516MO - Zanidatamab (Zani) + chemotherapy (CT) in first-line (1L) human epidermal growth factor receptor 2-positive (HER2+) advanced/metastatic colorectal cancer (mCRC)

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.

Clinical trial identification

NCT03929666, April 29, 2019.

Editorial acknowledgement

Medical writing support, under the direction of the authors, was provided by Mai Moawed, BPharm, of CMC Affinity, a division of IPG Health Medical Communications.

Legal entity responsible for the study

Jazz Pharmaceuticals.

Funding

Zymeworks Inc. and Jazz Pharmaceuticals.

Disclosure

S.Y. Rha: Financial Interests, Personal, Advisory Board: Indivumed, Amgen, LG Biochemical, Astellas, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: MSD, Daiichi Sankyo; Financial Interests, Personal, Steering Committee Member: Amgen; Financial Interests, Institutional, Funding: MSD, Lilly; Financial Interests, Institutional, Research Grant: BMS, Daichii Sankyo; Financial Interests, Institutional, Local PI: Indivumed, AstraZeneca; Financial Interests, Other, Drug supply for clinical trial: Merck; Financial Interests, Institutional, Coordinating PI, Drug supply for clinical trial: MSD; Financial Interests, Institutional, Local PI, Drug supply for clinical trial: Zymeworks; Financial Interests, Institutional, Local PI, Drug supply for clinical trial: BeiGene; Financial Interests, Local PI: Roche. K. Lee: Financial Interests, Personal, Advisory Role: Daiichi Sankyo, MSD, MetaFines, Astellas Pharma; Financial Interests, Institutional, Other, Honoraria: JW Pharmaceutical, Sanofi/Aventis, Astellas Pharma, Bayer, Daiichi Sankyo, Merck KGaA; Financial Interests, Institutional, Research Funding: MacroGenics, MSD, Ono Pharmaceutical, AstraZeneca/MedImmune, Merck KGaA, ALX Oncology, Zymeworks, BeiGene, Daiichi Sankyo, Taiho Pharmaceutical, Y-Biologics, Seagen, Bolt Biotherapeutics, Trishula Therapeutics, InventisBio, Leap Therapeutics, Astellas Pharma, MedPacto, Ildong Pharmaceutical, Roche, Amgen, Genome & Company, Arcus Biosciences, Elevar Therapeutics; Non-Financial Interests, Personal, Other, Uncompensated relationships: ALX Oncology. S. Lee: Financial Interests, Personal, Research Funding: Jeil Pharmaceutical Co., Yuhan Co. Y. Kang: Financial Interests, Personal, Advisory Board: Daehwa Pharmaceutical, Bristol Myers Squibb, Zymeworks, ALX Oncology, Amgen, Novartis, Macrogenics, Surface Oncology, Blueprint Medicines. S. Chandana: Financial Interests, Personal, Speaker’s Bureau: Natera; Financial Interests, Institutional, Research Funding: Merck, Novocure, Qualigen Therapeutics, Exact Sciences, Zymeworks, AstraZeneca, Mirati Therapeutics, Elevation Oncology, AbbVie, Adcentrx Therapeutics, Amgen, Cardiff Oncology, Deciphera, Genentech/Roche, Ideaya Biosciences, IGM Biosciences, Incyte, Ipsen, Janssen. A. Escalante: Financial Interests, Personal, Research Funding: AstraZeneca, Sanofi, MSD; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Pfizer, Novartis, Icon Clinical Research. C. Xie, P. Garfin: Financial Interests, Personal, Full or part-time Employment: Jazz Pharmaceuticals; Financial Interests, Personal, Stocks or ownership: Jazz Pharmaceuticals. S. Iqbal: Financial Interests, Personal, Speaker, Consultant, Advisor: Merck, AstraZeneca, Exelexis, BeiGene, Astellas; Financial Interests, Personal, Speaker’s Bureau: Astellas.