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LBA2_PR * EGFR MUTATION TESTING AND ONCOLOGIST TREATMENT CHOICE IN ADVANCED NSCLC: GLOBAL TRENDS AND DIFFERENCES

DOI:10.1093/annonc/mdv128.04
Authors:
J. Spicer
J. Spicer
J. Spicer
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Bernd Tischer at Kantar Health
Bernd Tischer
M. Peters
M. Peters
M. Peters
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advanced NSCLC
LBA2 PR EGFR MUTATION TESTING AND ONCOLOGIST
TREATMENT CHOICE IN ADVANCED NSCLC: GLOBAL
TRENDS AND DIFFERENCES
J. Spicer1, B. Tischer2, M. Peters3
1
Research Oncology Offices, Guy’s Hospital, London, UK
2
Kantar Health, Munich, Germany
3
Respiratory Medicine, Concord Repatriation General Hospital, Sydney, Australia
Aim: IASLC guidelines recommend EGFRmutation testing shouldbe performed at
diagnosis of advanced NSCLC (except for SCC) and resultsshould guide treatment
decisions. This is important as recent datahas shown that matching mutations to specific
TKI treatmentcan improve overall survival(OS). Our aim was to assess the prevalence of
mutation testing, attitudes and barriersto testing, and how results affect choice of therapy.
Methods: We conducted an online representative survey of 562 oncologists in 10
countries (Canada, France, Germany, Italy, Japan, South Korea, Spain, Taiwan, UK and
USA) between December 2014 and January 2015.
Results: Oncologists reported that EGFR mutation testing was requested prior to first
line therapy in 81% of stage IIIb/IV NSCLC patients. Separate from histology, the main
reasons for not testing were insufficient tissue, poor performance status (PS) and long
turnaround time. PS rarely prevented testing in Asia, compared to North America and
Europe. Mutation test results were available before administration offirst line therapy
in 77% of patients who were tested, with significant differences between countries
(range: 51% in France to 89% in Japan; p < .001). 80% of patients with mutations (M+)
were treated with TKIs (range: 60% in Canada to 91% in Taiwan). 23% of oncologists
do not consider EGFR mutation subtypes in making treatment decisions. In contrast,
49% reported that their decision, including specific TKI selection, is affected by the
mutation detected. 75% of oncologists stated that a clinically relevant increase in OS is
very important when choosing a first line therapy for EGFR M+ NSCLC.
Conclusions: There is incomplete implementation of guidelines for identification and
treatment of EGFR M+ NSCLC. Practices vary between countries and regions. Simple
barriers such as timely delivery of test results should be addressed. The reasons for
many EGFR M+ patients in some countries still receiving first line chemotherapy need
to be understood, especially as recent data shows OS benefit with specific TKI
treatment matched to mutation type. Oncologist education and closer guideline
concordance should improve outcomes.
Disclosure: J. Spicer: I have received payments not exceeding the cost of research for
clinical trials funded by Boehringer Ingelheim, served on advisory boards, and received
speaker fees from the company. B. Tischer: I do not have any personal financial interest
in products or processes involved in the research which was performed by Kantar
Health and funded by a pharmaceutical company. M. Peters: I do not haveany
personal financial interest in products or processes involved in the research. I have
previously received honoraria from Boehringer Ingelheim for development and
delivery of CME in unrelated therapy areas.
© European Society for Medical Oncology 2015. Published by Oxford University Press on behalf of the European Lung Cancer Conference (ELCC) 2015 organisers.
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts
doi:10.1093/annonc/mdv128.4
Annals of Oncology 26 (Supplement 1): i57–i61, 2015
by guest on December 7, 2016http://annonc.oxfordjournals.org/Downloaded from
... A study conducted by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) surveying physicians in the US revealed variations in physician practice behaviors for both routine/ reflexive testing and usage of testing results for treatment 13,14 . Moreover, Spicer et al. surveyed 562 oncologists in 10 countries and found EGFR mutation testing was requested in as insufficient tissue, poor performance status, and turn-around time for results, as well as discrepancies in practice behavior and knowledge as primary concerns in mutation testing. ...
... Prior studies addressing biomarker testing for NSCLC have targeted medical oncologists, pathologists and pulmonologists 13,14,26 , and the present study included medical oncologists, pulmonologists, radiation oncologists, and pathologists. Current guidelines recommend mutation testing for patients diagnosed with advanced-stage disease (stage IV) NSCLC as part of first-line therapy 12 ; however, we found that while 74% of physicians requested testing for stage IV cancers, there was a significant difference between medical oncologists and non-medical oncologists (93% and 52% respectively, p <.001). ...
... Costs of mutation testing were also identified in both locations as a barrier to mutation testing. This is in agreement with studies conducted by BIPI and Spicer et al, who identified insufficient tissue and costliness as key barriers amongst pulmonologists and pathologists 13,14 . Lack of up-to-date information was identified as a barrier more frequently by non-medical oncologists than by medical oncologists (37% vs. 17%) and, as stated prior, this is supported by a prior study on mutation testing and "higher genomic knowledge" 26 . ...
Use of Biomarker Testing in Lung Cancer Among Puerto Rico and Florida Physicians: Results of a Comparative Study
Article
  • Oct 2019
Background: Lung cancer biomarker-driven therapies are the gold standard of treatment and recent studies suggest a higher prevalence of specific targetable biomarkers among Hispanic/Latinos (H/L) than Non-Hispanic Whites (NHW). The study aimed (1) to identify Florida (FL) and Puerto Rico (PR) physicians' knowledge and perceived value of newer genomic data regarding race/ethnicity in relation to optimal lung cancer treatment and survival; and (2) to identify modifiable practice barriers both across and within each location regarding biomarker testing in lung cancer. Methods: A 25-item survey was administered to a stratified random sample of physicians in FL and PR (medical oncologists, radiation oncologists, pulmonologists, and pathologists). Questions targeted domains of biomarker knowledge, attitudes toward testing, barriers, and practice behaviors regarding lung cancer biomarker testing. Results: The response rate was 45%. Participants identified guiding treatment decisions (82%) and personalizing treatments for patients (78%) as key benefits to mutation testing. PR physicians were more likely (p=0.022) to believe H/L had an elevated incidence of targetable epidermal growth factor receptor (EGFR) mutations compared to NHW. They also perceived lack of appropriate testing resources as a primary barrier compared to FL physicians (43.6% vs. 20.6%, p<0.001), whereas FL physicians identified mutation tests not conducted routinely as part of patient diagnosis as a primary barrier (43.1% vs 24.2%, p= 0.008). Conclusions: Practice behaviors differed by specialty and between locations, and differences were noted concerning physician's preferences for ordering mutation testing, indicating a clear need for education among physicians in both locations. Impact: Educating physicians regarding biomarker testing is imperative to improve patient care.
... A pesar de las recomendaciones y del claro beneficio que presentan los que reciben el ITK para EGFR en primera línea, aún muchos no son testeados. Los principales motivos por los cuales los test de mutación no se solicitan son la falta de tejido tumoral disponible y el tiempo prolongado hasta obtener el resultado 15 . El uso de inhibidores de tirosina quinasa del EGFR en quienes presentan una mutación de sensibilidad es la mejor medicación ya que aumenta la SG en pacientes con Del 19, la supervivencia libre de progresión y la calidad de vida comparado con quimioterapia. ...
Importancia del test de mutación del receptor del factor de crecimiento epidérmico en cáncer de pulmón de células no pequeñas
Article
Full-text available
  • Nov 2015
El enfoque terapéutico personalizado del cáncer de pulmón de células no pequeñas (CPCNP) permite que pacientes con tumores que presentan un perfil genotípico definido, se beneficien de tratamientos dirigidos específicamente contra el mismo. En base al estudio de numerosas muestras tumorales, se ha informado la prevalencia de alteraciones genéticas (mutaciones), algunas de las cuales son pasibles de terapias blanco. En la práctica clínica se puede conocer el perfil genético del tumor mediante técnicas de biología molecular validadas y disponibles. Se cuenta también con guías y recomendaciones internacionales que establecen los subtipos histológicos y estadios clínicos que se deberían estudiar, a fin de identificar aquellos pacientes que puedan beneficiarse con un tratamiento dirigido. Dentro del conjunto de terapias dirigidas disponibles se encuentran los inhibidores de tirosina quinasa, particularmente útiles en el tratamiento del CPCNP portador de mutaciones del receptor del factor de crecimiento epidérmico (EGFR). Su uso en primera línea demostró un mayor beneficio que la quimioterapia, en términos de supervivencia libre de progresión, calidad de vida y supervivencia global. Para que un mayor número de pacientes adecuados se beneficien de estos avances terapéuticos es necesario advertir la importancia de la genotipificación tumoral.
... Surprisingly, less than half responded that their treatment decisions were influenced by detected mutations and 23% stated that EGFR mutation status did not affect first-line therapy decisions. 15 ...
Biomarker Testing for People With Advanced Lung Cancer in England
Article
Full-text available
  • Apr 2021
Introduction Optimal management of people with advanced non-small cell lung cancer (NSCLC) depends on accurate identification of predictive markers. Yet, real world data in this setting is limited. We describe the impact, timeliness and outcomes of molecular testing for patients with advanced NSCLC and good performance status in England. Methods In collaboration with Public Health England, patients with stage IIIB-IV NSCLC, with an Eastern Co-operative Oncology Group (ECOG) performance status (PS) of 0-2, in England, between June and December 2017 were identified. All English hospitals were invited to record information. Results Sixty of 142 invited hospitals in England participated in this study and submitted data on 1157 patients. During the study period, 83% of patients with advanced adenocarcinoma underwent molecular testing for three recommended predictive biomarkers (EGFR, ALK and PD-L1). 80% of patients with non-squamous carcinomas on whom biomarker testing was performed had adequate tissue for analysis on initial sampling. First line treatment with a tyrosine kinase inhibitor (TKI) was received by 71% of patients with adenocarcinoma and a sensitising EGFR mutation and by 59% of those with an ALK translocation. Of patients with no driver mutation and a PD-L1 expression of ≥ 50%, 47% received immunotherapy. Conclusions We present a comprehensive dataset for molecular testing in England. Whilst molecular testing is well established in England, timeliness and uptake of targeted therapies should be improved.
... However, the relatively small sample size may be attributed to the initial challenges of implementation of biomarker testing in Ontario in the early 2010s, along with its associated logistical difficulties (e.g., delayed turnaround times), which led chemotherapy to be used as the first-line treatment to avoid clinical deterioration [49,50]. A previous study has suggested that approximately one in four patients do not undergo biomarker testing [51]. ...
Cost-Effectiveness Analysis of Afatinib, Erlotinib, and Gefitinib as First-Line Treatments for EGFR Mutation-Positive Non-Small-Cell Lung Cancer in Ontario, Canada
Article
  • Mar 2021
Objective The objective of this study was to compare the cost effectiveness of first-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for the treatment of non-small-cell lung cancer.Methods This study used Ontario Cancer Registry-linked administrative data to identify patients with a primary diagnosis of lung cancer who received EGFR-TKIs as first-line treatment between 1 January, 2014 and 31 August, 2019. A net benefit regression approach accounting for baseline covariates and propensity scores was used to estimate incremental net benefits and incremental cost-effectiveness ratios. Outcome measures were calculated over a 68-month period and were discounted with an annual rate of 1.5%. Sensitivity analyses were conducted to assess and characterize the uncertainties.ResultsA total of 547 patients were included in the study, of whom 20.1%, 23.6%, and 56.3% received afatinib, erlotinib, and gefitinib, respectively. Erlotinib was dominated by afatinib and gefitinib. Compared to gefitinib, afatinib was associated with higher effectiveness (adjusted incremental quality-adjusted life-year: 0.21), higher total costs (adjusted incremental costs: $9745), and an incremental cost-effectiveness ratio of $46,506 per quality-adjusted life-year gained. Results from the sensitivity analyses indicated the findings of the base-case analysis were robust.Conclusions Contrary to previously published studies, our study established head-to-head comparisons of effectiveness and treatment-related costs of first-line EGFR-TKIs. Our findings suggest afatinib was the most cost-effective option among the three EGFR-TKIs.
... oncologists/pulmonologists and patients may be reluctant to delay treatment initiation, given the potential risk for clinical deterioration [73,74]. To minimise TAT, molecular testing should ideally be carried out in the same centre where the patient was pathologically diagnosed, and using standard operating procedures (SOPs). ...
The evolving landscape of biomarker testing for non-small cell lung cancer in Europe
Article
Full-text available
The discovery of oncogenic driver mutations rendering non-small cell lung cancer (NSCLC) targetable by small-molecule inhibitors, and the development of immunotherapies, have revolutionised NSCLC treatment. Today, instead of non-selective chemotherapies, all patients with advanced NSCLC eligible for treatment (and increasing numbers with earlier, less extensive disease) require fast and comprehensive screening of biomarkers for first-line patient selection for targeted therapy, chemotherapy, or immunotherapy (with or without chemotherapy). To avoid unnecessary re-biopsies, biomarker screening before first-line treatment should also include markers that are actionable from second-line onwards; PD-L1 expression testing is also mandatory before initiating treatment. Population differences exist in the frequency of oncogenic driver mutations: EGFR mutations are more frequent in Asia than Europe, whereas the converse is true for KRAS mutations. In addition to approved first-line therapies, a number of emerging therapies are being investigated in clinical trials. Guidelines for biomarker testing vary by country, with the number of actionable targets and the requirement for extensive molecular screening strategies expected to increase. To meet diagnostic demands, rapid screening technologies for single-driver mutations have been implemented. Improvements in DNA- and RNA-based next-generation sequencing technologies enable analysis of a group of genes in one assay; however, turnaround times remain relatively long. Consequently, rapid screening technologies are being implemented alongside next-generation sequencing. Further challenges in the evolving landscape of biomarker testing in NSCLC are actionable primary and secondary resistance mechanisms to targeted therapies. Therefore, comprehensive testing on re-biopsies, collected at the time of disease progression, in combination with testing of circulating tumour DNA may provide important information to guide second- or third-line therapies. Furthermore, longitudinal biomarker testing can provide insights into tumour evolution and heterogeneity during the course of the disease. We summarise best practice strategies for Europe in the changing landscape of biomarker testing at diagnosis and during treatment.
... However, the relatively small sample size could be attributed to the initial challenges in implementation of biomarker testing in Ontario in the early 2010s, along with logistical difficulties, for example, delayed turnaround times, which led chemotherapy to be used as the first-line treatment to avoid clinical deterioration [60,61]. A previous study has suggested approximately one in four patients do not undergo biomarker testing [62]. Furthermore, the ODB database captured only information related to publicly-funded medications; therefore, prescription medications covered by private insurance and compassionate supplies from manufacturers could not be considered. ...
Factors affecting treatment selection and overall survival for first-line EGFR-tyrosine kinase inhibitor therapy in non-small-cell lung cancer
Article
Full-text available
  • Feb 2021
Aim: To investigate the factors associated with treatment selection and overall survival for first-line EGFR-tyrosine kinase inhibitors (EGFR-TKIs) therapy among patients with non-small-cell lung cancer. Materials & methods: We conducted a retrospective cohort study of linked administrative health databases in Ontario, Canada. Results: A total of 1011 patients received an EGFR-TKI as first-line therapy. Treatment selection and overall survival associated with these treatments were affected by age, sex, geographical residency, comorbidities and different sites of metastasis. Conclusion: Though recent approval of osimertinib offers a potential new standard of care in the first-line setting, earlier generation TKIs remain pillars in treatment of non-small-cell lung cancer therapeutic armamentarium. Our findings may contribute to optimizing treatment sequencing of EGFR-TKIs to maximize clinical benefits.
... [22][23][24] Additional reasons for undergenotyping include lack of a standard institutional genotyping protocol, poor physician adherence to guidelines, poor patient performance status, patient death, and the delay associated with tissue results. 18,25,26 The use of comprehensive cfDNA using next-generation sequencing (NGS), if sufficiently sensitive, may alleviate many of these issues by providing CGP for all genomic targets with a noninvasive blood sample. ...
Biomarker Discovery and Outcomes for Comprehensive Cell-Free Circulating Tumor DNA Versus Standard-of-Care Tissue Testing in Advanced Non–Small-Cell Lung Cancer
Article
  • Nov 2021
Purpose Treatment guidelines for advanced non–small-cell lung cancer (aNSCLC) recommend broad molecular profiling for targeted therapy selection. This study prospectively assessed comprehensive next-generation sequencing (NGS) of cell-free circulating tumor DNA (cfDNA) compared with standard-of-care (SOC) tissue-based testing to identify guideline-recommended alterations in aNSCLC. PATIENTS AND METHODS Patients with treatment-naïve aNSCLC were tested using a well-validated NGS cfDNA panel, and results were compared with SOC tissue testing. The primary objective was noninferiority of cfDNA vs. tissue analysis for the detection of two guideline-recommended biomarkers ( EGFR and ALK) and an additional six actionable biomarkers. Secondary analyses included tissue versus cfDNA biomarker discovery, overall response rate (ORR), progression-free survival (PFS) to targeted therapy, and positive predictive value (PPV) of cfDNA. RESULTS The primary objective was met with cfDNA identifying actionable mutations in 46 patients versus 48 by tissue ( P < .05). In total, 0/186 patients were genotyped for all eight biomarkers with tissue, compared with 90.8% using cfDNA. Targetable alterations or KRAS were identified in 80.7% when cfDNA was used first versus 57.1% when tissue was used first. PPV for cfDNA-detected EGFR was 100.0% (25/25). ORR and PFS in patients receiving targeted therapy based on tissue or cfDNA were similar to those previously reported. Conclusion This prospective study confirms a previous report that comprehensive cfDNA testing is noninferior to SOC tissue testing in detecting aNSCLC-recommended biomarkers. Furthermore, cfDNA-based first-line therapy produced outcomes similar to tissue-based testing, demonstrating the clinical utility of comprehensive cfDNA genotyping as the initial genotyping modality in patients with treatment-naïve aNSCLC when tissue is insufficient or when all actionable biomarkers cannot be rapidly assessed.
... For this purpose, several associations including the National Comprehensive Cancer Network (NCCN) have issued guidelines which strongly emphasize not only testing for EGFR, ALK, ROS1, BRAF, and PD-L1 alterations but more importantly advise to conduct broader molecular profiling to identify rare mutational drivers [5,6]. In practice, it was reported that the majority of oncologists (60%) in North America did not utilize genomic alteration results in their treatment decision making [55,56]. ...
Precision medicine and actionable alterations in lung cancer: A single institution experience
Article
Full-text available
Objectives Oncology has become more reliant on new testing methods and a greater use of electronic medical records, which provide a plethora of information available to physicians and researchers. However, to take advantage of vital clinical and research data for precision medicine, we must initially make an effort to create an infrastructure for the collection, storage, and utilization of this information with uniquely designed disease-specific registries that could support the collection of a large number of patients. Materials and methods In this study, we perform an in-depth analysis of a series of lung adenocarcinoma patients (n = 415) with genomic and clinical data in a recently created thoracic patient registry. Results Of the 415 patients with lung adenocarcinoma, 59% (n = 245) were female; the median age was 64 (range, 22–92) years with a median OS of 33.29 months (95% CI, 29.77–39.48). The most common actionable alterations were identified in EGFR (n = 177/415 [42.7%]), ALK (n = 28/377 [7.4%]), and BRAF V600E (n = 7/288 [2.4%]). There was also a discernible difference in survival for 222 patients, who had an actionable alteration, with a median OS of 39.8 months as compared to 193 wild-type patients with a median OS of 26.0 months (P<0.001). We identified an unprecedented number of actionable alterations [53.5% (222/415)], including distinct individual alteration rates, as compared with 15.0% and 22.3% in TCGA and GENIE respectively. Conclusion The use of patient registries, focused genomic panels and the appropriate use of clinical guidelines in community and academic settings may influence cohort selection for clinical trials and improve survival outcomes.
... While genotyping tumor tissue is recommended for managing NSCLC, a subset of small specimens obtained by minimally invasive techniques remains inadequate or partially adequate for molecular studies. Consequently, these patients have to undergo a repeat biopsy or may even receive treatment without knowledge of mutational status [32]. The ability to genotype the FNA supernatant provides an opportunity to save the cellular material in tissue blocks/smears for other ancillary studies, including in situ hybridization assays (e.g. ...
Liquid biopsy assay for lung carcinoma using centrifuged supernatants from fine-needle aspiration specimens
Article
Full-text available
Introduction: Tumor mutation profiling is standard-of-care in lung carcinoma patients. However, comprehensive molecular profiling of small specimens, including core needle biopsy (CNB) and fine-needle aspiration (FNA) specimens, may often be inadequate due to limited tissue. Centrifuged FNA supernatants, which are typically discarded, have emerged recently as a novel liquid-based biopsy for molecular testing. In this study, we evaluate the use of lung carcinoma FNA supernatants for detecting clinically relevant mutations. Methods: Supernatants from lung carcinoma FNA samples (n = 150) were evaluated. Samples were further analyzed using next-generation sequencing (NGS) and ultrasensitive droplet digital PCR (ddPCR). Mutation profiles in a subset of samples were compared with results derived from paired tissue samples from the same patient (n = 67) and available plasma liquid biopsy assay (n = 45). Results: All 150 samples yielded adequate DNA and NGS were carried out successfully on 104 (90%) of 116 selected samples. Somatic mutations were detected in 82% of the samples and in 50% of these patients a clinically relevant mutation was identified that would qualify them for targeted therapy or a clinical trial. There was high overall concordance between the mutation profiles of supernatants and the corresponding tissue samples, with 100% concordance with concurrent FNA and 96% with concurrent CNB samples. Comparison of actionable driver mutations detected in supernatant versus plasma samples showed 84% concordance. Conclusions: FNA supernatants can provide a valuable specimen source for genotyping lung carcinoma especially in patients with insufficient tumor tissue, thereby reducing multigene mutation profiling failure rates, improving turnaround times, and avoiding repeat biopsies.
Understanding barriers to the introduction of precision medicine in non-small cell lung cancer: a qualitative interview study [version 1; peer review: 2 approved with reservations]
Article
Full-text available
  • Feb 2021
Background: While treatments targeting genetic mutations and alterations in non-small cell lung cancer (NSCLC) have been available since 2010, the adoption of such examples of precision medicine into clinical practice has historically been slow. This means that patients with NSCLC may not have received life improving and extending treatments which should have been available to them. The purpose of this qualitative interview study was to identify the barriers to the provision of examples of precision medicine for NSCLC. Methods: This study used semi-structured telephone interviews with clinicians, test providers and service commissioners to identify the perceived barriers to providing historical, current, and future examples of precision medicine in NSCLC. Participants were identified through mailing list advertisements and snowball sampling. The qualitative data was analysed using a framework analysis. Results: Interviews were conducted with 11 participants including: five oncologists; three pathologists; two clinical geneticists; and one service commissioner. A total of 17 barriers to the introduction of precision medicine for NSCLC were identified and these were grouped into five themes: the regulation of precision medicine and tests; the commissioning and reimbursement of tests and the testing process; the complexity of the logistics around providing tests; centralisation or localisation of test provision; and opinions about future developments in precision medicine for NSCLC. Conclusions: A number of barriers exist to the introduction of precision medicine in NSCLC. Addressing these barriers may improve access to novel life improving and extending treatments for patients.
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