Apart from TROP-2, HER2- and FRα, ESMO is full of new data releases of antibody-drug conjugates (ADCs) with novel targets such as B7-H4, CLDN18.2, conditionally active biologic (CAB)-ROR2, CDH3, and others that could redefine treatment paradigms. The focus on new targets reflects a growing interest in expanding ADC applications beyond traditional targets. Pharmaceutical companies like BioAtla, Sanofi, AbbVie, AstraZeneca, Keymed Biosciences, and others are gearing up at the conference to present insights into the effectiveness and safety of these novel ADCs, potentially setting new standards in cancer treatment, addressing unmet needs and broadening therapeutic options.

Unveiling the latest in ADC with novel targets

• Abstract Number – 606O
• Abstract Type – Proffered paper session 
• Indication – Advanced/metastatic solid tumors

Title: AstraZeneca's AZD8205's first-in-human data highlights B7-H4 ADC potential in advanced solid tumors

Executive Summary: The Phase I/II first-in-human study of AZD8205 marks a pivotal moment for the ADC landscape, potentially setting new standards for treating advanced and metastatic solid tumors.

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At the ESMO 2024 conference, significant attention is being drawn to AZD8205 (puxitatug samrotecan), a novel B7-H4–directed antibody-drug conjugate (ADC) that is making its debut in early clinical trials. This innovative ADC is being evaluated in a first-in-human study targeting advanced and metastatic solid tumors, potentially marking a new frontier in cancer therapy.

B7-H4 is a promising ADC target that is highly expressed in several solid tumors including cholangiocarcinoma (CCA) and breast cancer, ovarian cancer, and endometrial cancers, and is associated with poor prognosis.  AZD8205 is the first ADC bearing a novel proprietary topoisomerase I inhibitor (TOP1i) linker payload to enter the clinic. Robust AZD8205 anti-tumor response has previously been reported in B7-H4-expressing preclinical models across multiple tumor types. A proffered paper presentation at this year’s ESMO will share the dose escalation results from the BLUESTAR Phase I/IIa trial of B7-H4 ADC AZD8205 in patients with B7-H4-expressing advanced solid tumors. The study is currently investigating AZD8205 monotherapy in patients ≥18 years old (≥20 years for Japan) with CCA, breast, ovarian or endometrial cancers.  

In terms of ADCs as a class, ENHERTU and TRODELVY have set high standards in their respective niches. However, B7-H4 is a less explored target compared to HER2 and TROP2, which could provide AZD8205 with a unique positioning in the market. Its ability to target tumors expressing B7-H4, which are not sufficiently addressed by current ADCs, may open up new treatment opportunities and offer advantages in cases where other ADCs have limitations.

• Abstract Number – 1959O
• Abstract Type – Proffered paper session 
• Indication - Urothelial Carcinoma

Title: Beyond Single-Target ADCs, BL-B01D1, an EGFRxHER3 bispecific ADC’s innovative approach in urothelial carcinoma

Executive Summary: BL-B01D1, a first-in-class EGFRxHER3 bispecific ADC, represents a novel therapeutic strategy in urothelial carcinoma, with promising Phase I results to be showcased at ESMO 2024.

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BL-B01D1 is a potentially first-in-class EGFRxHER3 bispecific ADC. It is being jointly developed by SystImmune (Sichuan Biokin Pharma is the parent company) and Bristol Myers Squibb under an exclusive license and collaboration agreement, where SystImmune will be solely responsible for development, commercialization, and manufacturing in Mainland China, whereas, Bristol Myers Squibb gains an exclusive license in the rest of the world. 

BL-B01D1’s dual targeting of EGFR and HER3 represents a novel approach, potentially overcoming resistance mechanisms associated with single-target therapies. Both EGFR and HER3 are implicated in urothelial carcinoma pathogenesis, making them attractive targets for combined inhibition. Results from a Phase I study evaluating BL-B01D1 in patients with locally advanced or metastatic urothelial carcinoma will be revealed at the ESMO 2024. The data to be presented at the conference highlights continued progress in BL-B01D01 clinical development and builds upon the previously reported clinical data in lung and breast cancer patients at ASCO, ESMO, and SABCS in 2023. These data support the continued conviction that BL-B01D1 has a manageable safety profile and adds to the body of evidence that shows encouraging signals of efficacy across a wide variety of tumors. 

ADCs targeting single antigens, both Nectin-4 targeting PADCEV and TROP-2 targeting TRODELVY are already approved for urothelial carcinoma, with PADCEV leading the race after its approval in 1st line Urothelial Carcinoma in 2023 along with KEYTRUDA. The introduction of bispecific ADCs like BL-B01D1 is pushing the boundaries of targeted therapy, making it stand out in the ADC landscape. This positions BL-B01D1 as a versatile therapeutic option that may address the unmet medical needs of patients with limited treatment options.

Top Abstracts for ADCs with novel targets are given below: