tbuckley/cabot-search huggingface dataset:
Clinical significance of time interval between surgery and adjuvant chemotherapy in patients with gastric cancer after gastrectomy: A population-based cohort study using a nationwide claims database.
Authors: Chi Hoon Maeng, Hoseob Kim, Mina Kim
Journal: Journal of Clinical Oncology (2024)

333 Background: Adjuvant chemotherapy can reduce recurrence rates by eradicating microscopic metastases which may persist after curative resection. However, the optimal time interval (TI) between the surgery and chemotherapy remains controversial. Methods: The data were obtained from the NHIS of Korea. We included patients who underwent gastrectomy for gastric cancer between 2013 and 2018. To determine the optimal cut-off point of TI, a restricted cubic spline cox regression model was established, and categorized the population into three groups based on TI: the early group (≤ 20 days), the reference group (21-34 days), and the late group (≥ 35 days) with the reference interval group having the lowest mortality and recurrence. Propensity score matching was performed for each group. The primary outcomes were disease-free survival (DFS) and overall survival (OS). Results: During the study period, 98,556 patients underwent surgery for gastric cancer. After excluding ineligible participants, 6,602 patients were included in the analysis. The median DFS and OS did not differ significantly between the early and reference groups ( p=0.7258 and p=0.6056, respectively). In comparison between the late and reference groups, the median DFS was significantly lower in the late group ( p=0.0079). 5-year DFS were 77.6% and 81.3% in the late and reference groups, respectively. Furthermore, the late group showed worse OS than the reference group ( p=0.0336). OS at 5-year were 82.1% and 85.0% in the late and reference groups, respectively. In the multivariable analysis, DFS in the late group retained inferiority (aHR 1.138, 95% CI: 1.003-1.292, p=0.045). OS showed a worse trend without significance compared to the reference group (aHR 1.138, 95% CI: 0.984-1.317, p=0.0805). Conclusions: Adjuvant chemotherapy after gastrectomy in patients with gastric cancer should be initiated within five weeks of surgery. A delay of more than five weeks may have a detrimental effect on the subsequent disease course.
Identification of somatic alterations associated with brain metastases from a colorectal origin.
Authors: James S. Strong, Harrison M. Drebin, Henry S. Walch, Chengcheng Gui, Luke Roy George Pike, Nelson S. Moss, Francisco Sanchez-Vega, Jesse Joshua Smith
Journal: Journal of Clinical Oncology (2024)

210 Background: Colorectal brain metastases (cBM) confer a devastating prognosis with survival of less than 13 months. Identifying genomic signatures to predict and guide treatment for these patients would be a valuable adjunct. This study evaluated genomic and clinicopathological features specific to cBM. Methods: cBM patients from the MSK-MET cohort were evaluated in comparison to other colorectal cancer patients with extracranial metastases (cOM). Clinicopathologic features and genomic alterations were analyzed with MSK-IMPACT, a targeted DNA sequencing panel for solid tumors and matched blood specimens. We considered mutations, copy number alterations, and fusions. Analyses of genomic features were restricted to microsatellite stable (MSS) patients. q-values were computed using Benjamini-Hochberg correction to account for multiple hypothesis testing. Patient record review identified patients with sequenced matched samples from the primary colorectal tumor and the brain metastases, which were then examined for loss and gain of assessed genetic alterations. Results: Of 130 patients with cBM identified from the cohort, 20 samples were from brain metastases, 52 from the primary CRC, and 58 from other metastatic sites. Average time to diagnosis of cBM was 3.5 years after primary colorectal cancer diagnosis and average time to death was 10 months after cBM diagnosis. Compared to the 3,383 cOM patients, cBM patients had significantly higher rates of both MSS CRC primaries (p&lt;0.001, 122/130 cBM were MSS vs. 3,038/3,382 cOM) and primaries that originated in the rectum (p&lt;0.002, with 38/130 cBM primaries from the rectum vs. 695/3,382 cOM rectal primaries). Somatic alterations in the KRAS, BRCA2, CDK8 and ERCC5 genes were significantly more frequent in patients with cBM compared to cOM patients (all p&lt;0.001) (Table 1). Of the 9 patients who had matched primary and metastatic brain tissue sequenced, KRAS alterations were shared between the primary and brain metastasis in 2/9, ERBB3 and ERCC5 in 2/9, p53 in 6/9, and APC in 6/9 patients. In addition, newly acquired private alterations found only in the brain metastasis samples of matched patients included PIK3RI, ARID5B, NOTCH4, CYLD and SMAD4. Conclusions: We identify new genomic and clinical factors in cBM patients, including somatic alterations in potentially clinically actionable targets. To further explore potential clinical utility, these findings require validation in an independent cBM clinicogenomic dataset.[Table: see text]
FusionVAC22_01: A phase I clinical trial evaluating a DNAJB1-PRKACA fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion.
Authors: Michael Bitzer, Christopher Hackenbruch, Jens Bauer, Jonas S. Heitmann, Yacine Maringer, Annika Nelde, Helmut R. Salih, Juliane S. Walz
Journal: Journal of Clinical Oncology (2024)

TPS580 Background: The DNAJB1-PRKACA fusion transcript is the driver of tumor pathogenesis in fibrolamellar hepatocellular carcinoma (FL-HCC) as well as in other tumor entities, e.g. oncocytic neoplasms of the pancreas and bile duct, thus representing a broad target for novel therapies in cancer. Recently, the DNAJB1-PRKACA fusion protein was identified as a source for HLA-presented neoepitopes that can be targeted by T-cell-based immunotherapy (Bauer et al. Nat. Commun., 2022). The DNAJB1-PRKACA fusion-derived neoepitope FusionVAC-22 is in silico predicted to bind to 1,290 HLA class II alleles and contains HLA class I ligands from 13 of the 20 most frequent HLA class I alleles that cover 93.8% of the world population with at least one HLA allotype, enabling the broad application of FusionVAC-22-based immunotherapies. The first application of FusionVAC-22-based peptide vaccines adjuvanted with the TLR1/2 agonist XS15 emulsified in Montanide ISA 51 VG in two FL-HCC patients was well tolerated and showed the induction of profound and long-lasting T-cell responses. Of note, T-cell responses were accompanied by progression-free survival of both patients for so far 32 months and 13 months, respectively. Methods: Based on these encouraging results, we established a Phase I open-label, multicentric clinical trial to evaluate the immunogenicity along with safety and toxicity, as well as first signs of efficacy of the FusionVAC-22 based peptide vaccine, combined with the immune checkpoint inhibitor (ICI) atezolizumab, in 20 patients with locally advanced or metastatic FL-HCC or other malignant diseases that carry the DNAJB1-PRKACA fusion transcript. Further, key eligibility criteria include the absence of autoimmune phenomena due to prior immunotherapy agents (≥ grade 3) as well as tissue or organ allografts. The FusionVAC-22-based peptide vaccine is applied twice in a 4-weekly interval with the opportunity of a booster vaccination after 11 months. Atezolizumab application starts on day 15 after first vaccination and is continued 4-weekly for 1 year, followed by a 6-month follow-up. The primary objectives of the trial are immunogenicity, in terms of induction of peptide specific T-cell responses until 28 days after second vaccination, as well as safety and toxicity of the peptide vaccine in combination with ICI. Safety assessment is based on the frequency of adverse events according to CTCAE v5.0. Clinical efficacy is determined by iRECIST assessment on imaging. Furthermore, disease control rate, quality of life as well as overall and progression free survival will be assessed. Clinical trial information: NCT05937295 .
Repeat peptide receptor radionuclide therapy in neuroendocrine neoplasms: A NET Center of Excellence experience.
Authors: Udhayvir Singh Grewal, Alexander Paschke, Joseph S. Dillon, Chandrikha Chandrasekharan
Journal: Journal of Clinical Oncology (2024)

590 Background: Lu177 DOTATATE Peptide Receptor Radionucleotide Therapy (PRRT) was FDA approved in the United States in 2018 however this treatment modality has been widely available in European nations since early 2000s. Therefore, the data for the safety and efficacy of repeat PRRT are almost exclusively from European centers. We present a real-world experience with repeat PRRT in a cohort of US patients. Methods: We used our single-center longitudinal IRB approved neuroendocrine tumor (NET) registry to identify patients who had been previously treated with at least 1 dose of PRRT (PRRT 1, either Lu 177 DOTATATE or Y90 DOTATOC) and following disease progression were retreated with a second course of PRRT (PRRT 2). Patients who received alpha PRRT were not included. We reviewed patient, tumor and treatment characteristics, time to progression after PRRT 1 and PRRT 2 and toxicity. Results: A total of 153 patients received at least 1 dose of Lu-177 DOTATATE PRRT at our institution post FDA approval, out of which, 13/153 (8.5%) patients received repeat PRRT .2/13 patients were excluded due to lack of adequate follow up. All patients included were white (11/11, 100%). Median age of the participants was 65 years (IQR 63, 67) and 54.5% (6/11) patients were females. Most patients had grade 2 (9/11,81.8%) followed by grade 1 NET (2/11, 18.2%) and all except one patient included had a gastroenteropancreatic origin NET (10,11, 90.9%). 45.5% (5/11) patients received Lu-177 DOTATATE PRRT only both for PRRT1 and PRRT 2, while 54.5% (6/11) patients received Y90 DOTATOC PRRT for PRRT1. Median number of lines therapies before PRRT1 and PRRT were 2 (IQR 2,5) and 1 (IQR 1,2) respectively. Patients received a median of 3 (IQR 2, 4) and 3 (IQR 1,4) cycles for PRRT1 and PRRT2 respectively. At first restaging scan after PRRT1 (3-6 months), 54.5% and 45.5% patients had partial response (PR) and stable disease (SD) respectively. At first restaging scan after PRRT2 (3-6 months), 45.5%, 27.3% and 9.1% patients had SD, progressive disease (PD) and PR respectively; 2/11 patients (18.2%) died before first restaging scan. Median PFS for PRRT1 (n=11) was 22.5 months (IQR 12.7, 30.7). Median PFS (n=5) for PRRT2 was 10.9 months (IQR 10.05, 25.7). PFS was not reached for 1 patient after PRRT2. 1 (9.1%) patient each developed grade 2 nephrotoxicity and grade 3 thrombocytopenia after PRRT2. Conclusions: To our knowledge, this is the first of its kind analysis describing the safety and effectiveness of repeat PRRT in a US cohort. We show that repeat PRRT may benefit select patients and has an acceptable safety profile. Larger prospective clinical studies are required to identify patient groups that are more likely to benefit from repeat PRRT.
A multi-centre review of the efficacy of re-challenge with platinum doublet in patients with oesophagogastric cancer treated with first-line trastuzumab and chemotherapy.
Authors: Jamie Weaver, Rufqah Ali, Marie Mckay, Victoria Foy, Adeel Khan, Aimee Cunningham, Esther McQueenie, Vikki Owen-Holt, Kate Williams, Sara Valpione, Richard Hubner, Tom Waddell, Alia Alchawaf, Wasat Mansoor
Journal: Journal of Clinical Oncology (2024)

367 Background: HER2 amplification or overexpression is seen in 15-20% of metastatic oesophagogastric cancers. The ToGA trial showed an OS benefit for the use trastuzumab with platinum and fluoropyrimidine combination therapy (T-FP) in the first line setting. Second line trials of targeted agents have been disappointing with poor response rates and the current standard of care is paclitaxel and ramucirumab in combination. A recent phase 2 trial showed no OS benefit to continuing trastuzumab with second line chemotherapy but data regarding the efficacy of treatment beyond progression with re-introduction of first line chemotherapy (platinum and fluoropyrimidine) is limited and conflicting. Methods: We conducted a multi-centre retrospective review of patients treated with T-FP in the first-line setting between October 2014 and October 2022 at two large tertiary referral oncology centres in the United Kingdom. Baseline demographic factors and clinical data were collected and compared between responders and non-responders to re-challenge. PFS and OS were estimated using the Kaplan-Meier method. Results: Data was collected for 225 patients in total treated with first-line trastuzumab. We identified 20 patients who had received a re-challenge with FP-T. Best response to first-line treatment was partial response (PR) for 19/20 patients with 1/20 patients with stable disease (SD). There were no differences between baseline demographic factors or tumour pathological features between patients receiving a re-challenge and those treated with chemotherapy alone. The median platinum free interval was 17.8 months. For the re-challenge disease control rate was 75% with an overall response rate of 35% (7 PR, 0 CR). The median number of subsequent trastuzumab cycles was 7, with a median PFS of 6.1 months and median OS of 10 month. Multivariate Cox-regression analysis identified no factors predictive of response in the re-challenge setting. Conclusions: Re-challenge with trastuzumab plus FP chemotherapy is a possible option for patients with relapse. Larger studies will be required to identify predictive biomarkers to identify those patients most likely to benefit. The role of re-assessment of HER2 status at relapse in those receiving re-challenges requires prospective analysis.
Evaluating the safety and efficacy of the addition of liver radiation (RT) to atezolizumab and bevacizumab (A/B) in advanced hepatocellular carcinoma (HCC): A retrospective cohort analysis.
Authors: Timothy J. Brown, Uri Amit, Edgar Ben-Josef, Thomas Benjamin Karasic
Journal: Journal of Clinical Oncology (2024)

481 Background: Recently, the addition of stereotactic body RT to sorafenib in patients (pts) with advanced HCC demonstrated improved overall survival. However, A/B is the current standard of care for pts with advanced HCC based on IMBrave150. For these pts, RT may potentiate the antitumor immune response of A/B but carries the risk of bowel toxicity and impaired liver function. To date, there are limited data regarding safety and outcomes with the addition of liver RT to A/B in pts with advanced HCC. Here, we describe our single-center experience of adding RT to A/B for pts with advanced HCC. Methods: This single-center retrospective cohort study was conducted at the University of Pennsylvania. We identified all pts with HCC naïve to systemic therapy who received infusions of A/B and those who received RT to the liver within 30 days of starting A/B until discontinuation from 1/1/2020 until 2/2/2023. We assessed the real-world response rate (rwRR) determined from clinician impression after initiating A/B, safety outcomes, overall survival (OS), and time-to-progression (TTP) from initiation of A/B. Time-to-event outcomes were analyzed by the Kaplan-Meier method with log-rank test and Cox proportional hazards modeling. Results: We identified 49 pts (n=34 control, n=15 RT) with advanced HCC receiving first-line A/B. Those who received RT were more likely to have alcoholic liver disease (p=0.013) and were less likely to have ascites (p=0.04) but were otherwise balanced regarding demographics, prior locoregional therapies, presence of macrovascular invasion and extrahepatic spread, and baseline laboratories. The median RT dose was 63 Gy. The rwRR in the RT group was 73.3% (11/15) compared to 17.6% (6/34) in the control group (Risk Ratio (RR) 3.9, 95% CI 1.7-8.6, p&lt;0.001). Two pts in the control group (5.8%) and one patient in the RT group (6.7%) experienced clinically significant bleeding (RR=1.1 95% CI 0.1-11.6). In the RT group, three pts (20%) developed worsening liver dysfunction after completing RT, concerning for possible radiation-induced liver disease. Six pts in the control group and one patient in the RT group developed immune-related adverse events leading to discontinuation of A/B. The median OS in the RT group was 14.4 mos and 10.8 mos in the control group (Hazard Ratio (HR) death 0.49 (95% CI 0.20-1.22, p=0.12)). Median TTP was 6.4 months (mos) with RT compared to 5.8 mos in the control group (HR progression 0.72 (95%CI 0.35-1.46, p=0.36. Conclusions: In our retrospective cohort, the addition of liver RT to standard A/B resulted in increased responses and a non-significant improvement in outcomes without an increased risk of bleeding. An assessment of changes in liver dysfunction by Child-Pugh and ALBI score is ongoing. Overall, these data support prospective trials to evaluate the addition of RT to A/B.
Evaluation of the efficacy and safety of a 3-weekly TS-1 regimen as adjuvant therapy for stage II and III advanced gastric cancer: A pilot study.
Authors: Jihong Bae, Sun Jin Sym, Joo-Hwan Park, Young Saing Kim, Hee Kyung Ahn, EUN KYUNG CHO, Dong Bok Shin, Ji-Hyeon Park, Jun-Young Yang, Woon-Kee Lee
Journal: Journal of Clinical Oncology (2024)

350 Background: Adjuvant therapy for stage II and III advanced gastric cancer (AGC) is essential in improving patient outcomes. The standard therapy, TS-1 at 80 mg/m 2 /day for 4 weeks with a 2-week rest, is recommended for 1 year or 8 courses. This study investigates the efficacy and safety of a 3-weekly adjuvant TS-1 regimen in AGC patients. Methods: We conducted an analysis of 93 patients who underwent gastrectomy with D2 lymphadenectomy and initiated a 3-weekly adjuvant TS-1 regimen between February 2017 and May 2022. The novel regimen consisted of TS-1 at 80 mg/m2/day for 2 weeks, followed by a 1-week rest, with a treatment goal of 1 year or 16 courses. Results: Among the 93 patients, 12 (13%) experienced disease recurrence during a median follow-up of 24.6 months (range: 4.2 to 63.3 months). Of the Stage II patients (n=73), 7 cases (9.5%) had recurrent disease, while 5 cases (25%) in the Stage III group (n=20) experienced recurrence. Recurrence-Free Survival (RFS) rates at 1 year, 3 years, and 5 years were 92.0% (95%CI 86.5 to 97.9), 84.7% (95%CI,76.4% to 93.9%), and 78.6% (95%CI, 65.8% to 94.0%), respectively. A total of 80 patients (86%) completed the adjuvant 3-weekly TS-1 treatment for 1 year or 16 courses, while 25 patients (26.9%) completed the treatment with dose reductions. Adverse events, primarily Grade 1 or 2 diarrhea (28%) and nausea (20%), were manageable. Conclusions: The novel 3-weekly TS-1 regimen as adjuvant therapy exhibited favorable efficacy and tolerable toxicity in AGC patients. These findings suggest the need for further investigation of this regimen in future clinical studies.
Efficacy and safety of a combination of sintilimab, bevacizumab plus gemcitabine, and albumin-bound paclitaxel for initially unresectable gallbladder carcinoma: A prospective, single-arm phase II study.
Authors: Miao Wang, Jiamin Zhou, Weiqi Xu, Qi Pan, Anrong Mao, Ning Zhang, Yun Feng, Xigan He, Zhenhai Lin, Longrong Wang, Yongfa Zhang, Hongxu Zhu, Zhiwe Ding, Yixiu Wang, Bingran Yu, Ti Zhang, Lu Wang
Journal: Journal of Clinical Oncology (2024)

489 Background: Immune checkpoint inhibitors plus chemotherapy had demonstrated important therapeutic advantages in biliary tract cancers (TOP-AZ and Keynote-966). At present the data of gallbladder carcinoma (GBC) is in blank condition almost, and the effectiveness remains to be improved. Further, the addition of bevacizumab to PD-1 inhibitors has improved the clinical results in carcinomas, such as hepatocellular carcinoma, for which therapeutic options have been limited. This study intended to explore the safety and efficacy of sintilimab combined bevacizumab with chemotherapy in the first-line treatment of initially unresectable GBC. Methods: The study was an ongoing open-label, single-arm, phase II trial (Clinical Trial ID: NCT05757336), which consisted of 2 parts: safety-run-in part, where pts received sintilimab (200mg/kg, iv, d1, Q3W) + bevacizumab (7.5mg/kg, iv, d1, Q3W) + gemcitabine (1000mg/m2, iv, d1, Q3W) and albumin-bound paclitaxel (125mg/m2, iv, d1, Q3W), followed by experimental part to evaluate the efficacy and safety of this strategy. The primary endpoint was safety and objective response rate (ORR) assessed by RECIST v1.1. Secondary objectives included disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results: No DLT was reported at safety-run-in part. Up to the end of Sept 2023, 15 patients were enrolled with a median age of 60.4 years (range 46-75), 26.7% were male. Median follow-up time was 3.68 months. All patients completed at least one tumor response evaluation, confirmed ORR was 60.0% and DCR was 93.3%. Median PFS and OS was not reached yet. Grade 3 TRAEs occurred in 40.0% of patients (n=6), and the most common TRAEs (incidence≥5%) among them were rash (20.0%), AST elevation (6.7%), fever (6.7%), platelet count decreased (6.7%), fatigue (6.7%), pneumonitis (6.7%). Conclusions: The combination of sintilimab, bevacizumab and AG chemotherapy was tolerable and showed a promising ORR in initially unresectable GBC patients. This regimen could be a feasible and safe option for initially unresectable GBC, but this needs further validation. Clinical trial information: NCT05757336 .