Adverse events during first-line treatments for mCRC: The Toxicity over Time (ToxT) analysis of three randomised trials.

BACKGROUND: In clinical trials, the assessment of safety is traditionally focused on the overall rate of high-grade and serious adverse events (AEs). A new approach to AEs evaluation, taking into account chronic low-grade AEs, single patient's perspective, and time-related information, such as ToxT analysis, should be considered especially for less intense but potentially long-lasting treatments, such as maintenance strategies in metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: We applied ToxT (Toxicity over Time) evaluation to a large cohort of mCRC patients enroled in randomised TRIBE, TRIBE2, and VALENTINO studies, in order to longitudinally describe AEs throughout the whole treatment duration and to compare AEs evolution over cycles between induction and maintenance strategies, providing numerical and graphical results overall and per single patient. After 4-6 months of combination therapy, 5-fluorouracil/leucovorin (5-FU/LV) + bevacizumab or panitumumab was recommended in all studies except for the 50% of patients in the VALENTINO trial who received panitumumab alone. RESULTS: Out of 1400 patients included, 42% received FOLFOXIRI (5-FU/LV, oxaliplatin, and irinotecan)/bevacizumab, 18% FOLFIRI/bevacizumab, 24% FOLFOX/bevacizumab, 16% FOLFOX/panitumumab. Mean grade of general and haematological AEs was higher in the first cycles, then progressively decreasing after the end of induction (p < 0.001), and always remaining at the highest levels with FOLFOXIRI/bevacizumab (p < 0.001). Neurotoxicity became more frequent over the cycles with late high-grade episodes (p < 0.001), while the incidence but not the grade of hand-and-foot syndrome gradually increased (p = 0.91). Anti-VEGF-related AEs were more severe in the first cycles, then setting over at low levels (p = 0.03), while anti-EGFR-related AEs still affected patients during maintenance. CONCLUSIONS: Most of chemotherapy-related AEs (except for HFS and neuropathy) reach the highest level in the first cycles, then decrease, probably due to their active clinical management. Transition to maintenance allows relief from most AEs, especially with bevacizumab-based regimens, while anti-EGFR-related AEs may persist.

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.

An Immune-Related Gene Expression Signature Predicts Benefit from Adding Atezolizumab to FOLFOXIRI plus Bevacizumab in Metastatic Colorectal Cancer.

PURPOSE: AtezoTRIBE phase II randomized study demonstrated that adding atezolizumab to first-line FOLFOXIRI (5-fluorouracil, oxaliplatin, irinotecan) plus bevacizumab prolongs progression-free survival (PFS) of patients with metastatic colorectal cancer (mCRC), with a modest benefit among proficient mismatch repair (pMMR). DetermaIO is an immune-related 27-gene expression signature able to predict benefit from immune checkpoint inhibition in triple-negative breast cancer. In this analysis of AtezoTRIBE, we investigated the predictive impact of DetermaIO in mCRC. EXPERIMENTAL DESIGN: Patients with mCRC unselected for MMR status were randomly assigned (1:2) to FOLFOXIRI plus bevacizumab (control arm) or the same regimen with atezolizumab (atezolizumab arm). qRT-PCR by DetermaIO was performed on RNA purified from pretreatment tumors of 132 (61%) of 218 enrolled patients. A binary result (IOpos vs. IOneg) adopting the preestablished DetermaIO cut-off point (0.09) was obtained, and an exploratory optimized cut-off point (IOOPT) was computed in the overall population and in pMMR subgroup (IOOPTpos vs. IOOPTneg). RESULTS: DetermaIO was successfully determined in 122 (92%) cases, and 23 (27%) tumors were IOpos. IOpos tumors achieved higher PFS benefit from atezolizumab arm than IOneg (HR: 0.39 vs. 0.83; Pinteraction = 0.066). In pMMR tumors (N = 110), a similar trend was observed (HR: 0.47 vs. 0.93; Pinteraction = 0.139). In the overall population, with the computed IOOPT cut-off point (0.277), 16 (13%) tumors were IOOPTpos and they derived higher PFS benefit from atezolizumab than IOOPTneg (HR: 0.10 vs. 0.85, Pinteraction = 0.004). Similar results were found in the pMMR subgroup. CONCLUSIONS: DetermaIO may be useful to predict benefit of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in mCRC. The exploratory IOOPT cut-off point should be validated in independent mCRC cohorts.

Dissecting tumor lymphocyte infiltration to predict benefit from immune-checkpoint inhibitors in metastatic colorectal cancer: lessons from the AtezoT RIBE study.

BACKGROUND: Tumor immune cells influence the efficacy of immune-checkpoint inhibitors (ICIs) and many efforts aim at identifying features of tumor immune microenvironment able to predict benefit from ICIs in proficient mismatch repair (pMMR)/microsatellite stable (MSS) metastatic colorectal cancer (mCRC). METHODS: We characterized tumor immune cell infiltrate, by assessing tumor-infiltrating lymphocytes (TILs), Immunoscore, Immunoscore-IC, and programmed death ligand-1 (PD-L1) expression in tumor samples of patients with mCRC enrolled in the AtezoTRIBE study, a phase II randomized trial comparing FOLFOXIRI/bevacizumab/atezolizumab to FOLFOXIRI/bevacizumab, with the aim of evaluating the prognostic and predictive value of these features. RESULTS: Out of 218 patients enrolled, 181 (83%), 77 (35%), 157 (72%) and 162 (74%) specimens were successfully tested for TILs, Immunoscore, Immunoscore-IC and PD-L1 expression, respectively, and 69 (38%), 45 (58%), 50 (32%) and 21 (13%) tumors were classified as TILs-high, Immunoscore-high, Immunoscore-IC-high and PD-L1-high, respectively. A poor agreement was observed between TILs and Immunoscore or Immunoscore-IC (K of Cohen <0.20). In the pMMR population, longer progression-free survival (PFS) was reported for Immunoscore-high and Immunoscore-IC-high groups compared with Immunoscore-low (16.4 vs 12.2 months; HR: 0.55, 95% CI: 0.30 to 0.99; p=0.049) and Immunoscore-IC-low (14.8 vs 11.5 months; HR: 0.55, 95% CI: 0.35 to 0.85; p=0.007), respectively, with a significant interaction effect between treatment arms and Immunoscore-IC (p for interaction: 0.006) and a trend for Immunoscore (p for interaction: 0.13). No PFS difference was shown according to TILs and PD-L1 expression. Consistent results were reported in the overall population. CONCLUSIONS: The digital evaluation of tumor immune cell infiltrate by means of Immunoscore-IC or Immunoscore identifies the subset of patients with pMMR mCRC achieving more benefit from the addition of the anti-PD-L1 to the upfront treatment. Immunoscore-IC stands as the most promising predictor of benefit from ICIs.

Primary tumour side as a driver for treatment choice in RAS wild-type metastatic colorectal cancer patients: a systematic review and pooled analysis of randomised trials.

BACKGROUND: Retrospective subgroup analyses of previous trials in the first-line therapy of RAS wt metastatic colorectal cancer (mCRC) suggested a predictive impact of primary tumour side on the efficacy of anti-epidermal growth factor receptor (EGFR) agents. Recently, new head-to-head trials of doublets/bevacizumab versus doublets/anti-EGFR, PARADIGM and CAIRO5 were presented. PATIENTS AND METHODS: We searched for phase II and III trials comparing doublet chemotherapy plus an anti-EGFR or bevacizumab as the first-line treatment for RAS wt mCRC patients. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and radical resection rate result in the overall study populations and, according to the primary side, were pooled together in a two-stage analysis with random effects and fixed effect models. The interaction between sidedness and treatment effect was then analysed. RESULTS: We identified five trials (PEAK, CALGB/SWOG 80405, FIRE-3, PARADIGM and CAIRO5), including 2739 patients, 77% left- and 23% right-sided. Among patients with left-sided mCRC, the use of anti-EGFRs was associated with higher ORR (74% versus 62%, OR = 1.77 [95% confidence interval {CI} 1.39-2.26-0.88], p < 0.0001), longer OS (hazard ratio [HR] = 0.77 [95% CI 0.68-0.88], p < 0.0001) and not significantly longer PFS (HR = 0.92, p = 0.19). Among patients with right-sided mCRC, the use of bevacizumab was associated with longer PFS (HR = 1.36 [95% CI 1.12-1.65], p = 0.002) and not significantly longer OS (HR = 1.17, p = 0.14). A subgroup analysis confirmed a significant interaction effect between the primary tumour side and treatment arm in terms of ORR (p = 0.02), PFS (p = 0.0004) and OS (p = 0.001). No differences in the radical resection rate were found according to treatment and sidedness. CONCLUSIONS: Our updated metanalysis corroborates the role of the primary tumour location in the choice of the upfront therapy for RAS wt mCRC patients, leading to strongly recommend anti-EGFRs in left-sided tumours and to prefer bevacizumab in the right-sided.

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.

Circulating Tumor DNA as a Marker of Minimal Residual Disease After Radical Resection of Colorectal Liver Metastases.

PURPOSE: Prognostic tools to estimate the risk of relapse for patients with liver-limited metastatic colorectal cancer (LL-mCRC) undergoing resection with curative intent are needed. Circulating tumor DNA (ctDNA) as a surrogate of postsurgical minimal residual disease is a promising marker in localized CRC. We explored the role of postoperative ctDNA as a marker of minimal residual disease in patients with radically resected LL-mCRC. MATERIALS AND METHODS: Seventy-six patients with LL-mCRC were retrospectively included. DNA from tumor tissue was sequenced, and one somatic mutation was then assessed by digital droplet polymerase chain reaction in plasma samples collected after surgery to identify the persistence of ctDNA. Relapse-free survival and postresection overall survival were compared between patients with positive vs negative postoperative ctDNA. RESULTS: ctDNA was found in 39 (51%) of 76 patients with LL-mCRC. At a median follow-up of 77 months, 33 of 39 ctDNA-positive patients and 20 of 37 ctDNA-negative patients experienced disease relapse (P = .008). ctDNA-positive patients reported significantly shorter RFS than ctDNA-negative ones (median RFS 12.7 v 27.4 months hazard ratio, 2.09, P = .008). In the multivariable model including other prognostic covariates, this association was still significant (P = .046) and a trend toward shorter overall survival among ctDNA-positive patients was reported (hazard ratio, 1.65, P = .183). CONCLUSION: The detection of postsurgical ctDNA is an independent negative prognostic marker and identifies patients at high risk of relapse after liver metastases resection.

The Evolving Landscape of Immunotherapy in Locally Advanced Rectal Cancer Patients.

Standard treatments of localized rectal cancer are surgery or the multimodal approach with neoadjuvant treatments (chemo-radiotherapy, short-course radiotherapy, induction, or consolidation chemotherapy) followed by surgery. In metastatic colorectal cancer (mCRC), immune checkpoint inhibitors (ICIs) are now the first choice in patients with a deficient mismatch repair system/microsatellite instability (dMMR/MSI-H) and are being explored in combination with chemotherapy to rewire the immune system against malignant cells in subjects with proficient mismatch repair system/microsatellite low (pMMR/MSI-L) cancers, with promising signals of efficacy. Recently, some efforts have been made to translate ICIs in earlier stages of CRC, including localized rectal cancer, with breakthrough efficacy and an organ preservation rate of mono-immunotherapy in dMMR/MSI-H patients and promising anti-tumor activity of immunotherapy plus neoadjuvant (chemo)radiotherapy in pMMR/MSI-L subjects. Here, we present the rationale, results, and limitations of the most remarkable trials assessing ICIs in dMMR/MSI-H and pMMR/MSI-L localized rectal cancer patients, at the same time highlighting the most promising research perspectives that have followed these studies.

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.

Negative Ultraselection of Patients With RAS/BRAF Wild-Type, Microsatellite-Stable Metastatic Colorectal Cancer Receiving Anti-EGFR-Based Therapy.

PURPOSE: Several uncommon genomic alterations beyond RAS and BRAFV600E mutations drive primary resistance to anti-epidermal growth factor receptors (EGFRs) in metastatic colorectal cancer (mCRC). Our PRESSING panel (including PIK3CA exon 20/AKT1/PTEN mutations, ERBB2/MET amplifications, gene fusions, and microsatellite instability-high status) represented a paradigm of negative hyperselection with more precise tailoring of EGFR blockade. However, a modest proportion of hyperselected mCRC has intrinsic resistance potentially driven by even rarer genomic alterations. MATERIALS AND METHODS: A prospective data set at three Italian Academic Hospitals included 650 patients with mCRC with comprehensive genomic profiling by FoundationOne CDx and treated with anti-EGFRs. PRESSING2 panel alterations were selected on the basis of previous clinico-biologic studies and included NTRKs, ERBB3, NF1, MAP2K1/2/4, AKT2 pathogenic mutations; PTEN/NF1 loss; ERBB3, FGFR2, IGF1R, KRAS, ARAF, and AKT1-2 amplification; and EGFR rearrangements. These were collectively associated with outcomes in patients with hyperselected disease, ie, RAS/BRAF wild-type, PRESSING-negative, and microsatellite stable. RESULTS: Among 162 hyperselected patients, 24 (15%) had PRESSING2 alterations, which were mutually exclusive except in two samples and were numerically higher in right-sided versus left-sided cancers (28% v 13%; P = .149). Independently of sidedness and other factors, patients with PRESSING2-positive status had significantly worse progression-free survival and overall survival compared with PRESSING2-negative ones (median progression-free survival 6.4 v 12.8 months, adjusted hazard ratio 4.19 [95% CI, 2.58 to 6.79]; median overall survival: 22.6 v 49.9 months, adjusted hazard ratio 2.98 [95% CI, 1.49 to 5.96]). The combined analysis of primary tumor sidedness and PRESSING2 status allowed us to better stratify outcomes. CONCLUSION: Negative ultraselection warrants further investigation with the aim of maximizing the benefit of EGFR blockade strategies in patients with RAS and BRAF wild-type, microsatellite stable 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.

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.

Encorafenib plus cetuximab treatment in BRAF V600E-mutated metastatic colorectal cancer patients pre-treated with an anti-EGFR: An AGEO-GONO case series.

BACKGROUND: Encorafenib plus cetuximab is efficient in anti-EGFR-naïve patients with BRAFV600E mutated (BRAFm) metastatic colorectal cancer (mCRC). No data are available concerning the efficacy of BRAF inhibitors associated with anti-EGFRs (B + E) in patients previously treated with an anti-EGFR agent. METHODS: We retrospectively collected a series of patients with BRAFm mCRC treated with B + E after previous anti-EGFR treatment, in 14 centers. Progression-free survival (PFS) and overall survival (OS) were calculated from the start of treatment, and we reported objective response and disease control rates (ORR, DCR; RECIST V1.1). RESULTS: Twenty-five BRAFm mCRC patients were enrolled. Prior to B + E treatment, 4/10/11 patients were treated with 1/2/> 2 previous treatment lines. Ten patients received previous panitumumab, 14 cetuximab, 1 both. Immediate progression with previous anti-EGFR was reported for 7 patients. Anti-BRAF was encorafenib for 21 patients, dabrafenib for 4 patients, with cetuximab for 24 patients and panitumumab for 1 patient. ORR was 40% (10 patients) and DCR was 80% (20 patients). Median PFS and OS were 4.8 months (95% CI, 4.01-7.95) and 10.1 months (95% CI, 7.75-NR). DCR amongst patients with previous primary resistance to anti-EGFR (N = 7) was 100%. Two patients discontinued B + E due to drug-related adverse event. CONCLUSIONS: Though in a limited retrospective series of patients, these results show the efficacy of the combination of anti-BRAF and anti-EGFRs in BRAFm mCRC patients previously treated with an anti-EGFR. The use of this combination should thus not be ruled out in this population with limited therapeutic options.

Prognostic and Predictive Role of Body Mass Index (BMI) in Metastatic Colorectal Cancer (mCRC): A Pooled Analisys of Tribe and Tribe-2 Studies by GONO.

BACKGROUND: Obesity is associated with an increased risk of development and recurrence of colorectal cancer. The role of obesity in metastatic colorectal cancer patients (pts) is still unclear, especially in those treated with triplet plus bevacizumab (bev). The aim of our study was to evaluate the prognostic and predictive role of BMI in metastatic colorectal cancer pts treated with FOLFOXIRI plus bev or FOLFIRI/FOLFOX plus bev in the TRIBE and TRIBE-2 trial. MATERIALS AND METHODS: A total of 1160 pts enrolled in TRIBE and TRIBE-2 trials were included. Baseline height and weight were used to assign pts to one of the following BMI categories: underweight (group A = BMI <18.5 kg/m2; 52 pts), normal (group B = BMI 18.5-29.9 kg/m2; 952 pts) and obese (group C > 30 kg/m2; 156 pts). RESULTS: In our population, no differences in terms of PFS (P = .43) or OS (P = .99) resulted between 3 groups. No interaction effect between treatment arm and BMI was evident in terms of PFS (Group A HR: 0.65 [95%CI: 0.36-1.16]; Group B HR: 0.77 [95%CI: 0.67-0.88]; Group C HR: 0.67 [95%CI: 0.48-0.93]; P for interaction = .75) or OS (Group A HR: 0.57 [95%CI: 0.29-1.12]; Group B HR: 0.85 [95%CI: 0.73-0.99];Group C HR: 0.69 [95%CI: 0.48-1.01] P for interaction = .36). No statistically significant difference in terms of dose reductions due to toxicities were found according to BMI in the overall population (P = .48) and in pts treated with FOLFOXIRI plus bev (P = .57). CONCLUSION: BMI was neither prognostic or predictive for PFS and OS in our population. Our analyses showed that the advantage of FOLFOXIRI plus bev versus FOLFIRI/FOLFOX plus bev was independent from BMI.

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.

Bevacizumab-induced hypertension as a predictor of clinical outcome in metastatic colorectal cancer: An individual patient data-based pooled analysis of two randomized studies and a systematic review of the literature.

BACKGROUND: Retrospective series suggest that bevacizumab-induced hypertension (HTN) is a prognostic and potentially predictive biomarker of efficacy of the antiangiogenic drug in the upfront treatment of metastatic colorectal cancer (mCRC) patients. The immortal-time bias and the effect of pre-existing HTN might affect these findings. We conducted a pooled, post hoc analysis of 2 prospective randomized trials of chemotherapy plus bevacizumab in mCRC, and performed a systematic review of the available literature focusing on how the immortal-time bias was taken into account and how pre-existing HTN potentially requiring the use of antihypertensive drugs was managed. METHODS: The pooled-analysis included patients enrolled in the phase III TRIBE and TRIBE-2 studies that compared upfront FOLFOXIRI + bevacizumab to FOLFIRI or FOLFOX + bevacizumab, respectively. Association between HTN and survival outcomes was assessed by incorporating a time-dependent Cox regression model to consider the time-dependency of the probability of HTN onset during the treatment. The systematic review was conducted according to PRISMA guidelines. RESULTS: The systematic review retrieved 14 eligible and highly heterogeneous studies. A positive prognostic impact of bevacizumab-induced HTN was reported in the 58% of the analyses reporting Progression Free Survival (PFS) and in the 54% of the analyses reporting Overall Survival (OS) data. Immortal-time bias was incorporated in 4 studies (28%). In TRIBE and TRIBE-2 study populations (N = 1175), patients experiencing ≥ G2 HTN during first-line bevacizumab administration showed longer PFS (median: 14.7 versus 10.3 months, p < 0.001) and OS (median: 31.7 versus 24.2 months, p < 0.001). The association with OS retained statistical significance after correction for time-dependency (p = 0.003) and was confirmed in the multivariable model including HTN as a time-dependent variable (p = 0.02). Moreover, in patients with pre-existing HTN, no difference in terms of PFS and OS was observed compared with the subgroup of patients who never experienced ≥G2 HTN (HR 1.01, p = 0.86 and HR 1.02, p = 0.78 respectively. CONCLUSIONS: Bevacizumab-induced HTN during the first-line treatment of mCRC is an independent prognostic factor, also adopting a time-dependency correction. Toxicity should be interpreted as a time-dependent variable when exploring its association with clinical outcome.

Tumour mutational burden predicts resistance to EGFR/BRAF blockade in BRAF-mutated microsatellite stable metastatic colorectal cancer.

AIM: To unveil genomic and immunohistochemical expression profiles associated with primary resistance to EGFR/BRAF targeted therapy in patients with BRAF-mutated and microsatellite stable (MSS) metastatic colorectal cancer. EXPERIMENTAL DESIGN: In this multicenter case-control study on patients treated with EGFR/BRAF ± MEK blockade, we compared a primary resistance cohort (N = 20; RECISTv1.1 PD/SD, and progression-free survival [PFS] <16 weeks) versus a sensitive one (N = 19; RECISTv1.1 PR/CR, and PFS ≥16 weeks) in terms of clinical and genomic/expression data by means of comprehensive genomic profiling, tumour mutational burden (TMB), BRAF-mutant transcriptional subtypes (BM) classification and PTEN expression. RESULTS: Left-sided tumours (28% of the total) were enriched in the sensitive versus resistant cohort (53% versus 10%, P = 0.010). Genomic alterations in the PIK3CA/MTOR pathway, BM1 status and PTEN loss were similarly distributed among patients with resistant and sensitive tumours. Amplification of CCND1-3 genes were found only in patients with primary resistance (20% versus 0%, P = 0.106). TMB and prevalence of intermediate TMB (TMB-I 6-20 mutations/Mb) were higher in the resistant versus sensitive cohort (median TMB: 6 [IQR, 3-7.29] versus 3 [IQR, 1.26-3.5]; P = 0.013; TMB-I/H: 60% versus 11%; P = 0.001). Patients with TMB-I had shorter PFS (3.3 versus 5.9 months; HR = 2.19, 95%CI, 1.07-4.47, P = 0.031) and overall survival (6.3 versus 10.5 months; HR = 2.22, 95%CI, 1.02-4.81, P = 0.044). CONCLUSION: Despite the small sample size, the association of a relatively higher TMB with limited benefit from EGFR/BRAF blockade in patients with MSS and BRAF-mutated mCRC deserves prospective validation.

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.