Neoadjuvant tislelizumab and tegafur/gimeracil/octeracil (S-1) plus oxaliplatin in patients with locally advanced gastric or gastroesophageal junction cancer: Early results of a phase 2, single-arm trial

Abstract

BackgroundRecently, the combination of immunotherapy with chemotherapy has been recommended as first-line treatment of metastatic gastric/gastroesophageal junction (G/GEJ) in the clinical guidelines of many countries; the therapeutic potential of this application needs to be further investigated for neoadjuvant therapy of advanced G/GEJ cancer patients.MethodsWe performed a prospective, single-arm, open-label, phase 2 trial of the PD-1 inhibitor tislelizumab combined with S-1 plus oxaliplatin (SOX) in patients with advanced LAG/GEJ cancer. All patients underwent the three-cycle (21 days/cycle) treatment except for one patient who underwent two cycles. The primary endpoints were tumor major pathology response (MPR) and other events of tumor response assessed by the RECIST 1.1 and Becker criteria. Moreover, we constructed a few-shot learning model to predict the probability of MPR, which could screen those patients who might benefit from the neoadjuvant immunotherapy–chemotherapy scheme. This study was registered at https://clinicaltrials.gov/ct2/show/NCT0-4890392.ResultsThirty-two patients were enrolled; 17 patients (53.1%) achieved MPR (≤10% viable tumor cells) after treatment, and among them, 8 (25.0%) had a pathological complete response (pCR). The 1-year overall survival (OS) rate was 91.4% and the 1-year recurrence-free survival (RFS) rate was 90.0%. Adverse events occurred in 24 patients (65.6%) and grade III–IV adverse events were observed in 4 patients (12.5%) during the neoadjuvant period. Furthermore, we found commonly used preoperative assessment tools such as CT and EUS, which presented limited accuracy of tumor therapeutic response in this study; thus, we developed a therapeutic response predictive model that consisted of TNFα, IFNγ, IL-10, CD4, and age of patient, and the AUC of this FSL model was 0.856 (95% CI: 0.823–0.884).DiscussionOur study showed that the neoadjuvant PD-1 inhibitor tislelizumab combined with SOX had promising application potential and presented no increasing treatment-related adverse events in patients with advanced G/GEJ cancer. Moreover, the predictive model could help therapists to evaluate the therapeutic response of this scheme accurately.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT0-4890392, identifier [NCT04890392].

Efficacy and safety of camrelizumab combined with oxaliplatin and S‐1 as neoadjuvant treatment in locally advanced gastric or gastroesophageal junction cancer: A phase II, single‐arm study

“…In the present study, 24.1% (7/29) patients have signet‐ring cell carcinoma, much higher than in the phase II study with neoadjuvant sintilimab plus capecitabine and oxaliplatin (CapeOx regimen) (2.8%) 24 . The patients with ECOG performance status of 0 were 65.5% (19/29) in our study, lower than most of the above‐mentioned studies 23,24,26 . In addition, only 17.2% (5/29) patients in our study had positive PD‐L1 status, whereas the percentage of patients with positive PD‐L1 status in the study with neoadjuvant sintilimab plus CapeOx regimen and the DANTE study were 58.3% and 56.3%, respectively 24,26 .…”

“…Over the last decade, with the emergence of immunotherapy, accumulating evidence shows that adding ICIs to neoadjuvant chemotherapy could provide better clinical benefits than chemotherapy alone 21,22 . However, only a few phase II studies investigated neoadjuvant ICIs combined with chemotherapy in LAGC and GEJC patients, with pCR rates ranging from 19.4% to 25.0%, and MPR rates ranging from 44.4% to 63.3% 23–28 . Besides, in the randomized phase IIb DANTE study, the pCR rate was 25% in patients received neoadjuvant atezolizumab plus FLOT regimen, 24% in the neoadjuvant FLOT group, whereas the MPR rates between these two groups were 49% and 44%, respectively 26 .…”

Neoadjuvant PD-1 blockade plus chemotherapy versus chemotherapy alone in locally advanced stage II-III gastric cancer: A single-centre retrospective study

“…Additionally, one patient treated with the FLOT regimen plus camrelizumab achieved pCR with negative PD-L1 expression, MSS status and low TMB (3.55 muts/Mb), indicating that neoadjuvant PD-1 inhibitor-based therapy could benefit LAGC patients regardless of the immunogenic characteristics. A recent study innovatively proposed CD3, CD4, IL-10, IFN-γ and TNF-α as immune indicators for neoadjuvant PD-1-inhibitor-based immunotherapy in LAGC [37] ; however, the outcomes should be further verified by adequately powered studies.…”

PD-1 blockade plus chemoradiotherapy as preoperative therapy for patients with BRPC/LAPC: A biomolecular exploratory, phase II trial

“… 28 Tislelizumab combined with chemotherapy as neoadjuvant therapy has shown promising efficacy in esophageal squamous cell carcinoma 29 and locally advanced gastric/gastroesophageal junction cancer. 30 Radiotherapy or chemotherapy can upregulate PD-L1 expression, 31 thereby giving rise to a mode of treatment. Our study is a prospective evaluation to demonstrate the clinical benefit and safety of preoperative therapy that combined chemoradiotherapy and PD-1 inhibitor in patients with LAPC or BRPC.…”