic presentations.
Intraperitoneal Chemotherapy Strategies in Pancreatic Ductal Adenocarcinoma: A Systematic Review of Hyperthermic Intraperitoneal Chemotherapy, Normothermic Intraperitoneal Chemotherapy, and Pressurized Intraperitoneal Aerosol Chemotherapy
Ganatra, Nency, Jain, Pragya , Kamatham, Saivaishnavi , Adeoye, Oluwatayo , O’Donnell, Conor, Majeed, Umair , O'Donnell, C. , Jain, Pragya , O'Donnell, Conor D J , Majeed, Umair , Abdelhakeem, Ahmed , Elantably, Dina , Babiker, Hani M.

Cancers | January 6, 2026 | Volume: 18 | Issue: 2 | Pages: 182

10.3390/cancers18020182 Get It

Background: Peritoneal metastasis represents an aggressive disease pattern in pancreatic ductal adenocarcinoma (PDAC), traditionally associated with poor survival and limited therapeutic options. Emerging intraperitoneal chemotherapy strategies—including hyperthermic intraperitoneal chemotherapy (HIPEC), normothermic intraperitoneal paclitaxel (NIPEC/IP-PTX), and pressurized intraperitoneal aerosol chemotherapy (PIPAC)—have been investigated to improve local tumor control and survival outcomes. Methods: We systematically reviewed published studies evaluating HIPEC, NIPEC/IP-PTX, and PIPAC in PDAC, including adjuvant, cytoreductive, and palliative settings. Study characteristics, feasibility, perioperative outcomes, oncologic outcomes, and risk of bias were analyzed. Results: Across modalities, intraperitoneal treatment strategies demonstrated acceptable feasibility and safety profiles in appropriately selected patients. Adjuvant HIPEC following pancreatectomy showed reduced local–regional recurrence signals in limited cohorts. CRS + HIPEC among patients with isolated peritoneal metastases yielded encouraging multi-year survival in highly selected candidates achieving complete cytoreduction. NIPEC/IP-PTX demonstrated favorable ascites control, symptom relief, and potential conversion to resection in select patients. PIPAC was primarily used in unresectable, heavily pretreated, palliative peritoneal metastasis settings, with goals centered on disease stabilization, histologic regression, and symptom control rather than curative intent. Conclusions: Intraperitoneal chemotherapy strategies in PDAC appear feasible with signals of meaningful clinical benefit in select settings. While CRS + HIPEC may benefit carefully selected metastatic patients, NIPEC/IP-PTX and PIPAC hold value primarily in symptom control and disease stabilization. Larger prospective trials are needed to define patient selection, optimize treatment protocols, and clarify survival benefit.
Exploring survival outcomes in sarcomatoid hepatocellular carcinomas in the era of immunotherapy.
Kamatham, Saivaishnavi , Abdel-Razeq, Nayef Hikmat, Elalfy, Aya, Chiriboga, Guido , Starr, Jason S. , O’Donnell, Conor, Abdelhakeem, Ahmed , Mosalem, Osama , Babiker, Hani M. , Jones, Jeremy C , Majeed, Umair

Journal of Clinical Oncology | May 28, 2025 | Volume: 43 | Issue: 16_suppl | Pages: No page available

10.1200/jco.2025.43.16_suppl.e16330 Get It

e16330 Background: Sarcomatoid hepatocellular carcinoma (SHC) is a rare and aggressive variant of hepatocellular carcinoma (HCC), accounting for less than 2% of all primary liver cancers. Characterized by the presence of both epithelial and mesenchymal components, SHC demonstrates a high degree of cellular plasticity, often associated with epithelial-mesenchymal transition. This phenotypic heterogeneity contributes to its aggressive clinical behavior, including rapid tumor progression, early metastasis, and poor response to conventional therapies. As a result, patients diagnosed with SHC typically have a median survival of less than 12 months, significantly lower than that observed in patients with conventional HCC. Methods: We conducted a retrospective study at the Mayo Clinic Comprehensive Cancer Center, focusing on patients diagnosed with SHC between April 2017 and December 2023. The data collected included demographics, performance status, underlying risk factors, alpha-fetoprotein (AFP) levels, next generation sequencing (NGS) testing, and the treatment received. Results: A total of ten patients with confirmed diagnoses of SHC were included, with median age at the time of diagnosis 63.5 years (37-77), predimonantly male (9 out of 10), and identifying white (8 out of 10). Alcoholic cirrhosis was identified as an underlying risk factor in three patients, NASH cirrhosis in two, and HCV in two patients. The majority (6 out of 10) of the patients had localized disease, with 4 patients having denovo metastatic disease with abdominal lymph node involvement. Five patients had NGS testing (Tempus, Guardant 360, and ProvsSeq523), with resultant pathogenic variants including TP53 in 3 patients, NTRK3 fusion, IDH2, EGFR, TERT, MLH1, ARIS1A, and PALB2. Four patients were treated with combined Yitrrium-90 and systemic therapy. Three patient started systemic therapy, and two patients underwent surgical resection. Systemic Therapy used included combined Atezolizumab/ Bevacizuamab, Pembrolizumab/ Lenvatinib, Gemcitabine/ Docetaxel, Gemcitabine/ Cisplatin, Cabozantinib, and pembrolizumab monotherapy. The median overall survival for this group was 11.5 months; 95% confidence interval (CI): 4.66-40.1 months. Seventy percent experienced progression, with a median progression-free survival after first line of treatment of 2.5 months; 95% CI: 1-15.3 months. Conclusions: Sarcomatoid HCC remains aggressive and difficult to treat cancer with limited overall survival. Immunotherapy based regimens have limited efficacy for this HCC variant.
Safety and efficacy analysis of modified TOPAZ-1: A biweekly regimen of gemcitabine and cisplatin plus monthly durvalumab in advanced biliary tract cancer.
Kamatham, Saivaishnavi , Abdel-Razeq, Nayef Hikmat, Elalfy, Aya, Chiriboga, Guido , Fonkoua, Lionel Aurelien Kankeu , Wu, Christina, Starr, Jason S. , Ahn, Daniel H. , O’Donnell, Conor, Mosalem, Osama , Abdelhakeem, Ahmed , Jones, Jeremy C , Conboy, Caitlin B. , Sonbol, Mohamad Bassam , Babiker, Hani M. , Bekaii‐Saab, Tanios , Tran, Nguyen H. , Borad, Mitesh J. , Majeed, Umair

Journal of Clinical Oncology | May 28, 2025 | Volume: 43 | Issue: 16_suppl | Pages: No page available

10.1200/jco.2025.43.16_suppl.e16265 Get It

e16265 Background: The pivotal TOPAZ-1 trial established durvalumab plus gemcitabine and cisplatin (GC) as a new first-line standard of care for advanced biliary tract cancer (ABTC). However, weekly administration of GC can lead to significant toxicity limiting its tolerability in clinical practice. Based on previous studies, we implemented biweekly regimen of GC on days 1 and 15 together with durvalumab on day 1 of each 28-day cycle to optimize the treatment delivery and improve tolerability. Here, we report the Mayo Clinic experience with biweekly GC with monthly durvalumab in patients with ABTC. Methods: At our three-site institution, we retrospectively identified patients with ABTC between January 2021 and August 2024, who received biweekly GC with monthly durvalumab. Patient demographics, tumor characteristics, treatment details - treatment related adverse events (trAEs) graded according to the NCTCAE V5.0 were collected. Outcomes included median progression-free survival (mPFS), median overall survival (mOS) and clinically assessed overall response rate (ORR) and disease control rate (DCR). Results: 57 patients were included in our analysis, median age was 68 years (range 35-90), and 57.9% were females. 91.2% of patients had ECOG performance status of 0-1. 71.9% had intrahepatic cholangiocarcinoma, 19.3% extrahepatic cholangiocarcinoma and 8.7% gallbladder carcinoma. 70.2% had metastatic disease, 21 % locally advanced unresectable disease and 8.7% recurrent metastatic disease. Patients were followed for a median of 9.1 months (2.3-28.5). 91.2% of the patients received biweekly GC plus monthly durvalumab while 8.8% switched from weekly to biweekly GC plus monthly durvalumab due to treatment toxicities. Median number of treatment cycles was 5. Maintenance regimens included durvalumab (19.3%), gemcitabine/durvalumab (8.8%) and GC/durvalumab (8.8%). Median duration of follow up was 9.1 months (range 2.3 – 28.5). ORR was 36.9% and DCR was 72% (complete response 5.3%, partial response 31.6% and stable disease 35.1%). mPFS was 7.2 months, while mOS was 16 months. Grade(G) 3 or 4 trAEs included abnormal liver function tests (15.7%), infections (11.5%), anemia (8.7%), thrombocytopenia (5.2%), peripheral neuropathy (1.7%), acute kidney injury (1.7%). Immune-related AEs were noted in 6 patients (10.5%) including colitis, gastritis, hepatitis, myocarditis and hypothyroidism. There was no patient with severe neutropenia or febrile neutropenia. Only 5 patients (8.8%) stopped treatment due to trAEs. Conclusions: Biweekly GC on days 1 and 15 plus durvalumab on day 1 of each 28-day cycle is associated with a more favorable toxicity profile while maintaining efficacy similar to that observed in the TOPAZ-1 trial indicating that a de-escalation strategy is feasible with improvement in patient centered outcomes.
Modifiable risk-factors, genetic characteristics, and survival in early-onset cholangiocarcinoma.
O’Donnell, Conor, Shah, Priyanshi , Ness, Andrew, Pirozzi, Angelo , Okano, Naohiro, Kamatham, Saivaishnavi , Nunnelee, Jordan , Ness, Andrew, Majeed, Umair , Babiker, Hani M. , Borad, Mitesh J. , Okano, Naohiro , Mosalem, Osama , Ou, Fang‐Shu , Tran, Nguyen H.

Journal of Clinical Oncology | May 28, 2025 | Volume: 43 | Issue: 16_suppl | Pages: 4085-4085

10.1200/jco.2025.43.16_suppl.4085 Get It

4085 Background: Cholangiocarcinoma (CC) is a rare disease with an increasing incidence among younger adults, which is poorly understood. Genomic profiling of tumors is both prognostic and predictive of benefit for targeted therapies. We investigated if there are clinical and molecular differences between younger vs older patients with CC. Methods: We collected TEMPUS genetic data via retrospective chart review from tumors in young vs old patients seen at our institution, defined as ≤50 vs > 50 years of age at time of diagnosis. We included patients diagnosed with CC between January 2008 and July 2024 with available clinical follow up and TEMPUS genetic sequencing data. We collected mutation data on the following actionable genes: FGFR2, IDH1/2, BRCA1, BRCA2, BRAF, ATM, ERBB2/3, and KRAS. Patient characteristics and gene expression variables were compared using Chi-square, Fisher’s exact and Wilcoxon rank-sum tests. Kaplan-Meier, log rank tests and a multivariable Cox model were used for survival analysis. This study was IRB exempt. Results: We included 410 patients, 84 in the young group with median age at diagnosis of 40.8 years, and 326 in the old group with median age 68.5 years. 91.5% of patients were white. There was no difference in BMI between groups, however the older group had higher rates of hypertension (15.5% vs 57.7%), hyperlipidemia (6.0% vs 49.7%), cardiovascular disease (1.2% vs 20.6%), and type 2 diabetes (6.0% vs 21.5%), (all p < 0.01). Primary sclerosing cholangitis was more common in the young group (26.2% vs 4.3%, p < 0.01). ECOG status of 0 at first treatment was seen in 65.3% of young vs 52.5% of old patients (p = 0.02). FGFR2 alterations were more common in the young group (17.9% vs 8.0%, p < 0.01), while ATM mutations were more common in old vs young (5.5% vs 0%, p = 0.03). There was no age difference seen for the other genetic alterations. Mean tumor mutational burden was higher in the old group (4.1 vs 3.8 mut/mb, p = 0.01). MSI-high was found in 2% of cases with no difference between groups. There was no significant difference in overall survival between age groups. There was a numeric difference in overall survival in stage IV patients, though not statistically significant (17.8 months vs. 16.3 months, p = 0.08). In a multivariable Cox analysis, female sex, earlier stage at diagnosis and clinical trial enrollment were associated with favorable prognostics. Conclusions: Our data highlight relatively low rates of comorbidities associated with metabolic dysfunction in younger adults with CC, suggesting alternative factors are likely to explain the increasing incidence of early-onset disease. FGRFR2 is a more common pathogenic alteration among the young and could inform targeted therapies. Younger patients with CC may not have improved survival outcomes compared to their older counterparts. This underscores the aggressive nature of CC and the need for more effective therapies to improve outcomes.
The differential effect of stromal genes on gemcitabine/nab-paclitaxel (GN) and GN/cisplatin (GCN) outcomes in advanced pancreatic adenocarcinoma (aPDAC).
Mahadevia, Himil , Wu, Sharon , Starr, Jason S. , O’Donnell, Conor, Ahn, Daniel H. , Xiu, Joanne , Shawa, Hani El, Kulkarni, Ninad , McWilliams, Robert R. , Majeed, Umair , Jones, Jeremy C , Mosalem, Osama , Sledge, George W. , Philip, Philip A. , Goel, Sanjay , Spetzler, David B. , Singh, Harshabad , Borad, Mitesh J. , Bekaii‐Saab, Tanios , Babiker, Hani M.

Journal of Clinical Oncology | May 28, 2025 | Volume: 43 | Issue: 16_suppl | Pages: 4166-4166

10.1200/jco.2025.43.16_suppl.4166 Get It

4166 Background: GN is a front-line therapy for aPDAC. A Phase I/II study demonstrated that GCN has a higher overall response rate and median overall survival (mOS). Our previous study found no difference in outcomes among patients with DNA damage repair gene mutations; however, stromal gene expression correlated with mOS in patients receiving GCN. Here, we further evaluate differences in the outcomes with GCN and GN by site of biopsy. Methods: PDAC samples (n = 4,463) were analyzed by NGS (NextSeq/NovaSeq) or RNA (NovaSeq) (Caris Life Sciences, Phx, AZ). Expression of stromal and related genes ( ACTA2, ADIRF, HAS2, IL-6, MMP-2, MMP-9, SPARC, STAT3, TBGB1, TGFB2, TGFBR3, IDO1, HLA-DRB4, VEGFB) from different biopsy sites [high expression (H) >50% of RNA transcripts per million] was correlated with outcomes to GCN or GN. mOS was obtained from insurance claims and calculated from first treatment to last contact. The hazard ratio (HR) was calculated by the Cox proportional hazards model, and p-values were calculated using the log-rank test. Results: 4325 patients [primary biopsy (PT), n = 1,878; non-liver metastatic biopsy (N-LM), n = 818; Liver biopsy (LM), n = 1,629] received GN while 138 patients (PT, n = 45; N-LM, n = 28; LM, n = 65) received GCN. GCN was associated with longer mOS than GN [∆: 5.2 months (m), HR: 0.76, 95% CI 0.63-0.92, p = 0.01]. GCN was associated with longer mOS compared to GN in LM (∆: 5.6 m, HR: 0.66, 95% CI 0.50-0.87, p = 0.003), but it was not significant in PT (∆: 4.6 m, p = 0.13) and N-LM (∆: 4.4 m, p = 0.35). Median MMP2 (38.5 vs. 163.1 vs. 162.2), VEGFB (14.4 vs. 16.9 vs. 16.2) and TGFBR3 (11.4 vs. 15 vs. 16.4) expression were lower in LM compared to PT and N-LM while TGFB1 (41.6 vs. 34.5 vs. 39.8) and IL6 (1.61 vs. 1.19 vs. 1.41) expression were highest in LM (p < 0.05). In LM, IL6 -H (∆: -11 m, p = 0.037) and TGFB1 -H (∆: -5.9 m, p = 0.10) were associated with worse post-GCN survival compared to GN (p = 0.82 and p = 0.57). Whereas, in N-LM, TGFBR3 -H trended towards longer post-GCN survival (∆: 12 m, p = 0.18), while ADIRF -H trended towards shorter post-GCN survival (∆: -12 m, p = 0.056) compared to GN (p = 0.42 and p = 0.10). While in PT, MMP2 -H (∆: 11.3m, HR: 0.46, p = 0.16), TGFB1 -H (∆: 11.3 m, HR: 0.33, p = 0.09), HLA-DRB4 -H (∆: 12.9 m, HR: 0.44, p = 0.11) and VEGFB -H (∆: 10.7, HR: 0.34, p = 0.09) trended towards longer post-GCN survival compared to GN ( MMP2 -H, ∆: 3.4 m, p = 0.03, TGFB1 -H, p = 0.661, HLA-DRB4 -H, p = 0.67, VEGFB-H , ∆: 1.3 m, p = 0.03). Conclusions: GCN is associated with improved mOS compared to GN, especially in LM.Stromal gene expression in the liver differs from that in N-LM and the pancreas. While high stromal gene expression trends towards worse post-GCN survival in LM, it is associated with improved survival in N-LM and PT. Further validation is needed to understand the impact of stromal gene expression in different tumor sites on survival outcomes and signature development.
Exploring the prevalence of germline mutations in young-onset biliary tract cancer (BTC).
Chiriboga, Guido , Elalfy, Aya, Kamatham, Saivaishnavi , Abdel-Razeq, Nayef Hikmat, Shah, Priyanshi , Pirozzi, Angelo , Okano, Naohiro, Starr, Jason S. , O’Donnell, Conor, Mosalem, Osama , Abdelhakeem, Ahmed , Nunnelee, Jordan , Okano, Naohiro , Babiker, Hani M. , Tran, Nguyen H., Borad, Mitesh J. , Majeed, Umair

Journal of Clinical Oncology | May 28, 2025 | Volume: 43 | Issue: 16_suppl | Pages: 10587-10587

10.1200/jco.2025.43.16_suppl.10587 Get It

10587 Background: The American Society of Clinical Oncology (ASCO) and NCCN recommend germline testing for patients (pts) with biliary tract cancers (BTC), particularly those diagnosed at a young age. Prior studies estimate that approximately 15% of pts with BTC harbor pathogenic germline alterations. Germline testing can identify hereditary cancer syndromes, guide targeted therapy, and inform family counseling. This study aimed to further characterize and describe the prevalence of pathogenic germline variants (PGVs) in patients with young-onset BTC (YO-BTC). Methods: We conducted a retrospective review of medical records for pts diagnosed with YO-BTC (ages 18–55) across all Mayo Clinic tri-sites from January 2014 to October 2024. Data collected included results from germline DNA sequencing, tumor genetic testing, demographics, history of other malignancies, and family history of cancer. The primary outcome was the identification of pathogenic germline mutations associated with cancer predisposition. Results: Among 239 pts with YO-BTC, the median age at diagnosis was 43 years (range 19–55), with 62% female and 65.2% identifying as white. Clinical germline testing (e.g., Invitae, Ambry, Myriad) was performed in 123 pts (51.5%), revealing PGVs in 15 pts (12.1%), variants of uncertain significance (VUS) in 30 pts (24.3%), and likely benign variants in 4 pts (3.2%). Among those with PGVs, DNA repair mutations were the most common findings (10/15), including ATM (4), CHEK2 (2), BRCA2 (2), BAP1 (1), and PALB2 (1). One pt had a Lynch syndrome-associated mutation (MSH6), and four had mutations in other cancer-related genes (MUTYH, HOXB13, RMRP, and PIK3CA). Tumor genomic profiling (via CARIS, TEMPUS, or FoundationOne) was performed in 9 pts with PGVs, detecting the variant in 4 (44%), while liquid biopsy (Guardant) identified the PGV in 4 of 6 cases (66.6%).The majority of PGV carriers had advanced BTC (14/15), with intrahepatic cholangiocarcinoma being the most prevalent (11/15), while 4 had extrahepatic cholangiocarcinoma. Additionally, most PGV carriers had a first- or second-degree relative with a prior history of malignancy (14/15), and 3 pts had a second malignancy. Of the 15 pts with PGVs, 4 had BTC associated with primary sclerosing cholangitis. Conclusions: In this large institutional series of YO-BTC, PGVs were identified in 12.1% of pts, demonstrating a significant yield from germline testing in this population. Notably, tissue and liquid biopsies demonstrated different detection rates for PGVs, underscoring the variability in PGVs reporting across platforms. Germline testing through CLIA-approved methods should remain the standard of care. DNA repair pathway mutations, particularly ATM, CHEK2, and BRCA2, were the most frequently identified PGVs, highlighting their role in the pathogenesis of YO-BTC and their potential to guide treatment decisions.
Abstract CT190: A phase I/II pilot trial, single arm, open label, of gemcitabine, cisplatin, protein-bound paclitaxel (GCN) combined with Tumor Treatment Fields (TTFields) in patient with metastatic pancreatic adenocarcinoma
Starr, Jason S. , O’Donnell, Conor, Boni, Jacqueline, Stewart, Lashundra, Cameron, Josh, Kour, Oudom, Mody, Kabir , Ahn, Daniel H. , Bekaii-Saab, Tanios S , Babiker, Hani , Babiker, Hani M. , Jones, Jeremy C , Jones, Robin L. , Boni, Jacqueline, Stewart, Lashundra, Cameron, Josh, McWilliams, Robert R. , Bekaii‐Saab, Tanios , Borad, Mitesh J. , Majeed, Umair

Cancer Research | April 25, 2025 | Volume: 85 | Issue: 8_Supplement_2 | Pages: CT190-CT190

10.1158/1538-7445.am2025-ct190 Get It

Abstract Background: Pancreatic ductal adenocarcinoma (PDA) is a disease with guarded prognosis with a 5-year overall survival (OS) of 3.1% in patients with metastatic disease. The need for innovative treatments for this lethal disease is paramount. TTFields is a novel treatment modality that employs low intensity, alternating, and intermediate frequency electrical fields that abrogates cancer cell proliferation through different mechanisms. These include inhibition of mitosis, disruption of cancer cell membranes, metabolomic dysregulation of cancer cells, and immunogenic activation of the tumor microenvironment (TME). TTFields are approved in glioblastoma multiforme, non-small cell lung cancer and malignant mesothelioma. The PANOVA trial demonstrated promising efficacy for TTFields plus chemotherapy in patients with PDA. A trial of GCN in patients with PDA demonstrated exceptional efficacy in patients with metastatic disease. Here in, we present our ongoing clinical trial investigating the safety and efficacy of TTFields plus GCN in patients with PDA (NCT04605913). Methods: This a phase I/II trial with an initial safety run-in phase followed by the phase II portion. The primary objective of the trial is to determine the safety (CTCAE v 5.0) of GCN plus TTFields. Secondary objectives include determining the 6-month progression free survival (PFS) rate, overall response rate (ORR, RECIST v1.1), 12-month survival rate, OS, and QOL (EORTC QLQ-C30, version 3.0.2.3). Inclusion criteria include PDA with liver metastasis (patients can have additional sites of metastasis), ECOG 0-1, measurable disease, and ability to operate the Novo TTF-100L (P)/Novo TTF-200T system. Treatment consisted of TTFields (150 kHz 18 hours/day) and GCN (G: 1000 mg/m2, C 30 mg/m2, and N: 150 mg/m2 every 2 weeks, 28 days cycle), followed by a maintenance phase after 6 months (G: 1000 mg/m2 every 2 weeks) plus TTFields until progression. Six patients were to be enrolled in the phase I portion and if ≤1/6 patients experienced a dose limiting toxicity (DLT, treatment emergent adverse event, or skin toxicity of Gr4), the plan would be to move to a phase II trial enrolling 34 more patients. If 2/6 patients experienced a DLT, 6 patients would be enrolled in dose level -1 (GCN plus TTFields for 9 hours/day followed by the maintenance treatment) and if tolerated the phase II portion would start with dose level -1 regimen. The phase I portion was completed without any DLTs and the trial is currently enrolling to the phase II portion. The total number of patients (40) was powered to the 6-months PFS rate and ORR (estimated using the lower bound of exact one-sided 90% confidence intervals). The goal is to "reject" a 6-month PFS rate of 66% and an ORR of 71% (based on previous GCN trial). Time-to-event endpoints will be assessed using the Kaplan-Meier method. Citation Format: Hani M. Babiker, Jason Starr, Jeremy Jones, Conor O’Donnell, Robert Jones, Jacqueline Boni, Lashundra Stewart, Josh Cameron, Oudom Kour, Kabir Mody, Robert R. McWilliams, Daniel H. Ahn, Tanios Bekaii-Saab, Mitesh J. Borad, Umair Majeed. A phase I/II pilot trial, single arm, open label, of gemcitabine, cisplatin, protein-bound paclitaxel (GCN) combined with Tumor Treatment Fields (TTFields) in patient with metastatic pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT190.
Abstract CT189: Yttrium-90 radioembolization in combination with tremelimumab and durvalumab for treating patients with locally advanced, unresectable or oligo-metastatic intrahepatic cholangiocarcinoma who are not candidates for curative therapy
Starr, Jason S. , O’Donnell, Conor, JONES, R. FORBES, Boni, Jacqueline, Cameron, Josh, Kour, Oudom, Mody, Kabir , Toskich, Beau B. , Majeed, Umair , Jones, Robert, Boni, Jacqueline, Cameron, Josh, Borad, Mitesh J. , Babiker, Hani M.

Cancer Research | April 25, 2025 | Volume: 85 | Issue: 8_Supplement_2 | Pages: CT189-CT189

10.1158/1538-7445.am2025-ct189 Get It

Abstract BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a rare but aggressive cancer with limited curative options outside of surgical resection. Trans-arterial radioembolization (TARE) with yttrium-90 is a promising treatment with retrospective data showing an overall survival (OS) of up to 30 months. The single arm prospective MISHPEC trial combined TARE with gemcitabine and cisplatin showed an overall response rate (ORR) of 39% at 3 months along with a median OS of 22 months. PDL1 inhibitor (Durvalumab) has shown modest benefit in addition to chemotherapy in unresectable cholangiocarcinoma with three-year OS of 15% based on the TOPAZ-1 trial. ICC is a biologically cold tumor; preclinical data indicates that Yttrium-90 TARE can alter tumor microenvironment making it conducive to effector T cell recruitment and function leading to enhanced efficacy of immunotherapy. This provides the biological rationale of combining yittrium-90 TARE with systemic immunotherapy involving dual PDL1 and CTLA-4 inhibitors. Here in, we present our ongoing clinical trial investigating the safety and efficacy of yttrium-90 TARE combined with Durvalumab and Tremelimumab in patients with ICC (NCT06058663). METHODS: In this phase 1 study, yittrium-90 TARE will be combined with Durvalumab and Tremelimumab in 16 patients with unresectable or oligometastatic ICC. Eligible patients with histologically confirmed measurable disease must not have received any prior local therapies and any immunotherapy with ECOG PS of 0 or 1, adequate liver (Child Class A, ALBI 1 or 2) and renal function. Patients should also have a favorable mapping angiography based on an angiosomal analysis. Ablative radioembolization would be performed at least a dose of greater than 205 Gy MIRD to &gt;75% of tumor. Study treatment with Tremelimumab (x 1 dose of 300mg total) + Durvalumab 1500mg monthly will continue until unacceptable toxicities, or disease progression for up to 24 months. Durvalumab and Tremelimumab will be infused in two alternate schedules after yittrium-90 TARE. In cohort 1 (3 patients) immunotherapy will be delivered within 24 hours of TARE. In cohort 2 (3 patients) immunotherapy will be delivered 2 weeks after TARE. Subsequent patients will be enrolled in either cohort 1 or 2 based on the safety signal from the first 6 patients. Primary goal of the study is to determine safety of this combination. Secondary goals include ORR per RECIST 1.1, progression-free survival, overall survival, infield and out of field response rate and downstaging to resection. Correlative studies include ctDNA at baseline along with evolution through treatment, pre and post treatment biopsies to look at tumor microenvironment and post treatment dose volume histograms. Three patients have been accrued in the study thus far. Citation Format: Umair Majeed, Jason Starr, Conor O'Donnell, Robert Jones, Jacqueline Boni, Josh Cameron, Oudom Kour, Mitesh Borad, Hani Babiker, Kabir Mody, Beau Toskich. Yttrium-90 radioembolization in combination with tremelimumab and durvalumab for treating patients with locally advanced, unresectable or oligo-metastatic intrahepatic cholangiocarcinoma who are not candidates for curative therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT189.