A randomised phase II study evaluated the clinical efficacy of the combination of trastuzumab and pertuzumab with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT regimen) as perioperative treatment for patients with resectable, locally-advanced HER2–positive oesophagogastric adenocarcinoma. It is the first study to show significant improvement of the tumour remission by the combination of a doublet HER2-targeted antibody treatment with preoperative FLOT compared with FLOT alone in this setting. Improved pathologic complete response (pCR) rate and expected safety justify further investigation of HER2-targeted agents in the perioperative treatment of HER2-positive oesophagogastric adenocarcinoma. The findings are published by Dr. Ralf-Dieter Hofheinz of the Mannheim Cancer Center, University Hospital Mannheim in Mannheim, Germany and the AIO EGA Study Group colleagues on 16 June 2022 in the Journal of Clinical Oncology.
The authors wrote in the background that oesophagogastric adenocarcinoma, comprising gastric cancer and adenocarcinoma of the gastroesophageal junction, is associated with high disease-related mortality. Based on the results of the FLOT4 study, the FLOT is a standard chemotherapy regimen in the perioperative setting. HER2 overexpression and amplification are found in 15-20% of all oesophagogastric adenocarcinoma cases. The first targeted drug that has been shown to improve outcomes in metastatic setting is the HER2 antibody trastuzumab. Recently, the combination of trastuzumab with FLOT was shown to be safe as perioperative treatment in patients with locally advanced oesophagogastric adenocarcinoma. In the phase II HERFLOT study, a centrally assessed pCR rate >20% was reported and preliminary survival data are promising.
Pertuzumab, like trastuzumab, binds to HER2 but without competing with each other. Findings from the randomised phase III studies in the first-line metastatic setting of HER2-positive breast cancer and in adjuvant treatment for patients with lymph node positive HER2-positive early breast cancer provide a strong rationale to evaluate the efficacy and safety of trastuzumab and pertuzumab in combination with FLOT in the perioperative setting in patients with resectable, HER2-positive oesophagogastric adenocarcinoma.
In PETRARCA, the multicentre, randomised phase II/III study, patients with HER2–positive, resectable oesophagogastric adenocarcinoma were assigned to 4 pre- and post-operative cycles of either FLOT alone (arm A) or combined with trastuzumab and pertuzumab, followed by 9 cycles of trastuzumab/pertuzumab (arm B). The study primary endpoint for the phase II part was the pCR rate.
The study was closed prematurely, without transition into phase III, after results of the JACOB study were reported. A total, 81 patients were randomly assigned, 41 in arm A and 40 in arm B during the phase II part. The pCR rate was significantly improved with the trastuzumab/pertuzumab treatment, increasing from 12% in arm A to 35% in arm B (p = 0.02). Similarly, the rate of pathologic lymph node negativity was higher with trastuzumab/pertuzumab, increasing from 39% in arm A to 68% in arm B, whereas the R0 resection rate and surgical morbidity were comparable.
The mortality was equal in both arms, overall 2.5%. The median disease-free survival (DFS) was 26 months in arm A and not yet reached in arm B (hazard ratio [HR] 0.58; p = 0.14). After a median follow-up of 22 months, the median overall survival (OS) was not yet reached (HR 0.56; p = 0.24). The rates of DFS and OS at 24 months were 54% (95% confidence interval [CI] 38 to 71) and 77% (95% CI 63 to 90) in arm A and 70% (95% CI 55 to 85) and 84% (95% CI 72 to 96) in arm B, respectively.
More grade 3 and higher adverse events were reported with trastuzumab/pertuzumab, especially diarrhoea (5% in arm A versus 41% in arm B) and leukopenia (13% in arm A versus 23% in arm B).
The authors commented that the improved pCR rate in the PETRARCA and the anticipated safety profile in terms of both treatment-emerging adverse events and surgical morbidity, as well as the promising survival results justify further investigation of HER2-targeted agents in the perioperative treatment of HER2-positive oesophagogastric adenocarcinoma. Although negative phase III studies have been reported for trastuzumab-emtansin and pertuzumab in the metastatic setting, these drugs and newer HER2-targeting agents may be beneficial when used in the perioperative setting.
The results of the ongoing randomised phase II EORTC INNOVATION study evaluating the efficacy of HER2-targeted treatment in oesophagogastric adenocarcinoma using perioperative chemotherapy in combination with either trastuzumab or trastuzumab plus pertuzumab in comparison with chemotherapy will help to further elucidate a potential role of anti-HER2 agents in the perioperative treatment of patients with locally advanced, resectable oesophagogastric adenocarcinoma. However, until availability of these results, additional HER2-directed treatment should not be recommended outside clinical trials.
The study was supported by Roche.
Hofheinz R-D, 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. JCO; Published online 16 June 2022. DOI: 10.1200/JCO.22.00380