169 results found
Lythgoe MP, Mullish BH, Frampton A, et al., 2022, Polymorphic microbes: a new emerging hallmark of cancer, Trends in Microbiology, ISSN: 0966-842X
Samani A, Krell J, McNeish I, et al., 2022, Response to the letter entitled "Glomerular filtration rate estimation for carboplatin dosing in patients with gynaecological cancers"., ESMO Open, Vol: 7
Lythgoe M, Desai A, Gyawali B, et al., 2022, Cancer therapy approval timings, review speed and publication of pivotal registration trials in the US and Europe from 2010-2019, Jama Network Open, Vol: 5, ISSN: 2574-3805
Importance: Ensuring patients have access to safe and efficacious medicines in a timely manner is an essential goal for regulatory agencies, which has particular significance in oncology due to the significant unmet need for new therapies. The two largest regulatory agencies, the FDA and EMA have pivotal global roles, and their recommendations and approvals are frequently followed by other national regulators.Objective: To compare market authorization dates for new oncology therapies approved in the US and Europe over the past decade and to examine and contrast the regulatory activities of the FDA and EMA in the approval of new cancer medicines.Design, Setting and Participants: A review of the FDA and EMA regulatory databases to identify new oncology therapies approved in both the US and Europe from 2010 to 2019, and characterization of the timings of regulatory activities. Main Outcome Measures: Regulatory approval date, review time, submission of market authorization application, accelerated approval or conditional marketing authorisation status and proportion of approvals prior to peer-reviewed publication of pivotal trial results. Results: In total, 89 new concomitant oncology therapies were approved in the US and Europe from 2010 to 2019. The FDA approved 85 (95%) oncology therapies before European authorization and 4 (5%) therapies after. The median delay in market authorization for new oncology therapies in Europe was 241 days compared to the US. The median review time was 200 days and 426 days for the FDA and EMA, respectively. 60 (67%) new licensing applications were submitted to the FDA first, compared to 25 (28%) to the EMA. 35 (39%) oncology therapies were approved by the FDA prior to pivotal study publication, whereas only 8 (9%) by the EMA.Conclusion and Relevance: In this study we demonstrate that new oncology therapies are approved earlier in the US than Europe. The FDA receives licensing applications sooner and has shorter review times. However, mor
Giannone G, Ennis D, Mirza HB, et al., 2022, Targeting PI3K/AKT/mTOR pathway in platinum-resistant ovarian high-grade serous carcinoma: Translational analysis from the randomized phase II OCTOPUS trial, ESMO, Publisher: ELSEVIER, Pages: S384-S384, ISSN: 0923-7534
Cheng Z, Mirza H, Ennis DP, et al., 2022, The genomic landscape of early-stage ovarian high grade serous carcinoma, Clinical Cancer Research, Vol: 28, Pages: 2911-2922, ISSN: 1078-0432
Purpose: Ovarian high grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of volutionary advantage compared to early-stage tumours.Experimental Design: We performed targeted next generation sequencing and shallow whole genome sequencing (sWGS) on pre-treatment samples from 43 patients with FIGO stage I–IIA HGSC to investigate somatic mutations and copy number alterations (SCNA). We comparedresults to pre-treatment samples from 52 stage IIIC/IV HGSC patients from the BriTROC-1 study.Results: Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs 62.3 years respectively). TP53 mutations were near-universal in both cohorts (89% early-stage, 100% late-stage) and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2. We also did not observe cohort-specific focal SCNA that could explain biological behaviour. However, ploidy was higher in late-stage (median 3.0) than early-stage (median 1.9) samples. Copy number (CN) signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clustersthat were prognostic.Conclusions: Early stage and late stage HGSC have highly similar patterns of mutation and focal SCNA. However, copy number signature analysis showed that late-stage disease has distinct signature exposures consistent with whole genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early and late-stage or simply time-related markers of evolutionary fitness.
Fiorentino F, Krell J, de la Rosa CN, et al., 2022, DICE: Dual mTorc Inhibition in advanCed/recurrent Epithelial ovarian cancer resistant to standard treatment-a study protocol for a randomised trial investigating a novel therapy called TAK228, TRIALS, Vol: 23
Liu D, Yang QZC, Asim M, et al., 2022, The clinical significance of transfer RNAs present in extracellular vesicles, International Journal of Molecular Sciences, Vol: 23, ISSN: 1422-0067
Extracellular vesicles (EVs) are important for intercellular signalling in multi-cellular organ-isms. However, the role of mature transfer RNAs (tRNAs) and tRNA fragments in EVs has yet to be characterised. This systematic review aimed to identify up-to-date literature on tRNAs pre-sent within human EVs and explores their potential clinical significance in health and disease. A comprehensive and systematic literature search was performed, and the study was conducted in accordance with PRISMA guidelines. Electronic databases MEDLINE and EMBASE were searched up until 1st January 2022. From 685 papers, 60 studies were identified for analysis. The majority of papers reviewed focussed on the role of EV tRNAs in cancers (31.7%), with numerous other conditions represented. Blood and cell lines were the most common EV sources, representing 85.9% of protocols used. EV isolation methods included the most known methods, precipitation being the most common (49.3%). The proportion of EV tRNAs was highly variable, ranging be-tween 0.04% to >95% depending on tissue source. EV tRNAs are present in a multitude of sources and show promise as disease markers in breast cancer, gastrointestinal cancers, and other diseases. EV tRNA research is an emerging field, with increasing numbers of papers highlighting novel methodologies for tRNA and tRNA fragment discovery.
Clark J, Fotopoulou C, Cunnea P, et al., 2022, Novel ex vivo models of epithelial ovarian cancer: the future of biomarker and therapeutic research, Frontiers in Oncology, Vol: 12, Pages: 1-17, ISSN: 2234-943X
Epithelial ovarian cancer (EOC) is a heterogenous disease associated with variations in presentation, pathology and prognosis. Advanced EOC is typified by frequent relapse and a historical 5-year survival of less than 30% despite improvements in surgical and systemic treatment. The advent of next generation sequencing has led to notable advances in the field of personalised medicine for many cancer types. Success in achieving cure in advanced EOC has however been limited, although significant prolongation of survival has been demonstrated. Development of novel research platforms is therefore necessary to address the rapidly advancing field of early diagnostics and therapeutics, whilst also acknowledging the significant tumour heterogeneity associated with EOC. Within available tumour models, patient-derived organoids (PDO) and explant tumour slices have demonstrated particular promise as novel ex vivo systems to model different cancer types including ovarian cancer. PDOs are organ specific 3D tumour cultures that can accurately represent the histology and genomics of their native tumour, as well as offer the possibility as models for pharmaceutical drug testing platforms, offering timing advantages and potential use as prospective personalised models to guide clinical decision-making. Such applications could maximise the benefit of drug treatments to patients on an individual level whilst minimising use of less effective, yet toxic, therapies. PDOs are likely to play a greater role in both academic research and drug development in the future and have the potential to revolutionise future patient treatment and clinical trial pathways. Similarly, ex vivo tumour slices or explants have also shown recent renewed promise in their ability to provide a fast, specific, platform for drug testing that accurately represents in vivo tumour response. Tumour explants retain tissue architecture, and thus incorporate the majority of tumour microenvironment making them an attractive
Ma C, Pai RK, Schaeffer DF, et al., 2022, Recommendations for standardizing biopsy acquisition and histological assessment of immune checkpoint inhibitor-associated colitis, JOURNAL FOR IMMUNOTHERAPY OF CANCER, Vol: 10
Merali N, Chouari T, Kayani K, et al., 2022, A comprehensive review of the current and future role of the microbiome in pancreatic ductal adenocarcinoma, Cancers, Vol: 14, Pages: 1-34, ISSN: 2072-6694
Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second most common cause of cancer death in the USA by 2030, yet progress continues to lag behind that of other cancers, with only 9% of patients surviving beyond 5 years. Long-term survivorship of PDAC and improving survival has, until recently, escaped our understanding. One recent frontier in the cancer field is the microbiome. The microbiome collectively refers to the extensive community of bacteria and fungi that colonise us. It is estimated that there is one to ten prokaryotic cells for each human somatic cell, yet, the significance of this community in health and disease has, until recently, been overlooked. This review examines the role of the microbiome in PDAC and how it may alter survival outcomes. We evaluate the possibility of employing microbiomic signatures as biomarkers of PDAC. Ultimately this review analyses whether the microbiome may be amenable to targeting and consequently altering the natural history of PDAC.
Constantinou AP, Nele V, Doutch JJ, et al., 2022, Investigation of the thermogelation of a promising biocompatible ABC triblock terpolymer and its comparison with pluronic F127, Macromolecules, Vol: 55, Pages: 1783-1799, ISSN: 0024-9297
Thermoresponsive polymers with the appropriate structure form physical networks upon changes in temperature, and they find utility in formulation science, tissue engineering, and drug delivery. Here, we report a cost-effective biocompatible alternative, namely OEGMA30015-b-BuMA26-b-DEGMA13, which forms gels at low concentrations (as low as 2% w/w); OEGMA300, BuMA, and DEGMA stand for oligo(ethylene glycol) methyl ether methacrylate (MM = 300 g mol–1), n-butyl methacrylate, and di(ethylene glycol) methyl ether methacrylate, respectively. This polymer is investigated in depth and is compared to its commercially available counterpart, Poloxamer P407 (Pluronic F127). To elucidate the differences in their macroscale gelling behavior, we investigate their nanoscale self-assembly by means of small-angle neutron scattering and simultaneously recording their rheological properties. Two different gelation mechanisms are revealed. The triblock copolymer inherently forms elongated micelles, whose length increases by temperature to form worm-like micelles, thus promoting gelation. In contrast, Pluronic F127’s micellization is temperature-driven, and its gelation is attributed to the close packing of the micelles. The gel structure is analyzed through cryogenic scanning and transmission electron microscopy. Ex vivo gelation study upon intracameral injections demonstrates excellent potential for its application to improve drug residence in the eye.
Glover M, Hui G, Chiang R, et al., 2022, Disparity of race reporting in US Food and Drug Administration drug approvals for urinary system cancers from 2006 to 2021, BJU International, Vol: 129, Pages: 168-170, ISSN: 1464-4096
Samani A, Bennett R, Eremeishvili K, et al., 2022, Glomerular filtration rate estimation for carboplatin dosing in patients with gynaecological cancers, ESMO Open, Vol: 7, ISSN: 2059-7029
Background:Carboplatin remains integral for treatment of gynaecological malignancies and dosing is based on glomerular filtration rate (GFR). Measurement via radiotracer decay (nmGFR) is ideal. However, this may be unavailable. Therefore, GFR is often estimated using formulae that have not been validated in patients with cancer and/or specifically for gynaecological malignancies, leading to debate over optimal estimation. Suboptimal GFR estimation may affect efficacy or toxicity. Methods:We surveyed several UK National Health Service Trusts to assess carboplatin dosing practise. We then explored single-centre accuracy, bias and precision of various formulae for GFR estimation, relative to nmGFR, before validating our findings in an external cohort. Results:Across 18 Trusts, there was considerable heterogeneity in GFR estimation, including the formulae used (Cockcroft-Gault (CG) vs Wright), weight-adjustment and area under the curve (5 vs 6). We analysed 274 and 192 patients in two centres. Overall, CamGFR v2 (a novel formula for GFR estimation developed at Cambridge University Hospitals NHS Foundation Trust) excelled, showing the highest accuracy and precision. This translated into accuracy of hypothetical carboplatin dosing; nmGFR-derived carboplatin dose fell within 20% of the Cam GFR v2-derived dose in 86.5% and 87% of patients across the cohorts. Amongst the CG formula and its derivatives, using adjusted body weight in those with BMI ≥25 kg/m2 (CG-AdBW) was optimal. The Wright and unadjusted CG estimators performed most poorly. Conclusions:When compared with nmGFR assessment, accuracy, bias and precision varied widely between GFR estimators, with the newly developed Cam GFR v2 and CG-AdBW perfoming best. In general, weight (or body surface area)-adjusted formulae performed best, while the unadjusted CG and Wright formulae or the use of AUC6 (vs. nmGFR AUC5) produced risk of significant overdose. Thus, individual centres should validate their GFR estimation me
de la Rosa CN, Krell J, Day E, et al., 2022, Statistical analysis plan for the Dual mTorc Inhibition in advanCed/recurrent Epithelial ovarian, fallopian tube or primary peritoneal cancer (of clear cell, endometrioid and high-grade serous type, and carcinosarcoma) trial (DICE), Trials, Vol: 23, Pages: 1-8, ISSN: 1745-6215
BackgroundTreatment for ovarian cancer includes platinum-based chemotherapy, but many women become resistant to chemotherapy, becoming platinum-resistant. Standard of care for these women is weekly paclitaxel chemotherapy, but cancers can often become paclitaxel resistant. TAK228, an investigational dual TORC1/2 inhibitor, is an oral therapy that can be added to standard treatment. The DICE trial is a phase II international multicentre, parallel-group, superiority clinical trial with 1:1, open label randomisation which has the aim of investigating the effectiveness of TAK228 plus weekly paclitaxel. The planned sample size is 124 women (62 per treatment arm) with platinum-resistant ovarian cancer.ObjectiveTo outline the planned analyses for DICE in a statistical analysis plan (SAP) before database hard lock and the start of analysis. This ensures that bias is minimised during the analysis phase.ResultsThis SAP provides detailed descriptions of the analysis principles and statistical procedures for analysing primary and secondary outcomes of the trial. The primary outcome is overall progression-free survival (PFS). Secondary outcomes include progression-free survival (PFS) at 24 weeks, overall response rate (ORR), duration of response (DoR), time to progression (TTP), clinical benefit rate (CBR) at 4 months, Cancer Antigen 125 (CA125) response according to Gynaecological Cancer Intergroup (GCIG) criteria, overall survival (OS), safety and tolerability as assessed by adverse events and the quality-of-life questionnaires (EORTC QLQ-C30 and EORTC QLQ-OV28). This detailed description includes significance levels, sensitivity analyses and compliance analysis.DiscussionThe DICE trial will determine whether the addition of TAK228 to weekly paclitaxel chemotherapy shows a statistically significant improvement to participant’s progression free and overall survival and that the adverse events (AEs) and quality of life (QoL) are not significantly worse than t
Armbrust R, Chekerov R, Sander S, et al., 2021, Surgery due to mechanical bowel obstruction in relapsed ovarian cancer: clinical and surgical results of a bicentric analysis of 87 patients (Oct, 10.1007/s00404-021-06237-x, 2021), ARCHIVES OF GYNECOLOGY AND OBSTETRICS, Vol: 306, Pages: 291-292, ISSN: 0932-0067
Lythgoe MP, Ghani R, Mullish BH, et al., 2021, The Potential of Faecal Microbiota Transplantation in Oncology, Trends in Microbiology, ISSN: 0966-842X
Armbrust R, Chekerov R, Sander S, et al., 2021, Surgery due to mechanical bowel obstruction in relapsed ovarian cancer: clinical and surgical results of a bicentric analysis of 87 patients, ARCHIVES OF GYNECOLOGY AND OBSTETRICS, Vol: 305, Pages: 963-968, ISSN: 0932-0067
McGrane J, Shaw D, Anand A, et al., 2021, Ovarian Cancer Retrospective European (O'CaRE) observational study to assess burden of disease and time to next treatment in real-world clinical practice: Results from the United Kingdom (UK), Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: ELSEVIER, Pages: S741-S741, ISSN: 0923-7534
Lythgoe MP, Liu DSK, Annels NE, et al., 2021, Gene of the month: lymphocyte-activation gene 3 (LAG-3), JOURNAL OF CLINICAL PATHOLOGY, Vol: 74, Pages: 543-547, ISSN: 0021-9746
Lythgoe M, Cleary S, Kalofonou F, et al., 2021, 747P Real-world experience of rucaparib in patients with ovarian cancer: A multicentre United Kingdom study, Annals of Oncology, Vol: 32, Pages: S742-S742, ISSN: 0923-7534
BackgroundEpithelial Ovarian Cancer (EOC) is the 5th leading cause of female cancer deaths. Despite high responses to first-line therapy, 5-year survival remains poor at 29%. Rucaparib is a small molecule PARP inhibitor (PARPi) approved as monotherapy for maintenance treatment of recurrent EOC with prior complete/partial response to platinum-based chemotherapy, on the basis of the ARIEL3 trial. Despite the validity of clinical trial evidence, applicability to routine practice is limited and real-world evidence (RWE) is mandated.MethodsWe performed a multi-center retrospective study of patients with advanced EOC receiving rucaparib in the UK from June 2018, via an early access program.Results119 patients were included, with a median age of 66 years (range 26-89). Median ECOG at commencement was 1 (0-3). 91% (n=108) had high grade serous carcinoma and 24% (n=29) germline/somatic BRCA1/2mutation (BRCAm). Prior to rucaparib, patients had a median of 3 therapies (range 1-9) with 8% (n=10) receiving an alternate PARPi. Overall progression free survival (PFS) was 7.5 months (1.1-37.4), with a higher PFS of 9.1 months (1.1-35.5) in BRCAm patients. This is lower than observed in ARIEL3. However, if similar inclusion/exclusion criteria are applied to our RWE population, findings are analogous, with PFS of 10.2 and 16.6 months in the overall and BRCAm groups respectively. Treatment-related toxicity (any grade) was reported in 88% (n=105) of patients, most prevalent being nausea, fatigue, anaemia and other blood dyscrasias. 26% (n=32) of patients experienced a CTCAE grade 3/4 toxicity and 58% (n=69) required dose interruption/reduction. 13% (n=16) of patients discontinued therapy due to a treatment related adverse effect: most frequently fatigue, nausea or thrombocytopenia. No haematological malignancies were observed.ConclusionsOverall we found a lower incidence of any grade and grade 3/4 toxicity, and furthermore equivalent discontinuation rates to ARIEL3. A lower overall PFS
Lythgoe M, Adriani M, Stebbing J, et al., 2021, 543P Neoadjuvant MRx0518 treatment is associated with significant gene and metagene signature changes in solid tumours, Annals of Oncology, Vol: 32, Pages: S607-S607, ISSN: 0923-7534
BackgroundMRx0518 is an oral live biotherapeutic with potent immunostimulatory activity and anti-tumorigenic efficacy in murine models of lung (LLC1), kidney (Renca) and breast (EMT6) cancer. Previous reports have demonstrated a favourable safety profile in neoadjuvant and metastatic clinical settings, with emerging evidence of immune modulation. We performed a comprehensive analysis of the gene and metagene signature in cancer patients treated with MRx0518 monotherapy.MethodsTreatment-naïve patients with a histologically confirmed diagnosis of cancer scheduled for surgical resection were recruited from April 2019 to February 2020. Patients received 1 capsule of MRx0518 (1x1010 to 1x1011CFU) twice daily from inclusion until the day preceding surgery. Safety and tolerability (CTCAE v4.03) were the primary endpoints of this study. Comprehensive biomarker analysis was also performed in paired pre-treatment (diagnostic biopsy) and post-treatment (surgical specimen) samples using the NanoString IO 360 panel to explore gene and metagene signatures.Results31 samples were collected across tumour groups including breast (n=13) prostate (n=8), uterine (n=6), melanoma (n=2) and bladder (n=2). Differential expression analysis showed significant (p<0.05) increases in genes and metagenes associated with anti-tumour activity, including antigen presentation (AXL & CXCL12), innate immune processes (CHUK, RELA, PPARG & HRAS), interferon response (IFNGR1 & IFNGR2), Th1 cells and CD8+ cells following MRx0518 therapy, echoing preclinical findings. Novel changes, not previously detected in murine models, involving endothelial, mast cells, inflammatory myeloid and inflammatory chemokines were also observed, suggesting MRx0518 may have additional in vivo anti-tumorigenic effects. These changes were more pronounced in the breast cancer cohort.ConclusionsThis analysis, mirrors previous immunostimulatory activity and anti-tumorigenic efficacy observations seen in pre-clini
Lythgoe MP, Krell J, McNeish IA, et al., 2021, Safe administration of chemotherapy in mast cell activation syndrome, Journal of Oncology Pharmacy Practice, Vol: 27, Pages: 1005-1010, ISSN: 1078-1552
IntroductionMast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.Case reportWe present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Lythgoe M, Krell J, Warner JL, et al., 2021, Time intervals between U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) new cancer therapy approvals., Journal of Clinical Oncology, Vol: 39, Pages: 1575-1575, ISSN: 0732-183X
Background: Novel therapies are transforming cancer care. Regulatory review and approval are essential to deliver safe and efficacious innovations to patients. Studies prior to 2010 describe quicker approval decisions for new oncology drug registrations with the FDA compared to the EMA (median delay 238 days). Both regulatory agencies have subsequently improved procedures to expedite approval times. We compared regulatory market authorisation dates at the FDA and EMA for new oncology therapies from 2010-2020. Methods: New oncology therapeutic approvals between 2010-2020 were identified from the FDA and EMA regulatory databases. We analysed only initial approvals (not supplementary licenses) for active anti-cancer therapies (excluding biosimilars and supportive drugs). The delay in regulatory approval between the FDA and EMA was calculated in calendar days. We further analysed therapies by therapeutic class, evaluating for significant differences. Results: We identified 108 new therapy registrations during the study period. 104 (96.3%) therapies were approved by the FDA and 90 (83.3%) had EMA market authorisation. 4 (3.7%) drugs were not FDA registered, including 3 unsuccessful applications and 1 which sought licensing in a different indication. 18 (16.5%) drugs were not EMA registered, including 9 (8.8%) which did not pursue EMA licensing, 3 (2.9%) withdrawn licensing applications, 3 (2.9%) sought licensing in different tumour group/indication, 1 (0.9%) rejected application and 2 (1.9%) with applications under review at submission date. Of the 86 drugs approved by both agencies, 80 were approved first by the FDA and 6 by the EMA. The median delay in approval between the FDA and EMA was 227 days (IQR:124-354 days). Table shows approvals by therapeutic class. The shortest median time difference for approval was for monoclonal antibodies (171 days) with the longest for kinase inhibitors (281 days). Conclusions: This study shows more new oncology therapies are approved
Ahmed-Salim Y, Galazis N, Bracewell-Milnes T, et al., 2021, The application of metabolomics in ovarian cancer management: a systematic review, INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, Vol: 31, Pages: 754-774, ISSN: 1048-891X
Lythgoe MP, Krell J, Kenny L, et al., 2021, 157P Racial diversity and reporting in FDA registration trials for breast cancer from 2006 to 2021, Annals of Oncology, Vol: 32, Pages: S88-S88, ISSN: 0923-7534
BackgroundIn the USA, there are >250,000 diagnoses of breast cancer (BC) annually, with significant racial disparities in incidence, subtype and outcomes. FDA clinical trials guidance recommend 5 categories of race reporting (White, Black, Asian, American Indian/Alaskan Native [AIAN] & Native Hawaiian/Pacific Islander [NHPI]). Furthermore, International Committee of Medical Journal Editors (ICMJE) guidance recommend authors, as a minimum, provide descriptive data for race. We analysed racial diversity in BC drug registration trials and compliance with FDA/ICMJE guidance.MethodsWe performed a retrospective review of BC FDA market authorisations from 2006 to 2021. Clinical trial publications cited on the licensing label were identified and analysed. If race was under-reported (<3 groups), the study report on clinicaltrials.gov was analysed. The total proportion of racial group participation and number of registration trials with adequate reporting was determined.Results38 new licensing indications were identified, involving 41 trials and 23 drugs. Overall, 36,081 patients participated: 19,495 (54.0%) White, 4194 (11.6%) Asian, 748 (2.1%) Black, 228 (0.6%) AIAN, 8 (0.1%) NHPI, 840 (2.3%) other and 10568 (29.3%) unknown. The table shows breakdown by BC subtype. Race was reported in 29 (70%) licensing trial publications, of which 7 provided only limited data. For licensing trials where no race data was reported, a further 6 (14%) had information within the study report. In the 10 years prior to the introduction of new FDA guidance in 2016 only 50% of registration studies met FDA/ICJME race reporting requirements. Since 2016 this has improved to 85%
Lythgoe MP, Krell J, Savage P, et al., 2021, Race reporting and diversity in US food and drug administration (FDA) registration trials for prostate cancer; 2006-2020., Prostate Cancer and Prostatic Diseases, Vol: 24, Pages: 1208-1211, ISSN: 1365-7852
BACKGROUND: There is significant racial disparity in prostate cancer (PCa) in terms of incidence, treatment, and outcomes. Racial diversity and compliance with FDA race reporting guidelines in PCa drug registration trials are unknown. We analyzed racial diversity and race reporting in drug licensing trials for PCa. METHODS: New drug authorizations for PCa from 2006 to 2020 were identified. The corresponding licensing trial publications were analyzed to check compliance with current FDA recommendations for race reporting. If race was unreported, the clinical trial report was analyzed to determine participant recruitment by race and lead the recruiting country. RESULTS: During the study period, 17 new drug registrations for the management of PCa involving ten unique drugs were identified. In total, 18,455 participants were included in FDA registration trials, of which 76.3% were white or Caucasian, 7.9% Asian, 2.9% Black or African American, 0.5% American Indian or Alaskan Native, 0.1% Native Hawaiian or other Pacific Islander, 1.8% other or multiple races and 10.5% unknown. 53% of trials reported race in the licensing publication, however of this only 55% met current FDA recommendations. When the race was unreported in the licensing publication, 88% of studies had further information in the clinical study report. CONCLUSION: We found a significant under-representation of non-white participants in FDA drug registration trials for PCa. Race reporting in licensing publication is inconsistent and both FDA and International Committee of Medical Journal Editors guidelines are not being universally followed. Given the disproportionality of the disease burden of PCa, recruitment of Black and other minority participants to trials should be a research priority.
Lythgoe M, Julve M, Krell J, et al., 2021, Racial diversity and reporting in FDA registration trials for genitourinary (GU) cancers from 2006-20, Journal of Clinical Oncology, Vol: 39, Pages: 22-22, ISSN: 0732-183X
Background: GU cancers account for 1 in 5 of new cancer diagnoses in the USA. Significant racial disparities exist in terms of incidence, treatment and outcomes. Current FDA clinical trial guidance advises race reporting as a minimum of 5 categories (White/Caucasian, Black, Asian, American Indian or Alaskan Native [AIAN] and Native Hawaiian or Pacific Islander [NHPI]). Guidelines from the International Committee of Medical Journal Editors (ICMJE) recommend that authors should as a minimum, provide descriptive data for variables such as race and ethnicity. We analysed racial diversity in GU registration trials and compliance with FDA/ICMJE guidance in reporting. Methods: A retrospective review of new market authorisations in GU cancers from Jan 2006 to Oct 2020 was conducted utilizing the FDA website. Clinical trials cited on the licensing label for market authorization were recorded and corresponding registration trial publication identified. If race was unreported or partially reported (defined ≤3 groups), then the trial report on clinicaltrials.gov or FDA website was analysed. Total proportion of racial group participation and the proportion of registration trials with adequate reporting was determined. Results: We identified 42 new licensing indications, involving 33 unique drugs. Overall 30,316 patients participated in GU cancer registration trials; 21,068 (69.5%) White or Caucasian, 2516 (8.3%) Asian, 621(2%) Black or African American, 92 (0.3%) AIAN, 17 (0.1%) NHPI, 558 (1.8%) other or multiple races and 5463 (18%) unknown. Table shows breakdown by tumour group. Race reporting occurred in 23 (55%) registration trial publications, of which 5 provided only limited information (e.g. Caucasian only). For studies where no race information was reported, a further 10 (24%) had information within the trial report. In the 5 years prior to the introduction of FDA guidance in 2016 only 30% of registration studies met FDA/ICJME requirements. Since 2016 this has improve
Morgan RD, McNeish IA, Cook AD, et al., 2021, Objective responses to first-line neoadjuvant carboplatin-paclitaxel regimens for ovarian, fallopian tube, or primary peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 trial, The Lancet Oncology, Vol: 22, Pages: 277-288, ISSN: 1213-9432
BACKGROUND: Platinum-based neoadjuvant chemotherapy followed by delayed primary surgery (DPS) is an established strategy for women with newly diagnosed, advanced-stage epithelial ovarian cancer. Although this therapeutic approach has been validated in randomised, phase 3 trials, evaluation of response to neoadjuvant chemotherapy using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and cancer antigen 125 (CA125) has not been reported. We describe RECIST and Gynecologic Cancer InterGroup (GCIG) CA125 responses in patients receiving platinum-based neoadjuvant chemotherapy followed by DPS in the ICON8 trial. METHODS: ICON8 was an international, multicentre, randomised, phase 3 trial done across 117 hospitals in the UK, Australia, New Zealand, Mexico, South Korea, and Ireland. The trial included women aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, life expectancy of more than 12 weeks, and newly diagnosed International Federation of Gynecology and Obstetrics (FIGO; 1988) stage IC-IIA high-grade serous, clear cell, or any poorly differentiated or grade 3 histological subtype, or any FIGO (1988) stage IIB-IV epithelial cancer of the ovary, fallopian tube, or primary peritoneum. Patients were randomly assigned (1:1:1) to receive intravenous carboplatin (area under the curve [AUC]5 or AUC6) and intravenous paclitaxel (175 mg/m2 by body surface area) on day 1 of every 21-day cycle (control group; group 1); intravenous carboplatin (AUC5 or AUC6) on day 1 and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 2); or intravenous dose-fractionated carboplatin (AUC2) and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 3). The maximum number of cycles of chemotherapy permitted was six. Randomisation was done with a minimisation method, and patients were stratified accordi
Lythgoe MP, Krell J, Mahmoud S, et al., 2021, Development and economic trends in anticancer drugs licensed in the UK from 2015 to 2019, Drug Discovery Today, Vol: 26, Pages: 301-307, ISSN: 1359-6446
Analysis of new anticancer drugs licensed in the UK found that 44 new therapies were approved from 2015 to 2019. No other 5-year period has produced as many new therapies. Most new drugs are kinase inhibitors (KIs, N = 18) and monoclonal antibodies (mAbs, N = 16) with only one classical cytotoxic chemotherapy (CC) licensed. The average median treatment duration has risen by 55 days to 318 days (263 days in 2010–2014). Drug costs have escalated; an average treatment course now costs £62 343, compared to £35 383 in 2010–2014. New drugs are delivering significant clinical benefits with longer treatment durations. However, the financial burden is greater, heralding economic challenges for healthcare providers.
Lythgoe M, Stebbing J, Pickford E, et al., 2020, 805 Safety and emerging evidence of immune modulation of the live biotherapeutic MRx0518 in the neoadjuvant setting for patients awaiting surgical removal of solid tumours, Journal for ImmunoTherapy of Cancer, Vol: 8, Pages: A481-A482, ISSN: 2051-1426
Background The gut microbiome has emerged as a promising innovative therapeutic target for immune-stimulation treatment of solid tumours. MRx0518 is a novel, gut microbiome-derived oral live biotherapeutic. It has potent anti-tumorigenic efficacy in the preclinical setting including murine models of lung (LLC1), kidney (Renca) and breast (EMT6) cancer.1 In these models, a significant reduction in tumour growth has been demonstrated, including induction of immunostimulatory responses with tumour infiltration of NK cells, CD8+ and CD4+ T-cells. MRx0518 is under investigation in various oncological settings, including in combination with immune checkpoint inhibitors (NCT03637803) and radiotherapy (NCT04193904).Methods Treatment naïve patients were recruited from April 2019 to February 2020. Patients were eligible if they received a histologically confirmed diagnosis of cancer (solid tumours) scheduled for surgical resection. Patients received 1 capsule of MRx0518 (1x1010 to 1x1011 CFU) twice daily from inclusion until the day preceding surgery (maximum 28 days therapy). The primary study outcome is to evaluate safety and tolerability of MRx0518 monotherapy in treatment naïve patients. Additional exploratory outcomes including identifying surrogate biomarkers of efficacy, microbiome analysis, effect on metabonomic markers and identification of histological and genomic alterations in paired pre-treatment (diagnostic biopsy) and post-treatment (surgical specimen) samples.Results In part A, 17 patients received treatment, across tumour groups including breast (n=8), prostate (n=4), uterine (n=3), melanoma (n=1) and bladder (n=1). MRx0518 was well tolerated by all, with no grade 3/4 CTCAE toxicity reported, no severe adverse effects or treatment discontinuations. All patients proceeded to surgery, however the COVID-19 pandemic delayed surgery in 3 cases.Analysis of the first 5* patient paired samples utilising the NanoString Pan Cancer IO 360TM Gene Expression pan
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