Upfront Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Bevacizumab With or Without Atezolizumab for Patients With Metastatic Colorectal Cancer: Updated and Overall Survival Results of the ATEZOTRIBE Study.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report 4-year results of the phase II randomized AtezoTRIBE study. Eligible patients with metastatic colorectal cancer (mCRC) received first-line fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)/bevacizumab (control group, n = 73) or FOLFOXIRI/bevacizumab plus atezolizumab (experimental group, n = 145). We present overall survival (OS) and updated outcomes according to tumor immune-related biomarkers, both in the intention-to-treat (ITT) population and the cohort of patients with proficient mismatch repair (pMMR) tumors. Median follow-up was 45.2 months (IQR, 42.6-49.2). In the ITT population, median OS was 33.0 and 27.2 months for experimental and control groups, respectively (hazard ratio [HR], 0.78 [80% CI, 0.61 to 0.98]; P = .084). An interaction effect between Immunoscore Immune-Checkpoint (IC) and treatment arm was observed (Pint, .089), with higher benefit from atezolizumab in the Immunoscore IC-high group. In the pMMR cohort (N = 202), median OS was 30.8 and 29.2 months for experimental and control groups, respectively (HR, 0.80 [80% CI, 0.63 to 1.02]; P = .117). Interactions between treatment group and tumor mutational burden (TMB) and Immunoscore IC were reported (Pint, .043 and .092, respectively), with patients bearing TMB-high and Immunoscore IC-high tumors deriving higher benefit from the addition of atezolizumab. First-line FOLFOXIRI/bevacizumab plus atezolizumab improves OS in patients with mCRC. In the pMMR group, patients with Immunoscore IC-high and/or TMB-high tumors are identified as a subgroup of interest to further develop this treatment.

Primary Tumor Resection in Synchronous Metastatic Colorectal Cancer Patients Treated with Upfront Chemotherapy plus Bevacizumab: A Pooled Analysis of TRIBE and TRIBE2 Studies.

BACKGROUND: The decision to resect or not the primary tumor in asymptomatic patients with synchronous metastatic colorectal cancer (mCRC) is a complex and challenging issue for oncologists, especially when an antiangiogenic-based therapy is planned. METHODS: Patients enrolled in the phase III TRIBE and TRIBE2 studies that compared upfront FOLFOXIRI + bevacizumab to FOLFIRI or FOLFOX + bevacizumab, respectively, were included. We assessed the association of primary tumor resection (PTR) with progression-free survival (PFS), overall survival (OS), response rate (ORR), rate of grade > 2 adverse events (AEs), and serious gastrointestinal and surgical AEs in the overall population and according to the treatment arm. RESULTS: Of the 999 patients included, 513 (51%) underwent PTR at baseline. Longer PFS and OS were observed in resected patients compared to those with unresected primary tumors: 11.2 vs. 10.0 months (p < 0.001) and 26.6 vs. 22.5 (p < 0.001), respectively. In multivariate models, PTR was confirmed as an independent prognostic factor for better PFS (p = 0.032) and OS (p = 0.018). Patients with PTR experienced a higher incidence of grade 3 or 4 diarrhea (p = 0.055) and lower incidence of anemia (p = 0.053), perforation (p = 0.015), and serious gastrointestinal and surgical AEs (p < 0.001). No statistically significant differences were noted in incidence of bleeding (p = 0.39). The benefit of FOLFOXIRI + bevacizumab in terms of PFS (p for interaction: 0.46), OS (p for interaction: 0.80), ORR (p for interaction: 0.36), and incidence of grade 3 or 4 AEs was independent of PTR. CONCLUSIONS: PTR at baseline was independently associated with good prognosis in synchronous mCRC patients and with lower incidence of serious gastrointestinal and surgical AEs during upfront chemotherapy plus bevacizumab. The benefit and toxicity profile of FOLFOXIRI plus bevacizumab was independent of PTR.

Vessel-Guided Mesohepatectomy for Liver Partition and Staged Major Parenchyma-Sparing Hepatectomies with Super-Selective Portal Vein Embolization or Enhanced ALPPS to Achieve R0 Resection for Colorectal Liver Metastases at the Hepatocaval Confluence.

Background. R0 minor parenchyma-sparing hepatectomy (PSH) is feasible for colorectal liver metastases (CRLM) in contact with hepatic veins (HV) at hepatocaval confluence since HV can be reconstructed, but in the case of contact with the first-order glissonean pedicle (GP), major hepatectomy is mandatory. To pursue an R0 parenchyma-sparing policy, we proposed vessel-guided mesohepatectomy for liver partition (MLP) and eventually combination with liver augmentation techniques for staged major PSH. Methods. We analyzed 15 consecutive vessel-guided MLPs for CRLM at the hepatocaval confluence. Patients had a median of 11 (range: 0-67) lesions with a median diameter of 3.5 cm (range: 0.0-8.0), bilateral in 73% of cases. Results. Grade IIIb or more complications occurred in 13%, median hospital stay was 14 (range: 6-62) days, 90-day mortality was 0%. After a median follow-up of 17.5 months, 1-year OS and RFS were 92% and 62%. In nine (64%) patients, MLP was combined with portal vein embolization (PVE) or ALPPS to perform staged R0 major PSH. Future liver remnant (FLR) volume increased from a median of 15% (range: 7-20%) up to 41% (range: 37-69%). Super-selective PVE was performed in three (33%) patients and enhanced ALPPS (e-ALPPS) in six (66%). In two e-ALPPS an intermediate stage of deportalized liver PSH was necessary to achieve adequate FLR volume. Conclusions. Vessel-guided MLP may transform the liver in a paired organ. In selected cases of multiple bilobar CRLM, to guarantee oncological radicality (R0), major PSH is feasible combining advanced surgical parenchyma sparing with liver augmentation techniques when FLR volume is insufficient.

ShorTrip Trial: A Prospective, Multicentric Phase II Single-Arm Trial of Short-Course Radiotherapy Followed by Intensified Consolidation Chemotherapy With the Triplet FOLFOXIRI as Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer.

BACKGROUND: In patients with locally advanced rectal cancer (LARC) treated with preoperative (chemo) radiotherapy and surgery, adjuvant chemotherapy is poorly feasible and its benefit is questionable. In the last years, several total neoadjuvant treatment (TNT) strategies, moving the adjuvant chemotherapy to the neoadjuvant setting, have been investigated with the aim of improving compliance to systemic chemotherapy, treating micrometastases earlier and then reducing distant recurrence. PATIENTS AND METHODS: ShorTrip (NTC05253846) is a prospective, multicentre, single-arm phase II trial where 63 patients with LARC will be treated with short-course radiotherapy followed by intensified consolidation chemotherapy with FOLFOXIRI regimen and surgery. Primary endpoint is pCR. Among the first 11 patients who started consolidation chemotherapy, a preliminary safety analysis showed a high rate of grade 3 to 4 neutropenia (N = 7, 64%) during the first cycle of FOLFOXIRI. Therefore, the protocol has been emended with the recommendation to omit irinotecan during the first cycle of consolidation chemotherapy. After amendment, in a subsequent safety analysis focused on the first 9 patients treated with FOLFOX as first cycle and then with FOLFOXIRI, grade 3 to 4 neutropenia was reported in only one case during the second cycle. AIM OF THE STUDY: The aim of this study is to assess the safety and activity of a TNT strategy including SCRT, intensified consolidation treatment with FOLFOXIRI and delayed surgery. After protocol amendment, the treatment seems feasible without safety concern. Results are expected at the end of 2024.

Exploring the Outcome of Disappearance or Small Remnants of Colorectal Liver Metastases during First-Line Chemotherapy on Hepatobiliary Contrast-Enhanced and Diffusion-Weighted MR Imaging.

We aimed to evaluate the outcome of the disappearance or small remnants of colorectal liver metastases during first-line chemotherapy assessed by hepatobiliary contrast-enhanced and diffusion-weighted MR imaging (DW-MRI). Consecutive patients with at least one disappearing liver metastasis (DLM) or small residual liver metastases (≤10 mm) assessed by hepatobiliary contrast-enhanced and DW-MRI during first-line chemotherapy were included. Liver lesions were categorized into three groups: DLM; residual tiny liver metastases (RTLM) when ≤5 mm; small residual liver metastases (SRLM) when >5mm and ≤10 mm. The outcome of resected liver metastases was assessed in terms of pathological response, whereas lesions left in situ were evaluated in terms of local relapse or progression. Fifty-two outpatients with 265 liver lesions were radiologically reviewed; 185 metastases fulfilled the inclusion criteria: 40 DLM, 82 RTLM and 60 SRLM. We observed a pCR rate of 75% (3/4) in resected DLM and 33% (12/36) of local relapse for DLM left in situ. We observed a risk of relapse of 29% and 57% for RTLM and SRLM left in situ, respectively, and a pCR rate of about 40% overall for resected lesions. DLM assessed via hepatobiliary contrast-enhanced and DW-MRI very probably indicates a complete response. The surgical removal of small remnants of liver metastases should always be advocated whenever technically possible.

Colorectal neoplastic emergencies in immunocompromised patients: preliminary result from the Web-based International Register of Emergency Surgery and Trauma (WIRES-T trial).

Association of advanced age, neoplastic disease and immunocompromission (IC) may lead to surgical emergencies. Few data exist about this topic. Present study reports the preliminary data from the WIRES-T trial about patients managed for colorectal neoplastic emergencies in immunocompromised patients. The required data were taken from a prospective observational international register. The study was approved by the Ethical Committee with approval n. 17575; ClinicalTrials.gov Identifier: NCT03643718. 839 patients were collected; 753 (80.7%) with mild-moderate IC and 86 (10.3%) with severe. Median age was 71.9 years and 73 years, respectively, in the two groups. The causes of mild-moderate IC were reported such malignancy (753-100%), diabetes (103-13.7%), malnutrition (26-3.5%) and uremia (1-0.1%), while severe IC causes were steroids treatment (14-16.3%); neutropenia (7-8.1%), malignancy on chemotherapy (71-82.6%). Preoperative risk classification were reported as follow: mild-moderate: ASA 1-14 (1.9%); ASA 2-202 (26.8%); ASA 3-341 (45.3%); ASA 4-84 (11.2%); ASA 5-7 (0.9%); severe group: ASA 1-1 patient (1.2%); ASA 2-16 patients (18.6%); ASA 3-41 patients (47.7%); ASA 4-19 patients (22.1%); ASA 5-3 patients (3.5%); lastly, ASA score was unavailable for 105 cases (13.9%) in mild-moderate group and in 6 cases (6.9%) in severe group. All the patients enrolled underwent urgent/emergency surgery Damage control approach with open abdomen was adopted in 18 patients. Mortality was 5.1% and 12.8%, respectively, in mild-moderate and severe groups. Long-term survival data: in mild-moderate disease-free survival (median, IQR) is 28 (10-91) and in severe IC, it is 21 (10-94). Overall survival (median, IQR) is 44 (18-99) and 26 (20-90) in mild-moderate and severe, respectively; the same is for post-progression survival (median, IQR) 29 (16-81) and 28, respectively. Univariate and multivariate analyses showed as the only factor influencing mortality in mild-moderate and severe IC is the ASA score. Colorectal neoplastic emergencies in immunocompromised patients are more frequent in elderly. Sigmoid and right colon are the most involved. Emergency surgery is at higher risk of complication and mortality; however, management in dedicated emergency surgery units is necessary to reduce disease burden and to optimize results by combining oncological and acute care principles. This approach may improve outcomes to obtain clinical advantages for patients like those observed in elective scenario. Lastly, damage control approach seems feasible and safe in selected patients.

Total neoadjuvant treatment and organ preservation strategies in the management of localized rectal cancer: A narrative review and evidence-based algorithm.

The multimodal approach with total mesorectal excision preceded by neoadjuvant (chemo)radiotherapy represented the mainstay treatment for locally advanced rectal cancer (LARC) for a long time. However, the benefit of adjuvant chemotherapy in terms of distant relapse reduction is limited. Recently, chemotherapy regimens administered before surgery and incorporated with (chemo)radiotherapy in total neoadjuvant treatment protocols have been established as new options in the management of LARC. Meanwhile, patients with clinical complete response to neoadjuvant treatment can benefit from organ preservation strategies, aimed at sparing surgery and long-term post-operative morbidities, while preserving an adequate disease control. However, the introduction of a non-operative management in clinical practice is a matter of debate with some concerns regarding the risk of local recurrence and long-term outcomes. In this review, we discuss how these recent advances are reshaping the multimodal management of localized rectal cancer and propose an algorithm to place them in the clinical practice.

TK-1, TP, Ang-2, and Tie-2 mRNA expression in plasma-derived microvesicles of chemo-refractory metastatic colorectal cancer patients.

BACKGROUND: Trifluridine/tipiracil and regorafenib are indicated for metastatic colorectal cancer (mCRC) patients' refractory to standard chemotherapy. No prognostic or predictive biomarkers are available for these agents. METHODS: We assessed messenger ribonucleic acid (mRNA) expression of four biomarkers implicated in the mechanism of action of trifluridine/tipiracil (TK-1 and TP) and regorafenib (Ang-2 and Tie-2) in baseline plasma-derived microvesicles of chemo-refractory mCRC patients treated with these agents (trifluridine/tipiracil cohort and regorafenib cohort), to explore their prognostic and predictive role. RESULTS: Baseline characteristics of the two cohorts were not different. Ang-2 mRNA was not detectable. Only TK-1 expression measured as a continuous variable was associated with progression-free survival (HR=1.09, 95%CI: 0.99-1.21; p=0.07) and overall survival (HR=1.11, 95%CI: 1.00-1.22; p=0.04), confirmed at multivariate analysis for progression-free survival (p=0.02) with a positive trend for overall survival (p=0.08). Baseline mRNA levels of TK-1, TP and Tie-2 were not predictive of trifluridine/tipiracil and regorafenib benefit. CONCLUSION: Baseline mRNA levels of TK-1, TP and Tie-2 on plasma-derived microvesicles were not predictive of trifluridine/tipiracil and regorafenib benefit. Future studies should analyze the early modulation of these biomarkers to assess their potential predictive role.

Molecular screening with liquid biopsy for anti-EGFR retreatment in metastatic colorectal cancer: preliminary data from the randomized phase 2 PARERE trial.

Background: Retreatment with anti-EGFR monoclonal antibodies is a promising strategy in patients with RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) who achieved benefit from previous anti-EGFR exposure upon exclusion of mutations in RAS/BRAF genes according to circulating tumor DNA (ctDNA) analysis by means of liquid biopsy (LB). This treatment approach is now being investigated in the randomized phase II trial PARERE (NCT04787341). We here present preliminary findings of molecular screening. Methods: Patients with RAS/BRAFV600E wt mCRC according to tissue genotyping who benefited from previous anti-EGFR-based treatment (fluoropyrimidines, oxaliplatin, irinotecan, and antiangiogenics) and then experienced disease progression to EGFR targeting were eligible for screening in the PARERE trial. The next-generation sequencing (NGS) panel Oncomine™ was employed for ctDNA testing. Results: A total of 218 patients underwent LB, and ctDNA sequencing was successful in 201 of them (92%). RAS/BRAFV600E mutations were found in 68 (34%) patients and were mainly subclonal (median variant allele fraction [VAF] for KRAS, NRAS, and BRAF mutant clones: 0.52%, 0.62%, and 0.12%, respectively; p = 0.01), with KRASQ61H being the most frequently detected (31%). Anti-EGFR-free intervals did not predict ctDNA molecular status (p = 0.12). Among the 133 patients with RAS/BRAFV600E wt tumors according to LB, 40 (30%) harbored a mutation in at least another gene potentially implied in anti-EGFR resistance, mainly with subclonal expression (median VAF, 0.56%). In detail, alterations in PIK3CA, FBXW7, GNAS, MAP2K, ERBB2, BRAF (class I and II non-BRAFV600E), SMAD, EGFR, AKT1, and CTNNB1 occurred in 13%, 8%, 7%, 3%, 2%, 2%, 1%, 1%, 1%, and 1% cases, respectively. Co-mutations were detected in 13 (33%) out of 40 patients. Conclusions: This is the largest prospective cohort of mCRC patients screened with LB for anti-EGFR retreatment in a randomized study. ctDNA genotyping reveals that at least one out of three patients candidate for retreatment should be excluded from this therapy, and other potential drivers of anti-EGFR resistance are found in approximately one out of three patients with RAS/BRAFV600E wt ctDNA.

Immune-Checkpoint Inhibitors (ICIs) in Metastatic Colorectal Cancer (mCRC) Patients beyond Microsatellite Instability.

Immune-checkpoint inhibitors (ICIs) showed impressive results in terms of activity and efficacy in metastatic colorectal cancer (mCRC) patients bearing tumors with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). Despite that microsatellite status is the major predictive biomarker for the efficacy of ICIs, a proportion of dMMR/MSI-H mCRC tumors do not achieve benefit from immunotherapy due to the primary resistance. Deeper knowledge of biological mechanisms regulating dMMR/MSI-H CRC tumors and immune response may be useful to find new predictive biomarkers of ICIs benefit and tailor the use of immunotherapy even in dMMR/MSI-H mCRC patients. Moreover, several issues are still open, such as the secondary resection of metastases and the optimal duration of ICIs therapy in dMMR/MSI-H mCRC patients. Looking beyond microsatellite status, in a future perspective, several tools (i.e., Tumor Mutational Burden and PD-L1 expression) have been investigated to clarify their possible role as predictive biomarkers. Furthermore, a small subgroup of pMMR/MSS CRC tumors with a POLE mutation of the proofreading domain is characterized by hypermutated phenotype and might derive benefit from immune checkpoint inhibition. In the present work, we aim to review the most recent literature regarding treatment with ICIs in mCRC, focusing on dMMR/MSI-H and special subgroups of CRC patients. Hence, we summarize possible future targets and the most promising predictive biomarkers.

Impact of baseline gadoxetic acid-enhanced liver magnetic resonance and diffusion-weighted imaging in resectable colorectal liver metastases: A prospective, monocentric study.

BACKGROUND: Liver magnetic resonance imaging (MRI) utilizing hepatocyte-specific contrast agent and diffusion-weighted imaging (DWI) is currently used to properly stage colorectal liver metastases (CRLM) in patients candidate to liver surgery. However, the added value of liver MRI in choosing the treatment strategy in resectable CRLM over computed tomography (CT)-scan is not clear. PATIENTS AND METHODS: This is a prospective monocentric collection of consecutive cases of patients with CRLM conceived with the aim to assess the added value of liver MRI in changing the initial treatment strategy planned according to CT-scan. Potential changes in the initially planned strategy were defined as: - from upfront surgery to perioperative chemotherapy (fluoropyrimidine and oxaliplatin) - from upfront surgery to first-line systemic therapy (doublet or triplet plus a biological agent) - from perioperative chemotherapy to first-line systemic therapy. Hypothesising that MRI may induce a change in the choice of the treatment strategy in the 20% of cases (alternative hypothesis), against a null hypothesis of 5%, with one-tailed alpha and beta errors of 0.05 and 0.20 respectively, 27 patients were needed. The added value of liver MRI would have been considered clinically meaningful if at least 4 changes in the treatment strategy were observed. RESULTS: Among 27 enrolled patients, upfront surgery and perioperative chemotherapy strategies were chosen in 17 (63%) and 10 (37%) cases, respectively, based on CT-scan. After liver MRI, additional liver lesions were found in 8 patients (30%) and the initial strategy was changed in 7 patients (26%) (4 initially deemed candidate to upfront surgery and 3 initially sent to perioperative chemotherapy) that were treated with first-line systemic therapy. CONCLUSIONS: Our results support the indication of the current guidelines on the routine use of liver MRI in the initial workup of patients with resectable CRLM with an MRI-driven changes of initial treatment plan in a relevant percentage of cases.

Pattern of recurrence and survival after D2 right colectomy for cancer: is there place for a routine more extended lymphadenectomy?

BACKGROUND: Conventional Right Colectomy with D2 lymphadenectomy (RC-D2) currently represent the most common surgical treatment of right-sided colon cancer (RCC). However, whether it should be still considered a standard of care, or replaced by a routine more extended D3 lymphadenectomy remains unclear. In the present study, we aim to critically review the patterns of relapse and the survival outcomes obtained from our 11-year experience of RC-D2. METHODS: Clinical data of 489 patients who underwent RC-D2 for RCC at two centres, from January 2009 to January 2020, were retrospectively reviewed. Patients with synchronous distant metastases and/or widespread nodal involvement at diagnosis were excluded. Post-operative clinical-pathological characteristics and survival outcomes were evaluated including the pattern of disease relapse. RESULTS: We enrolled a total of 400 patients with information follow-up. Postoperative morbidity was 14%. The median follow-up was 62 months. Cancer recurrence was observed in 55 patients (13.8%). Among them, 40 patients (72.7%) developed systemic metastases, and lymph-node involvement was found in 7 cases (12.8%). None developed isolated central lymph-node metastasis (CLM), in the D3 site. The estimated 3- and 5-year relapse-free survival were 86.1% and 84.4%, respectively. The estimated 3- and 5-year cancer-specific OS were 94.5% and 92.2%, respectively. CONCLUSIONS: The absence of isolated CLM, as well as the cancer-specific OS reported in our series, support the routine use of RC-D2 for RCC. However, D3 lymphadenectomy may be recommended in selected patients, such as those with pre-operatively known CLM, or with lymph-node metastases close to the origin of the ileocolic vessels.

Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO.

PURPOSE: To verify whether the intensification of the upfront chemotherapy backbone with a modified schedule of modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) increases the activity of fluorouracil, leucovorin, and oxaliplatin when both regimens are combined with panitumumab as initial treatment for RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC). METHODS: TRIPLETE was a prospective, open-label, phase III trial in which previously untreated patients with unresectable RAS and BRAF wt mCRC were randomly assigned 1:1 to modified FOLFOX/panitumumab (control group) or mFOLFOXIRI/panitumumab (experimental group) up to 12 cycles, followed by fluorouracil/-leucovorin/panitumumab until disease progression. The primary end point was objective response rate (ORR) according to RECIST 1.1. Hypothesizing an ORR of 60% in the control group, 432 cases provided 90% power to a two-sided chi-square test for heterogeneity with a two-sided alpha error of .05 to detect ≥ 15% differences between arms (ClinicalTrials.gov identifier: NCT03231722). RESULTS: From September 2017 to September 2021, 435 patients were enrolled (control group/experimental group: 217/218) in 57 Italian sites. One hundred sixty (73%) patients treated with mFOLFOXIRI plus panitumumab and 165 (76%) patients treated with modified FOLFOX plus panitumumab achieved RECIST response (odds ratio 0.87, 95% CI, 0.56 to 1.34, P = .526). No differences in early tumor shrinkage rate (57%/58%, P = .878) and deepness of response (median: 48%/47%, P = .845) were reported, nor in R0 resection rate (25%/29%, P = .317). No significant difference between arms was reported in terms of progression-free survival (median progression-free survival: 12.7 in the experimental group v 12.3 months in the control group, hazard ratio: 0.88, 95% CI, 0.70 to 1.11, P = .277). CONCLUSION: The intensification of the upfront chemotherapy backbone in combination with panitumumab does not provide additional benefit in terms of treatment activity at the price of increased gastrointestinal toxicity in patients with RAS and BRAF wt mCRC.

Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (AtezoTRIBE): a multicentre, open-label, randomised, controlled, phase 2 trial.

BACKGROUND: Immune checkpoint inhibitors have not shown clinical benefit to patients with metastatic colorectal cancer who had proficient mismatch repair (pMMR) or microsatellite stable (MSS) tumours in previous studies. Both an active combination chemotherapy (FOLFOXIRI; fluorouracil, leucovorin, oxaliplatin, and irinotecan) and bevacizumab seem able to increase the immunogenicity of pMMR or MSS tumours. We aimed to provide preliminary evidence of benefit from the addition of the anti-PD-L1 agent atezolizumab to first-line FOLFOXIRI plus bevacizumab in patients with metastatic colorectal cancer. METHODS: AtezoTRIBE was a multicentre, open-label, randomised, controlled, phase 2 study of patients (aged 18-70 years with an Eastern Cooperative Oncology Group [ECOG] performance status of 0-2 and aged 71-75 years with an ECOG performance status of 0) with histologically confirmed, unresectable, previously untreated metastatic colorectal cancer and adequate organ function, who were recruited from 22 oncology centres in Italy. Patients were stratified according to centre, ECOG performance status, primary tumour site, and previous adjuvant therapy. A randomisation system incorporating a minimisation algorithm randomly assigned (1:2) patients via a masked web-based allocation procedure to two groups: the control group received first-line FOLFOXIRI (intravenous 165 mg/m2 irinotecan, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin, and 3200 mg/m2 fluorouracil as a 48 h infusion) plus bevacizumab (5 mg/kg intravenously), and the atezolizumab group received the same regimen plus atezolizumab (840 mg intravenously). Combination treatments were administered up to eight 14-day cycles followed by maintenance with fluorouracil and leucovorin plus bevacizumab with or without atezolizumab, according to randomisation group, until disease progression, unacceptable adverse events, or consent withdrawal. The primary endpoint was progression-free survival, analysed by the intention-to-treat principle. Safety was assessed in patients who received at least one dose of the study treatment. The study recruitment is completed. The trial is registered with Clinicaltrials.gov, NCT03721653. FINDINGS: Between Nov 30, 2018, and Feb 26, 2020, 218 patients were randomly assigned and received treatment (73 in the control group and 145 in the atezolizumab group). At the data cutoff (Aug 1, 2021), median follow-up was 19·9 months (IQR 17·3-23·9). Median progression-free survival was 13·1 months (80% CI 12·5-13·8) in the atezolizumab group and 11·5 months (10·0-12·6) in the control group (hazard ratio [HR] 0·69 [80% CI 0·56-0·85]; p=0·012; adjusted HR 0·70 [80% CI 0·57-0·87]; log-rank test p=0·018). The most frequent all-cause grade 3-4 adverse events were neutropenia (59 [42%] of 142 patients in the atezolizumab group vs 26 [36%] of 72 patients in the control group), diarrhoea (21 [15%] vs nine [13%]), and febrile neutropenia (14 [10%] vs seven [10%]). Serious adverse events were reported in 39 (27%) patients in the atezolizumab group and in 19 (26%) patients in the control group. Two (1%) treatment-related deaths (due to acute myocardial infarction and bronchopulmonary haemorrhage) were reported in the atezolizumab group; none were reported in the control group. INTERPRETATION: The addition of atezolizumab to first-line FOLFOXIRI plus bevacizumab is safe and improved progression-free survival in patients with previously untreated metastatic colorectal cancer. FUNDING: GONO Foundation, ARCO Foundation, F Hoffmann-La Roche, and Roche.

Treatments after second progression in metastatic colorectal cancer: A pooled analysis of the TRIBE and TRIBE2 studies.

BACKGROUND: The availability of new drugs in the chemo-refractory setting opened the way to the concepts of treatment sequencing in mCRC. However, the impact of later line options in the therapeutic route of metastatic colorectal cancer (mCRC) patients and the attrition rate across subsequent lines of therapy are not well established. METHODS: We performed a pooled analysis of treatments administered after the 2nd disease progression in 1187 mCRC patients enrolled in the randomized phase III TRIBE and TRIBE2 studies, where upfront FOLFOXIRI/bev was compared with FOLFOX or FOLFIRI/bev. Per each line, we assessed the attrition rate, treatment choices and clinical outcomes. RESULTS: 625 (53%), 326 (27%) and 136 (11%) patients received a systemic treatment after the 2nd, 3rd and 4th disease progression, respectively. PFS and objective response rate decreased along each line. RAS/BRAF wild-type patients received more likely a 3rd line (75%) compared with RAS (66%, p = 0.005) and BRAF (66%, p = 0.11) mutants. In 3rd line, 67% of RAS/BRAF wild-type patients received anti-EGFRs, achieving longer PFS with respect to other therapies (6.4 vs 3.9 months, p = 0.02). A trend towards longer 3rd line OS was observed in TRIBE patients (9.9 vs 7.2 months, p = 0.05). CONCLUSIONS: A relevant attrition rate across subsequent lines of therapy is evident, and more pronounced in RAS and BRAF mutated patients, thus highlighting the relevance of the choice of the upfront treatment. The efficacy of anti-EGFR agents among RAS/BRAF wild-type patients unexposed to anti-EGFRs is higher than other options. The reintroduction of chemotherapy remains frequent in clinical practice. TRIAL REGISTRATION: Clinicaltrials. gov Identifiers NCT00719797, NCT02339116.

Plasma levels of VEGF-A and VCAM-1 as predictors of drug-induced hypertension in patients treated with VEGF pathway inhibitors.

AIMS: Hypertension is a common toxicity induced by vascular endothelial growth factor (VEGF) pathway inhibitors. There are no validated markers of hypertension induced by these drugs. METHODS: We previously discovered that cancer patients with lower plasma levels of angiopoietin-2, VCAM-1 and VEGF-A are at high risk of developing severe hypertension when treated with bevacizumab. This study aimed to validate the predictive value of these markers in pretreatment plasma samples of an additional cohort of 101 colorectal cancer patients treated with regorafenib. The levels of angiopoietin-2, VCAM-1 and VEGF-A were measured by enzyme-linked immunosorbent assay (ELISA). The association between proteins and grade ≥2 regorafenib-induced hypertension was performed by calculating the odds ratio (OR) from logistic regression. Using the optimal cut-point of each protein, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for hypertension were estimated. RESULTS: Lower levels of VCAM-1 (P = .015, OR = 3.11, 95% CI 1.27-8.08) and VEGF-A (P = .007, OR = 3.47, 95% CI 1.40-8.75) were associated with a higher risk of hypertension. Levels of angiopoietin-2 were not associated with hypertension. The multivariable model indicates an independent effect of VCAM-1 (P = .018, OR = 3.18, 95% CI 1.25-8.68) and VEGF-A (P = .008, OR = 3.77, 95% CI 1.44-10.21). The presence of low levels of both VCAM-1 and VEGF-A had an OR of 9.46 (95% CI 3.08-33.26, P = 1.70 × 10-4 ) for the risk of hypertension (sensitivity of 41.4%, specificity of 93.1%, PPV of 70.6% and NPV of 79.8%). CONCLUSIONS: This study confirmed the value of VCAM-1 and VEGF-A levels in predicting hypertension induced by regorafenib, another VEGF pathway inhibitor.

FOLFOXIRI and bevacizumab in patients with early-onset metastatic colorectal cancer. A pooled analysis of TRIBE and TRIBE2 studies.

BACKGROUND: We performed a pooled analysis of TRIBE and TRIBE2 studies to assess the efficacy and safety of the intensification of upfront chemotherapy backbone - from doublets to the triplet FOLFOXIRI - in combination with bevacizumab (bev) in patients with early-onset metastatic colorectal cancer (EO-mCRC; aged <50 years) and to explore whether EO-mCRCs have a peculiar tumour genomic profiling. MATERIALS AND METHODS: Subgroup analyses according to age (<50 versus ≥50 years) and treatment (FOLFOXIRI/bev versus doublets/bev) were carried out for rates of any grade and grade ≥3 (≥G3) overall and singular adverse events, progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). Tumour genomic profiling was obtained using a DNA-based next-generation sequencing platform. RESULTS: Of 1187 patients included, 194 (16%) patients were aged <50 years. Females were more frequently diagnosed with EO-mCRC (P = 0.04). Patients aged <50 years showed a lower risk of ≥G3 neutropenia (P = 0.07), diarrhoea (P = 0.04), asthenia (P = 0.008) and a higher risk of any grade nausea (P < 0.01) and vomiting (P < 0.01). Patients receiving FOLFOXIRI/bev more frequently experienced ≥G3 chemotherapy-related adverse events respect to doublets/bev, regardless of age (Pinteraction = 0.60). FOLFOXIRI/bev was associated to a lower incidence of neutropenia (P = 0.04) and asthenia (P = 0.01) in patients <50 years old, than those aged ≥50 years. PFS, OS and ORR did not differ according to age (PFS P = 0.81, OS P = 0.44, ORR P = 0.50) and no interaction between age and the benefit from the intensification of upfront chemotherapy was observed (PFS Pinteraction = 0.72, OS Pinteraction = 0.54, ORR Pinteraction = 0.65). Genomic profiling was assessed in 296 patients, showing an enrichment of FBXW7 and POLE mutations in EO-mCRC. CONCLUSIONS: Upfront FOLFOXIRI/bev shows a favourable efficacy/safety balance in EO-mCRC. TRIAL REGISTRATION: Clinicaltrials.gov Identifiers NCT00719797, NCT0233-9116.

Early modulation of Angiopoietin-2 plasma levels predicts benefit from regorafenib in patients with metastatic colorectal cancer.

BACKGROUND: No biomarkers are currently available to predict the efficacy of trifluridine/tipiracil (FTD/TPI) in chemorefractory metastatic colorectal cancer. The multicohort REGOLAND study aims at exploring and validating circulating markers potentially able to predict benefit from regorafenib in this setting. MATERIAL AND METHODS: In the retrospective 'regorafenib exploratory cohort', including 105 patients treated with regorafenib, baseline (d1) plasma levels of angiogenesis-related biomarkers and their early modulation after 15 days (d15) of treatment were investigated for correlation with clinical outcome. Based on a pre-specified statistical hypothesis, main retrospective findings were prospectively challenged in the 'regorafenib validation cohort', including 100 patients treated with regorafenib. Prospectively validated putative biomarkers were then assessed in the control 'FTD/TPI cohort', including 93 patients treated with FTD/TPI. RESULTS: In the 'regorafenib exploratory cohort', the early (d15) increase of Angiopoietin-2 (Ang-2) was associated with longer progression-free survival (HR:0.57 [95%CI:0.38-0.88], P = 0.004) and a trend towards longer OS (HR:0.74 [95%CI:0.48-1.14], P = 0.165), than the early decrease. Similar results were prospectively confirmed in the 'regorafenib validation cohort' (HR for progression-free survival:0.72 [95%CI:0.48-1.08], P = 0.095; HR for OS:0.77 [95%CI:0.51-1.16], P = 0.204). No predictive impact was shown for the early modulation of Ang-2 in the 'FTD/TPI cohort'. High baseline Ang-2 levels predict poor prognosis in all the investigated cohorts, independently of other clinical prognostic variables. CONCLUSIONS: The early modulation of circulating Ang-2 predicts the efficacy of regorafenib. Baseline Ang-2 plasma levels are an independent prognostic biomarker in chemorefractory metastatic colorectal cancer.

The management of colorectal liver metastases amenable of surgical resection: How to shape treatment strategies according to clinical, radiological, pathological and molecular features.

Metastatic colorectal cancer (mCRC) patients have poor chances of long term survival, being < 15% of them still alive after 5 years from diagnosis. Nonetheless, patients with colorectal liver metastases (CRLM) may be eligible for metastases resection thus being able to achieve long-term disease remission and survival. The likelihood for patients with CRLM of being or becoming eligible for liver metastasectomy is increasing, thanks to the evolution of surgical techniques, the availability of active systemic treatments and the widespread diffusion of experienced multidisciplinary boards to manage these patients. However, disease relapse after liver surgery is common and occurs in two-thirds of resected patients. Therefore, adequate radiological staging and risk stratification is crucial for the optimal selection of patients candidate to surgery in order to maximize the benefit-risk ratio of liver metastasectomy and to individualize the treatment strategy. Based on the multidimensional assessment, three possible approaches are available: upfront liver surgery followed by adjuvant chemotherapy, perioperative chemotherapy preceding and following liver surgery, and an upfront systemic treatment including chemotherapy plus a targeted agent, both chosen according to patients' and tumours' characteristics, then followed by liver surgery if indicated. In this review, we describe the most important factors impacting the therapeutic choices in patients with resectable and potentially resectable CRLM, and we discuss the most promising factors that may reshape the future decision-making process of these patients.

Rationale and Study Design of the PARERE Trial: Randomized phase II Study of Panitumumab Re-Treatment Followed by Regorafenib Versus the Reverse Sequence in RAS and BRAF Wild-Type Chemo-Refractory Metastatic Colorectal Cancer Patients.

BACKGROUND: A recent phase II randomized Japanese study reported better survival with regorafenib followed at progression by cetuximab ± irinotecan compared with the reverse standard sequence in chemo-refractory and anti-EGFR-naïve, RAS wild-type (wt) mCRC patients. Nowadays the use of anti-EGFR antibodies is more frequently anticipated to the first-line of therapy especially in patients with left-sided RAS/BRAF wt tumours. However, retrospective analyses and phase II single-arm trials showed promising activity of re-using anti-EGFRs in metastatic colorectal cancer (mCRC) patients who previously achieved benefit from a first-line anti-EGFR-based treatment. Post-hoc analyses of these trials revealed that the detection of RAS mutations in circulating tumour DNA (ct-DNA) at the time of re-treatment may be useful to identify resistant patients. PATIENTS AND METHODS: PARERE (NCT04787341) is a prospective, open label, multicentre phase II study in which 214 RAS/BRAF wt chemo-refractory mCRC patients with previous benefit from first-line anti-EGFR-based treatment and RAS/BRAF wt ct-DNA in the liquid biopsy collected at the time of inclusion will be randomized in a 1:1 ratio to receive panitumumab followed after progression by regorafenib versus the reverse sequence. Primary endpoint is overall survival. Secondary endpoints are 1st-progression free-survival (PFS), 2nd-PFS, time to failure strategy, objective response rate, and safety. AIM OF THE STUDY: The aim of this study is to validate the role of anti-EGFR retreatment and its proper placement in the therapeutic route of mCRC patients selected according to the analysis of ct-DNA in liquid biopsy. Results are expected at the end of 2023.