Utility of FDG-PET in immunotherapy: results from a Phase II study of NSCLC patients undergoing therapy with the PD-L1 inhibitor, atezolizumab (MPDL3280A) (2016)

134 Objectives Atezolizumab is a humanized anti-PD-L1 IgG1 monoclonal antibody that can restore tumor-specific T-cell immunity by inhibiting the binding of PD-L1 to PD-1 and B7.1, leading to enhanced T-cell priming and reinvigoration of suppressed immune cells. Single-agent atezolizumab has shown durable responses across multiple tumor types. To date, limited data investigating the usefulness of FDG-PET in monitoring response to immunotherapy are available. FIR (NCT01846416) is a 3-cohort, single-arm Phase 2 study of atezolizumab in patients with PD-L1-expressing tumors. Cohorts included both chemotherapy-naive and previously treated stage IIIB/IV non-small cell lung cancer (NSCLC) patients. Single- and dual-time-point FDG-PET/CT imaging was performed in FIR to evaluate the utility of FDG-PET as a biomarker of response to immune checkpoint blockade, and to assess whether radiographic pseudoprogression (an initial increase in apparent tumor burden in the setting of an anti-tumor T-cell response) could be distinguished from true progression. Methods Patients received atezolizumab 1200 mg intravenously every 3 weeks. The primary endpoint was objective response rate (ORR) based on modified immune-related response criteria. All patients underwent single-time-point (60-min uptake time) FDG-PET scanning at baseline, at the time of the first tumor assessment (week 6), and (if feasible) at progression. PET scans were acquired according to a standardized scan protocol. Optional dual-time-point scans (additional acquisition at 180-min uptake time) were encouraged.. FDG-PET data were centrally analyzed using European Organisation for Research and Treatment of Cancer (EORTC) criteria. Metrics of whole-body metabolic tumor burden were also derived, including metabolic tumor volume of all sites of disease and percentage of injected dose. Retention index (RI; % difference between 60- and 180-min SUVs) was calculated for dual-time-point scans. Qualitative FDG-PET “immune signs” (elevated uptake in spleen and lymph nodes draining tumor sites) were also assessed. The FIR protocol was approved by the relevant institutional review boards, and all patients provided written informed consent. Results A total of 138 patients enrolled in FIR at 28 clinical sites in 5 countries. 103 patients had evaluable PET scans at both baseline and 蠅 1 post-baseline time point (17 patients had no scans or non-evaluable scans; 18 discontinued prior to post-baseline scans). 29 patients from 6 sites had evaluable dual-time-point scans at both baseline and on treatment. Patients with metabolic response by EORTC criteria on 6-week scans had a higher ORR (73.9% [17/23]) than metabolic non-responders (6.3% [5/80]). Baseline whole-body metabolic tumor burden was a significant negative prognostic marker for overall survival (OS), more so than baseline sum of longest dimensions of target lesions based on diagnostic computed tomography, whereas mean FDG avidity (SUVmax) at baseline was not informative. Response after apparent radiographic progression was seen in only 2 patients, so the utility of FDG-PET to distinguish pseudoprogression could not be determined. Neither baseline RI nor change in RI was a better predictor of OS or ORR than measures based on single-time-point data. 10 patients at baseline and 10 patients on treatment exhibited FDG-PET “immune signs,” but there was no clear relationship to response. Conclusions The utility of FDG-PET in patients with NSCLC on immune blockade therapy appeared to be similar to what has been reported with conventional chemotherapeutic treatments, with early metabolic response predicting subsequent benefit. Baseline whole-body metabolic tumor volume was a strong negative prognostic factor for OS. Summary dual-time-point data did not provide incremental value.