Zanidatamab (Zani) plus chemotherapy (CT) in first-line (1L) human epidermal growth factor receptor 2-positive (HER2+) advanced/metastatic colorectal cancer (mCRC)

초록

Background Zani, a HER2-targeted bispecific antibody, demonstrated antitumour activity with a manageable safety profile in heavily pretreated patients (pts) with HER2-expressing/amplified solid tumours, including mCRC, in a phase 1 study. Here, we report preliminary safety and antitumour activity of 1L zani + CT ± bevacizumab (bev) in HER2+ mCRC. Methods This phase 2, open-label study (NCT03929666) is evaluating 1L zani + CT ± bev in pts with HER2-expressing (IHC 3+) or amplified (FISH+) mCRC. Primary and secondary objectives are the assessment of safety/tolerability and antitumour activity, respectively. Eligible pts had an ECOG performance status (ECOG PS) of 0 or 1, had not received ≥1 prior cycle of a fluorouracil (5-FU)-based regimen for mCRC, and had no prior HER2-targeted agents. Pts received zani (1200 mg: pts <70 kg; 1600 mg: pts ≥70 kg; intravenous [IV] every two weeks) + mFOLFOX6-2 (leucovorin 400 mg/m2 IV and oxaliplatin 85 mg/m2 IV on days 1 and 15; 5-FU 1200 mg/m2/day IV on days 1-2 and 15-16) ± bev per physician’s choice (5 mg/kg IV on days 1 and 15). Dose-limiting toxicity (DLT) evaluation period was during the first treatment cycle. Results As of the latest data cut-off, 31 Oct 2023, enrolment was complete (N=13). All pts were treated (zani + mFOLFOX6-2, n=6; zani + mFOLFOX6-2 + bev, n=7); and had a median (range) follow-up of 15.4 (4-19) months. All pts had HER2+ tumours (IHC 3+/FISH+, 8 [62%]; IHC 2+/FISH+, 5 [38%]). Three pts had DLTs (zani + mFOLFOX6-2: diarrhoea, n=1; zani + mFOLFOX6-2 + bev: dehydration, fatigue, nausea, vomiting and ECOG PS deteriorated, n= 1; diarrhoea, n=1). No pts discontinued zani due to a DLT. All 13 pts had TRAEs. Grade 3-4 TRAEs occurred in 5 (38%) pts, 3 (23%) of whom experienced diarrhoea. There were 3 serious TRAEs (1 pt experienced dehydration, 1 colitis and acute kidney injury). There were no treatment-related deaths. In 11 evaluable pts, there were 10 confirmed partial responses (confirmed objective response rate 91% [95% CI: 59, 100]); 1 pt had stable disease. Median (range) duration of response was not reached (2.9-16.7+ months). Conclusions Zani ± bev demonstrated encouraging antitumor activity with a generally manageable safety profile in 1L HER2+ mCRC.