Herceptin Combo Shows Limited Benefit in Gastric/GEJ Cancer

Adding Herceptin and Perjeta to chemotherapy increased toxicity in patients with HER2+ gastric cancers.

Herceptin plus chemotherapy showed numerical improvements in overall survival (OS) and progression-free survival (PFS) for HER2-positive gastric and gastroesophageal junction (GEJ) cancers, although these benefits were not sustained following a change in the chemotherapy regimen, according to data from the phase 2 INNOVATION trial, which were presented at the 2025 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancer Symposium.

The major pathological response rate (mpRR) was 23.3% in patients who received chemotherapy alone (33 patients), 37% in those who received chemotherapy plus Herceptin (64 patients) and 26.4% among those who received chemotherapy in combination with Herceptin and Perjeta (pertuzumab; 64 patients). 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 Herceptin/Perjeta, chemotherapy/Herceptin and chemotherapy alone arms, respectively, were 12.5%, 16.7% and 8.3% when a cisplatin/Xeloda (capecitabine) or 5-flurorouracil backbone was administered. With a backbone of fluorouracil plus leucovorin, oxaliplatin and docetaxel (FLOT); folinic acid, fluorouracil and oxaliplatin (FOLFOX); or Xeloda/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/Herceptin arms, meaning that more than half of patients were alive without disease progression when this was assessed. In addition, data showed a median of 3.32 years in the Herceptin/Perjeta plus chemotherapy arm. Compared with chemotherapy alone, the risk of progression or death decreased with Herceptin/chemotherapy but increased with the addition of Perjeta.

Stratified PFS results showed 3-year rates of 57.1% in the chemotherapy alone arm, 64.2% in the chemotherapy/Herceptin arm and 50.4% in the Perjeta 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 three-year PFS rates were 68.4%, 65% and 53.3% in each respective arm.

The median OS was not reached across all 3 treatment arms in the overall population, with 3-year rates of 75.6% when using chemotherapy alone, 76.9% with the addition of Herceptin and 65.2% when adding Herceptin and Perjeta. The risk of death was numerically lower with Herceptin/chemotherapy versus chemotherapy alone but higher with Herceptin/Perjeta plus chemotherapy.

Before the trial amendment regarding the chemotherapy backbone, the three-year OS rates were 78.6% using chemotherapy alone, 83.6% when adding Herceptin and 68.3% with the addition of Herceptin and Perjeta. The three-year OS rates following the amendment were 73.3%, 72.2% and 62.2%, respectively.

“The INNOVATION study did not meet its primary end point. The combination of chemotherapy plus [Herceptin] and [Perjeta] was associated with higher toxicity and no advantage. [PFS] and [OS] were numerically improved when adding [Herceptin] to chemotherapy doublet, but not after the amendment when patients received FLOT,” Dr. Anna Dorothea Wagner, 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.

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

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

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 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 1B to 3 tumors and HER2 overexpression.

Of note, four cycles of FLOT were administered to 93.8%, 93.3% and 80.6% of the chemotherapy alone, chemotherapy/Herceptin and chemotherapy plus Herceptin/Perjeta arms, respectively. Wagner highlighted lower rates of FLOT dose intensity in the arm that received Perjeta, which included a median dose intensity of 87.9% for oxaliplatin, 85.5% for docetaxel, 93.2% for folinic acid and 82% for 5-fluorouracil.

Additional efficacy findings showed that RFS and OS improved in patients who achieved a mpR compared with those who did not.

Notable grade 3 (severe) side effects in the chemotherapy alone, chemotherapy/Herceptin and chemotherapy plus Herceptin/Perjeta arms, respectively, included diarrhea (5.9% versus 3% versus 26.1%) and neutrophil count decreases (32.4% versus 21.2% versus 21.7%). There were two patient deaths in the chemotherapy/Herceptin arm due to neutropenia plus pneumonia and sepsis in one patient and postoperative biliary peritonitis in another. Investigators noted two patient deaths in the Perjeta arm, which included one due to neutropenic sepsis with mucositis and one due to vast cerebral ischemia after surgery.

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Reference

"INNOVATION": integration of trastuzumab (T), with or without pertuzumab (P), into perioperative chemotherapy of HER-2 positive stomach cancer: overall survival results. Dr. Anna Dorothea Wagner, et al. J Clin Oncol.