Advancements in Gastroesophageal Cancer: FLOT Regimens, HER2 Inhibition, and Zolbetuximab
核心洞察
FLOT (docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil) is now the preferred regimen for localized adenocarcinoma (搜索), as radiation therapy has not shown improved outcomes.
The FDA approval of zolbetuximab plus chemotherapy marks a significant advancement for Claudin 18.2 (搜索) (CLDN18.2)-positive gastric/gastroesophageal junction (GEJ) tumors.
Research indicates that HER2 (搜索) inhibition alone is insufficient for HER2-positive GEJ adenocarcinomas due to intrinsic resistance, necessitating combination therapies.
Recent updates in gastroesophageal cancer treatment strategies highlight the evolving landscape of therapeutic options, with a focus on optimized chemotherapy regimens, targeted therapies, and immunotherapeutic approaches. Key discussions at the 42nd Annual Chemotherapy Foundation Symposium, led by Dr. Yelena Y. Janjigian, underscored the importance of personalized treatment strategies based on molecular profiling and clinical trial data.
FLOT as the Preferred Regimen
The phase 3 ESOPEC study (NCT02509286) established FLOT (docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil) as the superior regimen compared to neoadjuvant chemoradiation with the CROSS regimen (paclitaxel/carboplatin). Patients receiving FLOT experienced a median overall survival (OS) of 66 months compared to 37 months with CROSS, with 5-year OS rates of 50.6% and 38.7%, respectively. This data supports the use of FLOT as the standard of care for localized adenocarcinoma (搜索). Further, the phase 3 TOPGEAR study (NCT01924819) indicated that adding radiation therapy to chemotherapy did not improve OS outcomes, reinforcing the preference for FLOT-based regimens.
The MATTERHORN trial (NCT04592913) explored the addition of durvalumab to FLOT, demonstrating a statistically significant improvement in pathological complete response (pCR) rates in patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma (搜索). The pCR rates were 19% with durvalumab plus FLOT compared to 7% with FLOT plus placebo (odds ratio, 3.08; 95% CI, 2.03-4.67; P < .00001). However, the KEYNOTE-585 trial (NCT03221426) showed that the addition of pembrolizumab to FLOT did not yield a statistically significant improvement in event-free survival (HR, 0.81; 95% CI, 0.67-0.99; P = .0198).
HER2 Inhibition Strategies
Up to 30% of GEJ adenocarcinomas exhibit HER2 (搜索)-positive status, with a significant proportion harboring co-alterations in the RTK/RAS/PI3K pathway, leading to intrinsic resistance to HER2 inhibition alone. The FDA's 2021 approval of pembrolizumab plus trastuzumab, fluoropyrimidine, and platinum-containing chemotherapy, based on the KEYNOTE-811 trial (NCT03615326), marked a crucial advancement. However, this approval is restricted to patients with a PD-L1 combined positive score (CPS) of at least 1%.
Final analysis of KEYNOTE-811 revealed higher antitumor activity in patients with PD-L1 CPS at least 1%, with an overall response rate (ORR) difference of 14.7% (95% CI, 7.1%-22.2%) favoring the pembrolizumab regimen. Combination therapies with trastuzumab deruxtecan (T-DXd) are also under investigation, with the DESTINY-Gastric03 trial (NCT04379596) showing promising ORRs of 78% (95% CI, 62%-90%) in the T-DXd 6.4 mg/kg plus 5-FU/capecitabine cohort.
Microsatellite Instability and Immunotherapy
Data from the CheckMate 649 trial (NCT02872116) demonstrated that nivolumab plus FOLFOX (搜索) significantly improved overall survival in patients with microsatellite instability-high (MSI-H) disease, with a median OS of 38.7 months (95% CI, 8.4-not estimable) compared to 12.3 months (95% CI, 4.1-16.5) with chemotherapy alone (HR, 0.34; 95% CI, 0.16-0.74). In microsatellite stable disease, nivolumab plus FOLFOX also showed a survival benefit, with a median OS of 13.8 months (95% CI, 12.4-14.5) versus 11.5 months (95% CI, 10.8-12.5) with chemotherapy (HR, 0.79; 95% CI, 0.71-0.89).
Zolbetuximab in CLDN18.2-Positive Tumors
The FDA approval of zolbetuximab plus chemotherapy for Claudin 18.2 (搜索) (CLDN18.2)-positive gastric/GEJ tumors represents a significant regulatory decision. The phase 3 GLOW study (NCT03462719) and SPOTLIGHT trial (NCT03504397) demonstrated improved overall survival with zolbetuximab plus chemotherapy. In SPOTLIGHT, the median OS was 18.23 months (95% CI, 16.43-22.90) with zolbetuximab plus mFOLFOX6 versus 15.54 months (95% CI, 13.47-16.53) with placebo plus mFOLFOX6 (HR, 0.750; 95% CI, 0.601-0.936; P = .0053).
Dr. Janjigian emphasized the importance of biomarker-based therapy, prioritizing MSI-H status, HER2 (搜索) expression, PD-L1 CPS greater than 1%, and CLD18.2 high expression. Future directions include evaluating CLD18.2 antibody-drug conjugates in first- and second-line settings to further refine treatment strategies for gastroesophageal cancers.