Sintilimab Plus Chemotherapy Prolongs OS in Recurrent or Metastatic ESCC

The PD-1 inhibitor, sintilimab injection (Tyvyt), in combination with chemotherapy showed a statistically significant and clinically meaningful improvement in overall survival (OS) as frontline treatment of patients with unresectable, locally advanced recurrent or metastatic esophageal squamous cell carcinoma (ESCC), meeting the primary end point of the phase 3 ORIENT-15 clinical trial.¹

Developer of the sintilimab injection, Innovent Biologics, Inc, announced in a press release that the OS benefit was observed with the combination regardless of PD-L1 expression status in the patients evaluated. Further, sintilimab showed a consistent safety profile to what has been observed in prior studies with no new safety signals found. Results from the study will be presented during an upcoming medical meeting.

"More than half of new and fatal cases of esophageal cancer in the world occur in China every year. In China, esophageal cancer is the fifth most commonly diagnosed cancer and the fourth leading cause of death from cancer, and ESCC is the predominant histologic type. Treatment options for people with ESCC are limited. Chemotherapy is currently the main treatment for ESCC and, in recent years, immunotherapy has brought new hope in the treatment of this type of cancer, with some PD-1 inhibitors receiving approval as a second-line treatment for patients with ESCC in China,” said Lin Shen, MD, an oncologist at oncologist in the United Family New Hope Oncology Center at Peking University Cancer Hospital and institute in Beijing, China and the principal investigator of ORIENT-15, in a statement.

The median OS among the patient population is said to be only 10 months and therefore represents an unmet medical need. Previous research around the combination of nivolumab (Opdivo) and pembrolizumab (Keytruda) compared with chemotherapy showed that OS could be improved upon in the second-line setting, suggesting a possibility to bring the strategy into the frontline setting.²

In the multicenter, double-blind- randomized study, patients are assigned 1:1 to receive either sintilimab with either cisplatin plus paclitaxel or cisplatin plus fluorouracil in the experimental arm or placebo with chemotherapy in the control arm. Sintilimab is administered based on weight and those who are 60 kg are smaller receive 3 mg/kg by intravenous (IV) infusion every 3 weeks (Q3W) on day 1 while those who are 60 kg or bigger are given 200 mg IV every 3 weeks on day 1.¹

IV cisplatin is dosed at 75 mg/m² every 3 weeks on day 1 to all patients in the study. Those who received added IV paclitaxel are given 87.5 mg/m² every 3 weeks on days 1 and 8 for the first cycle followed by 175 mg/m² every 3 weeks on day 1. The patients who are selected to receive fluorouracil are dosed with 800 mg/m² of the drug by continuous IV infusion over 24 hours daily on days 1 through 5, every 3 weeks.

In addition to OS in the overall population and PD-L1-positive population, ORIENT-15 is assessing objective response rate, progression-free survival, disease control rate, and duration of response in the overall and PD-L1-positive groups, as secondary end points.

The study aims to enroll 676 patients aged 18 to 75 years old² who have histopathologically confirmed unresectable, locally advanced, recurrent, or metastatic ESCC, and ECOG performance status of 0 or 1, at least 1 measurable lesion per RECIST v1.1, as are no suitable chemoradiotherapy.¹ The study excludes individuals with ESCC with endoscopy-confirmed near-complete obstruction requiring interventional therapy, those with post stent implantation in the esophagus or trachea with risk of perforation, High risk of hemorrhage or perforations due to tumor invasion in adjacent organs, or have fistula formation, and hepatic metastasis > 50% of the total liver volume.

In terms of prior therapy, patients cannot enroll in ORIENT-15 if they have received a cumulative dose of cisplatin above 300 mg/m² within 12 months to randomization, systemic treatment for advanced or metastatic ESCC, palliative therapy for a local lesion within 2 weeks prior to the first dose of the study drugs, systemic treatment with Chinese traditional medicines with anti-cancer indications or immunomodulators within 2 weeks prior to the first dose of study treatment, and systemic immunosuppressants within 2 weeks prior to randomization.

“We are encouraged by these interim results of the ORIENT-15 study which demonstrated that sintilimab in combination with chemotherapy prolonged overall survival in the first-line treatment of patients with ESCC, regardless of PD-L1 status,” said Shen also stated.

_References:

_{1. Sintilimab in combination with chemotherapy meets overall survival primary endpoint in the global phase 3 ORIENT-15 study for the first-line treatment of esophageal squamous cell carcinoma. News release. Innovent Biologic, Inc. June 22, 2021. Accessed June 23, 2021.}

_{2. Shen L, Lu Z, Xu L, et al. Abstract CT211: ORIENT-15: A randomized, multicenter, double-blind, Phase III study of sintilimab + paclitaxel and cisplatin (TP) versus placebo + TP as first-line treatment in patients with unresectable locally advanced or metastatic esophageal squamous cell carcinoma. Clin Can Res. 2019; 79(13). doi:10.1158/1538-7445.AM2019-CT211}