First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in EGFR Mutation; Positive Non-small Cell Lung Cancer Patients

Small molecule tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR) are important agents in the treatment of non-small cell lung cancer (NSCLC) and have enhanced activity in the subpopulation of patients with NSCLC who harbor somatic activating mutations of the EGFR gene. This review summarizes the data describing the use of EGFR tyrosine kinase inhibitors in a genotype-directed population of NSCLC patients with EGFR mutations and discusses areas that require further study

A Phase II Study of Oxaliplatin, Pemetrexed, and Bevacizumab in Previously Treated Advanced Non-small Cell Lung Cancer

IntroductionSingle agent chemotherapy is standard for second and third line treatment of non-small cell lung cancer (NSCLC). Combination therapy to date has not proven to be superior to single agents in this setting, often adding toxicity without any additional efficacy. We investigated the activity and tolerability of the combination of oxaliplatin, pemetrexed, and bevacizumab in patients with previously treated advanced NSCLC.MethodsThis multicenter phase II trial evaluated the safety and efficacy of the combination of pemetrexed (500 mg/m2), oxaliplatin (120 mg/m2), and bevacizumab (15 mg/kg), given every 21 days, in patients with previously treated advanced NSCLC. Eligibility criteria included performance status 0 to 1, nonsquamous histology, and at least one prior chemotherapy regimen. Patients with treated brain metastases were allowed. The primary end point was response rate, with secondary endpoints of progression-free survival and overall survival.ResultsThirty-six patients were enrolled on this study. Treatment was well tolerated; the most common grade 3 toxicity was hypertension, which was easily managed with oral medications. The nine (25%) patients with treated brain metastases had no episodes of cerebral hemorrhage. Of the 34 patients evaluable for tumor response, none had complete response, nine (27%) had partial response, 15 (44%) had stable disease, and 10 (29%) had progressive disease. Median progression-free survival was 5.8 months (95% confidence interval 4.1–7.8 months) and median overall survival was 12.5 months (95% confidence interval 7.3–17 months).ConclusionsTreatment with oxaliplatin and pemetrexed in combination with the targeted antiangiogenic agent bevacizumab yielded promising efficacy with manageable toxicity in the previously treated advanced NSCLC population

Lung Screening Benefits and Challenges: A Review of The Data and Outline for Implementation

Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for almost a fifth of all cancer-related deaths. Annual computed tomographic lung cancer screening (CTLS) detects lung cancer at earlier stages and reduces lung cancer-related mortality among high-risk individuals. Many medical organizations, including the U.S. Preventive Services Task Force, recommend annual CTLS in high-risk populations. However, fewer than 5% of individuals worldwide at high risk for lung cancer have undergone screening. In large part, this is owing to delayed implementation of CTLS in many countries throughout the world. Factors contributing to low uptake in countries with longstanding CTLS endorsement, such as the United States, include lack of patient and clinician awareness of current recommendations in favor of CTLS and clinician concerns about CTLS-related radiation exposure, false-positive results, overdiagnosis, and cost. This review of the literature serves to address these concerns by evaluating the potential risks and benefits of CTLS. Review of key components of a lung screening program, along with an updated shared decision aid, provides guidance for program development and optimization. Review of studies evaluating the population considered "high-risk" is included as this may affect future guidelines within the United States and other countries considering lung screening implementation

Biodegradable nano-films for capture and non-invasive release of circulating tumor cells

Selective isolation and purification of circulating tumor cells (CTCs) from whole blood is an important capability for both clinical medicine and biological research. Current techniques to perform this task place the isolated cells under excessive stresses that reduce cell viability, and potentially induce phenotype change, therefore losing valuable information about the isolated cells. We present a biodegradable nano-film coating on the surface of a microfluidic chip, which can be used to effectively capture as well as non-invasively release cancer cell lines such as PC-3, LNCaP, DU 145, H1650 and H1975. We have applied layer-by-layer (LbL) assembly to create a library of ultrathin coatings using a broad range of materials through complementary interactions. By developing an LbL nano-film coating with an affinity-based cell-capture surface that is capable of selectively isolating cancer cells from whole blood, and that can be rapidly degraded on command, we are able to gently isolate cancer cells and recover them without compromising cell viability or proliferative potential. Our approach has the capability to overcome practical hurdles and provide viable cancer cells for downstream analyses, such as live cell imaging, single cell genomics, and invitro cell culture of recovered cells. Furthermore, CTCs from cancer patients were also captured, identified, and successfully released using the LbL-modified microchips

24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous Non–Small Cell Lung Cancer

Introduction Cohort G of KEYNOTE-021 (NCT02039674) evaluated the efficacy and safety of pembrolizumab plus pemetrexed-carboplatin (PC) versus PC alone as first-line therapy for advanced nonsquamous NSCLC. At the primary analysis (median follow-up time 10.6 months), pembrolizumab significantly improved objective response rate (ORR) and progression-free survival (PFS); the hazard ratio (HR) for overall survival (OS) was 0.90 (95% confidence interval [CI]: 0.42‒1.91). Herein, we present an updated analysis. Methods A total of 123 patients with previously untreated stage IIIB/IV nonsquamous NSCLC without EGFR and/or ALK receptor tyrosine kinase gene (ALK) aberrations were randomized 1:1 to four cycles of PC with or without pembrolizumab, 200 mg every 3 weeks. Pembrolizumab treatment continued for 2 years; maintenance pemetrexed was permitted in both groups. Eligible patients in the PC-alone group with radiologic progression could cross over to pembrolizumab monotherapy. p Values are nominal (one-sided p < 0.025). Results As of December 1, 2017, the median follow-up time was 23.9 months. The ORR was 56.7% with pembrolizumab plus PC versus 30.2% with PC alone (estimated difference 26.4% [95% CI: 8.9%‒42.4%, p = 0.0016]). PFS was significantly improved with pembrolizumab plus PC versus PC alone (HR = 0.53, 95% CI: 0.33‒0.86, p = 0.0049). A total of 41 patients in the PC-alone group received subsequent anti‒programmed death 1/anti‒programmed death ligand 1 therapy. The HR for OS was 0.56 (95% CI: 0.32‒0.95, p = 0.0151). Forty-one percent of patients in the pembrolizumab plus PC group and 27% in the PC-alone group had grade 3 to 5 treatment-related adverse events. Conclusions The significant improvements in PFS and ORR with pembrolizumab plus PC versus PC alone observed in the primary analysis were maintained, and the HR for OS with a 24-month median follow-up was 0.56, favoring pembrolizumab plus PC

Does EGFR Mutation Type Influence Patient-Reported Outcomes in Patients with Advanced EGFR Mutation-Positive Non-Small-Cell Lung Cancer? Analysis of Two Large, Phase III Studies Comparing Afatinib with Chemotherapy (LUX-Lung 3 and LUX-Lung 6)

Introduction: In LUX-Lung 3 and LUX-Lung 6, afatinib significantly improved progression-free survival (PFS) versus chemotherapy in patients with tumors harboring common epidermal growth factor receptor (EGFR) mutations (Del19/L858R) and significantly improved overall survival (OS) in patients with tumors harboring Del19 mutations. Patient-reported outcomes stratified by EGFR mutation type are reported. Patients and Methods Lung cancer symptoms and health-related quality of life (QoL) were assessed every 21 days until progression using the EORTC Quality of Life Core Questionnaire C30 and its lung cancer-specific module, LC13. Analyses of cough, dyspnea, and pain were prespecified and included analysis of percentage of patients who improved on therapy, time to deterioration of symptoms, and change over time. Global health status (GHS)/QoL was also assessed. Analyses were conducted for all patients with tumors harboring Del19 or L858R mutations and were exploratory. Results: Compared with chemotherapy, afatinib more commonly improved symptoms of, delayed time to deterioration for, and was associated with better mean scores over time for cough and dyspnea in patients with Del19 or L858R mutations. All three prespecified analyses of pain showed a trend favoring afatinib over chemotherapy. In both Del19 and L858R mutations, afatinib was also associated with improvements in GHS/QoL. Longitudinal analyses demonstrated statistically significant improvements in GHS/QoL for afatinib over chemotherapy for patients with tumors harboring Del19 mutations or L858R mutations. Conclusions: These exploratory analyses suggest first-line afatinib improved lung cancer-related symptoms and GHS/QoL compared with chemotherapy in patients with non-small-cell lung cancer with tumors harboring common EGFR mutations, with benefits in both Del19 and L858R patients. When considered with OS (Del19 patients only) and PFS benefits, these findings substantiate the value of using afatinib over chemotherapy in these patient groups. Electronic supplementary material The online version of this article (10.1007/s40271-017-0287-z) contains supplementary material, which is available to authorized users

Summary Statement Novel Agents in the Treatment of Lung Cancer: Fifth Cambridge Conference Assessing Opportunities for Combination Therapy

The promise of effective targeted therapy for lung cancer requires rigorous identification of potential targets combined with intensive discovery and development efforts aimed at developing effective "drugs" for these targets. We now recognize that getting the right drug to the right target in the right patient is more complicated than one could have imagined a decade ago. As knowledge of targets and development of agents have proliferated and advanced, so too have data demonstrating the biologic heterogeneity of tumors. The finding that lung cancers are genetically diverse and can exhibit several pathways of resistance in response to targeted agents makes the prospect for curative therapy more daunting. It is becoming increasingly clear that single-agent treatment will be the exception rather than the rule. This information raises important new questions about the development and assessment of novel agents in lung cancer treatment: (1) How do we identify the most important drug targets for tumor initiation and maintenance? (2) What is the best way to assess drug candidates that may only be relevant in a small fraction of patients? (3) What models do we use to predict clinical response and identify effective combinations? And (4) how do we bring combination regimens to the clinic, particularly when the agents are not yet approved individually and may be under development from different companies? The Fifth Cambridge Conference on Novel Agents in the Treatment of Lung Cancer was held in Cambridge, Massachusetts, on October 1-2, 2007, to discuss these questions by reviewing recent progress in the field and advancing recommendations for research and patient care. New information, conclusions, and recommendations considered significant for the field by the program faculty are summarized here and presented at greater length in the individual articles and accompanying discussions that comprise the full conference proceedings. A CME activity based on this summary is also available at www.informedicalcme.com/cme

EGFR mutation detection in circulating cell-free DNA of lung adenocarcinoma patients: analysis of LUX-Lung 3 and 6

Background: In the Phase III LUX-Lung 3/6 (LL3/LL6) trials in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma patients, we evaluated feasibility of EGFR mutation detection using circulating cell-free DNA (cfDNA) and prognostic and predictive utility of cfDNA positivity (cfDNA+). Methods: Paired tumour and blood samples were prospectively collected from randomised patients. Mutations were detected using cfDNA from serum (LL3) or plasma (LL6) by a validated allele-specific quantitative real-time PCR kit. Results: EGFR mutation detection rates in cfDNA were 28.6% (serum) and 60.5% (plasma). Mutation detection in blood was associated with advanced disease characteristics, including higher performance score, number of metastatic sites and bone/liver metastases, and poorer prognosis. In patients with common EGFR mutations, afatinib improved progression-free survival vs chemotherapy in cfDNA+ (LL3: HR, 0.35; P=0.0009; LL6: HR, 0.25; P<0.0001) and cfDNA− (LL3: HR, 0.46; P<0.0001; LL6: HR, 0.12; P<0.0001) cohorts. A trend towards overall survival benefit with afatinib was observed in cfDNA+ patients. Conclusions: Plasma cfDNA is a promising alternative to biopsy for EGFR testing. Detectable mutation in blood was associated with more advanced disease and poorer prognosis. Afatinib improved outcomes in EGFR mutation-positive patients regardless of blood mutation status