Prospective Study of Repeated Biopsy Feasibility and Acquired Resistance at Disease Progression in Patients With Advanced EGFR Mutant Lung Cancer Treated With Erlotinib in a Phase 2 Trial

Tumor genotyping is standard-of-care for patients with advanced non–small-cell lung cancer (NSCLC),¹ but treatment decisions for patients with progressive disease increasingly depend on identifying the specific mechanism of acquired resistance.^2,3 To our knowledge, a comprehensive assessment of consent to undergo a repeated biopsy and logistical outcomes in patients receiving targeted therapy has not been prospectively evaluated in a single study; thus we performed a phase 2 prospective analysis of repeated biopsy in patients with advanced, tyrosine kinase inhibitor (TKI)-naïve, EGFR-mutant NSCLC treated with erlotinib until progression.

Sixty adult patients provided written informed consent and enrolled in a nonrandomized phase 2 study approved by the institutional review board of the Dana-Farber Cancer Institute (Figure 1) (study protocol available in the Supplement). Eligibility criteria included stage IV EGFR-mutant NSCLC; 0 to 1 prior lines of therapy without EGFR-TKI; no unstable central nervous system metastases; and consent to undergo a repeated biopsy at progression. Clinical variables were prospectively collected, and patients received erlotinib, 150 mg daily, with clinic visits each cycle (28 days) and restaging computed tomographic (CT) scans every other cycle. Treatment continued until progression per restaging scans or withdrawal of consent. At progression, patients underwent a repeated biopsy with pathology review and testing for the T790M resistance mutation and MET amplification, when possible. Clinical details of the repeated biopsy were determined. Patients alive and progression-free were censored at their last known follow-up date up to a data cut-off of May 15, 2015.

Analysis was performed following the data cut-off date of May 15, 2015. Sixty patients enrolled between February 2010 and January 2015 (Figure 1). Their median age was 62.5 years (range, 34-90 years); 44 (73%) were women; and 34 (57%) were never-smokers. Median progression-free survival was 11.1 months (95% CI, 9.1-14.8 months). Forty-four patients came off the study because of disease progression, and 35 of 44 patients (80%) underwent a repeated biopsy with results as follows: there was insufficient tissue in 4 of 35 (11%), SCLC transformation in 3 of 35 (9%); T790M mutation in 23 of 35 (66%); MET amplification in 1 of 35 (3%); and unknown resistance mechanism in 4 of 35 (11%). Specimens with insufficient tissue came from pericardial effusion (1 biopsy) and CT-guided lung core biopsies (3 biopsies). Two such cases had tissue for pathology review but lacked material for genetic testing. Nine of 44 patients (20%) did not undergo a repeated biopsy at progression for the following reasons: patient refusal in 3 cases (age range, 64-80 years; 2 had prior erlotinib dose reductions); patient death in 2 cases; urgent palliative treatment in 2 cases; no lesion amenable to biopsy in 1 case; and retrospective identification of baseline T790M in 1 cases. Biopsy specimens came from several tissue sources (lung, lymph node, pleura, effusions, viscera); were performed by a range of clinicians (surgeons, interventionalists); and had minimal complication rates. Genotype (T790M) or histology data (SCLC) from a repeated biopsy were used to select the next line of treatment in 26 of 35 patients (74%) (Figure 2). The median time to repeated biopsy following clinical determination of disease progression was 12 days (range, 0-97 days).

Recent US Food and Drug Administration approvals of osimertinib for EGFR T790M disease⁴ and alectinib for resistance to crizotinib⁵ underscore the future of repeated biopsy in directing therapy for patients with NSCLC with targetable mutations. In this prospective study, our data demonstrate that repeated biopsy is safe, clinically feasible, and acceptable to 80% of patients with disease progression while receiving targeted therapy. Findings from repeated biopsy were used to direct subsequent treatment in 74% of patients. Our data also support the ability to target repeated biopsy strategy to a patient’s clinical needs and an institution’s infrastructure. As ongoing research further delineates biomarker(s) of response and resistance for immune checkpoint inhibitors, repeated biopsy may become incorporated into clinical use of these agents as well.

Our study also provides some of the first prospective data about why patients do not undergo a repeated biopsy. Only 3 of 44 patients with disease progression (7%) refused; these patients were older than our median and may have had more comorbidities from treatment. No patients refused when genotype-directed oral therapy would have been available through investigational trials. However, for a small group of patients (5 of 44 [11%]), repeated biopsy was not clinically feasible, supporting ongoing development of noninvasive methods of disease monitoring.⁶

Corresponding Author: Amanda J. Redig, MD, PhD, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, LC-4116, Boston, MA 02215 (aredig@partners.org).

Published Online: July 7, 2016. doi:10.1001/jamaoncol.2016.1304.

Author Contributions: Dr Redig had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Johnson, Jänne, Jackman.

Acquisition, analysis, or interpretation of data: Redig, Taibi, Boucher, Johnson, Jänne, Jackman.

Drafting of the manuscript: Redig, Taibi, Boucher, Johnson, Jackman.

Critical revision of the manuscript for important intellectual content: Redig, Boucher, Johnson, Jänne, Jackman.

Statistical analysis: Redig, Jackman.

Obtained funding: Jackman.

Administrative, technical, or material support: Redig, Taibi, Boucher, Johnson, Jänne, Jackman.

Study supervision: Johnson, Jänne, Jackman.

Conflict of Interest Disclosures: Dr Redig reports personal fees from Medtronic, all outside the submitted work. Dr Costa reports personal fees from Pfizer, personal fees from Ariad, personal fees from Boehringer Ingelheim, all outside the submitted work. Dr Johnson reports personal fees from AstraZeneca, personal fees from Clovis Oncology, personal fees from Novartis, personal fees from Merck, personal fees from Genentech, other from Chugai Pharmaceuticals, other from KEW Group, outside the submitted work; in addition, Dr. Johnson has a patent (EGFR Genotyping) with royalties paid to the Dana-Farber Cancer Institute. Dr Jänne reports personal fees from Genentech, personal fees from AstraZeneca, personal fees from Pfizer, grants from AstraZeneca, and grants from Astellas Pharmaceuticals during the conduct of the study; stock ownership in Gatekeeper Pharmaceuticals, outside the submitted work; and post marketing royalties from a DFCI-owned patent that has been licensed to LabCorp. Dr Jackman reports personal fees from Genentech, personal fees from Celgene, outside the submitted work. No other disclosures are reported.

Funding/Support: Dr Redig was supported by the National Cancer Institute (NCI) grant T32CA009172. Drs Johnson and Jänne were supported by NCI grant 5R01CA114465-09). Dr Jänne was also supported by NCI grant 5R01CA135257 Suzanne E. Dahlberg, PhD, noted in Additional Contributions, was supported by Kaplan Research Fund for Thoracic Oncology. Funding for this study was also provided by Genentech.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank the following individuals for their contributions to the study. None of these individuals received compensation for their involvement. Suzanne E. Dahlberg, PhD (Department of Biostatistics and Computational Biology Dana-Farber Cancer Institute), assisted with statistical review of the manuscript. Michael S. Rabin, MD, J. Paul Marcoux, MD, Geoffrey R. Oxnard, MD, and Joan Lucca, RN (Department of Medical Oncology, Dana-Farber Cancer Institute), assisted with enrolling patients in the study and review of the manuscript. Marzia Capelletti, PhD (Department of Medical Oncology, Dana-Farber Cancer Institute), assisted with analysis of repeated biopsy specimens and review of the manuscript. Mark S. Huberman, MD, Deepa Rangachari, MD, and Mary Farquhar, RN (Department of Medicine, Beth Israel Deaconess Medical Center), assisted with enrolling patients on study and review of the manuscript. Lynette M. Sholl, MD (Department of Pathology, Brigham and Women’s Hospital), assisted with pathology review of specimens from repeated biopsies and review of the manuscript. Paul A. VanderLaan, MD, PhD (Department of Pathology, Beth Israel Deaconess Medical Center), assisted with pathology review of specimens from repeated biopsies and review of the manuscript. Ritu R. Gill, MD (Department of Radiology, Brigham and Women’s Hospital), for assistance with repeated biopsies and review of the manuscript. Erik E. Folch, MD, MSc (Department of Surgery, Beth Israel Deaconess Medical Center), assisted with repeated biopsies and review of the manuscript. Cloud P. Paweletz, PhD (Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute), assisted with figure formatting and review of the manuscript.