Clinical Evaluation of Targeted Cancer Therapies

Abstract

Targeted cancer therapies -- drugs designed to exploit specific molecular vulnerabilities in tumour cells -- have transformed oncology since imatinib's approval for CML in 2001, yet real-world effectiveness often falls short of clinical trial efficacy, patient selection biomarkers remain imperfect, and resistance emerges in the majority of patients within 12-24 months. Over 90 targeted agents are now approved across solid and haematological malignancies, spanning kinase inhibitors, monoclonal antibodies, antibody-drug conjugates (ADCs), bispecific antibodies, and degraders, yet fewer than 30% of advanced cancer patients harbour an actionable molecular target matched by an approved drug. We evaluated five clinical evaluation frameworks for targeted therapies across 12,486 molecularly profiled cancer patients treated at four European comprehensive cancer centres (Vienna, Paris, Milan, and Barcelona) between 2016 and 2022, covering NSCLC, breast cancer, colorectal cancer, and melanoma. We compared: biomarker-matched monotherapy, combination targeted strategies, adaptive biomarker-driven trial designs, real-world evidence from molecular tumour boards, and ML-predicted treatment sequencing. Our Targeted Therapy Evaluation Score (TTES) integrates objective response rate, progression-free survival, overall survival benefit, biomarker-guided patient selection accuracy, and resistance management effectiveness. ML-predicted treatment sequencing achieved the highest TTES (0.924) by optimising the order and combination of targeted agents based on tumour molecular evolution patterns, while molecular tumour board-guided therapy (TTES 0.910) delivered the highest real-world response rates through expert multi-disciplinary interpretation of complex genomic profiles.