Ribociclib (CDK4/6) + everolimus (mTOR) + letrozole (aromatase) lifts ORR only in endocrine-pretreated recurrent endometrial cancer

Everolimus (oral mTORC1 inhibitor) plus letrozole (aromatase inhibitor) was tested with vs without ribociclib (CDK4/6 inhibitor) in a randomized Phase 2 recurrent endometrial cancer trial (NCT03008408). In the all-comer population, adding ribociclib did not significantly improve PFS (HR 0.78, 95% CI 0.4–1.4; p=0.38) or OS (HR 0.8, 95% CI 0.4–1.5; p=0.46), and the ORR numerically favored the ribociclib arm (44.1% vs 25.7%; p=0.11) with similar toxicity-related discontinuation (8.6% vs 11.4%). In the subgroup with prior endocrine therapy, ORR was higher with ribociclib (61.5% vs 0.0%; p<0.001), and within the ribociclib arm CTNNB1-mutant tumors had better outcomes than non-CTNNB1-mutant tumors (PFS HR 0.27, p=0.006; OS HR 0.24, p=0.004)—but because this is a biomarker/post-treatment-exposure slice of a Phase 2 study, it’s not yet a clean “beats SOC” story; in the broader post-platinum recurrent setting, lenvatinib+pembrolizumab delivers ORR 32% and mPFS ~6.6–6.7 months in pMMR disease but with very high grade ≥3 toxicity (89%).