Dual targeted therapy with pyrotinib and trastuzumab for HER2-positive advanced colorectal cancer: A phase 2 trial

Abstract

This trial was initiated to evaluate the efficacy and safety of pyrotinib in combination with trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent/metastatic colorectal cancer (CRC). In this single-arm, open-label, multicenter, phase 2 trial patients with HER2-positive recurrent/metastatic CRC were enrolled and received oral pyrotinib 400 mg once a day plus intravenous trastuzumab 8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks. The primary endpoint was the objective response rate (ORR). Disease control rate (DCR), progression-free survival (PFS), duration of response, and safety were assessed as secondary endpoints. From December 2019 to October 2021, a total of 20 patients were enrolled and 18 of them were evaluable for response. All patients were B-rapidly accelerated fibrosarcoma (BRAF) wild type. Four patients achieved partial response, with an ORR of 22.2% (4/18, 95% confidence interval [CI] 6.4-47.6) and DCR of 61.1% (11/18, 95% CI 35.8-82.7), while the ORR and DCR were 33.3% (4/12, 95% CI 13.8-60.9) and 83.3% (10/12, 95% CI 51.6-97.9), respectively, in RAS wild-type patients. At the time of cut-off day, median follow-up was 10.7 months (range 3.8-13.8). The median PFS was 3.4 months (95% CI 1.8-4.3) in the overall population and 4.3 months (95% CI 3.2-8.5) in the RAS wild-type group. The most common adverse event of grade ≥3 was diarrhea (13/20, 65.0%). Pyrotinib combined with trastuzumab showed promising antitumor activity and a manageable safety profile in patients with RAS/BRAF wild-type HER2-positive advanced CRC.

Keywords: RAS mutation; colorectal cancer; human epidermal growth factor receptor 2; pyrotinib; trastuzumab.

FIGURE 1

Trial profile. HER2, human epidermal growth factor receptor 2; mCRC, metastatic colorectal cancer.

FIGURE 2

Change in tumor size of patients with HER2‐positive metastatic colorectal cancer treated with pyrotinib + trastuzumab. One patient is excluded from this plot due to loss of detailed radiologic data as the computed tomography image was performed in a local hospital during the Covid‐19 pandemic with an assessment of stable disease by the local doctor. RAS, rat sarcoma; KRAS, Kirsten‐RAS; NRAS, neuroblastoma‐RAS; K, KRAS‐mutated; N, NRAS‐mutated; PD, progressive disease; PR, partial response; SD, stable disease; WT, RAS wild type.

FIGURE 3

Duration of treatment of patients with HER2‐positive metastatic colorectal cancer with pyrotinib plus trastuzumab. The red square symbol for PD represents that the treatment efficacy is evaluated as PD; while the brown symbol for PD refers to the time when the event of progressive disease happened. KRAS, Kirsten‐RAS; NRAS, neuroblastoma‐RAS; PD, progressive disease; PR, partial response; RAS, rat sarcoma; SD, stable disease.

FIGURE 4

Progression‐free survival by RAS mutation status. RAS mutated includes KRAS mutated and NRAS mutated. KRAS, Kirsten‐RAS; NRAS, neuroblastoma‐RAS; RAS, rat sarcoma.