013 | Innovative therapeutic approaches in solid tumors

Alessia Dottore¹, Rosalba Rossello², Francesco Ferraù¹ | ¹UOC Oncologia Medica, Ospedale “San Vincenzo”, Taormina [ME], Italy; ²UOS Oncologia Medica, Ospedale “Cutroni Zodda”, Barcellona Pozzo di Gotto [ME], Italy.

The treatment of solid tumors has undergone significant changes over the years. Traditional chemotherapy has gradually been abandoned in favor of innovative therapeutic approaches that have improved patient survival and quality of life. Precision medicine, using targeted therapies, immunotherapy, antibody-drug conjugates (ADCs), and tumor-agnostic therapies, is now commonplace. Modern molecular biology techniques have allowed us to better understand cancer, thanks to the identification of countless driver mutations (EGFR, ALK, BRAF, MEK, RET, ROS1, PARP). Targeted therapies have been developed, resulting in improved prognosis (particularly osimertinib, alectinib, dabrafenib, trametinib, selpercatinib and PARP inhibitors). Immunotherapy has revolutionized both cancer research and treatment by using the patient's own immune system to eradicate cancer and prevent recurrence. Antibodies are used to block immunosuppressive molecules, such as antibodies directed against the protein PD-1 (Programmed Cell Death-1), the protein PD-L1 (Programmed Death-1) ligand, and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) in several solid tumors, including pembrolizumab, nivolumab, cemiplimab and ipilimumab. Antibody-drug conjugates (ADCs) are cancer therapies that combine 3 components: 1) monoclonal antibodies designed to specifically target on cell surface; 2) cytotoxic chemotherapy (payload) that destroy cancer cells while sparing healthy tissue; 3) linker that attaches the payload to the antibody only releasing the payload at the desired target. Trastuzumab emtansine, Trastuzumab deruxtecan, Sacituzumab govitecan was approved for the treatment of people with HER2-positive breast cancer, Enfortumab vedotin was approved for adult patients with locally advanced or metastatic urothelial cancer, Mirvetuximab soravtansine was approved for treatment of adults with folate receptor alpha (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. Tumour-agnostics treatments are a new class of cancer therapies that target tumours not according to their location in the body, but by targeting a certain property of the tumour cells, called a biomarker. They are called “agnostic” because unlike typical cancer therapies, they can, in principle, fight tumours no matter where they originate. Small-molecule inhibitors have been approved to treat NTRK fusions and RET fusions and the complexity of tumour-agnostic therapies has increased with the approval of combination treatment for BRAFV600E-mutated solid tumours. Some approved drugs are larotrectinib, entrectinib and recently, repotrectinib for NTRK fusions and selpercatinib for RET fusions. The recent approval of these molecules has led to a true revolution in the treatment of solid tumors, moving from a "classic" approach based on histology to a "modern" approach based on molecular research. Nonetheless, open questions remain regarding equitable access to genomic profiling and the identification of bimarkers that predict which patients respond or not to therapy. Maintaining quality of life and managing emerging toxicities is also a key aspect.