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

Abstract

PURPOSE High pathologic complete response (pCR) rates and comparably good survival data were seen in a phase II trial combining perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy with trastuzumab for resectable, esophagogastric adenocarcinoma (EGA). The current trial evaluates the addition of trastuzumab and pertuzumab to FLOT as perioperative treatment for human epidermal growth factor receptor 2–positive resectable EGA. METHODS In this multicenter, randomized phase II/III trial, patients with human epidermal growth factor receptor 2–positive, resectable EGA (≥ clinical tumor 2 or clinical nodal–positive) were assigned to four pre- and postoperative cycles of either FLOT alone (arm A) or combined with trastuzumab and pertuzumab, followed by nine cycles of trastuzumab/pertuzumab (arm B). The primary end point for the phase II part was the rate of pCR. RESULTS The trial was closed prematurely, without transition into phase III, after results of the JACOB trial were reported. Eighty-one patients were randomly assigned (A: 41/B: 40) during the phase II part. The pCR rate was significantly improved with the trastuzumab/pertuzumab treatment (A: 12%/B: 35%; P = .02). Similarly, the rate of pathologic lymph node negativity was higher with trastuzumab/pertuzumab (A: 39%/B: 68%), whereas the R0 resection rate (A: 90%/B: 93%) and surgical morbidity (A: 43%/B: 44%) were comparable. Moreover, the inhouse mortality was equal in both arms (overall 2.5%). The median disease-free survival was 26 months in arm A and not yet reached in arm B (hazard ratio 0.58; P = .14). After a median follow-up of 22 months, the median overall survival was not yet reached (hazard ratio 0.56; P = .24). Disease-free survival and overall survival rates (95% CI) at 24 months were 54% (38 to 71) and 77% (63 to 90) in arm A and 70% (55 to 85) and 84% (72 to 96) in arm B, respectively. More ≥ grade 3 adverse events were reported with trastuzumab/pertuzumab, especially diarrhea (A: 5%/B: 41%) and leukopenia (A: 13%/B: 23%). CONCLUSION The addition of trastuzumab/pertuzumab to perioperative FLOT significantly improved pCR and nodal negativity rates at the price of higher rates of diarrhea and leukopenia.

Perspectives on the Management of Oligometastatic Disease in Esophago-Gastric Cancer

“…The HER-FLOT regimen was also found to be safe, with a promising pCR rate of >20% achieving pathological complete response (pCR) [ 70 , 71 ]. Furthermore, the German phase II study PETRARCA showed recently that the addition of trastuzumab and pertuzumab to perioperative FLOT is feasible and significantly improved pCR compared to FLOT only [ 72 ].…”

“…Thus, the shown high response rates of fluoropyrimidine plus platinum-based chemotherapy plus docetaxel and/or PD-1 or HER-2-directed therapy [ 25 , 26 , 49 , 70 , 72 ] make the combinations attractive especially in the limited metastatic disease to enable a possible surgical R0 resection.…”

HER2 Inhibition in Gastric Cancer—Novel Therapeutic Approaches for an Established Target

“…Pathological complete response was seen in 21.5% (n = 12/56) of patients with locally advanced HER2-positive gastric cancers following neoadjuvant combination therapy, exceeding the pre-specified threshold of 20% to warrant further investigation [ 95 ]. Dual HER2-inhibition using trastuzumab and pertuzumab with FLOT chemotherapy in the randomised PETRARCA study (n = 81) has also been shown to significantly improve pathological complete response (35% vs. 12%, p = 0.02) and nodal response (68% vs. 39%) over FLOT alone [ 96 ]. However, this was at the expense of higher rates of grade ≥3 diarrhoea (41% vs. 5%) and leukopenia (23% vs. 13%) with combination treatment when compared to FLOT chemotherapy.…”

Immune checkpoint inhibitors in resectable gastroesophageal cancers - a review

“…Of note, a randomized phase II study in Her 2 positive, resectable esophagogastric adenocarcinoma showed that a combination of two Her-2 targeted antibodies, trastuzumab and pertuzumab to the FLOT chemotherapy backbone improved pCR from 12% to 35%. 52 Unlike when combined with chemotherapy, addition of Her-2 targeted therapy does not appear to benefit patients undergoing chemoradiation. The randomized phase III RTOG 1010 study evaluated the efficacy of trastuzumab in Her-2 overexpressing, resectable, esophageal cancer patients undergoing chemoradiation.…”