Non-small cell lung cancer: an update on emerging EGFR-targeted therapies.

INTRODUCTION: Current research in EGFR-mutated NSCLC focuses on the management of drug resistance and uncommon mutations, as well as on the opportunity to extend targeted therapies' field of action to earlier stages of disease. AREAS COVERED: We conducted a review analyzing literature from the PubMed database with the aim to describe the current state of art in the management of EGFR-mutated NSCLC, but also to explore new strategies under investigation. To this purpose, we collected recruiting phase II-III trials registered on Clinicaltrials.govand conducted on EGFR-mutated NSCLC both in early and advanced stage. EXPERT OPINION: With this review, we want to provide an exhaustive overview of current and new potential treatments in EGFR-mutated NSCLC, with emphasis on the most promising newly investigated strategies, such as association therapies in the first-line setting involving EGFR-TKIs and chemotherapy (FLAURA2) or drugs targeting different driver pathways (MARIPOSA). We also aimed at unearthing challenges to achieve in this field, specifically the need to fully exploit already available compounds while developing new ones, the management of new emerging toxicities and the necessity to improve our biological understanding of the disease to design trials with a solid scientific rationale and to allow treatment personalization such in case of uncommon mutations.

Immunogenicity of two doses of BNT162b2 and mRNA-1273 vaccines for solid cancer patients on treatment with or without a previous SARS-CoV-2 infection.

Previous studies on the immunogenicity of SARS-CoV-2 mRNA vaccines showed a reduced seroconversion in cancer patients. The aim of our study is to evaluate the immunogenicity of two doses of mRNA vaccines in solid cancer patients with or without a previous exposure to the virus. This is a single-institution, prospective, nonrandomized study. Patients in active treatment and a control cohort of healthy people received two doses of BNT162b2 (Comirnaty, BioNTech/Pfizer, The United States) or mRNA-1273 (Spikevax, Moderna). Vaccine was administered before starting anticancer therapy or on the first day of the treatment cycle. SARS-CoV-2 antibody levels against S1, RBD (to evaluate vaccine response) and N proteins (to evaluate previous infection) were measured in plasma before the first dose and 30 days after the second one. From January to June 2021, 195 consecutive cancer patients and 20 healthy controls were enrolled. Thirty-one cancer patients had a previous exposure to SARS-CoV-2. Cancer patients previously exposed to the virus had significantly higher median levels of anti-S1 and anti-RBD IgG, compared to healthy controls (P = .0349) and to cancer patients without a previous infection (P < .001). Vaccine type (anti-S1: P < .0001; anti-RBD: P = .0045), comorbidities (anti-S1: P = .0274; anti-RBD: P = .0048) and the use of G-CSF (anti-S1: P = .0151) negatively affected the antibody response. Conversely, previous exposure to SARS-CoV-2 significantly enhanced the response to vaccination (anti-S1: P < .0001; anti-RBD: P = .0026). Vaccine immunogenicity in cancer patients with a previous exposure to SARS-CoV-2 seems comparable to that of healthy subjects. On the other hand, clinical variables of immune frailty negatively affect humoral immune response to vaccination.

Resistance to KRAS G12C Inhibition in Non-small Cell Lung Cancer.

PURPOSE OF REVIEW: Although the recent development of direct KRASG12C inhibitors (G12Ci) has improved outcomes in KRAS mutant cancers, responses occur only in a fraction of patients, and among responders acquired resistance invariably develops over time. Therefore, the characterization of the determinants of acquired resistance is crucial to inform treatment strategies and to identify novel therapeutic vulnerabilities that can be exploited for drug development. RECENT FINDINGS: Mechanisms of acquired resistance to G12Ci are heterogenous including both on-target and off-target resistance. On-target acquired resistance includes secondary codon 12 KRAS mutations, but also acquired codon 13 and codon 61 alterations, and mutations at drug binding sites. Off-target acquired resistance can derive from activating mutations in KRAS downstream pathway (e.g., MEK1), acquired oncogenic fusions (EML4-ALK, CCDC176-RET), gene level copy gain (e.g., MET amplification), or oncogenic alterations in other pro-proliferative and antiapoptotic pathways (e.g., FGFR3, PTEN, NRAS). In a fraction of patients, histologic transformation can also contribute to the development of acquire resistance. We provided a comprehensive overview of the mechanisms that limit the efficacy of this G12i and reviewed potential strategies to overcome and possibly delay the development of resistance in patients receiving KRAS directed targeted therapies.

First-Generation Epidermal Growth Factor Receptor Inhibitors Plus Antiangiogenic Drugs Versus Third-Generation Epidermal Growth Factor Receptor Inhibitors in Advanced Non-Small-Cell Lung Cancer: A Meta-Analysis.

PURPOSE: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) revolutionized the therapeutic landscape of non-small-cell lung cancer (NSCLC). However, despite significant survival improvement, the emergence of resistance mechanisms represents a common event. In this meta-analysis, we compared the efficacy and safety of third-generation EGFR-TKIs, the current standard of care, to first-generation EGFR-TKIs with antiangiogenic drugs for the first-line treatment of NSCLC harboring EGFR mutations. MATERIALS AND METHODS: Randomized controlled clinical trials (RCTs) reporting survival data published before September 1, 2022, were searched through the MEDLINE databases (PubMed), the Cochrane Database of Systematic Reviews, and Central Register of Controlled Trials (Wiley). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and grade 3 or higher treatment-related adverse events (≥3 TRAEs) data were analyzed. RESULTS: Twelve RCTs were included in our meta-analysis, with a total of 3,565 patients. We observed that third-generation EGFR-TKIs and first-generation EGFR-TKIs combined with antiangiogenic drugs provided a similar OS benefit over first-generation EGFR-TKIs in any of the subgroups. However, we indirectly observed a greater PFS benefit of third-generation EGFR-TKIs over first-generation EGFR-TKIs in females, never-smokers, in patients harboring exon 19 deletions, and in those with brain metastasis, as compared with using first-generation EGFR-TKIs plus antiangiogenic drugs. The ORR did not differ between the combination strategy and third-generation EGFR-TKIs. Finally, the risk of developing grade ≥3 TRAEs was higher using the combination of first-generation EGFR-TKIs and antiangiogenic drugs over first-generation EGFR-TKIs than third-generation EGFR-TKIs over first-generation EGFR-TKIs. CONCLUSION: This meta-analysis suggests that the combination strategy may provide an alternative to third-generation EGFR-TKIs, but more data are needed to determine the predictive clinicopathologic characteristics that can influence the treatment choice. Until then, third-generation EGFR-TKIs still represent the first choice in advanced NSCLC harboring EGFR mutations.