LOS ANGELES — Microsatellite instability-high (MSI-H) has been added as a recommended biomarker test for esophageal cancer in the 2026 update to the National Comprehensive Cancer Network (NCCN) guidelines. The change reflects growing evidence that MSI-H status identifies a subgroup of patients who derive benefit from immune checkpoint inhibitors over traditional chemotherapy.

During an education session at the American Society of Clinical Oncology (ASCO) meeting, experts the clinical importance of comprehensive biomarker testing in esophageal cancer. Zev Wainberg, MD, of UCLA Health in Los Angeles, emphasized that “biomarker testing has become really central for esophageal cancer.” Shadia Jalal, MD, a member of the NCCN esophageal cancer guidelines panel from the Indiana University Simon Comprehensive Cancer Center in Indianapolis, noted that “probably the most notable changes relate to the MSI-high, or deficient MMR, subgroup of patients.”

Advanced esophageal disease now has four validated biomarkers: mismatch repair (MMR), HER2, PD-L1, and Claudin 18.2. According to Wainberg, “Right now MMR [mismatch repair], HER2, PD-L1, and Claudin 18.2 are validated IHC [immunohistochemistry] markers and should be tested in all patients with advanced disease.” These four biomarkers are included in the NCCN recommendations for biomarker testing, and all have support from phase III clinical trials. Investigators continue to research additional promising biomarker prospects for advanced esophageal disease.

Jalal stressed the importance of biomarker testing even in the preoperative setting, particularly for adenocarcinomas. “Focusing for a moment on adenocarcinomas, you definitely want to do MSI testing and you definitely want to do PD-L1 expression by IHC,” she said. “Those two are very important, even when discussing preoperative treatment.” For patients with unresectable or metastatic disease, she added, “you absolutely need HER2 IHC testing and you need Claudin 18.2 testing because of the recent FDA approval of zolbetuximab [Vyloy].”

MSI-high gastroesophageal adenocarcinoma represents about 3% to 5% of advanced disease and is associated with chemoresistance. Wainberg explained, “We've known for awhile from [the Cancer Genome Atlas] that MSI-high gastroesophageal adenocarcinoma represents about 3% to 5% of advanced disease, and we know these patients are notoriously chemoresistant.” Phase III trials comparing chemotherapy to checkpoint inhibitors have shown a clear advantage for checkpoint inhibitors in this subgroup. Specifically, pembrolizumab (Keytruda) demonstrated an advantage in the KEYNOTE-062 trial, and nivolumab (Opdivo) showed benefit in the CheckMate 649 trial. Wainberg summarized, “A number of phase III trials that have compared chemotherapy to checkpoint inhibitors have shown there's a clear advantage to checkpoint inhibitors, such as pembrolizumab (Keytruda) in the KEYNOTE-062 trial and [nivolumab, Opdivo] in CheckMate 649, and others.”

For PD-L1–positive disease, three large randomized trials—RATIONALE-305, KEYNOTE-859, and CheckMate 649—have demonstrated consistent benefits in both progression-free survival (PFS) and overall survival (OS) among patients with gastric or gastroesophageal cancers and a combined positive score (CPS) ≥1. Wainberg noted, “Three large randomized trials -- RATIONALE-305, KEYNOTE-859, and CheckMate 649 -- showed that patients with gastric or gastroesophageal cancers that have a combined positive score (CPS) ≥1 'have a consistent benefit with very similar hazard ratios... for PFS [progression-free survival] and OS [overall survival].'” He added, “What has been more reassuring is we're starting to see long-term survival from these studies,” and pointed to “a shared tail of the [survival] curve in these studies, especially in the group of patients who are PD-L1 high.”

In these trials, 15% to 20% of patients who are PD-L1 high appear to be long-term survivors. Wainberg observed, “In these studies, 15% to 20% of patients who are PD-L1 high seem to be long-term survivors, which presents all sorts of interesting questions and raises the possibility that a number of these patients are indeed cured.”

HER2 remains the best validated target for gastroesophageal cancer. Monoclonal antibodies, antibody-drug conjugates (ADCs), and bispecific antibodies have all been validated for HER2-expressing gastroesophageal cancer. Patients treated with trastuzumab (Herceptin) plus chemotherapy have consistently shown improved outcomes compared to chemotherapy alone.

Over time, outcomes in HER2 trials—and even in their control arms—have improved, likely due to better baseline HER2 screening and the availability of second-line therapies like trastuzumab deruxtecan (T-DXd; Enhertu). In the HERIZON-GEA-01 trial, a substantial proportion of patients in the control arm received T-DXd after progression on trastuzumab and chemotherapy.

The HERIZON-GEA-01 trial reported a median overall survival of 19.2 months, and demonstrated that zanidatamab plus chemotherapy outperformed trastuzumab plus chemotherapy. Separately, the KEYNOTE-811 trial investigated the addition of pembrolizumab to trastuzumab and chemotherapy as first-line therapy for metastatic HER2-positive gastric or gastroesophageal cancer. At its third interim analysis, pembrolizumab improved progression-free survival and response rate but not overall survival.

However, an updated analysis later showed a overall survival advantage. A subgroup analysis suggested that patients with PD-L1 CPS <1 fared worse with the PD-1 inhibitor.

Despite advances, unanswered questions remain. These include whether patients require two years of checkpoint inhibitor therapy, whether chemotherapy can be de-escalated or omitted in some patients with microsatellite-stable cancers, and whether dual immune checkpoint inhibition—such as nivolumab plus ipilimumab (Yervoy)—is necessary. Wainberg acknowledged the role of clinical judgment, saying, “In my opinion, it has a lot to do with clinical factors,” and adding, “It really boils down to instinct, bulk of disease, all sorts of things that people are looking at.” He noted that “most studies now are centering on the role of immunotherapy in perioperative approaches, and hopefully, organ preservation,” which will rely on individualized decision-making.

Beyond current standards, researchers are exploring next-generation sequencing for clinical trial eligibility and investigating genomic biomarkers not yet validated in phase III studies. While BRAF or NTRK alterations are uncommon in esophageal cancer, they can be identified through next-generation sequencing, and immune checkpoint inhibitors may offer tumor-agnostic therapeutic options for these patients. Wainberg also the emergence of novel agents, stating, “Beyond [current] antibodies, new drugs targeting these proteins will start to become standard in bispecifics, ADCs [antibody-drug conjugates], and others.” He pointed to a surge in bispecific PD-L1/VEGF drugs now in large phase III trials, noting, “All of them have subtle differences with respect to their affinity for PD-1, PD-L1, or VEGF, and all of them are in advanced testing.”

The 2026 NCCN guideline update formalizes MSI-H as a critical biomarker in esophageal cancer, aligning clinical practice with robust phase III evidence showing superior outcomes with checkpoint inhibitors in this subgroup. This change ensures that a small but distinct population—3% to 5% of advanced cases—that is chemoresistant can receive optimal first-line therapy. The integration of MSI-H into standard testing, alongside HER2, PD-L1, and Claudin 18.2, reflects a broader shift toward precision oncology in gastroesophageal cancers, where treatment selection is increasingly driven by molecular profiling rather than histology alone.

The emphasis on long-term survival data and potential cures, particularly among PD-L1–high patients, signals a turning point in outcomes for a historically lethal malignancy. Ongoing research into perioperative immunotherapy, novel bispecific antibodies, and ADCs suggests that biomarker-guided strategies will continue to evolve, with the goal of improving survival while preserving quality of life and organ function.