Pembrolizumab–lenvatinib beyond immunotherapy progression in endometrial cancer: A real-world analysis.

5612 Background: The integration of immune checkpoint inhibitors (ICIs) into frontline therapy for advanced or recurrent endometrial cancer (aEC) has transformed treatment paradigms. However, the management of patients who experience disease progression after ICI-based therapy remains challenging. In the absence of prospective guidance, ICI rechallenge and ICI-based combinations beyond progression are already being used in clinical practice. In this real- world study, we aimed to evaluate the effectiveness of pembrolizumab-lenvatinib (PL) beyond ICI progression in patients with aEC. Methods: A retrospective study was conducted using the TriNetX database, defining two cohorts of aEC patients: 527 patients who received PL and 2,582 patients who did not receive PL but were treated with either paclitaxel or doxorubicin (chemotherapy, CHT cohort). Both cohorts had received an ICI-based regimen within the previous three years. Patients with any other malignancy were excluded. Propensity score matching (PSM) was used to balance cohorts for age, race, body mass index (BMI), major comorbidities, mismatch repair (MMR) status and prior olaparib exposure. The primary endpoint was overall survival (OS); secondary endpoints were treatment-related toxicities, including hypothyroidism and heart failure. OS was estimated using Kaplan–Meier methods, with hazard ratio (HR) used to compare OS and odds ratio (OR) used to compare toxicities. Results: After PSM, 521 matched pairs of patients (mean age +/- standard deviation: 66,4 +/- 9,6 years) were included in the PL and CHT cohorts, respectively, with well-balanced baseline characteristics. Asian patients were similarly represented in the two groups (7.3% vs 7.4%), most patients were obese (BMI ≥30: 59,3% vs 57,8%), only a small proportion had known MMR-deficient disease (2.1% and 1.9%), and just few of them were previously treated with olaparib (1.9%). After a median follow-up of 8.6 months (interquartile range, IQR 14.3) in the PL cohort and 11.5 months (IQR 16.7) in the CHT cohort; median OS was 27,4 months with PL and was not reached with CHT (HR = 2.25, 95% CI 1.76–2.89; p<0.001). Conclusions: The rise of ICIs in frontline therapy for aEC marks a paradigm shift and raises the question on how to manage patients who progress after prior immunotherapy. This is the first large, real-world cohort analysis to evaluate PL beyond immunotherapy progression in aEC. In this study, PL did not improve OS compared with CHT in patients previously exposed to ICIs. These findings suggest that PL may not be the optimal choice in this setting, and further work is needed to clarify the best post-ICI sequencing strategies and to develop approaches to overcome resistance.