Last year’s VHIO Scientific Report celebrated the incorporation of several new teams and promotions of VHIO researchers and clinical investigators as leaders of newly established groups across our programs. As the theme of this year’s report indicates, we have continued to ramp up our team science and clinical research in oncology by strengthening our scientific infrastructure and laying the groundwork for our future initiatives and partnerships—both nationally and internationally. All with one shared goal in mind: to curtail and one day conquer cancer.

Established in 2006 as an early trailblazer for translational cancer research and precision oncology by José Baselga, VHIO’s Founding Director, our institute has grown exponentially as a comprehensive cancer center of excellence internationally. As our institute continues to expand from strength to strength, this year we have been busy re-structuring some of our scientific programs that will enable us to further deliver on our research priorities.

Based on our strategic plan, we have re-organized preclinical and translational research under the umbrella of Biomedical Research. This division incorporates our Experimental Therapeutics, Immuno-Oncology and Tumor Microenvironment, Systems Oncology programs and groups, under the leadership of VHIO investigators and ICREA Research Professors Laura Soucek, Joan Seoane, and Marcos Malumbres, respectively. Our Clinical Research Division and Core Transversal Groups and Units remain under the stewardship of Enriqueta Felip and Elena Garralda (Clinical), and Paolo Nuciforo (Core).

VHIO’s Transversal Services program is co-directed by Alejandro Piris, Director of our Scientific Management Area, and Carlos López, Director of VHIO’s Business Development, Innovation and Systems Area. This division incorporates our Data Science Program, which now includes two recently established units: Biostatistics led by Guillermo Villacampa, and Data Engineering for Research headed by Anna Pedrola, both former investigators of VHIO’s Oncology Data Science (ODysSey) Group directed by Rodrigo Dienstmann.

Guillermo’s team implements innovative biostatistical methodologies to optimize study design, data analysis and interpretation to enhance clinical and preclinical research at VHIO. Launched at the beginning of this year, Anna’s group focuses on the standardization and digitization of data and creating and maintaining an optimal infrastructure and environment for institutional data storage and management.

I am thrilled to announce that the VHIO-CRIS Program for Precision Oncology and Digitalization launched this year as a new VHIO Institutional Program, supported by our most recent VHIO private patron, the Cris Contra el Cáncer Foundation, which officially joined our Board of Trustees in November 2024. With the goal of pioneering digitalization in precision oncology, this program will catalyze innovation in precision oncology and digitalization by enhancing multimodal data sharing across our research programs and groups.

By integrating diverse datasets, it will optimize data application for clinical support further strengthen VHIO’s Data Science Program. Aimed at establishing VHIO as an international reference in cutting-edge data analytics and large-scale research studies for the development of novel cancer therapies, this program will foster the creation of digital tools toward improving patient outcomes.

As I highlighted last year, the cross-cutting Severo Ochoa Digitalization Unit (SOUND), is part of VHIO’s accreditation as a Severo Ochoa Center of Excellence (2022-2026), and further strengthens our efforts aimed at accelerating the development and implementation of data science models and technology platforms in healthcare for personalizing patient care at VHIO. This unit is at the nexus of digital health and data science for research, clinical applications and patient-centered medicine.

In addition to these programs, VHIO continues to make important progress against cancer thanks to its other pioneering Institutional Programs as well as institutional support that we receive from our equally amazing, longstanding patrons—Generalitat de Catalunya, Fundació Privada CELLEX, Fundación FERO, "la Caixa" Foundation, and Fundación BBVA—as well as the institutional support by other funding bodies including our Asociación Española Contra el Cáncer - AECC Excellence Advanced Therapies Accelerator and AstraZeneca José Baselga Innovative Disruption (J-BID) programs.

Without this incredibly generous support, in addition to the backing and belief that we receive from many other VHIO supporters, funding entities, agencies and individuals, our shared commitment to reducing the devastating burden that this disease inflicts on society would, frankly, be impossible.

Additionally, I simply must mention the many extraordinary fundraising events, public outreach initiatives and patient engagement activities that were organized and celebrated throughout the year. These devoted initiatives further inspire us to accelerate our collective pace against cancer.

In 2024, we have continued to make important headway. This year, in collaboration with many other leading research centers and groups, both nationally and internationally, VHIO teams and talents (co) authored 527 scientific articles, including many published in the most prestigious scientific and medical journals. These important contributions, in parallel with the development and implementation of cutting-edge platforms and empowering technologies, have generated deeper insights into cancer biology and enable us to target the molecular drivers of this disease with increasing precision.

As I write each year, while I cannot possibly do justice to all of our contributions to translational cancer science and clinical research over the past year, I take this opportunity to highlight just a few of our studies, some of which were paradigm-shifting.

Bringing the first MYC inhibitor closer to the clinic

The first-in-human dose escalation phase I study of OMO-103, the first Omomyc-derived compound developed in-house by the VHIO and ICREA spin-off company Peptomyc, was designed to assess the safety and pharmacokinetics of this MYC inhibitor in patients with advanced solid tumors. The trial enrolled 22 patients who had received between 2 and 12 previous lines of treatment.

Laura Soucek and colleagues, including Elena Garralda, Director of VHIO’s Research Unit for Molecular Therapy of Cancer (UITM)–CaixaResearch and head of our Early Clinical Drug Development Group, published their findings in Nature Medicine1. They demonstrated the drug’s safety profile and early signs of anti-tumor clinical activity in some patients, supporting further investigation of OMO-103's clinical activity in combination with other therapies.

The investigators also analyzed tumor biopsies before and after treatment and observed a direct correlation between MYC deactivation and clinical benefit. They identified two potential blood biomarkers that could prove useful in the management of disease. They also detected a potential biomarker of pharmacodynamic activity that increases in blood when patients respond to treatment with OMO-103. Using liquid biopsy, this marker could enable us to identify tumor progression earlier and help guide treatment decisions more rapidly. We have also identified a predictive biomarker that, through a simple blood test, could help to predict those patients who could potentially derive benefit from treatment with OMO-103.

The findings support further investigation of OMO-103's clinical activity and have led the initiation of a phase Ib clinical trial evaluating OMO-103 in combination with standard of care in patients with metastatic pancreatic cancer.

Boosting the anti-tumor immune response in cervical cancer

Results of a study led by Joan Seoane, published in Clinical Cancer Research2, revealed that cervical cancer cells evade the host immune system through the inhibition of type I interferon and CXCL9 by the cytokine LIF. The viral proteins E6 and E7 from human papillomavirus (HPV) induce the expression of LIF via the NFκB pathway. The secreted LIF then represses type I interferon expressed in plasmacytoid dendritic cells (pDCs) and CXCL9 expressed in tumor-associated macrophages. This inhibits the infiltration of CD8 T cells into the tumor, preventing an antitumor immune response.

Importantly, blockade of LIF promotes the induction of type I interferon and CXCL9, leading to increased CD8 T cell tumor infiltration and sensitizing the tumor to immune checkpoint inhibitors (ICI). Conversely, patients with cervical cancer expressing high levels of LIF tend to be resistant to ICI. These findings suggest that combining antibodies against LIF and ICI could be a promising therapeutic strategy against cervical cancer expressing high levels of LIF.

Unravelling cell differentiation and proliferation in cancer

The cell cycle is tightly regulated by the balance between kinases and phosphatases. A key example is the interplay between the PP2A phosphatase and the CDK1 kinase during the final stages of cell division. In normal cells, CDK1 promotes cell cycle progression by phosphorylating substrates within the anaphase-promoting complex, while PP2A counteracts this activity through dephosphorylation, ensuring proper mitotic exit. In cancer, upstream inhibition of PP2A disrupts its tumor suppressor function, stabilizing oncoproteins and enabling uncontrolled proliferation.

Marcos Malumbres and colleagues created mouse models lacking two common subunits of PP2A, and found that these complexes work together to manage how chromosomes separate and organize during mitosis. Published in Cell Reports3, the work highlights the critical role of the kinase-phosphatase balance in maintaining chromosomal stability and shows how its disruption can lead to chromosomal instability, a hallmark of cancer. Specifically, reduced PP2A-B55 activity or CDK1 overexpression impairs mitotic fidelity, promoting errors that contribute to tumorigenesis and metastasis. The study supports the rationale for evaluating therapeutic strategies aimed at restoring PP2A activity or inhibiting CDK1 that may counteract genomic instability in cancers with dysregulation of this axis.

Novel CAR T-cell therapy shows promise in preclinical models of HER2-positive solid tumors

p95HER2 is expressed in one third of HER2+ tumors, which represent 4% of all tumors. Led by VHIO investigators, CAR T cells targeting p95HER2 have been developed to secrete the TECH2Me bispecific antibody that specifically recognizes tumor cells and, at the same time, activates immune cells within the tumor microenvironment.

Published in Nature Communications4, Joaquín Arribas and his VHIO colleagues have demonstrated the efficacy and safety of this dual mechanism. They achieved complete and durable antitumor responses in patient-derived models of HER2+ p95HER2-expressing solid tumors, without harming cells expressing normal levels of HER2.

These findings provide the rationale for the application of a first-in-human clinical trial to assess this therapeutic strategy in patients with HER2-driven solid tumors who have exhausted available therapeutic options. The development of this approach could represent a promising strategy to improve outcomes in a subset of patients with HER2+ tumors.

Liquid biopsy to help guide patient selection for personalized medicine in GIST

Published in Nature Medicine5, results of exploratory analysis from the phase 3 INTRIGUE clinical trial support the potential utility of liquid biopsy using circulating tumor DNA (ctDNA) to guide personalized treatment decision making in patients with advanced KIT-mutated gastrointestinal stromal tumor (GIST).

The INTRIGUE study investigated the efficacy and safety of second-line ripretinib compared to standard therapy sunitinib in patients with advanced GIST who had disease progression on imatinib. In the primary analysis, ripretinib did not meet the study’s endpoint of superiority compared with sunitinib. Similar clinical activity was however observed, and ripretinib was better tolerated in this patient population.

Directed by Michael C. Heinrich, Professor of Medicine at the Oregon Health & Science University Knight Cancer Institute, Portland, USA, and co-authored by César Serrano, retrospective ctDNA biomarker analysis explored the clinical activity of these two single-drug therapies.

Patients with primary KIT exon 11 mutations and secondary resistance mechanisms only in the KIT ATP-binding pocket (exons 13/14) had better progression-free survival (PFS) with sunitinib compared to ripretinib. Notably, patients with exon 11 mutations and secondary resistance mutations only in the KIT activation loop (exons 17/18) had better PFS with ripretinib versus sunitinib; 14.2 months versus 1.5 months, respectively.

This study paved the way for the initiation of the ongoing phase 3 INSIGHT trial, for which Serrano serves as a member of the Steering Committee. This study aims to evaluate the efficacy of ripretinib versus sunitinib in patients with KIT exon 11 + 17/18 mutations, confirmed by ctDNA analysis. This marks the first time that investigators are using liquid biopsy to guide treatment decision making in this patient population.

Next-generation PARP1-selective inhibitor in BRCA1/2-mutated tumors

Preclinical results from a VHIO-led study spearheaded by Violeta Serra and published in in Genome Medicine6, further support the use of PARP1-selective inhibitors in BRCA1/2-mutated tumors.

In collaboration with VHIO’s Hereditary Cancer Genetics Group, directed by Judith Balmaña, Serra’s findings showed that the PARP1-selective inhibitor saruparib elicited superior and durable antitumor activity in PDX models derived from patients with breast, ovarian or pancreatic cancer with genetic alterations in BRCA1 or BRCA2, compared to the clinically approved PARP inhibitor olaparib, which targets the PARP1 and PARP2 proteins.

Saruparib showed superior efficacy over olaparib. Preclinical complete response rate was 75% versus 37%, respectively, and preclinical median progression-free survival was 368 days in the saruparib-treated group compared to 90 days the olaparib-treated group.

Overall, the study demonstrated potent and durable antitumor activity of the PARP1 selective inhibitor in PDX models, supporting its clinical development as a new therapeutic option, alone or in combination with other DNA damaging agents, to overcome resistance to first-generation PARP inhibitors.

Paving the way for systemic targeted therapy in pseudomyxoma peritonei

Published in Clinical Cancer Research7, investigators from our Stem Cells and Cancer Group, headed by Héctor G. Palmer, present a proof-of-concept preclinical study that paves the way for developing precision oncology and systemic targeted therapy in pseudomyxoma peritonei (PMP), a rare form of cancer with very few therapeutic options available.

In collaboration with VHIO groups and colleagues at the San Joan Despí Moises Broggi Hospital, Barcelona, the investigators processed 120 PMP samples from 50 patients to generate the world’s largest collection of patient-derived organoid (PDO) and xenograft (PDX) mouse models from PMP patients, leading to the identification of druggable targets including KRAS and BRAF. For the first time, the investigators used intra-abdominal mucin biopsy to detect circulating tumor DNA (ctDNA) derived from cancer cells and observed that 80% of these preclinical models presented KRAS or BRAF mutations.

While KRAS mutations were more common, the team opted to evaluate the efficacy of BRAF inhibitor encorafenib in BRAFV600E models (BRAF inhibition could be the fastest option of molecularly matched therapy in this patient population, given that encorafenib monotherapy has already been approved for the treatment of other tumors). Proof-of-concept in vivo experiments showed that a systemic treatment with encorafenib significantly reduced tumor growth and prolonged survival in PDX models.

This study demonstrated for the first time that systemic targeted therapies can effectively control PMP tumors, pointing to BRAF signaling pathway inhibition as a potential new therapeutic opportunity for BRAFV600E PMP patients who have a poor prognosis. The next step will be to validate these data in other models to confirm whether KRAS inhibitors exhibit the same systemic antitumor activity in animal models.

Novel CRISPR-based tool deepens insights into genomic deletions and accelerates design of novel therapeutic strategies

Published in Nature Protocols8, Francisco Barriga in collaboration with Scott Lowe at the Memorial Sloan Kettering Cancer Center, New York, described the methodology of the two-stage MACHETE system—Molecular Alteration of Chromosomes with Engineered Tandem Elements—to overcome the limitations of previous approaches in successfully engineering cells with megabase-large deletions.

MACHETE is a novel tool to generate models for the in-depth study of genomic alterations frequently observed in cancer. This CRISPR/Cas9-based system involves the initial insertion of a self-destruct button into the targeted chromosome region for deletion. Using CRISPR/Cas9 to eliminate the region of interest, only cells that excise this region survive.

These cell models of large-scale deletions can be used to investigate why patients presenting chromosome alterations have a poorer prognosis due to the lower likelihood of response to certain therapies. This new conceptual framework for the study of large-scale chromosomal alterations should help researchers to better understand the functional relevance of these changes in treatment response and ultimately develop selective therapies that specifically target cells with these deletions.

Personalizing cancer care with pioneering imaging approaches

Jointly developed by VHIO investigators and researchers at the Bellvitge University Hospital’s Neuro-Radiology Unit in Barcelona, the Diagnosis in Susceptibility Contrast Enhancing Regions for Neuroncology (DISCERN) is an open access, deep learning tool based on the training of patterns using AI models based on magnetic resonance imaging (MRI) data. Published in Cell Reports Medicine9, results of this study, co-led by Raquel Perez-Lopez demonstrated the feasibility and accuracy of DISCERN as an enabler of accurate brain tumor diagnosis from perfusion MRI, outperforming current classification methods.

The investigators trained DISCERN to learn the characteristics of glioblastoma multiforme, brain metastasis from solid tumors, and primary central nervous system lymphoma on 50,000 voxels from 40 diagnosed patients. Validating this deep learning tool in more than 500 additional cases, results demonstrated 78% accuracy in the classification of these tumors, supporting its potential use as a non-invasive diagnostic tool.

Results of a study co-led by Joaquin Mateo and Raquel Lopez-Perez have identified whole-body magnetic resonance imaging (WB-MRI) as a novel biomarker of systemic treatment response in metastatic castration resistant prostate cancer (mCRPC) with bone metastases. Published in European Urology10, findings showed that WEB-MRI can provide quantitative markers to monitor responses and progression to therapy in bone metastases from prostate cancer.

Led by VHIO, the iPROMET mulitcenter trial was designed to objectively quantify changes in apparent diffusion coefficient (ADC) that measures the magnitude of diffusion of water molecules within tissue, and other quantitative WB-MRI parameters. The investigators have identified various biomarkers of response including the balance between tumor cell density and fat content in bones. Results show that a higher cell density of bone metastases together with a low percentage of fat fraction are associated with an increased risk of disease progression.

Data showed that these biomarkers, in addition to liquid biopsy, can predict treatment response and progression bone metastasis in mCRPC and therefore help guide treatment decision making in this patient population.

A paradigm shift in the treatment landscape for advanced non-small cell lung cancer

The phase 3 MARIPOSA randomized study enrolled 1,074 patients with EGFR-mutant advanced or metastatic non-small cell lung cancer (NSCLC) and was designed to evaluate the benefit of the bispecific antibody amivantamab plus lazertinib, a drug targeting EGFR, compared to standard treatment with osimertinib.

Positive findings from the interim analysis, presented at the 2023 ESMO Congress, demonstrated that the amivantamab-lazertinib combination reduced the risk of disease progression and death by 30% compared to osimertinib alone, with progression-free survival of 23.7 months versus 16.6 months, respectively.

Secondary analysis from MARIPOSA, published in Annals of Oncology11, evaluated progression-free data from this study in 636 patients with EGFR-mutated NSCLC who also presented with one of these poor prognosis markers: brain and liver metastases, p53 gene co-mutations or the presence of ctDNA. (These high-risk characteristics can occur in up to 85% of patients in this setting.)

Unveiled by Enriqueta Felip at the 2024 ASCO Annual Meeting, data showed that the amivantamab-lazertinib combination significantly reduced the risk of disease progression or death consistently across all high-risk subgroups. Patients who received osimertinib had a median progression-free survival of between 9.1 to 14.8 months, compared to 16.5 to 20.3 months in those patients who received the treatment combination. Amivantamab plus lazertinib reduced the risk of disease progression and death by 31% in patients with brain metastases, by 42% in patients with liver metastases at the start of treatment, and by 35% in patients with TP53 co-mutations. In those patients with EGFR mutations detected in circulating tumor DNA (ctDNA) in blood, the risk decreased by 32%.

In 2024, the FDA and European Commission approved the combination of amivantamab and lazertinib as frontline treatment for patients with locally advanced or metastatic NSCLC with EGFR mutations. Both approvals were based on earlier data from MARIPOSA.

A new framework to assess the tumor-agnostic potential of molecularly guided cancer therapies

Published in Annals of Oncology12, the European Society for Medical Oncology’s (ESMO) Precision Medicine Working Group (PMWG) chaired by Benedikt Westphalen of the Comprehensive Cancer Center Munich and University Hospital LMU Munich, together with a multidisciplinary team of international experts including VHIO’s Elena Garralda and Joaquin Mateo, also a member of the PMWG, have developed a new tool: the ESMO Tumor-Agnostic Classifier and Screener (ETAC-S).

Aimed at fostering and accelerating tumor-agnostic drug development, this new framework proposes a set of minimum requirements to screen and claim the tumor-agnostic potential of molecularly guided treatment options for steering drug development. The investigators reviewed publicly available data for seven tumor-agnostic indications approved ty the US Food and Drug Administration and/or the European Medicines Agency.

They then tested various scenarios considering three main factors: minimum objective response rate (ORR), number of tumor types studied, and number of evaluable patients per tumor type. They defined the minimum requirements that compose the screener and tested the tool using the tumor-agnostic indications approved during the first half of 2024.

Based on their findings, the group proposed that results of early phase trials be screened based on three minimum requirements to claim tumor-agnostic potential of the molecularly guided therapy under assessment: each given therapy must have shown an objective response in at least one out of five patients (ORR ≥20%) in two-thirds of the investigated tumour types (and in ≥4 tumor types) with at least five evaluable patients in each tumor type, in the setting of refractory disease.

The investigators also set out a conceptual taxonomy to classify the therapeutic effect of investigational therapies by considering the targeted driver molecular aberration crosstalk with tumor-specific modulating biology: tumour-agnostic, tumour-modulated, or tumour-restricted.

To refine the solidity of ETAC-S, further validation and future methodological work of the group is warranted. To define ETAC cutoffs between what is purely tumor-agnostic and what is tumour-modulated, the next step will be to review the literature for collecting data from publications of tentative tumour-agnostic drug development trials.

The power of three: immunotherapy combined with first-line standard of care in advanced cervical cancer

The randomized open-label phase 3 BEATcc academic trial (ENGOT-Cx10/GEICO 68-C/JGOG1084/GOG-3030) evaluated the PD-L1 immune checkpoint inhibitor (ICI) atezolizumab combined with a platinum doublet and bevacizumab for metastatic cervical cancer standard of care with first-line chemotherapy plus bevacizumab—irrespective of PD-L1 status—in patients with cervical cancer who are not candidates for curative-intent surgery and/or radiotherapy. Led by Ana Oaknin, this study is the first to add a PD-L1 inhibitor to the standard of care with bevacizumab plus platinum-based doublet chemotherapy in this setting.

This international study, published in The Lancet13, included 410 previously untreated patients with metastatic (stage IVB) or recurrent cervical cancer not amenable to curative surgery/radiation who were randomized 1:1 to receive standard therapy or the combination with the addition of atezolizumab. Median overall survival in patients treated with the combination of atezolizumab plus standard therapy was 32.1 months compared to 22.8 months in the control group. This significant improvement is unprecedented in this setting.

While the approval of the current standard of care was based on the results of the previous GOG 240 study, the two-year survival rate was less than 40%. Interim overall survival (OS) results from the BEATcc trial showed a two-year survival rate of 60% in patients who received atezolizumab plus bevacizumab and the chemotherapy doublet.

The investigators also observed significantly improved progression-free survival (PFS). Median PFS was 13.7 months in patients treated with the experimental combination and 10.4 months in the control arm.

These results, reported by Ana Oaknin at the 2023 ESMO Virtual Plenary, support the adoption of this regimen as a new first-line therapy option for these patients.

The promise of a next-generation ER degrader in advanced breast cancer

The phase 3 EMBER-3 open-label randomized clinical trial evaluated the efficacy and safety of the next-generation, brain-penetrant estrogen-receptor (ER) degrader, imlunestrant, as a monotherapy and in combination with abemaciclib.

This study enrolled 874 patients with ER+, human epidermal growth factor receptor (HER2)-negative advanced breast cancer who experienced disease recurrence or progression during or after aromatase inhibitor therapy, with or without a CDK4/6 inhibitor, who were assigned to receive imlunestrant, standard therapy, or imlunestrant-abemaciclib.

A report published in The New England Journal of Medicine14, led by Komal Jhaveri of the Memorial Sloan Kettering Cancer Center (MSKCC) and Weill Cornell Medical College in New York, with Cristina Saura as a co-author, showed that among patients with ER+, HER2- advanced breast cancer, imlunestrant improved progression-free survival (PFS) compared to standard therapy in patients with ESR1 gene mutations. The results were 5.5 months as compared with 3.8 months respectively, but not in the overall population. Among all patients, PFS was 5.6 months for imlunestrant versus standard therapy’s 5.5 months. In the imlunestrant-abemaciclib group, PFS was 9.4 months, which was significantly longer that the 5.5 months reported for those who received imlunestrant monotherapy.

These findings show that imlunestrant significantly prolonged PFS over standard therapy among patients with ESR1 mutations and that the addition of abemaciclib to imlunestrant benefited all patients. These promising results point to a new targeted therapy option in this patient population.

Patient-reported outcomes: the positive benefit-risk balance of new dual therapy in HR + HER2- breast cancer

In June 2024, the combination of novel AKT inhibitor capivasertib with fulvestrant for patients with ER+, HER2 negative breast cancer with one or more PIK3CA, AKT1, or PTEN-alterations following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy. This approval was based on results from the CAPItello-291 phase 3 multicenter trial published in The New England Journal of Medicine15, which was directed by Nicholas Turner at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, and co-led by Mafalda Oliveira.

Data from this study showed that this combination reduced the risk of disease progression or death by 50% in patients with tumors harboring specific biomarker alterations, with a median progression-free survival of 7.3 months in patients treated with this new combination compared to 3.1 months with placebo-fulvestrant.

Published in The Lancet Oncology16, the results of exploratory analysis of quality of life as a patient-reported outcomes (PROs), led by Mafalda Oliveira and Hope S. Rugo at the University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, showed that patients who received this treatment combination enjoyed a quality of life longer than those treated with standard of care. The capivasertib-fulvestrant combination extended time to deterioration of health and quality of life in patients to almost 25 months, compared to 12 months in those who received fulvestrant alone.

These findings further support the positive benefit-risk balance of this dual therapy in this setting. Developed by AstraZeneca, capivasertib is the only AKT inhibitor approved in the EU for the treatment of patients with ER+/HER2- locally advanced or metastatic disease with tumors harboring one or more alterations in PIK3CA, AKT1 or PTEN.

The approval of this novel AKT inhibitor represents an important development for the treatment of approximately half of patients with ER+ breast cancer in Europe who have tumors with these specific biomarker alterations. It will be important for clinicians to test and identify eligible patients who may derive benefit from this new combination.

Regulatory applications are currently under review in China and other countries. Similar indications for capivasertib in combination with fulvestrant are already approved in the US, Japan and several other countries based on the CAPItello-291 trial.

Advancing insights to guide treatment decision-making in large B-cell lymphoma

While the advent of CAR T-Cell therapy has revolutionized the treatment of patients with relapsed or refractory large B-cell lymphoma (LBCL), only 30-40% of patients infused with CAR T-cells achieve a durable remission. Patients who progress after this therapy have low response rates to salvage regimens and long-term outcomes are dismal. Led by investigators of our Experimental Hematology Group and the Advanced Therapies Program of Vall d’Hebron’s Hematology Service, a retrospective multicenter study was designed to advance insights into factors associated with treatment success toward improving treatment outcomes in this patient population.

Reported in the Journal of Clinical Oncology17, the results showed that patients with refractory LBCL who had received CAR T-cell therapy and treatment with bendamustine before apheresis had a shorter progression-free survival and overall response rate in comparison with the bendamustine-naïve group, irrespective of patient characteristics and dose received.

This retrospective study included clinical data of 439 patients who received CAR T-cell therapy in third or later line of treatment at 7 European sites. These patients were divided into two different cohorts based on whether they had been exposed to bendamustine prior to T-lymphocyte apheresis. Eighty (18%) patients had been exposed to this agent at a median of 6 months before T cell collection with a median of four cycles of treatment.

The investigators identified previous exposure as an independent factor associated with poorer outcomes following CAR T-cell therapy. Next, they sought to confirm if recent exposure to bendamustine led to worse results. Recent exposure to this agent correlated with poorer outcomes, irrespective of patient characteristics and dose received. The 42 patients who had received this agent 9 months before apheresis had a median overall survival of 4.6 months compared to 23.5 months in the bendamustine-naïve group.

While there are clinical guidelines on the limitations of using bendamustine due to its toxicity to patient lymphocytes, this study is the first to report on the impact of recent exposure (9 months) to this agent as an independent factor of poorer outcomes of CAR-T cell therapy in patients with LBCL. Bendamustine should be avoided whenever possible in patients with refractory large B-cell lymphoma who are potential candidates for CAR T-cell therapy.

Novel liquid biopsy methodology for the monitoring of disease evolution in prostate cancer

A study directed by Joaquin Mateo in Cancer Cell18 showed that analysis of DNA/RNA in circulating extracellular vesicles secreted into the bloodstream by tumor cells captures genomic and transcriptomic evolution in patients with metastatic prostate cancer.

The investigators analyzed liquid biopsies from a retrospective cohort of 53 metastatic castration-resistant prostate cancer patients who received treatment with hormone therapy or chemotherapy. The findings show that DNA and RNA contained in these circulating vesicles reflect the genomic and transcriptomic features in metastatic prostate cancer. Furthermore, results of mRNA expression analysis—performed for the first time in extracellular vesicles in liquid biopsies—enables the monitoring of on-therapy changes in these tumors. The transcriptomic profile of these tumors could also serve as a biomarker of response or resistance to therapy.

These findings could also expand the opportunities to study cancer from minimally invasive liquid biopsies.

First-line dual-agent immunotherapy improves outcomes in metastatic colorectal cancer

Led by Thierry Andre, Head of the Department of Medical Oncology at the Hôpital Saint Antoine in Paris, France, the phase 3 Checkmate 8HW trial evaluated first-line immunotherapy with nivolumab plus ipilimumab over chemotherapy in patients with microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC).

The study enrolled more than 300 patients with metastatic disease who had not previously received treatment; they were randomly assigned to receive immunotherapy with nivolumab plus ipilimumab or chemotherapy. Among these patients, 255 had confirmed MSI-H or dMMR tumors.

Published in The New England Journal of Medicine20, at a median follow-up of 31.5 months, progression-free survival was significantly better in patients who received the nivolumab-ipilimumab combination compared to those who were assigned to chemotherapy.

At 24 months, progression-free survival was 72% with nivolumab plus ipilimumab (compared with 14% with chemotherapy). The restricted median survival time at 24 months was 10.6 months longer with the immunotherapy combination than with chemotherapy, demonstrating that this investigational immunotherapy doublet delayed disease progression. Serious treatment-related adverse events occurred in 23% of the patients in the nivolumab plus ipilimumab group compared to almost 50% in the chemotherapy group.

The next step should be to evaluate the efficacy of this combination versus single agent immunotherapy as first-line treatment, which is currently recommended in this patient population.

The transformative power of collaboration

At the heart of VHIO’s ethos is collaboration, both nationally and internationally. We firmly believe in fostering, developing and expanding strong partnerships to advance and accelerate personalized and targeted therapies against cancer.

Among the many cross-border collaborations that we (co)-lead, VHIO participates in major EU consortia. Some of these include the Coordination and Support Action (CSA – 4.UNCAN.eu) of the UNderstand CANcer (UNCAN.eu) initiative or CCI4EU, and the Cancer Core Europe (CCE) consortium.

I am privileged to serve as Chair of the Cancer Core Europe (CCE) consortium. Founded in 2014, CCE is an alliance that connects seven renowned European cancer centers including VHIO. We are united by a shared vision to reshape the landscape of cancer research to strengthen the European Union’s competitiveness as an arena to rapidly translate preclinical discoveries to the clinic and deliver on the promise of precision oncology.

Organized across four main pillars—Clinical Trials and Translational Research, Virtual Data Center, Early Detection and Prevention, Education and Training—CCE’s activities are spearheaded by task force committees and working groups, the latest of which is dedicated to pathology to standardize diagnostic platforms within this consortium, and to provide specialist pathology expertise to support new clinical trials and novel arms of the Basket of Baskets (BoB) study.

This pioneering multicenter trial leverages the expertise of researchers and clinicians from all seven CCE centers. Designed to evaluate targeted agents in molecularly selected populations with advanced tumors, BoB is making significant strides in personalized cancer treatment. As of this year, this phase 2 open-label trial is led by Irene Braña, an Associate Investigator and Senior Consultant of VHIO’s UITM–CaixaResearch and Group Leader of Head and Neck Cancer at VHIO.

I am truly honoured to work alongside CCE’s exceptionally committed Board members and the many outstanding researchers and clinical investigators from each of the participating centers. I am pleased to recognize the work of Alejandro Piris, Director of our Scientific Management Area, Javier Carmona, Head of VHIO’s Scientific Strategy and Translational Programs Management, and Elena Chavarria, Head of Coordinated Projects, who are also part of CCE’s leadership team. I would also like to thank the VHIO Academy, led by Imma Falero, for its coordination of CCE’s annual Summer School in Translational Cancer Research, and Bianca Pont and her team for leading this consortium’s communication efforts.

The second Joint Action of the EU on Networks of Expertise on Cancer (JANE-2), coordinated by the Fondazione IRCCS Istituto Nazionale Tumori in Milan, is an ambitious initiative bringing together 121 partners from 29 European countries.

JANE-2 aims to establish seven specialized Networks of Expertise (NoE) to enhance cancer care across Europe. These patient-centered networks focus on personalized primary/secondary prevention, survivorship, palliative care, omic technologies, hi-tech medical resources, complex and poor-prognosis cancers, and adolescents and young adults with cancer. They will each support the European oncology community through the provision of clinical guidelines, quality-of-care criteria, economic models, educational resources, research promotion, and advocacy support.

VHIO is participating in four of JANE-2’s seven NoEs: poor-prognosis cancers including lung and pancreatic cancers to improve outcomes for patients by implementing strategies to enhance survival while maintaining quality of life, survivorship focused on developing integrative care programs for cancer survivors, and adolescents and young adults to address and respond to the specific needs of this patient population by strengthening the connectivity between pediatric and adult cancer services and delivering the seamless transition of care from prevention to survivorship.

Our collaboration in this initiative is coordinated by Claudia Valverde, a Medical Oncologist at Vall d’Hebron and Senior Investigator of VHIO’s Genitourinary (non-prostate) Tumors, Central Nervous System (CNS), Sarcomas, and Tumors of Unknown Origin Group.

The Last Word

We are in an era of extraordinary scientific progress and the international oncology community continues to gain wins against cancer. Thanks to the new wave of scientific discoveries and technological innovations, some of which have been spearheaded by VHIO cancer researchers and clinical investigators, we are collectively better equipped than ever to deliver even more transformative breakthroughs for our patients.

Despite these advances, 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). As an example, by 2030 CRC could become the deadliest cancer in young adults (20-49 years of age)23. Based on updated estimates from the International Agency for Research on Cancer (IARC)24, there were close to 20 million new cases of cancer in 2022 alongside 9.7 million deaths from cancer. As the statistics show, much work still needs to be done to curtail and one day conquer cancer.

Cancer research is a truly global endeavor. Ensuring continued strides against this disease depends 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, do even better in our collective efforts to beat cancer.