Metastatic Non-small Cell Lung Research Articles

Abstract A18: A systems biology approach to predict immunotherapy augmented abscopal effects

Abstract Introduction and Objectives: Radiation-induced abscopal effects are characterized by regression of tumor nodules outside the local radiation treatment field. Abscopal effects have been reported in metastatic lymphoma, melanoma, lung and breast cancer as well as renal cell carcinoma amongst others. Radiotherapy causes a perturbation to the local immune profile that is propagated throughout the lymphatic system, shifting systemic immune surveillance towards tumor eradication in distant, non-irradiated sites as well as circulating micrometastases. We hypothesize that abscopal effects could be triggered by targeting combined radiation and immunotherapy to immunogenic hubs in the patient-specific interconnected metastatic-lymphatic network. Materials and Methods: We develop a mathematical model of the systemic response to local radio-immunotherapy. Patient-specific positron emission tomography (PET) scans provide the size and location of each tumor nodule. Metastatic geography is mapped onto the lymphatic network and connections between metastatic sites and lymphatic nodes are calculated. We quantify immune signal flow through the lymphatic network and amplifications through metastatic sites. A local model describes the temporal coevolution of tumor size with effector and regulatory T cells. The local and global models are coupled to quantify systemic responses to local treatment of each tumor site. Results: The ‘virtual patient’ framework successfully simulates the abscopal effect reported for 2 patients with widely metastatic melanoma and non-small cell lung cancer. Model simulations suggest that only one or two tumor nodules in each patient serve as immunogenic hubs that could trigger an abscopal response. Radio-immunotherapy of any other lesion would result in local tumor control but systemic disease progression. Conclusions: Careful selection of immunogenic ‘hub’ nodules holds the key to successful abscopal disease control. The presented mathematical framework may help to identify the immunogenicity of each tumor nodule. Before serving as a novel decision support tool, rigorous calibration and validation remains to be pursued as more clinical abscopal data becomes available. Citation Format: Jan Poleszczuk, Sotiris Prokopiou, Mark Robertson-Tessi, Kimberly Luddy, Eduardo Moros, Mayer Fishman, Julie Djeu, Heiko Enderling. A systems biology approach to predict immunotherapy augmented abscopal effects. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A18.

Abstract 3891: Tackling the obstacles facing the implementation of a molecular screening program in an early drug development unit: The Jules Bordet Institute Program for Molecular Profiling of Metastatic Lesions - feasibility (Precision-f)

Abstract Introduction The identification of pathways involved in carcinogenesis, the emergence of high-throughput technologies enabling tumor molecular analysis and the development of targeted therapies have led to the concept of precision medicine. Higher response rates and longer survivals have been achieved in recent genomic-driven clinical trials. However, genomic-driven cancer medicine is hindered by multiple obstacles. Our aim was to assess the feasibility of incorporating real-time targeted gene sequencing (TGS) of DNA derived from metastatic biopsies into daily clinical practice. Experimental procedures Precision-f (NCT01932489) is a pilot trial conducted at the Jules Bordet Institute. Patients with metastatic colorectal cancer (CRC), melanoma or non-small cell lung (NSCLC) cancer were enrolled. Two FFPE blocks and one fresh frozen sample embedded in OCT were collected from newly performed metastatic biopsies as well as one whole blood sample. The FFPE samples were checked for tumor cellularity and 5×5 μm sections were cut and sent to 2 laboratories. Targeted gene sequencing was performed on DNA extracted for the same sample using the Illumina TruSeq Amplicon Cancer Panel performed on a MiSeq Desktop Sequencer, and the Life Technologies Ion AmpliSeq Cancer Hotspot Panel performed on an Ion Personal Genome Machine. Results were reported to the institutional sequencing tumor board for discussion, annotation and treatment assignment. The main objectives were the evaluation of biopsy quality, turnaround time, the presence of “actionable” alterations, technology cross-validity and treatment assignments. Results Thirty-four patients were enrolled between December 2013 and August 2014: 13 NSCLC patients, 11 CRC patients, 10 melanoma patients. Successful molecular results were achieved from 32/34 biopsies (94%). The most frequent site of biopsy was the liver (10) followed by the lung (7), the skin (5) and lymph nodes (5). 27/34 (79%) samples had ≥ 20% tumor cells. 31/34 (91%) of samples had > 10 ng of DNA for TGS. The median turnaround time for results reporting was 15 calendar days [8-22]. “Actionable” mutations were found for 66% (21/32) of patients, 76% (16/21) of which were treated with therapy according to the identified molecular alteration. Reasons for non-targeted therapy were: non-eligibility (2), unavailable drugs (2) and patient refusal (1). The results of the comparison of TGS data across the 2 platforms is ongoing and will be presented at the meeting. Conclusion The precision-f pilot trial has demonstrated the feasibility and clinical relevance of a molecular screening program in a clinical pharmacology unit. A Belgian national initiative will follow in order to enhance patient participation in genomic-driven clinical trials. Citation Format: Philippe G. Aftimos, Marion Maetens, Catherine Sibille, Jean-François Laes, Sylvain Brohée, Thierry Berghmans, Joseph Kerger, Alain Hendlisz, Alexandre Irrthum, Olivier De Henau, Amélie Deleporte, Stylianos Drisis, Denis Larsimont, Jalal Vakili, Christos Sotiriou, Martine Piccart, Ahmad Awada. Tackling the obstacles facing the implementation of a molecular screening program in an early drug development unit: The Jules Bordet Institute Program for Molecular Profiling of Metastatic Lesions - feasibility (Precision-f). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3891. doi:10.1158/1538-7445.AM2015-3891

A randomized Phase 3 study comparing first-line pemetrexed plus cisplatin followed by gefitinib maintenance (PC/G) with gefitinib monotherapy (G) in East Asian patients (pts) with locally advanced or metastatic nonsquamous non-small cell lung cancer (nSqNSCLC): Final survival results.

8041 Background: The primary analysis of this open-label, randomized, multicenter study found no significant difference in progression-free survival (PFS) between PC/G and G in pts with nSqNSCLC and unknown epidermal growth factor receptor (EGFR) mutation status, although the unadjusted hazard ratio (HR, PC/G vs G) favored PC/G (0.85, 95% CI: 0.63–1.13). Final overall survival (OS) data are reported here. Methods: Eligible pts were chemonaive, East Asian light ex-smokers/never-smokers aged ≥18 years with advanced nSqNSCLC, ECOG PS 0/1 and unknown EGFR mutation status. Pts (N = 236) were randomized (1:1) to PC/G (pemetrexed 500 mg/m2 + cisplatin 75 mg/m2for six 21-day cycles then gefitinib 250 mg/day) or G (gefitinib 250 mg/day). EGFR mutation status was determined for 76 pts; 52 (68.4%) had mutations. OS was analyzed (intent-to-treat population) by unadjusted Cox regression analysis. Results: Baseline characteristics were similar between groups (both N = 118). Median OS was similar in the PC/G and G group...

Hypercoagulation Screening As a Marker of Thrombosis and Poor Disease Prognosis in Cancer Patients: The Hypercan Prospective Study

Introduction Malignant tumor progression and poor prognosis have been repeatedly associated with the occurrence of hypercoagulation and overt thrombotic events. The HYPERCAN is an ongoing prospective Italian multicentre study, structured in two sub-projects that involve respectively non-cancer and cancer subjects. The HYPERCAN sub-project on cancer patients aims to evaluate whether thrombotic markers may predict for malignant disease recurrence and/or for venous thromboembolic events (VTE) in these patients.Methods Consecutive adult patients with limited resected or metastatic non-small cell-lung (NSCLC), gastric, colorectal, or breast cancers are enrolled, after informed written consent, and followed up for 5 years or death. Enrollment will be continued for up to 3 years (total 4,000 patients planned). Blood sample collection is planned according to tumor stage. Particularly, for metastatic disease, patient citrated whole blood is collected: 1. at enrollment, 2. after the 3rd cycle of anticancer therapy, 3. after the 6thcycle of anticancer therapy, 4. at the end of treatment, or earlier if disease progression. For patients with limited disease, whole blood samples are collected at enrollment (i.e. after surgery, before starting any medical anticancer treatment), and thereafter once a year for 4 years, or at disease recurrence. At each time point, information on treatment, clinical response, and disease outcome, are collected. Plasma samples and clinical information are centralized at the Division of Immunohematology and Transfusion Medicine - Bergamo Hospital (coordinating center). Patient plasma is tested for a preliminary panel of hemostatic markers (D-dimer, Fibrinogen) and thrombin generation (TG).Results Between April 2012 and February 2014, 1,113 cancer patients were enrolled into the study. Follow-up data were available for 1,045 patients (359 metastatic/686 limited-resected) with NSCLC (n=252), gastric (n=74), colorectal (n=163) and breast (n=556) cancers, with an observation median time of 340 days. Forty-eight patients (4.6%) developed VTE with a median time of 123 days from enrollment. VTE was more frequent in metastatic compared to limited resected cancer patients (9.2% vs 2.2%); colorectal and lung cancer patients showed the highest VTE rate, 8.5% and 7.9%, respectively, independently of tumor stage. Currently plasma from 474 patients (196 metastatic/278 limited resected) were tested. Increased D-dimer and fibrinogen levels at enrollment showed to be significant risk factors for VTE by Kaplan-Meier analysis (HR: 5.4, 95% CI 2.2-13.2 p=0.000 for D-dimer; HR: 4.3, 95% CI 1.8-10.4 p=0.004 for fibrinogen) as well as the endogenous thrombin potential (HR: 4.5, 95% CI 1.8-11.4 p=0.000) and the TG peak (HR: 4.0, 95% CI 1.5-10.2 p=0.009). In the group with limited resected disease, the cumulative incidence of recurrence was 3.2% with a median time of 186 days. Increased D-dimer and fibrinogen levels at enrollment were predictive for disease recurrence by Kaplan-Meier analysis (HR: 9.9, 95% CI 2.4-40.1 p=0.001 for D-dimer; HR: 5.9, 95% CI 1.5-23.6 p=0.012 for fibrinogen).Conclusions These early results reveal that tumor stage and site, as well as elevated levels of D-dimer, fibrinogen and TG at enrollment, are associated with an increased risk of VTE in cancer patients. In subjects with limited resected cancer, elevated D-dimer and fibrinogen levels also predict for disease recurrence. These results support the hypothesis that testing for relatively easy plasma markers of thrombosis may be worth for monitoring the cancer response to therapy beyond the thrombotic risk.Project funded by AIRC “5xMILLE” n. 12237 grant from the “Italian Association for Cancer Research (AIRC)”. DisclosuresNo relevant conflicts of interest to declare.

Abstract 4938: In vivo visualization using two-photon laser scanning microscopy of anti-c-MET antibody in peritoneal metastatic gastric cancer

Abstract Background: c-MET (hepatocyte growth factor receptor) gene is overexpressed in approximately 20% of gastric cancer. Onartuzumab, a MET-selective humanized one-armed monoclonal antibody, has been studied in metastatic Met-positive non-small cell lung cancer and expected to be introduced to MET-positive gastric cancer. Two-photon laser scanning microscopy (TPLSM) has revolutionized in vivo real-time imaging because of the benefits of higher resolution, increased tissue penetration, and reduced photodamage. We established a method of intravital imaging for intra-abdominal organs using TPLSM with an organ stabilizing system (Japanese Patent No.5268282). Aim: To visualize the binding of fluorescence labeled-antibody to its receptor of cancer cells in peritoneal metastatic xenografts of living mice using a TPLSM. Method: Human gastric cancer cell lines (NUGC4) were inoculated into the peritoneal cavity of green fluorescent protein (GFP) expressing nude mice to make macroscopic peritoneal metastases. In vitro study, the binding of Zenon Alexa Fluor 594 labeled anti-c-MET antibody to viable NUGC4 cells was imaged using fluorescence microscopy. In vivo study, the binding of fluorescence labeled-antibody to viable NUGC4 cells of peritoneal metastatic xenografts was imaged using a TPLSM. Result: Zenon Alexa Fluor 594 labeled anti-c-MET antibody (red) was bound to the surface of viable NUGC4 cells, and clearly visualized under a fluorescence microscopy. Peritoneal metastases with label-free NUGC4 cells (black) and murine stromal cells (green) were imaged under TPLSM in vivo real-time. Fluorescence labeled-antibody could be visualized within tumor vessels of peritoneal metastases after its intravenous administration. Thereafter, label-free NUGC4 cells were identified by the binding of fluorescence labeled- anti-c-MET antibody to c-MET of NUGC4 cells. Conclusion: We could visualize fluorescence labeled-antibody in peritoneal metastases of gastric cancer in living mice using a TPLSM. The binding of fluorescence labeled- anti-c-MET antibody to c-MET of viable NUGC4 cells was clearly imaged at high magnification and high resolution in vivo real-time. It is valuable to develop a method of in vivo optical pathology for therapeutic monoclonal antibodies using MPM on metastatic tumor xenografts. Citation Format: Shozo Ide, Koji Tanaka, Tadanobu Shimura, Masato Okigami, Satoru Kondo, Takahito Kitajima, Hiroki Imaoka, Yoshinaga Okugawa, Susumu Saigusa, Yuji Toiyama, Hiromi Yasuda, Masaki Ohi, Yasuhiro Inoue, Toshimitsu Araki, Keiichi Uchida, Yasuhiko Mohri, Masato Kusunoki. In vivo visualization using two-photon laser scanning microscopy of anti-c-MET antibody in peritoneal metastatic gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4938. doi:10.1158/1538-7445.AM2014-4938

Abstract 2793: Phenotype and expansion profile of peripheral γδ T cells in patients with gastrointestinal cancer

Abstract During the last decade, adoptive transfer of autologous γδ T cells has been paid much attention to as an alternative immunotherapy for several types of cancer. It has been reported that human γδ T cells have potent cytotoxic activity against many types of tumor cell lines or primary cultured cells in vitro. Clinical studies in patients with metastatic renal cell carcinoma and non-small cell lung carcinoma showed that infusion of autologous γδ T cells is feasible and well tolerated. One of the problems in this therapy, however, is the difficulty for culturing peripheral γδ T cells in patients with cancer. Compared with healthy individuals, stimulation with phosphoantigens or bisphosphonates results in less expansion of γδ T cells in some patients. The tendency can be remarkably seen especially in those who have lower number of γδ T cells in peripheral blood. It is still unclear whether it is a unique phenomenon caused by something of malignancy or just due to the culture methodology. In this study, we investigated the characteristics of peripheral Vγ9Vδ2 T cells in patients with gastrointestinal cancer including their phenotype, the percentage in PBMC, and the proliferation activity in response to synthetic phosphoantigen, 2-methyl-3-butenyl-1-pyrophosphate (2M3B1PP). PBMC were prepared from patients, and then the phenotype and the number of Vγ9Vδ2 T cells were measured by flow cytometry. To expand Vγ9Vδ2 T cells in vitro, PBMC were cultured in AIM-V medium supplemented with 100 IU/mL IL-2, 100μM 2M3B1PP, and 10% autologous plasma. The expansion of Vγ9Vδ2 T cells were also examined using flow cytometry. We found that the percentage of the Vγ9Vδ2 T cells in peripheral T cells varied a lot depending on the patients. While their percentage in healthy individual was approx. 1.5-9.0%, it exceeded 10% in some patients, and even over 20% in several patients. Phenotypic analysis revealed that almost all the Vγ9Vδ2 T cells in these particular patients were effector-memory type cells with CD45RA-/CD27-/CCR7- and they massively expanded by the stimulation with 2M3B1PP. These results suggest that Vγ9Vδ2 T cells in these patients have been constantly exposed and stimulated with some specific antigens. On the other hand, the percentage of Vγ9Vδ2 T cells in T cells of some patients was less than 1.0%, and in the conventional culture methods the cells' response to 2M3B1PP was too low for them to proliferate themselves. However, their proliferation rate markedly increased when PBMC were inoculated at the high density (i.e. 1.3 x 104 Vγ9Vδ2 T cells per cm2 or more). The high density culture for 14 days has made it possible to expand the number of Vγ9Vδ2 T cells to 100-1000 folds. We conclude that Vγ9Vδ2 T cells in patients with gastrointestinal cancer have the equivalent level of proliferation ability to healthy individual even though the initial percentage is low, and thus these cells could be a possible effector cell type in a novel immunotherapy for gastrointestinal cancer. Citation Format: Yasunobu Kobayashi, Mayuko Sakai, Izumi Fujita, Hiroshi Komine, Masanori Matsushita, Koichi Shimizu, Atsushi Aruga, Hirohito Kobayashi, Keishi Tanigawa. Phenotype and expansion profile of peripheral γδ T cells in patients with gastrointestinal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2793. doi:10.1158/1538-7445.AM2014-2793

Abstract 4663: KRAS, BRAF, and EGFR mutational analysis in ovarian, colon, and lung cancers by highly multiplex PCR/barcoded-magnetic-bead (BMB) suspension-array assays

Abstract Anti-epithelial growth factor receptor (EGFR) monoclonal antibodies and small molecule EGFR inhibitors have been used for treating metastatic colorectal cancer (mCRC) and non-small cell lung cancer (NSCLC), respectively. However, since a relatively large proportion of the mCRC and NSCLC patients carry the activating KRAS/BRAF mutations that can render these EGFR-targeted therapies ineffective, the KRAS/BRAF mutation testing is now required for such prescription. In contrast, epithelial ovarian cancer (EOC) thus far has been treated by surgery, radiotherapy, and/or chemotherapy depending on the tumor stages. However, it has been shown that a high percentage of tumors of the mucinous, endometrioid, low-grade serous, and other types of EOC patients also contain KRAS or BRAF somatic mutations, suggesting that drugs targeting the mediators of the EGFR pathway may have implications on treating EOC of certain types. The conventional analysis of the KRAS, BRAF, and EGFR mutations has been done by multiple reactions with one mutation target per reaction, thus requiring a large amount of precious patient sample for complete testing. Here we present three highly multiplex molecular diagnostic assays, utilizing amplification by allele-specific PCR and automatic detection by a platform designed around the barcoded-magnetic-bead (BMB) suspension-array technology, for detection of 12 KRAS (in codons 12 and 13), six BRAF (in codon 600), and 21 EGFR (in exons 18-21) mutations in mCRC, NSCLC, and EOC patient samples. The results indicate that, albeit all the reaction components are in single wells, these highly multiplex PCR/BMB assays, by comparing with the sequencing results, not only are sensitive and specific but also can conserve precious tissue specimens, save operating time and labor, reduce turnaround time, and increase assay throughput. Citation Format: Jason Lei, Julia Hsu, Peggy Jen, Daniel Huang, Andre Chung, Lloyd Kao, Miller Chang, Chiou-Chung Yuan, Wei-Hwa Lee, Chi-Tai Yeh, Dean Tsao. KRAS, BRAF, and EGFR mutational analysis in ovarian, colon, and lung cancers by highly multiplex PCR/barcoded-magnetic-bead (BMB) suspension-array assays. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4663. doi:10.1158/1538-7445.AM2014-4663

Phase 2 study evaluating efficacy and safety of everolimus with letrozole in advanced (unresectable or metastatic) non-small cell lung cancer (NSCLC) after failure of platinum-based treatment: A preliminary analysis of toxicity.

e19089 Background: Lung cancer is a common malignancy with NSCLC comprising the majority of the cases. Previous studies have demonstrated a role for both the estrogen pathway and mammalian target o...

Assessing Palliative Care Unit Inpatients for Residential Aged Care Placement: Is It Worth It?

Increasing demand for palliative care unit (PCU) admissions has led to a stronger focus on discharge planning. This has resulted in shorter inpatient length of stays (LOS), and stable patients not requiring specialist palliative care services being referred for placement in residential aged care facilities (RACFs). The process of placement is time-consuming and can be distressing to patients and families, so RACF placement should only be proposed in patients whose prognosis is relatively good (i.e., weeks to months). Our aim was to identify the outcomes of palliative care inpatients referred for residential aged care placement. A retrospective chart audit was conducted. The patients' outcomes (discharge or death and survival time) were recorded and analyzed using SPSS statistical software. Subjects were 100 consecutive inpatients from a 30-bed PCU who had been referred for RACF placement. Of the 100 patients referred for RACF placement 73 of 100 (73%) patients had a malignant diagnosis, whereas 27 (27%) had a noncancer diagnosis. Thirty-eight (38%) patients died before discharge, including 33 of 73 (45%) patients with cancer and 5 of 27 (13%) patients with nonmalignant conditions. In particular, 12 of 17 (71%) patients with metastatic non-small cell lung (NCSLC) cancer died before or soon after discharge. Over one-third of all patients died before discharge to an RACF could take place. The rate of death before discharge was higher among patients who had cancer. Patients suffering from NCSLC need to be more carefully selected for placement as only one-third of these patients survived to discharge.

32 Review of pemetrexed with platinum chemotherapy for locally advanced or metastatic non squamous non-small cell lung cancer (NSCLC) in Northern Ireland

32 Review of pemetrexed with platinum chemotherapy for locally advanced or metastatic non squamous non-small cell lung cancer (NSCLC) in Northern Ireland

Metronomic weekly paclitaxel in metastatic or recurrent non-small cell lung cancers.

e19095 Background: Metastatic non small cell lung cancer (NSCLC) has a median survival of 4 months in absence of therapy. We present our experience with metronomic weekly paclitaxel in patients with metastatic or recurrent NSCLC and those with poor performance status. Methods: This is a retrospective analysis of prospectively collected data of patients with metastatic or recurrent NSCLC without significant neuropathy who were heavily pretreated or platinum ineligible from Feb 2010 to Oct 2012 at our centre. Patients were treated with paclitaxel at 80 mg/m2 over 1 hour weekly and underwent regular follow up. Chemotherapy was discontinued on disease progression or intolerable side -effects or patients choice. Patients who received at least 4 cycles of chemotherapy were included in the analysis. Toxicity was graded according to CTCAEv4.03. Statistics were calculated using SPSSv18.0. The progression-free survival was calculated from date of start of paclitaxel till date of symptomatic deterioration, radiological progression or start of next line of therapy or death due to any cause. Overall survival was calculated from date of start of paclitaxel to the date of death due to any cause. Results: Of the 100 patients studied (median age = 57 y, range 29–77 y), 74% were males, 51% were smokers, 45% had comorbidities, 35% had PS>2 and 74% had adenocarcinoma. About 53% received >2 prior lines of chemotherapy. Patients received a mean of 16.9 cycles of paclitaxel (range 4-72) after which it was withheld in 63% due to PD (53% radiological, 10% clinical) and in 12% due to toxicity. The response rates were 37% (CR-3% and PR-34%) while 35% had SD. 9% required dose reduction while 32% had delay in dose administration. G.3 adverse events observed were 12%-anaemia, 10%-neutropenia, 2%-febrile neutropenia, 15%- sensory neuropathy and 4%-motor neuropathy. The median OS was 12 months while median PFS was 5 months. Conclusions: Weekly paclitaxel is a promising and well tolerated therapy for advanced NSCLC.

A phase III comparative study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus docetaxel in patients with previously treated advanced or metastatic squamous cell non-small cell lung cancer (NSCLC).

TPS8122 Background: NSCLC is the leading cause of cancer death worldwide, exceeding breast, colon and prostate cancer combined. Most patients (pts) are diagnosed with advanced/recurrent disease. NSCLC therapies have incrementally improved overall survival (OS), but benefit has reached a plateau (median OS for late stage pts is just 1 yr). Squamous cell carcinoma (SCC) represents one quarter of NSCLC cases and has limited treatment options. Pemetrexed and bevacizumab are not approved in SCC, and molecularly targeted therapies have limited application. Single-agent chemotherapy is standard of care following progression with platinum-based doublet chemotherapy (Pt-doublet), resulting in median OS of approximately 7 months. Immune checkpoint blockade in NSCLC may promote tumor regression by reversing tumor-induced immunosuppression and restoring the antitumor immune response. Programmed death-1 (PD-1), an immune checkpoint receptor that negatively regulates T-cell activation, is upregulated in tumor infiltrating lymphocytes; expression of its ligand PD-L1 has been associated with poor prognosis in NSCLC. Nivolumab, a PD-1 receptor blocking antibody, showed encouraging antitumor activity in SCC pts in a phase 1 study, with objective responses (ORs) in 4 pts (27%) and stable disease ≥24 weeks in 1 pt (7%) (3 mg/kg; n=15) (Gettinger S et al; ESMO 2012 [Abstr 1237PD]). We describe an ongoing open-label phase 3 study to compare the clinical benefit of nivolumab vs docetaxel in advanced/metastatic SCC pts following failure of Pt-doublet. Methods: A total of 264 pts will be randomized 1:1 to nivolumab monotherapy 3 mg/kg IV every 2 weeks or docetaxel 75 mg/m2 every 3 weeks until disease progression or unacceptable toxicity. Pts will be stratified by prior paclitaxel use and geographic region. Tumor response will be assessed using modified RECIST 1.1. The co-primary objectives are OR rate and OS. Secondary objectives include progression free survival, clinical benefit in PD ligand 1 (PD-L1+) and PD-L1– subgroups (archived tissue required for entry), durability of and time to OR, and pt proportion with symptom improvement. Clinical trial information: NCT01642004.

Serum miRNA signature to identify a patient’s resistance to high-dose radiation therapy for unresectable non-small cell lung cancer.

7580 Background: There is a growing literature on unique profiles of serum micro RNAs (miRNAs) expression to predict clinical outcome of metastatic and early stage non-small cell lung cancer (NSCLC). However, the predictive role of circulating miRNAs in unresectable NSCLC treated with definitive radiation therapy (RT) is unknown. Methods: 134 patients with inoperable/unresectable NSCLC treated with definitive RT (18-month minimum follow-up) were eligible. Serum samples were collected prospectively before treatment. 100 patients had enough serum and reliable miRNA profile quality, which were randomly divided into training and validation sets (50 patients each). MiRNA profiling was performed using real-time PCR-based array, containing a panel of 84 miRNAs detectable in human bodily fluids. Spiked-in cel-miR-39 was used for normalization. Stepwise regression Cox model building was used to build a miRNA signature on the training set, which was then assessed on the validation set both alone and with clinical factors. Results: The median age was 67 years; 76% were stages III and 79% received chemoradiation; the median physical dose was 70.0 Gy. A serum hsa-miR-885/hsa-miR-7 signature was identified as significant predictors for overall survival (OS) in the training set, which was validated by the validation set (p=0.02). After adjustment for GTV Volume and KPS, the only two significant clinical factors in univariate analysis, this signature remained significant (p=0.04). In the high-dose RT group (>70 Gy, n=45), individuals with low-risk had a significantly longer OS than patients with high-risk (70.7 vs. 18.8 months, p=0.007); while in the low-dose RT group (≤70 Gy, n=55), no significant association was observed (OS, 22.0 vs. 13.3 months, p=0.43). Conclusions: Circulating hsa-miR-885/hsa-miR-7 signature may be used as a putative non-invasive biomarker for predicting survival and radiation resistance in unresectable NSCLC, which may potentially help to select patients who will not benefit from high-dose radiation. Independent validation studies are needed to confirm our findings. Clinical trial information: NCT01190527.

Abstract 2357: Prognostic value of placental growth factor expression in patients with metastatic or recurrent non-small cell lung cancer.

Abstract Background: Placental growth factor (PIGF) is a proangiogenic factor, belonging to the VEGF family. It binds to VEGF receptor 1(VEGFR-1) and stimulates the growth, migration and survival of endothelial cells. PIGF also activates and attracts macrophages that release angiogenic molecules. Increased expression of PIGF has correlated with poor survival of patients in several solid tumors. However, PIGF expression is not consistently elevated in all malignancies. No reports on the clinical implications of PIGF expression in metastatic or recurrent non-small cell lung cancer (NSCLC) are currently available. We investigate the clinical significance of PIGF expression in metastatic or recurrent NSCLC. Patients and methods: A retrospective review was done for seventy four patients with metastatic or recurrent NSCLC. Immunohistochemical staining for PIGF and its receptor VEGF-R1, neurophilin-1 was performed. Results: Of 74 patients with NSCLC, 73 patients were positive for PIGF, and 72 patients were positive for neurophilin-1. For PIGF expression, significant correlations were demonstrated with female (p=0.007) and nonsquamous histology (p=0.045). Thirty five patients (47%) were classified into low PIGF expression groups, whereas 38 patients (51%) were grouped as showing high PIGF expression. Survival time for patients with high PIGF expressing NSCLC was significantly longer than that for patients displaying low PIGF expression (median survival time, 15.1 months vs. 9.0 months[log-rank, p=0.01]). However, the difference in time to progression between two groups was not statistically significant (median time to progression, 5.1 months vs. 3.9 months [log-rank, p=0.24]). Conclusions: Low expression of PIGF is associated with poor prognosis in patients with metastatic or recurrent NSCLC. Further studies on larger patients populations are warranted to validate the utility of PIGF as a prognostic biomarker in lung cancer. Citation Format: Jung Hoon Kim, Tae Jung Kim, Kyu Sang Lee, Yun Hwa Jung, In Sook Woo, Sook Hee Hong, Chi Wha Han, Jae Kil Park, Jae Ho Byun. Prognostic value of placental growth factor expression in patients with metastatic or recurrent non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2357. doi:10.1158/1538-7445.AM2013-2357

Weekly paclitaxel and bevacizumab as fourth-line treatment or beyond for metastatic nonsquamous non-small cell lung cancer.

e18066 Background: Paclitaxel (P) and bevacizumab (B) showed synergistic antitumor efficacy in preclinical models. In combination with carboplatin, PB prolonged progression-free survival (PFS) and overall survival (OS) in selected metastatic non-squamous Non Small Cell Lung Cancer (NSCLC) patients compared to carboplatin and paclitaxel. Currently, there are no standard treatments beyond third-line therapy in NSCLC. We sought to determine the efficacy of weekly paclitaxel and bevacizumab (wPB) in non-squamous NSCLC as fourth-line therapy or beyond. Methods: we retrospectively reviewed patients with metastatic non-squamous NSCLC who have been treated with wPB in our institution. Patients were identified from a prospective database. Treatment consisted in P 80mg/m² on days 1, 8, 15 and B 15mg/kg on day 1, every 3 weeks until progression or unacceptable toxicity. Patients were evaluated every 3 cycles. PFS and OS were calculated from the date of initiation of wPB and analyzed using the Kaplan-Meier method. Results: Twenty patients received at least one cycle of wPB between 2008 and 2011. All patients received wPB as fourth-line treatment or beyond. Eight patients (40%) had a partial response, 7 patients (35%) had stable disease and 5 patients (25%) had progressive disease. Grade 3-4 adverse events included neutropenia (20%), onycholysis (10%), infection (10%), pulmonary haemorrhage (5%), neuropathy (5%) and hypertension (5%). One patient died from a bowel perforation following second cycle of wPB. The median PFS was 6.4 months (CI95% 4.1-9) and the median OS was 9.6 months (CI95% 7-19.7). One patient who previously received bevacizumab as part of first-line chemotherapy and another patient harbouring an ALK rearrangement benefited from wPB during more than 8 months and 18 months, respectively. Conclusions: In our experience, wPB exhibited acceptable toxicity and had encouraging anti-tumor efficacy as fourth-line treatment or beyond in non-squamous NSCLC patients, supporting further evaluation in larger prospective studies.

A multicenter, randomized phase II study of sequential vinorelbine (V)/cisplatin (C)/bevacizumab (B) followed by docetaxel (D)/gemcitabine (G)/B versus D/C/B as a first-line therapy for advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC).

e18105 Background: The combination of D with G has been shown equally active compared to the platinum-based doublets, which is considered the cornerstone for the treatment of NSCLC, with a more favorable toxicity profile (Georgoulias V. Lancet 2001 357: 1478-84). Sequential therapy with four active drugs (two doublets) in NSCLC, including C, was recently investigated and attributed a promising response rate (Pallis A. Lung Cancer, 2006, 52(2): 165-71). Incorporation of B to the standard platinum-based regimen improved its clinical outcome. Aim of this trial was to compare the efficacy of sequential four drug treatment in combination with B to the standard non platinum-based regimen combined with B. Methods: Seventy-seven treatment naïve patients (pts) with stage IIIB and IV non-squamous NSCLC were randomized to receive V 60 mg/m2 PO on day 1 and 8, C 80mg/m2 IV on day 1 and B 15 mg/kg IVon day 1, for 3 cycles followed by D 75 mg/m2 IV, G 1100 mg/m2 IV and B 15 mg/kg IV, all on day 1 (Arm A) or D 75 mg/m2 IV, C 80mg/m2 IV and B 15 mg/kg IV on day. The cycles were repeated every 3 weeks for a total of 6 cycles. The primary endpoint of the study was response rate (RR) and the secondary outcome measures were overall survival (OS) and progression free survival (PFS). Results: Thirty-nine pts were randomized to the control arm (Arm B) and 38 pts to the sequential arm. Pt demographics were balanced in both the arms. The overall RR was 36.8% and 46.2% in arm A and B, respectively (p= 0.49). There were 3 complete responses, one in arm A. Median PFS was 6.87 and 5.53 months in arm A and B, respectively (p= 0.368). Median OS was 19.6 and 10.33, respectively (p= 0.239). The estimated 1 and 2-year survival for arm A versus B were 71.1% and 36% versus 45.3% and 28%, respectively. No statistically significant difference in the toxicity profile was observed between the 2 arms. Conclusions: Sequential treatment with four active drugs is feasible and safe. The combination attributes encouraging results compared to the standard platinum-based regimen.

Safety and efficacy of paclitaxel liposome monotherapy for the treatment of elderly patients with advanced non-small cell lung cancer: A prospective, multicenter, uncontrolled phase II study.

e18086 Background: Recently, a novel form of paclitaxel encapsuled within liposome was developed with increased solubility and a longer half life in vivo. The aim of this study was to evaluate the safety and efficacy of paclitaxel liposome as a single agent chemotherapy for elderly patients with NSCLC. Methods: This study was a prospective, uncontrolled, open-label, multi-center, registered phase II trial (ChiCTR-TNC-00000226).Patients aged over 70 years with metastatic or recurrent non-small cell lung cancer were enrolled. Eligibility criteria included presence of measurable lesions, an ECOG PS of 0-2 as well as adequate organ function. Patients received paclitaxel liposome at an escalating dose of 135mg/m2, 150 mg/m2 and 175 mg/m2 every 3 weeks, and were monitored for safety and efficacy. Results: From 8 participating centers, 42 patients were enrolled with a median age of 73 years (range 70-81). A total of 89 cycles of chemotherapy was administered. No complete response was observed. 6.7%, 14.2% and 7.7% of patients obtained partial response, and 13.3%, 42.9% and 38.5% had stable disease from the escalating dose groups, respectively. The toxicity was mainly neutropenia, thrombopenia and digestive tract toxicity.There were 4 (26.7%), 3 (21.4%) and 3 cases (25%) of grade 3 or 4 neutropenia in the three dose group. Other non-hematological toxicities over grade 3 were rare. Pre-mature cease of chemotherapy occurred in 1 (7.1%) and 2 (16.6%) patients from the dose group of 150 mg/m2 and 175 mg/m2 respectively, all because of persistent toxicity. Median follow-up was 12.4 months (1.0-22.3 months). TTP in three dose group was 1.2 months (95%CI, 1.1-1.3 months), 1.2 months (95%CI, 0.9-1.3 months) and 1.9 months (95%CI, 1.4-2.3 months). Median OS in the dose group of 135 mg/m2 was 4.9 months (95%CI, 1.0-11.5 month), and not reached in the other groups. Conclusions: Paclitaxel liposome administered at the dose of 150 mg/m2 every 3 weeks seems to be safe and effective among these three dose levels. Although the toxicity profile was mild, the overall therapeutic effects were disappoiting.

Bevacizumab Therapy for Choroidal Melanoma

Bevacizumab, an anti-angiogenic agent, has gained widespread use in ophthalmology for the treatment of neovascular conditions, such as age-related macular degeneration. Targeting angiogenesis has been proposed as a potential therapy for different kinds of malignancies, by limiting supply of oxygen and nutrients, and consequently tumour growth and metastasis. Bevacizumab has been approved by the US Food and Drug Administration, along with chemotherapy, for the treatment of metastatic colorectal carcinoma and non-small cell lung cancer. Nevertheless, a beneficial effect in the treatment of choroidal melanoma has yet to be demonstrated, despite elevated levels of vascular endothelial growth factor (VEGF). However, bevacizumab might have a role in the management of complications of radiation therapy.

A Phase II Study of Sorafenlb In Patients with Locally Advanced And/or Metastatic (stage 1MB or IV) Non-small Cell Lung Cancer (NSCLC) with a K-Ras Mutation

A Phase II Study of Sorafenlb In Patients with Locally Advanced And/or Metastatic (stage 1MB or IV) Non-small Cell Lung Cancer (NSCLC) with a K-Ras Mutation

Phase 2 Trial of Linifanib (ABT-869) in Patients with Advanced Non-small Cell Lung Cancer

This study assessed activity and safety of linifanib (ABT-869), a selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, in patients with locally advanced or metastatic non-small cell lung cancer. In this open-label trial (NCT00517790), patients who received one to two prior lines of systemic therapy were randomized to oral linifanib 0.10 mg/kg (low dose) or 0.25 mg/kg (high dose) once daily. Tumor responses were assessed by independent central imaging review every 8 weeks. The primary end point was progression-free rate at 16 weeks. Secondary end points included objective response rate, time to progression, progression-free survival, and overall survival. Safety was also assessed. Between August 2007 and October 2008, 139 patients were enrolled; 60% had two or more prior regimens, and 88% had nonsquamous cell carcinoma. The objective response rate (low dose and high dose) was 5.0% (3.1 and 6.8%), progression-free rate at 16 weeks was 33.1% (32.3 and 33.8%), median time to progression was 3.6 months (3.6 and 3.7 months), median progression-free survival was 3.6 months (3.5 and 3.6 months), and median overall survival was 9.0 months (10.0 and 8.3 months). The most common linifanib-related adverse events were fatigue (42%), decreased appetite (38%), hypertension (37%), diarrhea (32%), nausea (27%), palmar-plantar erythrodysesthesia (24%), and proteinuria (22%). These events were more common in the high-dose group. The most common linifanib-related grade 3 or 4 adverse event was hypertension (14%). Linifanib is active in advanced non-small cell lung cancer as second- or third-line therapy. Increased adverse event rates were observed at the high dose of linifanib.