Enfortumab vedotin for gastric and esophageal cancers

Enfortumab vedotin (EV), a Nectin-4–directed antibody–drug conjugate, has been evaluated for its antitumor activity and safety in patients with heavily pretreated gastric and esophageal cancers through the EV-202 study, a phase II, open-label, multicenter trial. Below is a detailed summary of the findings regarding its use in this context:

Study Design & Patient Population

• Objective: The study aimed to assess the efficacy and safety of EV in patients with advanced or metastatic gastroesophageal adenocarcinoma (GEA) and esophageal squamous cell carcinoma (ESCC) who had previously undergone platinum-based chemotherapy and immune checkpoint inhibitors.
• Dosing Regimen: Patients received EV intravenously at a dose of 1.25 mg/kg on days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity.

Primary and Secondary Endpoints

• Primary Endpoint: The objective response rate (ORR) was evaluated per RECIST v1.1.
• Secondary Endpoints: These included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.

Key Findings

1. Efficacy Results

• Gastroesophageal Adenocarcinoma (GEA) Cohort:

• ORR: 9.5% (4 out of 42 patients responded to treatment).

• DCR: 47.6%.

• Median DOR: 10.3 months.

• Median PFS: 3.1 months.

• Median OS: 8.3 months.

• Predefined efficacy threshold (≥17.5% ORR) was not met in this cohort.

• Esophageal Squamous Cell Carcinoma (ESCC) Cohort:

• ORR: 18.2% (8 out of 44 patients responded to treatment).

• DCR: 45.5%.

• Median DOR: 3.9 months.

• Median PFS: 2.1 months.

• Median OS: 7.4 months.

• Predefined efficacy threshold (≥17.5% ORR) was met in this cohort, indicating promising antitumor activity.

2. Nectin-4 Expression

• High expression of Nectin-4, the target of EV, was observed in the majority of patients (93.9% in GEA and 97.6% in ESCC).
• However, no clear correlation was identified between Nectin-4 expression levels and treatment response.

3. Safety Profile

• Treatment-related adverse events (AEs) were common, occurring in 85.7% of GEA patients and 95.5% of ESCC patients.
• Most AEs were manageable, with commonly reported mild AEs including pruritus, alopecia, dysgeusia, rash maculopapular, fatigue, and diarrhea.
• Severe AEs (Grade ≥3) were reported in approximately 28% of patients in both cohorts, including rash, hyperglycemia, and neutropenia.
• No treatment-related deaths were observed.
• Dose interruptions (~33%) and reductions (~25%) were required in some patients to manage toxicity.

4. Response Timing

• Median time to partial response was 1.7–1.8 months, suggesting early measurable effects in responders.

5. Comparison with Other Treatments

• The ORR observed with EV (9.5% in GEA, 18.2% in ESCC) was modestly higher than that reported with anlotinib monotherapy (8.4%), demonstrating EV's activity even in heavily pretreated populations.

6. Quality of Life

• Quality-of-life assessments (EQ-5D-5L and pain evaluations) indicated stable or slightly improved quality of life during EV treatment.

Clinical Implications

• For ESCC: EV demonstrated moderate efficacy and manageable safety, meeting the threshold for antitumor activity. This suggests that EV could serve as a potential salvage therapy for ESCC patients who have failed prior chemotherapy and immunotherapy. These results support further investigation of EV, particularly in combination regimens.
• For GEA: The efficacy of EV in GEA was limited, as the predefined threshold for efficacy was not met. This indicates that EV may have less clinical relevance in this subgroup.

Conclusion

Enfortumab vedotin showed manageable safety and moderate efficacy in patients with heavily pretreated gastric and esophageal cancers. While its clinical relevance was limited in gastroesophageal adenocarcinoma, it demonstrated promising activity in esophageal squamous cell carcinoma, warranting further exploration, particularly in combination with other therapies.