bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world validation of the Khorana risk score in gastric cancer patients receiving immune checkpoint inhibitors.
Authors: Song Junmin , Li Wing Fai , Yim Chaeseong , Gong Changlin , Chang Yu-Cheng , Chang Yu , Ahn Jaeun , Chi Kuan-Yu , Fahimuddin Muhammad , Chiang Cho Han
Published: January 2025

363

Background:
Thrombosis is a common cancer-related complication, particularly in gastric cancer. Studies show that immune checkpoint inhibitors (ICIs) increase the risk of venous thromboembolism (VTE) and arterial thrombosis. The Khorana risk score is widely used to assess thrombosis risk before starting chemotherapy. This study aimed to validate the Khorana score in gastric cancer patients receiving ICIs using a large global database.
Methods:
We used the TriNetX Global Collaborative Network, which contains de-identified data from over 120 million patients. We included patients diagnosed with gastric cancer who received ICIs between January 2014 and July 2023. The Khorana risk score was calculated based on lab values and BMI within two weeks before ICI initiation. Patients were divided into two cohorts: elevated risk (score 3-6) and intermediate risk (score 2). Cox-proportional hazard analyses were conducted over a one-year follow-up. The primary outcome was VTE (deep vein thrombosis [DVT] and pulmonary embolism [PE]). Secondary outcomes were arterial thrombosis, including myocardial infarction (AMI) and ischemic stroke, and all-cause mortality.
Results:
The study included 551 patients, with 362 in the intermediate risk and 189 in the elevated risk cohorts. The mean age was 64 in both cohorts, with the elevated group consisting of more males (76% vs. 63%) and a higher proportion of Black patients (11% vs. 6%). Pembrolizumab (49%) and nivolumab (47%) were the most used ICIs. Patients with elevated risk had a significantly higher risk of VTE (HR 1.74, 95% CI 1.18-2.58), DVT (HR 1.82, 95% CI 1.07-3.10), and PE (HR 1.74, 95% CI 1.07-2.84). However, no significant associations were found with arterial thrombosis (HR 1.28, 95% CI 0.74-2.20), including cerebral infarction (HR 1.05, 95% CI 0.51-2.16), or AMI (HR 1.46, 95% CI 0.70-3.05). The elevated risk cohort also had significantly higher mortality (HR 1.44, 95% CI 1.11-1.87).
Conclusions:
An elevated Khorana risk score is associated with a higher risk of VTE, but not arterial thrombosis, in gastric cancer patients treated with ICIs. Further studies are needed to determine how the Khorana score can be applied to predict ICI-related thrombosis and guide prophylactic anticoagulation.

Outcomes
Khorana risk score 3-6
Khorana risk score 2
Hazard ratio(95% CI)
P-value(Log-rank)

At risk patients
Cases
At risk patients
Cases

Venous thromboembolism
189
45
362
58
1.74 (1.18-2.58)
0.005

Deep vein thrombosis
189
25
362
30
1.82 (1.07-3.10)
0.025

Pulmonary embolism
189
29
362
36
1.74 (1.07-2.84)
0.025

Arterial thrombosis
189
21
362
34
1.28 (0.74-2.20)
0.375

Cerebral infarction
189
11
362
22
1.05 (0.51-2.16)
0.901

Acute myocardial infarction
189
12
362
17
1.46 (0.70-3.05)
0.317

All-cause mortality
189
93
362
145
1.44 (1.11-1.87)
0.006
Impact of tislelizumab + chemotherapy versus placebo + chemotherapy on patient-reported symptoms and disease progression by programmed death-ligand 1 expression in gastroesophageal adenocarcinoma: A post hoc analysis of the RATIONALE-305 trial.
Authors: Cruz-Correa Marcia , Oh Do-Youn , Xu Rui-Hua , Moehler Markus H. , Kato Ken , Barnes Frederick , Xu Yaling , Sheng Tao , Barnes Gisoo , Victor Timothy
Published: January 2025

365

Background:
The relationship between patient-reported outcome (PRO)-based symptom scores, recurrent PRO-based symptomatic deterioration events (RDEs), and terminal events such as progression-free survival (PFS) are rarely examined in the oncology therapeutic domain. Thus, we applied a 3-component joint model (JM) framework aiming to illuminate more clinically interpretable associations between PRO-based treatment effects, RDEs, and PFS among subgroups of patients with programmed death-ligand 1 (PD-L1) expression of ≥1%, ≥5%, and ≥10%.
Methods:
The final analytic sample included 378 patients in the tislelizumab + chemotherapy arm (T+C) vs 401 in the placebo + chemotherapy arm (P+C) for the PD-L1 ≥1% subgroup, 238 in the T+C arm vs 237 in the P+C for the PD-L1 ≥5% subgroup, and 118 in the T+C arm vs 125 in the P+C arm for the PD-L1 ≥10% subgroup. Symptom domain scores from the EORTC QLQ-C30 and QLQ-STO22 symptom were modeled. Change from baseline (CFBL) in each domain was analyzed every cycle up to cycle 6, then every other cycle thereafter (up to cycle 25). The joint model was applied to all PD-L1 subgroups and comprised three components: 1) linear mixed model (LMM) predicting CFBL symptom scores, 2) Cox proportional hazard (CPH) model for disease progression (PFS as terminal event), and 3) frailty (random effects for RDEs) CPH model for time to PRO-based RDEs. Osoba’s 10-point threshold was used to define RDEs.
Results:
In the LMM, significant treatment efficacy for the T+C arm compared with the P+C arm was observed for the GHS/QoL (
P
=0.0080) and dietary restriction scores (
P
=0.0475) in the PD-L1 ≥5% subgroup. In the PD-L1 ≥1% subgroup, compared with the P+C arm, the T+C arm was associated with less worsening in pain/discomfort (
P
=0.0376), upper gastrointestinal symptoms (
P
=0.0088), and dietary restrictions (
P
=0.0352). In the CPH model, the average hazard ratio indicated that compared with the P+C arm, the T+C arm was associated with a reduction in risk of disease progression across all PRO domains and PD-L1 subgroups. Lastly, the PRO-based RDE frailty predictions were strongly associated with PFS risk in the PD-L1 ≥1% and ≥5% subgroups for GHS/QoL, and in the PD-L1 ≥1% subgroup for physical functioning, fatigue, dysphagia-odynophagia, pain/discomfort, and dietary restrictions, as well as for pain/discomfort and dietary restrictions in the PD-L1 ≥5% subgroup.
Conclusions:
Through the 3-component JM, PRO-based effects were detected and demonstrated strong associations between PRO-based RDEs, and investigator-assessed PFS among varying PD-L1 expression levels. This framework may be a promising alternative for analyzing and interpreting PRO data in the context of PFS.
Patterns of immune checkpoint inhibitor utilization and PD-L1 testing in advanced gastroesophageal cancers using real-world data.
Authors: Kaur Jasmeet , Zhang Li , Hasler Jill S. , Dotan Efrat , Cann Christopher G
Published: January 2025

370

Background:
Globally, gastroesophageal cancer (GEC) is a leading cause of morbidity and mortality, with poor 5-year overall survival (OS). The addition of immune checkpoint inhibitors (ICIs) such as nivolumab and pembrolizumab to chemotherapy has resulted in significant improvement in OS of those patients (pts) with metastatic GEC (mGEC), most notably in those with tumors exhibiting high PD-L1 CPS scores. However, the pattern of ICI utilization in associated PD-L1 testing since the adoption of this treatment (tx) has yet to be elucidated. We evaluated the patterns of ICI utilization and PD-L1/CPS testing in the first-line tx of mGEC pre and post FDA approval of ICI use in this setting.
Methods:
Pts ≥ 18 years of age, with recurrent/metastatic squamous or adenocarcinoma GEC diagnosed after 2011 were included from the de-identified nationwide Flatiron Health, electronic health record-derived database. We presented the proportion of pts receiving ICI therapy, stratified by line of tx, as well as the proportion of patients who received PD-L1 testing at 6-month intervals. Pts demographics and clinical characteristics, including age, gender, race, ECOG score, documented insurance, and stage at diagnosis (dx) were described and compared using T or Wilcoxon rank-sum tests for continuous variables, and chi-square or Fisher’s exact tests for categorical data. We compared tx rates and PDL-1 testing across four time points: time 1: Jan-June 2020, prior to ASCO data presentation; time 2: July-Dec 2020, ASCO data presentation; time 3: Jan- June 2021, FDA label change; time 4: July 2021 to 6 m after FDA label change using Chi-square test.
Results:
A total of 9,573 pts were included with 1,593 (16.6%) receiving ICI-based tx. Among these, 62.3% were White, 7% Black. Descriptive statistics indicated that pts with ICI- tx tend to be younger (median age 65y vs. 66.7; (p <0.001). Within the total cohort, 74% pt were dx before FDA approval of ICI tx, while 26% pts were dx after FDA approval. PD-L1 testing was conducted in 4,065 (42.5%) pts. A total of 1,268 (13%) pts received first-line ICI-based tx. Of these, 154 pts (12.1%) were treated before FDA approval, while 1,114 pts (87.9%) received tx following FDA approval. The rate of first-line ICI tx significantly increased at each subsequent time point Time 2: 11.2% (p <0.0001), Time 3: 32.9% (p <0.0001), Time 4: 37.4% (p <0.0001). PD-L1 testing rates also increased over time, particularly after FDA label change. Testing rates at Time 1 was 68%. Comparatively, testing rates at subsequent time points were: Time 2 (67.2%; p 0.88), Time 3 (71.5%; p 0.324) and Time 4 (77.4%; p=0.004).
Conclusions:
The approval of ICIs for first-line tx of mGEC led to a significant increase in both ICI utilization and PD-L1/CPS testing rates. Despite these advancements, ongoing disparities in tx access and testing highlight the need for further research and efforts to ensure equitable care.
The prevalence of Lynch syndrome and associated clinicopathologic features in patients with mismatch repair deficient gastric cancer.
Authors: Lee Sun Mi
Published: January 2025

380

Background:
Approximately 2-4% of patients with primary colorectal cancer are estimated to be associated with Lynch syndrome. However, the prevalence of Lynch syndrome and associated clinicopathologic features in patients with mismatch repair-deficient (dMMR) gastric cancer (GC) is not well understood. In this study, we investigated the frequency of dMMR GCs in unselected GCs and the prevalence of Lynch syndrome, as well as associated clinicopathologic features and molecular alterations in dMMR GCs.
Methods:
A total of 847 cases of unselected GCs from 2010 to 2012 were collected at Jeju National University Hospital. Immunohistochemistry for mismatch repair proteins (MMR), including MLH1, MSH2, MSH6, and PMS2, and MSI analysis were performed on representative tumor sections of surgically resected specimens. Follow-up genetic counseling and genetic and/or epigenetic alterations of the MMR genes were also investigated.
Results:
Loss of one or more MMR proteins and microsatellite instability-high were observed in 72 patients; 67 patients showed loss of MLH1/PMS2, 2 patients showed loss of PMS2 alone, and 3 patients with MSH2/MSH6. Genetic counseling demonstrated that ten patients had a family history of LS-associated cancers and nine patients had a history of metasynchronous cancers. Of the 72 patients, 65 revealed hypermethylation of the promoter region of MLH1. The subsequent genetic germline tests demonstrated 2 patients with MLH1 mutation, 3 with MSH2 mutation, and 2 with PMS2 mutation.
Conclusions:
dMMR tumors were identified in 72 (8.5%) of 847 unselected primary GCs. This study estimated that 0.8% of patients with unselected GC and 9.7% of patients with dMMR GC fulfilled the revised Bethesda criteria and are associated with Lynch syndrome. The detection of dMMR GCs and necessary genetic counseling/tests based on revised Bethesda criteria would help find Lynch syndrome in patients with GC.

Clinical and immunophenotypical features of patients with dMMR GC.

Age

≤ 50 years
5 (6.9)

> 50 years
67 (93.1)

Other malignancy history except GAC

No
63 (87.5)

Yes
9 (12.5)

History of metachronous cancers

Esophageal cancer
1 (1.4)

Maxillary sinus cancer
1 (1.4)

Papillary thyroid cancer
1 (1.4)

Colorectal cancer
1 (1.4)

Pancreatic cancer
1 (1.4)

Breast cancer
1 (1.4)

Breast cancer and malignant GIST
1 (1.4)

Multiple HCCs
2 (2.8)

History of Family with LS related cancers

No
62 (86.1)

Yes
10 (13.9)

Fulfillment of the rBG

No
63 (87.5)

Yes
9 (12.5)

MMR proteins

Loss of MLH1 and PMS2
67 (93.1)

Loss of PMS2
2 (2.8)

Loss of MSH2 and MSH6
3 (4.2)

Germline mutation test

MLH1 mutations
2 (2.8)

MSH2 mutations
3 (4.2)

PMS2 mutations
2 (2.8)
An exploratory phase II trial of low-dose decitabine and sintilimab combined with chemotherapy in HER2-negative gastric or gastroesophageal junction adenocarcinoma.
Authors: Du Yunyi , Zhang Xiaoling , Ma Ning , Yang Wei , Yang Bo , Su Fei , Zong Liang , Hu Wenqing , Zhao Jun
Published: January 2025

390

Background:
Combining epigenetic modulator with PD-1 inhibitor may enhance treatment outcomes in cancer patients. This study aimed to evaluate the efficacy and safety of epigenetic drug decitabine, sintilimab (a PD-1 inhibitor), and chemotherapy in gastric cancer.
Methods:
In this single-arm, exploratory phase II trial, patients with HER2-negative, locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma were enrolled between August 12, 2021, and October 22, 2022. Treatment included low-dose decitabine (10 mg/m² for 5 days), sintilimab (a PD1 inhibitor, 200 mg every 21 days), and XELOX. The primary endpoint was objective response rate (ORR) and second endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. The protocol was approved by the ethics committee of the Changzhi Medical College Affiliated Changzhi People's Hospital (No. 2021K002). All patients provided written informed consent form before study participation. The trial is registered with Chinese Clinical Trial, number ChiCTR2100043312.
Results:
Sixteen patients were initially enrolled, with a median follow-up of 14.8 months. Eleven patients exhibited a PD-L1 combined positive score (CPS) < 5. In the per-protocol sets, 11 patients remained eligible for efficacy analysis. In the intention-to-treat analysis of all 16 patients, 9 achieved partial response and 2 had stable disease, resulting in an ORR of 69% and a DCR of 56%. As of the data cutoff on November 4, 2023, the median PFS was 11.1 months (95% CI, 5.1-not reached) and the median OS was 13.2 months (95% CI, 5.1-not reached). Treatment-related adverse events were generally well-tolerated, with most being grade 1-2. Three patients experienced severe AEs, including one fatal case of grade 4 immune-related pneumonia.
Conclusions:
The combination of low-dose decitabine, sintilimab, and chemotherapy appears promising strategy for locally advanced or metastatic G/GEJ adenocarcinoma, especially in patients with negative HER2 and low PD-L1 expression. These preliminary findings support further investigations to confirm the benefits and explore the underlying mechanisms. Clinical trial information: ChiCTR2100043312.

Objective response and disease response.

Full analysis set (n=16)
Efficacy analysis set (n=11)

Complete response
0
0

Partial response
9
9

Stable disease
2
2

Progressive disease
0
0

Non-evaluable*
5
NA

Objective response
9 (56%)
9 (81.8%)

Disease control
11 (69%)
11 (100%)

NA=not applicable.

*Included patients without any post-baseline response assessment.
Real-world safety of trastuzumab deruxtecan with gastric cancer: All-patient post-marketing surveillance study in Japan.
Authors: Kawakami Hisato , Uchino Kazuhiro , Hashimoto Wataru , Muro Kei
Published: January 2025

399

Background:
Interstitial lung disease and pneumonitis (ILD/p) is an important identified risk in the Japanese risk management plan of trastuzumab deruxtecan (T-DXd). In Japan, an all-patient post-marketing surveillance (PMS) study was conducted to investigate the incidence of ILD/p and factors associated with its development among patients with gastric cancer treated with T-DXd in the real-world setting.
Methods:
This is an observational, multicenter, PMS study (jRCT2001200001) with an observation period of 12 months that enrolled all patients who initiated T-DXd treatment for HER2-positive unresectable advanced or recurrent gastric cancer between Sep 2020 and Dec 2021. All suspected ILD/p events reported by physicians were adjudicated by an independent ILD adjudication committee; events adjudicated as drug-related ILD/p were summarized. The factors associated with the development of adjudicated drug-related ILD/p were investigated using a Cox proportional hazards model. Effectiveness endpoints included best overall response rate according to the RECIST 1.1 and overall survival, which was estimated using the Kaplan–Meier method.
Results:
The safety analysis set included 1070 patients (77.4% male, 89.9% ECOG performance status ≤1) with median age of 70 years (range: 23-100). Median initial dose and treatment duration of T-DXd were 6.4 mg/kg (range: 3.1-6.4) and 3.9 months (range: 0.7-12.0), respectively.The incidence of any grade, grade ≥3, and grade 5 adjudicated drug-related ILD/p were 9.6% (n=103), 2.8% (n=30) and 1.2% (n=13), respectively. Within 24 weeks from onset, 73.8% of adjudicated drug-related ILD/p had resolved, were resolving, or resolved with sequelae.A multivariate analysis identified that medical history and/or comorbidity of ILD/p [hazard ratio (HR) = 3.372, 95% confidence interval (95% CI): 1.431, 7.840], radiation pneumonitis (HR = 8.523, 95% CI: 2.006, 36.215), COPD or emphysema (HR = 1.962, 95% CI: 1.032, 3.731) and age ≥75 years (HR = 1.648, 95% CI: 1.058, 2.567) were factors of interest associated with the development of ILD/p in patients with gastric cancer. The overall response rate at 12 months post-treatment initiation of T-DXd was 34.2%. Overall survival after 364 days post-treatment initiation of T-DXd was 43.8% (median survival time: 303.0 days).
Conclusions:
The results suggest that the risk of ILD/p in this PMS study does not differ from that in the Destiny Gastric-01 study, and no new safety concerns were identified. Medical history and/or comorbidity of ILD/p, radiation pneumonitis, COPD or emphysema and age ≥75 years were identified as factors of interest associated with the development of ILD/p in patients with gastric cancer. Further investigation into the identified factors of interest may offer insights into the development of ILD/p among T-DXd treated gastric cancer patients in Japan. Clinical trial information: jRCT2001200001.
Preliminary phase 1/1b dose expansion results of the bifunctional EGFR/TGFβ inhibitor ficerafusp alfa (BCA101) with pembrolizumab in patients with squamous cell carcinoma of the anal canal.
Authors: Morris Van K. , Huffman Brandon , Eng Cathy , Dalal Rita P. , Salazar Rachel , Bohr David , Morton Kaitlin H. , Bedard Philippe
Published: January 2025

4

Background:
Anti-PD-1 monotherapy has limited efficacy in patients (pts) with advanced squamous cell cancer of the anal canal (SCAC). In KN-158, pembrolizumab (P) was reported to have an ORR of 10%, DCR of 25%, and a 12-month PFS rate of 15% in patients with incurable SCAC. TGFβ promotes immunosuppression within the tumor microenvironment, and inhibition of this pathway may improve tumor susceptibility to immune checkpoint blockade.Ficerafusp alfa (F)is a bifunctional EGFR/TGFβ inhibitor with manageable safety and favorable preliminary anti-tumor efficacy in advanced solid tumors (ESMO 2022 731MO). We evaluated the combination of F+P in pts with chemotherapy-refractory locally advanced/unresectable or metastatic SCAC.
Methods:
This single-arm, multicenter dose expansion from an ongoing phase I/Ib trial enrolled pts with ICI-naïve SCAC that was locally advanced/unresectable or metastatic, who had received 1-2 prior lines of chemotherapy. Pts received ficerafusp alfa (1500 mg IV on days 1, 8, 15) and pembrolizumab (200 mg IV on day 1) every 21-day cycle. The primary endpoint was safety (CTCAE v5), and secondary endpoints were radiographic response (RECIST 1.1), duration of response, progression-free survival, and overall survival.
Results:
Among 26 pts treated, 21 (81%) were female, and median age was 61 (range: 43-82). As of 7/2024, 22 pts are evaluable for efficacy. ORR was 32% (95% CI 13.9-54.9%). Six of the seven responses were confirmed, including one pt with a radiographic PR with pathologic CR to F+P. Seven pts (32%) achieved SD as best response, resulting in DCR of 64%. Median PFS was 2.8 months (95% CI 1.4-14.8) and the PFS rate at 12 months was 36%. G3 treatment-related adverse events were observed in 10/26 pts (38%, most common: Anemia (19%) and acneiform rash (12%)). TRAEs led to permanent discontinuation of study treatment in 2 pts (8%). The most common TRAEs of any grade were acneiform rash (13/26, 50%), epistaxis (46%) and headache (38%).
Conclusions:
The addition of ficerafusp alfa demonstrated encouraging efficacy, with increased ORR, DCR, and 12-month PFS relative to historical precedent with pembrolizumab alone. Safety and tolerability were acceptable. Further investigation of this combination in pts with advanced SCAC is warranted. Updated data will be presented. Study funded by Bicara Therapeutics Inc. with access to pembrolizumab in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (NCT04429542).

Clinical trial information:
NCT04429542

.
Impact of insurance status on mortality following surgical treatment of colorectal cancers.
Authors: Khosla Atulya Aman , Singh Aagamjit , Chitkara Akshit , Pustake Manas , Jatwani Karan , Rubens Muni , Ramamoorthy Venkataraghavan , Saxena Anshul , Jaiyesimi Ishmael A.
Published: January 2025

40

Background:
Healthcare disparities in colorectal cancer, driven by insurance status and socioeconomic factors, lead to delayed diagnoses and poorer surgical outcomes. We sought to examine the impact of insurance status on presentation, treatment, and in-hospital mortality in CRC patients undergoing colectomy using the Nationwide Inpatient Sample (NIS) database.
Methods:
We included patients aged 18-65 years diagnosed with colon cancer and undergoing colectomy, as identified by ICD-9-CM codes, who had private insurance, Medicaid, or no insurance from January 1, 2005, through December 31, 2014. The primary variable was insurance status; patient characteristics such as age, sex, race, income, and tumor type were analyzed. We used the Elixhauser comorbidity index to control for confounding and performed a subset analysis on patients without major comorbidities. The primary outcome was in-hospital postoperative death. Associations between this outcome and insurance status were analyzed using the Cox proportional hazard model, both in the full cohort and in a subset of patients without comorbidities, with models stratified by hospitals to account for clustering effects from variations in access to care.
Results:
The study cohort included 301,304 patients, of whom 238,158 (79.0%) were privately insured, 40,417 (13.4%) on Medicaid, and 22,729 (7.6%) were uninsured. Most patients were White (71.6%), followed by African American (12.6%), Hispanic (8.4%), Asian/Pacific Islander (3.8%), and Native American (0.5%). A total of 55.4% of cases took place in teaching hospitals. In the unadjusted analysis, the mortality rate for privately insured patients was 0.7% (95% CI, 0.6%-0.7%) compared with 2.1% for uninsured patients (95% CI, 1.7%-2.5%) and 1.5% for Medicaid recipients (95% CI, 1.2%-1.8%; p=0.001). After adjusting for patient characteristics and stratifying by hospital in patients with no comorbidity, uninsured patients still had a higher risk of experiencing in-hospital death (HR, 1.60; 95% CI, 1.24-2.07) compared with privately insured patients, while no significant disparity was found in Medicaid recipients (HR, 0.95; 95% CI, 0.75-1.22) (Table).
Conclusions:
Uninsured patients undergoing colectomy for colon cancer experienced the highest in-hospital mortality, a disparity not fully explained by overall health differences. These findings underscore the critical role of insurance coverage in improving surgical outcomes and highlight the need for policy interventions to reduce mortality disparities.

In-hospital mortality after surgery for colorectal cancer.

Covariate
Full sample
Patients With No Comorbidity
Patients With No Comorbidity in Urban Teaching Hospitals

Hazard Ratio (95% Cl)

Insurance

Private
Reference
Reference
Reference

Medicaid
0.95 (0.75-1.22)
1.38 (0.91-2.11)
1.66 (0.91-3.02)

Uninsured
1.60 (1.24-2.07)
2.12 (1.42-3.15)
2.28 (1.25-4.16)
Prognostic factors for gastric cancer patients with positive peritoneal cytology who underwent upfront surgery.
Authors: Abe Takashi , Terashima Masanori , Fujiya Keiichi , Hattori Taku , Takahashi Kyota , Matsumoto Yosuke , Koseki Yusuke , Furukawa Kenichiro , Tanizawa Yutaka , Bando Etsuro
Published: January 2025

400

Background:
Positive peritoneal cytology (CY1) is classified as Stage IV disease, the standard treatment for which is systemic chemotherapy. However, CY1 is often diagnosed after surgery in patients for whom staging laparoscopy is not indicated. In addition, the treatment strategy for patients with CY1 diagnosed during surgery is controversial. The Japanese guidelines recommend upfront surgery followed by adjuvant chemotherapy for patients diagnosed with CY1 during surgery. To identify patients with CY1 who are most likely to benefit from upfront surgery, we investigated prognostic factors in patients with CY1 who underwent upfront surgery.
Methods:
A total of 169 gastric cancer patients diagnosed as P0CY1 during or after surgery who underwent R1 resection other than positive resection margins were included. The diagnosis of CY1 was obtained by staging laparoscopy or during laparotomy in 69 patients and after surgery in 87 patients. Fourteen patients were initially diagnosed as CY0 by staging laparoscopy but were rediagnosed as CY1 after surgery. The clinicopathological factors of overall survival (OS) and progression-free survival (PFS) were investigated. Prognostic factors were identified using Cox regression models.
Results:
The median patient age was 72 years, and there were 108 males. The histological type was undifferentiated type in all of 102 patients. The macroscopic types were 0 in 10) patients 1 in 3, 2 in 27 3 in 84 and 4 in 45). cT grades and cN grades were cT1 in 3, cT2 in 7, cT3 in 12, cT4 in 147, cN0 in 65cN1 in 30), cN2 in 46 and cN3 in 28. The median OS and PFS were 25.1 months and 14.6 months, with 5-year OS rate and PFS rate of 30% and 23%, respectively. A multivariate analysis for OS identified macroscopic type 0-2, Charlson Comorbidity Index<3, and adjuvant chemotherapy as independent prognostic factors. Similarly, macroscopic type 0-2, tumor size <80 mm, and adjuvant chemotherapy were identified as independent prognostic factors for PFS. In a subgroup analysis of patients who received adjuvant chemotherapy, macroscopic type 0-2 was the only independent prognostic factor for PFS. The 5-year PFS rate in patients with macroscopic type 0-2 was 42%.
Conclusions:
Patients with macroscopic type 0-2 who are suitable for adjuvant chemotherapy may have benefit from upfront surgery, even if peritoneal cytology is positive.
Bifunctional anti-PD-L1/TGF-βRII agent SHR-1701 plus chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): Survival results of a phase II trial.
Authors: Wang Yi , Liu Hong , Wang Qingwei , Qiao Naian , Wang Jianbo , Tan Bingxu , Cheng Bo , Chu Yunxia , Zhao Changhong , Chen Xiaoyu , Cheng Yufeng
Published: January 2025

411

Background:
Recently, several clinical trials have demonstrated synergistic efficacy by combining immune checkpoint inhibitors (ICIs) with chemotherapy. However, only a subset of patients (pts) derived benefits. Combining ICIs with agents blocking immunosuppressive pathway may expand the clinical benefit of ICIs to more pts. Transforming growth factor β (TGF-β) participates in tumor immune escape. SHR-1701, a novel bifunctional fusion protein consisting of a monoclonal antibody targeting PD-L1 fused with the extracellular domain of TGF-β receptor II, was evaluated in a phase II trial (ChiCTR2000039909) to assess its efficacy and safety when combined with chemotherapy for pts with unresectable locally advanced, recurrent or metastatic ESCC in China.
Methods:
This trial enrolled treatment-naive pts with histologically or cytologically confirmed unresectable locally advanced, recurrent, or metastatic ESCC. Eligible pts received SHR-1701 (30mg/kg, iv, d1, q3w) in combination with up to six cycles of albumin-bound paclitaxel (125mg/m
2
, iv, d1, d8, q3w) and cisplatin (75mg/m
2
, iv, d1, q3w). For those without progressive disease, maintenance treatment was administered with SHR-1701 monotherapy until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety.
Results:
At the data cut-off, March 1, 2024, 24 pts had received at least one dose of the study treatment and were included in both the intention-to-treat (ITT) analysis and safety analysis sets. 3 and 12 pts achieved confirmed complete and partial responses, respectively. The confirmed ORR was 62.5% and DCR was 87.5%. With a median follow-up of 20.8 months (95% CI, 15.5-NR), the median duration of response was 9.1 months (95% CI, 6.9-NR). The median PFS was 10.8 months (95% CI, 7.8-NR) and the median OS was 26.1 months (95% CI, 8.6-NR). 12-month PFS and OS rates were 41.4% (95% CI, 22.5-76) and 64.8% (95% CI, 47.8-87.9), respectively. Grade 3-4 treatment-related adverse events occurred in 11 (45.8%) pts and no treatment-related death was observed.
Conclusions:
The results highlighted that SHR-1701 plus chemotherapy as first-line therapy maintained long-term, durable survival benefit in pts with advanced ESCC. Clinical trial information: ChiCTR2000039909.
Evaluation of event-free survival (EFS) as a surrogate for overall survival (OS) in patients with locally advanced esophageal carcinoma (LA EC) receiving definitive chemoradiotherapy (dCRT).
Authors: Shah Manish A. , Xue Weiguang , Ramakrishnan Karthik , Zhou Jenny , Meng Yan , Bordia Sonal , Valderrama Adriana
Published: January 2025

412

Background:
Drug development in esophageal cancer is rapidly evolving, and identifying surrogates for patient outcomes to accelerate clinical drug development remains an important unmet medical need. Although early clinical endpoints such as EFS, disease free survival (DFS) are proven to be valid surrogates for overall survival (OS) in early esophageal (Ajani JA
et al.
2022), gastric (Oba K
et al.
2013; Wainberg ZA
et al.
2023), and gastroesophageal junction tumors (Ronellenfitsch U.
et al.
2013) after disease resection, there are no such surrogacy data evaluating patients who underwent non-operative management. Specifically, there has been no prior systemic evaluation of the predictive value of EFS as a surrogate for OS among LA EC patients treated with dCRT. This study evaluated the trial-level correlation between EFS and OS in unresectable LA EC patients receiving dCRT.
Methods:
A systematic literature review was conducted to identify randomized controlled trials (RCTs) of dCRT interventions in unresectable LA EC (search cutoff date: April 2023). Studies reporting EFS (or similar outcomes such as progression free survival (PFS), defined as time from randomization to local, regional, or distant recurrence, or death) and OS were included. EFS and OS hazard ratios (HRs) of each treatment comparison were extracted. Correlation between the log(HR) of EFS and OS was assessed using weighted linear regression (WLR). The coefficient of determination (R
2
) was used to evaluate the strength of the correlation. A good surrogate was defined as an R
2
≥ 0.65 (Ciani
et al
. 2017) or an R
2
≥ 0.75 (Lassere
et al
. 2008). Leave-one-out cross-validations and sensitivity analyses were conducted to assess the robustness of the WLR model and correlation analyses, respectively.
Results:
The final analysis included 14 between-treatment comparisons from 11 RCTs (total number of patients = 2,812). We found a strong statistical correlation between EFS and OS, with an estimated slope coefficient of 0.91 (
p
< 0.001) and R
2
of 0.80 (95% confidence interval [CI]: 0.38, 0.96). In the leave-one-out cross validation, 71.4% of observed OS HRs fell within the predicted 95% CIs. Sensitivity analyses showed R
2
of 0.75 among studies conducted in China and R
2
of 0.73 after including studies that did not report EFS definition.
Conclusions:
In a pooled analysis of 11 clinical trials corresponding to over 2800 patients, we observed a strong statistical correlation between EFS and OS outcomes. This analysis supports the utility of EFS as a valid surrogate of OS in patients with unresectable LA EC receiving dCRT.
Results of a phase 2 trial of ramucirumab plus docetaxel as second-line treatment for patients with advanced gastric cancer (HGCSG 1903).
Authors: Sawada Kentaro , Kawamoto Yasuyuki , Harada Kazuaki , Ando Takayuki , Sogabe Susumu , Kobayashi Yoshimitsu , Dazai Masayoshi , Nakamura Michio , Hatanaka Kazuteru , Ishiguro Atsushi , Sato Atsushi , Nakano Shintaro , Shindo Yoshiaki , Hosokawa Ayumu , Ito Ken , Yoshikawa Ayumu , Iuchi Kayoko , Yokota Isao , Yuki Satoshi , Komatsu Yoshito ,   Hokkaido Gastrointestinal Cancer Study Group (HGCSG)
Published: January 2025

447

Background:
Ramucirumab (RAM) has shown efficacy in combination with paclitaxel (PTX) or irinotecan in the second-line treatment of advanced gastric cancer (AGC). However, the efficacy and safety regarding the combination therapy of RAM and docetaxel (DTX) have not been reported. We hypothesized that RAM plus DTX for patients with AGC could be as effective as RAM plus PTX and could reduce the incidence of neuropathy.
Methods:
HGCSG 1903 was a non-randomized, single arm, phase 2 trial carried out at 20 institutes in Japan. AGC patients with refractory or intolerance to primary chemotherapy were eligible. RAM (8 mg/kg on day1 and 15) plus DTX (60 mg/m
2
on day1) combination therapy administered in 28-day cycle were continued until disease progression or emergence of adverse events requiring discontinuation. The primary endpoint was response rate (RR) with threshold value of 10.7% and an expected value of 27.9%. A total of 35 cases are planned for registration. The secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. This trial was registered with Japan Registry of Clinical Trials, number jRCTs011200010.
Results:
Between Nov 2020 and Dec 2023, 36 patients were enrolled. Median age was 70 (range, 36–82); female/male were 7/29; ECOG PS 0/1, 16/20, respectively. One patient did not initiate study treatment at the onset of bowel obstruction after enrollment. In the efficacy and safety analysis set of 35 patients, RR was 25.7% (95%C.I., 12.5–43.3%) and disease control rate was 74.3% (95%C.I., 56.7–87.5%). Median OS and PFS were 11.9 months (95%C.I., 3.0–20.7) and 3.1 months (95%C.I., 2.1–4.2), respectively. Grade 3 or higher adverse events that occurred in more than 5% of patients were neutropenia (68.6%), leucopenia (57.1%), febrile neutropenia (17.1%), hypertension (14.3%), anorexia (11.4%), anemia (8.6%), and fatigue (5.7%). Grade 4 neutropenia occurred in 60.0% of patients. The protocol was amended to allow primary G-CSF prophylaxis during study period. The number of patients who received primary G-CSF prophylaxis after the amendment was 7/13 (53.8%). Neuropathy occurred in 65.7% of all grades, with no incidence of grade 3 or higher. No death and new safety signals with a causal relation to study treatment were observed.
Conclusions:
The primary endpoint of response rate was met in HGCSG 1903. Although neutropenia and febrile neutropenia may be more frequent, they were manageable. RAM plus DTX might be considered as an option for second-line treatment of patients with AGC. Clinical trial information: jRCTs011200010.
Clinical results of a phase 1 trial evaluating a HER2 directed CAR-T product selective for the tumor microenvironment (TME) in patients with GI and other solid tumor malignancies.
Authors: Zhou Yuhong , Li Qian , Li Wei , Lu Lili , Xiao Shuxiu , Cai Yijun , Liu Lintao , Frost Gregory Ian , Li Wendy
Published: January 2025

449

Background:
A major limitation of CAR-T in solid tumors has been the inability to safely target antigens shared between healthy and malignant tissue. One approach to improving selectivity is to regulate CAR affinity through the unique metabolism of the tumor microenvironment (TME). This first in human trial evaluated an autologous (41BB) CAR-T product encoding a tumor metabolism regulated HER2 CAR.
Methods:
This Phase 1, dose escalation, basket trial evaluated the safety, tolerability, pharmacokinetics and efficacy in 12 patients (pts) with HER2 IHC 3+ / FISH + Stage IV r/r solid tumor malignancies (gastric, esophageal, colorectal, breast). They had failed multiple lines of therapy (66.7% patients had failed 4~10 lines of therapies previously). Dose cohorts of 3E5 (n=3), 1E6 (n=3), or 1E7 (n=6) CAR-T cells/kg were evaluated with a 28-day in-patient DLT observation period. Cell product was manufactured from whole blood, with a 12-day closed process and release on day 17. Lymphodepletion regimen was 500 mg/m
2
Cy and 30 mg/kg
2
Flu X 3 prior to infusion of CAR-T.
Results:
Data cutoff 09/16/24. All 12 patients were evaluable for safety and efficacy. No DLTs, ICANS or SAEs were observed. For HER2 positive normal tissues of special concern (e.g. cardiomyocytes), longitudinal functional, biochemical and clinical cardiovascular tests showed no signs of OTOT. One patient experienced Grade 2 CRS and recovered. No AE’s lead to study discontinuation. In one patient, there were two Grade 3 AEs attributed to product (neutropenia and hypoxia); both which resolved. With a median follow-up of 302 days for cohort 3, 12-month survival rate in this cohort is 83.3%, compared to the 12-month survival rate of 33.3% for cohorts 1 and 2 combined. Encouraging signals of efficacy were observed with an ongoing (at 24 wks) deep PR (100% reduction SLD) in a GC patient. The median peak copy number of CAR-T cells in peripheral blood (n=12) was 1,818 copies/µg DNA (range 403 – 10,466).
Conclusions:
The tumor metabolism regulated HER2 CAR-T product was generally well tolerated, with no DLTs, and evidence of radiologic objective response in patients with gastroesophageal cancer. Combined, the safety and activity observed in this study suggests that a previously challenging solid tumor antigen may be safely targeted by a CAR with affinity regulated by the metabolism of the TME. Enrollment for the study was complete as of 28-Feb-2024 (NCT04511871).
Clinical trial information: NCT04511871
.
Impact of time to surgery on outcomes in patients with advanced esophageal squamous cell carcinoma following neoadjuvant therapy: An exploratory analysis of phase III trial JCOG1109.
Authors: Kita Ryosuke , Kato Ken , Machida Ryunosuke , Ito Yoshinori , Daiko Hiroyuki , Kawakubo Hirofumi , Sasaki Keita , Fukuda Haruhiko , Kimura Yasue , Akiyoshi Kohei , Koyanagi Kazuo , Hara Hiroki , Minashi Keiko , Amagai Kenji , Abe Tetsuya , Takeuchi Hiroya
Published: January 2025

458

Background:
JCOG1109, a multicenter three-arm phase III trial, evaluated three neoadjuvant treatment regimens for advanced esophageal squamous cell carcinoma (ESCC), cisplatin and 5-fluorouracil (CF), docetaxel, cisplatin, and 5-fluorouracil (DCF), and cisplatin, 5-fluorouracil, and radiation therapy (CF-RT). The trial demonstrated the superiority of neoadjuvant DCF therapy in improving overall survival (OS). This exploratory analysis investigates the impact of the interval time from completion of neoadjuvant therapy to surgery (time to surgery, TTS) on both short- and long-term outcomes across different neoadjuvant therapy regimens.
Methods:
This analysis included patients from JCOG1109 who underwent surgery after neoadjuvant therapy. Patients were categorized into four TTS subgroups within each arm, based on quartiles of the overall cohort. Short-term outcomes such as perioperative complications, as well as long-term outcomes including OS and progression-free survival (PFS) were evaluated across these TTS subgroups.
Results:
Of the 601 patients enrolled in JCOG1109, 546 patients proceeded to surgery following neoadjuvant therapy. The median TTS was 35 days (range: 16-81) for the CF arm, 38 days (range: 17-109) for the DCF arm, and 41 days (range: 14-98) for the CF-RT arm. Baseline characteristics were well-balanced across all TTS subgroups in each treatment arm. Short-term outcomes revealed that operative time and overall proportions of postoperative complications were comparable. However, in the CF-RT arm, a longer TTS was associated with increased blood loss (200 ml, 210 ml, 300 ml, 370 ml; p-value for trend test = 0.010) and tended to increase the risk of anastomotic leakage (6%, 7%, 14%, 18%; p-value for trend test = 0.073). No significant differences in OS or PFS were observed across TTS subgroups in any treatment arm, with hazard ratios indicating no clear trend toward improved or worsened long-term outcomes.
Conclusions:
The timing of surgery following neoadjuvant therapy does not appear to affect long-term prognosis in patients with advanced ESCC, irrespective of the neoadjuvant therapy regimen. However, for patients undergoing neoadjuvant CF-RT, earlier surgery may be advantageous in reducing the risk of increased surgical complexity and anastomotic leakage.
Anlotinib plus benmelstobart as adjuvant therapy in patients with esophageal squamous cell carcinoma: A phase II clinical trial (ALTER-E005).
Authors: Guo Changying , Li Xiaobing , Chen Shengjia , Ye Yongqiang , Mao Weimin
Published: January 2025

459

Background:
Surgery represents a primary radical treatment for esophageal cancer, However, the risk of recurrence remains noteworthy after surgical resection, underscoring the need for more effective and tolerable postoperative regimens for esophageal squamous cell carcinoma (ESCC). Benmelstobart, a novel PD-L1 blockade, demonstrated promising antitumor activity when combined with anlotinib, an antiangiogenic agent, in the treatment of various tumors including advanced ESCC (NCT05038813) and biliary tract cancer (NCT03996408). Therefore, ALTER-E005 study aimed to evaluate the efficacy and safety of combining anlotinib with benmelstobart as adjuvant therapy in patients (pts) with ESCC.
Methods:
This was a single-arm, multi-center phase Ⅱ clinical trial. Thirty pts (≥18 years) with histologically confirmed T1-2N1-3M0 or T3-4NanyM0 ESCC who had undergone radical (R0) resection with no recurrence 6 to 12 weeks after surgery and an ECOG PS ≤ 1 were eligible for enrollment. Enrolled pts received oral anlotinib (12 mg, days 1-14) and intravenous benmelstobart (1200 mg, day 1) every 3 weeks for up to 16 cycles or until disease recurrence. The primary endpoint was disease recurrence free (DFS). while secondary endpoints included safety, 1-year DFS rate, 3-year DFS rate, 1- year overall survival (OS) rate, and 3-year OS rate.
Results:
As of the data cut-off date (September 20, 2024), a total of 30 patients were enrolled with a median age of 67. Among the 30 surgically resected patients with ESCC, 26 (86.7%) had an ECOG score of 1, and 25 (83.3%) were male. According to the eighth edition of the AJCC Cancer Staging Manual, 9 (30.0%) were classified as stage Ⅱ, and 21 (70.0%) were classified as stage Ⅲ. As of the data cut-off date, the median follow-up time was 8.9 months (95% CI: 7.9-12.3). Four pts experienced disease recurrence, and the median duration of DFS has not yet been reached, with 6-month and 1-year DFS rates of 95.7% (95% CI, 72.9%-99.4%), 84.0% (95% CI, 57.7%-94.6%) respectively. Currently, 13 pts are still undergoing therapy. Out of the total 30 patients, 9 (30%) experienced grade 3 treatment-emergent adverse events (TEAEs). No grade 4 or higher TEAEs were observed. The grade 3 TEAEs included hand-foot syndrome (10.0%), hypertension (3.3%), abnormal liver function (3.3%), immune-related hepatitis (3.3%), pneumonia (3.3%), hyperglycemia (3.3%) Lymphocyte count decreased (3.3%), acute cholecystitis (3.3%) and syncope (3.3%).
Conclusions:
This study highlighted the promising efficacy and safety preliminarily of combining anlotinib with benmelstobart as adjuvant therapy in patients with ESCC who underwent radical (R0) resection and showed no recurrence 6 to 12 weeks after surgery.
Clinical trial information: NCT05252078
.
Fruquintinib combined with PD-1 inhibitors and chemotherapy in the first-line treatment of HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma (FDZL-FIX): A single-arm, open-label phase 2 study.
Authors: Wang Chenchen , Huang Mingzhu , Dai Yuedi , Feng Wanjing , Zhao Xiaoying , Zhu Xiaodong
Published: January 2025

461

Background:
For unresectable locally advanced or metastatic HER2-negative gastric cancer (GC), the combination of chemotherapy with immunotherapy, specifically PD-1 inhibitors, has emerged as a new standard of care in first-line treatment of advanced GC, but the patients’ outcomes remain poor. Early clinical studies investigating the combination of immunotherapy with anti-angiogenic drugs have demonstrated favorable efficacy. Therefore, it is worth exploring whether the addition of fruquintinib, a potent VEGFR-1,2,3 inhibitor, to the combination of PD-1 inhibitor and chemotherapy can further enhance the survival benefits for patients with unresectable locally advanced or metastatic HER2-negative GC.
Methods:
This is an open-label, single-center clinical study. The enrolled patients were all no less than 18 years old with HER2 negative locally advanced unresectable or metastatic gastric or gastrooesophageal junction adenocarcinoma, without any systemic anticancer treatment for advanced disease. Eligible patients received 6 cycles of combined first line treatment with fuquinitinib (4mg daily, d1-14, q3w, oral) combined with PD-1 inhibitor (sintilimab 200mg or nivolumab 360mg intravenously q3w) and chemotherapy (XELOX or SOX) regimen. The following maintenance treatment was fuquinitinib combined with PD-1 inhibitor and S-1/capecitabine until disease progression or intolerable toxicity. The primary endpoint was progress free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), duration of response (DoR), disease control rate (DCR) and safety.
Results:
At the cutoff date on Sep 18, 2024, a total of 27 patients were enrolled and received at least one dose of treatment. 23 patients had received the response evaluation, with an ORR of 60.9% (14/23; 95%CI 38.5-80.3) and DCR of 100% (23/23 95%CI 85.2-100.0). In the intention to treatment (ITT) population, the median PFS was 9.79 months (95% CI 5.29-NA). Safety profile indicated that 22.2% (6/27) experienced grade≥3 adverse events. The most common grade ≥ 3 adverse reactions mainly include neutropenia (7.4%, 2/27) and thrombocytopenia (7.4%%, 2/27).
Conclusions:
The combination of fruquintinib and chemotherapy with PD-1 blockade in the first-line treatment for unresectable locally advanced or metastatic HER2-negative GC had shown promising efficacy and acceptable safety profile. Enrollment in the trials is still ongoing.
Clinical trial information: NCT06158919
.