Biomarkers of Response to Immuno-chemotherapy & oliGometastatic Hypofractionated radioTherapy (BRIGHT) for Lung Cancer: Synergy of PET/CT Imaging and Peripheral Blood Assays

ABSTRACT
Management of patients with metastatic non-small cell lung cancer (NSCLC) requires navigation of an
increasingly diverse therapeutic landscape. Although immune checkpoint inhibitors (ICI) of anti-programmed
cell death 1 (PD1) and its ligand PDL1, in combination with chemotherapy (chemoICI), are standard of care for
metastatic NSCLC and have improved survival in some patients, the majority are subject to treatment-related
toxicity at significant financial burden with little clinical benefit. Radiation therapy can prolong survival in
patients with limited sites of metastatic disease (oligometastatic), or limited sites of progressive disease
(oligoprogression) on systemic therapy, but no consensus exists on which patients and lesions would benefit
from irradiation. Patient selection and treatment adaptation through early response assessment is an unmet
need to increase the effective combination of chemotherapy, immunotherapy, and radiation therapy in
metastatic NSCLC and improve outcomes. Biomarkers are critical to our understanding of complex response
patterns to chemoICI and radiation. In patients with newly diagnosed metastatic NSCLC starting chemoICI per
standard of care, we propose to assess and monitor treatment response by combining positron emission
tomography (PET) imaging of macroscopic disease burden and circulating immunologic biomarkers of occult
systemic disease burden in support of precision therapy through the following aims: (1) construct clinical PET
imaging and circulating immunologic biomarker signatures of chemoICI response patterns to risk stratify
patients into (a) early widespread progression, (b) oligoprogression, and (c) responsive disease; (2) construct
clinical PET imaging and circulating immunologic biomarker signatures of oligoprogressive radiation therapy
response patterns to identify patients and lesions that benefit from ablative radiation; and (3) correlate localized
clinical PET imaging and global circulating immunologic biomarkers with survival outcomes.
Fluorodeoxyglucose (FDG) PET scans and peripheral blood draws will be performed prior to chemoICI, 3
weeks into chemoICI, and 12 weeks into chemoICI. For patients who develop oligoprogressive disease, we will
acquire FDG PET scans and peripheral blood prior to and 1-month post radiation therapy. We will develop
combined quantitative PET imaging and circulating immunologic biomarker signatures of chemoICI and
radiation response that stratify patients into the following groups: (i) high-risk patients predicted to develop
rapid widespread progressive disease who require aggressive second-line systemic therapy, (ii) moderate-risk
patients predicted to develop oligoprogressive disease who require consolidation radiation to high-risk lesion
targets, (iii) low-risk patients predicted to have durable long-term response to first-line therapy. Successful
completion of this project will support the launch of a clinical trial on biomarker response-adaptive chemoICI
and radiation therapy in patients with metastatic non-small cell lung cancer, in order to improve cancer control
and survival.

Grant Number: 5R01CA258997-04
NIH Institute/Center: NIH
Principal Investigator: Stephen Bowen