Frontline Sintilimab Plus Chemo Improves OS in Esophageal Squamous Cell Carcinoma

The addition of sintilimab (Tyvyt) to chemotherapy significantly improved overall survival (OS) over chemotherapy alone when used as a first-line treatment in patients with unresectable, locally advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC), meeting the primary end point of the phase 3 ORIENT-15 trial (NCT03748134).¹

The clinically meaningful improvement achieved with sintilimab in combination with cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil over chemotherapy alone was observed regardless of PD-L1 expression status.

Moreover, the toxicity profile of sintilimab observed in the interim analysis conducted by the Independent Data Monitoring Committee proved to be consistent with what had been reported in prior studies with the agent. No additional safety signals were observed.

Results from the study will be shared at an upcoming medical conference, according to Innovent Biologics, Inc.

“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,” Prof. Shen Lin, of Peking University Cancer Hospital and Institute, stated in a press release. “We are encouraged by these interim results of the ORIENT-15 study which demonstrated that sintilimab in combination with chemotherapy prolonged OS in the first-line treatment of patients with ESCC, regardless of PD-L1 status.”

An immunoglobulin G4 monoclonal antibody, sintilimab binds to PD-1 molecules on the surface of T cells and blocks the PD-1/PD-L1 pathway. The agent was designed to reactivate T cells to eliminate cancer cells.

In the global, double-blind, multicenter phase 3 trial, investigators set out to examine sintilimab plus chemotherapy vs placebo plus chemotherapy in the frontline treatment of patients with unresectable, locally advanced, recurrent, or metastatic ESCC.

To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1, have at least 1 measurable lesion per RECIST v1.1 criteria, and not be candidates for definitive treatment like definitive chemotherapy and/or surgery.²

If they had ESCC with endoscopy-confirmed near-complete obstruction requiring interventional therapy, post stent implantation in the esophagus or trachea with risk of perforation, received system treatment for advanced or metastatic disease, received a cumulative dose of cisplatin of greater than 300 mg/m² within 12 months to randomization, or a high risk of hemorrhage or perforations because of tumor invasion in adjacent organs, they were excluded.

At the time of the interim analysis, 659 patients were enrolled to the trial. Study participants were randomized 1:1 to either sintilimab/chemotherapy or chemotherapy.

Sintilimab was given based on weight; those under 60 kg received the agent at 3 mg/kg every 3 weeks on day 1, and those 60 kg or heavier, the agent was 200 mg every 3 weeks. Cisplatin was given at a dose of 75 mg/m² on day 1 every 3 weeks. Paclitaxel was administered at a dose of 87.5 mg/m² every 3 weeks on day 1 and day 8 for the first cycle, and 175 mg/m² every 3 weeks on day 1 after the first cycle. Fluorouracil was given at a daily dose of 800 mg/m² on days 1 to 5 every 3 weeks.

The primary end points of the trial included OS in all randomized patients and OS in the PD-L1–positive population. Secondary end points include objective response rate, progression-free survival, disease control rate, and duration of response in the overall population and the PD-L1–positive population.

Previously, in China, sintilimab has been approved for the treatment of patients with relapsed or refractory classic Hodgkin lymphoma following 2 lines or later of systemic chemotherapy; for use in combination with pemetrexed and platinum chemotherapy in the frontline treatment of patients with nonsquamous NSCLC; and in combination with gemcitabine and platinum chemotherapy in the frontline treatment of squamous NSCLC.

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 Biologics, Inc. June 22, 2021. Accessed June 25, 2021. https://prn.to/3qsQA22
2. Sintilimab or placebo with chemotherapy in esophageal squamous cell carcinoma (ORIENT-15). ClinicalTrials.gov. Updated February 2, 2021. Accessed June 25, 2021. https://www.clinicaltrials.gov/ct2/show/NCT03748134