bluuebunny/crossref_metadata_2025 huggingface dataset:
A prospective evaluation of pelvic radiation vs. no radiation among patients with young-onset rectal cancer: Impact on patient-reported outcomes.
Authors: Corrigan Kelsey L , Holliday Emma , Guraieb-Trueba Montserrat , Peacock Oliver , Skibber John Michael , Bednarski Brian K. , Messick Craig , Tillman Matthew Murray , Johnson Benny , Smith Grace L. , Nguyen Sa Thi , Kundu Suprateek , Reinhardt Alec , Chang George J. , Das Prajnan , You Y. Nancy
Published: June 2023

3618

Background: The rise in young-onset rectal cancer (YORC) calls for better understanding of the long-term impact of radiation therapy(RT) on gastrointestinal(GI) toxicity and pelvic organ function. We aimed to prospectively capture the longitudinal trajectories of patient-reported outcomes(PROs) in YORC patients who received RT vs. no RT and to identify factors associated with unfavorable PROs. Methods: We prospectively enrolled 120 YORC patients undergoing curative-intent treatment. The validated EORTC QLQ-CR29 was self-administered at time intervals grouped as: 0-11 months, 12-23 months, and 24+ months post-resection. Responses were stratified by receipt of neoadjuvant RT (yes vs. no). The longitudinal change in PROs was described by a linear mixed effects model. Multivariate linear regression was used to determine the impact of treatment factors on long-term PROs. Results: The median age at diagnosis was 44. The majority (N = 92, 77%) presented with cT3,4/N+ disease. Preoperative therapy included: no RT (N = 38, 32%; 8 [7%] who received chemotherapy alone, and 30 [25%] who received no neoadjuvant therapy), vs. RT (N = 82, 68%; where 59 [72%] also received concurrent capecitabine). More patients in the RT group had advanced T stage (3 or 4; 94% vs. 56%, P< 0.001), distal tumor (median 7 vs. 12.5 cm from the anal verge, P< 0.01), and underwent abdominal perineal resection (19 vs. 0%, P< 0.001). After a median follow-up of 70 months, all were alive: 103 (86%) were disease-free, 9 (8%) had recurrence with successful salvage, and 8 (7%) had disease progression. In the RT group, sore skin improved at 12-23 and 24+ months (Estimate [ B]: -16.5, P= 0.03 and B: -14.4, P= 0.03), dyspareunia improved at 12-23 months ( B: -31.8, P< 0.01), and blood/mucus in stool improved at 24+ months ( B: -8.01, P< 0.01) vs. 0-11 months. At 24+ months, RT receipt was associated with worse stool frequency ( B: 26.4, P< 0.01), urinary frequency ( B: 18.4, P= 0.04), and flatulence ( B: 23.0, P= 0.02). Conclusions: YORC often require multimodality therapy including RT. Sore skin, dyspareunia, and blood/mucus in stool improved, but flatulence and frequency can persist beyond 2 years post RT. Proactive counseling and supportive measures are needed to inform treatment choices and mitigate long-term impact. [Table: see text]
Comparison of synchronous neoplasms at colonoscopic diagnosis of early-onset versus average-onset colorectal cancer.
Authors: Emiloju Oluwadunni Eunice , Saberzadeh Ardestani Bahar , Sinicrope Frank A.
Published: June 2023

3623

Background: Colorectal cancer (CRC) incidence has steadily increased in adults younger than 50 years (EO-CRC) since the 1990s, with a predominance in the left colon and rectum. Precursor lesions of CRCs are adenomas, including advanced adenomas, and sessile serrated polyps. Given that neoplastic development is age-related, we hypothesized that patients with early-onset CRC (EO-CRC) may have fewer adenomas compared to patients with average-onset CRC (AO-CRC) at diagnosis. Methods: We performed a retrospective review of electronic health records at Mayo Clinic or Mayo Health System [2012 to 2021] and randomly selected 150 patients with EO-CRC who met eligibility criteria and matched them with 150 AO-CRC patients based on gender and colonoscopy indication. Known hereditary syndromes or inflammatory bowel disease were excluded. At colonoscopy where CRC was diagnosed, we recorded findings of adenomas, advanced adenomas (> 1 cm, villous histology, or high-grade dysplasia), and sessile serrated polyps (SSP). Results: Median age at diagnosis was 43 years for EO-CRC and 67 years for AO-CRC. No significant differences in BMI, family history of CRC, MMR, BRAFV 600E KRAS status or SSPs were found between groups (all p > 0.05). Among patients with colon cancer, no difference was found for adenoma number yet patients with EO-colon cancer (EO-CC) had larger polyps [median of 10 mm vs 5 mm, p = 0.001] (Table) compared with AO-colon cancer (AO-CC). At least 1 adenoma was found in 56% and 47% of patients with EO-CC and AO-CC, respectively. Moreover, advanced adenomas were significantly more common in the EO-CC group compared with the AO-CC group (42% and 14%, p < 0.001) [ Table]. Among patients with rectal cancer, non-advanced adenomas were less frequent and although advanced adenoma were similar in frequency, they were more commonly located in the rectum in EO-rectal compared to AO-rectal cancers (Table). Conclusions: Patients with EO-colon cancer had a significantly higher likelihood of a synchronous advanced adenoma in the colon compared to those with AO-CRC. Together, these data suggest accelerated carcinogenesis throughout the colorectum in early onset patients, with increased risk for development of synchronous and metachronous CRC. [Table: see text]
Outcomes by occurrence of immune-mediated adverse events (imAEs) with tremelimumab (T) plus durvalumab (D) in the phase 3 HIMALAYA study in unresectable hepatocellular carcinoma (uHCC).
Authors: Lau George , Cheng Ann-Lii , Sangro Bruno , Kudo Masatoshi , Kelley Robin Kate , Tak Won Young , Gasbarrini Antonio , Reig Maria , Lim Ho Yeong , Tougeron David , De Toni Enrico N. , Tam Vincent C. , Mody Kabir , Gong Jun , McCoy Carrie L. , Gupta Charu , Makowsky Mallory , Negro Alejandra , Abou-Alfa Ghassan K.
Published: June 2023

4004

Background: Immune checkpoint inhibitor (ICI) studies have shown an association between the occurrence of imAEs and outcomes. In the Phase 3 HIMALAYA study (NCT03298451) in uHCC, STRIDE (Single T Regular Interval D) significantly improved overall survival (OS) vs sorafenib (S), and D monotherapy was noninferior to S. STRIDE and D had manageable safety (Abou-Alfa et al. NEJM Evid 2022). STRIDE is approved for uHCC in the United States and Japan and recommended for approval by the European Medicines Agency; D is approved in Japan. This exploratory analysis assessed the association between imAEs and outcomes in HIMALAYA. Methods: Safety was assessed in participants (pts) who received ≥1 dose of STRIDE (T 300 mg [one dose] plus D 1500 mg once every 4 weeks [Q4W]) or D (1500 mg Q4W). imAEs were AEs of special interest associated with drug exposure and consistent with an immune-mediated mechanism of action with no found alternate etiology. Median OS (mOS) and OS rates were estimated using the Kaplan–Meier method. OS hazard ratios (HRs) and 95% CIs were calculated using Cox modeling, with imAEs as a time-varying covariate and stratified by etiology (HBV/HCV/others), ECOG (0/1), and macro-vascular invasion (yes/no) for pts with vs without imAEs of any grade. Pts with >1 imAE were counted once. Results: In total, 388 pts (STRIDE) and 388 pts (D) were included in the analysis. Any grade imAEs, Grade 3 or 4 imAEs, and imAEs leading to discontinuation occurred in 139 (35.8%), 49 (12.6%), and 22 (5.7%) pts, respectively for STRIDE and 64 (16.5%), 25 (6.4%), and 10 (2.6%) pts, respectively for D. imAEs requiring high-dose steroids (≥40 mg prednisone or equivalent daily) occurred in 78 (20.1%) pts for STRIDE and 37 (9.5%) pts for D. An improvement in OS was seen with STRIDE in pts with imAEs vs pts without (HR, 0.73; 95% CI, 0.56–0.95). OS rates at 6, 12, and 24 months (mo) were higher for STRIDE in pts with imAEs vs pts without. The association between imAEs and OS was less clear for D and may be limited by small pt number. In a landmark analysis of pts with vs without imAEs within 6 mo of STRIDE (n=307) or D (n=287), OS HRs (95% CIs) were 0.65 (0.47–0.90) and 1.39 (0.95–2.04), respectively. Conclusions: In HIMALAYA, imAEs with STRIDE or D were manageable and generally low grade. In this exploratory analysis, the occurrence of imAEs was associated with improved OS for STRIDE, generally consistent with findings for other ICIs. Clinical trial information: NCT03298451 . [Table: see text]
A phase 2 randomized, open-label, multicentre study of sintilimab and anlotinib in combination with gemcitabine plus cisplatin (GemCis) as first-line therapy in patients (pts) with advanced biliary tract cancer (BTC): SAGC.
Authors: Jingjing Li , Xu Qi , Xu Xiaoqing , Cong Luo , Ying Jieer
Published: June 2023

4015

Background: BTC has a higher incidence in China rather than worldwide, with extremely poor prognosis, and the efficacy of standard first-line therapy is rather limited. TOPAZ-1 study suggested the immune check-point inhibitor plus chemotherapy as first line in advanced BTC significantly improved OS and PFS with manageable safety, but the median OS was just 12.8 months. SAGC is the first randomized controlled phase 2 trial to evaluate immune check-point inhibitor plus antiangiogenic targeted drug plus chemotherapy in advanced BTC as first-line treatment. Methods: Overall 80 advanced BTC were randomized 1:1 to receive sintilimab (200mg every 3 weeks [Q3W]) and anlotinib (10mg po qd, Days 1-14 Q3W) in combination with GemCis (Gem 1000 mg/m2 and Cis 25 mg/m2 on Days 1 and 8 Q3W) for up to 8 cycles, followed by sintilimab (200mg every 3 weeks [Q3W]) and anlotinib (10mg po qd, Days 1-14 Q3W) (SAGC group) or GemCis (Gem 1000 mg/m2 and Cis 25 mg/m2 on Days 1 and 8 Q3W) for up to 8 cycles until disease progression or unacceptable toxicity (GC group). The primary objective was to assess the progression-free survival (PFS). Secondary endpoints included, objective response rate (ORR), overall survival (OS) and safety. Next generation sequencing (NGS) was performed on pre-treatment available tumor tissue in 58 patients to screen dominant patients of the therapy. Results: At the time of the final data cutoff (Sep. 22,2022), median follow-up was 13.4 mo, and 65/80 pts (81.3%) had discontinued tx. The confirmed median PFS was 8.6 months for SAGC group vs. 6.2 months for GC group (HR 0·37, p < 0.01) and ORR was 52.8% for SAGC group vs. 29.4% for GC group. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 77.5% of pts receiving sintilimab plus anlotinib plus GemCis and 40% of pts receiving GemCis. The results from NGS suggested that patients with TMB-H and ARID1A-WT may benefit more from combination therapy. Conclusions: In pts with advanced BTC, sintilimab plus anlotinib plus GemCis significantly improved PFS and ORR vs GemCis with manageable safety, indicating sintilimab plus anlotinib plus GemCis may be a new first-line standard of care regimen. Clinical trial information: NCT04300959 .
A multicenter, open-label, randomized phase II study evaluating adjuvant gemcitabine plus cisplatin (GC) and capecitabine with concurrent capecitabine radiotherapy (CAPE-RT) in patients with operated gallbladder adenocarcinoma (GBC): The GECCOR-GB trial.
Authors: Ramaswamy Anant , Ostwal Vikas S. , Engineer Reena , Parulekar Manali , Mandavkar Sarika , Aier Nanda , Bhargava Prabhat Ghanshyam , Srinivas Sujay , Patkar Shraddha , KRISHNATRY RAHUL , Gudi Shivakumar , Kapoor Akhil , Pandey Durgatosh , Patel Swapnil , Shinghal Abhishek , Goel Alok , Dora Tapas Kumar , Chaudhary Debashish , Ankathi Suman Kumar , Goel Mahesh
Published: June 2023

4017

Background: Adjuvant gemcitabine plus cisplatin (GC) and concurrent chemo-radiotherapy are commonly used treatment options for resected GBC. Methods: GB-GECCOR is a multicentre, open-label randomized non-comparative phase II study in patients of Gallbladder cancer (GBC), with R0 or R1 resection within 3 months of randomization. Patients were randomized 1:1 to GC arm (Gem 1000 mg/m2 and Cisplatin 25mg/m2 on day 1 and 8, q 3 weeks) for 6 cycles or CAPE-RT arm {Capecitabine 1000mg/m2 BD on days 1-14, q 3 weeks for 2-4 cycles followed by chemoradiation (RT: 45 Gy over 25 fractions concurrent with capecitabine: 825mg/m2 twice) followed by 2-4 cycles of capecitabine for a total of 6 cycles}. The primary end point was 1-year disease-free survival (DFS). With 80% power to detect the difference between a 59% (minimum sufficient activity of the regimen) and a 77% (sufficient activity for future larger studies with the regimen) 1-year DFS rate assuming an attrition of 10%, a total of 90 patients were required for the study. Results: Between May 2019 and February 2022, 90 patients (45 in each arm), were included. Stage II and stage III GBC were seen in 50 (56%) and 40 patients (44%) respectively, with R0 resection observed in 86 patients (96%). Patient characteristics were well balanced between the 2 arms except for R1 resections which were greater in the CAPE-RT arm (p=0.041). With a median follow-up duration of 23 months, the 1-year DFS rate was 88.9% (95% CI: 79.5-98.3) in the GC group and 77.8% (95% CI: 65.4 – 90.2) in the CAPE-RT group, respectively. The most common AEs were grade 3/4 neutropenia in 6 patients (13.3%) in the GC group and grade 2/3 HFS in 14 patients (31.1.%) in the CAPE-RT group. The distant metastases were seen in 12 patients (26.6 %) in each arm and loco-regional metastases in 3 patients (6.6 %) in the GC arm. Conclusions: In this study of operated GBC, GC and CAPE-RT successfully achieved the minimum pre-specified DFS rates. Within the confines of a non-comparative randomised study, GC had narrowed the gap in survivals of stage III vs. stage II GBCs, which was not noted in the CAPE-RT arm. This study results give credence to the use of both regimens as reasonable standards of care till evaluation in larger phase 3 studies. Clinical trial information: CTRI/2019/05/019323 . [Table: see text]
FOOTPATH: A randomized, open-label phase-2 study of liposomal irinotecan + 5-FU and folinic acid (NAPOLI) versus sequential NAPOLI and mFOLFOX6 versus gemcitabine/nab-paclitaxel in treatment-naïve metastatic pancreatic cancer (mPDAC).
Authors: Westphalen Benedikt , Gaska Tobias , Reichert Maximilian , Quante Michael , Oettle Helmut , Waldschmidt Dirk Thomas , Schlenska-Lange Anke , Angermeier Stefan , Fischer von Weikersthal Ludwig , Bohle Wolfram , Vehling-Kaiser Ursula , Stahler Arndt , Kanzler Stephan , Lamberti Christof , Pelzer Uwe , Sinn Marianne , Blau Wolfgang , Boeck Stefan Hubert , Held Swantje , Heinemann Volker
Published: June 2023

4021

Background: The optimal first-line regimen in the treatment of mPDAC remains unknown. Recent data demonstrated superiority of 5-FU/liposomal irinotecan/oxaliplatin (NALIRIFOX) over gemcitabine/nab-paclitaxel. However, the question remains open if both irinotecan and oxaliplatin are required in first-line treatment and whether these agents can be given sequentially. Methods: Eligible patients with histologically confirmed diagnosis of mPDAC were randomized 1:1:1 to receive in Arm A standard treatment (gemcitabine 1000 mg/m2 + nab-paclitaxel 125 mg/m2) or investigational therapy applying in Arm B the NAPOLI regimen (liposomal irinotecan 80 mg/m2 + folinic acid 400 mg/m2 + 5-FU 2400 mg/m2) or in Arm C a sequence of NAPOLI and mFOLFOX6 (oxaliplatin 85mg/m2 + folinic acid 400mg/m2 + 5-FU 2400 mg/m2). Overall, 274 patients were enrolled at 48 sites in Germany. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate, disease control rate, duration of study treatment and safety. Results: In the full analysis set (n=265), neither treatment with NAPOLI (3.1 months, HR 1.224, p= 0.2123) nor the sequence of NAPOLI and mFOLFOX6 (6.0 months, HR 0.864 p= 0.0720) lead to a statistically significant improvement of PFS over gemcitabine/nab-paclitaxel (4.3 months). Median duration of treatment was 3.5 months in Arm A, 2.0 months in Arm B and 3.7 months in Arm C, respectively. In a first analysis of overall survival, OS in Arm A was 8.7 months (95% CI, 7.1-11.9 months) versus 7.9 months in Arm B (95% CI, 6.6-12.3 months; HR 1.178, P= 0.348) and 11.0 months in Arm C (95% CI, 8.4-13.6 months; HR 0.879, P=0.154). Overall, safety was comparable with published data, with higher rates of neutropenia and peripheral neuropathy in Arm A, while diarrhea was more frequent in Arms B and C. Conclusions: The study did not show superiority of either NAPOLI or the sequence of NAPOLI/mFOLFOX6 over standard therapy with gemcitabine/nab-paclitaxel. In view of the published evidence, the present data supports the hypothesis that sequential NAPOLI/mFOLFOX6 may be equally effective with regard to OS, but less toxic, compared to mFOLFIRINOX. Clinical trial information: NCT03487016 . [Table: see text]
Survival analysis by tumor response of nivolumab treatment in previously treated advanced gastric cancer from the DELIVER trial (JACCRO GC-08).
Authors: Sunakawa Yu , Sakamoto Yasuhiro , Kawabata Ryohei , Ishiguro Atsushi , Akamaru Yusuke , Kito Yosuke , Takahashi Masazumi , Matsuyama Jin , Yabusaki Hiroshi , Makiyama Akitaka , Suzuki Takahisa , Tsuda Masahiro , Yasui Hisateru , Hihara Jun , Takeno Atsushi , Inoue Eisuke , Ichikawa Wataru , Fujii Masashi
Published: June 2023

4039

Background: We conducted a prospective observational study, DELIVER trial (UMIN000030850), to evaluate the real-world effectiveness of nivolumab monotherapy in previously treated advanced gastric cancer (GC) and have reported comparable efficacy and safety data (Takahashi, et al. Gastric Cancer 2021). There are few evidence regarding the association between tumor response and survival time in later-line treatment with nivolumab alone for advanced GC. We therefore report results from post-hoc exploratory analyses of survival time by tumor response from the DELIVER trial. Methods: The DELIVER trial enrolled 501 patients (pts) with advanced gastric or GEJ adenocarcinoma treated with nivolumab alone. Primary endpoint was overall survival (OS), secondary endpoints were response rate (RR), disease control rate, progression-free survival (PFS), tumor regression rate / tumor progression rate at 1st evaluation, tumor growth rate, and safety. The exploratory analyses were performed for survival according to tumor response and depth of response (DpR) in pts with measurable lesions who were receiving nivolumab as 3rd or later-line treatment. The survival data was fixed at the timepoint of 2 years after the last enrollment. Results: 234 pts were evaluable (median age 70y [26-90], 79% male, ECOG PS0/1/2 46/43/11%, 32% pts with ascites). Median OS was 6.5 months (95%CI 5.3-8.2) and median PFS was 1.8 months (95%CI 1.6-2.0). The RR was 15.0% (95%CI 10.4-19.5) with 5 complete response (CR) and 30 partial response (PR). The median PFS and OS were not reached for pts with CR, 11.7 and 29.8 months for pts with PR, 3.8 and 11.4 months for pts with stable disease, and 1.5 and 4.2 months for pts with progressive disease, respectively. In addition, the median DpR was -14.1% and was associated with PFS and OS in the Spearman analysis (r=0.55 and r=0.44, respectively). When the DpR was divided into 5 groups according to tumor shrinkage, there was difference in PFS and OS. Conclusions: This exploratory analysis indicated the association between DpR and survival time in pts with advanced GC treated with nivolumab alone in later-line. Increasing DpR was associated with longer median PFS and OS. Clinical trial information: UMIN000030850 . [Table: see text]
Updated results of anlotinib combined with TQB2450 (PD-L1 blockade) as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, multicenter, open-label phase Ⅱ clinical trial.
Authors: Zhang Zhiye , Meng Xiangrui , Yang Xiuli , Hong Yong-Gui , Xia Jin , Chen Yunfang , Wu Tao , Shan Zheng-Zheng , Fan Qingxia , Wang Feng
Published: June 2023

4041

Background: PD-1 blockades combined with chemotherapy in first-line setting exhibited encouraging efficacy for patients with ESCC recently. However, the safety profile of conventional chemotherapy was still disappointing. Therefore, the chemotherapy-free regimen might be a promising strategy. As a novel multitarget TKI mainly targeting VEGFR1-3, anlotinib was a potential first-line combination therapy and second-line monotherapy for patients with ESCC in China. TQB2450 was a novel PD-L1 blockade developed by Chia Tai Tianqing Pharmaceutical Group Co., Ltd. (Nanjing, China). Therefore, this study was designed to explore the efficacy and safety of anlotinib combined with TQB2450 as first-line therapy in advanced ESCC. The preliminary results were reported in 2023 ASCO-GI Symposium (Abs 377) and the update results were reported here. Methods: Patients with previously untreated metastatic or locally advanced ESCC, whose age was between 18 and 75 years, with ECOG PS of 0 or 1 and life expectancy of > 3 months were eligible as the inclusion criteria. Eligible patients were administered with anlotinib (12mg, po, d1~14, q3w) plus TQB2450 (1200mg, iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 and iRECIST using CT scans every 2 cycles for the first 6 cycles, and every 3 cycles thereafter. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 46. The primary endpoint was ORR. Secondary endpoints included safety, PFS, DCR, DoR and OS. Results: From Mar 2022 to Sep 2022, a total of 46 patients were enrolled. At the data cut-off date (Dec, 2022), there were 1 CR (2.2%), 27 PR (58.7%), 14 SD (30.4%) and 4 NE (8.7%). Therefore, the preliminary ORR was 60.9% (95%CI: 45.4%~74.9%), DCR was 91.3% (95%CI: 79.2%~97.6%). The median PFS of the 46 pts was not yet available. Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-related adverse events in 46 patients with the incidence > 10% were hypertension (28%), hypothyroidism (20%), leukocytosis (20%), hyperthyroidism (17%), anemia (15%), fatigue (15%), neutrophil count decreased (11%), constipation (11%), sinus bradycardia (11%) and hand-foot syndrome (11%). The common grade ≥3 treatment-related adverse events were hypertension (4%), hand-foot syndrome (2%), hyponatremia (2%), platelet count decreased (2%) and lymphocyte count decreased (2%). Conclusions: Preliminary results suggested that anlotinib combined with TQB2450 as first-line therapy in advanced ESCC exhibited encouraging efficacy and manageable adverse events. And the conclusions needed to be confirmed in trials continued subsequently. Clinical trial information: NCT05038813 .
A phase 2 single-arm study of berzosertib in combination with irinotecan in patients with progressive TP53 mutant gastric and gastro-esophageal junction cancer.
Authors: Stockton Shannon , Soares Heloisa P. , Dayyani Farshid , Saeed Anwaar , Kim Edward S. , Jin Ning , Yacoub George Hosni , Whisenant Jennifer , Ayers G. Dan , Gore Steven , Das Satya (Nanu) , Berlin Jordan
Published: June 2023

4044

Background: TP53 mutations are reported in 30-70% of patients with metastatic/unresectable gastric (G) and gastro-esophageal junction (GEJ) adenocarcinoma and are associated with a poor prognosis. Novel therapeutics are needed. Gastrointestinal cancer cell lines with TP53 mutations demonstrate reliance on the ataxia telangiectasia and Rad3-related protein kinase (ATR) axis for DNA damage repair (DDR) in vitro. The ATR axis is triggered by single-strand DNA breaks and thus combining ATR inhibitors with topoisomerase I (TopI) inhibitors may have a synergistic effect, particularly in patients with TP53 mutant tumors. Irinotecan, a TopI inhibitor, is an established cytotoxic therapy for gastric and GEJ adenocarcinoma. We evaluated irinotecan in combination with the ATR inhibitor berzosertib (formerly M6620) in patients with TP53-mutated gastric and GEJ adenocarcinoma. Methods: This was a single-arm phase II study in third-line patients with G/GEJ cancers possessing TP53 mutations (exon 2 and exons 4-11). Patients received irinotecan 180 mg/m2 IV and berzosertib 270 mg/m2 IV on days 1 and 15 every 28 days. The primary endpoint was overall response rate (ORR) (Ha: 35% and Ho:15%). A subset of patients underwent biopsies on C1D1 post-irinotecan and C2D2 to evaluate the expression of DDR biomarkers Y-H2AX, KAP1 p-Ser 824, and p-ATR. Results: A total of 17 patients were enrolled. Of 16 efficacy-evaluable patients, one experienced a partial response. The ORR was 6.2% thus the primary endpoint was not met. The disease control rate was 56.2%. Median progression-free survival was 4.01 months [95% CI 2.07-Not Reached]. Median overall survival was 6.21 months [95% CI 4.83-8.61]. No new safety signals were observed with the experimental treatment combination and the most common ≥ grade 3/4 treatment-related adverse events were neutropenia (4/17, 23.5% patients), anemia (3/17, 17.6%), febrile neutropenia (2/17, 11.8%), and diarrhea (2/17, 11.8%). No grade 5 events occurred. Conclusions: Although the primary endpoint of ORR was not met, the combination of irinotecan and berzosertib in patients with TP53-mutated G/GEJ adenocarcinoma was well-tolerated and demonstrated anti-tumor activity comparable to other agents with published later-line data (e.g. ramucirumab+paclitaxel, TAS-102). Analyses of pharmacodynamic biomarkers of DNA damage repair are in process. While further clinical development of berzosertib is not planned, other ATR inhibitors are being explored in combination with irinotecan in gastrointestinal malignancies, including G/GEJ cancer. Clinical trial information: NCT03641313 . [Table: see text]
FLOT plus nivolumab in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction: Results from the randomized phase 2 IKF-S628/AIO-STO-0417 (Moonlight) trial of the AIO.
Authors: Lorenzen Sylvie , Goetze Thorsten Oliver , Hofheinz Ralf Dieter , Thuss-Patience Peter C. , Dechow Tobias Nicolaas , Riera-Knorrenschild Jorge , Schuch Gunter , Luley Kim Barbara , Koch Christine , Goekkurt Eray , Schmalenberg Harald , Ettrich Thomas Jens , Lindig Udo , Pink Daniel , Bitzer Michael , Bolling Claus , Homann Nils , Junge Sabine , Pauligk Claudia , Al-Batran Salah-Eddin
Published: June 2023

4045

Background: FOLFOX plus nivolumab (nivo) has become standard of care for first-line therapy of patients (pts) with esophagogastric adenocarcinomas. FLOT is a well-established standard of care triplet regime. Some physicians may consider a triplet in patients with aggressive disease. The aim of this Arm C part of the Moonlight trial was to evaluate the safety and efficacy of the combination of FLOT plus nivo. Methods: Moonlight is a multi-cohort phase-II trial. The results for Arm C evaluating FLOT + nivo (240 mg) q2w as first-line therapy in all-comers are presented here. Primary endpoint was progression-free survival at 6 months (PFS@6), main secondary endpoints were safety, OS, and overall response rate (ORR). Results: Fifty-two patients were enrolled. Baseline characteristics were: median age 61y, GEJ 65%. Sixty-five percent had centrally assessed PD-L1 CPS≥1 (available in 96% of pts). Pts. received a median number of 8 cycles of FLOT and nivo and 42% received further line treatment. FLOT plus nivo was well tolerated and feasible with the most frequent adverse events of ≥ grade 3 being decreased neutrophils (40.4%), anemia (5.8%) and thromboembolic events (7.7%). After a median follow-up of 9.4 months, 3- and 6-month progression-free survival rates were 85% and 42%, respectively. Median PFS was 6.6 months and median OS 10.8 months. ORR and disease control rate (DCR) were 54% and 87%, respectively. Compared to the pooled study cohorts A and A1 (n = 90 pts) utilizing mFOLFOX plus nivo and ipilimumab (non-randomized comparison), FLOT plus nivo was associated with greater DCR (87% vs. 78%) and 3-months PFS (85% vs. 72%). Conclusions: FLOT and nivo is feasible and seems to be associated with improved disease control in the early course of therapy. FLOT plus nivo may represent an option for select patients with aggressive, rapidly progressive disease. Clinical trial information: NCT03647969 .
Osemitamab in combination with capecitabine and oxaliplatin (CAPOX) as a first line treatment of advanced G/GEJ cancer: Updated data of cohort C from a phase I/IIa, multi-center study (TranStar102/TST001-1002).
Authors: Shen Lin , Liu Dan , Li Ning , Guo Weijian , Liu Tianshu , Li Hongli , Li Jiayi , Bai Yuxian , Deng Yanhong , Zhuang Zhi-xiang , Sun Meili , Fan Qingxia , Zhao Fuyou , Han Liang , Xia Zhenzhong , Wang Jianming , Qi Charlie , Xu Li , Qian Xueming , Germa Caroline
Published: June 2023

4046

Background: Adding a claudin18.2 antibody to a chemotherapy is a clinically validated approach for patients with high CLDN18.2 expressing tumors. TST001 is a best in class differentiated antibody whose improved CLDN18.2 affinity and enhanced antibody-dependent cellular cytotoxicity, leads to anti-tumor activity in low to medium CLDN18.2 expressors gastric cancer cells. Pre-clinical studies also showed that TST001 has stronger tumor regression effects than the IMAB362-analog at the same dose. Methods: The efficacy and safety of osemitamab with CAPOX as 1st line treatment with G/GEJ cancer was explored in a dose escalation and expansion phase 1/2 study in China (Cohort C, NCT04495296). Positive claudin18.2 expression (membranous staining ≥1+ intensity in≥10% of tumor cells) as assessed centrally using the LDT assay was required in the expansion phase only. Results: As of Dec 31, 2022, 64 patients were dosed with osemitamab in combination with CAPOX, 15 patients received osemitamab at doses ranging from 1 to 8 mg/kg Q3W in the dose escalation and 49 patients at 6 mg/kg in the dose expansion. The median follow up was 151 days. Patient characteristics were typical of 1st line G/GEJ cancer, with relatively higher percentage of peritoneal disease (48.4%). Nausea (65.4%), vomiting (46.2%) and hypoalbuminemia (65.4%) were the most common adverse events related to TST001 at dose of 6mg/kg in 52 patients (3 patients in dose escalation and 49 patients in dose expansion), most of them were grade 1 or 2 (only one patient experienced grade 3 nausea and vomiting, and one experienced grade 3 hypoalbuminemia). In the expansion cohort, 40 of the 45 patients with measurable lesions had at least one post-treatment tumor assessment. 27 achieved partial response (PR) of which 21 were confirmed. There was no obvious trend in improved efficacy with higher level of CLDN18.2 expression based on overall response rate (ORR). Progression free survival (PFS) and duration of response (DOR) were still immature. Conclusions: TST001 in combination with CAPOX as first-line treatment for the patients with G/GEJ cancer is safe and encouraging anti-tumor activities have been observed regardless of the CLDN18.2 expression levels above 1+ intensity in >=10% tumor cells per central LDT assay. Updated ORR, mPFS and mDOR will be presented at the time of the congress. Clinical trial information: NCT04495296 .
Multi-dimensional cell-free DNA-based liquid biopsy and early detection of gastric cancer.
Authors: Pengfei Yu , Wu Min , Ding Guangyu , Bao Hua , Du Yian , Xu Zhiyuan , Yang Litao , Fang Jingquan , Huang Xingmao , Lai Qian , Wei Jia , Yan Junrong , Yang Shanshan , He Peng , Tang Haimeng , Wu Xue , Shao Yang , Su Dan , Cheng Xiangdong
Published: June 2023

4060

Background: Gastric cancer is one of the most common cancer types. Most patients were diagnosed at advanced stages and experienced poor prognosis. A non-invasive assay for the detection of early-stage gastric cancer is highly desirable for reducing the gastric cancer-associated mortality. Methods: We prospectively collected a study cohort of 249 participants including 110 pathologically confirmed with stage I-II gastric cancer and 139 with non-cancerous conditions. A plasma sample was collected from each patient before conventional screening modalities for gastric cancer. We performed whole-genome sequencing with plasma samples and profiled four types of cell-free DNA (cfDNA) characteristics, fragment size pattern, copy number variation, nucleosome coverage pattern, and single nucleotide substitution. We used these differential profiles to develop an ensemble model to identify gastric cancer patients from non-cancer individuals. We further collected a validation cohort consisting of 73 gastric cancer patients and 94 non-cancer individuals to validate the cfDNA-based assay. Additionally, we compared the performance of our assay and conventional gastroscopy in a hypothetical 100,000 screening population by Monte Carlo simulation. Results: The liquid biopsy assay that incorporated four types of cfDNA characteristics was able to identify early-stage gastric cancer patients from non-cancer individuals at an AUROC of 0.962 in the study cohort and 0.972 in the validation cohort. At a specificity of 92.1% (128/139), it achieved a sensitivity of 88.2% (97/110) in the study cohort. With this threshold, in the validation cohort, 91.5% (86/94) of healthy individuals and 91.8% (67/73) of gastric cancer patients were correctly identified. In both study and validation cohorts, the inferred probabilities of cancer showed consistent trends to increase with pathological stages in the cancer group and disease statuses in the non-cancer group. Of note, our approach detected all gastric tumors located in the cardia and fundus (100.0%, 19/19), which could be challenging for gastroscopic examination. Additionally, through in-silico simulations, we showed that our cfDNA-based non-invasive assay may detect 96.3% more gastric cancer cases than conventional gastroscopy owing to higher sensitivity and anticipated better participant compliance in a large hypothetical screening population. Conclusions: We introduced a liquid biopsy assay using multiple dimensions of cfDNA characteristics that could accurately identify early-stage gastric cancer from non-cancerous conditions. As a cost-effective non-invasive approach, it may provide population-wide benefits for the early detection of gastric cancer.
Induction chemotherapy plus definitive chemoradiotherapy versus chemoradiotherapy alone in esophageal squamous cell carcinoma: Long-term results and exploratory analyses of a randomized controlled trial.
Authors: Xi Mian , Chen BaoQing , Liu Shi-Liang , Zhu Yujia , Zhao Lei , Liu Mengzhong
Published: June 2023

4061

Background: The previous results of our trial demonstrated that the addition of induction chemotherapy (IC) prior to definitive chemoradiotherapy (CRT) failed to significantly improve response rate or 3-year survival in patients with locally advanced esophageal squamous cell carcinoma (ESCC). Here, we report the long-term results and exploratory analyses to further evaluate the therapeutic value of IC in ESCC. Methods: This was a single-institution, open-label, randomized, phase II trial. Patients with previously untreated, unresectable, stage II–IVA ESCC were randomly assigned in a 1:1 ratio to receive induction docetaxel (75 mg/m2 on day 1) and cisplatin (75 mg/m2 on day 1) every 3 weeks for two cycles, followed by concurrent CRT, or CRT alone. The primary endpoint was overall response rate at 3 months after CRT. Second endpoints were overall survival (OS) and progression-free survival (PFS). The relationship between tumor response to IC and long-term survival was analyzed as an exploratory, post-hoc analysis. Moreover, baseline tumor biopsies were evaluated by RNA-seq to identify patients who are more likely to benefit from IC. Results: Between May 2015 and September 2017, 110 eligible patients were randomly assigned to the IC+CRT group (n=55) or the CRT group (n=55). The overall response rate was 74.5% in the IC+CRT group versus 61.8% in the CRT group (P=0.15). At a median follow-up of 74.9 months, the 5-year OS rate was 31.8% in the IC+CRT group and 29.1% in the CRT group (P=0.68; HR, 0.91; 95% CI, 0.58–1.43). Similarly, no significant differences were identified in 5-year PFS between groups (30.5% vs. 25.5%, P=0.51; HR, 0.86; 95% CI, 0.56 to 1.34). Patients who responded to IC had significantly better survival than nonresponders. Six key genes were identified based on RNA-seq and gene expression comparison between responders and nonresponders after IC. Risk-score model was constructed by these key genes and then validated. Conclusions: Addition of induction docetaxel plus cisplatin before definitive CRT still failed to provide an obvious survival benefit in ESCC based on long-term follow-up. However, this strategy did result in a significantly improved survival in IC responders. Our results also revealed potential molecular biomarkers to predict who may benefit from IC. Clinical trial information: NCT02403531 .
Development of an artificial intelligence algorithm for adjuvant chemotherapy based on a nationwide registry of patients with gastric cancer by the Japanese Gastric Cancer Association (JGCA).
Authors: Yamada Yasuhide , Kamada Ami , Kabeya Yoshinori , Yoshida Sumito , Harada Hitoshi , Urakawa Naoki , Kanaji Shingo , Nakamura Yuma , Nagashima Kengo , Takeuchi Hiroya , Doki Yuichiro , Kitagawa Yuko , Kodera Yasuhiro , Kakeji Yoshihiro
Published: June 2023

4063

Background: Recent marked advances in machine learning have led to expectations of the clinical application of artificial intelligence (AI) to support medical care. Methods: A survival analysis model which consisted of 31 covariates was adopted for AI algorithms using machine learning and these were constructed using clinical data sets for training. The performance of AI algorithms was evaluated in order to determine the optimal chemotherapy including surgery alone without any adjuvant chemotherapy with the highest survival rate for each patient. This involved using clinical data for verification to compare survival of an AI-recommended treatment group, for which therapy recommended by AI was actually administered, with an AI-deprecated group, for which therapy recommended by AI was not administered. Results: The clinical characteristics of 23653 patients and treatment are described in the Table from 2011 to 2018 in a nationwide registry of gastric cancer patients in Japan by the Japanese Gastric Cancer Association and were made available for this study. S-1 monotherapy was used the most frequently of all adjuvant chemotherapy in this study. We used the "restricted mean overall survival time" (RMST) of all the patients as metrics. The RMST in the AI-recommended and the AI-deprecated groups were 51.4 and 47.5 months, respectively. Patient data for the verification were matched baseline characteristics by the propensity score. This model predicted effectively overall survival after gastrectomy. The RMST of over 80 years old patients were 43.9 in the AI-recommended and 38.3 months in the AI-deprecated, respectively. This AI algorithm recommended adjuvant S-1 more frequently for patients with higher age, male, American Society of Anesthesiologists – physical status 2, Eastern Cooperative Oncology Group performance status 1, pT3/pT4, pN2/pN3, more than the upper normal limit of preoperative blood urea nitrogen, macroscopic types 2/3, differentiated adenocarcinoma, Roux-en-Y reconstruction, and Clavien-Dindo classification grade II/III. The RMST for pStage IIA/IIB/IIIA/IIIB/IIIC were 55.7/53.9/50.3/45.7/42.2 months in the AI-recommended and 55.1/50.7/43.9/36.9/32.0 months in the deprecated. This AI algorithm showed a higher survival rate in pStage III patients particularly. Conclusions: The AI algorithm could readily be integrated into clinical practice to choose adequate adjuvant chemotherapy for each patient based on each patient's baseline data because it trained and verified the nationwide registry has good predictive performance. [Table: see text]
Circulating tumor DNA as a marker of recurrence risk in locoregional esophagogastric cancers with pathologic complete response.
Authors: Lander Eric Michael , Huffman Brandon , Klempner Samuel J , Aushev Vasily N. , Ferguson Jenifer , Sharma Shruti , Jurdi Adham A , Liu Minetta C. , Eng Cathy , Gibson Michael K.
Published: June 2023

4066

Background: Following neoadjuvant therapy and definitive surgery, up to one-third of patients (pts) with gastroesophageal adenocarcinoma with a pathologic complete response (pCR; tumor regression grade 0 [TRG0]) will recur, while up to one-half of pts with a near-pCR (TRG1) experience recurrence. Our study aims to evaluate postoperative circulating tumor DNA (ctDNA) as a prognosticator of recurrence in pts with pCR or near-pCR after curative-intent neoadjuvant chemotherapy (NAC) or chemoradiation (CRT) and surgery. Methods: We retrospectively identified pts from 11 institutions with stages I-III esophagogastric cancers who completed neoadjuvant therapy and had TRG0 or TRG1 scores at the time of curative-intent surgery. Postoperative plasma samples were collected for ctDNA analysis within a 16-week molecular residual disease (MRD) window after definitive surgery and serially during follow-up from 9/19/19 to 2/21/22. MRD by ctDNA was assessed using a personalized, tumor-informed ctDNA assay (Signatera mPCR-NGS assay). The primary outcome was recurrence-free survival (RFS), measured from the date of surgery to the first documented sign of radiographic recurrence. Survival analysis was performed using the maximum likelihood bias reduction method for Cox regression. Results: We obtained 250 blood samples from 45 pts with esophageal (N=18), gastroesophageal junction (N=17), and gastric (N=10) adenocarcinomas who received either NAC or CRT. The median follow-up for this cohort was 22.8 months (range: 0.3-81.7 months). Despite pts achieving pCR (N=12) or near-pCR (N=33), ctDNA-positivity in the 16-week MRD window (N=21) correlated with higher rates of recurrence (66.7%; 2/3) compared to the absence of ctDNA (11.1%; 2/18). Detectable ctDNA was associated with a significantly shorter RFS (HR 23.0, 95% CI 2.0-268.1; p=0.012). 35 pts had ctDNA analyzed at any post-surgical time point, where the recurrence rate was 87.5% (7/8) in ctDNA-positive pts compared to 7.4% (2/27) in ctDNA-negative pts, exhibiting a further reduction in RFS (HR 44.8; 95% CI 5.4-369.7; p<0.0001). Out of 8 ctDNA-positive pts, two (25%) converted from ctDNA-positive to ctDNA-negative with subsequent treatment. Conclusions: Within the subgroup of pts with esophagogastric adenocarcinoma and favorable pathologic responses (TRG 0-1) following neoadjuvant treatment, the presence of post-operative ctDNA identified pts with elevated recurrence risk. If validated in larger cohort studies, testing for ctDNA may be a useful biomarker to select pts at risk for recurrence with potential to inform prospective clinical trials for direction of adjuvant therapy.
Long-term quality of life and nutritional results of stomach-preserving surgery after sentinel node evaluation in patients with early gastric cancer: A multicenter, randomized phase 3 trial (SENORITA).
Authors: Eom Bang Wool , Yoon Hong Man , Kim Young-Woo , Min Jae Seok , An Ji Yeong , Hur Hoon , Lee Young Joon , Cho Gyu Seok , Park Young-Kyu , Jung Mi Ran , Park Ji-Ho , Hyung Woo Jin , Jeong Sang-Ho , Kook Myeong-Cherl , Han Mira , Nam Byung-Ho , Ryu Keun Won
Published: June 2023

4070

Background: In the SENORITA trial, laparoscopic sentinel node navigation surgery (LSNNS) showed no significant difference in overall and disease specific survivals compared with laparoscopic standard gastrectomy (LSG). Here, we present the effect of stomach preservation surgery on QoL and nutritional outcomes, and identify risk factors affecting QoL in stomach preservation surgery. Methods: SENORITA was a prospective multicenter randomized trial. Patients diagnosed with early gastric cancer of 3 cm or less were randomly allocated (1:1) to LSNNS or LSG. The primary endpoint was 3-year disease-free survival. This analysis focuses on long-term quality of life and nutritional outcomes of patients who finally underwent stomach-preservation surgery in the LSNNS group. QoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and stomach module (STO22) at 3, 12, 24, and 36 months after surgery. Linear mixed model analyses were used to evaluate differences between treatment groups. This trial is registered with ClinicalTrials.gov, NCT01804998. Results: From March 2013 to March 2017, a total of 580 patients were randomly assigned in the SENROTA trial. Among them, 258 patients underwent sentinel node navigation surgery and 198 finally underwent stomach preservation surgery. QoL data was available in 194 patients and compared with those of 257 patients who underwent standard gastrectomy. The stomach-preservation group had better QoL in physical function, dyspnea, and appetite loss of C30 and dysphagia, pain, reflux symptoms, eating restriction, anxiety, taste change, body image, and total score of STO22. Regarding nutritional outcomes, body mass index, hemoglobin, protein, and albumin levels were significantly higher in the stomach-preservation group than in the gastrectomy group. In multivariate analyses, tumor location (greater curvature) was an independent favorable factor affecting global health status, reflux symptoms, eating restriction, and total score of STO22 at 3 months in the stomach-preservation group. Segmental resection was a risk factor for diarrhea and eating restriction at postoperative 3 year. Conclusions: The stomach-preservation surgery had better long-term QoL and nutritional outcomes compared with standard gastrectomy. These findings can help decision making about treatment for patients with early gastric cancer, especially or elderly or nutritionally high risk patients. Clinical trial information: NCT01804998 .
Response to programmed cell death protein 1 antibody in patients with Epstein-Barr virus-associated biliary tract cancer.
Authors: He Wen-Zhuo , Lin Han-Bin , Guo Gui-Fang , Xia Liang-Ping
Published: June 2023

4071

Background: Epstein-Barr virus-associated biliary tract cancer (EBVaBTC) has a distinct genomic landscape and increased infiltration of CD3+ and CD8+ T cells. However, the efficacy of immunotherapy in EBVaBTC remains largely unknown. The aim of this study is to assess the efficacy of programmed cell death protein 1 (PD-1) antibody in EBVaBTC. Methods: Consecutive patients with metastatic biliary tract cancer diagnosed at our institution from January 2017 to December 2021 were identified. In situ hybridization was performed to detect EBV. The objective response to PD-1 antibody was assessed. We also analyzed the immune microenvironment of EBVaBTC by multiplex immunofluorescence staining, and performed the proteomic characterization of EBVaBTC. Results: A total of 131 patients with BTC who received PD-1 antibody were identified, of which 9 (6.9%) had EBVaBTC. All EBVaBTC cases were intrahepatic cholangiocarcinoma. EBVaBTC was not associated with deficient mismatch repair but with lymphoepithelioma-like carcinoma and hepatitis B virus infection. Four (44.4%) patients achieved a partial response, and the remaining five (55.6%) patients had stable disease. The response lasted for at least 12 months in 8 (88.9%) patients with EBVaBTC, including 4 patients received PD-1 antibody monotherapy. Blood EBV-DNA was detectable in all 9 patients (100%) with EBVaBTC. Multiplex immunofluorescence staining revealed more abundant CD3+ and CD8+ T cells infiltration in EBVaBTC than that of mismatch repair deficient BTC. A total of 8,379 proteins were identified by proteomics. Comparison of EBVaBTC and paired normal tissue revealed 547 differentially expressed proteins. Enrichment analysis demonstrated that differentially expressed proteins in the EBVaBTC were associated with EBV infection and T cell activation. We also observed the expression of immune checkpoint other than PD-1, including LAG-3 and TIM-3. Conclusions: Identification of EBVaBTC may represent a subset of patients with promising response to immunotherapy. [Table: see text]