FDG PET SUV as a Biomarker of Abscopal and Low-Dose Radiation Responses in Checkpoint Inhibitor Resistant Tumors

Abstract

<h3>Purpose/Objective(s)</h3> Resistance to immune checkpoint inhibition (ICI) in advanced cancer correlates with poor outcome. High-dose radiation (HDR) can augment local as well as systemic ICI effects and induce responses outside the treatment field. Low-dose radiation (LDR) to secondary targets may further enhance responses by modulating the stroma and facilitating immune cell infiltration. Tumor FDG-PET maximum standardized uptake value (SUVmax) has been shown to predict patient (pt) outcomes and responses to immune agents. In a <i>post hoc</i> analysis of a phase II immunoradiation trial, we explored SUVmax as a biomarker of response to HDR +/- LDR in ICI-resistant metastatic cancer. <h3>Materials/Methods</h3> Study treatment consisted of HDR to 1-2 sites, +/- LDR secondary sites. We included 49 pts with baseline PET/CT in our analysis. Of these, 24 received HDR alone (secondary tumors untreated), and 25 received HD-RT plus LD-RT to 1+ additional lesion(s). Median HDR dose was 45 Gy (range 20-70 Gy) and for LDR was 7 Gy (range 1-10 Gy). ICI included We evaluated associations between pre-RT SUVmax and tumor responses per immune relate response criteria (irRC) with logistic regression for 134 untreated (UT) and 54 LDR treated lesions. <h3>Results</h3> Median baseline SUVmax for all lesions was 7.4 (range 0-28.4) and did not differ between UT vs LDR lesions (P = 0.2). Lesion-level objective responses (PR/CR) were greater for LDR (61%) vs UT (11%; P < 0.001). On UVA, SUVmax predicted likelihood of UT lesion OR (i.e., abscopal response), with non-avid tumors most likely to respond (43%), and SUVmax values of 2, 5, and 7 corresponding to likelihood of 30%, 15% and <10% (P < 0.001; AUC 0.78). A threshold SUVmax <5 identified tumors most likely to abscopal with a sensitivity of 67% and specificity of 77%. Responding tumors had a lower SUVmax (med 4.4, IQR 3.9-5.6) vs non-responding (med 7.7, IQR 5.2-12.8; P < 0.001). Likewise, SUVmax predicted LDR responses, with SUVmax of 0, 10, and 15 corresponding to likelihood of 83%, 61%, and 46% (P = 0.02, AUC 0.67). A threshold SUVmax <9 identified tumors most likely to respond to LDR with a sensitivity of 64% and specificity of 62%. Responding LDR tumors had lower SUVmax (med 7.7, IQR 4.8-10.5) vs non-responding (med 9.8, IQR 7.1-17.7; P = 0.0375). On MVA, SUVmax was the sole independent predictor of abscopal and LDR response, while other factors (age, gender, ICI, ALC, HDR dose, histology, tumor site) were not significant. <h3>Conclusion</h3> In summary, we found that LDR increased secondary tumor ORR in ICI-resistant pts treated with salvage HDR; that a lower baseline SUVmax predicted higher likelihood of OR; and that LDR effectively raised the SUVmax threshold that predicted OR likelihood. FDG-PET SUVmax represents a valuable biomarker that can be clinically implemented to stratify tumors for optimal treatment strategy.