Updated results and biomarker analyses from the phase I trial of A166 in patients with HER2-expressing locally advanced or metastatic solid tumors.
Authors: Hu Xichun , Zhang Jian , Liu Rujiao , Gao Shuiping , Wu Junyan , Wang Ying , Hao Yanrong , Ge Junyou , Qing Yan , Yi Shuli , Yang Qixian , Rao Huajing , Yuan Juanjuan 
Published: June 2022

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Background: A166, an antibody-drug conjugate, with an anti-HER2 antibody site-specifically conjugated to Duo-5 (anti-microtubule agent), via a stable protease-cleavable valine citrulline linker, has proved its safety and efficacy in patients with HER2 positive breast cancer (Xichun Hu et al. ASCO 2021). Here, we report updated data and biomarker analyses from this single-arm, multi-center, open-label, phase I trial (CTR20181301). Methods: This study has two parts: dose escalation and dose expansion. In the expansion part, dose cohorts were expanded at 4.8 and 6.0 mg/kg Q3W, and the primary endpoint was ORR, as assessed according to the RECIST 1.1. Next-generation sequencing was performed on tissue-derived DNA and blood-derived circulating tumor DNA (ctDNA). Results: As of Dec 10, 2021, in total 58 female pts were enrolled in the expansion dose cohorts. Median age was 53.5 years (range 26-71), 58 pts (100%) had prior HER2-targeted therapy with the median lines of 4, including 100% received trastuzumab ± pertuzumab, 94.8% received anti-HER2 TKIs, and 20.7% received anti-HER2 ADCs in the metastatic setting. Any grade treatment-related AEs (TRAEs) were documented in 100.0% (58/58) of pts. Common TRAEs were corneal epitheliopathy (98.3%), blurred vision (89.7%), peripheral sensory neuropathy (67.2%), muscular weakness (36.2%) and dry eyes (32.8%). Most common grade ≥3 TRAEs were corneal epitheliopathy (34.5%), blurred vision (22.4%) and ulcerative keratitis (10.3%). 7 pts had serious AEs, 3 of whom were possibly related to the study drug, including thrombosis, peripheral motor neuropathy and muscular weakness. TRAEs led to 39.7% (23/58) dose reduction and 1.7% (1/58) treatment discontinuation. All patients were evaluable for efficacy with the best ORR being 73.91% (17/23; 95% CI, 51.59 to 89.77) and 68.57% (24/35; 95% CI, 50.71 to 83.15), mPFS being 12.30 months (95% CI, 6.00 to not reached) and 9.40 months (95% CI, 4.00 to 10.40) in 4.8 and 6.0 mg/kg cohort, respectively. Of 23 pts treated at 4.8 mg/kg dose level, one had a confirmed and sustained complete response lasting 7+ months. At the time of the data cutoff, 24 pts (41.4%) continued to receive A166 treatment.NGS of 520 genes was performed on tissue-derived DNA and ctDNA of baseline tumor tissue samples (n = 42) and blood samples (n = 53), respectively, and post-treatment blood samples (n = 8). Univariate and multivariate analysis showed that baseline PIK3CA/PTEN status had no influence on the PFS, and gave an idea of FGFR1 amplification as a potential negative predictor of A166 efficacy in HER2-positive breast cancer. Conclusions: The previously demonstrated preliminary clinical benefit of A166-ADC was maintained with no new safety signals, which demonstrated manageable toxicity and encouraging anti-tumor activity in heavily pretreated HER2-positive metastatic breast cancer patients. Clinical trial information: CTR20181301.