Antibody-drug conjugates in advanced lung cancer: Is this a new frontier?

Over the past decade, the lung cancer landscape has been dominated by targeted and immunotherapeutic approaches that have drastically shifted treatment paradigms for patients with advanced non-small cell lung cancer (NSCLC). Despite these scientific and clinical advances, there are still many unmet needs underscoring the importance of novel strategies. Antibody-drug conjugates (ADCs) represent one such strategy that is beginning to alter the therapeutic strategies for patients with advanced NSCLC. The rationale of ADCs is simple: selectively deliver cytotoxic payloads through an antibody-mediated process to target antigens expressed by cancer cells, sparing normal tissue and inflicting damage to tumors. Although this concept has been the leading view, preclinical and clinical observations are demonstrating that only a nascent mechanistic understanding of these agents exists. In this review, we discuss the underlying biology of ADCs and their structure and potential mechanisms of action, examine approved and promising ADC targets in lung cancer, and review emerging ADC targets and combinatorial strategies. Importantly, we address the unanswered questions surrounding ADCs in lung cancer, including biomarker selection, treatment sequencing, and mechanisms of resistance, as well as management of unique ADC-associated toxicities.