A significantly longer overall survival was achieved with the human IgG4 monoclonal antibody sintilimab in patients with locally advanced or metastatic nonsquamous non–small cell lung cancer treated in the phase 3 ORIENT-11 clinical trial.
A significantly longer overall survival (OS) was achieved with the human IgG4 monoclonal antibody sintilimab (Tyvyt) in patients with locally advanced or metastatic nonsquamous non–small cell lung cancer (NSCLC) treated in the phase 3 ORIENT-11 clinical trial.1
"Sintilimab in combination with pemetrexed and platinum chemotherapy demonstrated a sustainable survival benefit after long-term follow-up in the ORIENT-11 study. These data showed that this sintilimab combination should be further evaluated as front-line therapy for patients with previously untreated, locally advanced, or metastatic nonsquamous NSCLC without EGFR or ALK genomic tumor aberrations, stated Zi Zhang, MD, professor, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, in a press release from Innovent Biologics, Inc.
ORIENT-11 (NCT03607539) is a randomized, double-blinded, phase 3 study of pemetrexed plus platinum chemotherapy administered with or without sintilimab in the frontline setting of locally advanced or metastatic nonsquamous NSCLC. Approximately 397 patients were included in the study and assessed for the primary end point of progression-free survival (PFS), as well as the secondary end points of OS, objective response rate, disease control rate, time to response, and duration of response.2
Patients were randomized 2:1 to receive either sintilimab 100 mg, 200mg, every 3 weeks combined with pemetrexed 500mg/m2 every 3 weeks, and platinum-based chemotherapy every 2 weeks or pemetrexed and platinum-based chemotherapy alone at the same dose. All treatment in the study was continued until radiographic disease progression, unacceptable toxicity, or any other conditions that require treatment discontinuation. There were also conditional allowances of crossover to the sintilimab arm.
At a median follow-up of 22.9 months, the median OS was not reached in the sintilimab arm compared with 16.8 months in the chemotherapy-only arm (HR, 0.60, 95% CI, 0.45-0.79; P = 0.0003). To be assessed for the primary end point, the median follow-up was 14.8 months, and the median PFS observed was 9.2 in the sintilimab arm versus 5.0 months in the control arms (HR, 0.49, 95% CI, 0.38–0.63; P <.0001).
Notably, the PFS and OS achieved with the addition of sintilimab to chemotherapy was observed across all subgroups evaluated.
Investigators of the study as looked at how immune signature profiles from tumor RNA and PD-L1 immunohistochemistry impacted clinical outcomes.
"Immunotherapy based on PD-1 and PD-L1 antibodies has revolutionized clinical practice of treating non-small cell lung cancer. However, the precise patient population who will benefit from immunotherapy-chemotherapy combination treatment is still unclear. We explored the gene expression profile in the tumor microenvironment and found that the infiltration of antigen-presenting cells and high expression of the MHC-II antigen presentation pathway correlated with improved outcomes in patients who received the sintilimab-pemetrexed-platinum chemotherapy combination. This finding contributes to a better understanding of the mechanism of action of the immunotherapy-chemotherapy combination which could help inform selection of suitable patients for future sintilimab studies,” said Wei Xu, MD, PhD, a co-author of the study and the vice president of Translational Medicine at Innovent Biologics, Inc, in the press release.
In patients with high or medium immune cell infiltration, the PFS was improved with the addition of sintilimab. Further, in patients with high major histocompatibility complex (MHC) class-II presentation pathway expression, the sintilimab combination led to a significant improvement in PFS (HR, 0.32, 95% CI, 0.19-0.54; P <.0001) and OS (HR, 0.36, 95% CI, 0.20-0.64; P =.0005). The study also showed that benefit could still be derived for those who had low or absent PD-L1 but high MHC-II expression.
Safety data from the ORIENT-11 study were previously presented during the World Conference on Lung Cancer 2020 Virtual Presidential Symposium. All but one patient in the study experienced adverse events (AEs). Grade 3 to 5 AEs were observed in 61.7% of patients treated with the sintilimab combination compared with 58.8% of patients who received placebo. Serious AEs were reported in 28.2% versus 29.8% of patients who received sintilimab versus chemotherapy alone, respectively.3
The most common AEs observed in the study were anemia, decreased neutrophil counts, decreased white blood cell counts, decreased platelet counts, increased aspartate aminotransferase (AST) levels, increased alanine aminotransferase (ALT) levels, nausea, decreased appetite, asthenia, vomiting, constipation, and pyrexia.
Six patients in the study died as a result of AEs in the sintilimab arm compared with 9 n the control arm. There was also treatment discontinuation due to AEs reported in 6.0% of the sintilimab arm versus 8.4% of the chemotherapy arm.
Immune-related AEs (irAEs) were reported in 43.2% of patients who received sintilimab versus 36.6% who received chemotherapy. Notably, 5.6% in the sintilimab arm were grade 3 to 5 compared with 6.1% of the chemotherapy arm.
The most common irAEs were hypothyroidism, rash, increased AST and ALT levels, increased blood TSH, hyperthyroidism, diarrhea, immune-mediated pneumonitis, decreased blood TSH, increased amylase levels, pruritis, and increased free thyroxine.
"We're excited to see that the results of ORIENT-11 show sintilimab in combination with pemetrexed and platinum chemotherapy can bring an overall survival benefit to patients with nonsquamous non-small cell lung cancer in the first-line treatment setting. Also, research of the tumor microenvironment is helping scientists find suitable biomarkers as potential targets for cancer treatment, Li Wang, senior vice president of Lilly China and head of Lilly China Drug Development and Medical Affairs Center, said in the press release. “These ORIENT-11 biomarker results published in the Journal of Thoracic Oncology will help us further understand the mechanism of action of this immunotherapy-based combination in order to identify patients who are more likely to respond to treatment."
1. Updated overall survival data and biomarker results from sintilimab ORIENT-11 study in first-line nonsquamous non-small cell lung cancer published in the Journal of Thoracic Oncology. News release. Innovent Biologics, Inc. August 5, 2021. Accessed August 10, 2021. https://prn.to/2VIN9sq
2. Yang Y, Sun J, Wang Z, et al. Updated overall survival data and predictive biomarkers of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic non-squamous nSCLC in the phase III ORIENT-11 study. J Thorac Oncol. 2021; S1556-0864(21)02330-3. doi:10.1016/j.jtho.2021.07.015.
3. Zhang L, Yang Y, Wang Z, et al. ORIENT-11: sintilimab + pemetrexed + platinum as first-line therapy for locally advanced or metastatic non-squamous NSCLC. Presented at: WCLC 2020 Virtual Presidential Symposium; August 8, 2020.