Publications
96 results found
Wang Y, Abu-Sbeih H, Tang T, et al., 2022, Endoscopic Severity Score of Immune-Mediated Colitis Is More Effective in Guiding Medical Treatment Than Clinical Severity Grade, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: S503-S504, ISSN: 0002-9270
Jenei K, Lythgoe MP, Prasad V, 2022, General payments from Biogen to U.S. physicians between 2015 and 2020., J Am Geriatr Soc, Vol: 70, Pages: 3035-3038
Lythgoe MP, Prasad V, 2022, Repositioning canakinumab for non-small cell lung cancer-important lessons for drug repurposing in oncology, British Journal of Cancer, Vol: 127, Pages: 785-787, ISSN: 0007-0920
Canakinumab is an anti-interleukin-1β monoclonal antibody approved for use in a range of immune-related disorders. During the clinical investigation (CANTOS trial) for prevention of cardiovascular complications, therapy was linked to a reduction in both the occurrence and mortality of lung cancer. This unexpected observation fuelled the rapid initiation of four large clinical trials to evaluate potential anticancer efficacy (in combination with chemotherapy and/or immunotherapy), before fully validating these observations in a dedicated study. The first two trials (CANOPY-1 and 2) have now been reported and have both have failed to meet their primary efficacy endpoints. In this article, we explore the scientific and clinical rationale behind the development of canakinumab in oncology, the repurposing approach utilised and implications this may have for the wider drug repurposing field in the development of new cancer medicines.
Jenei K, Lythgoe MP, Prasad V, 2022, CostPlus and implications for generic imatinib, LANCET REGIONAL HEALTH-AMERICAS, Vol: 13, ISSN: 2667-193X
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- Citations: 1
MirĂ³n-Barroso S, Correia JS, Frampton AE, et al., 2022, Polymeric carriers for delivery of RNA cancer therapeutics, Non-Coding RNA, Vol: 8, Pages: 58-58, ISSN: 2311-553X
As research uncovers the underpinnings of cancer biology, new targeted therapies have been developed. Many of these therapies are small molecules, such as kinase inhibitors, that target specific proteins; however, only 1% of the genome encodes for proteins and only a subset of these proteins has ‘druggable’ active binding sites. In recent decades, RNA therapeutics have gained popularity due to their ability to affect targets that small molecules cannot. Additionally, they can be manufactured more rapidly and cost-effectively than small molecules or recombinant proteins. RNA therapeutics can be synthesised chemically and altered quickly, which can enable a more personalised approach to cancer treatment. Even though a wide range of RNA therapeutics are being developed for various indications in the oncology setting, none has reached the clinic to date. One of the main reasons for this is attributed to the lack of safe and effective delivery systems for this type of therapeutic. This review focuses on current strategies to overcome these challenges and enable the clinical utility of these novel therapeutic agents in the cancer clinic.
Lythgoe MP, Sullivan R, 2022, Project Orbis: the UK experience after 1 year., Lancet Oncol, Vol: 23, Pages: 978-981
Lythgoe MP, Sullivan R, 2022, Approved anti-PD-1 monoclonal antibodies in China: A bridge too far for US approval, EUROPEAN JOURNAL OF CANCER, Vol: 169, Pages: 103-105, ISSN: 0959-8049
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- Citations: 2
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
Aravind P, Popat S, Barwick TD, et al., 2022, [F-18]Fluorothymidine(FLT)-PET imaging of thymidine kinase 1 pharmacodynamics in non-small cell lung cancer treated with pemetrexed., ASCO, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
Benjamin DJ, Prasad V, Lythgoe MP, 2022, FDA decisions on new oncological drugs, The Lancet Oncology, Vol: 23, Pages: 585-586, ISSN: 1470-2045
Talukder R, Makrakis D, Diamantopoulos LN, et al., 2022, Response and Outcomes to Immune Checkpoint Inhibitors in Advanced Urothelial Cancer Based on Prior Intravesical Bacillus Calmette-Guerin, CLINICAL GENITOURINARY CANCER, Vol: 20, Pages: 165-175, ISSN: 1558-7673
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- Citations: 2
Jenei K, Prasad V, Lythgoe MP, 2022, High US drug prices have global implications., BMJ, Vol: 376
Benjamin DJ, Xu A, Lythgoe MP, et al., 2022, Cancer drug approvals that displaced existing standard-of-care therapies, 2016-2021, Jama Network Open, Vol: 5, Pages: 1-9, ISSN: 2574-3805
Importance Although several cancer drugs receive US Food and Drug Administration (FDA) approval each month, it is unclear how many of these cancer drugs transform the treatment landscape significantly by tumor group. Specifically, it remains unclear how many of these newly approved cancer drugs displace the existing standard-of-care therapies for their indication vs being added to existing therapies.Objective To examine how many cancer drugs displace the standard-of-care therapies vs being added to existing therapy or filling breaks in systemic treatments in the metastatic setting, adjuvant setting, or maintenance setting.Design, Setting, and Participants Retrospective cross-sectional study using landmark trials leading to FDA approval of cancer drugs between May 1, 2016, and May 31, 2021. The study evaluated all FDA approvals for cancer drugs between May 1, 2016, and May 31, 2021, using the FDA Oncology (Cancer)/Hematologic Malignancies Approval Notifications website. All clinical trials leading to FDA approval of cancer drugs during this period were examined.Main Outcomes and Measures A drug was determined to have displaced the prior standard-of-care therapy by evaluating the comparator arm (or lack thereof) in the clinical trial leading to the drug’s approval and also by reviewing National Comprehensive Cancer Network Guidelines. Cancer drug approvals were categorized as first-line displacing if a drug was approved for use in the first-line setting and displaced the prior standard-of-care drug for an indication, first-line drug alternatives/new if a drug was approved for use in the first-line setting but did not displace the standard of care at the time of approval or was a new drug that was first of its class for an approved indication, add on if a drug was approved in combination with a previously approved therapy for a disease or if a drug was approved for use in the adjuvant or maintenance settings, and later line if a drug was approved for use in t
Lythgoe MP, Prasad V, 2022, The last word to new FDA draft guidance for cancer clinical trial eligibility criteria for patients with incurable cancer, Journal of Cancer Policy, Vol: 31, Pages: 100322-100322, ISSN: 2213-5383
Benjamin DJ, Lythgoe M, Raymakers AJN, et al., 2022, Cost effectiveness of newly approved second/third-line agents in metastatic urothelial carcinoma (mUC)., Journal of Clinical Oncology, Vol: 40, Pages: 574-574, ISSN: 0732-183X
<jats:p> 574 </jats:p><jats:p> Background: Over the past years, the treatment landscape of platinum-refractory mUC has drastically changed with the advent of immunotherapy. More recently, several new agents including enfortumab, erdafitinib, and sacituzumab have received F.D.A. approval for the treatment of platinum-refractory mUC. It is unclear if these newly approved therapies may be cost prohibitive for patients and/or hospitals/clinics compared to the recommended NCCN category 1 second-line agent, pembrolizumab. Methods: Using acquisition costs from our home institution’s cancer center pharmacy department, we calculated the total cost of treatment for each agent. We used phase II clinical trial data to determine the median duration of treatment for each therapy. For weight-based therapies, we used 70 kg as the weight for an average human adult. Results: The three newly approved therapies for mUC have total acquisition costs in descending order as follows: enfortumab vedotin ($153,697.50), edafitinib ($131,642.62), and sacituzumab govitecan ($63,198.07). Enfortumab and sacituzumab likely have higher total costs given both therapies require infusion center use for administration, and are associated with infusion center administration fees. In comparison, pembrolizumab (standard of care per NCCN guidelines) has a total acquisition cost of $51,343.60. Conclusions: Based off median duration of treatment, pembrolizumab has the lowest total acquisition cost compared to the three newly approved therapies for mUC. Further statistical analysis of this data set is ongoing. In particular, analysis will include out-of-pocket costs for patients as well as quality-adjusted life years (QALY).[Table: see text] </jats:p>
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
Lythgoe MP, Jenei K, Prasad V, 2022, Regulatory decisions diverge over aducanumab for Alzheimer’s disease, BMJ, Vol: 376, Pages: 1-2, ISSN: 1759-2151
Lythgoe MP, Sullivan R, 2022, Could the UK's fixed-fee subscription improve access to antimicrobials and other essential medicines in low-income and middle-income countries?, The Lancet Microbe
Lythgoe MP, Olivier T, Prasad V, 2021, The iceberg plot, improving the visualisation of therapy response in oncology in the era of sequence-directed therapy, EUROPEAN JOURNAL OF CANCER, Vol: 159, Pages: 56-59, ISSN: 0959-8049
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Haslam A, Lythgoe MP, Greenstreet Akman E, et al., 2021, Characteristics of Cost-effectiveness Studies for Oncology Drugs Approved in the United States From 2015-2020., JAMA Netw Open, Vol: 4
IMPORTANCE: Increasingly, cost-effectiveness analyses are being done to determine the value of rapidly increasing oncology drugs; however, this assumes that these analyses are unbiased. OBJECTIVE: To analyze the characteristics of cost-effectiveness studies and to determine characteristics associated with whether an oncology drug is found to be cost-effective. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cross-sectional study included 254 cost-effectiveness analyses for 116 oncology drugs that were approved by the US Food and Drug Administration from 2015 to 2020. EXPOSURES: Each drug was analyzed for the incremental cost-effectiveness ratio per quality-adjusted life year, the funding of the study, the authors' conflict of interest, the threshold of willingness-to-pay, from what country's perspective the analysis was done, and whether a National Institute for Health and Care Excellence cost-effectiveness analysis had been done. MAIN OUTCOMES AND MEASURES: The main outcome was the odds of a study concluding that a drug was cost-effective. RESULTS: There were 116 drug approvals with 254 studies and country perspectives. Of the country perspectives, 132 (52%) were from the US. Forty-seven of 78 drugs with cost-effective studies had been shown to improve overall survival, whereas 15 of 38 of drugs without a cost-effectiveness study had been shown to improve overall survival. Having a study funded by a pharmaceutical company was associated with higher odds of a study concluding that a drug was cost-effective than studies without funding (odds ratio, 41.36; 95% CI, 11.86-262.23). CONCLUSIONS AND RELEVANCE: In this cross-sectional study, pharmaceutical funding was associated with greater odds that an oncology drug would be found to be cost-effective. These findings suggest that simply disclosing potential conflict of interest is inadequate. We encourage cost-effectiveness analyses by independent groups.
Powell K, Lythgoe MP, Prasad V, 2021, The Oncologic Drugs Advisory Committee Votes of April 2021-Implications for the Fate of Accelerated Approval., JAMA Oncol, Vol: 7, Pages: 1607-1609
Lythgoe MP, Prasad V, 2021, How the US Food and Drug Administration’s approval of aducanumab for Alzheimer's disease has implication for oncology and beyond, European Journal of Cancer, Vol: 157, Pages: 68-70, ISSN: 0959-8049
Lythgoe MP, Ghani R, Mullish BH, et al., 2021, The Potential of Faecal Microbiota Transplantation in Oncology, Trends in Microbiology, ISSN: 0966-842X
Middleton P, Hsu C, Lythgoe M, 2021, Clinical outcomes in COVID-19 and cirrhosis: a systematic review and meta-analysis of observational studies, BMJ Open Gastroenterology, Vol: 8, Pages: 1-10, ISSN: 2054-4774
Background: Coronavirus Disease 2019 (COVID-19) continues to pose a significant healthcare challenge throughout the world. Co-morbidities including diabetes and hypertension are associated with a significantly higher mortality risk. However, the effect of cirrhosis on COVID-19 outcomes has yet to be systematically assessed.Objectives: To assess the reported clinical outcomes of patients with cirrhosis who develop COVID-19 infectionDesign/Method: Pubmed and Embase databases were searched for studies included up to 3rd February 2021. All English language primary research articles that reported clinical outcomes in patients with cirrhosis and COVID-19 were included. The study was conducted and reported in accordance with the PRISMA guidelines. Risk of bias was assessed using the QUIPS risk of bias assessment instrument for prognostic factor studies template. Meta-analysis was performed using Cochrane Revman 5.4 software using a random effects model.Results: 63 studies were identified reporting clinical outcomes in patients with cirrhosis and concomitant COVID-19. Meta-analysis of cohort studies which report a non-cirrhotic comparator yielded a pooled mortality odds ratio (OR) of 2.48 (95% CI 2.02 – 3.04). Analysis of a subgroup of studies reporting OR for mortality in hospitalised patients adjusted for significant confounders found a pooled adjusted OR 1.81 (CI 1.36-2.42).Conclusion: Cirrhosis is associated with an increased risk of all cause mortality in COVID-19 infection compared to non-cirrhotic patients. Patients with cirrhosis should be considered for targeted public health interventions to prevent COVID-19 infection such as shielding and prioritisation of vaccination.
Chiang RS, Glover M, Hui G, et al., 2021, Racial diversity and reporting in FDA registration trials for thoracic malignancies from 2006 to 2020., Journal of Clinical Oncology, Vol: 39, Pages: 1-1, ISSN: 0732-183X
Background: Black patients have a disproportionately high incidence and mortality from lung cancer. Despite the importance of clinical trials, there continue to be significant racial disparities in recruitment for pivotal registration studies. In 2016, the FDA recommended reporting racial enrollment with a minimum of 5 categories (White, Black, Asian, American Indian or Alaskan Native [AIAN] and Native Hawaiian or Pacific Islander [NHPI]). The International Committee of Medical Journal Editors also recommend reporting race and ethnicity. We evaluated race reporting and representation in registration trials for thoracic cancers. Methods: We reviewed the FDA website and identified all new drug licensing indications in thoracic malignancies (small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC) and mesothelioma) from 2006 to 2020. NSCLC was further classified as EGFR+, ALK+, other mutation and NOS (no driver mutation). Clinical trials cited on the licensing label for market authorization were recorded and the corresponding registration trial publication was identified. If race was unreported or underreported (defined as ≤3 groups) in the licensing study, then additional information was obtained from clinicaltrials.gov. We calculated the proportion of registration trials meeting FDA criteria and the proportion of each racial group in trials. Results: From 2006-2020, we identified 55 new licensing indications, involving 26 unique drugs; 5 approvals in SCLC, 49 approvals in NSCLC and 1 in mesothelioma. Prior to the FDA race reporting guidelines, 33% (6/18) of registration studies did not meet FDA requirements. This improved to 27% (10/37) after the guideline introduction. Overall 29,545 patients participated in thoracic registration trials; 66% White, 22% Asian, 2% Black, <1% AIAN, <1% NHPI, 1% other or multiple races and 9% unknown. Table shows race distribution by cancer subtype. Conclusions: Although improving, a substantial number of registrationa
Lythgoe MP, Prasad V, 2021, The FDA's latest move to expand eligibility for oncology trials - a double-edged sword?, Nature Reviews Clinical Oncology, Vol: 18, Pages: 745-746, ISSN: 1759-4774
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 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 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
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Abdelmalak R, Lythgoe MP, Evans J, et al., 2021, Exploration of novel prognostic markers in grade 3 neuroendocrine neoplasia, Cancers, Vol: 13, Pages: 1-12, ISSN: 2072-6694
Background: High-grade neuroendocrine tumours and carcinomas (NET/NECs) behave aggressively, typically presenting at an advanced stage. Prognosis is poor, with median survival between 5 and 34 months. The mainstay of treatment is palliative systemic therapy. However, therapy carries a risk of toxicity, which can reduce quality of life. Therefore, accurate prognostic scores for risk stratification of patients with high-grade NET/NECs are needed to help guide patient management to decide whether active treatment is likely to improve overall survival (OS). We aimed to compare the prognostic ability of published prognostic scores to predict OS in a cohort of patients with high-grade NET/NECs of any primary site. Methods: Treatment, biochemical and clinicopathological data were collected retrospectively from 77 patients with high-grade NET/NECs across three hospitals between 2016 and 2020. Variables including performance status (PS), Ki-67, age at diagnosis, previous treatment and presence of liver metastases were recorded. Pre-treatment neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, modified Glasgow prognostic score (mGPS), and gastrointestinal neuroendocrine carcinoma (GI-NEC) score were derived. Univariable and multivariable survival analyses were used to assess prognostic ability. Results: The median age of the cohort was 63 years (range: 31–85); 53% of subjects were female. Grade 3 NETs (G3-NETs) were identified in 32 patients and NECs in 45 patients. The median OS was 13.45 months (range: 0.87–65.37) with no difference observed between G3-NETs and NECs. Univariable analysis revealed that NLR (n = 72, p = 0.049), mGPS (n = 56, p = 0.003), GI-NEC score (n = 27, p = 0.0007) and Ki-67 (n = 66, p = 0.007) were significantly associated with OS. Multivariable analysis confirmed that elevated mGPS (p = 0.046), GI-NEC score (p = 0.036), and Ki-67 (p = 0.02) were independently prognostic for reduced OS across the entire cohort. mGPS was identified
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