Next-generation sequencing (NGS) has propelled the identification of numerous potential therapeutic targets, yet the clinical benefits of targeted therapies remain uncertain. Novel clinical trial designs, guided by biomarkers, are crucial for efficiently exploring the therapeutic potential of emerging gene-variation data. This article summarizes the advancements in basket, umbrella, and platform clinical trials, emphasizing their roles in precision medicine.
Basket Trials: Pan-Cancer Therapy Based on Drug-Target Relationships
Basket trials utilize drug-target relationships to explore pan-cancer therapies, employing two primary models: 'targets search drugs' and 'drugs identify targets.' These approaches aim to extend drug indications for confirmed proliferation-driven targets and to identify potential targets for drugs with proven efficacy across various tumor types.
Targets Search Drugs
The 'targets search drugs' model focuses on targets with confirmed pan-cancer, independent proliferation-driven capabilities, such as receptor tyrosine kinase (RTK) families (e.g., EGFR, HER2, MET, and FGFR) and their downstream MAPK/PI3K pathway signals (KRAS, BRAF, MEK, PI3K, AKT, and mTOR), as well as CDK4/6. Researchers can directly search for corresponding drugs upon detecting these targets in potentially beneficial cancer species.
EGFR, the most extensive proliferation-driven target in epithelial cancers, has shown efficacy in lung, colorectal, head and neck, pancreatic, and female reproductive system cancers. For instance, combining chemotherapy with EGFR-TKIs prolongs progression-free survival (PFS) in NSCLC patients to nearly 3 years. Similarly, HER2, another key molecule in the EGF receptor family, has demonstrated survival benefits in breast and gastric cancers, with promising remission rates in lung and digestive tract tumors.
Drugs Identify Targets
The 'drugs identify targets' model establishes therapeutic potential by identifying new targets of confirmed effective drugs across different tumor types. This approach relies on NGS to detect unknown gene variations, accelerating the verification of new targets' therapeutic value. PARP inhibitors, for example, have expanded potential effective targets from BRCA2 to homologous recombination deficiency (HRD) and DNA repair-related genes.
Olaparib and other PARP inhibitors have been approved for treating advanced ovarian, breast, prostate, and pancreatic cancers with BRCA mutations. Clinical studies have confirmed that PARP inhibitors also benefit these cancers with other HRD-related genes (RAD51, ATM, and PABL2) and HRD without germline BRCA mutations.
Umbrella Trials: Molecular-Subtype-Driven Therapy
Umbrella trials rapidly validate the effectiveness of multiple therapies for a specific disease, overcoming the limitations of traditional trial designs. These trials maximize the inclusion of individuals in precision medicine, aiming to find personalized treatment strategies. Accurate and thorough identification of molecular biological features is essential for the application of umbrella trial designs.
Lung-MAP, a well-known umbrella trial for squamous NSCLC, incorporates multiple treatment options to simultaneously evaluate biomarker-guided therapies. Similarly, the FUTURE trial for triple-negative breast cancer (TNBC) categorized patients into four subtypes based on multi-omics profiling, demonstrating improved progression-free survival with biomarker-guided therapy.
Platform Trials: Dynamic Screening of Optimal Treatments
Platform trials, as dynamic umbrella designs, represent another new trial design that has revolutionized clinical research and drug development. Compared with umbrella trials, the standards for experimental intervention or controls are dynamically changing, resulting in a more effective way to screen out optimal treatment in a long-term dynamic model. The I-SPY 2 trial, a pioneer in tumor platform trials, evaluates neoadjuvant therapies in breast cancer, exploring the effectiveness of different biomarkers and corresponding experimental drugs. This trial's adaptive randomization design allows for efficient, parallel evaluation of experimental drugs, with adjustments based on emerging evidence.
In triple-negative breast cancer, the combination of veliparib-carboplatin and standard chemotherapy resulted in significantly higher pathological complete response rates than standard therapy alone. The I-SPY 2 trial's success highlights the efficiency of platform trials in precision medicine, particularly in exploring molecular-biomarker-guided therapy.
