SHR-A1811 plus chemotherapy and BP102 as 1L therapy for HER2-expressing mCRC: Data from a phase Ib/II study.

3569 Background: HER2 expression is associated with poor prognosis in mCRC. SHR-A1811 (trastuzumab-rezetecan) is a HER2-directed ADC comprising a humanized monoclonal antibody, a cleavable tetrapeptide linker, and a topoisomerase I inhibitor payload. We evaluated the safety and preliminary efficacy of SHR-A1811 in combination with chemotherapy and BP102 (bevacizumab biosimilar) as 1L therapy for HER2-expressing mCRC. Methods: This open-label, multicenter phase Ib/II study (ClinicalTrials.gov: NCT06015048) used an i3+3 design in phase Ib to evaluate the safety and tolerability of SHR-A1811 + 5-FU/L-LV, ± oxaliplatin and/or BP102, and to select the phase II regimen. Phase II (proof-of-concept) assessed efficacy and safety in the 1L setting using SHR-A1811 3.2 mg/kg Q2W + 5-FU (300 mg/m² IV bolus, 1800 mg/m² continuous infusion over 46–48 h Q2W) + L-LV 200 mg/m² IV Q2W + BP102 5 mg/kg IV Q2W ± oxaliplatin 60 mg/m² IV Q2W. Tumor response was assessed per RECIST v1.1, and AEs were evaluated per CTCAE v5.0. Results: As of Dec 31, 2025 (data cutoff), 39 pts received SHR-A1811 + FOLFOX (-1) + BP102, and 11 pts received SHR-A1811 + 5-FU/L-LV + BP102. All were Asian with pMMR/MSS and BRAF wild-type disease. The median age was 58 (range, 30–71) and 57 (range, 42–72), respectively. 28/39 (71.8%) and 7/11 (63.6%) were male. ECOG PS was 1 in 24/39 (61.5%) and 6/11 (54.5%). HER2 positivity (IHC 3+ or IHC 2+/ISH+) was observed in 21/39 (53.8%) and 5/11 (45.5%). HER2 IHC 2+/ISH− was observed in 18/39 (46.2%) and 5/11 (45.5%). Liver metastases were present in 28/39 (71.8%) and 4/11 (36.4%). 15/39 (38.5%) and 5/11 (45.5%) had RAS mutations. Median follow-up was 10.4 m (range, 6.1–17.0) and 11.9 m (range, 3.3–19.0). ORR was 74.4% (29/39; 95% CI, 57.9–87.0) and 40.0% (4/10; 95% CI, 12.2–73.8). DCR was 97.4% (38/39; 95% CI, 86.5–99.9) and 90.0% (9/10; 95% CI, 55.5–99.8). mPFS was 15.6 m (95% CI, 11.3–NR) and 9.6 m (95% CI, 1.8–NR). In HER2 positive pts received SHR-A1811 + mFOLFOX6(-1) + BP102, ORR was 90.5% (19/21; 95% CI, 69.6-98.8), DCR was 100% (21/21; 95% CI, 83.9-100), 9m-PFS rate was 94.7% (95% CI, 68.1-99.2); among HER2 positive RAS mutant/wild type subgroups, 9m-PFS rate was 83.3% (95%CI, 27.3-97.5) and 100%. OS was immature. Grade ≥3 TRAEs occurred in 31/39 (79.5%) and 6/11 (54.5%) in the two cohorts, with the most common being decreased neutrophil count (56.4% vs 18.2%), decreased white blood cell count (17.9% vs 18.2%), anemia (12.8% vs 9.1%), and stomatitis (12.8% vs 0). TRAEs led to discontinuation of any drug in 4/39 (10.3%) (SHR-A1811: 1; chemo: 1; BP102: 3) and in none. TRAEs led to dose reductions in 12/39 (30.8%) and 3/11 (27.3%) (SHR-A1811: 3 vs 1; chemo: 11 vs 3). No TRAE-related deaths occurred. Conclusions: SHR-A1811 plus chemotherapy and BP102 as 1L therapy for HER2 intermediate or high-expressing mCRC demonstrated manageable safety and encouraging antitumor activity. Clinical trial information: NCT06015048 .