PURPOSE: We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor ( EGFR)–mutated advanced non–small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status. METHODS: Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR). RESULTS: On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR. CONCLUSION: Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with EGFR-mutated advanced NSCLC, including those with CNS metastases.

The phase III IUNO trial assessed the benefit of maintenance erlotinib versus erlotinib at progression in advanced/metastatic non-small-cell lung cancer (NSCLC) that had not progressed following four cycles of platinum-based chemotherapy. Patients had stage IIIB/IV NSCLC, no known epidermal growth factor receptor (EGFR)-activating mutation, and objective response or disease stabilization after platinum-based induction chemotherapy. Central EGFR-mutation testing was undertaken on tumors from patients with unknown or wild-type EGFR status following local testing. Patients were randomized to receive blinded maintenance erlotinib 150mg/day ('early erlotinib') or placebo. Those who progressed on placebo received open-label erlotinib ('late erlotinib'); patients who progressed on erlotinib received approved second-line chemotherapy or best supportive care. Primary endpoint: overall survival (OS). 643 patients were randomized to receive maintenance erlotinib (n=322) or placebo (n=321). As of March 23, 2015, 242 (75.2%) OS events had occurred with 'early erlotinib' versus 235 (73.2%) with 'late erlotinib'. Median OS was 9.7 and 9.5 months with 'early erlotinib' and 'late erlotinib', respectively (HR, 1.02, 95% CI: 0.85-1.22; log-rank p=0.82). No progression-free survival, objective response rate, or disease control rate benefit was observed with maintenance erlotinib. 410 patients entered the second-line phase of the study: 160 patients (50%) from the maintenance erlotinib arm and 250 patients (78%) from the maintenance placebo arm. The pattern of adverse events (AEs) was consistent with previous trials; 11 patients who received blinded erlotinib and 3 who received placebo died during the blinded maintenance phase due to nontreatment-related AEs. OS with maintenance erlotinib was not superior to second-line treatment in patients whose tumor did not harbor an EGFR-activating mutation. Safety results were consistent with the established safety profile of erlotinib. Thus, maintenance treatment with erlotinib in patients with advanced/metastatic NSCLC without EGFR-activating mutations is considered unfavorable.

Prognostic Significance of 14-3-3γ Overexpression in Advanced Non-Small Cell Lung Cancer 14-3-$3{\gamma}$;immunohistochemistry;non-small cell lung cancer;invasion;metastasis; The 14-3-3 protein has been shown to be involved in the cancer process. However, there is no understanding of the relationship between 14-3-$3{\gamma}$ (14-3-3 gamma) expression and prognosis in advanced non-small cell lung cancer. In this study, we therefore investigated the association between protein levels by immunohistochemistry and clinicopathological features of advanced NSCLC patients. Survival curves were estimated using the Kaplan-Meier method and tested by log-rank. Multivariate analysis was conducted with the Cox's regression model to determine independence of factors. p values less than 0.05 were considered significant. A total 153 patients were studied, with 54.3% being stage III and 45.8% stage IV. Fifty-one cases (33.3%) were squamous cell carcinomas, and 98 cases (64.1%) were adenocarcinomas. High 14-3-$3{\gamma}$ expression was seen in 59.5% and significantly correlated with lymph node metastasis (p=0.010) and distant metastasis (p=0.017). On Kaplan-Meier analysis, high 14-3-$3{\gamma}$ expression was associated with poorer survival with a marginal trend toward significance (p=0.055). On multivariate analysis, age, treatment, and 14-3-$3{\gamma}$ expression proved to be independent prognostic parameters. In vitro experiments indicated that 14-3-$3{\gamma}$ overexpression also played a potential role in cancer invasion. In conclusion, our data suggest that 14-3-$3{\gamma}$ overexpression is associated with invasion and a poor prognosis. Therefore, 14-3-$3{\gamma}$ may be a potential prognostic marker of advanced non-small cell lung cancer.

8004^ Background: Afatinib (A) is an oral, irreversible ErbB family blocker of EGFR, HER2, ErbB3 and ErbB4 signalling. LL3 compared A with cisplatin/pemetrexed in 345 pts recruited globally and LL6 compared A with gemcitabine/cisplatin in 364 Asian pts. The primary analysis (2012) showed improved progression-free survival (PFS) with A versus CT in the overall EGFR mut positive population (HR=0.58 [LL3], HR=0.28 [LL6]) and pts with common (Del19/L858R) EGFR mut (HR=0.47 [LL3], HR=0.25 [LL6]). The FDA has approved A for the first-line treatment of pts with advanced NSCLC harboring common EGFR mut. Here we present a pooled analysis of mature OS data among such pts. Methods: Treatment-naïve pts with EGFR mut stage IIIB/IV NSCLC were randomized 2:1 to 40 mg A or up to 6 cycles of standard CT and stratified by EGFR mut and race (LL3). The primary endpoint was PFS, with OS as a key secondary endpoint. Adverse events were also recorded. Results: The pooled analysis included 631/709 pts randomized into LL3 and LL6 with common EGFR mut (Del19=355, L858R=276); 419 pts received A and 212 received CT. At the time of analysis (January 2014), 404 (64%) pts had died. Median follow-up for OS was 36.5 months. Following progression, 78% of pts received subsequent systemic therapies (median of 3 regimens); 68% in the CT group received EGFR TKIs and 70% in the A group received CT. OS was significantly improved with A versus CT (median 27.3 vs 24.3 months, HR=0.81 [CI 0.66, 0.99; p=0.037]). Individual HRs for OS in LL3 and LL6 were consistent with the pooled analysis. Among Del19 pts the HR=0.59 (CI 0.45, 0.77; p<0.001) and in L858R pts the HR=1.25 (CI 0.92, 1.71; p=0.160). Updated PFS and safety findings were consistent with earlier primary reports. Conclusions: This pooled analysis reveals that first-line A significantly improves OS in pts with advanced NSCLC harboring common EGFR mut (Del19/L858R) compared with CT. This is the first analysis to show that genotype-directed therapy for EGFR mut pts can improve survival. Clinical trial information: NCT00949650, NCT01121393.

To determine the outcome and predictive factors of clinical success of bronchial artery embolization in life-threatening hemoptysis. We reviewed all bronchial artery embolization procedures performed for life-threatening hemoptysis between January 2008 and December 2018. The outcomes and predictive factors of clinical success following embolization were evaluated. One hundred and eighty-four bronchial artery embolization procedures performed in 145 patients were eligible for the study. The technical and clinical success rates of the procedures were 170/184 (92.4%) and 129/184 (70.1%), respectively. The unstable hemodynamics and prothrombin time/international normalized ratio >1.5 was associated with lower clinical success rate, while embolization of more than one vessel was associated with higher clinical success rate. Bronchial artery embolization is a safe and effective procedure for controlling bleeding in life-threatening hemoptysis. However, low clinical success rate was noted in patients with unstable hemodynamics and coagulopathy, while multiple vessel embolization was associated with higher clinical success.