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KN046, a bispecific antibody against PD-L1 and CTLA-4, plus chemotherapy as first-line treatment for metastatic NSCLC: A multicenter phase 2 trial.

ABSTRACT: KN046, a bispecific antibody targeting PD-L1 and CTLA-4, presents a promising therapeutic option for metastatic non-small cell lung cancer (NSCLC). In this multicenter phase 2 trial, patients with nonsquamous (non-sq) NSCLC receive pemetrexed, whereas those with sq-NSCLC receive paclitaxel, plus KN046 and carboplatin. Following four cycles, maintenance therapy includes KN046 with pemetrexed for non-sq-NSCLC and KN046 for sq-NSCLC. The objective response rate is 46.0%, and the median duration of response is 8.1 months. The median progression-free and overall survival are 5.8 and 26.6 months, respectively. The common adverse events include anemia (87.4%), loss of appetite (72.4%), and neutropenia (70.1%). The most prevalent immune-related adverse event is pruritus (28.7%). These findings indicate that first-line treatment with KN046 and chemotherapy is effective and tolerable in metastatic NSCLC patients, warranting further investigation in a larger phase 3 trial. The trial is registered at ClinicalTrials.gov (NCT04054531).

SUBMITTER: Zhao Y

PROVIDER: S-EPMC10983105 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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KN046, a bispecific antibody against PD-L1 and CTLA-4, plus chemotherapy as first-line treatment for metastatic NSCLC: A multicenter phase 2 trial.

Zhao Yuanyuan Y Chen Gang G Li Xingya X Wu Jingxun J Chang Baoping B Hu Sheng S Yang Shujun S Xu Ting T Liu Yilan Y Wang Ni N Zhang Li L Huang Yan Y

Cell reports. Medicine 20240301 3

KN046, a bispecific antibody targeting PD-L1 and CTLA-4, presents a promising therapeutic option for metastatic non-small cell lung cancer (NSCLC). In this multicenter phase 2 trial, patients with nonsquamous (non-sq) NSCLC receive pemetrexed, whereas those with sq-NSCLC receive paclitaxel, plus KN046 and carboplatin. Following four cycles, maintenance therapy includes KN046 with pemetrexed for non-sq-NSCLC and KN046 for sq-NSCLC. The objective response rate is 46.0%, and the median duration of ...[more]

PMID: 38508135

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Project description:BackgroundKN046 is a novel bispecific antibody targeting programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). This multicenter phase I trial investigated the safety, tolerability, pharmacokinetics (PK), and efficacy of KN046 in patients with advanced solid tumors.MethodsPatients who failed standard treatment were included. KN046 was administered at doses of 1, 3, and 5 mg/kg every 2 weeks (Q2W), 5 mg/kg every 3 weeks (Q3W), and 300 mg Q3W based on the modified toxicity probability interval method in the dose-escalation phase; the recommended dose was used in the expansion phase. Primary objectives were maximum tolerated dose (MTD) and recommended phase II dose (RP2D) in escalation and preliminary efficacy in expansion. Secondary objectives included PK, pharmacodynamics, safety, and tolerability of KN046. We also explored biomarkers based on PD-L1 expression, multiplex immunofluorescence (mIF) staining, and RNAseq-derived nCounter platform.ResultsTotally, 100 eligible patients were enrolled, including 59 with nasopharyngeal carcinoma (NPC), 36 with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), and those with other advanced solid tumors. The most common treatment-related adverse events (TRAEs) were rash (33.0%), pruritus (31.0%), and fatigue (20.0%). Grade ≥3 TRAEs were observed in 14.0% of participants. No dose-limiting toxicity occurred in the dose-escalation phase, and the MTD was not reached. The RP2D was determined as 5 mg/kg Q2W according to the pharmacokinetic-pharmacodynamic model, the preliminary exposure-response analysis, and the overall safety profile. Among 88 efficacy-evaluable participants, the objective response rate (ORR) was 12.5%, and the median duration of response was 16.6 months. In the NPC subgroup, the ORR was 15.4%, and the median overall survival (OS) was 24.7 (95% CI 16.3 to not estimable) months. In the EGFR-mutant NSCLC subgroup, the ORR was 6.3%. mIF analysis results showed patients with high CD8 expression showed longer median OS (27.1 vs 9.2 months, p=0.02); better prognosis was observed in patients with high CD8 and PD-L1 expression.ConclusionsKN046 was well tolerated and showed promising antitumor efficacy in advanced solid tumors, especially in patients with NPC. The combination of both CD8 and PD-L1 expression improved the prediction of KN046 response.Trial registration numbersNCT03733951 .

Project description:BackgroundThe combination of immune-checkpoint inhibitors and antiangiogenic agents can synergistically modulate the tumor microenvironment and represents a promising treatment option. Here, we evaluated the efficacy and safety of camrelizumab plus famitinib (a receptor tyrosine kinase inhibitor) as a first-line treatment for advanced or metastatic NSCLC patients with a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥1%, in an open-label, multicenter, phase 2 basket trial.MethodsEligible patients received camrelizumab (200 mg once every 3 weeks via intravenous infusion) plus oral famitinib at an initial dose of 20 mg once daily. The primary endpoint was the objective response rate (ORR), as assessed by the investigator per Response Evaluation Criteria in Solid Tumors V.1.1. Key secondary endpoints included disease control rate (DCR), duration of respons, progression-free survival (PFS), overall survival (OS), 12-month OS rate, and safety profile.ResultsOf the enrolled 41 patients, 21 (51.2%) had a PD-L1 TPS of 1-49%. As of the cut-off date on June 22, 2022, the combination regimen of camrelizumab and famitinib achieved an ORR of 53.7% (95% CI 37.4% to 69.3%) and a DCR of 92.7% (95% CI 80.1% to 98.5%). The median PFS was 16.6 months (95% CI 8.3 to not reached), and OS data were not yet mature, with an estimated 12-month OS rate of 76.8% (95% CI 60.0% to 87.3%). The most common treatment-related adverse events of grade 3 or higher included hypertension (22.0%), increased alanine aminotransferase (12.2%), decreased neutrophil count (9.8%), proteinuria (7.3%), decrease platelet count (7.3%), and hypokalemia (7.3%). One (2.4%) patient died from grade 5 hemoptysis, which was considered possibly related to the study treatment by the investigator.ConclusionCamrelizumab plus famitinib demonstrated promising antitumor activity in advanced or metastatic NSCLC patients and had an acceptable safety profile. These findings suggest that this combination regimen could be an alternative therapeutic option and warrant further investigation.Trial registration numberNCT04346381.

Dataset Information

KN046, a bispecific antibody against PD-L1 and CTLA-4, plus chemotherapy as first-line treatment for metastatic NSCLC: A multicenter phase 2 trial.

Publications

KN046, a bispecific antibody against PD-L1 and CTLA-4, plus chemotherapy as first-line treatment for metastatic NSCLC: A multicenter phase 2 trial.

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