tbuckley/cabot-search huggingface dataset:
Targeting replication stress in pancreatic cancer: A phase II trial investigating azenosertib in combination with gemcitabine in second-line advanced pancreatic cancer.
Authors: Brandon Huffman, Nora K. Horick, Alexandra Bird, Caroline Gibson, Lauren K. Brais, Christopher Graham, Benjamin L. Schlechter, Brian M. Wolpin, Andrew Aguirre, Alan D. D'Andrea, Geoffrey Ira Shapiro, James M. Cleary
Journal: Journal of Clinical Oncology (2024)

TPS4211 Background: A major unmet need in pancreatic cancer (PDAC) is molecularly targeted treatment options for patients who develop resistance to first-line platinum chemotherapy. While combined gemcitabine and nab-paclitaxel is commonly used after progression with first-line therapy, the efficacy in the second-line setting is fair, with recent phase clinical trial data demonstrating a median progression-free survival (PFS) of 2.7 months and a median overall survival of 6.6 months (1). In recent years, preclinical work has identified that replication stress is a potential PDAC vulnerability. The WEE1 kinase regulates the checkpoint governing the G2/M transition of the cell cycle to compensate for replication stress. The G2/M checkpoint is critically important in malignancies like PDAC where over 75% of tumors have p53 pathway deficits. Therapies that inhibit cancer cells’ ability to compensate for replication stress are particularly attractive in cancers that have genomic alterations that generate replication stress. It has been demonstrated that in vitro and in vivo PDAC models were exquisitely sensitive to WEE1 inhibition in combination with gemcitabine. Azenosertib (Zn-c3) is an orally available, highly selective, nanomolar inhibitor of the WEE1 kinase and when combined with gemcitabine in PDAC cell lines, synergistic cytotoxicity is observed. Methods: NCT06015659 is an ongoing phase II clinical trial with safety lead-in that is testing the azenosertib WEE1 inhibitor combined with gemcitabine in patients with advanced pancreatic cancer after progression or intolerance with FOLFIRINOX. Subjects are dosed once daily, days 1-5, 8-12, and 15-19 with azenosertib and receive gemcitabine 800 mg/m2 on days 1 and 8 of 21-day cycles. Up to 12 subjects are expected to enroll in the safety lead-in portion based on a typical 3 + 3 design. Once the recommended phase 2 dose is confirmed, we will use a Simon two-stage minimax design to evaluate efficacy where the null hypothesis is that the true 6-month PFS rate is ≤ 24% (unacceptable historical control data) and the alternative hypothesis is that the true 6-month PFS is ≥ 44%. Pretreatment and on-treatment tumor biopsies are incorporated into the trial to identify potential biomarkers of treatment response. Subjects must be able to swallow oral tablets and have measurable disease by RECIST v1.1; prior exposure to gemcitabine is not allowed. Enrollment began November 21, 2023, and is ongoing. 1. Huffman BM, Basu Mallick A, Horick NK, et al. JAMA Netw Open. 2023;6(1):e2249720. Clinical trial information: NCT06015659 .
Survival outcomes in patients with non-metastatic intrahepatic cholangiocarcinoma in United States: A nationwide analysis.
Authors: Aleenah Mohsin, Shahzaib Ahmad, Hadin Darain Khan, Nouman Aziz, Hamza Naeem, Shreyas S. Bellur, Mohammad Arfat Ganiyani, Diya Jayram, Manmeet Singh Ahluwalia
Journal: Journal of Clinical Oncology (2024)

e16277 Background: Intrahepatic cholangiocarcinoma (ICC) is one of the most aggressive primary liver malignancies contributing to notable morbidity and mortality. Surgical resection (Sx) is the mainstay of treatment for non-metastatic ICC. However, it is unclear if augmenting resection with chemotherapy (CT), radiotherapy (RT) or chemoradiation (CRT) confers survival benefit in non-metastatic ICC. This study aims to assess effective therapeutic option for non-metastatic ICC. Methods: We queried the National Cancer Database to identify patients diagnosed with non-metastatic (stage 0-3, M0) ICC between 2004 and 2020. We reported survival outcomes in the study cohort in concordance with STROBE guidelines. We analyzed median overall survival (mOS) and differences in survival using the Kaplan-Meier (KM) methodology and pair-wise log-rank test, respectively in 6 groups based on treatment: Sx, CT, RT, Sx+CT, Sx+CRT, and CRT. Results: The analysis included 20,005 patients diagnosed with non-metastatic ICC with a median age of 66 years (range: 15-90+ years). The population included White (83.6%), Black (8.3%), and Asian (3.9%). 50% of the patients were male, 91.9% were non-Hispanic, 88.8% had Charlson-Deyo score (CDS) of 0-1, 11.2% had CDS ≥2, 51.6% were treated at academic/tertiary care program. 24.0% of the cases had positive lymph nodes. 3,394 patients (23.9%) of the total patients underwent Sx, 4,313 (30.4%) patients underwent CT alone, 1,023 (7.2%) patients underwent RT, 2753 (19.3%) patients underwent Sx+CT, 1100 (7.7%) patients underwent Sx+CRT, and 1629 (11.5%) patients underwent CRT alone. Patients who underwent Sx alone had better mOS (46.3 months, 95% CI 42.8-48.9) than all other modalities, including Sx+CT (46.0 months, 95% CI 43.9-48.0, P = 0.10), Sx+CRT (44.5 months, 95% CI 35.6-50.4, P = 0.11), CT (12.4 months, 95% CI 11.9-12.8, P &lt; 0.01), RT (18.3 months, 95% CI 16.3-19.8, P &lt; 0.01), and CRT (18.1 months, 95% CI 17.0-19.4, P &lt; 0.01). Conclusions: Our study indicates that surgical resection yields the best survival outcomes when compared to other treatment modalities for nonmetastatic ICC. However, there is no significant difference in survival when surgery is combined with chemotherapy or chemoradiation in nonmetastatic ICC. Further prospective research is needed to refine treatment strategies and enhance outcomes for ICC patients. [Table: see text]
QUIC: Phase 2 study of gemcitabine, cisplatin, quemliclustat (AB680), and zimberelimab (AB122) during first-line treatment of advanced biliary tract cancers (BTC)—Big Ten Cancer Research Consortium study BTCRC-GI22-564.
Authors: John Ebben, Jens C. Eickhoff, Dustin A. Deming, Howard S. Hochster, Anita Ahmed Turk, Vaibhav Sahai, Nataliya Volodymyrivna Uboha
Journal: Journal of Clinical Oncology (2024)

TPS4195 Background: Despite recent approvals of immune checkpoint inhibitors with chemotherapy in the first-line setting, the median overall survival (mOS) for patients with advanced biliary tract cancer (BTC) remains less than 15 months. CD73 is a key enzyme responsible for the conversion of extracellular adenosine 5’-monophosphate into adenosine and may play an important role in creating an immunosuppressed tumor microenvironment. High expression of CD73 in BTC is associated with decreased OS. Quemliclustat (Q) is a potent, selective, reversible inhibitor of CD73. Q in combination with chemotherapy has demonstrated promising activity in patients with advanced pancreatic cancer without significant increase in adverse events. The BTCRC-GI22-564 study evaluates safety and preliminary efficacy of Q in combination with zimberelimab (Z), a monoclonal antibody targeting human PD-1, with gemcitabine and cisplatin (GC) as first-line therapy for patients with advanced BTC, QUIC (Q and Immunotherapy in Cholangiocarcinoma). Methods: This is an open label, single arm, phase II multi-site trial, evaluating Q and Z in combination with GC in patients with advanced BTC who have not received systemic treatment for advanced disease or who completed adjuvant therapy &gt; 6 months prior to development of recurrent disease. Chemotherapy is given on days 1, 8, 22 and 29 of each 42-day cycle as per local standards. Z is administered at a fixed dose of 360 mg via IV infusion every 3 weeks. Q is administered via IV infusion on days 1, 15, and 29. A safety run-in portion built into the study is planned to enroll 6 subjects to ensure there are no dose limiting toxicities (DLT). If a study defined DLT is observed, Q, gemcitabine and cisplatin will be reduced by 1 dose level, and an additional 6 subjects will be enrolled in the safety run-in portion. The primary efficacy endpoint is median progression free survival (mPFS) with null and alternative survival of 6.0 and 10.0 months, respectively. Based on an accrual rate of 3 patients per month, we expect to accrue 33-39 patients which will provide at least 83% power with a one-sided alpha of 0.1. Secondary endpoints include mOS, disease control rate, overall response rate, and duration of response. Correlative endpoints will assess clinical outcomes with immune infiltration within tumor microenvironment, CD73 and PD-L1 expression. The QUIC study is currently open to enrollment through BTCRC. Clinical trial information: NCT06048133 .
Longitudinal changes in triceps skinfold thickness and serum albumin during chemotherapy in patients with pancreatic cancer: Gender-based prognostic insights—A prospective cohort study.
Authors: Joo Kyung Park
Journal: Journal of Clinical Oncology (2024)

e16308 Background: Cachexia, characterized by distinct fat loss and poor nutritional status, is common in patients with pancreatic cancer. This study investigated the association between triceps skinfold thickness(TSF), indicative of body fat, and serum albumin levels, reflecting nutritional status, with overall survival(OS) in patients with pancreatic cancer. Methods: A prospective cohort of 353 patients with pancreatic cancer from April 2018 to June 2021 who received chemotherapy was queried. TSF(mm) and serum albumin(g/dL) were measured at baseline and every three weeks during follow-up. The optimal cutoffs for their six-month changes(six-month value minus initial value) were determined. We performed a landmark analysis of OS six months after the diagnosis of pancreatic cancer and assessed the factors influencing OS. Gender-specific survival analysis was conducted, culminating in the construction of nomograms for risk stratification. Results: Two hundred ninety-two patients survived over six months, with a median follow-up of 40.9 months. Changes in TSF, albumin, and protein levels over six months and initial albumin levels were independently associated with OS. Cancer stage, response to chemotherapy, and six-month serum CA 19-9 levels were also independent factors for OS. Gender-stratified analysis revealed gender-specific prognostic factors: TSF changes over six months£ 0 were associated with reduced OS (hazard ratio [HR], 1.84; 95% confidence interval [CI], 1.14–2.95) in men; initial albumin levels£ 3.5g/dl (HR, 5.73; 95% CI, 2.48–13.21) and albumin changes over six months£ -0.7g/dl (HR, 3.03; 95% CI, 1.51–6.07) were associated with reduced OS in women. Patients were categorized into low-, medium-, and high-risk groups for each gender based on nomogram scores, and increased risk levels were associated with elevated mortality risk. Conclusions: This was the first prospective cohort study to demonstrate that changes in TSF and albumin levels were associated with OS in pancreatic cancer patients undergoing chemotherapy in a gender-dependent manner.
Preliminary data of a phase Ib/II trial evaluating the efficacy and safety of adebrelimab, camrelizumab plus apatinib as first-line therapy in patients with advanced hepatocellular carcinoma.
Authors: Yin Long, Qiong Yang, Ziqi Huang, Xiaodong He, Jue Huang, Jianguo Liao, Yajin Chen, Hai Hu, Lei Zhang
Journal: Journal of Clinical Oncology (2024)

e16221 Background: The CARES-310 study has demonstrated that the combination of the anti-PD-1 antibody camrelizumab and the VEGFR2 tyrosine kinase inhibitor apatinib exhibits improved progression-free survival (PFS) and overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC). We conducted this study to investigate whether the addition of the anti-PD-L1 antibody adebrelimab to camrelizumab and apatinib would further improve clinical outcomes. Methods: This is a prospective, phase 1b/2 clinical trial employing the i3 + 3 dose escalation design. Eligibility includes adults with unresectable or metastatic HCC, a ECOG PS of 0 or 1, a Child-Pugh score ≤ 7, and at least one measurable lesion per RECIST v 1.1. In phase 1b, patients (pts) received adebrelimab (10 mg/kg or 20 mg/kg, I.V., D1, Q3W), camrelizumab (200mg, I.V., D1, Q3W), and apatinib (250 mg orally daily). Phase 2 is a single arm, open-label trial in the first-line setting. The primary objective were dose-limiting toxicity (DLT), maximal tolerated dose (MTD), and recommended phase II dose (RP2D). With α = 0.05 and 80% power, the pts needed for stage I and total of the Simon 2-stage design was 17 and 41 pts, respectively. Results: As of 4 February 2024, 6 HCC pts progressed after or were intolerant to first-line treatment (systemic therapy ± surgical resection) were treated in 1 dose cohorts. 1 DLT occurred (Grade 3 elevated blood bilirubin increased). The RP2D was adebrelimab (10 mg/kg), camrelizumab (200mg), and apatinib (250 mg). The most common drug-related AEs were Hypertension (83.3%) and Rash (50%); and Serum amylase increased, Itching, ALT/AST increased, and Hypothyroidism (each 33.3%). Immune-related AEs were similar to those seen with other checkpoint blockade agents. No drug-related AEs led to death. 1 pts (16.7%) discontinued due to drug-related AEs. Conclusions: The combination of Adebelimumab, Camrelizumab, and Apatinib demonstrated manageable safety for unresectable HCC. Enrollment in the phase II trial is ongoing and updated clinical data will be presented. Clinical trial information: NCT05924997 .
Deep learning for 4D modeling of glioblastoma multiforme with tumor treating fields (TTFields) therapy.
Authors: Andres Felipe Guerrero Ramirez, Cynthia Crystal Tang, Xiao-Tang Kong, Daniela Annenelie Bota, Peter D. Chang
Journal: Journal of Clinical Oncology (2024)

e14032 Background: Prediction of future tumor growth and recurrence are critical in the management of patients with glioblastoma multiforme (GBM). This study develops a deep learning method for estimating future areas of GBM spread across multiple timepoints using MRI in patients receiving tumor treating fields (TTFields) therapy. Methods: A single institutional database was queried to identify adult patients with histologically confirmed newly diagnosed and/or recurrent GBM undergoing TTFields therapy. For newly diagnosed GBM, patients received TTFields with temozolomide after maximal debulking surgery and chemoradiation therapy. For recurrent GBM, patients received TTFields as monotherapy. For each patient, all serial follow-up MRI exams were obtained, including T1 (pre-/post-contrast), T2, and T2/FLAIR sequences. On each exam, all regions of enhancing tumor core (excluding peritumoral edema, necrotic core, or resection cavity) were delineated and aligned across time points using nonlinear deformable registration. For any given pair of serial exams, a convolutional neural network (CNN) was designed to predict future GBM tumor on the follow-up exam given the precursor exam and time interval between the studies. The model is implemented as a 3D encoder-decoder architecture yielding a dense per-voxel prediction of future tumor probability optimized using a binary cross-entropy loss function. Class weights were used to develop high sensitivity and high positive predictive value (PPV) model variants. To generate final logit scores, time information is concatenated to the penultimate feature map as an additional feature channel, allowing the model to calibrate each estimate based on elapsed time between any pair of exams. Upon convergence, a 4D learned representation allows for prediction of spatial distribution of GBM tumor at any future time point. Results: A total of 123 patients (1112 total MR exams) were identified. For any given single patient, a median of 6 follow-up exams (IQR 2.5-12.5) at a median interval follow-up time of 46 days (IQR 15.75-63 days) between exams was observed. Upon five-fold cross-validation, the model demonstrated a 0.44 Dice score overlap between predicted and true areas of future GBM tumor growth. The high sensitivity model yielded a per-voxel sensitivity of 0.91 (IQR 0.77-0.99) and PPV of 0.26 (IQR 0.17 to 0.32), while the high PPV model yielded a per-voxel sensitivity of 0.14 (IQR 0.00 to 0.46) and PPV of 0.75 (IQR 0.56 to 0.94). Upon visual confirmation, model predictions across incremental time values for any given exam yielded expected gradual growth of tumor over time. Conclusions: A deep learning model can accurately predict future areas of GBM tumor growth in patients receiving TTFields therapy, with optimal performance that may be calibrated for high sensitivity or high PPV based on clinical use case.
Addressing cancer survivorship needs in geriatric survivors: Feasibility of a primary care–based survivorship clinic.
Authors: Maya Kavita Ramachandran, Natasha Steele, Jennifer Kim, Lidia Schapira, Ilana Yurkiewicz
Journal: Journal of Clinical Oncology (2024)

e13797 Background: The largest segment of the growing population of cancer survivors is at least 65 years of age, a population that is likely to have comorbidities and requires co-management between primary care and specialist physicians. The goal of this study was to characterize care for this patient population in a specialized primary care for cancer survivorship clinic that manages survivorship issues and ongoing primary care in one place. Methods: This study collected demographic and clinical data via electronic chart review of patients aged 65 and over who established care in the Primary Care for Cancer Survivorship clinic at an academic center from November 1, 2021 through November 30, 2023. Results: Out of 228 total patients who established primary care in the clinic, 63 patients were over the age of 65. The mean age of the group was 73, with the range 65 to 90. Seventy-three percent of patients were female, and 27% were male. The most common cancers were breast (38%), lung (10%), leukemia (13%), lymphoma (8%), prostate (8%), and multiple myeloma (6%). Twenty-five patients (40%) had active disease, 37 patients (58%) were post-treatment, and 1 patient was a “previvor” with Li-Fraumeni syndrome. Cancer surveillance was discussed with 81% of patients, and 2 patients (5% of post-treatment patients) were diagnosed with recurrent cancer. Secondary cancer screening was performed in 86% of patients, with no secondary cancers diagnosed. The most common referral sources were medical oncology from the same institution (40%), self-referrals (25%), and hematology (13%). The average number of visits per year was 2.8 with 61% in person and 29% via video. Cardiovascular risk was addressed in 98% of patients; 32% had at least one cardiovascular medication started and 17% were referred to a cardiologist for management. Long term and late effects were addressed in 84% of patients, including mental health (70%), bone health (65%), cognitive function (21%), cancer-related fatigue (13%), and sexual health (11%). Ten percent had end-of-life issues or goals of care addressed. Conclusions: This study demonstrates the feasibility of a primary care-based cancer survivorship clinic to address the ongoing needs of geriatric cancer survivors. Quality review of these patient encounters can identify gaps in care delivery and inform new models of comprehensive care for the growing geriatric cancer survivor population. [Table: see text]
Treatment outcomes of brain metastasis from primary renal cell carcinoma in United States: A National Cancer Database analysis.
Authors: Vivek Podder, Mohammad Arfat Ganiyani, Shahzaib Ahmad, Shreyas S Bellur, Muhammad Abbas Khokhar, Fathima Shehnaz Ayoobkhan, Manas Pustake, Diya K Jayram, Ahmad Ozair, Tulika Ranjan, Rohan Garje, Manmeet Singh Ahluwalia
Journal: Journal of Clinical Oncology (2024)

4561 Background: The advent of stereotactic radiosurgery (SRS) in treatment of brain metastasis (BM) has improved both clinical outcomes and survival in patients with BM. Recent studies suggest that immunotherapy presents a promising potential in the treatment of patients with BM. However, data regarding the effectiveness of combining SRS with immunotherapy for BM in metastatic renal cell carcinoma (RCC) remain largely unknown. We aim to delineate the impact of various treatment therapies including combination therapy for treatment of RCCBM. Methods: We queried the National Cancer Database (NCDB) to include patients with BM from mRCC from 2004 to 2020. We divided the patients into groups based on the treatment they received. Resultantly, 5 different treatment groups i.e., WRBT± immunotherapy, SRS± immunotherapy and immunotherapy alone were identified. We excluded patients with unknown treatment status. We analyzed survival outcomes using the Kaplan-Meier analysis and compared the effect of treatment modalities on survival with the log-rank test. Results: The NCDB yielded 6,446 patients diagnosed with BM from mRCC. In eligible cases, the median age was 63 years (range: 19-90+ years), 69.2% were male, 86.8% were White, 7.9% were Black, 41.9% had Medicare as primary payor, 27.7% had annual income &gt;$74,063, 79.3% belonged from metropolitan areas, 39.6% were treated at academic/research program, 68.3% had Charlson-Deyo score of 0, 44.6% had an unknown grade of the primary RCC. 1,705 (43.44%) patients who were given WBRT had a median overall survival (OS) of 5.65 months, 427 (10.88%) patients were treated with SRT + immunotherapy had an OS of 19.0 months, 987 (25.15%) patients who underwent SRT only had an OS of 9.7 months, 431 (10.98%) patients who received immunotherapy only showed an OS of 12.9 months, and 375 (9.55%) patients who underwent WBRT + immunotherapy had an OS of 12.78 months (log-rank p &lt;0.001). Conclusions: This national database analysis reveals that the combination of SRS with immunotherapy significantly increases the OS in RCCBM compared to immunotherapy, WBRT, or combination of WRBT and immunotherapy. Further prospective studies are warranted to confirm these findings. [Table: see text]