MATERIALS AND METHODS: Two EGFR mutation tests, a tissue-based assay (cobas® v1) and a tissue- and blood-based assay (cobas® v2) were used to analyze matched biopsy and blood samples (897 paired samples) from three Asian studies of first-line erlotinib with similar intent-to-treat populations. ENSURE was a phase III comparison of erlotinib and gemcitabine/platinum, FASTACT-2 was a phase III study of gemcitabine/platinum plus erlotinib or placebo, and ASPIRATION was a single-arm phase II study of erlotinib. Agreement statistics were evaluated, based on sensitivity and specificity between the two assays in subgroups of patients with increasing tumor burden.
RESULTS: Patients with discordant EGFR (tissue+/plasma-) mutation status achieved longer progression-free and overall survival than those with concordant (tissue+/plasma+) mutation status. Tumor burden was significantly greater in patients with concordant versus discordant mutations. Pooled analyses of data from the three studies showed a sensitivity of 72.1% (95% confidence interval [CI] 67.8-76.1) and a specificity of 97.9% (95% CI 96.0-99.0) for blood-based testing; sensitivity was greatest in patients with larger baseline tumors.
CONCLUSIONS: Blood-based EGFR mutation testing demonstrated high specificity and good sensitivity, and offers a convenient and easily accessible diagnostic method to complement tissue-based tests. Patients with a discordant mutation status in plasma and tissue, had improved survival outcomes compared with those with a concordant mutation status, which may be due to their lower tumor burden. These data help to inform the clinical utility of this blood-based assay for the detection of EGFR mutations.
MATERIALS AND METHODS: GLC-14, GLC-16 and GLC-19 SCLC cell lines derived from one patient, representing increasing progressive stages of disease were used. CSC marker expressions was determined by RT-qPCR and western blotting analyses, and heterogeneity was studied by CSC marker expression by immunofluorescence microscopy and flow cytometry. Colony formation assays were used to assess stem cell properties and therapy sensitivity.
RESULTS: Increasing expression of stem cell markers MYC, SOX2 and particularly CD44 were found in association with advancing disease. Single and overlapping expression of these markers indicated the presence of different CSC populations. The accumulation of more homogeneous double- and triple-positive CSC populations evolved with disease progression. Functional characterization of CSC properties affirmed higher proficiency of colony forming ability and increased resistance to γ-irradiation in GLC-16 and GLC-19 compared to GLC-14. GLC-19 colony formation was significantly inhibited by a human anti-CD44 antibody.
CONCLUSION: The progressive increase of MYC, SOX2 and particularly CD44 expression that was accompanied with enhanced colony forming capacity and resistance in the in vitro GLC disease progression model, supports the potential clinical relevance of CSC populations in malignancy and disease relapse of SCLC.
METHODS: Patients from FLAURA who received first-line osimertinib and from the AURA program (AURA, AURA2, AURA3) who received ≥ second-line osimertinib were included. Patients received osimertinib 80 mg once daily. Safety data were analyzed in patients who remained on treatment for ≥ 36 months. The post-study global safety database captured investigator-reported serious adverse events (SAEs) in patients who continued osimertinib beyond final data cut-off (DCO) of the studies. Best response data were analyzed in patients on treatment for ≥ 54 months (FLAURA) or ≥ 36 months (AURA program).
RESULTS: In FLAURA, 76 (28 %) and 36 (13 %) of 267 patients received first-line osimertinib for ≥ 36 and ≥ 54 months, respectively; median exposure: 52.5 and 64.5 months, respectively. Across the AURA program,124 (16 %) of 799 patients received ≥ second-line osimertinib for ≥ 36 months; median exposure: 44.7 months. Investigators reported on-study SAEs in 17 % (FLAURA) and 35 % (AURA program) of patients who continued treatment for ≥ 36 months. Post-study incidences of SAEs were 11 % (FLAURA) and 21 % (AURA program). On-study, adverse events (AEs) of cardiac effects (indicative of cardiac failure; grouped term) occurred in 7 % (FLAURA) and 5 % (AURA program) of patients; AEs of interstitial lung disease (ILD; grouped term) occurred in 0 (FLAURA) and 1 (AURA program) patient. No post-study SAEs were reported for the grouped terms cardiac effects and ILD. Most patients treated for ≥ 54 months (FLAURA) and ≥ 36 months (AURA program) had a best on-study response of partial response.
CONCLUSION: This analysis demonstrated that long-term treatment with osimertinib of ≥ 36 months was well tolerated in patients with EGFRm advanced NSCLC.