Staging Pitfalls, Biomarker-Guided Care, and Emerging Targets in Esophageal Cancer: Your Clinical Questions Answered

During Esophageal Cancer Awareness Month, OncLive® sat down with Peter Enzinger, MD, to break down and address key areas of uncertainty encountered in routine practice. The following FAQ, adapted from this conversation, provides insights into the clinical nuances shaping contemporary esophageal cancer diagnosis and management, including diagnostic and staging pitfalls, the role of curative-intent surgery and chemoradiation, and emerging biomarker-driven approaches of interest.

Enzinger serves as director of the Center for Esophageal and Gastric Cancer, institute physician, and a medical oncologist at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.

Read on to have your questions answered!

Q: What are the most common diagnostic or staging pitfalls you see in esophageal cancer, and when should patients be referred to a high-volume center?

A: A central challenge in esophageal cancer management is accurately determining whether a patient has localized or metastatic disease—a distinction with profound implications for treatment intent and outcome. Enzinger emphasized that this determination requires rigorous workup, because retrospective ambiguity about a patient’s disease stage can undermine interpretation of treatment responses.

“The main pitfall is that we often don’t know for certain if a patient is metastatic or not, and that often requires additional testing. And the testing does need to be completed, because if the patient has a good response, in retrospect, we won’t know if the patient was metastatic or not,” Enzinger stated.

He stressed that oncologists should not assume metastatic disease without thorough investigation and that a follow-up biopsy, MRI, or PET CT scan may be necessary to confirm staging. The distinction between localized and metastatic disease is, as Enzinger put it, “life and death in the localized disease setting.” Given this complexity, referral to a high-volume center with multidisciplinary expertise is strongly advised to ensure staging accuracy and appropriate treatment planning.

Q: How should staging be approached in newly diagnosed esophageal cancer, and what imaging or modalities are central to guide treatment decisions?

A: Newly diagnosed patients typically present after upper endoscopy, but Enzinger noted that complementary staging evaluations are frequently incomplete at the time of referral. He outlined 2 categories of workup that are often missing:

• Imaging: A PET CT scan is the primary staging modality, supplemented by MRI for anatomical detail and detection of equivocal findings.
• Biomarker profiling: Mismatch repair (MMR) status and PD-L1 combined positive score (CPS) are critical to identify; for metastatic patients, HER2 and Claudin 18.2 (CLDN18.2) expression must be obtained.

“Often the other tests are still lacking—that would include primarily a PET CT scan and then any sort of follow-up imaging, like an MRI. The other thing that often is missing is that we don’t have the biomarkers yet,” Enzinger observed.

Q: What is the current role of surgery in esophageal cancer? How do you determine which patients benefit most from surgery vs definitive chemoradiation or systemic therapy?

A: Surgery continues to anchor curative-intent treatment for esophageal cancer, but its application is increasingly histology-dependent. For esophageal squamous cell carcinoma (ESCC), many centers are moving away from upfront surgery, reserving resection for cases with residual disease following definitive chemoradiation. In contrast, surgery is integral to adenocarcinoma management, as chemotherapy alone rarely leads to complete responses.

“Surgery continues to be the most important curative treatment for this disease,” Enzinger said, while acknowledging that the field is evolving toward non-operative strategies as systemic therapies improve. He cited MSI-high esophageal cancers as an example where the paradigm has already shifted: “Most of these patients are cured without surgery.”

Enzinger expressed optimism that advances in targeted and immunotherapy approaches will eventually extend nonoperative approaches beyond MSI-high tumors to broader populations.

Q: Why are multidisciplinary approaches critical for esophageal cancer management, and what key specialties should be involved in early care planning?

A: Multidisciplinary tumor boards have long been a cornerstone of esophageal and gastric cancer management, though the composition of these teams is evolving in parallel with treatment paradigms. Historically, surgical oncology, radiation oncology, and medical oncology were all integral to upfront planning. However, Enzinger noted that as radiation has been deprioritized for adenocarcinoma, the core multidisciplinary team for these patients has effectively narrowed to 2 specialties: medical oncology and surgery.

Radiation oncology remains essential for patients with ESCC, for whom definitive chemoradiation continues to play a primary role. Enzinger summarized the practical effect: “For adenocarcinoma, treatment has frankly gotten simpler.”

Early involvement of all relevant specialties, even if their active role ultimately diminishes based on histology, remains important to ensure that individualized treatment planning accounts for all therapeutic modalities, he emphasized.

Q: Which emerging target therapies or biomarker-driven approaches have the most potential for esophageal cancer today?

A: Although chemotherapy remains a cornerstone, the treatment paradigm is increasingly defined by the identification of specific targets, most notably HER2 and CLDN18.2, Enzinger stated.

The advancement of CLDN18.2-directed therapy represents a significant shift for patients with HER2-negative disease, as evidenced by the October 2024 FDA approval of zolbetuximab (Vyloy) in combination with platinum- and fluoropyrimidine-containing chemotherapy for adult patients with untreated, locally advanced or metastatic, HER2-negative, CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma.¹

This approval was supported by findings from 2 phase 3 trials:^2,3

• SPOTLIGHT (NCT03504397): The median progression-free survival (PFS) with zolbetuximab with mFOLFOX6 (leucovorin, fluorouracil, and oxaliplatin. was 10.6 months (n = 283; 95% CI, 8.9-12.5) compared with 8.7 months (95% CI, 8.2-10.3) for those given placebo plus chemotherapy (n = 282; HR, 0.751; 95% CI, 0.598-0.942; 1-sided P = .0066). The median overall survival (OS) was 18.2 months (95% CI, 16.4-22.9) in the zolbetuximab arm vs 15.5 months (95% CI, 13.5-16.5) in the placebo arm (HR, 0.750; 95% CI, 0.601-0.936; 1-sided P = .0053).
• GLOW (NCT03653507): Zolbetuximab in combination with CAPOX (capecitabine [Xeloda] and oxaliplatin) generated a median PFS of 8.2 months (n = 254; 95% CI, 7.5-8.8) vs 6.8 months (95% CI, 6.1-8.1) for placebo plus CAPOX (n = 253; HR, 0.687; 95% CI, 0.544-0.866; 1-sided P = .0007). The median OS was 14.4 months (95% CI, 12.3-16.5) and 12.2 months (95% CI, 10.3-13.7), respectively (HR, 0.771; 95% CI, 0.615-0.965; 1-sided P = .0118).

HER2-targeted agents such as trastuzumab (Herceptin) and fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) have also been vital components of care.

Enzinger characterized zolbetuximab as representing the current threshold of approved targeted options, while underscoring the ambition to push beyond it. “The future is not only to expand these particular targets by having more ways in which we target HER2…and CLDN18.2, but we also want to expand to other targets. The hope is to expand these biomarker-driven therapies as quickly as possible,” Enzinger stated.

Additional targets with therapeutic potential include FGFR, MET, EGFR, EpCAM, and CEACAM.

Q: Are there any clinical trials or novel strategies that have the potential to change the standard of care in esophageal cancer?

A: Enzinger highlighted 3 key phase 3 trials with practice-changing potential in the near future:

• HERIZON-GEA-01 (NCT05152147): Zanidatamab-hrii (Ziihera) + chemotherapy ± tislelizumab (Tevimbra)⁴
  • Results from an interim analysis of HERIZON-GEA-01presented at the 2026 Gastrointestinal Cancers Symposium showed statistically significant OS and PFS benefit with the addition of the bispecific HER2-targeted antibody zanidatamab to standard platinum and fluorouracil-based therapy with/without tislelizumab vs trastuzumab and chemotherapy.
  • Of note, PFS and OS benefits were generally consistent with both zanidatamab-based regimens across key prespecified subgroups, including geographic region and PD-L1 tumor area positivity (TAP) score.
  • Enzinger expressed confidence that regulatory approval is likely, though the exact labeling—whether approval will be broad across checkpoint inhibitor combinations or specifically with tislelizumab—remains to be determined.
  • He also flagged an emerging downstream consideration: “We’re beginning to hear that T-DXd doesn’t seem to be as efficacious after zanidatamab as it is after trastuzumab-based therapies, so the downstream effects of more effective frontline therapy will also be interesting to follow.”
• KEYNOTE-975 (NCT04210115): Pembrolizumab (Keytruda) + chemoradiation in localized disease⁵
  • This ongoing trial is evaluating the addition of the PD-1 inhibitor pembrolizumab to definitive chemoradiation (dCRT) vs dCRT alone for patients with locally advanced esophageal cancer.
  • Enzinger noted that results are anticipated soon and expressed guarded optimism, particularly for SCC: “For SCC, I do see the potential there for having a statistically significant result, and potentially we’ll have immunotherapy available as well for the locally advanced patients.” He was more circumspect about the potential benefit in adenocarcinoma histology.
• LUCERNA (NCT06901531): Zolbetuximab + checkpoint inhibition in CLDN18.2–positive GEJ adenocarcinoma⁶
  • LUCERNA is comparing zolbetuximab plus pembrolizumab and chemotherapy with placebo, pembrolizumab, and mFOLFOX6 or CAPOX in the first-line setting for the treatment of patients with CLDN18.2-positive, HER2-negative, PD-L1–positive locally advanced or metastatic disease.
  • The trial is designed to address a key clinical gap in sequencing, as current regulatory approvals position both checkpoint inhibitors and zolbetuximab in the frontline setting, thereby limiting the ability to use both modalities sequentially.
  • The study is supported by results from earlier phase 2 trials such as cohort 4B of ILUSTRO (NCT03505320), which indicated favorable preliminary efficacy and safety for similar zolbetuximab-based combinations.⁷
  • Enzinger views the study as particularly compelling given its potential to address a key clinical sequencing dilemma: “LUCERNA is especially interesting because it tackles a real-world challenge we face—choosing between a checkpoint inhibitor and CLDN18.2-targeted therapy,” Enzinger explained. “Right now, these agents are largely confined to the frontline setting, which means that if you select one approach, you often lose the opportunity to use the other later.”

Additional studies of interest in gastric/GEJ cancers include:

• Phase 2/3 ROSETTA Gastric-204 (NCT07221149)
• Phase 3 DESTINY-Gastric04 (NCT04704934)
• Phase 3 ARTEMIDE-Gastric01 (NCT06764875)
• Phase 3 CLARITY-Gastric 01 (NCT06346392)

Enzinger also underscored the importance of sequencing considerations as frontline regimens become more potent—a topic that will require prospective study as the field evolves.

References

1. FDA approves zolbetuximab-clzb with chemotherapy for gastric or gastroesophageal junction adenocarcinoma. FDA. October 18, 2024. Accessed April 28, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zolbetuximab-clzb-chemotherapy-gastric-or-gastroesophageal-junction-adenocarcinoma
2. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2023;401(10389):1655-1668. doi:10.1016/S0140-6736(23)00620-7
3. Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med. 2023;29(8):2133-2141. doi:10.1038/s41591-023-02465-7
4. Elimova E, Rha SY, Shitara K, et al. Zanidatamab + chemotherapy (CT) ± tislelizumab for first-line (1L) HER2-positive (HER2+) locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma (mGEA): primary analysis from HERIZON-GEA-01. J Clin Oncol. 2026, 44(suppl 4):LBA285.doi:10.1200/JCO.2026.44.2_suppl.LBA285
5. A study of pembrolizumab (MK-3475) plus chemoradiation in participants with esophageal cancer (MK-3475-975/KEYNOTE-975). ClinicalTrials.gov. Updated November 15, 2024. Accessed April 28, 2026. https://clinicaltrials.gov/study/NCT04210115
6. Shitara K, Enzinger PC, Lordick F, et al. Zolbetuximab + pembrolizumab and chemotherapy as first-line treatment for patients with CLDN18.2-positive, HER2-negative, PD-L1-positive locally advanced unresectable or metastatic G/GEJ adenocarcinoma: phase 3, double-blind, randomized trial (LUCERNA). J Clin Oncol. 2026, 44(suppl 2):TPS473.doi:10.1200/JCO.2026.44.2_suppl.TPS473
7. Shitara K, Shoji H, Fazio N, et al. Phase 2 ILUSTRO trial of 1L zolbetuximab plus mFOLFOX6 and nivolumab in patients with CLDN18.2+ locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. J Clin Oncol. 2026,44(suppl 2):LBA284.doi:10.1200/JCO.2026.44.2_suppl.LBA284