Dr Ku on Subgroup Analyses of Frontline Zanidatamab +/- Tislelizumab By PD-L1 Status in HER2+ GEA

"Both tumors that were PD-L1 negative as well as PD-L1 positive seem to benefit from the addition of tislelizumab... it does suggest that... this triplet combination... could end up being a preferred regimen."

Geoffrey Ku, MD, medical oncologist and associate attending physician at Memorial Sloan Kettering Cancer Center, shared findings from a preplanned subgroup analysis of the phase 3 HERIZON-GEA-01 trial (NCT05152147), which evaluated a novel triplet combination for the frontline treatment of patients with HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma (GEA).

The analysis focused on the efficacy of zanidatamab-hrii (Ziihera) plus the anti–PD-1 antibody tislelizumab (Tevimbra) and chemotherapy compared with the standard-of-care combination of trastuzumab (Herceptin) and chemotherapy.

Subgroup data presented at the 2026 ASCO Annual Meeting demonstrated that the zanidatamab-based regimen provided superior progression-free survival (PFS) and overall survival (OS) benefits across all evaluated subgroups, notably regardless of PD-L1 status. This consistency was observed whether PD-L1 expression was measured by tumor area positivity (TAP) score or combined positive score (CPS). In the TAP analysis, patients with a TAP of 1% or higher achieved a median PFS of 11.3 months (95% CI, 9.6-18.5) with the zanidatamab triplet vs 8.3 months (95% CI, 6.9-9.7) with trastuzumab plus chemotherapy (HR, 0.65). Even more strikingly, those with a TAP score below 1% saw a median PFS of 18.5 months (95% CI, 9.7-25.2) vs 7.9 months (95% CI, 5.8-9.6), respectively (HR, 0.47). Similarly, the CPS analysis showed a median PFS of 12.3 months (95% CI, 9.7-18.5) for the zanidatamab arm in those with CPS of 1 or higher (HR, 0.62) and 18.5 months (95% CI, 9.7-25.2) for those with CPS below 1 (HR, 0.48).

The OS data mirrored these PFS gains across the board. For patients with a TAP score of 1% or higher, median OS was 26.4 months (95% CI, 18.7-35.9) with the zanidatamab regimen vs 21.2 months (95% CI, 17.7-25.2) with the trastuzumab arm (HR, 0.82). In the TAP-negative group (less than 1%), the survival benefit was particularly pronounced, with a median OS of 29.7 months (95% CI, 24.7-not evaluable [NE]) compared to 15.8 months (95% CI, 12.6-21.4; HR, 0.49). Consistent trends were also noted in the CPS subgroups, where OS reached 30.3 months (95% CI, 25.7-NE) in the CPS-negative cohort receiving the zanidatamab combination vs 15.7 months in the control arm (95% CI, 12.6-21.4; HR, 0.43).

Ku emphasized the clinical importance of these findings, particularly the observation that PD-L1 negative tumors—which comprised approximately one-third of the study population—derived significant benefit from the addition of tislelizumab. He contrasted this with other immunotherapy combinations, such as pembrolizumab plus trastuzumab and chemotherapy, where activity is primarily restricted to PD-L1 positive tumors. Ku noted that as long-term follow-up and further subgroup analyses are conducted, the field will gain a better sense of the robustness of this phenomenon. By demonstrating robust activity across the entire patient spectrum irrespective of PD-L1 status, the zanidatamab-tislelizumab-chemotherapy triplet has the potential to become a preferred frontline regimen for HER2-positive GEA.

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