CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema.

BACKGROUND: Hereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (KLKB1), with the goal of lifelong control of angioedema attacks after a single dose. METHODS: In this phase 1 dose-escalation portion of a combined phase 1-2 trial of NTLA-2002 in adults with hereditary angioedema, we administered NTLA-2002 at a single dose of 25 mg, 50 mg, or 75 mg. The primary end points were the safety and side-effect profile of NTLA-2002 therapy. Secondary and exploratory end points included pharmacokinetics, pharmacodynamics, and clinical efficacy determined on the basis of investigator-confirmed angioedema attacks. RESULTS: Three patients received 25 mg of NTLA-2002, four received 50 mg, and three received 75 mg. At all dose levels, the most common adverse events were infusion-related reactions and fatigue. No dose-limiting toxic effects, serious adverse events, grade 3 or higher adverse events, or clinically important laboratory findings were observed after the administration of NTLA-2002. Dose-dependent reductions in the total plasma kallikrein protein level were observed between baseline and the latest assessment, with a mean percentage change of -67% in the 25-mg group, -84% in the 50-mg group, and -95% in the 75-mg group. The mean percentage change in the number of angioedema attacks per month between baseline and weeks 1 through 16 (primary observation period) was -91% in the 25-mg group, -97% in the 50-mg group, and -80% in the 75-mg group. Among all the patients, the mean percentage change in the number of angioedema attacks per month from baseline through the latest assessment was -95%. CONCLUSIONS: In this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed. In exploratory analyses, reductions in the number of angioedema attacks per month were observed at all dose levels. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830.).

CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR. METHODS: After conducting preclinical in vitro and in vivo studies, we evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy, three in each of the two initial dose groups (0.1 mg per kilogram and 0.3 mg per kilogram), within an ongoing phase 1 clinical study. RESULTS: Preclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram. CONCLUSIONS: In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.).

Two polymorphic gene loci associated with treprostinil dose in pulmonary arterial hypertension.

OBJECTIVE: Prostacyclin infusion for pulmonary arterial hypertension (PAH) is an effective therapy with varied dosing requirements and clinical response. The major aim of this study was to determine new biologically-based predictors of prostacyclin treatment response heterogeneity. METHODS: Ninety-eight patients with hemodynamically defined PAH at two academic medical centers volunteered for registry studies. A stable dose of treprostinil was the quantitative phenotype for the genome-wide association study (GWAS). Candidate genes with the largest effect sizes and strongest statistical associations were further characterized with in silico and in-vitro assays to confirm mechanistic hypotheses. The clinical significance of these candidate predictors was assessed for mechanistically consistent physiologic effects in an independent cohort of patients. RESULTS: GWAS identified three loci for association with P < 10-6. All three loci had clinically significant effect sizes. Specific single-nucleotide polymorphisms (SNPs) at two of the loci: rs11078738 in phosphoribosylformylglycinamidine synthase and rs10023113 in CAMK2D encoded sequence changes with clear predicted consequences. Production of the primary mediator of prostacyclin-induced vasodilation, cyclic AMP, was reduced in human cell lines by the missense variant rs11078738 (p.L621P). Located in the promoter of CAMK2D, the allele of rs10023113 associated with a higher treprostinil dose has higher ventricular transcription of CAMK2δ. At initial diagnostic catheterization in a separate cohort of patients, the same allele of rs10023113 was associated with elevated right mean atrial and ventricular diastolic pressures. CONCLUSIONS: The quantitative phenotype of stable treprostinil dose identified two gene loci associated with pharmacodynamic response and right ventricular function in PAH worth further investigation.

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. METHODS: In vitro viability assays were performed on A2780, OVCAR-3, TOV-21G, and RL95-2 cells with nine drugs to produce high resolution exposure-response curves. Lab generated data were compared to publicly available datasets by IC20, IC50, and IC80 values, and the area between the logarithmic logistic regression curves. RESULTS: For exposure-response curve comparisons with clinically indicated drugs between lab generated and publicly available data, the majority had area-between-curves less than 20%, indicating similarity. However, 15 out of 40 of these dataset curves were incomplete as indicated by the lack of, or extrapolated, IC50 value. The common ovarian and uterine cancer drug, carboplatin, exemplified this incomplete status as all of the available dataset curves were incomplete and therefore non-informative. CONCLUSIONS: For gynecologic malignancy cell line models, experimental drug sensitivity data is comparable to the available data in PharmacoDB when exposure-response curves are complete. Incomplete exposure-response curves due to incomplete concentration ranges tested and related extrapolation of IC values can mislead individual drug/cell line pair data for downstream applications.

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. Radiological assessment of imaging was centrally reviewed to assess tumor response. Incidence of discordance in BOR between RECIST 1.1 and iRECIST as well as rate of pseudoprogression were measured. OS of patients with pseudoprogression was compared with that of those with uncontrolled disease. RESULTS: Of the 221 patients in this cohort, 136 patients developed PD as per RECIST v1.1 and 78 patients with PD continued treatment and imaging beyond initial RECIST 1.1-defined PD. Among the 78 patients who continued therapy and imaging post-progression, RECIST 1.1 and iRECIST were discordant in 10 patients (12.8%) and pseudoprogression was encountered in 14 patients (17.9%). OS of patients with pseudoprogression was longer than that of patients with uncontrolled disease/true progression (29.9 months versus 8.0 months, p value < 0.001). CONCLUSIONS: Effectiveness of immunotherapy in clinical trials depends on the criterion used to assess tumor response (RECIST 1.1 vs iRECIST) with iRECIST being more appropriate to detect pseudoprogression and potentially prevent premature termination of effective therapy. Pseudoprogression was associated with improved OS in comparison with that of patients with uncontrolled disease. KEY POINTS: • Discordance between iRECIST and RECIST 1.1 was found in 12.8% of unresectable melanoma patients on pembrolizumab who continued therapy beyond initial RECIST 1.1-defined progression. • Pseudoprogression, captured with iRECIST, occurred in 17.9% and was significantly associated with improved overall survival in comparison with uncontrolled disease.

Cancer pharmacogenomics: strategies and challenges.

Genetic variation influences the response of an individual to drug treatments. Understanding this variation has the potential to make therapy safer and more effective by determining selection and dosing of drugs for an individual patient. In the context of cancer, tumours may have specific disease-defining mutations, but a patient's germline genetic variation will also affect drug response (both efficacy and toxicity), and here we focus on how to study this variation. Advances in sequencing technologies, statistical genetics analysis methods and clinical trial designs have shown promise for the discovery of variants associated with drug response. We discuss the application of germline genetics analysis methods to cancer pharmacogenomics with a focus on the special considerations for study design.

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. RESULTS: Dose-limiting toxicities were predominantly related to VEGFR inhibition. The most frequent treatment-emergent adverse events ( > 30%) were: fatigue (48%), anorexia (34%), and hypertension (34%). Pharmacodynamic markers suggested that ilorasertib engaged VEGFR2 and Aurora B kinase, with the VEGFR2 effects reached at lower doses and exposures than Aurora inhibition effects. In Arm II, one basal cell carcinoma patient (40 mg twice daily (BID)) and one patient with adenocarcinoma of unknown primary site (230 mg BID) had partial responses. CONCLUSIONS: In patients with advanced solid tumours, ilorasertib treatment resulted in evidence of engagement of the intended targets and antitumour activity, but with maximum inhibition of VEGFR family kinases occurring at lower exposures than typically required for inhibition of Aurora B in tissue. CLINICAL TRIAL REGISTRATION: NCT01110486.

Clinical trials in the era of personalized oncology.

The rapid pace of discoveries in tumor biology, imaging technology, and human genetics hold promise for an era of personalized oncology care. The successful development of a handful of new targeted agents has generated much hope and hype about the delivery of safer and more effective new treatments for cancer. The design and conduct of clinical trials has not yet adjusted to a new era of personalized oncology and so we are more in transition to that era than in it. With the development of treatments for breast cancer as a model, we review the approaches to clinical trials and the development of novel therapeutics in the prior era of population oncology, the current transitional era, and the future era of personalized oncology.

First-in-human study of the antibody DR5 agonist DS-8273a in patients with advanced solid tumors.

Background DR5 is a transmembrane receptor that transduces extracellular ligand-binding to activate apoptosis signaling cascades. This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of a new monoclonal antibody potent DR5 agonist, DS-8273a, in subjects with advanced solid tumors. Methods The study comprised dose escalation and dose expansion cohorts. The dose escalation cohorts intended to determine the safety and to identify the maximum tolerated dose (MTD) or maximum administered dose (MAD) and to characterize the pharmacokinetics and pharmacodynamics by a conventional 3 + 3 design (starting at 2 mg/kg and escalating through 8, 16 and 24 mg/kg once every 3 weeks). In the dose expansion cohort, additional subjects were treated at the MAD for further evaluation of PK and safety. Results Thirty two subjects were enrolled and treated, 16 in the dose escalation cohorts and 16 in the dose expansion cohort. No subjects experienced a dose limiting toxicity (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14 (44%) of which were attributed to study-drug; all drug-related events were grade 1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea. Measures of plasma exposure increased dose-proportionally and the mean terminal elimination half-life was 11 days. Blood samples available from a subset of patients treated at 24 mg/kg revealed declines in myeloid derived suppressor cells (MDSC) at 2 weeks. No objective responses were observed in any subjects. Conclusions DS-8273a was well tolerated and demonstrated linear pharmacokinetics. Decreases in MDSC were temporally associated with DS-8273a exposure. This agent could be studied further in combination with other agents, pending further proof-of-target-engagement.

Bayesian inference for longitudinal data with non-parametric treatment effects.

We consider inference for longitudinal data based on mixed-effects models with a non-parametric Bayesian prior on the treatment effect. The proposed non-parametric Bayesian prior is a random partition model with a regression on patient-specific covariates. The main feature and motivation for the proposed model is the use of covariates with a mix of different data formats and possibly high-order interactions in the regression. The regression is not explicitly parameterized. It is implied by the random clustering of subjects. The motivating application is a study of the effect of an anticancer drug on a patient's blood pressure. The study involves blood pressure measurements taken periodically over several 24-h periods for 54 patients. The 24-h periods for each patient include a pretreatment period and several occasions after the start of therapy.

Evaluation of a novel rash scale and a serum proteomic predictor in a randomized phase II trial of sequential or concurrent cetuximab and pemetrexed in previously treated non-small cell lung cancer.

BACKGROUND: Candidate predictive biomarkers for epidermal growth factor receptor inhibitors (EGFRi), skin rash and serum proteomic assays, require further qualification to improve EGFRi therapy in non-small cell lung cancer (NSCLC). In a phase II trial that was closed to accrual because of changes in clinical practice we examined the relationships among candidate biomarkers, quantitative changes in tumor size, progression-free and overall survival. METHODS: 55 patients with progressive NSCLC after platinum therapy were randomized to receive (Arm A) cetuximab, followed by pemetrexed at progression, or (Arm B) concurrent cetuximab and pemetrexed. All received cetuximab monotherapy for the first 14 days. Pre-treatment serum and weekly rash assessments by standard and EGFRi-induced rash (EIR) scales were collected. RESULTS: 43 patients (20-Arm A, 23-Arm B) completed the 14-day run-in. Median survival was 9.1 months. Arm B had better median overall (Arm B = 10.3 [95% CI 7.5, 16.8]; Arm A = 3.5 [2.8, 11.7] months P = 0.046) and progression-free survival (Arm B = 2.3 [1.6, 3.1]; Arm A = 1.6 [0.9, 1.9] months P = 0.11). The EIR scale distributed ratings among 6 rather than 3 categories but ordinal scale rash severity did not predict outcomes. The serum proteomic classifier and absence of rash after 21 days of cetuximab did. CONCLUSIONS: Absence of rash after 21 days of cetuximab therapy and the serum proteomic classifier, but not ordinal rash severity, were associated with NSCLC outcomes. Although in a small study, these observations were consistent with results from larger retrospective analyses.

Effects of vascular endothelial growth factor signaling inhibition on human erythropoiesis.

Inhibition of vascular endothelial growth factor (VEGF) signaling increases red blood cell (RBC) counts, and erythropoiesis markers have been proposed to guide antiangiogenic therapy in humans. We analyzed RBC measurements in patients enrolled in three studies: a phase II trial of axitinib in thyroid cancer; a study of sorafenib in advanced solid tumors; and a randomized trial of fluorouracil, hydroxyurea, and radiation with and without bevacizumab for head and neck cancer. In the sorafenib trial, plasma erythropoietin concentrations were measured at baseline, day 8, and day 35. Over the first 84 days of treatment, RBC counts increased for each day on sorafenib (2.7 M/µL [95% confidence interval (CI), 1.5-3.9]) and axitinib (4.3 M/µL [95% CI, 2.2-6.5]). RBCs declined over the first 68 days of cytotoxic chemoradiotherapy alone (-12.8 M/µL per day [95% CI, -15.7 to -9.8]) but less so with added bevacizumab (-7.2 M/µL per day [95% CI, -9.5 to -4.9]). Erythropoietin levels increased, on average, by 9.5 mIU/mL between day 8 and day 35 of sorafenib exposure. No significant relationships between elevations in RBCs and changes in volume status or blood pressure or between elevations in erythropoietin and smoking status were found. VEGF signaling inhibition is associated with increased RBC and erythropoietin production in humans. The effects of these changes are subtle at physiologic doses and are unlikely to be clinically useful biomarkers for guiding the administration of or predicting treatment responses to VEGF pathway inhibitors.

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. Application of pharmacokinetic/pharmacodynamic (PK/PD) modeling to EHR data promises new insights on the real-world use of taxanes and strategies to improve therapeutic outcomes especially for populations who are typically excluded from clinical trials, including the elderly. This investigation: (i) leveraged previously published PK/PD models developed with clinical trial data and addressed challenges to fit EHR data, and (ii) evaluated predictors of paclitaxel-induced myelosuppression. Relevant EHR data were collected from patients treated with paclitaxel-containing chemotherapy at Inova Schar Cancer Institute between 2015 and 2019 (n = 405). Published PK models were used to simulate mean individual exposures of paclitaxel and carboplatin, which were linearly linked to absolute neutrophil count (ANC) using a published semiphysiologic myelosuppression model. Elderly patients (≥70 years) constituted 21.2% of the dataset and 2274 ANC measurements were included in the analysis. The PD parameters were estimated and matched previously reported values. The baseline ANC and chemotherapy regimen were significant predictors of paclitaxel-induced myelosuppression. The nadir ANC and use of supportive treatments, such as growth factors and antimicrobials, were consistent across age quantiles suggesting age had no effect on paclitaxel-induced myelosuppression. In conclusion, EHR data could complement clinical trial data in answering key therapeutic questions.

Tumor Dynamic Model-Based Decision Support for Phase Ib/II Combination Studies: A Retrospective Assessment Based on Resampling of the Phase III Study IMpower150.

PURPOSE: Model-based tumor growth inhibition (TGI) metrics are increasingly incorporated into go/no-go decisions in early clinical studies. To apply this methodology to new investigational combinations requires independent evaluation of TGI metrics in recently completed Phase III trials of effective immunotherapy. PATIENTS AND METHODS: Data were extracted from IMpower150, a positive, randomized, Phase III study of first-line therapy in 1,202 patients with non-small cell lung cancer. We resampled baseline characteristics and longitudinal sum of longest diameters of tumor lesions of patients from both arms, atezolizumab+ bevacizumab+chemotherapy (ABCP) versus BCP, to mimic Phase Ib/II studies of 15 to 40 patients/arm with 6 to 24 weeks follow-up. TGI metrics were estimated using a bi-exponential TGI model. Effect sizes were calculated as TGI metrics geometric mean ratio (GMR), objective response rate (ORR) difference (d), and progression-free survival (PFS), hazard ratio (HR) between arms. Correct and incorrect go decisions were evaluated as the probability to achieve desired effect sizes in ABCP versus BCP and BCP versus BCP, respectively, across 500 replicated subsamples for each design. RESULTS: For 40 patients/24 weeks follow-up, correct go decisions based on probability tumor growth rate (KG) GMR <0.90, dORR >0.10, and PFS HR <0.70 were 83%, 69%, and 58% with incorrect go decision rates of 4%, 12%, and 11%, respectively. For other designs, the ranking did not change with TGI metrics consistently overperforming RECIST endpoints. The predicted overall survival (OS) HR was around 0.80 in most of the scenarios investigated. CONCLUSIONS: Model-based estimate of KG GMR is an exploratory endpoint that informs early clinical decisions for combination studies.

Pertuzumab Plus Trastuzumab in Patients With Endometrial Cancer With ERBB2/3 Amplification, Overexpression, or Mutation: Results From the TAPUR Study.

PURPOSE: The TAPUR Study is a pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers harboring potentially actionable genomic alterations. Data from a cohort of patients with endometrial cancer (EC) with ERBB2 or ERBB3 (ERBB2/3) amplification, overexpression, or mutation treated with pertuzumab plus trastuzumab (P + T) are reported. METHODS: Eligible patients had advanced EC, no standard treatment options, measurable disease (RECIST v1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and tumors with ERBB2/3 amplification, overexpression, or mutation. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) or stable disease (SD) of at least 16 weeks (SD16+) duration. Secondary end points include safety, duration of response, duration of SD, progression-free survival (PFS), and overall survival (OS). RESULTS: Twenty-eight patients were enrolled from March 2017 to November 2019; all patients were evaluable for efficacy and toxicity. Seventeen patients had tumors with ERBB2/3 amplification and/or overexpression, eight with both ERBB2 amplification and ERBB2/3 mutations, and three with only ERBB2 mutations. Ten patients had DC (two partial response and eight SD16+); all 10 had ERBB2 amplification, and 6 of the 10 patients with DC had >1 ERBB2/3 alteration. DC and OR rates were 37% (95% CI, 21 to 50) and 7% (95% CI, 1 to 24), respectively; the median PFS and median OS were 16 weeks (95% CI, 10-28) and 61 weeks (95% CI, 24-105), respectively. One patient experienced a grade 3 serious adverse event (muscle weakness) at least possibly related to P + T. CONCLUSION: P + T has antitumor activity in heavily pretreated patients with EC with ERBB2 amplification and warrants additional study.

Management of cardiac toxicity in patients receiving vascular endothelial growth factor signaling pathway inhibitors.

BACKGROUND: Interfering with angiogenesis is an effective, widely used approach to cancer therapy, but antiangiogenic therapies have been associated with important systemic cardiovascular toxicities such as hypertension, left ventricular dysfunction, heart failure, and myocardial ischemia and infarction. As the use of vascular endothelial growth factor signaling pathway (VSP) inhibitors broadens to include older patients and those with existing cardiovascular disease, the adverse effects are likely to be more frequent, and cardiologists will increasingly be enlisted to help oncologists manage patients who develop adverse cardiovascular effects. METHODS: The Cardiovascular Toxicities Panel of the National Cancer Institute reviewed the published literature and abstracts from major meetings, shared experience gained during clinical development of VSP inhibitors, and contributed extensive clinical experience in evaluating and treating patients with cancer with cardiovascular disease. This report was edited and approved by the National Cancer Institute Investigational Drug Steering Committee. It presents the panel's expert opinion on the current clinical use and future investigation for safer, more expansive use of these drugs. RESULTS AND CONCLUSIONS: The panel recommends that physicians (1) conduct and document a formal risk assessment for existing cardiovascular disease and potential cardiovascular complications before VSP inhibitor treatment recognizing that preexisting hypertension and cardiovascular disease are common in patients with cancer, (2) actively monitor for blood pressure elevations and cardiac toxicity with more frequent assessments during the first treatment cycle, and (3) aggressively manage blood pressure elevations and early symptoms and signs of cardiac toxicity to prevent clinically limiting complications of VSP inhibitor therapy.

Sorafenib inhibits neuroblastoma cell proliferation and signaling, blocks angiogenesis, and impairs tumor growth.

BACKGROUND: More effective therapy for children with high-risk neuroblastoma is desperately needed. Preclinical studies have shown that neuroblastoma tumor growth can be inhibited by agents that block angiogenesis. We hypothesized that drugs which target both neuroblastoma cells and tumor angiogenesis would have potent anti-tumor activity. In this study we tested the effects of sorafenib, a multi-kinase inhibitor, on neuroblastoma cell proliferation and signaling, and in mice with subcutaneous human neuroblastoma xenografts or orthotopic adrenal tumors. PROCEDURE: Mice with subcutaneous neuroblastoma xenografts or orthotopic adrenal tumors were treated with sorafenib, and tumor growth rates were measured. Blood vessel architecture and vascular density were evaluated histologically in treated and control neuroblastoma tumors. The in vitro effects of sorafenib on neuroblastoma proliferation, cell cycle, and signaling were also evaluated. RESULTS: Sorafenib inhibited tumor growth in mice with subcutaneous and orthotopic adrenal tumors. Decreased numbers of cycling neuroblastoma cells and tumor blood vessels were seen in treated versus control tumors, and the blood vessels in the treated tumors had more normal architecture. Sorafenib treatment also decreased neuroblastoma cell proliferation, attenuated ERK signaling, and enhanced G(1) /G(0) cell cycle arrest in vitro. CONCLUSIONS: Our results demonstrate that sorafenib inhibits the growth of neuroblastoma tumors by targeting both neuroblastoma cells and tumor blood vessels. Single agent sorafenib should be evaluated in future phase II neuroblastoma studies.

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). In the validation set (n = 864), hazard ratios (HRs) evaluated the association of the signature with OS using RECIST1.1 as a benchmark of comparison. RESULTS: In the training set, the selected signature combined three features - change in tumour volume, change in tumour spatial heterogeneity, and tumour volume - to predict OS. In the validation set, RECIST1.1 classified patients in three categories: response (n = 166, 19.2%), stable disease (n = 636, 73.6%), and progression (n = 62, 7.2%). The HR was 3.93 (2.79-5.54). Using the same distribution for the signature, the HR was 21.04 (14.88-30.58), showing an incremental prognostic separation. Stable disease by RECIST1.1 was reclassified by the signature along a continuum where patients belonging to the most and least favourable signature quartiles had a median OS of 40.73 (28.49 to NA) months (n = 94) and 7.03 (5.66-7.89) months (n = 166), respectively. CONCLUSIONS: A signature combining three imaging features provides early prognostic information that can improve treatment decisions for individual patients and clinical trial analyses.