A Phase 3 Study of Consolidative Radiotherapy in Patients with Oligometastatic HER2 Negative Esophageal and Gastric Adenocarcinoma

By Nataliya V. Uboha, MD, PhD

@NataliyaUboha

The incidence of esophageal and gastric cancers in both male and female patients is on the rise, including increases in patients under the age of 50, who are commonly diagnosed in advanced stages. Stage IV disease is almost universally fatal, with 5-year survival rates of less than 5%. Systemic therapy plays a critical role in managing metastatic esophageal and gastric adenocarcinoma (EGA). Despite recent therapeutic advances, overall survival (OS) for patients with advanced EGA remains less than 2 years.

Multiple reports suggest that a subset of EGA patients who have limited burden of metastatic disease may benefit from more aggressive management. Surgical resection of disease in these patients did not result in improved survival in the phase 3 IKF-575/RENAISSANCE study. However, post-operative complications and high rates of systemic therapy discontinuation likely contributed to the negative study results.

Non-ablative locoregional therapies, such as stereotactic body radiation therapy (SBRT), provide excellent local tumor control and offer an alternative treatment strategy for patients with oligometastatic EGA. These therapies have several advantages over resection, including treatment of multiple disease sites concurrently, low associated toxicities, and continuation of systemic therapy without prolonged breaks.  

EA2183 is the first prospective study to evaluate the potential benefits of locoregional debulking with radiotherapy (XRT) in oligometastatic EGA. For this study, oligometastatic state is defined by the presence of ≤5 metastases at the time of diagnosis of advanced disease. Patients whose disease has not progressed during 3-6 months of standard first-line therapy are eligible for participation. Once enrolled, patients are randomized 2:1 to XRT to all sites of disease followed by continuation of systemic therapy or continuation of systemic therapy alone. Radiation therapy is administered over a maximum of 15 treatment days to minimize systemic therapy treatment breaks.

Amendment #5 was recently activated to update the trial’s design and expand eligibility. Please see below for the key changes. Please refer to the protocol and change memo for full details (available on the CTSU).

• Revised trial design, including
  • Removal of Step 1 Registration/Induction
    • Note: Effective with Add. #5, eligible patients will have received 3-6 months of prior first-line systemic therapy
  • Revised stratification factors
  • Expanded options for systemic therapy, while consolidating the study down to two arms
• Revised eligibility criteria, including
  • One to five (previously one to three) radiologically visible metastatic lesions are now permitted
  • Removed previous criteria relating to contraindications, patients who received nivolumab in addition to chemotherapy, and patients with active autoimmune disease
    • Note: Effective with Add. #5, patients must have received at least two chemotherapy agents during their first-line treatment
  • Removed previous criteria where palliative treatments were required to have a 2-week washout period
  • Removed Step 2 Randomization criteria
• Proton therapy is now permitted
• Therapeutic parameters table/study calendar significantly revised

The primary endpoint of this study is overall survival from the time of enrollment. Secondary endpoints include progression-free survival and the safety and tolerability of consolidative XRT. We hypothesize that consolidative XRT will result in improvement in OS from 12 to 18.7 months (HR=0.64). This trial is planned to randomize 216 patients to detect this difference with 85% power.

EA2183 is an instrumental study that has the potential to prolong OS and change the standard of care in a subset of patients with EGA. Enrollment to this study is ongoing.

Learn more about the EA2183 trial at ecog-acrin.org.

Dr. Uboha (University of Wisconsin/UW Carbone Cancer Center) is the study chair for this trial.

The study co-chairs are Lakshmi Rajdev, MD, MS (Mount Sinai Health System/The Tisch Cancer Institute), Michael Gibson, MD, PhD (Vanderbilt University/Ingram Cancer Center), and George Fisher, MD (Stanford University/Stanford Cancer Institute). The radiation oncology co-chair is Steven Lin, MD, PhD (MD Anderson Cancer Center).

The NCTN group study champions are Jon Strasser, MD (Christiana Care Health System) for Alliance and Kimberley Mak, MD, MPH (Boston University/Boston Medical Center) for NRG Oncology.