Objectives To illustrate and quantitate how herding in oncology drug development (five or more biopharmaceutical companies competing to develop modulators of an identical target) amplifies the number of patients enrolled in clinical trials of experimental drugs, and to estimate the cost of trials.Methods and analysis In the setting of globally based clinical trials in oncology drug development, two public databases (ClinicalTrials.gov and International Clinical Trials Registry Platform), registering clinical trials, were interrogated to determine patient enrolment numbers and clinical trial details for the development of inhibitors of the immune checkpoint protein TIGIT (T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains). Estimates were made of the costs of trials to biopharmaceutical companies and of the numbers of anonymous patients enrolled in clinical trials.Results 21 companies are or were seeking to have 30 TIGIT inhibitors approved for clinical use in a case of herding. Nearly 49 000 patients were enrolled in 220 clinical trials of TIGIT inhibitors between May 2016 and September 2025 at an estimated cost of between US$3.1 billion and US$3.6 billion. Development of 8 of 30 (27%) TIGIT inhibitors in oncology has been terminated to date (November 2025) due to their failure to demonstrate significant clinical activity or for strategic reasons. Nearly 15 000 patients were enrolled in these terminated trials. None of the TIGIT inhibitors had received marketing authorisation as of November 2025.Conclusions Because of the high attrition rate (95%) in the development of drugs for oncology, herding amplifies the loss of human and financial resources incurred during drug development, with large number of patients enrolled in clinical trials of experimental drugs that are unlikely to receive approval for clinical use. Herding concentrates resources at the expense of investment in a broader portfolio of drug development programmes with a spread of risk against attrition.

Greater collaboration needed to realize potential of molecular profiling initiatives for pediatric cancers.

Western blot detection of total and phosphorylated MET, AXL, FGFR1/2/3 and phosphorylated FRS2 in cell lines and tumor xenografts used in the study

The major challenges of climate change and health need a new type of transformative policy to enable innovation, overcoming “lock-in” to current, embedded policies. Recent policy developments in the Biden administration seem to share this perspective, with a novel focus on changing the U.S. innovation ecosystem. In this Perspective we express concern that aspects of the evolving “Mission-orientated” policy frameworks, notably the “Cancer Moonshot” which aims to reduce cancer mortality, have relied on a too narrow technoscientific model of innovation, reflecting the expertise of the chosen policy makers. Whilst the Cancer Moonshot policy, and concurrent European policies, define goals that may reduce cancer mortality, they are weak on the elaboration of the economic, organizational and cultural changes necessary to achieve these goals. Rather than being heavily technoscientific, effective innovation in healthcare has historically been sociotechnically based, relying on a network ecosystem with interactions between a wide diversity of actors with medical, technical, economic, sociological, epidemiological, and behavioural expertise, and with inclusion of the general public. We provide examples of some sociotechnical policies, including one addressing early detection and diagnosis of cancer in the community. We propose that a network model of systemic innovation should be initiated for ongoing iterations of cancer policies, with strong interactions within a broader group of experts who will not only define policy goals but also address their modes of implementation.

ImportanceThe development of oncology drugs is expensive and beset by a high attrition rate. Analysis of the costs and causes of translational failure may help to reduce attrition and permit the more appropriate use of resources to reduce mortality from cancer.ObjectiveTo analyze the causes of failure and expenses incurred in clinical trials of novel oncology drugs, with the example of insulin-like growth factor-1 receptor (IGF-1R) inhibitors, none of which was approved for use in oncology practice.Design, Setting, and ParticipantsIn this cross-sectional study, inhibitors of the IGF-1R and their clinical trials for use in oncology practice between January 1, 2000, and July 31, 2021, were identified by searching PubMed and ClinicalTrials.gov. A proprietary commercial database was interrogated to provide expenses incurred in these trials. If data were not available, estimates were made of expenses using mean values from the proprietary database. A search revealed studies of the effects of IGF-1R inhibitors in preclinical in vivo assays, permitting calculation of the percentage of tumor growth inhibition. Archival data on the clinical trials of IGF-1R inhibitors and proprietary estimates of their expenses were examined, together with an analysis of preclinical data on IGF-1R inhibitors obtained from the published literature.Main Outcomes and MeasuresExpenses associated with research and development of IGF-1R inhibitors.ResultsSixteen inhibitors of IGF-1R studied in 183 clinical trials were found. None of the trials, in a wide range of tumor types, showed efficacy permitting drug approval. More than 12 000 patients entered trials of IGF-1R inhibitors in oncology indications in 2003 to 2021. These trials incurred aggregate research and development expenses estimated at between $1.6 billion and $2.3 billion. Analysis of the results of preclinical in vivo assays of IGF-1R inhibitors that supported subsequent clinical investigations showed mixed activity and protocols that poorly reflected the treatment of advanced metastatic tumors in humans.Conclusions and RelevanceFailed drug development in oncology incurs substantial expense. At an industry level, an estimated $50 billion to $60 billion is spent annually on failed oncology trials. Improved target validation and more appropriate preclinical models are required to reduce attrition, with more attention to decision-making before launching clinical trials. A more appropriate use of resources may better reduce cancer mortality.

Supplementary Figure Legends

Kinase interaction map for S49076 at 100 nM

GAS6-mediated activation of AKT in MDA-MB-231 cells is dependent on AXL

Pharmacokinetic parameters of S49076 administered orally to female balb/c nu/nu mice

NASA’s Endurance sounding rocket (yard No. 47.001) will launch from Ny Ålesund, Svalbard in May 2022 on a solid fueled Oriole III-A launch vehicle. Its $\sim19$ minute flight will carry it to an altitude of $\sim780~\text{km}$ above Earth’s sunlit polar cap. Its objective is to make the first measurement of the weak “ambipolar” electric field generated by Earth’s ionosphere. This field is thought to play a critical role in the upwelling and escape of ionospheric ions, and thus potentially in the evolution of Earth’s atmosphere. The results will enable us to determine the importance to ion escape of this previously unmeasured fundamental property of our planet, which will aid in a better understanding of what makes Earth habitable. Endurance will carry six science instruments (with 16 sensors) that will measure the total electrical potential drop below the spacecraft, and the physical parameters required to understand the physics of what generates the ambipolar field. The mission will be supported by simultaneous observations of solar and geomagnetic activity.

Successful drug discovery is like finding oases of safety and efficacy in chemical and biological deserts. Screens in disease models, and other decision tools used in drug research and development (R&D), point towards oases when they score therapeutic candidates in a way that correlates with clinical utility in humans. Otherwise, they probably lead in the wrong direction. This line of thought can be quantified by using decision theory, in which 'predictive validity' is the correlation coefficient between the output of a decision tool and clinical utility across therapeutic candidates. Analyses based on this approach reveal that the detectability of good candidates is extremely sensitive to predictive validity, because the deserts are big and oases small. Both history and decision theory suggest that predictive validity is under-managed in drug R&D, not least because it is so hard to measure before projects succeed or fail later in the process. This article explains the influence of predictive validity on R&D productivity and discusses methods to evaluate and improve it, with the aim of supporting the application of more effective decision tools and catalysing investment in their creation.

Background: The development of oncology drugs is beset by a high attrition rate. The financial cost of this attrition has not been investigated. Lack of efficacy in oncology clinical trials contrasts with positive results interpreted from preclinical models. Their validity is questionable as is the decision-making which launches negative clinical trials.Methods: Inhibitors of the insulin-like growth factor 1 receptor (IGF1R) and their clinical trials in oncology were identified by searching PubMed and Clinical Trials.Gov (https://www.clinicaltrials.gov/ ). A proprietary commercial database from Evaluate Ltd was interrogated to provide the expenses incurred in these trials. Where data was not available, estimates were made of expenses using averages from the proprietary database. A search revealed studies of the effects of IGF1R inhibitors in preclinical in vivo assays, permitting calculation of the percentage tumour growth inhibition.Findings: We found 16 inhibitors of IGF1R studied in 183 clinical trials. None of the trials, in a wide range of tumour types, showed efficacy permitting drug approval. Over 12,000 patients entered trials of IGF1R inhibitors in oncology indications in the period 2003 to 2020. These incurred aggregate R&D expenses estimated of between $1.9 billion and $2.3 billion. We estimate that, currently, $50-60 billion per year is expended on failed oncology trials. Analysis of the results of preclinical in vivo assays of IGF1R inhibitors showed mixed activity and protocols that poorly reflected the treatment of advanced metastatic tumours.Interpretation: Failed clinical programmes to find active drugs in oncology incur substantial expenses. As attrition rates remain high, we express concern regarding the financial and social waste incurred. We concur that improved target validation and more appropriate preclinical models are required to reduce attrition, with more attention to decision making before launching clinical studies. We also suggest that a better use of resources may more effectively reduce cancer mortality.Funding Information: There was no funding associated with this study.Declaration of Interests: V.J, L.O and J.A.H have no interests to declare. J.W.S. is a director and shareholder of JW Scannell Analytics, which sells consulting services to the biopharmaceutical and financial services sectors, including to firms that are commercializing screening and disease models. He is CEO of Unify Pharmaceuticals Corp; a Director of Etheros Pharmaceuticals Corp and holds equity options in Ochre Bio.

Two recent policy documents by the European Union, 'Europe's Beating Cancer Plan' and its accompanying 'Conquering Cancer: Mission Possible' (CCMP), articulate broad policies aimed at reducing cancer mortality across Europe, for example, by promoting prevention and early detection. The focus for cancer treatment in these manifestos is the expansion of personalised cancer medicine (PCM). However, the CCMP document suggests that the uptake of PCM is "hampered by uncertainty about its outcomes". What are these outcomes and why this uncertainty? We address the limits of PCM in pathology-driven and pathology-agnostic PCM, briefly discussing the results of umbrella and basket trials. We suggest that the complexity, plasticity and genetic heterogeneity of advanced cancers will continue to thwart the impact of PCM, limiting it to specific pathologies, or rare subsets of them. Caution regarding the advancement of PCM is justified, and policymakers should be wary of the hype of lobbyists, who do not acknowledge the limits of PCM.

We read with interest the Article by Michael Pishvaian and colleagues1 documenting attempts to match gene sequencing of tumours with treatment, and we salute any attempt to improve the woeful survival of people with pancreatic cancer. However, the conclusion in the Summary, "These real-world outcomes suggest that the adoption of precision medicine can have a substantial effect on survival in patients with pancreatic cancer" is not borne out by their data. In their study, only 46 (2·5%) of 1856 patients had an actionable mutation and received matched treatment, which is hardly a substantial effect.

We describe our work to establish structure- and fragment-based drug discovery to identify small molecules that inhibit the anti-apoptotic activity of the proteins Mcl-1 and Bcl-2. This identified hit series of compounds, some of which were subsequently optimized to clinical candidates in trials for treating various cancers. Many protein constructs were designed to identify protein with suitable properties for different biophysical assays and structural methods. Fragment screening using ligand-observed NMR experiments identified several series of compounds for each protein. The series were assessed for their potential for subsequent optimization using 1H and 15N heteronuclear single-quantum correlation NMR, surface plasmon resonance, and isothermal titration calorimetry measurements to characterize and validate binding. Crystal structures could not be determined for the early hits, so NMR methods were developed to provide models of compound binding to guide compound optimization. For Mcl-1, a benzodioxane/benzoxazine series was optimized to a Kd of 40 μM before a thienopyrimidine hit series was identified which subsequently led to the lead series from which the clinical candidate S 64315 (MIK 665) was identified. For Bcl-2, the fragment-derived series were difficult to progress, and a compound derived from a published tetrahydroquinone compound was taken forward as the hit from which the clinical candidate (S 55746) was obtained. For both the proteins, the work to establish a portfolio of assays gave confidence for identification of compounds suitable for optimization.

In this issue of Annals of Oncology, Trédan et al. [1] describe the results of the ProfiLER trial, in which 2579 adult and paediatric patients with previously treated metastatic cancer underwent molecular profiling. Next-generation sequencing (NGS) with two panels was used to sequence 59 or 69 genes, as well as microarray-based comparative genomic hybridization, to define genetic changes that might be targeted for effective therapy. Oncologists in four academic institutions in and around Lyon, France, managed the patients; the authors are to be congratulated on overcoming the logistics of undertaking such a large multi-institution trial.

Escape from apoptosis is one of the major hallmarks of cancer cells. The B-cell Lymphoma 2 (BCL-2) gene family encodes pro-apoptotic and anti-apoptotic proteins that are key regulators of the apoptotic process. Overexpression of the pro-survival member BCL-2 is a well-established mechanism contributing to oncogenesis and chemoresistance in several cancers, including lymphoma and leukemia. Thus, BCL-2 has become an attractive target for therapeutic strategy in cancer, as demonstrated by the recent approval of ABT-199 (Venclexta™) in relapsed or refractory Chronic Lymphocytic Leukemia with 17p deletion. Here, we describe a novel orally bioavailable BCL-2 selective and potent inhibitor called S55746 (also known as BCL201). S55746 occupies the hydrophobic groove of BCL-2. Its selectivity profile demonstrates no significant binding to MCL-1, BFL-1 (BCL2A1/A1) and poor affinity for BCL-XL. Accordingly, S55746 has no cytotoxic activity on BCL-XL-dependent cells, such as platelets. In a panel of hematological cell lines, S55746 induces hallmarks of apoptosis including externalization of phosphatidylserine, caspase-3 activation and PARP cleavage. Ex vivo, S55746 induces apoptosis in the low nanomolar range in primary Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma patient samples. Finally, S55746 administered by oral route daily in mice demonstrated robust anti-tumor efficacy in two hematological xenograft models with no weight lost and no change in behavior. Taken together, these data demonstrate that S55746 is a novel, well-tolerated BH3-mimetic targeting selectively and potently the BCL-2 protein.

Escape from apoptosis is one of the major hallmarks of cancer cells. The B-cell Lymphoma 2 (BCL-2) gene family encodes pro-apoptotic and anti-apoptotic proteins that are key regulators of the apoptotic process. Overexpression of the pro-survival member BCL-2 is a well-established mechanism contributing to oncogenesis and chemoresistance in several cancers, including lymphoma and leukemia. Thus, BCL-2 has become an attractive target for therapeutic strategy in cancer, as demonstrated by the recent approval of ABT-199 (Venclexta™) in relapsed or refractory Chronic Lymphocytic Leukemia with 17p deletion. Here, we describe a novel orally bioavailable BCL-2 selective and potent inhibitor called S55746 (also known as BCL201). S55746 occupies the hydrophobic groove of BCL-2. Its selectivity profile demonstrates no significant binding to MCL-1, BFL-1 (BCL2A1/A1) and poor affinity for BCL-XL. Accordingly, S55746 has no cytotoxic activity on BCL-XL-dependent cells, such as platelets. In a panel of hematological cell lines, S55746 induces hallmarks of apoptosis including externalization of phosphatidylserine, caspase-3 activation and PARP cleavage. Ex vivo, S55746 induces apoptosis in the low nanomolar range in primary Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma patient samples. Finally, S55746 administered by oral route daily in mice demonstrated robust anti-tumor efficacy in two hematological xenograft models with no weight lost and no change in behavior. Taken together, these data demonstrate that S55746 is a novel, well-tolerated BH3-mimetic targeting selectively and potently the BCL-2 protein.

Abstract Cultivation of tumor tissue slices provides an ex vivo model capturing both tumor heterogeneity and its native microenvironment. Slices are commonly cultured either free-floating in medium or filter-supported. These conditions lead both to culture-dependent stress (free-floating culture condition) and intra-slice gradients regarding proliferation, marker expression and oxygen supply (filter-supported culture condition) (Davies et al Sci Rep (2015) 10.1038/srep17178). To facilitate homogenous supply with nutrients and oxygen, we developed a new method to culture tumor tissue slices. The precision-cut tissue slices (150µm to 300µm thickness) are kept in-between two organotypic supports and fixed in a special chamber allowing continuous perfusion with medium and drugs. The chamber is settled vertically inside of a 50 ml tube with air exchange capacity and connected with a syringe pump via a silicon tube. The whole system is cultured inside the cell culture incubator. Several different types of mouse xenografts (MCF-7, H1437) and primary human tumor (lung and ovarian cancer) tissue slices have been cultured with this new system and compared with the commonly used filter-support culture. Both breast and lung xenograft tissues slices showed a gradient of proliferation, HIF-1α and hormone receptor (ER) expression in the filter-supported culture condition but not with the new perfusion air culture system. The same results were obtained with primary tumor samples. Primary lung tumor and ovarian cancer tissue slices also showed a gradient of HIF-1α expression after cultivation in the filter-supported system but not in the new perfusion air culture system when cotton membranes are used as scaffold. In addition, the choice of the material of the organotypic support allows a variety of biological studies. Scaffolds from de-cellularized porcine intestine provide niches for migrating cells and are suited for studying tumor invasiveness. When used as organotypic support, primary ovarian cancer can be cultured up to 7 days with good tissue morphology and structure and migrating cells into the scaffold can be counted as a measure of invasiveness. When the tissues are sandwiched between polycarbonate membranes (pore size: 12 µm), oxygen gradients can be generated similar to gradients observed around vessels in vivo. Our perfusion air culture system facilitates the cultivation of tumor tissue slices due to its flexibility and adjustability of all culture conditions such as oxygen, scaffolds and flow rate parameters. It allows studying tumor slices under conditions closely resembling the in vivo situation. Citation Format: Kathrin Boepple, Meng Dong, Emma Davis, Julia Schueler, Heike Walles, John Hickman, Walter E. Aulitzky, Heiko van der Kuip. Perfusion air culture of tissue slices: A new method to cultivate tumor tissue with minimal culture-dependent tissue stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5040.

n engl j med 376;1 nejm.org January 5, 2017 95 (from 17.0% in 1976–1980 to 25.9% in 1988–1994). We find this implausible given that carcinogenic exposures typically take decades to manifest. Furthermore, an increased body-mass index is a very weak risk factor for breast cancer among postmenopausal women and among premenopausal women. In fact, it actually has a protective effect.2 Finally, the prevalence of obesity has subsequently increased by more than 10 percentage points (to 36.6% in 2011–20123) with no change in the incidence of breast cancer. Both Kopans and Brentnall et al. posit that the underlying incidence of clinically important breast cancer has changed. As we stated in our article, this variable is unknowable given that both increased awareness and increased screening increase the apparent incidence of disease. But the fact that the incidence of metastatic disease has remained stable for decades suggests that the underlying incidence has not markedly changed. Furthermore, as shown in Figure 1 of our article (available at NEJM.org), the apparent increase in incidence occurred rapidly. That alone points to a health services explanation, not a biologic one. A rapid increase limited to early-stage and small cancers is exactly what would be expected after increased awareness and the advent of screening. All physicians and patients wish that screening worked better. However, the biologic heterogeneity of what we call breast cancer conspires to limit the benefit of screening and results in its harm of overdiagnosis. Thankfully, advances in therapy have reduced mortality from the disease.