Iparomlimab and Tuvonralimab Plus Chemotherapy Before Surgery for Stage III Lung Cancer

Summary

Background: For patients with resectable stage III-N2b non-small cell lung cancer (NSCLC), optimal perioperative treatment strategies remain an area of active investigation. Iparomlimab and tuvonralimab (QL1706) is a novel bifunctional antibody combination targeting PD-1 and CTLA-4, designed to enhance anti-tumor immunity. Objective: This phase II, single-arm, multicenter study aims to evaluate the efficacy and safety of neoadjuvant iparomlimab and tuvonralimab (QL1706) in combination with platinum-based chemotherapy in patients with resectable stage III-N2b NSCLC. Study Design and Methods: A total of 28 patients will be enrolled across approximately 4 centers in China. Eligible patients (aged ≥18 years, ECOG PS 0-1) with histologically or cytologically confirmed, resectable stage III-N2b NSCLC (AJCC 9th edition) will receive three cycles of neoadjuvant therapy every three weeks. Patients with non-squamous carcinoma will receive iparomlimab and tuvonralimab (5 mg/kg) plus pemetrexed (500 mg/m²) and carboplatin (AUC 5). Patients with squamous carcinoma will receive iparomlimab and tuvonralimab (5 mg/kg) plus nab-paclitaxel (260 mg/m²) and carboplatin (AUC 5). Surgical resection will be performed within 6 weeks following completion of neoadjuvant therapy. Subsequent adjuvant treatment is at the discretion of the investigator. Key Eligibility Criteria: Key inclusion criteria include pathologically confirmed T\<sub\>any\</sub\>N2b disease with mediastinal nodal status confirmed by EBUS/EUS or mediastinoscopy, and the determination by multidisciplinary team (MDT) assessment that the tumor is completely resectable (R0). Key exclusion criteria include known EGFR or ALK positive mutations, prior anti-cancer therapy for current lung cancer, active autoimmune disease, or uncontrolled hepatitis B or C. Study Endpoints: The primary endpoint is the pathological complete response (pCR) rate. Secondary endpoints include major pathological response (MPR) rate, objective response rate (ORR), R0 resection rate, event-free survival (EFS), overall survival (OS), impact on surgical outcomes, and safety. Exploratory endpoints involve biomarker analysis including ctDNA. Sample Size Rationale: Assuming a null hypothesis pCR rate (P0) of 8.8% (based on historical data) and an expected pCR rate (P1) of 28%, with a two-sided α of 5% and 80% power, 24 patients are required. Factoring in a 15% inoperable rate, the total sample size is 28 patients. Statistical Analysis: The primary endpoint, pCR rate, and other binary endpoints will be summarized with frequencies, percentages, and their 95% confidence intervals calculated using the Clopper-Pearson method. Time-to-event endpoints (EFS, OS) will be analyzed using the Kaplan-Meier method. Safety data will be summarized descriptively. Clinical Trial Information: This study is sponsored by The Second Affiliated Hospital of Air Force Medical University, PLA. The Principal Investigator is Dr. Yan Xiaolong.

Timeline

Start

2026-05

Primary completion

2029-05

Completion

2029-12

Publications

• Background Provencio M, Nadal E, Gonzalez-Larriba JL, Martinez-Marti A, Bernabe R, Bosch-Barrera J, Casal-Rubio J, Calvo V, Insa A, Ponce S, Reguart N, de Castro J, Mosquera J, Cobo M, Aguilar A, Lopez Vivanco G, Camps C, Lopez-Castro R, Moran T, Barneto I, Rodriguez-Abreu D, Serna-Blasco R, Benitez R, Aguado de la Rosa C, Palmero R, Hernando-Trancho F, Martin-Lopez J, Cruz-Bermudez A, Massuti B, Romero A. Perioperative Nivolumab and Chemotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Aug 10;389(6):504-513. doi: 10.1056/NEJMoa2215530. Epub 2023 Jun 28.
• Background Cascone T, Awad MM, Spicer JD, He J, Lu S, Sepesi B, Tanaka F, Taube JM, Cornelissen R, Havel L, Karaseva N, Kuzdzal J, Petruzelka LB, Wu L, Pujol JL, Ito H, Ciuleanu TE, de Oliveira Muniz Koch L, Janssens A, Alexandru A, Bohnet S, Moiseyenko FV, Gao Y, Watanabe Y, Coronado Erdmann C, Sathyanarayana P, Meadows-Shropshire S, Blum SI, Provencio Pulla M; CheckMate 77T Investigators. Perioperative Nivolumab in Resectable Lung Cancer. N Engl J Med. 2024 May 16;390(19):1756-1769. doi: 10.1056/NEJMoa2311926.
• Background Provencio M, Awad MM, Spicer JD, Janssens A, Moiseyenko F, Gao Y, Watanabe Y, Alexandru A, Guisier F, Frost N, Franke F, Hiltermann TJN, He J, Tanaka F, Lu S, Coronado Erdmann C, Sathyanarayana P, Tran P, Devas V, Cascone T. Clinical outcomes with perioperative nivolumab by nodal status in patients with stage III resectable NSCLC: phase 3 CheckMate 77T exploratory analysis. Nat Cancer. 2026 Jan;7(1):169-181. doi: 10.1038/s43018-025-01104-z. Epub 2026 Jan 8.
• Background Zhao Y, Wang W, Liang H, Yang CJ, D'Amico T, Ng CSH, Liu CC, Petersen RH, Rocco G, Brunelli A, Liu J, He J, Huang W, Liang W, He J; AME Thoracic Surgery Collaborative Group. The Optimal Treatment for Stage IIIA-N2 Non-Small Cell Lung Cancer: A Network Meta-Analysis. Ann Thorac Surg. 2019 Jun;107(6):1866-1875. doi: 10.1016/j.athoracsur.2018.11.024. Epub 2018 Dec 14.
• Background Carter L, Apte V, Shukla A, Ghose A, Mamidi R, Petohazi A, Makker S, Banerjee S, Boussios S, Banna GL. Stage 3 N2 Lung Cancer: A Multidisciplinary Therapeutic Conundrum. Curr Oncol Rep. 2024 Jan;26(1):65-79. doi: 10.1007/s11912-023-01486-2. Epub 2024 Jan 2.
• Background Han B, Zheng R, Zeng H, Wang S, Sun K, Chen R, Li L, Wei W, He J. Cancer incidence and mortality in China, 2022. J Natl Cancer Cent. 2024 Feb 2;4(1):47-53. doi: 10.1016/j.jncc.2024.01.006. eCollection 2024 Mar.

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