e15554 Background: HER2 is an emerging treatment target for colorectal cancer (CRC). Previous phase 2 trials have demonstrated the promising antitumor activity of dual HER2 inhibition with trastuzumab plus lapatinib or pertuzumab in HER2-positive metastatic CRC. Pyrotinib, a novel irreversible HER2/EGFR dual tyrosine kinase inhibitor, has been approved for breast cancer in 2018 in China. The antitumor effect of pyrotinib was also shown in other solid tumors, such as lung cancer and gastric cancer. The randomized phase 3 PHOEBE trial proved that the efficacy of pyrotinib was better than lapatinib when in combination with capecitabine in HER2-positive local relapsed or metastatic breast cancer. We reported preliminary results of pyrotinib plus trastuzumab in patients with HER2-positive advanced CRC from an ongoing multicenter phase 2 trial (NCT04380012). Methods: Patients with confirmed recurrent/metastatic CRC, HER2-positive disease, and ECOG performance status 0-2, 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 objective response rate (ORR), as assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1. The data cutoff date was December 24, 2020. Results: From December 2019 to November 2020, a total of 11 patients were enrolled. The median age was 57 (range, 44-70) years and 73% (8/11) of patients were male. The number of prior therapy lines was 0, 1, and ≥2 in 1 (9%), 2 (18%), and 8 (73%) patients, respectively. One (9%) patient only showed HER2 overexpression, 7 (64%) showed HER2 amplification and overexpression, and 3 (27%) showed HER2 mutation and overexpression. The detection of co-mutations showed that 5 (45%) patients had KRAS mutations, 1 (9%) had NRAS mutation, and none had BRAF mutation. Three patients achieved partial response, with an ORR of 27% (3/11) in the total population, 50% (3/6) in KRAS wild-type patients, and 60% (3/5) in patients with wild type of both KRAS and NRAS, respectively. The disease control rate was 45% (5/11). The most common (occurring in at least 2 patients) grade ≥3 adverse event was diarrhea (73% [8/11]). Dose interruption owing to diarrhea occurred in 7 (64%) patients, and 5 (45%) patients reduced the dose to 320 mg due to diarrhea. No treatment-related death was observed. Conclusions: Pyrotinib combined with trastuzumab showed promising ORR with acceptable safety in patients with HER2-positive advanced CRC, suggesting a potential treatment option, especially in those without co-mutations. Clinical trial information: NCT04380012.
Safety, activity, and molecular heterogeneity following neoadjuvant non-pegylated liposomal doxorubicin, paclitaxel, trastuzumab, and pertuzumab in HER2-positive breast cancer (Opti-HER HEART): an open-label, single-group, multicenter, phase 2 trial