Randomized Phase III Study of Combination Osimertinib (AZD9291) and Bevacizumab versus Osimertinib (AZD9291) Alone as First-Line Treatment for Patients with Metastatic EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC)

By Helena Yu, MD

@HelenaYu923

EA5182 is an important phase 3 study to assess whether adding bevacizumab to osimertinib as first-line treatment improves outcomes for patients with metastatic, EGFR-mutant lung cancer. Patients are randomized 1:1 to receive either the combination of osimertinib plus bevacizumab or osimertinib alone. The study’s primary endpoint is progression-free survival (PFS).

For patients with metastatic EGFR-mutant lung cancers, the current first-line therapy is an EGFR tyrosine kinase inhibitor (TKI) like osimertinib. This is because multiple pivotal randomized studies demonstrated superiority of EGFR inhibitors over cytotoxic chemotherapy.¹ Osimertinib has shown improvements over earlier generation EGFR TKIs (erlotinib or gefitinib), with longer PFS (median PFS of 18.9 months versus 10.2 months) and overall survival (OS), positioning it as the most used first-line single agent EGFR TKI.²

As background, EGFR TKIs such as erlotinib have been combined with VEGF inhibitors leading to improvements in PFS. In a phase 2 study (JO25567), the median PFS was 16 months for combination erlotinib and bevacizumab compared to 9.7 months for erlotinib alone (HR 0.54, 0.0015).³ These results were also corroborated by a phase 3 randomized study.⁴ The RELAY study provided additional support by demonstrating that combination erlotinib and the VEGF inhibitor ramucirumab was superior to erlotinib alone (median PFS of 19.4 months versus 12.4 months), leading the Food and Drug Administration (FDA) to approve the combination.⁵

Recently, the RAMOSE study enrolled 139 patients to receive osimertinib with or without ramucirumab for first-line treatment. The median PFS by investigator assessment was 24.8 months for the combination versus 15.6 months with osimertinib monotherapy.⁶

Despite improvements in PFS and OS compared to its predecessors, single-agent osimertinib is only effective for a limited period, and few choices exist upon progression outside of chemotherapy-based approaches. Combination approaches to first-line treatment are needed to improve upon the current standard of care.

Recently, combination treatment with osimertinib and chemotherapy has demonstrated a PFS benefit in the FLAURA2 study, 25.5 months versus 16.7 months with osimertinib alone.⁷ However, the toxicity of the added chemotherapy is not insignificant, and this approach combines two active lines of therapy. Adding bevacizumab to osimertinib may enhance the activity of osimertinib with a more moderate toxicity profile and without utilizing two active lines of therapy.

Further, central nervous system (CNS) metastases continue to cause significant morbidity and mortality in this population. Both osimertinib and bevacizumab have notable central nervous system activity, which is critical as the cumulative incidence of CNS metastases exceeds 50% in these patients. Overall, the combination of osimertinib and bevacizumab could prolong PFS and delay the need for systemic chemotherapy, thereby favorably impacting patient quality of life, delaying CNS progression, and possibly culminating in an overall survival benefit. For these reasons, we have designed the EA5182 trial to study the combination of osimertinib and bevacizumab versus osimertinib alone as first-line treatment. 

The primary objective of the study is to evaluate the PFS of the combination versus osimertinib alone. Secondary objectives are to assess overall survival, overall response rate, time to CNS progression, and CNS progression-free survival and toxicity. Correlative objectives are to characterize the mechanisms of resistance to osimertinib and osimertinib with bevacizumab and to assess EGFR circulating tumor DNA clearance on study treatment as a biomarker of response to study treatment.

EA5182 is an important study that will help define the optimal first-line treatment for patients with EGFR-mutant lung cancer. Data from this study will also elucidate mechanisms of resistance to therapy, which will inform subsequent lines of therapy as well.

Learn more about the EA5182 trial at ecog-acrin.org.

Dr. Yu (Memorial Sloan Kettering Cancer Center) is the study chair for this trial. The study co-chair is Balazs Halmos, MD (Montefiore Einstein Comprehensive Cancer Center).

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