Effect of Osimertinib and Bevacizumab on Progression-Free Survival for Patients With Metastatic EGFR-Mutant Lung Cancers

Abstract

IMPORTANCEThe combination of erlotinib and bevacizumab as initial treatment of epidermal growth factor receptor (EGFR [OMIM 131550])-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.OBJECTIVES To determine the safety and tolerability of osimertinib and bevacizumab combination treatment and assess the 12-month PFS of the combination in patients with metastatic EGFR-mutant lung cancers. From August 15, 2016, to May 15, 2018 patients with metastatic EGFR-mutant lung cancers were enrolled in this interventional clinical trial, conducted 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. Statistical analysis was performed from August 1 to October 1, 2019. DESIGN, SETTING, AND PARTICIANTSINTERVENTIONS All patients received osimertinib, 80 mg daily, and bevacizumab, 15 mg/kg once every 3 weeks. MAIN OUTCOMES AND MEASURESThe primary objective of the phase 2 portion of the study was to determine the number of patients receiving the combination of osimertinib and bevacizumab who were progression free at 12 months. Secondary end points included overall response rate, median PFS, overall survival, and definition of the toxic effects of the combination treatment. RESULTS Among the 49 patients in the study (34 women; median age, 60 years [range, 36-83 years]), PFS at 12 months was 76% (95% CI, 65%-90%). The overall response rate was 80% (95% CI, 67%-91%), and median PFS was 19 months (95% CI, 15-24 months). Of the 6 patients with measurable central nervous system disease, all had a partial or complete central nervous system response. Persistent detection of EGFR-mutant circulating tumor (ct)DNA at 6 weeks was associated with 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). Identified mechanisms of resistance included squamous cell transformation (n = 2) pleomorphic transformation (n = 1), and acquired EGFR L718Q (n = 1) and C797S (n = 1) mutations. CONCLUSIONS AND RELEVANCEThe 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. A randomized phase 3 study comparing osimertinib and bevacizumab with osimertinib alone is planned.

Neutrophil-to-Lymphocyte Ratio Is a Predictive Biomarker in Patients with Epidermal Growth Factor Receptor (EGFR) Mutated Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Tyrosine Kinase Inhibitor (TKI) Therapy

“…FLAURA2 is a phase III randomized trial underway to determine if combining osimertinib with carboplatin/pemetrexed improves PFS and OS (ClinicalTrials.gov accessed on 22 March 2021 Identifier NCT04035486). Antiangiogenic agents are also being pursued (ClinicalTrials.gov accessed on 22 March 2021 Identifier NCT04181060) with a recent publication suggesting bevacizumab and osimertinib led to a favorable 1-year PFS [ 24 ] and other trials that are ongoing as well are trials adding the anti-angiogenic agentand ramucirumab (ClinicalTrials.gov accessed on 22 March 2021 Identifier NCT03909334). Studying the NLR in patients treated with angiogenic agents would also be useful in light of recent FDA approval of ramucirumab with erlotinib in front-line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 (L858R) mutations [ 25 ].…”

Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs

“…also reported that clearing of all EGFR cfDNA after osimertinib treatment predicts the efficacy of Osimertinib with significant improvement in PFS, ORR, and DCR in 82 patients with NSCLC using Cobas ® EGFR mutation test v2 ( 27 ). Another study showed that cfDNA presence at 6 weeks correlated with short PFS and OS in a phase 1/2 study of osimertinib plus bevacizumab as first-line therapy for advanced EGFR-mutant NSCLC using the QX200 BioRad PCR system ( 28 ). Buder A et al.…”

Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC

“…No regular scheduled brain imaging regardless of +/-brain mets Sample size: Data at 50% maturity will provide 90% power, 2-sided 5% significance level of "significant" PFS improvement Coordinating principal investigators: Pasi Jänne, David Planchard, Kunihiko Kobayashi FLAURA2 (NCT04035486) Schema arm osimertinib plus bevacizumab combination trial similar to the mPFS achieved by osiemritnib in AURA3. 93…”