Activity of EGFR TKIs in Caucasian Patients With NSCLC Harboring Potentially Sensitive Uncommon EGFR Mutations

BackgroundMolecular characterization of non–small-cell lung cancer (NSCLC), defined predictive and druggable mutations that greatly modified patient prognoses. The most frequent driver mutations detected in NSCLC are epidermal growth factor receptor (EGFR) mutations, accounting for approximately 90% of exon 19 deletions and exon 21 point mutations. The other EGFR mutations are classified as uncommon or nonclassical and include exon 18 point mutations, exon 20 insertions, and combined mutations, which present different sensitivity to tyrosine kinase inhibitor (TKI) targeting.Patients and MethodsWe collected data from EGFR TKI-naive patients with metastatic NSCLC, harboring EGFR exon 18 mutations and EGFR combined mutations treated with first- or second-generation EGFR TKIs. Efficacy end points were evaluated considering the activity of EGFR TKIs in exon 18 versus double-mutation EGFR groups.ResultsEighty-eight patients harboring uncommon EGFR mutations were evaluated in our analysis, and subdivided into 2 group: complex mutations (cohort A = 46 patients) and double mutations in exon 18 (cohort B = 42 patients). The results showed a median progression-free survival of 8.3 versus 12.3 months (hazard ratio [HR], 0.65; P = .06) and a median overall survival of 17.0 versus 31.0 months (HR, 0.62, P = .04) favoring the EGFR combination group. Within the combination group, no detrimental effect was associated with exon 20 mutations.ConclusionOur study confirmed that EGFR exon 18 and combination mutations might be considered potentially sensitive uncommon mutations, with a similar survival compared with the well known common EGFR mutations. Comparative analysis showed that patients with complex mutations achieved longer survival compared with the exon 18 group, without correlation with the presence of exon 20 mutations.     

Contemporary Assessment of Long-Term Survival Rates in Patients With Stage I Nonseminoma Germ-Cell Tumor of the Testis: Population-Based Comparison Between Surveillance and Active Treatment After Initial Orchiectomy

BackgroundHistorical data demonstrated similar survival outcomes in patients with stage I nonseminoma germ-cell tumor of the testis (NSGCTT) subjected to either surveillance or active treatment (AT) after orchiectomy. However, data with long-term follow-up are unavailable. We tested contemporary treatment rates and their effect on cancer-specific mortality (CSM) and other-cause mortality (OCM) relative to surveillance, as well as after stratification between chemotherapy (CHT) versus retroperitoneal lymph node dissection (RPLND).Patients and MethodsWe identified patients with stage I NSGCTT with initial orchiectomy within the Surveillance, Epidemiology, and End Results (SEER) database (1988-2015). Subsequent surveillance versus CHT versus RPLND use rates were reported. Cumulative incidence plots and multivariable competing-risks regression (CRR) models were used after propensity score (PS) matching. These tests first compared surveillance versus AT (CHT vs. RPLND) and subsequently CHT versus RPLND.ResultsOf 5034 patients with stage I NSGCTT, 61.2%, 24.9%, and 13.9%, respectively, underwent surveillance, CHT, and RPLND. Between 1988 and 2015, surveillance (estimated annual percentage change [EAPC]: +1.1%, P < .001) and CHT (EAPC: +2.3%, P < .001) rates increased. RPLND rates decreased (EAPC: ?5.7%; P < .001). After PS matching, CRR models failed to identify AT as an independent predictor of lower mortality relative to surveillance. However, after PS matching, CRR models identified RPLND as an independent predictor of lower CSM (hazard ratio, 0.26; P = .002) relative to CHT. No difference in OCM rates was recorded (hazard ratio, 1.25; P = .2).ConclusionSurveillance and CHT use rates increased while RPLND decreased in the last two decades. Virtually the same outcomes were recorded between surveillance and AT. However, within AT, RPLND was associated with lower CSM than CHT.     

Mutations in the KEAP1-NFE2L2 Pathway Define a Molecular Subset of Rapidly Progressing Lung Adenocarcinoma

IntroductionMolecular characterization studies revealed recurrent kelch like ECH associated protein 1 gene (KEAP1)/nuclear factor, erythroid 2 like 2 gene (NFE2L2) alterations in NSCLC. These genes encode two interacting proteins (a stress response pathway [SRP]) that mediate a cytoprotective response to oxidative stress and xenobiotics. Nevertheless, whether KEAP1/NFE2L2 mutations have an impact on clinical outcomes is unclear.MethodsWe performed amplicon-based next-generation sequencing to characterize the SRP in patients with metastatic NSCLC (Regina Elena National Cancer Institute cohort [n = 88]) treated with first-line chemotherapy. Mutations in the DNA damage response (tumor protein p53 gene [TP53], ATM serine/threonine kinase gene [ATM], and ATR serine/threonine kinase gene [ATR]) were concomitantly analyzed. In lung adenocarcinoma (LAC), we also determined the expression of phosphorylated ataxia telangiectasia mutated kinase and ataxia telangiectasia and Rad3-related protein. Two independent cohorts (the Memorial Sloan Kettering Cancer Center cohort and The Cancer Genome Atlas cohort) with data from approximately 1400 patients with advanced LAC were used to assess the reproducibility of the results.ResultsIn the Regina Elena National Cancer Institute cohort, patients whose tumors carried mutations in the KEAP1/NFE2L2 pathway had significantly shorter progression-free survival and overall survival than their wild-type counterparts did (log-rank p = 0.006 and p = 0.018, respectively). This association was driven by LAC in which KEAP1/NFE2L2 mutations were overrepresented in fast progressors and associated with an increased risk of disease progression and death. LACs carrying KEAP1/NFE2L2 mutations were characterized by elevated expression of phosphorylated ataxia telangiectasia mutated (pATM) kinase and ataxia telangiectasia and Rad3-related (pATR) protein in association with a pattern of mutual exclusivity with TP53 alterations. The relationship between KEAP1/NFE2L2 mutations and shorter survival was validated in the Memorial Sloan Kettering Cancer Center cohort (n = 1256) (log-rank p < 0.001) and in The Cancer Genome Atlas cohort (n = 162) (log-rank p = 0.039).ConclusionThese findings suggest that a mutant SRP represents a negative prognostic/predictive factor in metastatic LAC and that KEAP1/NFE2L2 mutations may define a molecular subtype of chemotherapy-resistant and rapidly progressing LAC.     

Correlations Between the Immune-related Adverse Events Spectrum and Efficacy of Anti-PD1 Immunotherapy in NSCLC Patients

BackgroundImmune-related adverse events (irAEs) developed during immunotherapy with anti-PD-1 agents, could be a predictive surrogate marker of clinical benefit in patients with advanced non–small-cell lung cancer (NSCLC).MethodsPatients with NSCLC, treated with anti-PD-1 agents, were retrospectively evaluated. Univariate and multivariate analyses were performed to evaluate the relationships between types of irAEs (differentiated according to system/organ involved and to single-site/multiple-site), overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). We further performed a 6-week landmark analysis.ResultsA total of 559 patients were enrolled; 231 patients (41.3%) developed irAEs of any grade and 50 patients (8.9%) G3/G4 events; 191 of them (82.6%) developed “single-site” irAEs and 40 (17.4%) “multiple-site” irAEs. At multivariate analysis, higher ORR was related to irAEs of any grade (P < .0001), “single-site” irAEs (P < .0001), endocrine (P = .0043) and skin irAEs (P = .0005). Longer PFS was related to irAEs of any grade (P < .0001), “single-site” irAEs (P < .0001), “multiple-site” irAEs (P = .0374), endocrine irAEs (P = .0084) and skin irAEs (P = .0001). Longer OS was related to irAEs of any grade (P < .0001), “single-site” irAEs (P < .0001), endocrine irAEs (P = .0044), gastrointestinal irAEs (P = .0437), skin irAEs (P = .0006), and others irAEs (P = .0378). At the 6-week landmark analysis, irAEs of any grade was confirmed an independent predictor of higher ORR, longer PFS, and longer OS.ConclusionOur study confirmed that irAEs are concordantly related to higher ORR, longer PFS, and longer OS with anti-PD-1 immunotherapy in patients with NSCLC.     

Contemporary Assessment of Survival Rates in Stage I Testicular Seminoma: A Population-Based Comparison Between Surveillance and Active Treatment After Orchiectomy

BackgroundWe tested contemporary surveillance and active treatment (AT) that included chemotherapy (CHT) and radiotherapy (RT) rates for stage I testicular seminoma patients, as well as cancer-specific mortality (CSM) and other-cause mortality (OCM) rates.Patients and MethodsWithin the Surveillance, Epidemiology, and End Results database (1988-2015) we identified 11,206 stage I testicular seminoma patients. Surveillance versus CHT versus RT use rates were investigated using estimated annual percentage change (EAPC) analyses. After propensity score (PS) matching, cumulative incidence plots and multivariable competing risks regression models (MCRRMs) tested for CSM and OCM.ResultsOf all 11,206 patients, 4434 (40%), 918 (8%), and 5854 (52%), respectively, underwent surveillance, CHT, or RT after initial orchiectomy. Surveillance (EAPC: 7.5%; P < .001) and CHT (EAPC: 13.5%; P < .001) rates increased over time, whereas RT rates decreased (EAPC: ?3.8%; P < .001). After PS matching, in MCRRMs surveillance was an independent predictor of CSM, relative to AT (hazard ratio [HR], 2.59; P = .04). Conversely, surveillance versus AT did not affect OCM (HR, 1.52; P = .051). All other analyses that focused on CSM and OCM, namely surveillance versus RT, surveillance versus CHT, and RT versus CHT resulted in nonsignificant differences (all P > .5).ConclusionSurveillance and CHT use in stage I testicular seminoma rates increased, whereas RT rate decreased over time. A protective effect of AT defined as either RT or CHT was identified on CSM, relative to surveillance. This protective effect was not described for OCM. No differences in survival were recorded, when individual management strategies (surveillance vs. RT vs. CHT) were compared with each other.