The World Health Organization (WHO) estimates that lung cancer causes 1.59 million deaths globally per year. Non-small cell lung cancer (NSCLC) accounts for 80%–90% of lung cancers. During the last 25 years, the distribution of histological types of NSCLC has changed: in the United States, squamous cell carcinoma (SCC), formerly the predominant histotype, decreased, while adenocarcinoma has increased in both men and women. In Europe, similar trends have occurred in men, while in women, both SCC and adenocarcinoma are still increasing [1][2].

During the upcoming IASLC World Conference on Lung Cancer (#WCLC19), to be held September 7-10, 2019 in Barcelona, Spain, Daiichi Sankyo is expected to updated results and new translational research data from two phase I studies evaluating investigational antibody-drug conjugates (ADCs) U3-1402 and DS-1062 in patients with advanced or metastatic non-small cell lung cancer (NSCLC).

The oral presentations feature updated safety and efficacy results for U3-1402, a potential first-in-class HER3 targeting ADC being evaluated in patients with EGFR mutated metastatic NSCLC that has become resistant to TKI therapy, and for DS-1062, a TROP2 targeting ADC being evaluated in patients with advanced NSCLC who have progressed on standard treatments or for whom no standard treatment is available. Translational research findings from both studies, including biomarker expression and genomic alterations, will be presented alongside patient response data.

ADC Bio
MabPlex
Lonza
 

“As we continue to report our progress in clinical development of U3-1402 and DS-1062 in NSCLC, we also will begin to showcase some of the advanced translational research being conducted in the trials,” said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.

“We are using cutting-edge tools to assess biomarker expression, genomic alterations and tumor burden; analyzing their relationships to treatment response; and pushing the boundaries of current science to fully leverage the potential of our ADCs in a precision medicine approach.”

Daiichi Sankyo’s U3 1402 is composed of patritumab*, a monoclonal antibody directed against the human epidermal growth factor receptor HER3 (ErbB3) linked to the topoisomerase I inhibitor DX 8951, a semisynthetic, water-soluble derivative of camptothecin, with potential antineoplastic activity.

DS-1062a is composed of a humanized monoclonal antibody against tumor-associated antigen (TAA) trophoblast cell surface protein 2 (calcium signal transducer 2; TROP2; TROP-2; TACSTD2) conjugated, via an enzymatically cleavable tetrapeptide-based linker, to the cytotoxic DNA topoisomerase I inhibitor and exatecan (DX-8951) derivative DXd (MAAA-1181a; MAAA-1181).

Propitiatory technology
Both U3-1402 and DS-1062 are designed using Daiichi Sankyo’s proprietary DXd ADC technology, in which a monoclonal antibody is attached by a tetrapeptide-based linker to a novel topoisomerase I inhibitor payload.

Each ADC is constructed to target and deliver chemotherapy inside cancer cells that express a specific cell surface antigen, and each has a customized drug to antibody ratio (DAR) designed to attain the intended safety and efficacy for the target under investigation.

U3-1402 and DS-1062 are Daiichi Sankyo’s second and third antibody-drug conjugate in clinical development for NSCLC, following [fam-] trastuzumab deruxtecan (DS-8201), which is being co-developed and co-commercialized globally in collaboration with AstraZeneca.

U3-1402 also is being evaluated in a phase I/II trial in patients with HER3 positive metastatic breast cancer.

Following are details of the Daiichi Sankyo presentations at WCLC:

AbstractTitleDate/Location
#1720Preliminary Phase 1 Results from U3-1402—a Novel HER3 Targeted Antibody Drug Conjugate – in EGFR TKI resistant, EGFR mutant NSCLCMini Oral Session MA21: Non EGFR/MET Targeted Therapies.

Tuesday, September 10, 2019. 14:30 – 16:00 CEST

#3854First-in-Human Phase 1 Study of DS-1062a (TROP2 Antibody Drug Conjugate) in Patients with Advanced Non-Small Cell Lung CancerMini Oral Session MA25: Precision Medicine in Advanced NSCLC.

Tuesday, September 10, 2019. 14:30 – 16:00 CEST

 

Note:
* Patritumab is a fully human monoclonal antibody directed against the membrane-bound receptor HER3 (ERBB3). The antibody binds to and inhibits HER3 activation, which may result in inhibition of HER3-dependent PI3K/Akt signaling and so inhibition of cellular proliferation and differentiation.

HER3, a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, is frequently overexpressed in solid tumors, including breast, lung, and colorectal tumors of epithelial origin. It has no active kinase domain itself but is activated through heterodimerization with other members of the EGFR receptor family that do.

Reference
[1] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90. doi: 10.3322/caac.20107. Epub 2011 Feb 4.[Pubmed]
[2] Forman D, Bray F, Brewster D. Cancer Incidence in Five Continents. Lyon: IARC Press 2013.