Predictors of Response to Salvage High-Dose plus Low-Dose Radiation in Checkpoint-Inhibitor Resistant Patients

Abstract

<h3>Purpose/Objective(s)</h3> Patients (pts) with immune checkpoint inhibitor (ICI)-resistant advanced cancer have poor outcomes and limited alternative treatment options. High-dose radiation therapy (HD-RT) can augment local and systemic ICI effects and lead to tumor regression outside of the treatment field (abscopal effect). Low-dose RT (LD-RT) to secondary sites may further enhance responses by modulating the stroma and facilitating immune cell infiltration. Prior studies suggest that high BED regimens may better stimulate antitumor immune responses than lower BED regimens. We explored BED and baseline pt factors as predictors of response to salvage HD-RT plus LD-RT in a <i>post hoc</i> analysis of an ongoing phase II trial. <h3>Materials/Methods</h3> We included 56 (of 60) enrolled pts with follow up imaging in our analysis. All had metastatic solid tumors that progressed on ICI. Study treatment consisted of HD-RT to 1-2 sites plus LD-RT to 1+ additional sites. HD-RT regimens included conventional RT, comprised of 20-60 Gy in 4-5 fractions (fx), or stereotactic body RT (SBRT), comprised of 27-36 Gy in 3 fx, 50 Gy in 4 fx, or 60-70 Gy in 10 fx. LD-RT consisted of 1-10 Gy total doses given in 0.5-2 Gy fxs, with 7 Gy/5 fx being the most frequent. We evaluated relationships between pt responses (disease control at 4mo post-RT, DC; overall objective response, OR; time-to-progression, TTP) and patient- and treatment-related factors with logistic 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> Of 56 pts, 20 received HD-RT with BED >100 (range 106-119) and 36 with BED <100 (range 28-96). DC (SD or PR/CR per immune related response criteria, irRC) was achieved in 28/54 pts (52%; 2 pts not evaluable for response). OR (PR/CR) occurred in 15/54 pts (28%). On UVA, HD-RT BED₁₀ was predictive of both DC (OR 1.02, P = 0.03) and OR (OR 1.03, P = 0.008). Other factors, including age, gender, histology, fx count, baseline absolute lymphocyte count (bALC), and metastatic burden (MB) did not affect DC or OR. Stratifying by BED₁₀, median PFS was greater for the BED >100 cohort than BED <100 cohort (6.5mo vs 2.5mo, HR 0.43, P = 0.009), as were DCR (78% vs 39%, OR 5.5, P = 0.01) and ORR (OR 61% vs 11%, OR 12.6, P < 0.001). Cox multivariable analysis indicated that 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. However, when stratified by IO-class (PD1/PDL1 vs CTLA-4/combo) and histology (NSCLC vs other), only BED remained consistently significant. <h3>Conclusion</h3> Salvage HD-RT plus LD-RT is a unique therapeutic approach that can re-induce disease control after ICI progression. HD-RT regimens with a higher BED₁₀ – optimally >100 – will likely provide the greatest chance of treatment success with this strategy. Larger randomized trials are needed to further explore the role of salvage RT in ICI resistance.