Later-Line Treatment Gaps in Esophageal Adenocarcinoma Underscore Need for Continued Therapeutic Development, Multidisciplinary Care

Nataliya Uboha, MD, PhD

Despite meaningful advances in biomarker-guided approaches and immunotherapeutic strategies, patients with advanced esophageal or gastroesophageal junction (GEJ) adenocarcinoma continue to face significant challenges related to supportive care and limited second- and later-line treatment options—underscoring the need for multidisciplinary management and ongoing research to expand therapeutic strategies beyond the first-line setting, according to Nataliya Uboha, MD, PhD.

“Comprehensive care requires collaboration across specialties, and patients who have access to this level of multidisciplinary support may experience improved outcomes. Nevertheless, there remains an urgent need for better therapies [in the second and third line],” Uboha, a faculty leader for the Early Phase Oncology Therapeutics Program at the University of Wisconsin Carbone Cancer Center, shared in an interview with OncLive®. “Several investigational agents are in development and entering clinical trials, but there have not yet been major updates in post–first-line treatment strategies.”

In the interview, Uboha expanded on the growing role of biomarkers in guiding both early-stage and advanced esophageal adenocarcinoma management; emphasized the need for comprehensive molecular testing to inform targeted therapy selection; and outlined highly anticipated data in the space that could aid efforts to overcome persistent gaps in supportive care and later-line treatment options.

Uboha, who also served as an associate professor and researcher in the Department of Medicine at the University of Wisconsin School of Medicine and Public Health in Madison, highlighted the significance of Esophageal Cancer Awareness Month and the importance of standard endoscopic procedures for earlier detection of esophageal cancer in a previous article.

OncLive: How do biomarkers help guide treatment decisions in esophageal adenocarcinoma?

Uboha: Biomarkers play a critical role in treatment decisions for patients, particularly those with esophageal adenocarcinomas, including GEJ adenocarcinoma.

In the early-stage setting, every patient with esophageal or GEJ adenocarcinoma should have their tumor evaluated for microsatellite instability–high [MSI-H] and mismatch repair–deficient [dMMR] protein expression. The treatment for these patients differs significantly. Tumors that are dMMR or MSI-H are exquisitely sensitive to immunotherapy. These patients should not receive chemotherapy prior to surgery; rather, they should receive immunotherapy.

In patients with more advanced disease, biomarker testing is essential to enable the selection of the most effective and personalized treatment. For adenocarcinoma, standard chemotherapy is FOLFOX [fluorouracil, leucovorin, and oxaliplatin]. The same applies to esophageal squamous cell carcinoma, where FOLFOX remains the backbone. However, additional agents may be added based on biomarker results.

Immunotherapy has demonstrated clinical activity in both esophageal adenocarcinoma and squamous cell carcinoma. Immune checkpoint inhibitors targeting PD-1—including pembrolizumab [Keytruda], nivolumab [Opdivo], and most recently atezolizumab [Tecentriq]—are effective primarily in tumors expressing PD-L1. Therefore, it is critical to assess PD-L1 expression to determine potential benefit from these agents.

For adenocarcinoma, additional biomarkers must also be tested. HER2 expression remains an important target. More recently, Claudin 18.2 [CLDN18.2] expression has emerged as a relevant biomarker, particularly in distal esophageal and GEJ adenocarcinomas. A new agent, zolbetuximab [Vyloy]—an anti-CLDN18.2 monoclonal antibody—has shown clinical benefit when added to first-line chemotherapy in patients with CLDN18.2-positive tumors.

What are some of the ongoing clinical trials with the potential to shift the esophageal cancer treatment paradigm?

The major trial that the field is currently awaiting results from is the [phase 3] MATTERHORN trial [NCT03794544]. Although not limited to esophageal cancer, the trial specifically includes patients with GEJ tumors—those located in the lower esophagus. In the United States, these lower esophageal tumors are biologically similar to gastric cancers.

The MATTERHORN trial is evaluating the addition of the anti–PD-L1 agent durvalumab [Imfinzi] to FLOT chemotherapy in patients with early-stage, potentially curable disease. A press release issued in March by the trial’s sponsor, AstraZeneca, indicated that the study met one of its primary end points [of event-free survival]. This is a noteworthy development, as the trial targets a curative-intent population, and an improvement in cure rates would be a significant advancement in the management of this disease.

Results from the MATTERHORN trial are expected to be presented at an upcoming scientific meeting, and this is currently one of the most anticipated studies in early-stage gastroesophageal adenocarcinoma.

There are also advances in the metastatic setting. New biomarkers are being identified in advanced GEJ adenocarcinoma, one of which is FGFR2b. Ongoing phase 3 trials are evaluating bemarituzumab, an anti-FGFR2b monoclonal antibody, in patients with advanced disease. These developments indicate that treatment for patients with advanced disease is becoming increasingly personalized. A critical component of treatment selection is comprehensive biomarker testing. Every patient should have their tumor molecularly characterized to identify gene mutations and protein expression profiles in order to tailor therapy as precisely as possible.

What challenges persist for patients with advanced esophageal or GEJ cancer? Is any research being conducted to address these?

There have been significant changes in first-line treatment for patients with advanced disease. However, one of the ongoing challenges is ensuring optimal support for patients throughout their treatment. This requires a multidisciplinary team approach. Nutritional support from registered dietitians is essential, especially given the disease's impact on appetite and weight. Oncology nurses play an indispensable role in the delivery and monitoring of chemotherapy. Nurse practitioners also contribute substantially to longitudinal patient management.

Patients with advanced disease often have complex symptom burdens and significant supportive care needs. Integration of palliative care is critical and should begin early in the course of disease management. Radiation oncologists are key partners in managing symptoms that may benefit from palliative radiotherapy, even in the metastatic setting.

Comprehensive care requires collaboration across specialties, and patients who have access to this level of multidisciplinary support may experience improved outcomes. Nevertheless, there remains an urgent need for better therapies. Although first-line treatments have improved, they are not curative in the metastatic setting. The need for effective second- and third-line options remains high. Several investigational agents are in development and entering clinical trials, but there have not yet been major updates in post–first-line treatment strategies.