Survival implications of systemic immunosuppression timing, dosage, and duration in immune checkpoint inhibitor therapy: A retrospective multicohort study

Summary: Abstract Body: Systemic immunosuppression (sISP) is known to be associated with poor overall survival (OS) in cancer patients treated with immune checkpoint inhibitors (ICIs). This study examined the impact of sISP timing, dosage, and duration on OS among ICI recipients. We identified 13,086 patients from Massachusetts General Hospital, Brigham and Women’s Hospital, and Dana-Farber Cancer Institute (MGBD). For independent validation, we included 26,172 patients from the TriNetX network by 1:2 propensity score matching on demographic and cancer-related variables. A computational approach was developed to extract sISP status from medication records and was validated by manual phenotyping. Multivariable survival analyses were performed using Accelerated Failure Time models. Time Ratios (TRs) and 95% Confidence Intervals (CIs) were reported, with TR<1 indicating a shorter OS time. We identified 3,649 (27.8%) and 4,526 (17.3%) sISP patients in the MGBD and TriNetX cohorts, respectively. At MGBD, sISP use within one year of ICI start was associated with worse OS compared to patients without sISP use (TR: 0.71; 95% CI: 0.64-0.79; p<0.0001). This association was accentuated in patients who received sISP closer to ICI start, with those receiving sISP within one month of ICI start having the poorest OS (TR: 0.49; 95% CI: 0.44-0.54; p<0.0001). Increased dosage and duration of sISP were associated with shorter OS. Dosages beyond 80 mg/day had a 55% OS loss, while durations longer than 7 days were associated with a 35% OS loss. These findings were independently validated in the TriNetX cohort. In summary, three key factors associated with significantly worse OS, including sISP use near ICI start, higher dosage of sISP, and longer sISP duration, regardless of indication. These results provide clinicians with valuable information to guide the sISP management in patients receiving ICI therapy. Guihong Wan¹, Nga Nguyen¹, Charles Lu¹, Sara Khattab¹, Boshen Yan¹, Munachimso Amadife¹, Bonnie Leung¹, Wenxin Chen¹, Shawn Kwatra², Kerry Reynolds¹, Nicole R. LeBoeuf¹, Alexander Gusev¹, Yevgeniy Semenov¹ 1. Harvard Medical School, Boston, MA, United States. 2. University of Maryland School of Medicine, Baltimore, MD, United States. Clinical Research: Epidemiology and Observational Research