# Worldwide Innovative Network (WIN) Consortium in Personalized Cancer Medicine: Bringing next-generation precision oncology to patients

Wafik S El-Deiry, Catherine Bresson, Fanny Wunder, Benedito A Carneiro, Don S Dizon, Jeremy L Warner, Stephanie L Graff, Christopher G Azzoli, Eric T Wong, Liang Cheng, et al.

► To cite this version:

Wafik S El-Deiry, Catherine Bresson, Fanny Wunder, Benedito A Carneiro, Don S Dizon, et al. Worldwide Innovative Network (WIN) Consortium in Personalized Cancer Medicine: Bringing next-generation precision oncology to patients. Oncotarget, 2025. hal-05022607

HAL Id: hal-05022607

https://hal.science/hal-05022607v1

Submitted on 7 Apr 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Worldwide Innovative Network (WIN) Consortium in Personalized Cancer Medicine: Bringing next-generation precision oncology to patients

Wafik S. El-Deiry<sup>1,2</sup>, Catherine Bresson<sup>1</sup>, Fanny Wunder<sup>1</sup>, Benedito A. Carneiro<sup>2</sup>, Don S. Dizon<sup>2</sup>, Jeremy L. Warner<sup>2</sup>, Stephanie L. Graff<sup>2</sup>, Christopher G. Azzoli<sup>2</sup>, Eric T. Wong<sup>2</sup>, Liang Cheng<sup>2</sup>, Sendurai A. Mani<sup>2</sup>, Howard P. Safran<sup>2</sup>, Casey Williams<sup>3</sup>, Tobias Meissner<sup>3</sup>, Benjamin Solomon<sup>3</sup>, Eitan Rubin<sup>4</sup>, Angel Porgador<sup>4</sup>, Guy Berchem<sup>5,6,7</sup>, Pierre Saintigny<sup>8,9</sup>, Amir Onn<sup>10</sup>, Jair Bar<sup>10,11</sup>, Raanan Berger<sup>10</sup>, Manon Gantenbein<sup>7</sup>, Zhen Chen<sup>12</sup>, Cristiano de Pádua Souza<sup>13</sup>, Rui Manuel Vieira Reis<sup>13,14</sup>, Marina Sekacheva<sup>15</sup>, Andrés Cervantes<sup>16</sup>, William L. Dahut<sup>17</sup>, Christina M. Annunziata<sup>17</sup>, Kerri Gober<sup>17</sup>, Khaled M. Musallam<sup>18</sup>, Humaid O. Al-Shamsi<sup>18</sup>, Ibrahim Abu-Gheida<sup>18</sup>, Ramon Salazar<sup>19</sup>, Sewanti Limaye<sup>20</sup>, Adel T. Aref<sup>21</sup>, Roger R. Reddel<sup>21</sup>, Mohammed Ussama Al Homsi<sup>22</sup>, Abdul Rouf<sup>22</sup>, Said Dermime<sup>22</sup>, Jassim Al Suwaidi<sup>22</sup>, Catalin Vlad<sup>23</sup>, Rares Buiga<sup>23</sup>, Amal Al Omari<sup>24</sup>, Hikmat Abdel-Razeq<sup>24</sup>, Luis F. Oñate-Ocaña<sup>25</sup>, Finn Cilius Nielsen<sup>26</sup>, Leah Graham<sup>27</sup>, Jens Rueter<sup>27</sup>, Anthony M. Joshua<sup>28,29</sup>, Eugenia Girda<sup>30</sup>, Steven Libutti<sup>30</sup>, Gregory Riedlinger<sup>30</sup>, Mohammed E. Salem<sup>31</sup>, Carol J. Farhangfar<sup>31</sup>, Ruben A. Mesa<sup>31</sup>, Bishoy M. Faltas<sup>32</sup>, Olivier Elemento<sup>32</sup>, C.S. Pramesh<sup>33</sup>, Manju Sengar<sup>33</sup>, Satoru Aoyama<sup>34</sup>, Sadakatsu Ikeda<sup>34</sup>, Ioana Berindan-Neagoe<sup>35,36</sup>, Himabindu Gaddipati<sup>37</sup>, Mandar Kulkarni<sup>37</sup>, Elisabeth Auzias<sup>38</sup>, Maria Gerogianni<sup>38</sup>, Nicolas Wolikow<sup>38</sup>, Simon Istolainen<sup>38</sup>, Pessie Schlafrig<sup>39</sup>, Naftali Z. Frankel<sup>39</sup>, Amanda R. Ferraro<sup>40</sup>, Jim Palma<sup>41</sup>, Alejandro Piris Gimenez<sup>42</sup>, Alberto Hernando-Calvo<sup>42</sup>, Enriqueta Felip<sup>42</sup>, Apostolia M. Tsimberidou<sup>43</sup>, Roy S. Herbst<sup>44</sup>, Josep Tabernero<sup>42</sup>, Richard L. Schilsky<sup>45</sup>, Jia Liu<sup>21,28,29</sup>, Yves Lussier<sup>1,46</sup>, Jacques Raynaud<sup>1</sup>, Gerald Batist<sup>47</sup>, Shai Magidi<sup>1</sup> and Razelle Kurzrock<sup>1,48</sup>

<footnote n="1"><sup>1</sup>Worldwide Innovative Network (WIN) Association – WIN Consortium, Chevilly-Larue, France</footnote>

<footnote n="2"><sup>2</sup>Legorreta Cancer Center at Brown University, Providence, RI 02912, USA</footnote>

<footnote n="3"><sup>3</sup>Avera Cancer Institute, Sioux Falls, SD 57105, USA</footnote>

<footnote n="4"><sup>4</sup>Ben-Gurion University of the Negev, Be'er Sheva, Israel</footnote>

<footnote n="5"><sup>5</sup>Centre Hospitalier du Luxembourg, Luxembourg</footnote>

<footnote n="6"><sup>6</sup>University of Luxembourg, Esch-sur-Alzette, Luxembourg</footnote>

<footnote n="7"><sup>7</sup>Luxembourg Institute of Health, Luxembourg</footnote>

<footnote n="8"><sup>8</sup>Department of Medical Oncology, Centre Léon Bérard, Lyon, France</footnote>

<footnote n="9"><sup>9</sup>University of Lyon, Claude Bernard Lyon 1 University, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France</footnote>

<footnote n="10"><sup>10</sup>Jusidman Cancer Center, Sheba Medical Center, Ramat Gan, Israel</footnote>

<footnote n="11"><sup>11</sup>Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel</footnote>

<footnote n="12"><sup>12</sup>Fudan University Shanghai Cancer Center, Shanghai, China</footnote>

<footnote n="13"><sup>13</sup>Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil</footnote>
¹⁴Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal

¹⁵I.M Sechenov First Medical State University, Moscow, Russian Federation

¹⁶INCLIVA Instituto de Investigación Sanitaria, Valencia, Spain

¹⁷American Cancer Society, Atlanta, Georgia, MD 21742, USA

¹⁸Burjeel Medical City (BMC), Mohamed Bin Zayed City, Abu Dhabi, UAE

¹⁹Medical Oncology Department. Institut Català d'Oncologia. Oncobell Program (IDIBELL), Universitat de Barcelona (Campus Bellvitge), CIBERONC, Barcelona, Spain

²⁰Sir H.N. Reliance Foundation Hospital and Research Centre, Mumbai, India

²¹ProCan, Children's Medical Research Institute, The University of Sydney, Australia

²²National Center for Cancer Care and Research Hamad Medical Corporation, Doha, Qatar

²³Oncology Institute Ion Chiricuta, Cluj, Romania

²⁴King Hussein Cancer Center, Amman, Jordan

²⁵Instituto Nacional de Cancerología (INCan), Mexico City, Mexico

²⁶Rigshospitalet, Copenhagen, Denmark

²⁷The Jackson Laboratory, The Maine Cancer Genomics Initiative, Bar Harbor, ME 04609, USA

²⁸The Kinghorn Cancer Centre, St Vincent's Hospital, Darlinghurst, Australia

²⁹School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia

³⁰Rutgers Cancer Institute, New Brunswick, NJ 08901, USA

³¹Wake Forest University Health Sciences/Atrium Health (WFUHS), Winston-Salem, NC 27157, USA

³²Weill Cornell Medical College, NY 10065, USA

³³Tata Memorial Centre, Affiliated to Homi Bhabha National Institute, Mumbai, India

³⁴Institute of Science Tokyo Hospital, Tokyo, Japan

³⁵University of Medicine and Pharmacy Iuliu Hatieganu, Cluj, Romania

³⁶Academy of Medical Sciences, Bucharest, Romania

³⁷Vyas Cancer Research (VCR Park), Maharanipeta, Visakhpatnam, Andhra Pradesh, India

³⁸Cure51, Paris, France

³⁹CHAIM Medical Resource Organization, NY 10950, USA

⁴⁰Cancer is an A*, LLC, Manalapan Township, NJ 07726, USA

⁴¹TargetCancer Foundation, Cambridge, MA 02139, USA

⁴²Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), Barcelona, Spain

⁴³The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA

⁴⁴Yale School of Medicine, New Haven, CT 06510, USA

⁴⁵The University of Chicago, Chicago, IL 60637, USA

⁴⁶The University of Utah, Salt Lake City, UT 84112, USA

⁴⁷Segal Cancer Centre, Jewish Hospital, McGill University, Montreal, Quebec, Canada

⁴⁸Medical College of Wisconsin, Milwaukee, WI 53226, USA

**Correspondence to:** Wafik S. El-Deiry, **email:** wafik@brown.edu

**Keywords:** precision oncology; N-of-1 basket trials; AI algorithms; digital pathology; drug access

**Received:** December 30, 2024

**Accepted:** February 27, 2025

**Published:** March 12, 2025

**Copyright:** © 2025 El-Deiry et al. This is an open access article distributed under the terms of the [Creative Commons Attribution License](https://creativecommons.org/licenses/by/4.0/) (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The human genome project ushered in a genomic medicine era that was largely unimaginable three decades ago. Discoveries of druggable cancer drivers enabled biomarker-driven gene- and immune-targeted therapy and transformed cancer treatment. Minimizing treatment not expected to benefit, and toxicity—including financial and time—are important goals of modern oncology. The Worldwide Innovative Network (WIN) Consortium in Personalized Cancer Medicine founded by Drs. John Mendelsohn and Thomas Tursz provided a vision for innovation, collaboration and global impact in precision oncology. Through pursuit of transcriptomic signatures, artificial intelligence (AI) algorithms, global precision cancer medicine clinical trials and input from an international Molecular Tumor Board (MTB), WIN has led the way in demonstrating patient benefit from precision-therapeutics through N-of-1 molecularly-driven studies. WIN Next-Generation Precision Oncology (WINGPO) trials are being developed in the neoadjuvant, adjuvant or metastatic settings, incorporate real-world data, digital pathology, and advanced algorithms to guide MTB prioritization of therapy combinations for a diverse global population. WIN has pursued combinations that target multiple drivers/hallmarks of cancer in individual patients. WIN continues to be impactful through collaboration with industry, government, sponsors, funders, academic and community centers, patient advocates, and other stakeholders to tackle challenges including drug access, costs, regulatory barriers, and patient support. WIN's collaborative next generation of precision oncology trials will guide treatment selection for patients with advanced cancers through MTB and AI algorithms based on serial liquid and tissue biopsies and exploratory omics including transcriptomics, proteomics, metabolomics and functional precision medicine. Our vision is to accelerate the future of precision oncology care.

INTRODUCTION

Cancer is a leading cause of morbidity and mortality worldwide, with rising incidence including among younger individuals [1]. In 2022, nearly 22 million new cases of cancer were reported, along with 9.7 million cancer-related deaths [2]. Despite significant advances in cancer diagnosis and treatment, the disease remains a major public health challenge around the world. One of the key factors contributing to the complexity of cancer is its diverse molecular landscape, which can vary not only between different types of cancer but also within cancer types and even within individual tumors [3]. As a result, personalized precision approaches to cancer diagnosis and treatment have become increasingly important in recent years [4–10]. While significant strides have been made in understanding cancer biology and developing treatments, there remains a substantial need for further advances in personalized and precise approaches to cancer diagnosis and treatment [11].

Traditional cancer treatment strategies often rely on histopathological assessments and clinical parameters to guide diagnosis and therapy selection. However, the heterogeneity within and between tumors, especially those in the advanced/metastatic

state, necessitates a more nuanced understanding of each patient's unique molecular profile to optimize treatment outcomes. Recent advances in molecular biology and high-throughput technologies have enabled the generation of large-scale genomic, transcriptomic, proteomic, immunomic, and epigenomic data from cancer patients. These molecular profiling techniques have provided valuable insights into the underlying molecular mechanisms driving cancer development and progression, as well as potential therapeutic targets [12–16]. Despite the wealth of data generated by these techniques, translating this information into clinically actionable insights remains a significant challenge. This is due in part to the complexity and heterogeneity of cancer [17], as well as the limitations of existing methods for analyzing and interpreting large-scale molecular data which is usually available on a limited number of patients. There is a need for advanced computational tools and algorithms capable of integrating data from multiple sources, including omics and clinical data, as well as functional assays and response to treatment. Effectively incorporating these data sources into clinical decision-making requires sophisticated data processing approaches [18]. Leveraging artificial intelligence (AI) algorithms to integrate and analyze these diverse datasets holds immense promise for advancing personalized
cancer diagnosis and treatment [19]. Importantly, operationalizing a new generation of trials, with designs that are necessarily novel to address the wealth of new data revealed by advanced molecular technologies, is also critically important. The WIN global consortium is ready to take up the challenge by bringing the best possible Precision Oncology trial to patients.

## About WIN

The WIN consortium comprises nearly forty (and growing) academic, industry, research institutions and patient advocates across 18 countries and five continents. It was founded in 2010 in France as a unique non-profit non-governmental organization by the late Dr. John Mendelsohn (Past-President, MD Anderson Cancer Center) and Dr. Thomas Tursz (Past-Director, Gustave Roussy) with subsequent leadership by Dr. Richard L. Schilsky (Past-President and former Chief Medical Officer, ASCO) and Dr. Josep Tabernero (Director of Oncology, Vall D'Hebrón Institute of Oncology) (Figure 1).

WIN was formed on the premise that we can accomplish more together than each organization can achieve working alone and has therefore brought together stakeholders and key opinion leaders in novel precision-based approaches to improve cancer treatment on a global scale.

The WIN consortium is a nimble collaborative global non-profit organization performing complex clinical trials at multiple sites across the world that address a diversity of populations [20]. WIN's strategy has been to perform proof-of-concept cancer trials designed to explore novel strategies to improve oncology therapeutics and early diagnosis. It has to date completed several novel investigator-led precision oncology studies (including Investigational Device Exemption (IDE) [8] and Investigational New Drug (IND) [21] studies) and shared progress over 15 years at convened international precision oncology symposia and high-impact publications [8, 21-27]. WIN is guided by an expert Scientific Advisory Board (SAB) of key opinion leaders in precision cancer medicine from WIN member institutions and non-members: Prof. Yves Lussier, Chair of the SAB, University of Utah School of Medicine, USA; Dr. Stanley Hamilton, Vice-Chair of the SAB, City of Hope Medical Center, California, USA; Dr. Roy S. Herbst, Yale School of Medicine, USA; Prof. Paul Hofman, Nice Sophie Antipolis University, France; Dr. John Quackenbush, Harvard T.H Chan School of Public Health, USA; Prof. Eytan Ruppin, National Institute of Health (NIH) Bethesda, USA; Dr. Lillian Siu, Princess Margaret Hospital, Canada; Prof. Ioana Berindan-Neagoe, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj, Romania; Dr. Anton Buzdin, I.M Sechenov First Medical State University, Russian Federation; Dr. Benedito A. Carneiro, Legorreta Cancer

at Brown University, USA; Prof. Gideon Rechavi, Sheba Medical Center, Israel; Dr. Gerald Batist, Segal Cancer Centre, Jewish Hospital, McGill University, Canada.

## WIN symposia

Regular high-quality educational WIN Symposia have been organized with world leaders in cancer research and precision oncology including Nobel laureates Prof. James P. Allison (2015 and 2024) and Prof. Jennifer Doudna (2019). WIN Symposia have enabled candid discussion across a spectrum of cancer care stakeholders and continuing collaboration with partnering institutions (Figure 2). The most recent WIN Symposium Program from March 2024 (https://winconsortium.org/files/WIN_SYMPOSIUM_2024_program_book.pdf) was held in Abu Dhabi, UAE and additional information with abstracts is available in a publication [28].

## WIN Molecular Tumor Board (MTB)

The WIN consortium currently convenes the only academic international Molecular Tumor Board (MTB) chaired/co-chaired by Drs. Razelle Kurzrock (Chief Medical Officer of WIN) and Wafik S. El-Deiry (Chair of WIN) that provides in-depth multidisciplinary input into complex advanced cancer cases incorporating patient, multi-omics and treatment factors into therapeutic recommendations (Figure 3 and Table 1).

## WINTHER N-of-1 trial

WIN's landmark study is the international N-of-1 WINTHER trial funded under the European Union Seventh Framework Program (FP7/grant agreement n°306125), ARC Foundation for Cancer Research (France) and Pfizer Oncology; results were published in Nature Medicine [8]. The study opened a new era in Precision Oncology by utilizing transcriptomic in addition to genomic data, for the first time in the world, to guide N-of-1 treatment selection. The WINTHER trial also introduced for the first time the investigation of normal tissue of origin of the cancer, to make gene expression data of an individual patient more accurate and reduce noise, and an algorithm ranking drugs by predicted efficacy. While the WINTHER trial did not meet its primary end-point of a 1.5× increase in PFS2/PFS1 in 50% of the patients, the trial demonstrated a 1.3× increase in PFS2/PFS1 in 30% of the patients. The goal was perhaps too ambitious at the time given the limitations in the field including lack of availability of drugs for many drivers of cancer, and it would be expected that this could improve in the future.

Importantly, WIN demonstrated, via the WINTHER trial, the ability to operationalize and conduct an international trial, which involved five countries from North America, Europe and the Middle East, working
collaboratively [8, 29]. Unique aspects included that the trial was patient-investigator centered with the ability to get the best drugs in the right combination as determined by the WIN MTB to the patients at the right time, efficiently. Typically, pharmaceutical industry-sponsored trials are much less able to deliver precision therapy to multiple cancer drivers as they are usually working with

individual molecules. From a clinical standpoint, the study demonstrated improvements in progression-free survival (PFS) and overall survival (OS) in heavily pre-treated patients who received high matching score therapies, where matching scores were derived from the algorithm for predicting efficacy, as compared to those with lower match scores.

## A WIN Consortium | Leadership History

**John Mendelsohn**, Past President MD Anderson Cancer Center, Houston, USA

Chair, WIN 2010 - 2018

<figure><img src="image_2.png" /></figure>

**Thomas Tursz**, Past General Director Gustave Roussy, Villejuif, France

Vice-Chair, WIN 2010 - 2012, 2016 - 2018

<figure><img src="image_3.png" /></figure>

**Alexander Eggermont**, Past General Director Gustave Roussy, Villejuif, France

Vice-Chair, WIN 2012 - 2016

<figure><img src="image_4.png" /></figure>

**Josep Tabernero**, Head Vall d'Hebron Institute of Oncology, Barcelona, Spain

Vice-Chair, WIN 2018 - 2023

<figure><img src="image_5.png" /></figure>

**Richard L.Schilsky**, Past President, former Executive VP and Chief Medical Officer, ASCO, USA

Chair, WIN 2018 - 2023

<figure><img src="image_6.png" /></figure>

**Wafik El-Deiry**, Director, Legorreta Cancer Center, Associate Dean, Oncologic Sciences, Warren Alpert Medical School, Brown University, Providence, USA

Chair, WIN 2024 -

<figure><img src="image_7.png" /></figure>

## B WIN Consortium | Leadership

<figure><img src="image_8.png" /><figcaption>**Catherine Bresson**</figcaption></figure>

Director, Operational Team, WIN Consortium

<figure><img src="image_9.png" /><figcaption>**Wafik El-Deiry**</figcaption></figure>

Chair, WIN Consortium; Director, Legorreta Cancer Center at Brown University (USA)

<figure><img src="image_10.png" /><figcaption>**Razelle Kurzrock**</figcaption></figure>

Chief Medical Officer, WIN Consortium; Prof. of Medicine, Associate Director Clinical Research, MCW Cancer Center and Linda T. & John A. Mellowes Chair of Precision Oncology (USA)

<figure><img src="image_11.png" /><figcaption>**Yves A. Lussier**</figcaption></figure>

Chairman, Scientific Advisory Board, WIN Consortium; Professor and Chair, Department of Biomedical Informatics, The University of Utah School of Medicine (USA)

<figure><img src="image_12.png" /><figcaption>**Jacques Raynaud**</figcaption></figure>

Senior adviser to WIN Strategy, Science and Fundraising, WIN Consortium

<figure><img src="image_13.png" /><figcaption>**Richard L. Schilsky**</figcaption></figure>

Chair Emeritus, WIN Consortium; Professor Emeritus, University of Chicago; past President and former Executive Vice President & Chief Medical Officer (ASCO) (USA)

<figure><img src="image_14.png" /><figcaption>**Marina Sekacheva**</figcaption></figure>

Head of the Membership Committee, WIN Consortium; Director of Personalized Oncology Institute, I.M. Sechenov First Moscow State Medical University, Sechenov University (Russia)

<caption>**Figure 1:** History and Leadership of WIN Consortium in 2024. (A) Leadership History of WIN Consortium, (B) Current WIN Consortium leadership.</caption>
Under the current leadership of its new Chair since election in December of 2023, Prof. Wafik S. El-Deiry, MD, PhD, FACP, WIN is growing globally and engaging with the cancer research and oncology communities in a collaborative manner throughout the world to expand the

global footprint of the organization and offer diversity of patients for future clinical trials. Building upon the WINTHER trial [8], deployment of novel algorithms for interpreting genomic and transcriptomic results have been developed by the group [22, 23] and ongoing efforts to

A

<table><thead><tr><th>Timings</th><th>Friday, 1st March 2024</th></tr></thead><tbody><tr><td>GST / UAE</td><td>08.30-09.00 Registration & Welcome Break</td></tr><tr><td colspan="2">Session 1: Grand Opening</td></tr><tr><td>09.00-09.50 Cancer Care and Research in the UAE</td><td>Prof. Humaid Al-Shamsi (Burjeel Holdings, UAE)</td></tr><tr><td>09.30-10.00 WIN Consortium: Past, Present, Future</td><td>Prof. Razelle Kurzrock (WIN Consortium/MCW Cancer Center, USA)<br>Prof. Wafik El-Deiry (WIN Consortium/Brown University, USA)</td></tr><tr><td>10.00-10.45 Opening Ceremony</td><td></td></tr><tr><td>10.45-11.15 Keynote Lecture - Immune Checkpoint Blockade in Cancer Therapy: New Insight into Mechanisms of anti-CTLA-4, anti-PD-1, and Combination</td><td>Prof. James Allison (Nobel Laureate, MD Anderson Cancer Center, USA)</td></tr><tr><td>11.15-11.45 Coffee Break, Exhibition Visit, Poster Viewing</td><td></td></tr><tr><td colspan="2">Session 2: Precision Genomics: From Bench to Bedside</td></tr><tr><td colspan="2">Chairpersons: Prof. Garth Powls (PHUS, USA), Prof. Wafik El-Deiry (WIN Consortium/Brown University, USA)</td></tr><tr><td>11.45-12.10 A Visionary Odyssey Beyond Boundaries: The Evolution of Tumor-Agnostic Drug Development in Precision Medicine</td><td>Dr. Vivek Subbiah (Sarah Cannon Research Institute, USA)</td></tr><tr><td>12.10-12.35 Therapeutic Targeting of EMT and Tumor Plasticity</td><td>Prof. Sendurai Mani (Brown University, USA)</td></tr><tr><td>12.35-13.00 Role of Liquid Biopsy in Targeted Therapy</td><td>Dr. Hatim Husain (UC San Diego, USA)</td></tr><tr><td>13.00-13.15 The Emirati Genome Program: A National Enabler of Precision Medicine</td><td>Dr. Mohamed Al Ameri (Department of Health Abu Dhabi, UAE)</td></tr><tr><td>13.15-13.30 Roadmap for Precision Genomics in Routine Cancer Care in the UAE</td><td>Prof. Faisal Khan (OncoHelix, Canada & col.AB, Burjeel Holdings, UAE)</td></tr><tr><td>13.30-13.40 Q&A</td><td></td></tr><tr><td>13.40-14.40 Lunch Break, Exhibition Visit, Poster Viewing</td><td></td></tr><tr><td colspan="2">Session 3: Precision Immunotherapy: The Next 5 Years</td></tr><tr><td colspan="2">Chairpersons: Prof. James Allison (MD Anderson Cancer Center, USA), Prof. Padmanee Sharma (MD Anderson Cancer Center, USA)</td></tr><tr><td>14.40-15.05 Integrating Clinical and Laboratory Research to Identify Mechanisms of Response and Resistance to Immune Checkpoint Therapy</td><td>Prof. Padmanee Sharma (MD Anderson Cancer Center, USA)</td></tr><tr><td>15.05-15.30 Role of Liquid Biopsy in Immunotherapy</td><td>Prof. Christian Rollo (Cahn School of Medicine at Mount Sinai and International Society of Liquid Biopsy (ISLB), USA)</td></tr><tr><td>15.30-15.55 Transcriptomics at WIN: Opening the Multi-omic Era</td><td>Dr. Vladimir Lazar (WIN Consortium, France)</td></tr><tr><td>15.55-16.10 Landscape of Immunotherapy in the UAE</td><td>Dr. Hassan Jaafar (Burjeel Medical City, UAE)</td></tr><tr><td>16.10-16.20 Q&A</td><td></td></tr><tr><td>16.20-16.35 Coffee Break, Exhibition Visit, Poster Viewing</td><td></td></tr><tr><td colspan="2">Session 4: Precision Research</td></tr><tr><td colspan="2">Chairpersons: Prof. Humaid Al-Shamsi (Burjeel Holdings, UAE), Prof. Khaled Musalam (Burjeel Holdings, UAE)</td></tr><tr><td>16.35-16.50 Landscape of Translational Cancer Clinical Trials in the UAE</td><td>Mohamed Mostafa (PDC-CRO, UAE)</td></tr><tr><td>16.50-17.40 Oral Abstracts and Awards</td><td></td></tr><tr><td>17.40-17.45 Day 1 Closing Remarks</td><td></td></tr></tbody></table>

<table><thead><tr><th>Timings</th><th>Saturday, 2nd March 2024</th></tr></thead><tbody><tr><td>GST / UAE</td><td>08.30-09.00 Registration & Welcome Break</td></tr><tr><td colspan="2">Session 5: Molecular Tumor Board</td></tr><tr><td colspan="2">Chairpersons: Prof. Razelle Kurzrock (WIN Consortium/MCW Cancer Center, USA), Prof. Wafik El-Deiry (WIN Consortium / Brown University, USA)</td></tr><tr><td>09.00-10.15 Interactive Session with Cases from the UAE</td><td></td></tr><tr><td colspan="2">Session 6: Radiation Oncology in Precision Medicine</td></tr><tr><td colspan="2">Chairpersons: Dr. Ibrahim Abu-Gheida (Burjeel Medical City, UAE), Dr. Shahin Fattahi (Burjeel Medical City, UAE)</td></tr><tr><td>10.15-10.40 A Genomic Adjusted Radiation Dosing Paradigm to Biologically Personalize Radiation Therapy</td><td>Dr. Jacob Scott (Cleveland Clinic, USA)</td></tr><tr><td>10.40-11.05 Radiotherapy as Immunotherapy for Cancer</td><td>Prof. Silvia Formanti (Well Cornell Medicine, USA)</td></tr><tr><td>11.05-11.15 Q&A</td><td></td></tr><tr><td>11.15-11.30 Coffee Break, Exhibition Visit, Poster Viewing</td><td></td></tr><tr><td colspan="2">Session 7: Precision Communityomics</td></tr><tr><td colspan="2">Chairpersons: Prof. Razelle Kurzrock (WIN Consortium/MCW Cancer Center, USA), Prof. Don Dizon (Brown University, USA)</td></tr><tr><td>11.30-11.55 Diversity and Equity in Precision Oncology</td><td>Prof. Don Dizon (Brown University, USA)</td></tr><tr><td>11.55-12.20 Tools for Precision Communityomics</td><td>Dr. Katherine Tossas (Virginia Commonwealth University, USA)</td></tr><tr><td>12.20-12.30 Q&A</td><td></td></tr><tr><td colspan="2">Session 8: Precision Diagnostics</td></tr><tr><td colspan="2">Chairpersons: Dr. Alison Finall (Burjeel Medical City, UAE), Dr. Pinaki Bose (OncoHelix, Canada & col.AB, Burjeel Holdings, UAE)</td></tr><tr><td>12.30-13.25 Industry Panel Discussion</td><td>Prof. Christian Rollo (Cahn School of Medicine at Mount Sinai and International Society of Liquid Biopsy (ISLB), USA)<br>Dr. Hatim Husain (UC San Diego, USA)<br>Dr. Helmy Eltouky (Guardant Health, USA)<br>Dr. Jason Hipp (Mayo Clinic, USA)<br>Dr. Justin Gunnay Tempus A (IL, USA)</td></tr><tr><td>13.25-13.30 Day 2 Closing Remarks</td><td>Chairpersons</td></tr><tr><td>13.30-14.30 Lunch Break</td><td></td></tr><tr><td colspan="2">Industry Satellite Symposia</td></tr><tr><td>14.30-16.00 Industry Symposia</td><td></td></tr></tbody></table>

B

<figure><img src="image_15.png" /><figcaption>**Figure 2:** March 2024 WIN symposium held in Abu Dhabi, UAE. (A) Scientific program, (B) selected photos of the March 2024 WIN Symposium held in Abu Dhabi, UAE. The WIN Symposia brings together an international faculty focused on precision oncology. In addition to the official Symposium events, several social and cultural experiences were enjoyed by participants. The interactions among leaders in the field foster new collaborations around the world.</figcaption></figure>
<figure><img src="image_16.png" /></figure>

<figure><img src="image_17.png" /><figcaption>**Figure 3:** The WIN Consortium has an active international molecular tumor board (MTB). (A) with input from experts from all over the world, making this an international effort. (B) WIN's MTB convenes virtually as well as during WIN Symposia (including in Barcelona, 2022 and Abu Dhabi, 2024) and reviews complex cases with molecular profiles to discuss the best personalized therapy for each patient. All cases are discussed after patients provide written informed consent that includes the sharing of deidentified data among WIN members and that allows publication. In 2024, several patients chose to attend the MTB and heard and/or participated in the discussion. Over the past year, the MTB has held more than 20 discussions, covering cases involving colorectal cancer, glioblastoma, rectal cancer, lung cancer, lymphoma, breast cancer, skin cancer, and CNS.</figcaption></figure>
<table><caption>Table 1: The WIN Consortium international molecular tumor board (MTB) leadership</caption><tr><td>Chair</td><td>Dr. R. Kurzrock</td><td>WIN Consortium, France<br>Medical College of Wisconsin, USA</td></tr><tr><td>Co-chair</td><td>Prof. W. S. El-Deiry</td><td>WIN Consortium, France<br>Legorreta Cancer Center at Brown University, USA</td></tr><tr><td>Co-chair</td><td>Prof. S. Ikeda</td><td>Institute of Science Tokyo Hospital, Japan</td></tr><tr><td>Co-chair</td><td>Prof. R. Berger</td><td>Sheba Medical Center, Israel</td></tr><tr><td>Co-Chair<br>Co-Moderator for Experimental<br>Therapeutics</td><td>Dr. S. Limaye</td><td>Sir HN Reliance Foundation Hospital and Research<br>Centre, India</td></tr><tr><td>Co-Moderator for Early-Phase Trials</td><td>Dr. B. Carneiro</td><td></td></tr><tr><td>Co-Moderator for Melanoma</td><td>Dr. M. Hadfield</td><td></td></tr><tr><td>Co-Moderator for Breast Cancer</td><td>Dr. S. L. Graff</td><td>Legorreta Cancer Center at Brown University, USA</td></tr><tr><td>Co-Moderator for Gynaecology Oncology</td><td>Prof. D.S. Dizon</td><td></td></tr><tr><td>Co-Moderator for Lung Cancer</td><td>Dr. C. G. Azzoli</td><td></td></tr><tr><td>Co-Moderator for Molecular Pathology</td><td>Dr. L. Cheng</td><td></td></tr><tr><td>Co-Moderator for Radiation Oncology</td><td>Dr. I. Abu-Gheida</td><td>Burjeel Medical City, UAE</td></tr><tr><td>Community Co-Moderator</td><td>Dr. J. Rueter</td><td>The Jackson Laboratory, Maine CGI, USA</td></tr><tr><td>Advisor</td><td>Dr. C. Williams</td><td>Avera Cancer Institute, USA</td></tr><tr><td>Advisor</td><td>Prof. P. Saintigny</td><td>Centre Léon Bérard, France</td></tr><tr><td>Advisor</td><td>Prof. X. Hu</td><td>Fudan University Shanghai Cancer Center, China</td></tr><tr><td>Advisor</td><td>Dr. H. Abdel-Razeq</td><td>King Hussein Cancer Center, Jordan</td></tr><tr><td>Advisor</td><td>Dr. J. Liu</td><td>Kinghorn Cancer Centre, St Vincent's Hospital,<br>Australia</td></tr><tr><td>Advisor</td><td>Dr. M. Basik</td><td>Segal Cancer Center, McGill University, Canada</td></tr><tr><td>Advisor</td><td>Dr. I. Braña</td><td>Vall d'Hebron Institute of Oncology, Spain</td></tr></table>

WIN's MTB leadership is constituted by both precision oncology and disease experts to guide the discussion.

establish personalized N-of-1 precision oncology trials with a focus on combinations, enrolling globally amongst the WIN membership are underway. By the end of 2024, the WIN Consortium has added 13 new members over the past year. New members' applications consisting in a questionnaire are submitted to the approval of the WIN governance bodies. The annual membership fee level varies depending upon the member category (industry, small and medium enterprise, nonprofit organizations or academic institutions) and the size of the member for academic institutions. Members are invited to participate in governance bodies and committees including in

leadership positions upon election time (with most mandates for a two-year term). Members are encouraged to submit project proposals or participate in WIN projects but have no obligation to do so.

## WIN committees

To facilitate progress towards its mission, in 2024 WIN began establishing a number of Committees including a Data Science Committee, a Biomarkers Committee, a Regulatory Issues in Precision Oncology Committee, a Novel Agents Committee, a Publications Committee.
Committee, and several Disease Committees including Thoracic Malignancies, GI Cancer, GU Malignancies, CNS Cancer, Breast Cancer, GYN Cancer, and Rare Cancers. Additional WIN Consortium Committees at the planning stage include Radiation Oncology, Digital Pathology, Artificial Intelligence in Precision Oncology, and Functional Precision Medicine.

The Data Science Committee is discussing data platforms and harmonization, data sharing issues, the role of AI in precision oncology, grant opportunities, and guidance publications. At its meetings on June 14, 2024, and September 30, 2024, chaired by Dr. Gerald Batist at Segal Cancer Centre, the Common Database Committee as it was known at the time developed some important agenda items for future progress.

At the June 14, 2024, WIN Consortium Common Database Committee meeting (Figure 4 and Table 2), it

was acknowledged that (1) common representation of the data is important and use of a simple international standard such as OHSDI was recommended. It was also agreed that (2) data protection laws and regulations must be taken into consideration as they are also changing and becoming stricter around the world, (3) specific consent from patient is needed, outlining exactly what would be done with the data (sharing etc.), (4) data of interest includes treatment, outcome, and should be sequential, (5) liquid biopsies should be included, (6) there is need to identify gaps in data that can improve different kinds of AI models, (7) having all the data in one location is preferable in terms of computation with large datasets, (8) partnering in a noncompetitive environment would be ideal. Share how to lift technical barriers, (9) transformation between different data structures/models is very complex, costly and time consuming. However, conversion modalities from different

<figure><img src="image_18.png" /><figcaption>Figure 4: Win consortium common database committee meeting on June 14, 2024.</figcaption></figure>
<table><caption>Table 2: WIN consortium common database committee participants</caption><thead><tr><td>Participants</td><td>Institutions</td></tr></thead><tbody><tr><td>Chair: Dr. Gerald Batist</td><td>Segal Cancer Centre, Jewish Hospital, McGill University, Canada</td></tr><tr><td>Prof. Yves Lussier</td><td>The University of Utah, School of Medicine, USA</td></tr><tr><td>Dr. Tobias Meissner</td><td>Chair of WIN Consortium Scientific Advisory Board</td></tr><tr><td>Dr. Benjamin Solomon</td><td>Avera Cancer Institute, USA</td></tr><tr><td>Dr. Casey Williams</td><td>Ben-Gurion University of the Negev, Israel</td></tr><tr><td>Dr. Eitan Rubin</td><td>Brown University, USA</td></tr><tr><td>Prof. Jeremy Warner</td><td>Burjeel Medical City, UAE</td></tr><tr><td>Dr. Brenda Rubenstein</td><td>Catalan Institute of Oncology (ICO), Spain</td></tr><tr><td>Dr. Khaled Musallam</td><td>Exactis, Canada</td></tr><tr><td>Dr. Juan Martin-Liberal</td><td>Fudan University Shanghai Cancer Center, China</td></tr><tr><td>Dr. Conxi Lázaro</td><td>Fundacao Pio XII – Hospital Cancer de Barretos, Brazil</td></tr><tr><td>Dr. David Cordero Romera</td><td>I.M Sechenov First Medical State University, Russian Federation</td></tr><tr><td>Winston Wu</td><td>Kinghorn Cancer Centre, St Vincent's Hospital, Australia</td></tr><tr><td>Prof. Zhen Chen</td><td>ProCan, Children's Medical Research Institute, Australia</td></tr><tr><td>Xiaoyi Shu</td><td>Sheba Medical Center, Israel</td></tr><tr><td>Luciane Sussuchi</td><td>Sir H.N. Reliance Foundation Hospital and Research Centre, India</td></tr><tr><td>Dr. Cristiano de Pádua Souza</td><td>Tata Memorial Hospital, India</td></tr><tr><td>Dr. Marina Sekacheva</td><td>University of Medicine and Pharmacy Iuliu Hatieganu, Romania</td></tr><tr><td>Dr. Jia Liu</td><td>Vall d' Hebron Institute of Oncology, Spain</td></tr><tr><td>Dr. Anthony Joshua</td><td>Wake Forest University Health Sciences (WFUHS), USA</td></tr><tr><td>Prof. Roger Reddel</td><td>Chair, WIN Consortium, France</td></tr><tr><td>Dr. Adel Aref</td><td>Legorreta Cancer Center at Brown University, USA</td></tr><tr><td>Dr. Raanan Berger</td><td>Chief Medical Officer, WIN Consortium, France</td></tr><tr><td>Dr. Sewanti Limaye</td><td>Advisor, WIN Consortium, France</td></tr><tr><td>Dr. C.S. Pramesh</td><td>WIN Consortium, France</td></tr><tr><td>Prof. Ioana Berindan-Neagoe</td><td>WIN Consortium, France</td></tr><tr><td>Dr. Alejandro Piris</td><td>WIN Consortium, France</td></tr><tr><td>Dr. Rodrigo Dienstmann</td><td>WIN Consortium, France</td></tr><tr><td>Dr. Carol Farhangfar</td><td>WIN Consortium, France</td></tr><tr><td>Dr. Mohamed Salem</td><td>WIN Consortium, France</td></tr><tr><td>Prof. Wafik S. El-Deiry</td><td>WIN Consortium, France</td></tr><tr><td>Dr. Razelle Kurzrock</td><td>WIN Consortium, France</td></tr><tr><td>Jacques Raynaud</td><td>WIN Consortium, France</td></tr><tr><td>Catherine Bresson</td><td>WIN Consortium, France</td></tr><tr><td>Fanny Wunder</td><td>WIN Consortium, France</td></tr><tr><td>Shai Magidi</td><td>WIN Consortium, France</td></tr></tbody></table>
standards do exist (using corporate partners), (10) some
of the WIN institutions have already invested resources
to do transformation to one type of standard, (11) that
WIN would consider innovative technologies which are
exploratory and how they will be captured in our database,
and (12) there would be further discussions about what
platform WIN should work with to integrate datasets.

Other WIN Consortium Committees were established in 2024. The Biomarkers Committee is concerned with novel tissue agnostic biomarkers, biomarker platforms and technologies, opportunities with industry, and grant opportunities. The Regulatory Issues in Precision Oncology Committee is concerned with FDA guidance on N-of-1 trials, access to off-label approved drugs, reimbursement of drugs used off-label, industry support for N-of-1 trials, and funding for Precision Oncology research. The Novel Agents Committee is focused on novel cancer treatment modalities, novel drug classes, novel cancer therapy agents, novel combinations, support for early-phase Precision Oncology Trials, and grant opportunities. The Publications Committee discusses the status of current publications, plans new publications in precision oncology as well as trials WIN is involved with, and plans for meeting abstracts. A WIN Symposium Organizing Committee works with collaborators and stakeholders in planning WIN's International Symposia. WIN consortium members based in 18 different countries and 5 continents endeavour to meet during the WIN symposia. However, the regular governance and committee meetings are held under the video conference format (and were held in teleconferences prior to the video conference era). All the meetings are exclusively held in English.

## Rationale for N-of-1

Regarding combination therapies that can be
used in precision oncology, it is important to note that
the vast majority of advanced/metastatic cancers have
multiple co-drivers in a background of tumor and host
heterogeneity. With ~300 drugs in oncology, there are
~45,000 two-drug combinations and ~4.5 million three-
drug combinations; it will take thousands of years to
conduct Phase Ib combination studies across tumor types
and sub-types and even longer to perform prospective
randomized clinical trials of novel drug combinations.
As such, the N-of-1 tumor agnostic (including rare
cancers) basket trial precision oncology paradigm that
individualizes treatment, including combinations, beyond
a main driver, makes sense going into the future. Some
compelling data comes from patient advocacy groups that
deal with rare cancers in particular, in addition to 15 years
of accumulating experience from N-of-1 trials.

It is expected that in the future patients with cancer
will be optimally treated according to precision oncology
algorithms. The N-of-1 design, particularly when the
MTB's decision takes into consideration an algorithmic

matching score, aims to offer a more personalized,
precise, and data-driven treatment approach compared to
standard-of-care or physician choice alone. By tailoring
treatments to individual patient characteristics with
input from pharmacogenomics, tumor 'omics' with
incorporation of real-time feedback including functional
organoid and in vivo assays, this method has the potential
to improve treatment outcomes and effectively address the
complexities of modern oncology.

The basic premises of the N-of-1 tumor-tissue
agnostic basket trials are: (i) initial dose reduction
followed by intra-patients dose modification (i.e.,
individualized dosing) can be a safe way to administer
previously unstudied combinations of drugs [8–10]; and
(ii) one can evaluate the efficacy of the matching algorithm
(e.g., the Matching Score) that reflects the degree of
matching of drugs with the tumor, in determining efficacy,
rather than the efficacy of individual therapeutic regimens
in each tumor type [8–10].

We hope this paradigm will be understood and
embraced more by all stakeholders including both industry
and regulatory bodies. Indeed, N-of-1 basket trials can
produce information on drug synergies and regimens
active in individual patients efficiently. There may be
similar patients that can be found and whose outcomes
can be evaluated via large-scale interrogation of millions
of computerized electronic medical records. Existing
approved drugs used in combinations are the lowest
hanging fruit for novel combination regimens as has been
demonstrated by trials such as WINTHER [8], SPRING
[21], and I-PREDICT [9, 10].

In 2024, the NCI has an innovative ComboMatch
Trial that combines targeted agents with chemotherapy
or other standard-of-care therapy. This is different from
what WIN is pursuing as far as combinations of multiple
agents that are individually tailored by the WIN MTB to
the patients' omics and AI analyses. The WIN Consortium
views this N-of-1 approach as the future of oncology in
general as has been emerging through studies in precision
oncology published in the literature as cited above since
2010.

## Drug access for N-of-1 basket trials

Drug access is particularly helped by patient
advocates and medication acquisition specialists. More
challenging is drug availability for compounds that are
investigational, mostly because of the numerous narrow
eligibility criteria for most clinical trials. WIN Consortium
leadership would argue it is very advantageous for industry
to understand and support the N-of-1 precision oncology
basket trials as a unique design with invaluable insight into
benefit from active combinations with specific targeted
agents or oncology treatment modalities, especially
given the vast heterogeneity of cancer and emerging
biomarkers [17, 18]. In the future, drug access, which can
sometimes be a limitation, could be incorporated as an input into algorithms based on the patient's geographical location to better address these challenges. The efforts of drug acquisition specialists and patient advocates can be incorporated into the management and conduct of precision oncology clinical trials.

**Next generation precision oncology trial design: World iterative next gen precision oncology study (WINGPO)**

WIN has conceptualized and evolved a next-generation clinical trial design in precision oncology known as World Iterative Next Gen Precision Oncology study (WINGPO) for patients with advanced cancer or with planned therapy that prolongs survival by less than 6 months or median survival of less than 2 years. WINGPO is an N-of-1 precision oncology navigational open basket study that provides cancer patients with optimal treatment selection (Figure 5). The drugs that might be considered will be FDA-approved drugs or combinations, drugs used off-label, or investigational agents subject to availability. Navigation to treatment clinical trials will also be considered. Combinations will be favored, if possible. The combinations that might be recommended are expected to be often suggested at a reduced dose to avoid toxicity as previously done in the I-PREDICT study [9, 10]. The best-matched therapy might not be available

in the country or might not be accessible for a given patient. Drug availability will be taken into consideration by the study Molecular Tumor Board (MTB), which has an active role in the WINGPO design, and will be aided by drug-procurement specialists and advocacy groups. We believe that progress through communication with the FDA and industry will facilitate drug access and enable more N-of-1 basket trials in different patient settings in the future.

The design of the WINGPO study includes iterative (at trial baseline and at progressions) collection of agnostic real-world data (RWD) and generation of required genomic and transcriptomic profiling. There are also embedded in the study evolving novel omics, including functional precision medicine (FPM) assays that utilizes patient-derived organoids, proteomics, transcriptomics, RNA modification and immunomics.

WINGPO molecular profiling investigations rely on tumor and blood samples at different sequential time points allowing comprehensive assessment of the baseline tumor biology, and detection of changes in the tumor as it evolves under therapeutic pressure and relates to the patient survival outcomes.

Various machine learning and AI models are designed to be tested continuously as the data becomes available to reveal new treatment strategies and overcome resistance. Upon enrollment, the data collected will be reviewed by an MTB of experts that will provide

<figure><img src="image_19.png" /><figcaption>**Figure 5: WINGPO N-of-1 precision oncology basket trial design in advanced cancer.** WINGPO, guided by WIN expert stakeholders Molecular Tumor Board (MTB), enables optimal personalized treatment for patients with advanced cancer based on comprehensive range of investigations, development of AI algorithm(s) for treatment response prediction (agnostic of technology), understanding mechanisms and molecular basis for responders versus non-responders, understanding mechanisms of resistance to treatment, and analyses of outcomes and omics in different populations around the world.</figcaption></figure>
several treatment options based on data available for
personalized Treatment A, as illustrated in Figure 5. Upon
progression under Treatment A, reiterative biopsy will be
performed, and bloods will be collected for genomic and
transcriptomic profiling and exploratory omics.

The MTB reconvenes to review updated data and recommend personalized Treatment B. AI algorithm(s) to predict and match therapeutic options are under consideration [30, 31]. Indeed, the iterative design permits biomarker validation in initial cohorts along with nomination to entry and therapy assignment in subsequent cohorts. The algorithm(s) predictions will be part of the data reviewed by the MTB to make their recommendations. The algorithm(s) will not be locked and will be constantly updated as new patients and new data are available. Similarly, investigations are not planned to be restricted and the trial plans to incorporate new tools and markers that may become available, given the quick evolution of the field.

The exploratory omics that are planned at this stage
include:

1. Immune checkpoint artificial reporter (IcAR) technology (Ben-Gurion University of the Negev-BGU): IcAR technology will employ two methodologies based on fresh tumor samples to profile targeted therapy and one methodology, which could be employed to fixed/fresh samples, to evaluate immune checkpoint (IC) blockers ligands and specific treatments. Staining of tumor samples for the presence of ligands to IC receptors was not proven as a successful predictor for the PD1-PDL1 pathway. Moreover, TMB/MSI as a predictive biomarker for responses to IC therapy does not point to a specific type of IC blocker or differentiate the need for single agent versus combination therapy. IcAR technology [32] is a functional assay based on artificial reporters that can be applied to fixed/fresh tumor samples (primary/secondary growth) and to exosomes derived from blood of cancer-bearing patient and quantify the functional availability of IC ligands to a specific IC receptor (PD1, CTLA4, LAG3) and generate a score per each IC and the specific IC blocker drug to be applied (e.g. score per sample for functional ligands to PD1 IC + the effect of cemiplimab treatment). Therefore, IcAR technology can be used for prediction based on the original tumor sample. Yet, we could study the input from this technology during treatment by monitoring blood samples taken during the treatment for the functional availability of IC ligands on exosomes secreted into the bloodstream from the tumor microenvironment.

2. PARIS (Personalized, Aimed, Robotic, Informatics, Sequencing) Assay (SEngine): The initial success rate of the assay, defined as deriving organoid cultures and performing drug screens which passed QC steps was 72.5%. Most of the early screen failures (~20%) were

due to inadequate quantity or viability of tumor cells at
the time of receipt. These issues have been addressed
through improved biopsy, shipping, and culture
conditions and strict eligibility criteria (wash out of
3 weeks from chemotherapies). The current screen
success rate is 92%. The PARIS assay identifies a drug
with good to exceptional activity in 94.2% of patient
derived tumor organoids (PDTOs) [33–39].

3. BH3 Profiling DBP (DFCI): The ability of DBP to predict response to therapy was demonstrated in several prospective murine studies, including GEMM and PDX; and several retrospective human studies [40–42].

4. Proteomics (ProCan): The proteomic technology allows the development of proteomic-based biomarkers (signatures) that are prognostic and predictive for response to treatment. This was shown in different types of solid tumors, including prostate cancer [43], pancreatic cancer [44], colorectal cancer [45], and melanoma [46], among others that are currently under development. This proteomic technology was also robust for developing diagnostic biomarkers [47, 48] to confirm tissue of origin and help diagnose cases of metastasis of unknown primary. ProCan's technology also has the capability to mine the proteomic data to identify drug targets and assess response to treatment, integrating this with other multi-omic data [49]. This will allow the identification of the pathways associated with response and resistance to specific drugs as well as the identification of novel drug targets that can be used for patients who run out of treatment options.

5. RNA-modifications (Brown University): RNA-modifications remain largely unexplored [50, 51]. Global analysis of modified nucleosides will be performed using an Exploris 240 Orbitrap Liquid Chromatography Mass Spectrometer (LC-MS) recently purchased by the Brown RNA Center. The analysis does not require intact RNA. Global nucleoside analysis will provide patterns of modified nucleosides to serve as signatures for diagnosis and also for comparing responses to treatment, where nucleoside patterns from normal tissue may serve as the baseline. Currently 100,000 to 1 million cells can be used but protocols are under development to analyze 1000 cells for RNA modifications from tRNA and ribosomes.

The one-arm, single-stage design will be used
to assess the preliminary efficacy of the study MTB-
driven personalized therapeutic approach. The primary
efficacy analyses will be based on the ratio between
the progression time on personalized therapy to the
progression time on prior therapy. The design of the
study as in other N-of-1 trials such as WINTHER,
poses the question of the use of the PFS comparison to
the PFS of the prior therapy when the latter is prior to
inclusion in the study. In this case, the so-called PFS0 remains uncontrolled and may be overstated as radiologic assessments done as part of standard-of-care are usually done at longer intervals than in a clinical trial (3 months vs. 2 months). To limit this substantial hurdle, either the prior treatment (PFS0) should be included in the study (which would be by far the best solution) or alternatively the study treatment assessments (PFS1 and subsequent) should be done at similar intervals than the PFS0, according to institutional calendar. But more generally, the issue of timing of first treatment assessment and regular follow up to monitor disease and identify early progression should be reconsidered as new surveillance tools such as circulating tumor DNA (ctDNA) based on non-invasive blood investigations become available [52]. Predicting responses to targeted therapies with ctDNA is already feasible as early as the first week, using urine or blood samples. Immunotherapies, however, may require a longer timeframe to gauge response via blood-based ctDNA [53, 54]. Waiting 2 or 3 months to assess whether a treatment is effective seems a long time that can potentially harm the patient. Depending upon therapy selected, leaving a patient under a treatment for several weeks where there is the possibility of assessing early response and more importantly early non-response can lead to the patient losing a window of opportunity for efficacy of another treatment. The WINGPO trial will aim to include regular monitoring of the disease with first assessment by ctDNA after the first week of treatment.

Precision oncology in the neoadjuvant and adjuvant cancer settings

Earlier-stage therapy of malignant tumors has provided a path towards cure and improved patient survival. A major goal in the practice of oncology is early detection and accurate diagnosis of cancer that is potentially curable. With the advent of targeted therapies and progress in precision oncology, it has become very important to determine the impact of these therapies as it relates to cure in earlier cancer stages. Recent landmark studies have begun to demonstrate the value of neoadjuvant immunotherapy in melanoma [55, 56] and colorectal cancer [57].

The FDA's Project Frontrunner [58] seeks to "encourage drug sponsors to consider when it may be appropriate to develop and seek approval of cancer drugs for advanced or metastatic disease, in an earlier clinical setting...". A number of advantages have been outlined by the FDA including earlier access to therapies, improved assessment of drug effects, comparisons of novel therapies with standard of care, and potential to improve treatments in the frontline setting.

The WIN Consortium developed in 2024 a trial schema to compare neoadjuvant versus adjuvant immunotherapy at earlier cancer stages as depicted in Figure 6. The proposed design, which integrates AI tools alongside the expertise of MTB specialists which have the final authority, was developed to gather important

<figure><img src="image_20.png" /><figcaption>**Figure 6:** Randomization to Neo-adjuvant or Adjuvant Immunotherapy for Patients with solid tumors with TMB high (≥16(a)) or MSI high (NEOVADJ-TMB-IO). N-of-1 clinical trial schema for neoadjuvant versus adjuvant immunotherapy in the treatment of early-stage cancer. Symbols are as described in Figure 5.</figcaption></figure>
data about the utility of this approach and its potential to enhance outcomes compared to real-world data controls. This does not necessarily suggest that standard-of-care should be changed in adjuvant or neoadjuvant settings but rather to compare them and try to improve the available therapies based on MTB input. This type of data with similar cohorts of patients will be critical evidence for any superiority of personalized treatment as compared to contemporary real-world data or matched control patients within actual trials. AI is not selecting therapies but rather assisting with analysis for the MTB that recommends optimal therapy. The MTB could for example provide options for stage 3 colorectal cancer or oligometastatic disease such as FOLFOX or immunotherapy based on MSI status -/+ targeted therapy such as a PI3K inhibitor or an NTRK or Her2 blocker or a KRAS drug -/+ anti-EGFR. The statistical design and power of the precision oncology trials will be critical for demonstrating superiority and not just non-inferiority, which can be done convincingly with contemporary real-world or even trial controls.

Personalized combination treatment based on a cancers' drivers along with personalized vaccine approaches in the adjuvant setting should be investigated more in a tissue agnostic manner. The data should drive the practice, but we won't know if we don't try.

## Mutations across borders

The WIN consortium (WIN) endeavours to systematically map driver mutation variations across diverse cancer types and countries. Capitalizing on WIN's global network, the study proposes to establish a database of driver mutation frequencies. By gathering de-identified data from WIN's sites around the world, we plan to compile a robust dataset detailing the frequency of specific mutations across various cancer types, stages, genders, ethnicities, from different diagnostic technologies, and tissue sources from which the diagnosis was derived. This data will be utilized to generate similarity trees, illustrating the genetic similarities and differences between countries. This will aid clinicians to interpret cancer research, allowing them to apply findings from genetically similar populations to their local patients more effectively. Additionally, artificial intelligence (AI) algorithms will be employed to identify enriched features, to investigate the association between feature measurements collected and literature, and to assess the predictive potential of these features. It will guide us towards the identification of novel risk factors, mutation patterns, and potential therapeutic targets and their prevalence in specific geographic areas. Based upon the initial data collected, questionnaires will be developed to the attention of WIN sites to query on genetic and environmental factors, treatment responses, and patient outcomes, if possible. This advanced database will enable answering an array

of scientific questions and therefore facilitate research and opportunities for clinical application. This unique resource of genetic and environmental cancer data will eventually be made available to the vast community. In summary, this international collaboration seeks to create through systematic mapping of driver mutations and AI, a globally integrated framework for cancer mutation analysis. It is expected to help clinicians across the world make sense of international research, guide them in selecting treatments tailored to their individual patients and improve outcomes.

## Iterative innovation

A cornerstone the WIN Consortium upholds involves innovation in the field of precision oncology. This has motivated the like-minded member organizations since its founding and continues to the present day. There are numerous technological advances in candidate biomarkers, omics, and AI tools. The WIN clinical trial designs allow for real-world testing of novel measurements and tools that can then be advanced into consideration by the MTB in later cohorts. The iterative nature of implementing innovations through continuous learning will always keep WIN at the forefront of advances that can serve patients. Thus, 'iterative innovation' represents a key aspect of the way the WIN Consortium remains focused on scientific discoveries and their translation.

## Challenges with FDA cancer drug approvals

In addition to the well-known issue of drug access in general in oncology, and more specifically in the setting of innovative clinical trials, there are additional interrelated challenges in precision oncology. The FDA historically has not approved cancer therapies on the basis of N-of-1 combination therapy clinical trials. While tissue agnostic approvals have occurred since 2017 with the use of immunotherapy to treat mismatch repair-deficient cancer, N-of-1 combination therapies based on N-of-1 trials have not yet led to specific approvals. As data accumulates, the FDA and other regulatory oversight bodies will need to be prepared to evaluate aggregated data involving similar cohorts of patients who are shown to benefit in N-of-1 basket trials. An openness to look at such data to bring effective combinations to patients at the earliest time is advantageous for patients, caregivers, payors, governments and drug manufacturers.

An openness by the FDA to consider for drug approval N-of-1 combination therapy clinical trial evidence as has been accumulating for 15 years in the field, for new indications, will encourage more effort to gain additional post-approval results. Importantly, the way FDA and other regulatory bodies view N-of-1 basket trials as far as potential drug approval in new
indications should stimulate drug manufacturers to
more enthusiastically support and participate in N-of-1
trials. There would certainly be ample opportunity in
this realm for real-world control arms. The potential
for drug combinations in N-of-1 basket trials includes
(or should include) all possible modalities in oncology,
small molecules, biologics, immunotherapy, on-label
use, off-label use, drug repurposing, and investigational
use.

As there is already a science to safely dose novel
drug combinations, the implementation of a large number
of N-of-1 trials is not only feasible but somewhat overdue.
The efficiency of N-of-1 trials in finding efficacy signals
of novel cancer therapy combinations dictates that the
field of oncology get beyond a traditional reluctance to
go beyond conventional clinical trial methodologies. One
of the major regulatory challenges involves the approval
of a companion diagnostic that can guide selection of
treatment in the n=1 setting so biomarker development
will need to occur alongside the machine learning
algorithm and the drug/drug combination in parallel.
The FDA can play an important role in catalyzing what
some would consider a revolutionary change to accelerate
progress in oncology.

Challenges with industry

Despite clear pathways established by regulatory
agencies [59], industry [51] and other stakeholders remain
reluctant to consider N-of-1 trials. In part, this is because
they are a new paradigm driven by what powerful new
technology has revealed, e.g., that each patient's tumor is
complex and unique. Beyond simply meeting the needs
and expressed wishes of the broader patient community,
N-of-1 trials have an opportunity to provide early proof-of-
principle including on-target efficacy, broader efficacy and
safety data in underrepresented populations, and establish

robust translational science platforms. Most importantly,
these are not “single patient” trials. Although each patient
may be treated in a unique manner because their tumor
biology is unique, specific matching algorithms can be
developed and the robustness of those algorithms assessed
[8, 10] making them applicable across large numbers if not
most cancer patients.

W.S.E-D. had the privilege of meeting FDA's
Dr. Richard Pazdur (Figure 7) after Dr. Pazdur gave
a fireside chat with numerous pearls. Dr. Pazdur
communicated the importance of getting drug approvals
right as far as safety and efficacy, the importance of
survival outcomes, confirmatory trials, the importance
of drug dosing, conflict of interest, level playing field,
and the resource intensiveness of drug withdrawals after
initial approval. Dr. Pazdur communicated that it is
important to simplify clinical trial designs in oncology
as trials have become very complex trying to ask and
answer too many things at once. When they briefly met,
Dr. El-Deiry mentioned the WIN Consortium and efforts
to advance the field of Oncology through N-of-1 clinical
trials.

The history of oncology for the last 80+ years has
been combination therapy with chemotherapy using drugs
with non-overlapping toxicities. With so many advances
in recent decades and knowledge about toxicities, the
founding principles of oncology come back into play in
the third decade of the 21st century. It can similarly be
argued that post-approval, N-of-1 trials have an important
role to play in finding additional indications based on
favorable results from combination therapies in similar
cohorts of patients.

Clinical trialists in 2024 are very familiar with
the exceedingly complex early-phase trial designs with
numerous combination arms that have monopolized patient
populations without optimizing potential benefits. It could
be argued that the availability of N-of-1 clinical trials

<figure><img src="image_21.png" /><figcaption>**Figure 7:** On April 5, 2024, WIN Consortium Chair El-Deiry meets Dr. Richard Pazdur, Director of FDA's Oncology Center of Excellence.</figcaption></figure>
offer an important aspect to the risk-benefit calculation in clinical trials in oncology. As to many oncologists, N-of-1 therapies based on omics, AI algorithms, and MTBs is the future of oncology. The real question is when does this happen in the mainstream? It is worth considering that buy in and participation by industry can play an important role in the evolution of improved patient care in oncology by providing individualized therapies in a personalized way for patients.

Dr. Kurzrock has pointed out that the FDA has found ways to fast track/accelerate approvals, for biomarker-driven therapies, requiring just a small number of patients (sometimes ~30 to 100 patients) for approval, providing that response rates are high and durable [60–62]. This is an important departure from traditional randomized trials of unselected patients that look for small improvements and require very large numbers of participants as well as years to perform. Finally, as shown by tumor-agnostic approvals [63–66], rare biomarkers in a single disease can become quite a large market once the targeted drug is applied to all cancers bearing the biomarker. Most importantly, giving the right drug(s) to patients, rather than combinations that include the right drug but also additional drugs that might not be of use to that patient (but add toxicity), is simply the right thing to do for patients with cancer.

## CONCLUSIONS

Our hypothesis is that comprehensive omics in tissues and blood as well as functional precision medicine, AI algorithms and MTB-guided N-of-1 drug selection will bring best-in-the-world iterative treatment options for patients with malignancies to prolong survival and ultimately save money and lives by treating the right patients with the right drugs/combinations. The WIN Consortium approach enables understanding of the molecular basis for responders versus non-responders, elucidate mechanisms of resistance to treatment, and analyze outcomes vis a vis omics in different populations around the world.

To bring precision oncology studies to fruition, whilst grant application opportunities are being pursued, interaction and collaboration with pharmaceutical companies, large and smaller biotechnology, and AI and genomics/omics companies are sought and will allow the WIN consortium to maximize impact through innovation and collaboration. Of particular importance is the patient voice and inclusion of patient advocacy groups in WIN as they push to accelerate the future of precision oncology and work with other stakeholders to address the challenges that are faced. The MTB is providing a forum for discussion of complex patient cases with omics, and these are in process of publication for educational purposes.

The WIN Consortium is in the process of establishing a one-year self-funded WIN International

Fellowship in Precision Medicine under the leadership of Drs. Kurzrock and El-Deiry. Candidates can be of any stage of training, faculty or industry, can have MD or PhD degree or be in training for MD or PhD degree. Opportunities include visit WIN member organizations for 3 months to one year if desired, self-funded, completion of at least one manuscript and/or at least one clinical trial written, submission and presentation of a WIN abstract at >1 WIN meeting and/or a national/international meeting, involvement and assistance with the WIN MTB as "mentern" —including write ups for publication, opportunity to serve on at least one WIN committee as trainee member. Since WIN includes a broad away of organizations, such as academic, industry, patient advocacy, etc., WIN consortium fellows have opportunity to work with one or more of these stakeholders in the precision oncology space. Fellows can assist with WIN consortium social media interviews and news. Successful fellows will receive a Certificate of Completion from the training at the end of the experience.

With our ground-breaking spirit and expertise in complex investigator-led studies, our global footprint and nimble organization, we can foster collaborations and alliances, leverage and maximize expertise, ensure equitable distribution of resources, and promote data sharing whilst always keeping the patients at the center of everything we do.

## AUTHOR CONTRIBUTIONS

W.S.E-D. and R.K. contributed with conceptualization; W.S.E-D., R.K. and C.B. ensured supervision; C.B. and S.M. contributed to visualization; W.S.E-D., R.K., C.B. and S.M. contributed to methodology; W.S.E-D., R.K., C.B. and S.M. wrote the original draft of the manuscript; C.B., F.W. and S.M. contributed to the project management; and all co-authors contributed to writing-review and editing.

## CONFLICTS OF INTEREST

- W.S.E-D. is Chair of the Worldwide Innovative Network (WIN) Association – WIN Consortium and Scientific Founder of Oncoceutics, Inc (acquired by Chimerix, Inc), SMURF-Therapeutics, and p53-Therapeutics. He is receiving or has received recent funding from NIH/NCI, American Cancer Society, The Warren Alpert Foundation, AACR-Novocure, D&D Phramatech, Chimerix, AstraZeneca, and Actuate Therapeutics. W.S.E-D. serves on the Executive Committee of the Caris Life Sciences Precision Oncology Alliance, and is co-Editor-in-Chief of Oncotarget, the journal that invited this manuscript as the inaugural "Special Article" in a Collection of articles on Precision Oncology".

- First author W.S.E-D. was not involved in the review of this manuscript or the decision to accept it.
- C.B. and F.W. are full time employees of Worldwide Innovative Network (WIN) Association - WIN Consortium.

- S.M. receives consulting honoraria from Worldwide Innovative Network (WIN) Association - WIN Consortium.

- R.K. has received research funding from Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, Omniseq, Pfizer, Sequenom, Sysmex, Takeda, and TopAlliance and from the NCI; as well as consultant and/or speaker fees and/or advisory board/consultant for Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, Inc., Biological Dynamics, Caris, Daiichi, Datar Cancer Genetics, EISAI, EMD Serono, EOM Pharmaceuticals, Iylon, Jackson Laboratories, LabCorp, Lanauria Therapeutics, Merck, NeoGenomics, Neomed, Pfizer, Precirix, Prosperdx, Quanta Therapeutics, Recordati, Regeneron, Roche, TD2/Volastra, Turning Point Therapeutics, X-Biotech; has an equity interest in CureMatch Inc.; serves on the Board of CureMatch and CureMetrix and XZOM, and is a co-founder of CureMatch.

- S.A.M. is a co-founder and Scientific Advisory Board Member of Sathgen Therapeutics, OneCellGen and Iylon Precision Oncology.

- Pi.S. receives consulting honoraria from HTG Molecular Diagnostics, Inivata, ArcherDx, Bristol Myer Squibb, Roche Molecular Diagnostics; research funding from Roche, AstraZeneca, Novartis, BMS Foundation, Illumina, and his institution from Omicure; travel and accommodation support from Illumina, Bristol Myer Squibb, AstraZeneca, Roche.

- J.L.W. receives consulting honoraria from Westat and The Lewin Group; has ownership in HemOnc.org LLC, all outside the submitted work.

- R.A.M. receives consulting honoraria from Novartis, Sierra Oncology, Genentech, Sierra, Bleupring, Geron, Telios, CTI, Incyte, Bristol Myer Squibb, Abbvie, GlaxoSmithKline, Morphosys, Huron.

- C.W.'s spouse is an employee of Roche/Genentech. C.W. has received research funding from Tempus, LabCorp, GeneDx, Ignite Proteomics, GlaxoSmithKline, Takeda, Sanofi, and Novartis.

- R.L.S. serves as PI of the ASCO TAPUR study which is supported by research grants to ASCO from the following companies: Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Genentech, Lilly, Merck, Pfizer, Seagen, Taiho. R.L.S. serves on the Board of Directors and has stock of Leap Therapeutics; also serves on the Board of Clarified Precision Medicine (stock options). R.L.S. is a compensated advisor to Cellworks, Flatiron Health, Illumina, ZephyrAI. R.L.S. is compensated as chair of a DSMB for Toray Pharmaceuticals.

- R.R.R. is an advisor to Tessellate Bio BV and Rejuveron Telomere Therapeutics.

- A.H.C. reports financial interests in Merus, (expert testimony, personal); and institutional Research Grant from Gilead. A.H.C. has received travel support from Bristol Myers Squibb, Kyowa Kirin, Merck Serono.

- S.L.G. reports stock ownership (current, personal) in HCA Healthcare; Consulting (all relationships ended, personal) from Pfizer, SeaGen, AstraZeneca, DaiichiSankyo, Gilead Sciences, Menarini Stemline, Genentech, Novartis, Lilly/Loxo@Lilly. S.L.G. reports institutional research funding from AstraZeneca/Daiichi Sankyo, Novartis, Daiichi Sankyo, Lilly, Roche.

- J.T. reports personal financial interest in form of scientific consultancy role for Accent Therapeutics, Alentis Therapeutics, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cartography Biosciences, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, Lilly, Menarini, Merus, MSD, Novartis, Ono Pharma USA, Peptomyc, Pfizer, Pierre Fabre, Quantro Therapeutics, Scandion Oncology, Scorpion Therapeutics, Servier, Sotio Biotech, Taiho, Takeda Oncology and Tolremo Therapeutics. Stocks: Oniria Therapeutics, Alentis Therapeutics, Pangaea Oncology and 1TRIALSP.

- A.P.G. reports financial interests in Oniria Therapeutics and Peptomyc.

- J.L. receives honoraria from MSD, is consulting or has advisory role in Taiho Pharmaceutical. Her institution is consulting or has advisory in Starpharma, Greywolf Therapeutics. Her institution receives research funding from Starpharma, Corvus Pharmaceuticals, Relay Therapeutics, ALX Oncology, IDEAYA Biosciences, Innovent Biologics, Greywolf Therapeutics, MSD, Regeneron, Bristol Myers Squibb, Abbvie, AVEO, Bayer, Merus, Nested Therapeutics, Carina Biotech, ImmVirX. J.L. receives travel, accommodation and expenses support from Starpharma, ImmVirX, MSD, Innovent Biologics.

- Sa.I. has received research funding from Canon Medical, Hitachi Systems, ACT Genomics, AMED, as well as speaker fees and advisory board for Pfizer, AstraZeneca, Guardant Health, Guardant Health AMEA, Roche, Chugai Pharmaceutical, Shionogi, Taiho, IQVIA, Bayer, ACT Med, Novartis, Molecular Health, MSD, Merck, and Sysmex; is a co-founder of AIM Precision Therapeutics.

- A.M.T. declares receipt of Clinical Trial Research Funding (received through the institution): OBI Pharma, Agenus, Vividion, Macrogenics, AbbVie, IMMATICS, Novocure, Tachyon, Parker Institute for Cancer Immunotherapy, Tempus, and Tvardi; fees for consulting or advisory roles for Avstera Therapeutics,
Bioeclipse, BrYet, Diaccurate, Macrogenics, NEX-I, and VinceRx.

- D.S.D. declares consulting for AstraZeneca, Clovis (Change&), GSK (DSMB), Puma (disparities), Immunogen (social media). D.S.D.'s institution receives funding for IST from Bristol Myers Squibb.

- R.S. reports: Esteve (invited speaker, personal), SACE Medhealth (commercial medical education company owned by wife until December 2023), TDD (Member of the Executive Committee – no financial interest), WNT Pharma (coordinating PI, personal and institutional, financial interest).

- E.F. reports receipt of personal honoraria for advisory board participation from Abbvie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, F. Hoffmann-La Roche, Genmab, Gilead, GSK, ITeos Therapeutics, Janssen, Johnson & Johnson, MSD, Novartis, Pierre Fabre, Pfizer, Regeneron, Turning Point, Daiichi Sankyo; personal speaker honoraria from Amgen, AstraZeneca, BMS, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Johnson & Johnson, Genentech, Gilead, Janssen, Medical Trends, Medscape, Merck Serono, MSD, Novartis, Peervoice, Pierre Fabre, Pfizer, Regeneron, Touch Oncology; Board of Director role: Grifols; financial support for meeting attendance and/or travel from AstraZeneca, Janssen, Roche.

- J.B. reports: Advisor: AbbVie, Amgen, AstraZeneca, Bayer, Beigene, MSD, Merck-Serono, Roche, Takeda; Writing/speaker engagement: BMS, Medison, Pfizer. Research funding: Immunai, OncoHost, MSD, AstraZeneca, Roche, Abbvie.

- A.M.J. reports stock and other ownership interest in Pricilium Therapeutics. A.M.J.'s institution reports consulting or advisory role in Janssen Oncology, Ipsen, AstraZeneca, Sanofi, Pfizer, Novartis, Merck Serono, Ideaya, IQvia, Bayer, Astellas Pharma, Grey Wolf Therapeutics, Medison, Starpharma, Eisai, Mayne Pharma and MSD Oncology; Research funding from Bristol-Myers Squibb, Janssen Oncology, Merck Sharp & Dohme, Mayne Pharma, Roche/Genentech, Bayer, Lilly, Pfizer, AstraZeneca, Corvus Pharmaceuticals, Lilly, Genentech, BeiGene, Myeloid Therapeutics and Immunocore. A.M.J. reports patients, rolyalties or other intellectual property in Cancer therapeutic methods.

- M.E.S. reports consulting or advisory roles in Taiho Pharmaceutical, Exelixis, Bristol Myers Squibb, Exelixis, QED Therapeutics, Novartis and Pfizer; Speakers' Bureau: Taiho Pharmaceutical, Daiichi Sankyo/Astra Zeneca, BMS, Merck (none in 2024).

- Se.L. is an employee of Sir H N Reliance Foundation Hospital and Research Centre. Se.L. Has a leadership role in Sir H N Reliance Foundation Hospital and Research Centre and Nova Precision AI, IMPACT India International MTB, is Co-Chair of Asia Pacific Coalition against Lung Cancer and Member WIN Consortium in Precision Oncology. Se.L. reports stock or other ownership interest in Nova Precision AI and is co-founder. Se.L. has consulting or advisory roles in AstraZeneca, Bristol-Myers Squibb, MSD, Boehringer Ingelheim, Merck, Roche and Novartis. Se.L. Reports speakers' bureau from AstraZeneca, MSD, Bristol-Myers Squibb, Boehringer Ingelheim, Merck, Roche and Novartis.

- I.A.G receives honoraria from AstraZeneca.

- R.S.H. is on the Board of Directors of Immunocore and Junshi Pharmaceuticals and in a leadership role at Friends of Cancer, American Association for Cancer Research, International Association for the Study of Lung Cancer, Southwest Oncology Group.

- R.S.H. is consulting or has advisory role and receives consulting fees in Junshi Pharmaceuticals, AstraZeneca, Amgen, ArriVent, Bristol-Myers Squibb, Candel Therapeutics, Inc., Catalym, Checkpoint Therapeutics, Cybrexa Therapeutics, Eli Lilly and Company, Genentech, Gilead, I-Mab Biopharma, Janssen, Mediflix, Merck and Company, Neuvogen, NextCure, Normunity, Novartis, Pfizer, Regeneron Pharmaceuticals, Roche, Sanofi.

- R.S.H. reports stock and other ownership interests in Immunocore, Checkpoint Therapeutics, and Normunity.

- R.S.H has received research support from Eli Lilly and Company.

- R.S.H. has received travel support from AstraZeneca, Friends of Cancer, Genentech, Merck and Company, American Association for Cancer Research, International Association for the Study of Lung Cancer, and Southwest Oncology Group.

- G.R. served on advisory boards for AstraZeneca, Pfizer, and Bayer in the past 2 years.

## FUNDING

- W.S.E-D. is an American Cancer Society Research Professor and is supported by the Mencoff Family University Professorship at Brown University. This work was supported by an American Cancer Society Fostering Innovation Award (W.S.E-D.).

- R.K. is funded in part by 5U01CA180888-08 and 5UG1CA233198-05.

- Pi.S. receives funding from LYRICAN+ (INCA-DGOS-INSERM 12563).

- J.L.W. receives funding from NIH, AACR, Brown Physicians Incorporated.
REFERENCES

1. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023; 73:17-48. https://doi.org/10.3322/caac.21763. [PubMed]

2. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74:229-63. https://doi.org/10.3322/caac.21834. [PubMed]

3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144:646-74. https://doi.org/10.1016/j.cell.2011.02.013. [PubMed]

4. Subbiah V, Gouda MA, Ryll B, Burris HA 3rd, Kurzrock R. The evolving landscape of tissue-agnostic therapies in precision oncology. CA Cancer J Clin. 2024; 74:433-52. https://doi.org/10.3322/caac.21844. [PubMed]

5. Tsimberidou AM, Iskander NG, Hong DS, Wheler JJ, Falchook GS, Fu S, Piha-Paul S, Naing A, Janku F, Luthra R, Ye Y, Wen S, Berry D, Kurzrock R. Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative. Clin Cancer Res. 2012; 18:6373-83. https://doi.org/10.1158/1078-0432.CCR-12-1627. [PubMed]

6. Hyman DM, Taylor BS, Baselga J. Implementing Genome-Driven Oncology. Cell. 2017; 168:584-99. https://doi.org/10.1016/j.cell.2016.12.015. [PubMed]

7. Adashek JJ, Subbiah V, Westphalen CB, Naing A, Kato S, Kurzrock R. Cancer: slaying the nine-headed Hydra. Ann Oncol. 2023; 34:61-69. https://doi.org/10.1016/j.annonc.2022.07.010. [PubMed]

8. Rodon J, Soria JC, Berger R, Miller WH, Rubin E, Kugel A, Tsimberidou A, Saintigny P, Ackerstein A, Braña I, Loriot Y, Afshar M, Miller V, et al. Genomic and transcriptomic profiling expands precision cancer medicine: the WINTHER trial. Nat Med. 2019; 25:751-58. https://doi.org/10.1038/s41591-019-0424-4. [PubMed]

9. Sicklick JK, Kato S, Okamura R, Schwaederle M, Hahn ME, Williams CB, De P, Krie A, Piccioni DE, Miller VA, Ross JS, Benson A, Webster J, et al. Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Nat Med. 2019; 25:744-50. https://doi.org/10.1038/s41591-019-0407-5. [PubMed]

10. Sicklick JK, Kato S, Okamura R, Patel H, Nikanjam M, Fanta PT, Hahn ME, De P, Williams C, Guido J, Solomon BM, McKay RR, Krie A, et al. Molecular profiling of advanced malignancies guides first-line N-of-1 treatments in the I-PREDICT treatment-naïve study. Genome Med. 2021; 13:155. https://doi.org/10.1186/s13073-021-00969-w. [PubMed]

11. Wahida A, Buschhorn L, Fröhling S, Jost PJ, Schneeweiss A, Lichter P, Kurzrock R. The coming decade in precision oncology: six riddles. Nat Rev Cancer. 2023; 23:43-54. https://doi.org/10.1038/s41568-022-00529-3. [PubMed]

12. Cancer Genome Atlas Research Network, and Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, Ellrott K, Shmulevich I, Sander C, Stuart JM. The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet. 2013; 45:1113-20. https://doi.org/10.1038/ng.2764. [PubMed]

13. Mertins P, Mani DR, Ruggles KV, Gillette MA, Clauser KR, Wang P, Wang X, Qiao JW, Cao S, Petralia F, Kawaler E, Mundt F, Krug K, et al, and NCI CPTAC. Proteogenomics connects somatic mutations to signalling in breast cancer. Nature. 2016; 534:55-62. https://doi.org/10.1038/nature18003. [PubMed]

14. Hoadley KA, Yau C, Hinoue T, Wolf DM, Lazar AJ, Drill E, Shen R, Taylor AM, Cherniack AD, Thorsson V, Akbani R, Bowlby R, Wong CK, et al, and Cancer Genome Atlas Network. Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer. Cell. 2018; 173:291-304.e6. https://doi.org/10.1016/j.cell.2018.03.022. [PubMed]

15. ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature. 2020; 578:82-93. https://doi.org/10.1038/s41586-020-1969-6. [PubMed]

16. El-Deiry WS, Goldberg RM, Lenz HJ, Shields AF, Gibney GT, Tan AR, Brown J, Eisenberg B, Heath EI, Phuphanich S, Kim E, Brenner AJ, Marshall JL. The current state of molecular testing in the treatment of patients with solid tumors, 2019. CA Cancer J Clin. 2019; 69:305-43. https://doi.org/10.3322/caac.21560. [PubMed]

17. El-Deiry WS, Taylor B, Neal JW. Tumor Evolution, Heterogeneity, and Therapy for Our Patients With Advanced Cancer: How Far Have We Come? Am Soc Clin Oncol Educ Book. 2017; 37:e8-15. https://doi.org/10.1200/EDBK_175524. [PubMed]

18. Acharya D, Mukhopadhyay A. A comprehensive review of machine learning techniques for multi-omics data integration: challenges and applications in precision oncology. Brief Funct Genomics. 2024; 23:549-60. https://doi.org/10.1093/bfgp/elae013. [PubMed]

19. Kourou K, Exarchos TP, Exarchos KP, Karamouzis MV, Fotiadis DI. Machine learning applications in cancer prognosis and prediction. Comput Struct Biotechnol J. 2014; 13:8-17. https://doi.org/10.1016/j.csbj.2014.11.005. [PubMed]

20. Liu J, Farrow M, Seymour L, Desai J, Loong HH, Ivy P, Koyoma T, Cook N, Blagden S, Garralda E, Massard C, Tolcher AW, Adashek JJ, et al. Accelerating the Future of Oncology Drug Development: The Role of Consortia in the Delivery of Precision Oncology Early Phase Clinical Trials. J Clin Oncol. 2025; 43:735-47. https://doi.org/10.1200/JCO-24-01534. [PubMed]

21. Solomon B, Callejo A, Bar J, Berchem G, Bazhenova L, Saintigny P, Wunder F, Raynaud J, Girard N, Lee JJ, Sulaiman R, Prouse B, Bresson C, et al. A WIN Consortium phase I study exploring avelumab, palbociclib, and axitinib
in advanced non-small cell lung cancer. Cancer Med. 2022; 11:2790-800. https://doi.org/10.1002/cam4.4635.
[PubMed]

22. Lazar V, Rubin E, Depil S, Pawitan Y, Martini JF, Gomez-Navarro J, Yver A, Kan Z, Dry JR, Kehren J, Validire P, Rodon J, Vielh P, et al. A simplified interventional mapping system (SIMS) for the selection of combinations of targeted treatments in non-small cell lung cancer. Oncotarget. 2015; 6:14139-52. https://doi.org/10.18632/oncotarget.3741.
[PubMed]

23. Lazar V, Magidi S, Girard N, Savignoni A, Martini JF, Massimini G, Bresson C, Berger R, Onn A, Raynaud J, Wunder F, Berindan-Neagoe I, Sekacheva M, et al. Digital Display Precision Predictor: the prototype of a global biomarker model to guide treatments with targeted therapy and predict progression-free survival. NPJ Precis Oncol. 2021; 5:33. https://doi.org/10.1038/s41698-021-00171-6.
[PubMed]

24. Lazar V, Girard N, Raymond E, Martini JF, Galbraith S, Raynaud J, Bresson C, Solomon B, Magidi S, Nechushtan H, Onn A, Berger R, Chen H, et al. Transcriptomics in Tumor and Normal Lung Tissues Identify Patients With Early-Stage Non-Small-Cell Lung Cancer With High Risk of Postsurgery Recurrence Who May Benefit From Adjuvant Therapies. JCO Precis Oncol. 2022; 6:e2200072. https://doi.org/10.1200/PO.22.00072.
[PubMed]

25. Lazar V, Raynaud J, Magidi S, Bresson C, Martini JF, Galbraith S, Wunder F, Onn A, Batist G, Girard N, Lassen U, Pramesh CS, Al-Omari A, et al. Comorbidity between lung cancer and COVID-19 pneumonia: role of immunoregulatory gene transcripts in high ACE2-expressing normal lung. Ther Adv Med Oncol. 2022; 14:17588359221133893. https://doi.org/10.1177/17588359221133893.
[PubMed]

26. Lazar V, Zhang B, Magidi S, Le Tourneau C, Raymond E, Ducreux M, Bresson C, Raynaud J, Wunder F, Onn A, Felip E, Tabernero J, Batist G, et al. A transcriptomics approach to expand therapeutic options and optimize clinical trials in oncology. Ther Adv Med Oncol. 2023; 15:17588359231156382. https://doi.org/10.1177/17588359231156382.
[PubMed]

27. Lazar V, Raymond E, Magidi S, Bresson C, Wunder F, Berindan-Neagoe I, Tijeras-Rabaland A, Raynaud J, Onn A, Ducreux M, Batist G, Lassen U, Cilius Nielsen F, et al. Identification of a central network hub of key prognostic genes based on correlation between transcriptomics and survival in patients with metastatic solid tumors. Ther Adv Med Oncol. 2024; 16:17588359241289200. https://doi.org/10.1177/17588359241289200.
[PubMed]

28. Abstracts Presented at the 2024 WIN Symposium in Partnership with Burjeel Holdings: March 1-2, 2024, Abu Dhabi, United Arab Emirates. J Immunother Precis Oncol. 2024; 7:217-41. https://doi.org/10.3640/JIPO-24-X2.
[PubMed]

29. Rodon J, Soria JC, Berger R, Batist G, Tsimberidou A, Bresson C, Lee JJ, Rubin E, Onn A, Schilsky RL, Miller WH, Eggermont AM, Mendelsohn J, et al. Challenges in initiating and conducting personalized cancer therapy trials: perspectives from WINTHER, a Worldwide Innovative Network (WIN) Consortium trial. Ann Oncol. 2015; 26:1791-98. https://doi.org/10.1093/annonc/mdv191.
[PubMed]

30. Mueller J, Parikh RB, Noble S. Evaluating Clinical Trial Inclusion/Exclusion Criteria from Claims Using Generative Artificial Intelligence. J Clin Oncol. 2023; 41. https://doi.org/10.1200/JCO.2023.41.16_suppl.e13566.

31. Bhandari S, Levonian Z, Robert A, Baxter JZ, Cain J, Flach J, Joseph-Thomas J, Mueller J. Digital Trial Solutions escreening: Software to rank patients by their predicted clinical trial eligibility using real-world data and machine learning. J Clin Oncol. 2023; 41. https://doi.org/10.1200/JCO.2023.41.16_suppl.e13587.

32. Kaufman B, Abramov O, Ievko A, Apple D, Shlapobersky M, Allon I, Greenspan Y, Bhattachrya B, Cohen O, Charkovsky T, Gayster A, Shaco-Levy R, Rouvinov K, et al. Functional binding of PD1 ligands predicts response to anti-PD1 treatment in patients with cancer. Sci Adv. 2023; 9:eadg2809. https://doi.org/10.1126/sciadv.adg2809.
[PubMed]

33. Pauli C, Hopkins BD, Prandi D, Shaw R, Fedrizzi T, Sboner A, Sailer V, Augello M, Puca L, Rosati R, McNary TJ, Churakova Y, Cheung C, et al. Personalized *In Vitro* and *In Vivo* Cancer Models to Guide Precision Medicine. Cancer Discov. 2017; 7:462-77. https://doi.org/10.1158/2159-8290.CD-16-1154.
[PubMed]

34. Margossian A, Richardson A, Churchill M, Schaub F, Rosati R, Appleyard L, Pollastro M, Katabian C, Motamedi K, Diaz R, Pereira S, Kemp C, Gadi VK, et al. Predictive value of a CLIA-approved organoid based drug sensitivity test. J Clin Oncol. 2020; 38:3630. https://doi.org/10.1200/JCO.2020.38.15_suppl.3630.

35. Narasimhan V, Wright JA, Churchill M, Wang T, Rosati R, Lannagan TRM, Vrbanac L, Richardson AB, Kobayashi H, Price T, Tye GXY, Marker J, Hewett PJ, et al. Medium-throughput Drug Screening of Patient-derived Organoids from Colorectal Peritoneal Metastases to Direct Personalized Therapy. Clin Cancer Res. 2020; 26:3662-70. https://doi.org/10.1158/1078-0432.CCR-20-0073.
[PubMed]

36. Puca L, Bareja R, Prandi D, Shaw R, Benelli M, Karthaus WR, Hess J, Sigouros M, Donoghue A, Kossai M, Gao D, Cyrta J, Sailer V, et al. Patient derived organoids to model rare prostate cancer phenotypes. Nat Commun. 2018; 9:2404. https://doi.org/10.1038/s41467-018-04495-z.
[PubMed]

37. King DA, Smith AR, Pineda G, Nakano M, Michelini F, Goedegebuure SP, Thypambil S, Liao WL, McCormick A, Ju J, Cioffi M, Zhang X, Hundal J, et al. Complete Remission of Widely Metastatic Human Epidermal Growth Factor Receptor 2-Amplified Pancreatic Adenocarcinoma
After Precision Immune and Targeted Therapy With Description of Sequencing and Organoid Correlates. JCO Precis Oncol. 2023; 7:e2100489. https://doi.org/10.1200/ PO.21.00489. [PubMed]

38. Al-Aloosi M, Prechtl AM, Chatterjee P, Bernard B, Kemp CJ, Rosati R, Diaz RL, Appleyard LR, Pereira S, Rajewski A, McDonald A, Gordon EJ, Grandori C. Case report: *ex vivo* tumor organoid drug testing identifies therapeutic options for stage IV ovarian carcinoma. Front Oncol. 2024; 13:1267650. https://doi.org/10.3389/fonc.2023.1267650. [PubMed]

39. Gray HJ, Chatterjee P, Rosati R, Appleyard LR, Durenberger GJ, Diaz RL, Swan HA, Peretti D, Pollastro M, Ainge T, Kapeli K, Pereira S, Margossian AL, et al. Extraordinary clinical response to ibrutinib in low-grade ovarian cancer guided by organoid drug testing. NPJ Precis Oncol. 2023; 7:45. https://doi.org/10.1038/s41698-023- 00379-8. [PubMed]

40. Montero J, Sarosiek KA, DeAngelo JD, Maertens O, Ryan J, Ercan D, Piao H, Horowitz NS, Berkowitz RS, Matulonis U, Jänne PA, Amrein PC, Cichowski K, et al. Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy. Cell. 2015; 160:977-89. https://doi. org/10.1016/j.cell.2015.01.042. [PubMed]

41. Garcia JS, Bhatt S, Fell G, Sperling AS, Burgess M, Keshishian H, Yilma B, Brunner A, Neuberg D, Carr SA, Ebert BL, Ballen K, Stone RM, et al. Increased mitochondrial apoptotic priming with targeted therapy predicts clinical response to re-induction chemotherapy. Am J Hematol. 2020; 95:245-50. https://doi.org/10.1002/ ajh.25692. [PubMed]

42. Bhola PD, Ahmed E, Guerriero JL, Sicinska E, Su E, Lavrova E, Ni J, Chipashvili O, Hagan T, Pioso MS, McQueeney K, Ng K, Aguirre AJ, et al. High-throughput dynamic BH3 profiling may quickly and accurately predict effective therapies in solid tumors. Sci Signal. 2020; 13:eay4151. https://doi.org/10.1126/scisignal.aay4151. [PubMed]

43. Zhong Q, Sun R, Aref AT, Noor Z, Anees A, Zhu Y, Lucas N, Poulos RC, Lyu M, Zhu T, Chen GB, Wang Y, Ding X, et al. Proteomic-based stratification of intermediate-risk prostate cancer patients. Life Sci Alliance. 2023; 7:e202302146. https://doi.org/10.26508/lsa.202302146. [PubMed]

44. Aref AT, Azad AKM, Anees A, Pathan M, Grealey J, Smith DL, Humphries EM, Bucio-Noble D, Koh JM, Sykes E, Williams SG, Lyons R, Lucas N, et al. A proteomic-based prognostic signature of pancreatic adenocarcinoma. Cancer Res. 2023; 83:2209. https://doi.org/10.1158/1538-7445. AM2023-2209.

45. Habib R, Aref A, Anees A, Pathan M, McLeod D, Balleine RL, Bucio-Noble D, Noor Z, Ma L, Wang L, Heads J, Lalee N, Loudon C, et al. A 19-Protein Signature to Predict Outcomes in a Cohort of Stage II and III CRC. 2023; 41. https://doi.org/10.1200/JCO.2023.41.16_suppl.3129.

46. Manda S, Aref AT, Sykes EK, Williams SG, Koh JM, Humphries EM, Bucio-Noble D, Lee-Smith D, Lucas

N, Xavier D, Menzies A, Silva ID, Newell F, et al. A six-protein signature predicts response and survival in patients with advanced cutaneous melanoma treated with immunotherapy. Cancer Res. 2023; 83:5479. https://doi. org/10.1158/1538-7445.AM2023-5479.

47. Cai Z, Noor Z, Aref AT, Boys EL, Xavier D, Lucas N, Williams SG, Koh JM, Poulos RC, Hains PG, Robinson PJ, Balleine R, Reddel RR, et al. Machine learning of cancer type and tissue of origin from proteomes of 1,277 human tissue samples and 975 cancer cell lines. Cancer Res. 2023; 83:5391. https://doi.org/10.1158/1538-7445. AM2023-5391.

48. Boys E, Liu J (Jenny), Cai Z, Noor Z, Mackenzie KL, Aref A, Sykes E, Xavier D, Lucas N, Williams S, Bucio-Noble D, Koh J, Hains P, et al. Pan-cancer diagnostic proteomic signature of tissue-of-origin (TOO) using data-independent acquisition mass spectrometry (DIA-MS) from 1289 human tissue samples. J Clin Oncol. 2023; 41:3120. https://doi. org/10.1200/JCO.2023.41.16_suppl.3120.

49. Gonçalves E, Poulos RC, Cai Z, et al. Pan-cancer proteomic map of 949 human cell lines reveals principles of cancer vulnerabilities. bioRxiv. 2022.02.26.482008. https:// doi.org/10.1101/2022.02.26.482008.

50. National Academies of Sciences, Engineering, and Medicine, and Division on Earth and Life Studies National Institutes of Health Warren Alpert Foundation. Toward Sequencing and Mapping of RNA Modifications: Proceedings of a Workshop—in Brief. Zierler M, Moss S, editors. Washington (DC): National Academies Press (US); 2023. [PubMed]

51. Alfonzo JD, Brown JA, Byers PH, Cheung VG, Maraia RJ, Ross RL. A call for direct sequencing of full-length RNAs to identify all modifications. Nat Genet. 2021; 53:1113-16. https://doi.org/10.1038/s41588-021-00903-1. [PubMed]

52. Adashek JJ, Janku F, Kurzrock R. Signed in Blood: Circulating Tumor DNA in Cancer Diagnosis, Treatment and Screening. Cancers (Basel). 2021; 13:3600. https://doi. org/10.3390/cancers13143600. [PubMed]

53. Husain H, Melnikova VO, Kosco K, Woodward B, More S, Pingle SC, Weihe E, Park BH, Tewari M, Erlander MG, Cohen E, Lippman SM, Kurzrock R. Monitoring Daily Dynamics of Early Tumor Response to Targeted Therapy by Detecting Circulating Tumor DNA in Urine. Clin Cancer Res. 2017; 23:4716-23. https://doi.org/10.1158/1078-0432. CCR-17-0454. [PubMed]

54. Jensen TJ, Goodman AM, Kato S, Ellison CK, Daniels GA, Kim L, Nakashe P, McCarthy E, Mazloom AR, McLennan G, Grosu DS, Ehrich M, Kurzrock R. Genome-Wide Sequencing of Cell-Free DNA Identifies Copy-Number Alterations That Can Be Used for Monitoring Response to Immunotherapy in Cancer Patients. Mol Cancer Ther. 2019; 18:448-58. https://doi.org/10.1158/1535-7163.MCT-18- 0535. [PubMed]

55. Blank CU, Lucas MW, Scoley RA, van de Wiel BA, Menzies AM, Lopez-Yurda M, Hoeijmakers LL, Saw
RPM, Lijnsvelt JM, Maher NG, Pulleman SM, Gonzalez M, Torres Acosta A, et al. Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma. N Engl J Med. 2024; 391:1696-708. https://doi.org/10.1056/NEJMoa2402604. [PubMed]

56. Patel SP, Othus M, Chen Y, Wright GP Jr, Yost KJ, Hyngstrom JR, Hu-Lieskovan S, Lao CD, Fecher LA, Truong TG, Eisenstein JL, Chandra S, Sosman JA, et al. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023; 388:813-23. https://doi.org/10.1056/NEJMoa2211437. [PubMed]

57. de Gooyer PGM, Verschoor YL, van den Dungen LDW, Balduzzi S, Marsman HA, Geukes Foppen MH, Grootscholten C, Dokter S, den Hartog AG, Verbeek WHM, Woensdregt K, van den Broek JJ, Oosterling SJ, et al. Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial. Nat Med. 2024; 30:3284-90. https://doi.org/10.1038/s41591-024-03250-w. [PubMed]

58. Project FrontRunner - Advancing Development of Oncology Therapies to the Early Clinical Setting. 2024. https://www.fda.gov/about-fda/oncology-center-excellence/project-frontrunner.

59. For Physicians: How to Request Single Patient Expanded Access (“Compassionate Use”). 2024. https://www.fda.gov/drugs/investigational-new-drug-ind-application/physicians-how-request-single-patient-expanded-access-compassionate-use.

60. Beaver JA, Howie LJ, Pelosof L, Kim T, Liu J, Goldberg KB, Sridhara R, Blumenthal GM, Farrell AT, Keegan P, Pazdur R, Kluetz PG. A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics: A Review. JAMA Oncol. 2018; 4:849-56. https://doi.org/10.1001/jamaoncol.2017.5618. [PubMed]

61. Fountzilas E, Tsimberidou AM, Hiep Vo H, Kurzrock R. Tumor-agnostic baskets to N-of-1 platform trials and real-world data: Transforming precision oncology clinical trial design. Cancer Treat Rev. 2024; 125:102703. https://doi.org/10.1016/j.ctrv.2024.102703. [PubMed]

62. Tsimberidou AM, Fountzilas E, Nikanjam M, Kurzrock R. Review of precision cancer medicine: Evolution of the treatment paradigm. Cancer Treat Rev. 2020; 86:102019. https://doi.org/10.1016/j.ctrv.2020.102019. [PubMed]

63. Subbiah V, Cassier PA, Siena S, Garralda E, Paz-Ares L, Garrido P, Nadal E, Vuky J, Lopes G, Kalemkerian GP, Bowles DW, Seetharam M, Chang J, et al. Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1/2 ARROW trial. Nat Med. 2022; 28:1640-45. https://doi.org/10.1038/s41591-022-01931-y. [PubMed]

64. Subbiah V, Velcheti V, Tuch BB, Ebata K, Busaidy NL, Cabanillas ME, Wirth LJ, Stock S, Smith S, Lauriault V, Corsi-Travali S, Henry D, Burkard M, et al. Selective RET kinase inhibition for patients with RET-altered cancers. Ann Oncol. 2018; 29:1869-76. https://doi.org/10.1093/annonc/mdy137. [PubMed]

65. Jørgensen JT. The Potential of Trastuzumab Deruxtecan as a Tissue Agnostic Drug. Oncology. 2023; 101:836-42. https://doi.org/10.1159/000533866. [PubMed]

66. Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, Chung HC, Kindler HL, Lopez-Martin JA, Miller WH Jr, Italiano A, Kao S, Piha-Paul SA, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020; 21:1353-65. https://doi.org/10.1016/S1470-2045(20)30445-9. [PubMed]