Mary J. Fidler

Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial

BACKGROUND Despite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. METHODS We did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries. Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1% of tumour cells were randomly assigned (1:1:1) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m(2) every 3 weeks. The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50% of tumour cells. We used a threshold for significance of p<0.00825 (one-sided) for the analysis of overall survival and a threshold of p<0.001 for progression-free survival. This trial is registered at ClinicalTrials.gov, number NCT01905657. FINDINGS Between Aug 28, 2013, and Feb 27, 2015, we enrolled 1034 patients: 345 allocated to pembrolizumab 2 mg/kg, 346 allocated to pembrolizumab 10 mg/kg, and 343 allocated to docetaxel. By Sept 30, 2015, 521 patients had died. In the total population, median overall survival was 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 10 mg/kg, and 8.5 months with docetaxel. Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (hazard ratio [HR] 0.71, 95% CI 0.58-0.88; p=0.0008) and for pembrolizumab 10 mg/kg versus docetaxel (0.61, 0.49-0.75; p<0.0001). Median progression-free survival was 3.9 months with pembrolizumab 2 mg/kg, 4.0 months with pembrolizumab 10 mg/kg, and 4.0 months with docetaxel, with no significant difference for pembrolizumab 2 mg/kg versus docetaxel (0.88, 0.74-1.05; p=0.07) or for pembrolizumab 10 mg/kg versus docetaxel (HR 0.79, 95% CI 0.66-0.94; p=0.004). Among patients with at least 50% of tumour cells expressing PD-L1, overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 14.9 months vs 8.2 months; HR 0.54, 95% CI 0.38-0.77; p=0.0002) and with pembrolizumab 10 mg/kg than with docetaxel (17.3 months vs 8.2 months; 0.50, 0.36-0.70; p<0.0001). Likewise, for this patient population, progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 5.0 months vs 4.1 months; HR 0.59, 95% CI 0.44-0.78; p=0.0001) and with pembrolizumab 10 mg/kg than with docetaxel (5.2 months vs 4.1 months; 0.59, 0.45-0.78; p<0.0001). Grade 3-5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 [13%] of 339 patients given 2 mg/kg, 55 [16%] of 343 given 10 mg/kg, and 109 [35%] of 309 given docetaxel). INTERPRETATION Pembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. These data establish pembrolizumab as a new treatment option for this population and validate the use of PD-L1 selection. FUNDING Merck & Co.

PTEN, RASSF1 and DAPK site-specific hypermethylation and outcome in surgically treated stage I and II nonsmall cell lung cancer patients.

The primary objective of this study is to identify prognostic site‐specific epigenetic changes in surgically treated Stage I and II nonsmall cell lung cancer (NSCLC) patients by quantifying methylation levels at multiple CpG sites within each gene promoter. Paraffin‐embedded tumors from stage Ib, IIa and IIb in training and validation groups of 75 and 57 surgically treated NSCLC patients, respectively, were analyzed for p16, MGMT, RASSF1, RASSF5, CDH1, LET7, DAPK and PTEN promoter hypermethylation. Hypermethylation status was quantified individually at multiple CpG sites within each promoter by pyrosequencing. Molecular and clinical characteristics with time to recurrence (TTR) and overall survival (OS) were evaluated. Overall average promoter methylation levels of MGMT and RASSF1 were significantly higher in smokers than in nonsmokers (p = 0.006 and p = 0.029, respectively). Methylation levels of the p16 promoter were significantly higher in squamous cell carcinoma than in adenocarcinoma (p = 0.020). In univariate analysis, hypermethylation of RASSF1 at CpG sites −53 and −48 and PTEN at CpG site −1310 were the significantly associated with shorter TTR (p = 0.002 and p < 0.000, respectively). Hypermethylation of PTEN at −1310 and DAPK at −1482 were most significantly associated with outcome in multivariate analysis. These results show that methylation of specific promoter CpG sites in PTEN, RASSF1 and DAPK is associated with outcome in early stage surgically treated NSCLC.

Targeting the insulin-like growth factor receptor pathway in lung cancer: problems and pitfalls.

The insulin-like growth factor (IGF) pathway is a complex pathway involving interactions between membrane-bound receptors, ligands, binding proteins, downstream effectors, and other receptor tyrosine kinase signaling cascades. The IGF pathway has been identified as a potential therapeutic target in non-small cell lung cancer (NSCLC) based on the following provocative factors. Preclinical observations in NSCLC have shown that this pathway is involved in tumor cell proliferation, survival, and invasiveness. In addition, IGF-1R protein expression is found in a significant number of non-small cell tumor specimens. Initial therapeutic efforts involved the development of monoclonal antibodies and tyrosine kinase inhibitors that target IGF-1R, a transmembrane receptor tyrosine kinase. Enthusiasm for targeting this pathway increased when a randomized phase II study showed that combining an anti-IGF-1R monoclonal antibody (figitumumab) with a platinum doublet resulted in a higher response rate and trends for superior progression-free survival and overall survival. Subsequently, a phase III study failed to confirm the promising results observed in the phase II trial. Currently, investigators are studying different monoclonal antibodies and tyrosine kinases targeting IGF-1R. In unselected patients, results presented thus far do not suggest efficacy of this agent. However, retrospective subgroup analyses suggest that circulating IGF-1 levels might identify patients who could benefit from treatment with an IGF-1R monoclonal antibody and may warrant further exploratory studies for predictive molecular markers. The purpose of this paper is to briefly discuss the IGF pathway and its relationship with other signaling pathways in lung cancer and to review the ongoing IGF clinical trials and efforts to identify predictive molecular markers.

The Potential Predictive Value of Cyclooxygenase-2 Expression and Increased Risk of Gastrointestinal Hemorrhage in Advanced Non-Small Cell Lung Cancer Patients Treated with Erlotinib and Celecoxib

Purpose: Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, potentiates antitumor effects of erlotinib in preclinical studies, and COX-2 is frequently expressed in non–small cell lung cancer (NSCLC). With these observations, we designed a phase II trial to evaluate the efficacy and safety of erlotinib plus celecoxib in advanced NSCLC. Experimental Design: Previously treated stage IIIB/IV NSCLC patients were given celecoxib at 400 mg orally twice daily and erlotinib at 150 mg orally daily until disease progression. Planned accrual was 40 patients. Tissue was collected for epidermal growth factor receptor (EGFR) analysis and COX-2 immunohistochemistry. Results: Twenty-six patients were enrolled (17 men, 9 women; median age, 66 years). Eighteen and 21 patients had tissue available for EGFR analysis and COX-2 immunohistochemistry, respectively. The median progression-free survival (PFS) and overall survival were 2.0 and 9.2 months, respectively. Eleven of 21 patients tested had increased tumor COX-2 expression, which was strongly associated with prolonged PFS (P = 0.048). Four patients on anticoagulation or with a history of peptic ulcer disease had grade 3/grade 4 upper gastrointestinal bleeding (GIB), prompting early study closure. Three patients with GIB had endoscopy that found peptic ulcers. Conclusions: The combination of erlotinib and celecoxib does not seem superior to erlotinib alone in unselected patients. However, longer PFS with high-tumor COX-2 expression suggests that trials of EGFR and COX-2 inhibitors may be warranted in this patient subset. GIB observed in our trial supports excluding patients with a history of peptic ulcer disease or those requiring therapeutic anticoagulation from future EGFR and COX-2 inhibitor studies.

Esophageal carcinoma advances in treatment results for locally advanced disease: review

The treatment results of patients with locally advanced esophageal carcinomas have evolved since the publication of the first trial of concurrent mitomycin C and 5-fluorouracil with radiotherapy (RT) in 1983. Subsequent studies refined and improved on the concurrent chemotherapy (chemo) with administration of cisplatin and 5-fluorouracil infusion (PF). Chemo (PF) before surgery improved overall survival (OS) in those patients in most of the randomized trials and in meta-analyses. Two courses of PF concurrent with irradiation followed by additional two courses of PF were superior to RT alone without surgery for both groups. Concurrent chemoradiotherapy followed by surgery was found to have statistically improved OS as compared with surgery only in randomized trials and meta-analyses. In most of these studies, it was found that those patients with pathologic complete response to the initial treatment(s) did better than those who had no improvement at all. Current treatment outcome for these diseases is disappointing; newer strategies including induction chemo with the optimal combination, proper dosage of each drug, and proper number of courses before concurrent chemoradiotherapy; improvement in RT; and immunotherapy with or without subsequent surgery are exciting and definitely need to be investigated in prospective randomized trial(s).The treatment results of patients with locally advanced esophageal carcinomas have evolved since the publication of the first trial of concurrent mitomycin C and 5-fluorouracil with radiotherapy (RT) in 1983. Subsequent studies refined and improved on the concurrent chemotherapy (chemo) with administration of cisplatin and 5-fluorouracil infusion (PF). Chemo (PF) before surgery improved overall survival (OS) in those patients in most of the randomized trials and in meta-analyses. Two courses of PF concurrent with irradiation followed by additional two courses of PF were superior to RT alone without surgery for both groups. Concurrent chemoradiotherapy followed by surgery was found to have statistically improved OS as compared with surgery only in randomized trials and meta-analyses. In most of these studies, it was found that those patients with pathologic complete response to the initial treatment(s) did better than those who had no improvement at all. Current treatment outcome for these diseases is disappointing; newer strategies including induction chemo with the optimal combination, proper dosage of each drug, and proper number of courses before concurrent chemoradiotherapy; improvement in RT; and immunotherapy with or without subsequent surgery are exciting and definitely need to be investigated in prospective randomized trial(s).

Treatment of advanced squamous cell carcinoma of the lung: a review

Lung cancer remains the single deadliest cancer both in the US and worldwide. The great majority of squamous cell carcinoma (SCC) is attributed to cigarette smoking, which fortunately is declining alongside cancer incidence. While we have been at a therapeutic plateau for advanced squamous cell lung cancer patients for several decades, recent observations suggest that we are on the verge of seeing incremental survival improvements for this relatively large group of patients. Current studies have confirmed an expanding role for immunotherapy [including programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition], a potential opportunity for VEGFR inhibition, and even future targets in fibroblast growth factor receptor (FGFR) and PI3K-AKT that collectively should improve survival as well as quality of life for those affected by squamous cell lung cancer over the next decade.

Patterns-of-failure after helical tomotherapy-based chemoradiotherapy for head and neck cancer: implications for CTV margin, elective nodal dose and bilateral parotid sparing.

OBJECTIVES There is debate about the optimal clinical target volume (CTV) expansion and prophylactic nodal dose (PND) in head and neck IMRT. We evaluated our patterns-of-failure (POF) after helical tomotherapy-based concurrent chemoradiotherapy (CCRT) to assess the oncologic safety of reducing the CTV, PND, and bilateral parotid sparing (BPS). MATERIALS AND METHODS All patients with locally advanced squamous cell carcinoma of the head and neck treated with curative intent CCRT between January 2007 and April 2013 at a single institution were included in this retrospective study. Locoregional recurrences (LRR) were overlaid on the treatment plan, and POF was determined relative to planned dose. RESULTS One hundred and fourteen patients treated with CCRT were evaluated, 74% of whom underwent BPS. The median follow-up for surviving patients was 29.3 months. The 3-year cumulative incidence of locoregional failure, distant metastasis, progression-free and overall survival were 20%, 20%, 56% and 73% respectively. The local failures (n = 12) were either entirely contained within or centered on the original gross tumor volume (GTV), and all but 2 regional recurrences were in GTV. There were no nodal failures in the low-dose or peri-parotid neck (including ipsilateral neck). DISCUSSION Nearly all LRR were located within the GTV suggesting that minimal-to-zero margin is required for CTV 70. The nodal recurrence pattern suggests the safety of routine bilateral parotid sparing and relatively low biologically equivalent dose (54 Gy in 33fx) to the low-risk neck.

PTEN and PIK3CA gene copy numbers and poor outcomes in non-small cell lung cancer patients with gefitinib therapy

Background:Preclinical studies in non-small cell lung cancer (NSCLC) suggest the interaction of PTEN and PI3K affects sensitivity to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We investigated outcomes in relation to PTEN, PIK3CA and EGFR gene copy number, and chromosome 7 (CEN7) polysomy in NSCLC patients treated with gefitinib.Methods:Fluorescent in situ hybridisation analyses of PTEN, PIK3CA, EGFR and CEN7 were performed on tumour specimens from patients treated on the expanded access gefitinib trial. Progression-free survival (PFS) and overall survival (OS) were correlated with outcomes in all patients and EGFR wild-type patients.Results:Progression-free survival (hazard ratio=2.54, P<0.001) and OS (hazard ratio=4.04, P<0.001) were significantly shorter in patients whose tumours had all of the following molecular patterns: CEN7 <4 copies per cell, PTEN loss (<2 copies in at least 20% of cells), and PIK3CA gain (>2 copies in at least 40% of cells) both in all and EGFR wild-type only patients.Conclusion:The combination of low CEN7 copy number, PTEN loss, and PI3KCA gain may be useful for identifying NSCLC patients unlikely to benefit from treatment with EGFR (TKIs), specifically in wild-type EGFR cases.

Cost-Effectiveness Analysis of Chemoradiation Therapy Versus Transoral Robotic Surgery for Human Papillomavirus–Associated, Clinical N2 Oropharyngeal Cancer

PURPOSE To perform a cost-effectiveness analysis of primary chemoradiation therapy (CRT) versus transoral robotic surgery (TORS) for clinical N2, human papillomavirus (HPV)-positive oropharyngeal carcinoma. METHODS AND MATERIALS We developed a Markov model to describe the health states after treatment with CRT or TORS, followed by adjuvant radiation therapy or CRT in the presence of high-risk pathology (positive margins or extracapsular extension). Outcomes, toxicities, and costs were extracted from the literature. One-way sensitivity analyses (SA) were performed over a wide range of parameters, as were 2-way SA between the key variables. Probabilistic SA and value of information studies were performed over key parameters. RESULTS The expected quality-adjusted life years (QALYs)/total costs for CRT and TORS were 7.31/

Prevalence and Predictors of Neoadjuvant Therapy for Stage IIIA Non-Small Cell Lung Cancer in the National Cancer Database: Importance of Socioeconomic Status and Treating Institution

50,100 and 7.29/