Dataset Information

Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

ABSTRACT:

Background

The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer.

Methods

Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enrolled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m2 docetaxel, 80 mg/m2 oxaliplatin, 200 mg/m2 calcium levofolinate, 2600 mg/m2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by 4 cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate.

Results

Thirty-two patients were enrolled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-one (96.9%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8%-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 16 (55.2%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2%-89.2%), 78.8% (95% CI, 65.1%-95.5%), and 70.9% (95% CI, 54.8%-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3%-93.1%) and 96.9% (95% CI, 84.3%-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status.

Conclusions

The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.

SUBMITTER: Li N

PROVIDER: S-EPMC11020066 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Publications

Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

Li Ning N Li Zhi Z Fu Qiang Q Zhang Bin B Zhang Jian J Wan Xiang-Bin XB Lu Chao-Min CM Wang Jin-Bang JB Deng Wen-Ying WY Ma Yi-Jie YJ Bie Liang-Yu LY Wang Meng-Yu MY Li Jing J Xia Qing-Xin QX Wei Chen C Luo Su-Xia SX

International journal of surgery (London, England) 20240401 4

<h4>Background</h4>The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer.<h4>Methods</h4>Eligible patients ...[more]

PMID: 38320099

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Project description:Immune checkpoint inhibitors have greatly improved the prognoses of diverse advanced malignancies, including gastric and gastroesophageal junction (G/GEJ) cancer. However, the role of anti-programmed cell death protein-1 treatment in the neoadjuvant setting remains unclear. This phase 2 study aimed to evaluate sintilimab plus CapeOx as a neoadjuvant regimen in patients with advanced resectable G/GEJ adenocarcinoma. Eligible patients with resectable G/GEJ adenocarcinoma stage cT3-4NanyM0 were enrolled. Patients received neoadjuvant treatment with sintilimab (3 mg/kg for cases <60 kg or 200 mg for those ≥60 kg on day 1) plus CapeOx (oxaliplatin at 130 mg/m2 on D1 and capecitabine at 1000 mg/m2 two times per day on D1-D14) every 21 days, for three cycles before surgical resection, followed by adjuvant treatment with three cycles of CapeOx with the same dosages after surgical resection. The primary endpoint was pathological complete response (pCR) rate. Secondary endpoints included objective response rate, tumor regression grade per Becker criteria, survival and safety. As of July 30, 2020, 36 patients were enrolled. Totally 7 (19.4%) patients had GEJ cancer, and 34 (94.4%) patients were clinical stage III cases. A total of 35 (97.2%) patients completed three cycles of neoadjuvant treatment, and 1 patients received two cycles due to adverse events. All patients underwent surgery and the R0 resection rate was 97.2%. In this study, pCR and major pathological response were achieved in 7 (19.4%, 95% CI: 8.8% to 35.7%; 90% CI: 10.7% to 33.1%) and 17 (47.2%, 95% CI: 31.6% to 64.3%) patients, respectively. Thirty-one patients received adjuvant treatment. By December 20, 2021, three patients died after disease relapse, and two patients were alive with relapse. Median disease-free survival (DFS) and overall survival (OS) were not reached. The 1-year DFS and OS rates were 90.3% (95% CI: 80.4% to 100.0%) and 94.1% (95% CI: 86.5% to 100.0%), respectively. The most common (>1 patient) grade 3 treatment-related adverse events during neoadjuvant treatment were anemia and neutropenia (n=5 each, 13.9%). No serious adverse events (AEs) or grade 4-5 AEs were observed. Sintilimab plus oxaliplatin/capecitabine showed promising efficacy with encouraging pCR rate and good safety profile in the neoadjuvant setting. This combination regimen might present a new option for patients with locally advanced, resectable G/GEJ adenocarcinoma. Trial registration; NCT04065282.

Project description:BackgroundAdding anti-angiogenics to neoadjuvant chemotherapy for localized gastric cancer is recognized as a promising strategy, but its clinical value remains to be defined.MethodsThis single-center, single-arm, phase 2 trial included patients with locally advanced (cT3/4aN+M0) adenocarcinoma of the stomach or gastroesophageal junction (GEJ) who received three cycles of intravenous oxaliplatin (135 mg/m2 on day 1), oral capecitabine (1000 mg/m2 twice daily on days 1 to 14), and oral apatinib for 21 days (250 mg once daily in the first two cycles, and further increased to 500 mg daily in the third cycle based on whether any adverse event of grade 3 or worse occurred), and an additional cycle of oxaliplatin plus capecitabine, followed by gastrectomy with D2 lymphadenectomy. The primary endpoint was the proportion of patients who achieved an objective response according to RECIST version 1.1.ResultsBetween April 28, 2017, and October 23, 2019, 37 patients were screened and 35 participants were included. Of the 32 patients assessable for efficacy and safety, objective responses were achieved in 25 (78.1%; 95% confidence interval [CI], 60.0% to 90.7%) patients. Thirty-one (96.9%) patients received R0 resection, two (6.3%) patients achieved pathological complete response, and 11 (34.4%) patients achieved pathological response. At the data cutoff date (September 30, 2021), the median event-free survival was 42.6 (95% CI, 16.2 to not reached) months, and the median overall survival was not reached. The most common grade 3 or 4 treatment-emergent adverse events were hypertension (9/32, 28.1%), thrombocytopenia (7/32, 21.9%), and neutropenia (5/32, 15.6%). Seven (21.9%) patients developed surgical complications, and the most common one was intra-abdominal abscess (4/32, 12.5%).ConclusionsThe concomitant use of apatinib, oxaliplatin, and capecitabine as neoadjuvant therapy showed promising efficacy and manageable safety profile in patients with locally advanced adenocarcinoma of the stomach or GEJ, and further phase 3 study is warranted.Trial registrationThis study was registered with ClinicalTrial.gov ( NCT03229096 ).

Project description:BackgroundPerioperative chemotherapy is the standard of care for patients with locally advanced gastric and gastroesophageal junction cancer. Recent evidence demonstrated the addition of programmed cell death protein 1 (PD-1) inhibitors enhanced therapeutic efficacy. However, the mechanisms of response and resistance remain largely undefined. A detailed multiomic investigation is essential to elucidate these mechanisms.MethodsWe performed whole-exome sequencing, whole-transcriptome sequencing, multiplex immunofluorescence and single-cell RNA sequencing on matched pretreatment and post-treatment samples from 30 patients enrolled in an investigator-initiated Phase 2 clinical trial (NCT04908566). All patients received neoadjuvant PD-1 inhibitors in combination with chemotherapy. A major pathologic response (MPR) was defined as the presence of no more than 10% residual viable tumor cells following treatment.ResultsBefore treatment, the positive ratio of CD3+T cells in both the tumor parenchyma and stroma was significantly higher in the non-MPR group compared with the MPR group (p=0.042 and p=0.013, respectively). Least absolute shrinkage and selection operator regression was employed for feature gene selection and 13 genes were ultimately used to construct a predictive model for identifying MPR after surgery. The model exhibited a perfect area under curve (AUC) of 1.000 (95% CI: 1.000 to 1.000, p<0.001). Post-treatment analysis revealed a significant increase in CD3+T cells, CD8+T cells and NK cells in the tumor stroma of MPR patients. In the tumor parenchyma, aside from a marked increase in CD8+T cells and NK cells, a notable reduction in macrophage was also observed (all p<0.05). Importantly, forkheadbox protein 3 (FOXP3), the principal marker for regulatory T cells (Treg) cells, showed a significant decrease during treatment in MPR patients. FOXP3 expression in the non-MPR group was significantly higher than in the MPR group (p=0.0056) after treatment. Furthermore, single-cell RNA sequencing analysis confirmed that nearly all Treg cells were derived from the non-MPR group.ConclusionsOur study highlights the critical role of dynamic changes within the tumor immune microenvironment in predicting the efficacy of neoadjuvant combined immunochemotherapy. We examined the disparities between MPR/non-MPR groups, shedding light on potential mechanisms of immune response and suppression. In addition to bolstering cytotoxic immune responses, specifically targeting Treg cells may be crucial for enhancing treatment outcomes.

Dataset Information

Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

Background

Methods

Results

Conclusions

Publications

Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

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