bluuebunny/crossref_metadata_2025 huggingface dataset:
Final survival results of ipilimumab or FOLFOX in combination with nivolumab and trastuzumab in previously untreated HER2 positive esophago gastric adenocarcinoma: The randomized AIO INTEGA trial.
Authors: Tintelnot Joseph , Stein Alexander , Paschold Lisa , Goekkurt Eray , Schultheiß Christoph , Thuss-Patience Peter C. , Lorenzen Sylvie , Ettrich Thomas Jens , Riera Knorrenschild Jorge , Jacobasch Lutz , Kubicka Stefan , Al-Batran Salah-Eddin , Reinacher-Schick Anke C. , Pink Daniel , Sinn Marianne , Lindig Udo , Hinke Axel , Hegewisch-Becker Susanna , Binder Mascha
Published: June 2023

4026

Background: In metastatic esophagogastric adenocarcinoma (EGA), the addition of PD-1 inhibitors (i) to chemotherapy has improved the outcome in selected patient populations. The randomized INTEGA trial investigated trastuzumab and PD-1i with FOLFOX or CTLA-4i in 1st line treatment of advanced HER2+ EGA. Methods: Patients with previously untreated, metastatic HER2+ (local IHC3+ or 2+/ISH+) EGA, and adequate organ function were randomized to trastuzumab and nivolumab (1mg/kg Q3W x4 /240mg Q2W for up to 12 months) in combination with ipilimumab (3mg/kg x4 Q3W; Ipi arm) or mFOLFOX6 (FOLFOX arm) accompanied by a large translational program. The primary endpoint was the 12month overall survival (OS) rate. The trial was registered at ClinicalTrials.gov, NCT03409848. Results: Between March 2018 and May 2020, 97 patients were enrolled and 88 randomized across 21 German sites with the following baseline characteristics: female/male 18/70, median age 60.5 (range 41-80), ECOG 0/1 54/34, GEJ/stomach 66/22. Central post hoc biomarker analysis on 82 evaluable patients showed PD-L1 CPS≥1/≥5 in 59/46 patients and confirmed HER2 (central IHC3+ or 2+/ISH+) positivity in 77 patients. The observed OS rate at 12 months was 70% (95% confidence interval (CI) 54-81%) in the FOLFOX arm, and 57% (95% CI 41-71%) in the Ipi arm. The progression free survival was 10.7 and 3.2 months, and the overall response rate was 53.5% and 34% in the FOLFOX and the Ipi arm, respectively. Although these data are in favor of the FOLFOX arm, the overall survival curves crossed with increased follow-up (median follow-up of 18.8 months) and thus the final median OS was 22.1 and 23.3 months, numerically favoring the Ipi arm. According to the centrally assessed CPS the OS was: 22.1 and 32.2 months in the CPS<5 group, and 22.7 and 12.6 months in the CPS≥5 group for the FOLFOX and the Ipi arm, respectively. Notably, the median tumor burden calculated as the sum of target lesions was numerically lowest in the Ipi arm with higher than median OS. Conclusions: In contrast to limited short term efficacy of the Ipi arm as reflected by the lower PFS, the Ipi arm showed favorable OS, that was inversely correlated to the CPS status. Further analysis of baseline clinical and molecular data to better identify the subgroup of patients benefitting the most of trastuzumab/nivolumab/ipilimumab will be presented at the meeting. Clinical trial information: NCT03409848 . [Table: see text]
Effect of autologous lymphocytes combined with chemotherapy as the first-line treatment of advanced gastric cancer.
Authors: Ma Xiaoting , Yang Lin
Published: June 2023

4037

Background: To evaluate the safety and initial efficacy of adoptive cell therapy (ACT) combined with SOX in first-line treatment of locally advanced unresectable or metastatic gastric adenocarcinoma/gastroesophageal adenocarcinoma. Methods: In this single-arm, single-center exploratory trial, patients with histologically confirmed locally advanced unresectable or metastatic gastric adenocarcinoma/gastroesophageal adenocarcinoma were randomly assigned (1:1) to receive ACT in combination with S-1 and oxaliplatin (SOX) or SOX alone. The primary endpoint was the incidence of adverse events (AEs). Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Results: Fifty-nine patients were enrolled in the study between November 20, 2014 and September 6, 2017. 31 patients received ACT combined with SOX (ACT-SOX) and 28 patients received SOX. The most common AEs in both groups were gastrointestinal reaction, leucopenia, neutropenia, anemia, thrombocytopenia, hyperbilirubinemia and elevated aspartate transaminase concentration, with a higher incidence in the SOX group. The median PFS for ACT-SOX and SOX were 6.9 and 4.9 months respectively (HR 0.80, p=0.45), and the median OS were 17.8 and 9.75 months (HR 0.76, p=0.34). Patients who received more than three injections of specific lymphocyte subsets benefited the most from combination therapy. Cox univariate and multivariate analysis showed that tumor metastasis to more than two organs was the main risk factor for PFS and OS. 29 patients in the ACT-SOX group and 25 in the SOX group had measurable lesions. The ORR of ACT-SOX group and SOX group was 55.2% and 32.0%, and DCR of two groups was 93.1% and 88.0%. Conclusions: The safety of ACT-SOX in first-line treatment of patients with locally advanced unresectable or metastatic gastric adenocarcinoma/gastroesophageal adenocarcinoma is good. Compared with SOX alone, although the PFS and OS of ACT-SOX did not reach statistical difference, it could further extend the time of PFS and OS, and the absolute improvement time of OS was about 8.05 months. Continuous benefit of ACT-SOX was observed through long-term follow-up. Clinical trial information: NCT02504229 .
Health-related quality of life (HRQOL) in patients (pts) with advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC) or esophageal adenocarcinoma (EAC): 36-month results of nivolumab plus chemotherapy (N+C) versus (C) from CheckMate 649.
Authors: Elimova Elena , Wyrwicz Lucjan , Chen Clara , Blum Steven Michael , Davenport Eric , Wang Jinyi , Kondo Kaoru , Moehler Markus H.
Published: June 2023

4038

Background: CheckMate 649 (NCT02872116) is a randomized, open-label, phase 3 study in first-line treatment of pts with advanced GC/GEJC/EAC. Primary results showed statistically significant improvement in overall survival (OS) for N+C versus C in all randomized pts. Prior analyses conducted for 24-month follow-up (FUP) showed pts receiving N+C maintained HRQOL and experienced delayed deterioration in HRQOL compared with pts receiving C. Here we report additional analyses of HRQOL with 36-month FUP data. Methods: Functional Assessment of Cancer Therapy–Gastric Cancer (FACT-Ga) and EQ-5D-3L results were collected at baseline (BL) and every 6 weeks while on treatment. Change from BL in FACT-Ga, EQ-5D Visual Analog Scale (VAS), and Utility Index (UI) scores were analyzed using mixed models. Time to first symptom deterioration (TTSD), time until definitive deterioration (TuDD), and time to improvement (TTI) were estimated with Kaplan-Meier estimators and stratified Cox models; deterioration/improvement events were based on prespecified meaningful thresholds for change scores. Results: A total of 1,581 pts were randomized to N+C (n = 789) and C (n = 792); of those, 1,360 pts had BL and post-BL PROs and were included in the PRO population (N+C [n = 694] and C [n = 666]). With additional follow-up, least-squares mean differences from BL remained comparable between groups across visits for HRQOL measurements with exceptions. FACT-Ga total score, GaCS, physical well-being (WB), and emotional WB tended to favor N+C; social WB tended to favor C. For all randomized pts, most time-to-event endpoints favored N+C; like the 24-month analysis, statistically significant delays in deterioration were maintained for TuDD (except FACT-G Social WB) and TTSD (only FACT-GaCS and FACT-Ga total). Conclusions: These results confirm the earlier 24-month FUP findings. Compared with C alone, N+C maintained HRQOL with decreased risk of deterioration in pts with previously untreated advanced or metastatic GC/GEJC/EAC. Together with improved OS, data continue to support N+C as a first-line standard treatment for GC/GEJC/EAC. Clinical trial information: NCT02872116 . [Table: see text]
Efficacy of ramucirumab combination chemotherapy as second-line treatment in patients with advanced adenocarcinoma of the stomach or gastroesophageal junction after exposure to checkpoint inhibitors and chemotherapy as first-line therapy within the prospective phase II IKF-S628/AIO-STO-0417 (MOONLIGHT) trial.
Authors: Masetti Michael , Al-Batran Salah-Eddin , Goetze Thorsten Oliver , Thuss-Patience Peter C. , Riera-Knorrenschild Jorge , Goekkurt Eray , Folprecht Gunnar , Ettrich Thomas Jens , Lindig Udo , Luley Kim Barbara , Pink Daniel , Dechow Tobias Nicolaas , Sookthai Disorn , Junge Sabine , Pauligk Claudia , Lorenzen Sylvie
Published: June 2023

4043

Background: FOLFOX plus nivolumab has become standard of care for first-line therapy of patients (pts) with advanced gastroesophageal cancer (aGEC). The efficacy of 2nd line VEGF-2 inhibition with ramucirumab (Ram) plus chemotherapy after progression to immunochemotherapy remains unclear. Methods: Medical records of consecutive pts with aGEC enrolled in the multi-centre randomized phase II AIO-STO-0417 trial who had tumor progression after 1st line FOLFOX plus nivolumab and ipilimumab were retrospectively analysed. Pts were divided into two groups based on the subsequent 2nd line therapy: Ram plus chemotherapy (ramucirumab group) or chemotherapy alone (control group). Outcomes were compared between both groups in the overall population and in subgroup analysis according to best response (CR/PR) under 1st line therapy and tumor PD-L1 expression. Results: In total, 83 pts (38 Ram group, 45 control group) were included. The most frequent 2nd line therapy in the Ram group was Ram plus paclitaxel (85%). In the overall population, median progression-free survival (PFS) in the Ram group was longerthan in the control group (4.5 vs. 2.9 months). Responders (CR/PR) to 1st line immunochemotherapy who received Ram containing 2nd line therapy (n = 15) showed a clearly prolonged median OS counted from start of 1st line therapy (28.9 vs. 16.5 months), as well as 2nd line OS (9.6 vs. 7.5 months), PFS (5.6 vs. 2.9 months) and DCR (53% vs. 29%) compared to the control group (n = 24). PD-L1 CPS ≥ 1 (status known for77% of pts) was 42% and 44% for the Ram and the control group, respectively. Patients with CPS ≥ 1 in the Ram group (n = 16) showed a trend towards better tumor control (ORR 25% vs. 10%, DCR 44% vs. 30%) and improved survival (total OS 11.5 vs. 8.0 months; 2nd line OS 6.5 vs. 3.9 months; PFS 4.5 vs. 1.6 months) compared to the control group (n = 20). Conclusions: Ramucirumab is effective as 2nd line treatment after progression on 1st line FOLFOX plus dual checkpoint inhibition, especially in patients with initial response and positive PD-L1 expression. Sequential angiogenesis inhibition with anti-VEGFR-2 targeting therapy following immunochemotherapy might be a promising option to overcome resistance to immunotherapy, which warrants further investigations in a larger cohort. Clinical trial information: NCT03647969 .
Heterogeneous baseline immune cell infiltration landscape as a predictor of pathological complete response in locally advanced esophageal squamous cell carcinoma (ESCC) following neoadjuvant chemotherapy and immunotherapy: Results from a single-arm, phase II clinical trial (SEEK-01).
Authors: Yao Guangyu , Wang Renfeng , Huang Zhiliang , Du Chaoxiang , Chen Borong , Lin Zhenyang , Zhang Tao , Wu Zhonghua , Fan Hong
Published: June 2023

4047

Background: Neoadjuvant immunotherapy and chemotherapy have shown promise in improving outcomes for patients with locally advanced ESCC, but the response to treatment can vary among patients. Therefore, there is a need to identify predictive biomarkers that can guide treatment decisions and improve patient outcomes. The infiltration of immune cells within the tumor microenvironment has been shown to be an important factor in cancer progression and response to treatment. In this study, we sought to explore the immune microenvironment prospectively related to treatment response of Neoadjuvant immunotherapy by scRNAseq. Methods: This was a single-arm phase II clinical trial, planned to enroll 20 locally advanced ESCC patients (cT2-4N0-1M0). After neoadjuvant chemotherapy (paclitaxel-albumin + carboplatin) combined with tislelizumab, patients received minimal invasive esophagectomy (MIE).Prior to neoadjuvant therapy, fresh tumor tissues were obtained via endoscopy and used for scRNAseq analysis, to evaluate the predictive capacity of the immune microenvironment. Pathological outcomes were assessed and divided into pCR, MPR defined as <10% residual tumor excluding pCR, and non-MPR defined as >10%. Results: Out of 18 enrolled patients, 15 completed neoadjuvant therapy and MIE surgery since March 2022. Of these 15 patients, 3 achieved pCR, 2 got MPR, and 10 were non-MPR, with a total of 51,208 single cells sequenced. Both groups showed similarly low expression of PD-L1 (5.7% vs. 2.3%). Comparing pCR to non-MPR patients, the former showed a significant increase in T lymphocytes (CD8+(17.1% vs.1.1%), Regulatory T(20.2% vs.4.0%)), plasma cell(22.0% vs.8.3%), and mature dendritic cell(1.5% vs.0.5%); a significant decrease in B cells(0.9% vs. 1.9%), neutrophils(1.7% vs.11.0%), and tumor cell, as well as a similar expression of macrophage(5.6% vs.6.6%) and monocyte, indicating a clear difference in the immune cell infiltration landscape between two groups. Furthermore, we identified a new subtype of plasma cell which was highly enriched in the non-MPR group, even though the pCR group showed a great increase in plasma cells in total. Conclusions: This study demonstrates the heterogeneity of baseline immune cell infiltration landscape in Locally Advanced ESCC, in which pCR and non-MPR patients exhibited entirely different profiles, and provide a potential predictor of response to neoadjuvant immunotherapy. Our findings suggest that baseline immune cell infiltration status, rather than pd-L1 expression, could accurately predict pCR or non-MPR before treatment, which could guide personalizing and minimize the need for trial-and-error approaches.
Effectiveness and safety of camrelizumab in advanced esophageal cancer: A prospective multicenter observational cohort studies (ESCORT-RWS).
Authors: Lu Zhihao , Zhao Jun , Yang Zhe , Li Na , Wang Junsheng , Yuan Shuanghu , Wang Yusheng , Li Suyi , Ran Fengming , Ji Yinghua , Zhang Yanqiao , Wang Chen , Wan Lixin , Wang Ming , Liang Liang , Dai Xiaofang , Cheng Guanghui , Li Wei , Zhen Peng , Shen Lin
Published: June 2023

4049

Background: Camrelizumab, an anti-programmed death 1 (PD-1) monoclonal antibody, has demonstrated survival benefits in patients with advanced or metastatic esophageal squamous cell carcinoma. However, the real-world effectiveness and safety of camrelizumab in patients with advanced esophageal cancer are largely unknown. Methods: In this prospective multicenter observational cohort study (NCT04616040), patients with advanced esophageal cancer who were scheduled to receive camrelizumab at the discretion of the physicians in charge were screened for inclusion. Clinical outcomes were treatment emergent adverse events (TEAEs), objective response rate (ORR), disease control rate (DCR), time to treatment discontinuation (TTD), progression free survival (PFS), and overall survival (OS). Results: Between Dec. 24, 2020 and Dec. 30, 2022, data were available for 624 patients (median age: 64.5 years; 74 [11.9%] aged ≥75 years; 515 [82.5%] men; 20 [3.2%] ECOG PS ≥2; 602 [96.5%] esophageal squamous cell carcinoma) from 42 institutions in China. All patients received at least one dose of camrelizumab-containing therapy, including 305 (48.9%) in the first-line, 238 (38.1%) in the second-line, and 81 (13.0%) in the third or later line settings. Most patients were treated with camrelizumab plus chemotherapy (487 [78.0%], primarily taxane and platinum-based chemotherapy in 284 [45.5%] patients), followed by camrelizumab plus antiangiogenic therapy (64 [10.3%]), camrelizumab monotherapy (46 [7.4%]), and camrelizumab plus antiangiogenic therapy and chemotherapy (27 [4.3%]). TEAEs occurred in 541 (86.7%) patients, most commonly anemia (41.2%), decreased white blood cell (38.5%), and decreased neutrophil count (28.5%). No new safety signals were noted. At the data cutoff (Dec. 30, 2022), 152 (24.4%) patients were still on treatment. The median follow-up estimated by the reverse Kaplan-Meier method and effectiveness outcomes are summarized in the Table. Conclusions: The real-world effectiveness and safety profiles of camrelizumab in advanced esophageal cancer patients are generally consistent with those observed in pivotal clinical trials. [Table: see text]
Circulating tumor DNA and association with CAR-T cell therapy response in gastric and pancreatic cancer patients.
Authors: Kubendran Sindhu , Boland Julia L. , Jurdi Adham A , Ween Audrey , Baker Gabriel , Ma Hong , Baffa Raffaele , Li Zonghai , Botta Gregory P.
Published: June 2023

4053

Background: Circulating tumor DNA (ctDNA) is a form of cell free DNA that can be used to detect and measure cancer molecular residual disease (MRD) before and after systemic therapy. There are no data pertaining to the assessment of MRD in patients with solid tumors treated with chimeric antigen receptor T-cell (CAR-T) therapy. Here, we evaluated a tumor-informed ctDNA assay in the setting of gastric and pancreatic malignancies treated with claudin18.2 (CT041)-targeted CAR-T cell therapy (NCT04404595). Methods: A single-center review between 7/1/2021 – 1/1/2023 identified 10 patients with pancreatic or gastric carcinoma who received CAR-T CT041 cell therapy. Eight patients were ctDNA positive prior to treatment and had blood samples serially drawn before and after CAR-T cell therapy. Banked plasma was analyzed for ctDNA using a tumor-informed Signatera, mPCR-NGS ctDNA assay (Natera, Inc.). The correlative prognostic value of ctDNA to predict response after CAR-T cell therapy was analyzed by RECIST 1.1 criteria. Results: Pre- and post-treatment serial ctDNA was available for 8 of 10 (3/5 gastric and 5/5 pancreatic cancer) patients and all 8 were ctDNA positive prior to CAR-T CT041 cell therapy. The median nadir of ctDNA was on day 14 after CT041 infusion.Of the 8 patients with detectable ctDNA, 5 (62.5%) became undetectable at some time after CT041 therapy, while 3 (37.5%)remained ctDNA positive throughout treatment. The disease control rate (DCR) was 80% for anytime negative ctDNA patients (4/5). Of patients with responsive disease after CT041 CAR-T, 2/3 (67%) achieved undetectable ctDNA and 1/3 (33%) had a ctDNA reduction by 95%. Both patients with stable disease developed undetectable ctDNA. In those patients with progressive disease, 1/3 (33%) had a negative anytime ctDNA. One patient with a complete response had undetectable ctDNA and target lesion response, then later developed progressive disease detectable by ctDNA 3 months prior to radiography. Overall survival was higher (9.1 months vs. 3.7 months) in those who achieved anytime undetectable ctDNA. Conclusions: Tumor-informed ctDNA correlates with response to CAR-T cell therapy in gastrointestinal malignancies. Ongoing clinical trials of CT041 CAR-T cell therapy will continue ctDNA analysis prospectively. Characteristics of initially ctDNA positive patients receiving CAR-T therapy. Clinical trial information: NCT04404595 . [Table: see text]
Adjuvant nab-paclitaxel plus S-1 versus capecitabine plus oxaliplatin for patients with stage III gastric adenocarcinoma after D2 dissection: A multicenter, open-label, randomized phase 3 study.
Authors: Pengfei Yu , Du Yian , Xu Zhiyuan , Yang Litao , Ying Jieer , Chen Ping , Wei Yunhai , Wu Yingjie , Zhang Xiaojing , Yan Zhilong , Chen Zhiheng , Xu Hongtao , Li Yong , Zheng Zhichao , Xu Nong , Cheng Xiangdong
Published: June 2023

4054

Background: Multiple clinical studies have shown that adjuvant chemotherapy could prolong the survival of patients after radical resection, it is necessary to explore better treatment options for patients with stage III gastric adenocarcinoma (GAC). We designed this study to evaluate the efficacy and safety of adjuvant nab-paclitaxel combined with S-1 (AS) versus capecitabine combined with oxaliplatin (CAPOX) in GAC. Methods: Patients with stage III GAC after D2 radical resection and achieved R0 resection were randomized 1:1 to receive adjuvant AS (nab-paclitaxel: 100 mg/m2, d1 and 8, q3w; S-1: 40-60 mg, bid, d1-14, q3w) or CAPOX (oxaliplatin: 130 mg/m2, d1, q3w; capecitabine: 1000 mg/m2, bid, d1-14, q3w) for 8 cycles. Stratification analysis was performed according to histological type (differentiated vs undifferentiated GAC) and AJCC 8th pathological staging (ⅢA vs ⅢB and ⅢC). The primary endpoint was 3-year disease-free survival (DFS) rate, secondary endpoints were overall survival (OS) and safety. Results: Between March 20, 2020 and January 17, 2023, 313 patients were randomized to receive AS (n = 156) or CAPOX (n = 157). Baseline characteristics were generally balanced between the two groups. Median follow-up time was 5.16 months. The 1-year DFS rates were 87.14% and 70.16%, in the AS and CAPOX groups, respectively. The median DFS and 3-year DFS rates were not reached. The 1-year OS rate was 88.47% in AS group, and 63.89% in CAPOX group. At date cutoff, 12 patients (peritoneal recurrence, 1 patient; locoregional recurrence, 3 patients; distant recurrence, 8 patients) relapsed in the AS group and 16 patients (peritoneal recurrence, 4 patients; locoregional recurrence, 5 patients; distant recurrence, 8 patients; tumor marker recurrence, 1 patient) relapsed in the CAPOX group; some patients had multiple recurrence sites. 2 patients (1 patient for GAC; 1 patient for other diseases) died in the AS group and 11 patients (9 patients for GAC; 2 patients for other diseases) died in the CAPOX group. The median relative dose intensity of nab-paclitaxel was 90.32%, of S-1 was 80.77%, of oxaliplatin was 77.44% and of capecitabine was 78.55%. The incidence of adverse events (AEs) of any grade and grade 3/4 were 79.49% and 39.74% in the AS group, 72.61% and 22.93% in the CAPOX group. In the AS and CAPOX groups, neutropenia (31.63% vs 20.13%), leukopenia (29.71% vs 17.25%), anemia (27.80% vs 23.00%) and thrombocytopenia (4.15% vs 17.25%) were the most common AEs. Conclusions: Compared with CAPOX regimen, AS regimen has better survival rates and acceptable tolerability. AS provided new potential adjuvant regimen for stage III gastric cancer after D2 resection. Clinical trial information: NCT04135781 .
Predicting role of circulating tumor DNA and blood-based tumor mutational burden in esophageal squamous cell carcinoma receiving chemoradiotherapy combined with toripalimab: Exploratory analyses from a phase II trial (EC-CRT-001).
Authors: Chen BaoQing , Liu Shi-Liang , Li Qiaoqiao , Liu Mengzhong , Yang Hong , Xi Mian
Published: June 2023

4056

Background: EC-CRT-001 is a phase II trial investigating the efficacy of toripalimab (an anti-PD1 antibody) combined with definitive chemoradiotherapy (CRT) in locally advanced esophageal squamous cell carcinoma (ESCC) and the results demonstrated encouraging antitumor activity and acceptable toxicity. This exploratory analysis was performed to evaluate the role of circulating tumor DNA (ctDNA) and blood-based tumor mutational burden (bTMB) for efficacy prediction. Methods: Forty-two patients from the phase II trial (NCT04005170) who received toripalimab (240 mg every 3 weeks for up to 1 year, or disease progression, or unacceptable toxicity) combined with definitive CRT (irradiation with 50.4 Gy in 28 fractions concurrent with 5 cycles of weekly paclitaxel in 50 mg/m2 and cisplatin in 25 mg/m2) were enrolled. Plasma samples were collected before, during, and after CRT. Targeted next-generation sequencing was performed on a total of 118 plasma samples and 35 matched tumor samples using a panel covering 474 cancer-associated genes. Results: Twenty-six (62%) of 42 patients achieved clinical complete response (cCR) at three months after CRT. ctDNA was detected in 29 (72.5%) of 40 patients at baseline. The positive rate of ctDNA decreased to 43.9% (20/41) during CRT and continued to descend to 27.0% (10/37) at the completion of CRT. A higher cCR rate was observed in patients with negative during-CRT ctDNA compared to those with detectable ctDNA (82.6% vs. 38.9%, P = 0.008). Patients with post-CRT detectable ctDNA also had poorer cCR rate (30.0% vs. 77.8%, P = 0.017). Within a median follow-up of 24.0 months (IQR 13.7-27.9), the median progression-free survival (PFS) was 12.2 months (95%CI: 8.4-16.0) and median overall survival (OS) was not reached for the whole cohort. Patients with during-CRT detectable ctDNA had shorter PFS compared to ctDNA-negative patients (HR = 2.57, 95%CI: 1.18-5.60, P = 0.014). Similarly, patients with post-CRT detectable ctDNA also had a significantly increased risk of disease progression (HR = 2.88, 95%CI: 1.21-6.83, P = 0.012) and death (HR = 3.67, 95%CI: 1.41-9.55, P = 0.004). Moreover, patients with higher bTMB ( > 1) detected during CRT were associated with a favorable OS (HR = 0.33, 95%CI: 0.13-0.88, P = 0.027). Improved PFS was also observed in those patients with higher post-CRT bTMB ( > 3) (HR = 0.28, 95%CI: 0.08-0.96, P = 0.042). Conclusions: Negative ctDNA status and higher bTMB during or after CRT were associated with better tumor response and favorable survival in ESCC patients who underwent definitive CRT combined with toripalimab. Dynamic ctDNA has great potential in predicting efficacy and risk of disease progression in ESCC. Clinical trial information: NCT04005170 .
Pembrolizumab, radiotherapy, and chemotherapy in neoadjuvant treatment of malignant esophago-gastric diseases (PROCEED): Assessment of pathologic response and toxicity in a prospective, phase II single-arm trial.
Authors: Karukonda Pooja , Czito Brian G. , Duffy Eileen , Uronis Hope Elizabeth , D'Amico Thomas A. , Strickler John H , Niedzwiecki Donna , Willett Christopher , Palta Manisha
Published: June 2023

4062

Background: A standard treatment paradigm for locally advanced, resectable, non-metastatic esophageal or gastric adenocarcinomas (EGA) is neoadjuvant chemoradiation (CRT) followed by surgery. Historical pathologic complete response (pCR) rates after CRT with carboplatin/paclitaxel in the CROSS trial are low at 23%. Efficacy of adjuvant immunotherapy has since been shown in this patient population. The main objectives of this trial were to investigate whether neoadjuvant CRT + pembrolizumab improves pCR compared to the historical control of CRT alone, and also determine the associated acute and post-surgical toxicity of this approach. Methods: Single-institution, prospective phase II trial (NCT03064490) evaluating the efficacy and safety of neoadjuvant pembrolizumab + CRT followed by adjuvant pembrolizumab in patients with locally advanced operable EGA. CRT (45 Gy/25 fractions with concurrent weekly carboplatin [AUC 2] and paclitaxel [50 mg/m2 of BSA]) with 3 cycles of pembrolizumab was administered as neoadjuvant therapy. Patients also received 3 cycles of adjuvant pembrolizumab after surgical resection if they did not experience ≥Grade 3 (G3) toxicity during neoadjuvant treatment. Baseline characteristics were collected. Pathologic response was scored from 0-3 per tumor regression grading. The percentage of patients with pCR (score of 0) are described. Acute toxicities are defined per CTCAE v4 and include relevant events occurring within 90 days after treatment. Results: Accrual is complete, with 35 patients with cT2-3N0-2M0 EGA enrolled from 10/10/2017-10/07/2022. 28/32 patients have completed neoadjuvant therapy and surgical resection. 89% of enrolled patients are male, and 94% are white. 97% have an esophageal primary, and 97% underwent R0 resection. 10/28 (35.7%: 95% CI: 17%, 53%) patients achieved a pCR. 22/32 patients have experienced treatment-related ≥G3 non-hematologic toxicity to date (94.2% G3, 5.8% G4). 18 patients experienced ≥G3 toxicity related to neoadjuvant therapy, with 53 events overall, the majority being GI (24.5%) or metabolic/nutritional disorders (24.5%). 10 patients experienced ≥G3 toxicity related to surgery, with 16 events overall, the majority being procedural complications (31.3%) and infectious disorders (31.3%). Conclusions: Patients undergoing neoadjuvant CRT + pembrolizumab for EGA experienced higher rates of pCR and acceptable rates of treatment-related toxicity compared to historical controls. This phase II trial demonstrates the safety and efficacy of this treatment paradigm, which warrants assessment in future prospective studies. Clinical trial information: NCT03064490 .
Five-year overall survival with S-1 plus docetaxel as adjuvant treatment in curatively resected pStage III gastric cancer in JACCRO GC-07.
Authors: Ichikawa Wataru , Yoshida Kazuhiro , Kodera Yasuhiro , Kitazawa Masato , Hirao Motohiro , Seto Yasuyuki , Hibi Kenji , Kinami Shinichi , Watanabe Masaya , Makino Shigeto , Kochi Mitsugu , Sano Takeshi , Kakeji Yoshihiro , Takeuchi Masahiro , Fujii Masashi
Published: June 2023

4065

Background: JACCRO GC-07 is a randomized controlled trial to explore postoperative S-1/docetaxel compared to S-1 alone after D2 gastrectomy for pStage III gastric cancer (GC) patients. The second interim analysis demonstrated that the significant improvement of RFS was obtained by S-1/docetaxel compared to S-1 alone. The study was terminated by the recommendation of independent data and safety monitoring committee (Yoshida K et al. J Clin Oncol 2019; 37:1296-1304). Preplanned analysis to evaluate RFS at 3 years, the primary endpoint, was also published (Kakeji Y et al. Gastric Cancer 2022; 25:186-196). We report the 5-years follow-up data from the trial. Methods: Patients with pStage III GC were randomly assigned to receive either S-1/docetaxel (S-1 80-120mg/body on days 1-14 with a 7-day rest followed by docetaxel 40mg/m2 on day 1 and S-1 80-120mg/body on days 1-14 every 21 days for 6 cycles followed by S-1 80-120mg/body on days 1-28 every 42 days for 4 cycles) or S-1 (80-120mg/body on days 1-28 every 42 days for 8 cycles) after D2 gastrectomy. Blocked randomisation was performed and stratified by the stage (IIIA, IIIB, IIIC) and histological type (differentiated or undifferentiated). The primary endpoint was 3y RFS and the secondary endpoints were OS, TTF and safety. This analysis presents the final preplanned assessment of outcomes after 5 years. Results: Of 915 randomly assigned patients, 912 patients were included in the intention-to-treat (ITT) analysis. In the final analysis, 426 recurrences and 373 deaths were confirmed among the ITT population during the median follow-up period of 63.72 months (3.52-111.87). The 5y RFS of 59.8% in the S-1/docetaxel group was significantly superior to 50.6% in the S-1 group (HR 0.726, 95% CI: 0.599-0.879, p = 0.0010) and the 5y OS was 67.9% in the S-1/docetaxel group and that of S-1 group was 60.3%, respectively (HR 0.752, 95% CI: 0.613-0.922, p = 0.0059), confirming the significant improving effect on the survival of the patient. Conclusions: Adjuvant treatment with S-1 plus docetaxel should be considered for patients with pStage III gastric cancer who underwent D2 gastrectomy without neoadjuvant chemotherapy. Clinical trial information: UMIN000010337 .
Neoadjuvant docetaxel, oxaliplatin, and s-1 plus surgery and adjuvant s-1 for resectable advanced gastric cancer: Final survival outcomes of the randomized phase 3 PRODIGY trial.
Authors: Kang Yoon-Koo , Kim Hyung-Don , Yook Jeong Hwan , Park Young-Kyu , Kim Young-Woo , Kim Jin Young , Ryu Min-Hee , Rha Sun Young , Chung Ik-Joo , Kim In-Ho , Oh Sang Cheul , Yoo Chang Hak , Kang Seok Yun , Zang Dae Young , Kim Sunju , Noh Sung Hoon
Published: June 2023

4067

Background: The phase 3 PRODIGY study compared neoadjuvant docetaxel, oxaliplatin and S-1 (DOS) chemotherapy followed by surgery followed by adjuvant S-1 with surgery followed by adjuvant S-1 for Korean patients with resectable locally advanced gastric cancer (LAGC) (Kang et al. J Clin Oncol. 2021). The planned analysis of the primary endpoint of PRODIGY showed that the addition of neoadjuvant DOS to surgery and adjuvant S-1 improved progression-free survival (PFS). We herein report the long-term follow-up outcomes, including overall survival (OS), from this trial. Methods: Patients with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma with clinical T2-3N+ or T4Nany disease were enrolled from 18 Korean study sites. Patients were randomly assigned to D2 surgery followed by adjuvant S-1 (40–60 mg orally twice a day, days 1–28 q6w for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1–14 q3w for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary endpoint was PFS. OS was the secondary endpoint. This analysis presents the final assessment of the outcomes after 5 years. Results: A total of 266 and 264 patients were randomly assigned to the CSC and SC arms, respectively, among which 238 and 246 patients were treated and included in the full analysis set. As of the data cut-off date (SEP-2022), the median follow-up duration of the surviving patients was 99.5 months (range, 68.6–127.7 months). As compared to SC, CSC significantly increased the OS (adjusted hazard ratio, 0.72; 95% CI, 0.54 to 0.97; stratified log-rank P=0.028) with a 5-year OS rate of 66.8% and 63.0% for the CSC and SC arms, respectively. CSC also significantly improved the PFS (adjusted hazard ratio, 0.71; 95% CI, 0.53 to 0.94; stratified log-rank P=0.019) with a 5-year PFS rate of 60.6% and 56.9% for the CSC and SC arms, respectively. Conclusions: The addition of neoadjuvant docetaxel, oxaliplatin and S-1 (DOS) chemotherapy, as part of perioperative chemotherapy, to surgery and adjuvant S-1 prolonged the OS and PFS of Asian patients with LAGC relative to patients treated with surgery and adjuvant S-1 alone. Neoadjuvant DOS chemotherapy should be considered one of the standard treatment options for patients with LAGC in Asia. Clinical trial information: NCT01515748 .
Neoadjuvant tislelizumab combined with chemoradiotherapy for resectable locally advanced esophageal squamous cell carcinoma (ESCC): Single arm phase II study.
Authors: Jin Peng , Gao Yong sheng , Fu Zheng , Yang Wen feng , Meng Xue
Published: June 2023

4068

Background: This study aimed to evaluate the safety and efficacy of neoadjuvant tislelizumab combined with chemoradiotherapy in patients with resectable esophageal squamous cell cancer. Methods: This is a prospective single-arm clinical trial. A total of 20 patients with newly diagnosed resectable esophageal cancer (cT1-2N+ / cT3-4aN0-3 M0) received 2 cycles of tislelizumab (200mg every 3 weeks for 2 cycles) concurrent with chemoradiotherapy (radiotherapy: 41.4Gy in 23 fractions; chemotherapy: Paclitaxel (Albumin bound) 100mg/m2, and Cisplatin 75 mg/m2 once every 3 weeks for 2 cycles.) Radical esophagectomy was performed within 4-6 weeks after neoadjuvant therapy. PET/CT was performed at baseline and before surgery. Primary endpoints included pathological response rate (pCR) and major pathological response rate (MPR), the secondary endpoints were disease free survival and safety. Exploratory endpoints include molecular imaging research and immune biomarker to further explore the factors affecting the efficacy of neoadjuvant therapy for esophageal cancer. Results: Twenty patients enrolled, all of whom received neoadjuvant tislelizumab combined with chemoradiotherapy. Eighteen patients underwent radical esophagectomy. One patient underwent radical chemoradiotherapy due to lymph node metastases after neoadjuvant therapy. One patient died of pneumonia before surgery. Among 18 patients who underwent surgery, R0 was 100% (18/18), 9 patients achieved pCR (50.0%), and 13 patients achieved MPR (72.2%). Most of treatment-related adverse event (TRAE) were grade 1-2, and the most common TRAE was anemia (15, 75.0%). The grade 3 TRAE included 1 leukopenia (5.0%), 1 neutropenia (5.0%), 1 liver damage (5.0%), and 1 elevated cardiac troponin T (5.0%). A significant decrease in SUVmax was observed in both pCR and no-pCR patients after treatment. Baseline SUVmax in no-pCR patients tended to be higher than pCR patients(p=0.0642). Furthermore, a significant increase in circulating CD4+ T cells, CD4+ effector memory T cells (TEM), and M1 were found after treatment. Among the patients with pCR, the CD4+ TEM and cDCs after treatment were higher than those in the no-pCR patients, while Tregs and M2 were lower. Conclusions: Neoadjuvant tislelizumab combined with chemoradiotherapy for locally advanced ESCC has promising efficacy and good safety. Clinical trial information: NCT05323890 . [Table: see text]
Transarterial chemoembolization combined with lenvatinib and camrelizumab for unresectable hepatocellular carcinoma: A prospective, single-arm, multicenter study.
Authors: Zhang Zhibo , Yan Maolin , Chen Yufeng , Wu Xukun , Yang Lanfang , Yin Zhengyu , Lu Hao , Zeng Yongyi , Zhang Hui , Huang Jingyao , Chen Jiafei , Wang Liang , Chen Zhongwu
Published: June 2023

4072

Background: Conversion therapy for unresectable hepatocellular carcinoma (uHCC) has attracted increasing interest in recent years. In 2020 ASCO annual meeting, one abstract reported that the combination therapy of tyrosine kinase inhibitor and anti-PD-1 antibody could be a promising conversion therapy for patients with initially uHCC. This study aims to evaluate the efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib and camrelizumab (TACE+LEN+CAM) as a conversion therapy for uHCC. Methods: This single-arm, prospective, multicenter study was conducted on patients diagnosed with HCC (with an Eastern Cooperative Oncology Group performance score (ECOG PS) of 0-1 and Child-Pugh class A) who were ineligible for surgery. Enrolled patients received camrelizumab (200 mg every 3 weeks) and lenvatinib (bodyweight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day) after TACE treatment. Surgery was performed after treatment response was assessed to meet the criteria of resection. Patients who did not meet the criteria for surgery continued to receive triple treatment until disease progression or intolerable toxicity. Primary endpoints were objective response rate (ORR)and safety. Secondary endpoints included percentage of patients amendable to surgery, the rate of radical (R0) resection, disease control rate (DCR). This study is registered with Chinese Clinical Trial Registry (ChiCTR2100050410). Results: Between Oct 25, 2021, and Jul 20, 2022, 55 patients were enrolled and received triple therapy (TACE+LEN+CAM). Of these, 37 (67.3%) patients had portal vein tumor thrombosis. Mean tumor diameter for all patients was 112 ± 83 mm. 52 (94.6%) patients with≤2 target lesions, and 3 (5.4%) patients with > 2 target lesions. As of data cutoff on Dec 20, 2022, the median follow-up was 6.7 months (IQR 5.0-9.89). According to modified RECIST criteria, tumor response in patients included complete response to treatment in 9 patients (18.0%), partial response in 27 (54.0%), stable disease in 6 (12.0%), and progressive disease in 7 (14.0%). The ORR was 72.0%, and the DCR was 84.0%. 26 patients underwent surgery after successful conversion therapy. The MPR and pCR rates in the surgery population were 69.2% and 23.1%, respectively. The conversion rate was 55.3% and the R0 resection rate was 100%. 23 (41.8%) of 55 patients had treatment-related adverse event (TRAEs) that were grade 3-5. No grade 3-5 TRAEs occurred after surgery. Conclusions: The triple therapy (TACE+LEN+CAM) significantly improved ORR and the surgical conversion rate of uHCC patients with a manageable safety. Future large-scale randomised trials are warranted. Clinical trial information: ChiCTR2100050410 .
Temporal patterns 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 , Sangro Bruno , Crysler Oxana V. , Sukeepaisarnjaroen Wattana , Lipatov Oleg , Morimoto Manabu , Archambeaud Isabelle , Burgio Valentina , Tuyet Phuong Le Thi , Chao Yee , Peron Jean-Marie , Berres Marie-Luise , Ko Yoo-Joung , McCoy Carrie L. , Gupta Charu , Makowsky Mallory , Negro Alejandra , Abou-Alfa Ghassan K.
Published: June 2023

4073

Background: In the Phase 3 HIMALAYA study (NCT03298451) in uHCC, STRIDE (Single T Regular Interval D) significantly improved overall survival versus sorafenib (S) and had manageable safety (Abou-Alfa et al. NEJM Evid 2022). STRIDE is approved for uHCC in the United States and Japan and is recommended for approval by the European Medicines Agency. In this exploratory post hoc analysis, we assessed temporal patterns of imAEs for the STRIDE regimen 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) or S (400 mg twice daily). Treatment causality was investigator-assessed. imAEs were defined as AEs of special interest associated with drug exposure and consistent with an immune-mediated mechanism of action for which no alternate etiology was clear. Safety was summarized descriptively overall and at specific time points after the start of treatment. Results: In total, 388 (STRIDE) and 374 (S) pts were included in the safety analysis. Median (range) duration of exposure was 5.5 (0.4–41.9) months for STRIDE (D exposure in STRIDE) and 4.1 (0.1–38.6) months for S. Any grade treatment-related AEs (TRAEs) and Grade 3 or 4 TRAEs were less frequent for STRIDE (75.8% and 25.8%, respectively) versus S (84.8% and 36.9%, respectively). Any grade imAEs and max Grade 3 or 4 imAEs occurred in 35.8% and 12.6% of pts, respectively for STRIDE. Any grade imAEs and max Grade 3 or 4 imAEs with STRIDE occurred at all time points assessed and were most likely to occur within the first three months after treatment. For STRIDE, any grade imAEs of gastrointestinal disorders and skin and subcutaneous tissue disorders were most common within the first month after treatment (3.9% and 3.1%, respectively), whereas any grade imAEs of endocrine disorders were most common between >1 and ≤2 months (6.7%). Conclusions: In HIMALAYA, AEs with STRIDE were manageable and generally low grade. Any grade TRAEs and Grade 3 or 4 TRAEs were less frequent for STRIDE versus S. Although imAEs with STRIDE could occur at any time, most were observed within the first three months after treatment. These findings continue to support STRIDE for the treatment of uHCC. Clinical trial information: NCT03298451 . [Table: see text]
Landmark analysis of OS by response status in previously treated patients (pts) with advanced hepatocellular carcinoma (aHCC): Post hoc analysis of the KEYNOTE-394 study.
Authors: Ren Zhenggang , Chen Zhendong , Fang Weijia , Ou Shuangyan , Ryoo Baek-Yeol , Meng Zhiqiang , Bai Yuxian , Chen Xiaoming , Liu Xiufeng , Xiao Juxiang , Ho Gwo Fuang , Mao Yimin , Wang Xin , Jieer Ying , Hao Chunyi , Shen Hujia , Lin Jianxin , Hatogai Ken , Siegel Abby B. , Qin Shukui
Published: June 2023

4074

Background: KEYNOTE-224 and KEYNOTE-240 landmark analyses showed that objective response (OR) in pembrolizumab (pembro)-treated pts was prognostic of longer OS after the landmark. Landmark analysis was performed using the KEYNOTE-394 study to determine whether response assessment before landmark is prognostic of longer OS after landmark time in pembro-treated pts. Methods: Adults with confirmed HCC, radiographic progression during or after treatment with or intolerance to sorafenib or oxaliplatin-based chemotherapy were eligible for KEYNOTE-394. Landmark analyses of OS for responders, pts with SD, and pts with other status in these analyses at 6, 12, 18, and 24 wk after randomization were performed on the pembro arm. Tumor imaging was performed every 6 wk after randomization. Responders (R) at each landmark were defined as pts with any response assessment of CR or PR before the landmark date; all other pts were defined as nonresponders (NR). SD at each landmark was defined as pts with a response assessment of SD and no better response before the landmark date. Other was defined as pts with responses of PD or a missing/not evaluable status. Response was assessed per RECIST v1.1 by blinded independent central review. HR and 95% CI for survival after the landmark are based on the Cox regression model with the Efron method for handling ties, with response status by the landmark time as a single covariate. Results: Median time from randomization to data cutoff date (June 30, 2021) was 33.8 mo (range, 18.7-48.8) for pembro. OS after landmark time was numerically longer for R vs NR, R vs pts with SD, and pts with SD vs pts with Other status. Conclusions: KEYNOTE-394 landmark analysis supports the prognostic association between OR with pembro before the landmark and OS after the landmark observed in KEYNOTE-224 and KEYNOTE-240 in previously treated pts with aHCC. Landmark analysis also suggested longer OS after the landmark for pts who achieved a better response to pembro before the landmark. Clinical trial information: NCT03062358 . [Table: see text]
Safety and efficacy of transarterial chemoembolization combined with tyrosine kinase inhibitors and camrelizumab in the treatment of patients with advanced unresectable hepatocellular carcinoma.
Authors: Li Jinpeng , Jia Yuntao , Han Huihui , Lin Yanyan , Song Jinlong
Published: June 2023

4079

Background: Combined systemic and local therapy is a promising treatment strategy for patients with advanced hepatocellular carcinoma (HCC). Transarterial chemoembolization (TACE), tyrosine kinase inhibitors (TKI) and PD-1 antibodies are all recommended for patients with unresectable HCC (uHCC). This study was aimed to evaluate the efficacy and safety of TACE combined with TKIs and camrelizumab in the treatment of uHCC. Methods: In this multicenter, single-arm phase II trial (ChiCTR2000039508), patients with intermediate-stage uHCC who had a Child-Pugh score ≤ 7 and had not received prior systemic anti-cancer treatment would receive treatment with TACE followed by immunotherapy with camrelizumab 200 mg every 3 weeks plus a TKI agent selected from lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg), sorafenib 400 mg bid or donafenib 200 mg bid until intolerable toxicity or disease progression. During the study treatment, patients assessed as eligible for resection would undergo surgery. The primary endpoint was objective response rate (ORR) per modified RECIST. Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response (DOR) and overall survival (OS). Results: From September 2020 to November 2021, 87 patients (81 men and 6 women; median age, 56 years) were enrolled. Among them, 43 (49.4%) patients had extrahepatic metastases, and 65 (74.7%) patients had HBV infection. As of September 28, 2022, the median duration of follow-up was 13.6 (0.83-24.9) months. A total of 34 patients (39.1%) died, and the median OS was not reached. The median PFS was 10.5 months (95% CI: 7.8-13.1). The ORR rate was 71.3% (62/87), and the DCR rate was 89.7% (78/87) per mRECIST. According to RECIST version 1.1, the ORR rate was 35.6% (31/87), and the DCR rate was 87.4% (76/87). The ORR and PFS showed consistent benefits in subgroups based on ECOG score, HBV infection, baseline alpha-fetoprotein level, combined TKI, and the number of TACE treatments. Ten patients (11.5%) successfully underwent conversion therapy and all achieved R0 resection. Two patients achieved a complete pathological response (pCR) and four achieved a major pathological response (MPR). The most common AEs were hypoproteinemia (92%), elevated lactate dehydrogenase (80.5%), elevated glutamic oxaloacetic transaminase (79.3%), elevated bilirubin (78.2%), abdominal pain (62.1%), nausea (33.3%), and RCCEP (26.4%). The incidence of grade 3-4 adverse reactions was 67.8%, and no treatment-related deaths occurred. Conclusions: TACE combined with TKI and camrelizumab showed promising clinical benefits. It can effectively control tumor progression and provide opportunities for resection with acceptable safety, which will bring great benefits to uHCC. Clinical trial information: ChiCTR2000039508 .