In search of goldilocks: the quest to optimize combination drug strategies for the management of advanced stage non-small-cell lung cancer

The past two decades have seen significant therapeutic advances in the management of advanced non-small cell lung cancer (NSCLC): from histology-focused chemotherapy regimens to personalized medicine where each patient is treated in accordance with the unique genetic and molecular features of their tumor. The evidence-based standard of care for frontline palliative systemic therapy in advanced NSCLC includes: (I) tyrosine kinase inhibitors (TKIs) for those with actionable alterations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), or B-Raf proto-oncogene (BRAF); or (II) immune checkpoint inhibitors (ICIs) alone or in combination with platinum doublet chemotherapy for those without actionable genetic alterations (1). Current expert guidelines recommend testing for alterations in EGFR, ALK, ROS1, and BRAF at a minimum in advanced stage lung adenocarcinomas and tumor programmed death ligand-1 (PD-L1) immunohistochemistry for all advanced NSCLCs (2). However, for the significant proportion (~75%) of patients with advanced NSCLC whose tumors do not harbor sensitizing genetic alterations, identifying more efficacious and tolerable strategies beyond sequential use of cytotoxic chemotherapies was an area of significant unmet need. Since the approval of ICIs by the United States Food and Drug Administration (FDA) in 2015, numerous ongoing efforts have focused on evolving better strategies for this large cohort of patients by incorporating immunebased therapies—either alone or in combination with other chemotherapeutic, immunologic, and/or biologic agents (3). In this editorial, we explore the recent explosion of data regarding immune-based combination therapies, placing the recently published IMpower 130 trial by West et al. into context, and emphasizing strategies to optimize their use.