1. Treatment of patients with tyrosine kinase inhibitor (TKI)-naïve epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) with osimertinib and ramucirumab resulted in a significantly longer progression-free survival (PFS) compared with osimertinib alone. 

Evidence Rating Level: 1 (Excellent)

Study Rundown: The current standard of care for patients with advanced EGFR-mutant NSCLC is treatment with third-generation EGFR TKIs, like osimertinib, alone or in combination with platinum-based chemotherapy. Emerging evidence from preclinical and clinical studies have suggested that EGFR-mutant NSCLC may be susceptible to inhibition of the vascular endothelial growth factor (VEGF) pathway. While the combination of ramucirumab, a monoclonal antibody targeting VEGFR2, with erlotinib, a first-generation TKI, has already been approved for EGFR-mutant NSCLC, the combination of ramucirumab and a third-generation TKI has not yet been investigated. This study therefore sought to investigate the efficacy of osimertinib and ramucirumab versus osimertinib alone in the treatment of patients with EGFR-mutant TKI-naïve NSCLC.  In this multicenter, randomized phase II trial, 159 patients with locally advanced or metastatic EGFR-mutant NSCLC from 11 centers across the United States were randomly assigned to receive either ramucirumab plus osimertinib or osimertinib alone in a 2:1 ratio. The study’s primary endpoint was PFS while secondary outcomes included objective response rate (ORR) and safety and tolerability. The median PFS was 24.8 months in patients receiving ramucirumab plus osimertinib compared to 15.6 months in patients receiving osimertinib monotherapy. With regards to safety and tolerability, the rates of adverse events (AE) were similar in both arms of this trial. Overall, this study found that treatment of patients with TKI-naïve EGFR-mutant NSCLC with ramucirumab plus osimertinib resulted in a significantly prolonged PFS compared to with osimertinib alone, supporting this combination as a possible treatment option for such patients. 

Click to read the study in Journal of Clinical Oncology

Relevant Reading: Osimertinib for Patients With Non–Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09)

In-Depth [phase II clinical trial]: Genetic alterations in the EGFR gene commonly lead to lung cancer oncogenesis. Presently, the standard of care for patients with locally advanced or metastatic EGFR-mutant NSCLC is treatment with third-generation EGFR TKIs, like osimertinib, given as monotherapy or in combination with platinum-based chemotherapy. In recent years, results from preclinical and clinical studies have suggested that EGFR-mutant NSCLC may be sensitive to inhibition of the vascular endothelial growth factor (VEGF) pathway. This randomized phase II trial therefore sought to investigate the efficacy of osimertinib and ramucirumab, a monoclonal antibody targeting VEGFR2, versus osimertinib alone in the treatment of patients with EGFR-mutant TKI-naïve NSCLC. 159 patients (median [range] = 65 [37-83], 71.2% female) were included from 11 centers across the United States via the Hoosier Cancer Research Network. Patients were included on the basis of being 18 years or older and having locally advanced or metastatic NSCLC with documented EGFR mutation and no previous exposure to TKI. After a median follow-up period of 16.6 months, the median PFS was 24.8 for patients receiving ramucirumab plus osimertinib versus 15.6 months in patients receiving osimertinib monotherapy (hazard ratio, 0.55 [95% CI, 0.32 to 0.93]; log-rank P = .023). The ORR was similar in both groups, being 76.3% (95% CI, 67.7 to 85.0) in patients receiving ramucirumab plus osimertinib and 80.4% (95% CI, 69.0 to 91.9) in patients receiving osimertinib monotherapy (χ2 P = .59). Similarly, there was no significant difference in disease control rate (DCR) between both groups. Rates of AE-related discontinuation were similar in both groups (9.7% versus 8.7% for ramucirumab plus osimertinib versus osimertinib monotherapy respectively).

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