Phase I study of LZM005, a HER2 antibody, as monotherapy or in combination with trastuzumab and docetaxel in patients with HER2-positive metastatic breast cancer.

person Cong Xue Department of Medical Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China info_outline Cong Xue, Herui Yao, Ying Lin, Xin An, Meiting Chen, Yugang Dong, Su Li, Yanxia Shi

Authors person Cong Xue Department of Medical Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China info_outline Cong Xue, Herui Yao, Ying Lin, Xin An, Meiting Chen, Yugang Dong, Su Li, Yanxia Shi Organizations Department of Medical Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, Sun Yat-sen University Cancer Center, Guangzhou, China, Department of Breast Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Livzon Mabpharm Inc, Other Foundation Background: LZM005 is a novel anti-HER2 antibody that binds with elevated affinity to the domain II of HER2. This phase I study assessed the safety, tolerability, pharmacokinetics (PK) and activity of LZM005, as monotherapy or combined with trastuzumab and docetaxel in patients with HER2-positive metastatic breast cancer. Methods: The phase I trial included phase Ia and Ib. Phase Ia was the monotherapy dosage escalation design. LZM005 was administered intravenously with 5mg/kg, 10mg/kg, 15mg/kg and 20mg/kg. The endpoints were dose limited toxicity (DLT) and maximum-tolerated dose (MTD), safety, tolerability and PK analysis. In phase Ib, LZM005 was combined with trastuzumab and docetaxel with MTD. The endpoints included safety and tolerability, response, PK and biomarker analysis. Results: From Jan 2017 to Feb 2020, 35 patients received LZM005 (15 monotherapy, 20 combination). No DLT was observed from 5mg/kg to 20mg/kg. In phase Ib two arms were set: 420mg arm and 525mg arm. The pharmacokinetics of LZM005 were similar to pertuzumab (Table). Common adverse events included increased transaminases, diarrhea and anemia in monotherapy and combination therapy. The common AE in phase Ia trial included diarrhea (21.4%), anemia (14.3%), elevated transaminase (14.3%). The common AE in phase Ib trial included anemia (44.1%), diarrhea (41.2%), fatigue (26.5%), elevated transaminases (23.5%), nausea (20.6%), rash (17.6%) and asymptomatic urinary tract infection (11.7%). All adverse events were manageable. No treatment-related death occurred. The clinical benefit rate and objective response rate was respectively 42.90% (6/14) and 7.14% (1/14) with monotherapy, with combination cohort was 100% (8/8) and 62.5% (5/8) in trastuzumab-naive, 83.3% (11/12) and 41.7% (5/12) in trastuzumab-pretreated patients. The median progression free survival was 22.5 weeks. Conclusions: LZM005 was well tolerated and showed potent activity in patients with HER2-positive metastatic breast cancer. Further evaluation was warranted. Clinical trial information: CTR20191921. PK parameters of LZM005 in Chinese patients. Group average±SD (%CV) 5 mg/kg (N=1) 10 mg/kg (N=4) 15 mg/kg (N=3) 20 mg/kg (N=6) AUC 0-21d(h*μg/ml) 22598.296±-(-) 37026.958±6856.2857(18.517) 57284.723±4943.5427(8.63) 59894.118±13138.0635(21.935) Cmax (µg/ml) 132.385±-(-) 219.402±39.0606(17.803) 345.502±36.8012(10.652) 340.037±40.5673(11.930) t1/2(h) 211.122±-(-) 374.983±63.2312(16.862) 244.263±57.0101(23.34) 215.294±72.6508(33.745) CL(ml/h) 10.433±-(-) 8.989±2.1178 (23.56) 11.576±3.8161(32.965) 16.279±5.4647 (33.568) Vss(ml) 3382.474±-(-) 4508.610±430.9516(9.558) 3708.281±354.6646(9.564) 4609.199±599.7108(13.011) Vz(ml) 2922.609±-(-) 4543.860±349.47 (7.691) 3855.877±770.0037(19.970) 4537.133±733.7645(16.172) Ctrough(mg/ml) 0±-(-) 0±-(-) 0±-(-) 0±-(-)