3492 - Chronotherapeutic Effects of Immune Checkpoint Inhibitors and Stereotactic Body Radiotherapy: Secondary Analysis of a Prospective Trial

Purpose/Objective(s): Immune checkpoint inhibitors (ICIs) and radiotherapy may exhibit chronotherapeutic effects, i.e. the time of day of their administration may modify their efficacy or toxicity (potentially owing to circadian regulation of mechanisms of antitumor immunity and/or radiosensitivity). The purpose of this study was to evaluate if chronotherapeutic effects were present in patients receiving stereotactic body radiotherapy (SBRT) plus ICIs for metastatic solid malignancies, hypothesizing that treatments later in the day would be associated with inferior oncologic outcomes.

Materials/Methods: This was a secondary analysis of a prospective phase I trial and its associated expansion cohort delivering ablative multi-site SBRT (2-4 metastases; most commonly delivering BED₁₀ > 100 Gy) followed by pembrolizumab (200mg q3weeks starting within 7 days) for advanced solid tumors previously treated with standard-of-care therapy. The time of day of ICI administrations and SBRT fractions were clinically recorded. The “Late Afternoon ICI” group was defined as =20% infusions after 1600 h (i.e. 4:00pm), similar to prior seminal studies. The “PM SBRT” group was defined as the majority of fractions being delivered after 1200 h. Overall survival (OS) and progression-free survival (PFS) were analyzed by the Kaplan-Meier method and Cox proportional hazards models. Covariates included number of radiated metastases and household median income (as estimated by the U.S. Census Bureau via ZIP code tabulation area), as socioeconomic variables may also confound the relationship between treatment timing and outcome.

Results: 101 patients (most common primary sites were ovarian [9%], pancreas [8%], cholangiocarcinoma [8%], non-small cell lung [7%], colon [7%]) received SBRT to 230 sites. On multivariable Cox regression, “Late Afternoon ICI” exhibited inferior OS (HR 1.6, P = 0.047; median OS 12.9 vs. 6.9 months), while “PM SBRT” was associated with improved OS (HR 1.7, P = 0.03; median 10.5 vs. 8.6 months). OS was also correlated with the number of irradiated metastases (HR 1.7, P = 0.03), but not estimated household income (P = 0.6). PFS was not statistically associated with “Late Afternoon ICI” (HR = 1.4, P = 0.19) or “PM SBRT” timing (HR 0.72, P = 0.15). There was no difference in CTCAE grade 3+ adverse events by treatment timing (17% “Late Afternoon” ICI vs. 11%, P = 0.4 and 13% “PM SBRT” vs. 15%, P = 0.8).

Conclusion: ICI administrations after 1600 h and SBRT delivery before 1200 h were associated with inferior survival after SBRT plus ICI for metastatic solid tumors. Further preclinical and prospective studies are warranted to further interrogate these chronotherapeutic effects to further improve patient outcomes.