Predictors of Systemic Responses Induced by Salvage Radiation after Progression on Immunotherapy

Abstract

<h3>Purpose/Objective(s)</h3> Radiation can induce systemic immune responses and tumor regression outside of the treatment field, a phenomenon known as the abscopal effect. Salvage high dose radiation (HD-RT) may reinvigorate antitumor immunity and re-induce disease control in patients (pts) with advanced cancer who have progressed on immune checkpoint inhibition (ICI). Prior studies suggest that BED ≥ 100 is optimal for disease control and may produce superior antitumor immune responses than lower BED regimens. We explored BED and pt factors as predictors of response to salvage HD-RT in a <i>post hoc</i> analysis of an ongoing phase II immunoradiation trial. <h3>Materials/Methods</h3> We included 50 enrolled trial pts in our analysis. All had metastatic solid tumors that progressed on ICI. Study treatment consisted of HD-RT to 1-2 sites, leaving at least 1 site untreated to monitor for abscopal response. Regimens included conventional RT, comprised of 20-30 Gy in 5 fractions (fx) or 45-52.5 Gy in 15 fx, or stereotactic body RT (SBRT), comprised of 24 Gy in 3 fx, 50 Gy in 4 fx, or 63-70 Gy in 9-10 fx. We evaluated relationships between response (disease control at 4mo post-RT, DC; overall objective response, OR; abscopal response, AR; time-to-progression, TTP) and patient- and treatment-related factors with logistic regression and Cox proportional hazard models. PFS and response outcomes were then assessed after stratifying by HD-RT BED₁₀ (BED>100 vs BED<100). <h3>Results</h3> Systemic disease control rate (DCR; SD or PR/CR per immune related response criteria, irRC) was 45% (24/49 pts; 1 pt not evaluable for response). OR (PR/CR) were observed in 8/49 pts (16%). AR (lesion-level CR/PR) were observed in 14/49 pts (29%). On multivariable analysis, HD-RT BED₁₀ (OR 111.9 P = 0.001) and baseline absolute lymphocyte count (bALC; OR 5.4 P = 0.02) predicted probability of DC, while gender, age, metastatic burden (MB), and fx count did not. Of 50 pts, 18 received HD-RT with BED >100 (range 107-119) and 32 with BED <100 (range 28-96). Stratifying by BED, median PFS was greater for the BED >100 cohort than BED <100 (8mo vs 2mo HR 0.45 P = 0.003), and DCR was 83% for BED >100 vs 28% for BED <100 (RR 2.96 P < 0.001). Although not statistically significant, ORR was also greater in BED >100 vs BED <100 (24% vs 12.5% P = 0.4), as was ARR (41% vs 22% P = 0.2). On Cox multivariable analysis, BED >100 (HR 0.27 P < 0.001), MB (HR 1.22 P < 0.001), and bALC (HR 0.43 P < 0.001) were independent predictors of TTP. Adjusting for IO class (PD1/PDL1 vs CTLA-4/combo) and histology (NSCLC vs other), each of these factors remained significant. <h3>Conclusion</h3> Salvage HD-RT after systemic progression on ICI may be a valid treatment option that is most likely to benefit pts with lower disease burden and stable ALC. RT regimens utilizing SBRT with BED₁₀ >100 will likely provide improved outcomes compared to lower BED regimens. Larger trials are indicated to validate optimal regimens and cohorts for this strategy.