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Purpose: We evaluated additional mutations in RAS wild-type (WT) metastatic colorectal cancer (mCRC) as prognostic and predictive biomarkers for the efficacy of added panitumumab to a 5-fluorouracil plus folinic acid (FU/FA) maintenance as pre-specified analysis of the randomized PanaMa trial., Patients and Methods: Mutations (MUT) were identified using targeted next-generation sequencing (NGS; Illumina Cancer Hotspot Panel v2) and IHC. RAS/BRAF V600E/PIK3CA/AKT1/ALK1/ERBB2/PTEN MUT and HER2/neu overexpressions were negatively hyperselected and correlated with median progression-free survival (PFS) and overall survival (OS) since start of maintenance treatment, and objective response rates (ORR). Univariate/multivariate Cox regression estimated hazard ratios (HR) and 95% confidence intervals (CI)., Results: 202 of 248 patients (81.5%) of the full analysis set (FAS) had available NGS data: hyperselection WT, 162 (80.2%); MUT, 40 (19.8%). From start of maintenance therapy, hyperselection WT tumors were associated with longer median PFS as compared with hyperselection MUT mCRC (7.5 vs. 5.4 months; HR, 0.75; 95% CI, 0.52-1.07; P = 0.11), OS (28.7 vs. 22.2 months; HR, 0.53; 95% CI, 0.36-0.77; P = 0.001), and higher ORR (35.8% vs. 25.0%, P = 0.26). The addition of panitumumab to maintenance was associated with significant benefit in hyperselection WT tumors for PFS (9.2 vs. 6.0 months; HR, 0.66; 95% CI, 0.47-0.93; P = 0.02) and numerically also for OS (36.9 vs. 24.9 months; HR, 0.91; 95% CI, 0.61-1.36; P = 0.50), but not in hyperselection MUT tumors. Hyperselection status interacted with maintenance treatment arms in terms of PFS (P = 0.06) and OS (P = 0.009)., Conclusions: Extended molecular profiling beyond RAS may have the potential to improve the patient selection for anti-EGFR containing maintenance regimens., (©2024 American Association for Cancer Research.)

Despite molecular selection, patients (pts) with RAS wildtype mCRC represent a heterogeneous population including diversity in metastatic spread. We investigated metastatic patterns for their prognostic and predictive impact on maintenance therapy with 5-fluorouracil/folinic acid ± panitumumab. The study population was stratified according to (1) number of involved metastatic sites (single vs multiple organ metastasis), liver-limited disease vs (2) liver metastasis plus one additional site, and (3) vs liver metastasis plus ≥two additional sites. Kaplan-Meier method and Cox regressions were used to correlate efficacy endpoints. Single organ metastasis was observed in 133 pts (53.6%) with 102 pts (41.1%) presenting with liver-limited disease, while multiple organ metastases were reported in 114 pts (46.0). Multiple compared to single organ metastases were associated with less favorable PFS (HR 1.48, 95% CI 1.13-1.93; P = .004) and OS (HR 1.37, 95% CI 0.98-1.93; P = .068) of maintenance therapy. While metastatic spread involving one additional extrahepatic site was not associated with clearly impaired survival compared to liver-limited disease, pts with liver metastasis plus ≥two additional sites demonstrated less favorable PFS (HR 1.92, 95% CI 1.30-2.83; P < .001), and OS (HR 2.38, 95% CI 1.51-3.76; P < .001) of maintenance therapy. Pmab-containing maintenance therapy appeared active in both pts with multiple (HR 0.58; 95% CI, 0.39-0.86; P = .006) as well as to a lesser numerical extent in pts with single organ metastasis (HR 0.83; 95% CI, 0.57-1.21; P = .332; Interaction P = .183). These data may support clinical decisions when EGFR-based maintenance therapy is considered., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Precision medicine has revolutionised cancer treatments; however, actionable biomarkers remain scarce. To address this, we develop the Oncology Biomarker Discovery (OncoBird) framework for analysing the molecular and biomarker landscape of randomised controlled clinical trials. OncoBird identifies biomarkers based on single genes or mutually exclusive genetic alterations in isolation or in the context of tumour subtypes, and finally, assesses predictive components by their treatment interactions. Here, we utilise the open-label, randomised phase III trial (FIRE-3, AIO KRK-0306) in metastatic colorectal carcinoma patients, who received either cetuximab or bevacizumab in combination with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI). We systematically identify five biomarkers with predictive components, e.g., patients with tumours that carry chr20q amplifications or lack mutually exclusive ERK signalling mutations benefited from cetuximab compared to bevacizumab. In summary, OncoBird characterises the molecular landscape and outlines actionable biomarkers, which generalises to any molecularly characterised randomised controlled trial., (© 2023. Springer Nature Limited.)

Background: The PanaMa trial demonstrated significant benefit in progression-free survival with the addition of panitumumab (Pmab) to fluorouracil and folinic acid (FU/FA) as maintenance therapy following first-line induction therapy with FOLFOX/Pmab in patients with RAS wild-type metastatic colorectal cancer. Here, we report health-related quality of life (HRQOL) analyses from the PanaMa trial., Methods: HRQOL outcomes were evaluated using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at every cycle of therapy until disease progression/death. HRQOL outcomes were mean and individual changes in EORTC QLQ-C30 from baselines (before induction therapy and before maintenance therapy) to each cycle of treatment. Comparative analyses were performed by randomisation status and treatment arm for induction- and maintenance-therapy, respectively. The trial is registered with clinicaltrials.gov (NCT01991873)., Results: At least one HRQOL questionnaire was completed by a total of 349/377 (93%) patients who received induction therapy, and by 237/248 (96%) patients who were randomised and received maintenance therapy. During induction therapy, most HRQOL dimensions remained stable or showed improvement, while appetite loss and diarrhoea significantly deteriorated. During maintenance therapy, HRQOL dimensions remained stable, while those that deteriorated during induction therapy showed significant improvement, without significant differences between the treatment arms., Conclusion: Maintenance therapy improves HRQOL dimensions that initially deteriorated during induction therapy while stabilising HRQOL in other dimensions. The addition of Pmab to FU/FA as maintenance therapy in patients with RAS wild-type metastatic colorectal cancer prolongs progression-free survival without negative impact on HRQOL., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alexej Ballhausen: Stock and other ownership interests: BioNTech SE. Honoraria: Amgen. Research funding: Amgen (Inst). Travel, Accommodations, Expenses: Amgen. Meinolf Karthaus: Consulting or advisory role: Amgen. Travel, Accommodations, Expenses: Amgen. Ullrich Graeven: Stock and other ownership interests: BioNTech SE. Honoraria: Boehringer Ingelheim, Amgen, AstraZeneca, Bristol Myers Squibb, MSD Oncology, Sanofi Aventis GmbH, Fujifilm, Novartis, Celltrion. Consulting or advisory role: Amgen, MSD Oncology. Research funding: Ipsen (Inst), MacroGenics (Inst). Travel, Accommodations, Expenses: Boehringer Ingelheim, GlaxoSmithKline. Lothar Müller: Travel, Accommodations, Expenses: Octapharma, Pierre Fabre. Ludwig Fischer von Weikersthal: Honoraria: Pierre Fabre, Lilly. Annabel Helga Sophie Alig: Honoraria: MSD. Travel, Accommodations, Expenses: Merck, BMS GmbH and Co. KG. Eray Goekkurt: Consulting or advisory role: MSD, Bristol Myers Squibb, AstraZeneca/Daiichi Sankyo, Pfizer. Annika Kurreck: Honoraria: Taiho Pharmaceutical, Amgen, Servier. Travel, Accommodations, Expenses: medac, Amgen, Servier. Arndt Stahler: Honoraria: Roche, Servier, Taiho Pharmaceutical. Consulting or advisory role: Bristol Myers Squibb/Pfizer, Novocure. Travel, Accommodations, Expenses: Amgen, Roche, Lilly, Pfizer. Stefan Kasper: Employment: University Hospital Essen. Honoraria: Bristol Myers Squibb, MSD Oncology, AstraZeneca, Merck Serono, Amgen, Roche, Servier, Amgen, Lilly, Sanofi/Aventis, Novartis, Pierre Fabre. Consulting or Advisory Role: Roche, Merck Serono, Amgen, MSD Oncology, Sanofi, Bristol Myers Squibb, Lilly, Servier, AstraZeneca, Janssen-Cilag, Novartis, Pierre Fabre, Incyte. Research funding: Merck Serono, Bristol Myers Squibb, Celgene, Lilly, Servier, Roche/Genentech. Travel, Accommodations, Expenses: Merck Serono, Lilly, Amgen, Sanofi, Roche, Pierre Fabre, BMS. Other relationship: Sanofi, Amgen, Merck Serono, Bristol Myers Squibb, Roche, Lilly. Volker Heinemann: Honoraria: Roche, Amgen, Sanofi, Merck, Servier, Pfizer, Pierre Fabre, AstraZeneca, MSD, Seagen. Consulting or advisory role: Merck, Amgen, Roche, MSD, Bristol Myers Squibb, MSD Oncology, Novartis, Pierre Fabre, TERUMO, GlaxoSmithKline, Servier/Pfizer, AstraZeneca, OncoSil, Nordic Bioscience. Research funding: Merck (Inst), Amgen (Inst), Roche (Inst). Travel, Accommodations, Expenses: Merck. Sebastian Stintzing: Honoraria: Merck KGaA, Roche, Amgen, Servier, MSD, Pfizer, Pierre Fabre, Bristol Myers Squibb GmbH, Nordic Bioscience, AstraZeneca. Consulting or advisory role: Merck Kgaa, Roche, Amgen, Pierre Fabre, Msd, Astrazeneca, Servier, Glaxosmithkline, Terumo, Nordic Bioscience, Seagen. Research Funding: Pierre Fabre (Inst), Roche Molecular Diagnostics (Inst), Merck Serono (Inst), Amgen (Inst). Travel, Accommodations, Expenses: Merck KGaA, Roche, Sanofi, Bayer, Sirtex Medical, Amgen, Lilly, Takeda, Pierre Fabre, AstraZeneca. Tanja Trarbach: Research funding: Amgen. Travel, Accommodations, Expenses: Ipsen, Takeda, OMT, AbbVie, Novartis, MSD, Sanofi/Aventis, Amgen, Johnson and Johnson/Janssen. Dominik Paul Modest: Honoraria: Merck Serono, Amgen, Servier, Bristol Myers Squibb, Taiho Pharmaceutical, Merck Sharp and Dohme, Pierre Fabre, Onkowissen, Sanofi, Lilly, AstraZeneca/MedImmune, Incyte, Takeda. Consulting or advisory role: Merck Serono, Amgen, Merck Sharp and Dohme, Roche, Servier, Incyte, Bristol Myers Squibb, Pierre Fabre, Lilly, Cor2Ed, IQVIA, Onkowissen. Research funding: Amgen (Inst), Servier (Inst). Travel, Accommodations, Expenses: Amgen, Merck Serono, Servier. No other potential conflicts of interest were reported., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Anti-EGFR antibodies plus doublet chemotherapy is the standard of care in RAS/BRAF wild-type metastatic colorectal cancer (mCRC). No phase-3 level of evidence is available to guide treatment de-escalation after anti-EGFR-based first-line. Several randomised clinical trials investigated de-intensification strategies with 5-fluorouracil/leucovorin (5-FU/LV) and/or anti-EGFR., Methods: We performed an individual patient data pooled analysis of Valentino, Panama, MACRO-2, COIN-B trials including RAS wild-type mCRC patients who received first-line therapy with FOLFOX plus panitumumab or cetuximab followed by pre-specified maintenance strategy. Only patients who started maintenance according to the assigned arm were included. Patients were categorised by type of maintenance (i.e. 5-FU/LV, anti-EGFR or 5-FU/LV + anti-EGFR). Progression-free survival (PFS) and overall survival (OS) were calculated from the start of maintenance; toxicity was evaluated for the maintenance treatment period., Results: A total of 518 patients were included in the pooled analysis. Overall, 123, 185 and 210 patients received maintenance with 5-FU/LV, anti-EGFR, 5-FU/LV + anti-EGFR, respectively. Median PFS was 5.6, 6.0 and 9.0 (P = 0.009) and OS was 25.7, 24.0 and 28.0 months (P = 0.134) in 5-FU/LV, anti-EGFR and 5-FU/LV + anti-EGFR arms, respectively. Monotherapy maintenance (either 5-FU/LV or anti-EGFR) was inferior to combination in terms of PFS (hazard ratios [HR] 1.26, P = 0.016) and non-significantly trending also in OS (HR 1.20, P = 0.111). An increase of overall any grade and grade ≥ 3 AEs and selected AEs was reported in combination compared to either 5-FU/LV or anti-EGFR arms., Conclusions: This pooled analysis including four randomised phase II supports the use of 5-FU/LV plus anti-EGFR as the preferred maintenance regimen. Data provide rational for a more individualised maintenance treatment approach based on tumour and patients features., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AR: Honoraria for lectures from Elma Academy and Servier. Travel support: Amgen. HW: honoraria as a speaker and/or in an advisory role from Pierre Fabre, Merck KGaA, Incyte, Merck Sharp Dohme, Servier, Bayer, Roche Genentech and SIRTEX. EA: Honoraria for advisory role from Amgen, Bayer, Bristol Myers Squibb, Merck, Roche, Sanofi. FM: Honoraria from Servier, Lilly, Pierre-Fabre and received research grants from Incyte. FP: Honoraria from Amgen, Bayer, Servier, Merck-Serono, Lilly, MSD, BMS, Astrazeneca, Astellas, Organon, Pierre-Fabre and received research grants from Bristol-Myers Squibb, Astrazeneca, Agenus, Incyte. DPM: Honoraria for lectures and advisory boards: Merck, Amgen, Servier, Pierre Fabre, Sanofi, Lilly, BMS, MSD, AstraZeneca, G1, Cureteq, Takeda, Taiho, Onkowissen.de; GSK, Seagen, COR2ED. Travel support: Amgen, Servier. Research funding (inst): Amgen, Servier. All other authors declared no disclosures., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: BRAF V600E mutation is associated with a poor outcome in metastatic colorectal cancer (mCRC). This clinical trial investigated the efficacy of triplet chemotherapy (fluorouracil, folinic acid, oxaliplatin, and irinotecan) combined with either cetuximab or bevacizumab in patients with previously untreated BRAF V600E -mutant mCRC., Patients and Methods: In this controlled, randomized, open-label phase II trial, 109 patients were randomly assigned, 107 of whom were included into the full analysis set (FAS). Patients were randomly assigned in a 2:1 ratio to receive either FOLFOXIRI plus cetuximab in the experimental arm (n = 72) or FOLFOXIRI plus bevacizumab in the control arm (n = 35). The primary end point was objective response rate (ORR) according to RECIST 1.1., evaluated in patients treated according to protocol (ATP population). Progression-free survival (PFS), overall survival (OS), toxicity, and feasibility were analyzed as secondary end points., Results: Eighteen patients discontinued study treatment before the first tumor assessment, thus resulting in the ATP population of 89 patients. In these patients, ORR was 51% (30/59) in the cetuximab-based experimental arm and 67% (20/30) in the bevacizumab-based control arm (odds ratio, 1.93; 80% CI, 1.06 to 3.52; P = .92 [one-sided]). In the full analysis set, median PFS was significantly inferior in the experimental arm (6.7 months v 10.7 months; hazard ratio [HR], 1.89; P = .006). Median OS analyzed at an event rate of 64.5% showed a trend toward shorter survival in cetuximab-treated patients (12.9 months v 17.1 months; HR, 1.4; P = .20)., Conclusion: To our knowledge, FIRE-4.5 is the first prospective and randomized study investigating first-line treatment of BRAF V600E -mutant mCRC. FOLFOXIRI plus cetuximab does not induce a higher ORR when compared with FOLFOXIRI plus bevacizumab in first-line treatment of BRAF V600E -mutant mCRC. Bevacizumab-based chemotherapy remains the preferable first-line treatment of patients with BRAF V600E -mutant mCRC.

Purpose: Consensus molecular subtypes (CMSs) were evaluated as prognostic and predictive biomarkers of patients with RAS wild-type metastatic colorectal cancer (mCRC) receiving fluorouracil and folinic acid (FU/FA) with or without panitumumab (Pmab) after Pmab + mFOLFOX6 induction within the randomized phase II PanaMa trial., Methods: CMSs were determined in the safety set (ie, patients that received induction) and full analysis set (FAS; ie, randomly assigned patients who received maintenance) and correlated with median progression-free survival (PFS) and overall survival (OS) since the start of induction or maintenance treatment and objective response rates (ORRs). Hazard ratios (HRs) and 95% CI were calculated by univariate/multivariate Cox regression analyses., Results: Of 377 patients of the safety set, 296 (78.5%) had available CMS data: CMS1/2/3/4: 29 (9.8%)/122 (41.2%)/33 (11.2%)/112 (37.8%) and unclassifiable: 17 (5.7%). The CMSs were prognostic biomarkers in terms of PFS ( P < .0001), OS ( P < .0001), and ORR ( P = .02) since the start of induction treatment. In FAS patients (n = 196), with CMS2/4 tumors, the addition of Pmab to FU/FA maintenance therapy was associated with longer PFS (CMS2: HR, 0.58 [95% CI, 0.36 to 0.95], P = .03; CMS4: HR, 0.63 [95% CI, 0.38 to 1.03], P = .07) and OS (CMS2: HR, 0.88 [95% CI, 0.52 to 1.52], P = .66; CMS4: HR, 0.54 [95% CI, 0.30 to 0.96], P = .04). The CMS interacted significantly with treatment in terms of PFS (CMS2 v CMS1/3: P = .02; CMS4 v CMS1/3: P = .03) and OS (CMS2 v CMS1/3: P = .03; CMS4 v CMS1/3: P < .001)., Conclusion: The CMS had a prognostic impact on PFS, OS, and ORR in RAS wild-type mCRC. In PanaMa, Pmab + FU/FA maintenance was associated with beneficial outcomes in CMS2/4, whereas no benefit was observed in CMS1/3 tumors.

Background: In a previous phase 3 trial, treatment with trifluridine-tipiracil (FTD-TPI) prolonged overall survival among patients with metastatic colorectal cancer. Preliminary data from single-group and randomized phase 2 trials suggest that treatment with FTD-TPI in addition to bevacizumab has the potential to extend survival., Methods: We randomly assigned, in a 1:1 ratio, adult patients who had received no more than two previous chemotherapy regimens for the treatment of advanced colorectal cancer to receive FTD-TPI plus bevacizumab (combination group) or FTD-TPI alone (FTD-TPI group). The primary end point was overall survival. Secondary end points were progression-free survival and safety, including the time to worsening of the Eastern Cooperative Oncology Group (ECOG) performance-status score from 0 or 1 to 2 or more (on a scale from 0 to 5, with higher scores indicating greater disability)., Results: A total of 246 patients were assigned to each group. The median overall survival was 10.8 months in the combination group and 7.5 months in the FTD-TPI group (hazard ratio for death, 0.61; 95% confidence interval [CI], 0.49 to 0.77; P<0.001). The median progression-free survival was 5.6 months in the combination group and 2.4 months in the FTD-TPI group (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.54; P<0.001). The most common adverse events in both groups were neutropenia, nausea, and anemia. No treatment-related deaths were reported. The median time to worsening of the ECOG performance-status score from 0 or 1 to 2 or more was 9.3 months in the combination group and 6.3 months in the FTD-TPI group (hazard ratio, 0.54; 95% CI, 0.43 to 0.67)., Conclusions: Among patients with refractory metastatic colorectal cancer, treatment with FTD-TPI plus bevacizumab resulted in longer overall survival than FTD-TPI alone. (Funded by Servier and Taiho Oncology; SUNLIGHT ClinicalTrials.gov number, NCT04737187; EudraCT number, 2020-001976-14.)., (Copyright © 2023 Massachusetts Medical Society.)

Objectives: Early tumor shrinkage (ETS) quantifies the objective response at the first assessment during systemic treatment. In metastatic colorectal cancer (mCRC), ETS gains relevance as an early available surrogate for patient survival. The aim of this study was to increase the predictive accuracy of ETS by using semi-automated volumetry instead of standard diametric measurements., Methods: Diametric and volumetric ETS were retrospectively calculated in 253 mCRC patients who received 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) combined with either cetuximab or bevacizumab. The association of diametric and volumetric ETS with overall survival (OS) and progression-free survival (PFS) was compared., Results: Continuous diametric and volumetric ETS predicted survival similarly regarding concordance indices (p > .05). In receiver operating characteristics, a volumetric threshold of 45% optimally identified short-term survivors. For patients with volumetric ETS ≥ 45% (vs < 45%), median OS was longer (32.5 vs 19.0 months, p < .001) and the risk of death reduced for the first and second year (hazard ratio [HR] = 0.25, p < .001, and HR = 0.39, p < .001). Patients with ETS ≥ 45% had a reduced risk of progressive disease only for the first 6 months (HR = 0.26, p < .001). These survival times and risks were comparable to those of diametric ETS ≥ 20% (vs < 20%)., Conclusions: The accuracy of ETS in predicting survival was not increased by volumetric instead of diametric measurements. Continuous diametric and volumetric ETS similarly predicted survival, regardless of whether patients received cetuximab or bevacizumab. A volumetric ETS threshold of 45% and a diametric ETS threshold of 20% equally identified short-term survivors., Key Points: • ETS based on volumetric measurements did not predict survival more accurately than ETS based on standard diametric measurements. • Continuous diametric and volumetric ETS predicted survival similarly in patients receiving FOLFIRI with cetuximab or bevacizumab. • A volumetric ETS threshold of 45% and a diametric ETS threshold of 20% equally identified short-term survivors., (© 2022. The Author(s).)

Background: In patients with RAS wild-type metastatic colorectal cancer, depth of response (DpR) has gained importance as a novel end-point in clinical trials. We investigated the overall DpR, as well as the prognostic and predictive impact of DpR to induction therapy (six cycles of 5-fluorouracil, leucovorin [FU/FA], oxaliplatin [FOLFOX] and panitumumab [Pmab]) on consecutive maintenance therapy (FU/FA plus Pmab or FU/FA alone) in patients treated within the PanaMa trial., Methods: Central radiological assessment was performed according to RECIST 1.1. DpR was defined as percentage change in tumour diameter within defined time intervals (induction therapy, maintenance therapy, total course of therapy). For prognostic and predictive analyses, median DpR (

Background: The randomised open-label phase III XELAVIRI trial failed to demonstrate non-inferiority of the sequential application of fluoropyrimidine plus bevacizumab followed by additional irinotecan at first progression (Arm A) versus initial combination of all agents (Arm B) for untreated metastatic colorectal cancer in the initial analysis of time-to-failure-of-strategy (TFS, 90% confidence boundary of 0.8). Here, we evaluate efficacy in the full analysis set (FAS), the per-protocol set, in addition to age-related and molecular subgroups., Methods: Median TFS, overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method and log-rank test. Cox regression models assessed hazard ratios (HRs) and confidence intervals (CIs) (TFS: 90%; OS, PFS: 95%)., Results: Of 421 patients, 390 (92.6%), 391 (92.9%) and 357 (84.8%) events for TFS, OS and PFS were observed in the FAS with a median follow-up of 54.2 months (Arm A) versus 52.9 months (Arm B). Non-inferiority of sequential treatment for TFS was missed in the FAS (HR 0.93; 90% CI, 0.79-1.10; P = 0.482) and not shown in the per-protocol set (HR 0.93; 90% CI, 0.75-1.13, P = 0.433). Formal non-inferiority for TFS was observed for patients older than 70 years (HR 1.06; 90% CI, 0.80-1.41; P = 0.670) and patients with RAS mutant tumours (HR 1.12; 90% CI, 0.87-1.43; P = 0.465). In RAS/BRAF wild-type tumours, combination treatment was significantly superior to sequential therapy in all end-points., Conclusions: In the overall population, XELAVIRI just missed to demonstrate the non-inferiority of sequential compared to combination therapy for TFS. However, the non-inferiority of sequential treatment was observed in elderly patients and RAS mutant tumours., Trial Registration: Trial registration ID (clinicaltrials.gov) NCT01249638., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The evidence on the efficacy of anticancer therapy is limited in older patients with metastatic colorectal cancer (mCRC). This retrospective analysis of phase III FIRE-3 trial assesses the efficacy of FOLFIRI plus either cetuximab or bevacizumab according to the patients' age and sidedness of primary tumour., Methods: The study endpoints overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between younger (<65 years) and older (≥65 years) patients, followed by stratification according to primary tumour sidedness. ORR was compared using Fisher´s exact test, OS and PFS were estimated by the Kaplan-Meier method and compared using the log-rank test. Univariate Cox regression analyses assessed hazard ratios and 95% confidence intervals for OS and PFS., Results: Overall, older patients with RAS WT tumours had a significantly shorter OS when compared to younger patients (25.9 months vs 29.3 months, HR 1.29; P = 0.02). Also the proportion of right-sided tumours was significantly greater in older patients (27.1% vs 17.9%; P = 0.029). Secondary resection rates were numerically higher in younger patients (25.4% vs. 17.6%, P = 0.068) than in older patients. This was primarily seen in the Cetuximab arm, where older patients underwent less likely resection (13.1% vs. 26%; P = 0.02). Older patients with left-sided tumours showed only a trend towards greater efficacy of cetuximab (HR 0.86; P = 0.38). In patients with right-sided primary tumours, older patients did not appear to benefit from cetuximab in contrast to younger patients (≥65 years: 16.6 months vs 23.6 months, HR 1.1; P = 0.87; <65 years: 21.9 months vs 16.4 months HR 1.5; P = 0.31)., Conclusions: In FIRE-3, OS was generally shorter in older patients in comparison to younger patients. This could be explained by the overrepresentation of right-sided tumours and a lower secondary resection rate in older patients. The efficacy of targeted therapy was dependent on tumour sidedness in older patients with RAS WT mCRC., Clinical Trial: FIRE-3 (NCT00433927)., (© 2022. The Author(s).)

Background: In metastatic colorectal cancer (mCRC), there are limited data on associations between early tumor shrinkage (ETS), depth of response (DpR), and patient characteristics., Methods: Data from patients with RAS wild-type mCRC who had participated in the PRIME (NCT00364013) and PEAK (NCT00819780) studies were analyzed retrospectively. ETS and DpR were assessed by baseline Köhne category/BRAF status (PRIME) and baseline tumor load (pooled PRIME and PEAK)., Results: Analysis populations included 436 to 665 patients. Patients' chances of achieving ETS of 30% or greater were 63.8%, 50.4%, and 41.9% in the low-, medium-, and high-risk Köhne categories, and 21.7% in those with BRAF mutations. Corresponding percentages for the highest DpR classification (71%-100%) were 47.7% (low risk), 23.6% (medium risk), 10.0% (high risk), and 4.2% (BRAF mutant). No clear relationship was observed between baseline tumor load and ETS or DpR. An ETS of 30% or greater and higher DpR values were associated with statistically significant prolongation of median progression-free survival and overall survival., Conclusion: Patients with mCRC categorized at baseline by the Köhne criteria as high risk or with BRAF mutations have lower chances of achieving an ETS of 30% or greater or a high DpR. Baseline tumor load was not predictive of ETS or DpR. Favorable ETS or DpR is associated with improved progression-free and overall survival., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Several independent serum biomarkers have been proposed as prognostic and/or predictive markers for colorectal cancer (CRC). To this date, carcinoembryonic antigen (CEA) remains the only recommended serological CRC biomarker. The present retrospective analysis investigates the prognostic value of several serum markers. A total of 256 patients with rectal cancer underwent surgery for curative intent in a university cancer center between January 1988 and June 2007. Preoperative serum was retrospectively analyzed for albumin, alkaline phosphatase (aP), beta-human chorionic gonadotropin, bilirubin, CA 125, cancer antigen 19-9, cancer antigen 72-4 (CA 72-4), CEA, CRP, CYFRA 21-1, ferritin, gamma-glutamyl transpeptidase, glutamate oxaloacetate transanunase, glutamate pyruvate transaminase, hemoglobin, haptoglobin, interleukin-6, interleukin-8, creatinine, lactate-dehydrogenase, serum amyloid A (SAA), and 25-hydroxyvitamin D. Cancer-specific survival (CSS) and disease-free survival (DFS) were estimated. Median follow-up time was 8.4 years. Overall 3- and 5-year CSS was 88.6 and 78.9 %, respectively. DFS rates were 72.8 % (3 years) and 67.5 % (5 years). Univariate analysis of CSS indicated aP, CA 72-4, CEA, and SAA as prognostic factors, while aP, CEA, and SAA were also prognostic with regard to DFS. Multivariate analysis confirmed SAA together with T and N stage as prognostic factors. According to UICC stage, CEA and SAA add prognostic value in stages II and III with regard to DFS and CSS, respectively. The combined use of CEA and SAA is able to identify patients with favorable and poor prognosis. In addition to tumor baseline parameters, routine analysis of SAA together with CEA provided markedly improved prognostic value on CSS and DFS in resected rectal cancer.