Targeted therapeutic options in early and metastatic NSCLC-overview

Abstract

The complex therapeutic strategy of non-small cell lung cancer (NSCLC) has changed significantly in recent years. Disease-free survival increased significantly with immunotherapy and chemotherapy registered in perioperative treatments, as well as adjuvant registered immunotherapy and targeted therapy (osimertinib) in case of EGFR mutation. In oncogenic-addictive metastatic NSCLC, primarily in adenocarcinoma, the range of targeted therapies is expanding, with which the expected overall survival increases significantly, measured in years. By 2021, the FDA and EMA have approved targeted agents to inhibit EGFR activating mutations, T790 M resistance mutation, BRAF V600E mutation, ALK, ROS1, NTRK and RET fusion. In 2022, the range of authorized target therapies was expanded. With therapies that inhibit KRASG12C, EGFR exon 20, HER2 and MET. Until now, there was no registered targeted therapy for the KRAS mutations, which affect 30% of adenocarcinomas. Thus, the greatest expectation surrounded the inhibition of the KRAS G12C mutation, which occurs in ∼15% of NSCLC, mainly in smokers and is characterized by a poor prognosis. Sotorasib and adagrasib are approved as second-line agents after at least one prior course of chemotherapy and/or immunotherapy. Adagrasib in first-line combination with pembrolizumab immunotherapy proved more beneficial, especially in patients with high expression of PD-L1. In EGFR exon 20 insertion mutation of lung adenocarcinoma, amivantanab was registered for progression after platinum-based chemotherapy. Lung adenocarcinoma carries an EGFR exon 20, HER2 insertion mutation in 2%, for which the first targeted therapy is trastuzumab deruxtecan, in patients already treated with platinum-based chemotherapy. Two orally administered selective c-MET inhibitors, capmatinib and tepotinib, were also approved after chemotherapy in adenocarcinoma carrying MET exon 14 skipping mutations of about 3%. Incorporating reflex testing with next-generation sequencing (NGS) expands personalized therapies by identifying guideline-recommended molecular alterations.

Keywords: NSCLC; central nervous system efficacy; driver oncogenes; molecular testing; targeted therapy.

FIGURE 1

Treatment recommendation for stage IV mNSCLC based on the ESMO 2023 guideline [1].

FIGURE 2

Treatment recommendation for EGFR mutant metastatic NSCLC based on the ESMO 2023 guideline [1].

FIGURE 3

Treatment recommendation for ALK translocated metastatic NSCLC based on the ESMO 2023 guideline [1].

FIGURE 4

Treatment recommendation for ROS1 translocated metastatic NSCLCbased on the ESMO 2023 guideline [1].

FIGURE 5

Frequency of oncogenic drivers for East-Asian and Western populations [134]. Bars are stratified according to proportions of brain metastases (BM) at diagnosis (blue) and BM development after diagnosis (orange) and pan-wild-type for all genetic alterations reported including rare ones (WT, green) [131]. For visual enhancement low frequencies of ALK, ROS1, RET genetical alterations are presented in a separate figure.