Anti-HER-2/neu vaccine may benefit gastric cancer patients

In patients with HER-2-overexpressing metastatic or advanced gastric/gastroesophageal (G/GEJ) adenocarcinoma, a regimen comprising standard-of-care chemotherapy and a HER2-targeting peptide vaccine induced antibody responses that corresponded with tumour size reduction, according to an analysis of the HERIZON study which looked into the correlation between antibody responses and clinical outcomes.

“HER-Vaxx is a B-cell peptide-based anti-HER-2/neu vaccine comprising trastuzumab’s binding site,” said the researchers. [Clin Cancer Res 2021;27:3649‐3660; BMC Cancer 2017;17:118] In the phase Ib HERIZON trial, this vaccine has been shown to be safe and to deliver a progression-free survival benefit in patients with Her2/neu-overexpressing G/GEJ cancer. [Cancer Research 2021;81:CT107]

In the current phase II trial, researchers sought to evaluate antibody and clinical responses to the vaccine when added to chemotherapy in patients with stage III/IV HER-2-overexpressing GC that is naïve to HER2/neu therapy. Thirty-six patients (median age 66 years) were randomized 1:1 to receive standard chemotherapy with or without the anti-HER-2/neu vaccine. [ESMO GI 2023, abstract PD-8]

The vaccine was administered intramuscularly at a dose of 50 µg at days 0, 14, 35, and 77, followed by a booster dose every 63 days until disease progression. Chemo was started at day 0 and repeated every 21 days for a maximum of six cycles. The chemo regimen used was either oxaliplatin plus capecitabine or cisplatin plus fluorouracil or capecitabine.

After ≥3 vaccinations, the vaccine-chemo regimen induced significant levels of HER-2/neu-specific IgG and IgG1 (p<0.001 for both) at all timepoints. Among those who only received chemotherapy, there was no specific induction of anti-HER-2/neu antibodies.

The levels of specific IgG (p=0.001) and IgG1 (p=0.016) antibodies inversely correlated with tumour diameters.

In the vaccine arm, no significant correlation was observed between the antitumour effect and antibody responses (p=0.082 for IgG2, p=0.153 for IgG3, and p=0.236 for IgG4).

Overall survival, safety data

There was a significant survival benefit with the vaccine-chemo regimen as opposed to chemo alone (median overall survival, 14.0 vs 8.3 months; hazard ratio, 0.558, two-sided 80 percent confidence interval, 0.349–0.895; p_one-sided=0.054). Duration of response was longer with vaccine-chemo compared with chemo only (30 vs 19 weeks).

There were similar incidences of grade ≥3 treatment-emergent adverse events (TEAEs) between the vaccine-chemo and chemo-alone arms (42 percent for both). Four patients in the chemo-only arm discontinued treatment owing to TEAEs; in the vaccine-chemo arm, the corresponding number was two.

Each treatment arm had a grade 5 event – COVID infection (vaccine-chemo arm) and respiratory failure (chemo-only arm). AEs were mostly mild, with only five grade ≥3 AEs reported in each arm.

Important cancer treatment target

HER-2/neu is a member of the EGFR family that is overexpressed in 6–30 percent of gastric cancers. “It is one of the most important targets in human malignancies,” the researchers noted.

Taken together, in patients with HER-2/neu overexpressing gastric cancer, the anti-HER-2/neu vaccine produced robust anti-HER-2 IgG and IgG1 subclass antibody responses and the magnitude of these antibody responses correlated with tumour reduction, the researchers said.

“The present data, its previously shown favourable safety profile, and the improved OS data … validate the proof of concept for a first-in-class B-cell immunotherapy based on HER-2/neu peptides,” they concluded.