Leptomeningeal metastases in non-small-cell lung cancer.

Leptomeningeal metastasis is a complication of advanced non-small-cell lung cancer (NSCLC). Diagnosis and monitoring of leptomeningeal metastasis are challenging, and are based on neurological, radiographic, and cerebrospinal fluid findings. Substantial progress has been made in several key aspects of management of leptomeningeal metastasis, including improved characterisation of the genetic profiles, generation of clinically relevant animal models, advances in cerebrospinal fluid liquid biopsy with improved cytology and genotyping analysis, and the development of therapeutic agents with greater CNS penetration. This Review discusses cumulative data on multiple treatment modalities with a particular focus on recent advances in molecularly targeted therapies in subtypes of patients with leptomeningeal metastasis from NSCLC. Future research is needed to further understand the biology of leptomeningeal metastasis and the mechanisms of resistance to treatment.

Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: Adjuvant chemotherapy for resected early-stage non-small-cell lung cancer (NSCLC) provides a modest survival benefit. Bevacizumab, a monoclonal antibody directed against VEGF, improves outcomes when added to platinum-based chemotherapy in advanced-stage non-squamous NSCLC. We aimed to evaluate the addition of bevacizumab to adjuvant chemotherapy in early-stage resected NSCLC. METHODS: We did an open-label, randomised, phase 3 trial of adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and who had completely resected stage IB (≥4 cm) to IIIA (defined by the American Joint Committee on Cancer 6th edition) NSCLC. We enrolled patients from across the US National Clinical Trials Network, including patients from the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) affiliates in Europe and from the Canadian Cancer Trials Group, within 6-12 weeks of surgery. The chemotherapy regimen for each patient was selected before randomisation and administered intravenously; it consisted of four 21-day cycles of cisplatin (75 mg/m2 on day 1 in all regimens) in combination with investigator's choice of vinorelbine (30 mg/m2 on days 1 and 8), docetaxel (75 mg/m2 on day 1), gemcitabine (1200 mg/m2 on days 1 and 8), or pemetrexed (500 mg/m2 on day 1). Patients in the bevacizumab group received bevacizumab 15 mg/kg intravenously every 21 days starting with cycle 1 of chemotherapy and continuing for 1 year. We randomly allocated patients (1:1) to group A (chemotherapy alone) or group B (chemotherapy plus bevacizumab), centrally, using permuted blocks sizes and stratified by chemotherapy regimen, stage of disease, histology, and sex. No one was masked to treatment assignment, except the Data Safety and Monitoring Committee. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00324805. FINDINGS: Between June 1, 2007, and Sept 20, 2013, 1501 patients were enrolled and randomly assigned to the two treatment groups: 749 to group A (chemotherapy alone) and 752 to group B (chemotherapy plus bevacizumab). 383 (26%) of 1458 patients (with complete staging information) had stage IB, 636 (44%) had stage II, and 439 (30%) had stage IIIA disease (stage of disease data were missing for 43 patients). Squamous cell histology was reported for 422 (28%) of 1501 patients. All four cisplatin-based chemotherapy regimens were used: 377 (25%) patients received vinorelbine, 343 (23%) received docetaxel, 283 (19%) received gemcitabine, and 497 (33%) received pemetrexed. At a median follow-up of 50·3 months (IQR 32·9-68·0), the estimated median overall survival in group A has not been reached, and in group B was 85·8 months (95% CI 74·9 to not reached); hazard ratio (group B vs group A) 0·99 (95% CI 0·82-1·19; p=0·90). Grade 3-5 toxicities of note (all attributions) that were reported more frequently in group B (the bevacizumab group) than in group A (chemotherapy alone) were overall worst grade (ie, all grade 3-5 toxicities; 496 [67%] of 738 in group A vs 610 [83%] of 735 in group B), hypertension (60 [8%] vs 219 [30%]), and neutropenia (241 [33%] vs 275 [37%]). The number of deaths on treatment did not differ between the groups (15 deaths in group A vs 19 in group B). Of these deaths, three in group A and ten in group B were considered at least possibly related to treatment. INTERPRETATION: Addition of bevacizumab to adjuvant chemotherapy did not improve overall survival for patients with surgically resected early-stage NSCLC. Bevacizumab does not have a role in this setting and should not be considered as an adjuvant therapy for patients with resected early-stage NSCLC. FUNDING: National Cancer Institute of the National Institutes of Health.

Medical Treatment in Elderly Patients with Non-Small Cell Lung Cancer.

OPINION STATEMENT: Lung cancer is the leading cause of cancer-related deaths worldwide. In the USA, ≈60 % of lung cancer cases are diagnosed in elderly patients (≥65 years of age). However, elderly patients are underrepresented in clinical studies, leading to a paucity of evidence to guide treatment decisions. Several treatment barriers exist in elderly patients, including comorbidities and poor performance status. In addition, lack of reliable geriatric assessment tools and physician reluctance to treat may contribute to undertreatment in this population. For decades, systemic chemotherapy for elderly patients with advanced non-small cell lung cancer (NSCLC) was either omitted or given as monotherapy, frequently with significant dose reductions, potentially compromising the efficacy of these therapies. Recent analyses of elderly subgroups from multiple clinical trials provide evidence for improved outcomes associated with platinum-based doublet chemotherapies vs monotherapy. Moreover, in the new era of precision medicine, molecularly targeted therapies and more recently immune-targeting therapies (anti-PD-1 and anti-PD-L1 agents) exhibit relatively milder toxicities but superior clinical outcomes in subgroups of patients compared with conventional cytotoxic chemotherapies. Further clinical trials will be needed to confirm similar safety and efficacy profiles of these therapeutic approaches in the elderly compared with their younger counterparts. In this article, we review available evidence from clinical studies and also present expert consensus on the management of NSCLC in the elderly, including treatment in the adjuvant setting and treatment of advanced disease. Screening tools, such as the Comprehensive Geriatric Assessment, that help to identify the right population of elderly patients suitable for systemic treatment are also discussed.

Emerging drugs for squamous cell lung cancer.

INTRODUCTION: The management of advanced NSCLC has been shifted by histology-driven treatment and molecularly targeted therapy, especially in lung adenocarcinoma. However, as the second most common histology in NSCLC, the treatment options for squamous cell lung cancer (SQCLC) remain very limited. AREAS COVERED: The review first discusses the role of histology in management of NSCLC and new cytotoxic agents in SQCLC, and then addresses genomic characterization and potential molecular targets in SQCLC. The article then provides an overview for several major categories of novel molecularly targeted therapies and immune-based strategies with particular attention to ongoing SQCLC trials. EXPERT OPINION: The key challenges in drug development are to uncover novel actionable targets and to identify predictive biomarkers. Progress in genomic analysis has identified some promising targetable genes and oncogenic pathways in SQCLC with a wave of targeted agents being tested in clinical trials. Immunotherapy has also raised great interest in management of SQCLC, especially agents targeting immune check points, cytotoxic T-lymphocyte antigen-4, programmed death-1 receptor and its ligands. Better understanding of tumor biology and development of novel targeted therapies will help to facilitate more effective personalized therapy for patients with this devastating illness.

Emerging treatment for advanced lung cancer with EGFR mutation.

INTRODUCTION: Lung cancer is the leading cause of cancer-related death worldwide. It is usually diagnosed at advanced stage for which platinum-based chemotherapy had been the standard approach, although with limited clinical benefits. Discovery of oncogenic EGFR mutations in lung cancer have shifted the treatment paradigm with molecularly targeted therapies. AREAS COVERED: EGFR tyrosine kinase inhibitors (TKIs) have become the first-line choice in patients with advanced NSCLC harboring EGFR activating mutations. However, resistance to targeted therapy develops inevitably during the course of treatment. Multiple mechanisms of acquired resistance have been discovered, most commonly the secondary mutation of T790M in exon 20. The second- and third-generation EGFR TKIs are holding promise to overcome T790M-associated acquired resistance and currently being tested in clinical trials. In this article, we focus on the emerging approaches to overcome the different mechanisms of resistance to targeted therapies in patients with EGFR-mutant advanced NSCLC. EXPERT OPINION: It is essential to uncover the complex mechanisms underlying the progression of lung cancer after upfront EGFR TKIs. Next generation, in particular, the third generations of EGFR TKIs have been developed against acquired T790M mutation with promising clinical activity and better toxicity profile. Combination of targeted therapies has also been explored. Further studies are needed to detect the real-time changes of the resistance mechanisms and to develop new therapeutic strategies for lung cancer patients with EGFR mutations.

Treatment of non-small-cell lung cancer with erlotinib or gefitinib.

A 64-year-old woman receives the diagnosis of metastatic non-small-cell lung cancer (NSCLC), which has progressed during treatment with carboplatin, paclitaxel, and bevacizumab. Erlotinib therapy is recommended.

Mechanisms of resistance to vascular endothelial growth factor blockade.

Angiogenesis is essential for the growth of primary tumors and for their metastasis. This process is induced by factors, such as vascular endothelial growth factors (VEGFs), that bind to transmembrane VEGF receptors (VEGFRs). VEGF-A is the primary factor involved with angiogenesis; it binds to both VEGFR-1 and VEGFR-2. The inhibition of angiogenesis by obstructing VEGF-A signaling has been investigated as a method to treat solid tumors, but the development of resistance to this blockade has complicated treatment. The major mechanisms of this resistance to VEGF-A blockade include signaling by redundant receptors, such as the fibroblast growth factors, angiopoietin-1, ephrins, and other forms of VEGF. Other major mechanisms of resistance are increased metastasis of hypoxia-resistant tumor cells, recruitment of cell types capable of promoting VEGF-independent angiogenesis, and increased circulation of nontumor proangiogenic factors. Additional mechanisms of resistance to VEGF-A blockade include heterogeneity of responsiveness among tumor cells, use of anti-VEGF-A agents at insufficient doses or for insufficient duration, altered sensitivity to anti-VEGF-A agents by mutations in endothelial cells or vascular remodeling, maintenance of vascular sleeves that allow for easy regrowth of tumor vasculature upon discontinuation of therapy, vascular cooption, and intussusceptive angiogenesis. An understanding of these mechanisms may lead to the development of targeted therapies that overcome this resistance. Some of these approaches include the combined inhibition of redundant angiogenic pathways, proper patient selection for various therapies based on gene expression profiles, blockade of cellular migration by inhibition of colony-stimulating factor, or the use of agents to disrupt vascular architecture.

First-in-human study of inhaled Azacitidine in patients with advanced non-small cell lung cancer.

BACKGROUND: Aerosolized Azacitidine has been shown to inhibit orthotopic lung cancer growth and induce re-expression of methylated tumor suppressor genes in murine models. We hypothesized that inhaled Azacitidine is safe and effective in reversing epigenetic changes in the bronchial epithelium secondary to chronic smoking. PATIENTS AND METHODS: We report the first in human study of inhaled Azacitidine. Azacitidine in aqueous solution was used to generate an aerosol suspension of 0.25-5 µm particle size. Main inclusion criteria: Stage IV or recurrent NSCLC with predominantly lung involvement, ≥1 prior systemic therapy, ECOG PS 0-1, and adequate pulmonary function. Patients received inhaled Azacitidine daily on days 1-5 and 15-19 of 28-day cycles, at 3 escalating doses (15, 30 and 45 mg/m2 daily). The primary objective was to determine the feasibility and tolerability of this new therapeutic modality. The key secondary objectives included pharmacokinetics, methylation profiles and efficacy. RESULTS: From 3/2015 to 2/2018, eight patients received a median number of 2 (IQR = 1) cycles of inhaled Azacitidine. No clinically significant adverse events were observed, except one patient treated at the highest dose developed an asymptomatic grade 2 decreased DLCO which resolved spontaneously. One patient receiving 12 cycles of therapy had an objective and durable partial response, and two patients had stable disease. Plasma Azacitidine was only briefly detectable in patients treated at the higher doses. Moreover, in 2 of 3 participants who agreed and underwent pre- and post-treatment bronchoscopy, the global DNA methylation in the bronchial epithelium decreased by 24 % and 79 % post-therapy, respectively. The interval between last inhaled treatment and bronchoscopy was 3 days. CONCLUSIONS: Inhaled Azacitidine resulted in negligible plasma levels compared to the previously reported subcutaneous administration and was well-tolerated. The results justify the continued development of inhaled Azacitidine at non-cytotoxic doses for patients with lung-confined malignant and/or premalignant lesions.

Seroconversion rates following COVID-19 vaccination among patients with cancer.

As COVID-19 adversely affects patients with cancer, prophylactic strategies are critically needed. Using a validated antibody assay against SARS-CoV-2 spike protein, we determined a high seroconversion rate (94%) in 200 patients with cancer in New York City that had received full dosing with one of the FDA-approved COVID-19 vaccines. On comparison with solid tumors (98%), a significantly lower rate of seroconversion was observed in patients with hematologic malignancies (85%), particularly recipients following highly immunosuppressive therapies such as anti-CD20 therapies (70%) and stem cell transplantation (73%). Patients receiving immune checkpoint inhibitor therapy (97%) or hormonal therapies (100%) demonstrated high seroconversion post vaccination. Patients with prior COVID-19 infection demonstrated higher anti-spike IgG titers post vaccination. Relatively lower IgG titers were observed following vaccination with the adenoviral than with mRNA-based vaccines. These data demonstrate generally high immunogenicity of COVID-19 vaccination in oncology patients and identify immunosuppressed cohorts that need novel vaccination or passive immunization strategies.

Impact and Diagnostic Gaps of Comprehensive Genomic Profiling in Real-World Clinical Practice.

PURPOSE: next-generation sequencing based comprehensive genomic profiling (CGP) is becoming common practice. Although numerous studies have shown its feasibility to identify actionable genomic alterations in most patients, its clinical impact as part of routine management across all cancers in the community remains unknown. METHODS: we conducted a retrospective study of all patients that underwent CGP as part of routine cancer management from January 2013 to June 2017 at an academic community-based NCI-designated cancer center. CGP was done in addition to established first tier reflex molecular testing as per national guidelines (e.g., EGFR/ALK for non-small cell lung cancer (NSCLC) and extended-RAS for colorectal cancer). RESULTS: 349 tests were sent for CGP from 333 patients and 95% had at least one actionable genomic alteration reported. According to the reported results, 23.2% had a Food and Drug Administration (FDA) approved therapy available, 61.3% had an off-label therapy available and 77.9% were potentially eligible for a clinical trial. Treatment recommendations were also reviewed within the OncoKB database and 47% of them were not clinically validated therapies. The CGP results led to treatment change in only 35 patients (10%), most commonly in NSCLC. Nineteen of these patients (54% of those treated and 5% of total) had documented clinical benefit with targeted therapy. CONCLUSION: we demonstrate that routine use of CGP in the community across all cancer types detects potentially actionable genomic alterations in a majority of patients, however has modest clinical impact enriched in the NSCLC subset.

Survival Disparities in Black Patients With EGFR-mutated Non-small-cell Lung Cancer.

BACKGROUND: Little is known about the difference between black and non-black patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), particularly regarding survival. We thus characterized the EGFR expression profile, clinical characteristics, and survival outcome in these patients. PATIENT AND METHODS: We reviewed the cancer registry and patient charts at a New York-Bronx network (n = 2773) treating a large population of minority patients, for non-squamous NSCLC (n = 1986) diagnosed between 2009 and 2015. Survival was adjusted for smoking, gender, age, weight, and stage. RESULTS: The EGFR mutation rate was 15% (98/652) in tested patients (black, 14%; non-black, 16%). There was no significant difference between the 2 cohorts with respect to age at diagnosis, gender, presenting stages, and socioeconomic status. On the other hand, weight was noted to be heavier in black patients with EGFR-mutated NSCLC than their non-black counterparts (P = .012). After adjusting for gender, age, smoking status, weight, and stage, the multivariate analysis revealed no racial disparity in survival among patients with wild-type EGFR (P = .774); However, among patients with EGFR-mutated NSCLC, black patients had shorter survival in comparison with non-black patients (P = .001), with 2-year survival rates being 33% versus 61%, respectively. Such shorter survival was also observed among EGFR-inhibitor treated patients with common EGFR mutations (P = .040). CONCLUSIONS: To our knowledge, this is the first report of inferior survival among black patients with NSCLC with EGFR mutations, relative to non-black patients. The survival disparities suggest the need of more tailored management for this patient population.

Case Fatality Rate of Cancer Patients with COVID-19 in a New York Hospital System.

Patients with cancer are presumed to be at increased risk from COVID-19 infection-related fatality due to underlying malignancy, treatment-related immunosuppression, or increased comorbidities. A total of 218 COVID-19-positive patients from March 18, 2020, to April 8, 2020, with a malignant diagnosis were identified. A total of 61 (28%) patients with cancer died from COVID-19 with a case fatality rate (CFR) of 37% (20/54) for hematologic malignancies and 25% (41/164) for solid malignancies. Six of 11 (55%) patients with lung cancer died from COVID-19 disease. Increased mortality was significantly associated with older age, multiple comorbidities, need for ICU support, and elevated levels of D-dimer, lactate dehydrogenase, and lactate in multivariate analysis. Age-adjusted CFRs in patients with cancer compared with noncancer patients at our institution and New York City reported a significant increase in case fatality for patients with cancer. These data suggest the need for proactive strategies to reduce likelihood of infection and improve early identification in this vulnerable patient population. SIGNIFICANCE: COVID-19 in patients with cancer is associated with a significantly increased risk of case fatality, suggesting the need for proactive strategies to reduce likelihood of infection and improve early identification in this vulnerable patient population.This article is highlighted in the In This Issue feature, p. 890.

Nanoparticle albumin bound-paclitaxel for treatment of advanced non-small cell lung cancer: an evaluation of the clinical evidence.

INTRODUCTION: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel), a microtubule inhibitor, has demonstrated clinical efficacy in the treatment of advanced non-small cell lung cancer (NSCLC) either as monotherapy or in combination. Nab-paclitaxel was developed to reduce the toxicities associated with solvent-bound paclitaxel (sb-paclitaxel). Areas covered: This review first focuses on the clinical trials evaluating the efficacy and tolerability of nab-paclitaxel in NSCLC at different settings. The approval of nab-paclitaxel in combination with carboplatin at the front-line setting for advanced NSCLC was based on the key phase III study, which showed that nab-paclitaxel/carboplatin was associated with superior overall response rate and favorable toxicity profile compared to sb-paclitaxel/carboplatin. The review also addresses the nab-paclitaxel pharmacology, other combinations (e.g. immunotherapy with PD-1/PD-L1 inhibitors), potential biomarkers (e.g. caveolin-1), and special subgroups (e.g. the elderly, squamous histology). Expert opinion: Existing data has established the role of nab-paclitaxel in the management of advanced NSCLC. Emerging evidence, such as preliminary results from Keynote-407 and IMpower 131 studies, indicates that novel combinations of nab-paclitaxel/carboplatin and PD-1/PD-L1 inhibitors could further improve clinical benefits with manageable toxicity. Nevertheless, in order to better position nab-paclitaxel and to improve patient selection, future studies are warranted to further understand its mechanism of action, predictive biomarkers, and potential synergism with other agents.

Impact of Primary Care Access on Mortality of Lung Cancer Patients in an Underserved Community.

BACKGROUND: Lack of access to primary care physicians (PCPs) may be an important contributor to mortality differences attributed to race/ethnicity. This study examined the effects of primary care access on mortality of lung cancer patients in an underserved community. METHODS: Medical records of all newly diagnosed patients with primary lung cancer from 2012 to 2016 at a National Cancer Institute (NCI)-designated center in Bronx, New York were reviewed. Demographic data, PCP status, and residence in primary care shortage areas (PCSAs) were collected. Survival data from time of first imaging to death or the end of follow-up on January 1, 2018 were recorded. Survival analysis was performed using Kaplan-Meier and Cox hazards modeling. RESULTS: Among 1062 patients, 874 (82%) were PCSA residents, 314 (30%) were Hispanic, and 445 (42%) were African American. PCSA residents were likely Hispanics (P<0.001), African Americans (P<0.001), of lower income (P<0.001), and had advanced disease at diagnosis (P=0.01). Patients without established PCPs had more comorbidities (P=0.04), more advanced disease (P<0.001), and less in-network cancer treatment (P<0.001). PCSA residence (P=0.03, hazard ratio [HR]=1.27) and no established PCP (P<0.001, HR=1.50) were associated with increased mortality. In multivariable modeling, lack of established PCP remained a predictor of increased mortality (P=0.02, HR=1.25). DISCUSSION: Among newly diagnosed lung cancer patients, lack of established PCP is associated with increased mortality. Hispanics and African Americans increasingly resided in PCSAs, suggesting race/ethnicity mortality differences may be mediated by primary care shortage. Patients without PCPs had worse health outcomes. Effective health policy efforts to reduce mortality in lung cancer patients must include approaches to improve primary care access.

Erlotinib induces mitochondrial-mediated apoptosis in human H3255 non-small-cell lung cancer cells with epidermal growth factor receptorL858R mutation through mitochondrial oxidative phosphorylation-dependent activation of BAX and BAK.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib shows potent antitumor activity in some non-small-cell lung cancer (NSCLC) cell lines and is approved by the Food and Drug Administration as second and third line treatment for NSCLC. However, the molecular mechanisms by which erlotinib induces apoptosis remain to be elucidated. Here, we investigated the effect of erlotinib on apoptotic signal pathways in H3255 cells with the EGFR(L858R) mutation. Erlotinib induces apoptosis associated with the activation of caspases in a dose- and time-dependent manner. Erlotinib did not alter the expression of apoptotic receptors FAS and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), although it induced caspase-8 activation and BID cleavage. In addition, cell death caused by erlotinib was not prevented by coincubation with FAS and TRAIL antagonists, ZB-4 monoclonal antibody and TRAIL/Fc recombinant, suggesting that erlotinib-induced apoptosis is not associated with receptor-mediated pathways. Erlotinib induces loss of mitochondrial membrane potential and release of cytochrome c and second mitochondria-derived activator of caspases/direct IAP binding protein with low pI from mitochondria. Furthermore, erlotinib causes BAX translocation to mitochondria, BAX and BAK conformational changes, and oligomerization. Erlotinib did not induce reactive oxygen species generation, and cotreatment with antioxidants did not alter erlotinib-induced activation of BAX and BAK and apoptosis. However, cotreatment with inhibitors of mitochondrial oxidative phosphorylation significantly blocked erlotinib-induced activation of BAX and BAK and cell death. Benzyloxycarbiny-VAD-fluoromethyl ketone had no effect on erlotinib-induced BAX and BAK activation but effectively prevented apoptosis. Overexpression of BCL-2 caused a significant attenuation of erlotinib-induced cell death, but no effect on BAX and BAK activation. Down-regulation of BAX and BAK gene expression with small interfering RNA led to an effective reduction of erlotinib-induced apoptosis. Our data indicate that activation of BAX and BAK plays a critical role in the initiation of erlotinib-induced apoptotic cascades.

Erlotinib: recent clinical results and ongoing studies in non small cell lung cancer.

The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib has shown to provide clinical benefit to patients with non-small cell lung cancer (NSCLC) after failure of front-line chemotherapy in a double-blind placebo-controlled clinical trial. More importantly, because of its unique mechanism of action, erlotinib seems to provide higher clinical benefit to specific subgroups of patients. The continued development of erlotinib in NSCLC is focused on the following areas: (a) validating clinical and molecular markers of clinical benefit in front-line therapy, (b) developing therapies for acquired and naturally resistant tumors, (c) revisiting combinations with chemotherapy, (d) developing combinations with antiangiogenesis agents, and (e) understanding the biological significance of the skin toxicity and developing rational approaches for its treatment. Clinical studies addressing these five areas are ongoing and are briefly described in this review.

Schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in human non-small cell lung cancer cells.

PURPOSE: This study was undertaken to select the optimal combination schedule of erlotinib and pemetrexed for the treatment of relapsed non-small cell lung cancer (NSCLC) using a panel of human NSCLC lines. EXPERIMENTAL DESIGN: Human NSCLC cell lines, with variable expression of the known molecular determinants of erlotinib sensitivity, were exposed to pemetrexed and erlotinib using different schedules. Antitumor effect was measured by growth inhibition by cell count and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell cycle distribution and apoptosis by flow cytometry, and expression of cell cycle mediators by immunoblots. The cytotoxic interaction between pemetrexed and erlotinib (i.e., synergistic, additive, or antagonistic) was determined by median effect analysis. RESULTS: When cells were exposed to concurrent pemetrexed and erlotinib or sequential pemetrexed followed by erlotinib, cytotoxic synergism was observed in both erlotinib-sensitive and erlotinib-resistant human NSCLC cell lines. This was independent of the mutation status of epidermal growth factor receptor or K-Ras genes. Synergism was associated with a combination of cell cycle effects from both agents. In contrast, exposure of cells to erlotinib followed by pemetrexed was mostly antagonistic in erlotinib-sensitive cells and additive at best in erlotinib-resistant cells. Antagonism was associated with erlotinib-induced G(1)-phase blockade of erlotinib-sensitive cells, which protects cells from pemetrexed cytotoxicity. Pemetrexed induced an epidermal growth factor receptor-mediated activation of the phosphatidylinositol 3-kinase/AKT pathway, which was inhibited by erlotinib and a specific phosphatidylinositol 3-kinase inhibitor, LY294002. CONCLUSIONS: The combination of pemetrexed and erlotinib is synergistic in NSCLC in vitro if exposure to erlotinib before pemetrexed is avoided, particularly in tumors that are sensitive to erlotinib. Based on these findings, a randomized phase II study comparing the progression-free survival between an intermittent combination of erlotinib and pemetrexed (experimental arm) and pemetrexed alone (control arm) in patients with relapsing NSCLC has been initiated.

p53 aerosol formulation with low toxicity and high efficiency for early lung cancer treatment.

PURPOSE: To develop an optimal nonviral aerosol formulation for locoregional treatment of early lung cancer. EXPERIMENTAL DESIGN: The formulation was made of polylysine/protamine combination (AND) as the carrier and p53 gene (p53sm) as therapeutic agent. To estimate the aerosol deposition, the aerodynamic size of the AND-p53sm was measured with extrusion-precipitation method. To accurately determine the dose, the aerosol efficiency in mice was measured with a fluorescent dye. The transfection efficiency and DNA protection function of the aerosolized formulation in cultured cells and mouse lungs were detected with reporter gene assays and/or reverse transcription-PCR. The preclinical safety and efficacy of AND-p53sm were studied in healthy mice and mice bearing orthotopic human non-small-cell lung cancer (NSCLC) xenograft. RESULTS: After aerosolization, AND is 3- to 17-fold more effective than commonly used PEI or cationic lipid formulations in transfecting the NSCLC cells (relative light units, 1,494 versus 534 and 86; P < 0.003). Aerodynamic size of AND-p53sm ranged 0.2 to 3 mum is the optimal aerosol droplets for deposition in the entire human respiratory tract. Significant gene expression was detected in the lungs of mice given aerosolized AND-p53sm and AND-luciferase. Aerosolized AND-p53sm significantly prolonged the life of mice bearing orthotopic human NSCLC xenografts, and it was more effective than an optimal i.v. cisplatin chemotherapy (increased life span, 93% versus 25%; P = 0.014). Inhalation of AND produced low and reversible pulmonary toxicity and no systemic toxicity. CONCLUSIONS: This optimal formulation is suitable for delivering biological materials to human lung with aerosol administration. This therapeutic strategy is an option for patients with early lung cancer and bronchoalveolar carcinoma.

Phase I study of aerosolized SLIT cisplatin in the treatment of patients with carcinoma of the lung.

PURPOSE: To investigate the safety and pharmacokinetics of aerosolized Sustained Release Lipid Inhalation Targeting (SLIT) Cisplatin in patients with lung carcinoma. EXPERIMENTAL DESIGN: Phase I, dose-escalating study of SLIT Cisplatin given in two sessions daily. Safety data, including laboratory variables, adverse events, pulmonary function tests, and radiographic imaging, were collected and analyzed for all patients to determine toxicity. Pharmacokinetic monitoring was done during the first course. RESULTS: Seventeen patients and one tracheostomy patient on compassionate use received treatment. Aerosolized cisplatin was well tolerated. No dose-limiting toxicity was observed at the maximum delivered dose. Safety data showed no hematologic toxicity, nephrotoxicity, ototoxicity, or neurotoxicity. Most common adverse events were nausea (64.7%), vomiting (47.1%), dyspnea (64.7%), fatigue (64.7%), and hoarseness (47.1%). Pharmacokinetic data showed very low plasma platinum levels only with the longest repeated inhalations. Common Toxicity Criteria grade 2 decrease in forced expiratory volume in one second and diffusing lung capacity for carbon monoxide after one course occurred both in two patients and grade one decrease in forced expiratory volume in one second and diffusing lung capacity for carbon monoxide in six and five patients, respectively. Direct airway deposition via the tracheostomy resulted in clinical deterioration after two cycles best described as bronchitis, completely reversible within days. Overall response: stable disease in 12 patients and progressive disease in 4 patients (one patient received one cycle). CONCLUSIONS: Aerosolized liposomal cisplatin was found to be feasible and safe.