Sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in previously untreated PD-L1-positive advanced triple-negative breast cancer (TNBC): primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study

Abstract

Background:AlthoughPD-1/PD-L1inhibitorspluschemohaveexpandedtreatmentoptionsfor previously untreated PD-L1–positive advanced TNBC, there still remains a critical unmet need to improve outcomes. SG previously demonstrated significant clinical benefit in pretreated metastatic TNBC (mTNBC). We report results from the ASCENT-04/KEYNOTE-D19 study in patients with previously untreated, PD-L1–positive (CPS $ 10; 22C3 assay) locally advanced unresectableormTNBC.Methods:Patientswererandomized1:1toSG(10mg/kgIV,day1&8)+ pembro (200 mg, day 1, max 35 cycles) in 21-day cycles or chemo (gemcitabine + carboplatin, paclitaxel, nab-paclitaxel) + pembro until disease progression or unacceptable toxicity. Ran domizationwasstratifiedbycurativetreatment-freeinterval,geography,andpriorexposureto anti–PD-(L)1 therapy in the curative setting. Primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR). Key secondary endpoints include overall survival(OS);objectiveresponserate(ORR)anddurationofresponse(DOR)byBICR;andsafety. Results: 443 patients were randomized at a 1:1 ratio: 221 to SG + pembro and 222 to chemo + pembro. The median follow-up was 14 mo. SG +pembroshowedasignificant improvement in PFS by BICR compared with chemo + pembro (hazard ratio [HR], 0.65; 95% CI, 0.51-0.84; P = .0009;Table). MedianDORwas16.5moforSG+pembrovs9.2moforchemo+pembro(Table). AlthoughOSdatawereimmature,apositiveearlytrendinOSimprovementwasalsonoted.The mostfrequent($10%ofpatients)grade$3treatment-emergentadverseevents(TEAEs)with SG + pembro were neutropenia (43%) and diarrhea (10%); and with chemo + pembro were neutropenia (45%), anemia (16%), and thrombocytopenia (14%). Conclusions: SG + pembro led to a statistically significant and clinically meaningful improvement in PFS vs chemo + pembro with durable responses, no new safety concerns for SG or pembro, and a lower rate of treatmentdiscontinuationduetoTEAEsinpatientswithpreviouslyuntreated,PD-L1–positive advanced TNBC.ThesedatasupporttheuseofSG+pembroasapotentialnewstandardofcare treatment inthis patient population