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disruptive science and clinical innovation in oncology

At a glance Foreword by VHIO’s Director Introducing VHIO
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VHIO in 2025: Driving progress through disruptive science and clinical innovation in oncology

Josep Tabernero
Director
The Vall d’Hebron Institute of Oncology (VHIO)

Tackling cancer is a global endeavor, and VHIO remains at the heart of advancements in oncology, driven through transformative collaborative research, and (co) leading the new wave of scientific discoveries and technological innovations. Such remarkable progress in fighting this disease has been made thanks to historic breakthroughs and recent game changers in the field—latterly, including precision screening, novel immunotherapies, and prevention strategies—to name but a few. A recent article published in The Economist1 , brings into context the immense challenge we have faced in tackling cancer.

Back in 1971, then US president Richard Nixon spurred on by the technological successes seen in the Apollo lunar missions, sought to eliminate cancer – with expectations of a “cure” set in years.

Given that we still do not have a “cure”, and cancer remains a major cause of death, it may appear as though we are failing in our aim to tackle cancer. But that is the wrong conclusion.

50 years ago, cancer was called “The Big C” – a catch-all phrase that today seems naïve and archaic. Especially, now we are aware – for example – of more than a dozen types of breast cancer alone, characterized by genetics, cell type, stage of disease, and each one with their own therapeutic regime and treatment protocol. This is immense progress!

And, as we enter a new era where explorers are returning to the moon, my aspiration for VHIO, together with the global oncology community, is to dive ever deeper into the biology of cancer, seeking to identify the mechanisms that initiate and underpin the formation of cancers—the fundamentals of the disease—and we remain resolutely steadfast in our efforts to collectively curtail and one day conquer cancer.

Despite significant progress, cancer remains one of the most urgent healthcare challenges globally. Comprehensive data recently published in The Lancet2, the Global Burden of Disease 2023 Cancer Collaborators reported on the cancer burden for 47 cancer types and groups in 204 countries and territories in 1990-2023 with projections to 2050.

Results of the new analysis show a rapid increase in the global number of cancer cases and deaths between 1990-2023. Without urgent action and targeted funding, a further 30.5 million people are estimated to be newly diagnosed, and 18.6 million are expected to die from cancer before 2050. Over half of new cases and two-thirds of deaths are forecast to occur in low- and middle-income countries.

Interestingly, the authors noted that when applying statistical adjustments to accommodate the aging population, and population growth, the global case and mortality rates are not forecast to rise. While this is encouraging, we are still far from achieving the UN Sustainable Development Goal (SDG) to reduce non-communicable disease mortality by a third from 2015 to 2030. Much work clearly still needs to be done to reduce the burden of cancer across countries and worldwide.

Within VHIO, our research programs and teams are committed to advancing disruptive science and clinical innovation in oncology to accelerate the pace of progress against cancer. Established in 2006 by José Baselga, VHIO’s Founding Director, we were an early pioneer of translational cancer science and precision oncology. Today our institute continues grow from strength to strength and evolve in tune with the rapidly changing landscape of precision oncology.

Artificial Intelligence (AI), is already showing great potential, with promising clinical applications including cancer diagnosis, precision medicine, patient stratification, and new drug design.

At the end of this year, we warmly welcomed Albert Antolin as Group Leader of our newly created AI-Driven Drug Discovery Group. Combining computational and experimental approaches, this group focuses on accelerating the discovery of new cancer medicines.

Applying AI and data science, Albert’s team will work to design safer and more effective small-molecule therapeutics. With expertise in data science, chemistry, and cancer biology, this group will work closely with clinicians, translational scientists, and industry partners to drive advances in the field of systems chemistry and foster the early clinical development of new therapeutic compounds.

In line with our strategic plan, we have re-organized our experimental hematology research program. This restructure incorporates our Cell Engineering and Hematologic Immunotherapy, Lymphoid Malignancies, and Myeloid Malignancies Research groups, under the leadership of Pere Barba, Pau Abrisqueta, and David Valcárcel, respectively. The previous director of this VHIO program, Francesc Bosch, joined Enriqueta Felip and Elena Garralda, at the end of 2025, as co-Director of our Clinical Research Division.

Similarly, Elena Élez’s group—formerly our colorectal cancer program—has now been reorganized as VHIO’s Gastrointestinal Tract Tumors, with Jaume Capdevila (formerly a senior clinical investigator at VHIO), now leading our re-structured Hepatobiliary Pancreatic Cancer and Endocrine Tumors Group.

In July, Joan Carles officially stepped down as Head of our Genitourinary (non-prostate), Central Nervous System Tumors (CNS), Sarcomas, and Tumors of Unknown Origin Group, and co-lead of our Prostate Cancer Group. Cristina Suárez, a former Medical Oncologist and Clinical Investigator of Joan’s team, was appointed Group Leader in August. We will continue to benefit from Joan’s renowned expertise in this field as a Senior Investigator of Cristina’s group. Our Prostate Cancer Group remains under the stewardship of Joaquin Mateo.

Following the departure of Ana Oaknin at the end of December, Lorena Fariñas-Madrid—a former member of Ana’s group—has taken the reins as the new leader of VHIO’s Gynecological Malignancies Group.

In addition to optimizing our organizational structure, research programs, groups and units, VHIO continues to make important headway against cancer thanks to the support we receive from our patrons—Generalitat de Catalunya, Fundació Privada CELLEX, Fundación FERO, ”la Caixa” Foundation, Fundación BBVA, and the CRIS contra el Cáncer Foundation—as well as the institutional support by other funding bodies including the Asociación Española Contra el Cáncer (AECC) Excellence, Severo Ochoa Center of Excellence, and the AstraZeneca José Baselga Innovative Disruption (J-BID) programs.

Without this incredibly generous support, along with the backing and belief that we receive from many other VHIO supporters, funding entities, agencies and individuals, our devotion and commitment to reducing the devastating burden of this disease would be absolutely impossible.

I must also acknowledge the many remarkable fundraising events, public outreach initiatives and patient engagement activities that were organized and celebrated throughout the year. These wonderful initiatives further galvanize our collective efforts to tackle cancer.

Scientific Achievements in 2025

Carried out in collaboration with many other cancer researchers, clinical investigators, colleagues and peers—both nationally and internationally—we collectively continue to win important gains against cancer, some of which have been (co) led by VHIO cancer researchers and clinical investigators.

In 2025, VHIO teams and talents (co) authored 559 scientific articles. Along with the development and integration of avant-garde platforms and innovative technologies, these contributions have provided precious new insights into cancer biology and the molecular drivers of disease, which will enable us to more effectively and precisely target the vulnerabilities of tumor types and the molecular drivers of disease.

While I cannot possibly do justice to all of these advances in translational cancer science and clinical research over the past year, many of which were published in some of the most prestigious scientific and medical journals, I would like to highlight a handful of studies, some of which were paradigm-shifting (listed in order of VHIO programs and groups by this report’s index).

César Serrano, Group Leader of Sarcoma Translational Research at VHIO and Medical Oncologist at the Vall d’Hebron University Hospital.

Consensus Guidelines for Next-Generation Sequencing in Sarcoma

Published in JAMA Oncology3, a consensus review provides recommendations for using next-generation sequencing (NGS) in the diagnosis and clinical management of sarcoma. Lead author César Serrano and colleagues offer guidelines for the evidence-based use of these technologies in this rare and heterogeneous group of tumors.

From a diagnostic standpoint, the investigators recommend that genomic sequencing should not be used routinely, as most diagnoses can be established using classical histological criteria. Similarly, current evidence does not support routine clinical NGS for all patients, given the limited number of identified actionable genetic alterations.

The group emphasized that the benefit of NGS-based targeted therapies depends largely on the specific disease subtype and available scientific evidence. Decisions to perform NGS—and the interpretation of those results—should only occur at specialized sarcoma centers with multidisciplinary teams. While not yet a routine tool for every patient, specialized genomics will enable more accurate diagnoses and better-targeted treatments for selected patients.

Rodrigo A. Toledo, Head of VHIO’s Biomarkers and Clonal Dynamics Group.

Ultrasensitive Liquid Biopsy for Predicting and Monitoring Immunotherapy Response

A VHIO-led study published in Clinical Cancer Research4 underscores the efficacy of analyzing circulating tumor DNA (ctDNA) using a highly sensitive liquid biopsy platform. Co-directed by Rodrigo A. Toledo and Elena Garralda, this work demonstrates how this tool can evaluate early response, predict survival, and monitor tumor progression in patients with advanced cancers who received immunotherapy in the context of phase I clinical trials.

These are the first results from IMMUNOMICS-VHIO, a platform for discovering liquid biopsy biomarkers. The investigators analyzed 1,455 longitudinal plasma ctDNA samples obtained from 136 patients with refractory metastatic solid tumors across 24 cancer types, followed by an independent validation in 66 patients (374 samples). They discovered that lower baseline ctDNA levels associated with better progression-free survival and overall survival. Three weeks after starting treatment, changes in ctDNA levels correlated with disease control; complete clearance of ctDNA from the blood strongly associate with radiological response and prolonged survival. Additionally, ctDNA dynamics helped distinguish true tumor progression from pseudoprogression and predicted outcomes in patients continuing on immunotherapy after initial progression.

Laura Soucek, an ICREA Research Professor, Director of VHIO’s Experimental Therapeutics Program, Head of our Models of Cancer Therapies Group, and co-Founder and CSO of Peptoymc S.L. Jonathan R. Whitfield, a Senior Investigator of the Soucek lab.

MYC: From ‘Undruggable’ Target to Clinical Trials

In a review article for Nature Reviews Drug Discovery5, Laura Soucek and Jonathan R. Whitfield, provide an expert overview of strategies to inhibit MYC, focusing on the most recently described inhibitors and those that have reached clinical trials.

For two decades, Laura and her team have focused on MYC inhibition as a therapeutic strategy in cancer. As their review highlights, targeting MYC has been particularly challenging and long-considered undruggable. Recent efforts aimed at developing MYC inhibitors have enabled the initiation of early clinical trials to assess their therapeutic potential.

The Omomyc therapeutic mini-protein (OMO-103), developed at VHIO by the spin-off Peptomyc, is the first MYC inhibitor to complete a phase I clinical trial, demonstrating safety and early signs of clinical activity. It is currently being evaluated in a phase Ib trial in metastatic pancreatic cancer and a phase II trial in high-grade osteosarcoma.

MYC targeting by Omomyc also continues to show high promise in preclinical settings. Published in Cell Reports6, a study led by investigators of our Mouse Models of Cancer Group —first authored by Fabio Giuntini, a member of Laura’s team—show that Omomyc induces tumor DNA damage in patient-derived preclinical models of BRCA1/2-mutated triple-negative breast cancer (TNBC), an effect enhanced when combined with poly (ADP-ribose) polymerase inhibitors (PARPi).

Mechanistically, Omomyc downregulates DNA damage repair (DDR) gene expression and increases DNA damage in TNBC models, including PARPi-resistant systems. The combination with PARPi produces a synergistic antitumor effect in vitro and in vivo, leading to increased DNA damage, apoptosis, and improved tumor control compared to either agent alone.

Notably, PARPi-resistant PDXs showed a significantly higher MYC transcriptional activity compared to sensitive ones, which is reversed by Omomyc. In samples from patients with TNBC obtained pre-treatment with PARPi, the transcriptomic signature of MYC enabled the researchers to predict response to treatment, suggesting that this biomarker could help identify patients who are more likely to benefit from this therapy.

These findings position MYC as a driver of PARPi resistance and support Omomyc as a therapeutic strategy to enhance PARPi efficacy and overcome resistance in TNBC.

Joan Seoane, an ICREA Research Professor, Director of VHIO’s Immuno-Oncology and Tumor Microenvironment Program, Head of our Gene Expression and Cancer Group, and co-Founder of Mosaic Biomedicals.

Promising New Strategy to Improve the Diagnosis and Monitoring of Glioblastoma

Glioblastoma is a complex disease and one of the most challenging tumor types to treat. Traditional biopsies are invasive, costly, and often fail to capture the full heterogeneity of the tumor. Developing non-invasive approaches that capture the intrinsic heterogeneity of these tumors remains a major priority.

Leukemia Inhibitory Factor (LIF) is a pleiotropic cytokine secreted by tumor cells to evade the immune system—contributing to tumor progression and resistance to therapy—and has emerged as a promising therapeutic target. Joan Seoane and Raùl Herance, Head of the Molecular Imaging and Therapy Group at the Vall d’Hebron Research Institute (VHIR), and colleagues have developed a zirconium-89–labeled radiopharmaceutical that enables visualization of LIF expression by PET imaging.

Published in ACS Pharmacology & Translational Science7, this strategy may help optimize patient stratification based on LIF expression and support treatment decision-making, while longitudinal monitoring could improve assessment of disease progression and therapeutic response.

José A. Seoane, Head of VHIO’s Cancer Computational Biology Group.

The Exposome and Tumor Initiation

Published in Trends in Cancer8, a review co-authored by José A. Seoane and colleagues at the Institute for Research in Biomedicine (IRB Barcelona), examines how environmental exposures—the exposome—contribute to cancer initiation through epigenetic reprogramming and cellular plasticity, and how these processes may provide opportunities for prevention, early detection, and disease interception.

Drawing on recently published studies by other groups, the authors highlight how lifestyle and environmental factors can foster cancer development by inducing phenotypic changes that reshape cellular identity and function.

Key takeaways include the role of regenerative plasticity in conferring neoplastic potential to genetically-predisposed cells and the influence of microbial ecosystems in modulating whether the host environment supports or restrains tumor growth.

On a related note, cancer prevention and the role of environmental exposures in tumor initiation are emerging research priorities in the lab of José A. Seoane. Illustrative of this direction, a preprint article9 with publication anticipated in 2026 examines the impact of the exposome on early-onset colorectal cancer through epigenetic signatures, providing novel mechanistic insights underlying the rising incidence of this disease in younger populations.

Raquel Perez-Lopez, Head of VHIO’s Radiomics Group.

SALSA: Artificial Intelligence for Automated Liver Tumor Analysis

Published in Cell Reports Medicine10, a VHIO-led study directed by Raquel Perez-Lopez—carried out in collaboration with other VHIO groups—demonstrated the potential of a novel, CT-based deep learning-driven tool to enhance liver cancer (hepatocellular carcinoma) diagnosis, treatment planning, and response evaluation: SALSA – System for Automatic Liver tumor Segmentation And detection. This tool automatically detects and delineates both primary and metastatic liver tumors on computed tomography (CT) scans.

For its development and training, investigators integrated a well-validated segmentation framework with a large dataset comprising 1,598 CT scans in 1,306 patients with cancer, which included 4,908 primary or metastatic liver tumors. SALSA achieved high accuracy tumor detection with precision of over 99% at the patient level, and a lesion-by-lesion detection precision of almost 82% in the external validation cohort. Showing precise and automated identification and delineation of liver cancer on CT images, this AI-driven tool provides precise quantification of tumor burden with no prior manual prompt requirements. Validation across several test and external cohorts demonstrated the efficacy and reliability of this novel tool, matching and often surpassing the accuracy of expert radiologists.

These results support SALSA as a promising candidate for clinical implementation as a medical device for automated cancer detection, staging, and treatment response evaluation.

Enriqueta Felip, co-Director of VHIO’s Clinical Research Division, Head of our Thoracic Tumors Group, and Deputy Director of the Medical Oncology Department at the Vall d'Hebron University Hospital.

The Long-Term Impact of Adjuvant Atezolizumab in Resected NSCLC

The IMpower010 global, multicenter, open-label, randomized phase III study compared immunotherapy atezolizumab with best supportive care (BSC) in patients with stage IB-IIIA non-small cell lung cancer (NSCLC) after complete resection and treatment with adjuvant platinum-based chemotherapy. The trial enrolled 1,280 patients who were randomly assigned to receive atezolizumab or BSC, and also included patients with tumors harboring EGFR mutations or ALK rearrangements.

Reported at the 2025 ASCO Annual Meeting and concomitantly published in Journal of Clinical Oncology11—with Enriqueta Felip as first and corresponding author—the updated 5-year disease-free survival (DFS) data as well as the second interim overall survival data continue to show a positive overall survival trend compared to BSC, with the greatest benefit observed in patients with PD-L1 expression ≥50%.

Across key subgroups, atezolizumab improved DFS, particularly in stage II–IIIA patients with PD-L1 ≥1%, although statistical significance boundaries were not crossed in all analyses. Benefits were less consistent in tumors harboring EGFR or ALK alterations.

Overall, these results demonstrate durable DFS benefit with adjuvant atezolizumab, supporting its use in PD-L1–selected populations, especially those with high PD-L1 expression.

Cristina Saura, Head of VHIO’s Breast Cancer Group and the Breast Cancer Unit at the Vall d’Hebron University Hospital.

Potential New Combination Strategies in HER2+ Metastatic Breast Cancer

Results from interim analysis of the international, multicenter, randomized phase III DESTINY-Breast09 study, co-authored by Cristina Saura, have demonstrated that the combination of antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) plus monoclonal antibody pertuzumab significantly improved progression-free survival (PFS) and reduced the risk of disease progression or death by 44% in patients with HER2-positive (HER2+) metastatic breast cancer who had not previously received other HER2-directed therapy or chemotherapy in the context of advanced disease.

The findings, first reported at the 2025 ASCO Annual Meeting, showed a median PFS of 40.7 months with trastuzumab deruxtecan plus pertuzumab compared to 26.9 months for standard-of-care. Confirmed objective response rate (ORR) with the trastuzumab deruxtecan/pertuzumab combination was 85.1%, with a median duration of response that exceeded three years (39.2 months) versus 26.4 months with standard first-line therapy.

DESTINY-Breast09 is the first trial in more than a decade to show an improvement in outcomes in the first-line setting compared to standard of care in patients with previously untreated HER2+ metastatic breast cancer, results of which published in The New England Journal of Medicine12.

The reported data reinforce the importance of optimizing HER2-targeted approaches to patients with HER2+ metastatic breast cancer as first-line therapy to better control the disease from the outset. Results suggest that the combination of trastuzumab deruxtecan with pertuzumab from the time of diagnosis could delay disease progression, postponing the need for a second line of treatment.

Santiago Escrivá-de-Romaní, a Clinical Investigator of VHIO’s Breast Cancer Group and Medical Oncologist at Vall d’Hebron.

An ongoing multicenter phase II study is evaluating HER2-targeted bispecific antibody zanidatamab plus CDK4/6 inhibitor palbociclib and endocrine therapy fulvestrant as a treatment combination in heavily pretreated patients with HER2-posisive/HR-positive metastatic breast cancer who have progressed on prior HER2-targeted therapies.

Published in The Lancet Oncology13, with Santiago Escrivá-de-Romaní as first and corresponding author, primary results show that this triplet combination achieves promising antitumor activity, with a 6-month progression-free survival rate of 66.7% and a favorable safety profile, supporting further clinical development.

Eva Muñoz-Couselo, Group Leader of Melanoma and Other Cutaneous Tumors at VHIO and Medical Oncologist at the Vall d'Hebron University Hospital.

Context-Dependent Activity of Nivolumab–Relatlimab in Melanoma

The global phase I/III randomized RELATIVITY-047 study evaluated the immunotherapy combination of nivolumab and relatlimab versus to nivolumab monotherapy in previously untreated metastatic or unresectable advanced melanoma. The combination doubled progression-free survival (10.1 versus 4.6 months), improved response rates and showed a manageable safety profile, with subsequent analyses demonstrating an overall survival benefit that supported regulatory approval.

Based on these positive results, the investigators evaluated whether this combination could improve recurrence-free survival in patients after complete resection of stage III-IV melanoma. Co-authored by Eva Muñoz-Couselo, and presented at the ESMO Congress 2025 by lead author Georgina V. Long, with simultaneous publication in Nature Medicine14, the phase III double-blind RELATIVITY-098 international study enrolled 1,093 patients randomized to receive nivolumab plus relatlimab or nivolumab alone for up to one year. In contrast to the metastatic setting, the combination did not improve relapse-free survival compared to nivolumab monotherapy, with similar efficacy observed across both arms.

Translational analyses across the two trials suggest that the absence of macroscopic disease after surgery and the lower levels of LAG-3-positive T cells may limit the added benefit of LAG-3 blockade, in contrast to advanced disease where these cells are more abundant and the combination is effective (as observed in RELATIVITY-047).

These findings underscore the importance of disease context in immunotherapy response and underscore the need to tailor adjuvant strategies based on the underlying tumor-immune biology.

Joaquin Mateo, Head of VHIO’s Prostate Cancer Group and Medical Oncologist at the Vall d’Hebron University Hospital.

RAD51 biomarker could complement next-generation sequencing in personalizing prostate cancer treatment

Published in Cell Reports Medicine15, a study led by Joaquin Mateo and investigators from our Prostate Cancer Group—together with other VHIO groups—supports the use of RAD51 testing as a functional biomarker to complement next-generation sequencing (NGS) in metastatic prostate cancer (mPC).

Alterations in DNA damage repair pathways, including homologous recombination repair (HRR) genes, occur in 20%-25% of advanced prostate cancer cases and underpin sensitivity to PARP inhibitors, representing a key advance in precision oncology. However, limitations of NGS in routine practice highlight the need for complementary biomarkers to improve patient stratification.

The VHIO-developed RAD51 assay enables functional assessment of HRR deficiency. In this study, HRR status was evaluated in 219 primary or metastatic biopsies from 187 patients with advanced prostate cancer using both NGS and RAD51 immunofluorescence. Approximately 21% of evaluable samples showed a RAD51-low score, indicating HRR deficiency, with high sensitivity and specificity for detecting tumors with BRCA1/2 alterations. Clinically, patients with RAD51-low tumors experienced longer progression free survival on treatment with PARPi or platinum-based chemotherapy.

These findings demonstrate the feasibility and clinical utility of RAD51 as a complementary biomarker to NGS, particularly in settings with limited tissue availability, and support its integration to refine patient selection for HRR-targeted therapies.

Irene Braña, Head of VHIO’s Head and Neck Cancer Group and Medical Oncologist at the Vall d’Hebron University Hospital.

Pembrolizumab in Head and Neck Cancer

The randomized, active-controlled, open label phase III KEYNOTE-689 clinical trial was designed to evaluate the efficacy and safety of immunotherapy pembrolizumab, given before and after surgery, combined with standard-of-care (SOC) with radiotherapy, with or without chemotherapy, compared to SOC alone in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).

The study enrolled 714 patients, 321 of whom received pembrolizumab before and after surgery, alongside SOC with preoperative radiotherapy, with or without chemotherapy. Patients were also characterized based on their PD-L1 Combined Positive Score (CPS).

Event-free survival at 36 months was 57.6% in the pembrolizumab group versus 46.4% in the control group across all participants; 59.8% versus 45.9% in patients with CPS ≥10 (more responsive to immunotherapy); and 58.2% versus 44.9% in patients with CPS ≥1. The benefits were statistically significant in the three groups.

The findings, previously reported at the AACR Annual Meeting 2025 by Ravindra Uppaluri of the Brigham Cancer Center and Harvard Medical School in Boston, showed that adding pembrolizumab before and after surgery significantly improved event-free survival. Co-authored by Irene Braña, results of this study—published in The New England Journal of Medicine16—open up new therapeutic opportunities to reduce the risk of recurrence in high-risk patients and point to a potential new SOC.

Jaume Capdevila, Head of VHIO’s Hepatobiliary Pancreatic Cancer and Endocrine Tumors Group and Medical Oncologist at the Vall d’Hebron University Hospital.

Belzutifan for Rare Paragangliomas

The international, open-label, single-arm, multi-cohort phase II LITESPARK-015 trial evaluated the efficacy and safety of the hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor belzutifan in patients with unresectable or metastatic paraganglioma. Co-authored by Jaume Capdevila, findings were presented at ESMO Congress 2025 by first author Camilo Jimenez of the University of Texas MD Anderson Cancer Center, and published simultaneously in The New England Journal of Medicine17.

Prior genomic studies identified HIF2α as a key oncogenic driver in paraganglioma, with alterations in the EPAS1 gene contributing to tumorigenesis and metastatic progression. Belzutifan, a selective HIF2α inhibitor, currently approved for treating adults with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma and other NETs, and is also approved in the U.S. for the treatment of advanced renal cell carcinoma in combination with immunotherapy.

In LITESPARK-015, 72 patients were treated, achieving an objective response rate of 26.4%, and stable disease in 58.3%, with durable responses (median duration of 20.4 months) and a median progression-free survival of 22 months. Median overall survival was not reached. Clinical benefit was further supported by sustained reduction in antihypertensive medication, reflecting control of tumor-related symptoms.

These data, together with a manageable safety profile, led the FDA to approve belzutifan in this setting, representing a first step toward positioning this inhibitor as first-line therapy in paraganglioma and illustrating the translational impact of genomic discoveries in rare cancers.

Elena Élez, Head of VHIO’s Gastrointestinal Tract Tumors and Medical Oncologist at the Vall d’Hebron University Hospital.

New First-Line Strategy for BRAF-Mutated Metastatic Colorectal Cancer

Co-led by Scott Kopetz at the University of Texas MD Cancer Center and myself, the BREAKWATER open-label, randomized phase III study international trial evaluated first-line treatment with targeted therapies encorafenib and cetuximab plus a mFOLFOX6 chemotherapy regimen compared to standard therapy in patients with previously untreated BRAF V600E-mutant metastatic colorectal cancer.

Results of progression-free survival (PFS) and updated interim overall survival (OS) analyses from this study were presented by first author Elena Élez at the 2025 ASCO Annual Meeting and published simultaneously in The New England Journal of Medicine18.

A total of 637 patients with previously untreated BRAF V600E-mutant mCRC were randomly assigned to receive the combination of encorafenib and cetuximab, with or without the mFOLFOX6 chemotherapy regimen with fluorouracil, leucovorin and oxaliplain, or standard therapy. Results showed a clinically meaningful and statistically significant overall survival improvement with the investigational combination versus standard-of-care treatment. The median overall survival was 30.3 months in patients assigned to encorafenib and cetuximab plus chemotherapy, compared to 15.1 months

We observed improved PFS, with a median of 12.8 months in patients treated with encorafenib and cetuximab plus mFOLFOX6 compared to 7.1 months in those who received standard treatment. Results also showed a 47% reduction in the risk of disease progression or death and a 51% reduction in the risk of death with the investigational combination compared to standard treatment.

This new first-line treatment strategy showed unprecedented benefits for patients with BRAF V600E-mutant metastatic colorectal cancer, which has profound implications in the prognosis for this patient population.

Perioperative Immunotherapy in Gastric Cancer

The global, randomized phase III MATTERHORN clinical trial assessed the efficacy of the combination of perioperative durvalumab and standard FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) chemotherapy versus placebo plus FLOT in patients with resectable, localized gastric and gastroesophageal junction cancers.

948 patients were randomized (1:1) to receive treatment with durvalumab in combination with FLOT or placebo plus chemotherapy prior to surgery. This was followed by adjuvant durvalumab plus chemotherapy, then durvalumab monotherapy, or placebo plus chemotherapy and placebo monotherapy after surgery.

Presented at the 2025 ASCO Annual Meeting by lead study and corresponding author Yelena Y. Janjigian at the Memorial Sloan Kettering Cancer Center, New York and concomitantly published in The New England Journal of Medicine19, results of second interim analysis of efficacy and safety showed that at a median follow-up of 31.5 months, median event-free survival and median overall survival were not reached in patients assigned to the investigational combination. Median event-free survival of 32.8 months and median overall survival of 47.2 months were observed in patients who received placebo plus FLOT.

MATTERHORN is the first global, randomized phase 3 study to show superior event-free survival with an immunotherapy combination versus standard-of-care (SOC) in this setting. Findings from this study support this therapeutic strategy as a potential new SOC for patients with resectable, localized gastric and gastroesophageal junction cancers.

Cristina Suárez, Head of VHIO’s Genitourinary (non-prostate), Central Nervous System Tumors (CNS), Sarcomas, and Tumors of Unknown Origin Group, and Medical Oncologist at the Vall d’Hebron University Hospital.

Investigational Triplets for Renal Cell Carcinoma

KEYMAKER-U03 is an international, multicenter, open-label, phase I/II umbrella trial evaluating different combinations of pembrolizumab-based immunotherapy and targeted treatments for advanced clear cell renal cell carcinoma (ccRCC). First results from sub-study 03A were presented by first and corresponding author Cristina Suárez at ESMO Congress 2025, and published simultaneously in Annals of Oncology20.

A total of 353 patients were randomized to receive one of several investigational combinations or the reference regimen of pembrolizumab plus lenvatinib as first-line therapy. Combinations included favezelimab-, vibostolimab-, or quavonlimab-based regimens with pembrolizumab and lenvatinib, as well as a triplet of pembrolizumab, belzutifan, and lenvatinib.

Among these, the pembrolizumab-belzutifan-lenvatinib triplet showed the most promising antitumor activity, with an objective response rate (ORR) of 78% and a median progression-free survival (PFS) of 31.8 months as compared to 20.8 months in the reference arm. The pembrolizumab–quavonlimab–lenvatinib combination also achieved a high response rate (71%) but did not improve progression-free survival, while the remaining regimens showed more limited efficacy.

Ongoing phase III evaluation in the LITESPARK-012 trial will determine whether these findings translate into clinical benefit, focusing on the two most active triplet combinations. If confirmed, these strategies could expand first-line treatment options in advanced ccRCC.

Guillermo Villacampa, Head of VHIO’s Statistics Unit.

Validation of the HER2DX Test in Early-Stage HER2+ Breast Cancer

First authored by Guillermo Villacampa, results of a study published in The Lancet Oncology21, validated the HER2DX genomic test in early-stage HER2-positive (HER2+) breast cancer.

This work integrates a systematic review and individual patient-level meta-analysis of more than 2,500 patients across 11 clinical studies. HER2DX emerged as a strong predictor of both event-free survival and overall survival, providing additional prognostic insights beyond standard clinical-pathological variables and traditional clinical factors.

Incorporating HER2DX risks scores, clinical information, and survival outcomes, findings showed that patients classified as low-risk by HER2DX had a six-year event-free survival rate of 93.6% versus 82.9% for those considered high-risk. This association was consistent across subgroups, regardless of tumor stage, nodal stage, pathological complete response, or hormone receptor status.

These findings support the integration of HER2DX into clinical decision-making to refine risk stratification and guide treatment intensity. The study also included contributions from Ana Vivancos at VHIO. HER2DX was developed by REVEAL GENOMICS, a spin-off of Hospital Clínic de Barcelona, IDIBAPS, the University of Barcelona, and VHIO.

Rodrigo Dienstmann, Head of our Oncology Data Science Group (ODysSey).

A Decade of VHIO’s Precision Medicine Program: Measured by Performance Indicators

My final selection among the many VHIO (co)-led contributions this year is a core study published in ESMO Open22. Led by Rodrigo Dienstmann, and co-authored by several VHIO group leaders, this retrospective analysis reports a decade-long experience since the implementation of VHIO’s Precision Medicine Program (PMP) in 2014.

The study evaluates whether a continuously evolving molecular diagnostics framework can deliver sustained clinical value by improving the detection of actionable alterations and expanding access to matched therapies. To address this, investigators analyzed tumor profiling outcomes, incorporating the role of multidisciplinary molecular tumor boards in standardizing interpretation and prioritizing treatment decisions.

Program performance was assessed using key performance indicators, including the proportions of patients with tier I-V alterations—classified by the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT)—and those receiving matched therapies. Their analysis also considered factors such as advances in molecular diagnostics as well as the evolving clinical trial portfolio requiring biomarkers.

Overall, the results demonstrate how VHIO’s PMP has successfully enabled robust actionable alteration detection and facilitated access to matched therapies for more than a decade underscoring the value of longitudinal program evaluation in sustaining institutional precision oncology initiatives.

2025: A Trio of Institutional Program Renewals

Driven by our wonderful private patrons, three of our Institutional Programs have been renewed for the next four years—each set to launch in 2026. These important initiatives are instrumental in driving the development of cutting-edge technologies, innovative therapies, and platforms in precision oncology.

Supported by funding received from the ”la Caixa” Foundation, our CaixaResearch Advanced Oncology Research Program, has been renewed for the period 2026-2030.

This program enables investigators and multidisciplinary teams of VHIO’s Research Unit for Molecular Therapy of Cancer (UITM) – CaixaResearch, to design and conduct an expanding portfolio of phase I-II clinical trials with targeted anti-cancer therapies against novel targets, and accelerate transformative research focused on unravelling the complexities of clinical resistance mechanisms.

This renewal will be instrumental in further strengthening this unit as a reference center in precision oncology by developing novel therapies based on tumor profiles, optimizing treatment strategies through innovative clinical trial designs including multi-modular basket studies and umbrella trials, and harnessing these advances to bring innovative drugs including first-in-class treatments and new combinations to patients.

Powered by the Fundación FERO’s Institutional Advanced Molecular Diagnostics Program (DIAMAV), our comprehensive Molecular Prescreening Program facilitates the clinical implementation of emerging cancer biomarkers that help to optimize the selection of patients being considered for enrolment in early phase clinical trials. This program serves as a cornerstone of precision medicine at VHIO. Over the past decade it has provided access to advanced molecular diagnostics to more than 12,000 cancer patients.

FERO’s renewal of its DIAMAV program will enable the continued development of advanced molecular diagnostics against cancer, increased patient access to such cutting-edge technologies, acceleration of the implementation of liquid biopsies, and further position VHIO as a reference in early cancer detection and precision oncology.

This year, we completed the BBVA Foundation Comprehensive Program of Cancer Immunotherapy and Immunology (CAIMI-II). This program, has successfully consolidated VHIO as a leading European center in translational immune-oncology and advanced cell therapies, through the integration of discovery science, biomarker development, clinical research, and manufacturing capabilities in the development of more precise and effective immune-based cancer therapies.

Considering the many scientific discoveries, regulatory achievements and talent development initiatives that have been driven thanks to CAIMI-II, the follow-on CAIMI-III will deliver continuity and further expand this strategic program, reinforcing VHIO’s long-term commitment to advancing next-generation cancer immunotherapies.

In addition to these three program renewals, the ongoing VHIO-CRIS Precision Intelligence & Oncology Network for Enhanced Evidence & Research (PIONEER) Institutional Program, is driven by the support we receive from another of our wonderful private patrons—the CRIS contra el Cáncer Foundation.

Key initiatives include developing digital platforms for analyzing, integrating, and visualizing multimodal oncology data, and creating AI-driven tools and models to integrate and visualize medical imaging alongside other cancer research data—genomic, imaging, clinical, and more—generated at our institute.

I also have to thank the equally generous institutional support that we receive from other organizations, which are funding three additional and ongoing programs of excellence in precision oncology:

Since 2022, VHIO is accredited and awarded as a Severo Ochoa Center of Excellence, and we are the first research institute linked to the national healthcare system to have received this distinction. This accolade reflects our Institute’s important contributions to cancer science and precision medicine in oncology at a global level. It also confirms VHIO’s scientific leadership and proven capacity to advance frontier research, generate high-impact results, as well as attract and retain research talent. This Institutional Program, further strengthens VHIO’s research programs and teams in advancing cancer discovery and precision medicine in oncology.

Another of our key Institutional Programs is supported by the Asociación Española Contra el Cáncer – AECC (Spanish Association Against Cancer) Excellence Program through the Advanced Therapies Accelerator Program. Through this initiative, we aim to establish VHIO as an international reference in the rapidly emerging field of gene and cellular therapies and contribute to the expansion of Europe’s product development in this area. In this program, I am pleased to report that we completed the construction of our Advanced Therapies Accelerator Unit’s cleanroom in 2025, a key milestone for the project, and essential laboratory infrastructure for gene and cell therapy manufacture.

Supported by AstraZeneca, the AstraZeneca José Baselga Innovative Disruption (J-BID) Program, honors the legacy of José Baselga, VHIO’s founding director, by championing the disruptive innovation that defined his vision and work.

In 2025, the J-BID Program supported four VHIO groups leading pioneering research projects with high potential for breaking new ground in our understanding of cancer and reveal novel actionable insights.

For more information on each of these programs as well as key highlights and contributions in 2025, click here.

The Power of Collaborative Precision Oncology

To advance and accelerate personalized and targeted therapies against cancer, we firmly believe in identifying, fostering and participating in strategic partnerships of excellence—both nationally and internationally.

Connecting expertise across borders through strong collaborations, networks, and consortia continues to spur transformative cancer science. These collective efforts also drive great progress in discovering new cancer medicines as well as harnessing these advances to bring innovative therapies including first-in-class treatments and new combinations to people with cancer.

Elena Garralda, co-Director of VHIO’s Clinical Research Program, Head of our Early Clinical Drug Development Group, Director of VHIO’s Research Unit for Molecular Therapy of Cancer (UITM) – CaixaResearch, and Medical Oncologist at Vall d’Hebron.

Co-authored by world-leading experts in oncology, including VHIO’s Elena Garralda as Member of Cancer Core Europe’s (CCE) Clinical Trials and Translational Research pillar, a review article published in the Journal of Clinical Oncology23 provides an excellent overview of the importance of early phase clinical trials (EPCT), and the role that EPCT consortia have in delivering such trials.

In this paper the authors, led by Jia (Jenny) Liu at the Kinghorn Cancer Centre, St Vincent’s Hospital in Sydney, explore the challenges EPCT consortia face, including enrolling suitable patients and streamlining start-up.

In the review paper, 15 EPCT consortia were identified including two in the United States, three in Europe, five in Asia-Pacific, two intercontinental consortia, and three within private oncology networks. While the authors recognize that this list is by no means exhaustive, and that these consortia vary in their scope, funding, and structure—from government-funded models such as the National Cancer Institute Experimental Clinical Trials Networks through charitably funded and private research organizations—the article highlights the importance of collaboration among the respective project partners as well as tightly connected teamwork in the delivery of goals.

In their summary the authors demonstrate how EPCT networks can best play a role in collaborative research to provide patient-centric biomarker-matched treatments, and streamline the execution of clinical trials to improve timelines and cost efficiency.

Towards More Equitable Personalized Cancer Care in Europe

In line with VHIO’s strategic commitment to advancing cancer care and knowledge across Europe, we also collaborate as partners in several work packages of flagship European initiatives, including EU4Health Programme plus other Joint and Support Actions. These further strengthening our prominence and (co) leadership in shaping the future of cancer care for patients in Spain and Europe-wide.

Coordinated by our Scientific Management Area, our institute is now participating in two additional EU4Health projects—the 4-year JA PCM Joint Action and 3-year SPARC Support Action—both of which launched in late 2025.

Co-funded by the European Union, the EU4Health Program’s Joint Action on Personalized Cancer Medicine (JA PCM) brings together a consortium of more than 140 European partners from 29 countries with a shared goal: to accelerate cross-border collaboration, strengthen European knowledge networks, form synergies with EU initiatives, and promote equitable access to personalized cancer medicine throughout Europe.

Led by Sciensano in Belgium, this consortium’s goal is to create a lasting European framework for personalized oncology that is sustainable, measurable, and patient-centered, as well as expand access to and knowledge of personalized cancer medicine across Europe.

By adopting a life course perspective—developing healthcare management pathways that address the needs of healthy individuals (prevention and risk assessment), cancer patients (diagnosis and treatment), cancer survivors (follow-up and quality of life)—this multi-perspective approach aims to ensure that personalized cancer medicine benefits individuals along the patient journey.

Specifically, VHIO is leading a pilot program focused around supranational Molecular Tumor Boards (MTBs) for rare and complex cases as well as two task areas: building a personalized cancer medicine treatment network, and advanced trainings for health care professionals.

Co-funded by the European Union, the EU4Health SPARC—Support of Personalized Medicine Approaches in Cancer—is a Support Action of JA PCM. Coordinated by the Universidad Politécnica de Madrid (UPM), this project connects 17 partners across 8 EU countries and aims to accelerate the adoption and integration of personalized medicine in cancer care across European healthcare systems.

Structured around six interlinked pillars, SPARC aims to improve diagnostics, access to care, and outcomes for both common and rare cancers across Europe – with a strong focus on patient involvement. The project promotes the use of precision medicine tools and cross-border collaboration, engaging healthcare professionals, policymakers, patients, and researchers to harmonize practices and integrate personalized approaches into national healthcare systems.

Headed by VHIO’s Alejandro Piris, Principal Investigator for the project and Director of our Scientific Management Area, several of our investigators will play an important role in the Joint Action.

Led by Alberto Hernando, Clinical Investigator of VHIO’s UITM-Caixa Research, we will coordinate a pilot to establish the supranational Molecular Tumor Board (MTB) for rare and complex cancer cases.

In parallel, Rodrigo Dienstmann, Group Leader of VHIO’s Oncology Data Science (ODysSey) Group, will lead efforts to standardize and harmonize data collection across MTBs. Additionally, Judith Balmaña, Head of VHIO’s Hereditary Cancer Genetics Group, is involved in Arm 1, which focuses on cancer prevention and early detection.

VHIO joins Europe’s Leading Cancer Prevention Network

Announced in summer 2025, VHIO became a core member Cancer Prevention Europe (CPE), a pan-European consortium of organizations which aims to reduce morbidity and mortality from cancer in European populations, through the prevention and earlier diagnosis of the disease. Coordinated by the International Agency for Research on Cancer (IARC), it fosters collaboration among research institutions, public health bodies, and policymakers to transform scientific insights into impactful strategies that benefit European citizens. Through coordination of research, sharing best practise, and driving policy change, CPE’s core aims are: the implementation of effective preventive measures, accelerating the translation of research into national and international guidelines, and identifying innovative strategies for cancer prevention.

CPE’s strategic agenda for the coming years calls for the development of high-quality, multicentre research initiatives based on the principles of open science and cross-border collaboration. It also envisions the creation of a European Knowledge Hub on Cancer Prevention—a centralized resource to collect and disseminate evidence, identify research gaps, and support the design of future studies. It also focuses on education and capacity-building, aimed at training a new generation of multidisciplinary researchers equipped to lead Europe’s prevention efforts into the future.

Javier Carmona, Head of Scientific Strategy and Translational Programs at VHIO, represents our institute and will lead our participation to help shape the future of cancer prevention and policy at the European level. VHIO’s membership of CPE not only underscores its leadership in translational oncology and precision medicine but also strengthens our ability and reach to influence how research translated into real-world preventive strategies.

The Last Word

As I noted at the start of this foreword, I believe we are in a new era of immense scientific progress in cancer, with new insights coming through AI-driven research, but also through improved collaborations across all fields of oncology – from early stage diagnosis, strategic design of new therapeutics, improved clinical trial design, and greater knowledge of the fundamentals of biology that lead to cancer.

It has been an outstanding year at VHIO, and now our whole team of cancer researchers and clinical investigators are collectively better equipped than ever to deliver even more transformative breakthroughs for our patients.

We do not sit still. In this coming year we will announce our 2026-2029 Strategic Plan. This will come into effect as our institute turns 20 in January next year. To mark this milestone birthday, our wonderful VHIO communications team, directed by Bianca Pont, is organizing various celebratory activities and initiatives. But more about that another time!

While we continue to plan for the future, the statistics today around cancer speak for themselves. Cancer remains one of the most urgent health challenges globally. The incidence of several cancer types is on the rise and in some tumor types we are seeing more young patients, particularly in colorectal cancer (CRC).

Based on current estimates from the International Agency for Research on Cancer (IARC)24, we are seeing around 20 million new cases of cancer each year globally, alongside 9.7 million deaths. As such, much work still needs to be done to ensure we continue to make strides against this disease.

However, continued progress against cancer also relies on robust and consistent funding, policy making tailored to the needs and specificities of each geographical region, the sharing of resources and infrastructures, and the further strengthening of international collaboration.

The cancer research community must continue to stand together to ensure the stability and growth of research worldwide. Pressing urgently ahead, we must collectively continue to battle against the unthinkable scale and associated implications of this disease. One life claimed by cancer is one too many.

We can and will continue to do even better in our collective efforts to beat cancer.

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