Evolving Precision First-Line Systemic Treatment for Patients with Unresectable Non-Small Cell Lung Cancer

The armamentarium of first-line systemic therapy for patients with unresectable non-small cell lung cancer (NSCLC) has been rapidly expanding over the past two decades. Currently, about 50% of patients with NSCLC do not need chemotherapy as first-line treatment. For these patients, molecularly targeted therapy and immune checkpoint inhibitor therapy have significantly improved progression-free survival and overall survival with favorable toxicity profiles. Patient demographics and clinical features are not sufficient for the selection of these treatments. An unmet need of precision oncology is to select the most appropriate therapeutic regimen with maximal efficacy and minimal unwanted toxicity for individual patients with NSCLC based on the assessment of their molecular and immune biomarkers at diagnosis. In this review, we summarize the current data and propose a practical algorithm for implementing precision biomarker testing at diagnosis and selecting the most appropriate first-line systemic therapy for patients with unresectable, advanced, or metastatic NSCLC. First-line systemic therapy for patients with advanced or metastatic non-small cell lung cancer (NSCLC) has rapidly evolved over the past two decades. First, molecularly targeted therapy for a growing number of gain-of-function molecular targets has been shown to improve progression-free survival (PFS) and overall survival (OS) with favorable toxicity profiles compared to platinum-containing chemotherapy and can be given as first-line systemic therapy in similar to 25% of patients with NSCLC. Actionable genetic alterations include EGFR, BRAF V600E, and MET exon 14 splicing site-sensitizing mutations, as well as ALK-, ROS1-, RET-, and NTRK-gene fusions. Secondly, inhibitors of programmed cell death protein 1 or its ligand 1 (PD-1/L1) such as pembrolizumab, atezolizumab, or cemiplimab monotherapy have become a standard of care for similar to 25% of patients with NSCLC whose tumors have high PD-L1 expression (total proportion score (TPS) >= 50%) and no sensitizing EGFR/ALK alterations. Lastly, for the remaining similar to 50% of patients who are fit and whose tumors have no or low PD-L1 expression (TPS of 0-49%) and no sensitizing EGFR/ALK aberrations, platinum-containing chemotherapy with the addition of a PD-1/L1 inhibitor alone or in combination of a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor improves PFS and OS compared to chemotherapy alone. The objectives of this review are to summarize the current data and perspectives on first-line systemic treatment in patients with unresectable NSCLC and propose a practical algorithm for implementing precision biomarker testing at diagnosis.