A randomized phase II study comparing erlotinib with or without bevacizumab in patients with advanced non–small cell lung cancer (NSCLC) with EGFR mutation.
Authors: Lee Youngjoo , Kim Hye Ryun , Hong Min Hee , Lee Ki Hyeong , Park Keon Uk , Lee Geon Kook , Kim Hyae Young , Lee Soo-Hyun , Lim Kun Young , Yoon Sung Jin , Cho Byoung Chul , Han Ji-Youn 
Published: June 2022

9107 Background: Synergistic anti-tumor effect of double blocking EGFR and VEGF pathways is proven by preclinical and clinical data. This study evaluated whether an addition of bevacizumab to erlotinib improves clinical outcomes in patients (pts) with untreated advanced EGFR-mutated NSCLC. Methods: This is an open-label, multi-center, randomized phase II study conducted in South Korea. Key eligibility was age ≥ 19 years old, untreated stage IIIB/IV NSCLC, EGFR exon 19 deletion or exon 21 L858R mutation, and ECOG performance status of 0 or 1. Asymptomatic brain metastasis (BM) was permitted without local treatment. Pts were randomly assigned to receive either oral erlotinib (E) 150 mg/day alone or erlotinib plus bevacizumab (E+B) at 15 mg/kg intravenously every 3 weeks. Primary endpoint was progression-free survival (PFS) with secondary endpoints including response rate (RR), overall survival (OS), and toxicity. Results: Between Dec 16, 2016, and Mar 8, 2019, a total of 127 pts were randomly assigned to receive E (n=63) or E+B (n=64). Median follow-up duration was 38.9 months. Fifty-nine (46.5%) pts had baseline BM. While the prevalence of baseline BM was similar between both arms (45.3% vs. 47.6%), more pts of the E arm received radiotherapy for BM before the study enrollment, compared to the E+B arm (40.0% vs. 10.3%). A trend toward improved PFS was observed with the E+B arm compared to the E arm (median PFS, 17.5 months vs 12.4 months; hazard ratio [HR] = 0.74 [95% confidence interval (CI), 0.51–1.08], P= 0.119). The RR was similar between both arms (85.9% vs. 83.9%; P= 0.746). The most significant PFS benefit from the E+B was found in the subgroup with baseline BM (median PFS, 18.6 months vs 10.3 months; HR = 0.54 [95% CI, 0.31–0.95], P= 0.032). The 12-month and 24-month cumulative central nervous system (CNS) progression rate was 4.4% and 6.8% in the E+B arm compared to 15.1% and 32.5% in the E arm. Thus, the E+B arm significantly reduced the risk for CNS progression than the E arm (HR = 0.33 [95% CI, 0.11–0.93], P= 0.035). Grade 3 or worse adverse events occurred in 56.6% of the E+B arm while 20.6% of the E arm. The E+B arm tended to increase the incidence or severity of some erlotinib-related adverse effects: grade 3 skin rash (17.2% vs. 4.8%) and any grade paronychia (60.9% vs. 46.0%), and oral mucositis (51.6% vs. 33.3). At the time of disease progression, more pts in the E arm showed EGFR T790M positivity (82% vs. 64%) and received 3rd generation EGFR tyrosine kinase inhibitor as the 2nd line therapy (58% vs. 22%) compared to the E+B arm. OS data are immature (events: 34%, HR = 1.24 [95% CI, 0.68–2.26]). Conclusions: A trend to improvement in PFS was observed with the combination of erlotinib and bevacizumab vs. erlotinib alone in advanced EGFR-mutated NSCLC. Especially, the PFS benefit from this combination was most significant in the pts with BM. Clinical trial information: NCT03126799.