From the European Medicines Agency to Project Orbis: new activities and challenges to facilitate UK oncology drug approval following Brexit.

The departure of the UK from the European Union (EU) and affiliated European regulatory bodies, including the European Medicines Agency, on Dec 31, 2020, has resulted in the Medicines and Healthcare products Regulatory Agency becoming an independent national regulator. This change has required a fundamental transformation of the UK drug regulatory landscape, creating both opportunities and challenges for future development of oncology drugs. New UK pharmaceutical policies have sought to make the UK 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 show regulatory innovation and international collaboration through approval of new cancer medicines. In this Policy Review, we examine the new UK regulatory frameworks, policies, and global collaborations affecting new oncology drug approvals after departure from the EU. We explore some of the challenges that might lie ahead as the UK creates new and independent regulatory review and approval processes for the next generation of cancer medicines.

The evidence base of US Food and Drug Administration approvals of novel cancer therapies from 2000 to 2020.

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.

Additional consensus recommendations for conducting complex innovative trials of oncology agents: a post-pandemic perspective.

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.

Racial Diversity and Reporting in United States Food and Drug Administration Registration Trials for Thoracic Malignancies from 2006 to 2020.

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 to 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.

Repositioning canakinumab for non-small cell lung cancer-important lessons for drug repurposing in oncology.

Canakinumab is an anti-interleukin-1ß 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.

Association of prior local therapy and outcomes with programmed-death ligand-1 inhibitors in advanced urothelial cancer.

OBJECTIVES: To compare clinical outcomes with programmed-death ligand-1 immune checkpoint inhibitors (ICIs) in patients with advanced urothelial carcinoma (aUC) who have vs have not undergone radical surgery (RS) or radiation therapy (RT) prior to developing metastatic disease. PATIENTS AND METHODS: We performed a retrospective cohort study collecting clinicopathological, treatment and outcomes data for patients with aUC receiving ICIs across 25 institutions. We compared outcomes (observed response rate [ORR], progression-free survival [PFS], overall survival [OS]) between patients with vs without prior RS, and by type of prior locoregional treatment (RS vs RT vs no locoregional treatment). Patients with de novo advanced disease were excluded. Analysis was stratified by treatment line (first-line and second-line or greater [second-plus line]). Logistic regression was used to compare ORR, while Kaplan-Meier analysis and Cox regression were used for PFS and OS. Multivariable models were adjusted for known prognostic factors. RESULTS: We included 562 patients (first-line: 342 and second-plus line: 220). There was no difference in outcomes based on prior locoregional treatment among those treated with first-line ICIs. In the second-plus-line setting, prior RS was associated with higher ORR (adjusted odds ratio 2.61, 95% confidence interval [CI]1.19-5.74]), longer OS (adjusted hazard ratio [aHR] 0.61, 95% CI 0.42-0.88) and PFS (aHR 0.63, 95% CI 0.45-0.89) vs no prior RS. This association remained significant when type of prior locoregional treatment (RS and RT) was modelled separately. CONCLUSION: Prior RS before developing advanced disease was associated with better outcomes in patients with aUC treated with ICIs in the second-plus-line but not in the first-line setting. While further validation is needed, our findings could have implications for prognostic estimates in clinical discussions and benchmarking for clinical trials. Limitations include the study's retrospective nature, lack of randomization, and possible selection and confounding biases.

Immune checkpoint inhibitors in advanced upper and lower tract urothelial carcinoma: a comparison of outcomes.

OBJECTIVES: To compare clinical outcomes between patients with locally advanced (unresectable) or metastatic urothelial carcinoma (aUC) in the upper and lower urinary tract receiving immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: We performed a retrospective cohort study collecting clinicopathological, treatment, and outcome data for patients with aUC receiving ICIs from 2013 to 2020 across 24 institutions. We compared the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) between patients with upper and lower tract UC (UTUC, LTUC). Uni- and multivariable logistic and Cox regression were used to assess the effect of UTUC on ORR, OS, and PFS. Subgroup analyses were performed stratified based on histology (pure, mixed) and line of treatment (first line, subsequent line). RESULTS: Out of a total of 746 eligible patients, 707, 717, and 738 were included in the ORR, OS, and PFS analyses, respectively. Our results did not contradict the hypothesis that patients with UTUC and LTUC had similar ORRs (24% vs 28%; adjusted odds ratio [aOR] 0.73, 95% confidence interval [CI] 0.43-1.24), OS (median 9.8 vs 9.6 months; adjusted hazard ratio [aHR] 0.93, 95% CI 0.73-1.19), and PFS (median 4.3 vs 4.1 months; aHR 1.01, 95% CI 0.81-1.27). Patients with mixed-histology UTUC had a significantly lower ORR and shorter PFS vs mixed-histology LTUC (aOR 0.20, 95% CI 0.05-0.91 and aHR 1.66, 95% CI 1.06-2.59), respectively). CONCLUSION: Overall, patients with UTUC and LTUC receiving ICIs have comparable treatment response and outcomes. Subgroup analyses based on histology showed that those with mixed-histology UTUC had a lower ORR and shorter PFS compared to mixed-histology LTUC. Further studies and evaluation of molecular biomarkers can help refine patient selection for immunotherapy.

Lifileucel: the first cellular therapy approved for solid tumours.

The US Food and Drug Administration (FDA) approval of lifileucel, for advanced melanoma, represents the first cellular therapy to reach the clinic for solid cancers. Here, we summarise this landmark approval, consider the associated regulatory pathway, and evaluate the challenges that remain to ensure effective implementation of this advanced 'living' therapy.

The evolving posology and administration of immune checkpoint inhibitors: subcutaneous formulations.

Immune checkpoint inhibitors (ICIs) have transformed cancer care. Recently, atezolizumab gained its first global approval in a subcutaneous (SC) formulation by the UK medicines regulator, being notable as the first time an FDA- and/or European Medicines Agency (EMA)-approved ICI has been licensed via this administration route. Here, we discuss this approval, other SC ICIs in development, and the benefits and challenges of this administration route, including potential implications for patient care.

Gene of the month: cancer testis antigen gene 1b (NY-ESO-1).

Cancer testis antigen gene 1B (CTAG1B) and its associated gene product; New York oesophageal squamous carcinoma 1 (NY-ESO-1), represent a unique and promising target for cancer immunotherapy. As a member of the cancer testis antigen family (CTA), the protein's restricted expression pattern and ability to elicit spontaneous humoural and cellular immune responses has resulted in a plethora of novel modalities and approaches attempting to harness its immunotherapeutic anti-cancer potential. Here, we discuss the structure and function of CTAG1B/NY-ESO-1 in both health and disease, immunohistochemical detection, as well as the most promising advances in the development of associated anti-cancer therapies. From cancer vaccines to engineered cellular therapy approaches, a multitude of immunotherapies targeting CTA's are coming to the forefront of oncology. Although the efficacy of such approaches have yet to provide convincing evidence of durable response, early phase clinical trial data has resulted in some exciting findings which will have significant potential to act as a platform for future practice changing technologies.

Hormonal treatment for newly diagnosed metastatic prostate cancer: a population-based study from the California cancer registry.

INTRODUCTION: To evaluate how often men with metastatic prostate cancer (mPC) receive standard of care treatment with androgen deprivation therapy (ADT). METHODS: Men aged ≥20 years with newly diagnosed mPC (stage IV) between 2010 and 2018 were identified using California Cancer Registry data. Receipt of hormonal therapy as initial cancer treatment was examined by patient/tumor characteristics at time of diagnosis. Chi-square tests and logistic regression, adjusted for covariates, were performed to assess association between receipt of hormonal therapy and patient/tumor characteristics. RESULTS: We identified 13,680 men with newly diagnosed mPC, of which 3637 had local metastasis (N1) only while 9596 had distant metastasis (M1) with or without N1 disease. 21.8 % (n = 2980) of men did not receive ADT. The highest rate of receiving ADT was among men between ages 75-84 (81.6%) and the lowest rate was in men over 85 (76.0%). Asian men had the largest proportion receiving ADT (n = 962, 81.5%) with remaining subgroups having similar proportion of men receiving ADT (76.8% to 77.2%). Once adjusted for covariates, regression results showed men with a higher Gleason score (8-10) were more likely to receive ADT (OR 2.04, 1.82-2.27, p = < 0.001) as well as men with distant sites of metastatic disease (OR 4.02, 3.62-4.46, p = < 0.001). Men residing in neighborhoods with the lowest socioeconomic status were least likely to receive ADT (OR 0.79, 0.68-0.93, p = 0.0032). No differences in receipt of ADT were observed by race/ethnicity. DISCUSSION: Despite significant advancements in the treatment of mPC in recent years, over one-fifth of patients did not receive ADT, which is the backbone for all new systemic therapies. This dataset might help address some of the prostate cancer care disparities in California.

Cancer Drug Approvals That Displaced Existing Standard-of-Care Therapies, 2016-2021.

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 the second-, third-, or later-line settings. Results: Between May 1, 2016, and May 31, 2021, there were 207 FDA cancer drug approvals in oncology and malignant hematology. Of these 207 approvals, 28 drugs (14%) were first-line displacing therapies. A total of 32 drugs (15%) were first-line drug alternatives/new drugs. A total of 61 drugs (29%) were add-on therapies. Finally, 86 drugs (42%) were approved as later-line therapies. Conclusions and Relevance: In this study, most cancer drug approvals between 2016 and 2021 were in the later-line settings as opposed to displacing the current standard-of-care therapy for the approved indication. These later-line drugs may benefit patients with few alternatives but add to the cost of care because competition in the drug markets is a key factor in leading to lower drug prices.