SUMMARY: The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.
Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21. Patients with advanced EGFR-mutated NSCLC, following initial clinical response to first, second and third generation EGFR-TKIs therapies, will inevitably advance to a progressive disease course. These patients often receive platinum-based chemotherapy, with limited clinical benefit. Immune checkpoint inhibitors given alone have low efficacy in the treatment of patients with metastatic NSCLC with oncogenic-driven tumors. There is a highly unmet medical need for these patients with resistant disease.
Sintilimab is an immunoglobulin G4, anti-PD-1 monoclonal antibody, which binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.
ORIENT-31 is a prospective, randomized, double-blind, multi-center Phase III study, which evaluated Sintilimab, with or without a Bevacizumab biosimilar injection (IBI305), in combination with chemotherapy (Pemetrexed and Cisplatin), in patients with EGFR-mutated locally advanced or metastatic non-squamous NSCLC, who have progressed following EGFR TKI treatment. Patients were randomized in a 1:1:1 ratio to receive Sintilimab 200 mg IV plus Bevacizumab biosimilar 15 mg/kg IV combined with Pemetrexed 500 mg/m2 IV and Cisplatin 75 mg/m2 IV (Arm A), Sintilimab combined with Pemetrexed and Cisplatin (Arm B), or chemotherapy alone with Pemetrexed and Cisplatin (Arm C), all agents administered every 3 weeks for 4 cycles followed by maintenance treatment with Sintilimab plus Bevacizumab and Pemetrexed in Arm A, Sintilimab and Pemetrexed in Arm B, and Pemetrexed alone in Arm C. Treatment was continued until radiographic disease progression or unacceptable toxicity. Eligible patients included patients with disease progression following first or second generation EGFR TKI and confirmed as T790M negative, or T790M positive but further progressed on third generation EGFR TKI, or patients with disease progression following third generation EGFR TKI as first line treatment. The median age was 57 years, 36% of patients had brain metastasis, 64% of patients had received First or Second generation TKIs without T790M mutation, 28% had received First or Second generation TKIs and then a Third generation TKI for T790M mutation, and 8% patients received first line Third generation TKI. The target accrual was 480 patients and by the data cutoff date of the first interim analysis, 444 patients were enrolled. The Primary endpoint was Progression Free Survival (PFS) as assessed by an Independent Radiographic Review Committee (IRRC). Secondary endpoints included Overall Survival (OS), PFS as assessed by investigators, Objective Response Rate (ORR) and Safety. The median follow up at first interim analysis was 9.8 months.
Sintilimab plus Bevacizumab biosimilar in combination with chemotherapy (Arm A), demonstrated a statistically significant and clinically meaningful improvement in PFS, compared with Arm C (chemotherapy alone group). The median PFS was 6.9 months in Arm A, and 4.3 months in Arm C (HR=0.46; P<0.0001). Additionally, the key Secondary endpoints of ORR and Duration of Response (DOR) were improved in Arm A compared with Arm C, and the results of PFS, ORR and DOR assessed by the investigator were consistent with the results assessed by IRRC. The prespecified PFS futility analysis that compares Arm A to Arm B (Sintilimab and chemotherapy group) did not cross futility stopping boundary. The PFS data of Arm B versus Arm C were immature.
The authors concluded that in this first prospective, double-blind, Phase III study among patients with EGFR mutated NSCLC who had progressed after EGFR TKIs, this quadruple regimen of Sintilimab plus Bevacizumab biosimilar in combination with chemotherapy, significantly improved Progression Free Survival, compared with chemotherapy alone.
VP9-2021: ORIENT-31: Phase III study of sintilimab with or without IBI305 plus chemotherapy in patients with EGFR mutated nonsquamous NSCLC who progressed after EGFR-TKI therapy. Lu S, Wu L, Jian H, et al. Published:November 19, 2021DOI:https://doi.org/10.1016/j.annonc.2021.10.007.