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.).

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.

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.

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.

Selective adipocyte loss of Angiopoietin-2 prompts female-specific obesity and metabolic syndrome.

Thermogenic fat differentiation and function can be promoted through multiple pathways, resulting in a common cell phenotype characterized by the expression of Uncoupling Protein-1 and the ability to dissipate energy, but local and systemic stimuli are necessary to promote adequate thermogenic fat vascularization, which is a precondition for the transport of substrate and the dissipation of heat. Angiopoietin-2 is an important driver of vascularization, and its transcription is in part promoted by estrogen signaling. In this study we demonstrate that adipose tissue-specific knock out of Angiopoietin-2 causes a female-specific reduced thermogenic fat differentiation and function, resulting in obesity and impaired glucose tolerance with end-organ features consistent with metabolic syndrome. In humans, angiopoietin-2 levels are higher in females than in males, and are inversely correlated with adiposity and age more strongly in pre-menopause when compared to post-menopause. Collectively, these data indicate a novel and important role for estrogen-mediated Angiopoietin-2 adipose tissue production in the protection against calorie overload in females, and potentially in the development of postmenopausal weight gain.

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.

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. DESIGN, SETTING, AND PARTICIPANTS: This prognostic study used radiomics and machine learning to retrospectively analyze CT images obtained at baseline and first follow-up and their associated clinical metadata. Data were prospectively collected in the KEYNOTE-002 (Study of Pembrolizumab [MK-3475] Versus Chemotherapy in Participants With Advanced Melanoma; 2017 analysis) and KEYNOTE-006 (Study to Evaluate the Safety and Efficacy of Two Different Dosing Schedules of Pembrolizumab [MK-3475] Compared to Ipilimumab in Participants With Advanced Melanoma; 2016 analysis) multicenter clinical trials. Participants included 575 patients with a diagnosis of advanced melanoma who were randomly assigned to training and validation sets. Data for the present study were collected from November 20, 2012, to June 3, 2019, and analyzed from July 1, 2019, to September 15, 2021. INTERVENTIONS: KEYNOTE-002 featured trial groups testing intravenous pembrolizumab, 2 mg/kg or 10 mg/kg every 2 or every 3 weeks based on randomization, or investigator-choice chemotherapy; KEYNOTE-006 featured trial groups testing intravenous ipilimumab, 3 mg/kg every 3 weeks and intravenous pembrolizumab, 10 mg/kg every 2 or 3 weeks based on randomization. MAIN OUTCOMES AND MEASURES: The performance of the signature CT imaging features for estimating OS at the month 6 posttreatment landmark in patients who received pembrolizumab was measured using an area under the time-dependent receiver operating characteristics curve (AUC). RESULTS: A random forest model combined 25 imaging features extracted from tumors segmented on CT images to identify the combination (signature) that best estimated OS with pembrolizumab in 575 patients. The signature combined 4 imaging features, 2 related to tumor size and 2 reflecting changes in tumor imaging phenotype. In the validation set (287 patients treated with pembrolizumab), the signature reached an AUC for estimation of OS status of 0.92 (95% CI, 0.89-0.95). The standard method, Response Evaluation Criteria in Solid Tumors 1.1, achieved an AUC of 0.80 (95% CI, 0.75-0.84) and classified tumor outcomes as partial or complete response (93 of 287 [32.4%]), stable disease (90 of 287 [31.3%]), or progressive disease (104 of 287 [36.2%]). CONCLUSIONS AND RELEVANCE: The findings of this prognostic study suggest that the radiomic signature discerned from conventional CT images at baseline and on first follow-up may be used in clinical settings to provide an accurate early readout of future OS probability in patients with melanoma treated with single-agent programmed cell death 1 blockade.

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.

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.).

First-in-Human Study of PF-06647020 (Cofetuzumab Pelidotin), an Antibody-Drug Conjugate Targeting Protein Tyrosine Kinase 7, in Advanced Solid Tumors.

PURPOSE: We investigated safety, tolerability, pharmacokinetics, and antitumor activity of the protein tyrosine kinase 7 (PTK7)-targeted, auristatin-based antibody-drug conjugate (ADC) PF-06647020/cofetuzumab pelidotin (NCT02222922). PATIENTS AND METHODS: Patients received PF-06647020 intravenously every 3 weeks at 0.2-3.7 mg/kg or every 2 weeks at 2.1-3.2 mg/kg, in sequential dose escalation, following a modified toxicity probability interval method. In dose expansion, pretreated patients with advanced, platinum-resistant ovarian cancer, non-small cell lung cancer (NSCLC), or triple-negative breast cancer (TNBC) received PF-06647020 2.8 mg/kg every 3 weeks. RESULTS: The most common, treatment-related adverse events for PF-06647020 administered every 3 weeks were nausea, alopecia, fatigue, headache, neutropenia, and vomiting (45%-25%); 25% of patients had grade ≥ 3 neutropenia. Two patients experienced dose-limiting toxicities (grade 3 headache and fatigue) at the highest every 3 weeks dose evaluated. The recommended phase II dose was 2.8 mg/kg every 3 weeks. The overall safety profile observed with PF-06647020 administered every 2 weeks was similar to that of the every 3 weeks regimen. Systemic exposure for the ADC and total antibody generally increased in a dose-proportional manner. Antitumor activity was observed in treated patients with overall objective response rates of 27% in ovarian cancer (n = 63), 19% in NSCLC (n = 31), and 21% in TNBC (n = 29). Responders tended to have moderate or high PTK7 tumor expression by IHC. CONCLUSIONS: This PTK7-targeted ADC demonstrated therapeutic activity in previously treated patients with ovarian cancer, NSCLC, and TNBC at a dose range of 2.1-3.2 mg/kg, supporting further clinical evaluation to refine dose, schedule, and predictive tissue biomarker testing in patients with advanced malignancies.

Identifying Novel Drug Targets by iDTPnd: A Case Study of Kinase Inhibitors.

Current FDA-approved kinase inhibitors cause diverse adverse effects, some of which are due to the mechanism-independent effects of these drugs. Identifying these mechanism-independent interactions could improve drug safety and support drug repurposing. Here, we develop iDTPnd (integrated Drug Target Predictor with negative dataset), a computational approach for large-scale discovery of novel targets for known drugs. For a given drug, we construct a positive structural signature as well as a negative structural signature that captures the weakly conserved structural features of drug-binding sites. To facilitate assessment of unintended targets, iDTPnd also provides a docking-based interaction score and its statistical significance. We confirm the interactions of sorafenib, imatinib, dasatinib, sunitinib, and pazopanib with their known targets at a sensitivity of 52% and a specificity of 55%. We also validate 10 predicted novel targets by using in vitro experiments. Our results suggest that proteins other than kinases, such as nuclear receptors, cytochrome P450, and MHC class I molecules, can also be physiologically relevant targets of kinase inhibitors. Our method is general and broadly applicable for the identification of protein-small molecule interactions, when sufficient drug-target 3D data are available. The code for constructing the structural signatures is available at https://sfb.kaust.edu.sa/Documents/iDTP.zip.

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.

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.

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. Retrospectively, radiologists performed semiautomated measurements of all metastatic lesions on CT images. Using exponential growth modeling, tumor regression (d) and growth (g) rates were estimated for each patient's unidimensional and volumetric measurements. RESULTS: Exponential growth modeling of volumetric measurements detected different empiric mechanisms of effect for each drug: panitumumab marginally augmented the decay rate [tumor half-life; d [IQR]: 36.5 days (56.3, 29.0)] of chemotherapy [d: 44.5 days (67.2, 32.1), two-sided Wilcoxon P = 0.016], whereas aflibercept more significantly slowed the growth rate [doubling time; g = 300.8 days (154.0, 572.3)] compared with chemotherapy alone [g = 155.9 days (82.2, 347.0), P ≤ 0.0001]. An association of g with overall survival (OS) was observed. Simulating clinical trials using volumetric or unidimensional tumor measurements, fewer patients were required to detect a treatment effect using a volumetric measurement-based strategy (32-60 patients) than for unidimensional measurement-based strategies (124-184 patients). CONCLUSIONS: Combined tumor volume measurement and estimation of tumor regression and growth rate has potential to enhance assessment of treatment effects in clinical studies of colorectal cancer that would not be achieved with conventional, RECIST-based unidimensional measurements.

Cancer Clinical Investigators Should Converge with Pharmacometricians.

The applied quantitative science pharmacometrics has significantly enhanced cancer therapeutics development. Pharmacometrics is now improving our understanding of complex diagnostics. Through the concept of convergence and methods of quantitative and systems pharmacology, pharmacometrics is poised to interconnect mathematical models of disease and therapy to advance cancer care.See related article by Colomban et al., p. 5342.

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). A parametric OS model was built with TTG estimates and assessed for prediction of the hazard ratio (HR) for survival. RESULTS: Individual lesions had consistent dynamics within individuals. Between-lesion variability in rate constants was lower (typically < 27% CV) than inter-patient variability (typically > 50% CV). Estimates of TTG were consistent (around 12 weeks) across tumor size assessments. TTG was highly significant in a log-logistic parametric model of OS (median over 12 months). When individual lesions were considered, TTG of the fastest progressing lesions best predicted OS. TTG obtained from the lesion-level analyses were slightly better predictors of OS than estimates from the sums, with ILV marginally better than ILD. All models predicted VELOUR HR equally well and all predicted study success. CONCLUSION: This analysis revealed consistent TGI profiles across all tumor size assessments considered. TTG predicted VELOUR HR when based on any of the tumor size measures.