Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Patients With EGFR T790M–Mutated Non–Small Cell Lung Cancer Previously Treated With Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor

Abstract

IMPORTANCE Although treatment with first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) plus antiangiogenic inhibitor has shown promising efficacies in patients with EGFR-mutated lung adenocarcinoma, recent single-arm studies have suggested that osimertinib plus antiangiogenic inhibitor might not work synergistically. OBJECTIVE To explore the efficacy and safety of osimertinib plus bevacizumab compared with osimertinib alone in patients with lung adenocarcinoma with EGFR T790M mutation. DESIGN, SETTING, AND PARTICIPANTS Patients with advanced lung adenocarcinoma that progressed with prior EGFR-TKI treatment (other than third-generation TKI) and acquired EGFR T790M mutation were enrolled. This study comprises a lead-in part with 6 patients and a subsequent phase 2 part. In phase 2, patients were randomized to osimertinib plus bevacizumab or osimertinib alone in a 1:1 ratio. INTERVENTIONS The combination arm received oral osimertinib (80 mg, every day) plus intravenous bevacizumab (15 mg/kg, every 3 weeks) until progression or unacceptable toxic effects. The control arm received osimertinib monotherapy. MAIN OUTCOMES AND MEASURES The primary end point was progression-free survival (PFS) assessed by investigators. Secondary end points consisted of overall response rate, time to treatment failure, overall survival, and safety. RESULTS From August 2017 through September 2018, a total of 87 patients were registered (6 in the lead-in part and 81 in the phase 2 part [intention-to-treat population]). Among those randomized, the median (range) age was 68 (41-82) years; 33 (41%) were male; 37 (46%) had an Eastern Cooperative Oncology Group performance status of 0; and 21 (26%) had brain metastasis. Although the overall response rate was better with osimertinib plus bevacizumab than osimertinib alone (68% vs 54%), median PFS was not longer with osimertinib plus bevacizumab (9.4 months vs 13.5 months; adjusted hazard ratio, 1.44; 80% CI, 1.00 to 2.08; P = .20). Median time to treatment failure was also shorter in the combination arm vs the osimertinib arm (8.4 months vs 11.2 months; P = .12). Median overall survival was not different in the combination arm vs osimertinib arm (not reached vs 22.1 months; P = .96). In the combination arm, common adverse events of grade 3 or higher were proteinuria (n = 9; 23%), hypertension (n = 8; 20%). CONCLUSIONS AND RELEVANCE In this randomized clinical trial comparing osimertinib plus bevacizumab vs osimertinib alone, the combination arm failed to show prolongation of PFS in patients with advanced lung adenocarcinoma with EGFR T790M mutation.

Osimertinib in EGFR-Mutated Lung Cancer: A Review of the Existing and Emerging Clinical Data

“…Recently in a phase 2 study, the addition of bevacizumab to osimertinib was not shown to be beneficial in previously treated EGFR TKIs patients with the T790M mutation. 132 …”

Triple therapy with osimertinib, bevacizumab and cetuximab in EGFR‑mutant lung cancer with HIF‑1α/TGF‑α expression

“…with EGFR-TKI and cetuximab could be a reasonable strategy for treating patients with EGFR-mutant lung cancer, clinical trials have failed to show that the combination of afatinib and cetuximab is superior to afatinib monotherapy (15). EGFR-TKIs have been successfully combined with anti-angiogenic agents such as bevacizumab or ramucirumab to treat patients with lung cancer harboring EGFR mutations (12,14); however, a recent randomized clinical trial revealed that the combination of osimertinib and bevacizumab failed to show superior progression-free survival compared to osimertinib monotherapy (29). Multiple negative predictive biomarkers have been reported for the effect of EGFR-TKIs (6-11); however, the predictive factor for combination therapies including EGR-TKIs and bevacizumab has not yet been identified.…”

Targeting the Epidermal Growth Factor Receptor in EGFR-Mutated Lung Cancer: Current and Emerging Therapies

“…A subsequent phase III randomized clinical trials demonstrated a longer median PFS in patients who received erlotinib and bevacizumab versus patients who received erlotinib monotherapy (16.9 vs. 13.3, p = 0.016); however, final OS analysis did not demonstrate a benefit with the addition of bevacizumab [102,103]. In addition, a recent phase II randomized clinical trial failed to demonstrate improved median PFS in patients with EGFR-mutated lung adenocarcinoma harboring T790M who progressed on prior early generation EGFR TKIs and were randomized to either osimertinib versus osimertinib plus bevacizumab [104].…”