Therapeutic Evolution in Gastroesophageal Adenocarcinoma

The histologic evolution of gastroesophageal cancer from primarily squamous cell to adenocarcinoma has led to a separate evolution in treatment approaches.

Surgery, whenever feasible, remains foundational for both histologies. Treatment approaches diverge with systemic therapy. Chemotherapy, radiation therapy, and adjuvant immunotherapy have key roles in management of resectable squamous cell cancer. However, perioperative systemic therapy has moved to the forefront for resectable gastroesophageal adenocarcinoma (GEA).

“We have more cumulative evidence supporting the perioperative approach with chemotherapy plus immunotherapy — based on the MATTERHORN trial — as the way to go for patients with adenocarcinoma histology,” said Anwaar Saeed, MD, of the University of Pittsburgh Medical Center. “This was proven positive in gastroesophageal junction cancer, which is an adenocarcinoma, but we extrapolate that evidence to include esophageal adenocarcinoma because biologically, they’re very close.”

“We have evidence from perioperative trials that [perioperative therapy that includes immunotherapy] is better than chemotherapy alone or chemoradiation,” she added. “So right now, we do not do radiation for patients with adenocarcinoma, based on what I would consider category A evidence.”

On the other hand, the CROSS trial established neoadjuvant chemoradiation as standard of care for resectable squamous cell carcinoma. The randomized CheckMate 577 trial showed that adjuvant nivolumab (Opdivo) improved outcomes in selected patients.

“If we have a patient with esophageal squamous cell carcinoma, we typically treat with a combination of concurrent chemotherapy plus radiation, then they go to surgery, and if they have residual disease or other high-risk factors, we give them adjuvant nivolumab for 12 months,” said Saeed.

“Immunotherapy, in general, works better in squamous cell carcinoma than adenocarcinoma,” she added. “This is not just seen in esophageal squamous but in many other squamous histologies, like anal squamous cell carcinoma, for example.”

Precision-Medicine Approaches

The emergence of adenocarcinoma as the predominant histology of gastroesophageal cancer also fueled a search for targeted therapies to develop precision-medicine approaches to the disease.

“The rise of esophageal adenocarcinoma has transformed treatment,” Saeed told MedPage Today. “Adenocarcinoma behaves biologically very differently from squamous cell carcinoma… . This shift has pretty much moved the field toward more biomarker-driven approaches. That’s because adenocarcinoma is more likely to express targetable alterations, tumor alterations, making targeted therapy and precision oncology increasingly relevant to this esophageal cancer population.”

The targeted therapy era in GEA began with the recognition of a HER2-expressing subgroup, which accounts for 15-20% of all GEA. The randomized ToGA trial showed that adding trastuzumab (Herceptin) to chemotherapy improved overall survival in advanced HER2-positive esophageal cancer versus chemotherapy alone. More than a decade later, KEYNOTE-811 established pembrolizumab (Keytruda) plus trastuzumab and chemotherapy as the first-line standard. Trastuzumab deruxtecan (T-DXd, Enhertu) staked a claim at the head of second line for HER2-expressing cancers in DESTINY-Gastric04.

Earlier this year, the HERIZON-GEA-01 trial established a new first-line standard for unresectable/metastatic HER2-positive GEA when the bispecific antibody zanidatamab (Ziihera) plus the PD-1 inhibitor tislelizumab (Tevimbra) and chemotherapy significantly improved overall survival versus trastuzumab and chemotherapy. The HERIZON-GEA-01 regimen, with or without the immune checkpoint inhibitor (ICI), recently received FDA approval as initial treatment for unresectable/metastatic HER2-positive GEA.

Beyond HER2, the search for potential targets and biomarkers in GEA included an early interest in Claudin 18.2, a cell adhesion molecule expressed in almost 40% of GEA. The interest led to development of the Claudin 18.2 inhibitor zolbetuximab (Vyloy), which significantly improved progression-free survival and overall survival in the phase III SPOTLIGHT and GLOW trials, providing the basis for FDA approval as first-line therapy for HER2-negative GEA.

The latest version of the National Comprehensive Cancer Network (NCCN) esophageal cancer guidelines recommend testing all patients with resectable esophageal cancer for HER2, Claudin 18.2, and PD-L1 expression, as well as mismatch repair deficiency/microsatellite instability high. Patients with unresectable disease should be tested for HER2 and Claudin 18.2, said Shadia Jalal, MD, of the Indiana University Simon Comprehensive Cancer Center in Indianapolis, and a member of the NCCN esophageal panel.

Additionally, patients considered for clinical trials might warrant consideration of next-generation sequencing, as the tumor-agonistic approval status of certain ICIs makes the agents potential therapeutic candidates for patients with BRAF or NTRK alterations, said Jalal.

Need for More Biomarkers, Guidance

Numerous other potential biomarkers are under investigation as targets for therapeutic development and to provide guidance for treatment decisions. Potential targets include existing biomarkers (such as VEGF, EGFR, HER3), glycoproteins, adhesion molecules, other ICI targets, and targets of various cellular therapies.

“A lot more targets need to be validated in phase III trials,” said Zev Wainberg, MD, of UCLA Health in Los Angeles, during the American Society of Clinical Oncology meeting earlier this year. “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.”

Better biomarker-directed guidance for use of immunotherapy remains a key unanswered question for GEA, said Saeed.

“One of the gaps [in knowledge] is identifying markers that could accurately take the patient who would respond to immunotherapy,” she said. “The markers that we test for nowadays are not mutually exclusive. For example, the patient who has high PD-L1 [expression] could also be HER2 positive and Claudin 18.2 positive. If a patient is positive for all of these, which therapy are you going to start with? We don’t have the evidence that would tell us whether we should start with this drug versus that drug. This is a common question that community oncologists raise.”

Better immunotherapy approaches also remains a key need.

“There have been a lot of advancements in terms of incorporating PD-1 therapy into the chemotherapy landscape, but not much as far as other novel immune therapeutics, such as bispecific T-cell engagers, bispecific antibodies, CAR T cells, and other immune technologies or approaches,” said Saeed. “So, we’re looking forward to the era of having all of these options, or at least more options, for our patients.”