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

@HelenaYu92

 

EA5182 is an important phase III 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 recently 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 commonly 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 progression-free survival. In a phase II 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 III 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 compared to 12.4 months), leading the FDA to approve the combination.⁵ The main criticism of these earlier studies is that the first-generation EGFR TKIs are no longer commonly utilized.

Despite improvements in PFS and OS compared to its predecessors, single-agent osimertinib is only effective for a limited period of time, and limited 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.

Overall, the combination of osimertinib and bevacizumab could prolong progression-free survival and delay the need for systemic chemotherapy, thereby favorably impacting patient quality of life, delaying central nervous system (CNS) progression, and possibly culminating in an overall survival benefit. For these reasons, we have opened 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 progression-free survival of the combination versus osimertinib alone. Secondary objectives include to assess overall survival, overall response rate, time to CNS progression, and CNS progression-free survival and toxicity. Correlative objectives include 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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^{2. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(2):113-25.↩}

^{3. Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15(11):1236-44.↩}

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^{5. Nakagawa K, Garon EB, Seto T, Nishio M, Ponce Aix S, Paz-Ares L, et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(12):1655-69.↩}