Results of 2 studies presented at 2021 ESMO demonstrate superior efficacy of sintilimab plus chemotherapy versus chemotherapy alone in certain gastrointestinal cancers.
The addition of sintilimab (Tyvyt) to chemotherapy in patients with unresectable, locally advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC) or unresectable, locally advanced, recurrent, or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma was able to improve overall survival (OS) versus chemotherapy alone, according to results of 2 studies that were presented during the 2021 European Society for Medical Oncology Congress.1,2
First results from the phase 3 ORIENT-15 trial (NCT03748134) in ESCC and the phase 2 ORIENT-16 clinical trial in GEJ showed that sintilimab was well tolerated in both groups of patients. Lin Shen, MD, PhD, with Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) at Peking University Cancer Hospital and Institute, Beijing, China, added that sintilimab improved survival in patients with ESCC across all subgroups.
“Sintilimab plus chemo showed significant overall survival benefits versus chemo alone in patients with advanced or metastatic ESSC, regardless of PD-L1 expression level,” Shen said. “Consistent benefits were observed in prespecified groups. PFS and the duration of response (DOR) are significantly improved.”
Sintilimab is an immunoglobulin G4 monoclonal antibody that binds to PD-1 molecules on the surface of T cells and blocks the PD-1/PD-L1 pathway. The agent is designed to reactivate T cells to eliminate cancer cells.
In ORIENT-15 investigators randomized 1:1 659 patients to either sintilimab with cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil or chemotherapy alone. Eligible 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.
Patients were excluded 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.
Sintilimab was administered by weight; those under 60 kg received 3 mg/kg every 3 weeks on day 1. Patients 60 kg or heavier received 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 included OS in all randomized patients and OS in the PD-L1–positive population. Secondary end points include objective response rate (ORR), progression-free survival (PFS), disease control rate, and DOR in the overall population and the PD-L1–positive population.
The median age was approximately 63. Nearly all patients were Chinese, 86% were male, and 87% had metastatic disease. Approximately three-quarters of patients in both treatment groups had an Eastern Cooperative Performance Score (ECOG) of 0 or 1.
The median OS favored the experimental arm in all patients (n=327) at 16.7 months (95% CI, 14.8-21.7) vs 12.5 months (95% CI, 11.0-14.5) in the 332-patient control arm (HR, 0.628; 95% CI, 0.508-0.777, P < .0001). In patients with a PD-L1 Combined Positive Score (CPS) of ≥10, the median OS again favored the combination arm (n=188) at 17.2 months (95% CI, 15.5-not calculable) vs 13.6 months (95% CI, 11.3-15.7) in the 193-patient chemotherapy arm (HR, 0.638; 95% CI, 0.480-0.848, P = .0018).
Similarly, median progression-free survival (PFS) was superior was superior in all patients (7.2 months vs 5.7 months; HR, 0.558; 95% CI, 0.461-0.676; P < .0001) and those who were PD-L1–positive (8.3 months vs 6.4 months; HR, 0.580; 95% CI, 0.449-0.749; P <.0001).
The ORR was 66.1% (95% CI, 60.9%-71.2%) vs 45.5% (95% CI, 40.1%-50.8%), in favor of sintilimab/chemotherapy in the overall population (95% CI, 12.9-27.6, P < .0001). The confirmed median DOR was 9.7 months (95% cI, 7.1-13.7) vs 6.9 months
(95% CI, 5.6-7.2), again favoring the experimental arm (95% CI, 0.473-0.803). ORR was 78.7% vs 57.5% in CPS ≥10 patients, with a median DOR of 8.5 months vs 5.5 months.
Of those who received at least 1 drug dose, treatment-related adverse event (TRAE) rates were 98.2% in both treatment groups. Grade 3 or greater TRAE rates were 59.9% in the sintilimab/chemotherapy arm vs 54.5% in the chemotherapy alone arm. Discontinuation rates from TRAEs were 20.8% vs 12.3%, respectively, while death rates from TRAEs were 2.8% vs 1.8%.
In this double-blind, multicenter, phase 2 trial, 650 patients were randomly assigned 1:1 to sintilimab plus oxaliplatin and capecitabine or the chemotherapy doublet alone. Sintilimab was administered at the same dose as ORIENT-15. Patients in both arms received 130 mg/m2 oxaliplatin and 100 mg/m2 capecitabine.
Treatment 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 PFS in the PD-L1-positive subgroup, ORR, DOR, disease control rate, and the number of patients with adverse events.
Eligible adults aged 18 to 75 years of age with histologically confirmed GEJ 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.
“This is the first double blind phase 3 study in the Chinese gastric cancer population that demonstrated a statistically significant overall survival benefits with sintilimab in combination with chemotherapy in the primary end points of both CPS5or higher and all randomized patients,” said lead author Jianming Xu, of Fifth Medical Center of People's Liberation Army General Hospital in China. “Safety profile is well manageable in sintilimab plus chemo.
“Sintilimab plus chemo provides a new standard first-line treatment option for these patients.”
The median age was 62.0 years in the experimental arm and 60.0 in the chemotherapy arm. More patients weighed 60 kg or more in the sintilimab arm (51.4% vs 47.7%). Approximately 72% of patients in both arms had an ECOG performance score of 1. More than 91% of patients in both arms had metastatic disease. In this trial, patients with a CPS ³5 were considered PD-L1 positive.
At a median follow-up of 18.8 months, the median OS was 15.2 months (95% CI, 12.9-18.4) in the 327-patient experimental arm vs 12.3 months (95% CI, 11.3-13.8) in the 323-patient chemotherapy arm (HR, 0.766; 95% CI, 0.626-0.936; P = .0090) in the total population. In the CPS ³5 population, the median OS was 18.4 months (95% CI, 14.6-not calculable) in the 197-patient experimental arm vs 12.9 months (95% CI, 11.1-15.4) in the 200-patient control arm (HR, 0.660; 95% CI, 0.505-0.864; P = .0023). Investigators observed OS benefit at all pre-specified CPS cutoffs (CPS ≥1, 5, and 10).
As in ORIENT-15, PFS was superior with sintilimab in the total population (7.1 vs 5.7 months; HR, 0.636; 95% CI, 0.525-0.771; P <.0001) and in the CPS ≥5 population (7.7 vs 5.8 months; HR 0.628; 95% CI, 0.489-0.805; P = .0002).
In all patients with measurable disease, the ORR was 58.2% (95% CI, 52.3%-64.2%) vs 48.4% (95% CI, 42.3%-54.6%) in favor of sintilimab, with a median DOR of 9.8 months (95% CI, 8.3-17.4) and 7.0 months (95% CI, 5.5-8.3), respectively. In the PD–L1-positive population, the unconfirmed ORR was 72.8% in the experimental arm vs 59.6% in chemotherapy arm. with a median DOR of 8.4 vs 5.5 months, respectively.
Overall, 196 (59.8%) patients in the experimental arm and 168 (52.5%) in the chemotherapy arm experienced grade ≥3 TRAEs. Six (1.8%) patients in the sintilimab arm died of TRAEs compared with 2 (0.6%) in the chemotherapy arm. Eighty-six (26.2%) in the experimental arm and 70 (21.9%) in the control arm experienced serious TRAEs.