Real World Outcomes of Pembrolizumab and Reduced-Dose Lenvatinib in Recurrent Endometrial Cancer by Platinum and p53 Status.

Objectives: The objective of this study was to evaluate the efficacy of pembrolizumab and lenvatinib in recurrent endometrial cancer (EC) by platinum resistance status and p53 status, and to compare outcomes between patients who started lenvatinib at doses of 10 mg or less versus standard starting doses. Methods: A retrospective study was conducted in patients with recurrent EC treated with pembrolizumab and lenvatinib between March 2019 and February 2023. Primary outcomes were objective response rate (ORR) and progression-free survival (PFS) by platinum status, p53 status, and lenvatinib dose. Secondary outcomes included adverse events and lenvatinib-related toxicity. Noninferiority was assessed using the Wald confidence interval and a propensity score-matched cohort. Results: Among 59 patients, 85% had high-grade histology, 75% were platinum-resistant, and 67.8% harbored p53 mutations. The overall ORR was 37%. There were no significant differences in ORR or PFS by grade, platinum status, or starting dose. On multivariable analysis, p53 mutation and ECOG < 2 were independently associated with improved PFS. The 10 mg lenvatinib dose demonstrated the longest median treatment duration (74 days) with improved tolerability. When stratifing lenvatinib starting dose as ≤ 10 mg versus > 10 mg, ORR was 50% and 26%, respectively. The lower dose group met criteria for noninferiority. Conclusions: In a heavily pretreated, high grade, platinum resistant population, pembrolizumab and lenvatinib showed activity comparable to prior studies despite a more resistant cohort. Reduced lenvatinib doses of 10 mg or less were associated with noninferior ORR and lower toxicity, supporting dose optimization. In addition, p53 mutation was independently associated with prolonged PFS, suggesting it may be a biomarker of response. KEY MESSAGES: What is already known on this topic:Pembrolizumab plus lenvatinib has been an emerging treatment for recurrent endometrial cancer, showing survival benefit in pMMR tumors. However, most data are from clinical trials with less heavily pretreated patients, and uncertainty remains about efficacy in platinum-resistant, p53-mutated, high-grade tumors and the optimal starting dose of lenvatinib given its toxicity.What this study adds:In a real-world cohort enriched for platinum-resistant, high-grade, p53-mutated, heavily pre-treated endometrial cancers, lenvatinib plus pembrolizumab achieved an objective response rate consistent with prior trials. A reduced starting dose of lenvatinib (≤10 mg) was non-inferior to higher doses, better tolerated, and associated with fewer dose reductions. Additionally, p53 mutation and good ECOG status predicted improved progression-free survival.How this study might affect research, practice or policy:These findings suggest that reduced-dose lenvatinib may maintain efficacy while improving tolerability in heavily pretreated high-grade tumors and platinum resistant, p53 mutated patients, supporting individualized dosing strategies. They also highlight p53 mutation as a potential predictive biomarker, warranting larger studies.