EXPERIMENTAL DESIGN: Tumor tissue EGFRm status was determined at screening using the central cobas tissue test or a local tissue test. Baseline circulating tumor (ct)DNA EGFRm status was retrospectively determined with the central cobas plasma test.
RESULTS: Of 994 patients screened, 556 were randomized (289 and 267 with central and local EGFR test results, respectively) and 438 failed screening. Of those randomized from local EGFR test results, 217 patients had available central test results; 211/217 (97%) were retrospectively confirmed EGFRm positive by central cobas tissue test. Using reference central cobas tissue test results, positive percent agreements with cobas plasma test results for Ex19del and L858R detection were 79% [95% confidence interval (CI), 74-84] and 68% (95% CI, 61-75), respectively. Progression-free survival (PFS) superiority with osimertinib over comparator EGFR-TKI remained consistent irrespective of randomization route (central/local EGFRm-positive tissue test). In both treatment arms, PFS was prolonged in plasma ctDNA EGFRm-negative (23.5 and 15.0 months) versus -positive patients (15.2 and 9.7 months).
CONCLUSIONS: Our results support utility of cobas tissue and plasma testing to aid selection of patients with EGFRm advanced NSCLC for first-line osimertinib treatment. Lack of EGFRm detection in plasma was associated with prolonged PFS versus patients plasma EGFRm positive, potentially due to patients having lower tumor burden.
METHODS: This is a multicenter observational study of first-line afatinib in Malaysian patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small cell lung cancer (NSCLC). Patients' demographic, clinical and treatment data, as well as resistance mechanisms to afatinib were retrospectively captured. The statistical methods included Chi-squared test and independent t-test for variables, Kaplan-Meier curve and log-rank test for survival, and Cox regression model for multivariate analysis.
RESULTS: Eighty-five patients on first-line afatinib from 1st October 2014 to 30th April 2018 were eligible for the study. EGFR mutations detected in tumors included exon 19 deletion in 80.0%, exon 21 L858R point mutation in 12.9%, and rare or complex EGFR mutations in 7.1% of patients. Among these patients, 18.8% had Eastern Cooperative Oncology Group performance status of 2-4, 29.4% had symptomatic brain metastases and 17.6% had abnormal organ function. Afatinib 40 mg or 30 mg once daily were the most common starting and maintenance doses. Only one-tenth of patients experienced severe side-effects with none having grade 4 toxicities. The objective response rate was 76.5% while the disease control rate was 95.3%. At the time of analysis, 56 (65.9%) patients had progression of disease (PD) with a median progression-free survival (mPFS) of 14.2 months (95% CI, 11.85-16.55 months). Only 12.5% of the progressed patients developed new symptomatic brain metastases. The overall survival (OS) data was not mature. Thirty-three (38.8%) patients had died with a median OS of 28.9 months (95% CI, 19.82-37.99 months). The median follow-up period for the survivors was 20.0 months (95% CI, 17.49-22.51 months). Of patients with PD while on afatinib, 55.3% were investigated for resistance mechanisms with exon 20 T790 M mutation detected in 42.0% of them.
CONCLUSIONS: Afatinib is an effective first-line treatment for patients with EGFR-mutant advanced NSCLC with a good response rate and long survival, even in patients with unfavorable clinical characteristics. The side-effects of afatinib were manageable and T790 M mutation was the most common resistance mechanism causing treatment failure.
METHODS: Eligible Asian patients (enrolled at Asian sites) who were at least 18 years of age (≥20 years in Japan) and had untreated EGFR-mutated advanced NSCLC were randomized 1:1 to receive osimertinib (80 mg, orally once daily) or an SoC EGFR TKI (gefitinib, 250 mg, or erlotinib, 150 mg, orally once daily). The primary end point was investigator-assessed progression-free survival (PFS). The key secondary end points were overall survival, objective response rate, central nervous system efficacy, and safety.
RESULTS: The median PFS was 16.5 versus 11.0 months for the osimertinib and SoC EGFR TKI groups, respectively (hazard ratio = 0.54, 95% confidence interval: 0.41-0.72, p < 0.0001). The overall survival data were immature (24% maturity). The objective response rates were 80% for osimertinib and 75% for an SoC EGFR TKI. The median central nervous system PFS was not calculable for the osimertinib group and was 13.8 months for the SoC EGFR TKI group (hazard ratio = 0.55, 95% confidence interval: 0.25-1.17, p = 0.118). Fewer adverse events of grade 3 or higher (40% versus 48%) and fewer adverse events leading to treatment discontinuation (15% versus 21%) were reported with osimertinib versus with an SoC EGFR TKI, respectively.
CONCLUSION: In this Asian population, first-line osimertinib demonstrated a clinically meaningful improvement in PFS over an SoC EGFR TKI, with a safety profile consistent with that for the overall FLAURA study population.
METHODS: In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival.
RESULTS: The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%).
CONCLUSIONS: Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation-positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125 .).
RESULTS: In total, 12 different BCR::ABL1 KD mutations were identified by SS in 22.6% (19/84) of patients who were resistant to TKI treatment. Interestingly, NGS analysis of the same patient group revealed an additional four different BCR::ABL1 KD mutations in 27.4% (23/84) of patients. These mutations are M244V, A344V, E355A, and E459K with variant read frequency below 15%. No mutation was detected in 18 patients with optimal response to TKI therapy. Resistance to TKIs is associated with the acquisition of additional mutations in BCR::ABL1 KD after treatment with TKIs. Additionally, the use of NGS is advised for accurately determining the mutation status of BCR::ABL1 KD, particularly in cases where the allele frequency is low, and for identifying mutations across multiple exons simultaneously. Therefore, the utilization of NGS as a diagnostic platform for this test is very promising to guide therapeutic decision-making.
METHODS: The details of patients diagnosed with unresectable NSCLC treated with TKI followed by lung resection from 2010 to 2020 were retrieved from our database. The primary endpoint was 3-year overall survival (OS), whereas the secondary endpoints were a 2-year progression-free survival (PFS), feasibility, and the safety of pulmonary resection. The statistical tests used were Fisher's exact test, Kruskal Wallis test, Kaplan-Meier method, Cox proportional hazards model, and Firth correction.
RESULTS: Nineteen out of thirty-two patients were selected for the study. The patients underwent lung surgery after confirmed tumor regression (17 [89.5%]) and regrowth (two [10.5%]). All surgeries were performed via video-assisted thoracoscopic surgery: 14 (73.7%) lobectomies and five (26.3%) sublobar resections after a median duration of 5 months of TKI. Two (10.5%) postoperative complications and no 30-day postoperative mortality were observed. The median postoperative follow-up was 22 months. The 2-year PFS and 3-year OS rates were 43.9% and 61.5%, respectively. Patients who underwent surgery for regressed disease showed a significantly better OS than for regrowth disease (HR=0.086, 95% CI 0.008-0.957, p=0.046). TKI-adjuvant demonstrated a better PFS than non-TKI adjuvant (HR=0.146, 95% CI 0.027-0.782, p=0.025).
CONCLUSION: Lung surgery after TKI treatment is feasible and safe and prolongs survival via local control and directed consequential therapy. Lung surgery should be adopted in multimodality therapy for initially unresectable NSCLC.