PHERFLOT Trial: Perioperative Promise in HER2+ Esophagogastric Adenocarcinoma

Adding pembrolizumab (Keytruda) and trastuzumab (Herceptin) to 5-fluorouracil-leucovorin-oxaliplatin-docetaxel (FLOT) chemotherapy for treatment of patients with HER2-positive (HER+) esophagogastric adenocarcinoma (EGA) induced antitumor responses with a favorable safety profile in preliminary findings of the single-arm phase 2 PHERFLOT trial (NCT05504720), supporting its feasibility as a perioperative chemoimmunotherapy option.¹

Of 31 enrolled patients, the combination induced a pathological complete response (pCR) rate of 48.4% (95% CI, 30.2%–66.9%) following 4 cycles of therapy. Responses were particularly enriched in those who had high PD-L1 combined positive scores (CPS; CPS ≥10) and whose tumors strongly expressed HER2 (immunohistochemistry 3+), with respective pCRs of 63.6% (95% CI, 30.8%–89.1%) and 52.0% (95% CI, 31.3%–72.2%). After accounting for the 1 patient who declined surgery without disease progression, 30 patients proceeded to R0 resection; half of those patients achieved pCR (n = 15; 50.0%).

While FLOT chemotherapy is the standard perioperative approach for esophageal and gastric cancers, outcomes remain suboptimal, with a projected 31% increase in esophageal cancer incidence and mortality over the next 2 decades.² These results indicate the potential value of adding immunotherapy––a HER2-targeted antibody and an immune checkpoint inhibitor––to the standard chemotherapy regimen to enhance outcomes and address this rising burden of disease, although future randomized trials are needed to confirm these treatment effects.

“These outstanding outcomes may be offset by increased perioperative morbidity,” wrote Stein et al, study authors, in the Nature Medicine publication.¹ “Accordingly, future trials of this or similar protocols should evaluate whether organ preservation strategies might be appropriate for patients who achieve complete responses and/or whether other therapy de-escalation strategies might be feasible for these patients.”

Safety Findings

The safety profile of the combination was expected and consistent with established toxicity profiles, demonstrating a net positive feasibility outcome. While all patients experienced at least 1 adverse event (AE), most were attributable to chemotherapy. The most common grade ≥3 AEs reported included diarrhea (38.7%), decreased neutrophil count (25.8%), sepsis (19.4%), and weight loss (16.1%).

In the intention-to-treat population, 48.4% experienced grade ≥3 serious AEs, 32.3% of which were attributed to pembrolizumab and 22.6% to trastuzumab. Diarrhea was the most common grade ≥3 treatment-related AE, occurring in 12 (38.7%) patients. This event was attributed to FLOT in 83.3% of cases (n = 10) and to pembrolizumab and trastuzumab in 50.0% of cases (n = 6).

Two patients experienced fatal serious AEs which were deemed unrelated to the therapy, and 2 patients discontinued therapy due to toxicity.

Trial Design and Patient Characteristics

The PHERFLOT trial is a single-arm, open-label phase 2 trial evaluating the efficacy of perioperative pembrolizumab, trastuzumab, and FLOT chemotherapy followed by pembrolizumab plus trastuzumab alone in patients with HER2+ localized EGA compared with historical controls.³ A total of 31 patients with nonmetastatic, resectable HER2+ EGA were enrolled across 11 sites in Germany. Most tumors were localized at the esophagogastric junction type I (35.5%) and type II (32.3%), followed by the stomach (22.6%) and esophagogastric junction type III (9.7%).

The neoadjuvant treatment regimen consisted of 200 mg of intravenous pembrolizumab and trastuzumab every 3 weeks for 3 cycles before surgery, with concurrent FLOT chemotherapy. Following surgery, patients received 4 additional 2-week cycles of the same chemoimmunotherapy, followed by up to 11 cycles of pembrolizumab and trastuzumab alone over the course of approximately 1 year.

The study has co-primary end points of pCR and disease-free survival, the latter of which was immature at the time of analysis. Secondary end points include other efficacy and tolerability measures such as overall response rate, R0 resection rate, overall survival, feasibility rate, and safety.

REFERENCES

1. Stein A, Goekkurt E, Al-Batran SE, et al. Perioperative pembrolizumab, trastuzumab and FLOT in HER2-positive localized esophagogastric adenocarcinoma: a phase 2 trial. Nat Med. Published online October 18, 2025. doi:10.1038/s41591-025-03979-y

2. Xie Z, Lin J, Li Z, et al. Esophageal cancer trends in the US from 1992 to 2019 with projections to 2044 using SEER data. Sci Rep. 2025;15(1). doi:10.1038/s41598-025-01674-z

3. Evaluating pembrolizumab, trastuzumab and FLOT as perioperative treatment of HER2-positive, localized esophagogastric adenocarcinoma. ClinicalTrials.gov. Updated June 6, 2025. Accessed November 7, 2025. https://clinicaltrials.gov/study/NCT05504720