Progress in HER2-Positive Gastroesophageal Adenocarcinoma

After a period of relative inactivity, therapeutic development in HER2-positive gastroesophageal adenocarcinoma (GEA) has evolved rapidly over the past 5 years, establishing a new standard of care that was supplanted by another earlier this year.

In the phase III HERIZON-GEA-01 trial, the bispecific antibody zanidatamab (Ziihera) plus chemotherapy significantly improved progression-free survival (PFS) and overall survival (OS) versus trastuzumab and chemotherapy as first-line treatment for metastatic HER2-positive GEA. Adding the PD-1 inhibitor tislelizumab (Tevimbra) to zanidatamab and chemotherapy also outperformed the anti-HER2 antibody and chemotherapy.

The zanidatamab combinations took the first-line handoff from pembrolizumab (Keytruda) plus trastuzumab and chemotherapy, established as the first-line standard in the KEYNOTE-811 trial. However, a subgroup analysis of KEYNOTE-811 showed that the benefit owed almost entirely to patients with PD-L1-expressing tumors, as well as evidence of potential harm in the PD-L1-negative subgroup.

Prior to KEYNOTE-811, the GEA field had gone through a prolonged dry spell without therapeutic advances, said John Strickler, MD, of Duke University Medical Center in Durham, North Carolina, at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO-GI) — since 2010 to be precise, when the randomized phase III ToGA trial showed that adding trastuzumab to chemotherapy significantly improved OS versus chemotherapy alone in HER2-positive gastric cancer.

“So, the last 5 years have been very exciting for drug development in the gastroesophageal space,” said Strickler.

Trail to Success

Approximately 15-20% of GEAs are HER2-positive, he noted. The cancers arise more often in the esophagus or gastroesophageal junction, and HER2 expression often occurs in association with PD-L1 expression, “which may explain why immunotherapies are so active for this group of patients,” he said.

The emergence of more effective therapies for GEA has made testing for HER2 expression an essential component of treatment. Every patient with metastatic GEA should undergo HER2 testing with immunohistochemistry (IHC) at diagnosis, said Strickler. IHC alone is sufficient for 3+ expression (overexpression), whereas cancers with intermediate or HER2+ results should also be assessed by fluorescence in situ hybridization.

The recent FDA approval of zanidatamab plus tislelizumab and chemotherapy for unresectable/metastatic GEA codified the HERIZON-GEA-01 regimen as the current first-line standard of care for unresectable/metastatic GEA.

The search for effective treatment options beyond first line led to multiple negative trials, said Strickler. The DESTINY-Gastric clinical trials search finally produced a winner in trastuzumab deruxtecan (T-DXd, Enhertu). In the phase II DESTINY-Gastric01 trial, conducted in Japan and South Korea, single-agent T-DXd outperformed chemotherapy for PFS and OS in third line and beyond. The single-arm phase II DESTINY-Gastric02 produced almost identical PFS and OS as second-line or later therapy in patients from the U.S. and Europe.

Finally, the global phase III DESTINY-Gastric04 trial showed the superiority of T-DXd versus ramucirumab (Cyramza) plus paclitaxel as second-line therapy for HER2-positive GEA, significantly improving response rate, PFS, and OS. T-DXd was associated with a substantially higher rate of pneumonitis/interstitial lung disease, which should be kept in mind when treating patients with the drug, said Strickler.

Loss of HER2 Expression

A recent analysis of real-world data for 101 patients treated with T-DXd in second line or beyond raised a key point related to use of T-DXd. All the patients had received prior trastuzumab-containing therapy. HER2 status was reassessed in 33 patients and showed a 39% rate of conversion to HER2-negative status. The response rate with T-DXd was substantially lower in the patients who lost HER2 expression.

“Loss of HER2 expression has been seen in 30-70% of patients post-progression on trastuzumab-based therapy,” said Strickler. “Whatever molecule we choose in the second-line setting and beyond needs to be well suited to manage that heterogeneity. I think trastuzumab-deruxtecan is well suited to the challenge.”

In addition to testing all patients for HER2 status at diagnosis, retesting should be considered after progression on first-line trastuzumab-based therapy, he added.

A study reported at the ASCO-GI symposium added to the HER2 heterogeneity discussion. Investigators retrospectively analyzed data for 858 patients with advanced HER2-positive gastrointestinal cancers treated with anti-HER2 therapy (749 with gastroesophageal cancers). Patients were categorized as HER2-positive or negative on the basis of presence or absence of definite/probable pathogenic HER2 non-amplification mutations.

In the gastroesophageal subgroup, OS and PFS were longer in patients with HER2 amplification versus no amplification. In patients with HER2 amplification, neither PFS nor OS differed significantly between patients with deleterious HER2 mutations versus none. In the non-esophageal cohort, a trend toward worse OS and PFS was observed in patients with HER2 mutations with amplification versus those with amplification but no pathogenic mutations.

“Our study identifies a lack of benefit with [HER2-directed therapy] in HER2 mutation-positive EGC [esophagogastric cancer] in the absence of HER2 amplification/overexpression,” the investigators concluded. “This highlights the importance of HER2 amplification rather than the presence of a HER2 non-amplifying mutation for EGC. In EGC, coexisting HER2 mutation does not have a negative effect on [HER2-targeted therapy] in the setting of HER2 amplification. However, there may be a negative impact with coexisting HER2 mutations in the setting of HER2-amplified non-EGC.”

The search continues for more effective therapies for HER2-positive GEA, as reflected in publications and presentations at the ASCO-GI symposium and the 2026 ASCO annual meeting:

• HLX22 — A novel HER2-directed antibody that binds to a different epitope from trastuzumab

• Zongertinib — An anti-HER2 tyrosine kinase inhibitor (TKI)

• Disitamab vedotin — An antibody-drug conjugate targeting HER2, already approved for gastric/gastroesophageal junction cancer in China

“This is an exciting time for our patients with HER2-positive gastroesophageal cancer,” said Strickler. “We’re seeing very interesting activity from new TKIs, antibody-drug conjugates, immunotherapy cell therapies, antibodies, and bispecifics. I’m very optimistic that in the years to come, we’re continuing to make progress, both with respect to survival and quality of life for these patients.”