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

As of September 20, 2024, a total of 16 clinical studies of the Iparomlimab/Tuvonralimab combination antibody had been initiated (see Investigator's Brochure for details). A total of 1,160 subjects had received treatment with the combination antibody, of whom 766 received monotherapy and 394 received combination therapy. The safety profile of the Iparomlimab/Tuvonralimab combination antibody is consistent with its therapeutic class, with a relatively low incidence of treatment-related Grade 3 or higher toxicities. In monotherapy studies, more than half of the patients experienced treatment-emergent adverse events related to the combination antibody (77.5%), but the incidence of ≥Grade 3 events related to the combination antibody was low (25.4%). Any-grade immune-related adverse events (irAEs) were reported in 47.6% of patients; these were primarily low-grade, resolved after treatment, and considered manageable, with a ≥Grade 3 incidence of 11.9%. In studies of the combination antibody combined with chemotherapy, the AE profile was consistent with the established AE profiles of currently available immune checkpoint inhibitors and standard chemotherapy drugs. Based on the current safety information for the Iparomlimab/Tuvonralimab combination antibody, the safety profile of the investigational drug is considered generally consistent with that exhibited by currently marketed major PD-1 and CTLA-4 immune checkpoint inhibitors, with no unexpected serious safety risks observed. The investigational drug demonstrates a favorable safety and tolerability profile. Four studies have been initiated independently in the lung cancer field, all with protocols involving combination with chemotherapy. The DUBHE-L-201/QL1706-201 study is a single-arm, non-randomized, open-label, single-center Phase II clinical study evaluating the safety and efficacy of the Iparomlimab/Tuvonralimab combination antibody combined with chemotherapy ± bevacizumab as first-line treatment for advanced non-small cell lung cancer. The study was divided into five cohorts. Cohorts 1-4 focused on first-line treatment for stage IIIB-IV NSCLC without EGFR/ALK alterations: Cohort 1 enrolled 17 patients with squamous carcinoma, treated with the combination antibody combined with paclitaxel and carboplatin Q3W for 2 cycles, followed by maintenance with the combination antibody; Cohort 2 enrolled 11 patients with squamous carcinoma, treated with the combination antibody combined with paclitaxel and carboplatin Q3W for 4 cycles, followed by maintenance with the combination antibody; Cohort 3 enrolled 12 patients with non-squamous carcinoma, treated with the combination antibody combined with pemetrexed and carboplatin Q3W for 2 cycles, followed by maintenance with the combination antibody; Cohort 4 enrolled 20 patients with non-squamous carcinoma, treated with the combination antibody combined with pemetrexed, carboplatin, and bevacizumab Q3W for 4 cycles, followed by maintenance with the combination antibody, pemetrexed, and bevacizumab. Cohort 5 enrolled 31 patients with non-squamous carcinoma harboring EGFR-sensitive mutations who had progressed on EGFR-TKI therapy, treated with the combination antibody combined with pemetrexed, carboplatin, and bevacizumab Q3W for 4 cycles, followed by maintenance with the combination antibody, pemetrexed, and bevacizumab. The incidence of TRAEs leading to discontinuation was 8.3% in first-line cohorts 1-4 and 3.2% in the EGFR-TKI resistant cohort 5. In first-line treatment, the ORR was 45.0%, median PFS was 6.8 months, the incidence of ≥Grade 3 TRAEs was 31.7%, TRSAE incidence was 25.0%, the incidence of TRAEs leading to dose interruption was 63.3%, the incidence leading to study discontinuation was 8.3%, and no TRAEs led to death. In the EGFR-TKI resistant cohort 5, the ORR was 54.8%, median PFS was 8.5 months, and median OS was 26.5 months. The DUBHE-L-209/QL1706-209 study is a single-arm, multicenter Phase II clinical study of the Iparomlimab/Tuvonralimab combination antibody combined with carboplatin and etoposide as first-line treatment for extensive-stage small cell lung cancer (ES-SCLC), designed to evaluate safety, tolerability, efficacy, PK characteristics, and immunogenicity. The study enrolled a total of 40 patients with untreated ES-SCLC. During the intensive treatment phase, patients received the combination antibody combined with carboplatin and etoposide Q3W for 4-6 cycles, followed by maintenance with the combination antibody alone. The incidence of ≥Grade 3 TEAEs was 90%, SAE incidence was 50%, irAE incidence was 15%, TEAEs leading to death occurred in 5%, and no TRAEs led to discontinuation or death. The ORR was 89.7%, and median PFS was 5.7 months. The DUBHE-L-303/QL1706-303 study (NCT05690945 / CTR20223309) is a randomized, double-blind, active-controlled, multicenter Phase III clinical study designed to evaluate the efficacy and safety of the Iparomlimab/Tuvonralimab combination antibody combined with chemotherapy versus tislelizumab combined with chemotherapy in patients with PD-L1 negative, driver gene-negative locally advanced or metastatic NSCLC. The study plans to enroll 650 subjects, randomized 1:1 into two groups. The study includes a screening period (≤28 days from ICF signing to first dose), a treatment period (subjects receive study treatment until end of treatment), and a follow-up period (including safety follow-up and survival follow-up). Subjects will receive the following regimens until disease progression, intolerable toxicity, withdrawal of consent, non-compliance, investigator decision to withdraw, or other protocol-specified reasons (Iparomlimab/Tuvonralimab combination antibody/tislelizumab treatment for a maximum of 2 years \[35 cycles\]). Experimental Group: Iparomlimab/Tuvonralimab combination antibody + pemetrexed + carboplatin (non-squamous), or Iparomlimab/Tuvonralimab combination antibody + paclitaxel + carboplatin (squamous), for 4 cycles, then enter maintenance phase, continuing with Iparomlimab/Tuvonralimab combination antibody + pemetrexed (non-squamous) or Iparomlimab/Tuvonralimab combination antibody alone (squamous). Control Group: Tislelizumab + pemetrexed + carboplatin (non-squamous), or tislelizumab + paclitaxel + carboplatin (squamous), for 4 cycles, then enter maintenance phase, continuing with tislelizumab + pemetrexed (non-squamous) or tislelizumab alone (squamous). The DUBHE-L-304/QL1706-304 study (NCT05487391/CTR20222281) is a randomized, double-blind, placebo-controlled, multicenter Phase III clinical study evaluating the safety and efficacy of the Iparomlimab/Tuvonralimab combination antibody combined with platinum-based chemotherapy versus placebo combined with platinum-based chemotherapy as adjuvant therapy in patients with completely resected stage I-IIIB NSCLC without EGFR-sensitive mutations and ALK fusion genes. This study randomizes subjects 1:1 into two groups, with approximately 316 subjects in each group (experimental and control). Subjects will receive either the Iparomlimab/Tuvonralimab combination antibody or placebo, concurrently with adjuvant chemotherapy for 2-4 cycles. The Iparomlimab/Tuvonralimab combination antibody or placebo will be administered for 16 cycles, unless: disease recurrence; intolerable adverse events; intercurrent illness preventing continued treatment; investigator decision to withdraw subject; subject withdrawal of consent; subject pregnancy; non-compliance with trial treatment or procedures; other administrative reasons. In summary, based on relevant study results, perioperative immunotherapy can significantly improve EFS and pCR in patients with N2 stage disease without increasing surgical difficulty, providing a new treatment option for patients with resectable NSCLC, especially those with poorer prognosis stage III-N2 disease. Therefore, this study protocol aims to explore the efficacy and safety of the Iparomlimab/Tuvonralimab combination antibody combined with chemotherapy in the perioperative treatment of resectable stage III-N2b NSCLC, with the expectation of exploring a more effective and safer new perioperative immunotherapy regimen.