155TiP - Exploring mechanisms of action and resistance to innovative therapeutic drugs: UNLOCK program

Background

Recent advancements in cancer research have significantly improved the understanding of tumor biology and immunology, leading to the development of innovative treatments. However, the mechanisms of action (MoA) and mechanisms of resistance (MoR) to these drugs remain poorly understood, requiring focused research strategies. Phase I/II trials offer a unique opportunity to integrate molecular and biological analyses of treatment response alongside primary trial endpoints, aiming to overcome resistance and redefine effective drug combinations. The Unlock program's scope is to better understand MoA/MoR for innovative drugs by performing clinical, fundamental, and translational research.

Trial Design

Unlock is a research, prospective, single-center program within STING trial (NCT04932525), employing high-throughput sequencing technologies at baseline, on-treatment, and resistant biopsies of patients (pts) with metastatic cancer. Over 5 years (2023 – 2029), the program planned to enroll 500 pts participating in phase I and dedicated phase II clinical trials or receiving recently approved innovative drugs at Gustave Roussy. Eligible participants are ≥ 18 years old, have histologically confirmed malignant tumors, and are included in first-in-human (FIH) and first-in-class (FIC) clinical trials, having provided informed consent. The spectrum of innovative therapies includes epigenetic modifiers, bi-specific T-cell engagers (BITEs), radioligands, antibody-drug conjugates (ADCs), and next-generation tyrosine kinase inhibitors (TKIs). Updates on eligible therapies will be conducted twice a year. Enrolled pts benefit from systematic liquid and tumor biopsies as shown in Figure 1. Whole Exome Sequencing (WES) and RNA-seq in pre- and post-treatment samples are performed to identify resistance alterations in the overall population. Tumor dynamics is studied on pre- and on-treatment tumor and blood samples using circulating tumor cells (CTCs), single-cell RNA sequencing, and spatial transcriptomic, to address specific scientific questions. Molecular findings on tumors are validated through circulating tumor DNA (ctDNA) and patient derivate xenografts (PDXs) developed from fresh samples.

Editorial acknowledgement

Clinical trial identification

NCT04932525.

Legal entity responsible for the study

The authors.

Funding

Gustave Roussy.

Disclosure

M.F. Mosele: Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Personal, Full or part-time Employment: Pegascy. D. Vasseur: Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche. S. Ponce Aix: Financial Interests, Institutional, Invited Speaker: Roche. C. Massard: Financial Interests, Personal, Other: Amgen, Astellas Pharma, AstraZeneca, Bayer, BeiGene, Blueprint Medicines, Bristol Myers Squibb, Celgene, Debiopharm Group, Faron Pharmaceuticals, Genentech/Roche, Innate Pharma, Ipsen, Janssen, Lilly, MSD, Novartis, Orion, Pfizer, PharmaMar, Sanofi, and T. F. André: Financial Interests, Personal, Advisory Board: Lilly France; Financial Interests, Institutional, Advisory Board: AstraZeneca, Daiichi Sankyo, Roche, Lilly, Pfizer, Owkin, Novartis, Guardant Health, N-Power Medicine, Servier, Gilead, Boston Pharmaceuticals; Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Novartis, Pfizer, Roche, Daiichi Sankyo, Guardant Health, Owkin. A. Italiano: Financial Interests, Personal, Other: Bayer, Daiichi Sankyo, Lilly, Epizyme, Novartis, Roche, Ipsen; Financial Interests, Personal, Advisory Role: Roche, Daiichi Sankyo, Immune Design, Epizyme, Bayer, Lilly; Financial Interests, Personal and Institutional, Research Grant: Roche, Bayer, AstraZeneca/MedImmune, PharmaMar, MSD Oncology, Merck Serono. L. Friboulet: Financial Interests, Personal, Research Grant: Debiopharm and Incyte, Relay Therapeutics, Sanofi, and Nuvalent; Non-Financial Interests, Personal, Other: Illumina, Guardant Health. Y. Loriot: Financial Interests, Personal, Advisory Board: Merck KGaA, Pfizer, Gilead, Seattle Genetics, Tahio; Financial Interests, Personal, Other, Lectures, Advisory Boards: MSD, AstraZeneca, Astellas, Janssen; Financial Interests, Personal, Other, Lectures, Advisory Boards: Roche, BMS; Financial Interests, Institutional, Research Grant: Janssen, Sanofi, MSD, Roche, Celsius; Financial Interests, Institutional, Invited Speaker: Janssen, Pfizer, Janssen, MSD, Janssen, Exelixis, AstraZeneca, Pfizer, Merck KGaA, BMS, Astellas, Gilead, Incyte; Financial Interests, Personal, Invited Speaker: MSD, Astellas, Gilead/Immunomedics, Basilea, Tahio; Non-Financial Interests, Personal, Member: ESMO, ASCO, AACR; Non-Financial Interests, Personal, Other, scientific committee: ARC. All other authors have declared no conflicts of interest.