bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world experience on the efficacy and tolerability of biweekly trifluridine/tipiracil with or without bevacizumab in metastatic colorectal cancer.
Authors: Ang Choon Seong , Low Qin Jian , Ho Carol LF , Walsh Robert John , Asokumaran Yugarajah , Choo Joan RE , Chan Gloria HJ , Ho Jingshan , Ang Yvonne , Tan Hon Lyn , Yong Wei-Peng , Sundar Raghav , Chee Cheng Ean
Published: June 2022

3584

Background: Trifluridine/tipiracil (TAS-102) is currently approved as third-line treatment in metastatic colorectal cancer (mCRC). However, there is paucity of real-world data on the tolerability and efficacy with biweekly dosing as monotherapy or in combination with bevacizumab. In this study, we present our center’s experience with biweekly TAS-102 with or without bevacizumab in mCRC patients (pts). Methods: We performed a single center retrospective observational study of pts receiving TAS-102 between 2018 and 2021. Results: A total of 83 pts were included (53 men, 30 women), with a median age of 64 years. Majority of pts were treated with TAS-102 in the 3rd-line (48.2%) and 4th-line (28.9%) setting. Almost all (94.0%) were of ECOG ≤ 1 at the initiation of treatment. The mean number of cycles administered was 3.8 and bevacizumab (5mg/kg on Day 1, every 2 weeks) was used in combination with TAS-102 in 18 pts (21.7%). Majority of pts (84.3%) were given TAS-102 using the biweekly regimen (35mg/m2 BD, on Day 1-5 and 15-19, q28 days) rather than standard regimen (35mg/m2 BD, on Day 1-5 and 8-12, q28 days) following a change in institutional practice. Fifteen pts (18.1%) had their initial dose reduced to 30mg/m2 BD at prescriber's discretion. Median PFS and OS were 2.37 and 10.15 months, respectively. In terms of tolerability, fatigue (any grade, 42.2%) and neutropenia (any grade, 44.6%) were the two most common adverse events reported. Grade 3 or higher neutropenia and febrile neutropenia were 16.9% and 3.6%, respectively. Dose reduction during treatment was required in 15 pts (18.1%), dose delay in 31 pts (37.3%) and six pts (7.2%) discontinued treatment due to toxicity. More than half (54.2%) had at least an additional line of therapy (regorafenib, clinical trials or re-challenge previous chemotherapy agents) following disease progression with TAS-102. Conclusions: We report the largest real-world experience with biweekly TAS-102. Our pts treated with TAS-102 had comparable median PFS to the RECOURSE cohort but with significantly better OS as more than half continued to receive treatment. Biweekly dosing of TAS-102 with or without bevacizumab is well tolerated with significantly lower rates of Grade 3 neutropenia compared to the published data in the literature.
Clinical outcomes following termination of immunotherapy due to long-term benefit in MSI-H colorectal cancer.
Authors: Simmons Kristen , Kee Bryan K. , Raghav Kanwal Pratap Singh , Johnson Benny , Kopetz Scott , Willis Jason , Dasari Arvind , Vilar Sanchez Eduardo , Ludford Kaysia , Parseghian Christine Megerdichian , Lee Michael Sangmin , Le Phat , Shen John Paul Y.C. , Overman Michael J. , Morris Van K.
Published: June 2022

3585

Background: Immune checkpoint blockade therapy improves survival in patients (pts) with microsatellite instability-high (MSI-H) advanced colorectal cancer (CRC). Oncologists often discontinue immunotherapy after 2 years of disease control based on prior trial data. Recurrence outcomes following discontinuation of immunotherapy and clinicopathologic features associated with recurrence remain underreported given the recent advent of these agents for pts with MSI-H advanced CRC. Methods: Records from pts with MSI-H CRC from MD Anderson Cancer Center who received immunotherapy between 2015-2022 and stopped after clinical benefit were reviewed. Median survival was estimated according to the Kaplan-Meier method. Associations between the event of recurrence and coexisting mutations ( KRAS, NRAS, BRAFV600E, PIK3CA, APC, TP53, POLE/POLD), metastatic site (lung, liver, lymph nodes, or peritoneum), primary tumor sidedness (right vs. left colon), and prior immunotherapy (anti-PD-(L)1 alone or with anti-CTLA-4 antibodies) were measured by Fisher’s exact tests. Results: Thirty-six pts with MSI-H CRC without progression on immunotherapy were reviewed. Of these 29 and 7 received anti-PDL1 antibody alone or in combination with anti-CTLA-4 antibody, respectively. Median exposure to prior immunotherapy was 24 months (range, 5-43). After a median follow-up of 19 months (95% CI, 14-26) after stopping immunotherapy, 30 of 36 pts (83%) remained without disease progression. For the 6 patients with progression after stopping, median time to relapse was 13 months (range, 5-31). Median disease-free survival (DFS) was not reached. The estimated 1-year, 2-year, and 3-year DFS probabilities were 90% (95% CI, 79-100), 79.1% (95% CI, 64-98), and 68% (95% CI, 47-98), respectively. Median overall survival from the time that immunotherapy was stopped was 54 months (95% CI, 47-NA). Only 1 pt died due to unrelated illness. There were no observed associations between disease recurrence and co-existing mutations, metastatic organ involvement, primary tumor sidedness, or immunotherapy used. Conclusions: Most pts with MSI-H advanced CRC who achieve initial clinical benefit and do not progress on immunotherapy do not recur after treatment is stopped. Our data suggest that favorable outcomes do occur following cessation of immunotherapy in this setting even with concomitant prognostically unfavorable clinical features (RAS, BRAFV600E mutations; liver, peritoneal metastases).
Preliminary results of raltitrexed in Chinese patients with metastatic colorectal cancer: A prospective, multicenter, real-world study.
Authors: Li Jin , Qin Shukui , Zhou Ai-Ping , Zhang Yanqiao , Yuan Xianglin , Qin Baoli , Zeng Shan , Shen Lin , Yuan Ying , Zhu Liangjun , Wang Weibo , Zhang Xianwen , Liang Jun , Ye Feng , Chen Ping , Wang Huaizhang , Yu Zhengyan , Fang Yong , Yue Lu , Xiong Jianping
Published: June 2022

3591

Background: Raltitrexed-based chemotherapy regimen is one of the common regimens for the treatment of metastatic colorectal cancer (mCRC). This prospective observational real-world study aimed to evaluate the safety and effectiveness of raltitrexed administered to Chinese patients with mCRC in real life setting. Methods: This is a prospective, multicenter, real-world study. Prospectively registered Patients received second-line treatment of raltitrexed plus irinotecan combined with or without target therapy until progression disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), quality of life (QOL) and safety. Totally,1000 patients were required for primary point testing. Results: Between May 2018 and December 2021,a total of 1039 patients from 57 centers were screened for enrollment,among which 271 patients were treated with raltitrexed plus irinotecan, 753 patients accepted target therapy (bevacizumab or cetuximab) additionally, and 15 patients combined with other drugs. Overall mPFS was 6.8 months (95%CI: 6.5-7.1),ORR was 20.2%, and DCR was 85.7%; The ORR of combined with or without target therapy were 21.6% and 16.2% ( p = 0.038),respectively, the DCR were 88.2% and 79.0% ( p < 0.001). The mPFS of combined without or with target therapy were 5.2 months (95% CI: 4.7 to 5.7) and 7.3 months respectively (95% CI: 7.0-7.7) [HR = 0.67, 95% CI 0.56̃0.80, p < 0.001], The mPFS of combined with bevacizumab or cetuximab were 7.4 months (95% CI: 7.0 -7.8) and 6.8 months (95% CI: 5.9-7.7) [HR = 1.15, 95% CI 0.88̃1.51, p = 0.3]. mOS has not yet reached. Majority of treatment-related adverse events (TEAEs) were grade I or II. The most common grade III or IV TRAEs reported by 116 patients (11.2%) were aspartate aminotransferase increased (4.0%), alanine aminotransferase increased (3.7%), neutrocytopenia (2.7%), glutamyltransferase increased (2.5%), leukocytopenia (1.1%). Conclusions: The real-world study confirmd that raltitrexed was an effective and safe regimen for the second-line treatment in Chinese patients with mCRC, especially combined with target therapy additionally, which was aligned with previous trials. Clinical trial information: ChiCTR1800016185.
PKUCH 04 trial: Total neoadjuvant chemoradiation combined with neoadjuvant PD-1 blockade for pMMR/MSS locally advanced middle to low rectal cancer.
Authors: WU Aiwen , Li Yingjie , Ji Dengbo , Zhang Li , Zhang Xiaoyan , Cai Yong , Zhang Yangzi , Yao Yunfeng , Wang Lin , Leng Jiahua , Zhan Tiancheng , Sun Ying-Shi , Li Zhongwu
Published: June 2022

3609

Background: Total neoadjuvant therapy (TNT) with induction chemotherapy and chemoradiation is the standard of care for locally advanced rectal cancers. Incorporation of PD-1 blockade in the neoadjuvant setting is promising for mismatch repair deficient (dMMR) patients, yet the efficacy of TNT combined with PD-1 blockage for pMMR/MSS patients is little unknown. The purpose of this study is to evaluate the clinical benefit of neoadjuvant PD-1 blockade combined with TNT in pMMR/MSS locally advanced rectal cancer. Methods: We designed a prospective, single-arm, phase II study on locally advanced dMMR/MSS rectal cancer (PKUCH 04 trial). Patients will receiving neoadjuvant regimen (PD-1 inhibitor, camrelizumab, also called SHR01210, 200mg d1, oxaliplatin 130mg/m2 d1, capecitabine 1250mg/m2 bid1-14, for three cycles, then long course chemoradiation (IMRT, 1.8Gy/f*25f), then another two cycles of CapeOx (oxaliplatin 130mg/m2 d1, capecitabine 1250mg/m2 bid1-14, q3wks) if no disease progression occurs. The primary endpoint was pathologic complete response (pCR) rate, and the secondary outcome include adverse event and surgical complication. Tumor assessment was carried out after induction, chemoradiation, and before the decision of either surgery or watch and wait. Results: A total of 27 patients were screened and finally 25 patients were eligible for further analysis, with median age 58 years (range 31-70). The median distance from the anal verge was 5.3 cm (1.2-10). 76% were male, 76% had N2 disease, 56% positive MRF, 80% positive EMVI. All patients have completed the induction and chemoradiation phases. 21 patients underwent TME surgery, of which 7 had pathological complete response (33.3%). Four achieved clinical complete or near complete response and chose watch and wait. 7 had major pathological remission (over 90% remission). Another 7 had partial pathological remission. No progressive disease was found. 14 had LAR, 7 APR, and. The surgical complication rate was 14.3%, and the mortality rate was 0. The common adverse events included nausea (80%), lymphopenia (80%), paresthesia (76%), reactive cutaneous capillary endothelial proliferation (72%), neutropenia (68%). Grade 3 adverse events include lymphopenia (24%), diarrhea (8%), and thrombocytopenia (4%) and no grade 4 or 5 events were observed. Till January 2022, no recurrence or regrowth was found. Conclusions: Total neoadjuvant chemoradiation combined with neoadjuvant PD-1 blockade is safe and effective which can achieve good regression and sphincter preservation for pMMR/MSS rectal cancer. This suggests a potential new paradigm for treatment of pMMR/MSS locally advanced rectal cancer and necessitates further investigation. Clinical trial information: NCT04340401.
Surgical and pathological outcome, and pathological regression, in patients receiving perioperative atezolizumab in combination with FLOT chemotherapy versus FLOT alone for resectable esophagogastric adenocarcinoma: Interim results from DANTE, a randomized, multicenter, phase IIb trial of the FLOT-AIO German Gastric Cancer Group and Swiss SAKK.
Authors: Al-Batran Salah-Eddin , Lorenzen Sylvie , Thuss-Patience Peter C. , Homann Nils , Schenk Michael , Lindig Udo , Heuer Vera , Kretzschmar Albrecht , Goekkurt Eray , Haag Georg Martin , Riera Knorrenschild Jorge , Bolling Claus , Hofheinz Ralf-Dieter , Angermeier Stefan , Ettrich Thomas Jens , Siebenhuener Alexander , Kopp Christina , Pauligk Claudia , Goetze Thorsten Oliver , Gaiser Timo
Published: June 2022

4003

Background: DANTE evaluates atezolizumab in the perioperative treatment of resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma in combination with FLOT. Here, we report interim results. Methods: DANTE is a multicenter, investigator-initiated, phase IIb trial. Patients (pts) with resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N+) were randomized to receive 4+4 cycles of periop. FLOT chemotherapy (arm B) or the same regime with additional atezolizumab at 840 mg, q2w, followed by atezolizumab monotherapy for 8 cycles at 1200 mg, q3w (arm A). The primary endpoint is progression-free survival. The secondary endpoints surgical outcome (pTNM, R0 resection rate and periop. morbidity/mortality), path. regression and safety are reported here. TNM stage was evaluated by local pathologists and path. regression (Becker-Classification) by local and central pathologists. PD-L1 and MSI status were centrally evaluated. Results: In total, 295 pts were randomized (A, 146; B, 149) with baseline characteristics as follows: median age 61y, male 74%, intestinal type 42%, GEJ 61%, cT3/4 77%, N+ 78%. Twenty-five pts (8.5%) were MSI; 50% had PD-L1 CPS ≥1, 23% PD-L1 CPS ≥5 and 15% PD-L1 CPS ≥10. Pre-op FLOT cycles were completed in 93% of pts and post-op cycles in 43% of pts, with no difference between arms. Surgical morbidity (A, 45%; B, 43%) and mortality (overall 2.5%) were comparable between arms, as were R0-resection rates (arm A, 92% vs. arm B, 91%). Downsizing favored arm A vs B (pT0, 23% vs 15%; pN0, 68% vs 54%). Increases in path. regression rates were seen, particularly with higher PD-L1 expression (Table). Conclusions: The analysis shows beneficial effects of atezolizumab combined with FLOT vs FLOT alone on path. stage and path. regression that seem to be more pronounced with higher PD-L1 expression. Sponsor: Institut für Klinische Krebsforschung IKF am Krankenhaus Nordwest. EudraCT: 2017-001979-23. Clinical trial information: NCT03421288. [Table: see text]
The association of B7-H6 expression to the immune microenvironment in gastric cancer.
Authors: Chen Jian , Li Deqin , Sun Dengjun , Song Shujie , Zhang Weiwei , Luo Ningning , Ge Minghui , Li Mengmeng , Qi Yingxue , Zhu Xiaofeng , Sun Tingting , Qi Chuang
Published: June 2022

4025

Background: B7-H6, also known as NCR3LG1, is a promising molecule in B7 family and a ligand of natural killer (NK) -cell-activating receptor NKp30. B7-H6 can bind NKp30 and induce NK activation and cytokine secretion to exert anti-tumor effects. Studies have reported that the B7-H6 expression is significantly correlated with post-operative prognosis and distant metastasis status in patients with cancer. In patients with gastric cancer, B7-H6 high expression is significantly associated with longer OS. However, the effects of B7-H6 on immunotherapy and immune microenvironment are unknown. Herein, we used the data from TCGA database of gastric cancer to analyze the influence of B7-H6 expression on immune microenvironment. Methods: The gene expression profile and clinical data in gastric cancer were extracted from TCGA database ( http://cancergenome.nih.gov ). According to the previous reported article, 15 was chosen as the cutoff value for the expression of B7-H6, and the expression of B7-H6 is divided into two groups, high group (B7-H6 expression＞15) and low group (B7-H6 expression≤15). Kaplan-Meier analysis was used to verify the influence of B7-H6 expression on OS prognosis. “Cell Type Identification by Estimating Relative Subsets of RNA Transcripts” (CIBERSORT) algorithm was used to analyze the proportion of immune-related cells in the two groups. “Estimation of STromal and Immune cells in Malignant Tumours using Expression data” (ESTIMATE) algorithm was used to analyze stromal and immune scores in the two groups. The differences of immune-related signatures between the two groups were calculated according to previous reports. Results: Kaplan-Meier survival analysis showed that high group was significantly associated with longer overall survival (p value = 0.016), which was consistent with previous reports. The result of CIBERSORT algorithm showed that the proportion of activation immune correlation CD8(+) T cells and NK active cells was significantly higher in low group than in high group (p＜0.05). Meanwhile, the proportion of immune suppressive correlation CD4 resting memory T cell was significantly lower in low group than in high group (p＜0.05). The result of ESTIMATE algorithm showed that the stromal score, immune score, and ESTIMATE score in low group were significantly higher than in high group (p＜0.01). The immune-related signatures, including immune signature, expanded immune signature, TLS signature, myeloid cell chemotaxis, tertiary lymphoid structure, were significantly higher in low group than in high group (p＜0.05). Conclusions: The low B7-H6 expression was correlated with better immune microenvironment. The effect of B7-H6 expression on immunotherapy needs to be further explored.
Choice of PD-L1 immunohistochemistry assay influences clinical eligibility for gastric cancer immunotherapy.
Authors: Tay Ryan Yong Kiat , Yeong Joe Poh Sheng , Lum Jeffrey , Teo Chong Boon , Tan Benjamin Kye Jyn , Chan Yiong Huak , Choo Joan RE , Jeyasekhran Anand , Miow Qing Hao , Loo Lit-Hsin , Yong Wei-Peng , Sundar Raghav
Published: June 2022

4026

Background: Immune checkpoint inhibitors (ICI) are now standard-of-care treatment for patients with metastatic gastric cancer (GC). To guide patient selection for ICI therapy, programmed death ligand-1 (PD-L1) biomarker expression is routinely assessed via immunohistochemistry (IHC). Regulatory approval for ICIs is granted based on PD-L1 expression status, scored using metrics such as the combined positive score (CPS). However, with an increasing number of approved ICIs, each paired with a different PD-L1 antibody IHC assay used in their respective landmark trials, there is an unmet clinical and logistical need for harmonization. We thus investigated the interchangeability between the Dako 22C3, Dako 28-8 and Ventana SP-142 assays in GC PD-L1 IHC. Methods: In this cross-sectional study, samples were obtained via biopsy or resection of gastric cancer at the National University Hospital, Singapore. We scored 362 GC samples for PD-L1 CPS, tumor proportion score (TPS) and immune cells (IC) using a multiplex immunohistochemistry/immunofluorescence technique. 344 samples were developed into a tissue microarray (TMA), while 18 samples were used as whole slides for orthogonal validation. The samples selected for whole slide analysis were obtained from GC patients treated with ICI therapy. Results: The percentage of PD-L1 positive samples at clinically relevant CPS ≥1, ≥5 and ≥10 cut-offs (Table) for the 28-8 assay were approximately two-fold higher than that of the 22C3 (CPS≥1: 70.3% vs 49.4%, p<0.001; CPS≥5: 29.1% vs 13.4%, p<0.001; CPS≥10: 13.7% vs 7.0%, p=0.004). The mean CPS score on 28-8 assay was nearly double that of the 22C3 (6.39 ±14.5 vs 3.46±8.98, p<0.001). At the clinically important CPS≥5 cut-off, there was only moderate concordance between the 22C3 and 28-8 assays. Conclusions: Our findings suggest that scoring PD-L1 CPS with the 28-8 assay may result in higher proportion of PD-L1 positivity and higher PD-L1 scores compared to assessment with the 22C3 and other assays. Clinically, this could lead to a larger number of patients eligible and approved for ICI therapy. If assays are viewed and used interchangeability, a substantial number of patients may be inaccurately denied or granted treatment with ICIs based on the assay chosen. As such, until stronger evidence of inter-assay concordance is found, we urge caution in treating the assays as equivalent.[Table: see text]
VOYAGER (KSCC1902): A single-arm, multicenter, phase II study of early induction of nivolumab during second-line treatment with taxane ± ramucirumab for advanced gastric or gastro-esophageal junction cancer.
Authors: Katsuya Hiroo , Makiyama Akitaka , Kashiwada Tomomi , Shinohara Yudai , Hu Qingjiang , Otsu Satoshi , Yoneda Akira , Emi Yasunori , Ishibashi Nobuya , Kojiro Eto , Nakamura Masato , Shimokawa Mototsugu , Oki Eiji , Saeki Hiroshi , Mori Masaki
Published: June 2022

4028

Background: Although nivolumab prolonged overall survival in 3rd or later line treatment for advanced gastric cancer in the ATTRACTION-2 study, only a small number of patients respond or achieve stable disease. Previous reports have shown that low tumor burden at the start of treatment was potentially associated with efficacy to immunotherapy in some types of tumors, but it has not been studied in advanced gastric cancer. We conducted a clinical trial to evaluate the early induction of nivolumab. Methods: Eligible patients were unresectable advanced or recurrent gastric or gastro-esophageal junction cancer, histologically confirmed to be adenocarcinoma regardless of PD-L1 expression. Patients who were refractory to or intolerant of fluoropyrimidines had a complete or partial response after at least three cycles of taxane ± ramucirumab, and were confirmed to be either of the following conditions; disease progression by imaging tests, an increase of tumor markers, exacerbation of symptoms, and intolerant of pretreatment. Patients received 240mg/body nivolumab every 2 weeks. The primary endpoint was the rate of progression-free survival (PFS) at 6 months (M), and the secondary endpoints included safety, overall survival (OS), response rate (RR), time to treatment failure (TTF), and duration of response (DOR). Based on assuming a threshold PFS at 6M of 16% and an expected PFS of 30% with the early induction of nivolumab, 39 patients were required for a power of 0.8 with a one-sided α of 0.1. Results: Between September 2019 and February 2021, 42 patients were enrolled in this study. The characteristics of patients were male/female: 28/14, median age: 71 years (range: 39-87), and performance status 0/1/2: 21/19/2. The PFS at 6M was 35.7% (80% confidence interval 26.4-45.1%), which means this trial met the primary endpoint. The median PFS and OS were 4.0M (95%CI:2.3–5.7) and 10.9M (95%CI:9.9–16.0), respectively. Of 34 patients with baseline target legions, RR was 17.5% (all confirmed partial response) and the rate of stable disease was 41.2%. TTF, and DOR were 3.6M (95%CI:2.2–5.1), and 14.3M (95%CI:3.9–14.3), respectively. No new safety signals were observed. Conclusions: This study demonstrated an improvement of PFS at 6M in patients with advanced gastric cancer and might justify the strategy of early induction of nivolumab. Clinical trial information: jRCTs071190025.
Zanidatamab (zani), a HER2-targeted bispecific antibody, in combination with chemotherapy (chemo) and tislelizumab (TIS) as first-line (1L) therapy for patients (pts) with advanced HER2-positive gastric/gastroesophageal junction adenocarcinoma (G/GEJC): Preliminary results from a phase 1b/2 study.
Authors: Lee Keun Wook , Bai Li-Yuan , Jung Minkyu , Ying Jieer , Im Young Hyuck , Oh Do-Youn , Cho Jae Yong , Oh Sang Cheul , Chao Yee , Li Huiyan , Zhou Ping , Bao Yuanyuan , Kang Yoon-Koo
Published: June 2022

4032

Background: Zani, also known as ZW25, is a novel HER2-targeted bispecific antibody that targets two distinct extracellular domains of HER2. Zani has shown preliminary antitumor activity and tolerability in pts with HER2+ gastroesophageal adenocarcinoma as monotherapy/with chemo in Phase 1/2 studies (NCT02892123, NCT03929666). TIS, an anti-PD-1 antibody, has demonstrated antitumor activity in pts with advanced solid tumors. Combining anti-HER2 therapy with anti-PD-1 therapy and chemo increased tumor response in G/GEJC in a Phase 3 clinical trial. Methods: Cohort 2 of this ongoing open-label, Phase 1b/2 study was in pts with untreated locally advanced/metastatic HER2+ G/GEJC (NCT04276493). Cohort A received zani 30 mg/kg IV, Cohort B received zani 1800 mg IV (weight < 70 kg) or 2400 mg IV (weight ≥ 70 kg), both with TIS 200 mg IV and capecitabine/oxaliplatin (CAPOX) Q3W. Primary endpoints were safety and investigator (INV)-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included INV-assessed duration of response (DoR), disease control rate (DCR) and progression-free survival (PFS). Results: As of Nov 26, 2021, 33 pts with a median age of 64.0 years (range: 29.0–80.0) were assigned to Cohort A (n=19) or B (n=14). Median study follow-up was 7.7 months (range: 2.1–19.0) and the median number of treatment cycles was 10 (range: 1–28), 20 (60.6%) pts remained on treatment. All pts were efficacy evaluable ([EE], n=33), confirmed ORR was 72.7% (95% CI: 54.5, 86.7). Median PFS was 10.9 months (95% CI: 6.9, NE). Efficacy data are summarized in the Table. All pts experienced ≥ 1 treatment emergent adverse event (TEAE), and 24 (72.7%) pts experienced ≥ Grade 3 TEAEs. All pts experienced treatment related TEAEs (trTEAEs), 20 (60.6%) pts experienced ≥ Grade 3 trTEAEs and trTEAEs leading to death occurred in two (6.1%) pts. Immune-mediated AEs (imAEs) occurred in nine (27.3%) pts, of which seven (21.2%) pts experienced ≥ Grade 3 imAEs. Conclusions: Zani, TIS and CAPOX combination demonstrated a manageable safety profile and antitumor activity as 1L therapy for pts with HER2+ G/GEJC. Clinical trial information: NCT04276493. [Table: see text]
A phase II study evaluating KN026 monotherapy in patients (pts) with previously treated, advanced HER2-expressing gastric or gastroesophageal junction cancers (GC/GEJC).
Authors: Xu Jianming , Liu Rongrui , Ying Jieer , Wu Jun , Ye Feng , Xu Nong , Zhang Yanqiao , Zhao Rusen , Xiang Xiaojun , Wang Jianhong , Lin Xiaoyan , Xu Huiting , Gao Shegan , Luo SuXia , Guo Baohong , Li Xionghui , Su Yangzhi , Wang Qian
Published: June 2022

4040

Background: Outcomes of second or later-line treatment for pts with advanced GC/GEJC remain inferior. KN026 is a novel HER2-targeted bispecific antibody composed of VH regions of trastuzumab and pertuzumab, targeting the HER2 juxtamembrane domain (IV) and the dimerization domain (II) simultaneously. KN026 has shown promising antitumor efficacy in preclinical and phase I studies. Here we present the results of KN026 monotherapy in previously treated, advanced HER2-expressing GC/GEJC. Methods: In this multi-center, single-arm, open-label, 2-cohort phase II study, adult pts with previously treated, advanced GC/GEJC were assigned into a HER2 high-level cohort (Cohort 1: IHC3+ or IHC 2+ ISH+) or a HER2 low-level cohort (Cohort 2: IHC 1+/2+ ISH- or IHC 0/1+ISH+). KN026 was given intravenously in 10 mg/kg QW, 20 mg/kg Q2W, or 30 mg/kg Q3W. Primary endpoints were objective response rate (ORR) and duration of response (DoR) assessed by investigators per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety outcomes. This trial is registered at ClinicalTrials.gov (NCT03925974). Results: At data cut-off (Oct. 29, 2021), 45 pts were enrolled and treated with KN026; 39 were eligible for response evaluation (25 pts in Cohort 1 and 14 pts in Cohort 2). In Cohort 1, ORR was 56% (95%CI 35%-76%) with 14 PR; the median DoR was 9.7 months (mo) (95%CI 4.2-not evaluable (NE)). At a median follow-up of 14.7 mo (95%CI 9.4-16.5), the median PFS was 8.3 mo (95%CI 4.2-11.4), and median OS was 16.3 mo (95% CI 11.0- NE). In Cohort 2, ORR was 14% (95%CI 2%-43%), with median DoR being 6.2 mo (95%CI 3.2-NE). At a median follow-up of 27.5 mo (95%CI 4.1-NE), the median PFS was 1.4 mo (95%CI 1.4-4.1), and median OS was 9.6 mo (95% CI 3.5-14.9). The table shows efficacy in Cohort 1 pts who have progressed on the prior trastuzumab treatment. KN026-related adverse events (TRAEs) were observed in 37 (82%) pts; the most common TRAEs (any grade) were increased aspartate aminotransferase (12, 27%), increased alanine aminotransferase (9, 20%), rash (7,16%), anemia (7,16%), and infusion-related reaction (7,16%). Four pts reported 5 grade 3 TRAEs, including infusion-related reaction, renal hydrocele, ureteral stenosis, increased blood pressure, and abnormal hepatic function (1 each). No grade 4 or 5 TRAEs occurred. Conclusions: KN026 monotherapy yielded promising efficacy with mild to moderate toxicities in pts with previously treated, advanced GC/GEJC. Further investigation is warranted. Clinical trial information: NCT03925974. [Table: see text]
Clinical efficacy of laparoscopic sentinel node navigation surgery for early gastric cancer: Five-year results of SENORITA trial.
Authors: Hur Hoon , Lee Young Joon , Kim Young-Woo , Min Jae-Seok , Yoon Hong Man , An Ji Yeong , Eom Bang Wool , 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 2022

4050

Background: A phase III multicenter randomized controlled clinical trial (SEntinel Node ORIented Tailored Approach [SENORITA] trial) has been performed to confirm the oncologic safety of laparoscopic sentinel node navigation surgery (LSNNS) for early gastric cancer (EGC). The results did not show the non-inferiority of LSNNS relative to laparoscopic standard gastrectomy (LSG) in terms of 3-year disease-free survival (DFS), the primary endpoint of the SENORITA trial even though the improved quality of life (QOL) in the LSNNS group. However, the long-term oncologic outcomes of LSNNS have not been compared with conventional surgery. This study was planned to investigate the comparison of LSG and LSNNS for EGC in terms of 5 years survival. Methods: We collected 5-year follow-up data of 527 patients recruited in the SENORITA trial. The overall survival (OS), disease-free survival (DFS), and recurrence pattern were evaluated in full analysis sets of both LSG (n = 269) and LSNNS (n = 258). Results: The mean follow-up period was 58.5 and 57.7 months in LSNNS and LSG groups. There was no statistically significant difference in 5-year OS (p = 0.7403) and DFS (p = 0.0561) between LSG and LSNNS. In terms of DFS, additional five events in the LSG group and 7 in LSNNS occurred after a 3-year follow-up until 5-years. Primary site recurrence in 1 LSNNS, and metachronous gastric cancer occurred in one LSG and two in LSNNS were diagnosed from 3 to 5-year follow-up period. Other organ cancer developed in two vs. three and other deaths occurred in two v s. one in each group, respectively, from 3 to 5-year follow-up. Overall survival events were 6 in LSG and 7 in LSNNS, and disease-specific death events were two patients in both groups until five years. Conclusions: Although the SENORITA trial did not show non-inferiority of LSNNS in the primary endpoint, 3-year DFS relative to LSG, the 5-year DFS and OS did not reveal the statistical difference between the two groups. Considering the benefit of LSNNS regarding the postoperative QOL, LSNNS could be recommended as an alternative treatment option of LSG for EGC. Clinical trial information: NCT01804998.
Ramucirumab, avelumab, and paclitaxel (RAP) as second-line treatment in gastro-esophageal adenocarcinoma, a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).
Authors: Thuss-Patience Peter C. , Högner Anica , Goekkurt Eray , Stahl Michael , Kretzschmar Albrecht , Schädlich Bärbel , Goetze Thorsten Oliver , Stocker Gertraud , Reichardt Peter , Kullmann Frank , Pink Daniel , Bartels Prisca , Ballhausen Alexej , Jarosch Armin , Hinke Axel , Binder Mascha , Stein Alexander
Published: June 2022

4051

Background: Combination of ramucirumab and paclitaxel is a standard second line therapy in gastro-esophageal adenocarcinoma (GEAC) (RAINBOW trial, Wilke et al., 2014). We integrated the PD-L1 inhibitor avelumab into this regimen aiming for synergistic efficacy. Methods: In a multicenter phase II trial (NCT03966118) pts with metastatic GEAC, after progression on platinum / fluoropyrimidine based palliative 1st-line, ECOG 0 or 1, were treated with ramucirumab 8 mg/kg (d1,15) + avelumab 10 mg/kg (d1,15) + paclitaxel 80 mg/m² (d1,8,15), q4w. Sample size calculation was based on a Simon 2-stage design with overall survival rate at 6 months as the primary endpoint (H0≤50%, H1≥65%). Results: 60 pts were enrolled, 59 were evaluable (ITT), median age 64.0 yrs (range 18-81), male 80%, female 20%, primary gastric 52%, GEJ 48%, histology intestinal 59.6%, diffuse 24.6%, mixed 15.8%. Previous treatment with platin/fluoropyrimidine 100%, previous taxanes 66%. At central pathology MSI-H 7%, PD-L1 CPS < 5: 54%; ≥5: 41%, NA 5%. Response by investigator (%) CR 3.4, PR 27.1, SD 49.2, PD 20.3; DCR 79.7%, independent radiology review will be presented. DOR: 8.2 mo (95%CI 6.7-9.7), PFS 5.4 mo (95%CI 4.2-6.6); 6-mo OS rate 71.2%; 12-mo OS rate 45.8%; med OS (ITT) 10.6 mo (95%CI 8.2-13.1), med OS CPS < 5: 9.4 mo (95%CI 7.2-11.2), CPS ≥5: 14.0 mo (95%CI 12.8-15.3), translational data (ct-DNA) will be analysed. Treatment was generally well tolerated and no unexpected toxicities occurred: Grade 3/4 AE above 5%: anemia 5%, leucopenia 12%, neutropenia 22%, diarrhea 5%, pain 10%, peripheral neuropathy 10%, hypertension 5%, non-neutropenic infection 5% including 1 CTC grade 5 due to an esophago-tracheal fistula. Conclusions: The med OS of 10.6 mo (in a population of 66% pretreated with taxanes) compares very favourably to 8.6 mo in the Western population RAINBOW trial (Shitara et al., 2016) and 7.6 mo in the RAMIRIS trial (Lorenzen et al., 2022). PD-L1 CPS≥ 5 seems to predict for an even better efficacy (med OS 14.0 mo). Second-line RAP is a very efficacious and well tolerated combination. Clinical trial information: NCT03966118.
Tumor microenvironment (TME) dynamics following capecitabine/oxaliplatin (CapeOx) plus pembrolizumab in patients with advanced gastric cancer.
Authors: An Minae , Lee Song-Yi , Kim Seung Tae , Kang Won Ki , Lee Jeeyun
Published: June 2022

4053

Background: Immune checkpoint inhibition (ICI) has made significant breakthroughs in several tumor types including gastric cancer (GC) in recent years. However, single-agent pembrolizumab demonstrated remarkable and durable response in MSI and EBV GC because they are immune-enriched types. Recently, we reported on-treatment remodeling of the TME during chemotherapy in MSS AGC ( Cancer Discov. 2021). We defined altered features including decreased tumor-associated macrophages (TAM), M1- macrophages repolarization and recruitment of NK cells, effector T cells. Methods: This phase 2, open-label, single-arm study was designed to assess the safety and efficacy of the CapeOx-pembrolizumab combination in advanced gastric cancer patients with HER2-negative. 38 patients were enrolled onto our CapeOx plus Pembrolizumab trial (NCT #04249739). All patients had MSS status with EBV-negative. Endoscopic biopsies were collected at baseline, after 1 cycle of chemotherapy alone and after 4 to 5 cycles of CapeOx + pembrolizumab to understand the impact of treatment to tumor TME. We performed coupling whole exome sequencing and whole transcriptome sequencing. Molecular features were extracted by exonic analysis. TME subtype was estimated by gene expression analysis. Results: Between 2020 and 2021, 38 patients were enrolled. There were 2 CR, 25 PR, 11 SD as best response.First, we found a number of somatic mutations (median 157.5, range 7-25,719) in pre-and on-treatment samples. Despite the creation and destruction of somatic mutation, we observed that ancestor mutations including TP53, MUC6 and APC previously reported in TCGA GC cohort, were preserved. At baseline (before chemotherapy), patients were classified to 5 immune-enriched (IE) subtye, 21 immune-depleted (D) subtype, ETC. Second, we observed a dynamic change following one cycle of CapeOx before the addition of pembrolizumab to chemotherapy. Nine (23.68%) out of thirty eight patients with immune-depleted or fibrotic pre-treatment TME became immune-favorable during treatment. Interestingly, seventeen (58.62%) out of twenty nine patients with immune-unfavorable pre-treatment TME became immune-favorable following CapeOx plus Pembrolizumab chemotherapy. Conclusions: This is the first study to demonstrate TME change during CapeOx plus pembrolizumab at molecular levels and will have clinically meaningful performance in patients with metastatic GC. Clinical trial information: NCT#04249739.
Circulating tumor DNA and recurrence risk in stage II-III gastric cancer.
Authors: Yuan Shu-Qiang , Huang You-Sheng , Nie Run-Cong , Chen Yingbo , Wang Si-Yu , Sun Xiaowei , Li Yuanfang , Liu Ze-Kun , Chen Yan-Xing , Yao Yi-Chen , Xu Yu , Qiu Haibo , Liang Yao , Wang Wei , Zhou Zhiwei , Xu Rui-hua , Wang Feng
Published: June 2022

4054

Background: Circulating tumor DNA (ctDNA) is a promising biomarker for detecting molecular residual disease (MRD) and relapse after definitive treatment in multiple solid cancers. However, the significance of ctDNA is rarely clarified in locoregional gastric cancer (GC). Here, we conducted a prospective and observational study to evaluate the utility of ctDNA in predicting the recurrence risk of GC. Methods: From October 2016 to June 2019, 100 patients with stage II/III resectable GC were recruited in this study (NCT02887612). Primary tumors and plasma samples were collected perioperatively and after adjuvant chemotherapy (ACT). Somatic variants were captured via a targeted sequencing panel of 425 cancer-related genes. The plasma of patients was defined as ctDNA positive only if one or more variants detected in the plasma presented in at least 2% of the primary tumors. All the patients received curative-intent standard-of-care therapy. Results: Preoperative ctDNA was detectable in 38 (38.0%) patients but showed limited value for predicting recurrence. After surgery (median days, 4), the plasma of 25 (25.0%) patients were still ctDNA positive and they had higher recurrence risk than the non-positive patients (hazard ratio [HR], 2.74 (95% CI: 1.37–5.48); P = 0.003). Forty-one patients had evaluable plasma after ACT and 10 (24.4%) of them who were ctDNA positive had remarkably higher recurrence and death risk compared with ctDNA-negative patients (recurrence-free survival [RFS] HR = 14.99 (95% CI: 3.08–72.96); P < 0.001; overall survival HR, 11.88 (95% CI: 2.38–59.24); P < 0.001). In particular, post-ACT ctDNA achieved better predictive performance (sensitivity, 77.8%; specificity, 90.6%) than both postoperative ctDNA and post-treatment tumor biomarkers (i.e., CEA, CA199, and CA72-4). In all multivariate analyses, ctDNA positivity was an independent factor of RFS. Patients with ERBB4 mutation in their primary tumors had poorer RFS compared to those were ERBB4 wildtype (HR = 3.46 (95% CI: 1.32–9.03); P = 0.007). A comprehensive model incorporating ctDNA status for recurrence risk prediction showed a higher concordance index (0.78; 95%CI, 0.71–0.84) than the model without ctDNA status (0.71; 95%CI, 0.64–0.79; P = 0.009). Conclusions: Postoperative and post-ACT ctDNA was associated with MRD and high risk of relapse in patients with stage II/III GC and can be utilized to guide GC management in post-surgical settings.
Prognostic role of tumor stroma ratio, tumor-infiltrating lymphocytes, and tumor budding in patients with intestinal-type gastric cancer after radical resection.
Authors: Sha Dan , Tian Chunfang , Sinicrope Frank A. , Jing Haiyan , Wang Jinshen , Song Wei
Published: June 2022

4055

Background: Tumor microenvironmental (TME) features including tumor stroma ratio (TSR), tumor infiltrating lymphocytes (TILs) and tumor budding (TB), may be associated with tumor metastatic potential. We sought to identify the association of these features with prognosis of patients with resectable intestinal-type gastric cancer. Methods: Radical resection of gastric carcinoma (> 15 LNs removed) was performed in 493 patients (stage I, n=225; stage II, n=119; stage III, n=149) at two university hospitals between 2010 and 2016. Cutpoints were as follows: TSR (50%), TILs (median), and TB (Bd0-Bd3). TME features and their association with clinicopathological characteristics, time-to-recurrence (TTR) and overall survival (OS) were analyzed by univariate and multivariate Cox methods.. Results: Among 493 patients, high TSR, low TILs and high TB (Bd1-Bd3) were significantly associated with higher histological grade, larger tumor size, and increased T and N stages. Each of these features was significantly associated with poorer TTR and OS at 5 years. In Cox multivariable analysis, N stage and TSR were the only variables that were significantly associated with TTR and OS (Table). The relative contribution (%) of TSR to TTR ranked second (17.5%) behind N stage (49.2%) and ahead of TILs (7.2%) and TB (0.1%). Conclusions: Among TME features, TSR was the most robust and was significantly and independently associated with TTR and OS. The relative contribution of TSR to TTR was second only to nodal status. [Table: see text]
Neoadjuvant atezolizumab plus docetaxel/oxaliplatin/capecitabine in non-metastatic gastric and gastroesophageal junction adenocarcinoma: The PANDA trial.
Authors: Verschoor Yara L. , Kodach Liudmila , van den Berg José , van Sandick Johanna W. , van Dieren Jolanda , Balduzzi Sara , Grootscholten Cecile , Veenhof Xander , Hartemink Koen , Vollebergh Marieke A. , Owers E.C. , Bartels-Rutten Annemarieke , den Hartog Peggy , van Leerdam Monique E , Schumacher Ton , Voest Emile E. , Haanen John B. A. G. , Chalabi Myriam
Published: June 2022

4059

Background: Immune checkpoint blockade improves clinical outcomes for patients with gastric and gastro-esophageal junction (GEJ) cancers, but its efficacy and impact on the tumor microenvironment in non-metastatic, resectable disease remains largely unknown. Peri-operative FLOT, the current standard-of-care, leads to pathologic complete responses (pCR) and major pathologic responses (MPR) in 16% and 37% of patients, respectively. An important open question is whether PDL-1 blockade monotherapy can prime the tumor microenvironment in a favorable manner, prior to combination with chemotherapy. Methods: We report results from the phase 2 PANDA trial (NCT03448835) of neoadjuvant atezolizumab (anti-PDL-1) plus docetaxel, oxaliplatin, and capecitabine (DOC) in patients with resectable gastric or GEJ adenocarcinoma. Patients received a single cycle of atezolizumab monotherapy, followed by 4 cycles of atezolizumab+DOC. Tumor tissue was collected at baseline, after atezolizumab monotherapy, the first atezolizumab+DOC, and at resection. The primary endpoints were safety and feasibility in 20 patients, and secondary endpoints included MPR (<10% viable tumor rest) and disease-free survival. Results: Twenty patients, of which 18 with mismatch repair (MMR) proficient and two with MMR-deficient tumors, were evaluable for safety and efficacy analyses. MPR was observed in 14/20 patients (70%; 95% CI 46–88%), including 9 pCR (45%; 95% CI 23-68%). Among patients with intestinal type adenocarcinoma, 12/15 (80%; 95% CI 52-96%) had an MPR, with 9/15 (60%; 95% CI 32-84%) pCR. Treatment was well tolerated, with two patients (10%) experiencing a grade 3 immune adverse event. At a median follow-up of 29 months (IQR 16-34), 15 patients (75%) were alive and disease-free. None of the patients with an MPR recurred. All patients underwent resections without treatment-related delays and no unexpected surgical complications were documented. Translational analyses, including baseline PDL-1 CPS score and whole exome sequencing (WES), plus CD8 T-cell infiltration and RNA sequencing at 4 timepoints will be presented at the meeting. Conclusions: Our data show that the addition of atezolizumab to neoadjuvant chemotherapy leads to promising pathologic responses in gastric/GEJ adenocarcinoma, which appears to be higher than in historical controls, with no recurrences in responders. These data should be validated in a large randomized controlled trial. Clinical trial information: NCT03448835.
REGOMUNE: A phase II study of regorafenib plus avelumab in solid tumors—Results of the oesophageal or gastric carcinoma (OGC) cohort.
Authors: Cousin Sophie , Metges Jean Philippe , Bellera Carine A. , Guégan Jean Philippe , Adenis Antoine , Gomez-Roca Carlos A. , Cassier Philippe Alexandre , Hollebecque Antoine , Cantarel Coralie , Palmieri Lola Jade , Kind Michèle , Soubeyran Isabelle , Palussière Jean , Bessede Alban , Italiano Antoine
Published: June 2022

4060

Background: Combination VEGF and PD-1/PD-L1 axis blockade has shown benefit in various tumors and is emerging as a promising combination strategy. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of regorafenib (R) (160 mg QD 3weeks/4) + avelumab (A) (10 mg/kg every 2 weeks) combination in advanced or metastatic oesophageal or gastric carcinoma (OGC) patients (pts). The primary endpoint was the confirmed objective response rate, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline. Results: Between Dec. 2018 and Mar. 2021, 49 pts were enrolled in 6 centers: 33 adenocarcinoma (ADK), 16 squamous cell carcinoma (SCC). Median age was 63.9 (range 33 – 80). Median follow-up was 14.5 months. Median number of previous treatment lines was: 2 (range 1 – 6). 29 (59.2%) pts experienced at least 1 dose modification or treatment interruption due to an adverse event related to treatment. The most common grade 3/4 adverse events were : Hypertension (12.2% of pts), palmar-plantar erythrodysesthesia syndrome (10.2%), and hypophosphatemia (8.2%). No death was related to the treatment. Among the 42 (29 ADK and 13 SCC) pts who had at least one imaging tumor assessment, 8 (19.1%) achieved a partial response, 5 (17.2%) and 3 (23.1%) in the ADK and SCC group respectively. 12 pts (28.6%) demonstrated stable disease and 22 pts (52.3%) had progressive disease. The median PFS and OS were 1.9 months (95%CI 1.8 – 3.5) and 7.5 months (95%CI 4.5 – 15.7) respectively. Conclusions: The R+A combination is associated with encouraging antitumor activity in patients with OGC. Full Biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03475953.