George Kafatos

Prevalence of RAS mutations and individual variation patterns among patients with metastatic colorectal cancer: A pooled analysis of randomised controlled trials.

BACKGROUND The use of epidermal growth factor receptor inhibitors to treat metastatic colorectal cancer (mCRC) patients requires prior confirmation of tumour wild type (WT) RAS mutation status (exons 2/3/4 for KRAS or NRAS). This retrospective pooled analysis aims to robustly estimate RAS mutation prevalence and individual variation patterns in mCRC patients. METHOD Individual patient data from five randomised, controlled panitumumab studies (three phase III, one phase II and one phase Ib/II) were pooled for this analysis. The phase III studies included mCRC patients independent of RAS mutation status; the phase II and Ib/II studies included mCRC patients with confirmed WT KRAS exon 2 status. Four studies conducted RAS testing using Sanger sequencing; one study used a combination of next-generation sequencing and Sanger sequencing. In order to assign overall RAS status, the mutation status of all exons 2/3/4 KRAS or NRAS was required to be known. RESULTS Data from 3196 mCRC patients from 36 countries were included in the analysis. The overall unadjusted RAS mutation prevalence in mCRC patients was 55.9% (95% confidence interval (CI): [53.9-57.9%]), with the following distribution observed: KRAS exon 2 (prevalence 42.6% [40.7-44.5%]); KRAS exon 3 (3.8% [2.9-4.9%]); KRAS exon 4 (6.2% [5.0-7.6%]); NRAS exon 2 (2.9% [2.1-3.9%]); NRAS exon 3 (4.2% [3.2-5.4%]); NRAS exon 4 (0.3% [0.1-0.7%]). Differences in RAS mutation prevalence estimates were observed by study (p=0.001), gender (p=0.030), and by country (p=0.028). CONCLUSIONS This analysis provides robust estimates of overall RAS mutation prevalence and individual variation patterns in mCRC patients.

Panitumumab Use in Metastatic Colorectal Cancer and Patterns of KRAS Testing: Results from a Europe-Wide Physician Survey and Medical Records Review.

Background From 2008–2013, the European indication for panitumumab required that patients’ tumor KRAS exon 2 mutation status was known prior to starting treatment. To evaluate physician awareness of panitumumab prescribing information and how physicians prescribe panitumumab in patients with metastatic colorectal cancer (mCRC), two European multi-country, cross-sectional, observational studies were initiated in 2012: a physician survey and a medical records review. The first two out of three planned rounds for each study are reported. Methods The primary objective in the physician survey was to estimate the prevalence of KRAS testing, and in the medical records review, it was to evaluate the effect of test results on patterns of panitumumab use. The medical records review study also included a pathologists’ survey. Results In the physician survey, nearly all oncologists (299/301) were aware of the correct panitumumab indication and the need to test patients’ tumor KRAS status before treatment with panitumumab. Nearly all oncologists (283/301) had in the past 6 months of clinical practice administered panitumumab correctly to mCRC patients with wild-type KRAS status. In the medical records review, 97.5% of participating oncologists (77/79) conducted a KRAS test for all of their patients prior to prescribing panitumumab. Four patients (1.3%) did not have tumor KRAS mutation status tested prior to starting panitumumab treatment. Approximately one-quarter of patients (85/306) were treated with panitumumab and concurrent oxaliplatin-containing chemotherapy; of these, 83/85 had confirmed wild-type KRAS status prior to starting panitumumab treatment. All 56 referred laboratories that participated used a Conformité Européenne-marked or otherwise validated KRAS detection method, and nearly all (55/56) participated in a quality assurance scheme. Conclusions There was a high level of knowledge amongst oncologists around panitumumab prescribing information and the need to test and confirm patients’ tumors as being wild-type KRAS prior to treatment with panitumumab, with or without concurrent oxaliplatin-containing therapy.

RAS mutation prevalence among patients with metastatic colorectal cancer: A meta-analysis of real-world data

Aim: A confirmed wild-type RAS tumor status is commonly required for prescribing anti-EGFR treatment for metastatic colorectal cancer. This noninterventional, observational research project estimated RAS mutation prevalence from real-world sources. Materials & methods: Aggregate RAS mutation data were collected from 12 sources in three regions. Each source was analyzed separately; pooled prevalence estimates were then derived from meta-analyses. Results: The pooled RAS mutation prevalence from 4431 tumor samples tested for RAS mutation status was estimated to be 43.6% (95% CI: 38.8–48.5%); ranging from 33.7% (95% CI: 28.4–39.3%) to 54.1% (95% CI: 51.7–56.5%) between sources. Conclusion: The RAS mutation prevalence estimates varied among sources. The reasons for this are not clear and highlight the need for further research.

Series: Pragmatic trials and real world evidence: Paper 8. Data collection and management

Pragmatic trials can improve our understanding of how treatments will perform in routine practice. In a series of eight papers, the GetReal Consortium has evaluated the challenges in designing and conducting pragmatic trials and their specific methodological, operational, regulatory, and ethical implications. The present final paper of the series discusses the operational and methodological challenges of data collection in pragmatic trials. A more pragmatic data collection needs to balance the delivery of highly accurate and complete data with minimizing the level of interference that data entry and verification induce with clinical practice. Furthermore, it should allow for the involvement of a representative sample of practices, physicians, and patients who prescribe/receive treatment in routine care. This paper discusses challenges that are related to the different methods of data collection and presents potential solutions where possible. No one-size-fits-all recommendation can be given for the collection of data in pragmatic trials, although in general the application of existing routinely used data-collection systems and processes seems to best suit the pragmatic approach. However, data access and privacy, the time points of data collection, the level of detail in the data, and the lack of a clear understanding of the data-collection process were identified as main challenges for the usage of routinely collected data in pragmatic trials. A first step should be to determine to what extent existing health care databases provide the necessary study data and can accommodate data collection and management. When more elaborate or detailed data collection or more structured follow-up is required, data collection in a pragmatic trial will have to be tailor-made, often using a hybrid approach using a dedicated electronic case report form (eCRF). In this case, the eCRF should be kept as simple as possible to reduce the burden for practitioners and minimize influence on routine clinical practice.

Data collection in Pragmatic Trials

Pragmatic trials can improve our understanding of how treatments will perform in routine practice. In a series of eight papers, the GetReal Consortium has evaluated the challenges in designing and conducting pragmatic trials and their specific methodological, operational, regulatory, and ethical implications. The present final paper of the series discusses the operational and methodological challenges of data collection in pragmatic trials. A more pragmatic data collection needs to balance the delivery of highly accurate and complete data with minimizing the level of interference that data entry and verification induce with clinical practice. Furthermore, it should allow for the involvement of a representative sample of practices, physicians, and patients who prescribe/receive treatment in routine care. This paper discusses challenges that are related to the different methods of data collection and presents potential solutions where possible. No one-size-fits-all recommendation can be given for the collection of data in pragmatic trials, although in general the application of existing routinely used data-collection systems and processes seems to best suit the pragmatic approach. However, data access and privacy, the time points of data collection, the level of detail in the data, and the lack of a clear understanding of the data-collection process were identified as main challenges for the usage of routinely collected data in pragmatic trials. A first step should be to determine to what extent existing health care databases provide the necessary study data and can accommodate data collection and management. When more elaborate or detailed data collection or more structured follow-up is required, data collection in a pragmatic trial will have to be tailor-made, often using a hybrid approach using a dedicated electronic case report form (eCRF). In this case, the eCRF should be kept as simple as possible to reduce the burden for practitioners and minimize influence on routine clinical practice.

RAS mutation prevalence among patients with metastatic colorectal cancer: A meta-analysis of real-world data.

513 Background: Guidelines for prescribing anti-EGFR therapy for metastatic colorectal cancer (mCRC) require prior testing to confirm RAS (exons 2, 3, 4 of KRAS and NRAS) wild-type status in Europe and the USA. There is limited published evidence reporting the prevalence of RAS mutations in patients with mCRC in a real-world setting. The aim of this study was to use data from a range of real-world sources to obtain RAS mutation prevalence estimates for different geographic regions. Methods: Aggregated RAS mutation prevalence data were collected from 13 sources, including individual pathology centers (n = 7), mCRC registries (n = 3), and Amgen-sponsored studies (n = 3). Data sources included in this study originated in Europe (n = 10), the Middle East (n = 2), and South America (n = 1). A meta-analysis of all collected data was carried out to investigate the effect of heterogeneity amongst the data sources and obtain pooled RAS prevalence estimates for each, using a mixed regression model. Results: Aggrega...