Investigation Continues for Highly Potent Antibody-Drug Conjugate in HER2-Expressing Solid Tumors

Xihun Hu, MD, PhD

Oncologists treating patients with HER2-expressing solid tumors can now refer patients for enrollment in a phase 2 trial of the novel drug A166, that has shown high potency in these tumors.

“This drug, A166, is an antibody-drug conjugate, so it's especially for HER2-positive cancers. This drug will use the high-tech knowledge that is a good link to connect to the anti-microtubular agents,” Xihun Hu, professor and director of the Department of Medical Oncology, Shanghai Cancer Center, Fudan University, told Targeted Oncology™, in an interview.

The open-label, phase 1/2 first-in-human study is designed for patients with HER2-expressing or amplified disease who progressed on or did not respond to available standard therapies.¹

Phase 1 of the study has been completed and A166 demonstrated a manageable safety profile and promising antitumor activity with clinically meaningful responses observed in the HER2-positive breast cancer population.

Xihun Hu mentioned “We used the 3 + 3 approach. At the 6.0 mg/kg dose level, the objective response rate reached over 70%. So, it's a highly potent agent. Regarding the toxicity, we didn't find any chemotherapy-related myelosuppression, nausea, or vomiting. But there were some toxicities in the skin as well as eye toxicity. I think that mostly this toxicity was grade 1 or 2, and we didn’t see any dose-limiting toxicity in this phase 1 trial.”

Fifty-seven patients were included in the phase 1 portion of the study. The cohort had a median age of 53 years (range, 26-74) and were predominantly female (n = 50). Most patients included in phase 1 tested positive for HER2 expression (n = 51), and 6 patients were HER2 low. Most of the cohort (61.4%) had been treated with 5 or more prior lines of therapy.²

Among the 36 patients with HER2-positive breast cancer who had measurable disease, the best ORR observed at the 4.8 mg/kg-dose level was 59.1%, and in the 6.0 mg/kg group was 71.4%. The median progression-free survival (PFS) was not reached, but there was 1 patient treated at the 4.8 mg/kg-dose level who remained progression-free for more than 19 months.

The safety analysis showed that any-grade treatment-related adverse events (TRAEs) occurred in 96.5% of patients. Of the TRAEs observed, 31.6% were grade 3 or higher. The most common any-grade AEs reported during phase 1 were corneal epitheliopathy (73.7%), vision blurred (59.6%), peripheral sensory neuropathy (26.3%), dry eye (21.1%), anemia (19.3%), and hyponatremia (19.3%). The most common grade 3 or higher AEs reported were corneal epitheliopathy (17.5%), hypophosphatemia (5.3%), and dry eye (5.3%).

Serious AEs were also seen in 4 patients, of which 2 events were related to A166. Dose reduction occurred in 5.3% of patients treated with the novel antibody drug conjugate, and 5.3% also discontinued treatment due to AEs.

“Because this agent has shown to be highly potent and safe, we want to start a registrational phase 2 trial in the patients who failed trastuzumab [Herceptin] and tyrosine kinase inhibitors. We also want to get approval, and then we’ll design another confirmative trial to try to prove our findings,” Hu told Targeted Oncology™.

The phase 2 primary end point is the percentage of patients with an objective response to A166. This efficacy end point will be explored using the recommended phase 2 dose of A166. The secondary end points of phase 2 include the number of patients with TRAEs, duration of response, the number of patients who develop measurable anti-drug antibodies, PFS, and overall survival.

To be eligible for the study, patients are required to be at least 18 years old with histologically confirmed incurable, locally advanced, or metastatic cancer and evaluable or measurable HER2-positive or HER2-expressing disease. Patients are also required to have an ECOG performance status of 0 or 1 with adequate laboratory test results at baseline. Patients must have either recovered from acute toxicities from prior therapy or have them resolved to grade 1 prior to joining the study.

Eight treatment centers in the United States, including in Florida, Massachusetts, Michigan, New York, Oklahoma, Oregon, Texas, and Virginia are actively recruiting patients for the phase 2 study of A1600 in patients with relapsed/refractory HER2-expressing or HER2-amplified solid tumors.¹

_References:

_{1. Study of A166 in Patients with relapsed/refractory cancers expressing HER2 antigen or having amplified HER2 gene. Clinicaltrials.gov. Accessed August 20, 2020. https://bit.ly/3y5bshG}

_{2. Hu X, Zhang J, Liu R, et al. Phase I study of A166 in patients with HER2-expressing locally advanced or metastatic solid tumors. J Clin Oncol. 2021;39(suppl 15):abstr 1024. doi: 10.1200/JCO.2021.39.15_suppl.1024}