Sintilimab Plus Chemotherapy Doublet Extends OS in Advanced Gastric and GEJ Cancers

Sintilimab in combination with the chemotherapy agents oxaliplatin and capecitabine improved overall survival (OS) in patients with unresectable, locally advanced, recurrent, or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma compared with chemotherapy alone, reaching the predefined primary end point of the phase 2 ORIENT-16 clinical trial.¹

Achievement of OS improvement in the study was observed in both the intention-to-treat population and in the subgroup of patients with PD-L1-positive tumors, according to interim analysis results announced in a press release by Innovent Biologic, Inc. Sintilimab also demonstrated a safety profile that was consistent with what has been observed in prior studies. No new safety signals were noted.

“ORIENT-16 is the first phase 3 clinical trial in China to demonstrate an anti-PD-1 antibody in combination with chemotherapy significantly prolonged overall survival in the first-line treatment of advanced gastric cancer. Gastric cancer is one of the most common malignant tumor types globally and nearly half of all cases are diagnosed in China. The prognosis of advanced gastric cancer is very poor. Currently, chemotherapy is the primary treatment option and targeted agents have offered limited benefit. The results of the ORIENT-16 study have the potential to bring a new and more effective treatment option to people with gastric cancer," stated the study’s principal investigator Jianming Xu, of Fifth Medical Center of People's Liberation Army General Hospital in China.

The ORIENT-16 of sintilimab as treatment of patients with unresectable, locally advanced, recurrent, or metastatic gastric or GEJ adenocarcinoma was launched to verify the clinical benefit of sintilimab following the demonstration of efficacy signals in a phase 1b study. Prior to the clinical trial development of sintilimab, there had not been any agents developed for this patient population for some time.²

The randomized, double-blind, multicenter ORIENT-16 trial enrolled 650 patients who were randomized 1:1 to sintilimab plus oxaliplatin and capecitabine or the chemotherapy doublet alone. Those enrolled who weigh less than 60 kg received sintilimab at 3mg/kg every 3 weeks (Q3W), and those whose weight is 60kg or greater received sintilimab 200mg Q3W. Sintilimab is administered on day 1 by intravenous (IV) infusion and combined with oxaliplatin 130 mg/m2 given Q3W on day 1 by IV infusion and capecitabine 100 mg/m2 given orally according to each patient’s body surface area Q3W on day 1 through 14. Doses of oxaliplatin and capecitabine were the same in the chemotherapy-only arm.

All treatment in the study is continued until disease progression, unacceptable toxicity, patient withdrawal, physician decision, or until after 24 months of treatment.

The secondary end points of the study include progression-free survival in the PD-L1-positive subgroup, objective response rate, duration of response, disease control rate, and the number of patients with adverse events.^2,3

To be included in ORIENT-16 both male and female patients aged 18 to 75 years of age with histologically confirmed disease were required to have an ECOG performance status of 0 or 1, measurable disease per RECIST v1.1, adequate organ function, and an expected survival of a least 12 weeks. Patients could not have received prior chemotherapy, radiotherapy, or a combination of both in either the neoadjuvant of adjuvant settings within 6 months of joining the study. Pregnant women were not permitted to enroll and all women were required to consent to contraception in order to enroll. All patients also were required to have tumor tissue available for biopsies.

"While immunotherapy has greatly changed the treatment paradigm for many malignancies, it has not yet in gastric cancer. The treatment options for advanced gastric cancer are very limited and the ORIENT-16 study aimed to help address this unmet medical need. These results are very encouraging and confirmed the clinical value of sintilimab plus chemotherapy in the first-line treatment of advanced gastric cancer, said Zhou Hui, senior vice president of Clinical Development of Innovent stated, in a press release.¹”

“Today, sintilimab is one of a few PD-1 inhibitors that has shown to be efficacious in the first-line treatment of five major types of cancer – nonsquamous non-small cell lung cancer, squamous non-small cell lung cancer, hepatocellular carcinoma, esophageal squamous cell carcinoma, and gastric cancer," Hui continued.

_References:

_{1. Innovent Announces sintilimab in combination with chemotherapy meets the primary endpoint of overall survival in the phase 3 ORIENT-16 study for the first-line treatment of advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. News release. Innovent Biologics, Inc. August 15, 2021. Accessed August 16, 2021. https://yhoo.it/3xSlenl}

_{2. Xu J, Jin Y, Liu Y, et al. Abstract CT213: ORIENT-16: Sintilimab plus XELOX vs placebo plus XELOX as 1st line treatment for unresectable advanced gastric and GEJ adenocarcinoma. AACR Annual Meeting Proceedings. 2019. 79(13). doi: 10.1158/1538-7445.AM2019-CT213}

_{3. Efficacy and safety evaluation of sintilimab or placebo in combination with Xelox as first line treatment in patients with gastric cancer. Clinicaltrials.gov. Accessed August 16, 2021. https://bit.ly/3k3Nf6N}