Nuria Mulet

Institut Català d'Oncologia

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Josep Tabernero

Universitat de Vic - Universitat Central de Catalunya

EÉ

Elena Élez

Vall d'Hebron Hospital Universitari

Guillem Argilés

Memorial Sloan Kettering Cancer Center

Giulia Martini

University of Campania "Luigi Vanvitelli"

Iosune Baraibar

Vall d'Hebron Hospital Universitari

Javier Ros

Vall d'Hebron Hospital Universitari

Ana Vivancos

Vall d'Hebron Institute of Oncology

José Luis Cuadra‐Urteaga

Vall d'Hebron Hospital Universitari

Cristina Santos

Institut Català d'Oncologia

Rodrigo Dienstmann

Vall d'Hebron Institute of Oncology

Cooperative Institutions

Vall d'Hebron Hospital Universitari

Vall d'Hebron Institute of Oncology

Institut Català d'Oncologia

Centro de Investigación Biomédica en Red de Cáncer

Universitat Autònoma de Barcelona

Institut d'Investigació Biomédica de Bellvitge

Hebron University

Vall d'Hebron Institut de Recerca

Duran i Reynals Hospital

CIBBIM-Nanomedicine

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BRAF, MEK and EGFR inhibition as treatment strategies in BRAF V600E metastatic colorectal cancer

Therapeutic Advances in Medical Oncology (2021)

Javier Ros Iosune Baraibar Emilia Sardo Nuria Mulet Francesc Salvà

Introduction: BRAF driver mutations are found in up to 15% of patients with colorectal cancer (CRC) and lead to constitutive activation of BRAF kinase and sustained RAS/RAF/MEK/ERK pathway signaling. BRAF mutations define a sub-population characterized by a poor prognosis and dismal median survival. Following successful outcomes with BRAF inhibition in BRAF mutant metastatic melanoma, this approach was evaluated in metastatic colorectal cancer (mCRC). The development and combination of targeted therapies against multiple signaling pathways has proved particularly successful, with improved survival and response rates. Areas covered: This review addresses the development of therapeutic strategies with inhibitors targeting MAPK/ERK and EGFR signaling in BRAF V600E mutated mCRC, focusing on encorafenib, binimetinib and cetuximab. A pharmacological and clinical review of these drugs and the therapeutic approaches behind their optimization are presented. Expert opinion: Exploiting knowledge of the mechanisms of resistance to BRAF inhibitors has been crucial to developing effective therapeutic strategies in BRAF-V600E mutant mCRC. The BEACON trial is a successful example of this approach, using encorafenib and cetuximab with or without binimetinib in patients with previously treated BRAF V600E mutant mCRC, showing an impressive improvement in clinical outcomes and tolerable toxicity compared with chemotherapy, establishing a new standard of care in this setting.

V600E

Targeted Therapy

10.1177/1758835921992974

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Citations (45)

513P Prospective evaluation of the G8 screening tool for predicting survival in elderly patients with colon cancer

Annals of Oncology (2020)

G. Soler Raquel Legido Xavier Pérez M. Martínez-Villacampa Cristina Santos

Geriatric oncology

Performance status

10.1016/j.annonc.2020.08.623

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Establishment of patient-derived tumor organoids to functionally inform treatment decisions in metastatic colorectal cancer

ESMO Open (2023)

Giulia Martini Valentina Belli Stefania Napolitano Vincenza Ciaramella Davide Ciardiello

Metastatic colorectal cancer (mCRC) patients tend to have modest benefits from molecularly driven therapeutics. Patient-derived tumor organoids (PDTOs) represent an unmatched model to elucidate tumor resistance to therapy, due to their high capacity to resemble tumor characteristics.We used viable tumor tissue from two cohorts of patients with mCRC, naïve or refractory to treatment, respectively, for generating PDTOs. The derived models were subjected to a 6-day drug screening assay (DSA) with a comprehensive pipeline of chemotherapy and targeted drugs against almost all the actionable mCRC molecular drivers. For the second cohort DSA data were matched with those from PDTO genotyping.A total of 40 PDTOs included in the two cohorts were derived from mCRC primary tumors or metastases. The first cohort included 31 PDTOs derived from patients treated in front line. For this cohort, DSA results were matched with patient responses. Moreover, RAS/BRAF mutational status was matched with DSA cetuximab response. Ten out of 12 (83.3%) RAS wild-type PDTOs responded to cetuximab, while all the mutant PDTOs, 8 out of 8 (100%), were resistant. For the second cohort (chemorefractory patients), we used part of tumor tissue for genotyping. Four out of nine DSA/genotyping data resulted applicable in the clinic. Two RAS-mutant mCRC patients have been treated with FOLFOX-bevacizumab and mitomycin-capecitabine in third line, respectively, based on DSA results, obtaining disease control. One patient was treated with nivolumab-second mitochondrial-derived activator of caspases mimetic (phase I trial) due to high tumor mutational burden at genotyping, experiencing stable disease. In one case, the presence of BRCA2 mutation correlated with DSA sensitivity to olaparib; however, the patient could not receive the therapy.Using CRC as a model, we have designed and validated a clinically applicable methodology to potentially inform clinical decisions with functional data. Undoubtedly, further larger analyses are needed to improve methodology success rates and propose suitable treatment strategies for mCRC patients.

FOLFOX

10.1016/j.esmoop.2023.101198

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Citations (19)

Up-to-date role of aflibercept in the treatment of colorectal cancer

Expert Opinion on Biological Therapy (2021)

Nadia Saoudi Francesc Salvà Javier Ros Iosune Baraibar David Marmolejo

Introduction: Colorectal cancer (CRC) is a major public health problem. Despite major progress understanding the biological basis of this tumor added to the incorporation of optimized diagnostic and therapeutic strategies, prognosis after progression on first-line standard treatment remains poor. Several antiangiogenic treatments have demonstrated improvement in overall survival (OS) in the second-line treatment being aflibercept, a fully humanized recombinant protein, one of them. The results of the VELOUR study showed that the addition of aflibercept to second-line FOLFIRI improved OS and progression-free survival.Areas covered: A literature review of published clinical studies was performed in order to discuss the clinical data on aflibercept in mCRC from early drug development to real-world data.Expert opinion: The combination of aflibercept with FOLFIRI provides a statistical improvement in OS and in all the efficacy endpoints analyzed in the VELOUR trial, showing efficacy independently on time to progression, molecular status, prior biological treatment, or age. Further studies are needed to find new biomarkers and molecular characterization in order to better select patients that could benefit from this treatment.

Aflibercept

FOLFIRI

10.1080/14712598.2021.1935231

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Incorporating traditional and emerging biomarkers in the clinical management of metastatic colorectal cancer: an update

Expert Review of Molecular Diagnostics (2020)

Iosune Baraibar Javier Ros Nuria Mulet Francesc Salvà Guillem Argilés

Molecular profiling has led to significantly longer survival in metastatic colorectal cancer (mCRC) patients. Clinical guidelines recommend testing for KRAS/NRAS, BRAF and MSI status, and new biomarkers such as HER2 amplification and NTRK fusions have emerged more recently in refractory CRC, supported by overwhelming clinical relevance. These biomarkers can guide treatment management to improve clinical outcomes in these patients.Preclinical and clinical data over the last decade were reviewed for known and novel biomarkers with clinical implications in refractory CRC. Molecular alterations are described for classic and novel biomarkers, and data for completed and ongoing studies with targeted and immunotherapies are presented.Use of targeted therapies based on biomarker testing in CRC has enabled impressive improvements in clinical outcomes in refractory patients. BRAF, MSI, NRAS and KRAS should be tested upfront in all patients given their indisputable therapeutic implications. Other molecular alterations such as HER2 and NTRK are emerging. Testing for these alterations may further improve outcomes for refractory CRC patients. Nonetheless, many key aspects remain to be defined including the optimal timing and technique for testing, the most adequate panel, and whether all patients should be tested for all alterations.

Molecular biomarkers

10.1080/14737159.2020.1782194

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Citations (11)

Young-onset colorectal cancer: A call for action.

Journal of Clinical Oncology (2021)

Iosune Baraibar Francesc Salvà R. Comas Javier Ros A. Mota García

10563 Background: Young-onset colorectal cancer (YOCR) is defined as diagnosis below the age of 50. Over the past decades, the incidence of YOCRC has increased at an alarming rate, but causes and pathogenesis still remain unknown. Early detection of colorectal cancer (CRC) has demonstrated to improve survival. Despite these facts, adults < 50 years old are not yet included in screening programs and YOCRC is not well characterized. We aimed to characterize the clinical and molecular characteristics of YOCRC in patients (pts) diagnosed at our institution. Methods: Consecutive pts with a diagnosis of CRC below the age of 50 visited for the first time at Vall d’Hebron University Hospital in Spain between January 2017 and October 2020 were included in the analysis. Data of clinicopathologic features and treatment were collected retrospectively from medical records. Results: 205 pts met the inclusion criteria, 111 (54%) were females, 8 (4%) presented a personal history of cancer at diagnosis and 109 (53%) a family history of cancer. Age at diagnosis was: < 30: 10 (5%), {30 – 40): 52 (25%), {40-45): 51 (25%), {45-50): 92 (45%). Site of primary tumor was: right colon: 50 (24%), left colon: 107 (52%): rectum: 48 (24%). Stage at diagnosis was I: 3 (1%), II: 14 (7%), III: 60 (29%), IV: 128 (63%). 6 of 14 (43%) and 44 of 60 patients (73%) with stage II and III CRC presented disease progression after initial treatment, respectively. Molecular status was: KRAS mutation: 74 (36%), NRAS mutation: 7 (3%), BRAF mutation: 12 (6%), MSI-H: 12 (6%). 43 pts (21%) had documentation of genetic counseling. Median (range) number of lines of treatment for metastatic disease was 3 (1-7), 53 pts (30%) received at least 4 lines of treatment. Median (range) number of metastatic sites was: 2 (1-6). 114 patients (55.6%) had died at the cut-off timepoint. Conclusions: YOCR is usually diagnosed with a more advanced stage than standard-onset CRC, with a poorer course of the disease. Further studies in young adults with CRC should address this phenomenon to understand the underlying causes, and prioritize genetic counseling. Our results support the unmet need of initiating screening programs in adults younger than 50 years, the urgency for a global consensus and a call for action.

10.1200/jco.2021.39.15_suppl.10563

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Citations (1)

1443 POSTER High Blood Neutrophil-to-lymphocyte Ratio as an Indicator of Poor Prognosis in Advanced Non Small Cell Lung Cancer

European Journal of Cancer (2011)

D. Torrejon Castro S. Cedrés Guillem Argilés Isaac Núñez Víctor Rodríguez-Freixinós

10.1016/s0959-8049(11)70936-4

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Real-world data on overall survival (OS) impact of anti-EGFR sequence in patients (pts) with microsatellite stable (MSS) all-RAS and BRAF^V600E wild-type metastatic (met) colorectal cancer (CRC).

Journal of Clinical Oncology (2018)

Elena Élez Guillem Argilés R. Comas Ariadna García Nuria Mulet

3551 Background: Pts with MSS all-RAS and BRAFV600E wild-type met CRC are more likely to respond to anti-EGFR drugs, irrespective of treatment (tx) line, particularly if left-sided primaries (prim). The best sequence of targeted agents is still under investigation in molecularly-selected pts. Methods: From a prospective clinical-molecular cohort of CRC pts, the subset with all-RAS and BRAFV600E wild-type tumors (2010-2016) plus MSS status (2015-2016) was used to investigate the impact of anti-EGFR sequence (1st vs. 2nd/3rd lines) in OS after met diagnosis. A propensity-score-weighted (PSW) Cox proportional hazard model was built to adjust for tx selection bias based on stage at diagnosis (dx), number and site of met, type of first-line chemotherapy (chem), and curative resection of met. Results: In total, 913 pts were registered in the database and 416 (45%) fulfilled the molecular criteria. From these pts, 98% received two chem regimens, 70% anti-EGFR tx, 60% anti-angiogenic tx and 45% had surgery of met. Clinical variables associated with no administration of anti-EGFR tx were older age at dx, single met site and surgery of met (p < .05). The only factor linked to preference for anti-EGFR tx as 1st line was year: 30% from 2010-2014 and 56% from 2015-2016 (p < .01). In anti-EGFR treated pts not eligible to curative surgery of met (n = 152), OS in pts with left-sided prim (splenic flexure-rectum, 85% of all cases) was 47.5 months and in those with right-sided prim (cecum to transverse, 15%) it was 33.6 months (HR 1.58; CI95% 1.03-2.41; p = .04). In a PSW Cox model with molecularly-selected pts (n = 275), offering an anti-EGFR regimen at 1st line in pts with left-sided prim did not impact on OS (HR = 0.96, CI95% 0.8-1.2, p = .72). The same was true for right-sided prim (HR = 1.26, CI95% 0.8-2.1, p = .36; interaction p = .32). Conclusions: In a real-world cohort before the “sidedness” era we found that anti-EGFR sequence did not affect OS of pts with left-sided prim, but 1st line therapy was preferred setting in more recent years. Only 15% of molecularly-selected pts have poor outcome right-sided prim, limiting subgroup analysis.

Targeted Therapy

10.1200/jco.2018.36.15_suppl.3551

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A randomised phase 2 study comparing different dose approaches of induction treatment of regorafenib in previously treated metastatic colorectal cancer patients (REARRANGE trial)

European Journal of Cancer (2022)

Guillem Argilés Nuria Mulet Manuel Valladares‐Ayerbes J.M. Viéitez Cristina Grávalos

Regorafenib

10.1016/j.ejca.2022.09.037

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Citations (11)

Triple-drug chemotherapy regimens in combination with an anti-EGFR agent in metastatic colorectal cancer - prospects from phase II clinical trials

Expert Opinion on Investigational Drugs (2019)

Ignacio Matos Alba Noguerido Javier Ros Nuria Mulet Guillem Argilés

The addition of monoclonal antibody (mAb) epidermal growth factor receptor (EGFR) inhibitors to classic chemotherapy doublet backbones has improved survival of metastatic colorectal cancer (mCRC). However, the role of triple-drug chemotherapy regimens in combination with an anti-EGFR mAb inhibitor is not yet clear.The activity of triple-drug chemotherapy regimens when combined with an anti-EGFR mAb in mCRC patients is examined. We describe the overall safety and tolerability profiles based on a literature review of all published phase I and II clinical trials in this setting. Drug exposure, tumor mutational status, and metastases resectability are discussed. A review of PubMed and abstracts of major oncology congresses from 2009 to 2018, with MeSH and full-text search terms for clinical trials of anti-EGFR for 'metastatic' or 'advanced' 'colorectal cancer/adenocarcinoma' was implemented. Only English language publications were included.Efficacy data from phase II trials are promising, but the safety profiles are not as encouraging; the development of severe diarrhea and acneiform rash limit the drug exposure that is critical for improved outcomes. Phase II studies of these triplet chemotherapy/anti-EGFR mAb combinations have focused on conversion therapy in liver-limited disease or in the first-line setting in advanced disease. The identification of biomarkers of response and toxicity may support the use of personalized medicine and more precise design of phase III trials.

Tolerability

EGFR Inhibitors

10.1080/13543784.2019.1599860

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Citations (8)