Effect of Osimertinib and Bevacizumab on Progression-Free Survival for Patients With Metastatic EGFR-Mutant Lung Cancers: A Phase 1/2 Single-Group Open-Label Trial

Abstract

Importance: The 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.

Design, setting, and particiants: From August 15, 2016, to May 15, 2018, 49 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.

Interventions: All patients received osimertinib, 80 mg daily, and bevacizumab, 15 mg/kg once every 3 weeks.

Main outcomes and measures: The 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 relevance: 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. A randomized phase 3 study comparing osimertinib and bevacizumab with osimertinib alone is planned.

Trial registration: ClinicalTrials.gov Identifier: NCT02803203.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Yu, Dr Schoenfeld, Mr Makhnin, Dr Rizvi, Dr Tsui, Ms Falcon, Dr Houck-Loomis, Dr Meng, Dr Yang, Mr Tobi, Dr Heller, Ms Ahn, Dr Hayes, Dr Young Dr Arcila, Dr Berger, Dr Chaft, Dr Ladanyi, and Dr Riely reported receiving grants from the National Institutes of Health/National Cancer Institute during the conduct of the study. Dr Yu reported receiving grants and personal fees from AstraZeneca; grants and nonfinancial support from Lilly; grants from Astellas Pharma, Daiichi, Novartis, and Pfizer outside the submitted work; and having a patent US20170273982A1 pending and a patent WO2017164887A1 pending. Dr Schoenfeld reported receiving grants from Creative Educational Concepts outside the submitted work. Dr Tsui reported receiving travel support and speaker honorarium from Nanodigmbio; speaker honoraria from Cowen and BoA Merrill; and research support from ThermoFisher Scientific, EPIC Sciences, and Prostate Cancer Foundation outside the submitted work; and having a patent pernding to US provisional application. Dr Young reported receiving grants, personal fees, and personal stock from Agios; personal fees from Puma, NordicNeuroLabs, and ICON plc; and personal stock from Amgen, Celgene, Merck, and Regeneron outside the submitted work. Dr Arcila reported serving as a speaker for and receiving personal fees from Biocartis and Invivoscribe outside the submitted work. Dr Berger reported receiving personal fees from Roche; grants from Illumina and Grail; and having a patent pending for Systems and Methods for Detecting Cancer Via cfDNA Screening. Dr Chaft reported receiving grants and personal fees from Genentech/Roche, AstraZeneca/MedImmune, Merck, and Bristol-Meyers Squibb outside the submitted work. Dr Ladanyi reported receiving personal fees from Astra-Zeneca, Bristol-Myers Squibb, Takeda, Bayer, and Merck; and grants from Helsinn Therapeutics, Merus, LOXO Oncology, and 14ner Oncology outside the submitted work. Dr Riely reported receiving nonfinancial support from Genentech and grants from AstraZeneca during the conduct of the study; grants from Novartis, Roche, Genentech, Millennium, GlaxoSmithKline, Pfizer, Infinity Pharmaceuticals, Mirati, Merck, and ARIAD; nonfinancial support from Merck Sharp & Dohme outside the submitted work; and having patents pending for US20170273982A1 and WO2017164887A8. Dr Kris reported receiving personal fees from AstraZeneca, Pfizer, and Regeneron, outside the submitted work; receiving honoraria for participation in educational programs from WebMD, OncLive, Physicians Education Resources, Prime Oncology, Intellisphere, Creative Educational Concepts, Peerview, i3 Health, Paradigm Medical Communications, AXIS, Carvive Systems, AstraZeneca, and Research to Practice; receiving funds for travel and lodging, and food and beverage from AstraZeneca, Pfizer, Regeneron, and Genentech; serving as a consultant for Daiichi-Sankyo; providing editorial support for preparation of a scientific meeting presentation for Genentech; and being an employee of Memorial Sloan Kettering Cancer Center, which has received research funding from the National Cancer Institute, the Lung Cancer Research Foundation, Genentech Roche, and PUMA Biotechnology for research conducted by Dr Kris. MSK has licensed testing for EGFR T790M to MolecularMD. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

Figure 2.. Outcomes With Combination Osimertinib-Bevacizumab

A, Swimmers plot with progression-free survival (PFS) and overall survival (OS) for each patient shown with current status of study treatment and sorted by circulating tumor (ct)DNA clearance at 6 weeks. Gray circles indicate patients who withdrew from the study without progression. Arrows indicate patients who continued therapy. Xs indicate death. B, PFS in patients with EGFR-mutant lung cancer who received osimertinib and bevacizumab.

Figure 3.. Response Profiles of Combination Osimertinib/Bevacizumab

A, Best overall response to osimertinib and bevacizumab. The maximum percentage change in measurable tumor target lesions (using Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1 criteria) at the time of best response from baseline. B, Overall best central nervous system (CNS) response to osimertinib and bevacizumab. The maximum percentage change in measurable tumor target lesions (RECIST, version 1.1 criteria) at the time of best response from baseline. The dotted horizontal lines represent –30% change from baseline (cutoff for partial response).

Figure 4.. Association of Circulating Tumor (ct)DNA Persistence With Survival

A, Progression-free survival (PFS) in patients with EGFR-mutant lung cancer stratified by clearance of ctDNA after 6 weeks of treatment with osimertinib and bevacizumab. B, Overall survival (OS) in patients with EGFR-mutant lung cancer stratified by clearance of ctDNA after 6 weeks of treatment with osimertinib and bevacizumab. NR indicates not reached.