Trastuzumab Combo Shows ‘Noteworthy’ Activity in HER2+ Gastric/GEJ Cancer

"The results of the [phase 1b/2] HER-RAM study [NCT04888663] demonstrated noteworthy antitumor activity of trastuzumab combined with ramucirumab and paclitaxel in previously treated patients with HER2-positive [gastric or] GEJ cancer," according to the study authors.

A second-line combination of trastuzumab (Herceptin) plus ramucirumab (Cyramza) and paclitaxel showed meaningful clinical activity in the phase 1b/2 HER-RAM study (NCT04888663) among patients with HER2-positive gastric or gastroesophageal junction (GEJ) cancer, according to findings published in the Journal of Clinical Oncology.

The objective response rate (ORR) was 54.0% (n = 27; 95% CI, 39.3%-68.2%), which included a single complete response (CR). The disease control rate (DCR) was 96.0% (95% CI, 86.3%-99.5%). Investigators compared these outcomes with results reported in 131 patients in the KCSG-ST19-16 study (NCT04192734), in which treatment consisted of ramucirumab and paclitaxel alone. The ORR and DCR in these patients was 29.0% (95% CI, 21.4%-37.6%) and 78.6% (95% CI, 70.6%-85.3%), respectively.

The median progression-free survival (PFS) in the HER-RAM study was 7.1 months (95% CI, 4.8-9.4), and the median overall survival (OS) was 13.6 months (95% CI, 9.4 to 17.7). In the KCSG-ST19-16 study, median PFS was 4.7 months (P = .019), and median OS was 9.8 months (P = .063).

“Although trastuzumab plus chemotherapy is the recommended first-line treatment for HER2-positive [gastric or] GEJ cancer, ramucirumab plus paclitaxel has been primarily used as second-line therapy regardless of HER2 expression, necessitating investigation of the implication regarding continuous HER2 inhibition after the failure of first-line treatment,” the investigators wrote. “The results of the HER-RAM study demonstrated noteworthy antitumor activity of trastuzumab combined with ramucirumab and paclitaxel in previously treated patients with HER2-positive [gastric or] GEJ cancer.”

Investigators of the open-label trial enrolled and treated 50 patients at 5 Korean hospitals between February 2018 and March 2021. Patients had a median age of 60 years (range, 29-82). Most were male (80%), had an ECOG performance status of 0 (60%), and had primary gastric cancer at enrollment (94%).

In the first line, all patients received trastuzumab in combination with fluoropyrimidine and platinum. The median follow-up was 27.5 months (95% CI, 17.4-37.6). Data cutoff was September 7, 2021.

Additionally, most patients did not have a prior gastrectomy (54%). Most had only a single metastatic site (54%), and peritoneal metastasis (56%). Liver metastasis affected 36% of patients.

Patients received ramucirumab first as an intravenous infusion lasting approximately 60 minutes, with a maximum infusion rate of 25 mg/min. They then received trastuzumab as an intravenous infusion at a loading dose of 4 mg/kg on the first day of the first cycle, and subsequently at a dose of 2 mg/kg. They also received an intravenous infusion of paclitaxel on days 1, 8, and 15 of the 28-day cycle.

The primary end point in the phase 2 portion was PFS, and the secondary end points included ORR and DCR according to RECIST v1.1 criteria. Investigators also assessed OS, time to response, duration of response (DOR), and safety as secondary end points.

Other reported findings from the HER-RAM study included a 1-year OS rate of 55.3% (95% CI, 41.1%-69.5%). Additionally, the median time to response was 1.4 months (range, 1-4.1) among responders. Two patients had progressive disease at first evaluation. Tumor shrinkage occurred in 84% of patients. At data cutoff, an ongoing CR persisted in 1 patient, and the DOR was 6.7 months (95% CI, 1.5-11.9).

Treatment-related adverse effects (TRAEs) of grade 3 or 4 occurred in 70% of patients. The most common TRAEs of any grade were neutropenia (64%), peripheral sensory neuropathy (32%), anorexia (32%), and anemia (30%). The most common TRAE of grade 3/4 was neutropenia (52%).

“Our findings show that HER2 remains an actionable therapeutic target after progression on first-line therapy in HER2-positive [gastric or] GEJ cancer. The clinical benefits of combined blockade of HER2 and angiogenic pathways should be explored in the future, emphasizing the implications of HER2 heterogeneity and dynamics in advanced [gastric or] GEJ cancer,” the investigators concluded. “Additionally, the results of future studies should be interpreted in the context of ongoing investigations of novel anti-HER2 agents.”

Reference

Kim CG, Jung M, Kim HS, et al. Trastuzumab combined with ramucirumab and paclitaxel in patients with previously treated human epidermal growth factor receptor 2-positive advanced gastric or gastroesophageal junction cancer. J Clin Oncol. Published online June 26, 2023. doi:10.1200/JCO.22.02122