Allelic Context of EGFR C797X-Mutant Lung Cancer Defines Four Subtypes With Heterogeneous Genomic Landscape and Distinct Clinical Outcomes.

INTRODUCTION: EGFR C797X (C797S or C797G) mutation is the most frequent on-target mechanism of resistance to osimertinib. The hypothesis that the allelic context of C797X/T790M has implications for treatment is on the basis of sporadic reports and needs validation with larger cohorts. METHODS: We identified patients with EGFR C797X-mutant NSCLC from nine centers who progressed on osimertinib, all analyzed in a single laboratory through next-generation sequencing. We analyzed genomic profiles and assessed associations between clinical outcomes and C797X status. RESULTS: A total of 365 EGFR C797X-mutant cases were categorized into four subtypes on the basis of allelic context: in cis (75.3%), in trans (6.4%), cis&trans (10.4%), and C797X-only (7.9%). Genomically, the cis&trans subtype displayed the highest frequency of concurrent alterations at osimertinib resistance sites (21.1%), while the in cis subtype had the lowest (8.4%). Clinically, cis&trans patients exhibited the worst progression-free survival (PFS) on both previous (median 7.7 mo) and subsequent treatment (median 1.0 mo) and overall survival (median 3.9 mo). In subsequent treatments, in cis patients exhibited superior PFS with combined brigatinib and cetuximab (median 11.0 mo) compared with other regimens (p = 0.005), while in trans patients exhibited variable outcomes with combined first or second- and third-generation EGFR inhibitor (PFS range: 0.7-8.1 mo, median 2.6 mo). Notably, subtype switching was observed after subsequent treatments, predominantly toward the in cis subtype. CONCLUSIONS: Allelic context could define four EGFR C797X-mutant NSCLC subtypes with heterogeneous genetic landscapes and distinct clinical outcomes. Subsequent treatments further complicate the scenario through subtype switching.

The predictive value of YAP-1 and POU2F3 for the efficacy of immuno-chemotherapy in extensive-stage SCLC patients.

INTRODUCTION: Recently, several clinical trials of immunotherapy for extensive-stage small-cell lung cancer (ES-SCLC) have shown limited benefits because of unselected patients. Thus, we aimed to explore whether YES-associated protein 1 (YAP-1) and POU domain class 2 transcription factor 3 (POU2F3) could identify SCLC patients with durable benefits from immunotherapy as potential biomarkers. METHODS: We performed IHC of YAP-1 and POU2F3, and RNA-seq on tissues of ES- SCLC patients. An open-source plugin based on IHC-profiler was conducted to calculate the expression levels of YAP-1 and POU2F3. RESULTS: Patients with ES-SCLC were retrospectively investigated in the Guangdong Provincial People's Hospital from January 2018 to July 2021, and 21 patients whoever received atezolizumab plus etoposide/carboplatin (ECT) regimen also had tissue samples reachable. The median IHC-score of YAP-1 in responders (CR/PR patients) was significantly lower than in nonresponders (SD/PD patients) at 13.97 (95% CI: 8.97-16.30) versus 23.72 (95% CI: 8.13-75.40). The IHC-score of YAP-1 and PFS showed a negative correlation by Spearman (r=-0.496). However, POU2F3 did not show a correlation with efficacy. Besides, patients with YAP-1 high expression had IL6, MYCN, and MYCT1 upregulated, while analysis of immune cell infiltration only showed that M0 macrophages were significantly higher. CONCLUSIONS: The expression of YAP-1 negatively correlated with the efficacy of ECT in ES-SCLC patients while POU2F3 did not reveal the predictive value. However, prospective investigations with a large sample size are needed.

Clinical outcomes of EGFR+/METamp+ vs. EGFR+/METamp- untreated patients with advanced non-small cell lung cancer.

BACKGROUND: MET dysregulation has been implicated in the development of primary and secondary resistance to EGFR tyrosine kinase inhibitor (TKI) therapy. However, the clinicopathological characteristics and outcomes of patients harboring EGFR-sensitive mutations and de novo MET amplifications still need to be explored. METHODS: A total of 54 patients from our hospital with non-small cell lung cancer harboring EGFR-sensitive mutations and/or de novo MET amplifications were included in this study. Survival rates were estimated by the Kaplan-Meier method with log-rank statistics. Lung cancer organoids (LCOs) were generated from patient-derived malignant pleural effusion to perform drug sensitivity assays. RESULTS: Fifty-four patients with the appropriate clinicopathological characteristics were enrolled. MET FISH was performed in 40 patients who were stratified accordingly into two groups: EGFR+/METamp- (n = 22) and EGFR+/METamp + (n = 18). Survival rates for EGFR+/METamp- and EGFR+/METamp + patients respectively, were as follows: the median progression-free survival (PFS) was 12.1 and 1.9 months (p<0.001); the median post-progression overall survival (pOS) was 25.6 and 11.6 months (p = 0.023); the median overall survival (OS) was 33.2 and 12.7 months (p = 0.013). Drug testing conducted in LCOs derived from malignant pleural effusion from EGFR+/METamp + patients showed that dual targeted therapy was more effective than TKI monotherapy. CONCLUSION: EGFR+/METamp + patients treated with first-line TKI monotherapy had poor clinical outcomes. Dual targeted therapy showed potent anticancer activity in the LCO drug testing assay, suggesting that it is a promising first-line treatment for EGFR+/METamp + patients. Randomized controlled trials are needed to further validate these results.