tbuckley/cabot-search huggingface dataset:
Survival outcomes with adjuvant immunotherapy after hepatic resection in patients with intermediate/advanced (BCLC stage B/C) hepatocellular carcinoma: Insights from a propensity-matched multicenter study.
Authors: Tian Yang, Ming-Da Wang, Xiao Xu, Jia-Hao Xu, Zhong-Qi Fan, Yong-Kang Diao, Zhong Chen, Hang-Dong Jia, Fu-Bao Liu, Yong-Yi Zeng, Xian-Ming Wang, Chao Li, Timothy M. Pawlik, Wan Yee Lau, Feng Shen, Guo-Yue Lv
Journal: Journal of Clinical Oncology (2024)

4096 Background: With the growing interest in adjuvant immunotherapy for reducing recurrence and improving prognosis after hepatic resection in hepatocellular carcinoma (HCC), particularly in high-risk patients, this study aims to evaluate the impact of adjuvant immunotherapy on long-term recurrence and survival in patients with intermediate/advanced HCC. Methods: A prospective multicenter database was utilized to identify patients who underwent curative-intent resection for Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC. Propensity score matching (PSM) was employed to equate recurrence-free survival (RFS) and overall survival (OS) between patients receiving adjuvant immune checkpoint inhibitors (ICIs) and those who did not. Multivariate Cox-regression analysis was used to identify independent predictors of RFS and OS. Results: Out of 627 patients, 109 (23.3%) received adjuvant immunotherapy, with most ICI-related adverse reactions being grade I-II. The ICI agents used among these 109 patients were tislelizumab (51.4%, n=56), sintilimab (29.3%, n=32), camrelizumab (9.2%, n=10), pembrolizumab (6.4%, n=7), and toripalimab (3.7%, n=4). All patients receiving adjuvant immunotherapy completed at least 3 months of ICI treatment, with no patients discontinuing the treatment due to irAEs. PSM resulted in 99 matched pairs with comparable baseline characteristics. In this cohort, patients receiving adjuvant immunotherapy showed significantly improved median RFS (29.6 vs. 19.3 months, P=0.031) and OS (35.1 vs. 27.8 months, P=0.036) compared to those who did not. Multivariable analyses confirmed adjuvant immunotherapy as an independent factor for better RFS (HR: 0.630; 95% CI: 0.435-0.914; P=0.015) and OS (HR: 0.601; 95% CI: 0.401-0.898; P=0.013). Subgroup analyses suggested prognostic benefits of adjuvant immunotherapy in both intermediate and advanced-stage HCC. Conclusions: This real-world observational study indicates that adjuvant immunotherapy is associated with improved RFS and OS in patients undergoing curative-intent resection for intermediate/advanced HCC. These findings support the need for future randomized controlled trials to establish definitive evidence for this high-risk population.
Predictors of short-term death and long-term survival in advanced hepatocellular carcinoma (HCC) treated with contemporary tyrosine kinase inhibitors (TKI) or immunotherapy: A multicenter analysis from the HCC-CHORD consortium.
Authors: Pooya Dibajnia, Mark Freeman, Tharani Krishnan, Cha Len LEE, Ravi Ramjeesingh, Joao Paulo Solar Vasconcelos, Hanna Lyubetska, Esther Provost, Jessica Li, Philip Q. Ding, Howard J Lim, Jennifer J. Knox, Vallerie Lynn Gordon, Winson Y. Cheung, Vincent C. Tam, Brandon M. Meyers
Journal: Journal of Clinical Oncology (2024)

4098 Background: Advances in systemic therapy for HCC have increased treatment options, including TKIs and immunotherapy combinations. Variables that predict patient outcomes may be helpful in personalizing treatment decisions. The aim of this study was to identify predictors of short-term death (STD) and long-term survival (LTS) for HCC patients. Methods: Retrospective review of patients with advanced HCC who received a TKI or immunotherapy combinations was conducted between Aug 2018 to Aug 2022 in the Canadian provinces of British Columbia, Alberta, Nova Scotia, Manitoba, as well as from select institutions in Ontario (n = 2). Prior locoregional therapies were permitted. Variables examined were: Barcelona Clinic Liver Cancer (BCLC) stage, Child-Pugh class, albumin-bilirubin (ALBI) grade, alpha fetoprotein (AFP) level, microvascular invasion (MVI), and distant metastases. Multivariate logistic regression was used to determine independent predictors of STD (patient survival &lt; 6 months vs others) and LTS (patient survival &gt; 18 months vs others). Results: 520 patients with the following baseline characteristics were included: median age 66, 84.6% male, 87.4% ECOG performance status 0-1, 69.7% BCLC stage C, and 88.7% Child-Pugh A. First-line treatments were primarily: lenvatinib 57.3%, sorafenib 8.1%, and atezolizumab/bevacizumab 31.7%. Median progression-free survival was 7.4 months (95% CI: 6.2 to 8.4), and overall survival was 17.1 months (95% CI:, 15.1 to 18.8). Independent predictors of STD were (odds ratio): ALBI grade (2.26), MVI (2.13), and distant metastases (2.14). These three factors were also predictive for LTS: ALBI grade (0.45), MVI (0.49), and distant metastases (0.36). Child-Pugh class, AFP, and BCLC stage were not predictive of STD nor LTS (Table). Conclusions: This study supports higher ALBI grade, MVI and distant metastases as predictors of STD, while lower ALBI grade, absence of MVI and lack of distant metastases were predictive of LTS in HCC patients treated with contemporary TKIs or immunotherapy combination regimens. These predictors may help guide treatment decisions in patient populations underrepresented in clinical trials, including patients with Child-Pugh B7 score who are often excluded. [Table: see text]
Atezolizumab plus bevacizumab (A+B) as first-line systemic therapy for advanced hepatocellular carcinoma (HCC): A multi-institution analysis of patient outcomes based on Child Pugh (CP) and ALBI liver function.
Authors: Michael H. Storandt, Tyler J. Zemla, Kanchi Patell, Nikolas Naleid, Jennifer Gile, Nguyen H. Tran, Sakti Chakrabarti, Zhaohui Jin, Amit Mahipal
Journal: Journal of Clinical Oncology (2024)

4099 Background: A+B is standard of care for advanced HCC in the first line setting, although was only evaluated in patients with CP class A liver function in IMbrave150. We sought to determine outcomes of patients in the real-world setting. Methods: We conducted a multi-institution retrospective analysis of patients with HCC who received A+B as first-line systemic therapy between March 2018 and November 2023, at Mayo Clinic and University Hospitals Seidman Cancer Center. Treatment response was evaluated, and progression free survival (PFS) and overall survival (OS) were determined using the Kaplan Meier method. Multivariate analyses were performed using Cox proportional hazard regression method. Results: Among patients with HCC (n=322), 226, 86, and 10 had CP-A, -B, and -C liver function, while 120, 177, and 25 had ALBI grade 1, 2, and 3 liver function. Median age was 66.5 years, 78.6% were male, and 82.6% were white. Liver disease causes included hepatitis B (5.3%) and C (34.8%), ethanol use (26.1%), and non-alcoholic steatohepatitis (15.5%). Macrovascular invasion was seen in 42.9%, and 30.4% had extrahepatic metastatic disease. Median OS for patients with CP-A5/6 was 21.6 months, B7 (n=49) was 9.1 months, and B8-C12 was 4.7 months ( p&lt;0.0001). Median OS by ALBI grade was 34.9, 11.7, and 4.7 months for grades 1, 2, and 3. Median PFS was 8.9, 6.4, and 2.7 months for CP-A5/6, B7, and B8-C12 ( p&lt;0.0001). Median PFS by ALBI grade was 11.0, 6.4, and 3.7 months for grades 1, 2, and 3 ( p=0.0001). Among patients with CP-A, those with ALBI grade 1 had mOS of 34.9 months versus 14.2 months for those with grade 2. Partial response was seen in 29.2%, 19.8% and 10.0% of patients with CP-A, -B, and -C, while 32.7%, 33.7%, and 40.0% had stable disease. In a univariate analysis, factors predictive of shorter OS included CP-B7 or CP-B8-C12, ALBI grade 2 or 3, hepatitis B, poorer ECOG performance status (PS), macrovascular invasion, non-white race, and lack of prior surgery or embolization. In multivariate analyses, CP score, ALBI grade, hepatitis B, ECOG PS, and macrovascular invasion were significantly associated with survival. There was significant interaction between CP and ALBI grade (Table). Conclusions: A+B remains a viable option in patients with CP-B7 liver function, although benefit is significantly less than those with CP-A. ALBI score has predictive value and can identify two prognostic groups among those with CP-A liver function. [Table: see text]
The NEO-RT trial: A phase 3 randomized trial of neoadjuvant chemotherapy, excision and observation versus chemoradiotherapy for early rectal cancer, CCTG CO.32.
Authors: Hagen Fritz Kennecke, Christopher J. O'Callaghan, Dongsheng Tu, Roger Leung, Kristopher Dennis, Lisa A. Kachnic, Jonathan M. Loree, Mark Whiteford, William A. Hall, Stacey A. Cohen, Christopher G Cann, Noam Avraham VanderWalde, Steven J. Nurkin, Therese Juul, Winson Y. Cheung, David Paul Horowitz, Gordon Locke, Carl J. Brown
Journal: Journal of Clinical Oncology (2024)

TPS3646 Background: There is significant interest in organ-sparing management of rectal cancer. Data from the National Cancer Database suggest that in 2020 only 20% of US patients with stage I rectal cancer are managed non-operatively. The phase II CCTG CO.28/NEO trial previously reported high rates of tumor downstaging, organ preservation and excellent rectal function among patients with T1-T3abN0 rectal adenocarcinoma treated with 3 months of FOLFOX/CAPOX followed by Transanal Endoscopic Surgery (TES). The phase III CO.32/NEO-RT trial (NCT06205485) will compare two organ sparing strategies for patients with stage I rectal cancer. Methods: Eligible patients with clinical stage T1/2 N0 adenocarcinoma with preserved mismatch repair (MMR) will be randomized 1:1 to ARM A, 3 months of FOLFOX or CAPOX versus ARM B, chemoradiation (54 Gy) followed by tumor restaging within 16 weeks of start of therapy. Patients with histological high grade, mucinous or deficient MMR and those that can be treated with tumor excision alone are excluded. The primary endpoint is tumor downstaging to clinical Complete Response (cCR) by pelvic MRI, endoscopy and digital rectal exam. Subsequent TES is recommended for all patients with tumor response and may be done within 24 weeks of treatment begin, followed by 5 years (y) of observation with serial MRI (q6m x 2y then annually) and endoscopy (q4m x 2y, then q6m during year 3, then annually). The co-primary endpoint is Quality Of Life (QOL) measured by the Low Anterior Resection Score (LARS). In a non-inferiority comparison between treatment arms, if the cCR is assumed to be 45% in ARM B and if there is no true difference between ARMS A and B, then 250 patients are required to be 80% sure that the upper limit of a one-sided 90% confidence interval will exclude a difference in favor of chemoradiation of more than 14%. Results: The approved CCTG CO.32 trial is expected to open February, 2024 at Canadian CCTG and US Alliance, ECOG-ACRIN, NRG, and SWOG NCTN sites with an estimated accrual duration of 4 years. Conclusions: The results of this study will have a major impact on the treatment of patients with stage I rectal cancer. Both arms offer the potential of organ preservation and results will inform whether induction chemotherapy is non-inferior to ChemoRT and compare patient QOL and functional outcomes. Clinical trial information: NCT06205485 .
Total neoadjuvant therapy with split-course hypofraction radiotherapy combined with CAPOX and envafolimab followed by local excision for locally advanced very low rectal cancer (TRACE-LE): An open-label, single-arm, multicenter, phase II trial.
Authors: Weizhong Jiang, Pan Chi, Kaixiong Tao, Dongbo Xu, Chunkang Yang, Rong Zheng, Benhua Xu, Ying Huang, Zhifen Chen, Shenghui Huang, Zongbin Xu
Journal: Journal of Clinical Oncology (2024)

TPS3647 Background: In the treatment of patients with locally advanced very low rectal cancer, neoadjuvant chemoradiotherapy followed by total mesorectal excision (TME) is considered a standard therapeutic approach. Short-course hypofractionated radiotherapy, in combination with subsequent chemotherapy, has been shown to be comparable to long-term chemoradiotherapy in terms of neoadjuvant therapy effects in rectal cancer. Additionally, it has been observed that hypofractionated radiotherapy, when combined with programmed death L-1 (PD-L1) blockade, can enhance the immune response. This study aims to investigate efficacy and safety of organ preservation in patients with locally advanced very low rectal cancer by utilizing total neoadjuvant therapy involving split-course hypofraction radiotherapy in conjunction with CAPOX and Envafolimab (a humanized single-domain anti-PD-L1 antibody fused to an Fc fragment). Methods: TheTRACE-LE trail is an open-label, single-arm, multicenter, phase II trial. The target sample is 72 participants. Key eligibility criteria include individuals aged 18-75, confirmed rectal adenocarcinoma, cT3-4N0/cT1-4N1-2 with lower margin ≤ 2cm from anorectal ring's upper edge (MRI) and ECOG performance status of 0-2. The treatment protocol include preoperative split-course hypofractionated radiotherapy (5×7Gy), in conjunction with 6 cycles of CAPOX chemotherapy and Enverolimab (300 mg subcutaneous injections) administered in a 3-week treatment cycle. The primary outcome measure is organ preservation, specifically the rectum intact, owing to no radical total mesorectal excision (TME), no locoregional regrowth unless amenable to limited, curative (R0) salvage surgery by local excision (LE) and no permanent stoma (including a never reversed protective stoma, or a stoma owing to toxicities and/or poor functional outcomes). The secondary outcome measures encompass ypT0-1 rate, pathological complete response (pCR) rate, acute and late toxicity as per NCICTCAE V.5.0, local recurrence rate, local regional recurrence rate, disease-free survival, quality of life, and anorectal function. Clinical trial information: NCT05970900 .
A single-sample gene-expression classifier for the intrinsic consensus molecular subtypes in colorectal cancer.
Authors: Petros Tsantoulis, Yourae Hong, Pratyaksha Wirapati, Ting Pu, Allyson Peddle, Thomas McKee, Sabine Tejpar
Journal: Journal of Clinical Oncology (2024)

e15587 Background: An analysis of colorectal cancer epithelial cells showed two intrinsic subtypes called iCMS2 and iCMS3, in addition to the bulk consensus subtypes (CMS1-4). The intrinsic subtypes are prognostically important. We present a robust method for calculating the iCMS subtypes in individual samples, as opposed to batches, applicable in a clinical setting. Methods: We selected the subset of iCMS genes (N = 201) with the strongest epithelial expression in colorectal cancer, aiming to reduce the signal from other cell types. We then calculated gene expression centroids by taking the per-gene mean expression of 8 random samples from three non-batch corrected datasets (1779 samples total) that were previously used to derive the iCMS subtypes. Thirty-two centroids were calculated per dataset and per iCMS, for a total of 192 centroids. The single sample classifier (SSC) calculates the most likely iCMS class based on the class of the nearest centroid by non-parametric correlation distance. A confident call is made when the correlation is at least 0.1 and distance from the nearest centroid of the opposite iCMS class is greater than 0.05. Results: The SSC achieved 98.3% agreement with the reference calls in training data. The SSC was applied to unseen data for validation, by classifying non-batch corrected samples one at a time. The same data were clustered with the reference published iCMS public dataset and the reference iCMS was estimated at the batch level by proximity to reference samples in the hierarchical tree structure. Concordance between reference and SSC calls was 91.4% in non-batch corrected data and only modestly improved to 93.9% when batch correction was applied, showing the robustness of this approach. Concordance remained acceptable even when non-confident SSC calls were included (86.9%). The proportion of calls that were judged confident with the SSC was 77.9%, slightly lower than the proportion of confident reference calls (87.6%). In addition, the SSC was applied to data from the VELOUR trial, for which reference iCMS calls were also available. The SSC iCMS was prognostic (HR 0.601 for OS in iCMS2 vs iCMS3, P &lt; 0.00001) and performed at least as well as the reference iCMS (HR 0.669, P = 0.0004). Conclusions: The SSC reproduces the iCMS classification and appears robust to batch effect. The SSC calls are prognostic in clinical trial data. The SSC R package is available for download (https://github.com/CRCrepository/iCMS.SSC). [Table: see text]
SWOG S2107: Randomized phase II trial of encorafenib and cetuximab with or without nivolumab for patients with previously treated, microsatellite stable, <i>BRAF<sup>V600E</sup></i> metastatic and/or unresectable colorectal cancer.
Authors: Van K. Morris, Katherine A. Guthrie, Scott Kopetz, Rimini Breakstone, Thomas Benjamin Karasic, Zishuo Ian Hu, Sarah Colby, Marwan Fakih, Sepideh Gholami, Philip Jordan Gold, E. Gabriela Chiorean, Philip A. Philip
Journal: Journal of Clinical Oncology (2024)

TPS3640 Background: Patients with microsatellite stable (MSS), BRAF V600E metastatic colorectal cancer (mCRC) experience poor survival outcomes. Second-line treatment with the BRAF inhibitor encorafenib (E) and anti-EGFR antibody cetuximab (C) is an approved treatment combination, with overall response rate (ORR) of 20% and median progression-free survival (PFS) of 4.1 months. Anti-PD-1 antibodies like nivolumab (N) are ineffective as monotherapy for patients with MSS, BRAF V600E mCRC. In preclinical models of MSS, BRAF V600E CRC, inhibition of BRAF and EGFR induces loss of expression of mismatch repairs genes and promotes a microsatellite instability-high phenotype, which may prime these tumors for response to immunotherapy. In support of these findings, a single-institution clinical trial of E + C + N for 26 patients with MSS, BRAF V600E mCRC reported an ORR of 50% and median PFS of 7.2 months. We hypothesize that the addition of N to E + C will improve median PFS for patients with MSS, BRAF V600E mCRC. Methods: In this prospective phase II clinical trial (N=84), patients with previously treated MSS, BRAF V600E mCRC are randomized 2:1 into 2 arms, respectively: experimental treatment (E + C + N) or standard treatment (E + C). No prior BRAF, EGFR, or immunotherapy agents are allowed. All patients receive E (300 mg PO daily) and C (500 mg/m 2 IV every 14 days), and patients in the experimental arm receive N (480 mg IV every 28 days). The primary endpoint is PFS. Secondary endpoints include overall survival, best overall response, duration of response, and safety/tolerability. Using a one-sided α= .10 and power 80%, we target an improvement in median PFS from 4.2 to 7.3 months (hazard ratio 0.57). Additional patient specimens will be collected for exploratory correlative research. As of 2/2024, 50 of 84 planned participants have been enrolled. Clinical trial information: NCT05308446 .
Triplet chemotherapy combined with anti-EGFR treatment in RAS wild-type colon cancer: A network meta-analysis.
Authors: Paola Di Nardo, Fabiola Giudici, Debora Basile, Marco de Scordilli, Sara Torresan, Martina Bortolot, Simone Rota, Luisa Foltran, Michela Guardascione, Arianna Fumagalli, Claudia Noto, Alessandra Guglielmi, Elena Ongaro, Fabio Puglisi
Journal: Journal of Clinical Oncology (2024)

e15592 Background: The optimal first-line treatment for RAS wild-type (wt) metastatic colorectal cancer (mCRC) remains undetermined. Recently, several studies have explored the efficacy of first-line treatment regimens, including triplet chemotherapy (CT) combined with an anti-EGFR antibody, in comparison to either doublet CT combined with an anti-EGFR antibody, triplet CT combined with an anti-VEGF treatment, or triplet CT alone. However, none of these trials yielded conclusive results. Hence, we conducted a systematic review and an explorative network meta-analysis (NMA) of the available data. Methods: A systematic review was conducted, encompassing all phase II/III randomized clinical trials (RCTs) that compared a regimen consisting of triplet CT associated with an anti-EGFR treatment against different first-line systemic regimens for RAS-wt mCRC patients. Both pairwise and NMA were performed to establish direct and indirect comparisons of overall response rate (ORR) using a random effects model within the frequentist framework. Results: 7 RCTs (TRIPLETE, VOLFI, TRICE, PANIRINOX, AIO-CELIM2, FOCULM, DEEPER), involving a total of 1283 patients, were included in the analysis. Overall, 4 arms were identified, encompassing all possible combinations of CT, anti-EGFR treatment, and anti-VEGF treatment: arm A (triplet + anti-EGFR), arm B (doublet + anti-EGFR), arm C (triplet alone), and arm D (triplet + anti-VEGF). A benefit was demonstrated for all treatments associated with targeted therapy when compared to triplet alone; no difference was observed among groups A, B and D. Results of selected NMA comparisons are shown in the table 1. Additionally, we conducted a pairwise meta-analysis for ORR, which, due to available comparisons, was only feasible for groups A vs. B, A vs. C, and A vs. D; the results of this analysis confirmed the NMA findings (group A vs. group C, pooled OR: 4.23 (2.06 – 8.68)). Conclusions: Through indirect comparisons, no significant ORR benefit was found for triplet CT associated with anti-EGFR treatment compared to doublet CT combined with anti-EGFR treatment or triplet CT combined with anti-VEGF. All regimens incorporating targeted treatment demonstrated superior performance compared to triplet CT alone. Our findings do not advocate for the routine use of triplet CT associated with anti-EGFR treatment in this patient population; however, we await mature OS data from a few of the trials included in our analysis. [Table: see text]