Impact of apatinib in combination with osimertinib on EGFR T790M-positive lung adenocarcinoma.

BACKGROUND: The purpose of this study was to investigate the anti-tumor activities and the mechanisms of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib, combined with the anti-angiogenic target drug apatinib, in the treatment of lung adenocarcinoma. We investigated the effects of these drugs in vitro in PC9 (E19 del) and H1975 (E21 L858R/E20 T790M) cell lines, as well as in vivo in both mouse and human experiments. METHODS: PC9 and H1975 cells were cultured in 96-well plates and incubated with osimertinib (1-100 nmol/L), or apatinib (100-1,000 nmol/L), or a combination of the two agents, for 48 h. Cell viability was determined using a Cell Counting Kit-8. The protein expression of EGFR and its downstream signaling pathway members (AKT and ERK) was detected by western blot. For in vivo experiments, BALB/c nude mice were subcutaneously inoculated with H1975 cells in a xenograft model of adenocarcinoma. Mice bearing tumors were treated with osimertinib alone or in combination with apatinib, and tumor growth curves were obtained. Furthermore, we evaluated the efficacy and safety of combined osimertinib and apatinib therapy in three patients with EGFR T790M positive lung adenocarcinoma, who had been previously sensitized to osimertinib but developed an acquired resistance. RESULTS: In vitro experiments revealed that osimertinib combined with apatinib increased the growth inhibition of PC9 and H1975 cells, simultaneously reducing the protein expression of phosphorylated EGFR and its downstream signaling pathway members in H1975 cells, compared to osimertinib treatment alone. In vivo experiments revealed that the combination of osimertinib and apatinib decreased tumor volume in an H1975 cell xenograft model, compared to osimertinib monotherapy at different dosages. All three patients with T790M positive lung adenocarcinoma that progressed following osimertinib treatment responded to continuous osimertinib in combination with apatinib, with a progression-free survival (PFS) range of 5-7 months. CONCLUSIONS: Apatinib can enhance the anti-tumor activity of osimertinib in the treatment of T790M positive lung adenocarcinoma. Further clinical studies are needed to confirm these results.

Meta-analysis of the impact of de novo and acquired EGFR T790M mutations on the prognosis of patients with non-small cell lung cancer receiving EGFR-TKIs.

PURPOSE: The purpose of this meta-analysis was to explore the influences of pretreatment de novo and posttreatment-acquired epidermal growth factor receptor (EGFR) T790M mutations in patients with advanced non-small cell lung cancer (NSCLC) who had received tyrosine kinase inhibitors (TKIs). METHODS: We searched PubMed, Embase, and the China National Knowledge Infrastructure database for eligible literature. Data were extracted to assess the hazard ratios (HRs) for progression-free survival (PFS), overall survival (OS), and post-progression survival (PPS) and the relative ratios (RRs) for objective response rate (ORR). RESULTS: This meta-analysis included 22 studies comprising 1,462 patients with NSCLC who harbored activating EGFR mutations and were treated with EGFR-TKIs. Compared to pretreatment T790M mutation-negative NSCLC, pretreatment T790M mutation-positive NSCLC was associated with decreased PFS (HR 2.23, P<0.001) and OS (HR 1.55, P=0.003). A trend toward significance of worsening ORR (RR 0.86, P=0.051) was evident. The acquired T790M mutation was correlated with improved PFS (HR 0.75, P=0.006) and PPS (HR 0.57, P<0.001), compared to patients without the T790M mutation who progressed after EGFR-TKI treatment. There were no significant differences in OS or ORR between patients with acquired T790M mutation-positive and T790M mutation-negative NSCLC. However, in the tumor tissue rebiopsy subgroup, patients with acquired T790M mutation had improved OS (HR 0.60, P<0.001) compared to T790M mutation-negative patients. In the plasma ctDNA subgroup, acquired T790M mutation decreased the OS (HR 1.87, P<0.001). CONCLUSION: Pretreatment T790M mutation was associated with worse PFS and OS in patients with advanced NSCLC treated with EGFR-TKIs, while acquired T790M mutation was associated with longer PFS and PPS than T790M mutation-negative NSCLC. The effects on OS were different between acquired T790M mutation detected from rebiopsy of tumor tissue and that detected from plasma ctDNA.

Is pulmonary artery a dose-limiting organ at risk in non-small cell lung cancer patients treated with definitive radiotherapy?

PURPOSE: Our previous study suggested that some pulmonary artery (PA) dosimetric parameters were associated with mortality in unresectable non-small cell lung cancer (NSCLC) treated with definitive radiotherapy. The present study aims to analyze the impact of both PA and heart dosimetric parameters on survival of patients with NSCLC treated with definitive conventional fractionated radiotherapy (CFRT) in another independent research center and further determine whether the PA should be considered a dose-limiting organ at risk (OAR) for patients receiving thoracic CFRT. METHODS: We performed a retrospective analysis of successive patients with medically inoperable or unresectable NSCLC treated with definitive radiotherapy or chemoradiotherapy from August 2010 to September 2014. Clinical and pathological information, PA and heart dosimetric factors, and follow-up data were collected from each patient's records and evaluated as potential prognostic factors for survival. Survival probabilities were estimated by the Kaplan-Meier method and compared by the log rank test. Cox proportional hazards regression models were performed to determine the independent predicators of survival. The optimal cutoff points of continuous dosimetric variables were determined by Youden index in receiver operating characteristic (ROC) analysis. RESULTS: This study analyzed the records of 141 patients, 50.4% had adenocarcinoma, 71.6% had stage III disease, and 55% patients received concurrent chemoradiotherapy. Radiation dose ranged from 60 to 76 Gy in 30-38 fractions. Median follow up was 16.9 months. Median overall survival (OS) was 20.5 months (95% confidence interval [CI] 10.3-30.7 months), and 1-, 2-, 3-year OS rates were 75.2%, 58.2% and 56%, respectively. Univariate and multivariate analysis showed that Karnofsky Performance Status (KPS) score, Charlson's Comorbidity Index (CCI), T and N stage, PA invasion grade and the percentage of PA volume that received 40 to 55 Gy (PA V40-55) were significantly associated with OS. No significant associations were found between heart dosimetric factors and OS. Median OS of patients with PA invasion grade 0, 1, 2, and 3 were 41.8, 27.8, 12.7 and 7.5 months, respectively (P < 0.001). PA V40, V45, V50 and V55, using thresholds of 80%, 68%, 45%, and 32%, respectively, were independent predictors for OS. CONCLUSIONS: PA invasion grade and PA V40-55 appear associated with OS in patients with NSCLC treated with definitive CFRT. We propose that PA be considered as a dose-limiting OAR for such patients.

Meta-analysis Exploring the Effectiveness of S-1-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer.

S-1 is a new oral fluoropyrimidine formulation that comprises tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. S-1 is designed to enhance antitumor activity and to reduce gastrointestinal toxicity. Several studies have demonstrated that both S-1 monotherapy and S-1 combination regimens showed encouraging efficacies and mild toxicities in the treatment of lung squamous cell carcinoma and adenocarcinoma. However, it is unclear whether S-1 can be used as standard care in advanced non-small cell lung cancer (NSCLC). The purpose of this meta-analysis was to assess the efficacy and safety of S-1-based chemotherapy, compared with standard chemotherapy, in patients with locally advanced or metastatic NSCLC. Thirteen randomized controlled trials (RCTs) involving 2,134 patients with a similar ratio of different pathological types were included. In first-line or second-line chemotherapy, compared with standard chemotherapy, S-1-based chemotherapy showed similar efficacy in terms of median overall survival (mOS), median progression free survival (mPFS), and objective response rate (ORR) (all P > 0.1), and significantly reduced the incidence of grade ≥ 3 hematological toxicities. In patients with locally advanced NSCLC receiving concurrent chemoradiotherapy, compared with standard chemoradiotherapy, significantly improved survival in the S-1-based chemotherapy was noted in terms of mOS and mPFS (risk radio [RR] = 1.289, P = 0.009; RR = 1.289, P = 0.000, respectively) with lower incidence of grade ≥ 3 neutropenia (RR = 0.453, P = 0.000). The present meta-analysis demonstrates that S-1-based chemotherapy shows similar benefits in advanced NSCLC and improves survival in locally advanced NSCLC, compared with standard treatment.