Biomarkers for Esophageal Cancer Continue to Evolve

Biomarker discovery has played an essential role in the development of more effective therapy for multiple types of solid tumors, including esophageal cancer.

The applicability of biomarkers in esophageal cancer continues to evolve. For patients with resectable disease, the search is ongoing for markers that can reliably guide perioperative therapy, said Zev Wainberg, MD, of UCLA Health in Los Angeles, during an education session at the American Society of Clinical Oncology meeting. Advanced disease has four validated biomarkers, and investigators are homing in on several other promising prospects.

“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,” said Wainberg. “Beyond [current] antibodies, new drugs targeting these proteins will start to become standard in bispecifics, ADCs [antibody-drug conjugates], and others. Beyond IHC, genomic biomarkers are being tested in advanced disease but are not yet validated in phase III studies.”

The four markers cited by Wainberg have found a place in National Comprehensive Cancer Network (NCCN) recommendations for biomarker testing. MMR — specifically microsatellite instability-high (MSI-H) — figures prominently in the 2026 update to the NCCN guidelines for esophageal cancer, said Shadia Jalal, MD, of the Indiana University Simon Comprehensive Cancer Center in Indianapolis.

“Probably the most notable changes relate to the MSI-high, or deficient MMR, subgroup of patients,” Jalal, a member of the NCCN esophageal cancer guidelines panel, told MedPage Today. “We have data from other malignancies, such as colon cancer, where it’s unclear whether [that subgroup] will benefit from neoadjuvant chemotherapy, but if they get neoadjuvant immune checkpoint inhibitors, they do have a good chance of responding, both radiologically and pathologically.”

“Biomarker testing has become really central for esophageal cancer,” she added. “Focusing for a moment on adenocarcinomas, you definitely want to do MSI testing and you definitely want to do PD-L1 expression by IHC. Those two are very important, even when discussing preoperative treatment. If patients have unresectable or metastatic disease, you absolutely need HER2 IHC testing and you need Claudin 18.2 testing because of the recent FDA approval of zolbetuximab [Vyloy].”

For potential participants in clinical trials, next-generation sequencing warrants consideration. Some immune checkpoint inhibitors have tumor-agnostic approvals, making them potential therapeutic options for appropriately selected patients with BRAF or NTRK alterations. Though uncommon in esophageal cancer, patients with those mutations can be identified by next-generation sequencing, said Jalal.

All validated biomarkers for advanced esophageal cancer have support from phase III trials.

MSI-H

“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,” said Wainberg. “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.”

Still, some questions remain unanswered, such as the need for chemotherapy at all or the need for dual immune checkpoint inhibition, such as nivolumab plus ipilimumab (Yervoy).

“In my opinion, it has a lot to do with clinical factors,” said Wainberg. “It really boils down to instinct, bulk of disease, all sorts of things that people are looking at. … Most studies now are centering on the role of immunotherapy in perioperative approaches, and hopefully, organ preservation, so we’re going to be using our clinical judgment.”

Looking at the next step for patients with disease that progresses after an immuno-oncology regimen, he noted that, in many instances, progression is oligometastatic. Does chemotherapy have a role or, because most lesions are chemoresistant, should the focus shift to other therapeutic targets of interest?

PD-L1

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],” said Wainberg.

“What has been more reassuring is we’re starting to see long-term survival from these studies,” he continued. “We’re starting to see that there is a shared tail of the [survival] curve in these studies, especially in the group of patients who are PD-L1 high. 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.”

Key unanswered questions are whether patients need 2 years of checkpoint inhibitor therapy and whether chemotherapy can be de-escalated or even omitted entirely in some patients with microsatellite-stable cancers.

“These are questions I sometimes struggle with in my clinic,” said Wainberg. “Also, will bispecific antibodies replace these drugs entirely? There is a surge of bispecific PD-L1/VEGF drugs that are going into massive phase III testing. … 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.”

HER2

This is the best validated target “because we’ve got drugs for it,” noted Wainberg. Monoclonal antibodies, ADCs, and bispecific antibodies have all been validated for HER2-expressing gastroesophageal cancer. Patients who received trastuzumab (Herceptin) plus chemotherapy consistently improved versus chemotherapy, but interestingly, outcomes in the trials have improved over time, he said. The improvements in follow-up analyses meant that outcomes in the control arms of the trials also improved over time, indicating that “we’re doing a much better job of strict baseline screening for HER2.”

The improved outcomes have paved the way for second-line therapies, such as trastuzumab deruxtecan (T-DXd; Enhertu). In the recent HERIZON-GEA-01 trial of zanidatamab (Ziihera) and tislelizumab (Tevimbra), a substantial proportion of patients in the control arm received T-DXd following progression on trastuzumab and chemotherapy, leading to a median OS of 19.2 months, Wainberg said.

The KEYNOTE-811 trial investigated the addition of pembrolizumab to chemotherapy and trastuzumab as first-line therapy for metastatic HER2-positive gastric or gastroesophageal cancer. At the third interim analysis, pembrolizumab had improved PFS and response rate but not OS. Additionally, a subgroup analysis suggested patients with PD-L1 CPS <1 fared worse with the PD-1 inhibitor. An updated analysis showed a significant OS advantage and, perhaps more important, no survival detriment for the PD-L1 low group.

HERIZON-GEA-01 introduced a new consideration to the therapeutic options. The trial evaluated the addition of the bispecific antibody zanidatamab to chemotherapy, with or without the PD-1 inhibitor tislelizumab, versus trastuzumab and chemotherapy. The results had some striking observations, said Wainberg.

Adding the bispecific to immunotherapy and chemotherapy resulted in an OS exceeding 2 years, a landmark for patients with HER2-positive gastroesophageal cancer. Zanidatamab plus chemotherapy also outperformed the trastuzumab-chemotherapy control arm, although the difference in OS did not achieve statistical significance. Notably, while the three-drug arm was not directly compared to zanidatamab and chemotherapy, the two arms had nearly identical PFS, and OS was similar but did not achieve statistical significance for zanidatamab-chemotherapy versus trastuzumab-chemotherapy.

“That raises the question of what is the role of PD-L1,” said Wainberg.

However, KEYNOTE-811 and HERIZON-GEA-01 used different measures of PD-L1 expression — CPS versus tumor area positivity, respectively.

“I think personally we need a little bit longer follow-up time to see the true impact of the PD-1 inhibitor,” he said.

Claudin 18.2

The SPOTLIGHT and GLOW trials validated Claudin 18.2 as a biomarker for the subgroup of patients with advanced gastric or gastroesophageal cancer responsive to zolbetuximab. Both trials showed that adding the Claudin 18.2 inhibitor improved the OS hazard by about 25% versus chemotherapy.

However, studies have shown considerable biomarker overlap between Claudin 18.2 and PD-L1, noted Wainberg. About 15% to 20% of patients with advanced gastroesophageal cancer have tumors that are both Claudin 18.2-positive and PD-L1 CPS >10.

“It’s probably far greater than that,” he said. “If you lower the cutoff for Claudin 18.2, which all of the new drugs are testing, we’re going to find almost uniform overlap, in my opinion, between PD-L1-positive and Claudin 18.2-positive.”

Studies have shown some interesting trends, Wainberg pointed out. Claudin-positive patients tend to have a lower CPS than Claudin-negative patients. The positive patients tend to be younger and more likely to have diffuse histology. Recently published results from the phase II ILUSTRO study showed that adding zolbetuximab to nivolumab and chemotherapy resulted in an overall response rate of 68% as first-line therapy for unresectable/metastatic gastric or gastroesophageal cancer and an “almost unprecedented” 18-month PFS, said Wainberg.

These results support ongoing evaluation in the phase III LUCERNA trial, which just completed enrollment. Primary results will not be reported for at least 2 years. In the meantime, three different phase III trials yielded negative results for adding a PD-(L)1 inhibitor to frontline treatment for advanced gastric cancer.

“These were biomarker-selected trials,” said Wainberg. “The point being that just because we had a fantastic median PFS in a single-arm study, that doesn’t mean we’ll be able to replicate that in a phase III trial. We’ll have to wait for the results.”

Outcomes for advanced/metastatic gastroesophageal cancer are better than ever but the field still has a long way to go.

“A lot more targets need to be validated in phase III trials, and they need not be exclusively IHC directed,” said Wainberg. “How many patients do we see with CDH1 and ARID1A mutations who are being left behind by perhaps too much direction in certain biomarkers? A large unmet need exists for these patients, and we need to refocus our energy on novel target discovery.”