78 results found
Lythgoe M, Sullivan R, Blagden S, 2023, UK oncology approvals in 2022: global regulatory collaboration and new regulatory pathways deliver New anti-cancer therapies, The Lancet Oncology, Vol: 24, Pages: 963-966, ISSN: 1213-9432
Lythgoe M, 2023, Another setback for cancer research in the UK, BMJ: British Medical Journal, ISSN: 0959-535X
Aboagye E, Aravind P, Popat S, et al., 2023, A subset of non-small cell lung cancer patients treated with pemetrexed show 18f-fluorothymidine ‘flare’ on positron emission tomography, Cancers, Vol: 15, Pages: 1-14, ISSN: 2072-6694
Thymidylate synthase (TS) remains a major target for cancer therapy. TS inhibition elicits increases in DNA salvage pathway activity, detected as a transient compensatory “flare” in 3′-deoxy-3′-[18F]fluorothymidine positron emission tomography (18F-FLT PET). We determined the magnitude of the 18F-FLT flare in non-small cell lung cancer (NSCLC) patients treated with the antifolate pemetrexed in relation to clinical outcome. Method: Twenty-one patients with advanced/metastatic non-small cell lung cancer (NSCLC) scheduled to receive palliative pemetrexed ± platinum-based chemotherapy underwent 18F-FLT PET at baseline and 4 h after initiating single-agent pemetrexed. Plasma deoxyuridine (dUrd) levels and thymidine kinase 1 (TK1) activity were measured before each scan. Patients were then treated with the combination therapy. The 18F-FLT PET variables were compared to RECIST 1.1 and overall survival (OS). Results: Nineteen patients had evaluable PET scans at both time points. A total of 32% (6/19) of patients showed 18F-FLT flares (>20% change in SUVmax-wsum). At the lesion level, only one patient had an FLT flare in all the lesions above (test–retest borders). The remaining had varied uptake. An 18F-FLT flare occurred in all lesions in 1 patient, while another patient had an 18F-FLT reduction in all lesions; 17 patients showed varied lesion uptake. All patients showed global TS inhibition reflected in plasma dUrd levels (p < 0.001) and 18F-FLT flares of TS-responsive normal tissues including small bowel and bone marrow (p = 0.004 each). Notably, 83% (5/6) of patients who exhibited 18F-FLT flares were also RECIST responders with a median OS of 31 m, unlike patients who did not exhibit 18F-FLT flares (15 m). Baseline plasma TK1 was prognostic of survival but its activity remained unchanged following treatment. Conclusions: The better radiological response and longer survival observed in patients with an 18F-FLT flare suggest the
Lythgoe M, Sullivan R, 2023, Outsourcing UK regulatory decisions – A double edged sword?, The Lancet, Vol: 402, Pages: 24-25, ISSN: 0140-6736
Lythgoe M, 2023, The evidence base of US Food and Drug Administration approvals of novel cancer therapies from 2000 to 2020, International Journal of Cancer, Vol: 152, Pages: 2474-2484, ISSN: 0020-7136
Concerns have been raised that regulatory programs to accelerate approval of cancer drugs in cancer may increase uncertainty about benefits and harms for survival and quality of life (QoL). We analyzed all pivotal clinical trials and all non-pivotal randomized controlled trials (RCTs) for all cancer drugs approved for the first time by the FDA between 2000 and 2020. We report regulatory and trial characteristics. Effects on overall survival (OS), progression-free survival and tumor response were summarized in meta-analyses. Effects on QoL were qualitatively summarized. Between 2000 and 2020, the FDA approved 145 novel cancer drugs for 156 indications based on 190 clinical trials. Half of indications (49%) were approved without RCT evidence; 82% had a single clinical trial only. OS was primary endpoint in 14% of trials and QoL data were available from 25%. The median OS benefit was 2.55 months (IQR, 1.33-4.28) with a mean hazard ratio for OS of 0.75 (95%CI, 0.72-0.79, I2 = 42). Improvement for QoL was reported for 7 (4%) of 156 indications. Over time, priority review was used increasingly and the mean number of trials per indication decreased from 1.45 to 1.12. More trials reported results on QoL (19% in 2000-2005; 41% in 2016-2020). For 21 years, novel cancer drugs have typically been approved based on one single, often uncontrolled, clinical trial, measuring surrogate endpoints. This leaves cancer patients without solid evidence that novel drugs improve their survival or QoL and there is no indication towards improvement.
Lythgoe M, Dama P, Frampton AE, et al., 2023, Immune modulation and the oral live biotherapeutic product, MRx0518, in treatment-naïve patients with cancer: Updated safety data., Journal of Clinical Oncology, Vol: 41, Pages: 3145-3145, ISSN: 0732-183X
<jats:p> 3145 </jats:p><jats:p> Background: Live biotherapeutic products (LBPs) are emerging novel anti-cancer therapies. MRx0518 is a gut microbiome-derived oral LBP, consisting of a single strain of Enterococcus gallinarum, which has demonstrated potent anti-tumorigenic efficacy pre-clinically. We have previously shown MRx0518 monotherapy is associated with significant genomic, immune, microbiome, and metabolomic changes, consistent with anti-cancer efficacy in treatment-naïve patients. Here, we report long-term subject follow-up, and further signals of immune modulatory changes from flow cytometry analysis. Methods: NCT03934827 is a Phase 1B single-centre study in treatment-naive patients with confirmed cancer, planned for surgical resection. 17 patients (8 breast, 4 prostate, 3 uterine, 1 bladder & 1 melanoma) received MRx0518 (1x10<jats:sup>10</jats:sup>-1x10<jats:sup>11</jats:sup>CFU) BID monotherapy for 7-28 days from inclusion until surgery. Safety data was collected from dosing until 1-year following cessation. Exploratory analysis included evaluation of pre- and post-treatment peripheral blood mononuclear cells (PBMCs) by multiparametric flow cytometry for leucocyte activation, indicative of anti-cancer efficacy. Results: A total of 29 adverse events (AEs), all CTCAE grade 1 (96%) and grade 2 (4%), were reported. Only 8 (28%) were deemed related to MRx0518. No grade 3/4 toxicities or serious AEs were recorded. At 30-days, and 1-year follow-up no further serious AEs occurred. At a median follow-up of 41 months, 13 (76%) patients remain cancer-free, with 2 (11%) reoccurrences and 2 (11%) lost to follow-up. Analysis of pre- and post-treatment PBMCs identified statistically significant increases in CD3<jats:sup>+</jats:sup>CD56<jats:sup>+</jats:sup> (p<0.0005), natural killer cells (p<0.005), natural killer T-cells (p<0.01), CD8<jats:sup>+</jats:sup>
Lythgoe M, Lewison G, Aggarwal AK, et al., 2023, A bibliometric analysis of immuno-oncology research: Is a new global leader emerging?, Journal of Clinical Oncology, Vol: 41, Pages: e13593-e13593, ISSN: 0732-183X
<jats:p> e13593 </jats:p><jats:p> Background: The last decade has witnessed an increase in cancer research globally, and a transformation of the anti-cancer armamentarium. The biggest innovation has been development of immuno-oncology (IO) therapies, and specifically immune checkpoint inhibitors (ICIs), targeting CTLA-4 and PD-(L)1, reshaping treatment paradigms for many cancers (e.g., melanoma). Since the first ICI approval in 2011, research from countries in the European Union (EU) and North America has dominated this field. However, more recently research authored in China has emerged as a potential leader. In this study we analysed cancer and IO research outputs since 2011, exploring emerging national trends, and focusing on ICI development. Methods: IO research articles were identified using a high-resolution bibliometric method, previously validated. Relevant articles were identified from the Web of Science, utilising a complex search strategy of pre-defined keywords, including the 9 FDA-approved ICI and 8 ICI approved in China-only. Additional search filters were used to determine secondary characteristics including country (assigned a fractional count based on proportional authorship), collaborations, and tumour site. Results: Since 2011, over 175,000 cancer research articles have been published globally. The number of articles published annually has increased steadily, largely driven by increasing outputs from Chinese authors. China is now the leading global publisher of cancer research accounting for 18% of all outputs in 2021, and has consistently surpassed US and EU total outputs since 2019. Over the past decade there has been a steady increase in total IO research outputs, rising by 378% (n = 2926) compared to 2011. China began publishing significant IO research in 2014 and has risen rapidly to dominate this field. In 2021, China accounted for 37% of total IO outputs. The US was previously dominant, however there has been a steady decl
Lythgoe M, 2023, The FDA’s latest draft guidance on accelerated approvals — one step forward, two steps back?, Nature Reviews Clinical Oncology, Vol: 20, Pages: 577-578, ISSN: 1759-4782
Lythgoe M, Lewison G, Aggarwal A, et al., 2023, The rise of immuno-oncology in China - a challenge to western dominance?, The Lancet Oncology, Vol: 24, Pages: 439-441, ISSN: 1213-9432
Lythgoe M, Krell J, Bower M, et al., 2023, From the European Medicines Agency to Project Orbis: new activities and challenges to facilitate UK oncology drug approval following Brexit, The Lancet Oncology, Vol: 24, Pages: e150-e160, ISSN: 1213-9432
The departure of the UK from the European Union (EU) and affiliated European regulatory bodies on the 31st December 2020, including the European Medicines Agency, (EMA), has resulted in the Medicines and Healthcare products Regulatory Agency (MHRA) becoming an independent national regulator. This has required a fundamental transformation of the UK drug regulatory landscape, creating both opportunities and challenges for future oncology drug development. New UK pharmaceutical policy has sought to establish the UK as an attractive market for drug development and regulatory review, by offering expedited review pathways coupled to strong collaborative relations with other leading international medicines regulators, outside of Europe. Oncology is a key global therapy area for both drug development and regulatory approval, and the UK government has been keen to demonstrate regulatory innovation and international collaboration in the approval of new cancer medicines. In this review, we examine the new UK regulatory frameworks, policies, and global collaborations affecting new oncology drug approvals following departure from the EU. We explore some of the challenges which may lie ahead as the UK forges ahead with new and independent regulatory review and approval processes for the next generation of cancer medicines.
Rizwan N, Pottinger D, Singh R, et al., 2023, 216P Differences in immune checkpoint inhibitor (ICI) approvals made by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for thoracic malignancies, Journal of Thoracic Oncology, Vol: 18, Pages: S156-S156, ISSN: 1556-0864
Benjamin DJ, Lythgoe M, Rezazadeh A, 2023, Financial toxicity from newly approved second-/third-line agents in metastatic urothelial carcinoma, BJU International, Vol: 131, Pages: 691-693, ISSN: 1464-4096
Lythgoe M, 2023, Modernising the US FDA's Accelerated Approval pathway, The Lancet Oncology, Vol: 24, Pages: 203-205, ISSN: 1470-2045
On Dec 29, 2022, US President Joe Biden signed The Consolidated Appropriations Act into law. This wide-reaching Act contains notable reforms to the US Food and Drug Administration (FDA) statutory and regulatory frameworks. The legislation amends key regulatory frameworks, including changes to the FDA-expedited approval programme, Accelerated Approval. 1 This pathway has been substantial for drug development globally since its introduction in 1992, permitting early regulatory approval based on surrogate endpoints likely to predict clinical benefit for drugs treating serious or life-threatening conditions. 2 A further confirmatory study is typically required to validate true clinical benefit to permit conversion to standard approval, or in the case of a negative result, potentially medicine withdrawal. Recent scrutiny of the Accelerated Approval pathway, particularly after the approval of aducanumab for Alzheimer's disease, and the notable withdrawal of several cancer medicines (eg, bevacizumab in breast cancer), has led many to call for urgent reform of this pathway. 3 , 4 As Accelerated Approval is predominately used in oncology, with cancer drugs accounting for 85% of use over the past decade, reforms are highly relevant for new cancer drug development and approval. 2 We will therefore highlight key reforms, and potential opportunities and challenges these could present.
Blagden SP, Yu L-M, Ellis S, et al., 2023, Additional consensus recommendations for conducting complex innovative trials of oncology agents: a post-pandemic perspective, British Journal of Cancer, Vol: 128, Pages: 474-477, ISSN: 0007-0920
In our 2020 consensus paper, we devised ten recommendations for conducting Complex Innovative Design (CID) trials to evaluate cancer drugs. Within weeks of its publication, the UK was hit by the first wave of the SARS-CoV-2 pandemic. Large CID trials were prioritised to compare the efficacy of new and repurposed COVID-19 treatments and inform regulatory decisions. The unusual circumstances of the pandemic meant studies such as RECOVERY were opened almost immediately and recruited record numbers of participants. However, trial teams were required to make concessions and adaptations to these studies to ensure recruitment was rapid and broad. As these are relevant to cancer trials that enrol patients with similar risk factors, we have added three new recommendations to our original ten: employing pragmatism such as using focused information sheets and collection of only the most relevant data; minimising negative environmental impacts with paperless systems; and using direct-to-patient communication methods to improve uptake. These recommendations can be applied to all oncology CID trials to improve their inclusivity, uptake and efficiency. Above all, the success of CID studies during the COVID-19 pandemic underscores their efficacy as tools for rapid treatment evaluation.
Khaki AR, Lythgoe MP, Prasad V, 2023, Adjuvant checkpoint inhibitor trials: Is disease-free survival an appropriate endpoint?, Journal of Cancer Policy, Vol: 35, Pages: 1-2, ISSN: 2213-5383
Chiang RS, Desai A, Glover MJ, et al., 2023, Racial diversity and reporting in United States Food and Drug Administration registration trials for thoracic malignancies from 2006-2020, Cancer Investigation, Vol: 41, Pages: 43-47, ISSN: 0735-7907
There is significant racial disparity in thoracic malignancies in terms of epidemiology and outcomes. We analyzed race reporting and racial diversity in the registration trials of drugs approved by the FDA for thoracic malignancies from 2006-2020. We found a significant under-representation of non-white participants in FDA drug registration trials in thoracic malignancies. Furthermore, though almost all trials report some race information, FDA guidelines are not universally followed. There is a disproportionate disease burden of lung cancer in under-represented race communities, and clinical trials should prioritize racial diversity and inclusion efforts.
Lythgoe MP, Mullish BH, Frampton A, et al., 2022, Polymorphic microbes: a new emerging hallmark of cancer, Trends in Microbiology, Vol: 30, Pages: 1131-1134, ISSN: 0966-842X
Recognition of the microbiome (and ‘polymorphic microbes’ within them) as a new emerging hallmark of cancer reflects a wide body of rapidly evolving research. Microbes may be directly carcinogenic, impact host immune responses to promote malignancy, and key effectors in determining anti-cancer therapy efficacy. Manipulation of the microbiome is showing promise as an opportunity to influence cancer outcomes.
Lythgoe M, 2022, No new ‘mabs’ in medicine – New nomenclature for monoclonal antibodies, British Journal of Pharmacology, Vol: 179, Pages: 5338-5339, ISSN: 0007-1188
Lythgoe M, Mullish B, Frampton A, et al., 2022, 627 Oral administration of MRx0518 in treatment-naïve cancer patients is associated with compositional taxonomic and metabolomic changes indicative of anti-tumorigenic efficacy, SITC 37th Annual Meeting (SITC 2022) Abstracts, Publisher: BMJ Publishing Group Ltd
Rizwan N, Khaki AR, Desai A, et al., 2022, 427 Approval timings and review speed of immune checkpoint inhibitors (ICIs) in cancer therapy between the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) from 2010-2022, SITC 37th Annual Meeting (SITC 2022) Abstracts, Publisher: BMJ Publishing Group Ltd
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 Reg Health Am, Vol: 13
Mirón-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 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
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
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
Jenei K, Prasad V, Lythgoe MP, 2022, High US drug prices have global implications., BMJ, Vol: 376
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