Dual HER2-targeted therapy with pyrotinib plus inetetamab and adebrelimab in previously treated HER2-amplified metastatic colorectal cancer: A prospective, single-arm, phase II clinical trial.

e15532 Background: Various approaches to HER2 inhibition have been explored for HER2-positive metastatic colorectal cancer (mCRC). However, there is still a need for further improvement in efficacy, especially for those have undergone prior HER2-targeted therapy. Herein, we report the preliminary results of the efficacy and safety of adebrelimab, a novel anti-PD-L1 antibody, combined with dual HER2-targeted therapy-pyrotinib (a pan-HER2 receptor tyrosine kinase inhibitor) and inetetamab (an anti-HER2 monoclonal antibody)-in previously treated HER2-amplified mCRC. Methods: Patients (pts) with metastatic HER2-amplified CRC and having received systemic anti-tumor therapy were enrolled. Adebrelimab (20mg/kg) plus inetetamab (6mg/kg) were given intravenously once every 3 weeks, combined with pyrotinib (240mg for ≤50kg, or 320mg for＞50kg, orally) daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: As of December 30, 2025, 21 patients received treatment and were evaluable for safety and efficacy in the intention-to-treat population. The median age was 49 years (range, 27-75). This was a highly pretreated cohort: 38.1% (8/21) had received ≥3 prior lines of therapy, 4 patients had prior immunotherapy, and 4 had prior HER2-targeted therapies. Among 20 patients with post-baseline assessments, 17 (85.0%) experienced target lesion shrinkage. ORR was 60.0% (95% CI, 36.05-80.88) with 12 partial responses, including two patients pretreated with anti-HER2 ADCs who achieved maximum lesion reductions of 55.28% and 44.12%, respectively. DCR was 85.0% (95% CI, 62.11-96.79). Median time to response was 1.45 months (range 1.38–2.79). With a median PFS of 7.2 months (95% CI, 6.1-NR), 9 patients remain on treatment. Treatment-related adverse events occurred in 10 patients (48%), predominantly grade 1-2 diarrhea (24%). Grade 3 events were reported in 2 patients (10%), including one led to treatment discontinuation. Conclusions: The novel triple combination of adebrelimab, pyrotinib, and inetetamab represents a viable and active strategy for HER2-amplified mCRC after prior therapy. The observed efficacy in patients refractory to prior HER2-targeted therapies, including ADCs, warrants further investigation of this regimen in this population with limited options. Clinical trial information: ChiCTR2000038709.