Abstract CT213: ORIENT-16: Sintilimab plus XELOX vs placebo plus XELOX as 1st line treatment for unresectable advanced gastric and GEJ adenocarcinoma

Xu, Jianming; Jin, Yongshuai; Liu, Ying; Zhou, Hui; Wang, Yan

doi:10.1158/1538-7445.am2019-ct213

Cited by 9 publications

(6 citation statements)

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“…CheckMate 649 is the most robust dataset to date to report PD-L1 CPS ≥ 5 prevalence using an analytically validated assay (28-8 pharmDx) in gastric, GEJ or oesophageal adenocarcinoma. The phase 3 ORIENT-16 trial in China reported a similar PD-L1 CPS ≥ 5 prevalence of approximately 60% using the 22C3 PharmDx assay 17 , 18 . In CheckMate 649, the magnitude of survival benefit continued to be enriched with nivolumab plus chemotherapy versus chemotherapy in patients with higher PD-L1 CPS, consistent with results at 12-month follow-up 5 .…”

Section: Discussionmentioning

confidence: 95%

Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer

Shitara

Ajani

Moehler

et al. 2022

Nature

198

173

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Standard first-line chemotherapy results in disease progression and death within one year in most patients with human epidermal growth factor receptor 2 (HER2)-negative gastro-oesophageal adenocarcinoma1–4. Nivolumab plus chemotherapy demonstrated superior overall survival versus chemotherapy at 12-month follow-up in gastric, gastro-oesophageal junction or oesophageal adenocarcinoma in the randomized, global CheckMate 649 phase 3 trial5 (programmed death ligand-1 (PD-L1) combined positive score ≥5 and all randomized patients). On the basis of these results, nivolumab plus chemotherapy is now approved as a first-line treatment for these patients in many countries6. Nivolumab and the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor ipilimumab have distinct but complementary mechanisms of action that contribute to the restoration of anti-tumour T-cell function and induction of de novo anti-tumour T-cell responses, respectively7–11. Treatment combining 1 mg kg−1 nivolumab with 3 mg kg−1 ipilimumab demonstrated clinically meaningful anti-tumour activity with a manageable safety profile in heavily pre-treated patients with advanced gastro-oesophageal cancer12. Here we report both long-term follow-up results comparing nivolumab plus chemotherapy versus chemotherapy alone and the first results comparing nivolumab plus ipilimumab versus chemotherapy alone from CheckMate 649. After the 24.0-month minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in overall survival versus chemotherapy alone in patients with PD-L1 combined positive score ≥5 (hazard ratio 0.70; 95% confidence interval 0.61, 0.81) and all randomized patients (hazard ratio 0.79; 95% confidence interval 0.71, 0.88). Overall survival in patients with PD-L1 combined positive score ≥ 5 for nivolumab plus ipilimumab versus chemotherapy alone did not meet the prespecified boundary for significance. No new safety signals were identified. Our results support the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastro-oesophageal adenocarcinoma.

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Section: Discussionmentioning

confidence: 95%

Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer

Shitara

Ajani

Moehler

et al. 2022

Nature

198

173

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“… 21 In vitro, compared to nivolumab or pembrolizumab, sintilimab has a higher binding affinity and is able to bind with more PD-1 molecules on CD3 + T cells, and has better T cell activating characteristics. 21 In a phase 1b study (NCT03745170), sintilimab combined with oxaliplatin/capecitabine has shown promising efficacy in gastric cancer with an ORR of 85% 22 which warranted a phase 3 ORIENT-16 study (NCT03745170) to further investigate the therapeutic potential of sintilimab in combination with chemotherapy in patients with advanced G/GEJ cancers. 23 The interim results from ORIENT-16 study were orally presented on 2021 ESMO, in which sintilimab was demonstrated to be the first PD-1 inhibitor to show superior OS and PFS with an acceptable safety profile, in combination with chemo, in Chinese patients with G/GEJ cancer regardless of PD-L1 expression status.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of Sintilimab in Combination with Concurrent Chemoradiotherapy for Locally Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma (SHARED): Study Protocol of a Prospective, Multi-Center, Single-Arm Phase 2 Trial

Wei¹,

Lu²,

Liu³

et al. 2022

CMAR

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Purpose Concurrent chemoradiotherapy (cCRT) is the mainstay therapy of locally advanced gastric (G) and gastroesophageal junction (GEJ) cancers with a poor prognosis. Programmed cell death receptor-1 (PD-1) inhibitor has been approved and recommended to treat ≥3 line G/GEJ patients. A significant clinical benefit of PD-1 inhibitors in addition to cCRT has been observed in locally advanced lung cancer. Sintilimab, a humanized IgG4 monoclonal antibody with high affinity and specificity for PD-1, has shown promising efficacy with an overall response rate of 85% in combination with chemotherapy in gastric cancer in a phase Ib study (NCT02937116). Patients and Methods SHARED is a prospective, multicentre, single-arm Phase II trial in China, exploring the efficacy of sintilimab in combination with cCRT in locally advanced G/GEJ adenocarcinoma. According to a Simon optimal two-stage clinical design, 34 patients will be enrolled. All the eligible patients will receive one cycle of induction chemotherapy (S-1 plus nab-PTX) combined with sintilimab, followed by cCRT (radiotherapy plus nab-PTX) combined with sintilimab. Prior to the surgery, patients will receive another cycle of chemotherapy (S-1 plus nab-PTX) combined with sintilimab. In the adjuvant setting, all participants will be treated with 3 cycles of chemotherapy (S-1 plus nab-PTX) combined with sintilimab. The primary endpoint is the rate of pathological complete response (pCR). The secondary endpoints include disease-free survival (DFS), major pathological response (MPR), R0 resection rate, surgical AEs, overall survival (OS), event-free survival (EFS), and safety profile. Moreover, the prognostic value of tumor biomarkers and immune biomarkers will be explored. Conclusion SHARED is designed to primally evaluate the efficacy and safety of sintilimab in combination with cCRT in locally advanced G/GEJ cancers and to prospectively validate the prognostic value of tumor biomarkers and immune biomarkers.

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“…The ATTRACTION-4 study in Asian population showed a comparable safety profile in the nivolumab-chemotherapy group compared with that in the placebo-chemotherapy group, with neutropenia being the most common grade 3 to 4 adverse event ( 13 ). The ORIENT-16 study in the Chinese population found that the incidence rate of grade ≥3 TRAEs in the sintilimab-chemotherapy group was comparable with that in the chemotherapy group (59.8% vs. 52.5%, p = 0.063) ( 51 ). A meta-analysis comparing the safety of different combinations of immunotherapy and chemotherapy regimens showed that the incidence rate of TRAE ≥3 grade was similar between PD-1 inhibitor with oxaliplatin-based chemotherapy and that with cisplatin-based chemotherapy (RR = 0.86, 95% CI, 0.66–1.12), whereas, among patients with oxaliplatin-based chemotherapy, the incidence rate of TRAE ≥3 times was comparable between those combining nivolumab and those combining sintilimab ( 52 ).…”

Section: Discussionmentioning

confidence: 99%

Combining neoadjuvant chemotherapy with PD-1/PD-L1 inhibitors for locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma: A systematic review and meta-analysis

et al. 2023

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BackgroundImmune checkpoint inhibitors (ICIs) have shown promising prospects in locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma (GC/GEJC) immunotherapy, but their efficacy in neoadjuvant settings remains unclear. This study aimed to assess the efficacy and safety of integrating programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors into neoadjuvant chemotherapy (NACT) of GC/GEJC treatment.MethodsPubMed, Cochrane Library, Embase, ClinicalTrials.gov, and main oncology conference databases were systematically searched up to 19 November 2022, and randomized controlled trials (RCTs) and cohort studies that evaluated the efficacy and safety of PD-1/PD-L1 inhibitors plus NACT were included. The main outcomes were pathological complete response (pCR), major pathological response (MPR), R0 resection rate, and treatment-related adverse events (TRAEs).ResultsA total of 753 patients from 20 prospective studies were included in this meta-analysis. The pooled pCR and MPR rates from studies reporting were 21.7% [95% confidence interval (CI), 18.1%–25.5%] and 44.0% (95% CI, 34.1%–53.8%), respectively. The pooled incidence rate of total TRAEs was 89.1% (95% CI, 82.7%–94.3%), and the incidence rate of grade 3 to 4 TRAEs was 34.4% (95% CI, 17.8%–66.5%). The pooled R0 resection rate was reported to be 98.9% (95% CI, 97.0%–99.9%). Subgroup analysis has not found significant differences in efficacy and safety among different PD-1/PD-L1 inhibitors. Moreover, the efficacy in patients with positive PD-L1 expression (combined positive score ≥1) was comparable with that in the entire study population [pCR, 22.5% vs. 21.2% (p > 0.05); MPR, 48.6% vs. 43.7% (p > 0.05)].ConclusionThis systematic review and meta-analysis found that PD-1/PD-L1 inhibitors combined with NACT for locally advanced GC/GEJC were well tolerated and may confer therapeutic advantages. The integration of ICIs into NACT has shown the potential for application in any PD-L1 expression population.

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Abstract CT213: ORIENT-16: Sintilimab plus XELOX vs placebo plus XELOX as 1st line treatment for unresectable advanced gastric and GEJ adenocarcinoma

Cited by 9 publications

References 0 publications

Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer

Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer

Efficacy and Safety of Sintilimab in Combination with Concurrent Chemoradiotherapy for Locally Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma (SHARED): Study Protocol of a Prospective, Multi-Center, Single-Arm Phase 2 Trial

Combining neoadjuvant chemotherapy with PD-1/PD-L1 inhibitors for locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma: A systematic review and meta-analysis

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