A randomized prospective trial evaluating duration of PD-1 and PD-L1 inhibitor therapy in advanced solid tumors.

Abstract

2514 Background: Immune checkpoint inhibitors (IO) have revolutionized the treatment of advanced solid tumors. Despite their widespread adoption, the optimal duration of IO has not been clearly established, and this remains an unmet clinical need. Methods: In our prospective trial, patients (pts) with advanced solid tumors who achieved at least stable disease (SD) after 1 year of standard-of-care PD-1/PD-L1 inhibitors were randomized 1:1 to either stop or continue IO beyond one year. Pts who stopped IO and then progressed could be retreated with IO at physician discretion. Primary endpoint was cure rate, defined as the proportion of pts without progressive disease, death, or initiation of new treatment (including re-treatment with IO) at five years. Cure rate was calculated using Kaplan-Meier (KM) estimates with 95% confidence intervals (CI) and compared between arms using a multivariable logistic regression model to adjust for pre-specified stratification factors of tumor type and expected efficacy by IO indication, and reported as an odds ratio (OR) with CI and p-value. Secondary endpoints included PFS, OS, and incidence of iRAEs. Median PFS and OS were estimated from KM curves, with hazard ratios (HR) and p-values obtained from stratified Cox proportional hazards models. All analyses were conducted using R version 4.4.2. Results: From 2019 to 2025, leveraging our central hub and community network, a total of 161 pts (Stop = 81, Continue = 80) were enrolled. The trial was closed early due to slow accrual (goal 578 pts). Median age was 71 and the most common tumor types were: NSCLC(39.8%), mismatch repair-deficient tumors(18.6), RCC(11.8%), HNSCC(8.1%), and melanoma (7.5%). There was no difference in baseline characteristics between arms. With a median follow up of 43.2 months (mo), cure rate was 45% (32%-63%)in the stop arm vs 38% (27-54%) in the continue IO arm (OR 2.26, 95% CI [0.62-8.22], p = 0.22). Median PFS was 55.4(27.5-NR) vs. 31.2 mo(20-NR) HR 0.77, 95% CI (0.48-1.24), p = 0.28 and median OS was NR (55.4 vs. NR) vs. 53.5 mo(40.8-NR) HR 0.54, 95%CI (0.3-0.99), p = 0.04 for the stop vs continue IO arms, respectively. In the continue IO arm, the median number of IO doses was 11 (range 0-36) and 52 of these pts discontinued IO with the most common reason being disease progression (42.3%), and 7.7% discontinued for toxicity. In the stop IO arm, 17 pts who progressed were retreated with IO; 20% achieved subsequent partial response and the median PFS was 10.5 mo(6.5-NR) and median OS was 26.7 mo(10.5-NR) after retreatment. Conclusions: Our trial is unique as a prospective randomized evaluation of length of IO treatment in advanced solid tumors. Cure rates and PFS were similar across arms and OS was improved in pts that discontinued IO at 1 year. These findings suggest that stopping IO at 1 year may be as effective as indefinite IO therapy, though validation in a larger, adequately powered trial is needed. Clinical trial information: NCT04157985 .