Addition of Trastuzumab/Pertuzumab to Perioperative FLOT Chemotherapy in HER2-Positive Esophagogastric Adenocarcinoma

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In the German phase II PETRARCA trial of the AIO EGA Study Group, reported in the Journal of Clinical Oncology, Hofheinz et al found that the addition of trastuzumab and pertuzumab to perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) improved both the pathologic complete response rate and node-negativity rate in patients with HER2-positive resectable esophagogastric adenocarcinoma.

As noted by the investigators, release of the negative results of the JACOB trial—which evaluated the addition of pertuzumab to chemotherapy plus trastuzumab in this setting—during the PETRARCA trial led to slowed recruitment and resulted in the decision to terminate enrollment and to discontinue the planned transition to a phase III trial.

Study Details   

In the multicenter trial, 81 patients were randomly assigned between June 2016 and August 2018 to receive trastuzumab/pertuzumab plus FLOT (n = 40) or FLOT alone (n = 41). FLOT was given in four preoperative and four postoperative 2-week cycles consisting of docetaxel at 50 mg/m2, oxaliplatin at 85 mg/m2, leucovorin at 200 mg/m2, and fluorouracil at 2,600 mg/m2 as a 24-hour infusion once on day 1. Trastuzumab (8 mg/kg initial dose, 6 mg/kg maintenance dose) and pertuzumab (840 mg) were given every 3 weeks in three preoperative and three postoperative cycles, followed by nine cycles of both without chemotherapy.

The primary endpoint was the pathologic complete response rate.

Efficacy Outcomes

Centrally assessed pathologic complete response was achieved in 14 (35%, 95% confidence interval [CI] = 20%–50%) of 40 patients in the trastuzumab/pertuzumab plus FLOT group vs 5 (12%, 95% CI = 2%–22%) of 41 in the control group (P = .019). N0 status was achieved in 27 (68%) vs 16 (39%) patients. R0 resection was achieved in 93% vs 90% of patients.


  • The addition of trastuzumab and pertuzumab to FLOT significantly improved pathologic complete response rate.
  • Pathologic complete response rates were 35% vs 12% and node-negative rates were 68% vs 39%.

At a median follow-up of 22 months, death had occurred in 7 vs 11 patients (hazard ratio [HR] = 0.56, 95% CI = 0.21–1.47, P = .228); overall survival rates at 24 months were 84% vs 77%. Median disease-free survival was not reached vs 26 months (HR = 0.58, 95% CI = 0.28–1.19, P = .130), with 24-month rates of 70% vs 54%.

Adverse Events

Grade 3 or 4 treatment-related adverse events were more common in the trastuzumab/pertuzumab plus FLOT group; most commonly, diarrhea (41% vs 5%), neutropenia (28% vs 30%), and leukopenia (23% vs 13%). Grade 1 or 2 weight loss was observed in 38% vs 10% of patients. No differences in cardiotoxicity were observed, and no deaths due to study drug toxicity were observed. Surgical morbidity was observed in 44% vs 43% of patients. Surgery-related mortality was not observed in either group at 30 days, and occurred in one patient in each group at 60 days.

The investigators stated: “[T]he JACOB trial reported no benefit for the addition of pertuzumab to chemotherapy plus trastuzumab for HER2-positive esophagogastric adenocarcinoma, which is contrary to the promising results seen in the PETRARCA trial. It should be noted that both studies used different chemotherapy treatments. Although the JACOB trial used cisplatin plus capecitabine or fluorouracil, we used the taxane-based triplet FLOT…. Recent studies for breast cancer indicated a synergistic therapeutic effect between trastuzumab and chemotherapy, especially when taxanes are used.”

They concluded, “The addition of trastuzumab/pertuzumab to perioperative FLOT significantly improved pathologic complete response and nodal negativity rates at the price of higher rates of diarrhea and leukopenia.”

Ralf-Dieter Hofheinz, MD, of Mannheim Cancer Center, University Hospital Mannheim, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Roche. For full disclosures of the study authors, visit

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