Safety and efficacy of neoadjuvant disitamab vedotin in combination with pertuzumab with or without toripalimab for HER2-positive breast cancer: An open-label phase II trial.

e12596 Background: Patients with early-stage HER2-positive breast cancer need more effective neoadjuvant treatment choices. Disitamab vedotin is a novel humanized anti-HER2 antibody conjugated with monomethyl auristatin E via a cleavable linker. This phase 2 trial was conducted to evaluate the safety and efficacy of neoadjuvant disitamab vedotin + pertuzumab (group A) or disitamab vedotin + pertuzumab + toripalimab (group B) in patients with previously untreated HER2-positive breast cancer. Methods: Patients with invasive breast cancer (T2-3N0-3M0) and central lab-confirmed HER2-positive status (IHC 3+, or IHC 2+/ISH+) were randomized (stratified by hormone receptor (HR) status [HR+ vs HR-], and clinical N stage [N+ vs N-]) at 1:1 to receive disitamab vedotin (2.0 mg/kg, IV, Q2W) + pertuzumab (initial dose of 840 mg followed by 420 mg, IV, Q3W) or disitamab vedotin + pertuzumab + toripalimab (3.0 mg/kg, IV, Q2W) for up to 18 weeks. Radical surgery (RS) was performed within 3-6 weeks after the last neoadjuvant treatment. Radiological tumor assessment was performed every 6 weeks and assessed by investigators per RECIST v 1.1 during neoadjuvant treatment. The primary endpoint was total pathological complete response (tpCR, defined as ypT0/Tis and ypN0) rate; secondary endpoints included breast pathological complete response (bpCR, ypT0/Tis) rate, objective response rate (ORR) and safety. Data cutoff date for this analysis was December 30, 2024. Results: Thirty-one patients were enrolled with 16 patients in group A (median age: 47.0 years; clinical stage III: 50.0%; clinical stage T3: 12.5%; N+: 100%; HR+: 81.3%; IHC 3+: 56.3%) and 15 in group B (median age: 50.0 years; clinical stage III: 60.0%; clinical stage T3: 20.0%; N+: 100%; HR+: 86.7%; IHC 3+: 73.3%). Among the 15 patients in group A and 14 in group B who underwent RS, the tpCR rate was 20.0% (95% CI: 4.33-48.09) and 50.0% (23.04-76.96), respectively. The bpCR rates were consistent with tpCR rates. ORR was 73.3% (95% CI: 44.9-92.2) and 93.3% (68.1-99.8) for groups A and B, respectively. Up to 20.0% (95% CI: 4.33-48.09) patients had residual cancer burden score 0-1 in group A and 64.3% (35.14-87.24) in group B. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in eight (50.0%) patients in group A and six (40.0%) patients in group B; no grade 5 TRAEs occurred in either group. Conclusions: The combination of disitamab vedotin, pertuzumab and toripalimab showed promising antitumor activity and manageable safety profiles. This regimen may offer a potential chemotherapy-free treatment option for patients in this population. The synergistic effects between HER2-directed antibody-drug conjugates (ADCs), immune checkpoint inhibitors and HER2-directed monoclonal antibodies are worthy of further exploration. Clinical trial information: NCT06178159 .