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Background WNT974 is a small molecule inhibitor of Wnt signaling that specifically inhibits porcupine O-acyltransferase. This phase Ib dose-­escalation study evaluated the maximum tolerated dose of WNT974 in combination with encorafenib and cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer with RNF43 mutations or RSPO fusions. Patients and Methods Patients received once-daily encorafenib and weekly cetuximab, in addition to once-daily WNT974, in sequential dosing cohorts. In the first cohort, patients received 10-mg WNT974 (COMBO10), which was reduced in subsequent cohorts to 7.5-mg (COMBO7.5) or 5-mg (COMBO5) after dose–limiting toxicities (DLTs) were observed. Primary endpoints were incidence of DLTs and exposure to WNT974 and encorafenib. Secondary endpoints were anti-tumor activity and safety. Results Twenty patients were enrolled (COMBO10, n = 4; COMBO7.5, n = 6; COMBO5, n = 10). DLTs were observed in 4 patients, including grade 3 hypercalcemia (COMBO10, n = 1; COMBO7.5, n = 1), grade 2 dysgeusia (COMBO10, n = 1), and lipase increased (COMBO10, n = 1). A high incidence of bone toxicities (n = 9) was reported, including rib fracture, spinal compression fracture, pathological fracture, foot fracture, hip fracture, and lumbar vertebral fracture. Serious adverse events were reported in 15 patients, most frequently bone fracture, hypercalcemia, and pleural effusion. The overall response rate was 10% and disease control rate 85%; most patients achieved stable disease as their best response. Conclusion Concerns surrounding the safety and lack of preliminary evidence of improved anti-tumor activity of WNT974 + encorafenib + cetuximab, compared with previous encorafenib + cetuximab data, ultimately led to study discontinuation. Phase II was not initiated. Trial registration ClinicalTrials.gov, NCT02278133

Purpose: Encorafenib + cetuximab (E+C) is an effective therapeutic option in chemorefractory BRAFV600E metastatic colorectal cancer (mCRC). However, there is a need to improve the efficacy of this molecular-targeted therapy and evaluate regimens suitable for untreated BRAFV600E in patients with mCRC. Experimental Design: We performed a series of in vivo studies using BRAFV600E mCRC tumor xenografts. Mice were randomized to receive 5-fluoruracil (5-FU), irinotecan, or oxaliplatin regimens (FOLFIRI or FOLFOX), (E+C) or the combination. Patients received long-term treatment until disease progression, with deescalation strategies used to mimic maintenance therapy. Transcriptomic changes after progression on cytotoxic chemotherapy or targeted therapy were assessed. Results: Antitumor activity of either FOLFIRI or E+C was better as first-line treatment as compared with second-line, with partial cross-resistance seen between a cytotoxic regimen and targeted therapy with an average 62% loss of efficacy for FOLFIRI after E+C and a 45% loss of efficacy of E+C after FOLFIRI (P < 0.001 for both). FOLFIRI-treated models had upregulation of epithelial–mesenchymal transition (EMT) and MAPK pathway activation, where E+C treated models had suppressed MAPK signaling. In contrast, with chemotherapy with E+C, EMT and MAPK signaling remained suppressed. FOLFOX or FOLFIRI, each in combination with E+C, were the most active first-line treatments as compared with E+C or to chemotherapy alone. Furthermore, FOLFOX in combination with E+C as first-line induction therapy, followed by E+C ± 5-FU as maintenance therapy, was the most effective strategy for long-term disease control. Conclusions: These results support the combination of cytotoxic chemotherapy and molecular-targeted therapy as a promising therapeutic approach in the first-line treatment of BRAFV600E mCRC.

Colorectal cancer; Metastasis; Targeted therapies Cáncer colorrectal; Metástasis; Terapias dirigidas Càncer de colorectal; Metàstasi; Teràpies dirigides DESTINY-CRC01 (NCT03384940) was a multicenter, open-label, phase 2 trial assessing the efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing metastatic colorectal cancer (mCRC) that progressed after ≥2 prior regimens; results of the primary analysis are published. Patients received T-DXd 6.4 mg/kg every 3 weeks and were assigned to either: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+), cohort B (IHC 2+/ISH−), or cohort C (IHC 1+). Primary endpoint was objective response rate (ORR) by independent central review in cohort A. Secondary endpoints included ORR (cohorts B and C), duration of response, disease control rate, progression-free survival, overall survival, pharmacokinetics, and safety of T-DXd. 86 patients were enrolled (53 in cohort A, 15 in cohort B, and 18 in cohort C). Results of the primary analysis are published, reporting an ORR of 45.3% in cohort A. Here, we report the final results. No responses occurred in cohorts B or C. Median progression-free survival, overall survival, and duration of response were 6.9, 15.5, and 7.0 months, respectively. Overall serum exposure (cycle 1) of T-DXd, total anti-HER2 antibody, and DXd were similar regardless of HER2 status. Most common grade ≥3 treatment-emergent adverse events were decreased neutrophil count and anemia. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8 patients (9.3%). These findings support the continued exploration of T-DXd in HER2-positive mCRC. This study was sponsored by Daiichi Sankyo and funded by both Daiichi Sankyo and AstraZeneca. The sponsor was involved in data collection, analysis, interpretation, and preparation of the manuscript. We thank the patients who participated in this study, as well as their families and caregivers. We also thank the staff and investigators at all the study sites. We thank Masato Fukae, PhD, and Emi Kamiyama, PhD, for the analysis of the pharmacokinetic parameters, both of whom are employed by Daiichi Sankyo. Under the guidance of the authors, assistance in medical writing and editorial support was provided by Cindy M. Rigby, PhD, and Marianna B. Johnson, PhD, of ApotheCom, and was funded by Daiichi Sankyo.

Consensus; Metastatic colorectal cancer; Treatment Consens; Càncer colorectal metastàtic; Tractament Consenso; Cáncer colorrectal metastásico; Tratamiento Metastatic colorectal cancer (mCRC) is a heterogenous disease caused by various genetic alterations. The BRAFV600E mutation occurs in approximately 8–12% of patients and is characterised by an aggressive clinical course and poor prognosis. Here we review the current knowledge on BRAFV600E-mutant mCRC and provide a series of consensus statements on its clinical management. The treatment landscape for BRAFV600E-mutant mCRC has changed greatly due to the emergence of molecular targeted therapies (including BRAF inhibitors) and immune checkpoint inhibitors. A scientific literature search identified available data on molecular testing, treatments, and clinical monitoring of patients with BRAFV600E-mutant mCRC. Consensus statements were discussed and developed by a European expert panel. This manuscript provides consensus management guidance for different clinical presentations of BRAFV600E-mutant mCRC and makes recommendations regarding treatment sequencing choices. To guide appropriate clinical management and treatment decisions for mCRC patients, tumour tissue analysis for DNA mismatch repair/microsatellite status and, at a minimum, KRAS, NRAS, and BRAF mutational status is mandatory at the time of diagnosis. Finally, we discuss the rapidly evolving treatment landscape for BRAFV600E-mutant mCRC and define priorities for the development of novel therapeutic strategies that are needed to improve patient outcomes. This work was supported by an unrestricted medical education grant from Pierre Fabre, whose only involvement was to select the chair and to fund LiNK Health Group to provide independent medical writing support to the author group. Pierre Fabre had no sight of the article during development and no editorial involvement.

Background Therapeutic options are limited in patients with unresectable metastatic colorectal cancer (mCRC) ineligible for intensive chemotherapy. The use of trifluridine/tipiracil plus bevacizumab (TT-B) in this setting was evaluated in the TASCO1 trial; here, we present the final overall survival (OS) results. Methods TASCO1 was an open-label, non-comparative phase II trial. Patients (n = 153) were randomised 1:1 to TT-B (trifluridine/tipiracil 35 mg/m2 orally twice daily on days 1–5 and 8–12, and bevacizumab intravenously 5 mg/kg on days 1 and 15 of each 28-day cycle) or capecitabine plus bevacizumab (C-B; capecitabine, 1250 mg/m2 orally twice daily on days 1–14 and bevacizumab 7.5 mg/kg intravenously on day 1 of each 21-day cycle). Final OS was analysed when all patients had either died or withdrawn from the study. Adjusted multivariate regression was used to investigate the effects of pre-specified variables on OS. Results At 1 September 2020, median OS was 22.3 months (95% CI: 18.0–23.7) with TT-B and 17.7 months (95% CI: 12.6–19.8) with C-B (adjusted HR 0.78; 95% CI: 0.55–1.10). No variables negatively affected OS with TT-B. Safety results were consistent with prior findings. Conclusions TT-B is a promising therapeutic regimen in mCRC patients ineligible for intensive chemotherapy. Clinical trial information NCT02743221 (clinicaltrials.gov)

Colorectal cancer; Microsatellite stable; Tyrosine kinase inhibitors Cáncer colorrectal; Microsatélite estable; Inhibidores de la tirosina cinasa Càncer colorectal; Microsatèl·lit estable; Inhibidors de la tirosina cinasa Immune checkpoint inhibitors have reshaped the prognostic of several tumor types, including metastatic colorectal tumors with microsatellite instability (MSI). However, 90-95% of metastatic colorectal tumors are microsatellite stable (MSS) in which immunotherapy has failed to demonstrate meaningful clinical results. MSS colorectal tumors are considered immune-cold tumors. Several factors have been proposed to account for this lack of response to immune checkpoint blockade including low levels of tumor infiltrating lymphocytes, low tumor mutational burden, a high rate of WNT/β-catenin pathway mutations, and liver metastases which have been associated with immunosuppression. However, studies with novel combinations based on immune checkpoint inhibitors are showing promising activity in MSS colorectal cancer. Here, we review the underlying biological facts that preclude immunotherapy activity, and detail the different immune checkpoint inhibitor combinations evaluated, along with novel immune-based therapies, to overcome innate mechanisms of resistance in MSS colorectal cancer.

Biomarkers; Colorectal cancer; Maintenance therapy Biomarcadors; Càncer colorectal; Teràpia de manteniment Biomarcadores; Cáncer colorrectal; Terapia de mantenimiento Purpose MODUL is an adaptable, signal-seeking trial of biomarker-driven maintenance therapy following first-line induction treatment in patients with metastatic colorectal cancer (mCRC). We report findings from Cohorts 1 (BRAFmut), 3 (human epidermal growth factor 2 [HER2]+) and 4 (HER2‒/high microsatellite instability, HER2‒/microsatellite stable [MSS]/BRAFwt or HER2‒/MSS/BRAFmut/RASmut). Methods Patients with unresectable, previously untreated mCRC without disease progression following standard induction treatment (5-fluorouracil/leucovorin [5-FU/LV] plus oxaliplatin plus bevacizumab) were randomly assigned to control (fluoropyrimidine plus bevacizumab) or cohort-specific experimental maintenance therapy (Cohort 1: vemurafenib plus cetuximab plus 5-FU/LV; Cohort 3: capecitabine plus trastuzumab plus pertuzumab; Cohort 4: cobimetinib plus atezolizumab). The primary efficacy end-point was progression-free survival (PFS). Results Cohorts 1, 3 and 4 did not reach target sample size because of early study closure. In Cohort 1 (n = 60), PFS did not differ between treatment arms (hazard ratio, 0.95; 95% confidence intervals 0.50–1.82; P = 0.872). However, Cohort 1 exploratory biomarker data showed preferential selection for mitogen-activated protein kinase (MAPK) pathway mutations (mainly KRAS, NRAS, MAP2K1 or BRAF) in the experimental arm but not the control arm. In Cohort 3 (n = 5), PFS ranged from 3.6 to 14.7 months versus 4.0 to 5.4 months in the experimental and control arms, respectively. In Cohort 4 (n = 99), PFS was shorter in the experimental arm (hazard ratio, 1.44; 95% confidence intervals 0.90–2.29; P = 0.128). Conclusions Vemurafenib plus cetuximab plus 5-FU/LV warrants further investigation as first-line maintenance treatment for BRAFmut mCRC. MAPK-pathway emergent genomic alterations may offer novel therapeutic opportunities in BRAFmut mCRC. Cobimetinib plus atezolizumab had an unfavourable benefit:risk ratio in HER2‒/MSS/BRAFwt mCRC. New strategies are required to increase the susceptibility of MSS mCRC to immunotherapy. This work was supported by F. Hoffmann-La Roche Ltd.

The phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n =?22; chemotherapy, n =?26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1?57.8) months with pembrolizumab and 43.9 (range 36.6?55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months?NR) with pembrolizumab versus 10.4 (95% CI 6.3?22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26?1.20). Median OS was NR (range 13.8 months?NR) versus 30.0 (14.7?NR) months (HR 0.65, 95% CI 0.27?1.55) and ORR was 50% (95% CI 28?72) versus 46% (95% CI 27?67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002. FUNDING INFORMATION: The study was designed under the responsibility of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, in conjunction with the steering committee. The study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Pembrolizumab was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication. ACKNOWLEDGMENTS: This work was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. We thank the patients and their families and caregivers for participating in this trial, and all investigators and site personnel. Medical writing and editorial assistance were provided by Jemimah Walker, PhD, Mehak Aggarwal, PharmD, and Doyel Mitra, PhD, CMPP, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Atezolizumab; Bevacizumab; Metastatic colorectal cancer Atezolizumab; Bevacizumab; Cáncer colorrectal metastásico Atezolizumab; Bevacizumab; Càncer colorectal metastàtic Background MODUL is an adaptable, signal-seeking trial designed to test novel agents in predefined patient subgroups in first-line metastatic colorectal cancer (mCRC). Patients and methods Patients with measurable, unresectable, previously untreated mCRC received induction with ≤8 cycles of FOLFOX + bevacizumab followed by randomization to maintenance treatment comprising control [fluoropyrimidine (FP)/bevacizumab: 5-fluorouracil 1600-2400 mg/m2 46-h intravenous (i.v.) infusion day 1 q2 weeks plus leucovorin 400 mg/m2 2-h infusion i.v. day 1 q2 weeks or capecitabine 1000 mg/m2 b.i.d. orally days 1-14 every 21 days; bevacizumab 5 mg/kg 15-30-min i.v. infusion q2 weeks] or experimental treatment in one of four biomarker-driven cohorts. In patients with BRAF wild-type (BRAFwt) tumors (cohort 2), experimental treatment was FP/bevacizumab + atezolizumab (800 mg 60-min i.v. infusion q2 weeks). Primary efficacy endpoint was progression-free survival (PFS; intent-to-treat population). Enrollment is complete; efficacy and safety findings from cohort 2 are presented. Results Four hundred and forty-five patients with BRAFwt mCRC were randomized (2 : 1) to maintenance in cohort 2. At a median follow-up of 10.5 months, PFS outcome hypothesis was not met [hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.72-1.17; P = 0.48]; overall survival (OS) was immature. At a median follow-up of 20.3 months (2-year survival follow-up), PFS benefit was also not met (HR 0.95; 95% CI 0.77-1.18; P = 0.666); OS HR with nearly two-thirds of patients with events was 0.83 (95% CI 0.65-1.05; P = 0.117). No new safety signals were identified. The most common grade ≥3 treatment-emergent adverse events (TEAEs) for experimental versus control arms were hypertension (6.1% versus 4.2%), diarrhea (3.1% versus 2.1%), and palmar-plantar erythrodysesthesia syndrome (1.0% versus 2.5%). Four patients experienced TEAEs with fatal outcome, two were study treatment-related: hepatic failure (experimental arm) and large intestine perforation (control arm; bevacizumab-related). Conclusions Adding atezolizumab to FP/bevacizumab as first-line maintenance treatment after FOLFOX + bevacizumab induction for BRAFwt mCRC did not improve efficacy outcomes. This work was supported by F. Hoffmann-La Roche Ltd (no grant number). The sponsor was involved in the study design and was responsible for the overall study management (monitoring), drug supply, data management, statistical analysis, and drug safety process. The Trial Master Files are maintained electronically by the sponsor. The sponsor was involved in the writing of this report, alongside the authors, all of whom had access to the raw data. The corresponding author had full access to all of the data and the final responsibility for submitting the article for publication on behalf of all authors.

Colorectal cancer; Predictive markers; Tumour biomarkers Cáncer colorrectal; Marcadores predictivos; Biomarcadores tumorales Càncer colorrectal; Marcadors predictius; Biomarcadors tumorals Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFV600E colorectal cancer (mCRCBRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCBRAF-V600E treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12–0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10–0.71; P = 0.008), in patients with MSS-RNF43mutated versus MSS-RNF43wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCBRAF-V600E tumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients. VHIO would like to acknowledge the Cellex Foundation for providing research facilities and equipment, the FERO Foundation for their funding support, the Consorcio Centro de Investigación Biomédica en Red de Cáncer (CIBERONC, CB16/12/00259) from the Institute of Health Carlos III (ISCIII), Ministry of Science and Innovation, and the Department of Health (Generalitat de Catalunya, SLT008/18/00198 and SLT008/18/00205) for their support on this research. Authors acknowledge financial support from the State Agency for Research (Agencia Estatal de Investigación) (CEX2020-001024-S / AEI / 10.13039 /501100011033). This research is funded by the SCITRON program; Novartis funded the genomics characterization by WES of samples from 28 patients from the discovery cohort and had no influence on data analysis/interpretation or writing of the paper (3003145512 to R.A.T.). S.Li. is financially supported by a Chinese Scholarship Council PhD fellowship (201909370083 to S. Li). R.P.-L. is supported by a CRIS Foundation Talent Award (TALENT19-05), the FERO Foundation, the Instituto de Salud Carlos III-Investigación en Salud (PI18/01395 and PI21/01019 to R.P.-L.) and the Prostate Cancer Foundation (Young Investigator Award). This work was supported by the Miguel Servet-I Research Award from ISCIII of the Ministry of Economy (CP17/00199 to R.A.T.), the Olga Torres Foundation Award to emerging researchers (2601 to R.A.T.), the ISCIII-FEDER (PI17/00947 and PI20/00968 to E.E.), and the Fundación AECC (CLSEN19001ELEZ to E.E.) and Ministry of Science and Innovation (Europa Redes y Gestores, ECT2020-000827 to E.E.).

Metabolism; Resistance; Vaccines Metabolisme; Resistència; Vacunes Metabolismo; Resistencia; Vacunas Background Immune check-point blockade (ICB) has shown clinical benefit in mismatch repair-deficient/microsatellite instability high metastatic colorectal cancer (mCRC) but not in mismatch repair-proficient/microsatellite stable patients. Cancer vaccines with autologous dendritic cells (ADC) could be a complementary therapeutic approach to ICB as this combination has the potential to achieve synergistic effects. Methods This was a Phase I/II multicentric study with translational sub-studies, to evaluate the safety, pharmacodynamics and anti-tumor effects of Avelumab plus ADC vaccine in heavily pre-treated MSS mCRC patients. Primary objective was to determine the maximum tolerated dose and the efficacy of the combination. The primary end-point was 40% progression-free survival at 6 months with a 2 Simon Stage. Results A total of 28 patients were screened and 19 pts were included. Combined therapy was safe and well tolerated. An interim analysis (Simon design first-stage) recommended early termination because only 2/19 (11%) patients were disease free at 6 months. Median PFS was 3.1 months [2.1–5.3 months] and overall survival was 12.2 months [3.2–23.2 months]. Stimulation of immune system was observed in vitro but not clinically. The evaluation of basal RNA-seq noted significant changes between pre and post-therapy liver biopsies related to lipid metabolism and transport, inflammation and oxidative stress pathways. Conclusions The combination of Avelumab plus ADC vaccine is safe and well tolerated but exhibited modest clinical activity. Our study describes, for the first-time, a de novo post-therapy metabolic rewiring, that could represent novel immunotherapy-induced tumor vulnerabilities. The study was funded by grants from the FIS PI17/00732 from Instituto de Salud Carlos III, Premi Fi de Residència Emili Letang from Hospital Clínic Barcelona, Plan Nacional de I + D (PID-107139RB-C21 to DB-R and PID2020-115051RB-I00 to MC) and Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD). The study was funded with Grants from Catalan Agency for Management of University and Research Grants (AGAUR) (2014-SGR-474, 2017-SGR-1174 and 2017-SGR-1033), Fundació la Marató de TV3 (201330.10), Instituto de Salud Carlos III (PI13/01728 and PI19/00740) and Fundacion Olga Torres (Modalitat A. 2019/2020) to JM. IMMETCOLS signature is under patent protection (EP21382772.8.) This research was financially supported by GEMCAD and (OR Avelumab was provided) by Merck, S.L.U., Madrid, Spain, an affiliate of Merck KGaA, Darmstadt, Germany, as part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: https://doi.org/10.13039/100009945) and Pfizer.

Immunotherapy; Metastatic colorectal cancer; Precision medicine Inmunoterapia; Cáncer colorrectal metastásico; Medicina de precisión Immunoteràpia; Càncer colorectal metastàtic; Medicina de precisió Colorectal cancer (CRC) represents approximately 10% of all cancers and is the second most common cause of cancer deaths. Initial clinical presentation as metastatic CRC (mCRC) occurs in approximately 20% of patients. Moreover, up to 50% of patients with localized disease eventually develop metastases. Appropriate clinical management of these patients is still a challenging medical issue. Major efforts have been made to unveil the molecular landscape of mCRC. This has resulted in the identification of several druggable tumor molecular targets with the aim of developing personalized treatments for each patient. This review summarizes the improvements in the clinical management of patients with mCRC in the emerging era of precision medicine. In fact, molecular stratification, on which the current treatment algorithm for mCRC is based, although it does not completely represent the complexity of this disease, has been the first significant step toward clinically informative genetic profiling for implementing more effective therapeutic approaches. This has resulted in a clinically relevant increase in mCRC disease control and patient survival. The next steps in the clinical management of mCRC will be to integrate the comprehensive knowledge of tumor gene alterations, of tumor and microenvironment gene and protein expression profiling, of host immune competence as well as the application of the resulting dynamic changes to a precision medicine-based continuum of care for each patient. This approach could result in the identification of individual prognostic and predictive parameters, which could help the clinician in choosing the most appropriate therapeutic program(s) throughout the entire disease journey for each patient with mCRC. Fortunato Ciardiello was supported by a grant from Regione Campania (I-Cure Research Project Cup 21C17000030007). Andres Cervantes was supported by grants from the Instituto de Salud Carlos III (PI18/01909 and PI21/00689). Fortunato Ciardiello reports institutional research grants from Amgen, Merck KGaA, Merck Sharp & Dohme, Pfizer, Pierre Fabre, Roche, and Servier; and service on advisory boards for Bayer, Merck KGaA, Merck Sharp & Dohme, Pierre Fabre, Roche, and Servier outside the submitted work. Davide Ciardiello reports a travel grant from Sanofi outside the submitted work. Stefania Napolitano reports honoraria from Bristol Myers Squibb and Novartis outside the submitted work. Josep Tabernero reports advisory board or scientific consultancy fees from Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Roche, Genentech, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck KGaA, Merus, Merck Sharp & Dohme, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, SotioBiotech, Taiho, Tessa Therapeutics, and TheraMyc outside the submitted work. Andres Cervantes reports institutional research grants from Genentech, Merck KGaA, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astellas, Takeda, and Fibrogen; and honoraria or speaker’s fees from Amgen, Merck KGaA, Roche, Bayer, Servier, and Pierre Fabre outside the submitted work. Giulia Martini reports no conflicts of interest.

Gender; Toxicity; Tumour biology Gènere; Toxicitat; Biologia tumoral Género; Toxicidad; Biología tumoral Historically women were frequently excluded from clinical trials and drug usage to protect unborn babies from potential harm. As a consequence, the impact of sex and gender on both tumour biology and clinical outcomes has been largely underestimated. Although interrelated and often used interchangeably, sex and gender are not equivalent concepts. Sex is a biological attribute that defines species according to their chromosomal makeup and reproductive organ, while gender refers to a chosen sexual identity. Sex dimorphisms are rarely taken into account, in either preclinical or clinical research, with inadequate analysis of differences in outcomes according to sex or gender still widespread, reflecting a gap in our knowledge for a large proportion of the target population. Underestimation of sex-based differences in study design and analyses has invariably led to 'one-drug' treatment regimens for both males and females. For patients with colorectal cancer (CRC), sex also has an impact on the disease incidence, clinicopathological features, therapeutic outcomes, and tolerability to anticancer treatments. Although the global incidence of CRC is higher in male subjects, the proportion of patients presenting right-sided tumours and BRAF mutations is higher among females. Concerning sex-related differences in treatment efficacy and toxicity, drug dosage does not take into account sex-specific differences in pharmacokinetics. Toxicity associated with fluoropyrimidines, targeted therapies, and immunotherapies has been reported to be more extensive for females with CRC than for males, although evidence about differences in efficacy is more controversial. This article aims to provide an overview of the research achieved so far into sex and gender differences in cancer and summarize the growing body of literature illustrating the sex and gender perspective in CRC and their impact in relation to tumour biology and treatment efficacy and toxicity. We propose endorsing research on how biological sex and gender influence CRC as an added value for precision oncology.

Antiangiogenic therapy; Circulating miRNAs; Colorectal cancer Terapia antiangiogénica; MiARN circulantes; Cáncer colorrectal Teràpia antiangiogènica; MiARN circulants; Càncer colorectal The benefit of adding the antiangiogenic drug aflibercept to FOLFIRI regime in metastatic colorectal cancer (CRC) patients resistant to or progressive on an oxaliplatin-based therapy has been previously demonstrated. However, the absence of validated biomarkers to predict greater outcomes is a major challenge encountered when using antiangiogenic therapies. In this study we investigated profiles of circulating microRNAs (miRNAs) to build predictive models of response to treatment and survival. Plasma was obtained from 98 metastatic CRC patients enrolled in a clinical phase II trial before receiving FOLFIRI plus aflibercept treatment, and the circulating levels of 754 individual miRNAs were quantified using real-time PCR. A distinct signature of circulating miRNAs differentiated responder from non-responder patients. Remarkably, most of these miRNAs were found to target genes that are involved in angiogenic processes. Accordingly, some of these miRNAs had predictive value and entered in predictive models of response to therapy, progression of disease, and survival of patients treated with FOLFIRI plus aflibercept. Among these miRNAs, circulating levels of hsa-miR-33b-5p efficiently discriminated between responder and non-responder patients and predicted the risk of disease progression. Moreover, the combination of circulating VEGF-A and miR-33b-5p levels improved clinical stratification of metastatic CRC patients who were to receive FOLFIRI plus aflibercept treatment. In conclusion, our study supports circulating miRNAs as valuable biomarkers for predicting better outcomes in metastatic CRC patients treated with FOLFIRI plus aflibercept. Funding was provided by Sanofi.

Guideline; Rectal cancer; Total neoadjuvant therapy Pauta; Càncer de recte; Teràpia neoadjuvant total Pauta; Cáncer de recto; Terapia neoadyuvante total The management of localized rectal cancer requires a multidisciplinary approach to optimize outcomes, reduce morbidity and prevent under or overtreatments. While early stages may obtain benefit of local resections without any additional therapies, locally advanced rectal cancer becomes a challenge defining the better sequential strategy of surgery, radiotherapy and chemotherapy. The latest results of international phase III studies have positioned the total neoadjuvant therapy as a potential new standard of care in high risk rectal cancers, however, the best schedule is still not well defined.

BackgroundDespite unprecedented benefit from immune checkpoint inhibitors (ICIs) in patients with mismatch repair deficient (dMMR)/microsatellite instability high (MSI-H) advanced gastrointestinal cancers, a relevant proportion of patients shows primary resistance or short-term disease control. Since malignant effusions represent an immune-suppressed niche, we investigated whether peritoneal involvement with or without ascites is a poor prognostic factor in patients with dMMR/MSI-H metastatic colorectal cancer (mCRC) and gastric cancer (mGC) receiving ICIs.MethodsWe conducted a global multicohort study at Tertiary Cancer Centers and collected clinic-pathological data from a cohort of patients with dMMR/MSI-H mCRC treated with anti-PD-(L)1 ±anti-CTLA-4 agents at 12 institutions (developing set). A cohort of patients with dMMR/MSI-high mGC treated with anti-PD-1 agents±chemotherapy at five institutions was used as validating dataset.ResultsThe mCRC cohort included 502 patients. After a median follow-up of 31.2 months, patients without peritoneal metastases and those with peritoneal metastases and no ascites had similar outcomes (adjusted HR (aHR) 1.15, 95% CI 0.85 to 1.56 for progression-free survival (PFS); aHR 0.96, 95% CI 0.65 to 1.42 for overall survival (OS)), whereas inferior outcomes were observed in patients with peritoneal metastases and ascites (aHR 2.90, 95% CI 1.70 to 4.94; aHR 3.33, 95% CI 1.88 to 5.91) compared with patients without peritoneal involvement. The mGC cohort included 59 patients. After a median follow-up of 17.4 months, inferior PFS and OS were reported in patients with peritoneal metastases and ascites (aHR 3.83, 95% CI 1.68 to 8.72; aHR 3.44, 95% CI 1.39 to 8.53, respectively), but not in patients with only peritoneal metastases (aHR 1.87, 95% CI 0.64 to 5.46; aHR 2.15, 95% CI 0.64 to 7.27) when compared with patients without peritoneal involvement.ConclusionsPatients with dMMR/MSI-H gastrointestinal cancers with peritoneal metastases and ascites should be considered as a peculiar subgroup with highly unfavorable outcomes to current ICI-based therapies. Novel strategies to target the immune-suppressive niche in malignant effusions should be investigated, as well as next-generation ICIs or intraperitoneal approaches.

Purpose: The purpose of this article is to evaluate the safety of two regorafenib dose-escalation approaches in refractory metastatic colorectal cancer (mCRC) patients.Patients and methods: Patients with mCRC and progression during or within 3 months following their last standard chemotherapy regimen were randomised to receive the approved dose of regorafenib of 160 mg QD (arm A) or 120 mg QD (arm B) administered as 3 weeks of treatment followed by 1 week off, or 160 mg QD 1 week on/1 week off (arm C). The primary end-point was the percentage of patients with G3/G4 treatment-related adverse events (AEs) in each arm.Results: There were 299 patients randomly assigned to arm A (n = 101), arm B (n = 99), or arm C (n = 99); 297 initiated treatments (arm A n = 100, arm B n = 98, arm C n = 99: pop-ulation for safety analyses). G3/4 treatment-related AEs occurred in 60%, 55%, and 54% of patients in arms A, B, and C, respectively. The most common G3/4 AEs were hypertension (19, 12, and 20 patients), fatigue (20, 14, and 15 patients), hypokalemia (11, 7, and 10 pa-tients), and hand-foot skin reaction (8, 7, and 3 patients). Median overall survival was 7.4 (IQR 4.0-13.7) months in arm A, 8.6 (IQR 3.8-13.4) in arm B, and 7.1 (IQR 4.4-12.4) in arm C.Conclusions: The alternative regorafenib dosing schedules were feasible and safe in patients with mCRC who had been previously treated with standard therapy. There was a higher nu-merical improvement on the most clinically relevant AEs in the intermittent dosing arm, particularly during the relevant first two cycles. Clinicaltrials.gov identifier: NCT02835924.(C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Efficacy; Metastatic colorectal cancer Eficacia; Cáncer colorrectal metastásico Eficàcia; Càncer colorectal metastàtic Objetivo: El objetivo de la presente revisión sistemática es analizar los datos publicados sobre la eficacia y seguridad de las dosis superiores a los 180 mg/m2 de irinotecán recomendadas en la ficha técnica en pacientes con cáncer colorrectal metastásico tratados con el esquema FOLFIRI y con genotipo UGT1A1*1/*1 y *1/*28. Método: Se realizó una revisión sistemática mediante una búsqueda bibliográfica en Medline y Embase de los artículos publicados hasta diciembre de 2021. Los métodos utilizados se basaron en los recomendados según Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA). Los criterios para la inclusión de los estudios se definieron previamente en base a los dos objetivos secundarios que aborda esta revisión: 1) Analizar la magnitud de la diferencia de la respuesta clínica y 2) estudiar la magnitud de la diferencia de los efectos adversos a irinotecán a dosis altas, en comparación con las dosis descritas en la ficha técnica para el esquema FOLFIRI en pacientes con cáncer colorrectal metastásico con el genotipo UGT1A1*1/*1 o *1/*28. Resultados: La estrategia de búsqueda reportó un total de 98 referencias, de las que 13 fueron seleccionadas para el análisis, 7 (53,8%) evaluando tanto eficacia como seguridad y 6 (46,2%) únicamente seguridad. En relación con los estudios que evaluaron eficacia y seguridad, 6 (85,7%) se mostraron favorables al aumento de dosis en términos de tasa de respuesta objetiva y supervivencia libre de progresión e, incluso, en 2 de ellos en supervivencia global. Los estudios que evaluaron seguridad apuntan a que dosis de irinotecán superiores a 180 mg/m2 son toleradas por la mayor parte de los pacientes UGT1A1*1/*1 y *1/*28. Conclusiones: La presente revisión sistemática muestra la conveniencia de valorar el ajuste de dosis de irinotecán dentro del esquema FOLFIRI en función de los polimorfismos del gen UGT1A1, con un potencial aumento de las probabilidades de una adecuada respuesta clínica. Objective: The purpose of this systematic review is to analyze the published data on the efficacy and safety of doses higher than 180 mg/m2 of irinotecan recommended in the drug’s summary of product characteristics in metastatic colorectal cancer patients with genotypes UGT1A1*1/*1 or *1/*28 who are treated with the FOLFIRI regimen. Method: A systematic review of the literature was carried out in Medline and Embase searching for articles published up to December 2021. The methods used were based on the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The criteria for the inclusion of studies were previously defined based on the two secondary goals addressed in this review: 1) To analyze the magnitude of the differences in clinical responses and 2) To study the magnitude of the differences in adverse effects of irinotecan at high doses, as compared to the doses described in the summary of product characteristics corresponding to the FOLFIRI regimen in patients with metastatic colorectal cancer with genotypes UGT1A1*1/* 1 or *1/*28. Results: The search yielded a total of 985 references, of which 13 were selected for analysis. Seven evaluated both efficacy and safety and six only safety. With regard to the studies that evaluated both efficacy and safety, six out of seven (85.7%) were in favor of increasing irinotecan dose according to the objective response rate and progression-free survival. Two of them even recommended dose increases based on overall survival. Irinotecan safety studies suggest that doses higher than 180 mg/m2 are tolerated by most UGT1A1*1/*1 and *1/*28 patients. Conclusions: The present systematic review shows the advisability of considering adjusting the dose of irinotecan when used as part of the FOLFIRI regimen based on the polymorphisms of the UGT1A1 gene as this may increase the likelihood of an adequate clinical response.

Purpose Panitumumab plus FOLFOX (P-FOLFOX) is standard first-line treatment for RAS wild-type (WT) metastatic colorectal cancer. The value of panitumumab rechallenge is currently unknown. We assessed addition of panitumumab to FOLFIRI (P-FOLFIRI) beyond progression to P-FOLFOX in patients with no RAS mutations in liquid biopsy (LB). Methods In this randomized phase II trial, patients were assigned (3:2 ratio) to second-line P-FOLFIRI (arm A) or FOLFIRI alone (arm B). LB for circulating tumor DNA analysis was collected at study entry and at disease progression. Primary endpoint was 6-month progression-free survival. Two-stage Simon design required 85 patients to be included (EudraCT 2017-004519-38). Results Between February 2019 and November 2020, 49 patients were screened (16 RAS mutations in LB detected) and 31 included (18 assigned to arm A and 13 to arm B). The study was prematurely closed due to inadequate recruitment. Serious adverse events were more frequent in arm A (44% vs. 23%). Overall response rate was 33% (arm A) vs. 7.7% (arm B). Six-month progression-free survival rate was 66.7% (arm A) and 38.5% (arm B). Median progression-free survival was 11.0 months (arm A) and 4.0 months (arm B) (hazard ratio, 0.58). At disease progression, RAS or BRAF mutations in LB were found in 4/11 patients (36%) in arm A and 2/10 (20%) in arm B. Conclusions The BEYOND study suggests a meaningful benefit of P-FOLFIRI beyond progression to P-FOLFOX in metastatic colorectal cancer patients with WT RAS status selected by LB. This strategy deserves further investigation.

Colorectal cancer is the second leading cause of cancer deaths worldwide, with a 5-year relative survival of 14% in patients with metastatic colorectal cancer (mCRC). Patients with BRAF V600E mutations, which occur in ∼10%-15% of patients with mCRC, have a poorer prognosis compared with those with wild-type BRAF tumours. The combination of the BRAF inhibitor encorafenib with the epidermal growth factor receptor inhibitor cetuximab currently represents the only chemotherapy-free targeted therapy approved in the USA and Europe for previously treated patients with BRAF V600E-mutated mCRC. As a class, BRAF inhibitors are associated with dermatologic, gastrointestinal, and renal events, as well as pyrexia and secondary skin malignancies. Adverse event (AE) profiles of specific BRAF inhibitors vary, however, and are affected by the specific agents given in combination. In patients with mCRC, commonly reported AEs of cetuximab monotherapy include infusion reactions and dermatologic toxicities. Data from the phase III BEACON CRC study indicate that the combination of encorafenib with cetuximab has a distinct safety profile. Here we review the most frequently reported AEs that occurred with this combination in BEACON CRC and best practices for managing and mitigating AEs that require more than standard supportive care., Highlights • Encorafenib + cetuximab has a distinct safety profile in patients with BRAF V600E-mutated metastatic colorectal cancer. • Effective management strategies can mitigate the impact of AEs, prolonging treatment duration and benefits. • We provide guidance on managing gastrointestinal, skin, and renal AEs. • Specific guidance is given for the management of arthralgia, myalgia, fatigue, asthenia, headache, and pyrexia.

Simple Summary Given that most patients with MSS mCRC do not respond to immunotherapy agents or do not have durable clinical responses, there is an unmet clinical need to obtain predictors of response to immunotherapy and rational immunotherapy-based combination therapies for this entity. In this review, we present the efforts that have been made to date in the clinical setting to develop immunotherapy-based combinations for MSS mCRC and the rationale that lies behind each strategy. Abstract In recent years, deepening knowledge of the complex interactions between the immune system and cancer cells has led to the advent of effective immunotherapies that have revolutionized the therapeutic paradigm of several cancer types. However, colorectal cancer (CRC) is one of the tumor types in which immunotherapy has proven less effective. While there is solid clinical evidence for the therapeutic role of immune checkpoint inhibitors in mismatch repair-deficient (dMMR) and in highly microsatellite instable (MSI-H) metastatic CRC (mCRC), blockade of CTLA-4 or PD-L1/PD-1 as monotherapy has not conferred any major clinical benefit to patients with MMR-proficient (pMMR) or microsatellite stable (MSS) mCRC, reflecting 95% of the CRC population. There thus remains a high unmet medical need for the development of novel immunotherapy approaches for the vast majority of patients with pMMR or MSS/MSI-low (MSI-L) mCRC. Defining the molecular mechanisms for immunogenicity in mCRC and mediating immune resistance in MSS mCRC is needed to develop predictive biomarkers and effective therapeutic combination strategies. Here we review available clinical data from combinatorial therapeutic approaches using immunotherapy-based strategies for MSS mCRC.

Biomarkers; Colorectal cancer; Immunotherapy Biomarcadors; Càncer colorectal; Immunoteràpia Biomarcadores; Cáncer colorrectal; Inmunoterapia The search for immunotherapy biomarkers in Microsatellite Instability High/Deficient Mismatch Repair system (MSI-H/dMMR) metastatic colorectal cancer (mCRC) is an unmet need. Sixteen patients with mCRC and MSI-H/dMMR (determined by either immunohistochemistry or polymerase chain reaction) treated with PD-1/PD-L1 inhibitors at our institution were included. According to whether the progression-free survival with PD-1/PD-L1 inhibitors was longer than 6 months or shorter, patients were clustered into the IT-responder group (n: 9 patients) or IT-resistant group (n: 7 patients), respectively. In order to evaluate determinants of benefit with PD-1/PD-L1 inhibitors, we performed multimodal analysis including genomics (through NGS panel tumour-only with 431 genes) and the immune microenvironment (using CD3, CD8, FOXP3 and PD-L1 antibodies). The following mutations were more frequent in IT-resistant compared with IT-responder groups: B2M (4/7 versus 2/9), CTNNB1 (2/7 versus 0/9), and biallelic PTEN (3/7 versus 1/9). Biallelic ARID1A mutations were found exclusively in the IT-responder group (4/9 patients). Tumour mutational burden did not correlate with immunotherapy benefit, neither the rate of indels in homopolymeric regions. Of note, biallelic ARID1A mutated tumours had the highest immune infiltration and PD-L1 scores, contrary to tumours with CTNNB1 mutation. Immune microenvironment analysis showed higher densities of different T cell subpopulations and PD-L1 expression in IT-responders. Misdiagnosis of MSI-H/dMMR inferred by discordances between immunohistochemistry and polymerase chain reaction was only found in the IT-resistant population (3/7 patients). Biallelic ARID1A mutations and Wnt signalling activation through CTNNB1 mutation were associated with high and low T cell immune infiltrates, respectively, and deserve special attention as determinants of response to PD-1/PD-L1 inhibitors. The non-MSI-H phenotype in dMMR is associated with poor benefit to immunotherapy. Our results suggest that mechanisms of resistance to immunotherapy are multi-factorial. This research was funded by Merck Research Grants (Call 2018) in the Area of Colorectal Cancer Clinical Investigation.

Advanced; Colorectal cancer Avanzado; Cáncer colorrectal Avançat; Càncer colorrectal Background Treatment options are limited for participants with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed after two or more prior therapies. Studies have shown that blockade of both lymphocyte-activation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) can improve antitumor activity. Here, we evaluate the antitumor activity of the LAG-3 antibody favezelimab alone or in combination with pembrolizumab in participants with MSS mCRC. Patients and methods Eligible participants with MSS PD-1/programmed death-ligand 1 (PD-L1) treatment-naive mCRC that progressed on two or more prior therapies received 800 mg favezelimab, 800 mg favezelimab plus 200 mg pembrolizumab, or 800 mg favezelimab/200 mg pembrolizumab co-formulation, every 3 weeks. The primary endpoint was safety, the secondary endpoint was objective response rate (ORR), and exploratory endpoints included duration of response, progression-free survival (PFS), and overall survival (OS). Results At the data cut-off date of 23 October 2020, a total of 20 participants received favezelimab alone, 89 received favezelimab plus pembrolizumab (including as favezelimab/pembrolizumab co-formulation); 48 had PD-L1 combined positive score (CPS) ≥1 tumors. At this interim analysis median follow-up was 5.8 months with favezelimab and 6.2 with favezelimab plus pembrolizumab. Treatment-related adverse events (TRAEs) were 65% with favezelimab and 65.2% with favezelimab plus pembrolizumab. Grade ≥3 TRAEs were 15% with favezelimab and 20% with favezelimab plus pembrolizumab. No grade 5 TRAEs occurred. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15.0%) with favezelimab, and fatigue (16.9%) with favezelimab plus pembrolizumab. Confirmed ORR was 6.3% with favezelimab plus pembrolizumab, with median duration of response of 10.6 months (range 5.6-12.7 months), median OS of 8.3 months (95% confidence interval 5.5-12.9 months), and median PFS of 2.1 months (1.9-2.2 months). In an exploratory analysis of PD-L1 CPS ≥1 tumors, the confirmed ORR was 11.1%, median OS was 12.7 months (4.5 to not reached), and median PFS was 2.2 months (1.8-4.2 months) with favezelimab plus pembrolizumab. Conclusions Favezelimab with or without pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, particularly in participants with PD-L1 CPS ≥1 tumors. This work was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (no grant number).

Trifluridine/tipiracil is currently approved for metastatic colorectal cancer (mCRC) refractory to available therapies. However, there is no consensus on factors that predict treatment outcomes in daily practice. We assessed the early clinical experience with trifluridine/tipiracil in Spain and potential survival markers. This was a retrospective cohort study of mCRC patients who participated in the trifluridine/tipiracil early clinical experience programme in Spain. The primary outcome was overall survival (OS). Associations between OS and patient characteristics were assessed using multivariate Cox regression analyses. A total of 379 patients were included in the study. Trifluridine/tipiracil was administered for a median of 3.0 cycles and discontinued mainly due to disease progression (79.2%). The median OS was 7.9 months, with a 12-month OS rate of 30.5%. Cox analyses revealed that the following variables independently enhanced OS: ≤2 metastatic sites, no liver metastasis, alkaline phosphatase &lt, 300 IU, trifluridine/tipiracil dose reductions, and neutrophil/lymphocyte ratio &lt, 5. Grade ≥ 3 toxicities were reported in 141 (37.2%) patients, including mainly afebrile neutropaenia (23.2%), anaemia (12.1%), and thrombocytopaenia (5.3%). This study supports the real-life efficacy and safety of trifluridine/tipiracil for refractory mCRC and identifies tumour burden, liver metastasis, alkaline phosphatase, dose reductions, and neutrophil/lymphocyte ratio as survival markers.

BRAF mutation; Metastatic colorectal cancer; Prognostic markers Mutación BRAF; Cáncer colorrectal metastásico; Marcadores pronósticos Mutació BRAF; Càncer colorectal metastàtic; Marcadors pronòstics Background Colorectal cancer (CRC) is still a leading cause of cancer-related deaths in the United States and worldwide, despite recent improvements in cancer management. CRC, like many malignancies, is a heterogeneous disease, with subtypes characterized by genetic alterations. One common mutation in CRC is in the BRAF gene (most commonly V600E substitution). This occurs in ∼10% of patients with metastatic CRC (mCRC) and is a marker of poor prognosis. Design Herein, we review the clinical and translational literature on the role of the BRAF V600E mutation in the pathogenesis of mCRC, its mechanisms as a prognostic marker, and its potential utility as a predictive marker of treatment response. We then summarize the current evidence-based recommendations for management of BRAF V600E-mutated mCRC, with a focus on recent clinical research advances in this setting. Results The current standard therapies for first-line treatment of BRAF-mutated mCRC are chemotherapy with bevacizumab as well as 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab in patients with a good performance status. Combination strategies involving mitogen-activated protein kinase (MAPK) pathway blockade have shown promising results for the treatment of patients with BRAF V600E-mutated mCRC. The Binimetinib, Encorafenib, And Cetuximab cOmbiNed to treat BRAF-mutant ColoRectal Cancer (BEACON CRC) study represents the largest study in this population to date and has given strong clinical evidence to support BRAF and epidermal growth factor receptor inhibition with the combination of encorafenib plus cetuximab. Conclusions The treatment of BRAF-mutated mCRC has evolved rapidly over the last several years. Recently, combination strategies involving MAPK pathway blockade have shown promising results in BRAF V600E-mutated mCRC, and other potential targets continue to be explored. In addition, a greater understanding of the role of BRAF V600E mutation in the pathogenesis of CRC should also continue to fuel advances in the management of patients with mCRC harboring this genetic aberration. This work was supported by Array BioPharma, which was acquired by Pfizer in July 2019 (no grant number).

Neoplasias gastrointestinales; Inmunoterapia Neoplàsies gastrointestinals; Immunoteràpia Gastrointestinal neoplasms; Immunotherapy Background The efficacy of immune checkpoint inhibitors (ICIs) in patients with microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC) is unprecedented. A relevant proportion of subjects achieving durable disease control may be considered potentially ‘cured’, as opposed to patients experiencing primary ICI refractoriness or short-term clinical benefit. We developed and externally validated a nomogram to estimate the progression-free survival (PFS) and the time-independent event-free probability (EFP) in patients with MSI-high mCRC receiving ICIs. Methods The PFS and EFP were estimated using a cure model fitted on a developing set of 163 patients and validated on a set of 146 patients with MSI-high mCRC receiving anti-programmed death (ligand)1 (PD-(L)1) ± anticytotoxic T-lymphocyte antigen 4 (CTLA-4) agents. A total of 23 putative prognostic factors were chosen and then selected using a random survival forest (RSF). The model performance in estimating PFS probability was evaluated by assessing calibration (internally—developing set and externally—validating set) and quantifying the discriminative ability (Harrell C index). Results RFS selected five variables: ICI type (anti-PD-(L)1 monotherapy vs anti-CTLA-4 combo), ECOG PS (0 vs >0), neutrophil-to-lymphocyte ratio (≤3 vs >3), platelet count, and prior treatment lines. As both in the developing and validation series most PFS events occurred within 12 months, this was chosen as cut-point for PFS prediction. The combination of the selected variables allowed estimation of the 12-month PFS (focused on patients with low chance of being cured) and the EFP (focused on patients likely to be event-free at a certain point of their follow-up). ICI type was significantly associated with disease control, as patients receiving the anti-CTLA-4-combination experienced the best outcomes. The calibration of PFS predictions was good both in the developing and validating sets. The median value of the EFP (46%) allowed segregation of two prognostic groups in both the developing (PFS HR=3.73, 95% CI 2.25 to 6.18; p

Colorectal cancer; Encorafenib; Quality of life Cáncer colorrectal; Encorafenib; Calidad de vida Càncer colorectal; Encorafenib; Qualitat de vida Background In the BEACON CRC study (NCT02928224), encorafenib plus cetuximab with binimetinib {9.3 versus 5.9 months; hazard ratio (HR) [95% confidence interval (CI)]: 0.60 [0.47-0.75]} or without binimetinib [9.3 versus 5.9 months; HR (95% CI): 0.61 (0.48-0.77)] significantly improved overall survival (OS) compared with the previous standard of care (control) in patients with BRAF V600E metastatic colorectal cancer (mCRC). Quality of life (QoL) was a secondary endpoint, assessed using validated instruments. Patients and methods BEACON CRC was a randomized, open-label, phase III study comparing encorafenib plus cetuximab with or without binimetinib and the investigator’s choice of irinotecan plus cetuximab or FOLFIRI plus cetuximab (chemotherapy control) in patients with previously treated BRAF V600E mCRC. Patient-reported QoL assessments included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC) and Functional Assessment of Cancer Therapy—Colorectal (FACT-C). The primary outcome for these tools was time to definitive 10% deterioration. Results Encorafenib plus cetuximab, both with and without binimetinib, was associated with longer median times to definitive 10% deterioration versus the control group in the EORTC Global Health Status scale [HR (95% CI): 0.65 (0.52-0.80) versus 0.61 (0.49-0.75), respectively] and the FACT-C functional well-being subscale [HR (95% CI): 0.62 (0.50-0.76) versus 0.58 (0.47-0.72), respectively]. Consistent results were observed across all subscales of the EORTC and FACT-C instruments. QoL was generally maintained during treatment for the global EORTC and FACT-C scales. Conclusions In addition to improving OS, encorafenib plus cetuximab with or without binimetinib delays QoL decline in previously treated patients with BRAF V600E-mutant mCRC. This study was sponsored by Array BioPharma Inc, which was acquired by Pfizer, United States; National Cancer Institute, United States in July 2019. This work was also supported by the Cancer Center Core Grant [grant number P30 CA 008748] to Memorial Sloan-Kettering Cancer Center.

Background We evaluated the time to progression (TTP) and survival outcomes of second-line therapy for metastatic colorectal cancer among adults aged 70 years and older compared with younger adults following progression on first-line clinical trials. Methods Associations between clinical and disease characteristics, time to initial progression, and rate of receipt of second-line therapy were evaluated. TTP and overall survival (OS) were compared between older and younger adults in first- and second-line trials by Cox regression, adjusting for age, sex, Eastern Cooperative Oncology Group Performance Status, number of metastatic sites and presence of metastasis in the lung, liver, or peritoneum. All statistical tests were 2-sided. Results Older adults comprised 16.4% of patients on first-line trials (870 total older adults aged >70 years; 4419 total younger adults aged ≤70 years, on first-line trials). Older adults and those with Eastern Cooperative Oncology Group Performance Status >0 were less likely to receive second-line therapy than younger adults. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariable analysis (odds ratio = 1.11, 95% confidence interval = 1.02 to 1.21, P = .01). Older and younger adults enrolled in second-line trials experienced similar median TTP and median OS (median TTP = 5.1 vs 5.2 months, respectively; median OS = 11.6 vs 12.4 months, respectively). Conclusions Older adults were less likely to receive second-line therapy for metastatic colorectal cancer, though we did not observe a statistical difference in survival outcomes vs younger adults following second-line therapy. Further study should examine factors affecting decisions to treat older adults with second-line therapy. Inclusion of geriatric assessment may provide better criteria regarding the risks and benefits of second-line therapy.

Fruquintinib, a novel, highly selective, small-molecule tyrosine kinase inhibitor of VEGF receptors (VEGFRs)-1, -2 and -3, is approved in China for the treatment of metastatic colorectal cancer. FRESCO-2, a global, randomized, double-blind, placebo-controlled, Phase III study, is investigating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. Key inclusion criteria include: progression on or intolerance to TAS-102 and/or regorafenib; and prior treatment with approved chemotherapy, anti-VEGF therapy, and, ifLay abstract Fruquintinib is a drug that slows down, reduces or prevents the growth of vessels that supply blood to certain tumors. Fruquintinib is approved in China for the treatment of cancer of the colon and rectum that has spread to these parts of the body from the primary site of cancer: metastatic colorectal cancer. The FRESCO-2 study is being conducted globally to determine how safe and effective fruquintinib is at treating patients with metastatic colorectal cancer that has grown or spread following other forms of treatment, such as chemotherapy. About 687 patients will be enrolled globally to receive either fruquintinib or a matching placebo in a 2:1 ratio, respectively. The FRESCO-2 study is enrolling patients in the USA, Europe, Australia and Japan.

Background In preclinical studies trifluridine/tipiracil (FTD/TPI) plus oxaliplatin (Industriestrasse, Holzkirchen, Germany) sensitised microsatellite stable (MSS) metastatic colorectal cancer (mCRC) to anti-programmed cell death protein-1; the addition of oxaliplatin or bevacizumab (F Hoffmann- la ROCHE AG, Kaiseraugst, Switzerland) enhanced the antitumour effects of FTD/TPI. This study aimed to investigate the safety and efficacy of FTD/TPI plus oxaliplatin and either bevacizumab or nivolumab (Uxbridge business Park, Uxbridge, United Kingdom) in patients with mCRC who had progressed after at least one prior line of treatment. Patients and methods In 14-day cycles, patients received FTD/TPI 35 mg/m2 (twice daily, days 1-5) plus oxaliplatin 85 mg/m2 (day 1), and, on day 1, either bevacizumab 5 mg/kg (cohort A) or nivolumab 3 mg/kg (cohort B). Patients in Cohort B had confirmed MSS status. Results In total, 54 patients were enrolled: 37 in cohort A and 17 in cohort B. Recruitment in cohort B was stopped early due to the low response rate (RR) observed at interim analyses of efficacy. The most common adverse events (AEs) in cohort A were neutropenia/decreased neutrophils (75.7%), nausea (59.5%), vomiting (40.5%), diarrhoea (37.8%), peripheral sensory neuropathy (37.8%), fatigue (35.1%) and decreased appetite (35.1%). In cohort B, the most common AEs were neutropenia/decreased neutrophils (70.6%), diarrhoea (58.8%), nausea (47.1%), vomiting (47.1%), fatigue (47.1%), asthenia (41.2%), paraesthesia (41.2%), thrombocytopenia/decreased platelets (35.3%) and decreased appetite (35.3%). Confirmed objective RR was 17.1% in cohort A and 7.1% in cohort B; the corresponding values for median progression-free survival in the two cohorts were 6.3 and 6.0 months. Conclusion FTD/TPI plus oxaliplatin and bevacizumab or nivolumab had an acceptable safety profile and demonstrated antitumour activity in previously treated patients with mCRC., Highlights • This study evaluated the safety and efficacy of FTD/TPI plus oxaliplatin and either bevacizumab or nivolumab in mCRC patients. • FTD/TPI plus oxaliplatin in combination with bevacizumab or nivolumab had an acceptable and manageable safety profile. • Antitumour activity was observed following treatment with FTD/TPI plus oxaliplatin and bevacizumab. • Despite a modest RR with the addition of nivolumab, survival data were promising in these poor-prognosis patients.

Ablació; Càncer colorectal; Metàstasis del fetge Ablación; Cáncer colorrectal; Metástasis en el hígado Ablation; Colorectal cancer; Liver metastases The prognosis for oligometastatic colorectal cancer has improved in recent years, mostly because of recent advances in new techniques and approaches to the treatment of oligometastases, including new surgical procedures, better systemic treatments, percutaneous ablation, and stereotactic body radiation therapy (SBRT). There are several factors to consider when deciding on the better approach for each patient: tumor factors (metachronous or synchronous metastases, RAS mutation, BRAF mutation, disease-free interval, size and number of metastases), patient factors (age, frailty, comorbidities, patient preferences), and physicians’ factors (local expertise). These advances have presented major challenges and opportunities for oncologic multidisciplinary teams to treat patients with limited liver and lung metastases from colorectal cancer with a curative intention. In this review, we describe the different treatment options in patients with limited liver and lung metastases from colorectal cancer, and the possible combination of three approaches: systemic treatment, surgery, and local ablative treatments. This research received no external funding.

Simple Summary The survival of patients with metastatic colorectal cancer (mCRC) has been improved over the years and now reaches 30–40 months. However, few therapeutic options are available after failure of first- and second-line treatments. In fact, prognosis of chemo-refractory mCRC remains poor. Therefore, new therapeutic strategies are needed. Emerging evidence suggest that retreatment with epidermal growth factor (EGFR) inhibitors after a treatment break, in patients that obtained a clinical benefit by previous anti-EGFR, could lead to prolonged survival. The rationale beyond this “rechallenge” strategy is that after a “treatment holiday” EGFR resistant cancer cells decay, restoring the sensibility to EGFR blockade. In this review we analyze the current knowledge of retreatment with EGFR inhibitors, examine the role of novel biomarkers that can guide the appropriate selection of patients. Finally, we discuss future perspectives and on-going clinical trials. Abstract The prognosis of patients with metastatic colorectal cancer (mCRC) who progressed to the first and the second lines of treatment is poor. Thus, new therapeutic strategies are needed. During the last years, emerging evidence suggests that retreatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MAbs) in the third line of mCRC patients, that have previously obtained clinical benefit by first-line therapy with anti-EGFR MAbs plus chemotherapy, could lead to prolonged survival. The rationale beyond this “rechallenge” strategy is that, after disease progression to first line EGFR-based therapy, a treatment break from anti-EGFR drugs results in RAS mutant cancer cell decay, restoring the sensitivity of cancer cells to cetuximab and panitumumab. In fact, rechallenge treatment with anti-EGFR drugs has shown promising clinical activity, particularly in patients with plasma RAS and BRAF wild type circulating tumor DNA, as defined by liquid biopsy analysis at baseline treatment. The aim of this review is to analyze the current knowledge on rechallenge and to investigate the role of novel biomarkers that can guide the appropriate selection of patients that could benefit from this therapeutic strategy. Finally, we discuss on-going trials and future perspectives.

Inhibidor de BRAF; Binimetinib; Cáncer de colon BRAF inhibitor; Binimetinib; Colon cancer Inhibidor de BRAF; Binimetinib; Càncer de còlon 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. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from Instituto de Salud Carlos III (ISCIII) FIS/FEDER (PI17/00947, PI20/00968) and from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 635342.

Imatges per ressonància magnètica; Neoplàsies rectals; Microambient tumoral Imagen de resonancia magnética; Neoplasias rectales; Microambiente tumoral Magnetic Resonance Imaging; Rectal neoplasms; Tumor Microenvironment Objective This study evaluated the correlation between intratumoural stroma proportion, expressed as tumour-stroma ratio (TSR), and apparent diffusion coefficient (ADC) values in patients with rectal cancer. Methods This multicentre retrospective study included all consecutive patients with rectal cancer, diagnostically confirmed by biopsy and MRI. The training cohort (LUMC, Netherlands) included 33 patients and the validation cohort (VHIO, Spain) 69 patients. Two observers measured the mean and minimum ADCs based on single-slice and whole-volume segmentations. The TSR was determined on diagnostic haematoxylin & eosin stained slides of rectal tumour biopsies. The correlation between TSR and ADC was assessed by Spearman correlation ( r s ). Results The ADC values between stroma-low and stroma-high tumours were not significantly different. Intra-class correlation (ICC) demonstrated a good level of agreement for the ADC measurements, ranging from 0.84–0.86 for single slice and 0.86–0.90 for the whole-volume protocol. No correlation was observed between the TSR and ADC values, with ADC mean r s = -0.162 ( p= 0.38) and ADC min r s = 0.041 ( p= 0.82) for the single-slice and r s = -0.108 ( p= 0.55) and r s = 0.019 ( p= 0.92) for the whole-volume measurements in the training cohort, respectively. Results from the validation cohort were consistent; ADC mean r s = -0.022 ( p= 0.86) and ADC min r s = 0.049 ( p= 0.69) for the single-slice and r s = -0.064 ( p= 0.59) and r s = -0.063 ( p= 0.61) for the whole-volume measurements. Conclusions Reproducibility of ADC values is good. Despite positive reports on the correlation between TSR and ADC values in other tumours, this could not be confirmed for rectal cancer. This study received financial support from “ Genootschap Landgoed Keukenhof .” Author R.P.L.’s work is supported by a PCF-Young Investigator Award . The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Esdeveniments adversos; Càncer colorectal metastàtic; Regorafenib Eventos adversos; Cáncer colorrectal metastásico; Regorafenib Adverse events; Metastatic colorectal cancer; Regorafenib Over the past 20 years, management of patients with metastatic colorectal cancer (mCRC) has improved considerably, leading to increased overall survival and more patients eligible for third- or later-line therapy. Currently, two oral therapies are recommended in the third-line treatment of mCRC, regorafenib and trifluridine/tipiracil. Selecting the most appropriate treatment in the third-line setting poses different challenges compared with treatment selection at earlier stages. Therefore, it is important for physicians to understand and differentiate between available treatment options and to communicate the benefits and challenges of these to patients. In this narrative review, practical information on regorafenib is provided to aid physicians in their decision-making and patient communications in daily practice. We discuss the importance of appropriate patient selection and adverse events management through close patient monitoring and dose adjustments to ensure patients stay on treatment for longer and receive as much benefit as possible. We also highlight key physician–patient communication points to facilitate shared decision-making. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Bayer.

Biomarcadors; Càncer colorectal; Classificació molecular Biomarcadores; Cáncer colorrectal; Clasificación molecular Biomarkers; Colorectal cancer; Molecular classification Colorectal cancer (CRC) is a heterogeneous disease representing a therapeutic challenge, which is further complicated by the common occurrence of several molecular alterations that confer resistance to standard chemotherapy and targeted agents. Mechanisms of resistance have been identified at multiple levels in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAFV600E, and in the HER2 and MET receptors. These alterations represent oncogenic drivers that may co-exist in the same tumor with other primary and acquired alterations via a clonal selection process. Other molecular alterations include DNA damage repair mechanisms and rare kinase fusions, potentially offering a rationale for new therapeutic strategies. In recent years, genomic analysis has been expanded by a more complex study of epigenomic, transcriptomic, and microenvironment features. The Consensus Molecular Subtype (CMS) classification describes four CRC subtypes with distinct biological characteristics that show prognostic and potential predictive value in the clinical setting. Here, we review the panorama of actionable targets in CRC, and the developments in more recent molecular tests, such as liquid biopsy analysis, which are increasingly offering clinicians a means of ensuring optimal tailored treatments for patients with metastatic CRC according to their evolving molecular profile and treatment history

Aflibercept; Teràpia anti-angiogènica; Càncer colorectal Aflibercept; Terapia anti-angiogénica; Cáncer colorrectal Aflibercept; Anti-angiogenic therapy; Colorectal cancer Background: Metastatic colorectal cancer (mCRC) represents a substantial health burden globally and an increasing challenge in Asian countries. Treatment options include chemotherapy plus a vascular endothelial growth factor (VEGF) inhibitor (such as bevacizumab, aflibercept or ramucirumab), or anti-epidermal growth factor receptor (EGFR) therapies. Aflibercept, a recombinant fusion protein, has been approved for treatment of mCRC in combination with FOLFIRI for patients whose disease progresses during or after treatment with an oxaliplatin-containing regimen, based on its efficacy and tolerability profile in clinical trials. This report aims to provide an overview of both clinical and real-world evidence and experience on the use of aflibercept in routine clinical practice, with a focus on European, American and Asian populations. Methods: A literature search was conducted in PubMed (on 28th February 2019) using the search terms ("aflibercept") and ("Colorectal"OR"CRC") to identify publications containing information on aflibercept-containing regimens. Results: The adverse events (AE) profile was similar between geographical locations. Across trials, real-world and retrospective studies, grade ≥ 3 hypertension and proteinuria were amongst the most frequently reported AEs. Conclusions: The safety profile of aflibercept is generally manageable and comparable across various geographic locations. This research was funded by Sanofi.

BRAF mutation; Cetuximab; Colorectal cancer Mutación BRAF; Cetuximab; Cáncer colorrectal Mutació BRAF; Cetuximab; Càncer colorectal B-type RAF (BRAF)-V600E mutations in metastatic colorectal cancer (mCRC) have been described in up to 12% of the patients. This mutation confers a bad prognostic and poor response with standard chemotherapy. Unlike the scenario for BRAF mutant melanoma, successful BRAF blockade in mCRC has emerged as a complex path, primarily due to the complex underlying biology of mCRC. The BEACON trial has reshaped the therapeutic landscape of BRAF mCRC demonstrating the benefit of the BRAF inhibitor encorafenib in combination with the anti-epidermal growth factor receptor cetuximab. This paper aims to review the main features of BRAF mCRC as well as to review the development of targeted therapy and biomarkers in this specific population. Finally, a deep insight into the underlying biology and molecular classification of BRAF-V600E mCRC has also been performed. The words ‘BRAF-V600E mutation’, ‘colorectal cancer’, ‘BRAF inhibitors’, ‘consensus molecular subtypes’, ‘encorafenib’, and ‘cetuximab’ were used to identify the clinical trials from phase I to phase III related to the development of BRAF inhibitors in this population. A deep search among international meetings (American Society of Clinical Oncology and European Society of Medical Oncology) has been performed to incorporate the last trials presented. BRAF-V600E mCRC is a challenging disease, mostly because of its molecular biology. The BEACON trial has been the most important therapeutic change in the last decade. Nevertheless, new information regarding biomarkers or novel combinations including BRAF inhibitors plus immune checkpoint inhibitors are also promising.