Non-Small Cell Lung Cancer

Results from the LIBRETTO-432 study indicate that adjuvant selpercatinib substantially improves event-free survival in patients with early-stage RET fusion-positive non-small cell lung cancer (NSCLC). This finding establishes selpercatinib as a new standard of care for this rare disease. Nevertheless, challenges persist regarding patient identification and access to RET fusion screening.

Homozygous MTAP loss is frequently observed in oncogene-driven non-small-cell lung cancers (NSCLC), particularly in EGFR, ALK, and RET altered subtypes. While this loss did not significantly impact the response to first-line targeted therapies, it creates a selective vulnerability to PRMT5 inhibitors. Preclinical studies demonstrated that the PRMT5 inhibitor BMS-986504 is active in MTAP-deleted NSCLC models and can enhance the efficacy of existing targeted therapies. These findings suggest a novel combined therapeutic strategy for NSCLC patients with MTAP loss.

The phase II ORCHARD study investigated the efficacy and safety of combining osimertinib with datopotamab deruxtecan (Dato-DXd) in patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC) who had progressed on first-line osimertinib. Two Dato-DXd doses (4 mg/kg and 6 mg/kg) were evaluated. Both cohorts demonstrated clinical benefit, with objective response rates (ORR) of 43% and 36% respectively. Median progression-free survival (PFS) was 9.5 months for the 4 mg/kg dose and 11.7 months for 6 mg/kg, while median overall survival (OS) reached 19.8 months and 26.2 months. Although the 6 mg/kg dose was associated with higher toxicity, it was manageable, and this dose is suggested as the preferred starting dose given the overall benefit-risk profile.

The prospective, multicenter ELIOS study characterized acquired resistance mechanisms to first-line osimertinib in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). By analyzing paired tumor biopsies taken pre-treatment and post-progression, the study identified frequent alterations including MET amplification, CDKN2A/CDKN2B and MTAP deletions, and the EGFR C797S mutation. Proteogenomic analysis also revealed high TROP2 expression, irrespective of genetic alterations. The findings highlight the heterogeneous nature of resistance and the complementary utility of tissue and liquid biopsies for alteration detection. This study emphasizes the need for therapeutic strategies targeting multiple resistance pathways.

This study modeled the cost-effectiveness of various genomic testing strategies for patients with advanced non-small-cell lung cancer (NSCLC) in Australia. It compared combinations of sampling methods (tissue biopsy, liquid biopsy) and molecular tests (single-gene, small, or large panels). Results indicated that large genomic panel strategies, while more expensive, yielded the highest gains in quality-adjusted life years (QALYs). The analysis concluded that these comprehensive genomic testing approaches are potentially cost-effective, despite a notable budget impact on the healthcare system.

This single-center retrospective study assessed the clinical utility of comprehensive genomic profiling (CGP) in 108 patients with advanced or recurrent non-small cell lung cancer (NSCLC) after standard treatments. CGP detected druggable genetic aberrations in 37% of patients, with EGFR mutations being the most common. Resistance mechanisms were identified in nearly half of patients re-biopsied after targeted therapy. Although CGP-guided therapy was recommended for 35.2% of patients, only 16.6% received it, showing a trend towards prolonged overall survival for this subgroup. The study concludes that CGP can identify actionable mutations missed by conventional diagnostics, thus providing additional therapeutic opportunities in NSCLC.

This prospective study evaluated gene expression profiling of seven genes (EGFR, FGFR2, PIK3CA, PTEN, SMAD4, STK11, TP53) in cell-free RNA (cfRNA) from exhaled breath condensate (EBC) in patients with advanced lung adenocarcinoma. Results indicated that PIK3CA showed the best diagnostic performance in distinguishing patients from healthy controls. High expression of FGFR2 and PIK3CA was associated with significantly shorter overall survival, highlighting their prognostic relevance. EGFR expression demonstrated a strong correlation between EBC and plasma, and low EGFR expression was linked to longer survival in patients receiving chemotherapy alone. This non-invasive EBC-based approach offers potential for molecular characterization and patient stratification.

This retrospective observational study, conducted using the Italian ATLAS Registry, evaluated the efficacy and safety of amivantamab in 119 patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations. Most patients had previously received platinum-based chemotherapy, with or without immunotherapy. Amivantamab, administered as a single agent in subsequent lines, demonstrated an objective response rate of 37.5%, a median progression-free survival of 9.6 months, and a median overall survival of 16.9 months. The safety profile was manageable, with grade 3-4 treatment-related adverse events reported in 10.9% of patients, confirming data from the CHRYSALIS trial in a heavily pretreated real-world population.

This study characterized the molecular architecture of the tumor microenvironment (TME) in lung adenocarcinoma (LUAD) with somatic BRCA1/2 mutations, using single-cell sequencing and multi-omics data. BRCA1/2 mutations are linked to increased genomic instability and poor prognosis, yet predict better clinical outcomes with immune checkpoint blockade (ICB) treatment. BRCA1 mutations correlate with an upregulated type I IFN/IFN-γ signature and CD8+ T cell activation, while BRCA2 mutations are associated with inflammatory responses and enhanced MHC-II antigen presentation, influencing CD4+ T cell differentiation. The study also identified tissue-resident memory T cell (Trm) subsets as predictors of ICB response and found that a cancer-promoting program activated by BRCA1 is vulnerable to histone deacetylase inhibitors.