Efficacy and safety of KN026 in combination with KN046 in patients with locally advanced unresectable or metastatic HER2-positive other solid tumors.
Authors: Gong Jifang , Chen Lei , Sun Meili , Ni Mingli , Zhao Rusen , Wang Xiangcai , Ying Jieer , Zhang Yanming , Zhuang Zhi-xiang , Li Xionghui , Lv Yuan , Shen Lin 
Published: June 2023

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Background: Besides breast cancer (BC) and gastric cancer, HER2 is also widely expressed in other solid tumors, such as colorectal cancer (CRC), NSCLC, gallbladder cancer (GBC), renal pelvis cancer (RPC), pancreatic ductal adenocarcinoma (PDAC), etc. The reports of immunotherapy combined with HER2-targeted therapy are limited. KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes. KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD-1 and CTLA-4 interaction with CD80/CD86. Methods: KN026-203 study (NCT04521179) is an open-label, phase II, multi-center study to evaluate the efficacy and safety of KN026 (30mg/kg, Q3W, C1D1 and C1D8 loading) combined with KN046 (5mg/kg, Q3W) in patients (pts) with HER2-positive (defined as HER2 IHC 3+ or HER2 gene amplification) solid tumors. The study consisted of 3 cohorts, including HER2 positive gastric or gastroesophageal cancer (GC/GEJ), BC and other solid tumors. Pts received treatment until disease progression or unacceptable toxicity. Tumor assessments were scheduled every 6 weeks. The primary endpoints were ORR and DOR. The efficacy and safety of KN026 combined with KN046 were reported. Results: As of 10 November 2022, 26 pts with HER2 positive tumor other than BC and GC/GEJ were enrolled, including 15 CRC, 5 NSCLC, 4 GBC, 1 RPC and 1 PADC pts. All those pts had previous systemic treatment. The median age was 56 (range 37 ~ 67) years. 15 (57.7%) pts had liver metastasis. 92.3% of pts and all CRC pts had received ≥2 lines prior treatment. 5 (19.2%) and 6 (23.1%) pts had received prior anti-HER2 and anti-PD-(L)1 therapy, respectively. All 26 pts were assessed according to RECIST v1.1. The confirmed ORR was 53.8% (95% CI: 33.4, 73.4) with mDOR 6.8 months (95% CI: 2.9, 15.3). The mPFS was 5.6 months (95% CI: 2.9, 16.5) and 12-month OS rate was 80.4% (95% CI: 59.1, 91.4) with median follow-up time 16.6 months. For 15 CRC pts, the ORR was 53.3% (95% CI: 26.6, 78.7) with mDOR 11.7 months (95% CI: 3.2, NE). The mPFS was 12.2 months (95% CI: 2.7, NE) .12-month OS rate was 80.0% (95% CI: 50.0, 93.1) with median follow-up time 16.0 months. Common TRAEs were infusion related reaction (38.5%), AST increased (34.6%), ALT increased (26.9%), conjugated bilirubin increased (26.9%), rash (26.9%), anemia (26.9%) and blood bilirubin increased (26.9%). Most of them were Grade 1 or 2. The most common ≥ Gr3 TRAEs were conjugated bilirubin increased (7.7%) and AST increased (7.7%). There was no treatment related death. Conclusions: KN026 combined with KN046 treatment had demonstrated favorable efficacy and safety profile in HER2 positive other solid tumors (non-GC/GEJ and non-BC). Especially very promising efficacy were observed in ≥3 lines HER2 positive CRC. Based on these results, a pivotal study was planned to verify the efficacy and safety of KN026 and KN046 combo. Clinical trial information: NCT04521179 .