Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC)

Final results from the phase 1b/2 BEGONIA study (Abstract 555MO; Peter Schmid)   

Full results from Arm 7 and first results from Arm 8 of the P1b/2 BEGONIA trial reported for Dato-DXd + durvalumab in 1L mTNBC showed signs of promising antitumor activity across both arms (Arm 7: ORR 79%, mPFS 14 mos; Arm 8: ORR 82%, mPFS immature). These data provide early proof-of-concept for P3 TROPION-Breast05 trial for this combo (topline data expected 2026+), and signals future direct competition with ASCENT-04.

• Key Takeaways/Potential Implications 
  • Final data for Arm 7 and initial data for Arm 8 of the P1/2 BEGONIA study demonstrated promising antitumor activity across both arms
    • Arm 7 (1L mTBNC regardless of PD-L1 status) demonstrated durable responses with clinically meaningful mPFS (14 mos) and ORR (79%), above the historic PD-(L)1 + chemo mPFS benchmark of ~9 mos
    • Arm 8 (1L PD-L1+ TNBC) had insufficient follow-up to assess mPFS, though showed a clinically meaningful cORR (82%) also above the historic PD-(L)1 + chemo ORR benchmark of 53% and ORR benchmark of 60% for Trodelvy + pembro in ASCENT-04
  • Updated BEGONIA results provide early signal for P3 TROPION-Breast05 trial, demonstrating Dato-DXd + durvalumab combination has promising activity in 1L PD-L1+ TNBC
    • Pending TB-05 results in 2026+, confirmation of PFS and OS benefit could set the combo to directly compete with ASCENT-04, though will be a later entrant to market in H2 2027
    • Additionally, Trodelvy will likely benefit from combination with pembrolizumab, which has established BC credibility compared to durvalumab’s lack of BC approval
  • The discussant highlighted potential added value of durvalumab to Dato-DXd in 1L TNBC regardless of PD-L1 status, though noted long-term toxicities, including financial, were uncertain
    • While tolerability of Dato-DXd + durvalumab was manageable, the high observed cases of stomatitis will likely require additional prophylactic measures and potential dosing adjustments
      • Ocular adverse events also underscore the need for enhanced ophthalmologic surveillance, which may have added cost and compromise potential gains in QoL
• Study Information 
  • P1/2 BEGONIA (NCT03742102): Dato-DXd + durvalumab in 1L mTNBC
  • N = 95 (62 [Arm 7] vs 33 [Arm 8])
    • Arm 7 allows any PD-L1 status
      • 11.3% PD-L1 high tumors; 87.1% PD-L1 low tumors
    • Arm 8 required PD-L1+ status
    • All patients must have had no prior treatment for mTNBC
  • 1EP: safety, tolerability
  • 2EP: PFS, cORR, DOR
• Efficacy (Dato-DXd + durvalumab)
  • Arm 7 (median f/u 35 mos):
    • cORR: 79% (observed regardless of PD-L1 status)
    • mDOR: 17.6 mos
    • mPFS: 14.0 mos
  • Arm 8 (median f/u 10.7 mos):
    • cORR: 82%
    • mDOR and mPFS were immature 
      • Note: Arm 8 enrollment predominantly originated from Asian centers, attributable to rapid accrual
• Safety (Arm 7 vs Arm 8)
  • Any Gr TRAE: 100% vs 100%
  • Gr 3/4 TRAE: 48% vs 24%
  • TEAE leading to death: 2% vs 0%
  • Most frequently reported any Gr AESI for Dato-DXd
    • Stomatitis: 69% vs 82%
    • Dry eye: 27% vs 12%
    • Keratitis: 16% vs 3%
    • Vision blurred: 8% vs 15%
    • Oropharyngeal pain: 11% vs 15%
  • Any TEAEs leading to treatment discontinuation of either treatment: 19% vs 9%
    • Discontinuation of Dato-DXd: 19% vs 6%
    • Discontinuation of durvalumab: 5% vs 6%
  • Adjudicated drug-related ILD/pneumonitis occurred in 3 (5%) pts in Arm 7 (Gr 2: n=2; Gr1: n=1) and 1 (3%) pt in Arm 8 (Gr 2)