Real-world determinants of response to combination Lenvatinib/Pembrolizumab in MMR-proficient advanced and/or recurrent endometrial cancer

Project aims/goals

With the rise in the global incidence of endometrial cancer (EC), there is a growing need to address the poor outcomes and low 5-year survival among EC patients with advanced, distant or recurrent disease. Until recently, there were no recommended standard therapy for these patients after failure of chemotherapy. 

In recent years, the introduction of immune checkpoint inhibitors has provided a novel approach in the treatment of recurrent EC. Briefly, tumor cell receptor PD-L1 and PDL-2 can bind PD-1 receptors on T cells, and inactivate T cells in the tumor microenvironment to evade immune recognition. The benefit was first noticed in mismatch-repair (MMR) deficient tumors, including ECs. However, for MMRproficient (MMRp) ECs, there was, until recently, still an unmet need for novel effective therapeutic strategies. 

Lenvatinib, a multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1 through 3, has been shown to have modest efficacy as second-line treatment for recurrent EC. With these data, a phase III multi-centre trial was conducted and published in the NEJM in 2022, demonstrating significantly longer survival in EC patients treated with Lenvatinib/Pembrolizumab combination compared to physician’s choice chemotherapy (doxorubicin or paclitaxel). This study consisted mainly of MMRp ECs, and led to the approval and recent adoption of this combination therapy in this subset of EC patients. However, 88.9% of the patients who received lenvatinib plus pembrolizumab experienced adverse events of grade 3 or higher, compared to 72.7% of those who received chemotherapy leading to dose reductions and interruptions. Since clinical studies do not always represent real-life medical settings, we aim to evaluate this treatment outside of a clinical study protocol in patients with MMRp EC who have advanced/recurrent disease post-chemotherapy. Furthermore, with the recent molecular studies demonstrating that EC is made up of multiple disease entities, these clinical trials did not take into consideration the genomic heterogeneity and immune profile of these tumors that can influence response rates to this treatment strategy. The scope of this study is to to better understand the cancer biology and clinical correlation of MMRp ECs and response to Lenvatinib/Pembrolizumab combination, which represent a novel cohort to contribute to MOHCCN and responds to one of the four Areas of Interest. The overall goal is to collect, clinically annotate and molecularly characterize the tumor profile of these ECs within our institution. Although the adoption of this treatment strategy represents a step forward for EC patients, more studies are required to further personalize treatment for EC patients beyond MMR status. Thus, the possibility to study their genomic and immune landscapes opens the door to identify potential cancer vulnerabilities that accelerate the adoption of Precision Medicine strategies that can improve patient outcomes.