Zanidatamab (ZW25) in combination with mFOLFOX6-2 (5-fluorouracil [5-FU], leucovorin, and oxaliplatin), with or without bevacizumab (Avastin), has demonstrated promising antitumor activity and a manageable safety profile in the first-line treatment of patients with HER2-positive, unresectable, locally advanced, recurrent, or metastatic colorectal cancer (mCRC). These findings were presented at the 2024 ESMO Congress from part 1 of a phase 2 study (NCT03929666).
Efficacy Outcomes
After a median follow-up of 15.4 months (range, 4-19), the confirmed overall response rate (cORR) in patients treated with zanidatamab plus mFOLFOX6-2 (n = 6) was 83.3% (95% CI, 35.9%-99.6%). All responders experienced a partial response (PR), and the only non-responder had stable disease. In the arm combining zanidatamab, mFOLFOX6-2, and bevacizumab (n = 5), the cORR was 100% (95% CI, 47.8%-100%), with all patients achieving a PR. Across both treatment arms, the cORR was 90.9% (95% CI, 58.7%-99.8%), and the disease control rate was 100% (95% CI, 71.5%-100%). The median duration of response (DOR) for the overall population was not reached (NR; range, 2.9+ to 16.7+).
Safety Profile
Two dose-limiting toxicities (DLTs) of diarrhea were reported—one in each treatment group—and were resolved with medication. Serious treatment-related adverse events (TRAEs) were observed in 15.4% of patients (n = 2), including one patient with dehydration and another with colitis and acute kidney injury. Notably, no patients discontinued zanidatamab due to TRAEs, and no treatment-related deaths occurred.
Investigator Comments
According to lead study author Sun Young Rha, MD, director of Songdang Institute for Cancer Research, Yonsei University College of Medicine, Yonsei University Health System in Seoul, Korea, “Zanidatamab in combination with chemotherapy showed encouraging antitumor activity with a generally manageable safety profile as a first-line treatment for patients with HER2-positive mCRC.”
About Zanidatamab
Zanidatamab is a dual HER2-targeted bispecific antibody that binds to two distinct HER2 domains. Prior phase 1 study (NCT02892123) results showed that zanidatamab monotherapy yielded a cORR of 38% and a clinical benefit rate of 58% with a manageable safety profile in heavily pretreated mCRC patients (n = 26).
Study Design and Patient Characteristics
The phase 2 study enrolled patients with unresectable, locally advanced, recurrent, or metastatic CRC with HER2-expressing (immunohistochemistry IHC 3+) or HER2-amplified disease. Key inclusion criteria were no prior HER2-targeted agents, no prior systemic therapy for advanced disease (though one prior cycle of 5-FU–based chemotherapy was permitted), RAS and BRAF wild-type disease, and an ECOG performance status of 0 to 1.
Patients received zanidatamab at 1200 mg (for those under 70 kg) or 1600 mg (for those 70 kg or more) on days 1 and 15 of each 28-day cycle, plus mFOLFOX6-2 (leucovorin at 400 mg/m2 and oxaliplatin at 85 mg/m2 on days 1 and 15, plus 5-FU at 1200 mg/m2 on days 1, 2, 15, and 16); or the same zanidatamab plus mFOLFOX6-2 regimen with bevacizumab at 5 mg/kg on days 1 and 15.
Tumor assessments were conducted every 6 weeks per RECIST 1.1 criteria, with DLTs evaluated during the first 28-day cycle. Primary endpoints included DLTs, AEs, laboratory abnormalities, and dose reductions; secondary endpoints included ORR, DOR, and progression-free survival (PFS).
In part 1, 13 patients were treated; 12 were evaluable for DLTs, and 11 for response. The median age was 55 years (range, 35-83), with most patients ≤65 years (84.6%). The majority were Asian (76.9%), and the rest were White (23.1%). 30.8% were female. ECOG performance status was 0 (30.8%) or 1 (69.2%). HER2 status was primarily IHC 3+/FISH+ (61.5%), with the remainder IHC 2+/FISH+ (38.5%).
Additional Observations
The median PFS for all efficacy-evaluable patients was NR (95% CI, 8.2-NR).
Treatment-emergent AEs and TRAEs were seen in all patients (n = 13). Grade 1/2 and grade 3/4 TRAEs occurred in 61.5% and 38.5% of the overall population, respectively. Common TEAEs included diarrhea (any-grade, 84.6%; grade 3/4, 23.1%), nausea (69.2%; 7.7%), peripheral sensory neuropathy (53.8%; 7.7%), fatigue (30.8%; 7.7%), infusion-related reactions (30.8%; 0%), stomatitis (30.8%; 0%), decreased ejection fraction (23.1%; 7.7%), and vomiting (23.1%; 7.7%).
