Dr. John Mendelsohn, Chairman, Worldwide Innovative Networking (WIN) Consortium in personalized cancer medicine
“Our mission is to rapidly translate personalized cancer medicine discoveries into standards of patient care worldwide.” Dr. John Mendelsohn, Chairman, Worldwide Innovative Networking (WIN) Consortium in personalized cancer medicine

WINning together

WIN was formed on the premise that we can accomplish more together than each organization can achieve working alone. We aim to improve cancer patients’ survival and quality of life. View WIN's history and unique attributes:

WIN represents a global collaboration of cancer centers, life science and biotech organizations, pharmaceutical and technology companies, health plans, and not-for-profit organizations.
The Worldwide Innovative Networking (WIN) Consortium in personalized cancer medicine was initiated in 2010 with leadership from leading cancer centers worldwide. WIN is a non-profit, non-governmental organization headquartered in Paris.

WIN was created to accelerate the pace and reduce the cost of translating novel cancer treatments to the bedside by developing and applying, through worldwide clinical trials and research projects, the most promising advances in genomic-based cancer research. WIN aims to initiate research projects each year in a global consortium guided by an independent scientific advisory board.

WIN now includes 43 institutional members. These stakeholders have come together from all parts of the world to address the challenge of increasing the efficacy of cancer diagnostics and therapeutics by understanding the genetics and biology of each individual’s tumor and accounting for genetic differences across diverse populations—from North and South America, Europe, Asia, and the Middle East.

Our goal is to significantly improve outcomes for patients around the globe. We aim to increase the number of patients worldwide that have access to innovative, global clinical trials in the area of genomic-based cancer therapeutics. Global diversity and inclusion of all stakeholders is WIN’s most important and differentiating asset.
WIN is comprised of organizations representing all stakeholders in personalized cancer medicine.
WIN enables cross-sector collaborations designed to accelerate the speed and efficacy with which breakthroughs in personalized cancer medicine can be realized and brought to patients worldwide.

Our members include leading academic, pharmaceutical, life science, not-for-profit, health IT, and healthpayer organizations.
Our members include 30 leading academic centers representing 18 countries and four continents, enabling coordinated studies with a global patient population.
The response to a genetically-targeted therapy can vary due to differences in ethnicity and environment. WIN's global studies are designed to identify and account for this variability, enhancing the speed and efficacy with which novel discoveries can be made and brought to patients around the world.

WIN's first trial, WINTHER, is currently being carried out through a collaboration between six academic centers in five countries, with key support from Europe (EUFP7), Fondation ARC, Pfizer and other pharma companies.
WIN prioritizes cross-sector interaction designed to enhance learning across and between continents and healthcare sectors.
WIN Symposia, held annually in Paris, brings together hundreds of leaders representing all stakeholders from around the world in a forum designed to promote the exchange of ideas and information.

Clinical trials and projects

WIN members collaboratively design and carry out global studies designed to achieve breakthroughs for patients worldwide. Our distinguished Scientific Advisory Board oversees WIN studies. Current trials include:

SPRING 01 (Survival Prolongation by Rationale Innovative Genomics) proof of concept trial is the first trial exploring the tri-therapy strategy in first line of advanced/metastatic non-small cell lung cancer (NSCLC), following the historical success of this approach in AIDS and tuberculosis for which only tri-therapy demonstrated long term efficacy.
The WIN SPRING trial will be conducted in the USA, France, Spain, Luxembourg and Israel in the following cancer centers: University of California - San Diego's Moores Cancer Center, Avera Cancer Institute (Sioux Falls, Arizona), Institut Curie (Paris), Centre Léon Bérard (Lyon), Hôpital Paris Saint-Joseph (Paris), Vall d'Hebron Institute of Oncology (Barcelona), Centre Hospitalier de Luxembourg (Luxembourg), and Chaim Sheba Medical Center (Israel).

The trial is sponsored by the WIN Consortium and funded by ARC Fondation for cancer research (France). The drugs are donated by Pfizer Inc.
WINTHER, the WIN Consortium's first global personalized cancer medicine trial, is an ongoing global study carried out at multiple leading academic cancer centers around the world.
WINTHER aims to validate a breakthrough concept that would offer treatment guided by each patients biology for the vast majority of cancer patients.

With multiple cancer centers representing four countries - as well as partner biotech and pharma companies - WINTHER exemplifies WIN's commitment to innovative, collaborative studies that make effective, personalized medicine a reality for patients worldwide.
WIN is currently planning innovative global clinical trials that represent the next generation of studies focused on lung cancer.
European funded trials WINTHER EU FP7 funded and CHEMORES EU FP6 funded established foundations for WIN future global strategy for lung cancer currently under development.

The concept underlying the new strategy is developed in the following publications:
WIN provides a legal and fundraising framework that enables collective fundraising while protecting its members' intellectual property.
The WIN platform enables multiple organizations from different sectors to productively collaborate while providing for the protection of intellectual property. Each project or clinical trial has its own specific contract or funding mechanism.

People leadership

WIN leaders are selected for their contributions and commitment to making effective, personalized cancer medicine a reality for patients around the world. They guide WIN's strategic, operational, and scientific direction.

John Mendelsohn Photo
John Mendelsohn

Director, Khalifa Institute for Personalized Cancer Medicine and Past-President, the University of Texas MD Anderson Cancer Center (USA)

Richard L. Schilsky Photo
Chairman, WIN Scientific Advisory Board
Richard L. Schilsky

Senior Vice President and Chief Medical Officer, American Society of Clinical Oncology (ASCO); Chairman, WIN SAB

Razelle Kurzrock Photo
Chair, Clinical Trials Committee
Razelle Kurzrock

Chief, Division of Hematology & Oncology, Sr. Deputy Center Director for Clinical Science, University of California San Diego Moores Cancer Center (USA)

Vladimir Lazar Photo
Chief Scientific and Operating Officer
Vladimir Lazar

Chief Scientific and Operating Officer, WIN Consortium

Our members

WIN members include 43 leading organizations representing all stakeholders in personalized cancer medicine covering 20 countries and 4 continents. Our shared vision is delivering the promise of effective, personalized cancer medicine to patients worldwide.

WIN Symposia

WIN Symposia, held annually in Paris, gather leaders representing a breadth of stakeholders from around the world to learn, share, and collaborate. Visit http://www.winsymposium.org for registration and additional information.

WIN 2018 Symposium logotype

WIN 2018 Symposium

June 25, 2018 - June 26, 2018

We are excited to celebrate our 10th year Anniversary edition of the WIN Symposia at the WIN Symposium 2018 in Paris, France on 25-26 June 2018.

The WIN Symposium Organizing Committee has chosen “Global Implementation of Precision Oncology: WINning the War against Cancer” as the theme for this celebratory event.

For more details, please visit our dedicated symposium website: https://www.winsymposium.org

WIN 2017 Symposium logotype

WIN 2017 Symposium

June 26, 2017 - June 27, 2017

The WIN 2017 Symposium with the theme ‘Expediting Global Innovation in Precision Cancer Medicine’ was held in Paris, France, June 26-27, 2017. The overarching goal of our symposium was to share information to promote and accelerate cutting edge investigations and use of personalized, targeted cancer therapy.

WIN 2016 Symposium logotype

WIN 2016 Symposium

June 27, 2016 - June 28, 2016

The WIN 2016 Symposium “Innovative Approaches to Improve Cancer Patient Outcomes”, June 27-28th was the eighth in a series of symposia dedicated to advancing personalized cancer medicine. It was a successful unique forum that brought leaders representing all stakeholders - academia, pharma, biotech / life sciences, regulatory, and health payer - together from around the globe.

What people are saying

Avera To Enroll First Patients in Landmark Lung Cancer Tri-Therapy Clinical Trial
Sioux Falls,Jan. 19, 2018(GLOBE NEWSWIRE)

SIOUX FALLS, S.D. — The first patients in the world will be able to enroll in a new cancer study at Avera as part of an international collaboration that looks to transform care for lung cancer patients.

This clinical trial that received the approval of the FDA is Avera’s latest collaboration as part its membership in the Worldwide Innovative Networking (WIN) Consortium.

“We’re taking a bold step in a new direction so lung cancer patients have hope for more treatment options after diagnosis. This latest step in our collaboration with WIN represents one clinical trial but is part of our larger goal to revolutionize cancer care through personalized medicine,” said Benjamin Solomon, MD, the lead investigator for the study at Avera and medical oncologist with Avera Cancer Institute. “If successful, this study could lead to a complete paradigm shift in our approach to lung cancer treatment with a goal of realizing big improvements in outcomes for patients.”

More than 60 percent of non-small cell lung cancer cases are detected in an advanced stage, and less than 5 percent of these patients are alive five years after diagnosis.

In the Survival Prolongation by Rationale Innovative Genomics (SPRING) trial, patients will be given a three-drug protocol that incorporates immunotherapy (avelumab) and two other targeted therapies (palbociclib and axitinib). All patients will be given the same drug combination and their response rates will be tracked to see which patients respond best.

Through the WIN Consortium, an Avera research team under Solomon’s leadership has helped design and implement the clinical trial from the ground up.

“This breakthrough research is happening in Sioux Falls, S.D., because of the high level of expertise and commitment available here,” said Vladimir Lazar, MD, PhD, founder and Chief Scientific and Operating Officer of the WIN Consortium. “With these clinical trials we want to go beyond what is now possible so patients around the world can have more hope when they get a lung cancer diagnosis.”

Because cancer evolves as it grows, it can acquire more genomic complexity over time. DNA sequencing and RNA expression levels in tumor and normal tissues will help guide care by analyzing the patient’s cancer genomic abnormalities to determine the specific changes that have occurred. A multi-drug combination has the potential to treat lung cancer by blocking multiple cancer pathways that develop as a result of these genomic changes.

For the most effective results, researchers work to pair the drug combinations that may work best to combat each lung cancer genomic abnormality. To accomplish this, WIN developed an algorithm, SIMS (Simplified Interventional Mapping System), which is hypothesized to better predict personalized treatment for cancer patients.

The end goal is to pair every lung cancer genomic abnormality with an effective drug combination. This may lead to dozens of clinical trials aimed at accomplishing this goal. In the future, this treatment algorithm could potentially be expanded to other tumor types such as colon or breast cancer.

The SPRING trial will be led by Razelle Kurzrock, MD, (University of California San Diego, Moores Cancer Center) and co-led by Enriqueta Felip, MD, (Vall d'Hebron Institute of Oncology). It will be launched in five countries and eight WIN member sites. Avera, one of two sites in the U.S., is the first to begin enrolling patients.

The SPRING trial will be conducted in two phases. Phase I will explore the safety of the drug combination and determine the optimal doses for Phase II, which will explore the efficacy of this tri-therapy regimen in first-line treatment of metastatic non-small cell lung cancer. The trial will have strict eligibility criteria and limited enrollment.

About Avera Health

Avera Health is an integrated health system comprised of more than 330 locations in 100 communities in a five-state region. A full continuum of care is offered through 32 hospitals, 200+ clinics, retirement communities, home care, sports and fitness centers, with award-winning care in 60+ medical specialties. With more than 17,000 employees and physicians, Avera is the largest private employer in South Dakota. Avera is distinguished through technology and innovation. We are home to the world’s most extensive telemedicine network, and a world-class genomics program that translates the latest cancer research directly to patient care. As a health care ministry, we carry on the legacy of the Benedictine and Presentation Sisters, delivering care in an environment guided by our values of compassion, hospitality and stewardship. For more information about Avera, see our website at Avera.org

About the WIN Consortium

Founded in 2010, WIN is unique structurally in that it brings together organizations from academia, business and not-for-profits to focus on translating the latest advances in personalized cancer medicine into the standard of care. WIN is built on the recognition that all stakeholders in personalized cancer therapy must collaborate and share information, in order to effectively bring the latest innovations in personalized cancer care to the patient. WIN is a non-profit organization formed by 40 renowned members: Academic cancer centers (32 centers in 17 countries), companies (Pfizer, Merck KgaA, Covance, Illumina, HTG Molecular, Blue Cross Blue Shield Association, etc.), non-profit organizations such as Fondation ARC, European Cancer Patient Coalition, SurviveIt. The SPRING trial will be presented during the WIN Symposium “WINning the War against Cancer” in Paris (France) on June 25-26, 2018. For further information, please visit www.winconsortium.org and www.winsymposium.org.
When my son died of cancer I decided to wage war on the disease myself
Friday, November 10, 2017
LONDON, UK (The Independent Digital Newspaper)

This story begins when my son was diagnosed with cancer at the age of eight. Like most patients who are lucky to be in an international city, he received nine consecutive lines of treatment, one after another, prescribed in the exact order of “cancer textbooks”: from nasty chemotherapy to sophisticated targeted drugs.

Were these drugs the right match for the tumour of my child? No, they were just thrown at him in a blind manner, hoping for the best.

The worst happened - my son Gaspard died.

I kept asking myself how cancer could remain a fatality in an era when the human genome – our genetic code – has been deciphered and can be manipulated to cure rare diseases; when AIDS is under control; when cars do not need drivers; and man is conquering space?

Here started my personal war against cancer. I had no strategy, no troops, no weapons to face the enemy, only my grief and determination to make things change.

Yet I knew change was needed. Treatment options have not really varied for years; research silos remain unbreakable; the costs of treatment are exorbitant; and advances in genomic-based treatment of cancer are unacceptably slow.

And so it came to pass that a year after my son’s death, in October 2010, a small group of prominent oncologists established a global collaboration of cancer centres, drug makers, technology and insurance companies built on refusal of the status quo. The network was ambitiously named the Worldwide Innovative Networking (WIN) Consortium in personalised cancer medicine, and I soon joined as director of operations.

The good news when it comes to cancer is that some important breakthroughs have been achieved recently with the introduction of targeted and immune drugs. Indeed, evidence is building in clinical trials, research and case reports to suggest that patient outcomes are improved when a specific targeted medicine can be matched to an identified anomaly of the tumour’s DNA (a “genomic aberration”).

However, the bad news is that in the majority of cases, this does not work or it works only briefly. Not all advanced solid tumours harbour potentially “actionable” genomic anomalies that can be treated with a targeted therapy. So far the approach has benefited only a small portion of patients, for a variety of confounding factors. We lack tools to understand which DNA anomaly is important versus not important, we have difficulties to predict whether a drug that targets an identified anomaly will be effective in terms of patient’s outcome. In other words we still do not know how to match a patient’s cancer to the right drug.

Even those cancer patients who are “lucky enough” to have a tumour harbouring an anomaly that can be treated with a targeted therapy, are almost guaranteed to relapse once the disease develops resistance.

In the meantime the statistics are staggering. 14 million new cancer cases are registered every year. By 2030, the global burden is expected to grow to 21.7 million new cancer cases. This means that cancer will affect everyone in the world, sooner or later, directly or indirectly. The ‘emperor of all maladies’ already claims 8.8 million deaths per year, making cancer a leading cause of death worldwide, with lung cancer being the top killer.

Lung cancer develops silently and when the first clinical symptoms appear, it is often too late - the patient is already in an advanced stage of the disease that is then incurable.

Over the past 50 years lung cancer treatment has been largely ineffective. As Dr. Razelle Kurzrock, senior deputy director for clinical science at UCSD's Moores Cancer Center and Head of WIN Clinical Trials Committee, said in a recent interview: "we were blindly throwing drugs at [patients] hoping something will stick".

Around 14 per cent of non-small cell lung cancer (NSCLC) patients with stage IIIA disease survive five years after diagnosis; with stage IIIB disease the five-year survival rate is only 5 per cent. When the disease has spread to other parts of the body, the five-year survival rate drops to 1 per cent. Unfortunately 60% of patients are diagnosed at late stage IV.

With the current path of drug and biomarker development, it will take decades to achieve significant improvement in cancer outcomes. Personalised oncology, aimed at giving the right treatment to each patient, is therefore a long and winding road that has left many patients on the side.


Cancer is complex and pernicious, yet it does not develop in vacuum, but rather in an individual. Precisely because cancer is so complex, giving patients one targeted therapy does not make much biological sense. It may produce response in some patients, but responders will inevitably develop resistance and succumb to the disease. It is time to look at patients as individuals and to develop combination treatments, or ‘cocktails’. But how can we determine personalised therapy combinations that can be used to treat lung cancer, or other deadly malignancies? There is no clear answer yet.

The easiest way to cure cancer is to prevent it. Global tobacco control is critical to achieve this goal. When lung cancer is detected at an early stage, surgery and adjuvant therapies are enough to achieve cure. But what if the patient arrives too late, having an advanced form of the disease? How can we deliver the gift of time and quality of life that my son was denied? The strategy here resides in switching from the current monotherapy rule given in consecutive lines, towards the rational combination(s) of targeted drugs. But how many drugs do we need to combine together?

There are many trials under way exploring combinations of two drugs. With few exceptions they do not yet achieve the goal of prolonging life significantly. Patients and their families are expecting more than only a few additional weeks or months of life.

The strategy for lung cancer treatment and all other solid tumours has to be multiple modalities and multiple drugs that are optimized for each individual. Like in any war we need a strategy adjusted to the enemy who is shrewd, mutable and agile.

Our research team hypothesised that three targeted therapies with different modes of action, hitting different biological pathways simultaneously, will overwhelm cancer. This strategy is expected to achieve what targeted single agents have failed to do so far in precision oncology, especially in lung cancer — stave off cancer resistance and prolong long-term survival. The triple-therapy hypothesis is that all patients could be treated in a personalised way (and not only a minority whose tumour harbours a known targetable DNA anomaly), and that the patient outcomes would be significantly improved. Indeed, the strategy has been successfully implemented in patients with AIDS, whose viral load is effectively controlled with triple-therapy thus reducing AIDS to a chronic disease.

However, cancer is far more complex than AIDS, and one triple-therapy will not fit all lung cancer patients. The pathways that cancer uses to thrive are many more than we thought before, propelling us to conclude that patients will need several tri-therapy combinations to fight cancer.


Two innovative tactics and weapons were developed to make this tri-therapy approach possible. First, three drugs were selected among those already existing on the market; second, an algorithm based on a new biomarker technology was put in place. The latter explores a broad spectrum of analyses that ‘imprint’ the disease, a routine procedure even in the most advanced clinical trials. They include the investigation of the tumour DNA but also the gene expression of the tumour tissue in comparison to the healthy tissue of the patient.

The algorithm is able to integrate billions of bytes of data with the purpose of identifying meaningful individual biological anomalies or pathways that can be targeted with a ‘cocktail’. In terms of military strategy and tactics, the objective being pursued is to ‘hit them (the relevant pathways) where it hurts’.

This novel strategy is ready to be tested. The US Food and Drug Administration (FDA) has already given its blessing to the launch of a unique WIN Consortium trial in first line therapy (that is for non-treated patients) of metastatic NSCLC.

While the first proof of concept trial is getting off the ground with the first tri-therapy, a second combination is coming. The more tri-therapy combinations are studied, the faster we obtain more options for patients and elucidate the ability of the algorithm to match patients to the right combinations. With more than one therapeutic option, patients will be able to switch to different combinations as resistance emerges and extend survival for many more years than is currently possible.

One could say that this is a nice strategy but still a hypothesis until proven by clinical trials. The major risk here is losing time – to be too late for those who wait for a miracle. For the sake of the patients, we cannot afford to wait for the results of the first tri-therapy trial before we move to the next. My dream is to have within 5 years clear answers and build substantial knowledge to make a quantum jump in treating lung cancer patients who have been left without significant survival improvement for the past 50 years.

We need many more strategies to win the war against cancer, apart from research intuition and foresight. Tough political battles lie ahead of us: we have to convince drug developers to collaborate; we will need ambassadors and supporters to convey our message; we have to persuade governments to help. We are all at war against a common enemy.

Catherine Bresson is Director, Operational Team of the WIN Consortium
ecancer Medical Science Conference Report Highlights from the WIN 2017 Symposium 'Expediting Global Innovation in Precision Cancer'
ecancer Medical Science Conference Report
Will Davies

The Worldwide Innovative Networking (WIN) symposium brings together representatives from academic institutions, pharmaceutical partners, technology companies and charitable organisations from across the globe for an annual summit, discussing ongoing research and the latest developments in precision medicine. Now, in its seventh year, the aims of the WIN consortium’s annual meeting, to foster communication and collaboration between members and deliver clinical trial results that improve the care and outcomes of patients are presented in open dialogue to encourage debate and discussion.

This year, the meeting was held in Paris, France from 26–27 June and consisted of six plenary sessions, two debates, and poster presentations from attendees. In keeping with the consortium’s goals, presentations and posters focused on the development and integration of new therapies and updates in genome-based medicine.

Among the presentations at this year’s meeting, much of the focus fell on design and implementation of new designs of clinical trials, moving away from decades-long assessments of thousands of patients towards a nimble, adaptive design fitting the edicts of personalised medicine and delving into greater depths within genomic data, ranging beyond genome analysis to chart new targets in ligandomics, proteogenomics and more.

This year’s symposium was opened with a cheerful welcome from WIN chairman Dr John Mendelsohn (MD Anderson Cancer Centre, Houston, TX, USA), who had much reason to speak warmly to the audience. In the intervening year between this symposium and the last, more and more targeted drugs have entered clinical trials as monotherapy and combinations, more still have reached US/European approval, and the concept of genomic sequencing is even reaching the lay public. Looking forward from this point, Dr Mendelsohn offered a short wish list for technical and social support for personalised medicine platforms and practitioners. Among them were as follows:
• diagnostic platforms that can support treatment decisions, providing a summary of detected biomarkers, suitable trials to which the patient may be recruited and response rates to current care,
• the integration of Big Data into the patient’s own journey through disease onset, diagnosis, treatment and aftercare, as well as taking that data forward to inform and improve outcomes for subsequent patients,
• biomarkers beyond genes alone, and making full use of transcriptomics, proteomics and molecular imaging to give the most refined, up-to-date and wholly personalised view of a patient’s biology in the moment that they are diagnosed and treated.

It is no small order to turn a capacity-led healthcare system on its head to pour tremendous resources and enormous cost into the absolute understanding of a momentary glimpse of a single tumour specimen. But these wishes are perhaps not so far away, as the next two days made clear.

The first to take on the challenge of delivering an answer to these high ideals was Dr José Baselga (Memorial Sloan Kettering Cancer Center, New York, USA), in his keynote lecture on genomic-driven clinical studies in breast cancer. Breast cancer benefits from years of focus and development in identifying biomarkers for disease subtypes and risk, with survival rates rapidly improving in a single generation. With an eye to the future, Dr Baselga set out his own forecast on implementing genome-driven oncology. It handily tacks close to Dr Mendelsohn’s own dreams, and Dr Baselga illustrated his ideal process of samples arriving from solid and liquid biopsies for sequencing, analysis to guide selection of targeted therapy, which is deployed in adaptive combinations, and reacting to markers for evolution or disease progression through ongoing sample surveillance. To offer some current context, he also introduced phase-I studies of PI3Kinase inhibitor taselisib, which is now escalating to a phase-III trial named SANDPIPER in combination with fulvestrant. This combination, he hopes, will improve specificity and reduce toxicity for breast cancer patients. AKT inhibitors were another treatment option discussed, as monotherapy or in combination with immunotherapy, which is where many see personalised therapy as offering the most promise.

The first plenary session opened with a theme that defined the rest of the day: innovation in clinical trial design. The first two presentations came courtesy of Dr Laura Esserman (University of California San Francisco, USA) and Dr Donald A. Berry (MD Anderson Cancer Center, Houston, TX, USA), two of the leads behind the I-SPY2 trial for breast cancer. I-SPY2 is notable for its adaptive randomisation technique and 12 experimental arms.
Berry built on this trial format in setting out how he sees the course of trial design evolving to match pace with new understandings of cancer biology; progression from ‘learning’ in adaptive phase-I studies to ‘confirming’ in phase II ought to be a smooth flow, with identified markers or subtypes driving adaptiveness and with re-randomisation open to patients.

Similar thoughts were echoed by Dr J. Jack Lee (MD Anderson Center, Houston, TX, USA), who gave a mathematical twist to designs with his presentation on Bayesian adaptive designs. Much as in the I-SPY2 trial, Lee endorses moving trials of personalised therapies towards smaller, focused phase-III trials from adaptive arms. Given the very nature of personalised medicine, the scale and rigidity of traditional trials recruiting thousands of patients seems ill matched to countering a continually evolving disease.

These aspects of cancer were characterised by Dr Razelle Kurzrock (University of California, San Diego Moores Cancer Center, USA) as ‘malignant snowflakes’, each metastatic tumour being unique and requiring equally nimble therapy combinations to match. Taking example from new paradigms in treating CML, Dr Kurzrock advocated being ready to bring treatments to earlier stages in the course of disease development, edging up towards the cytotoxic combinations discussed on day 2 by Prof René Bernards.

Much of the hopes and guidance Dr Kurzrock had previously outlined were discussed further in the subsequent debate session on trends in clinical trial design. Here, she clearly articulated a counter to concerns of personalised therapies disappearing into a rabbit hole of subtyping when treating disease—of course patients are individuals, but the strategy applies to all of them. Drafting a global strategy suitable for differing healthcare providers proved further contentious, with concerns of next-generation sequencing used post hoc as an expensive confirmation of disease relapse. For others concerned about the costs in terms of economic and human outcomes, the long game of disease management remained a priority.

Immunotherapy, of course, is proving effective in treating solid tumours, with PD1 antibodies rarely out of the headlines since their success and subsequent approval for first-line treatment of metastatic NSCLC from ESMO 2016. So, when Dr Patrice Denèfle (Institute Roche for Research & Translational Medicine, France) opened proceedings of the second plenary session, it is with little surprise that he highlighted immune-based combinations and new tactics in his talk on integrating data into drug and biomarker discovery. Beyond pointing out that there are over 800 ongoing immunotherapy combination trials, volume and scale were key points in Dr Denèfles’ presentation.

He spoke of raising a T-cell army with tumour vaccines, of one target in therapy being not enough in treatment regimens, of too much information being generated from genome networks for any single brain too hold. Solutions to these challenges being at the core of the WIN consortium’s mission—combined therapies and open, integrated genomic databases, has Dr Denèfle preaching to the choir. The onus is now on the audience to, as Denefle says, ‘Do now what patients need next’.

On the subject of what comes next, the field of personalised oncology would be loath to rest on its laurels. Sign posts for research, which may come to take the world by storm could be found across the rest of the session, with Dr Geneviève Almouzni (Institut Curie, France) outlining the steps in replication regulation that might open treatment pathways through their cellular chaperones, histone variants which function as ‘architects of chromatin organisation’, and epigenetic changes in patients, down to their non-coding RNA. The path she wove from chromatin as a functional molecule in space and time to impacts on signalling and epigenetic expression illustrated the shifting backdrop of a living human cell with fascinating mechanistic insights, even without the context of wider roles in tissues and organs. If, as Dr Almouzni promised, epigenetics is to be most active area of drug development, the simple approach to personalised therapy of treating mutations found in a patient’s tumour may have to take on new layers of complexity.

Similarly, Dr Giorgio Massimini (Merck KgaA, Germany) reported a hot topic in cancer drug design—the DNA damage-response pathway. With new components showing promise as druggable targets, and a growing catalogue of success in prostate and ovarian cancer with olaparib PARP inhibition, Dr Massimini’s view from the helm of phase-I trials for ATR kinase inhibitors as monotherapies and in combination is a welcome addition to a growing arsenal.

The third plenary session, immunological approach to personalised medicine, tapped in to the aforementioned triumphs of immune modulatory agents and outlines ongoing work to anchor that success in new trials. Unsurprisingly combinations come to the fore, as in Prof Antoni Ribas’ (University of California Los Angeles, USA) talk on new biomarkers for response to immunotherapy. With ongoing discussions of the use of surrogate biomarkers, the utility of liquid biopsy for sample collection, and Prof Ribas’ proposed combinations of BRAF, MEK and anti-PD1 therapy for melanoma, there seems little room for any tumour cells escaping.

This total encapsulation of tumour biology and behavior was only furthered by Dr Roy Baynes (MSD, USA), who also examined the enrolment of patients and architecture of collaborative research groups. In his session on histology-agnostic development of immune oncology agents, Dr Baynes reported on the immunogenic potential of cancer cells with hampered DNA damage repair, as identified via microsatellite instability assays, meaning patients may be suitable for pembrolizumab monotherapy and enrolment in combination trials. In regards to challenges faced in enrolling patients to multihistology enrichment basket studies, Dr Baynes noted a barrier to patient enrolment of diagnostic test positivity was a requirement, as was the enrolment of a ‘reasonable numbers’ of patients. This dovetailed neatly into the earlier debates of clinical trial construction, with some favouring the smaller, nimble adaptive trials, as did Dr Baynes’ position that cancer centres may do well to organise clinics not by tumour type, but by biomarker status in the future.

Patients and positivity remained centre stage with the last presenter of this session, Dr Steve Anderson (COVANCE, USA), who took the baton of patient enrolment and spoke on the challenges of stratifying patients for immunotherapy. Within the context of research conducted at COVANCE as a clinical research organisation, Dr Anderson highlighted many of the biomarkers for target and response identified by Prof Ribas, above, including neo-antigen burden, genomic instability and markers down to a patient’s history of infection in their virome as means for sorting and strategising patient approaches when treating with immune therapies.

Looking back at Dr Mendelsohn’s wish list from the morning, you would be hard pressed to find any deeper integration of biomarker data.

Personalised medicine does not all take place at the microlevel though, with the patient and their well-being existing in much larger scale. Prof Guido Kroemer’s (Gustave Roussy, France) presentation took macro-level treatment of disease very much to heart (or rather stomach) as he gave fascinating insights into apoptotic pathways that can influence treatment response. Chief among these was the impact of fasting states on immune-independent autophagy, which could be mimicked with protein deacytelating cis-regulatory molecules. Proofs of concept here came by examining the changes in metabolomes of mouse models and human volunteers, including Prof Kroemer himself.

The final presentation of Monday returned to the molecular level but offered a promise of population wide delivery of personalised therapies as Prof Hans-Georg Rammensee (University of Tübingen, Germany) spoke about patient-specific peptide vaccines. Delving again into the proteome, Rammensee began with identifying tumour specific antigens, cancer-bound peptides believed to be highly immunogenic but often sequestered, which may attract and bind to circulating T cells. This ligandome, as he describes it, may hold the key to designing personal cancer vaccines, tailored on a patient-to-patient basis to make the most of detected mutations and amplify immune responses, with a turnaround of weeks from initial tumour resection. Between the use of adjuvant therapies and immune-modulation to further prime the tumour microenvironment and sharpen the senses of circulating T cells, it might almost be all of Dr Mendelsohn’s dreams come true at once. Anchoring this potential to proven clinical results and achieving regulatory approval remains a step in need of taking, but if ever there was an audience able to take up that challenge, a WIN symposium would be where to find them.

The next hour was given over to a second debate considering the place of immunotherapy approaches in precision cancer care.

Beginning with one of the major stories from recent months, the first topic for debate was the difference in reported outcomes for pembrolizumab versus nivolumab in lung cancer, with pembrolizumab approved for first-line treatment, whereas nivolumab (submitted for approval in a broader patient population) was not. Antoni Ribas, one of the debate moderators, noted the potential for observation bias in non-responding patients being potentially hyper-progressors and emphasised that understanding non-response is as important as pursuing patients who do respond.

The conversation then turned to one of construction, considering the different forms of antibodies and whether their design, inclusive of an FC region or not, may affect clinical performance and macrophage interference. The comparison was made of avelumab, a monoclonal antibody with an FC region to bind IgG1, compared to atezolizumab and durvalumab, which lack such activity. Of all these PD-L1-targeted therapies, avelumab seems to be the most well tolerated, most specific, and yield the most durable response [1], so FC incorporation may be key to future therapy structures.

Future therapies are where the conversation, inevitably, turned. The consortium’s focus on combination therapies surfaced again, with discussion on inter-company co-operation in testing and trial design, though, as the moderators were sure to point out, those clinical trials will require pre-clinical evidence of treatment schedule, dosing, and use in a humanised model. A counterpoint was made to take the previously suggested modifications to trial execution forward to the earliest stages—generate a small trial for the agent or combination in question, sequence patient samples before, during and after to observe responses and figure out what worked where, for whom, and why, in a post hoc fashion. Such investigative biology, for lack of a better term, would require radical changes in treatment and trial design, regulation, interpretation and incorporation into wider health strategy.

Special thanks were given to the winners for best poster presentation, Vivek Subbiah (MD Anderson Cancer Center, Houston, TX, USA) for his research on combining vandetanib and everolimus in RET-rearranged lung cancer, and Prof Ui-Soon Koon (University of Hong Kong, Hong Kong) for her investigation of a biomarker for tamoxifen-resistant breast cancer.

Sessions resumed the following morning with the 4th plenary topic of ‘Next great steps in cancer therapy’, and a return to the omic-focused content that could well define this conference, and the future of oncology. First, Olli Kallioniemi (Karolinska Institutet, Stockholm, Sweden) discussed novel models for personalising cancer therapies and delivering once again on Mendelsohn’s wish of using genomic data as guidance in trials. Pointing to the comparative ease of liquid biopsy to guide treatment choices in leukaemia, he highlighted the success of axitinib to treat relapse BCR Abl disease after the onset of resistance.

However, heightened mutational understanding of acute myeloid leukaemia has not been matched by increased survival prospects, leading Kallioniemi to introduce his Individual Systems Medicine. The flow of data here is simple; from sample gathering through sensitivity testing, biobanking and profiling down to the signalome, to generate results that are acted on in treatment or trial selection, during which further samples are gathered. To prove the point further, he illustrated the sequencing data from patients, which has revealed expected, and unexpected, clustering of treatment efficacies. Drugs of the same families offered predictable synergy, but sequencing of select patients data revealed vulnerabilities to combinations, which have not yet been clinically assessed in larger populations.

So ought these patients be eligible for exploratory treatments with a novel combination as an n-of-1 trial? As the debate panel from Monday noted, hurdles in approval, regulation and reimbursement of such a scheme persist.

Speaking of which, Henry Rodriguez (National Cancer Institute, USA) took the stage next to offer a summary of the CPTAC programs of the National Institute of Health, which have so far seen ~2000 users accessing almost 300TB of proteogenomics data, in a completely open and free fashion. Rodriguez also introduced the APOLLO program (apparently named independently of the Beau Biden Moonshot Initiative) to routinely sequence patients and screen for targeted therapy opportunities. Between the global collaboration, open data and integration of genomic screening into therapy selection, Dr Mendelsohn must be very happy to have had so many items on his opening wish list addressed by the end of the same symposium.

Sequencing and selection of therapy was similarly discussed by Peter Lichter (DKFZ, Germany), with a focus on targeting mutations in the Sonic Hedgehog gene family, which he has found to be driving paediatric medulloblastomas, with Smoothin inhibitors, and using algorithmic assessments of disease predisposition. Among medulloblastoma subgroups, he also noted the chance of enhancer hijacking, in which a tumourigenic gene alteration is translocated to be downstream of enhancement regions, causing significant acceleration of disease. Current research is at the level of animal models to determine site-specific inhibition for these cases, but the future patients afflicted by these rarer aggressive subtypes is looking brighter already.

Stefan Fröhling (DKFZ, Germany) gave further insight, relating the design and initial outcomes of the NCT MASTER platform (Molecularly Aided Stratification for Tumour Eradication Research). Again, sample processing led to genome and RNA sequencing led to analysis and evaluation, eventually sorting patients into different intervention groups. This then funnels into the INFORM group for paediatric patients, discussed by Stefan Pfister later, and the MASTER MATCH groups for rare adult tumours.

Martine Piccart (Institute Jules Bordet, Belgium), next to speak, gave a comprehensive review of past and current work to determine biomarkers for breast cancer, opening with a summary of the APHINITY trial that ‘we won’t do better for HER2 disease’. So, given the tremendous improvement in survival curves over the last 15 years, she talked instead of damage control and reduction, highlighting the CLEOPATRA trial of added docetaxel as improving progression free survival, and the PANACEA trial now bringing PD1 antibodies into play. Another novel combination comes in the form of the ZEPHIR trial, utilising zircon-labelled trastuzumab with PET/CT scanning to pre-emptively screen for patients unlikely to benefit from further trastuzumab emtansine. In her overview, Piccart repeatedly emphasised the view of patients at the heart of trials and treatment regimens—‘Patients don’t want pathologic complete responses, they want to be alive. Complete responses can relapse’. She also noted that, for efforts in staging treatments as neo-adjuvant or adjuvant interventions, ‘In neoadjuvant, we have markers. None have shown predictive use in adjuvant settings’. What we are left with then is not precision medicine, she said, but stratified choices; making sure that any patient gets their best treatment.

The next two speakers gave alternate views on the development and application of personalised therapies: Dr Jean-François Martini (Pfizer Inc., USA) presented the industry view of attempting to discern and design drugs against clinically relevant biomarkers, including the development of S-Trac assay for sunitinib, but it was the work of Vanessa Michelini (IBM Watson Health, USA) that caught the attention and imagination of the audience. IBM Watson Health is subset of the broader IBM Watson framework, in which databases are fed thousands of research papers, building a vast library of interconnected data. When presented with a patient’s biomarker profile, Watson Health returns a suggested course of treatment, based on literature available. The obvious hyperbole of computers replacing doctors was quickly dismissed, though the platform’s 90% concordance with physician’s choices for treating breast cancer, as presented at the San Antonio Breast Cancer Symposium in 2016 [2], was touted as a promising indicator for a future in which a quorum of options and opinions can quickly give a treatment of best fit. Given the wealth of genomic data currently being generated, and conference attendees’ clearly stated goals of adding further depth and breadth of information captured, such a platform seems to be the only way to handle the challenge.

The last presentation of the fifth plenary session came courtesy of Prof Caroline Robert (Institut Gustave Roussy, Paris, France), touching on two conference themes in her research on combination therapies with an immune-based component. In this case, the combination was with tyrosine kinase inhibitors to treat melanoma. Checkpoint therapies and BRAF/MEK-targeted therapies have shown tremendous gains for patient survival and recovery in isolation, and Prof Robert related results from pre-clinical trials on novel combination schedules to stay one step ahead of resistance development. As TKIs enter a new clinical generation, and those working on checkpoint inhibitors look to either broaden their targets or sharpen the edge of response curves, the prospect of both working in tandem seems an exciting one, and worth keeping a close eye on between now and WIN 2018 for trial expansion.

Prof René Bernards (NKI, the Netherlands) opened the final session with his work on selecting drug combinations based on synthetic lethality. The one-two punch theory of staggered synergy seeks to keep tumours from developing a secure niche and resistance. He made the case for treating BRAF melanomas that have acquired MEK resistance with histone deacetylases—the metabolic compensation of tumour cells leaves them uniquely susceptible to the toxic levels of reactive oxygen species generated, whereas healthy host tissue remains intact. Taking this to a more broadly applicable strategy, Prof Bernards described a possible opportunity in selectively inducing senescence in cancer cells as the opening salvo, followed by a senolytic chaser to expunge all traces of cancer regardless of any one resistance pathway. Cell culture and animal models are currently in trials and have so far shown an exciting possibility for repurposed sertraline; based on results of an experimental molecule XL413 that induces senescence in hepatocellular carcinoma cells, the Zoloft generic seems to selectively induce apoptosis. More on this as it develops.

The research of Dr Daniel F. Hayes (University of Michigan Comprehensive Cancer Center, Ann Arbor, USA) lent itself very handily to audience interests as well, focusing on the incorporation of serial liquid biopsies into trials for selection and surveillance of patients and responses. Seeing as this has been on the wish list and idealised work flow of several prior presenters, any steps towards its practical application were welcome.

Dr Reinhard Büttner (University Hospital of Cologne, Cologne, Germany) spoke further on determining vulnerabilities in tumours, in this case through the Network Genomic Medicine framework in Germany. Given his focus on lung cancer, the past years watershed success of PD1-targeted therapies cannot be avoided, and he outlined how capture-based sequencing and profiling for PD-L1 can be delivered with point-of-access pathology for rapid results. Dr Büttner also took the story of cancer development back to its beginnings—looking for germline or acquired mutations to establish risk, limiting environmental exposure, and encouraging early detection, much as in Dr Leroy Hoods P4 platform, below.

Next, Dr Stefan Pfister (DKFZ, Germany) picked up research first touched upon by Stefan Fröhling and Peter Lichter, reporting on the INFORM (INdividualised therapy For relapsed Malignancies in childhood and adolescence) program for personalised, population-based paediatric oncology. A rare cancer overall, paediatric brain tumours are most lethal in their age group, and Dr Pfister described how the sequencing of samples from children across 50 cancer centres is delivering rapid, rational targeting options and contrasts these results to standard chemotherapy. While these results were an expected expansion following Dr Pfister’s 2014 introduction of INFORM, the changing state of sequencing availability and circulating sample biopsy places them in interesting context and may serve as a useful framework for future interventions.

The final presentation of Robert G. Bristow (Princess Margaret Cancer Centre, Canada) looked at prognosis and prospects for prostate cancer patients in an age of targeted therapy. With prostate cancer still the most common malignancy in men worldwide, Bristow offered new insights into the genomic hallmarks of different disease types. He described the genomic rearrangements separating metastatic castration-resistant prostate cancer from sporadic disease, and a characteristic methylome. Bristow went on to introduce the concept of a ‘nimbosus’ in prostate cancer cells—a gathering of intraductal carcinoma cells with cribiform architecture (IDC/CA ) associated with genomic instability, metastatic spread and high lethality. Between these and BRCA/Wnt-mutant cells posing a challenge requiring intensive therapies, he advised finding treatment targets outside of the shifting sea of mutational targets for comparatively simple tumours. As for what shape those targets take, there remain many other -omics yet to explore.

Those thoughts led neatly to the last discussion session of the symposium, a roundtable session considering the challenges of implementing precision medicine and what that means for other diseases. Already, the FDA has approved ivacaftor as a precision medicine for cystic fibrosis [3].
Participants in this session provided a broad-ranging discussion of the challenges in implementation of cancer precision medicine with a focus on identifying treatment combinations likely to be uniquely effective in individual patients and strategies to manage the high cost of cancer care that is likely to be further exacerbated with the use of expensive drugs in combination.
With the concluding remarks of Leroy Hood (Institute for Systems Biology, USA) again exhorting P4 systems medicine and scientific wellness, a long-view attitude to health that comes somewhere between sociology and engineering in which a healthy lifestyle with regular omni-omic surveillance can reveal cancer precursors long before a patient would normally seek treatment, the symposium drew to a close. Where last year’s conference looked to a future of immunotherapy and combinations, this year saw Dr Mendelsohn’s opening wish list met with ready answers and expansion in mind. The future is coming, fast. Ready or not.

Will Davies
Cancer Intelligence, 13 King Square Avenue, Bristol, BS2 8HU, UK
Email: will@ecancer.org
FDA Allows WIN Consortium to Proceed with Targeted Tri-Therapy Clinical Trial in First Line Treatment of Metastatic Non Small Cell Lung Cancer
Wednesday, August 09, 2017

VILLEJUIF, France--(BUSINESS WIRE)-- WIN Consortium (WIN) received the US Food and Drug Administration (FDA)’s approval to start the clinical investigation of a novel therapeutic approach using a combination of three targeted therapies for the first line treatment of patients with advanced Non Small Cell Lung Cancer (NSCLC). The Survival Prolongation by Rationale Innovative Genomics (SPRING) trial will aim to enroll patients who are usually offered first line platinum-based chemotherapy. Patients with documented targetable driver alterations (EGFR mutations, ALK rearrangements, ROS1 and MET exon 14 skipping mutations) will be excluded. The population of NSCLC patients without actionable oncogenic driver mutations, envisioned for the enrollment in SPRING trial, represents the vast majority of patients with metastatic NSCLC (~80% in the Caucasian population).

With over 60% of NSCLC detected in an advanced or metastatic stage, and less than 5% of patients alive at 5 years, a paradigm changing strategy for treating the deadliest cancer is needed. WIN’s novel approach is based on the utilization of the tri-therapy combination of targeted drugs, following the historical success of this approach in AIDS and tuberculosis. Similarly, our concept relies on the association of three targeted drugs that used in combination are expected to be highly potent, whereas used alone in monotherapy they produce only modest clinical outcome.

"Nevertheless, it is important to acknowledge a significant difference between cancer and AIDS which lies in the higher biological complexity and heterogeneity of cancer compared to AIDS. In AIDS, one tri-therapy combination is effective for a majority of patients, whereas in cancer it is expected that many combinations will be needed to treat all patients effectively. WIN Consortium has developed new technologies for tailoring combinations for each individual patient" said Dr. John Mendelsohn, Chairman of WIN. "WIN’s trial, entitled SPRING, is therefore a first proof of concept of this novel approach in the treatment of lung cancer, and will test as a first combination three drugs from WIN’s big pharma members, Merck’s Avelumab combined with Pfizer’s Palbociclib and Axitinib" added Dr. Mendelsohn.

SPRING’s investigator initiated research will be led by Dr. Razelle Kurzrock (University of California San Diego, Moores Cancer Center) and co-led by Dr. Enriqueta Felip (Vall d'Hebron Institute of Oncology) and is planned to be launched in 5 countries and 8 WIN member sites: University of California San Diego Moores Cancer Center and Avera Cancer Institute (Dr. Benjamin Solomon), USA; Institut Curie (Dr. Nicolas Girard), Centre Léon Bérard (Dr. Pierre Saintigny) and Hôpital Paris Saint-Joseph (Dr. Eric Raymond), France; Vall d'Hebron Institute of Oncology, Spain; Centre Hospitalier de Luxembourg (Dr. Guy Berchem); and Chaim Sheba Medical Center (Dr. Jair Bar), Israel.

The SPRING trial will start with a Phase I portion to explore the safety of the combination and determine the optimal doses for the Phase II that will explore the efficacy of this tri-therapy regimen in first line treatment of metastatic NSCLC. The trial will also aim to validate a novel algorithm SIMS (Simplified Interventional Mapping System) developed by WIN and designed to match each patient’s tumor biology to a specific drug combination. For this purpose, both tumor and normal lung tissue biopsies will be obtained and explored in the SPRING trial. DNA and RNA analysis will be performed by Dr. Brandon Young at Avera WIN Precision Oncology Laboratory in San Marcos, California on biopsies using, respectively, Illumina NGS (next generation sequencing) and HTG Molecular’s expression (mRNA and microRNA) EdgeSeq technology used in conjuction with Illumina (NGS). Data integration for the SIMS algorithm will be performed by Ben-Gurion University of the Negev (Dr. Eitan Rubin), Israel.

"It is an unprecedented cooperation between our WIN members from academia, industry and research organizations" said Dr. Vladimir Lazar, WIN Chief Scientific and Operating Officer. "Eight clinical sites will activate the study, drugs will be provided by Pfizer Inc., DNA and RNA analysis technologies by Illumina and HTG Molecular and pharmacovigilance by Covance. In particular, we are grateful to Foundation ARC on cancer research in France for financial support to initiate the SPRING trial. We are welcoming the support of any other organization or private donors, wishing to join this unique global effort dedicated to lung cancer patients" added Dr. Lazar.

"It is very exciting to see this endeavor becoming more concrete and this unprecedented cooperation materializing. We are looking forward to the activation of our clinical sites. We will need more combinations to be launched rapidly and other pharma companies to join us in this effort", said Dr. Razelle Kurzrock, trial global coordinator, and Head of WIN Clinical Trials Committee. "WIN has the potential and expertise to test other combinations and has the technologies needed to match patients’ tumor biology profile with the appropriate combination”.

About WIN Consortium
WIN Consortium is a French based non-profit network of 41 world-class academic medical centers, industries (pharmaceutical and diagnostic companies), health payer, research organizations and foundation and patient advocates spanning 17 countries and 4 continents, aligned to deliver now the progress in cancer treatment that is awaited by so many patients and families around the world.

For further information, please visit www.winconsortium.org.

WIN Consortium
Catherine Bresson:
Director Operational Team
Vladimir Lazar, Tel: +33661091522
Chief Scientific and Operating Officer