HER2 Bispecific Anbenitamab Improves Outcomes vs Chemo in Gastric Cancer

Anbenitamab (KN026), a novel HER2-targeted bispecific antibody, demonstrated superior progression-free survival (PFS) and overall survival (OS) outcomes when added to chemotherapy in patients with previously treated gastric or gastroesophageal junction (GEJ) cancer, according to findings from the KC-WISE/KN026-001 trial (NCT05427383) presented at the 2025 European Society for Medical Oncology Congress.¹

In the phase 2/3 trial, anbenitamab plus chemotherapy resulted in a 75% reduction in risk of progression or death and a 71% reduction in risk of death vs chemotherapy alone. Additionally, it was well tolerated without added cardiac toxicity.

“The KC-WISE study demonstrates that for patients with HER2-positive gastric or GEJ adenocarcinoma who have progressed on prior trastuzumab (Herceptin)-based therapy, anbenitamab in combination with chemotherapy provides significant and clinically meaningful benefits,” said Jianming Xu, MD, professor at the Fifth Medical Center, Chinese PLA General Hospital, in Beijing, China, in his presentation.

Anbenitamab is a bispecific antibody that binds 2 distinct domains of HER2. Xu cited the need for additional treatment as many patients treated with trastuzumab, chemotherapy, and immunotherapy experience progression within 1 year.

The multicenter, double-blind study randomly assigned 188 patients to receive anbenitamab plus chemotherapy or chemotherapy alone. The coprimary end points were PFS by independent review committee (IRC) and OS.

All patients in the trial were Chinese. The median age of patients was 64 in the anbenitamab arm and was 61 in the control arm, and the majority in both arms were male. In the anbenitamab arm, 84.2% had an ECOG performance status of 1 compared with 80.6% in the control arm, with the rest having a performance status of 0. The majority had gastric rather than GEJ cancer and had a HER2 status of 3 or greater by immunohistochemistry.

All 95 patients in the anbenitamab arm had stage IVB disease whereas 89 of 93 in the control arm did; 2 each had stage III and IVA disease. All patients had metastatic disease, with 24.2% having metastases in at least 3 organs in the anbenitamab arm compared with 36.6% in the control arm. Liver metastases were present in 56.8% of the anbenitamab arm compared with 51.6% in the control arm.

In terms of prior treatment, 15.8% and 17.2% of the respective experimental and control arms had received 2 or more prior lines of therapy. Immunotherapy had been given in 54.7% of the anbenitamab arm and 60.2% of the control arm, and irinotecan was used as chemotherapy in 28.4% of the anbenitamab arm and 29.0% of the control arm, with the rest receiving a taxane (paclitaxel or docetaxel).

At data cutoff of April 3, 2025, the median PFS was 7.1 months with anbenitamab plus chemotherapy vs 2.7 months with chemotherapy alone (HR, 0.25; 95% CI%, 0.17-0.39; P = 5.44 10^-12). The respective PFS rates were 54.0% vs 11.8% at 6 months, 38.8% vs 3.9% at 9 months, and 23.8% vs 0% at 12 months.

The median OS was also significantly improved at 19.6 months vs 11.5 months, respectively (HR, 0.29; 95% CI, 0.17-0.50; P = 1.56 10^-6). At 6 months, 94.9% of patients receiving anbenitamab plus chemotherapy were alive vs 67.7% with chemotherapy; at 12 months the rate was 79.1% vs 48.0%, at 18 months it was 66.4% vs 27.9%, and at 24 months it was 47.3% vs not estimable, respectively.

According to Xu, PFS and OS benefits were consistent across prespecified subgroups including combined chemotherapy type, HER2 expression, number of previous therapies, and number of metastatic organs with an HR below 0.5 favoring anbenitamab plus chemotherapy in most groups.

The secondary end points also favored the anbenitamab arm. The overall response rate by IRC was 55.8% for anbenitamab plus chemotherapy vs 10.8% for chemotherapy alone, with similar investigator-assessed rates of 49.5% vs 16.1%, respectively. The disease control rate was 80.0% vs 41.9% by IRC and 84.2% vs 45.2% by investigator assessment. Median duration of response by IRC was 8.2 months with anbenitamab vs 2.9 months with chemotherapy alone and by investigator assessment was 8.3 months vs 2.9 months, respectively.

Patients treated with anbenitamab plus chemotherapy received a median of 6.5 cycles whereas those receiving chemotherapy alone received a median of 3.0 cycles. Treatment-emergent adverse events (TEAEs) were reported in 96.8% of the anbenitamab arm and 96.8% of the control arm; 60.6% reported TEAEs of grade 3 or higher with anbenitamab plus chemotherapy vs 51.6% with chemotherapy alone.

TEAEs leading to dose reduction occurred in 43.6% in the anbenitamab arm vs 31.2% in the control arm, and TEAEs leading to treatment interruption occurred in 56.4% vs 40.9%, respectively. TEAEs that led to treatment discontinuation were reported in 10.6% with anbenitamab vs 3.2% with chemotherapy alone. One TEAE leading to death was reported in the experimental arm which was related to disease progression and not treatment; there were also 8 TEAEs leading to death in the control arm.

The most common treatment-related adverse events (TRAEs) with anbenitamab were hematologic toxicities including anemia (66.0%), leukopenia (58.5), and neutropenia (52.1) as well as diarrhea (48.9%). Cardiac toxicity, which was an adverse event of special interest, was 3.2% in the anbenitamab plus chemotherapy arm vs 3.2% with chemotherapy alone.

In the post-presentation discussion, chairs Sarah Derks, MD, of Amsterdam UMC in the Netherlands, and Filippo Pietrantonio, MD, of Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, discussed the choice of control arm of single-agent irinotecan or taxane chemotherapy and commented that ramucirumab (Cyramza) plus chemotherapy is a current standard of care. Additionally, they noted that data from earlier this year supported the use of trastuzumab deruxtecan (Enhertu) in patients previously treated with trastuzumab, and suggested that the very favorable HRs for anbenitamab justify trials comparing it to other agents in this setting.

“Collectively, these results strongly suggest that anbenitamab plus chemotherapy represents a new and valuable treatment option for this patient population in the second-line and later-line settings,” concluded Xu.

REFERENCE:

1. Xu J, Zhao J, Liu Y, et al. Anbenitamab in combination with chemotherapy for previously treated HER2 positive gastric or gastroesophageal junction carcinomas (GC/GEJC): interim analysis of KC-WISE. Presented at: ESMO 2025 Congress; October 17–20, 2025; Berlin, Germany. Abstract LBA78.