Immunotherapy, which harnesses the body’s own immune system to fight cancer, has become a significant advance in the treatment of esophageal cancer. This disease, which affects the tube connecting the throat to the stomach, is historically challenging to treat, especially once it has spread. The effectiveness of immunotherapy is measured through specific clinical metrics that help determine the likelihood of tumor shrinkage and prolonged patient survival.
Understanding Immunotherapy and Esophageal Cancer Types
The primary form of immunotherapy used for esophageal cancer involves immune checkpoint inhibitors, which are specialized antibody drugs. These inhibitors, such as PD-1/PD-L1 blockers, work by essentially “taking the brakes off” the immune system’s T-cells. Cancer cells often express the PD-L1 protein, which binds to the PD-1 protein on T-cells, acting as an “off switch” that prevents the immune cell from attacking the tumor. Blocking this interaction allows the T-cells to recognize and destroy the cancer cells, reactivating the body’s natural defense mechanism.
Esophageal cancer is broadly divided into two major histological types, and the response to immunotherapy often differs between them. Esophageal Adenocarcinoma (EAC) typically arises in the lower part of the esophagus and is more common in Western countries, often linked to chronic acid reflux and obesity. Esophageal Squamous Cell Carcinoma (ESCC) usually develops in the upper or middle part of the esophagus and is more prevalent in Eastern countries, with strong associations to tobacco and alcohol use.
Because of the distinct biological characteristics of these two subtypes, success rates with immune checkpoint inhibitors are not universal. ESCC is often considered more immunogenic than EAC, meaning it may respond better to these therapies.
Measuring Efficacy: Response Rates and Survival Data
Success in oncology is measured using several key metrics, including Objective Response Rate (ORR), Progression-Free Survival (PFS), and Overall Survival (OS). ORR is the percentage of patients whose tumors shrink or disappear entirely. PFS is the length of time a patient lives without the disease getting worse, and OS is the total time from diagnosis or treatment start until death.
Immunotherapy, often used in combination with chemotherapy, has shown success in the first-line treatment of advanced or metastatic esophageal cancer. For patients with ESCC, adding a PD-1 inhibitor to chemotherapy in the CheckMate 648 trial resulted in a median Overall Survival of 13.2 months compared to 10.7 months for chemotherapy alone. The ORR for the combination therapy was over 50% for ESCC patients, significantly higher than the chemotherapy-alone rate of under 33%. A chemotherapy-free regimen of two different checkpoint inhibitors also showed a median OS of 12.8 months.
For the broader population including both ESCC and EAC, trials like KEYNOTE-590 demonstrated that adding a PD-1 inhibitor to chemotherapy improved median OS to \(12.4\) months compared to \(9.8\) months with chemotherapy alone. The ORR for this combination across all patients was \(45.0\%\) compared to \(29.3\%\) for the control group. In the second-line setting, PD-1 inhibitor monotherapy has also shown benefit for patients whose cancer progressed after initial chemotherapy. One trial reported a median OS of \(10.9\) months for patients with ESCC compared to \(8.4\) months with chemotherapy. In the post-operative setting, the CheckMate 577 trial showed that adding an immune checkpoint inhibitor significantly improved disease-free survival for patients with residual disease after chemoradiation and surgery, effectively doubling the time patients remained cancer-free compared to placebo.
Contextualizing Treatment Selection and Biomarkers
The variability in success rates across patients is largely due to the presence of specific biological markers, which help predict who will benefit most from immunotherapy. The single most important predictive factor in esophageal cancer is the PD-L1 Combined Positive Score (CPS). This score measures the percentage of PD-L1 expression on both tumor cells and surrounding immune cells, and it is a key determinant for treatment eligibility and expected outcome.
A higher PD-L1 CPS generally correlates with a greater likelihood of response to immune checkpoint blockade. For instance, in one trial, patients with a high PD-L1 expression (CPS \(\geq 10\)) who received a PD-1 inhibitor plus chemotherapy saw their median Overall Survival jump to \(13.9\) months compared to \(8.8\) months for those receiving chemotherapy alone. While patients with lower CPS scores may still receive a benefit, the magnitude of the improvement is smaller, highlighting the importance of this biomarker.
Immunotherapy is utilized in different clinical scenarios, including first-line treatment for advanced disease, second-line treatment after initial therapy failure, and in the neoadjuvant/adjuvant settings. First-line treatment for advanced disease often involves combination therapy with chemotherapy, offering the largest survival gains. In contrast, the neoadjuvant (before surgery) or adjuvant (after surgery) use of immunotherapy is aimed at reducing the risk of recurrence and improving long-term cure rates.
Immunotherapy Compared to Traditional Treatment Strategies
The introduction of immunotherapy has redefined the benchmarks for success in advanced esophageal cancer, moving beyond the capabilities of traditional chemotherapy and chemo-radiotherapy alone. In the first-line setting for advanced disease, adding a PD-1 inhibitor to chemotherapy has consistently resulted in a meaningful extension of Overall Survival, with some studies showing a tripling of the five-year survival rate compared to chemotherapy alone. This benefit represents a major shift in the standard of care.
Traditional systemic chemotherapy regimens typically have a less durable response, and patients often experience more severe systemic side effects like bone marrow suppression and hair loss. Immunotherapy, while having its own unique set of side effects related to immune over-activation, offers a generally improved safety profile compared to conventional cytotoxic drugs, leading to better quality of life for many patients. The ability of immunotherapy to produce long-lasting, durable responses is a defining feature of its clinical success over previous standards.