All times are listed in CEST (Central European Summer Time)
- Ravindran Kanesvaran (Singapore, Singapore)
- Christophe Massard (Villejuif, France)
1312O - From regulating off-label use to creating an environment for drug repurposing in oncology
- Sahar Van Waalwijk van Doorn-Khosrovani (Tilburg, Netherlands)
Abstract
Background
Use of anticancer drugs for unapproved indications poses significant challenges to the health care system; Off-label use often lacks robust scientific evidence and due to high treatment costs reimbursement restrictions may apply.
Methods
The assembled Dutch Health Insurance Companies (HIC) and the Dutch Society for Medical Oncology (NVMO) have jointly implemented measures to regulate and facilitate off-label access.
Results
The NVMO has created a desk to assess and implement all valuable free-of-charge and expanded-access programmes. Besides, a dedicated off-label assessment committee has been appointed to work closely with the Drug Evaluation Committee of HIC in appraising the evidence of specific off-label use of anticancer drugs and arranging reimbursement. The main focus of these committees are off-patent drugs (or drugs close to patent expiry) that have no market exclusivity and for which the marketing authorisation holder(s) will probably not request an extension of indication. Furthermore, the HIC have embedded the Drug Rediscovery Protocol (DRUP), a national adaptive, multi-drug, pan-cancer trial within their framework to stimulate evidence generation. By introducing the ‘Personalised reimbursement’ scheme, the HIC have made it possible to reimburse drugs for patients that are clearly benefitting from therapies within the DRUP trial.
Conclusions
While regulation of off-label use may seem restrictive, we believe that by establishing a joint framework for evaluating data and reimbursement decisions we can stimulate evidence generation and rational use of costly drugs. By providing clinical recommendations that are based on transparent and standardised assessments we can also reduce practice variation and improve the quality of healthcare. EMA has recently launched an initiative to support hospitals and non-profit organisations in generating evidence on off-label use and to authorise new indications. Ideally, a European framework should be established in which regulatory approval as well as HTA assessment are realised centrally, along with clear and rapid pathways to reimbursement decisions in each member state. In this way valuable anticancer drugs can be accessible to all within a more reasonable timeframe.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
E.E. Voest: Financial Interests, Personal, Advisory Board, Hourly rate, to charity: Biogeneration Ventures; Financial Interests, Institutional, Advisory Board, Hourly rate, no compensation in 2019-2020: InteRNA; Financial Interests, Institutional, Invited Speaker, DRUP trial: Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Clovis Oncology, Eisai, Ipsen, MSD, Novartis, Pfizer, GSK, Seattle Genetics; Financial Interests, Institutional, Invited Speaker, DRUP trialDRUG Access Protocol: Bayer, Roche; Financial Interests, Institutional, Invited Speaker, DRUG Access Protocol: Sanofi; Non-Financial Interests, Supervisory Board: HMF – Hartwig Medical Foundation; Non-Financial Interests, Principal Investigator, Senior group leader: Oncode Institute; Non-Financial Interests, Advisory Role, Editorial Board: JAMA Oncology; Non-Financial Interests, Leadership Role, Board of Directors: Cancer Core Europe. All other authors have declared no conflicts of interest.
1313O - Assessment of investigational new drugs (INDs) approved in USA and Europe after early phase trials using the ESMO-magnitude of clinical benefit scale (ESMO-MCBS)
- Justin T. Moyers (Orange, United States of America)
Abstract
Background
Increasingly regulatory approval for novel agents is sought following early phase single-arm trials. However, many countries’ governmental agencies require value assessment of new agents to determine reimbursement. The ESMO-MCBS provides an evaluation framework based on treatment efficacy, response duration, adverse events, quality of life, and phase 4 data scored from 1-5 with scores
Methods
INDs approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) between 2010 and April 2022 based on single-arm early phase 1 and/or 2 trials were reviewed. INDs were assessed using form 3 of the ESMO-MCBS from published data available at time of approval.
Results
Among 94 approved IND, 34 (36%) were approved based on single arm trial data. INDs were 23 ( 68% ) targeted kinase inhibitors, 4 (12%) antibody directed cytotoxics, 5 (15%) immunotherapeutics, and 2 (6%) other. Alectinib, sonidegib, and crizotinib were the only INDs to meet the threshold for substantial benefit at the time of FDA/EMA approval (score=4). Whereas 12 (34%) had scores of 0 to 2 and the majority (n=19; 56%) had scores of 3. Results of patient reported outcomes (n=6; 17%) were uncommon at time of approval and only 1 (16%) illustrated an improved quality of life. 14/19 (74%) INDs which had published later phase trials achieved ESMO-MBCS score >4 subsequently in controlled studies. 28 of 34 FDA approved INDs (82%) were also approved by EMA. EMA approvals followed FDA approvals at a median of 10 months (range: 0 to 24). FDA and EMA approved INDs had median score of 3.0 vs 2.5 for INDs approved by FDA alone (p=0.5). 44% of INDs (n=15) provided a meaningful benefit with duration of response >12 months (n=9) and/or objective response rate >50% (n=12).
Conclusions
Only 3 early phase approvals met threshold for substantial benefit by ESMO-MBCS criteria despite clinical benefits seen in >40% of patents with INDs. Revision and recalibration of ESMO-MCBS is warranted to match the desires of patients, oncologists, and their governmental organizations to license effective drugs from early phase studies.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
V. Subbiah: Financial Interests, Personal, Advisory Board, One time advisory board: Incyte, Novartis, Eli Lilly/ Loxo Oncology; Financial Interests, Personal, Advisory Board, One time ad board: Roche, Pfizer; Financial Interests, Personal, Advisory Board, Ad hoc advisory board: Relay Therapeutics; Financial Interests, Institutional, Invited Speaker, Research funding to conduct Clinical trial: Eli Lilly/Loxo Oncology, Blueprint medicines, Novartis, Boston Pharmaceuticals, Pfizer, Turning Point Therapeutics, Amgen, Bayer, Roche/ Genentech, Exelixis, Berg Pharma, N W Biotherapeutics, Relay Therapeutics, AbbVie, Agensys, Inhibrx, Dragonfly therapeutics, Takeda; Financial Interests, Institutional, Invited Speaker, Research funding to conduct clinical trial: Shasqi; Other, I am employed at the University of Texas MD Anderson Cancer Center: The University of Texas MD Anderson Cancer Center; Other, I receive research funding from NCI: National Cancer Institute, USA. All other authors have declared no conflicts of interest.
Invited Discussant 1312O and 1313O
- Panagiotis Kanavos (London, United Kingdom)
Q&A
1314O - Cost-effectiveness of molecularly matched off-label therapies for end-stage cancer: The MetAction precision medicine study
- Anne H. Ree (Lorenskog, Norway)
Abstract
Background
Precision cancer medicine (PCM), the expensive and often modestly efficacious off-label treatment with medications matched to the tumour genome of end-stage cancer, challenges the healthcare resources. We compared health effects, costs and cost-effectiveness of our MetAction PCM study with corresponding data from comparator populations given best supportive care (BSC) in two external randomised controlled trials.
Methods
We designed three partitioned survival models to evaluate the healthcare costs and quality-adjusted life years (QALYs) as the main outcomes. Cost-effectiveness was calculated as the incremental cost-effectiveness ratio (ICER) of PCM relative to BSC with an annual willingness-to-pay (WTP) threshold of EUR 56,384 (NOK 605,000). One-way and probabilistic sensitivity analyses addressed uncertainty.
Results
We estimated total healthcare costs (relating to next-generation sequencing (NGS) equipment and personnel wages, molecularly matched medications to the patients with an actionable tumour target and follow-up of the responding patients) and the health outcomes for the MetAction patients
Conclusions
Our health economic modelling compared patients with end-stage cancer analysed by NGS for the opportunity to provide molecularly matched therapies, with comparator populations instead receiving BSC, and showed that the high ICERs of PCM were driven by costs relating to the NGS diagnostics and molecularly matched medications, with a likelihood for the strategy to be cost-effective defying WTP constraints. Reducing drug expenses to half the list price would likely result in an ICER at the WTP threshold, which can be an incentive to a public-private partnership of sharing the costs of molecularly matched medicines in PCM, exemplified by the models used in the ongoing IMPRESS-Norway and Dutch DRUP trials.
Clinical trial identification
NCT02142036.
Legal entity responsible for the study
Oslo University Hospital.
Funding
Research Council of Norway Grant 218325.
Disclosure
A.H. Ree: Financial Interests, Personal, Invited Speaker: Merck Sharp & Dohme, Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb. K. Flatmark: Financial Interests, Institutional, Funding: Bayer Pharma. H.G. Russnes: Financial Interests, Institutional, Invited Speaker: AstraZeneca, Pfizer, InCyte, Merck, Roche. All other authors have declared no conflicts of interest.
1315O - Key learnings from building: A precision cancer medicine implementation initiative for Norway
- Kjetil Tasken (Oslo, Norway)
Abstract
Background
European countries with publicly funded health care struggle with implementation of precision cancer medicine (PCM).
Methods
We set out three aims in 2019: i) To establish access to advanced molecular diagnostics for stratification of patients to trials; ii) To increase the volume of trials with a PCM approach to gain experience; and iii) In parallel work for implementation of PCM into standard of care. Work proceeded along four lines: i) Sign-up to a nation-wide, bottom-up initiative with a few common priorities; ii) Aligning with top-down approaches from the Ministry and regional health care systems; iii) Exploring the possibility of a public-private partnership and iv) Coordinating with other PCM initiatives internationally.
Results
Over the past two years we have built the InPreD-Norway national infrastructure for precision cancer diagnostics allowing stratification into PCM trials with a national molecular tumor board (publicly reimbursed, screened >300 in the first year), the IMPRESS-Norway national researcher-initiated PCM intervention trial (https://impress-norway.no), which opened for inclusion Q2 2021 and runs at all hospitals that treat cancer patients (22 sites, 17 hospital trusts; ), the INSIGHT/INCLUDE projects for research on control cohorts, use of real world evidence (RWE), health economics and reimbursement models, ethics, legal aspects and governance, and the CONNECT public-private partnership (https://www.connectnorway.org) for PCM implementation with 28 partners (16 pharma & biotech, 9 public and 3NGO partners) that provides a forum for policy discussions of reimbursement models and regulatory framework. Key learnings include how to build nation-wide initiatives, the importance of aligning top-down instructions with bottom-up approaches navigating politics and policies at multiple levels, that health economics and reimbursement models are necessary aspects and the need to understand different corporate cultures and create win-wins to make a public-private partnership work.
Conclusions
Unique aspects of our experience include the nation-wide initiative, reimbursement of the molecular diagnostics w. population effect, drug reimbursement in our PCM trial and the public-private partnership model.
Legal entity responsible for the study
Oslo University Hospital.
Funding
This abstract is presented by the authors on behalf of the on behalf of the InPreD consortium and national Molecular Tumor Board, the IMPRESS consortium, the INSIGHT/INCLUDE projects and the CONNECT Public-Private Partnership. Funding for the InPreD national infrastructure for advanced molecular cancer diagnostics for stratification of patients to PCM trials comes from The Regional Health Authorities for South-Eastern, Western, Middle and Northern Norway, the Cancer Society, the Radium HospitalFoundation and other regional funds and testing is reimbursed as health care in Norway. Funding for the IMPRESS-Norway national PCM trial comes from the Norwegian Clinical Treatment Research Programme (KLINBEFORSK), the Norwegian Cancer Society, the Nordic Trial Alliance/NordForsk, as well as company contributions so far from Roche, Novartis, Incyte, Eli Lilly and AstraZeneca and also include collaboration projects with RocheFoundation Medicine and Illumina. Company contributions to IMPRESS-Norway are regulated by separate agreeements with Oslo University Hospital as coordinating institution. Participation in the CONNECT Public-Private Partnership is regulated by a consortium agreement that handles conflicts of interest and regulates interaction with the publicly funded infrastructure InPreD-Norway and the investigator-initiated and publicly funded trial IMPRESS-Norway.
Disclosure
All authors have declared no conflicts of interest.
1316O - Improved nationwide survival of sarcoma patients 10 years after establishment of the NETSARC+ reference center network
- Jean-Yves Blay (Lyon, France)
Abstract
Background
Treatment of sarcomas within networks of reference center is associated with improved outcome. We report on the nationwide impact of the NETSARC+ network on sarcoma survival since 2010 in France.
Methods
NETSARC+ is a national network of 26 reference sarcoma centers with multidisciplinary tumor boards (MDTB) active since 2010, in charge of mandatory pathology review, and collection of patients characteristics in the
Results
43,975 patients with sarcomas and tumors of intermediate malignancy were included in the NETSARC+ database since 2010 (n=9,266 [2010-12], n=12,247 [2013-15], n=22,435 [2016-20]). Median age is 59 years, 50.5% are women, 13.2% were metastatic at diagnosis. The 3 most frequent histotypes were liposarcomas, leiomyosarcomas, and UPS. Over the 3 periods, the percentage of patients 1) biopsied before surgery increased from 63% to 76%, 2) presented to the MDTB before the 1st treatment increased from 32% to 45%, 3) operated in reference centers increased from 55% to 59%, 4) re-operated after 1st surgery decreased from 13% to 9% (p<0.0001 for all tests across the 3 periods, and for comparisons between the 2 exhaustive periods 2 vs 3). With a median follow-up of 14 months in the whole series, the overall survival was significantly superior in the series of patients operated in the period 2017-20 vs 2013-2016 vs 2010-12 (p<0.0001). Comparison of survival in the two most recent exhaustive periods showed a superior survival for patients in 2016-20 vs 2013-15 periods (HR=0.82) in patients aged >18 (HR=0.81), both metastatic (HR=0.68) and non-metastatic (HR=0.82) (p<0.0001 for all). A 24% reduction of the relative risk of death at 12 months was observed in the 2016-20 period.
Conclusions
The implementation of the NETSARC+ national reference network since 2010 in France is associated with an improvement of the overall survival nationwide in sarcoma patients.
Legal entity responsible for the study
Centre Leon Berard.
Funding
Institut National du Cancer (INCA): NETSARC+, LYRICAN, INTERSARC European Commission: EURACAN.
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant 1314O, 1315O and 1316O
- Christophe Massard (Villejuif, France)