The landscape of gastroesophageal cancer treatment has undergone a significant shift, with the FLOT combination regimen (docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil) emerging as the new standard of care for localized adenocarcinoma. This development comes as recent clinical evidence demonstrates that radiation therapy provides no additional benefit in this setting.
According to Dr. Yelena Y. Janjigian, associate professor at Weill Cornell Medical College and chief of Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, the superiority of FLOT over radiation-based approaches represents a paradigm shift in treatment strategy.
Superior Survival Outcomes with FLOT
The phase 3 ESOPEC study delivered compelling evidence supporting FLOT's efficacy, revealing a median overall survival of 66 months for patients receiving neoadjuvant and adjuvant FLOT, compared to 37 months for those treated with the CROSS regimen (paclitaxel/carboplatin) plus radiation. The five-year overall survival rates stood at 50.6% and 38.7%, respectively, highlighting FLOT's significant survival advantage.
Further reinforcing these findings, the phase 2/3 TOPGEAR study demonstrated that adding radiation therapy to chemotherapy provided no survival benefit in the perioperative setting. Patients receiving chemotherapy alone achieved a median overall survival of 49 months, compared to 46 months in the chemoradiotherapy group.
Exploring FLOT Combinations
Building on FLOT's success, researchers are investigating various combination approaches. The phase 3 MATTERHORN trial evaluated the addition of durvalumab to FLOT, achieving a significant improvement in pathological complete response rates (19% vs 7%) in gastric and gastroesophageal junction adenocarcinoma patients.
However, not all combinations have proven successful. The phase 3 KEYNOTE-585 trial, which studied pembrolizumab plus chemotherapy, failed to demonstrate statistically significant improvements in event-free survival compared to chemotherapy alone.
HER2-Positive Disease Developments
For HER2-positive gastroesophageal cancers, which comprise up to 30% of cases, significant progress has been made with combination therapies. The FDA's approval of pembrolizumab plus trastuzumab with chemotherapy marked an important advancement, particularly for patients with PD-L1 combined positive scores of at least 1%.
Promising results have also emerged from the DESTINY-Gastric03 trial, where fam-trastuzumab deruxtecan-nxki (T-DXd) combinations showed impressive response rates of up to 78% in first-line treatment.
Emerging Biomarker-Driven Approaches
The treatment landscape continues to evolve with biomarker-driven therapies. The CheckMate 649 trial demonstrated superior outcomes with nivolumab plus FOLFOX in microsatellite instability-high (MSI-H) disease, achieving a median overall survival of 38.7 months compared to 12.3 months with chemotherapy alone.
Recent developments also include the approval of zolbetuximab plus chemotherapy for CLDN18.2-positive tumors, though Dr. Janjigian notes that anti-PD-1 agents may be more effective for certain tumor locations, particularly proximal tumors.
Moving forward, the field is prioritizing biomarker-based therapy selection, with a hierarchical approach considering MSI-H status, HER2 expression, PD-L1 status, and CLDN18.2 expression. This strategic approach, combined with the establishment of FLOT as the preferred regimen, represents a significant step forward in the treatment of gastroesophageal cancer.
