Additional Advances in Esophagogastric Cancer Research and Clinical Trials

The treatment of esophagogastric cancer has undergone a profound transformation in recent years, driven by advances in immunotherapy, precision biomarker testing, and a growing recognition that early, coordinated multidisciplinary care is essential to improving outcomes. In this edition of Additional Advances, Yelena Janjigian, MD, Medical Oncologist and Chief of the GI Oncology Service at Memorial Sloan Kettering Cancer Center, discusses the latest developments in esophagogastric cancer management and the critical role of translating these advances into meaningful patient benefit.

A Paradigm Shift: Chemoimmunotherapy in the Perioperative Setting

Perhaps the most significant recent advancement in esophagogastric cancer is the definitive demonstration that incorporating immunotherapy into the perioperative setting—before and after surgical resection—substantially improves outcomes. Dr. Janjigian describes this as a fundamental shift in the treatment paradigm.

"The biggest advancement we've made is definitively demonstrating that using a mutual blockade in early-stage cancer in the perioperative setting, meaning before we take the cancer out of the patient, improves outcomes and survival," she explained. Specifically, initiating chemoimmunotherapy immediately after diagnosis can result in complete pathologic response or significant downstaging, with very few cancer cells remaining at the time of surgery. "In those patients, the likelihood of cure is nearly 100% with long-term follow-up," Dr. Janjigian explained, noting that “cure” refers to long-term overall survival benefit—a remarkable benchmark for a disease historically associated with poor prognosis.

The MATTERHORN study was pivotal in bringing durvalumab to the perioperative setting. Notably, durvalumab demonstrated benefit irrespective of programmed death-ligand 1 (PD-L1) status, broadening its potential applicability. This finding has shifted the focus of ongoing development toward other tumor-specific biomarkers, including HER2, CLDN18.2, and microsatellite instability (MSI), which may further refine patient selection and optimize outcomes.

The Critical Role of Accurate Staging and Biomarker Testing

A recurring theme in Dr. Janjigian's commentary is the danger of understaging and the consequences of proceeding to surgery without adequate preoperative evaluation. She highlighted that patients who appear to be early-stage on imaging may harbor more advanced disease, and that proceeding directly to surgery in these cases represents a missed therapeutic opportunity.

"If you start with chemoimmunotherapy immediately after diagnosis, there's a chance of complete response or a significant downstaging," she said. Conversely, patients who undergo surgery first and are found to have positive margins or more advanced pathologic staging lose the benefit of neoadjuvant immune priming. "It's a really devastating loss of an opportunity to educate the immune system, to get the response assessment in vivo, and to improve outcome in these patients," Dr. Janjigian emphasized.

She also stressed the importance of listening to the patient during staging. "You have to talk to the patient. And if they're saying, ‘I'm losing weight’ or ‘I'm really not nutritionally in the same place as I was,’ no matter what the staging imaging shows, this is not an early-stage tumor." She recommends erring on the side of perioperative chemoimmunotherapy, supplementing imaging with PET scans, CT scans, laparoscopy, and cytology to ensure all accurate, updated data informs the treatment plan.

Comprehensive prospective biomarker testing is equally essential. Dr. Janjigian urges clinicians to test all adenocarcinoma patients for microsatellite instability, PD-L1, HER2, and CLDN18.2. "Please do prospective biomarker testing on all your patients," she said, noting that these results directly guide therapeutic selection and clinical trial eligibility.

Multidisciplinary Collaboration as a Standard of Care

Dr. Janjigian is emphatic that optimal outcomes in esophagogastric cancer cannot be achieved by any single specialty in isolation. Surgeons, medical oncologists, pathologists, radiologists, and nurses must communicate proactively before treatment decisions are made. "To advance this disease, we need to communicate and properly develop a treatment plan before we jump into surgery," she said.

She acknowledges the practical realities of busy clinical environments but encourages creative solutions. "Most hospitals don't have the time for clinicians to sit together in the same room. Everyone is so fast-paced, but we're just a phone call away." For clinicians in community settings or lower-volume centers, she strongly recommends referring patients to centers of excellence where clinical trial participation is available. "If you can, please refer patients to a center of excellence where they can participate in a clinical trial, because that definitely advances the field forward."

Reasons for Optimism

Dr. Janjigian closed with a message of hope, contrasting the current landscape with the pessimism that characterized esophagogastric cancer management in the early 2000s. "The nihilistic approach that was taken in early 2000s is very much outdated. We need to be hopeful that even in patients with metastatic disease, but certainly in localized disease, there's a substantial chance of cure." With new HER2-targeted agents entering the market, five-year survival data emerging from landmark trials such as CheckMate 649, and a rapidly evolving targeted therapy landscape, she urges all clinicians—even those seeing only one or two of these patients per month—to stay current through reputable online resources, peer consultation, and continuing medical education.

Key Takeaways

• Perioperative chemoimmunotherapy is a paradigm shift: Initiating treatment before surgery can yield near-complete pathologic responses and dramatically improve cure rates.

• Accurate staging is non-negotiable: Clinical understaging leads to missed opportunities for neoadjuvant therapy; supplement imaging with PET, CT, laparoscopy, and cytology when indicated.

• Comprehensive biomarker testing is essential for all adenocarcinomas: MSI, PD-L1, HER2, and CLDN18.2 should be tested prospectively to guide treatment selection.

• Multidisciplinary communication before surgery is critical: Premature surgical intervention without oncologic input can result in suboptimal outcomes.

• Refer to centers of excellence: Clinical trial participation advances the field and may offer patients access to emerging therapies.

• Optimism is warranted: Nihilistic approaches from the early 2000s are now outdated—cure is an achievable goal in localized disease.

About Dr. Janjigian

Yelena Y. Janjigian, MD, is the Chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center. She specializes in the treatment of gastrointestinal (GI) cancers, including esophageal, gastric, colorectal, anal, liver, and pancreatic cancers. Dr. Janjigian has led several seminal studies that changed practice and established a standard of care for these diseases. Her research focuses on defining the therapeutically relevant molecular characteristics of the GI tract, developing new treatments, and improving patient outcomes.