Perioperative trastuzumab and pertuzumab in combination with FLOT versus FLOT alone for HER2-positive resectable esophagogastric adenocarcinoma: Final results of the PETRARCA multicenter randomized phase II trial of the AIO.

Abstract

4502 Background: Perioperative FLOT is a standard of care for resectable, esophagogastric adenocarcinoma (EGA). This trial evaluates the addition of trastuzumab (tras) and pertuzumab (per) to FLOT for HER2-positive resectable patients (pts). Methods: PETRARCA is a prospective, multicenter, randomized, investigator initiated trial planned as a phase II/III investigation. We report the phase II part of this trial. Pts with HER2+ resectable EGA (≥ cT2 or cN+) were enrolled. Pts were randomized 1:1 to 4 pre- and post-operative cycles of FLOT (Docetaxel 50 mg/m²; Oxaliplatin 85 mg/m²; Leucovorin 200 mg/m²; 5-FU 2600 mg/m², q2w) (Arm A) or the same regimen with tras 8/6 mg/kg and per 840 mg q3w, followed by 9 cycles tras/per (arm B). Primary endpoint for the phase II part was the rate of pathological complete remission (pCR). Main secondary endpoints were DFS, OS and safety. Results: The trial closed prematurely and did not proceed to phase III. In total, 81 pts were randomized (A, 41; B, 40). Baseline characteristics were balanced (overall, male 79%; median age 60; cT3/T4 86%; cN+ 85%; GEJ 75%). 93% in arm A and 90% in arm B completed pre-OP treatment as planned. More pts had at least one dose modification in arm B (A, 44%; B, 70%). The pCR rate was significantly improved with tras/per (A, 12%; B, 35%; p = 0.02). Likewise, the rate of pathological lymph node negativity was higher with tras/per (A, 39%; B, 68%). R0-resection rate (A, 90%; B, 93%) and surgical morbidity (A: 43%; B, 44%) were comparable. Moreover, in-house mortality was equal in both arms (overall 2.5%). Median DFS was 26 months in arm A and not yet reached in arm B (HR 0.58, p = 0.14). After a median follow-up of 22 months median OS was not yet reached. DFS and OS rates [with 95% CI] at 24 months were 54% [38-71%] and 77% [63-90%] in arm A and 70% [55-85%] and 84% [72-96%] in arm B, respectively. In terms of toxicity more ≥ grade 3 adverse events were reported with tras/per (75% vs. 85%), especially diarrhea (5% vs. 41%) and leukopenia (13% vs 23%). Conclusions: The addition of tras/per to perioperative FLOT significantly improved pCR and nodal negativity rates in pts with Her2+ resectable esophagogastric adenocarcinoma at the price of higher rates of diarrhea and leukopenia. Clinical trial information: NCT02581462 .

Gastric cancer: a comprehensive review of current and future treatment strategies

“…PETRARCA trial showed that the addition of both Trastuzumab and Pertuzumab to FLOT in perioperatively significantly improved the compete pathological response rate (35% vs 12%) with improvement in node-negative outcome (68% vs. 39%). However, due to increased toxicities when adding both HER2 agents including grade3/4 diarrhea (41% vs 5%) and leukopenia (23% vs. 13%), this study is not being moved to the phase III [46].…”

Biomarkers for Precision Treatment in Gastric Cancer

“…Based on these post hoc subgroup analyses, trastuzumab was approved in many countries in addition to the cisplatin-fluoropyrimidine doublet, representing the standard of care in the first-line treatment for patients with HER2-positive disease [2]. Additionally, several trials are currently investigating the efficacy of anti HER2 agents in the adjuvant and neoadjuvant settings for HER2 positive GC [12][13][14][15]; one of them, i.e., the PETRARCA study, has suggested improved pathological complete response rates for neoadjuvant chemotherapy and HER2 directed therapy [15].…”

Towards Personalization in the Curative Treatment of Gastric Cancer

“…An example of a study in the curative setting is the PERTRARCA study by the FLOT-AIO group, of which the results were recently presented at the ASCO annual meeting (78). Patients with resectable HER-2 positive esophagogastric carcinoma were randomized between four perioperative cycles of FLOT with or without trastuzumab, followed by nine cycles of trastuzumab plus pertuzumab.…”