ADC Programs

IKS014

HER2-directed ADC for HER2+ solid tumors

IKS014 is currently in Phase 1 dose expansion studies for the treatment of patients with advanced HER2+ solid tumors

Phase 1 dose escalation (n = 71) has completed and Dose Expansion is underway.

IKS014 shows promising anti-cancer activity across a range of HER2+ and HER2-low solid tumors, with a best-in-class tolerability profile

Note: As ‘FS-1502’, the drug is currently in a Phase 3 trial in China, where it is licensed to Fosun Pharma, for the treatment of HER2+ advanced or metastatic breast cancer vs Kadcyla.

IKS014 development status

ADC

IKS014

Target

HER2

Indication

HER2-associated Breast, Gastric, Esophageal, Lung and other solid tumors

Research Pre-clinical Clinical

In Phase 1 dose escalation studies, IKS014 shows promising anti-cancer activity and a favorable tolerability profile

IKS014 is well-tolerated across dose cohorts with anticipated adverse effects being predominantly Grade 1 or 2.

The safety population (June 2025 data cut) included 62 patients who received at least one dose of study drug, with doses ranging from 40 mg/m² (around 1.0 mg/kg) to 120 mg/m² (approx. 3.2 mg/kg). The recommended dose for Dose Expansion is 105 mg/m² (around 2.8 mg/kg).

The safety profile is characterized by anticipated adverse events which included low-grade ocular surface AEs, pneumonitis and hypokalemia.

Ocular events were low-grade, (G1 or G2), with only one patient (who did not receive any ocular prophylaxis) experiencing a G3 event at the highest dose tested. No G3 events were observed for the 2.8 mg/kg dose. Ocular toxicities were predominantly low-grade dry eye and, unlike other MMAF-directed ADCs, were not associated with the cornea.

In addition, and distinct from other GER2-directed ADCs, no ≥Gr 3 pneumonitis events were reported; at 105 mg/m² there were two events (one G1 event and 1 G2 event) across 10 patients.

Hypokalemia was predominantly G1/ G2 and addressed with oral K+ supplementation. GI toxicities (nausea, vomiting and diarrhea) were low in frequency and grade across dose cohorts. In the 105 mg/m² group, only one patient experienced vomiting (G1), whilst no patients suffered diarrhea.

IKS014 is also associated with substantially lower frequency and grade of GI toxicities and fatigue than other HER2-directed ADCs including Kadcyla and Enhertu.

Anti-tumor activity was observed across dose levels and tumor indications

Amongst 11 patients with advanced breast cancer treated at doses ≥ 90 mg/m², ORR was 64%. Responses were seen in all 4 patients with HER2+ disease, including 3 patients who had previously received Enhertu

Among 10 patients with pre-treated HER2+ esophageal cancer, 5 achieved a response including complete regression in one patient with non-measurable disease

PRs were observed in patients with gall bladder, ovarian, endometrial, gastric and GEJ cancers, as well as NSCLC.

At the data cut-off, 55 patients were evaluable for efficacy according to RECIST. The median duration of follow-up was approximately 6.6 months.

Encouraging anti-tumor activity was was seen across all dose levels. Partial responses (PRs) and unconfirmed PRs (uPR) were observed in a variety of tumor indications including breast, lung, esophageal, ovarian, gallbladder and GEJ cancers in both HER2+ and HER2-low tumors.

Responses were noted in 18 patients: 13 PR, 4 uPR, 1 CR (patient with non-measurable disease). Durable responses were noted across tumor indications and dose levels. The overall response rate for relevant cohorts, (doses of ≥ 90mg/m²) was comparable with Enhertu DESTINY-PanTumor-02.

IKS014 shows good efficacy across a range of tumors and doses

Phase 1 Part I enrolled patients with a wide range of tumors and a mix of HER2+ and HER2-low expression.

21 of the 49 patients referenced in the waterfall plot had HER2-low disease. PRs were observed in patients with breast (3), ovarian (1) and gall bladder (1) cancers.

2 PRs were seen in the lowest dose cohort of 40 mg/m² (gall bladder and esophageal cancers)

Clinical trial overview

NCT05872295 is an open label, uncontrolled non-randomized multi-center, 2 part study assessing IKS014 in patients with HER2+ solid tumors that is either relapsed, refractory to, or intolerant of existing therapy/ies, or for which no standard of care is available.

Part I dose escalation has been completed and was a 3+3 design study, with a primary objective of safety (MTD). There are 5 dose cohorts in this study, with doses ranging from 40 mg/m²to 120 mg/m²(approx. 1.0 to 3.2 mg/kg). The Recommended Dose for Part II (Dose Expansion) is 105 mg/m²(around 2.8 mg/kg)

Part II is a dose expansion study in specified indications, with a primary objective of Objective Response Rate (ORR)

HER2 expression is defined as IHC3+, IHC2+/FISH+ or FISH+ and HER2-low expression is defined as IHC1+ or IHC2+/FISH-

Patients will be recruited across sites in Australia, the US, Singapore and New Zealand

Site locations

Australia

Australia Linear Clinical Research, 1 Hospital Avenue, B-Block, 1st Floor, Nedlands WA 6009, Australia

Peninsula & South Eastern Haematology and Oncology Group (PSEHOG), South Building, 5 Susono Way, Frankston VIC 3199

Frankston Hospital, 2 Hastings Rd, Frankston VIC 3199, Australia

Concord Repatriation General Hospital, Hospital Rd, Concord NSW 2139

Westmead Breast Cancer Institute, Block F/189 Cnr Hawkesbury & Darcy Rd, Westmead NSW 2145

Macquarie University Hospital, Sydney NSW

Singapore

National Cancer Center (NCCS), 30 Hospital Boulevard, Singapore

Tan Tock Seng Hospital (TTSH), Novena 308433

New Zealand

Auckland City Hospital, 2 Park Road, Auckland 1023

US

Hoag Memorial, Newport Beach, 1 Hoag Dr Bldg, 41 3rd floor Ste 302, CA 92663

Dana Farber Cancer Institute, Mayer Building, 440 Brookline Ave., Boston, MA 02215

Tennessee Oncology

Differentiation by design

IKS014 is comprised of an anti-HER2 antibody, engineered for site-specific conjugation of an MMAF payload.

The choice of MMAF enables use in patients who have previously received Enhertu and/ or Kadcyla.

A beta-glucuronide liker is used for tumor-selective enzymatic payload release, enabling precision targeting to cancer cells and a reduction in payload-associated toxicities.

Tumor-selective payload activation drives a differentiated clinical profile

Phase 1 clinical studies have confirmed an improved safety profile compared with other HER2-directed ADCs, including Enhertu and Kadcyla.

Compared with Enhertu and Kadcyla, there is significantly less neutropenia and thrombocytopenia and, importantly, a lack of dose-limiting ILD or respiratory disorders.

Also, unlike Blenrep - the on-market benchmark MMAF-containing ADC, IKS014 is not associated with dose-limiting corneal toxicity or loss of visual acuity. Whereas Blenrep is associated with serious events in 50-63% of patients, with ≥G3 corneal exam findings of >70%, keratopathies in 44% of patients and discontinuation in 1 in 8 patients. IKS014 is only associated with low-grade events such as dry eye and keratitis. The lack of high-grade corneal toxicities is a clear consequence of the glucuronide-driven tumor-selective payload release mechanism.

Additionally, IKS014 has a significantly lower prevalence and grade of GI toxicities such as nausea, vomiting and diarrhea, and fatigue compared with Enhertu and Kadcyla..

This enhanced safety profile does not come at the expense of efficacy - at the median follow-up of 5.2 months, FS-1502 showed a similar ORR in this patient population to Enhertu at a similar data cut-off point.

The profile safety profile observed with IKS014 is consistent with that seen with FS-1502 in Fosun's Phase 1 study, (data shown below).

Iksuda has Best in class TI for HER2-directed therapies

Preclinical data has shown that IKS014 is associated with a significantly superior TI over Kadcyla and Enhertu.

Efficacy was similar or better than Enhertu and superior to Kadcyla in xenograft models for breast and gastric with moderate-to-high HER2 expression, whilst GLP toxicology confirmed a differentiated toxicity profile and an HNSTD of >12-fold the minimal effective dose (MED).

Preclinically, the advanced ADC design of IKS014 was shown to avoid dose-limiting ocular toxicities that are associated with MMAF-based ADCs, and respiratory, blood & lymphatic toxicities that are dose-limiting for other anti-HER2 ADCs including Enhertu.

	KadCYLA (T-DM1)	ENHERTU	XMT-1522	IKS014
Company	Genetech/ Roche	Daiichi Sankyo/ AstraZeneca	Mersana/ Takeda	Iksuda
Payload (DAR)	DM1 (3.4)	DXd (7.7)	Auristatin D (15)	MMAF (2)
MED (JIMT-1)	>20mg/kg	>10mg/kg	1mg/kg	1mg/kg
HNSTD	30mg/kg	30mg/kg	2.5mg/kg	12mg/kg
TI	<1.5	<3	2.5	12