Osimertinib versus Standard of Care EGFR TKI as First-Line Treatment in Patients with EGFRm Advanced NSCLC: FLAURA Asian Subset

Introduction

Here we report efficacy and safety data of an Asian subset of the phase III FLAURA trial (NCT02296125), which compares osimertinib with standard of care (SoC) EGFR tyrosine kinase inhibitors (TKIs) in patients with previously untreated advanced NSCLC with tumors harboring exon 19 deletion (Ex19del)/L858R EGFR TKI–sensitizing mutations.

KEYNOTE-033: Randomized phase 3 study of pembrolizumab vs docetaxel in previously treated,PD-L1-positive,advanced NSCLC

KEYNOTE-033 (NCT02864394) was a multicountry, open-label, phase 3 study that compared pembrolizumab vs docetaxel in previously treated, programmed death-ligand 1 (PD-L1)-positive, advanced non-small cell lung cancer (NSCLC), with most patients enrolled in mainland China. Eligible patients were randomized (1:1) to pembrolizumab 2 mg/kg or docetaxel 75 mg/m² every 3 weeks. Primary endpoints were overall survival (OS) and progression-free survival and were evaluated sequentially using stratified log-rank tests, first in patients with PD-L1 tumor proportion score (TPS) ≥50% and then in patients with PD-L1 TPS ≥1% (significance threshold: P < .025, one-sided). A total of 425 patients were randomized to pembrolizumab (N = 213) or docetaxel (N = 212) between 8 September 2016 and 17 October 2018. In patients with a PD-L1 TPS ≥50% (n = 227), median OS was 12.3 months with pembrolizumab and 10.9 months with docetaxel; the hazard ratio (HR) was 0.83 (95% confidence interval [CI]: 0.61-1.14; P = .1276). Because the significance threshold was not met, sequential testing of OS and PFS was ceased. In patients with a PD-L1 TPS ≥1%, the HR for OS for pembrolizumab vs docetaxel was 0.75 (95% CI: 0.60-0.95). In patients from mainland China (n = 311) with a PD-L1 TPS ≥1%, HR for OS was 0.68 (95% CI: 0.51-0.89). Incidence of grade 3 to 5 treatment-related AEs was 11.3% with pembrolizumab vs 47.5% with docetaxel. In summary, pembrolizumab improved OS vs docetaxel in previously treated, PD-L1-positive NSCLC without unexpected safety signals; although the statistical significance threshold was not reached, the numerical improvement is consistent with that previously observed for pembrolizumab in previously treated, advanced NSCLC.     

SHP-1 promoter 2 methylation in cerebrospinal fluid for diagnosis of leptomeningeal epithelial-derived malignancy (carcinomatous meningitis)

Current diagnostic methods for leptomeningeal metastasis (LM) from epithelial-derived malignancy (EDM) have limited sensitivity. Here, we explored SHP-1 promoter 2 methylation (SHP1P2)—an epithelial-specific methylation marker previously proven as risk stratification and potential diagnostic marker in non-small cell lung cancer—for EDM with LM. We prospectively recruited 136 patients who were diagnosed EDM with LM (n?=?25), EDM without LM (n?=?14), non-EDM with LM (n?=?8), and benign meningeal diseases (n?=?89). The primary cancer sites for EDM with LM were lung (n?=?17), breast (n?=?5), and colon (n?=?3). We performed quantitative analyses of cell-free (cfSHP1P2) and whole fraction (wSHP1P2) from cerebrospinal fluid (CSF); results were correlated with the clinicopathological data, including CSF cytology. Median cfSHP1P2 and wSHP1P2 were 3.08 [range: 0–163.5] and 9.35 [0.69–91.63] ng/ml, respectively, in EDM with LM; 0 [0–0.08] and 0.23 [0–7.84] ng/ml in EDM without LM; and were undetectable in most cases of benign meningeal diseases and non-EDM with LM. The cut-off values of 0.22 ng/ml for methylated cfSHP1P2 and 0.59 ng/ml for wSHP1P2 were the best to discriminate EDM with LM from EDM without LM (sensitivity: 79–100?%; specificity: 83–100?%), as well as from other benign conditions (sensitivity: 85–100?% specificity: 78–100?%). CSF cytology yielded 76?% sensitivity for diagnosing EDM with LM. Further validation of CSF SHP1P2 methylation detection as a role of adjunctive tool for LM from EDM should be interested based on our study.     

Promoter hypermethylation of CCNA1, RARRES1, and HRASLS3 in nasopharyngeal carcinoma

In search for putative tumor suppressor genes critical of nasopharyngeal carcinoma (NPC), we analyzed the available information from the expression profiling in conjunction with the comprehensive alleotyping published data relevant to this malignancy. Integration of this information suggested eight potential candidate tumor suppressor genes, CCNA1, HRASLS3, RARRES1, CLMN, EML1, TSC22, LOH11CR2A and MCC. However, to confirm the above observations, we chose to investigate if promoter hypermethylation of these candidate genes would be one of the mechanisms responsible for the de-regulation of gene expression in NPC in addition to the loss of genetic materials. In this study, we detected consistent hypermethylation of the 5' element of CCNA1, RARRES1, and HRASLS in NPC tissues with prevalence of 48%, 51%, and 17%, respectively. Moreover, we found a similar profile of promoter hypermethylation in primary cultured NPC cells but none in normal nasopharyngeal epithelium or leukocytes, which further substantiate our hypothesis. Our data indicate that CCNA1, RARRES1, and HRASLS3 may be the putative tumor suppressor genes in NPC.     

The role of SHP-1 promoter 2 hypermethylation detection of lymph node micrometastasis in resectable stage I non-small cell lung cancer as a prognostic marker of disease recurrence

Background

Despite adequate surgical management of stage I non-small cell lung cancer (NSCLC), many patients still relapse. Nodal micrometastases which cannot be detected by the standard hematoxylin and eosin (H&E) method are the postulated mechanism. We conducted a study of an epithelial-specific methylation marker, SHP-1 promoter 2 (SHP1P2) methylation, as a potential molecular marker to determine its association with a high risk of disease relapse.

Material and method

Lymph nodes from stage II–IIIA NSCLC patients were examined to explore the potential role of SHP1P2 methylation in detecting metastatic carcinoma according to H&E staining. Further study was done in lymph nodes from stage I NSCLC patients who underwent curative resection and follow-up at The King Chulalongkorn Memorial Hospital, Bangkok, Thailand. No adjuvant treatment was given, according to the standard treatment in that stage. Patients who relapsed within 40 months after resection were defined as high risk.

Results

The nodal SHP1P2 methylation level from stage II–IIIA NSCLC patients was significantly higher in the metastasis group, median 674 [0–3536] ng, compared with the no metastasis group, median 230 [0–3832] ng (p = 0.004). One-hundred and ninety-eight lymph nodes from stage I NSCLC patients were analyzed, including hilar and mediastinal nodes. With a median follow-up period of 65 [46–109] months, high SHP1P2 methylation levels of more than 140 ng in hilar lymph nodes were associated with early relapse, with sensitivity and specificity of 85 and 54 %, respectively (hazard ratio 5.3; 95 % confidence interval 5.0–5.6; p < 0.0001).

Conclusion

A high level of SHP1P2 methylation of hilar lymph nodes from stage I NSCLC patients is associated with early relapse of disease.     

Central nervous system lymphoma and Epstein-Barr virus in immunocompetent patients in Thailand

A series of 11 apparently immunocompetent patients with primary non-Hodgkin's lymphoma of the central nervous system (NHL-CNS) together with six patients with systemic lymphoma involving the spinal cord and/or brain were studied for immunophenotyping and the presence of Epstein-Barr virus (EBV). Immunohistochemistry and polymerase chain reaction (PCR) were performed on paraffin-embedded tissues. Nine of 11 primary NHL-CNS and all six secondary CNS lesions were of B cell origin. The EBV sequences were detected in six primary tumors and four systemic lesions by PCR while the immuno-histochemical marker for the EBV-latent membrane protein was positive in five primary lesions and three secondary neoplasms. Our results suggest that the association of EBV and NHL-CNS is not only restricted to patients with immunosuppression but that it includes a broad spectrum of conditions in which this relationship occurs in patients without immunodeficiency. The mortality rate is high particularly in patients with EBV-associated NHL-CNS.