Search

The randomized FIRE-4.5 (AIO KRK0116) trial compared first-line therapy with FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus either cetuximab or bevacizumab in B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E-mutant metastatic colorectal cancer (mCRC) patients. This study was accompanied by a prospective translational project analyzing cell-free circulating tumor DNA (ctDNA) in plasma to test whether ctDNA analysis may help to guide clinical treatment decision making. FIRE-4.5 included mCRC patients with BRAF V600E mutation detected by tissue-based analyses. Liquid biopsies (LBs) were collected at baseline (pre-treatment) and during therapy. Digital droplet PCR (ddPCR) technology was applied for determination of BRAF mutations and the in vitro diagnostics (IVD)-certified ONCOBEAM RAS procedure for analysis of RAS mutations. The BRAF V600E variants in ctDNA were analyzable in 66 patients at start of the therapy, at baseline. No BRAF V600E mutations were detected in 26% (17/66) of patients and was associated with a significantly longer progression-free survival (PFS: 13.2 vs 6.5 months; HR 0.47; P = 0.014) and overall survival (OS: 36.8 vs 13.2 months; HR 0.35; P = 0.02) as compared to ctDNA mutant patients. Patients with detectable BRAF mutations showed a clear superiority of FOLFOXIRI plus bevacizumab with regard to PFS (10.4 vs 5.7 months; HR 0.4; P = 0.009) and OS (16.6 vs 11.6 months; HR 0.5; P = 0.15), while this was not the case for BRAF wild-type patients. Follow-up LBs were obtained from 51 patients. Patients converting from BRAF V600E mutant to a BRAF V600 wild-type status (36%, N = 18) had a superior PFS (8.6 vs 2.3 months; P = 0.0002) and OS (17.4 vs 5.1 months; P < 0.0001) compared to patients with stable or increased mutational allele frequency (12%, N = 6). Those patients also achieved a significantly greater disease control rate (89% vs 20%; P = 0.008). In conclusion, LB evaluating ctDNA is informative and may help to guide treatment in patients with BRAF V600E-mutated mCRC., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Introduction: The phase 2 RAMONA study demonstrated that second-line nivolumab ± ipilimumab immunotherapy was feasible and effective in older patients with advanced esophageal squamous cell cancer (ESCC). Here, we presented results from functional status (FS) and quality-of-life (QoL) analyses., Materials and Methods: Patients aged ≥65 years with advanced ESCC and disease progression following first-line therapy were enrolled for study treatment with nivolumab ± ipilimumab. Geriatric assessments (GA) consisting of G8 and GoGo/SlowGo evaluation, and quality of life (QoL) assessments with EORTC QLQ-C30 questionnaires were conducted at baseline and during the treatment. A post hoc analysis was performed to compare therapy efficacy, toxicity, and QoL between age groups (≥70 years vs. <70 years) and functionality groups (G8 > 14 vs. ≤14 and GoGo vs. SlowGo)., Results: In 66 treated patients with a median age of 70.5 years, older patients had non-inferior overall survival and tumor response compared to younger patients, with no increased treatment-related adverse events. Fitter patients (G8 > 14, GoGo) had a clinically, yet not statistically significant, survival advantage than less fit patients (G8 ≤ 14, SlowGo) patients. Moreover, FS by G8 and GoGo/SlowGo significantly correlated with QoL. Overall, QoL was impaired at baseline but remained stable in all scales over the course of immunotherapy., Discussion: The administration of nivolumab ± ipilimumab second-line immunotherapy in older patients with ESCC did not show age-dependent effects and maintained QoL. GA could identify functional deficits and limitations of QoL and should be implemented in the context of immunotherapy., Clinicaltrials: gov: NCT03416244., Competing Interests: Declaration of Competing Interest NMB reports research funding and receipt of equipment from Deutsche Forschungsgemeinschaft. RDH reports advisory for Amgen, Astra Zeneca, Bristol Myers Squibb, Boehringer, Daichi, Lilly, Merck, MSD, Pierre Fabre, Roche, and Servier; honoraria for lectures and presentations from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer, Daichi, Lilly, medac, Merck, MSD, Pierre Fabre, Roche, Saladax, Sanofi, and Servier; and consulting fees from Amgen, Astra Zeneca, Bayer, BMS, Boehringer, Daichi, Lilly, medac, Merck, MSD, Pierre Fabre, Roche, Saladax, Sanofi, and Servier. AV reports consultancy and advisory role for AstraZeneca, Amgen, BeiGene, Böhringer Mannheim, BMS, BTG, Daichi-Sankyo, EISAI, Incyte, Ipsen, MSD, PierreFabre, Roche, Servier, Sirtex, Tahio and Terumo. MdW reports research funding from Pfizer, Abbvie, Novartis, Astellas, Bristol Myers Squibb, AstraZeneca and MorphoSys; speaker's honoraria from AstraZeneca and Janssen; travel or accommodation expenses from Astellas and Janssen. RJ reports consulting fees from Roche and Bayer; payments for lectures and presentations from Dr. Falk Pharma and Bristol Myers Squibb; for writing of manuscripts from Boston Scientific and Springer Nature; advisory for Heidelberg University Hospital; and leading the Endoscopy section of the German Society of Gastroenterology. GS reports consulting fees from Servier, Pharmacosmos, Bristol Myers Squibb, Amgen and travel support from Daichi-Sankyo. PTP reports consulting fees from Bristol Myers Squibb, AstraZeneca, and MSD. TL is Scientific Head at CROLLL GmbH. HB is an employee of a commercial provider of clinical statistics and programming services (Staburo GmbH, Munich). MPE reports funding for conducting the trial from AIO-Studien-gGmbH which is the regulatory sponsor of the trial, and advisory for Bristol Myers Squibb. NH reports advisory for Bristol Myers Squibb. All remaining authors declare no conflicts of interests., (Copyright © 2024. Published by Elsevier Ltd.)

Background: In the pivotal phase III RECOURSE trial, trifluridine/tipiracil (FTD/TPI) improved progression-free and overall survival (PFS, OS) of patients with pre-treated metastatic colorectal cancer (mCRC). Subsequently, the TALLISUR trial provided post-authorisation efficacy and safety data and patient-reported outcomes on quality of life (QoL) in a German patient cohort. The present analysis reports the final data on efficacy, safety and QoL and investigates the impact of baseline characteristics and associated prognostic subgroups on outcome., Methods: In this prospective, multi-centre, Germany-wide, phase IV study, patients with pre-treated mCRC were given the choice to receive either FTD/TPI or best supportive care (BSC). To assess the primary endpoint, QoL, EORTC QLQ-C30 questionnaires were employed. Secondary endpoints included QoL assessed through EQ-5D-5L questionnaires, OS, PFS and safety. Additionally, 3 subgroups were defined according to a post-hoc analysis of the RECOURSE trial: best, good and poor prognostic characteristics (BPC, GPC, PPC). Patients with < 3 metastatic sites at inclusion and/or ≥ 18 months from diagnosis to inclusion were considered to have GPC. GPC patients without liver metastasis at inclusion were considered to have BPC. All remaining patients were considered to have PPC., Results: Of 195 patients, 186 decided to receive FTD/TPI and 9 to receive BSC. The low number of patients in the BSC-arm did not allow statistically meaningful analyses. Treatment with FTD/TPI was associated with maintained QoL. For all patients, median OS was 6.9 months (95% CI 6.1 - 8.3) and for the defined subgroups (BPC n = 20 vs GPC n = 65 vs PPC n = 121) 12.2, 7.9 and 6.8 months (95% CI 6.0 - 18.2, 6.2 - 13.3, 5.4 - 8.1). The most frequent TEAEs were neutropenia (29.6%), anaemia (24.7%) and nausea (23.7%). Febrile neutropenia occurred in 1.1%., Conclusions: Treatment of patients suffering from pre-treated mCRC with FTD/TPI was associated not only with prolonged survival and delayed progression, but also with maintained QoL. Independent of other baseline characteristics such as ECOG performance status and age, low metastatic burden and indolent disease were factors associated with favourable outcome., Clinical Trial Registration: EudraCT-Number 2017-000292-83, first registration 19/06/2017., (© 2024. The Author(s).)

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.)

Most patients with metastatic colorectal cancer (mCRC) have limited treatment options following standard-of-care therapy. VEGFR-tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity in mCRC in combination with immune checkpoint inhibitors (ICIs), particularly in patients without liver metastases. The TKI zanzalintinib (XL092) targets VEGFR, MET and TAM kinases, proteins that are involved in tumor growth, angiogenesis, metastasis and immunosuppression. Zanzalintinib has immunomodulatory properties that may enhance response to ICIs. Presented is the design of STELLAR-303, a global, phase III, open-label, randomized study evaluating zanzalintinib plus atezolizumab versus regorafenib in patients with non-MSI-H mCRC who progressed during/after or are refractory/intolerant to standard-of-care therapy. The primary end point is overall survival in patients without liver metastases. Clinical Trial Registration: NCT05425940 (ClinicalTrials.gov).

Accurately evaluating cognitive load during work-related tasks in complex real-world environments is challenging, leading researchers to investigate the use of eye blinking as a fundamental pacing mechanism for segmenting EEG data and understanding the neural mechanisms associated with cognitive workload. Yet, little is known about the temporal dynamics of eye blinks and related visual processing in relation to the representation of task-specific information. Therefore, we analyzed EEG responses from two experiments involving simulated driving (re-active and pro-active) with three levels of task load for each, as well as operating a steam engine (active vs. passive), to decode the temporal dynamics of eye blink activity and the subsequent neural activity that follows blinking. As a result, we successfully decoded the binary representation of difficulty levels for pro-active driving using multivariate pattern analysis. However, the decoding level varied for different re-active driving conditions, which could be attributed to the required level of alertness. Furthermore, our study revealed that it was possible to decode both driving types as well as steam engine operating conditions, with the most significant decoding activity observed approximately 200 ms after a blink. Additionally, our findings suggest that eye blinks have considerable potential for decoding various cognitive states that may not be discernible through neural activity, particularly near the peak of the blink. The findings demonstrate the potential of blink-related measures alongside EEG data to decode cognitive states during complex tasks, with implications for improving evaluations of cognitive and behavioral states during tasks, such as driving and operating machinery.

Assessing drivers' cognitive load is crucial for driving safety in challenging situations. This research employed the occurrence of drivers' natural eye blinks as cues in continuously recorded EEG data to assess the cognitive workload while reactive or proactive driving. Twenty-eight participants performed either a lane-keeping task with varying levels of crosswind (reactive) or curve road (proactive). The blink event-related potentials (bERPs) and spectral perturbations (bERSPs) were analyzed to assess cognitive load variations. The study found that task load during reactive driving did not significantly impact bERPs or bERSPs, possibly due to enduring alertness for vehicle control. The proactive driving revealed significant differences in the occipital N1 component with task load, indicating the necessity to adapt the attentional resources allocation based on road demands. Also, increased steering complexity led to decreased frontal N2, parietal P3, occipital P2 amplitudes, and alpha power, requiring more cognitive resources for processing relevant information. Interestingly, the proactive and reactive driving scenarios demonstrated a significant interaction at the parietal P2 and occipital N1 for three difficulty levels. The study reveals that EEG measures related to natural eye blink behavior provide insights into the effect of cognitive load on different driving tasks, with implications for driver safety., (© 2023. The Author(s).)

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.)

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.

Demographic change is leading to an increasing proportion of older employees in the labor market. At the same time, work activities are becoming more and more complex and require a high degree of flexibility, adaptability, and cognitive performance. Cognitive control mechanism, which is subject to age-related changes and is important in numerous everyday and work activities, plays a special role. Executive functions with its core functions updating, shifting, and inhibition comprises cognitive control mechanisms that serve to plan, coordinate, and achieve higher-level goals especially in inexperienced and conflicting actions. In this review, influences of age-related changes in cognitive control are demonstrated with reference to work and real-life activities, in which the selection of an information or response in the presence of competing but task-irrelevant stimuli or responses is particularly required. These activities comprise the understanding of spoken language under difficult listening conditions, dual-task walking, car driving in critical traffic situations, and coping with work interruptions. Mechanisms for compensating age-related limitations in cognitive control and their neurophysiological correlates are discussed with a focus on EEG measures. The examples illustrate how to access influences of age and cognitive control on and in everyday and work activities, focusing on its functional role for the work ability and well-being of older people., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Getzmann, Reiser, Gajewski, Schneider, Karthaus and Wascher.)

Patients with haematological malignancies (HM) are at high risk of developing invasive fungal disease (IFD) with high morbidity and attributable mortality. We reviewed data published until September 2021 to update the 2017 antifungal prophylaxis recommendations of the German Society of Haematology and Medical Oncology (DGHO). The strong recommendation to administer antifungal prophylaxis in patients with HM with long-lasting neutropenia, i.e. <500 cells/μL for >7 days remains unchanged. Posaconazole remains the drug of choice for mould-active prophylaxis in these patients. Novel treatment options in HM, such as CAR-T-cell treatment or novel targeted therapies for acute myeloid leukaemia (AML) were considered, however, data are insufficient to give general recommendations for routine antifungal prophylaxis in these patients. Major changes regarding specific recommendations compared to the 2017 edition are the now moderate instead of mild support for the recommendations of isavuconazole and voriconazole. Furthermore, published evidence on micafungin allows recommending it at moderate strength for its use in HM. For the first time we included recommendations for non-pharmaceutical measures regarding IFD, comprising the use of high-efficiency particulate air (HEPA) filters, smoking, measures during construction work and neutropenic diets. We reviewed the impact of antifungal prophylaxis with triazoles on drug-drug interactions with novel targeted therapies that are metabolized via cytochrome p450 where triazoles inhibit CYP3A4/5. The working group recommends reducing the dose of venetoclax when used concomitantly with strong CYP3A4 inhibiting antifungals. Furthermore, we reviewed data on the prophylactic use of novel antifungal agents. Currently there is no evidence to support their use in a prophylactic setting in clinical practice., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Driving safety strongly depends on the driver's mental states and attention to the driving situation. Previous studies demonstrate a clear relationship between EEG measures and mental states, such as alertness and drowsiness, but often only map their mental state for a longer period of time. In this driving simulation study, we exploit the high temporal resolution of the EEG to capture fine-grained modulations in cognitive processes occurring before and after eye activity in the form of saccades, fixations, and eye blinks. A total of 15 subjects drove through an approximately 50-km course consisting of highway, country road, and urban passages. Based on the ratio of brain oscillatory alpha and theta activity, the total distance was classified into 10-m-long sections with low, medium, and high task loads. Blink-evoked and fixation-evoked event-related potentials, spectral perturbations, and lateralizations were analyzed as neuro-cognitive correlates of cognition and attention. Depending on EEG-based estimation of task load, these measures showed distinct patterns associated with driving behavior parameters such as speed and steering acceleration and represent a temporally highly resolved image of specific cognitive processes during driving. In future applications, combinations of these EEG measures could form the basis for driver warning systems which increase overall driving safety by considering rapid fluctuations in driver's attention and mental states., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Chemotherapy-induced nausea and the subsequent vomiting (CINV) are adverse effects of cancer treatment associated with considerable burden for the patient. CINV has a significant negative impact on quality of life. The consequent loss of fluids and electrolytes can lead to impaired renal function or weight loss, which may lead to hospitalization. If CINV later results in anticipatory vomiting, this complicates both CINV prophylaxis and further chemotherapy, which can endanger the continuation of cancer treatment. The introduction of high-dose dexamethasone as well as 5‑HT3 and NK1 receptor antagonists has led to a significant improvement of CINV prophylaxis since the 1990s. Recommendations on CINV prophylaxis are in available in guidelines. Adherence to these guidelines results in better outcomes., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

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.

The novel coronavirus SARS-CoV-2 and the associated infectious disease COVID-19 pose a significant challenge to healthcare systems worldwide. Patients with cancer have been identified as a high-risk population for severe infections, rendering prophylaxis and treatment strategies for these patients particularly important. Rapidly evolving clinical research, resulting in the recent advent of various vaccines and therapeutic agents against COVID-19, offers new options to improve care and protection of cancer patients. However, ongoing epidemiological changes and rise of new virus variants require repeated revisions and adaptations of prophylaxis and treatment strategies to meet these new challenges. Therefore, this guideline provides an update on evidence-based recommendations with regard to vaccination, pharmacological prophylaxis and treatment of COVID-19 in cancer patients in light of the currently dominant omicron variants. It was developed by an expert panel of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO) based on a critical review of the most recent available data., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: We demonstrate and discuss the use of mobile electroencephalogram (EEG) for neuroergonomics. Both technical state of the art as well as measures and cognitive concepts are systematically addressed., Background: Modern work is increasingly characterized by information processing. Therefore, the examination of mental states, mental load, or cognitive processing during work is becoming increasingly important for ergonomics., Results: Mobile EEG allows to measure mental states and processes under real live conditions. It can be used for various research questions in cognitive neuroergonomics. Besides measures in the frequency domain that have a long tradition in the investigation of mental fatigue, task load, and task engagement, new approaches-like blink-evoked potentials-render event-related analyses of the EEG possible also during unrestricted behavior., Conclusion: Mobile EEG has become a valuable tool for evaluating mental states and mental processes on a highly objective level during work. The main advantage of this technique is that working environments don't have to be changed while systematically measuring brain functions at work. Moreover, the workflow is unaffected by such neuroergonomic approaches.

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 (

Introduction: In further-line mCRC treatment, median progression-free survival (PFS) is rather short, and many patients do not benefit from any antitumor treatment and should therefore be treated according to best-supportive care. A risk score based on standard laboratory values using markers of tumor inflammation aims to define a patient cohort with high treatment benefit and might offer insights into tumor biology. As regorafenib has been dropped off the German market due to an unfavorable risk-benefit ratio, patient selection is key for any further-line treatment option., Methods: We used Cox regression analysis to determine laboratory markers that are independent prognostic factors of OS and PFS outcome. The influence of these variables was weighted using an estimator, which was calculated using Cox regression analysis. The estimators were implemented as multiplication factors, resulting in a risk score. A cut-off value for the resulting risk values was then determined via Cox regression analysis resulting in a low- and high-risk subgroup., Results: Using data of 82 patients, a risk score identifying long-term survival in patients with last-line mCRC treatment could be calculated. The following parameters were associated with significantly longer survival in multivariate analysis: NLR ≤5 (p = &lt;0.001), AP ≤200 U/L (p = 0.001), CRP ≤3.2 mg/dL (p = &lt;0.001). The following estimator values were used to calculate a risk score: NLR: 0.132 (p = 0.046), AP: 0.004 (p = 0.014), and CRP: 0.032 (p = 0.039). Implementing the estimators as multiplication factors yielded the following risk score: 0.132*NLR + 0.004*AP + 0.032*CRP = Risk value. Cox regression resulted in low- and high-risk subgroups with risk values below and above 1.4, respectively. In the group with a low-risk score (&lt;1.4), patients had a median OS of 10.5 months after initiating regorafenib. Patients with a high-risk score (&gt;1.4) survived only 3.3 months after starting therapy with regorafenib (n = 43, p &lt; 0.001, HR = 3.76)., Conclusions: The presented composite risk score stratifies patients into two prognostic subgroups characterized by standard laboratory values. Patients with signs of systemic inflammation characterized by elevated NLR, AP, and CRP have a high composite risk score and a significant shorter overall survival. Although this score needs to be prospectively validated in larger cohorts, it may be used to stratify patients suitable for further-line treatment studies., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: In metastatic colorectal cancer (mCRC), the efficacy of immune checkpoint blockade (ICB) has so far been limited to patients with microsatellite instability high tumors (MSI-H). Unfortunately, most mCRC patients suffer from non-immunogenic microsatellite stable (MSS) tumors. Therefore, new combinatorial strategies are urgently needed to enhance the immunogenicity of MSS tumors to finally increase the number of patients benefiting from ICB., Methods: The AVETUX trial aimed to combine the PD-L1 antibody avelumab with the standard of care chemotherapy combination FOLFOX and the anti-EGFR antibody cetuximab. Furthermore, we performed a central radiological review of the pre- and on-treatment computed tomography scans to better define the individual response to treatment., Results and Discussion: In total, 43 patients were treated of which 39 patients were confirmed as RAS/BRAF wildtype in central tissue review and finally response evaluated. A final progression-free survival (PFS) of 11.1 (range: 0.8 to 22.3 months) and a herein updated final overall survival (OS) of 32.9 months (range: 0.8 to 47.1 months) was reached. We observed a strong median depth of response of 67.5% tumor shrinkage and deepness of response correlated significantly with survival. On the other hand, early tumor shrinkage was not an indicator of better outcome at a cut-off of 20% (median values). In a next step, we correlated the individual best radiological response with potential ICB response biomarkers and found that the clonality and diversity, but not frequency of tumor infiltrating lymphocytes (TiLs) and peripheral blood mononuclear cells (PBMCs), strongly correlated with response. In summary, we report the final overall survival of the AVETUX trial and propose T cell clonality and diversity as a potential marker to predict response to chemo-immunotherapy combinations in MSS mCRC by performing a central radiological review., Clinical Trial Registration: ClinicalTrials.gov, identifier (NCT03174405)., Competing Interests: AS received institutional research grants from Merck, BMS, Roche, Sanofi, Servier and honoraria for lectures and advisory board meetings by Merck, Roche, Amgen, Lilly, Sanofi- Aventis, Servier, Bayer, BMS, MSD and Sirtex. S-EA-B has an advisory role with Merck, Roche, Celgene, Lilly, Nordic Pharma, Bristol- Myers Squibb, Astellas and MSD Sharp & Dohme; is a speaker for Roche, Celgene, Lilly, Nordic Pharma, AIO gGmbH, MCI, promedicis, Forum für Medizinische Fortbildung and Taiho pharma; he is CEO/founder of IKF Klinische Krebsforschung GmbH at Northwest Hospital; and has received research grants from Sanofi, Merck, Roche, Celgene, Vifor, Medac, Hospira, Lilly, Eurozyto, German Cancer Aid (Krebshilfe), German Research Foundation and the Federal Ministry of Education and Research. UP received institutional research grants from Celgene, BMS, Amgen, Lilly, Roche, Sanofi and Servier and honoraria for lectures and advisory board meetings by Roche, Celgene, Amgen, Lilly, Sanofi- Aventis, Servier, Bayer and BMS. AH received honoraria for lectures from Roche. CB received institutional research grants and honoraria for lectures and advisory board meetings from Merck, BMS, Roche, Sanofi, Servier, Bayer, BMS, Astrazeneca, Lilly, Mundipharma, Hexal, MSD and GSO. MBi received institutional research grants from Merck, BMS, Hexal, German Cancer Aid (Krebshilfe), German Research Foundation and the Federal Ministry of Education and Research as well as honoraria for lectures and advisory board meetings by Celgene, Janssen, Gilead, Merck, Roche, Amgen, Sanofi-Aventis and BMS., (Copyright © 2022 Tintelnot, Ristow, Sauer, Simnica, Schultheiß, Scholz, Goekkurt, von Wenserski, Willscher, Paschold, Lorenzen, Riera-Knorrenschild, Depenbusch, Ettrich, Dörfel, Al-Batran, Karthaus, Pelzer, Hinke, Bauer, Massa, Seliger, Wickenhauser, Bokemeyer, Hegewisch-Becker, Binder and Stein.)

Purpose: This trial investigates the addition of panitumumab to chemotherapy with fluorouracil/folinic acid and oxaliplatin (FOLFOX) in a 2:1 randomised, controlled, open-label, phase II trial in RAS wild-type colorectal cancer patients with R0/1-resected liver metastases., Experimental Design: The primary endpoint was progression-free survival (PFS) two years after randomisation. The experimental arm (12 weeks of biweekly mFOLFOX6 plus panitumumab followed by 12 weeks of panitumumab alone) was considered active if the two-year PFS rate was ≥65%. Based on historical data, a two-year PFS rate of 50% was estimated in the control arm (12 weeks of biweekly FOLFOX). The trial was performed with a power of 80% and an alpha of 0.05. Secondary endpoints included overall survival (OS) and toxicity. The trial is registered with ClinicalTrials.gov, NCT01384994., Results: The full analysis set consists of 70 patients (pts) in the experimental arm and 36 pts in the control arm. The primary endpoint was missed with a two-year PFS of 35.7% with FOLFOX plus panitumumab and 30.6% in the control arm. In comparative analyses, trends towards improved PFS (HR 0.83; 95%CI, 0.52-1.33; P = 0.44) and OS (HR 0.70; 95% CI, 0.34-1.46; P = 0.34) were observed in favour of the panitumumab-based study arm. No new or unexpected safety signals were observed with FOLFOX plus panitumumab following liver resection., Conclusion: The PARLIM trial failed to demonstrate a two-year PFS rate of 65% after resection of colorectal liver metastases. The positive trends in survival endpoints may support future trials evaluating treatment with anti-EGFR agents after resection of liver metastases., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The overall survival of patients with advanced and refractory oesophageal squamous cell carcinoma, mostly aged 65 years and older, is poor. Treatment with PD-1 antibodies showed improved progression-free survival and overall survival. We assessed the safety and efficacy of combined nivolumab and ipilimumab therapy in this population., Methods: This multicentre, open-label, phase 2 trial done in 32 sites in Germany included patients aged 65 years and older with oesophageal squamous cell carcinoma and disease progression or recurrence following first-line therapy. Patients were treated with nivolumab (240 mg fixed dose once every 2 weeks, intravenously) in the safety run-in phase and continued with nivolumab and ipilimumab (nivolumab 240 mg fixed dose once every 2 weeks and ipilimumab 1 mg/kg once every 6 weeks, intravenously). The primary endpoint was overall survival, which was compared with a historical cohort receiving standard chemotherapy in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03416244., Findings: Between March 2, 2018, and Aug 20, 2020, we screened 75 patients with advanced oesophageal squamous cell carcinoma. We enrolled 66 patients (50 [76%] men and 16 [24%] women; median age 70·5 years [IQR 67·0-76·0]), 44 (67%) of whom received combined nivolumab and ipilimumab therapy and 22 (33%) received nivolumab alone. Median overall survival time at the prespecified data cutoff was 7·2 months (95% CI 5·7-12·4) and significantly higher than in a historical cohort receiving standard chemotherapy (p=0·0063). The most common treatment-related adverse events were fatigue (12 [29%] of 42), nausea (11 [26%]), and diarrhoea (ten [24%]). Grade 3-5 treatment-related adverse events occurred in 13 (20%) of 66 patients. Treatment-related death occurred in one patient with bronchiolitis obliterans while on nivolumab and ipilimumab treatment., Interpretation: Patients aged at least 65 years, with advanced oesophageal squamous cell carcinoma might benefit from combined nivolumab and ipilimumab therapy in second-line treatment., Funding: Bristol Myers Squibb., Competing Interests: Declaration of interests MPE reports receiving funding to conduct the trial from AIO Studien, the regulatory sponsor of the trial, and serving as an advisor with Bristol Myers Squibb. NMB reports receiving research funding and receipt of equipment from Deutsche Forschungsgemeinschaft. RH reports serving as an advisor with Amgen, Astra Zeneca, Bristol Myers Squibb, Boehringer, Daichi, Lilly, Merck, MSD, Pierre Fabre, Roche, and Servier; honoraria for lectures and presentations from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer, Daichi, Lilly, medac, Merck, MSD, Pierre Fabre, Roche, Saladax, Sanofi, and Servier; and consulting fees from Amgen, Astra Zeneca, Bayer, BMS, Boehringer, Daichi, Lilly, medac, Merck, MSD, Pierre Fabre, Roche, Saladax, Sanofi, and Servier. AV reports serving as an advisor with Roche, Bayer, Bristol Myers Squibb, Lilly, Eisai, AstraZeneca, IPSEN, MSD, Sirtex, BTG, Servier, Terumo, and Imaging Equipment; and consulting fees and honoraria for lectures from Roche, Bayer, Bristol Myers Squibb, Lilly, Eisai, Astra Zeneca, IPSEN, MSD, Sirtex, BTG, Servier, Terumo, and Imaging Equipment. RJ reports receiving consulting fees from Roche and Bayer; payments for lectures and presentations from Dr Falk Pharma and Bristol Myers Squibb; for writing of manuscripts from Boston Scientific and Springer Nature; serving as an advisor with Heidelberg University Hospital; and leading the Endoscopy section of the German Society of Gastroenterology. PTP reports receiving consulting fees from Bristol Myers Squibb, AstraZeneca, and MSD. TGa reports receiving honoraria from Bristol Myers Squibb, MSD, and Roche for presentations and advisory functions. JNK reports receiving consulting fees from Owkin and Panakeia as well as honoraria for lectures from MSD and Eisai. MM reports employment with AIO Studien, who was the regulatory sponsor of the trial. NH reports serving as an advisor with Bristol Myers Squibb. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: In a prospective non-interventional study involving 2,173 patients, we showed that use of the oral fixed combination of netupitant 300 mg and palonosetron 0.5 mg (NEPA) for prevention of chemotherapy (Ctx)-induced nausea and vomiting has beneficial effects on the quality of life (QoL) of patients with various types of cancers receiving highly or moderately emetogenic Ctx. Here, we report on the effects on QoL, effectiveness, and tolerability of NEPA in patients with breast cancer exposed to anthracycline-cyclophosphamide (AC)-based Ctx., Methods: This is a post hoc subanalysis of a prospective non-interventional study in 1,197 patients with breast cancer receiving up to 3 cycles of doxorubicin or epirubicin plus cyclophosphamide and NEPA. NEPA administration was per the summary of product characteristics., Results: In cycle 1 of Ctx, a large proportion of patients (84%) reported "no impact on daily life" (NIDL) due to vomiting; 53% of patients reported NIDL due to nausea. The complete response rate was 86/88/81% in the acute/delayed/overall phase in cycle 1, and NEPA was well tolerated throughout the study., Conclusion: The real-world beneficial effects of NEPA prophylaxis on QoL were confirmed for patients with breast cancer receiving AC. NEPA was effective with a good safety profile in this patient population in clinical practice., Competing Interests: J.S.: honoraria, travel expenses, RIEMSER Pharma GmbH. C.M.K.: honoraria, Amgen, Eli Lilly, Novartis, Mundipharma, Pfizer, PharmaMar, RIEMSER, Roche, Tesaro; consulting or advisory role, Amgen, Axios, Eli Lilly, Hilotherm, Mundipharma, NewCo, Novartis, Pfizer, RIEMSER, Roche, Tesaro; research funding, AstraZeneca, Axios, MSD Sharp & Dohme (Merck), NewCo, Novartis, Pfizer, PharmaMar, RIEMSER, Seattle Genetics, Immunomedics; travel, accommodations, expenses, Amgen, Hexal, Immunomedics, Pfizer, PharmaMar, Tesaro, Teva Oncology. C.H.: advisory board, AstraZeneca, Lilly, Pfizer, Roche. S.B.: lectures, studies and support for congress participation, Amgen, Roche, Novartis, Pfizer, Riemser, Lilly, Clovis, GSK, Onkovis, AstraZeneca, MSD. M.H.: honoraria, Pfizer, AstraZeneca, iOMEDICO, MMF, Amgen; research funding, RIEMSER, Indivumed. J.K.-S. and D.R.: nothing to disclose. E.F.: RIEMSER employee. M.K.: ad board, travel grant, Helsinn Healthcare, RIEMSER Pharma GmbH., (Copyright © 2021 by S. Karger AG, Basel.)

Chemotherapy-induced nausea and vomiting (CINV) is a common adverse event associated with many anticancer therapies and can negatively impact patients' quality of life and potentially limit the effectiveness of chemotherapy. Currently, CINV can be prevented in most patients with guideline-recommended antiemetic regimens. However, clinicians do not always follow guidelines, and patients often face difficulties adhering to their prescribed treatments. Therefore, approaches to increase guideline adherence need to be implemented. NEPA is the first and only fixed combination antiemetic, composed of netupitant (oral)/fosnetupitant (intravenous) and palonosetron, which, together with dexamethasone, constitute a triple antiemetic combination recommended for the prevention of CINV for patients receiving highly emetogenic chemotherapy and for certain patients receiving moderately emetogenic chemotherapy. Thus, NEPA offers a convenient and straightforward antiemetic treatment that could improve adherence to guidelines. This review provides an overview of CINV, evaluates the accumulated evidence of NEPA's antiemetic activity and safety from clinical trials and real-world practice, and examines the preliminary evidence of antiemetic control with NEPA in daily clinical settings beyond those described in pivotal trials. Moreover, we review the utility of NEPA in controlling nausea and preserving patients' quality of life during chemotherapy, two major concerns in managing patients with cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: The randomized PANAMA trial investigated the efficacy of panitumumab (Pmab) when added to maintenance therapy with fluorouracil and folinic acid (FU/FA) in patients with RAS wild-type metastatic colorectal cancer., Methods: Following first-line induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab, responding patients (stable disease or partial or complete remission) were randomly assigned (1:1, open-label) to maintenance treatment with either FU/FA plus Pmab or FU/FA alone. The primary objective was to demonstrate superiority of progression-free survival (PFS, time from random assignment until progression or death) in favor of FU/FA plus Pmab with a hazard ratio (HR) of 0.75, a power of 80%, and a significance level of 10%. Secondary end points included overall survival, objective response rate of maintenance therapy, and toxicity. Survival end points were analyzed by the Kaplan-Meier method and compared by log-rank test and Cox regressions. Dichotomous variables were compared by Fisher's exact test; odds ratios were indicated when appropriate. The trial is registered with ClinicalTrials.gov (NCT01991873)., Results: Overall, 248 patients were randomly assigned and received maintenance therapy with either FU/FA plus Pmab (125 patients) or FU/FA alone (123 patients). At data cutoff, with 218 events (of 218 needed), PFS of maintenance therapy was significantly improved with FU/FA plus Pmab (8.8 months v 5.7 months; HR, 0.72; 80% CI, 0.60 to 0.85; P = .014). Overall survival (event rate 54%) numerically favored the FU/FA plus Pmab arm (28.7 months v 25.7 months; HR, 0.84; 95% CI, 0.60 to 1.18; P = .32). Objective response rates were 40.8% in patients receiving FU/FA plus Pmab versus 26.0% in patients receiving FU/FA alone (odds ratio, 1.96; 95% CI, 1.14 to 3.36; P = .02). The most frequent Common Terminology Criteria for Adverse Event grade ≥ 3 event during maintenance therapy was skin rash (7.2%)., Conclusion: In RAS wild-type metastatic colorectal cancer, maintenance therapy with FU/FA plus Pmab induced a significantly superior PFS compared with FU/FA alone. If active maintenance therapy is aspired following induction therapy with FU/FA and oxaliplatin plus Pmab, FU/FA plus Pmab appears to be the most favorable option., Competing Interests: Dominik Paul ModestHonoraria: Merck Serono, Amgen, Roche, Servier, Bristol Myers Squibb, Taiho Pharmaceutical, Merck Sharp & Dohme, Pierre Fabre, Onkowissen, Sanofi, LillyConsulting or Advisory Role: Merck Serono, Amgen, Merck Sharp & Dohme, Roche, Servier, Incyte, Bristol Myers Squibb, Pierre Fabre, Lilly, Cor2Ed, IQvia, OnkowissenResearch Funding: Amgen, ServierTravel, Accommodations, Expenses: Amgen, Merck Serono, Servier Meinolf KarthausConsulting or Advisory Role: AmgenTravel, Accommodations, Expenses: Amgen Stefan FruehaufStock and Other Ownership Interests: AbbVie, Bristol Myers Squibb/Pfizer, Johnson & Johnson/Janssen, Merck Ullrich GraevenHonoraria: Daiichi Sankyo, Boehringer Ingelheim, Amgen, Servier, AstraZeneca, Bristol Myers Squibb, MSD OncologyConsulting or Advisory Role: Merck KGaA, Bristol Myers Squibb, Hexal, Amgen, Celgene, Johnson & Johnson, MSD OncologyTravel, Accommodations, Expenses: Merck KGaA, Amgen, Boehringer Ingelheim, GlaxoSmithKline Lothar MüllerHonoraria: Roche Alexander Otto KönigHonoraria: Ipsen, Pierre FabreConsulting or Advisory Role: Roche Pharma AG Ludwig Fischer von WeikersthalHonoraria: Novartis, Roche Pharma AG, AstraZeneca, Pierre Fabre, Lilly GmbH Albrecht KretzschmarHonoraria: Roche Pharma AG, Merck Serono, Shire, Amgen, Medac, Servier, Sanofi, MSD, Bristol Myers Squibb, Bayer Schering Pharma, Aspen Pharma, Roche PharmaConsulting or Advisory Role: Roche Pharma AG, Shire, AmgenTravel, Accommodations, Expenses: PharmaMar, Merck Serono, Ipsen, Medac Eray GoekkurtConsulting or Advisory Role: MSD, Bristol Myers Squibb, Roche, Sanofi Annika KurreckHonoraria: ServierTravel, Accommodations, Expenses: Roche, Medac Arndt StahlerHonoraria: Roche, Servier, Taiho PharmaceuticalTravel, Accommodations, Expenses: Amgen, Roche, Lilly, Pfizer Anke Reinacher-SchickHonoraria: Amgen, Roche, Pfizer, Sanofi/Aventis, Merck Serono, Celgene, Lilly, Bristol Myers Squibb, Servier, MSD, Aurikamed, IOMEDICO, Promedicis, MCI Group, AstraZenecaConsulting or Advisory Role: Amgen, Roche, Pfizer, Merck Serono, Celgene, Bristol Myers Squibb, Servier, Baxalta, MSD, AstraZeneca, Pierre FabreResearch Funding: Roche, Celgene, Ipsen, Amgen, Alexion Pharmaceuticals, AstraZeneca, Lilly, Servier, AIO-Studien, Georgius Agricola Stiftung Ruhr, Rafael Pharmaceuticals, ERYTECH Pharma, BioNTechTravel, Accommodations, Expenses: Ipsen, Amgen, Roche, Servier, MCI Group, Pierre Fabre, AstraZeneca, Merck Serono, MSD Stefan KasperHonoraria: Bristol Myers Squibb, MSD Oncology, AstraZeneca, Merck Serono, Amgen, Roche, Servier, Lilly, Sanofi/AventisConsulting or Advisory Role: Roche, Merck Serono, Amgen, MSD Oncology, Sanofi, Bristol Myers Squibb, Lilly, AstraZeneca, Servier, Janssen-CilagResearch Funding: Merck Serono, Bristol Myers Squibb, Celgene, Lilly, Servier, Roche/GenentechTravel, Accommodations, Expenses: Merck Serono, Lilly, Amgen, Sanofi, RocheOther Relationship: Sanofi, Amgen, Merck Serono, Bristol Myers Squibb, Roche, Lilly Volker HeinemannHonoraria: Roche, Celgene, Amgen, Sanofi, Merck, Sirtex Medical, Baxalta, Lilly, Boehringer Ingelheim, Taiho Pharmaceutical, ServierConsulting or Advisory Role: Merck, Amgen, Roche, Sanofi, Boehringer Ingelheim, Celgene, Sirtex Medical, Baxalta, Servier, Halozyme, MSD, Bristol-Myers Squibb, MSD OncologyResearch Funding: Merck, Amgen, Roche, Celgene, Boehringer Ingelheim, Sirtex Medical, Shire, ServierTravel, Accommodations, Expenses: Merck, Roche, Sirtex Medical, Amgen, Servier, Shire, MSD, Bristol Myers Squibb Sebastian StintzingHonoraria: Merck KGaA, Roche, Amgen, Bayer, Sanofi, Lilly, Pierre Fabre, Takeda, Taiho Pharmaceutical, Servier, MSDConsulting or Advisory Role: Merck KGaA, Roche, Sanofi, Bayer, Amgen, Boehringer Ingelheim, Lilly, Takeda, MSD, Servier, Pierre FabreResearch Funding: Pierre Fabre, Roche Molecular Diagnostics, Merck SeronoTravel, Accommodations, Expenses: Merck KGaA, Roche, Sanofi, Bayer, Sirtex Medical, Amgen, Lilly, Takeda, Pierre Fabre Tanja TrarbachResearch Funding: AmgenTravel, Accommodations, Expenses: Ipsen, Takeda, OMT, AbbVie, Novartis, MSD, Sanofi/Aventis, Amgen, Johnson & Johnson/JanssenNo other potential conflicts of interest were reported.