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Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is the most frequently altered oncogene in Non-Small Cell Lung Cancer (NSCLC). KRAS mutant tumors constitute a heterogeneous group of diseases, different from other oncogene-derived tumors in terms of biology and response to treatment, which hinders the development of effective drugs against KRAS. Therefore, for decades, despite enormous efforts invested in the development of drugs aimed at inhibiting KRAS or its signaling pathways, KRAS was considered to be undruggable. Recently, the discovery of a new pocket under the effector binding switch II region of KRAS G12C has allowed the development of direct KRAS inhibitors such as sotorasib, the first FDA-approved drug targeting KRAS G12C, or adagrasib, initiating a new exciting era. However, treatment with targeted KRAS G12C inhibitors also leads to resistance, and understanding the possible mechanisms of resistance and which drugs could be useful to overcome it is key. Among others, KRAS G12C (ON) tricomplex inhibitors and different combination therapy strategies are being analyzed in clinical trials. Another area of interest is the potential role of co-mutations in treatment selection, particularly immunotherapy. The best first-line strategy remains to be determined and, due to the heterogeneity of KRAS, is likely to be based on combination therapies.

Patients harboring EGFR exon 20 insertion (EGFRex20ins) advanced Non-Small Cell Lung Cancer (NSCLC) represent a poor prognosis population of oncogene-addicted cancers in need of targeted therapy, since they are resistant to available EGFR tyrosine kinase inhibitor (TKIs) and there is limited efficacy data of immunotherapy.New drugs targeting EGFRex20ins are under development, such as mobocertinib, an antiEGFR TKI or amivantamab, a bispecific antibody targeting EGFR and MET, which have shown promising results in pre-treated patients. The activity of mobocertinib after treatment with amivantamab and vice versa is currently unknown.We present a 49-year-old, non-smoking woman with advanced EGFRex20ins NSCLC who had a significant response to mobocertinib after several treatments, including amivantamab. We discuss new treatments in development for patients with EGFRex20ins NSCLC.

Objective: Long-term survivors (LS) of non-small cell lung cancer (NSCLC) without driver alterations, displaying an overall survival (OS) of more than 3 years, comprise around 10% of cases in several series treated with chemotherapy. There are classical prognosis factors for these cases [stage, Eastern Cooperative Oncology Group (ECOG), etc.], but more data are required in the literature. In this multi-center study, we focused on LS of advanced NSCLC with OS above 36 months to perform a clinical-pathological and molecular characterization. Methods: In the first step, we conducted a clinical-pathological characterization of the patients. Afterwards, we carried out a genetic analysis by comparing LS to a sample of short-term survivors (SS) (with an OS less than 9 months). We initially used whole-genome RNA-seq to identify differentiating profiles of LS and SS, and later confirmed these with reverse transcription-polymerase chain reaction (RT-PCR) for the rest of the samples. Results: A total of 94 patients were included, who were mainly men, former smokers, having adenocarcinoma (AC)-type NSCLC with an ECOG of 0–1. We obtained an initial differential transcriptome expression, displaying 5 over- and 33 under-expressed genes involved in different pathways: namely, the secretin receptor, surfactant protein, trefoil factor 1 (TFF1), serpin, Ca-channels, and Toll-like receptor (TLRs) families. Finally, RT-PCR analysis of 40 (20 LS/20 SS) samples confirmed that four genes (surfactant proteins and SFTP) were significantly down-regulated in SS compared to LS by using an analysis of covariance (ANCOVA) model: SFTPA1 (P = 0.023), SFTPA2 (P = 0.027), SFTPB (P = 0.02), and SFTPC (P = 0.047). Conclusions: We present a sequential genetic analysis of a sample of NSCLC LS with no driver alterations, obtaining a differential RNA-seq/RT-PCR profile showing an abnormal expression of SF genes.

Objectives: Neurotrophic tropomyosin receptor kinase (NTRK) fusions might be an off-target resistance mechanism to ALK Tyrosine Kinase Inhibitors (TKIs) in the same way as it has been suggested with activating epidermal growth factor receptor (EGFR) TKIs. Materials and methods: DNA and RNA next-generation sequencing (NGS) was performed on the resected brain metastasis of a patient with advanced ALK Rearranged Non–Small Cell Lung Carcinoma (NSCLC) after resistance to several ALK TKIs including third generation ALK inhibitor, for pathological diagnosis and molecular resistance mechanism analysis. Results and conclusion: NGS revealed an EML4-NTRK3 fusion that was confirmed by Immunohistochemistry (IHC) and Fluorescence in situ hybridization (FISH). Despite having two potential targetable fusions, the patient did not respond to entrectinib, a multi-targeted pan-RTK, ROS1 and ALK inhibitor. NGS: analysis in blood or tissues samples should be encouraged once resistance develops to TKIs in patients with ALK rearrangements, as actionable fusions, mutations or amplifications might arise as resistance mechanism and some patients could benefit from targeted therapy.

Sarcomatoid carcinoma is a subtype of non-small cell lung cancer (NSCLC) characterized by mesenchymal – epithelial transition component and awful prognosis. In this report, based on a case of stage IV lung sarcomatoid carcinoma with an extraordinary evolution and survival over 4 years, we address unresolved questions about the treatment of this cancer. We also make a literature review about the key factors that characterize this histology and that should be considered when treating those patients. Sarcomatoid carcinoma presents with mutations as KRAS, EGFR, ALK or MET in up to 70% of cases, and an important expression of PD-L1 (also called B7-H1), which can influence treatment of those patients with new drugs as immune checkpoint inhibitors. Immunotherapy has changed the horizon of patients with stage IV lung cancers without driver mutations, as their survival has improved extraordinary. Moreover, radical treatments are being considered in long survivors with oligometastatic disease. In this report, we review targeted and radical therapy, treatment duration and the mechanisms responsible of disease evolution of sarcomatoid tumors. Keywords: Sarcomatoid, Pleomorphic, Immunotherapy, Long survivor, Lung cancer

KRAS mutations represent one of the most prevalent oncogenic driver mutations in non-small cell lung cancer (NSCLC). For many years we have unsuccessfully addressed KRAS mutation as a unique disease. The recent widespread use of comprehensive genomic profiling has identified different subgroups with prognostic implications. Moreover, recent data recognizing the distinct biology and therapeutic vulnerabilities of different KRAS subgroups have allowed us to explore different treatment approaches. Small molecules that selectively inhibit KRAS G12C or use of immune checkpoint inhibitors based on co-mutation status are some examples which anticipate that personalized treatment for this challenging disease is finally on the horizon.