Preparing Health Systems for Tumour-Agnostic Treatment Tumour-agnostic therapies will play an important role in a new era of personalised healthcare, challenging existing diagnostic and value assessment frameworks. The 2017 A.T. Kearney Foreign Direct Investment Confidence Index: Glass Half Full 1 Advances in oncology have resulted in several revolutionary treatment modalities, which have made inroads into the way we fight cancer. One of these breakthroughs entails the development of medicines that target specific mutations or genomic alterations in different tumours, resulting in a complete and lasting response to treatment in affected patients.1, 2 This new class of treatments is known as “tumour-agnostic” or “histology-independent” therapies because of how they target the genomic alteration within a tumour, regardless of where in the body it has formed. By the end of 2018, the Food and Drug Administration (FDA) had approved two medicines for tumour-agnostic indications, paving the way for their commercialisation in the US. However, these types of therapies face significant challenges in adoption due to both how these new technologies will be assessed for value and reimbursed, and to the diagnostic infrastructure required to ensure that the patients most likely to respond to these treatments are identified and can gain timely access. This report was commissioned by F. Hoffmann-La Roche in November 2018 to review the landscape for tumour-agnostic treatment in the five largest European healthcare markets (Germany, France, Italy, United Kingdom and Spain) and Canada. The research is based on a review of publicly available industry reports, articles, recent publications and 30 interviews with oncologists, regulators, health technology assessors, policymakers, pathologists and payers across these markets. The objective of the landscape review was to better understand the challenges and opportunities faced by tumour-agnostic therapies entering European and Canadian health systems, focusing specifically on the: (a) levels of awareness and prioritisation of tumour agnostics in cancer policy, (b) market entry pathways and approach to value assessment and reimbursement, and (c) readiness of diagnostic infrastructure required for patient identification. These considerations shaped the assessment of countries’ readiness to support access to tumour-agnostic therapies and their availability to patients. This paper summarises findings from this research and offers an insight into the tumour-agnostic landscape. It provides advice on the topics that stakeholders will need to address to ensure timely patient access to tumour-agnostic treatments. The report is structured as follows: • A paradigm shift in cancer treatment—presents a background of the tumour-agnostic concept and drug development • Tumour-agnostic landscape assessment approach—provides a brief overview of the research framework used to assess individual country landscapes • Key challenges for tumour-agnostic patient access—outlines the key barriers faced by tumour-agnostic treatments in gaining access and reimbursement • Recommendations for policymakers, regulators, payers and industry—highlights crucial issues for stakeholders to address to ensure tumour-agnostic treatments can be successfully integrated into clinical practice • Opportunities for multi-stakeholder collaboration—identifies ways in which industry, policymakers, regulators, payers, clinicians and patient representatives can work together to improve patient care in oncology 1 Lasting response is considered greater than six months. 2 Li Yan and Wei Zhang, Precision medicine becomes reality—tumor type-agnostic therapy (Cancer Communications, 2018 38:6) Report on the Readiness of Health Systems for the Introduction of Tumour-Agnostic Treatment 1 A Paradigm Shift in Cancer Treatment Personalised healthcare is a vital contributor to the future of healthcare provision, with targeted treatments, advanced diagnostics and large-scale analysis of health data providing an unprec- edented opportunity to save or prolong lives and reduce the longer-term cost of care. Cancer is increasingly approached as a genomic disease, with research efforts helping to identify the specific genomic alterations that drive the onset and progression of disease. R&D’s main objective now is to develop new treatments that will target these oncogenic drivers. This in turn has led to significant progress in genomic profiling, next-generation sequencing (NGS) and data analytics—allowing clinicians to recognise the mutations that drive the growth of cancer cells, identify biomarkers and find the patients who are more likely to respond to treatments. Tumour-agnostic therapies are an important subcategory of personalised medicines and constitute a new era in patient care and drug development. These therapies are distinct from traditional anti-cancer treatments in that they target specific genomic alterations within the tumour, regardless of where in the body the tumour started growing or the tissue it developed from. This constitutes a paradigm shift in how oncology patients are diagnosed and treated, because tumour-agnostic indications have a mutation-specific designation rather than an anatomical or histological one. As of March 2019, the FDA had approved two tumour-agnostic indications based on the presence of a common biomarker across tumour types. Pembrolizumab was granted accelerated approval for the treatment of patients with unresectable or metastatic, microsatellite instability–high (MSI-H) or mismatch-repair–deficient (dMMR) solid tumours in May 2017, and larotrectinib for solid tumours with neurotrophic receptor tyrosine kinase (NTRK) gene fusion in November 2018.3, 4 These accelerated approvals relied on consultation between manufacturers and the FDA because of the study methodologies used to investigate these small and specific subpopulations. Due to the limited numbers of patients, it was not feasible to study each individual tumour type (from an anatomical point of view) for an individual licencing application and investigators chose to conduct a small number of multi-cohort, single-arm studies, also known as basket trials.5 Pembrolizumab was consequently approved based on five studies in 149 patients across 15 histologies, whereas larotrectinib was studied in three trials including 176 patients across 12 histologies. This represents significantly less data for each tumour type than would usually be expected for tumour type-specific regulatory submissions. Subsequently, Marketing Authorisation Applications (MAA) for both larotrectinib and entrectinib, two molecules targeting NTRK fusions, have been submitted to the European Medicines Agency (EMA), with pembrolizumab opting not to seek regulatory approval for a tumour-agnostic indication in Europe. A further ~10 tumour-agnostic therapies, targeting the same or various other mutations—including the receptor tyrosine kinases, anaplastic lymphoma kinase (ALK), c-ROS oncogene 1 (ROS1), and rearranged during transfection (RET)—are in early development.6 Tumour-agnostic indications create a new way of thinking about treatment, targeting patients based on a highly specific rare driver mutation (for example, present in less than 1 percent of solid tumours) rather than on tumour type.7 While regulatory agencies are demonstrating 3 Food and Drug Administration, FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication (last updated: 30/05/2017) 4 Food and Drug Administration, FDA approves larotrectinib for solid tumors with NTRK gene fusions (last updated: 17/12/2018) 5 American Society of Clinical Oncology, Clinical Trial design and Methodology (accessed: 25/02/2019) 6 Graber K, Tissue-agnostic cancer drug pipeline grows, despite doubts (Nat Rev Drug Discov. 2018 Apr;17(4):227-229) Report on the Readiness of Health Systems for the Introduction of Tumour-Agnostic Treatment 2 openness to a labelling approach that recognises the histologically independent nature of these therapies and the associated evidence challenges, our research suggests that current approaches to value assessment and the diagnostic infrastructure are not fully adequate for this. As a result, patients’ access to these breakthrough therapies could be adversely impacted. Decision-makers in oncology are yet to be exposed to the specific challenges these therapies present, such as the small populations in which these mutations may occur within any one tumour type or limited clinical trial data and the need for high-quality diagnostic tests such as broad panel NGS. To ensure effective patient access, these stakeholders will need to be fully aligned on the distinct nature of these therapies, the benefits provided to patients and their broader value to the healthcare system. Tumour-Agnostic Landscape Assessment Approach Our review of the tumour-agnostic landscape in the five major EU markets (Germany, France, Italy, UK and Spain) and Canada was conducted through country-level expert interviews and comprehensive secondary research based on an assessment framework, structured around three over-arching access focus areas (see figure 1): Figure The tumour-agnostic landscape assessment framework is structured around three focus areas Focus area Enablers Awareness and • Clinical and scientific community awareness and understanding of tumour-agnostic therapies prioritisation and genomic proiling • Existence and discussion of tumour agnostics in clinical associations, including tissue-specific and rare cancer