Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single-arm phase II study

2.1 Study design and participants

This study is a single-arm, open-labeled, phase II trial carried out at 31 academic hospitals or cancer centers in China. Eligible patients were at least 18 years old with a life expectancy of more than 12 weeks; histologically confirmed, locally advanced or metastatic GC or GEJA; an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; at least one unresectable, measurable tumor lesion according to the Response Evaluation Criteria In Solid Tumors (RECIST version 1.1); adaptable function of the heart, liver, and kidney; and documented histologically confirmed HER2 overexpression (defined as IHC 3+ or 2+). Main exclusion criteria included carcinomatous meningitis or untreated central nervous system metastases. Patients who had received the following treatments within 4 weeks before enrolment were not eligible: chemotherapy (6 weeks of nitrosourea and mitomycin C, 2 weeks of oral 5-fluorouracil); radiotherapy (2 weeks of palliative local radiotherapy for bone metastases); targeted treatment; immunotherapy; traditional Chinese medicine treatment (if the instructions clearly mentioned anti-tumor effect); T-DM1 or participated in clinical studies of ADCs; any clinical investigational drug; a major surgery; any live vaccine (or had any vaccine planned to be received during the study). The study protocol was approved by a relevant institutional review board or ethics committee at each study center. This study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent before enrolment.

2.2 Procedures

All eligible patients received 2.5 mg/kg of RC48 (RemeGen, Yantai, Shandong, China) alone by intravenous infusion during 30-90 min (60 min is recommended) every two weeks. Computed tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis was performed at baseline (within 28 days before RC48 treatment initiation) and every six weeks afterwards for the evaluation of tumor response by an independent review committee (IRC) using RECIST version 1.1. Patients remained on the study until withdrawal for progressive disease (PD), intolerable adverse events (AEs), death, withdrawal of consent, loss to follow-up, or for other reasons at the discretion of the investigator. Dose interruptions and reductions were permitted to manage AEs (Supplementary Table S1).

Safety assessments were performed at each study visit. All AEs were monitored and graded according to the Common Terminology Criteria for Adverse Events version 4.03. The last safety monitoring was performed on day 28 after the last treatment.

2.3 Outcomes

The primary endpoint of this study was the proportion of patients achieving an IRC confirmed objective response, defined as a complete response (CR) or partial response (PR), according to RECIST version 1.1. The ORR was based on the best overall response. The secondary endpoints were ORR assessed by investigators, progression-free survival (PFS; the period from the first study dose until disease progression or death, whichever occurred first), OS (the time from the first dose until death or loss to follow-up), duration of response (DOR; the time from the first documentation of objective response to the first documentation of disease progression or death), time to progression (TTP; the time from the date of the first dose to the first documentation of disease progression assessed by IRC or death from tumor progression), disease control rate (DCR; the proportion of patients with CR, PR, or stable disease [SD]), and safety. Toxicity was assessed by using National Cancer Institute-Common Toxicity Criteria for Adverse Events version 4.03.

2.4 Statistical analyses

The sample size was estimated based on an assumed ORR of 20% among patients who failed at least two systemic treatments. This study was designed to have at least 85% power at a one-sided significance level of 2.5% to reject the null hypothesis of a proportion of patients with an ORR of 10% or less in this population. Considering an assumed drop-out rate of 10%, we planned to recruit 125 patients. The proportion of patients achieving an objective response or disease control was calculated during the study, and 95% confidence intervals (CIs) were calculated by using the Clopper-Pearson method. The Kaplan-Meier method was used to calculate PFS and OS and plot survival curves. The median survival was calculated according to the curve, and the 95% CI was estimated via the Greenwood formula [20]. Fisher's exact test was used to compare ORR between subgroups. OS and PFS in each subgroup were compared using log-rank tests. All statistical analyses were two-sided, and P < 0.05 was considered statistically significant. SAS version 9.2 (SAS Institute Inc., Cary, NC, USA) was used for statistical analyses.

3.1 Patients

Between July 10, 2018, and December 6, 2019, 179 patients were assessed, of whom 125 patients were found eligible for this study and treated with at least one dose of RC48. As of November 20, 2020, one patient (0.8%) continued to receive RC48 treatment. The most common reasons for treatment termination were disease progression (76 patients, 60.8%) and AEs (16 patients, 12.8%; Figure 1).

As of November 20, 2020, 125 patients were included in the full analysis set, and the 12-month follow-up data were collected. Their baseline characteristics are shown in Table 1. The median treatment duration was 12.0 weeks (range, 2.0-38.0 weeks), and the median follow-up was 7.6 months (range, 0.8-23.7 months). Among the 125 patients, 97 (77.6%) had GC, and 28 (22.4%) had GEJA; 59 (47.2%) had received three or more lines of treatment in the past. Most of the patients were in poor condition, and only 29 (23.2%) had an ECOG performance status of 0 (Table 1).

3.2 Efficacy

All 125 patients were treated with RC48 at 2.5 mg/kg alone. The overall ORR assessed by the IRC was 24.8% (95% CI: 17.5%-33.3%). The median DOR was 4.7 months (95% CI: 3.4-6.9 months; Supplementary Figure S1), and the DCR was 42.4% (95% CI: 33.6%-51.6%; Table 2, Figure 2).

PFS and TTP were calculated based on the IRC assessment. As of November 20, 2020, 107 patients (85.6%) reported disease progression or died. The median PFS was 4.1 months (95% CI: 3.7-4.9 months), and the 6-month PFS rate was 26.2% (Table 2, Figure 3A). TTP events such as disease progression or death due to progression were seen in 87 patients (69.6%), with a median TTP of 4.2 months (95% CI: 3.9-5.4 months; Table 2). Nighty-seven patients (77.6%) died, with a median OS of 7.9 months (95% CI: 6.7-9.9 months) and a 1-year survival rate of 33.3% (95% CI: 25.0%-41.9%; Table 2, Figure 3B).

Subgroup analysis was conducted according to age, ECOG performance status, primary site, tumor burden, number of metastatic sites, HER2 status, previous trastuzumab treatment, previous taxane treatment, and number of previous lines of therapy. The patients over 65 years old showed significantly prolonged PFS than younger patients (P = 0.044), whereas no other subgroups showed significant benefits in their ORR, PFS, or OS results (Supplementary Tables S2-S3 and Supplementary Figure S2).

3.3 Safety

Adverse events are summarized in Table 3. All patients reported at least one AE. The most common AEs included decreased white blood cell (WBC) count (53.6%), asthenia (53.6%), hair loss (53.6%), decreased neutrophil count (52.0%), anemia (49.6%), and increased aspartate aminotransferase levels (AST; 43.2%). Grade 3-5 RC48-related AEs (Supplementary Table S4) were observed in 40 patients (32.0%), of which the most common were decreased neutrophil count (14.4%), decreased WBC count (14.4%), and anemia (5.6%).

Indeed, in this study, hematological abnormalities were the commonest AEs. The rates of decreased WBC count and neutrophil count, and anemia were all over 40%. Abnormal liver function was also common, mainly manifested by increased AST (43.2%) and alanine aminotransferase levels (32.0%) and were predominantly grade 1 or 2 (Table 3). Grade 3 and 4 abnormal blood electrolyte levels were also reported, including in 8 patients (6.4%) with hyponatremia and 7 (5.6%) with hypokalemia. Serious adverse events (SAEs) were observed in 45 patients (36.0%), including intestinal obstruction in 7 patients (5.6%), upper gastrointestinal bleeding in 5 patients (4.0%), decreased neutrophil count in 4 patients (3.2%), and liver function abnormality in 3 patients (2.4%). Regarding intestinal obstruction, the commonest SAE, 4 cases were of grade 2, 2 were of grade 3, and the grade was not reported in 1 case. RC48-related SAEs were observed in 20 patients (16.0%) and manifested mainly as decreased neutrophil count (3.2%). AEs that resulted in dose interruption, drug suspension, or discontinuation were observed in 13 (10.2%), 63 (50.4%), and 18 (14.4%) patients, respectively. Seven patients (4.7%) died during the study, which were not related to RC48 (Supplementary Table S5).

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

The clinical trial protocol was approved by the institutional review board of each center. Each subject provided written informed consent before enrollment.

CONSENT FOR PUBLICATION

Not applicable.

DATA SHARING

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

AUTHORS' CONTRIBUTIONS

LS and YB designed the trial, wrote the protocol, and coordinated the study. ZP, TL, JW, AW, YH, LY, XZ, NF, SL, ZL, KG, JL, JX, QF, RX, LZ, EL, YS, GY, CB, YL, JZ, JY, XL, NX, CG, YS, DM, GD, SL, and TD enrolled patients. JF managed, analyzed, and interpreted the data. ZP, TL, and JW drafted the manuscript. All authors reviewed and revised the paper, and approved the submitted version.