Effect of Erlotinib Plus Bevacizumab vs Erlotinib Alone on Progression-Free Survival in Patients With Advanced EGFR-Mutant Non-Small Cell Lung Cancer: A Phase 2 Randomized Clinical Trial.

Key PointsQuestionIs the combination of erlotinib and bevacizumab superior to erlotinib alone to treat epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer? FindingsThis phase 2 randomized clinical trial found that compared with erlotinib alone, the combination of erlotinib and bevacizumab did not result in superior progression-free survival. MeaningThe combination of erlotinib and bevacizumab does not have superior efficacy compared with erlotinib alone. This phase 2 multicenter randomized clinical trial including 88 patients compares progression-free survival, and secondarily overall survival, overall response rate, and adverse events, in patients with stage 4 EGFR-mutant non-small cell lung cancer treated with erlotinib plus bevacizumab vs erlotinib alone. ImportanceErlotinib is a standard first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Median progression-free survival (PFS) with erlotinib is approximately 10 months. ObjectiveTo determine whether adding bevacizumab to erlotinib treatment results in superior progression-free survival compared with erlotinib alone. Design, Setting, and ParticipantsThis phase 2 randomized clinical trial compared erlotinib plus bevacizumab with erlotinib alone in EGFR-mutant NSCLC. The trial was conducted in 17 US academic and community medical centers among 88 patients with EGFR exon 19 deletion or exon 21 L858R mutation based on local testing and stage 4 NSCLC who were eligible for bevacizumab. Patients were enrolled between November 2, 2012, and August 22, 2016, and followed up for a median (range) of 33 (0.7-62.5) months. Data were analyzed on August 28, 2018, and included data from November 2, 2012, to August 20, 2018. InterventionsPatients were randomized with equal allocation to 150 mg of oral erlotinib daily alone or with 15 mg/kg of intravenous bevacizumab every 3 weeks. Study therapy continued until disease progression, unacceptable adverse event, or withdrawal of consent. Main Outcomes and MeasuresThe primary outcome was PFS as assessed by the investigator; secondary outcomes were objective response rate (ORR), adverse events, and overall survival (OS). Analysis was designed to detect a hazard ratio (HR) of 0.667 for PFS (an improvement from a median PFS of 10 to 15 months). ResultsAmong 88 patients enrolled, the median (range) age was 63 (31-84) years; 62 patients (70%) were female; 75 (85%) were white, 8 (9%) were African American, 3 (3%) were Asian, and for 2 (2%), data on race were not available. Forty-eight patients (55%) were never smokers, 45 patients (51%) were of Eastern Cooperative Oncology Group performance status 1, and 59 patients (67%) had EGFR exon 19 deletion. Compared with erlotinib, the combination did not result in a significant difference in PFS (HR,0.81; 95% CI, 0.50-1.31; P=.39; median PFS 17.9 [combination] and 13.5 months [erlotinib]), ORR (81% vs 83%; P=.81), and OS (HR,1.41; 95% CI, 0.71-2.81; P=.33; median OS, 32.4 months [combination] and 50.6 months [erlotinib]). Adverse events of grade 3 or higher observed in 5 or more patients in the combination and erlotinib arms were skin eruption in 11 (26%) vs 7 (16%) patients, diarrhea in 4 (9%) vs 6 (13%) patients, hypertension in 17 (40%) vs 9 (20%) patients, and proteinuria in 5 (12%) vs 0 (0%) patients. Conclusions and RelevanceErlotinib plus bevacizumab compared with erlotinib did not result in a significant improvement in PFS in EGFR-mutant NSCLC. Trial RegistrationClinicalTrials.gov identifier: NCT01532089.