Trastuzumab Combo Shows Nonsignificant Advantages in Gastric/GEJ Cancer

Adding trastuzumab and pertuzumab to chemotherapy conferred higher toxicity among patients with HER2-positive gastric cancers in the INNOVATION trial.

Trastuzumab (Herceptin) plus chemotherapy numerically improved overall survival (OS) and progression-free survival (PFS) among patients with HER2-positive gastric and gastroesophageal junction (GEJ) cancers, although these outcomes were not sustained following an amendment of the chemotherapy backbone, according to findings from the phase 2 INNOVATION trial (NCT02205047) presented at the 2025 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancer Symposium.¹

The major pathological response rate (mpRR) was 23.3% in patients who received chemotherapy alone (n = 33), 37.0% in those who received chemotherapy plus trastuzumab (n = 64), and 26.4% among those who received chemotherapy in combination with trastuzumab and pertuzumab (Perjeta; n = 64). Investigators administered surgery to 84.8%, 98.4%, and 92.2% of patients in each respective arm.

When stratifying results by the chemotherapy backbone, the mpRR in the chemotherapy plus trastuzumab/pertuzumab, chemotherapy/trastuzumab, and chemotherapy alone arms, respectively, were 12.5%, 16.7%, and 8.3% when a cisplatin/capecitabine (Xeloda) or 5-flurorouracil backbone was administered. With a backbone of fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT); folinic acid, fluorouracil, and oxaliplatin (FOLFOX); or capecitabine/oxaliplatin (CAPOX), the respective mpRRs were 37.9%, 53.3%, and 33.3%.

Across the overall population, the median PFS was not reached (NR) in the chemotherapy monotherapy and chemotherapy/trastuzumab arms, while data showed a median of 3.32 years (95% CI, 1.56-NR) in the trastuzumab/pertuzumab plus chemotherapy arm. Compared with chemotherapy alone, the risk of progression or death decreased with trastuzumab/chemotherapy (HR, 0.84; 95% CI, 0.43-1.63) but increased with the addition of pertuzumab (HR, 1.32; 95% CI, 0.70-2.49).

Stratified PFS results showed 3-year rates of 57.1% (95% CI, 28.4%-78.0%) in the chemotherapy alone arm, 64.2% (95% CI, 42.5%-79.5%) in the chemotherapy/trastuzumab arm, and 50.4% (95% CI, 30.1%-67.6%) in the pertuzumab triplet arm before investigators instituted a protocol amendment that changed the chemotherapy backbone to FLOT across the study’s European sites. Following this protocol amendment, the 3-year PFS rates were 68.4% (95% CI, 42.8%-84.4%), 65.0% (95% CI, 47.5%-78.0%), and 53.3% (95% CI, 35.4%-68.3%) in each respective arm.

The median OS was NR across all 3 treatment arms in the overall population, with 3-year rates of 75.6% (95% CI, 57.1%-87.0%) when using chemotherapy alone, 76.9% (95% CI, 64.1%-85.6%) with the addition of trastuzumab, and 65.2% (95% CI, 51.3%-76.1%) when adding trastuzumab and pertuzumab. The risk of death was numerically lower with trastuzumab/chemotherapy vs chemotherapy alone (HR, 0.89; 95% CI, 0.42-1.88) but higher with trastuzumab/pertuzumab plus chemotherapy (HR, 1.29; 95% CI, 0.62-2.66).

Before the trial amendment regarding the chemotherapy backbone, the 3-year OS rates were 78.6% (95% CI, 47.3%-92.5%) using chemotherapy alone, 83.6% (95% CI, 62.0%-93.5%) when adding trastuzumab, and 68.3% (95% CI, 46.3%-82.8%) with the addition of trastuzumab and pertuzumab. The 3-year OS rates following the amendment were 73.3% (95% CI, 47.2%-87.9%), 72.2% (95% CI, 54.3%-84.0%), and 62.2% (95% CI, 42.6%-76.8%), respectively.

“The INNOVATION study did not meet its primary end point. The combination of chemotherapy plus trastuzumab and pertuzumab was associated with higher toxicity and no advantage. [PFS] and [OS] were numerically improved when adding trastuzumab to chemotherapy doublet, but not after the amendment when patients received FLOT,” Anna Dorothea Wagner, MD, PD & MER, a consultant, senior lecturer, and head of the Gastrointestinal Cancer Clinic in the Department of Oncology at the University Hospital of Lausanne, Switzerland, stated in the presentation.¹

“On the basis of its very high [mpRR], the addition of trastuzumab to chemotherapy may be considered, especially when tumor downsizing is needed to achieve a curative resection,” she added.¹

Investigators of this open-label phase 2 trial randomly assigned patients 1:2:2 to receive chemotherapy alone in arm A, chemotherapy plus trastuzumab in arm B, or chemotherapy in combination with trastuzumab and pertuzumab in arm C. All patients received neoadjuvant and adjuvant chemotherapy consisting of CAPOX, modified FOLFOX6, FLOT, cisplatin/capecitabine, or 5-fluorouracil. Additionally, patients received perioperative trastuzumab in arm B and perioperative trastuzumab/pertuzumab in arm C.

Following the publication of findings from the phase 2/3 FLOT-4 trial (NCT01216644) in 2019, investigators of the INNOVATION trial amended the protocol to incorporate FLOT as the chemotherapy backbone in European sites.²

The trial’s primary end point was the mpRR, defined as the proportion of patients with less than 10% viable tumor cells following neoadjuvant therapy per central review. Secondary end points included recurrence-free survival (RFS), PFS per RECIST v1.1 criteria, and OS.

Patients with HER2-positive gastric and GEJ adenocarcinoma amenable to gastrectomy or esophagectomy were eligible for enrollment on the trial. Other requirements for study entry included having IB to III tumors and HER2 overexpression per central testing.

Of note, 4 cycles of FLOT were administered to 93.8%, 93.3%, and 80.6% of the chemotherapy alone, chemotherapy/trastuzumab, and chemotherapy plus trastuzumab/pertuzumab arms, respectively. Wagner highlighted lower rates of FLOT dose intensity in the arm that received pertuzumab, which included a median dose intensity of 87.9% for oxaliplatin, 85.5% for docetaxel, 93.2% for folinic acid, and 82.0% for 5-fluorouracil.

Additional efficacy findings showed that RFS (HR, 0.26; 95% CI, 0.13-0.53; P = .0008) and OS (95% CI, 0.25; 95% CI, 0.10-0.59; P = .0041) improved in patients who achieved a mpR compared with those who did not.

Notable grade 3 adverse effects (AEs) in the chemotherapy alone, chemotherapy/trastuzumab, and chemotherapy plus trastuzumab/pertuzumab arms, respectively, included diarrhea (5.9% vs 3.0% vs 26.1%) and neutrophil count decreases (32.4% vs 21.2% vs 21.7%). There were 2 patient deaths in the chemotherapy/trastuzumab arm due to neutropenia plus pneumonia and sepsis in 1 patient and postoperative biliary peritonitis in another. Investigators noted 2 patient deaths in the pertuzumab arm, which included 1 due to neutropenic sepsis with mucositis and 1 due to vast cerebral ischemia after surgery.

References

1. Wagner A, Grabsch H, Mauer M, et al. EORTC-1203 GITC "INNOVATION": integration of trastuzumab (T), with or without pertuzumab (P), into perioperative chemotherapy of HER-2 positive stomach cancer: overall survival results. J Clin Oncol. 2025;43(suppl 4):LBA331. doi:10.1200/JCO.2025.43.4_suppl.LBA331
2. Al-Batran SE, Homann N, Pauligk C, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019;393(10184):1948-1957. doi:10.1016/S0140-6736(18)32557-1