Ethnic diversity in treatment response for colorectal cancer: proof of concept for radiomics-driven enrichment trials.

Background: Several barriers hamper recruitment of diverse patient populations in multicenter clinical trials which determine efficacy of new systemic cancer therapies.

Purpose: We assessed if quantitative analysis of computed tomography (CT) scans of metastatic colorectal cancer (mCRC) patients using imaging features that predict overall survival (OS) can unravel the association between ethnicity and efficacy.

Methods: We retrospectively analyzed CT images from 1584 mCRC patients in two phase III trials evaluating FOLFOX ± panitumumab (n = 331, 350) and FOLFIRI ± aflibercept (n = 437, 466) collected from August 2006 to March 2013.

Model-based approach to identify predictors of paclitaxel-induced myelosuppression in "real-world" administration.

Taxanes are currently the most frequently used chemotherapeutic agents in cancer care, where real-world use has focused on minimizing adverse events and standardizing the delivery. Myelosuppression is a well-characterized, adverse pharmacodynamic effect of taxanes. Electronic health records (EHRs) comprise data collected during routine clinical care that include patients with heterogeneous demographic, clinical, and treatment characteristics.

Early Readout on Overall Survival of Patients With Melanoma Treated With Immunotherapy Using a Novel Imaging Analysis.

Importance: Existing criteria to estimate the benefit of a therapy in patients with cancer rely almost exclusively on tumor size, an approach that was not designed to estimate survival benefit and is challenged by the unique properties of immunotherapy. More accurate prediction of survival by treatment could enhance treatment decisions.

Objective: To validate, using radiomics and machine learning, the performance of a signature of quantitative computed tomography (CT) imaging features for estimating overall survival (OS) in patients with advanced melanoma treated with immunotherapy.

An imaging signature to predict outcome in metastatic colorectal cancer using routine computed tomography scans.

Background & Aims: Quantitative analysis of computed tomography (CT) scans of patients with metastatic colorectal cancer (mCRC) can identify imaging signatures that predict overall survival (OS).

Methods: We retrospectively analysed CT images from 1584 mCRC patients on two phase III trials evaluating FOLFOX ± panitumumab (n = 331, 350) and FOLFIRI ± aflibercept (n = 437, 466). In the training set (n = 720), an algorithm was trained to predict OS landmarked from month 2; the output was a signature value on a scale from 0 to 1 (most to least favourable predicted OS).

Evaluation of publicly available in vitro drug sensitivity models for ovarian and uterine cancer.

Objective: Publicly available data on drug sensitivity for cancer cell lines have been curated into a single, integrated database, PharmacoDB. The contributing datasets report modeled estimates of drug effect from high throughput assays. These databases have been informative for developing new broad insights, but the reliability of these data specifically for drugs used to treat ovarian and uterine cancers in related cell lines has not been reported.

Comparing RECIST 1.1 and iRECIST in advanced melanoma patients treated with pembrolizumab in a phase II clinical trial.

Objectives: To compare tumor best overall response (BOR) by RECIST 1.1 and iRECIST, to explore the incidence of pseudoprogression in melanoma treated with pembrolizumab, and to assess the impact of pseudoprogression on overall survival (OS).

Methods: A total of 221 patients with locally advanced/unresectable melanoma who received pembrolizumab as part of KEYNOTE-002 trial were included in this study.

Enhanced Detection of Treatment Effects on Metastatic Colorectal Cancer with Volumetric CT Measurements for Tumor Burden Growth Rate Evaluation.

Purpose: Mathematical models combined with new imaging technologies could improve clinical oncology studies. To improve detection of therapeutic effect in patients with cancer, we assessed volumetric measurement of target lesions to estimate the rates of exponential tumor growth and regression as treatment is administered.

Experimental Design: Two completed phase III trials were studied (988 patients) of aflibercept or panitumumab added to standard chemotherapy for advanced colorectal cancer.

Vol-PACT: A Foundation for the NIH Public-Private Partnership That Supports Sharing of Clinical Trial Data for the Development of Improved Imaging Biomarkers in Oncology.

Purpose: To develop a public-private partnership to study the feasibility of a new approach in collecting and analyzing clinically annotated imaging data from landmark phase III trials in advanced solid tumors.

Patients And Methods: The collection of clinical trials fulfilled the following inclusion criteria: completed randomized trials of > 300 patients, highly measurable solid tumors (non-small-cell lung cancer, colorectal cancer, renal cell cancer, and melanoma), and required sponsor and institutional review board sign-offs. The new approach in analyzing computed tomography scans was to transfer to an academic image analysis laboratory, draw contours semi-automatically by using in-house-developed algorithms integrated into the open source imaging platform Weasis, and perform serial volumetric measurement.

Comparison of tumor size assessments in tumor growth inhibition-overall survival models with second-line colorectal cancer data from the VELOUR study.

Purpose: To compare lesion-level and volumetric measures of tumor burden with sum of the longest dimensions (SLD) of target lesions on overall survival (OS) predictions using time-to-growth (TTG) as predictor.

Methods: Tumor burden and OS data from a phase 3 randomized study of second-line FOLFIRI ± aflibercept in metastatic colorectal cancer were available for 918 patients out of 1216 treated (75%). A TGI model that estimates TTG was fit to the longitudinal tumor size data (nonlinear mixed effect modeling) to estimate TTG with: SLD, sum of the measured lesion volumes (SV), individual lesion diameters (ILD), or individual lesion volumes (ILV).

Clinical pharmacodynamic/exposure characterisation of the multikinase inhibitor ilorasertib (ABT-348) in a phase 1 dose-escalation trial.

Background: Ilorasertib (ABT-348) inhibits Aurora and VEGF receptor (VEGFR) kinases. Patients with advanced solid tumours participated in a phase 1 dose-escalation trial to profile the safety, tolerability, and pharmacokinetics of ilorasertib.

Methods: Ilorasertib monotherapy was administered at 10-180 mg orally once daily (Arm I, n = 23), 40-340 mg orally twice daily (Arm II, n = 28), or 8-32 mg intravenously once daily (Arm III, n = 7), on days 1, 8, and 15 of each 28-day cycle.

Predicting Response to Histone Deacetylase Inhibitors Using High-Throughput Genomics.

Background: Many disparate biomarkers have been proposed as predictors of response to histone deacetylase inhibitors (HDI); however, all have failed when applied clinically. Rather than this being entirely an issue of reproducibility, response to the HDI vorinostat may be determined by the additive effect of multiple molecular factors, many of which have previously been demonstrated.

Methods: We conducted a large-scale gene expression analysis using the Cancer Genome Project for discovery and generated another large independent cancer cell line dataset across different cancers for validation.

Serum C-Telopeptide Collagen Crosslinks and Plasma Soluble VEGFR2 as Pharmacodynamic Biomarkers in a Trial of Sequentially Administered Sunitinib and Cilengitide.

Purpose: Fit-for-purpose pharmacodynamic biomarkers could expedite development of combination antiangiogenic regimens. Plasma sVEGFR2 concentrations ([sVEGFR2]) mark sunitinib effects on the systemic vasculature. We hypothesized that cilengitide would impair microvasculature recovery during sunitinib withdrawal and could be detected through changes in [sVEGFR2].

Technical considerations in the development of circulating peptides as pharmacodynamic biomarkers for angiogenesis inhibitors.

To determine the biological reproducibility and estimate relevant covariates for candidate circulating biomarkers of angiogenesis, we conducted 3 sub-studies with ≤15 subjects each. In study 1, 6 healthy subjects provided 13 blood samples across 14-24 days. In study 2, 15 advanced solid tumor patients provided single blood samples before, and approximately 8 and 40 days after sorafenib treatment.