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. Primary and secondary endpoints compared RECIST1.1 response at month-2 and delta tumor volume at month-2, respectively. An ancillary study compared imaging phenotype using a peer-reviewed radiomics-signature combining 3 imaging features to predict OS landmarked from month-2. Analysis was stratified by ethnicity. RESULTS: In total, 1584 patients were included (mean age, 60.25 ± 10.57 years; 969 men). Ethnicity was as follows: African (n = 50, 3.2%), Asian (n = 66, 4.2%), Caucasian (n = 1413, 89.2%), Latino (n = 27, 1.7%), Other (n = 28, 1.8%). Overall baseline tumor volume demonstrated Africans and Caucasians had more advanced disease (p < 0.001). Ethnicity was associated with treatment response. Response per RECIST1.1 at month-2 was distinct between ethnicities (p = 0.048) with higher response rate (55.6%) in Latinos. Overall delta tumor volume at month-2 demonstrated that Latino patients more likely experienced response to treatment (p = 0.021). Radiomics phenotype was also distinct in terms of tumor radiomics heterogeneity (p = 0.023). CONCLUSION: This study highlights how clinical trials that inadequately represent minority groups may impact associated translational work. In appropriately powered studies, radiomics features may allow us to unravel associations between ethnicity and treatment efficacy, better elucidate mechanisms of resistance, and promote diversity in trials through predictive enrichment. CLINICAL RELEVANCE STATEMENT: Radiomics could promote clinical trial diversity through predictive enrichment, hence benefit to historically underrepresented racial/ethnic groups that may respond variably to treatment due to socioeconomic factors and built environment, collectively referred to as social determinants of health. KEY POINTS: •Findings indicate ethnicity was associated with treatment response across all 3 endpoints. First, response per RECIST1.1 at month-2 was distinct between ethnicities (p = 0.048) with higher response rate (55.6%) in Latinos. •Second, the overall delta tumor volume at month-2 demonstrated that Latino patients were more likely to experience response to treatment (p = 0.021). Radiomics phenotype was also distinct in terms of tumor radiomics heterogeneity (p = 0.023).

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.

Modeling Tumor Growth Using Partly Conditional Survival Models: A Case Study in Colorectal Cancer.

PURPOSE: There are multiple approaches to modeling the relationship between longitudinal tumor measurements obtained from serial imaging and overall survival. Many require strong assumptions that are untestable and debatable. We illustrate how to apply a novel, more flexible approach, the partly conditional (PC) survival model, using images acquired during a phase III, randomized clinical trial in colorectal cancer as an example. METHODS: PC survival approaches were used to model longitudinal volumetric computed tomography data of 1,025 patients in the completed VELOUR trial, which evaluated adding aflibercept to infusional fluorouracil, leucovorin, and irinotecan for treating metastatic colorectal cancer. PC survival modeling is a semiparametric approach to estimating associations of longitudinal measurements with time-to-event outcomes. Overall survival was our outcome. Covariates included baseline tumor burden, change in tumor burden from baseline to each follow-up time, and treatment. Both unstratified and time-stratified models were investigated. RESULTS: Without making assumptions about the distribution of the tumor growth process, we characterized associations between the change in tumor burden and survival. This change was significantly associated with survival (hazard ratio [HR], 1.04; 95% CI, 1.02 to 1.05; P < .001), suggesting that aflibercept works at least in part by altering the tumor growth trajectory. We also found baseline tumor size prognostic for survival even when accounting for the change in tumor burden over time (HR, 1.02; 95% CI, 1.01 to 1.02; P < .001). CONCLUSION: The PC modeling approach offers flexible characterization of associations between longitudinal covariates, such as serially assessed tumor burden, and survival time. It can be applied to a variety of data of this nature and used as clinical trials are ongoing to incorporate new disease assessment information as it is accumulated, as indicated by an example from colorectal cancer.

Challenges to Using Big Data in Cancer.

Big data in healthcare can enable unprecedented understanding of diseases and their treatment, particularly in oncology. These data may include electronic health records, medical imaging, genomic sequencing, payor records, and data from pharmaceutical research, wearables, and medical devices. The ability to combine datasets and use data across many analyses is critical to the successful use of big data and is a concern for those who generate and use the data. Interoperability and data quality continue to be major challenges when working with different healthcare datasets. Mapping terminology across datasets, missing and incorrect data, and varying data structures make combining data an onerous and largely manual undertaking. Data privacy is another concern addressed by the Health Insurance Portability and Accountability Act, the Common Rule, and the General Data Protection Regulation. The use of big data is now included in the planning and activities of the FDA and the European Medicines Agency. The willingness of organizations to share data in a precompetitive fashion, agreements on data quality standards, and institution of universal and practical tenets on data privacy will be crucial to fully realizing the potential for big data in medicine.

Case Studies for Overcoming Challenges in Using Big Data in Cancer.

The analysis of big healthcare data has enormous potential as a tool for advancing oncology drug development and patient treatment, particularly in the context of precision medicine. However, there are challenges in organizing, sharing, integrating, and making these data readily accessible to the research community. This review presents five case studies illustrating various successful approaches to addressing such challenges. These efforts are CancerLinQ, the American Association for Cancer Research Project GENIE, Project Data Sphere, the National Cancer Institute Genomic Data Commons, and the Veterans Health Administration Clinical Data Initiative. Critical factors in the development of these systems include attention to the use of robust pipelines for data aggregation, common data models, data deidentification to enable multiple uses, integration of data collection into physician workflows, terminology standardization and attention to interoperability, extensive quality assurance and quality control activity, incorporation of multiple data types, and understanding how data resources can be best applied. By describing some of the emerging resources, we hope to inspire consideration of the secondary use of such data at the earliest possible step to ensure the proper sharing of data in order to generate insights that advance the understanding and the treatment of cancer.

Reverse Engineering of Digital Measures: Inviting Patients to the Conversation.

Background: Digital measures offer an unparalleled opportunity to create a more holistic picture of how people who are patients behave in their real-world environments, thereby establishing a better connection between patients, caregivers, and the clinical evidence used to drive drug development and disease management. Reaching this vision will require achieving a new level of co-creation between the stakeholders who design, develop, use, and make decisions using evidence from digital measures. Summary: In September 2022, the second in a series of meetings hosted by the Swiss Federal Institute of Technology in Zürich, the Foundation for the National Institutes of Health Biomarkers Consortium, and sponsored by Wellcome Trust, entitled "Reverse Engineering of Digital Measures," was held in Zurich, Switzerland, with a broad range of stakeholders sharing their experience across four case studies to examine how patient centricity is essential in shaping development and validation of digital evidence generation tools. Key Messages: In this paper, we discuss progress and the remaining barriers to widespread use of digital measures for evidence generation in clinical development and care delivery. We also present key discussion points and takeaways in order to continue discourse and provide a basis for dissemination and outreach to the wider community and other stakeholders. The work presented here shows us a blueprint for how and why the patient voice can be thoughtfully integrated into digital measure development and that continued multistakeholder engagement is critical for further progress.

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.

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.

Validation of ctDNA Quality Control Materials Through a Precompetitive Collaboration of the Foundation for the National Institutes of Health.

We report the results from a Foundation for the National Institutes of Health Biomarkers Consortium project to address the absence of well-validated quality control materials (QCMs) for circulating tumor DNA (ctDNA) testing. This absence is considered a cause of variance and inconsistencies in translating ctDNA results into clinical actions. METHODS: In this phase I study, QCMs with 14 clinically relevant mutations representing single nucleotide variants, insertions or deletions (indels), translocations, and copy number variants were sourced from three commercial manufacturers with variant allele frequencies (VAFs) of 5%, 2.5%, 1%, 0.1%, and 0%. Four laboratories tested samples in quadruplicate using two allele-specific droplet digital polymerase chain reaction and three (amplicon and hybrid capture) next-generation sequencing (NGS) panels. RESULTS: The two droplet digital polymerase chain reaction assays reported VAF values very close to the manufacturers' claimed concentrations for all QCMs. NGS assays reported most single nucleotide variants and indels, but not translocations, close to the expected VAF values. Notably, two NGS assays reported lower VAF than expected for all translocations in all QCM mixtures, possibly related to technical challenges detecting these variants. The ability to call ERBB2 copy number amplifications varied across assays. All three QCMs provided valuable insight into assay precision. Each assay across all variant types demonstrated dropouts at 0.1%, suggesting that the QCM can serve for testing of an assay's limit of detection with confidence claims for specific variants. CONCLUSION: These results support the utility of the QCM in testing ctDNA assay analytical performance. However, unique designs and manufacturing methods for the QCM, and variations in a laboratory's testing configuration, may require testing of multiple QCMs to find the best reagents for accurate result interpretation.

Minimal Residual Disease in Myeloma: Application for Clinical Care and New Drug Registration.

The development of novel agents has transformed the treatment paradigm for multiple myeloma, with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow-based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in patients with multiple myeloma. Complementary liquid biopsy-based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid-based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real-world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory multiple myeloma, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in multiple myeloma is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes.

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.

International liquid biopsy standardization alliance white paper.

The promise of precision medicine as a model to customize health care to the individual patient is heavily dependent upon new genetic tools to classify and characterize diseases and their hosts. Liquid biopsies serve as a safe alternative to solid biopsies and are thus a useful and critical component to fully realizing personalized medicine. The International Liquid Biopsy Standardization Alliance (ILSA) comprises organizations and foundations that recognize the importance of working towards the global use of liquid biopsy in oncology practice to support clinical decision making and regulatory considerations and seek to promote it in their communities. This manuscript provides an overview of the independent liquid biopsy- and standardization-based programs engaged with ILSA, their objectives and progress to date, and the tools and resources each is developing to contribute to the field. It also describes the unique areas of effort as well as synergy found within the group.

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. RESULTS: The median duration of contracting with five sponsors was 12 months. Ten trials in 7,085 patients that covered 12 treatment regimens across 20 trial arms were collected. To date, four trials in 3,954 patients were analyzed. Source imaging data were transferred to the academic core from 97% of trial patients (n = 3,837). Tumor imaging measurements were extracted from 82% of transferred computed tomography scans (n = 3,162). Causes of extraction failure were nonmeasurable disease (n = 392), single imaging time point (n = 224), and secondary captured images (n = 59). Overall, clinically annotated imaging data were extracted in 79% of patients (n = 3,055), and the primary trial end point analysis in each trial remained representative of each original trial end point. CONCLUSION: The sharing and analysis of source imaging data from large randomized trials is feasible and offer a rich and reusable, but largely untapped, resource for future research on novel trial-level response and progression imaging metrics.