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

Abstract

Importance: Erlotinib 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.

Objective: To determine whether adding bevacizumab to erlotinib treatment results in superior progression-free survival compared with erlotinib alone.

Design, setting, and participants: This 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.

Interventions: Patients 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 measures: The 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).

Results: Among 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 relevance: Erlotinib plus bevacizumab compared with erlotinib did not result in a significant improvement in PFS in EGFR-mutant NSCLC.

Trial registration: ClinicalTrials.gov identifier: NCT01532089.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Jänne reported receiving grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, personal fees from Pfizer, personal fees from Merrimack Pharmaceuticals, personal fees from Roche/Genentech, personal fees from Chugai Pharmaceuticals, personal fees from ACEA Biosciences, personal fees from Novartis Oncology, grants and personal fees from Takeda Oncology, and grants and personal fees from Daiichi Sankyo during the conduct of the study; personal fees from LOXO Onxology, grants and personal fees from Eli Lilly, personal fees from Araxes Pharmaceuticals, personal fees from Ignyta, personal fees from SFJ Pharmaceuticals, personal fees from Voronoi, and personal fees from Biocartis, personal fees from Mirati, outside the submitted work; and receiving postmarketing royalties from a Dana Farber Cancer Institute–owned patent on EGFR Mutations licensed to LabCorp. Dr Stinchcombe reported receiving grants from Genentech/Roche and AstraZeneca during the conduct of the study; personal fees from Regneron, Takeda, AstraZeneca, Novartis, Genentech/Roche, and G1 Therapeutics outside the submitted work. Dr Weiss reported receiving personal fees from Genentech, grants and personal fees from AstraZeneca, grants and personal fees from Celgene, personal fees from Nanobiotix, grants and personal fees from Pfizer, personal fees from Boston Biomedical, personal fees from Boehringer Ingelheim, grants and personal fees from G1 Therapeutics, personal fees from EMD Serono, personal fees from Regeneron, grants from Merck, personal fees from Immunicum, personal fees from Biomarck, grants and personal fees from Pfizer, and grants from Astellas outside the submitted work. Dr Bazhenova reported receiving personal fees from Astra Zeneca, personal fees from Genentech, personal fees from Takeda, Pfizer, and Novartis outside the submitted work. Dr Vokes reported receiving personal fees from AbbVie, Amgen, AstraZeneca, Biolumina, BMS, Celgene, Eli Lilly, EMD Serono, Genentech, Merck, Novartis, and Regeneron outside the submitted work. Dr Paweletz reported receiving personal fees and travel support from AstraZeneca Korea, and personal fees and travel support from BioRad outside the submitted work and having a patent EGFR plasma genotyping pending to the Dana Farber Cancer Institute. Dr Bertino reported receiving personal fees from Takeda Oncology outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

aPrescreening data were not collected, and patients were registered only once they were determined to be eligible. Thus, only data for the registered and randomized patients were available. bPatient received erlotinib plus bevacizumab rather than single-agent erlotinib.

Figure 2.. Progression-Free and Overall Survival in 88 Patients With Non–Small Cell Lung Cancer Treated With Erlotinib vs Erlotinib Plus Bevacizumab