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

Abstract

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 ~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 ~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 ~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.

Keywords: CTLA-4; NSCLC; PD-1; PD-L1; biomarkers; first-line therapy; immune biomarkers; immune checkpoint inhibitors; molecular targets.

Figure 1

The chronological milestones for the management of NSCLC. Over the past few decades, many advances have contributed to the improved OS for patients with nonresectable, LA/mNSCLC, which includes first-line platinum-based combination chemotherapy, second-line single-agent chemotherapy or unselected molecularly targeted therapy, histology-directed chemotherapy, and tumor genotyping for molecular biomarkers, and first- and second-generation molecularly targeted therapies in the United States. Notably, patients with metastatic lung adenocarcinoma have benefited most from these therapeutic advances.

Figure 2

Schema for biomarker-driven precision diagnosis and treatment for NSCLC. This schema illustrates the clinical workflow, emphasizing the importance of multidisciplinary collaboration in implementing biomarker-driven precision diagnosis and treatment selection. It highlights the integration of histopathological, molecular, and immunological biomarkers at the time of NSCLC diagnosis to guide treatment selection. This holistic approach ensures that patients receive personalized therapy based on their individual biomarker profile, ultimately optimizing treatment outcomes.

Figure 3

Schema for first-line systemic therapy for unresectable LA/mNSCLC. The landscape of first-line systemic treatment for patients with unresectable, LA/mNSCLC has evolved significantly over the past two decades. Compared to platinum-based chemotherapy doublets, molecularly targeted therapy and ICI therapy have prolonged survival with improved quality of life for the majority of patients with NSCLC. First, the detection of one of the 7 actionable oncogene alterations predicts a response rate of 60–80% to a matched TKI in approximately 25% of patients with NSCLC. Another 25% of patients with NSCLC benefit from a first-generation inhibitor against PD-1 or PD-L1 checkpoints. Thus, about 50% of patients with LA/mNSCLC do not need chemotherapy as first-line treatment. One exception to TKI targeted therapy is the NSCLC with osimertinib-resistant EGFR E20ins, for which the addition of dual EGFR and MET antibody amivantamab to carboplatin and pemetrexed was recently approved as the first-line treatment in March 2024. For those patients with oncogene-driven NSCLC, ICIs have not been shown to have any significant clinical activity. Several combination strategies of chemoimmunotherapy have been developed for the rest of ~50% of patients with NSCLC whose tumors do not have targetable genomic aberrations or high PD-L1 expression. Reference: 2024 NCCN V4, access date 28 April 2024.