Dataset Information

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.

ABSTRACT:

Background

Current treatment options for human epidermal growth factor receptor 2 (HER2)-overexpressing gastric cancer at third-line have shown limited clinical benefit. Further, there is no specific treatment for HER2 immunohistochemistry (IHC) 2+ and fluorescence in-situ hybridization-negative patients. Here, we report the efficacy and safety of a novel anti-HER2 antibody RC48 for patients with HER2-overexpressing, advanced gastric or gastroesophageal junction cancer.

Methods

Patients with HER2-overexpressing (IHC 2+ or 3+), locally advanced or metastatic gastric or gastroesophageal junction cancer who were under at least second-line therapy were eligible and received RC48 2.5 mg/kg alone every 2 weeks. The primary endpoint was the objective response rate (ORR) assessed by an independent review committee. Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, time to progression, disease control rate, and safety.

Results

Of 179 patients screened, 125 were eligible and received RC48 treatment. The ORR was 24.8% (95% confidence interval [CI]: 17.5%-33.3%). The median PFS and OS were 4.1 months (95% CI: 3.7-4.9 months) and 7.9 months (95% CI: 6.7-9.9 months), respectively. The most frequently reported adverse events were decreased white blood cell count (53.6%), asthenia (53.6%), hair loss (53.6%), decreased neutrophil count (52.0%), anemia (49.6%), and increased aspartate aminotransferase level (43.2%). Serious adverse events (SAEs) occurred in 45 (36.0%) patients, and RC48-related SAEs were mainly decreased neutrophil count (3.2%). Seven patients had adverse events that led to death were not RC48-related.

Conclusions

RC48 showed promising activity with manageable safety, suggesting potential application in patients with HER2-overexpressing, advanced gastric or gastroesophageal junction cancer who have previously received at least two lines of chemotherapy.

SUBMITTER: Peng Z

PROVIDER: S-EPMC8626607 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:On September 22, 2017, the U.S. Food and Drug Administration (FDA) granted accelerated approval for pembrolizumab (Keytruda, Merck & Co., Inc., Whitehouse Station, NJ) for the treatment of patients with recurrent, locally advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after two or more systemic therapies, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy, and whose tumors express programmed death-ligand 1 (PD-L1), as determined by an FDA-approved test. Approval was based on demonstration of durable overall response rate (ORR) in a multicenter, open-label, multicohort trial (KEYNOTE-059/Cohort 1) that enrolled 259 patients with locally advanced or metastatic gastric or GEJ adenocarcinoma. Among the 55% (n = 143) of patients whose tumors expressed PD-L1 based on a combined positive score ?1 and either were microsatellite stable or had undetermined microsatellite instability or mismatch repair status, the confirmed ORR as determined by blinded independent central review was 13.3% (95% CI, 8.2-20.0); 1.4% had complete responses. Response durations ranged from 2.8+ to 19.4+ months; 11 patients (58%) had response durations of 6 months or longer, and 5 patients (26%) had response durations of 12 months or longer. The most common (?20%) adverse reactions of pembrolizumab observed in KEYNOTE-059/Cohort 1 were fatigue, decreased appetite, nausea, and constipation. The most frequent (?2%) serious adverse drug reactions were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. Pembrolizumab was approved concurrently with the PD-L1 immunohistochemistry 22C3 pharmDx test (Dako, Agilent, Santa Clara, CA) for selection of patients with gastric cancer for treatment with pembrolizumab based on PD-L1 tumor expression. IMPLICATIONS FOR PRACTICE: This report presents key information on the basis for Food and Drug Administration approval of pembrolizumab for the treatment of patients with locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1. The report discusses the basis for limiting the indication to patients with PD-L1-expressing tumors and the basis for recommending that PD-L1 status be assessed using a fresh tumor specimen if PD-L1 expression is not detected in an archival gastric or GEJ cancer specimen.

Project description:BackgroundThe addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer.MethodsEligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enrolled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m2 docetaxel, 80 mg/m2 oxaliplatin, 200 mg/m2 calcium levofolinate, 2600 mg/m2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by 4 cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate.ResultsThirty-two patients were enrolled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-one (96.9%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8%-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 16 (55.2%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2%-89.2%), 78.8% (95% CI, 65.1%-95.5%), and 70.9% (95% CI, 54.8%-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3%-93.1%) and 96.9% (95% CI, 84.3%-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status.ConclusionsThe study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.

Project description:Background Nivolumab combined with chemotherapy has been shown to improve prognosis in patients with untreated, human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer (GC) and programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥5. However, the available first-line treatment options for advanced GC are limited. Analysis of efficacy and safety of other programmed cell death protein 1 (PD-1) antibodies combined with chemotherapy may provide alternative treatment options. Methods This retrospective study included patients with untreated, HER2-negative, unresectable locally advanced, or metastatic GC or gastroesophageal junction (GEJ) cancer who received either camrelizumab combined with oxaliplatin plus S-1 (SOX)/capecitabine plus oxaliplatin (CapeOX) or SOX/CapOX alone between November 2020 and April 2022. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety were evaluated. Results This study included 49 patients in camrelizumab plus chemotherapy group and 54 in chemotherapy group. The baseline clinical characteristics beyond Epstein-Barr virus (EBV) status and PD-L1 CPS had no difference between combination group and chemotherapy group. ORR and DCR were significantly higher in combination therapy group than in chemotherapy group (59.18% vs. 38.89%, P=0.048; 83.67% vs. 62.96%, P=0.018). The median PFS in combination group was significantly longer than chemotherapy group [10.03 vs. 6.24 months, hazard ratio (HR) 0.603, 95% confidence interval (CI): 0.368–0.989, P=0.045]. The OS was not mature at the time of the OS analysis, with 40% patients died. Subgroup analyses showed that PFS was longer in patients with PD-L1 CPS ≥1 compared with CPS <1 and in patients with a neutrophil-lymphocyte ratio (NLR) <2.38 compared with ≥2.38. The most common grade 3–4 treatment-related adverse events (TRAEs) were granulocytopenia (57% in combination group vs. 54% in chemotherapy group), anemia (39% vs. 33%, respectively), and thrombocytopenia (39% vs. 33%, respectively). The proportion of reactive cutaneous capillary endothelial proliferation (RCCEP, 73% vs. 0%) was higher in combination group relative to chemotherapy group; all were grades 1–2. Conclusions Among patients treated with camrelizumab combined with chemotherapy, the clinical outcomes were superior to those patients treated with chemotherapy. However, these promising findings need to be confirmed in future clinical trials.