Frontline Zanidatamab Plus Chemo ± Bevacizumab Is Safe, Active in HER2+ mCRC

Zanidatamab (ZW25) combined with mFOLFOX6-2 (5-fluorouracil [5-FU], leucovorin, and oxaliplatin) with or without bevacizumab (Avastin) demonstrated antitumor activity and safety in the first-line treatment of patients with HER2-positive unresectable, locally advanced, recurrent, or metastatic colorectal cancer (mCRC), according to findings from part 1 of a phase 2 study (NCT03929666) presented at the 2024 ESMO Congress.¹

At a median follow-up of 15.4 months (range, 4-19), the confirmed overall response rate (cORR) was 83.3% (95% CI, 35.9%-99.6%) in patients treated with zanidatamab plus mFOLFOX6-2 (n = 6). All responders achieved a partial response (PR), and the lone non-responder had stable disease. In the zanidatamab plus mFOLFOX6-2 and bevacizumab arm (n = 5), the cORR was 100% (95% CI, 47.8%-100%) with all patients experiencing 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+).

Two dose-limiting toxicities (DLTs) of diarrhea were documented—one in each treatment group—and resolved with concomitant medication. Serious treatment-related adverse effects (TRAEs) were noted in 15.4% of patients (n = 2), including one patient who experienced dehydration and another patient who had colitis and an acute kidney injury. However, no patients discontinued zanidatamab due to TRAEs, and no treatment-related deaths were reported.

“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,” 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, explained during her presentation.

Zanidatamab is a dual HER2-targeted bispecific antibody that binds to two distinct HER2 domains. Previous findings from a phase 1 study (NCT02892123) demonstrated zanidatamab monotherapy generated a cORR of 38% and a clinical benefit rate of 58%, alongside a manageable safety profile, in patients with heavily pretreated mCRC (n = 26).²

Phase 2 Study Design and Patient Population

The phase 2 study enrolled patients with unresectable, locally advanced, recurrent, or metastatic CRC.¹ Patients needed to have HER2-expressing (immunohistochemistry IHC 3+) or HER2-amplified disease per central assessment. Key eligibility criteria included no prior HER2-targeted agents; no prior systemic therapy for advanced disease, although 1 prior cycle of 5-FU–based chemotherapy was allowed; RAS and BRAF wild-type disease; and an ECOG performance status of 0 to 1.

Enrolled patients were assigned to receive zanidatamab at 1200 mg (for patients with a body weight under 70 kg) or 1600 mg (for patients with a body weight of at least 70 kg) on days 1 and 15 of each 28-day cycle plus mFOLFOX6-2 comprised of 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 regimen of zanidatamab plus mFOLFOX6-2 in combination with bevacizumab at 5 mg/kg on days 1 and 15.

Tumor assessments occurred once every 6 weeks per RECIST 1.1 criteria, and DLTs were evaluated during the first 28-day cycle.

Primary end points of the study included DLTs, AEs, laboratory abnormalities, and dose reductions; secondary end points consisted of ORR, DOR, and progression-free survival (PFS).

A total of 13 patients were treated in part 1; 12 were evaluable for DLTs, and 11 were evaluable for response. The median age of the 13 treated patients was 55 years (range, 35-83). The majority of patients were 65 years of age or younger (84.6%). Most patients were Asian (76.9%), and the remainder were White (23.1%). Additionally, 30.8% of patients were female. Patients had an ECOG performance status of 0 (30.8%) or 1 (69.2%).

HER2 status was predominantly IHC 3+/fluorescence in situ hybridization (FISH)+ (61.5%), and the remainder had a HER2 status of IHC 2+/FISH+ (38.5%). None of the patients in the zanidatamab plus mFOLFOX6-2 arm had prior cancer surgery; 57.1% of those in the zanidatamab plus mFOLFOX6-2 and bevacizumab arm had undergone prior surgery.

Additional Efficacy and Safety Findings

The median PFS for all efficacy-evaluable patients was NR (95% CI, 8.2-NR).

Treatment-emergent AEs and TRAEs were observed in all patients across both treatment arms (n = 13). In the overall population, the rates of grade 1/2 and grade 3/4 TRAEs were 61.5% and 38.5%, respectively.

The most 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%).

References

1. Rha SY, Lee KW, Lee S, et al. Zanidatamab plus chemotherapy in first-line human epidermal growth factor receptor 2-positive (HER2+) advanced/metastatic colorectal cancer (mCRC). Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract 516MO.
2. Meric-Bernstam F, Beeram M, Hamilton E, et al. Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study. Lancet Oncol. 2022;23(12):1558-1570. doi:10.1016/S1470-2045(22)00621-0