Benefit-Risk Profile of Trastuzumab/Pertuzumab With FLOT Regimen Comes Into Question in HER2-positive Gastric Cancer

Trastuzumab and pertuzumab with a chemotherapy regimen of fluorouracil, leucovorin, oxaliplatin, and docetaxel increased response, and high-grade toxicity, in patients with HER2-positive gastric or gastroesophageal junction cancer.

Patients with HER2-positive gastric or gastroesophageal junction cancer experienced a significant improvement in pathologic complete response (pCR) with the addition of trastuzumab (Herceptin) and pertuzumab (Perjeta) to a chemotherapy regimen of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT), according to results from the phase 2/3 PETRARCA trial (NCT02581462).1 However, the improved pCR rates were accompanied by high rates of diarrhea and leukopenia.

The phase 2 findings, which were published in the Journal of Clinical Oncology, showed that patients who added theHER2-directed antibody doublet to FLOT (arm B; n = 40) achieved a pCR rate of 35% compared with 12% for the 41 patients treated with FLOT alone (arm A; P = .02). Additionally, the rate of pathologic lymph node negativity was 68% vs 39%, respectively. Notably, the median disease-free survival (DFS) was not reached (NR) in arm B compared with 26 months in arm A (HR, 0.58; P = .14). The median follow-up in arm B was 25 months vs 21 months in arm A.

At the same time, more grade 3 or higher adverse events (AEs) were reported in arm B than arm A. The rate of grade 3 or higher diarrhea between the 2 arms were 41% vs 5%, respectively, and rate of leukopenia was 23% vs 13%.

The multicenter, unblinded trial randomly assigned patients 1:1 to arm A or arm B. In arm A, patients received FLOT in 4 preoperative and 4 postoperative biweekly cycles. Docetaxel was given at a dose of 50 mg/m2, oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and fluorouracil 2,600 mg/m2 as a 24-hour infusion given once on day 1 of each cycle.

Patients in arm B received the same dosing schedule of FLOT plus3 preoperative and 3 postoperative cycles of trastuzumab 8 mg/kg for the initial dose followed by a 6 mg/kg maintenance dose 3 times per week and pertuzumab 840 mg triweekly, both given once on day 1. This was followed by 9 cycles of trastuzumab in combination with pertuzumab without chemotherapy. Treatment was discontinued in the event of unacceptable toxicity, disease progression, death, or at the patient’s request.

Adult patients were eligible for enrollment if they had an ECOG performance status of 2 or less, no preceding cytotoxic or targeted therapy, and no previous tumor resection, among other inclusion criteria. Patients with known brain metastases, chronic inflammatory bowel disease, or other severe internal disease or acute infection were excluded from the study.2

The primary end point of the phase 2 part of the trial was pCR rate per Becker classification. Secondary end points included margin-free (R0) resection rate, median DFS, overall survival (OS), and safety and tolerability.

Baseline patient characteristics were well-balanced between the 2 arms; the median age was 61 years (range, 24-77) vs 59.5 years (range, 36-83) in arm A and arm B, respectively. Most patients in both arms were male (83% vs 75%), had an ECOG performance status of (71% vs 78%), and grade 2 disease according to World Health Organization criteria (56% vs 53%).1

Additional results from the trial exhibited that the investigational regimen led to a benefit in terms of 24-month DFS rates, at 77% (95% CI, 63%-90%) in arm B and 54% (95% CI, 38%-71%) in arm A. The 24-month OS rates were 84% (95% CI, 72%-96%) and 70% (95% CI, 55%-85%), respectively. The median OS figures were not NR at a median follow-up of 22 months (HR, 0.56; P = .24).

Nearly all (98%) patients who received study treatment underwent surgery afterwards and R0 resection was achieved in 93% and 90% of patients in arm B and arm A, respectively. Investigators noted that 14 patients in arm B had no visible tumor cells compared with 5 in arm A.

In the safety population, 58% of patient in arm A (n = 40) experienced a serious AE compared with 67% of patients in arm B (n = 39). Commonly reported grade 1/2 AEs in arm A included nausea (50%), diarrhea (45%), and fatigue (45%). In arm B, grade 1/2 AEs consisted of fatigue (54%), diarrhea (51%), and nausea (49%). Serious AEs with a fatal outcome occurred in 1 patient in arm A and 2 patients in arm B.

PETRARCA was closed without a transition into phase 3 following the reporting of results from the phase 3 JACOB trial (NCT01774786).

“The improved pathologic response rate in PETRARCA and the anticipated safety profile in terms of both treatment-emerging [AEs] and surgical morbidity as well as the promising survival results justify further trials with HER2-targeted agents in the perioperative treatment of HER2-positive esophagogastric adenocarcinoma,” study authors wrote in conclusion.


  1. Hofheinz RD, Merx K, Haag GM, et al. FLOT versus FLOT/trastuzumab/pertuzumab perioperative therapy of human epidermal growth factor receptor 2–positive resectable esophagogastric adenocarcinoma: a randomized phase ii trial of the AIO EGA study group. J Clin Oncol. 2022;40(32):3750-37361. doi:10.1200/JCO.22.00380
  2. FLOT vs. FLOT/herceptin/pertuzumab for perioperative therapy of HER-2 expressing gastric or GEJ cancer (PETRARCA). Updated August 11, 2020. Accessed November 30, 2022.