Lung Cancer Clinical Trials Research Articles

Non-small cell lung cancer clinical trials requiring biopsies with biomarker-specific results for enrollment provide unique challenges.

Clinical trials in lung cancer increasingly require patients to provide fresh tumor tissue as a prerequisite to enrollment. The effects of this requirement on enrollment rates, enrollment durations, and patient selection have not been fully elucidated. The authors retrospectively reviewed data generated by patients who consented to 1 or more interventional lung cancer clinical trials at the University of California-Los Angeles Jonsson Comprehensive Cancer Center between January 2013 and December 2014. Trials were considered to require a biopsy when enrollment was conditional on the procurement of tissue without intervening therapy between procurement and enrollment. In total, 311 patients underwent 368 screening incidents for 1 or more of 19 trials. Trials that required a new biopsy had a longer median screening duration (34 vs 14 days) than trials that did not require a biopsy (P < .001). Trials that required a biopsy had a greater screen failure rate (49.1% vs 26.5%; P < .001), which was largely driven by patients who did not undergo the required biopsy or lacked the required biomarker. Worsening performance status led to the majority of screen failures (56.5%) among biomarker-eligible patients. Although the scientific benefits of obtaining a new biopsy and requiring specific results for trial enrollment are clear, these requirements lead to a lengthening of the screening period, which, in some patients, is associated with clinical decline before enrollment. Implications for the interpretation of data from studies of this design should be explored. Cancer 2017;123:4800-7. © 2017 American Cancer Society.

MA 18.09 Enrollment of Minorities, the Elderly, and Women in Lung Cancer Clinical Trials

MA 18.09 Enrollment of Minorities, the Elderly, and Women in Lung Cancer Clinical Trials

MS 10.03 Community Outreach - Engaging in Primary Care

Lung cancer clinical trials are critical to advancing our understanding of disease characteristics, diagnostic criteria and treatment options. With evolving molecular testing and immunotherapies, clinical trials are increasingly complex and challenging to conduct at the site level. This report highlights the role of the Lung Cancer Clinical Research Nurse (LC-CRN) as vital to supporting patient participation and physician involvement for lung cancer trials. We also review new challenges with immunotherapies, nuances of sending tissue for molecular testing and importance of managing patient and family expectations.

Evaluating Patient Reported Outcomes Commonly Used In Current Lung Cancer Clinical Trials

Evaluating Patient Reported Outcomes Commonly Used In Current Lung Cancer Clinical Trials

Hedgehog Inhibition Upregulates TRK Expression to Antagonize Tumor Suppression in Small Cell Lung Cancer Cells.

Previously we have shown that tropomyosin-related kinase B (TRKB) and Hedgehog (Hh) signalling pathways induce malignant phenotypes in many cancer types. However, results from small cell lung cancer (SCLC) clinical trials using TRK and Hh inhibitors have been disappointing. One reason for this may be the existence of crosstalk between TRKB and Hh signalling pathways. In this study, we detected negative crosstalk between the TRKB and Hh-GLI1 signalling pathways. The human small cell lung carcinoma cell line, SBC-5, was used. Using small interfering RNA to inhibit TRKB and Hh signalling, whether TRKB and Hh signaling contribute to proliferation and invasiveness in SBC-5 cells were investigated. TRKB expression in GLI1 siRNA-transfected SBC-5 cells was higher than that of control cells. GLI1-knockdown alone did not affect invasiveness of SBC-5 cells. However, combined knockdown of TRKB and GLI1 significantly decreased invasiveness. Moreover, combined TRKB and GLI1 knockdown inhibited proliferation and migration to a greater extent than when either was inhibited alone. These results suggest that Hh inhibition increases TrkB expression to counter tumor suppression in SBC-5 cells. The combined use of TRKB and Hh inhibitors may, therefore, be useful for the treatment of refractory SCLC.

Thoracic Oncology Clinical Trial Eligibility Criteria and Requirements Continue to Increase in Number and Complexity

IntroductionEligibility criteria and screening procedures are designed to optimize the scientific yield and maximize the safety of clinical trials. However, they may also heighten trial complexity, hinder enrollment, decrease generalizability, and increase costs. We analyzed the types and number of eligibility criteria and screening procedures among thoracic oncology clinical trials sponsored or endorsed by the Eastern Cooperative Oncology Group. MethodsWe identified trials and obtained protocols from the Eastern Cooperative Oncology Group website. Eligibility criteria were grouped and categorized as comorbidity (classified by organ system), administrative requirements, prior treatment, and measurable disease requirements. Associations between trial characteristics and eligibility criteria were analyzed by using the Kruskal-Wallis and Wilcoxon tests. ResultsA total of 74 lung cancer trials activated in 1986–2016 were identified. The total number of eligibility criteria was associated with trial principal therapy (a median of nine for surgical, 18 for radiation, and 20 for medical therapy [p = 0.02]), trial primary end point (a median of 20 for overall survival, 28 for progression-free survival, and 17 for other [p = 0.001]), number of therapies (p = 0.05), and year of activation (a median of 16 for 1986–1995, 19 for 1996–2005, and 27 for 2006–2016 [P < 0.001]). The increase in trial eligibility requirements over time was limited to medical therapy trials. Over time, there was also an increase in blood test screening procedures (p = 0.05) but not in imaging, cardiac assessment, or pulmonary function screening procedures. ConclusionsThe number of eligibility criteria and screening procedures in medical therapy lung cancer clinical trials continues to rise. Continued efforts to simplify protocol eligibility and procedures are warranted to promote trial adherence, enrollment, completion, and generalizability.

Nanoplatforms for Circulating Tumor Cell Detection in Lung Cancer.

Analysis of circulating tumor cells (CTCs)2 and circulating tumor DNA, known as liquid biopsy, has received increasing attention because of its many potential clinical applications in the individual management of patients with cancer. Although CTC detection is currently more challenging than the analysis of circulating tumor DNA, one can obtain more information at the DNA, RNA, and protein levels from CTCs, and use CTCs for functional analyses. Thus, CTCs can also provide an important insight into tumor heterogeneity and enable investigation of biological mechanisms driving metastasis. Large-scale clinical studies have shown the accuracy of CTC counts as predictors of prognosis and response to therapy in different tumor entities (1). At present, there are >160 clinical trials for lung cancer alone listed on ClinicalTrials.gov, in which CTCs are used as investigative biomarkers. The availability of highly sensitive and flexible CTC analysis methods, particularly among patients with lung cancer, is of the highest clinical relevance. Further, approximately 70% of patients with non-small cell lung cancer (NSCLC) are diagnosed at stage III to IV, when a resection is no longer beneficial. Thus, only small biopsies are available from these patients, and these biopsies are not always sufficient to reflect the vast intratumoral heterogeneity of NSCLC; therefore, some druggable alterations may be overlooked. In the metastatic setting, if biopsies are collected, they are usually obtained from single sites and accordingly do not reflect the known tumor cell heterogeneity between different metastatic sites. CTCs are released from all sites and thus not only represent the cells with a high metastatic potential but also mirror the heterogeneity of the different tumor cells. Another benefit of CTC analyses compared with that of solid biopsy analyses is that blood analysis can be performed sequentially to monitor patients undergoing cancer therapy. However, the potential benefits of CTC analysis …

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Abstract 2245: Evaluation of new rexinoids for lung cancer

Abstract Lung cancer remains the leading cause of cancer deaths around the world. It is estimated that there will be over 150,000 deaths in the United States alone from this disease every year. With no significant improvement in 5 year survival rates over the past 30 years, effective prevention or early intervention is a promising approach to reduce the high mortality of lung cancer. Rexinoids are selective ligands for retinoid X receptors (RXR), which regulate the expression of a wide variety of genes. As transcription factors, rexinoids play important roles in proliferation, differentiation, and apoptosis, which are highly relevant in cancer. Bexarotene is the only synthetic rexinoid that has been approved by the FDA and is used for the treatment of refractory cutaneous T-cell lymphoma. It has also been tested in various clinical trials for lung cancer and breast cancer. However, Bexarotene is not potent or selective enough for RXRs, causing limited efficacy and unacceptable toxicities. Therefore, we synthesized a series of new rexinoids and screened them for their ability to inhibit nitric oxide (NO) production in RAW264.7 macrophage-like cells stimulated with LPS. Several of these compounds inhibited NO production at nanomolar concentrations. Based on this screening and other in vitro assays, two new rexinoids were chosen for in vivo testing. Female A/J mice were injected i.p. with vinyl carbamate (16 mg/kg). One week later, the mice were fed control diet or rexinoids in diet (40-80 mg/kg diet) for 16 weeks. Tumor number, size and histopathology were then evaluated. All of the rexinoids reduced the number and size of the lung tumors. However, Bexarotene only reduced the average number of tumors by 8-17%, while a new pyrimidine-analog of Bexarotene—henceforth, pyrimidine-Bexarotene—reduced the number of tumors by 24-28%. The average tumor burden on lung sections was also reduced by pyrimidine-Bexarotene by 59% compared to the controls (from 0.47 ± 0.19 mm3 in the control group to 0.19 ± 0.05 mm3 in the treated group). In contrast, average tumor burden was 0.35 ± 0.08 mm3 in the group treated with Bexarotene, a reduction of 26%. Notably, the percentage of high grade tumors (both histological and nuclear characteristics) were significantly (p&amp;lt;0.05) higher in the mice fed Bexarotene (63%) than in the control group (38%), while the percentage of high grade tumors was only 34% in the pyrimidine-Bexarotene group. Since a major side effect of rexinoids is an elevation in triglyceride levels, we measured total triclycerides in both liver and plasma. Pyrimidine-Bexarotene reduced triclyceride levels in the liver (7.17 ug/kg tissue) compared to Bexarotene (8.23 ug/kg tissue) and plasma (3.6mg/ml vs. 4.8mg/ml, respectively; p&amp;lt;0.05). These studies suggest that new rexinoids can be synthesized that are superior to Bexarotene for prevention of lung cancer. Additional synthesis and testing of new rexinoids will be performed to further enhance the potency and selectivity of this promising class of drugs. Citation Format: Di Zhang, Ana S. Leal, Sarah E. Carapellucci, Kayla Zydeck, Nicole Chaaban, Michael B. Sporn, Carl E. Wagner, Karen T. Liby. Evaluation of new rexinoids for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2245. doi:10.1158/1538-7445.AM2017-2245

Abstract 621: Tumor suppressor TUSC2 immunogene therapy is synergistic with anti-PD1 in lung cancer syngeneic mouse models

Abstract TUSC2, a pro-apoptotic tumor suppressor gene whose expression is lost or decreased in most lung cancers, activates the innate immune system through initiation of broad spectrum cytokine secretion and natural killer (NK) cell activation. TUSC2 delivered systemically by nanovesicles has mediated tumor regression in metastatic non-small cell lung cancer clinical trials. We studied the effect of TUSC2 on immune cell populations and the anti-tumor activity of TUSC2 in combination with anti-PD1 checkpoint blockade in two syngeneic mouse models: C57BL/6 mice subcutaneously injected with murine lung adenocarcinoma cell line CMT/167-luc cells (KrasG12V mutation) and 344SQ (KrasG12D allele and a knock-in Trp53R172HΔG allele) adenocarcinomas which metastasize to the lung in 129S2 mice. Tumor growth was monitored by scoring ex-vivo luminescence using the IVIS Imaging System 200. Multi-color flow cytometry was used for immune profiling of circulating immune cells after nanovesicle mediated TUSC2 intravenous injection. Cytokine gene expression in response to TUSC2 in sorted immune subpopulations was determined by real-time PCR. Tumor growth was significantly reduced with TUSC2 treatment compared with no treatment in both subcutaneous and metastatic mouse models. Synergistic anti-tumor activity was observed when TUSC2 was combined with anti-PD1 verified in five independent experiments. In the lung metastasis model, mice treated with TUSC2 + anti-PD1 lived significantly longer than with single agent treatment. Circulating NK cells increased three fold following TUSC2 nanovesicle intravenous injection both in tumor free and tumor bearing mice which correlated with tumor regression and survival. Cytotoxic T lymphocyte responses were increased whereas Tregs and MDSCs decreased with TUSC2 alone and TUSC2+anti-PD1 treatment. The levels of T cell checkpoint markers PD1, CTLA-4, LAG-3, and TIM-3 evaluated by flow cytometry were decreased after TUSC2 treatment. TUSC2 anti-tumor response was abolished when NK cells were depleted indicating NK cells are important mediators of the TUSC2 treatment effect. Single cell suspension analysis by flow cytometry showed high numbers of NK cells infiltrating lung tumor metastases after TUSC2 treatment. The number of tumor nodules in the lung was significantly less following treatment with TUSC2 nanovesicles compared with control. IL-15 gene expression which mediates NK cell proliferation, was increased by TUSC2. In conclusion, systemic TUSC2 nanovesicle immunogene therapy combined with checkpoint blockade showed synergistic anti-tumor efficacy and activated the immune system through upregulation of NK cells and CTL and downregulation of regulatory cells. Citation Format: Ismail M. Meraz, Mourad Majidi, RuPing Shao, Meng Feng, Xiaobo Cao, David Rice, Boris Sepesi, Lin Ji, Jack Roth. Tumor suppressor TUSC2 immunogene therapy is synergistic with anti-PD1 in lung cancer syngeneic mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 621. doi:10.1158/1538-7445.AM2017-621

Medical research: Personalized test tracks cancer relapse.

Genomic analysis of lung-tumour evolution has been used to create personalized blood tests that enable successful clinical monitoring for early signs of cancer relapse — a promising step on the road to precision medicine. See Article p.446 Circulating tumour DNA (ctDNA) has proven useful for detecting and monitoring cancer progression from plasma samples. The authors have applied a bespoke multiplex-PCR next-generation sequencing approach to profile ctDNA in the prospective TRACERx lung cancer clinical trial study. The assay tracks clonal and subclonal variants, in pre- and post-surgery samples. In pre-surgery samples ctDNA detection is associated with histological subtype and other pathological variables and correlates with tumour volume. Blinded longitudinal profiling suggests that ctDNA detection also associates with relapse, and provides insight into the evolutionary patterns of tumour cell subclones during progression. These results advance our understanding of how liquid biopsies can be applied clinically to improve monitoring of cancer.

The application of electronic medical records (EMRs) as a virtual comparator arm in a lung cancer clinical trial: A case study.

e18098 Background: Single-arm and open-label clinical studies are common in oncology drug development, leading to a frequent need for contextualization of results and provision of other means of comparison for cost-effectiveness models. The utility of current approaches such as naïve comparisons, historical control benchmarking, and match-adjusted interventional controls is limited. An alternative approach is the use of routinely collected data from Electronic Medical Records (EMRs). This study sought to determine if overall survival (OS) in advanced non-small cell lung cancer patients from a clinical trial comparator arm could be replicated using EMR data. Methods: De-identified EMR-derived patient data from Flatiron Health were matched via propensity scores to Project Data Sphere clinical trial data for study NCT00457392 of sunitinib plus erlotinib versus erlotinib alone to compare overall survival outcomes. A Cox regression model stratified for dataset was used to estimate the hazard ratio and 95% confidence interval for OS. Results: The Kaplan Meier curves were comparable for the first period after start of treatment, but differed after median survival was reached, with the Flatiron dataset achieving longer median OS. This deviation was strongly associated with differences in post-erlotinib treatment options introduced between the clinical trial period and the EMR period. Splitting the Flatiron data in two, related to the period from which the data were obtained (pre- or post-2013), resulted in a better match for the period closer to the trial [HR: 1.12 (0.93,1.35), P = 0.219] than for the later period [HR: 1.23 (1.01,1.5), P = 0.039]. Conclusions: Our results demonstrate that the time period in which EMR data are collected is important when matching to trial data. EMR data can contextualize the OS benefit for single-arm or uncontrolled trials run in the same time period. Further exploration of time-varying effects on OS is warranted.

Assessment of actionability of cancer genomic testing panels based on a structured clinical trial knowledge base.

6533 Background: Today’s oncologist is responsible for choosing appropriate cancer genomics tests to inform patient treatment from multiple available platforms, weighing cost, availability, sensitivity and specificity, and clinical actionability. Knowledge-driven clinical decision support tools can assist clinicians in choosing the panel that is most informative in a given clinical space. Methods: Using a queryable knowledgebase of &gt;1800 active clinical trials containing structured eligibility criteria curations for diagnosis and genomic alterations, we compared two CLIA-regulated genomic panels for clinical actionability over the landscape of solid, breast, and lung cancer clinical trials. Results: The larger panel (73 genes) was more actionable than the smaller panel (62 genes) in the breast cancer (10x more trials returned) and solid tumor (2.7x more trials returned) clinical trial space, while the smaller panel returned 1.2x more trials in the lung cancer space (see table). Conclusions: This analysis demonstrates that patient diagnosis has a significant effect on the potential clinical actionability of a given genomic panel. Further, this analysis demonstrates the clinical utility of knowledge-driven clinical decision support tools for test selection, especially given the often-limited tumor sample available, cost of genomic panel testing, and continuously shifting trial landscape. [Table: see text]

Changes in numbers of randomized (RCT) versus non-randomized (NRCT) clinical trials from 2004-2016: Evidence of shifting cancer drug development pathway.

2543 Background: Trials using randomized designs have been conducted for decades to demonstrate efficacy of novel anti-cancer drugs (NACD). Recently, several NACD have shown high antitumor activity in early phase studies, prompting suggestions that NRCT could expedite drug development. We sought to determine what changes have occurred in numbers of NACD RCT vs NRCT conducted from 2004-2016. Methods: We reviewed a database of NACD clinical trials conducted by INC (excluding phase I and I/II trials) and classified them by RCT vs NRCT, grouped by year (≤ 2010 or &gt; 2010). We queried Citeline Trialtrove database for industry sponsored, phase 2 trials (P2T) initiated from 2006-2016 and examined numbers of RCT vs NRCT by year.A more detailed analysis of non-small cell lung cancer (NSCLC) clinical trials based on drug type category - Immunooncology (IO) vs. all other mechanims of action (NIO) was performed. Results: 190 INC-conducted trials were reviewed. 58 trials (31%) were performed ≤ 2010 and 132 trials (69%) &gt; 2010. Over this period, NRCT (n = 107, 56%) outnumbered RCT (n = 83, 44%). Whereas RCT outnumbered NRCT from 2004-2010 (74% vs 52%), after 2010, NRCT outnumbered RCT (58% vs 42%). Citeline Trialtrove search revealed 4776 industry sponsored P2T initiated from 2006-2016. The total number of P2T started annually was highest in 2007 (n = 621), decreasing to a low of 375 in 2016. The proportion of phase 2 RCT demonstrated an increase from 27% (n = 166) in 2006 to a peak plateau of 37-39% from 2011-2014, followed by a drop to 33% in 2015 and 29% in 2016. Among IO studies, RCT declined in 2015-6 vs. previous years, and a decreased for all NACD in 2016 vs. previous years also was noted. For studies in NSCLC, declines in RCT were evident from 2015-6 vs. previous years ( 45% in 2007-14 vs. 25% in 2015-6). Conclusions: Our data indicate a trend toward fewer trials of NACD using randomized designs and more studies using non-randomized designs, with overall fewer P2T initiated in the past year. This change reflects shifts in NACD development pathways, related to a better understanding of cancer biology, drive to develop personalized treatment and a more flexible regulatory drug approval process.

Outcomes of research biopsies in clinical trials of EGFR mutation-positive non-small cell lung cancer patients pretreated with EGFR-tyrosine kinase inhibitors

Research biopsies (RBs) are crucial for developing novel molecular targeted agents. However, the safety and diagnostic yields of RBs have not been investigated in EGFR mutation-positive non-small cell lung cancer (NSCLC) patients pretreated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We searched the medical records of NSCLC patients who participated in lung cancer clinical trials and underwent mandatory RBs between 2012 and 2014at our institution. Only patients with EGFR mutation-positive NSCLC pretreated with at least 1 EGFR-TKI were enrolled. Of 140 enrolled patients, 73 (52.1%) and 59 (42.1%) had exon 19 deletions and exon 21 L858R mutation, respectively. Before RBs, 108 (77.1%), 83 (59.3%), and 36 (25.7%) patients had been treated with gefitinib, erlotinib, and afatinib, respectively. Computed tomography-guided percutaneous core needle biopsy was the most frequently used modality among 181 RBs performed (50.8%), followed by ultrasonography-guided (32.0%) and endoscopic RBs (16.0%). The most common RB sites were the lung (69.6%), pleura (8.8%), and liver (6.1%). Pathologic examinations revealed malignant cells in most RB specimens (72.9%). Complications due to RBs included pneumothorax (11.6%), bleeding (6.1%), and infection (1.1%). Only 1 patient required chest tube placement for pneumothorax, and 2 patients underwent endotracheal intubation because of bleeding. RBs in this patient population were generally safe. Pneumothorax was the most frequent complication; bleeding, while infrequent, increased the risk of severe events. The diagnostic yields and complications of any particular modality should therefore be discussed with prospective clinical trial participants.

Time and Effort Required for Tissue Acquisition and Submission in Lung Cancer Clinical Trials

BackgroundIncreasingly, analysis of tumor tissue samples for predictive and pharmacodynamic biomarkers is incorporated into lung cancer clinical trials. We determined the time and effort required for tissue acquisition and submission. Patients and MethodsWe analyzed data from patients enrolled from 2009 to 2016 at UT Southwestern onto lung cancer trials with mandatory or optional submission of tumor tissue. We collected dates of treatment-related events and staff communications; nature of tissue requirement and biomarker analysis; and location of archival tissue. Associations between case characteristics, clinical intervals, and number of staff communications were analyzed by Fisher's exact test, Wilcoxon 2-sample test, and Kruskal-Wallis test. ResultsWe identified 129 patients enrolled onto 19 clinical trials, of whom 108 (84%) ultimately received study therapy. For cases in which tissue submission was required if available or optional, 16% and 0%, respectively, had tissue sent. The median interval between consent and treatment was 28 (interquartile range, 11-43) days if tissue was requested and 7 (interquartile range, 6-13) days if tissue was not requested (P < .001). Among cases with requested tissue, the median number of related research staff communications was 3 (range, 0-10). Over time, the number of staff communications increased (P < .001). Location of archival tissue was not associated with number of staff communications or treatment intervals. ConclusionLung cancer clinical trial requirements for tissue acquisition and submission affect the time to treatment initiation and require increasing staff effort. Improved systems to expedite these processes, as well as use of blood- or imaging-based biomarkers, may help address these issues.

Comparison of the rexinoids Bexarotene and Pyrimidine‐Bexarotene in a preclinical model of lung carcinogenesis

Lung cancer remains the leading cause of cancer deaths around the world. It is estimated that there will be over 150,000 deaths in the United States alone from this disease every year. With no significant improvement in 5 year survival rates over the past 30 years, effective prevention or early intervention is a promising approach to reduce the high mortality of lung cancer. Rexinoids are selective ligands for retinoid X receptors (RXR), which regulate the expression of a wide variety of genes. As transcription factors, rexinoids play important roles in proliferation, differentiation, and apoptosis, which are highly relevant in cancer. Bexarotene is the only synthetic rexinoid that has been approved by the FDA and is used for the treatment of refractory cutaneous T‐cell lymphoma. It has also been tested in various clinical trials for lung cancer and breast cancer. However, Bexarotene is not potent or selective enough for RXRs, causing limited efficacy and unacceptable toxicities. Therefore, we synthesized a series of new rexinoids and screened them for their ability to inhibit nitric oxide (NO) production in RAW264.7 macrophage‐like cells stimulated with LPS. Several of these compounds inhibited NO production at nanomolar concentrations. Based on this screening and other in vitro assays, two new rexinoids were chosen for in vivo testing. Female A/J mice were injected i.p. with vinyl carbamate (16 mg/kg). One week later, the mice were fed control diet or rexinoids in diet (40–80 mg/kg diet) for 16 weeks. Tumor number, size and histopathology were then evaluated. All of the rexinoids reduced the number and size of the lung tumors. However, Bexarotene only reduced the average number of tumors by 8–17%, while a new pyrimidine‐analog of Bexarotene—henceforth, pyrimidine‐Bexarotene—reduced the number of tumors by 24–28%. The average tumor burden on lung sections was also reduced by pyrimidine‐Bexarotene by 59% compared to the controls (from 0.47 ± 0.19 mm3 in the control group to 0.19 ± 0.05 mm3 in the treated group). In contrast, average tumor burden was 0.35 ± 0.08 mm3 in the group treated with Bexarotene, a reduction of 26%. Notably, the percentage of high grade tumors (both histological and nuclear characteristics) were significantly (p&lt;0.05) higher in the mice fed Bexarotene (63%) than in the control group (38%), while the percentage of high grade tumors was only 34% in the pyrimidine‐Bexarotene group. Since a major side effect of rexinoids is an elevation in triglyceride levels, we measured total triclycerides in both liver and plasma. Pyrimidine‐Bexarotene reduced triclyceride levels in the liver (7.17 ug/kg tissue) compared to Bexarotene (8.23 ug/kg tissue) and plasma (3.6mg/ml vs. 4.8mg/ml, respectively; p&lt;0.05). These studies suggest that new rexinoids can be synthesized that are superior to Bexarotene for prevention of lung cancer. Additional synthesis and testing of new rexinoids will be performed to further enhance the potency and selectivity of this promising class of drugs.

Economic burden of clinical trials in lung cancer in a German Comprehensive Cancer Center

ObjectivesThe recent success of individualized lung cancer therapy has triggered fundamental changes in clinical research strategies. To date there is a strong focus on early proof of concept trials in genetically preselected small patient subgroups. This analysis focuses on the economic burden caused by such trials for advanced lung cancer patients in a German Comprehensive Cancer Center (CCC). MethodsThe profit margins between recruiting groups with ≤3 and >3 patients were compared. Clinical and economic data from clinical trials for advanced lung cancer (LC), pharma-sponsored trials (PhST) as well as investigator initiated trials (IIT), conducted between 2011 and 2015 at the Center for Integrated Oncology (CIO) Cologne, were analyzed using a profit-center calculation model. Results161 patients were enrolled in 27 clinical trials. The key economic parameter determining costs and payments was the ‘trial visits’. In comparison of the two groups (A≤3; B>3 patients enrolled) we found negative profit margins for the low recruiting group (€ −1444). Concerning the number of visits significant differences were found between PhST and IIT (p=0.009). Additionally, sub-analysis show structural differences in cost composition by conducting PhST and IIT. ConclusionTrials with low patient numbers and IIT, do not cover the cost. To ensure adequate, cost-covering compensation by pharmaceutical companies CCCs have to thoroughly calculate the cost of early proof of concept trials. The findings of this study also underline the need for novel structures in public funding for investigator-initiated clinical trials in precision medicine.

Model-based meta-analysis of safety for immune checkpoint inhibitor combinations and monotherapy.

89 Background: Immune checkpoint inhibitors (ICIs) have shown efficacy across multiple cancer types; however, ICIs are also associated with immune-mediated (im) adverse events (AEs) especially when used in combination. Methods: Published safety data from 35 melanoma and non-small cell lung cancer clinical trials was normalized for drug exposure using drug concentrations at 50% inhibition (IC50). Pharmacokinetic models from FDA, EMEA, and our own model were used to compare AEs across 4 ICIs: anti-PD-1 (nivolumab, pembrolizumab) and anti-CTLA-4 (ipilumumab, tremelimumab). Data was analyzed by ICI target and organ class (ie, GI, skin, liver, lung, and endocrine). To test dependence of AE rate (%) on drug dose dependence (DD) we calculated mean AE rates for low and high halves of the dose range, and used Pearson’s χ2-squared test for statistical significance (SS) ( p&lt; 0.05). Results: We found AEs to be DD for anti-CTLA-4 monotherapies and anti-CTLA-4 + anti-PD-1 combinations, whereas DD was not SS for anti-PD-1 monotherapies (Table). For anti-CTLA-4 drugs DD was SS for GI, hepatic, skin, and endocrine AEs. In combination, there was DD upon anti-CTLA-4, but data were insufficient to confirm SS. For PD-1 drugs there was no significant DD found. Conclusions: For anti-PD-1 therapy, no DD for Grade 3/4 AEs was found across organ classes. However, for anti-CTLA-4 therapies, DD was SS for GI, skin, hepatic, and endocrine im AEs. Although not all data were sufficient to confirm SS, dose intensity of anti-CTLA-4 may be an important determinant of AEs, when co-administered with anti-PD-1. [Table: see text]

SC06.03 Intraoperative Therapies in Malignant Pleural Mesothelioma

SC06.03 Intraoperative Therapies in Malignant Pleural Mesothelioma