Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.

BACKGROUND: Approximately 25% of all patients with non-small-cell lung cancer present with resectable stage IB-IIIA disease, and although perioperative chemotherapy is the standard of care, this treatment strategy provides only modest survival benefits. On the basis of the activity of immune checkpoint inhibitors in metastatic non-small-cell lung cancer, we designed a trial to test the activity of the PD-L1 inhibitor, atezolizumab, with carboplatin and nab-paclitaxel given as neoadjuvant treatment before surgical resection. METHODS: This open-label, multicentre, single-arm, phase 2 trial was done at three hospitals in the USA. Eligible patients were aged 18 years or older and had resectable American Joint Committee on Cancer-defined stage IB-IIIA non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0-1, and a history of smoking exposure. Patients received neoadjuvant treatment with intravenous atezolizumab (1200 mg) on day 1, nab-paclitaxel (100 mg/m2) on days 1, 8, and 15, and carboplatin (area under the curve 5; 5 mg/mL per min) on day 1, of each 21-day cycle. Patients without disease progression after two cycles proceeded to receive two further cycles, which were then followed by surgical resection. The primary endpoint was major pathological response, defined as the presence of 10% or less residual viable tumour at the time of surgery. All analyses were intention to treat. This study is registered with ClinicalTrials.gov, NCT02716038, and is ongoing but no longer recruiting participants. FINDINGS: Between May 26, 2016, and March 1, 2019, we assessed 39 patients for eligibility, of whom 30 patients were enrolled. 23 (77%) of these patients had stage IIIA disease. 29 (97%) patients were taken into the operating theatre, and 26 (87%) underwent successful R0 resection. At the data cutoff (Aug 7, 2019), the median follow-up period was 12·9 months (IQR 6·2-22·9). 17 (57%; 95% CI 37-75) of 30 patients had a major pathological response. The most common treatment-related grade 3-4 adverse events were neutropenia (15 [50%] of 30 patients), increased alanine aminotransferase concentrations (two [7%] patients), increased aspartate aminotransferase concentration (two [7%] patients), and thrombocytopenia (two [7%] patients). Serious treatment-related adverse events included one (3%) patient with grade 3 febrile neutropenia, one (3%) patient with grade 4 hyperglycaemia, and one (3%) patient with grade 2 bronchopulmonary haemorrhage. There were no treatment-related deaths. INTERPRETATION: Atezolizumab plus carboplatin and nab-paclitaxel could be a potential neoadjuvant regimen for resectable non-small-cell lung cancer, with a high proportion of patients achieving a major pathological response, and manageable treatment-related toxic effects, which did not compromise surgical resection. FUNDING: Genentech and Celgene.

Characteristics and outcomes of lung cancer in solid organ transplant recipients.

OBJECTIVES: Lung cancer is the third most common malignancy that develops in patients following solid organ transplantation and is the leading cause of cancer deaths in the general population. The aims of this study are to examine the characteristics of patients who developed lung cancer following solid organ transplantation at our institution and to compare their outcomes to those of lung cancer patients without a history of transplant. MATERIALS AND METHODS: We performed a single-institution retrospective study of 44 solid organ transplant recipients who developed lung cancer and compared their characteristics to a cohort of 74 lung cancer patients without a history of transplant. We performed propensity score weighted analyses to compare outcomes between the two groups, including a cox proportional hazards model of overall survival. RESULTS: 52 % of post-transplant patients who developed lung cancer were diagnosed with stage III or IV disease. In the propensity score weighted analysis that accounted for age at diagnosis, sex, lung cancer stage at diagnosis, Charlson comorbidity index score, and ECOG performance score, post-transplant patients were more likely to have squamous cell histology (p < 0.01) and had worse overall survival compared to the non-transplant cohort (HR = 1.88, 95 % CI 1.13-3.12, p = 0.02). The difference in survival remained significant after accounting for differences in lung cancer histology and treatment (HR = 2.40, 95 % CI 1.27-3.78, p < 0.01). CONCLUSIONS: When compared to non-transplant patients with lung cancer, post-transplant patients have worse overall survival after accounting for differences in age, sex, lung cancer stage, comorbidities, and performance status. This survival difference is not solely attributable to differences in tumor histology and treatments received. This may suggest that post-transplant malignancies are more aggressive and difficult to treat.

Synchronous Pulmonary Adenocarcinomas.

OBJECTIVES: To determine concordance/discordance between morphology and molecular testing (MT) among synchronous pulmonary carcinomas using targeted next generation sequencing (NGS), with and without comprehensive molecular review (CMR), vs analyses of multiple singe genes (non-NGS). METHODS: Results of morphologic and MT assessment were classified as concordant, discordant, or indeterminate. For discordant cases, comprehensive histologic assessment (CHA) was performed. RESULTS: Forty-seven cases with 108 synchronous tumors were identified and underwent MT (NGS, n = 23 and non-NGS, n = 24). Histology and MT were concordant, discordant, and indeterminate in 53% (25/47), 21% (10/47), and 26% (12/47) of cases, respectively. CHA of the 10 discordant cases revised results of three cases. CONCLUSIONS: There is discordance between histology and MT in a subset of cases and MT provides an objective surrogate for staging synchronous tumors. A limited gene panel is sufficient for objectively assessing a relationship if the driver mutations are distinct. Relatedness of mutations require CMR with a larger NGS panel (eg, 50 genes).

Effects of ß-Adrenergic Antagonists on Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Locally advanced non-small cell lung cancer (NSCLC) is highly resistant to chemoradiotherapy, and many cancer patients experience chronic stress. Studies that suggest stimulation of ß-adrenergic receptors (ß-AR) promotes tumor invasion and therapy resistance. We investigated whether ß-AR inhibition with beta-blockers acts as a chemotherapy and radiation sensitizer in vitro and in patients treated with chemoradiation for locally advanced NSCLC. METHODS: We investigated the effects of the non-selective beta-blocker propranolol on two human lung adenocarcinoma cell lines (PC9, A549) treated with radiation or cisplatin. We retrospectively evaluated 77 patients with Stage IIIA NSCLC who received induction chemoradiation followed by surgery. Pathological and imaging response, metastatic rate, and survival were analyzed using SPSS v22.0 and PrismGraphpad6. RESULTS: Propranolol combined with radiation or cisplatin decreased clonogenic survival of PC9 and A549 cells in vitro (p < 0.05). Furthermore, propranolol decreased expression of phospho-protein kinase A (p-PKA), a ß-adrenergic pathway downstream activation target, in both cell lines compared to irradiation or cisplatin alone (p < 0.05). In patients treated for Stage IIIA NSCLC, 16 took beta-blockers, and 61 did not. Beta-blockade is associated with a trend to improved overall survival (OS) at 1 year (81.3% vs 57.4%, p = 0.08) and distant metastasis-free survival (DMFS) (2.6 years vs. 1.3 years, p = 0.16). Although beta-blocker use was associated with decreased distant metastases (risk ratio (RR) 0.19; p = 0.03), it did not affect primary tumor pathological response (p = 0.40) or imaging response (p = 0.36). CONCLUSIONS: ß-AR blockade enhanced radiation and cisplatin sensitivity of human lung cancer cells in vitro. Use of beta-blockers is associated with decreased distant metastases and potentially improved OS and DMFS. Additional studies are warranted to evaluate the role of beta-blockers as a chemoradiation sensitizer in locally advanced NSCLC.

PD-L1 expression in non-small cell lung carcinoma: Comparison among cytology, small biopsy, and surgical resection specimens.

BACKGROUND: One immunotherapeutic agent for patients with advanced non-small cell lung carcinoma, pembrolizumab, has a companion immunohistochemistry (IHC)-based assay that predicts response by quantifying programmed death-ligand 1 (PD-L1) expression. The current study assessed the feasibility of quantifying PD-L1 expression using cytologic non-small cell lung carcinoma specimens and compared the results with those from small biopsy and surgical resection specimens. METHODS: PD-L1 expression was quantified using the IHC-based 22C3 pharmDx assay, with "positivity" defined as staining in ≥50% viable tumor cells; ≥ 100 tumor cells were required for test adequacy. For cytology specimens, IHC was performed on cell block sections. RESULTS: A total of 214 specimens were collected from 188 patients, 206 of which (96%) were found to be adequately cellular, including 36 of 40 cytology (90%) and 69 of 72 small biopsy (96%) specimens. There was no significant difference noted with regard to the feasibility of PD-L1 IHC on small biopsy specimens compared with surgical resection specimens (P = .99), or between the percentage of PD-L1-positive cytology and histology (including surgical resection and histologic small biopsy) specimens (P = .083). PD-L1 expression was found to be concordant among samples from 21 of 23 patients from whom > 1 specimen was collected (91%). There also was no significant difference observed with regard to rates of PD-L1 positivity when comparing age, sex, diagnosis, and specimen site. CONCLUSIONS: Quantification of PD-L1 expression is feasible on cytology specimens, and the results are comparable to those obtained from surgical resection and small biopsy specimens, including in matched specimens and using a single predictive IHC marker. Future studies will be necessary to determine the comparative value of other antibodies and their ability to predict response to immunotherapy. Cancer Cytopathol 2017;125:896-907. © 2017 American Cancer Society.

Next-Generation Sequencing of Pulmonary Sarcomatoid Carcinoma Reveals High Frequency of Actionable MET Gene Mutations.

PURPOSE: To further understand the molecular pathogenesis of pulmonary sarcomatoid carcinoma (PSC) and develop new therapeutic strategies in this treatment-refractory disease. MATERIALS AND METHODS: Whole-exome sequencing in a discovery set (n = 10) as well as targeted MET mutation screening in an independent validation set (n = 26) of PSC were performed. Reverse transcriptase polymerase chain reaction and Western blotting were performed to validate MET exon 14 skipping. Functional studies for validation of the oncogenic roles of MET exon 14 skipping were conducted in lung adenosquamous cell line H596 (MET exon 14 skipped and PIK3CA mutated) and gastric adenocarcinoma cell line Hs746T (MET exon 14 skipped). Response to MET inhibitor therapy with crizotinib in a patient with advanced PSC and MET exon 14 skipping was evaluated to assess clinical translatability. RESULTS: In addition to confirming mutations in known cancer-associated genes (TP53, KRAS, PIK3CA, MET, NOTCH, STK11, and RB1), several novel mutations in additional genes, including RASA1, CDH4, CDH7, LAMB4, SCAF1, and LMTK2, were identified and validated. MET mutations leading to exon 14 skipping were identified in eight (22%) of 36 patient cases; one of these tumors also harbored a concurrent PIK3CA mutation. Short interfering RNA silencing of MET and MET inhibition with crizotinib showed marked effects on cell viability and decrease in downstream AKT and mitogen-activated protein kinase activation in Hs746T and H596 cells. Concurrent PIK3CA mutation required addition of a second agent for successful pathway suppression and cell viability effect. Dramatic response to crizotinib was noted in a patient with advanced chemotherapy-refractory PSC carrying a MET exon 14 skipping mutation. CONCLUSION: Mutational events of MET leading to exon 14 skipping are frequent and potentially targetable events in PSC.

Does lung cancer mutation status and targeted therapy predict for outcomes and local control in the setting of brain metastases treated with radiation?

BACKGROUND: We investigated effects of genetic alterations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma viral oncogene homolog (KRAS) on overall survival (OS) and local control after stereotactic radiosurgery for brain metastases in non-small cell lung cancer (NSCLC). METHODS: A cohort of 89 out of 262 NSCLC patients (2003-2013) treated with gamma knife radiosurgery for brain metastases had genotyping available and were selected as our study population. RESULTS: Median follow-up was 12 months. Median OS rates for the EGFR, KRAS, echinoderm microtubule-associated protein-like 4 (EML4)-ALK mutated, and wild-type cohorts were 17, 7, 27, and 12 months, respectively (P = .019), and for targeted versus nontargeted therapy 21 and 11 months, respectively (P = .071). Targeted therapy was a strong predictor of increased OS on univariate (P = .037) and multivariate (P = .022) analysis. Gender, primary tumor controlled status, recursive partitioning analysis class, and graded prognostic assessment score were associated with OS (P < .05). On multivariate analysis, positive EGFR mutational status was a highly significant predictor for decreased survival (hazard ratio: 8.2; 95% CI: 2.0-33.7; P = .003). However, when we recategorized EGFR-mutant cases based on whether they received tyrosine kinase inhibitor, OS was no longer significantly shorter (hazard ratio: 1.5; P = .471). Median OS for patients with and without local failure was 17 and 12 months, respectively (P = .577). Local failure rates for EGFR, KRAS, EML4-ALK mutated, and wild-type cohorts by lesion were 8.7%, 5.4%, 4.3%, and 5.1%, respectively. CONCLUSIONS: This study suggests that EGFR tyrosine kinase mutation and ALK translocation results in improved survival to targeted therapies and that mutation status itself does not predict survival and local control in patients with brain metastases from NSCLC.

Histologic assessment of non-small cell lung carcinoma after neoadjuvant therapy.

Chemotherapy or chemoradiation is often used in Stage IIIA non-small cell lung carcinoma before surgical resection (neoadjuvant therapy). In reviewing the histopathology of such tumors after resection, the recognition that the pathologic changes are related to prior therapy and the assessment of tumor regression are both of importance. To refine histologic parameters for tumor regression and describe patterns of tumor reaction to therapy, we identified 30 lobectomy or pneumonectomy specimens from 1996-2000 in which neoadjuvant therapy was received before surgical resection. Histologic patterns of treatment-induced tumor regression were analyzed semiquantitatively and included necrosis, fibrosis, mixed inflammatory infiltrate, foamy macrophages, and giant cells. To identify clinical and histologic parameters that correlate with treatment response, the 30 specimens were graded for tumor regression. No correlation was found between tumor regression and age, gender, or type of therapy (chemoradiation versus chemotherapy alone). Squamous cell carcinoma showed a significantly higher rate of response than adenocarcinoma (P =.04), with a significant number of adenocarcinomas in the nonresponder subgroup (P =.05). Tumor size reduction by radiologic assessment, when compared with histologic regression, did not reveal a statistically significant association. However, a positive correlation was found between extent of fibrosis and radiologic estimate of size reduction.