Tumor Hypoxia Response After Targeted Therapy in EGFR-Mutant Non-Small Cell Lung Cancer: Proof of Concept for FMISO-PET

Abstract

Hypoxia is associated with resistance to radiotherapy and chemotherapy. Functional imaging of hypoxia in non-small cell lung cancer (NSCLC) could allow early assessment of tumor response and guide subsequent therapies. Epidermal growth factor receptor (EGFR) inhibition with erlotinib reduces hypoxia in vivo. [18F]-Fluoromisonidazole (FMISO) is a radiolabeled tracer that selectively accumulates in hypoxic cells. We sought to determine whether FMISO positron emission tomography (FMISO-PET) could detect changes in hypoxia in vivo in response to EGFR-targeted therapy. In a preclinical investigation, nude mice with human EGFR-mutant lung adenocarcinoma xenografts underwent FMISO-PET scans before and 5 days after erlotinib or empty vehicle initiation. Descriptive statistics and analysis of variance (ANOVA) tests were used to analyze changes in standardized uptake value (SUV), with pooled analyses for the mice in each group (baseline, postvehicle, and posterlotinib). In a small correlative pilot human study, patients with EGFR-mutant metastatic NSCLC underwent FMISO-PET scans before and 10 to 12 days after erlotinib initiation. Changes in SUV were compared to standard chest computed tomography (CT) scans performed 6 weeks after erlotinib initiation. The mean (±standard error of the mean; SUVmean) of the xenografts was 0.17 ± 0.014, 0.14 ± 0.008, and 0.06 ± 0.004 for baseline, postvehicle, and posterlotinib groups, respectively, with lower SUVmean among the posterlotinib group compared to other groups (P < .05). Changes on preclinical PET imaging were striking, with near-complete disappearance of FMISO uptake after erlotinib initiation. Two patients were enrolled on the pilot study. In the first patient, SUVmean increased by 21% after erlotinib, with progression on 6-week chest CT followed by death after 4.8 months. In the second patient, SUVmean decreased by 7% after erlotinib, with regression on 6-week chest CT accompanied by clinical improvement; the patient had stable disease at 14.5 months. In conclusion, we observed that FMISO-PET can detect changes in hypoxia levels after EGFR-directed therapy in EGFR-mutant NSCLC. Further study is warranted to determine its utility as an imaging biomarker of early response to EGFR-directed therapy.

Keywords: EGFR; FMISO; PET; erlotinib; hypoxia; lung cancer.

Conflict of interest statement

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: LVS reports receiving research grant support from Genentech, and advising for Clovis Oncology, Merrimack Pharmaceuticals, AstraZeneca, and GSK.

© The Author(s) 2015.

Figures

Figure 1

Pooled analyses among epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer flank xenografts, with 3 mice in the baseline group, 3 mice in the vehicle group, and 3 mice in the erlotinib group. A star (⋆) indicates a statistically significant difference at the P < .05 level. A, The average standardized uptake value (SUV)mean of the tumors was 0.17±0.014, 0.14±0.008, and 0.06±0.004 in the baseline, postvehicle, and posterlotinib [18F]-fluoromisonidazole (FMISO) positron emission tomography (PET) scans, respectively. B, The average SUVmax of the tumors were 0.23 ± 0.015, 0.19 ± 0.013, and 0.09 ± 0.083 in the baseline, postvehicle, and posterlotinib FMISO-PET scans, respectively.

Figure 2

Axial (first column), sagittal (second column), coronal (third column), and three-dimensional (3D) maximal intensity projection (MIP; fourth column) from [18F]-fluoromisonidazole (FMISO) positron emission tomography (PET)/computed tomography (CT) scans among epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer flank xenografts. Red arrows indicate primary tumor location; all xenografts were established in the same location in the right upper flank in each mouse. A, Baseline FMISO-PET/CT on a representative mouse before any treatment. B, Follow-up FMISO-PET/CT after that same mouse received erlotinib. C, Follow-up FMISO-PET/CT on another representative mouse after receiving empty vehicle alone.

Figure 3

Axial fluoromisonidazole (FMISO) positron emission tomography (PET)/computed tomography (CT) fusion with lung windowing (first column), axial FMISO-PET (second column), and coronal FMISO-PET (third column) in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. Red arrows indicate primary tumor location. A, Patient #1, before erlotinib. B, Patient #1, after starting erlotinib. C, Patient #2, before erlotinib. D, Patient #2, after starting erlotinib.

Figure 4

Chest computed tomography (CT) scans with lung windowing (axial) in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. Red arrows indicate primary tumor location. A, Patient #1, before erlotinib (top) and 1.5 months after erlotinib initiation (bottom) obtained as part of routine clinical care. This patient experienced radiographic progression and clinical decline and died from disease 4.8 months after erlotinib initiation. B, Patient #2, before erlotinib (top) and 1.5 months after erlotinib initiation (bottom) obtained as part of routine clinical care. This patient experienced radiographic regression and clinical improvement and was alive with stable disease at last follow-up 14.5 months since erlotinib initiation.