Efficacy and safety of neoadjuvant disitamab vedotin (DV) in combination with toripalimab (Tor) and concurrent/sequential chemotherapy (chemo) in patients with HR-negative, HER2-low breast cancer: A randomized multicenter phase 2 study.

598 Background: For patients (pts) with triple-negative early breast cancer (BC), recommended neoadjuvant regimens include chemo with or without immunotherapy, which achieve a modest rate of pathological complete response (pCR). Emerging data suggest that anti-HER2 antibody-drug conjugates (ADCs) have antitumor activity in HER2-low advanced BC. Notably, DV (anti-HER2 ADC) has shown encouraging efficacy both as monotherapy and in combination with Tor (PD-1 inhibitor) in pts with HER2-low advanced disease. We evaluated the efficacy and safety of neoadjuvant DV-containing regimens in pts with hormone receptor (HR)-negative HER2-low BC in a randomized phase 2 trial. Here, we report results from the pts receiving DV plus Tor combined with concurrent/sequential chemo. Methods: Eligible pts were aged ≥18 years with untreated histologically confirmed HR-negative and HER2-low (centrally confirmed as IHC 1+, or IHC 2+/ISH-) BC (T1cN1-2M0 or T2-3N0-2M0 as per AJCC 8th edition) who were planned to undergo curative-intent breast cancer surgery. Pts randomized to group A received DV (2.0 mg/kg Q2W) + Tor (3.0 mg/kg Q2W) + carboplatin (AUC 3 Q2W or AUC 1.5 QW) for 18 weeks. Pts randomized to group B received DV + Tor for 12 weeks followed by epirubicin (90 mg/m 2 Q3W) + cyclophosphamide (600 mg/m 2 Q3W) + Tor for additional 12 weeks. Stratification factors were PD-L1 status (positive or negative) and clinical staging (stage II or III). After neoadjuvant treatment, surgery was performed. Enrollment in group B was closed after 28 pts had been randomized to this group, while enrollment in group A continued. The primary endpoint was total pCR (tpCR, defined as ypT0/TisN0) rate; secondary endpoints included breast pCR (bpCR, defined as ypT0/Tis) rate, objective response rate (ORR), and safety. Results: 40 pts were enrolled in group A (median age: 46.0 years; clinical stage III: 37.5%; clinical N+: 82.5%; IHC 1+: 72.5%; PD-L1 CPS < 10: 37.5%) and 28 in group B (54.0; 42.9%; 82.1%; 67.9%; 32.1%). The tpCR was achieved in 25 pts (62.5% 95% CI: 45.8-77.3) in group A and 14 pts (50.0% 31.9-71.3) in group B. The bpCR rate was 65.0% (95% CI: 48.3-79.4) and 53.6% (35.3-74.5) for groups A and B, respectively. The corresponding ORR was 92.5% (95% CI: 79.6-98.4) and 75.0% (55.1-89.3), respectively. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 29 (72.5%) of pts in group A and 23 (82.1%) in group B. Serious TRAEs occurred in 6 (15.0%) and 7 (25.0%) of pts, respectively. Immune-related adverse events occurred in 3 (7.5%) of pts in group A and 7 (25.0%) in group B. No grade 5 TRAEs occurred. Conclusions: Both treatment regimens showed manageable safety profiles; DV + Tor + carboplatin showed numerically better efficacy in pts with previously untreated, HR-negative, HER2-low, early BC. Clinical trial information: NCT06227117 .