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.
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.
Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m 2 docetaxel, 80 mg/m 2 oxaliplatin, 200 mg/m 2 calcium levofolinate, 2600 mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate.
Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) 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, 21 (72.4%) 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.
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.
Li N
，Li Z
，Fu Q
，Zhang B
，Zhang J
，Wan XB
，Lu CM
，Wang JB
，Deng WY
，Ma YJ
，Bie LY
，Wang MY
，Li J
，Xia QX
，Wei C
，Luo SX
... -
《-》
Perioperative Safety and Effectiveness of Neoadjuvant Therapy with Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel Plus Apatinib in Locally Advanced Gastric Cancer.
The trend in neoadjuvant therapy for locally advanced gastric cancer (LAGC) is to use more drugs or therapies in combination. This study aimed to assess the safety and effectiveness of neoadjuvant chemotherapy with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) plus apatinib in the treatment of LAGC.
We collected clinical data from patients with LAGC who received neoadjuvant FLOT and apatinib therapy and underwent surgery from January 2017 to December 2020. Patients were divided into either the FLOT group (in which patients received FLOT neoadjuvant therapy and surgery) or the FLOTA group (in which patients received FLOT plus apatinib neoadjuvant therapy and surgery).
The FLOT and FLOTA groups contained 44 and 31 patients, respectively. There were significant differences between the FLOT and FLOTA groups in the objective response rate (50.00% vs. 80.65%, respectively, p = 0.008) and average change from baseline in the target lesion size (-26.16 ± 34.61 vs. -54.32 ± 36.11, respectively, p < 0.001). There were also significant differences in the pretreatment clinical tumor-node-metastasis (cTNM) and post treatment cTNM stages for the FLOT group (p = 0.001) and for the FLOTA group (p < 0.001). There were no significant differences between the FLOT and FLOTA groups in post neoadjuvant therapy cTNM stages (p = 0.525), R0 rate (p = 0.397), tumor regression grade (p = 0.397), or post treatment pathological TNM stage (p = 0.180). Some neoadjuvant therapy-related adverse events occurred significantly more frequently in the FLOTA group, including diarrhea (all grades), pain (all grades), oral mucositis (all grades), and hand-foot syndrome (all grades).
The FLOTA regimen can achieve better perioperative efficacy and acceptable toxicity compared with that of the FLOT regimen in neoadjuvant treatment of LAGC. The FLOTA regimen for neoadjuvant therapy for LAGC merits further study.
Zhang Y
，Zhang B
，Yang J
，Zhang J
，Zhang W
... -
《Cancer Management and Research》
Combined systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI) predicts chemotherapy response and prognosis in locally advanced gastric cancer patients receiving neoadjuvant chemotherapy with PD-1 antibody sintilimab and XELOX: a
Previous studies have confirmed that systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI) can predict the prognosis and chemotherapy efficacy of various malignant tumors. However, to the best of our knowledge, no study investigated the SII combined with PNI score to predict the efficacy of anti-programmed death 1 (anti-PD-1) antibody sintilimab and XELOX regimen (capecitabine plus oxaliplatin) in the treatment of locally advanced gastric cancer. This study aims to evaluate the predictive value of pre-treatment SII-PNI score on the sensitivity of sintilimab immunotherapy combined with XELOX chemotherapy in patients with locally advanced gastric cancer.
We registered a prospective clinical study involving 30 locally advanced gastric cancer patients from March 2020 to July 2021. The pre-treatment SII and PNI were calculated from peripheral blood samples, and the cut-off value was calculated by receiver operating characteristic. The SII-PNI score ranged from 0 to 2 and were categorized into the following: score of 2, high SII (≥ 568.5) and low PNI (≤ 52.7); score of 1, either high SII or low PNI; score of 0, no high SII nor low PNI.
All patients were evaluated by RECIST1.1 criteria after four cycles of sintilimab immunotherapy combined with XELOX chemotherapy, including 5 patients with TRG 3 and 25 patients with non-TRG 3. The SII-PNI score of non-TRG 3 patients was significantly lower than that of TRG 3 patients (P = 0.017). The medial progression free survival of patients with low SII-PNI score was significantly better than that of patients with high SII-PNI score (P < 0.001). Multivariate analysis showed that SII-PNI score was an independent prognostic factor for predicting progression-free survival (P = 0.003).
The pre-treatment SII-PNI score is a significant indicator for predicting chemosensitivity of locally advanced patients after sintilimab immunotherapy combined with XELOX chemotherapy, which can help to identify high-risk groups and predict prognosis.
The registered name of the trial is "Prospective clinical study of sintilimab combined with chemotherapy for neoadjuvant therapy in locally advanced gastric cancer". Its Current Controlled Trials number is ChiCTR2000030414. Its date of registration is 01/03/2020.
Ding P
，Guo H
，Sun C
，Yang P
，Kim NH
，Tian Y
，Liu Y
，Liu P
，Li Y
，Zhao Q
... -
《BMC GASTROENTEROLOGY》
Sintilimab Plus Apatinib and Chemotherapy as Second‑/Third-Line treatment for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: a prospective, Single-Arm, phase II trial.
The prognosis of patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer remains poor. Given the robust development of immunotherapy and targeted therapy during the last decades, we aimed to investigate if the combination of traditional second-line chemotherapy with sintilimab and apatinib could bring survival benefits for these patients.
In this single-center, single-arm, phase II trial, patients with previously treated advanced gastric or GEJ adenocarcinoma received specific dose level of intravenous paclitaxel or irinotecan (investigator's choice), 200 mg intravenous sintilimab on day 1, and 250 mg oral apatinib once daily continuously in each cycle until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoints were objective response rate and progression-free survival. The secondary endpoints were mainly overall survival and safety.
From May 2019 to May 2021, 30 patients were enrolled. At the data cutoff date (March 19, 2022), the median follow-up duration was 12.3 months and 53.6% (95% CI, 33.9-72.5%) patients achieved objective response. The median progression-free survival and overall survival were 8.5 months (95% CI, 5.4-11.5) and 12.5 months (95% CI, 3.7-21.3), respectively. Grade 3-4 adverse events included hematological toxicities, elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated alkaline phosphatase, elevated gamma-glutamyl transpeptidase, hyperbilirubinemia and proteinuria. The most frequent grade 3-4 adverse event was neutropenia (13.3%). No serious treatment-related adverse events or treatment-related deaths occurred.
Sintilimab plus apatinib and chemotherapy demonstrates promising anti-tumor activity with manageable safety profile in patients with previously treated advanced gastric or GEJ cancer.
ClinicalTrials.gov: NCT05025033, 27/08/2021.
Zhang L
，Wang W
，Ge S
，Li H
，Bai M
，Duan J
，Yang Y
，Ning T
，Liu R
，Wang X
，Ji Z
，Wang F
，Zhang H
，Ba Y
，Deng T
... -
《BMC CANCER》
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