LAUSR

It was with great enthusiasm that I read the recently published KEYNOTE 775. Pembrolizumab plus lenvatinib showed unprecedented results for advanced, recurrent, or metastatic endometrial cancer with improvements in overall survival, progressionfree survival, response rates, and duration of response compared with physicians’ choice of chemotherapy (doxorubicin or paclitaxel). The study included patients who progressed after platinum (which could be prior adjuvant/neoadjuvant therapy or in the metastatic setting) and mainly highrisk histologies. It is noteworthy that the control arm performed just as expected, showing that the benefits of pembrolizumab plus lenvatinib are robust. Does this mean, however, that all patients with advanced, recurrent, or metastatic endometrial cancer should receive this combination after a platinum failure? Maybe not. We should keep in mind that in this scenario we are talking about palliative treatment. Tolerability and adverse events/toxicities are important issues that need to be addressed when deciding the best option for our patients. About 60–70% of patients needed some kind of dose reduction or interruption, and 30% of patients discontinued lenvatinib because of adverse events. Scrutinizing the KEYNOTE 775 protocol, we can observe that only a minority of patients had lowgrade histology. In this population, hormonal therapy (alone or combined with mammalian target of rapamycin or cyclin inhibitors) can achieve good response and disease control, especially in oligometastatic disease. Also, in this scenario of oligometastatic disease, resection or radioablation can also achieve excellent disease control. Patients in the KEYNOTE 775 who received neoadjuvant or adjuvant therapy and had a platinumfree interval of over 12 months needed to receive another systemic therapy prior to study inclusion. Rechallenge with platinum in patients with longer progressionfree interval had already shown good responses, and this could be another good option in this setting. Indeed, in the subgroup cohort of patients with progressionfree interval of ≥12 months, there was no statistically significant difference between arms. Another very important group of patients included in KEYNOTE 775 is the group with mismatch repair deficiency or high microsatellite instability. In this scenario, the combination showed a 40% response rate (14% complete and 26% partial response), with durable responses (not reached yet). Single agent pembrolizumab (KEYNOTE 158) or dostarlimab (GARNET) had already shown interposable efficacy, with fewer adverse events. Most endometrial cancers are microsatellite stable tumors and have low response rates to immunotherapy. Transforming these cold tumors into hot tumors is an area of current research. The combination of pembrolizumab plus lenvatinib in endometrial cancer is a successful example of this strategy. However, treatment of recurrent and/or advanced endometrial cancer (as in all patients with cancer) must be personalized as one size does not fit all.