Therapeutic advances in non-small cell lung cancer: Focus on clinical development of targeted therapy and immunotherapy

Abstract

Lung cancer still contributes to nearly one-quarter cancer-related deaths in the past decades, despite the rapid development of targeted therapy and immunotherapy in non-small cell lung cancer (NSCLC). The development and availability of comprehensive genomic profiling make the classification of NSCLC more precise and personalized. Most treatment decisions of advanced-stage NSCLC have been made based on the genetic features and PD-L1 expression of patients. For the past 2 years, more than 10 therapeutic strategies have been approved as first-line treatment for certain subgroups of NSCLC. However, some major challenges remain, including drug resistance and low rate of overall survival. Therefore, we discuss and review the therapeutic strategies of NSCLC, and focus on the development of targeted therapy and immunotherapy in advanced-stage NSCLC. Based on the latest guidelines, we provide an updated summary on the standard treatment for NSCLC. At last, we discussed several potential therapies for NSCLC. The development of new drugs and combination therapies both provide promising therapeutic effects on NSCLC.

Keywords: combination therapy; drug resistance; immunotherapy; non‐small cell lung cancer (NSCLC); targeted therapy.

FIGURE 1

Timeline illustrating the development of treatment strategies for NSCLC. Surgery and cytotoxic chemotherapy have been introduced to NSCLC in 1960s and 1970s, for the first‐time improving prognosis of NSCLC. Antiangiogenesis therapy for nonsquamous NSCLC was approved by FDA in 2006, limited by its insufficient efficacy as monotherapy. The first‐line use of ALK TKIs and EGFR TKIs renewed the treatment strategies for NSCLC in early 2010s. Immunotherapy has developed rapidly during last 5 years. Pembrolizumab in combination with chemotherapy, approved in 2017, brings new hope for patients without targetable mutations. The combination therapies are presented in mixed colors

FIGURE 2

Treatment algorithm for NSCLC patients at early stage. Surgery is recommended for early‐stage NSCLC patients. For patients at stage IIA–IIIB, adjuvant therapy is required. Locally advanced or metastatic NSCLC should receive systemic therapy. The staging strategy is based on the guideline of National Comprehensive Cancer Network (NCCN) (2021)

FIGURE 3

Treatment algorithm for advanced NSCLC. Advanced NSCLC consists of metastatic NSCLC and unresectable locally advanced NSCLC. EGFR, ALK, KRAS, ROS1, BRAF, NTRK1/2/3, MET, RET, and PD‐L1 expressions are included in the molecular testing. For patients without targetable mutations, pembrolizumab + carboplatin + (nab‐) paclitaxel is recommended. ^†For patients with EGFR exon 19 deletion or exon 21 L858R, erlotinib, afatinib, gefitinib, and dacomitinib are also recommended. However, when the disease progresses on these TKIs, patients are recommended for a second molecular testing for T790M mutation test. ^‡Patients who are intolerant to crizotinib may be switched to ceritinib, alectinib, or brigatinib. ^§Entrectinib is recommended for patients with CNS metastasis. ^¶Single‐agent vemurafenib is a treatment option if the combination of dabrafenib + trametinib is not tolerated