Background: In the multicenter, open-label, randomized, phase 3 Study 309/KEYNOTE-775, LEN + pembro had significant PFS and overall survival benefits, and improved objective response rate vs TPC in pts with aEC following systemic platinum-based treatment (Makker 2022, NEJM). These results were seen in all-comer pts and in pts with DNA mismatch repair proficient (pMMR) disease. Here, we assessed PFS on next line of therapy (PFS2) of each arm. Methods: Pts with aEC and 1 prior platinum-based chemotherapy regimen (or up to 2 if 1 was given in neoadjuvant/adjuvant setting) were randomized (1:1) to receive LEN 20 mg orally QD + pembro 200 mg IV Q3W or TPC (doxorubicin at 60 mg/m² IV Q3W or paclitaxel at 80 mg/m² IV QW [3 weeks on; 1 week off]). Randomization was stratified by MMR status (determined centrally); pts with pMMR tumors were further stratified by Eastern Cooperative Oncology Group performance status, geographic region, and history of pelvic radiation. In this prespecified exploratory analysis, PFS2 (defined as the time from randomization to disease progression on next line of treatment or death, whichever came first) was analyzed per investigator assessment in the pMMR and all-comer populations. Results: 827 Pts (pMMR, n=697; MMR deficient [dMMR], n=130) were randomized to LEN + pembro (n=411) or TPC (n=416). At data cutoff (October 26, 2020), 567 pts (LEN + pembro, n=282; TPC, n=285) had discontinued study treatment and 315 (LEN + pembro, n=115; TPC, n=200) had received a subsequent systemic anticancer therapy (Table): most commonly doxorubicin (n=58) in the LEN + pembro arm and paclitaxel (n=57) in the TPC arm. Median PFS2 was longer in the LEN + pembro arm vs the TPC arm in the pMMR population (14.4 vs 9.8 mo; HR 0.62, 95% CI 0.50–0.75) and in the all-comer population (16.0 vs 9.5 mo; HR 0.56, 95% CI 0.46–0.67). Additionally, the PFS2 rate at 6 months favored LEN + pembro vs TPC in the pMMR population (82.0% vs 74.8%) and in the all-comer population (81.7% vs 72.5%). Conclusions: Clinically meaningful improvements in PFS2 were seen in the LEN + pembro group compared with TPC in pMMR and all-comer pts. Clinical trial information: NCT03517449.