EA5231 – A Randomized Phase 3 Trial of Checkpoint Blockade in Lung Cancer Patients in the Adjuvant Setting Based on Pathologic Response Following Neoadjuvant Therapy (CLEAR)

A common treatment approach for patients with stage II to IIIB (N2) operable non-small cell lung cancer (NSCLC) is neoadjuvant chemo-immunotherapy, surgery, and then additional immunotherapy. However, at the current time, even after these multiple treatments, lung cancer often persists or recurs. These patients need better options to improve their outcomes and lower the risk of recurrence.

Patients at the highest risk of recurrence are those who do not have a pathologic complete response (pCR) to their neoadjuvant treatment—a large group at nearly 80%. Researchers believe that the absence of a pCR is a signal that these patients may be resistant to single-agent immune checkpoint inhibitors, which are commonly given as adjuvant treatment. In response, a new clinical trial, EA5231/CLEAR, is evaluating an investigational new drug (AZD6738/ceralasertib) added to standard post-surgery immunotherapy with durvalumab. The PD-L1 checkpoint inhibitor durvalumab is approved by the US Food and Drug Administration (FDA) as a standalone therapy for resected NSCLC.

Several studies in advanced NSCLC have shown promising activity when durvalumab is given together with ceralasertib, a targeted cancer therapy. Ceralasertib is an ataxia telangiectasia and rad3-related (ATR) inhibitor that appears to enhance the effectiveness of immunotherapy.

EA5231/CLEAR is a randomized, phase 3 trial for patients who have undergone neoadjuvant chemo-immunotherapy and who are not found to have a pCR at the time of surgery. Patients will be randomized 1:1 to receive either durvalumab alone (standard-of-care) or durvalumab with ceralasertib. Patients in both groups will receive their assigned adjuvant treatment for a total of 12 cycles, and all patients will be followed for up to 10 years. The study’s primary objective is to evaluate improvement in disease-free survival (DFS).

To be eligible for the study, patients must have stage II to select IIIB (N2 but excluding N3) NSCLC with no known EGFR or ALK genetic alterations. They must have received at least three cycles of standard-of-care neoadjuvant chemo-immunotherapy followed by surgery, and they must have confirmed non-pCR status. Patients may register at any point from the initiation of neoadjuvant chemo-immunotherapy through post-surgery.

Other patients with a pCR after surgery may be offered a complementary study led by the SWOG Cancer Research Group, S2414/INSIGHT. The INSIGHT trial is testing adjuvant therapy with durvalumab compared to observation to explore the possibility that this group of patients at lower risk for recurrence may be able to safely receive less therapy than is standard. Together, these two studies aim to confirm if pCR status following neoadjuvant treatment can be leveraged as a biomarker to predict response and guide further treatment.

Learn more about EA5231/CLEAR at ecog-acrin.org.

The study chair for this trial is Dwight Owen, MD, MSc (The Ohio State University Comprehensive Cancer Center) and the co-chair is Charu Aggarwal, MD, MPH (University of Pennsylvania/Abramson Cancer Center). The community co-chair is Mei Tang, MD (Greater Baltimore Medical Center).