Updated results and biomarker analyses from the phase I trial of A166 in patients with HER2-expressing locally advanced or metastatic solid tumors.

Abstract

1037 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.

Emerging Targeted Therapies for HER2-Positive Breast Cancer

“…A166. A166 is a trastuzumab-based ADC linked to duostatin-5, an anti-microtubule agent, which in a phase 1/2 clinical trial demonstrated good tolerability and a promising antitumor effect in heavily pretreated breast cancer patients (NCT03602079) [ 123 , 124 , 125 ].…”

Antibody–drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment

“…For instance, some important toxicities of the new ADCs were not commonly observed either with T-DM1 or other HER2-targeted agents, namely ocular toxicities, an important class of AEs observed with trastuzumab duocarmazine, A166, ARX788, and other agents. 62,63,68 Beyond HER2: investigational ADCs exploring other targets for the treatment of BC Although considerable research efforts have been employed in the search for new therapeutic targets in the last decades, it was only with the approval of SG for the treatment of TNBC in 2021 that an ADC targeting a non-HER2 target was incorporated into clinical practice. 28 The benefit demonstrated with this anti-Trop-2 agent proved the concepts that a new generation of ADC could effectively target proteins that are highly expressed in tumors, even if they are not part of hyperactivated oncogenic driver pathways.…”

“…For instance, some important toxicities of the new ADCs were not commonly observed either with T-DM1 or other HER2-targeted agents, namely ocular toxicities, an important class of AEs observed with trastuzumab duocarmazine, A166, ARX788, and other agents. 62 , 63 , 68 …”

Rational Identification of Novel Antibody‐Drug Conjugate with High Bystander Killing Effect against Heterogeneous Tumors

“…[30] Yamazaki et al successfully constructed dual-payload ADCs carrying MMAE and monomethyl auristatin F (MMAF) and attributed their significant therapeutic effect against HER2 heterogeneous tumors to the bystander effect of MMAE. [31] Although several ongoing clinical trials have revealed the potential of novel permeable payloads in treating heterogeneous tumors, [32,33] the lack of comprehensive method for rational identification of bystander payloads and ADCs limited the clinical potential of this strategy.…”