bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 2 study of trastuzumab deruxtecan as neoadjuvant treatment for HER2-positive gastric and gastroesophageal junction adenocarcinoma (EPOC2003).
Authors: Takahari Daisuke , Kawazoe Akihito , Machida Nozomu , Minashi Keiko , Yamagata Yukinori , Hara Hiroki , Omori Takeshi , Yamamoto Manabu , Yasui Hisateru , Nakayama Izuma , Yamada Takanobu , Kano Masayuki , Yoshikawa Takaki , Wakabayashi Masashi , Komura Yu , Sato Akihiro , Kuwata Takeshi , Kojima Motohiro , Kinoshita Takahiro , Shitara Kohei
Published: January 2024

309

Background: Currently no HER2 directed therapy is available in the perioperative setting for gastric and gastroesophageal junction (GEJ) cancer. Trastuzumab deruxtecan (T-DXd) received regulatory approval based on the encouraging efficacy demonstrated in the DESTINY-Gastric01 and DESTINY-Gastric02 studies in pretreated patients (pts) with metastatic gastric and GEJ cancer. This multicenter phase 2 study aimed to evaluate the clinical activity and safety of neoadjuvant T-DXd for locally advanced gastric and GEJ cancer. Methods: Eligible pts possessed previously untreated locally advanced gastric and GEJ adenocarcinoma with clinical stage of T2-4 and/or N+ without distant metastasis. The main cohort enrolled pts exhibiting HER2-positivity, defined as IHC 3+ or IHC 2+ with ISH+ by local assessment. An exploratory cohort included patients with HER2-low expression (IHC1+ or 2+ with ISH negative) with serum HER2-ECD exceeded 11.6 ng/ml. Treatment included three cycles of T-DXd administered every 3 weeks, followed by surgery. The primary endpoint was the major pathological response (MPR) rate by central assessment, with an expected rate of 45% and a futility threshold of 20%. The planned sample size in the main cohort was 27 pts with one-sided alpha of 10% and power of 90%, while an additional 10 pts would be enrolled into the exploratory cohort. Pre- and post-treatment samples were subjected to biomarker analyses. Clinical trial identification: NCT05034887. Results: Between November 2021 and November 2022, 27 pts were enrolled into the main cohort from seven Japanese sites. The majority of the pts had IHC3+ (24pts). The primary sites were gastric (16 pts) and GEJ (11 pts). Clinical stages ranged from II/III/IVa: 2/21/4 pts. Of the cohort, 26 pts completed planned 3 courses of T-DXd and one pt discontinued because of toxicity. R0 resection was achieved in 25 pts, with one undergoing R1 resection. The MPR rate as the primary endpoint was 14.8% (80% CI 6.6 % - 27.5 %) which did not surpass the predefined 20%. The pCR rate was 3.7% (95% CI 0.1 % - 19.0 %). There were no new safety signals during T-DXd treatment and during the post-surgery phase. Biomarker analyses remain ongoing. Conclusions: T-DXd monotherapy showed modest single agent activity for locally advanced HER2-positive gastric or GEJ adenocarcinoma in this phase 2 study. An additional cohort combining perioperative T-DXd with capecitabine and durvalumab is planned, to assess whether treatment efficacy and outcomes can be enhanced. Clinical trial information: NCT05034887 .
Larynx-preserving treatment strategy for patients with resectable cervical esophageal squamous cell carcinoma.
Authors: Tsubosa Yasuhiro , Inoue Masazumi , Tokizawa Kazunori , Mayanagi Shuhei
Published: January 2024

311

Background: Preservation of the larynx is an important treatment strategy for cervical esophageal squamous cell carcinoma (CESCC), because surgery for CESCC often involves laryngectomy. At our hospital, we actively perform dCRT (cisplatin + 5-fluorouarcil + radiation 60Gy) to preserve laryngeal function. In this study, we compared the treatment results of esophagectomy and definitive chemoradiation (dCRT) for resectable CESCC and examined larynx-preserving treatment strategies. Methods: Patients who were treated for resectable CESCC at our hospital from January 2003 to March 2019 were divided into surgery group and dCRT group for the initial treatment. All patients were eligible for both treatments. The treatment results were compared retrospectively. Results: Of all 61 patients, 23 patients received surgery and 38 received dCRT. There was no significant difference in patients’ characteristics between 2 groups. In surgery group, 19 cases lost their laryngeal function by surgery (82.6%). Recurrence was observed in 7 cases, of which only 3 case was local. In CRT group, 33 cases (86.8%) achieved complete response, of which 16 cases relapsed. 8 cases (21.1%) lost their laryngeal function by additional surgery after dCRT. There was no significant difference in 5-year survival rate between two groups (surgery, 60.8%; dCRT, 70.1%; p = 0.750). In dCRT group, 5-year laryngeal-preserving survival rate was 64.8%, and esophageal stenosis before treatment was the independent risk factor for non-larynx preservation. 5-year laryngeal-preserving survival rate was 78.5%, and 5-year survival rate was 85.4% for non-stenotic cases in dCRT group, which were significantly higher than those for stenotic cases. 5-year laryngeal-preserving survival rate was also high in the patients with Ce localized tumor (72.6%). In those patients, non-stenotic patients and cT1-T3 patients had significantly high 5-year laryngeal-preserving survival rate (87.5% and 92.3%). Conclusions: dCRT for CESCC was comparable to surgery in terms of long-term prognosis, and the rate of larynx preservation was high. Among the cases where the tumor was localized to Ce, the laryngeal preservation rate was particularly high in non-stenotic cases and cases with cT1-T3, and dCRT should be actively indicated for these cases.
Role of immunotherapy in gastroesophageal cancer with liver metastasis: A meta-analysis of phase III randomized clinical trials.
Authors: Bawek Sawyer , Gurusinghe Sayuri , Aijaz Ali , Attwood Kristopher , Mukherjee Sarbajit
Published: January 2024

319

Background: Recent studies have demonstrated a poor response to immunotherapy in patients with colorectal cancer with liver metastasis. The role of immune checkpoint inhibitors (ICIs) for patients with gastroesophageal (GE) cancer with liver metastasis remains unclear. Our objective was to investigate if ICIs are beneficial in patients with GE cancer with liver metastasis. Methods: We searched PubMed, Embase, ESMO, and ASCO Meeting Abstracts for phase III randomized clinical trials (RCTs) testing ICIs in metastatic/advanced GE cancer from 2017 to 2023. All phase III RCTs of metastatic GE cancer treated with ICIs that had available data on liver metastasis were analyzed. A meta-analysis was conducted on the survival outcomes (overall and progression-free survival), where hazard ratios were obtained, with 95% confidence intervals, using the standard random effects model. To assess the heterogeneity of the study outcomes, the I2 statistic was obtained. The I2 statistic represented the variability in the meta-analysis attributed to study heterogeneity. These analyses were applied to the overall cohort of studies, as well as within the liver metastasis (yes or no) sub-cohorts. All analyses were conducted in SAS v9.4 (Cary, NC) at a significance level of 0.05. Results: Seven Phase III RCTs were includedthat had available data on overall survival and/or progressive free survival in patients with liver metastasis. Of these, six were in the frontline setting and one in the later line. Overall, 6,109 patients were included. Overall survival was similar among all patients (HR 0.72 [0.67,0.77], p<0.001, I2=0.0%), patients with no liver metastasis (HR 0.73 [0.67,0.81], p<0.001, I2=0.0%), and patients with liver metastasis (HR 0.74 [0.67,0.81], p<0.001, I2=0.0%), indicating that ICIs’ benefit on OS is consistent. Progression-free survival (PFS) was also similar among all patients (HR 0.63 [0.57,0.70], p<0.001, I2=54.7%); those with no liver metastasis (HR 0.62 [0.51,0.76], p<0.001, I2=62.3%), and with liver metastasis (HR 0.66 [0.57,0.76], p<0.001, I2-0.0%). Funnel plots were used to identify a potential bias for studies included in the analysis and showed no significant sources of bias for OS and PFS. Conclusions: In this meta-analysis, ICIs were beneficial in patients with GE cancer with and without liver metastasis. However, the majority of the trials were in the frontline setting where ICIs were combined with chemotherapy. Further subgroup analyses should be performed with individual patient-level data to identify patients who respond best to ICIs.
Applying the fragility index to randomized controlled trials evaluating total neoadjuvant therapy for rectal cancer.
Authors: McKechnie Tyler , Brennan Kelly , Eskicioglu Cagla , Farooq Ameer , Patel Sunil
Published: January 2024

32

Background: A relatively novel summary measure that is not commonly reported in randomized controlled trials (RCTs) is the fragility index (FI). FI describes the number of additional events required for an outcome to lose statistical significance. It has been applied to a number of medical subspecialities such as critical care, orthopedic surgery and colorectal surgery. Recently, there has been significant interest in, and adoption of, total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC). A number of RCTs have assessed TNT, but the robustness of these practice changing RCTs has never been evaluated. As such, we designed the present study to assess the robustness of the RCTs evaluating TNT for LARC using the FI. Methods: Relevant articles were identified through a recently published review article by Johnson et al. in the Canadian Journal of Surgery, that narratively reviewed all of the previously published RCTs evaluating TNT for LARC. We manually searched Google Scholar and PubMed to identify any other relevant RCTs. Outcomes within these RCTs that were either dichotomous outcomes or time to event outcomes were eligible for inclusion if the reported effect size had an associated p-value of less than 0.05. The main outcome was the FI for each statistically significant outcome. Walsh et al.’s method of calculating FI was utilized. A RCTs results were considered fragile if the FI was less than the loss to follow up for a given outcome. Correlations between FI and research characteristics were assessed using the Spearman’s rank correlation coefficients. Results: Ten RCTs were identified with 25 outcomes having statistically significant differences between groups (p-values < 0.05). Eleven outcomes were time-to-event outcomes, while the remainder were dichotomous outcomes. About half (n=13) were oncologic outcomes (i.e., survival, recurrence), while the rest (n=12) were short- and long-term complications. The median FI was 2 (interquartile range [IQR] 1-16). The number of patients lost to follow-up exceeded the FI in 17 outcomes (68.0%) and thus these results were considered “fragile”. Lower FI was associated with high risk of bias (rho=-0.5594) and higher loss to follow-up (i.e., greater than 5% vs. less than 5%) (rho=-0.4394), while higher FI was associated with large sample size (i.e., greater than 500 patients vs. less than 500 patients) (rho=0.5120). Conclusions: The robustness of outcomes from trials assessing TNT for LARC was found to be questionable. Most of these outcomes were fragile, as determined by the FI. In most cases, two or less additional events would have resulted in a loss of statistical significance of the reported results. Those using the results of these studies, including clinicians and health policy experts, should apply caution when interpreting these types of trials.
Clinicopathological characteristics and lymph node metastasis rates in early gastric lymphoepithelioma-like carcinoma: Implications for endoscopic resection.
Authors: Kim Tae-Se , Min Byung-Hoon , Min Yang Won , Lee Hyuk , Lee Jun Haeng , Rhee Poong-Lyul , An Ji Yeong , Kim Jae J.
Published: January 2024

321

Background: We aimed to clarify the clinicopathological features and the rate of lymph node metastases (LNM) of early gastric lymphoepithelioma-like carcinoma (LELC). Methods: We compared the clinicopathological characteristics of 82 LELC and 5758 well- or moderately differentiated (WD or MD) tubular adenocarcinoma patients who received gastrectomy for single early gastric cancer (EGC). Results: Compared to the control group, early LELC patients were younger, had a higher prevalence of proximally located tumors, more frequent Epstein-Barr virus (EBV) infection, more frequent deep submucosal invasion (SM2 or SM3, 85.4% versus 29.9%, P < 0.001) but less frequent lymphatic invasion (4.9% versus 16.2%, P = 0.009). Among tumors with deep submucosal invasion, early LELC patients had smaller tumor sizes, less frequent lymphatic invasion (5.7% versus 40.1%, P < 0.001) and a lower rate of LNM (7.1% versus 19.4%, P = 0.016) than the control group. LNM rates of LELC patients with mucosal, shallow submucosal invasion (SM1) and deep submucosal invasion were 0%, 0%, and 7.1%, respectively. Lymphatic invasion was the only significant risk factor in the regression analysis for LNM in LELC patients. Among 12 patients with mucosal or shallow submucosal invasion and 27 patients with deep submucosal invasion having small tumor sizes (less than 2 cm) and no lymphatic invasion, there was no LNM. Conclusions: Given the low rate of LNM, the same curability criteria of ESD for WD or MD EGC may be applied to early LELC and even more flexibly for those considered non-curative ESD only because of deep submucosal invasion.
A randomized phase III study comparing 2-weekly docetaxel, cisplatin and 5-FU (bDCF) with cisplatin and 5-FU (CF) in patients with metastatic or recurrent esophageal cancer: JCOG1314 (MIRACLE).
Authors: Tsushima Takahiro , Hironaka Shuichi , Tsubosa Yasuhiro , Kato Ken , Nomura Motoo , Hara Hiroki , Kitagawa Yuko , Koyanagi Kazuo , Kajiwara Takeshi , Takegawa Naoki , Matsubara Hisahiro , Baba Hideo , Morita Masaru , Masuzawa Toru , Hasegawa Hiroko , Kojima Takashi , Machida Ryunosuke , Sasaki Keita , TAKEUCHI HIROYA , Kadowaki Shigenori
Published: January 2024

322

Background: For metastatic or recurrent esophageal cancer, 2-drug combination of cisplatin and 5-FU (CF) has long been a standard of care before the emergence of immune checkpoint inhibitors (ICIs). Previous phase I/II study of 3-drug combination, 2-weekly docetaxel plus CF (bDCF) showed promising antitumor activity (JCOG0807). We conducted JCOG1314, a randomized phase III study to confirm the survival superiority of bDCF over CF. Methods: Main eligibility criteria were metastatic or recurrent esophageal cancer; histologically proven squamous cell carcinoma or adenocarcinoma; age 20 to 75; no previous systemic therapy for metastatic disease. Patients were randomly assigned to CF arm (cisplatin 80 mg/m2 on day 1, and 5-FU 800 mg/m2 on days 1-5, every 28 days), or bDCF arm (docetaxel 30 mg/m2 on day 1 and day 15 in addition to CF, every 28 days). The primary endpoint was overall survival (OS). To detect a 3-month difference in median OS [hazard ratio (HR) = 0.73] with study-wise, one-sided alpha level of 5% and power of 75%, 240 patients were required. Results: A total of 240 patients were randomly assigned to bDCF (n = 121) and CF (n = 119) between September 2014 to April 2021. Patient background in bDCF/CF arm was median age, 65/64 years; ECOG performance status 0, 69%/75%; metastatic disease, 63%/67%, ≥2 metastatic organs, 59%/56%; squamous cell carcinoma, 94%/97%. As a data cut-off of April 2023, all 240 patients discontinued protocol treatment. The reasons for treatment discontinuation in bDCF/CF arm were disease progression, 58%/71%; adverse events (AEs), 35%/27%; refusal, 1%/1%; others, 7%/5%, respectively. With a median follow-up of 15.3 months (m), bDCF arm was not superior to CF arm in terms of OS with a median of 16.2 m versus 14.8 m [HR, 0.90; 95% confidence interval (CI), 0.68–1.19; p = 0.23], however, progression-free survival (PFS) in bDCF arm was favorable compared to CF arm with a median of 6.0 m versus 5.2 m (HR, 0.68; 95% CI, 0.52–0.88). Response rate in bDCF/CF arm was 52.8%/45.6%. Major grade 3 or 4 AEs observed in bDCF/CF arm were neutropenia (37.8%/27.1%); anorexia (25.2%/16.1%); fatigue (10.1%/15.3%); hyponatremia (13.4%/13.6%). No treatment related death was observed. Subsequent therapy in bDCF/CF arm was provided for 87%/89% of patients. Conclusions: JCOG1314 did not reach its primary objective, although bDCF was associated with significant increases in PFS. CF is still the standard therapy in patients with metastatic or recurrent esophageal cancer if ICIs are not applicable. Clinical trial information: jRCTs031180143 .
MORPHEUS-EC: A phase Ib/II open-label, randomized study of first-line tiragolumab (tira) + atezolizumab (atezo) + chemotherapy (CT) in patients (pts) with esophageal cancer (EC).
Authors: Sun Jong-Mu , Chao Yee , Kim Sung-Bae , Rha Sun Young , Evans T.R. Jeffry , Strickland Andrew , Wainberg Zev A. , Chau Ian , Pelles-Avraham Sharon , Ajani Jaffer A. , Malhotra Ritu , Liu Qingyuan , Li Sijing , Cha Edward , Rahalkar Swapna , Allen Simon , Hsu Chih-Hung
Published: January 2024

324

Background: TIGIT is a novel inhibitory immune checkpoint on activated T cells and NK cells. Tira (anti-TIGIT) may synergize with other immunotherapies, e.g. PD-L1/PD-1 inhibitors. The MORPHEUS platform comprises multiple phase Ib/II trials to identify early efficacy signals and safety of treatment (tx) combinations across cancers. We report interim data from MORPHEUS-EC (NCT03281369) evaluating the combination of tira + atezo with CT in pts with untreated locally advanced unresectable or metastatic EC. Methods: Eligible pts (locally advanced unresectable, or metastatic EC with no prior systemic treatment; ECOG PS 0–1) were randomized to receive: cisplatin 80mg/m2 + 5-FU 800mg/m2/24 hours on Days 1–5 of each cycle (CT); atezo 1200mg + cisplatin + 5-FU (atezo + CT); or tira 600mg + atezo + cisplatin + 5-FU (tira + atezo + CT) in 21-day cycles. Primary endpoint: investigator (INV)-assessed objective response rate (ORR). Key secondary endpoints: INV-assessed progression-free survival (PFS), overall survival (OS), safety. Results: 152 pts were randomized to: CT (n=24; control); atezo + CT (n=65) or tira + atezo + CT (n=63). As of 14 Mar 2023, median follow-up was 8.7 months (mo) in the CT arm, 11.4 mo in the atezo + CT arm and 10.9 mo in the tira + atezo + CT arm. Pt characteristics were generally balanced between arms. ORR was 47.8% (CT) vs 53.8% (atezo + CT) vs 67.7% (tira + atezo + CT). Median PFS was 4.1 mo (CT) vs 6.8 mo (atezo + CT) vs 6.9 mo (tira + atezo + CT) (Table). ORR and PFS benefit was generally consistent across all pre-specified subgroups, including PD-L1 status. There was a numerical improvement in OS with tira + atezo + CT vs atezo + CT and CT alone (Table). Grade 3–5 adverse events (AEs) were 82.6% vs 83.1% vs 85.5% and treatment-related Grade 4/5 AEs were 4.3% vs 7.7% vs 14.5% for CT vs atezo + CT vs tira + atezo + CT. AEs leading to any tx discontinuation were 21.7%, 16.9% and 35.5%, respectively. Conclusions: Clinically meaningful improvements in INV-assessed ORR and PFS and a trend of improved OS were observed with tira + atezo + CT when compared with CT and atezo + CT. These results support the contribution of both tira and atezo in combination with CT. The safety profile was consistent with the known risks of the individual tx. Clinical trial information: NCT03281369 . [Table: see text]
Survival outcomes in patients with resectable gastric cancer treated with total neoadjuvant therapy.
Authors: Song Yun , Hirata Yuki , Ajani Jaffer A. , Blum Murphy Mariela A. , Li Jenny Jing , Das Prajnan , Minsky Bruce D. , Mansfield Paul F. , Ikoma Naruhiko , Badgwell Brian D.
Published: January 2024

338

Background: Perioperative chemotherapy is the standard of care for patients diagnosed with advanced gastric cancer. However, the use of total neoadjuvant therapy (TNT), which includes both chemotherapy and chemoradiation, is increasing in other malignancies. The purpose of this study is to determine overall survival (OS) in a contemporary cohort of gastric cancer patients treated with TNT and surgical resection. Methods: Patients diagnosed with microsatellite-stable clinical T2+ or N+ gastric adenocarcinoma (January 2012 to June 2022) were identified from a prospectively maintained institutional database. Those who underwent staging laparoscopy and received neoadjuvant chemotherapy and chemoradiation therapy, followed by gastrectomy, were included in the study. OS and variables associated with OS were determined using standard statistical methods. Results: Of 203 study patients, the median (interquartile range) age was 61 (50-69.5) years and 50 (24.6%) had tumor involving the gastroesophageal junction. The most common TNT sequence was chemotherapy followed by chemoradiation, which was utilized in 173 (85.2%) patients. The chemotherapy regimen typically given was fluorouracil and oxaliplatin in 149 (73.4%) patients. The most common radiation dose was 45 Gy in 25 fractions (169 [83.3%] patients), with 18 (8.9%) patients receiving 30 Gy in 10 fractions. One hundred ninety-seven (97.0%) patients completed all their planned neoadjuvant therapy. Surgical resection included total gastrectomy in 108 (53.2%), adjacent organ resection in 24 (11.8%), and extended (D1+/D2) lymphadenectomy in 193 (95.1%) patients. Pathologic complete response was achieved (pCR) in 32 (15.8%) patients. The median OS was 8.4 (95% confidence interval [CI] 6.5-not reached) years, and the 5-year OS rate was 65.2% (95% CI 57.8-73.5%). Patients with pCR had a 5-year OS rate of 89.1% (95% CI 78.1-100.0%). On multivariable analysis, D1+/D2 lymphadenectomy (HR 0.21 [95% CI 0.088-0.51]), post-treatment pathologic (yp) T (ypT3 vs ypT0, HR 3.11 [95% CI 1.09-8.82]; ypT4 vs ypT0, HR 5.51 [95% CI 1.64-18.5]) and N stages (ypN1 vs ypN0, HR 2.41 [95% CI 1.13-5.13]; ypN2 vs ypN0, HR 2.43 [95% CI 1.14-5.20]; ypN3 vs ypN0, HR 4.70 [95% CI 2.09-10.6]), incidental distant metastasis at time of resection (HR 3.75 [95% CI 1.50-9.37]), and postoperative complications (HR 2.06 [95% CI 1.21-3.52]) were associated with OS. Conclusions: TNT is associated with a high rate of treatment completion and promising long-term OS for patients with resectable gastric cancer. Comparative studies with perioperative treatment and predictors of tumor response will be important in identifying patients suitable for TNT.
Prophylactic para-aortic lymph node dissection after neoadjuvant chemotherapy for gastric cancer with bulky lymph node metastasis.
Authors: Kenichiro Furukawa , Matsumoto Yosuke , Soneda Wataru , Koseki Yusuke , Fujiya Keiichi , Tanizawa Yutaka , Bando Etsuro
Published: January 2024

344

Background: Neoadjuvant chemotherapy (NAC) followed by D2 gastrectomy with para-aortic lymph node dissection (PAND) is the standard treatment for gastric cancer with extensive lymph node metastasis (ELM) in Japan. ELM includes bulky lymph node metastasis along the celiac artery and its branches (Bulky N2) and metastasis of para-aortic lymph nodes (PAN). However, the benefit of PAND for gastric cancer with Bulky N2 but without PAN involvement is unclear. The aim of this study was to evaluate the efficacy of prophylactic PAND after NAC for this subgroup of patients. Methods: We retrospectively reviewed 21 patients who underwent NAC followed by curative (R0) gastrectomy for Bulky N2 (+) but PAN (-) gastric cancer from 2008 to 2019. Bulky lymph node was defined as one lymph nodes ≥ 3cm or two adjacent lymph nodes ≥ 1.5cm each. PAN metastasis included no. 16a2/16b1 lymph node metastasis. PAND was defined as systematic lymph node dissection of PAN. Patients were divided into two groups: a D2+PAND group (11 patients) and a D2 group (10 patients). We compared the clinicopathological features, recurrence patterns, and survival outcomes between the two groups. Results: The most common NAC regimen was S-1+cisplatin (12 patients: 57%), and other regimens in D2+PAND group included docetaxel+S-1+cisplatin or oxaliplatin. The D2+PAND group had longer operation time (p=0.006), and tended toward more undifferentiated histological type (p=0.063), better pathological response (p=0.086), and higher rate of adjuvant chemotherapy (p=0.090) than the D2 group. The ypStage was similar between the two groups. Pathological PAN metastasis was detected in two patients (18%) in D2+PAND group. Recurrence occurred in seven (70%) patients in D2 group and three (27%) patients in D2+PAND group, and lymph node recurrence was observed in four (40%), and one (10%) patients, respectively. The D2+PAND group had significantly better overall survival, recurrence-free survival, and disease-specific survival than the D2 group (p=0.008, 0.008, and 0.020, respectively). Conclusions: Prophylactic PAND after NAC may reduce recurrence risk for locally advanced gastric cancer with Bulky N2 but without PAN involvement.
Safety and efficacy of nanosomal docetaxel lipid suspension (NDLS) in patients with advanced gastric adenocarcinoma.
Authors: Ostwal Vikas S. , SHARMA ATUL , Ghosh Joydeep , Reddy Rakesh , K Lakshmi Priyadarshini , Srinivas B. J. , Raghu Raman Ramaiyer , Kota Rajesh , Panda Soumya Surath , Agarwal Amit , Seshachalam Arun , Nemade Bhushan Tapiram , Ahmad Ateeq , Sheikh Saifuddin , Ali Shoukath M , Paithankar Mahesh , Patel Lav , Rajani Anil , Bunger Deepak , Ahmad Imran
Published: January 2024

348

Background: Nanosomal docetaxel lipid suspension (NDLS) was developed to overcome toxicity issues associated with conventional docetaxel. Docetaxel, cisplatin, 5-fluorouracil (5-FU; DCF) or modified DCF (mDCF) is one of the recommended first-line regimens for patients with metastatic gastric adenocarcinoma (GAC). However, majority of the patients experienced grade 3/4 toxicities with DCF regimen using conventional docetaxel. The present study evaluated the safety and efficacy of NDLS-based mDCF/DCF regimens in patients with metastatic GAC. Methods: In this multicentric, open-label, clinical trial, patients with previously untreated metastatic GAC were enrolled. Patients received either mDCF [NDLS 40 mg/m2 on day 1 (D1), C 40 mg/m2 on D2 or D3, 5-FU 400 mg/m2 bolus on D1, leucovorin 400 mg/m2 on D1, 5-FU 1000 mg/m2/day continuous infusion D1 & 2; q2w] for 9 cycles, or DCF [NDLS 75 mg/m2 on D1, C 75 mg/m2 on D1, 5-FU 750 mg/m2/day for 5 days given as continuous infusion; q3w] for 6 cycles. Prophylactic GCSF (Granulocyte Colony Stimulating Factor)/Peg-GCSF support was allowed in all patients. The primary endpoint was overall response rate (ORR) at week 18. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety outcomes. Patients were followed up to 1 year. Results: Fifty-two patients were enrolled, with mean (±SD) age of 52 (±9.6) years & male:female ratio of 32:20. Thirty-eight patients qualified for modified intent-to-treat (mITT) analysis for efficacy evaluation (mDCF: 33; DCF:5). At week 18, ORR was 57.9% & DCR was 81.6% in mITT population. In the per-protocol population (n=26), ORR was 61.5% at 18 weeks (mDCF:63.6%; DCF:50%). Safety set included all 52 patients. Any grade adverse events (AEs) were reported in 90.4% (n=47) of the patients; with 40.4% experiencing grade 3/4 AEs. All-grade AEs reported in ≥10% of the patients included anemia, neutropenia, abdominal pain, diarrhea, nausea, vomiting, fatigue, mucositis, decreased appetite, peripheral neuropathy; with majority of AEs being grade 1/2. Most common grade 3/4 AE was neutropenia; observed in 17.3% (n=9) patients (mDCF: 14%; DCF: 33.3%). Conclusions: NDLS-based regimens demonstrated efficacy & improved safety profile in the treatment of metastatic GAC. Clinical trial information: CTRI/2018/01/011450 . [Table: see text]
Evaluation of the efficacy and safety of a 3-weekly TS-1 regimen as adjuvant therapy for stage II and III advanced gastric cancer: A pilot study.
Authors: Bae Jihong , Sym Sun Jin , Park Joo-Hwan , Kim Young Saing , Ahn Hee Kyung , CHO EUN KYUNG , Shin Dong Bok , Park Ji-Hyeon , Yang Jun-Young , Lee Woon-Kee
Published: January 2024

350

Background: Adjuvant therapy for stage II and III advanced gastric cancer (AGC) is essential in improving patient outcomes. The standard therapy, TS-1 at 80 mg/m2/day for 4 weeks with a 2-week rest, is recommended for 1 year or 8 courses. This study investigates the efficacy and safety of a 3-weekly adjuvant TS-1 regimen in AGC patients. Methods: We conducted an analysis of 93 patients who underwent gastrectomy with D2 lymphadenectomy and initiated a 3-weekly adjuvant TS-1 regimen between February 2017 and May 2022. The novel regimen consisted of TS-1 at 80 mg/m2/day for 2 weeks, followed by a 1-week rest, with a treatment goal of 1 year or 16 courses. Results: Among the 93 patients, 12 (13%) experienced disease recurrence during a median follow-up of 24.6 months (range: 4.2 to 63.3 months). Of the Stage II patients (n=73), 7 cases (9.5%) had recurrent disease, while 5 cases (25%) in the Stage III group (n=20) experienced recurrence. Recurrence-Free Survival (RFS) rates at 1 year, 3 years, and 5 years were 92.0% (95%CI 86.5 to 97.9), 84.7% (95%CI,76.4% to 93.9%), and 78.6% (95%CI, 65.8% to 94.0%), respectively. A total of 80 patients (86%) completed the adjuvant 3-weekly TS-1 treatment for 1 year or 16 courses, while 25 patients (26.9%) completed the treatment with dose reductions. Adverse events, primarily Grade 1 or 2 diarrhea (28%) and nausea (20%), were manageable. Conclusions: The novel 3-weekly TS-1 regimen as adjuvant therapy exhibited favorable efficacy and tolerable toxicity in AGC patients. These findings suggest the need for further investigation of this regimen in future clinical studies.
Preliminary results of surufatinib (Suru) plus standard chemotherapy (ChT) as second line (2L) treatment of advanced gastric cancer (aGC): A single-arm, phase 2 clinical trial.
Authors: Han Ting , Lin Xiaolin , Zhuo Meng , Jiao Feng , Cui Jiujie , Qiu Xiaoxia , Xiao Xiuying
Published: January 2024

353

Background: Limited options are available for aGC patients who have failed first line (1L) systemic treatment, and single-agent ChT with paclitaxel (Pac) or irinotecan (Iri) remains the mainstay. Recent studies have suggested improved efficacy with the combination of ChT and antiangiogenic agents in the 2L setting. Suru is a tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1 and CSF-1R. This trial is aimed to evaluate the efficacy and safety of Suru plus Pac or Iri as 2L treatment for aGC. Methods: This single-arm, single center, phase 2 trial was designed to enroll up to 35 histologically confirmed HER2-negative aGC patients with evaluable disease who failed 1L ChT with or without immunotherapy (IO). Eligible patients were administered 21-day cycles of Suru (250mg, po, qd) plus Pac (150mg/m2, iv, d1) or Iri (125mg/m2, iv, d1, d8) per investigator choice for 6 cycles, followed by Suru (250mg, po, qd) maintenance if no disease progression (PD), until intolerable toxicity, PD, or death. The primary endpoint was ORR (per RECIST v1.1), and secondary endpoints included DCR, PFS, OS, and safety. Results: As of Sep 11, 2023, 15 patients were enrolled, and 6 patients remained on treatment. The median follow-up time was 5.77 (95% CI: 3.37~10.13) months. Among all 15 patients, the median age was 66 (range: 33-76) years, 14 (93.3%) were male, and 14 (93.3%) had an ECOG PS of 1. Ten (66.7%) patients had received prior anti-PD-1 antibodies, and all 15 patients received Pac as the standard ChT. All 15 patients were evaluable for tumor response, with 5 PR, 9 SD, and 1 PD as their best overall response (BOR). The ORR and DCR were 33.3% and 93.3%, respectively. The median PFS was 5.23 months, while the OS data was immature yet. The ORR, DCR and PFS seemed comparable between patients with and without prior IO. In terms of safety, the combined treatment was generally well tolerated, treatment-related Grade 3/4 adverse events included neutropenia (6, 40%), leukopenia (1, 6.7%), lymphopenia (1, 6.7%), and proteinuria (1, 6.7%). There were no treatment-related serious adverse events or treatment-related deaths. Conclusions: These results suggested promising anti-tumor activity and a manageable safety profile of Suru plus standard ChT in 2L treatment of aGC. The trial is still ongoing, and more data will be disclosed in the future. Clinical trial information: ChiCTR2200063336 . [Table: see text]
Phase I trial of short-course chemoradiotherapy followed by chemotherapy as total neoadjuvant therapy for patients with potentially resectable gastric cancer.
Authors: Badgwell Brian D. , Das Prajnan , Ikoma Naruhiko , Blum Murphy Mariela A. , Li Jenny Jing , Estrella Jeannelyn , Minsky Bruce D. , Mansfield Paul F. , Ajani Jaffer A.
Published: January 2024

362

Background: The purpose of this phase I trial was to evaluate the safety and toxicity of preoperative short-course chemoradiotherapy (CXRT) in patients with potentially resectable gastric or gastroesophageal adenocarcinoma as part of a total neoadjuvant therapy (TNT) approach. Methods: Patients with potentially resectable gastric or gastroesophageal adenocarcinoma received CXRT consisting of 30 Gy in 10 fractions with concurrent capecitabine or fluorouracil, followed by systemic therapy for 2 months and then surgery. The primary objective was safety of CXRT with secondary endpoints of pathologic complete response, perioperative complications, and overall survival (OS). Results: A total of 24 patients were treated between March 2021 and December 2022. Ten patients (42%) presented with bleeding and 3 (13%) presented with gastric outlet obstruction. Two patients (8%) had cirrhosis. Clinical nodal involvement was reported in 12 patients (50%). Twenty patients (83%) had poorly differentiated tumors, and 13 (54%) had signet ring cell histology. All patients completed CXRT. CXRT treatment-related toxic effects included grade 3 lymphopenia in 7 patients (29%), grade 4 lymphopenia in 1 (4%), and grade 3 anemia in 1 (4%). After CXRT, 22 patients (92%) completed 2 months of chemotherapy, 1 patient (4%) with a microsatellite-high tumor completed immunotherapy, and 1 patient (4%) underwent resection without systemic therapy. All patients underwent attempted resection, and gastrectomy was performed in 20 (83%). R0 resection rate was 95%. Pathologic complete response was observed in 2 patients (8%), and ≤ 1% viability was observed in an additional 4 (17%). Three patients had surgical complications (grade I in 1 patient [4%], grade IIIb in 1 [4%], and grade IVa in 1 [4%]); there were no deaths within 90 days. The median follow-up time was 20 months, and median OS was not reached. One- and 3-year OS rates from the date of diagnosis were 96% and 80%, respectively. Conclusions: Short-course CXRT (30 Gy in 10 fractions) may be safely used as part of a planned TNT approach. Rates of treatment completion, pathologic response, and survival were promising, supporting further research into TNT for gastric cancer. Clinical trial information: NCT04523818 .
A phase 2, open-label study of amivantamab in patients with previously treated advanced or metastatic gastric or esophageal cancer.
Authors: Kotani Daisuke , Yamaguchi Kensei , Kato Ken , Hara Hiroki , Miura Akinori , Satoh Taroh , Komine Keigo , Kunisaki Chikara , Yabusaki Hiroshi , Hagiwara Akiko , Suzuki Noriko , Toyoizumi Kiichiro , Curtin Joshua C , Chowdhury Sanjib , Knoblauch Roland Elmar , Doi Toshihiko
Published: January 2024

363

Background: Amivantamab (Ami) is a bispecific antibody targeting epidermal growth factor receptor (EGFR) and mesenchymal epithelial transition receptor (Met) and has immune cell directing activity. Gastric cancer (GC), gastroesophageal junction (GEJ) cancer and esophageal cancer (EC) have been known to express EGFR and Met and these expressions have correlated with poor prognosis. Methods: This open-label, multicenter phase 2 study aims to evaluate the antitumor activity and safety of Ami monotherapy in patients (pts) with advanced or unresectable GC, GEJ cancer and EC who had received at least 2 prior lines (GC/GEJ) or 1 prior line (EC) of systemic therapy. Pts who express varying degrees of EGFR, Met, or both as determined by immunohistochemistry (IHC) were enrolled. Ami was administered intravenously at the recommended Phase 2 dose (RP2D) of 1,050 mg (or 1,400 mg if body weight ≥80 kg) in 28-day cycles. The primary endpoint was objective response rate (ORR) (RECIST 1.1). No hypothesis was planned but approximately 30 pts were to be enrolled in GC and EC cohorts, respectively. Secondary endpoints included disease control rate (DCR), pharmacokinetics (PK) and safety. Results: At the data cut-off of Jul-2023, a total of 59 pts received the RP2D. The 29 and 30 pts had GC/GEJ (all adenocarcinoma) and EC (29 squamous-cell and 1 adenocarcinoma), respectively. Median ages were 66 in GC/GEJ and 60 in EC, and 82.8% and 80.0% of pts were male, and median durations of study treatment were 0.99 and 2.64 months, respectively. The ORRs were 4.3% for GC/GEJ and 10.7% for EC and DCRs were 26.1% and 67.9%, respectively. The Met-high-expression (IHC score ≥2+) tended to be associated with better response of ORR 13.3% and DCR 80.0% compared to Met-low-expression (IHC score 1+/0) of ORR 7.7% and DCR 53.8% in EC. Transcriptomic analysis results from paired baseline/on-treatment EC biopsies will be presented. All 59 pts had adverse events (AEs) and 64.4% of them had AEs with the maximum grade of ≤2. Serious AEs occurred in 27.1% of pts. Conclusions: Ami showed clinical meaningful antitumor activity in EC, especially in Met-high-expression tumors. There was minimal monotherapy activity in GC. No new safety signals were identified in pts with GC and EC, which appeared to be acceptable. Clinical trial information: NCT04945733 .
Camrelizumab plus apatinib after progression on immune checkpoint inhibitors in patients with advanced esophageal squamous cell carcinoma (CAP 02 Re-challenge): A single-arm multicenter, phase II trial.
Authors: Meng Xiangrui , Wang Junsheng , Xia Jin , Wu Tao , Luo Zhiquan , Hong Yong-Gui , Lu Ping , Guo Yanzhen , Ji Yinghua , Zhang Min , Yang Liuzhong , Cheng Peng , Liang Wenchang , Shan Zhengzheng , Fan Qingxia , Wang Feng
Published: January 2024

364

Background: The optimal therapies for patients with advanced esophageal squamous cell carcinoma (ESCC) who have progressed after immune checkpoint inhibitors (ICIs) are unclear. This phase II single-arm study aimed to assess the efficacy and safety of re-challenge with camrelizumab plus apatinib in this population. Methods: This study enrolled patients with unresectable locally advanced, locally recurrent, or metastatic ESCC who had experienced prior progression on ICI treatment. Enrolled patients received camrelizumab 200 mg intravenously every two weeks along with daily oral apatinib 250 mg. Treatment continued until disease progression, unacceptable toxicity, or patient withdrawal of consent. The primary endpoint was the confirmed objective response rate (ORR). Secondary endpoints included disease control rate (DCR), duration of response (DOR), time to response (TOR), progression-free survival (PFS), overall survival (OS), 3- and 6-month PFS rates, 6-, 9- and 12-month OS rates, and safety. Results: From September 1, 2021, to March 29, 2023, 49 eligible patients were enrolled and given treatment. Among 38 treated patients who had at least one post-baseline efficacy measurement, the ORR and confirmed ORR were 36.8% (95% CI 21.8–54.0) and 13.2% (95% CI 4.4–28.1); the DCR was 89.5% (95% CI 75.2–97.1); the median DOR was 3.0 months; and the median TOR was 2.2 months. Among the 49 treated patients, the median PFS was 4.6 months (95% CI 3.8–6.5) and OS was 7.5 months (95% CI 5.5–13.6). Patients who were both PD-L1 positive and had responded to previous ICI therapy had the longest median PFS (5.7 months, 95% CI 3.9–not reached) and OS (9.6 months, 95% CI 7.5–not reached). Grade ≥ 3 treatment-related adverse events occurred in 34.7% of patients (17/49). Conclusions: This study showed promising efficacy and an acceptable safety profile of camrelizumab plus apatinib for patients with advanced ESCC who had progressed after ICI therapy. The subset of patients who were both PD-L1 positive and had a prior ICI response seemed to benefit most. Clinical trial information: NCT03736863 .
A multi-centre review of the efficacy of re-challenge with platinum doublet in patients with oesophagogastric cancer treated with first-line trastuzumab and chemotherapy.
Authors: Weaver Jamie , Ali Rufqah , Mckay Marie , Foy Victoria , Khan Adeel , Cunningham Aimee , McQueenie Esther , Owen-Holt Vikki , Williams Kate , Valpione Sara , Hubner Richard , Waddell Tom , Alchawaf Alia , Mansoor Wasat
Published: January 2024

367

Background: HER2 amplification or overexpression is seen in 15-20% of metastatic oesophagogastric cancers. The ToGA trial showed an OS benefit for the use trastuzumab with platinum and fluoropyrimidine combination therapy (T-FP) in the first line setting. Second line trials of targeted agents have been disappointing with poor response rates and the current standard of care is paclitaxel and ramucirumab in combination. A recent phase 2 trial showed no OS benefit to continuing trastuzumab with second line chemotherapy but data regarding the efficacy of treatment beyond progression with re-introduction of first line chemotherapy (platinum and fluoropyrimidine) is limited and conflicting. Methods: We conducted a multi-centre retrospective review of patients treated with T-FP in the first-line setting between October 2014 and October 2022 at two large tertiary referral oncology centres in the United Kingdom. Baseline demographic factors and clinical data were collected and compared between responders and non-responders to re-challenge. PFS and OS were estimated using the Kaplan-Meier method. Results: Data was collected for 225 patients in total treated with first-line trastuzumab. We identified 20 patients who had received a re-challenge with FP-T. Best response to first-line treatment was partial response (PR) for 19/20 patients with 1/20 patients with stable disease (SD). There were no differences between baseline demographic factors or tumour pathological features between patients receiving a re-challenge and those treated with chemotherapy alone. The median platinum free interval was 17.8 months. For the re-challenge disease control rate was 75% with an overall response rate of 35% (7 PR, 0 CR). The median number of subsequent trastuzumab cycles was 7, with a median PFS of 6.1 months and median OS of 10 month. Multivariate Cox-regression analysis identified no factors predictive of response in the re-challenge setting. Conclusions: Re-challenge with trastuzumab plus FP chemotherapy is a possible option for patients with relapse. Larger studies will be required to identify predictive biomarkers to identify those patients most likely to benefit. The role of re-assessment of HER2 status at relapse in those receiving re-challenges requires prospective analysis.
The role of exosomal LINC00853 in gastric cancer progression.
Authors: Lee Sang Kil
Published: January 2024

378

Background: Examination of various substances contained in exosomes (EXOs) as biomarkers is being actively conducted. Long non-coding RNAs (lncRNAs) are garnering interest in the diagnosis of gastric cancer. In this experiment, we attempted to obtain lncRNAs that drive the onset and recurrence of gastric cancer and elucidate the mechanism to observe their potential as exosomal biomarkers. Methods: LncRNA expression profiling was conducted using ArrayStar Human LncRNA array 2.0 for the patient’s tissues who underwent endoscopic resection that reflected early gastric cancer onset and recurrence. The proliferation, apoptosis, invasion, and migration of AGS and MKN74 cells were measured after treatment with pcDNA over expressing vector and two different siRNAs. To observe the interaction between lncRNA and MAP17, RNA immunoprecipitation (IP) and electrophoretic mobility shift assay were conducted. EXOs were extracted from patient samples and gastric cancer cell lines, which were then administered to gastric cancer cells. Results: Five target lncRNAs (LINC00853, LINC00634, LINC01535, GAPLINC, and AC017002.1) were selected by performing a lncRNA microarray analysis. The validation results showed that LINC00853 was upregulated in gastric cancer tissues compared to that in paired adjacent non-cancer tissues. LINC00853 induced proliferation and suppressed apoptotic signaling of AGS and MKN74 cells. LINC00853 promoted the invasion and migration of AGS and MKN74 cells. LINC00853 bound with its neighbor gene MAP-17 and activated it via the downstream PDZK1/AKT signaling pathway. LINC00853 and MAP-17 cooperatively acted as oncogenes in gastric cancer. EXOs derived from patients with gastric cancer and those from gastric cancer cell lines (AGS, MKN74) contained LINC00853. Knock-down of LINC00853 decreased LINC00853 expression in EXOs, which, in turn, reduced the oncogenicity of LINC00853 exosome in AGS cells. Cellular and exosomal LINC00853 exert an oncogenic effect via MAP-17-related cell signaling in gastric cancer. Conclusions: Exosomal LINC00853 can be a candidate biomarker of occurrence of recurrence of gastric cancer.
Microsatellite instability (MSI) in patients with gastric cancer (GC) and correlation with PD-L1 expression.
Authors: Sun Henian , Nered Sergey , Tryakin Alexey , Abgaryan Mikael , Artamonova Elena , Stroganova Anna , Stilidi Ivan
Published: January 2024

389

Background: GC is a heterogeneous disease with a range of molecular subtypes. The TCGA (Cancer Genome Atlas) and ARCG (Asian Cancer Research Group) classified tumors with MSI status as a specific group. Programmed cell death receptor 1 (PD-1) and its ligand (PD-L1) are playing a progressively important role in tumor immunology and cancer treatment. The present study investigated the relationship between MSI and PD-L1 expression. Methods: We analyzed GC patients who received treatment from September 2019 to March 2023 at N.N. Blokhin National Medical Research Center of Oncology. All patients were analyzed for microsatellite instability using PCR. PD-L1 expression was assessed based on a combined positive score (CPS) using PD-L1 IHC (immunohistochemistry) 22C3 pharmDx. Results: We studied 453 localized GC and 273 metastatic GC. Of the 726 tumors, 60 (8.26%) had MSI-H tumors. The frequency of MSI-H in localized and metastatic GC is 51 (11.26%) out of 453 and 9 (3.30%) out of 273 (p<0.001). 106 patients were evaluated for expression PD-L1, 46 (43.40%) localized GC и 60 (56.60%) metastatic GC. PD-L1 is expressed in 45.28 % (48/106) of GC patients. PD-L1 CPS ≥ 1 was significantly associated with MSI-H status (P < 0.05). Details about the correlation between MSI and the expression PD-L1 can be found in the table. Conclusions: The prevalence of MSI-H in localized GC is significantly higher than metastatic GC (11.26% vs. 3.30%, p<0.001). A higher proportion showed PD-L1 expression (73.91%) in MSI-H than in MSS tumors, suggesting that MSI-H status is associated with PD-L1 (p< 0.05). These results provide a basis for identifying GC patients who may benefit from anti-PD-1/PD-L1 therapy. [Table: see text]