Gene Grant Finley

Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC

BACKGROUND The cancer‐cell–killing property of atezolizumab may be enhanced by the blockade of vascular endothelial growth factor–mediated immunosuppression with bevacizumab. This open‐label, phase 3 study evaluated atezolizumab plus bevacizumab plus chemotherapy in patients with metastatic nonsquamous non–small‐cell lung cancer (NSCLC) who had not previously received chemotherapy. METHODS We randomly assigned patients to receive atezolizumab plus carboplatin plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP) every 3 weeks for four or six cycles, followed by maintenance therapy with atezolizumab, bevacizumab, or both. The two primary end points were investigator‐assessed progression‐free survival both among patients in the intention‐to‐treat population who had a wild‐type genotype (WT population; patients with EGFR or ALK genetic alterations were excluded) and among patients in the WT population who had high expression of an effector T‐cell (Teff) gene signature in the tumor (Teff‐high WT population) and overall survival in the WT population. The ABCP group was compared with the BCP group before the ACP group was compared with the BCP group. RESULTS In the WT population, 356 patients were assigned to the ABCP group, and 336 to the BCP group. The median progression‐free survival was longer in the ABCP group than in the BCP group (8.3 months vs. 6.8 months; hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.52 to 0.74; P<0.001); the corresponding values in the Teff‐high WT population were 11.3 months and 6.8 months (hazard ratio, 0.51 [95% CI, 0.38 to 0.68]; P<0.001). Progression‐free survival was also longer in the ABCP group than in the BCP group in the entire intention‐to‐treat population (including those with EGFR or ALK genetic alterations) and among patients with low or negative programmed death ligand 1 (PD‐L1) expression, those with low Teff gene‐signature expression, and those with liver metastases. Median overall survival among the patients in the WT population was longer in the ABCP group than in the BCP group (19.2 months vs. 14.7 months; hazard ratio for death, 0.78; 95% CI, 0.64 to 0.96; P=0.02). The safety profile of ABCP was consistent with previously reported safety risks of the individual medicines. CONCLUSIONS The addition of atezolizumab to bevacizumab plus chemotherapy significantly improved progression‐free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD‐L1 expression and EGFR or ALK genetic alteration status. (Funded by F. Hoffmann–La Roche/Genentech; IMpower150 ClinicalTrials.gov number, NCT02366143.)

Primary tumor microRNA signature predicts recurrence and survival in patients with locally advanced esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) is an aggressive cancer necessitating the development of improved risk stratification tools for personalized care. Previously, microRNAs have been shown to correlate with the progression and prognosis of various cancer types; however, the value in EAC remains largely unexplored. We performed global microRNA profiling on 32 formalin-fixed, paraffin-embedded EAC specimens to identify microRNAs associated with progression. Literature search and pathway analysis further refined output to five significantly deregulated candidate biomarkers. Four of the five microRNAs (miR-652-5p, miR-7-2-3p, miR-3925-3p, and miR-219-3p) were validated by qRT-PCR. Survival outcomes were evaluated in testing set of 26 stage II/III EAC patients to determine the prognostic relevance of the selected microRNAs. In the testing set, miR-652-5p and miR-7-2-3p expressions were significantly associated with progression-free survival (p-value = .00771 and p-value = .00293). The highest area under receiver operating characteristic (ROC) curve was 0.8212 for the combination of miR-652-5p and miR-7-2-3p. Collectively, our findings demonstrated that the miR-652-5p/miR-7-2-3p signature may serve as a promising prognostic marker in patients with locally advanced EAC.

PI3K/mTOR Dual Inhibitor, LY3023414, Demonstrates Potent Antitumor Efficacy Against Esophageal Adenocarcinoma in a Rat Model.

Objective: The purpose of the current study is to determine the efficacy of a PI3K/mTOR dual inhibitor, LY3023414, on established EAC in an in vivo model. Background: Esophageal adenocarcinoma (EAC) is a highly lethal cancer with limited treatment options. The PI3K/mTOR pathway is upregulated in EAC and may be a target for novel therapies. Methods: Esophagojejunostomy was performed on Sprague-Dawley rats to induce carcinogenesis, and LY3023414 was cyclically administered intraperitoneally between 32 and 40 weeks postsurgery to treatment animals. Magnetic resonance imaging (MRI) and histology were used to determine clinical response. Immunohistochemistry, immunofluorescence, and Western blot were used to validate apoptosis by cleaved caspase-3, proliferation by Ki67, and pathway inhibition, respectively. Results: Mean MRI tumor volume increased by 109.2% in controls (n = 32) and decreased by 56.8% in treatment animals (n=17) (P < 0.01). Treatment with LY3023414 demonstrated tumor volume increase in 0% (control = 46.4%) (P < 0.01), decrease in 58.8% (control = 7.1%) (P < 0.01), and stable volume in 41.2% (control = 46.4%) (P = 0.77). EAC prevalence in controls increased by 25%; whereas, prevalence in treatment animals decreased by 29.4% (P < 0.01). Approximately, 75% of treatment animals presenting with residual masses on MRI had a histological response >50%. Increased apoptosis by cleaved caspase-3 (P = 0.03) and decreased proliferation by Ki67 (P < 0.01) were demonstrated in the treatment arm, when compared with the control arm. On Western blot analysis of pathway checkpoints, p-mTOR (p=0.03) and PI3K-&agr; (P = 0.04) were downregulated in treatment responsive residual tumors, when compared with controls. Conclusions: LY3023414 demonstrates efficacy against EAC in a preclinical model, establishing the rationale for clinical testing.

Preclinical Study of AUY922, a Novel Hsp90 Inhibitor, in the Treatment of Esophageal Adenocarcinoma.

Objective: To assess the efficacy of heat-shock protein 90 (Hsp90) inhibitor, NVP-AUY922-AG (AUY922), in the treatment of esophageal adenocarcinoma (EAC) in vitro and in vivo. Background: EAC is a leading cause of cancer death, and current treatment options are limited. Hsp90, a chaperone protein that regulates several oncoproteins, is upregulated in EAC, and may be a novel target for therapy. Methods: In vitro, EAC cell lines were utilized to evaluate AUY922, alone and in combination with 5-fluorouracil (5-FU) and cisplatin. BrdU ELISA and flow cytometry were used to assess proliferation and measure apoptosis, respectively. Western blot and RT-PCR were performed to quantitate Hsp90 pathway expression. In vivo, esophagojejunostomy was performed on rats and treatment animals received AUY922 32 to 40 weeks postoperatively. Drug efficacy was evaluated with magnetic resonance imaging (MRI), endoscopic biopsy, gross histological evaluation, and Hsp90 pathway expression. Results: In vitro, AUY922 demonstrated antiproliferative activity in both cell lines and showed enhanced efficacy with cisplatin and 5-FU. Western Blot and RT-PCR demonstrated downregulation of CDK1 and CDK4 and upregulation of Hsp72. In vivo, AUY922 showed decrease in tumor volume in 36.4% of rats (control = 9.4%), increase in 9.1% (control = 37.5%), and stable disease in 54.5% (control = 43.7%). Necropsy confirmed the presence of EAC in 50% of treatment animals and 75% of control animals. mRNA expression, pre- and posttreatment, demonstrated significant downregulation of MIF, Hsp70, Hsp90&bgr;, and CDK4, and upregulation of Hsp72. Conclusions: AUY922 exhibits antitumor efficacy in vitro and in vivo for EAC, suggesting the need for human clinical trials.

Dose escalation and associated predictors of survival with consolidative thoracic radiotherapy in extensive stage small cell lung cancer (SCLC): A National Cancer Database (NCDB) propensity-matched analysis

PURPOSE Randomized studies have demonstrated a survival benefit for consolidative thoracic radiotherapy (TRT) in extensive stage (ES) small cell lung cancer (SCLC), however the radiation dose and optimal selection criteria are often debated. METHODS We analyzed 3280 stage IV SCLC treated with double-agent chemotherapy and TRT within the National Cancer Data Base (NCDB) and evaluated the differences in selection patterns and survival outcomes for patients who received at least 45 Gy of TRT and those who received <45 Gy. Univariable and multivariable analyses identified characteristics predictive of overall survival. Propensity-adjusted Cox proportional hazard ratios for survival were used to account for indication bias between the two dose arms. RESULTS There were 1621 patients in the <45 Gy group (most common 30 Gy) and 1659 patients in the 45 Gy or higher group (most common 45 Gy). White patients, T1-T3 lesions, an absence of brain/liver/bone metastases, and starting TRT after 12 weeks of chemotherapy were associated with the higher dose group. With multivariable analysis, TRT to at least 45 Gy was an independent predictor of improved survival (HR = 0.78, P < 0.001) along with female gender, age <65, lower comorbidity score, starting TRT 12 weeks after chemotherapy, and the absence of brain/liver/bone metastases (P < 0.01). Propensity adjusted regression model showed a persistent correlation between a higher dose and survival (HR = 0.74, P < 0.001). Survival at 1 and 2 years for the 45 Gy or higher arm was 58.1% and 25.2% compared to 43.8% and 15.1% for the <45 Gy arm (P < 0.001). CONCLUSION In the largest analysis of consolidative thoracic radiotherapy in ES-SCLC to date, dose escalation to at least 45 Gy was an independent predictor for increased survival. These findings may be validated in ongoing prospective studies.

Rare cause of atrial fibrillation: a thymic mass

A 62-year-old African-American man admitted to the emergency room with chest pain and exertional dyspnoea. He was found to be in rapid atrial fibrillation with pulmonary oedema. A transoesophageal echocardiogram performed prior to cardioversion showed a depressed left ventricular function (ejection fraction 30%) and an extracardiac heterogeneous echodensity compressing the right atrium and the superior vena cava. CT of the chest confirmed an anterior mediastinal mass measuring 13.5×6.6×10.1 cm, exerting a mass effect on the right atrium with mediastinal and right hilar adenopathy. CT-guided biopsy of the mediastinal mass revealed thymic carcinoma (squamous cell subtype). The metastatic workup was negative. The mass was deemed surgically unresectable due to its proximity to the heart. Chemotherapy was initiated with carboplatin/paclitaxel every 3 weeks with plans for intensity modulated radiotherapy after one to two cycles of chemotherapy. The patient recently had a repeat CT scan of the chest showing regression of the tumour.