Treatment-Free Interval as a Prognostic Factor for Survival Outcomes in Patients with Advanced or Recurrent Endometrial Cancer Treated with Pembrolizumab Plus Lenvatinib: A Multi-Institutional Real-World Cohort Study

Background/Objectives: The treatment-free interval (TFI) predicts benefit from platinum rechallenge in gynecological cancers, but its prognostic value in patients receiving second-line pembrolizumab plus lenvatinib for recurrent endometrial cancer (EC) is unknown. We evaluated whether the TFI is associated with survival and toxicity in this setting. Methods: Using the TriNetX Research Network (122 healthcare organizations, United States and Europe), we identified adults aged 18–90 years with advanced or recurrent EC between January 2018 and June 2026 who received three to six cycles of first-line carboplatin plus paclitaxel, progressed, and then received pembrolizumab plus lenvatinib. Patients were stratified by TFI (<6 months, Cohort 1; ≥6 months, Cohort 2) and matched 1:1 by propensity score. The primary outcome was overall survival (OS), compared using Kaplan–Meier and Cox proportional-hazards methods; adverse-event risks were exploratory outcomes compared using z-tests for the risk difference, without adjustment for multiple comparisons. Results: Of 420 eligible patients, 119 remained in each cohort after matching, with balanced baseline characteristics. Median OS was 10.0 months in Cohort 1 versus 23.6 months in Cohort 2 (hazard ratio 1.60, 95% confidence interval 1.12–2.29; p = 0.009), and 3-year OS was 32.5% versus 40.5%. Grade 3 anemia occurred earlier and more often in Cohort 1 (hazard ratio 1.74, 95% confidence interval 1.10–2.76; p = 0.017), whereas hypothyroidism was less frequent (31.9% versus 47.1%; p = 0.017); the remaining adverse events did not differ significantly between cohorts. Conclusions: A TFI ≥ 6 months is associated with significantly longer OS and a largely similar toxicity profile. The TFI is a readily available, real-world evidence-based reference for the prognosis and for the comparative adverse-event profile of the two TFI groups in this setting.