Phase I Study of A166, a Novel Antibody-Drug Conjugate in Advanced HER2-expressing Solid Tumors

doi:10.21203/rs.3.rs-2179560/v1

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Phase I Study of A166, a Novel Antibody-Drug Conjugate in Advanced HER2-expressing Solid Tumors

https://doi.org/10.21203/rs.3.rs-2179560/v1

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published 18 Apr, 2023

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Purpose: In this phase I study, the safety, pharmacokinetics, and antitumor activity of a novel HER2 targeted antibody–drug conjugate A166 were evaluated in patients with HER2-expressing advanced solid tumors.

Experimental Design: Patients received A166 at doses of 0.1, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8, or 6.0 mg/kg Q3W.

Results: In total, 81 patients who had progressed on standard treatment were enrolled. No dose-limiting toxicity was observed. The most common treatment-related adverse events at grade 3 or higher were corneal epitheliopathy (30.9%), blurred vision (18.5%), dry eyes (7.4%), and peripheral sensory neuropathy (6.2%). The C_max and area under curve of Duo-5, its free payload, were about 0.1% and 0.2% of those of the ADC, respectively. For all assessable HER2-positive breast cancer patients enrolled in 4.8 mg/kg and 6.0 mg/kg cohorts, corresponding ORR was 73.9% (17/23) and 68.6% (24/35), respectively; and median PFS was 12.3 and 9.4 months, respectively.

Conclusions: A166 had a recommended phase II dose of 4.8 mg/kg, manageable toxicity, good stability in the circulation and promising antitumor activities in HER2-positive breast cancer patients.

Trial registration: CTR20181301 (www.chinadrugtrials.org.cn)

Biological sciences/Cancer/Breast cancer

Biological sciences/Cancer/Cancer therapy/Drug development

HER2

antibody-drug conjugate

metastatic breast cancer

Human epidermal growth factor receptor 2 (HER2) is a targetable gene alteration. The overexpression or amplification of HER2 negatively impacts the survival of patients with both early and advanced disease. Biologicals targeting HER2 are the standard of care in the treatment of cancers, such as breast and gastric cancers. The introduction of HER2-targeted therapies, most notably trastuzumab, pertuzumab, antibody-drug conjugates (ADCs, e.g., Trastuzumab emtansine [T-DM1] and trastuzumab deruxtecan [DS-8201]), and tyrosine kinase inhibitors (TKIs, e.g., lapatinib, neratinib, pyrotinib, and tucatinib) has led to dramatic improvements in the prognosis of patients with HER2-positive breast cancer.¹ T-DM1 was once a second-line standard of care with an objective response rate (ORR) of 43.6% and a median progression-free survival (PFS) of approximately 9.6 months.² DS-8201, a third-generation ADC, achieved the superiorities of PFS and ORR over T-DM1 in a phase III study (Destiny-Breast 03), and has become a new standard of care for second-line therapy.³ As an optimal third- or later-line therapy, DS-8201 was effective in T-DM1 resistant or refractory patients, and achieved a tumor response rate of 61.4% and a median PFS of 19.4 months in the pivotal phase II HER2-positive metastatic breast cancer trial.⁴ Despite these advances, there are still unmet needs for continuous blockade with new-developed HER2-targeted agents, since advanced breast cancer is still an incurable disease and there are no standard of care for patients who have failed two lines of anti-HER2 regimens in China.

A166 is a HER2-targeted ADC composed of a novel cytotoxic drug (Duo-5, anti-microtubule agent) with site-specific conjugation to a humanized anti-HER2 antibody via a stable protease-cleavable valine citrulline linker. The anti-HER2 antibody component has the same amino acid sequence as trastuzumab. The unique linker is stable in plasma and selectively cleaved by lysosomal cathepsins that are upregulated in cancer cells, which effectively prevents the premature release of toxin molecules outside tumor cells, and reduces systemic toxicity.⁵ A166 exhibited better tumor growth inhibition than T-DM1 at a dose of 3 mg/kg in xenograft models.⁶ These unique properties make A166 a more optimized anti-HER2 agent. Results from its first-in-human study in US (ClinicalTrials.gov number, NCT03602079) showed preliminary antitumor activity in patients with relapsed or refractory advanced HER2-altered solid cancers, mostly non-breast cancers (i.e., HER2-positive gastric cancer, HER2-expressing ovarian cancer, HER2-mutated non-small cell lung cancer), with objective responses occurring in 36% of the patients at the dose levels of 3.6 mg/kg and 4.8 mg/kg.⁷

According to regulatory requirements, we simultaneously conducted an independent single-arm phase I study in China to determine the safety, tolerability, pharmacokinetics, and clinical activity of A166 in Chinese patients with HER2-expressing locally advanced or metastatic solid tumors (CTR20181301).

Study design and patient selection

Patients were eligible for enrollment if they were ≥ 18 years of age and had a histologically confirmed locally advanced/metastatic HER2-expressing solid tumors (including breast cancer), Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate bone marrow and organ function. Patients were excluded if they had history of intolerance of trastuzumab, symptomatic brain metastasis, or prior anti-tumor treatment for brain metastases within 3 months before the first study treatment. Assessment of HER2 positivity for breast cancer and colorectal cancer was according to the Guideline for HER2 detection in breast cancer (the 2014 and 2019 versions), for gastric cancer was according to the Guidelines for HER2 detection in gastric cancer (the 2016 version).^8-10

This two-part study consisted of dose escalation and dose expansion parts. Dose escalation was conducted using a standard 3+3 design. We selected a conservative starting dose of 0.1 mg/kg, calculated as about one-twelfth of the human equivalent dose (3.2 mg/kg) of the highest non-severely toxic dose in cynomolgus monkeys (10 mg/kg). Doses were escalated up to 6.0 mg/kg. While only one patient received A166 at dose of 0.1 as required, three patients at each dose level were required at doses of 0.3, 0.6, 1.2, 2.4, 3.6, 4.8, and 6.0 mg/kg intravenously every 3 weeks until disease progression, withdrawal of informed consent, or intolerable toxicity. The first 21-day treatment cycle was designed for the observation of dose-limiting toxicity (DLT), which was defined as grade ≥ 3 non-hematological toxicity, except for grade 3 nausea, vomiting, or diarrhea lasting ≤ 3 days after optimal supportive treatment, treatment interruption for > 14 days due to toxicity, grade 4 neutrophil count reduction lasting for > 7 days (or > 3 days after optimal supportive treatment), febrile neutropenia, grade 4 thrombocytopenia, grade 3 thrombocytopenia with bleeding, or grade 4 anemia. Dose escalation proceeded when all three patients completed the safety evaluation at a given dose level with DLTs in less than one-third of patients.

The study protocol and all amendments were approved by the Ethics Committee of Fudan University Shanghai Cancer Center (approval no.: 1806186-13). The study was conducted in accordance with the Declaration of Helsinki guidelines and international standards of good clinical practice. Written informed consent was obtained from all participants.

End points

The primary endpoints of this study were assessment of the safety and tolerability of A166 and identification of the maximum tolerated dose (MTD). Secondary endpoints included assessment of pharmacokinetic parameters and preliminary anti-tumor effect.

Safety and anti-tumor effect assessments

Safety assessments included documentation of adverse events (AEs), serious adverse events (SAEs), vital signs, clinical laboratory examination, as well as findings from the physical, cardiac, and ophthalmological examinations. The severity of AEs was graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4.03). We established an ocular AEs special task force comprised of study investigators and ophthalmologists. All patients were referred to an ophthalmologist (Dr. Z.Q. Yu of The Eye and ENT Hospital of Fudan University) for baseline assessment, including ophthalmologic examinations for visual acuity, dry eye syndrome and ocular surface diseases, e.g., corneal epitheliopathy and keratitis. Patients were referred to the ophthalmologist in every cycle and any time additionally if the patient had ocular signs and symptoms or if the investigator deemed it necessary. All investigators were trained for the clinical grading of ocular AEs and implementing the study algorithm. The task force determined the subsequent drug administrations in specific scenarios, such as discontinuing A166 permanently or restarting A166 at the original or lower dose, while optimizing the management algorithm to align with the patient outcomes.

The efficacy was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1 every 9 (± 1) weeks from the first drug infusion. Patients were followed up for an additional 24 months after the last visit or until death, whichever occurred first.

Pharmacokinetics and immunogenicity assessments

The concentration of A166, total antibody (TA, conjugated and unconjugated), and Duo-5 (free payload) were detected using validated bioanalytical assays for pharmacokinetic (PK) studies. Plasma samples were collected at pre-dose and post-dose 0.5 (±1/4), 4 (±1/2), 8 (±1), 24 (±2), 48 (±4) hours (h), and 8 (±1), 11 (±1), 15 (±1), and 18 (±1) days from the end of infusion in cycles 1 and 5, as well as pre-dose and post-dose 30 (±15) minutes in cycles 2–4, and at the end of treatment (EOT). In the dose expansion part, plasma samples for PK were collected at pre-dose and post-dose 30 (±15) minutes in cycles 1–5, and at EOT.

Blood samples for anti-drug antibody analyses were collected at pre-dose in cycles 1–6, 9, 13, 17, and every eight cycles thereafter, as well as 28 days after the last dose. Antidrug antibodies to A166 were detected using electrochemiluminescence immunoassay.

Statistical analysis

Statistical computation was performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). The objective response rate (ORR) and disease control rate (DCR) with 95% confidence interval (CI) were calculated using the Clopper–Pearson method based on the binomial distribution. Time-to-event statistics were calculated using the Kaplan-Meier method and the associated confidence intervals (Cis) using the Brookmeyer-Crowley method. All statistical tests were two-tailed, with significance defined as p < 0.05. The PK parameters for A166, TA, and Duo-5 were calculated using non-compartmental approaches implemented in WinNonlin 8.1.

Patient disposition and baseline characteristics

In total, 81 patients with advanced solid tumors were enrolled in the study between August 1, 2018 and May 13, 2021. Patient demographics and baseline characteristics of the study population are summarized in Table 1. Breast, colorectal, and gastric or gastroesophageal junction cancers were present in 90.1% (73/81), 7.4% (6/81), and 2.5% (2/81) of patients. HER2 expression was available for all 81 patients: 64.2% (52/81) were immunohistochemistry (IHC) 3+, 24.7% (20/81) were IHC 2+ and FISH positive, 2.5% (2/81) were IHC2+ but FISH negative, and 8.6% (7/81) were IHC 1+.

The dose escalation set included 22 patients: one at 0.1 mg/kg and three at each of 0.3, 0.6, 1.2, 2.4, 3.6, 4.8, and 6.0 mg/kg dose levels. The dose expansion set included 59 patients: 24 at 4.8 mg/kg and 35 at 6.0 mg/kg. All 81 patients were evaluable for toxicity analysis, whereas 80 were evaluable for tumor response. At the time of the data analysis on July 13, 2022, A166 treatment was discontinued for 68 (84.0%) of the 81 patients, most commonly due to progressive disease in 62 patients, treatment-related AEs (TRAEs) in 5 patients, and protocol deviation in 1 patient.

In total 81 patients, 90.1% (73/81) had received at least 3 prior lines of systemic therapy in the metastatic setting. For 66 HER2-positive (IHC 2+ and FISH+, or IHC 3+) breast cancer patients, all had prior HER2-targeted therapy with the median prior line of 4, including 100% (66/66) received trastuzumab ± pertuzumab, 89.4% (59/66) received anti-HER2 TKIs, and 25.8% (17/66) received anti-HER2 ADCs in which 11 received T-DM1, 5 received ARX-788,¹¹ and 1 received TAA013.

Safety

All 81 patients received at least one dose of A166 and were included in the safety analysis. No DLTs were observed in the dose escalation part, thus, the maximum tolerated dose (MTD) was not reached. TRAEs of any grade were documented in 98.8% (80/81) patients (Table 2). Across all dose levels, the most frequent TRAEs of any grade were corneal epitheliopathy (84.0%), blurred vision (74.1%), peripheral sensory neuropathy (53.1%), dry eyes (32.1%), muscular weakness (28.4%), anemia (23.5%), blood creatine phosphokinase increased (22.2%), alopecia (22.2%), alanine aminotransferase (ALT) increased (18.5%), aspartate aminotransferase (AST) increased (18.5%), myoglobin blood increased (17.3%), hyponatraemia (16.0%), and hypomagnesemia (16.0%) (Table 2). TRAEs grading ≥ 3 occurred in 40 patients (49.4%) and included corneal epitheliopathy (30.9%), blurred vision (18.5%), dry eyes (7.4%), peripheral sensory neuropathy (6.2%), anemia (2.5%), hyponatraemia (2.5%), muscular weakness (2.5%), and leucopenia (1.2%).

SAEs related to treatment were reported in four patients (thrombosis [n=1], muscular weakness [n=1], and peripheral sensory neuropathy [n=2]). Only one death occurred during the treatment, which was attributed to progressive disease. TRAEs led to dose reduction and treatment discontinuation in 30.9% (25/81) and 6.2% (5/81) patients, respectively.

PK characteristics

Compared with the 81 patient data set, the PK analysis included 80 patients, one participant at dose of 0.1 mg/kg was excluded due to lack of PK data. Serum concentration–time profiles for A166 ADC in cycle 1–5 at different dose cohorts are shown in Figure 1A. Pharmacokinetic analysis of serum concentrations revealed that the exposure of A166 ADC were increased with each increasing dose level, and did not exhibit dose accumulation at 0.3–1.2 mg/kg, while this ADC had a limited accumulation at 2.4–6.0 mg/kg. At the recommended doses for expansion part (4.8 and 6.0 mg/kg), the accumulation ratio of C_max was around 1.46-1.51, and area under curve (AUC) was around 1.97-2.15 of A166 ADC, respectively (Table S1). The PK parameters of A166 ADC, TA and Duo-5 for each dose cohort over cycle 1 are summarized in Table S1. Overall, low concentrations of free Duo-5 were observed and the PK characteristics of TA were similar to A166 ADC after administration of A166. At 4.8 and 6.0 mg/kg, the t_1/2 of A166 ADC was 8.83 and 8.33 days after the first dose of A166, respectively. The C_max and AUC of Duo-5 were about 0.1% and 0.2% of the total A166 ADC, respectively (Figure 1B).

In this study, anti-A166 antibody was detected in 12 (14.8%) of 81 patients, 10 of whom were antibody positive at pre-dose, due to prior trastuzumab treatment. The remaining two patients were tested positive in cycle 2 (before dosing) and 6 (before dosing). However, there were no differences in exposure, safety or efficacy of A166 ADC in antibody-positive patients compared to the negative ones.

Efficacy

In total, 80 patients were available for efficacy assessment, one patient from 4.8 mg/kg group was not evaluated because of rapid deterioration of general condition. An objective partial tumor response was observed in 43 patients. A166 showed activity at 3.6 mg/kg, and a dose-response effect was observed with more partial responses in patients treated at 4.8 mg/kg or higher. The doses of 4.8 mg/kg and 6.0 mg/kg A166 were chosen for further investigation in the dose expansion part. At the time of the data cutoff, the median treatment duration was 6.3 months (range, 1.4-34.3) in 4.8 mg/kg cohort and 5.4 months (range, 1.4-23.3) in 6.0 mg/kg cohort, and the median duration of follow-up was 20.3 months (range, 1.9-34.4) in 4.8 mg/kg cohort and 14.8 months (range, 3.1-28.4) in 6.0 mg/kg cohort.

In this phase I trial, for 58 HER2-positive breast cancer patients treated at 4.8 or 6.0 mg/kg (Table 3), ORR was 70.7% (41/58, 95% CI, 57.3–81.9) and DCR was 81.0% (47/58, 95% CI, 68.6–90.1). The waterfall, swimmer, and spider plots of tumor burden alteration over time for each patient are shown in Figures 2A, 2B, and 2C, respectively. Seventeen of 23 patients (17/23, 73.9%, 95% CI, 51.6-89.8) achieved a response in 4.8 mg/kg cohort, whereas 24 of 35 patients (24/35, 68.6%, 95% CI, 50.7-83.2) achieved a response in 6.0 mg/kg cohort. Median PFS was 12.3 months (95% CI, 6.0–not reached) in 4.8 mg/kg cohort and 9.4 months (95% CI, 4.0-10.4) in 6.0 mg/kg cohort.

Among patients who showed a response, one patient (4.8 mg/kg) with a diagnosis of hormone receptor-negative, HER2-positive breast cancer and lymph node metastasis showed a duration of response lasting approximately 2 years, and the treatment is still continuing. After six cycles of therapy, the CT scan revealed that the target lesion completely disappeared (Figure S1).

This was the first-in-human clinical study in China of A166, a HER2-targeted ADC harboring a microtubule inhibitor payload, in patients with advanced solid tumors, mostly metastatic breast cancer. A significant advantage of A166 is its excellent stability in the circulation. The design of A166 includes the highly stable valine citrulline linker, which reduces the exposure to free payload. The C_max and AUC of Duo-5 was about 0.1% and 0.2% of those of total A166 (ADC) on a molar basis, respectively. The lower C_max of free Duo-5, compared with the payloads of T-DM1 and DS-8201 (Table S2), suggested that A166 was highly stable in the systemic circulation.^12,13As expected, compared to other approved ADCs for breast cancer, exceptionally fewer systemic AEs often associated with chemotherapy drugs were observed in this study, such as gastrointestinal and hematological toxicities (Table S3).^14-16

The most common TRAEs with A166 were ocular AEs, which were manageable. Ocular AEs were dose-related with one grade 2 AE in only one patient (7.7%, table 2) when dosed at 2.4 mg/kg and lower. Fortunately, all ocular AEs were reversible and occurred approximately after cycle 2, and most were grade 1 or 2, which were easy to clinically diagnose and to assess severity through protocol-assigned eye examinations. During the trial, we followed the optimized management algorithm created by the ocular AEs special task force. Patients received artificial tears prophylactically, while ocular lubricants and eyedrops with bovine serum or topical steroids were only applied during the non-DLT observation period, according to ophthalmologist’s discretion, depending on the occurrence or grading of epitheliopathy. Treatment delay and dose reduction were used for grade 3 or 4 ocular AEs. In addition, unplanned visits were encouraged in the protocol in case ocular symptoms appeared or deteriorated. Using this strategy, A166 induced corneal epitheliopathy was generally well managed and reversible in our patients (Figure S2), which was further supported by a report in American patients by Sharma et al.¹⁷ As previously reported, ocular surface AEs occurred more often in ADCs with auristatin-F or maytansinoid DM4 as the payload (i.e., Belantamab mafodotin) and conventional tubulin-binding chemotherapeutic agents (i.e., docetaxel and paclitaxel).^18-23 In our trial, the percentages of ocular AEs of grade 1, 2, 3, 4 and 5 at the most severity in 4.8 mg/kg cohort were 33.3%, 22.2%, 44.4%, 0% and 0%, respectively, which is in the similar range to the corresponding 8%, 17%, 45%, 1% and 0% reported for FDA-approved 2.5 mg/kg Belantamab mafodotin for 95 patients with multiple myeloma.²⁴ However, we didn’t observe any grade 4 ocular AE，corneal perforation or blindness. We are now still taking proactive measures to optimize prophylaxis, treatment and surveillance for ocular AE and exploring the complex underlying mechanisms.^24-26

Another significant advantage of A166 was its strong antitumor activity. We found that in the 4.8 mg/kg group, A166 showed encouraging anti-tumor activity in heavily pretreated HER2-positive metastatic breast cancer with an ORR of as high as 73.9% and median PFS of longer than 12 months, which was equal to or higher than those of currently available HER2-directed regimens and new agents under development. Importantly, the anti-tumor activity was also observed in sub-group of patients who had been pre-treated with T-DM1, trastuzumab, HER2-TKI, or both trastuzumab and HER2-TKI. Both ORR and PFS were numerically higher at 4.8 mg/kg than 6.0 mg/kg (ORR, 73.9% vs. 68.6%, respectively, PFS, 12.3 vs. 9.4 months, respectively), justifying that 4.8 mg/kg dose was selected as recommended phase II dose for the A166 pivotal phase II study (CTR20212088).

A166 has promising antitumor activity in HER2-positive breast cancer patients at 4.8 mg/kg with manageable toxicity, which led to governmental approval of a pivotal phase II registration trial in HER2-positive patients who have progressed on at least two prior lines of anti-HER2 therapies. Several ongoing studies are investigating the efficacy and safety of A166 in different HER2-expressing solid tumor types, including HER2-low breast cancer, NSCLC (CTR20210516), and urothelial carcinoma (CTR20211319). These studies will enhance our understanding of A166 efficacy and safety in various settings.

Data availability

All data relevant to the manuscript are contained within the main and supplemental text. Source/raw data are available upon request.

Declaration of Interest Statement

Jian Zhang, Rujiao Liu, Shuiping Gao, Wenhua Li, Yang Chen, Yanchun Meng, Chang Liu, Wenyue Jin, Xichun Hu: No potential conflicts of interest. Shuli Yi, Yan Qing, Junyou Ge: employment with Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.

Sponsor

This study was sponsored by the Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.

Grant support

This work was supported in part by a grant from the National Natural Science Foundation of China (grant no. 82072915) and the Project of the Shanghai Municipal Health Commission (grant no. 202140397).

Acknowledgements

The authors thank all the patients who agreed to participate in this study. The authors also thank Yan Qing, Shuli Yi, Juanjuan Yuan, Hong Chen, Bin Fan, Haochuan Zheng, Lin Zhu, Zhijiao Qiao and Junyou Ge from Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd (China) for their professional assistance with manuscript preparation.

Author Contributions Section

Conception and design: Xichun Hu and Jian Zhang
Data collection and assembly: All authors
Data analysis and interpretation: Jian Zhang, Rujiao Liu, and Xichun Hu
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

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FigureS1.jpg
Figure S1. One partial response with tumor shrinkage at 4.8 mg/kg after six cycles of treatment (B) compared to baseline (A).
FigureS2.tif
Figure S2. Corneal epitheliopathy (%) over time.
TableS1.docx
Table S1. Pharmacokinetic Properties of A166 ADC, Total Antibody and Duo-5
TableS2.docx
Table S2. The Exposure of ADC and Free Payload of A166 Compared to T-MD1 and DS-8201
TableS3.docx
Table S3. Comparison of Toxicity between A166 and Other ADC Drugs in Breast Cancer

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Phase I Study of A166, a Novel Antibody-Drug Conjugate in Advanced HER2-expressing Solid Tumors

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