Systematic review of 2L+ ADC strategies in triple-negative breast cancer (TNBC).

e15009 Background: TNBC is highly aggressive with limited treatment options in the 2L+ setting, underscoring critical unmet clinical needs. Recent strategies leverage precision targeting therapies involving antibody-drug conjugates (ADCs). Here, we explore these strategies and their potential to redefine current treatment paradigms in TNBC. Methods: A comprehensive search was performed in LARVOL CLIN, an outcomes database with over 100K trials to identify P2/3 trials evaluating ADCs in 2L+ TNBC. Trials were assessed using digitized KM data and HRs extracted from forest plots. Results: 7 trials evaluating 2L+ ADCs in TNBC had mature data (Table 1). ASCENT, EVER-132-001, and NCT05113966 examined 3L+ sacituzumab govitecan (SG); OptiTROP-Breast01 evaluated 3L+ sacituzumab tirumotecan (ST); METRIC examined 2/3L glembatumumab vedotin (GV); EV-202 assessed 2L+ enfortumab vedotin (EV) efficacy and DESTINY-Breast04 evaluated 2L+ trastuzumab deruxtecan (T-DXd). ASCENT and OptiTROP-Breast01 met their primary endpoint with significantly improved PFS, and enhanced OS and ORR compared to standard-of-care (SoC). Their safety profiles highlight common but manageable hematologic toxicity. In contrast, METRIC failed to meet its primary endpoint with outcomes and risk/benefit comparable to SoC. EVER-132-001 has promising outcomes with SG in the Chinese population, with higher mOS, mPFS and ORR compared to ASCENT, though caution is required with cross-trial comparisons. SG after Trilaciclib (NCT05113966), in contrast to SG monotherapy, exhibited fewer adverse events (AE), especially neutropenia and diarrhea, and slightly higher preliminary mOS. In EV-202, EV showed comparable efficacy and AEs to SG. Finally, DESTINY-Breast04 showed interesting T-DXd efficacy signals. Conclusions: Emerging data from P2/3 trials highlight ADCs potential in the 2/3L setting for TNBC. SG has established its superiority over SoC, receiving FDA approval for TNBC after 2+ prior systemic therapies, ³1 for metastatic stage. Its combination with CDK/6 inhibitors should be further evaluated. Novel agents, ST, EV and T-DXd show promising results, prompting further investigation and validation of ADCs in heavily pretreated TNBC patients. Trials summary. OptiTROP-Breast01 METRIC ASCENT NCT05113966 EVER-132-001 EV-202 DESTINY-Breast04 P3, N=254 P2, N=327 P3, N=529 P2, N=30 P2, N=80 P2, N=329 P3, N=557 Target TROP2 GPNMB TROP2 TROP2 TROP2 NECTIN4 HER2 Intervention ST GV SG SG + Trilaciclib SG EV T-DXd N=130 N=218 N=267 N=30 N=80 N=42 N=40 Control SoC SoC SoC - - - SoC N=133 N=108 N=262 N=18 OS HR 0.53* 1.06 0.52* 0.58 mOS, months NR vs 9.4 8.9 vs 8.7 11.8 vs 6.9 15.9 14.7 12.9 17.1 vs 8.3 PFS HR 0.32* 0.95