Osimertinib–Bevacizumab Combo Effective for Metastatic EGFR+ Lung Cancers

In a single-arm study of adults with stage IV EGFR-positive lung cancers, first-line combination therapy with bevacizumab and osimertinib was tolerated and yielded efficacy without significant toxicity (JAMA Oncol. 2020;6[7]:1-8).

“The combination of erlotinib and bevacizumab as initial treatment of [EGFR-mutant] lung cancers improves progression-free survival (PFS) compared with erlotinib alone. Because osimertinib prolongs PFS compared with erlotinib, this trial was designed to study the combination of osimertinib and bevacizumab as first-line treatment,” wrote lead investigator Helena A. Yu, MD, Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, and colleagues.

A total of 49 patients (median age, 60 years) with metastatic EGFR-positive lung cancers were enrolled in the interventional study between August 15, 2016, and May 15, 2018, which took place at a single academic cancer center.

“In the phase 1 portion of the study, a standard 3 + 3 dose de-escalation design was used to determine the maximum tolerated dose of osimertinib and bevacizumab. In the phase 2 portion of the study, patients were treated at the maximum tolerated dose defined in the phase 1 portion,” the investigators explained.

All patients were given osimertinib 80 mg daily and bevacizumab 15 mg/kg once every 3 weeks. Between August 1, 2019, and October 1, 2019, Dr Yu and colleagues conducted a statistical analysis.

The main end point of the phase 2 portion of the study was to determine the proportion of patients given osimertinib plus bevacizumab who were progression free-at 12 months. The secondary end points included overall response rate, median PFS, overall survival, and toxicities.

The 12-month PFS rate was 76% (95% CI, 65%-90%), the overall response rate was 80% (95% CI, 67%-91%), and the median length of PFS was 19 months (95% CI, 15-24 months). Among 6 patients with measurable central nervous system disease, all of them had a partial or complete central nervous system response.

The presence of EGFR-mutant circulating tumor (ct)DNA at 6 weeks was tied to shorter median PFS (clearance at 6 weeks, 16.2 months; 95% CI, 13 months to not reached; and no clearance at 6 weeks, 9.8 months; 95% CI, 4 months to not reached; P = .04) and median overall survival (clearance at 6 weeks, not reached; and no clearance at 6 weeks, 10.1 months; 95% CI, 6 months to not reached; P = .002).

Squamous cell transformation, pleomorphic transformation, and acquired EGFR L718Q and C797S mutations were among the mechanisms of resistance detected.

“The combination of osimertinib and bevacizumab met the study's prespecified effectiveness end point. Persistent EGFR-mutant circulating tumor DNA at 6 weeks was associated with early progression and shorter survival,” Dr Yu and colleagues concluded.

“A randomized phase 3 study comparing osimertinib and bevacizumab with osimertinib alone is planned,” they added.—Hina M. Porcelli