In the phase II portion of a single-center phase I/II trial reported in JAMA Oncology, Yu et al found that the combination of first-line osimertinib and bevacizumab resulted in a high rate of 1-year progression-free survival in patients with metastatic EGFR-mutant lung cancer.
As stated by the authors, “The combination of erlotinib and bevacizumab as initial treatment of EGFR-mutant lung cancers improves progression-free survival compared with erlotinib alone. Because osimertinib prolongs progression-free survival compared with erlotinib, this trial was designed to study the combination of osimertinib and bevacizumab as first-line treatment.”
In the trial, 49 patients enrolled between August 2016 and May 2018 at Memorial Sloan Kettering Cancer Center received osimertinib at 80 mg daily and bevacizumab at 15 mg/kg once every 3 weeks, the maximum-tolerated dose identified in the phase I portion of the trial.
The primary outcome measure was progression-free survival at 1 year, with the treatment strategy to be considered promising with improvement from a historical rate of 51% to a rate of 70%.
Progression-Free Survival and Responses
Progression-free survival at 12 months was 76%. Median progression-free survival was 19 months (95% confidence interval = 65%–90%). A total of 19 patients were treated beyond disease progression, with 5 of these remaining in the study with continued clinical benefit at last analysis.
Objective response was observed in 39 patients (80%), with 9 additional patients (18%) having stable disease (1 patient was not assessed for response). Central nervous system response was observed in each of six patents with measurable disease, including complete response in two. Median overall survival had not been reached, with 89% of patients remaining alive at 1 year.
Persistent detection of EGFR-mutant circulating tumor DNA at 6 weeks was associated with shorter median progression-free survival (9.8 months vs 16.2 months with clearance, P = .04) and median overall survival (10.1 months vs not reached, P = .002).
Mechanisms of resistance identified in analysis of paired samples from 23 patients with disease progression included squamous cell transformation in 2, pleomorphic transformation in 1, and acquired EGFR L718Q and C797S mutations in 1 each.
The most commonly reported grade 3 or 4 adverse events were hypertension (31%), proteinuria (12%), and decreased lymphocytes (8%). Treatment-related grade 4 toxicity was observed in one patient due to proteinuria. Adverse events led to discontinuation in one patient due to reduced ejection fraction. Reduction of the osimertinib dose to 40 mg was required in 13 patients. No treatment-related deaths were reported.
The investigators concluded, “The combination of osimertinib and bevacizumab met the study’s prespecified effectiveness endpoint. Persistent EGFR-mutant circulating tumor DNA at 6 weeks was associated with early progression and shorter survival. A randomized phase II study comparing osimertinib and bevacizumab with osimertinib alone is planned.”
Helena A. Yu, MD, of the Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by a Memorial Sloan Kettering Cancer Center Support Grant/Core Grant from the National Cancer Institute. For full disclosures of the study authors, visit jamanetwork.com.