tbuckley/cabot-search huggingface dataset:
Surrogate endpoints for overall survival in advanced hepatocellular carcinoma: A meta-analysis.
Authors: Yacob Saleh, Zeynep Baskurt, Abdul Rehman Farooq, Rachel Anne Goodwin, Jennifer J. Knox, Eric X Chen
Journal: Journal of Clinical Oncology (2024)

563 Background: Recent advances in systemic therapies have resulted in improved overall survivals (OS) for patients with advanced hepatocellular carcinoma (aHCC). The most commonly utilized primary endpoint for phase III trials in aHCC is OS. A robust surrogate endpoint (SEP) can reduce time and financial costs of future trials and accelerate regulatory approvals of new therapies. We conducted a literature-based meta-analysis to evaluate SEPs for OS in aHCC. Methods: Randomized controlled trials evaluating systemic therapies in aHCC published 2007 - 2023 were identified through a systemic literature search of Cochrane and Medline databases as well as of abstracts presented at ASCO and ESMO meetings. Hazard ratios (HR) for OS and progression-free survival (PFS) and time to progression (TTP) were extracted. ΔORR was calculated as the difference in overall response rates (ORR) between control and experimental arms. Pearson correlation and mixed-effects meta-regression analyses were performed. Surrogate threshold effect (STE) was determined for each comparison when possible. A p &lt; 0.05 was considered to be statistically significant. Results: 26 trials were identified in the first-line setting with 14,827 patients and 11 trials in the subsequent-line setting with 5,316 patients. In first-line trials, immunotherapy (IO) is associated with higher ORR than other agents (p=0.003). There are statistically significant correlations between HRs of PFS/TTP/ΔORR and OS (Table). The relationship between HR-PFS and HR-OS persists in trials with or without IO, but only in trials enrolling &lt; 30% patients of non-viral aetiologies. In subsequent-line trials, there are statistically significant correlations between HRs of PFS/TTP and OS (Table). STE for HR PFS is 0.68 and 0.87 respectively for 1 st and subsequent line trials. Conclusions: There are moderate to strong correlations between PFS and OS in aHCC in first-line and subsequent line trials. STE for HR-PFS of 0.68 in first-line and 0.87 in subsequent-line settings can guide sample size calculation in future clinical trials. [Table: see text]
Clinical utility of upfront circulating tumor DNA (ctDNA) genotyping to guide first-line therapy in patients (pts) with metastatic colorectal cancer (mCRC): A GOZILA substudy.
Authors: Yu Aoki, Yoshiaki Nakamura, Yoshito Komatsu, Hiroya Taniguchi, Yu Sunakawa, Manabu Shiozawa, Chiyoe Kitagawa, Takashi Ohta, Nobuhisa Matsuhashi, Kentaro Yamazaki, Shogen Boku, Naoki Takahashi, Taito Esaki, Hisato Kawakami, Yoshinori Kagawa, Tomohiro Nishina, Kensei Yamaguchi, Hideaki Bando, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2024)

157 Background: The clinical utility of upfront ctDNA genomic profiling is not established in treatment (tx)-naïve pts with mCRC. Methods: GOZILA is a nationwide plasma genomic profiling study using Guardant360 CDx for advanced solid tumors. We assessed ctDNA molecular profile and its association with treatment efficacy in pts with mCRC who were enrolled in GOZILA from January 2018 to July 2022 and underwent ctDNA genotyping before initiation of first-line systemic tx. ctDNA fraction was defined as the maximum variant allelic frequency of somatic alteration and pts were classified into three groups based on ctDNA fraction: low (&lt;1%), middle (≥1% and &lt;10%) and high (≥10%) ctDNA fraction groups. Results: This study included 418 pts with mCRC receiving upfront ctDNA genotyping. Median turnaround time of ctDNA test was 7 days, comparable with standard-of-care (SOC) tissue RAS/BRAF testing (7 days) and microsatellite instability (MSI) testing (8 days). Pathogenic alterations were detected in 384 pts (92%), and concordance rates for RAS and BRAF mutation (mut) compared to SOC tissue-based testing were 91% and 97%, respectively. Based on biomarkers identified by ctDNA genotyping, 142 (40%) pts were treated with matched targeted tx: anti-EGFR antibody for RAS/BRAF wild-type (n=137), BRAF inhibitor for BRAF V600E mutation (n=4), and anti-PD-1 antibody for MSI high (n=1). Low, middle, and high ctDNA fraction groups included 87, 97 and 234 pts, respectively, and had significantly different median progression-free survival (PFS) (p&lt;0.01, table) and overall survival (OS) (p&lt;0.01, table), respectively. In 13 pts who repeated ctDNA test before second-line tx, those with elevated ctDNA fraction compared to upfront ctDNA had significantly shorter PFS (median, 3.8 vs. 8.1 months; HR, 5.7, 95% CI, 0.9 to 35.1) and OS (median, 8.2 vs. 17.4 months; HR, 11.3, 95% CI, 1.2 to 105.9) of second-line tx that those with not elevated ctDNA fraction. Conclusions: Upfront ctDNA genotyping successfully identified actionable genomic alterations in pts with mCRC. ctDNA fraction in upfront ctDNA was significantly associated with efficacy of first-line tx and ctDNA fraction monitoring may be useful in determination of subsequent tx. [Table: see text]
Impact of site of metastases in pancreatic ductal adenocarcinoma.
Authors: Adeel Arshad, Songzhu Zhao, Lai Wei, Julie Stephens, Ashish Manne, Anne M. Noonan, Shafia Rahman
Journal: Journal of Clinical Oncology (2024)

708 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) has a 5-year survival rate of 3%. We examined the clinical significance of the metastatic site on outcomes in mPDAC using the Surveillance, Epidemiology, and End Results (SEER) database. Methods: We analyzed the data on mPDAC from SEER database from 2010-2020 and categorized into three groups: mPDAC with, liver-only (LO) metastasis (mets), multi-organ mets including the liver (IL), and multi-organ mets excluding the liver (EL). Patient demographics and disease characteristics were summarized using the mean for continuous variables and proportions for categorical variables. Overall survival (OS) was calculated from time of diagnosis to death or censored at a loss to follow-up. The survival curve was plotted using the Kaplan-Meier method and log-rank p-value was reported. The Cox regression model was used to study the association of site of distant metastasis on overall survival, controlling for potential confounders (age, race, treatment, etc.) Results: We identified 22642 patients with mPDAC; 15844, 4250, and 2548 with LO, IL, EL mets respectively. The mean age at diagnosis was 66 years with the majority being white (78.4%), non-Hispanic (87.1%), and from metropolitan counties (88.5%). The median OS was 4 months, 3 months, and 6 months (log-rank p&lt;0.001) for LO, IL, and EL groups respectively, with 2-year survival being 4.84%, 2.56% and 7.89% respectively (log-rank p&lt;0.001). Multivariate analysis showed a higher risk of mortality in LO (31.5%, hazards ratio (HR)=1.315, p&lt;0.001) and IL groups (69.2% HR=1.692, p&lt;0.001) than EL group (Table). Conclusions: The site of distant metastasis is an independent prognostic factor for survival in patients with mPDAC, with liver-only mets or multi-organ mets including liver having worse OS than extrahepatic mets. [Table: see text]
Integrated multi-omics profiling to dissect the spatiotemporal evolution of metastatic hepatocellular carcinoma.
Authors: Yun-Fan Sun, Zefan Zhang, Jia Fan
Journal: Journal of Clinical Oncology (2024)

556 Background: Comprehensive molecular analyses of metastatic hepatocellular carcinoma (HCC) are lacking. Methods: Here, we generated genomic, transcriptomic, and T cell repertoire data coupled with digital pathology and digital spatial profiling of 257 primary, 28 relapsed, and 176 metastatic regions from 182 HCC patients. Results: Primary tumors rich in hypoxia signatures tended to give rise to polyclonal dissemination, which was associated with a poor clinical outcome. Genomic divergence between primary and metastatic HCC was high, and early dissemination was prevalent. The remarkable neoantigen intratumor heterogeneity observed in metastases was associated with decreased T cell reactivity, which may have resulted from disruptions to neoantigen presentation. We identified macroevolutionary somatic copy number alterations as highly selected events driving metastasis. Furthermore, we found that subclonal Wnt pathway mutations were not selected during spreading, whereas subclones without Wnt mutations showed a strong selective advantage for metastasis and were characterized by a reactive microenvironment rich in activated fibroblasts favoring an invasive tumor cell phenotype. Finally, metastases without Wnt mutations exhibited higher enrichment of immunosuppressive B cells that mediated terminal exhaustion of CD8+ T cells via HLA-E – NKG2A checkpoint axis. Conclusions: Collectively, our results provide a multi-dimensional dissection of the complex evolutionary process of metastasis.
Prospective observational study investigating the impact of treatment sequence using regorafenib and FTD/TPI for metastatic colorectal cancer on overall survival (OSERO study).
Authors: Akihiko Chida, Takeshi Kawakami, Tetsutaro Hamano, Toshiki Masuishi, Seiichiro Mitani, Hisateru Yasui, Atsushi Ishiguro, Takayuki Ando, Kentaro Sawada, Kazuaki Harada, Naoki Takahashi, Shogen Boku, Tomomi Kashiwada, Taito Esaki, Masataka Yagisawa, Keiji Sugiyama, Kouji Yamamoto, Satoshi Yuki, Kentaro Yamazaki, Eiji Oki
Journal: Journal of Clinical Oncology (2024)

103 Background: Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) with or without bevacizumab (BEV) are widely used as a later-line treatment for patients (pts) with metastatic colorectal cancer (mCRC). It is still unclear which is the preferable treatment strategy to start with, either REG, FTD/TPI, or FTD/TPI + BEV in clinical practice. Methods: We conducted a non–intervention, prospective, observational study in pts with mCRC at 41 sites. The key eligibility criteria were ECOG performance status (PS) 0 or 1, pts refractory to or intolerant of fluoropyrimidine, oxaliplatin, irinotecan, anti–angiogenesis, and anti–EGFR therapy if RAS status were wild type, and pts who plan to receive sequential treatment with REG and FTD/TPI BEV. Pts who starts with REG are enrolled in cohort A, FTD/TPI in cohort B, or FTD/TPI plus BEV in cohort C. The primary endpoint is overall survival (OS) of each group. Results: Between September 2020 and December 2022, a total of 501 pts were enrolled and 455 were identified as full analysis set. Pts’ characteristics of cohort A (149 pts) / B (80 pts) /C (226 pts) were as follows: median age 64.0 / 65.5 / 67.0 years, male 53.0 / 52.5 / 55.3%, ECOG PS 0 52.3 / 31.3 / 48.7%, tumor location right–sided 33.6 / 27.5 / 20.4%, RAS wild type 35.6 / 41.3 / 43.4%, and BRAF V600E mutant type 6.7 / 7.5 / 4.0 %. Pts who received subsequent with FTD/TPI BEV in cohort A / REG in cohort B / REG in cohort C were 62.4 / 37.5 / 62.8%. The median OS of cohort A / B / C was 11.8 / 7.1 / 10.2 months. Cox hazard model revealed hazard ratio (HR) 1.40 (95% confidence interval [CI] 1.01–1.94; p = 0.043) for cohort B, and HR 1.04 (95% CI 0.80–1.34; p = 0.784) for cohort C compared with cohort A. After adjusting age, ECOG PS, tumor location, the number of metastatic sites, the adjusted HR were 1.29 (95% confidence interval [CI] 0.87–1.91; p = 0.213) for cohort B, and 1.00 (95% CI 0.75–1.34; p = 0.998) for cohort C compared with cohort A. Conclusions: This study demonstrates that the OS are comparable regardless of whether REG, FTD/TPI, or FTD/TPI + BEV is administered first. Clinical trial information: UMIN000040586 .
Sequential or up-front triple combination with durvalumab, tremelimumab, and bevacizumab for patients with unresectable hepatocellular carcinoma (HCC): MONTBLANC.
Authors: Enrico N. De Toni, Julia Mayerle, Bettina Oehrle, Max Seidensticker, Lorenza Rimassa, Ursula Ehmer, Andreas Geier, Florian P Reiter, Thomas Jens Ettrich, Alexander B Philipp, Daniel Christoph Rössler, Najib Ben Khaled
Journal: Journal of Clinical Oncology (2024)

TPS574 Background: Escalation of treatment from one to two combined immune checkpoint inhibitors (CPI) has dramatically increased objective and clinical response in advanced hepatocellular carcinoma (HCC) patients. Establishing strategies with more than two CPI agents to further increase response while maintaining a manageable toxicity is therefore a top priority. The upfront simultaneous use of three or more CPI can yield a strong initial response to treatment, but it may also increase treatment-related toxicity. An alternative approach, which prioritizes safety over immediate response, involves utilizing different CPI doublets in a sequential manner. However, this design entails switching to a different combination only after radiological progression is observed, and recurrent progressions may lead to deteriorating liver function and treatment resistance. Trials of immunotherapy of HCC conducted in recent years showed that the efficacy of CPI, when used simultaneously, outweighs the drawbacks of their combined toxicity and that early radiological response to treatment, or the lack thereof, is a predictor of clinical outcome. In addition, failure of trials using broad-spectrum tyrosine kinase inhibitors (TKI) and CPI suggest that antibodies or narrow-spectrum TKI should be used for future CPI-based combinations in HCC studies. Based on these considerations, the MONTBLANC study is the first trial to assess the effectiveness of up-front triple treatment with a combination of the three currently approved immunological agents for HCC and to implement the concept of treatment escalation determined by lack of early radiological response (as opposed to treatment progression). Methods: The MONTBLANC study is a randomized, 2-arm phase II study on the efficacy of combinations of durvalumab, tremelimumab, and bevacizumab in patients with advanced HCC. Patients with preserved liver function (Child-Pugh A) with unresectable tumors or not amenable to local or locoregional treatment are randomized to an early escalation arm (A) or a triple treatment arm (B). Patients in arm A receive combined durvalumab and tremelimumab (STRIDE regimen). Treatment is escalated by the addition of bevacizumab upon detection of disease progression or in the absence of radiological response by the 4th month of treatment. Patients in arm B receive up-front STRIDE and bevacizumab. Treatment will continue until unacceptable toxicity or progression under the Bev-containing regimen. The primary endpoint is overall response rate (ORR). Clinical trial information: NCT05844046 .
Clinical characteristics and survival analysis in patients with isolated pulmonary metastases from colorectal cancer (CRC).
Authors: Javier Soto Alsar, Roberto Jiménez Rodríguez, Natalia Gutiérrez Alonso, Marianela Bringas Beranek, Rocío Martín Lozano, Carlos López Jiménez, Irene Gonzalez Caraballo, David Salomon Juliao Caamaño, Ana Gutierrez, Andrés Muñoz, Laura Ortega Morán, Pilar Aitana Calvo Ferrandiz, Gabriela Torres Pérez-Solero, Miguel Martin, Pilar Garcia-Alfonso
Journal: Journal of Clinical Oncology (2024)

60 Background: Recent studies seem to indicate that patients with metastatic colorectal cancer (mCRC) with exclusive pulmonary metastatic disease have better outcomes than those with other metastatic sites. The aim of this study is to identify differences in clinical and survival characteristics between the two groups in a cohort of a third level hospital. Methods: We retrospectively analyzed a sample of 569 patients with mCRC in a tumor registry from 2015 to 2021, studying clinical and molecular characteristics, as well as overall survival data of patients with isolated pulmonary metastases, versus the rest of patients. Results: Of the total sample analyzed, 61 patients (10.7%) had isolated pulmonary metastases. In these patients, several clinical characteristics were more frequent: primary rectal tumor (52.5% vs 23.4%, p &lt; 0.000), resected primary tumor (95.1% vs 78.9%, p = 0.0026), metachronous metastatic disease (62.3% vs 42%, p = 0.0025) and complete response rate to the first line of treatment (19.3% vs 9.9%, p = 0.026). Furthermore, analytically, these patients were more likely to have normal CEA (75% vs 38.3%, p &lt; 0.000), CA 19.9 (84.3% vs 57.7%, p = 0.0002) and LDH (91.1% vs 66.5%, p = 0.0007) levels. In our cohort, we found no statistically significant differences in tumor mutational status (KRAS, NRAS, BRAF, PI3K and HER2). There were no patients with exclusive pulmonary metastatic disease and microsatellite instability (MSI). 70.3% of patients with isolated pulmonary metastases received lung metastasectomy, and up to 58.3% received a second metastases surgery. We also found a numerical benefit in terms of overall survival (OS) in patients with exclusive metastatic lung disease, although it did not reach statistical signification (median OS 77.3 vs 58.1 months, HR for death 0.70, 95% CI, 0.49 – 1.01, p = 0.083). Conclusions: In our cohort, patients with isolated pulmonary metastases were more likely to have rectal tumors, primary tumor resection, metachronous metastatic disease, higher rate of complete responses and normal CEA, CA 19.9 and LDH levels, with a possible benefit in terms of OS.
Care delivery and patient self-management for people with primary liver cancer receiving 4R care sequence plans.
Authors: George Therapondos, Christine B. Weldon, Lingling Du, Jonathan Mizrahi, Carol Palmer, Amanda Medina, Tyler Allan Sandow, Juan Gimenez, Ari Cohen, Michelle O'Brien, Amie Tan, Julia R. Trosman
Journal: Journal of Clinical Oncology (2024)

465 Background: The 4R Oncology Model (4R=Right information/care/patient/time) supports patient self-management 1 and quality improvement. 2 Here we report the impact of using 4R Care Sequence plans for patients with primary liver cancer cared for by a multi-disciplinary liver cancer team. Methods: We tested the impact of 4R care sequence plans on patient self-management and care delivery referrals at a liver cancer program via patient surveys. 4R Plans were provided to patients with primary liver cancer from Jan – Aug ’23 (4R cohort). Patient-reported data were analyzed to compare the control cohort of patients who received care pre-4R, Jan - Dec ’22 (N=42) to the 4R cohort (N=17). Statistical analysis used Fisher’s exact test. Results: Patient survey response rates: Control cohort 54% (42/78), 4R cohort 55% (17/31). Comparing the control cohort to the 4R cohort respectively, patients were male (52%, 65%), White (64%, 64%), Black (26%, 18%), average age (63.2, 64.7), and reported income less than $30,000 (45%, 53%). The 4R cohort significantly improved care delivery in three metrics, and directionally improved in the other care delivery metrics as compared to the control cohort (table). All four patient self-management metrics significantly improved in the 4R cohort vs. the control cohort (Table). Conclusions: The use of 4R Care Sequence plans for patients with primary liver cancer facilitated improvements in care delivery and patient self-management metrics. While there were directional improvements in all metrics, there is opportunity and room for additional improvements. The team will continue to work on efforts to improve these metrics and optimize the use of 4R Care Sequence plans for patients with primary liver cancer. 1. Trosman, JCOOP 2021. 2. Liu, JCOOP 2022. [Table: see text]
Serologic, radiographic, and tissue-based markers associated with major pathologic response after treatment with neoadjuvant immunotherapy in patients with resectable hepatocellular carcinoma.
Authors: Michael Brian LaPelusa, Shadi Chamseddine, Lianchun Xiao, Elshad Hasanov, Priya Bhosale, Yehia I. Abugabal, Betul Gok Yavuz, Shalini S. Yadav, Hop Sanderson Tran Cao, Li Xu, Zishuo Ian Hu, Sunyoung S. Lee, Divya Sakamuri, Michael A. Curran, Sonali Jindal, Gabriel Dan Duda, Padmanee Sharma, Aliya Qayyum, Ahmed Omar Kaseb
Journal: Journal of Clinical Oncology (2024)

561 Background: Neoadjuvant immunotherapy can induce a major pathologic response (MPR) in patients with resectable hepatocellular carcinoma (HCC), which may be associated with prolonged recurrence-free survival. This study aimed to understand which variables correlate with achieving an MPR. Methods: Patients with resectable HCC who received either neoadjuvant nivolumab plus ipilimumab or nivolumab alone and underwent surgery were included. 18 patients had baseline and post-treatment computed tomography, alpha-fetoprotein (AFP), and elastography. 17 of these patients had baseline and post-treatment tissue available for immunohistochemistry. Patients were classified into two groups: MPR, defined as necrosis of &gt;70%, and no MPR. Data was summarized using descriptive statistics and compared using Wilcoxon rank sum test. P value &lt;0.05 was considered statistically significant. Results: Statistically significant differences in objective response (OR) and changes in CD8, Granzyme B, and PD-1 expression were identified upon comparison of patients with an MPR to those without an MPR (Table 1). Additionally, numerical differences in baseline tumor size, change in AFP, and both non-tumor and tumor liver fibrosis (at baseline, after treatment, and interim change) were identified upon comparison of patients with an MPR to those without an MPR. Conclusions: Our data show that large baseline tumor size, greater OR, reduction in AFP, increase in liver and tumor fibrosis, and increase in CD8, Granzyme B, and PD-1 expression after receipt of neoadjuvant immunotherapy are associated with achieving an MPR in patients with resectable HCC. [Table: see text]
Preoperative risk factors related to relapse-free survival after R0 resection of gallbladder cancer.
Authors: Sang Hun Lee, Yong Mi Seol, Dong Uk Kim
Journal: Journal of Clinical Oncology (2024)

566 Background: Gallbladder (GB) cancer shows high prevalence in South Korea, and tends to be fatal. In surgically fit patients, radical resection aiming R0 margin combined with lymphadenectomy is the mainstay of curative-intent therapy. In spite of R0 resection, however, high recurrence rate is observed in GB cancer, demanding a need to find out risk factors related to recurrence after surgery. Methods: This is a single center, retrospective cohort study conducted on 148 patients with GB cancer who underwent R0 resection between January 1st, 2014 and December 31st, 2019. Several variables were analyzed with statistical tools to identify risk factors related to prognosis. Relapse free survival (RFS), defined as time from treatment of disease to any event, was analyzed with Cox regression analysis. Results: Based on statistical analysis, risk factors related to RFS were age over 65 (hazard ratio [HR] 3.82, 95% confidence interval [CI] 1.71 – 8.56, p= .001), glycated hemoglobin (HbA1c) level more than 6.5% (HR 2.72, 95% CI 1.31 – 5.66, p=0.007), surgical T stage more than T3 (HR 5.60, 95% CI 3.05 – 10.25, p&lt;0.001), surgical N stage more than N1 (HR 4.07, 95% CI 2.25 – 7.36, p&lt;0.001), pathologic differentiation of moderate or poor differentiation (HR 2.80, 95% CI 1.46 – 5.37, p=0.002), reversed albumin-globulin ratio (HR 0.16, 95% CI 0.06 – 0.40, p&lt;0.001), and high gamma glutamyl peptidase (GGT) level (HR 1.00, 95% CI 1.00 – 1.00, p&lt;0.001). Conclusions: Advanced pathologic stage and high inflammatory marker levels, reflecting high tumor burden, were related with poor surgical outcome. Interestingly, high HbA1c level was related to reduced RFS as well. In conclusion, active screening for early detection, reducing inflammatory conditions, and managing diabetes might enhance RFS after R0 resection of GB cancer. [Table: see text]