Predictor Of Objective Response Research Articles

Prospective Trial Using Internal Pair-Production Positron Emission Tomography to Establish the Yttrium-90 Radioembolization Dose Required for Response of Hepatocellular Carcinoma

Toprospectively assess the threshold dose for objective response of hepatocellular carcinoma (HCC), using 90Y internal pair-production positron emission tomography (PET) to quantify the radiation dose delivered to hepatic tumors after radioembolization. A prospective study was performed under institutional review board approval from 2012 to 2014. Thirty-five patients with primary and secondary liver tumors undergoing 90Y treatment were recruited. Eight patients did not meet inclusion criteria, and 27 patients with HCC were included for analysis. Time-of-flight PET imaging was performed immediately after radioembolization and voxel values converted into 90Y activity. The radioembolization dose was calculated from PET images, and image segmentation was performed with volumetric analysis of dose deposition within tumors. Radiographic response was assessed on follow-up imaging. Treated HCC showed 84% objective response, 11% stable disease, and 5% progressive disease according to modified RECIST 1.1 response criteria. Responders had a higher median 90Y tumor dose than nonresponders (225Gy vs 83Gy, P < .01). Logistic regression models show tumor dose (P=.002) strongly predicted objective response. All nonresponders had tumor dose <200Gy. No statistical difference for patient age, tumor volume, multifocal or extrahepatic disease, portal vein invasion, or injected 90Y activity was found between responders and nonresponders. Hepatocellular carcinoma that resulted in objective response after radioembolization had a greater median tumor dose of 225Gy, compared with 83Gy in nonresponders. Delivered tumor dose can be assessed by PET and significantly impacts treatment response in HCC.

Abstract 5049: Application of population pharmacokinetic and exposure-response modeling for DS-8201a, a HER2-targeting ADC, predicts 50% ORR in patients with heavily pretreated breast cancer

Abstract Background: Antibody-drug conjugates (ADC) provide a wider therapeutic index by allowing specific targeting of cytotoxic agents to tumor cells. DS-8201a is a novel HER2-targeting ADC which contains a high average drug-to-antibody-ratio (DAR) of 7-8 molecules of a topoisomerase I inhibitor (exatecan derivative, DXd) per antibody. Preclinical data demonstrated a broader antitumor activity of DS-8201a than T-DM1 (the only FDA approved HER2-targeting ADC), including efficacy against T-DM1 resistant and HER2 low-expressing tumors. The first-in-human (FIH) study, comprising a dose escalation (Part 1) and expansion (Part 2), is being conducted in patients with HER2+ breast cancer (BC), gastric cancer (GC), and other HER2 expressing tumors. This analysis was aimed to assess DS-8201a population pharmacokinetics (POPPK) and exposure-response (E-R) relationships for efficacy and key safety endpoints using data available so far, and to support Phase 2 dose selection. Methods: Preliminary data were obtained from Part 1 portion of the FIH study, in which a total of 23 patients with BC or GC received intravenous DS-8201a doses ranging from 0.8 to 8.0 mg/kg tri-weekly. Firstly, the POPPK model of DS-8201a and DXd in serum was developed and the individual-predicted exposures were derived. An exposure-driven, tumor growth inhibition (TGI) model was then fit to the longitudinal tumor sum of longest diameter (SLD) data. Additionally, the E-R relationships for thrombocytopenia (TCP) and gastrointestinal (GI) toxicity were assessed using a cell lifespan model and a logistic regression model, respectively. Results: A 2-compartment PK model with parallel linear and nonlinear elimination and a 1-compartment model with linear release and elimination best characterized the serum concentration-time profiles for DS-8201a and DXd, respectively. The TGI model for tumor SLD indicated a DS-8201a-exposure-dependent drug efficacy across the dose range tested. Model-based simulations showed that predicted % of patients exceeding pre-clinical efficacious DS-8201a concentration (4260 ng/mL) at trough was 86.7 to 95.9% during 6.4 mg/kg tri-weekly dosing, and predicted objective response rate (ORR) was approximately 50.5% in the Part 1 patient population with BC or GC. The cell lifespan modelling for TCP indicated that increased DS-8201a exposure was associated with a greater risk of grade 3 or 4 TCP but the predicted probability was low for doses of 6.4 mg/kg or below. No to minimal relationships with exposures of DS-8201a or DXd were observed for the GI toxicity. Conclusion: A series of model-based simulations demonstrated that 50% ORR was expected at 6.4 mg/kg DS-8201a tri-weekly, with limited increases in the risk of TCP and GI toxicity relative to lower doses, which supports the selection of this dose for Phase 2. Citation Format: Kazutaka Yoshihara, Seiko Endo, Kenji Tamura, Toshihiko Doi, Taro Tokui. Application of population pharmacokinetic and exposure-response modeling for DS-8201a, a HER2-targeting ADC, predicts 50% ORR in patients with heavily pretreated breast 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 5049. doi:10.1158/1538-7445.AM2017-5049

Abstract 2990: Polyfunctional anti-CD19 CAR T cells determined by single-cell multiplex proteomics associated with clinical activity in patients with advanced non-Hodgkin’s lymphoma

Abstract Introduction: Autologous anti-CD19 CAR T cells have shown promising clinical efficacy in B cell malignancies, with T cell expansion and blood levels for IL-15, IL-10 and Granzyme B as correlates of objective response and toxicity (Kochenderfer et al. J Clin Oncol 2016; 34:LBA3010). It is unclear, however, which key immune programs in CAR T cells impact their in vivo expansion and clinical outcome. We evaluated in detail the functionality of anti-CD19 CAR T cells by using single-cell proteomics analysis (Lu et al. PNAS 2015;113:607-615). We explored how the polyfunctionality of pre-infusion CAR T cell products, post-stimulation with the CD19 antigen in vitro, associated with CAR T cell expansion in vivo and objective response. Methods: Product T cells were separated into CD4+ or CD8+ T cell subsets using microbeads. CD4+ or CD8+ fractions were then co-cultured with CD19-K562 targets or NGFR-K562 control cells, at a 1:2 ratio for 20 hrs. Single cells were then analyzed using a 32-plex panel of secreted cytokines, chemokines, and cytotoxic molecules. Specifically, T cells were loaded onto a single-cell barcode chip capable of assaying 32 secreted proteins/cell. The polyfunctional profile and strength (pSI) of each sample was determined (Ma et al. Cancer Discov 2013;3:418-429) and analyzed relative to in vivo expansion of the CAR T cells and patient response to the CAR T cell therapy. CAR T cell expansion in blood was measured by quantitative PCR. Results: Single-cell pSI of patient CAR T cells showed a statistically significant association (p = 0.011) with objective response (complete or partial response) to the therapy. While product pSI showed variability across patients, the median pSI was 2+ times higher for responders versus non-responders. The polyfunctional profiles for both CD4+ and CD8+ cells were dominated by effector molecules, stimulatory cytokines and chemokines. Polyfunctional CD4+ and CD8+ subsets with IFN-γ, IL-8 and/or MIP-1α correlated best with patient outcome, with CD8+ T cells showing co-expression of Granzyme B, and CD4+ T cells also comprising IL-17A+IL8+ and IL5+IL8+ subsets. While CAR expansion in vivo also correlated with objective response (p = 0.032), the association between product pSI and CAR cell expansion in vivo did not reach statistical significance (p = 0.079), suggesting that they bring independent contributions to predicting objective response. In support of that, a composite index integrating pSI and CAR T cell expansion in vivo associated best with clinical response (p = 0.005). Conclusion: Polyfunctionality of CAR T cells, in conjunction with their expansion in vivo, correlates with clinical outcome in an anti-CD19 CAR T cell clinical trial. Single-cell multiplexed proteomics measurements may provide powerful insight into the clinical performance of CAR T cell products. [J.R. and P.P. contributed equally to this study.] Citation Format: John Rossi, Patrick Paczkowski, Yueh-wei Shen, Kevin Morse, Brianna Flynn, Alaina Kaiser, Colin Ng, Kyle Gallatin, Tom Cain, Rong Fan, Sean Mackay, James Heath, Steven A. Rosenberg, James N. Kochenderfer, Jing Zhou, Adrian Bot. Polyfunctional anti-CD19 CAR T cells determined by single-cell multiplex proteomics associated with clinical activity in patients with advanced non-Hodgkin’s lymphoma [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 2990. doi:10.1158/1538-7445.AM2017-2990

Dynamic contrast-enhanced MR imaging pharmacokinetic parameters as predictors of treatment response of brain metastases in patients with lung cancer.

To determine the diagnostic accuracy of pharmacokinetic parameters measured by dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in predicting the response of brain metastases to antineoplastic therapy in patients with lung cancer. Forty-four consecutive patients with lung cancer, harbouring 123 newly diagnosed brain metastases prospectively underwent conventional 3-T MRI at baseline (within 1month before treatment), during the early (7-10 weeks) and midterm (5-7 months) post-treatment period. An additional DCE MRI sequence was performed during baseline and early post-treatment MRI to evaluate baseline pharmacokinetic parameters (K trans, k ep, v e, v p) and their early variation (∆K trans, ∆k ep, ∆v e, ∆v p). The objective response was judged by the volume variation of each metastasis from baseline to midterm MRI. ROC curve analysis determined the best DCE MRI parameter to predict the objective response. Baseline DCE MRI parameters were not associated with the objective response. Early ∆K trans, ∆v e and ∆v p were significantly associated with the objective response (p = 0.02, p = 0.001 and p = 0.02, respectively). The best predictor of objective response was ∆v e with an area under the curve of 0.93 [95% CI = 0.87, 0.99]. DCE MRI and early ∆v e may be a useful tool to predict the objective response of brain metastases in patients with lung cancer. • DCE MRI could predict the response of brain metastases from lung cancer • ∆v e was the best predictor of response • DCE MRI could be used to individualize patients' follow-up.

Quantitative Characterization of the Exposure-Response Relationship for Cancer Immunotherapy: A Case Study of Nivolumab in Patients With Advanced Melanoma.

To inform the benefit–risk assessment of nivolumab in patients with advanced melanoma, analyses of efficacy and safety exposure–response (E–R) relationships were conducted with data from patients with advanced melanoma enrolled in two clinical studies (phase I and phase III) who received nivolumab 0.1–10.0 mg/kg every 2 weeks. E‐R efficacy analyses were performed by relating the nivolumab time‐averaged concentration after the first dose (Cavg1) to two endpoints: RECIST objective response (OR) and overall survival (OS). E–R safety analyses characterized the relationship between nivolumab Cavg1 and the hazard of all‐causality adverse events leading to discontinuation or death (AE‐DC/D). Nivolumab exposure represented by Cavg1 was not a significant predictor of OR, OS, or the hazard of AE‐DC/D. E–R efficacy and safety relationships were relatively flat over the exposure range.

Role of Genetic Polymorphisms on Response to R-Chopregimen in Diffuse Large B-Cell Lymphoma Patients: An Interim Analysis of a Multicenter Prospective Pharmacogenetic Study

Introduction: Standard chemotherapy represented by the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) regimen is successful in about 60% of patients (pts) with diffuse large B-cell lymphoma (DLBCL). Pts who do not benefit from this treatment, due to the development of tumor drug resistance, have a very poor prognosis.Currently, knowledge on reasons of treatment related failures in DLBCL are scanty and predictive biomarker of response are largely unknown. We hypothesized that polymorphisms of gene involved in the pharmacokinetics and pharmacodynamics of drugs included in R-CHOP regimen may play a role in predicting the outcome in DLBCL pts.Thus, we designed a multicentre prospective pharmacogenetic trial aimed at identifying gene polymorphisms potentially predictive of drug efficacy/resistance in DLBCL pts treated with R-CHOP. An interim analysis on the first 80 enrolled ptswas planned and has been performed.Methods: The study included chemonaive DLBCL pts at various stages of disease candidate to an R-CHOP standard treatment. The Ethical Committee of each participating centre approved the pharmacogenetic protocol, and all pts signed a written informed consent.According to the aims of this interim analysis, the impact of single nucleotide polymorphisms (SNPs) on R-CHOP efficacy was evaluated by objective response (OR) rate at the end of treatment.The efficacy of R-CHOP was evaluated according to the Cheson criteria by performing standard hematochemical and instrumental (TC and FDFG-PET) tests and defining complete remission (CR), partial remission (PR), non response or progressive disease (PD).Genomic DNA wasextracted from peripheral blood of 80 pts. Twentysingle nucleotide polymorphisms (SNPs) from18candidate genes (ABCB1, ABCC1, ABCC2, ABCG2, CYBA, CYP2C9, FCGR2A, GSTP1, IL2, MLH1, NCF4, NQO1, NQO2, RAC2, TNF, TOP2A, TP53, TUBB)involved in pharmacokinetics and pharmacodynamics of R-CHOP (www.pharmgkb.org) have been analysed by a genotyping array based on Affimetrix methodology.Univariate analysis was performed to evaluate associations between polymorphisms and clinical/pathological characteristics or OR (Fisher exact test). Multivariate logistic regression analysis was performed to estimate adjusted odds ratios along with the corresponding 95% confidence intervals for the polymorphisms and OR.Results: Median age was 63 years. There were 37 men and 43 women. 47.5 % of pts were in stage I-II,52.5 % of pts in stage III-IV. 27.5% of ptshad bulky disease, 43.8 % of pts had involvement of extranodal site. 47.5% of pts had pathological LDH value. According to the revised IPI, 15 % pts were in the low risk group, 58.7 % in the intermediate risk group, and 26.3 % in the high risk group.Overall, 468 courses of R-CHOP had been administered (mean: 5.85 courses, range: 4-6).81% of pts had CR to R-CHOP whereas the remaining showed PR (14%) or PD(5%).No statistically significant correlation was found between OR and clinical characteristics of pts.However, stage III-IV pts showed a worst OR than stage I-II pts (77% vs 87% of CR, respectively); pts with bulky disease had worst OR than non-bulky disease pts(73% vs 84.5% of CR, respectively); ptswith R-IPI 3-5 a worst OR than pts with R-IPI 0-2 (71.5% vs 85% of CR, respectively).Univariate and multivariateanalysis identified TOPOII rs13695as a predictor of OR (p=0.042). Pts with CT or TT genotypesshowed worst OR than CC wild-type homozygous pts (odds ratio 3.070, CI95% 1.113-13.457). Also, a statistical trend toward significance was observed for MLH1 rs1800734 polymorphism (p=0.062): ptswith homozygous genotype for the mutant allele showed a better OR than wild-type and heterozygous pt genotypes.Conclusions: No significant relationship between clinical/pathological characteristics and OR was observed.Our preliminary data show that SNPs affecting a gene involved in doxorubicin pharmacodynamics, i.e. the drug target TOPOII, as well asone of the major components of DNA mismatch repair, i.e. MLH1 gene,may predict response in DLBCL pts treated with R-CHOP.These preliminary results from the interim analysis are promising and warrant completion of pt accrual to reach the planned number of cases at the end of our study.AcknowledgmentsThis work was supported by a grant from the Associazione Giacomo Onlus, Castiglioncello (LI), Italy to E.M. and Cassa di Risparmio di Firenze, Firenze, Italy to S.N. DisclosuresNo relevant conflicts of interest to declare.

Streptozocin-Based Chemotherapy in Patients with Advanced Neuroendocrine Neoplasms--Predictive and Prognostic Markers for Treatment Stratification.

Background and AimChemotherapy with streptozocin (STZ) in combination with 5-FU or doxorubicin (Dox) represents a standard of care for patients with metastatic pancreatic neuroendocrine neoplasms (pNEN). However, predictive markers for patient selection are still missing. The aim of this study was a retrospective evaluation of the clinicopathological characteristics of pNEN patients receiving STZ-based chemotherapies and to identify predictive and prognostic markers.Patients and MethodsWe retrospectively analyzed 77 patients treated at our center between 1995 and 2013. The median overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier and Cox regression methods, respectively. Uni- and multivariate analyses were performed.ResultsThe median PFS (mPFS) in patients receiving STZ/5-FU/Dox was 16 months with a median OS (mOS) of 28 months. Objective response rate (ORR) and disease control rate (DCR) were 34% and 72%, respectively. Biochemical response and positive octreotide scintigraphy predicted objective response. Univariate analysis revealed Ki-67 > 10% and the absence of biochemical or objective response by imaging as independent risk factors for shorter PFS. Additionally, performance status (PS) and resection of the primary tumor were observed to influence mOS. Treatment was well tolerated with less than 10% grade 3 and 4 toxicities.ConclusionsSTZ-based chemotherapy is an effective and well-tolerated treatment option in patients with well differentiated neuroendocrine neoplasms. Positive octreotide scintigraphy and biochemical response predict objective response.

Baseline and Early MR Apparent Diffusion Coefficient Quantification as a Predictor of Response of Unresectable Hepatocellular Carcinoma to Doxorubicin Drug-Eluting Bead Chemoembolization

PurposeTo investigate baseline and early apparent diffusion coefficients (ADC) derived from diffusion-weighted imaging (DWI) as a predictor of objective response (OR) and survival in unresectable hepatocellular carcinoma (HCC) treated with doxorubicin drug-eluting bead (DEB) transcatheter arterial chemoembolization. Materials and MethodsIn a prospective study, 57 patients underwent DEB chemoembolization. Dynamic contrast-enhanced magnetic resonance imaging and DWI were performed at baseline and 1 and 3 months after DEB chemoembolization. OR was evaluated per modified Response Evaluation Criteria In Solid Tumors (mRECIST) and European Association for the Study of the Liver (EASL) guidelines. Baseline ADCs of tumors that showed OR at 1 and 3 months were compared with nonresponding tumor ADCs by two-sample t test and receiver operating characteristic curves. Additionally, ADC changes at 30 days were correlated with OR. Finally, Kaplan–Meier analysis was used to compare survival between patients with lesions demonstrating more restricted baseline diffusion and others. ResultsAt 1 month, 33 patients (60%) showed OR (21 complete responses and 12 partial responses). At baseline, tumors with OR at 1 month showed significantly more restricted diffusion (0.731 × 10−3 mm2/s) compared with others (1.057 × 10−3 mm2/s; P = .031). No difference between response rates at 1 and 3 months according to mRECIST and EASL was observed. For an area under the curve of 0.965, the sensitivity and specificity of predicting objective tumor response at 1 month using a baseline HCC ADC of 0.83 × 10−3 mm2/s were 91% and 96%, respectively. In addition, patients with lesions with a baseline ADC < 0.83 × 10−3 mm2/s showed prolonged survival compared with others (P < .001). ConclusionsIn unresectable HCC, a baseline ADC < 0.83 × 10−3 mm2/s is a predictor of survival and treatment response at 1 and 3 months after DEB chemoembolization with high sensitivity and specificity.

Abstract 1617: Analysis of single mouse tumor response results from the Pediatric Preclinical Testing Program (PPTP)

Abstract Traditional approaches to evaluating antitumor agents using human tumor xenograft models have usually used 8-10 mice in control and treatment groups against a limited panel of tumor models. However, with increasing evidence of molecular/genetic subsets of tumors within a histotype, there is a need to establish panels of tumors that accurately reflect such heterogeneity. The consequences of evaluating agents in a large number of models is that it is highly resource consuming. An alternative approach is to use fewer animals per tumor line, allowing a greater number of models to be evaluated that capture greater molecular/genetic heterogeneity of the cancer type. We analyzed 67 agents evaluated by the PPTP to determine whether a single mouse, chosen by a random number generating routine in Excel, predicted the median response for groups of mice (solid tumors n = 10; acute lymphoblastic leukemias n = 8). Agents evaluated included standard cytotoxic agents, tyrosine kinase inhibitors, receptor-binding antibodies, and anti-angiogenic agents. Data were analyzed to determine predictive value for 79 xenograft models, and to identify classes of antitumor agent where predictive value of single mouse experiments was poor. The individual tumor response was compared to the group median response using response criteria developed in the PPTP. A total of 2106 comparisons were made. The single tumor response accurately predicted the group median response in 1684 comparisons (79.34%). Models had a range for accurate prediction (0.583 - 0.918). Allowing for mis-prediction of + or - one response category, the overall prediction rate increased to 95.63%. Single tumor results accurately predicted objective response rates (ORR) determined by group response, in 66 of 67 studies. There was a single study where single mouse data incorrectly predicted an agent as ‘active’ (&amp;gt;20% ORR). For most tumor models the single mouse appears to give results similar to groups of 8-10 mice. Importantly, even allowing for slight inaccuracy (± 1 response category), the single mouse experiment identified all active agents, and in the worse case over-predicted activity in one tumor histotype. The advantage of the single mouse experimental design is that it allows for inclusion of models that encompass greater molecular heterogeneity, thus recapitulating the clinical heterogeneity more accurately. Potentially, this design also reduces the numbers of mice used for experimentation. However, to generate these patient derived xenograft models, particularly solid tumors at diagnosis and relapse will require national and international coordination through organizations such as the Children's Oncology Group. Citation Format: Brendan Murphy, Han Yin, John M. Maris, Anders E. Kolb, Richard Gorlick, Patrick C. Reynolds, Min Kang, Stephen T. Keir, Raushan Kurmasheva, Igor Dvorchik, Jianrong Wu, Catherine Billups, Malcolm A. Smith, Peter J. Houghton. Analysis of single mouse tumor response results from the Pediatric Preclinical Testing Program (PPTP). [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 1617. doi:10.1158/1538-7445.AM2015-1617

Gene expression of metastatic biopsies for prediction of response to palliative chemotherapy in breast cancer.

1044 Background: To date, no clinically useful predictive tests for chemotherapy in breast cancer (BC) are available. Several studies have tried to identify predictive gene expression signatures in the neoadjuvant setting, but no data are available for metastatic BC. Methods: Patients with advanced breast cancer were treated with epirubicin and paclitaxel with or without capecitabine as first-line treatment in the Swedish Phase 3 TEX trial. For 111 patients, a metastatic biopsy was obtained at baseline for gene expression profiling (Affymetrix array GPL10379). PAM50 molecular subtypes and published gene modules related to immune response or proliferation were investigated as predictors of objective response to chemotherapy (by RECIST 1.0) and progression-free survival (PFS). Results: 102 patients were evaluated and 58 had an objective response. Table shows the PAM50 classification and the response within each subtype. Nine patients achieved a complete response, 6 of them were classified as basal-like and ...

Decreased levels of serum cytokeratin 19 fragment CYFRA 21-1 predict objective response to chemotherapy in patients with non-small cell lung cancer

Diagnostic tools capable of predicting early responses to chemotherapy are required to improve the individual management of cancer patients. The present study aimed to evaluate the prognostic significance of the serum tumor markers CYFRA 21-1, carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), carbohydrate antigen (CA) 125, and CA 19-9 for predicting responses to different chemotherapy regimens in patients with non-small cell lung cancer (NSCLC). A total of 276 patients with postoperative stage I–IV NSCLC were retrospectively reviewed. The five tumor markers were measured before and after at least two cycles of chemotherapy using an electrochemiluminescent assay. Multivariate analysis revealed that performance status, age, postoperative stage and surgery were significantly associated with the response to chemotherapy. High baseline CYFRA 21-1 and CA 19-9 levels were associated with poor effectiveness of chemotherapy. Significant reductions in CYFRA 21-1 levels were associated with a positive response to various chemotherapy regimens. CEA, CA 125 and CA 19-9 expression was only associated with a positive response in patients receiving paclitaxel, docetaxel, pemetrexed and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). NSE expression was only associated with a positive response to gemcitabine. Receiver operating characteristic (ROC) curve analysis indicated that CYFRA 21-1 is the most sensitive of the tumor markers in predicting the response to chemotherapy. Serum CYFRA 21-1 is a useful surrogate marker for predicting the response to different chemotherapy regimens used to treat NSCLC and is a more sensitive marker than CEA, CA125, CA19-9 and NSE.

An EZH2 polymorphism is associated with clinical outcome in metastatic colorectal cancer patients

Despite therapeutic innovations, metastatic colorectal cancer (mCRC) is still characterized by poor prognosis and few molecular markers predict the risk of progression. Polycomb group genes (PcGs) are epigenetic modifiers involved in tumor suppressor gene silencing. PcG member EZH2 mediates gene silencing through histone-H3 lysine-27 methylation. In colorectal cancer (CRC), EZH2 overexpression predicts shorter survival. Recently, four EZH2 single-nucleotide polymorphisms (SNPs) have been described. The present study was aimed at evaluating the correlation between EZH2 SNPs and outcome parameters in mCRC patients. DNA was extracted from blood samples of 110 mCRC patients treated with first-line 5-fluorouracil, folinic acid, irinotecan (FOLFIRI) and bevacizumab. Genotyping was carried out by real-time PCR. Genotype was used to predict objective response, progression-free survival (PFS) and overall survival (OS). EZH2 messenger RNA levels were evaluated on lymphocytes of a parallel cohort of 50 CRC patients. One allelic variant (rs3757441 C/C versus C/T or T/T) was significantly associated with shorter PFS and OS (P < 0.01 and P < 0.05, respectively). At multivariate analysis, the same variant resulted an independent predictor of PFS and OS (P < 0.05). The C/C variant was associated with significantly higher EZH2 expression (P < 0.05). An EZH2 SNP may be useful to predict clinical outcome in mCRC patients.

Tesetaxel: Development of a weekly dosing schedule for an oral advanced-generation taxane.

e13045 Background: Tesetaxel, a novel, orally absorbed taxane that is not a substrate for P-glycoprotein, has demonstrated antitumor activity in pts with breast, gastric, and other solid tumors. Neutropenia is the most common dose-limiting effect. To date, tesetaxel has solely been administered using a once every 3 weeks schedule with an MTD of 27 mg/m2. Since other taxanes such as docetaxel and paclitaxel exhibit schedule-dependent effects, we evaluated a weekly dosing regimen of tesetaxel in escalating fixed doses. Threshold models predict taxane pharmacodynamics, and times above a threshold concentration (tC) correlate with both tumor response and toxicity; for paclitaxel, for instance, tC > 0.05 micromol/L was the best predictor of objective response and severe neutropenia (Joerger et al., Clin Cancer Res, 2007). Methods: Eligible pts had advanced solid tumors, ECOG PS 0-2, and adequate organ function. Tesetaxel was given once weekly for 3 weeks in 28-day cycles, beginning at a flat dose of 25 mg per cycle (e.g., 10 mg in Weeks 1 and 2 and 5 mg in Week 3), with progressive increase in total dose per cycle to 30, 45, 60 mg, and continued escalation in 15-mg increments to the MTD. Serial blood samples were collected, and parent compound was assayed by HPLC. Results: To date, 12 pts (3 pts/level) have been treated. Weekly dosing has been well tolerated up to 60 mg. No dose-limiting reactions have been observed, and the MTD has not been reached. Tesetaxel has a long T1/2 (~180 hrs), and low plasma concentrations in the range of 0.3–2.5 nmol/mL were detectable prior to the next dose. There was no substantial drug accumulation over multiple cycles. Conclusions: Weekly oral administration of tesetaxel is feasible and provides long-term, low-level exposure to this taxane. Given threshold effects observed with other taxanes, this finding may similarly predict clinical outcome and toxicity with tesetaxel. The MTD of this weekly regimen has not been reached, but exceeds the MTD of the every-3-week regimen.

Baseline Levels and Decrease in Serum Soluble Intercellular Adhesion Molecule-1 During Chemotherapy Predict Objective Response and Survival in Patients Who Have Advanced Non–Small-Cell Lung Cancer

BackgroundThis study assesses the predictive and prognostic roles of serum soluble intercellular adhesion molecule-1 (sICAM-1) and vascular endothelial growth factor (VEGF) during chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC). Patients and MethodsChanges in serum levels of sICAM-1 and VEGF during first-line conventional chemotherapy were studied prospectively using an enzyme-linked immunosorbent assay at baseline and after every two courses of therapy in 124 patients who have advanced NSCLC. Data were correlated with radiologic objective response and survival. ResultsThe prognostic values of serum sICAM-1and VEGF were explored in 115 advanced NSCLC patients and 61 patients were evaluated for radiologic and serologic responses after two chemotherapy courses. Of the 115 patients, 79 patients had baseline serum sICAM-1 levels greater than 232.84 ng/mL, which is the cut-off value for distinguishing malignant tumors from benign. Statistically significant correlations were observed between baseline sICAM-1 levels and odds ratios and between a sICAM-1 response and odds ratios (8.05 and 5.40, respectively). However, there was no correlation between baseline VEGF levels and odds ratios (P = .543). The median progression-free survival from response assessment was 4 months. In a multivariate analysis, performance status (hazard ratio [HR], 1.47; 95% confidence interval [CI] (95% CI), 1.03-2.10), disease stage (HR, 1.43; 95% CI, 1.07-1.90), baseline sICAM-1 (HR, 1.12; 95% CI, 1.01-1.21), and sICAM-1 response (HR, 0.58; 95%CI, 0.39-0.88), were confirmed as independent prognostic factors for survival. ConclusionBaseline sICAM-1 and sICAM-1 responses appeared to be reliable surrogate markers of chemotherapy efficacy and were prognostic factors in patients with advanced NSCLC.

Development of a modeling framework to simulate efficacy endpoints for motesanib in patients with thyroid cancer

To develop a modeling framework that simulates clinical endpoints (objective response rate and progression-free survival) to support development of motesanib. The framework was evaluated using results from a phase 2 study of motesanib in thyroid cancer. Models of probability and duration of dose modifications and overall survival were developed using data from 93 patients with differentiated thyroid cancer and 91 patients with medullary thyroid cancer, who received motesanib 125 mg once daily. The models, combined with previously developed population pharmacokinetic and tumor growth inhibition models, were assessed in predicting dose intensity, tumor size over time, objective response rate, and progression-free survival. Dose-response simulations were performed in patients with differentiated thyroid cancer. The predicted objective response rate and median progression-free survival in patients with differentiated thyroid cancer was 15.0% (95% prediction interval, 7.5%-23.7%) and 40 weeks (95% prediction interval, 32-49 weeks), respectively, compared with the observed objective response rate of 14.0% and median progression-free survival of 40 weeks. The simulated median objective response rate increased with motesanib starting dose from 13.5% at 100 mg once daily to 38.0% at 250 mg once daily. However, simulated median progression-free survival was independent of starting dose, ranging from 40.5 weeks (95% prediction interval, 38.6-46.9 weeks) at 100 mg once daily to 40.0 weeks (95% prediction interval, 38.6-46.8 weeks) at 250 mg once daily. Dose-response simulations confirmed the appropriateness of 125-mg once-daily dosing; no clinically relevant improvement in progression-free survival would be obtained by dose intensification. This modeling framework represents an important tool to simulate clinical response and support clinical development decisions.

Correlation between Changes in Serum Level of CEA and CYFRA 21-1 and Objective Response of Chemotherapy.

Serum levels of tumor markers are associated with tumor metabolism or apoptosis, changes of which after chemotherapy may reflect tumor response to treatment. The aim of this study was to assess the predictive role of changes in serum levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) during chemotherapy in patients with advanced non-small cell lung cancer. Changes in serum levels of CEA and CYFRA 21-1 were investigated retrospectively after one cycle of chemotherapy in 42 patients with advanced NSCLC. Correlations between the changes and radiological objective response were analyzed. After two cycles of chemotherapy, radiological objective response rate was 28.6%. At baseline, gender, age, clinical stage, serum levels of CEA and CYFRA 21-1 were not different between patients with objective response (OR) and no response (NR). After one cycle of chemotherapy, compared to baseline level, declines in serum levels of CEA and CYFRA 21-1 were observed in patients with OR, but have no statistical significance. In contrast, reduction of CEA and CYFRA 21-1 over baseline after one cycle of chemotherapy showed statistically significant difference between OR and NR. When reduction percentages of CEA and CYFRA 21-1 were used to predict objective response of chemotherapy, the area under the ROC curve (AUC) was 0.875 for CEA and 0.919 for CYFRA 21-1. According to the ROC curve, a 22% reduction of CEA yielded a sensitivity of 58.3% and a specificity of 97%, 51% reduction of CYFRA 21-1 with a sensitivity of 83.3% and a specificity of 93.3%. When above reduction percentages were used as cutoffs for prediction of radiological objective response, combination of the CEA and CYFRA 21-1 yielded a sensitivity of 91.7% and a specificity of 86.7%. Reduction percentages of CEA and CYFRA 21-1 during chemotherapy could be used to evaluate chemotherapy efficacy in patients with advanced NSCLC. The cutoffs of reduction percentage need further research.

Sequential Sorafenib and Sunitinib for Renal Cell Carcinoma

Sorafenib and sunitinib are 2 tyrosine kinase inhibitors that were recently approved for renal cell carcinoma. In many patients sequential administration of the 2 drugs occurs because of the lack of sustained efficacy of the first agent. We determined the efficacy and safety of sequential administration. To determine whether cross-resistance occurs between these 2 drugs we analyzed the outcome in 90 consecutive patients with renal cell carcinoma from 4 sites in France who had received the 2 drugs sequentially. All patients received sorafenib followed by sunitinib or vice versa. From 2003 to 2006, 68 patients received sorafenib, while 22 received sunitinib first. In the sorafenib-sunitinib group median progression-free survival was 26 weeks with sorafenib and 28 with sunitinib. In the sunitinib-sorafenib group median progression-free survival was 22 weeks with sunitinib and 17 with sorafenib. Median overall survival was 135 weeks in the sorafenib-sunitinib group and 82 weeks in the sunitinib-sorafenib group (HR 0.49, 95% CI 0.16 to 0.96, p = 0.04). The average duration of sequential administration was 61 and 49 weeks, respectively, in the sorafenib-sunitinib and sunitinib-sorafenib groups. Each sequence was well tolerated and no increase in grade 3-4 toxicity was observed. Overall this retrospective study supports the conclusion of the lack of absolute cross-resistance between tyrosine kinase inhibitors. In this renal cell carcinoma population sorafenib followed by sunitinib was associated with longer survival than sunitinib followed by sorafenib. However, this observation needs further confirmation.

Pilot study of early repeated 18F-FDG PET during cycle 1 to predict objective response to chemotherapy in advanced non-small cell lung cancer (NSCLC)

8003 Background: FDG-PET already showed to be an early assessment of anticancer treatment effectiveness in different solid tumours after the first cycle of chemotherapy. Aim of this pilot study in patients (pts) with advanced NSCLC was to test if a second 18F-FDG PET repeated two weeks after the start of chemotherapy is predictive of subsequent response and survival. Patients and Methods: Twenty two pts with clinical stage IIIB (n=1) or IV (n=21) NSCLC receiving front line platinum-based chemotherapy within a clinical trial were consecutively and prospectively enrolled. Male/female ratio was 18/4, adenocarcinoma 11, squamous 6, NSCLC-NOS 5. All pts underwent 18F-FDG PET scan at baseline (PET1), 15 days after the beginning (PET2) and at the end of chemotherapy. Assessment of disease by spiral CT scan of the chest and abdomen was performed at baseline and every other cycle. Tumour response was evaluated according to RECIST criteria and analysis of PET scans (including the % change in the standardized uptake values [SUV] between baseline and subsequent FDG PET in the primary tumour (ΔSUV) as well as an overall assessment of all visible lesions) completed and recorded before response evaluation by CT. Results: Pts were dichotomized in two groups (responders and non-responders) based on the overall assessment of FDG PET changes in all visible lesions between PET1 and PET2. Among PET responders, TC scan performed after 2 cycles showed objective response (OR) in 55% of the cases (6/11) while only 1 OR (10%) in non-responders (Fisher exact test, p=0.04). Mean ΔSUV in the primary tumour in PET responders was -40% and in non responders -9%. Overall PET response overestimate CT response in 6/21 cases while underestimate it in 3/21 cases. Adopting different cut-off values for baseline SUV or ΔSUV of the primary lesion no correlation was found with progression-free or overall survival. A non significant trend for improved PFS was found in overall responders (25 weeks) vs non-responders (19 weeks). Data on OS are still immature. Conclusion: This pilot study indicates that in advanced NSCLC early PET restaging during cycle 1 may predicts subsequent OR to CT scan after 2 cycles. This findings are worth of a prospective validation in a larger study. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca, Bayer, Eli Lilly, Roche, sanofi-aventis

Use of Von-Hippel Lindau (VHL) mutation status to predict objective response to vascular endothelial growth factor (VEGF) -targeted therapy in metastatic renal cell carcinoma (RCC)

5012 Background: The clinical response to VEGF-targeted therapy in metastatic RCC is robust, yet variability in outcome exists. VHL is often mutated in RCC, but the relation to therapeutic outcome is unclear. Identification of tumor molecular characteristics associated with outcome would aid in patient selection and interpretation of clinical trials. Materials and Methods: Patients with metastatic, clear-cell RCC with available baseline frozen or paraffin-embedded tumor samples who received VEGF-targeted monotherapy with sunitinb, sorafenib, axitinib or bevacizumab at Cleveland Clinic or University of California San Francisco, were included. Patient characteristics, VHL gene status (mutated or not mutated) and objective response rate (ORR) were documented. ORR was investigator-assessed per RECIST criteria. Fisher’s exact test and logistic regression models were used to assess ORR in univariate and multivariate analyses, respectively. Results: One-hundred twenty-three patients were evaluable. The ORR was 36.5% for the entire cohort. VHL mutation was found in 48% of patients and was seen across all three exons. Patients with VHL mutation had an ORR of 46% versus 28% for pts without a mutated VHL gene (p=0.06). In multivariate analysis, presence of a VHL mutation remained an independent prognostic factor associated with improved ORR (p=.02) when multiple clinical prognostic factors (ECOG PS, hemoglobin, corrected calcium, LDH, prior radiation, prior therapy and number of metastatic sites) were also considered. Conclusion: This is the first large study testing the impact of VHL mutation on response to VEGF-targeted agents in metastatic RCC. Although objective responses were more likely among patients with mutated VHL gene, lack of VHL mutation did not preclude a response. Additional tissue analysis and identification of biomarkers relevant to response to VEGF-targeted agents in metastatic RCC are warranted. [Table: see text]

Evaluation of HER-2/Neu Amplification and Other Biological Markers as Predictors of Response to Neoadjuvant Anthracycline-Based Chemotherapy in Primary Breast Cancer

The value of HER-2/neu status as a predictor of response to anthracycline-based chemotherapy is still a matter of debate. We evaluated the contribution of HER-2/neu gene amplification and other biologic markers in predicting response to different doses of neoadjuvant anthracycline-based chemotherapy. Clinical and pathologic records of 115 primary breast cancer patients were reviewed. Forty-eight and 67 patients received high (doxorubicin > or =20 mg/m2/wk; epirubicin > or =30 mg/m2/wk) and moderate-low anthracycline dose intensity regimens, respectively. Pathologic diagnosis, hormonal receptor status (HR), Ki67, and HER-2/neu status were assessed on tumor samples before neoadjuvant chemotherapy. HER-2/neu was determined by fluorescence in situ hybridization (FISH). HER-2/neu amplification was observed in 29/115 (25%) tumors, 18 from moderate-low-dose and 11 from high-dose group. In the univariate analysis, a high Ki67 index (> or =20%) and positive clinical axillary nodes were predictive of an objective tumor response (P = 0.033 and 0.001, respectively). In the multivariate analysis, Ki67 was the only factor predictive of response (OR = 3.08, 95% CI = 1.1-8.5, P = 0.03). HER-2/neu status was not a factor in predicting objective response to different anthracycline dose intensities. The same finding was observed with regards to HR and Ki67. In our series, no significant dose-response relationship was found according to HER-2/neu status.