作者
Mansoor Raza Mirza,Sudarshan Sharma,Jørn Herrstedt,Mark S. Shahin,David Cibula,Emily Fleming,Francesco Raspagliesi,Joseph Buscema,Lars Hanker,Robert L. Coleman,Ingrid Boere,Kami Wolfe Schneider,Lucy Gilbert,Brian M. Slomovitz,Michael Teneriello,Matthew A. Powell,Sue Ghosh,S. Stevens,Kari L. Ring,Ashley Stuckey
摘要
In the phase 3 RUBY trial (NCT03981796) dostarlimab (D) + carboplatin-paclitaxel (CP) significantly improved PFS vs CP alone in the mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H; HR, 0.28) and overall population (HR, 0.64) with a favorable OS trend (HR, 0.64). Four molecular EC subgroups were identified for prognostic and potential predictive value. Validated surrogate methods more readily available include POLε mutation (mut), dMMR, TP53 abnormal, and no specific molecular profile (NSMP). Here, we present exploratory efficacy outcomes by molecular classification. Patients (pts) with pA/rEC were randomised 1:1 to receive dostarlimab, or placebo (PBO), plus CP, followed by dostarlimab or PBO monotherapy for up to 3 years. POLε and TP53 status were determined by DNAseq; MMR/MSI status was determined by testing used for study enrollment (immunohistochemistry, polymerase chain reaction, or next generation sequencing). Order of classification was POLεmut → dMMR/MSI-H → TP53mut → NSMP. PFS and OS were assessed for each subgroup. Of 494 pts enrolled and randomised, mutational data were available for 400 pts (81.0%), classified as: 5 (1.3%) POLεmut, 91 (22.8%) dMMR/MSI-H, 88 (22.0%) TP53mut, and 216 (54.0%) NSMP. PFS and OS results favored the D+CP arm in the dMMR/MSI-H, TP53mut, and NSMP subgroups, with the largest benefit observed in the dMMR and TP53mut groups. No pts with POLεmut progressed in either arm as of data cut (Table). Safety was reported previously. Dostarlimab+CP is associated with improved PFS and OS in the dMMR/MSI-H, NSMP, and TP53 subgroups and adds prognostic value in pA/rEC. Patients with POLεmut had the best prognosis, as expected. Further research may help to validate these exploratory findings.