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Purpose In 2016, the University of Munich Molecular Tumor Board (MTB) was implemented to initiate a precision oncology program. This review of cases was conducted to assess clinical implications and functionality of the program, to identify current limitations and to inform future directions of these efforts. Methods Charts, molecular profiles, and tumor board decisions of the first 1000 consecutive cases (01/2016–03/2020) were reviewed. Descriptive statistics were applied to describe relevant findings. Results Of the first 1000 patients presented to the MTB; 914 patients received comprehensive genomic profiling. Median age of patients was 56 years and 58% were female. The most prevalent diagnoses were breast (16%) and colorectal cancer (10%). Different types of targeted or genome-wide sequencing assays were used; most of them offered by the local department of pathology. Testing was technically successful in 88%. In 41% of cases, a genomic alteration triggered a therapeutic recommendation. The fraction of patients receiving a tumor board recommendation differed significantly between malignancies ranging from over 50% in breast or biliary tract to less than 30% in pancreatic cancers. Based on a retrospective chart review, 17% of patients with an MTB recommendation received appropriate treatment. Conclusion Based on these retrospective analyses, patients with certain malignancies (breast and biliary tract cancer) tend to be more likely to have actionable variants. The low rate of therapeutic implementation (17% of patients receiving a tumor board recommendation) underscores the importance of meticulous follow-up for these patients and ensuring broad access to innovative therapies for patients receiving molecular tumor profiling.

Analyses of tumor response to treatment with Dox and different doses of pHPMA-Dox conjugate in the A2780cis tumor model.

Analyses of tumor microenvironment in the 1411HP and A2780cis tumor model.

Survival plot (Kaplan-Meier) for the therapy study with 1411HP tumor-bearing mice. Cum. survival of mice under respective therapy (PBS, free Dox, pHPMA-Dox conjugate and pHPMA precursor) is displayed.

Physico-chemical characterization of pHPMA conjugates

pH dependent development of cytotoxicity (SRB-assay) of the copolymer-Dox conjugate in 1411HP and A2780cis cells.

The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing doxorubicin attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention effect and (II) pH-sensitive site-specific drug release due to an acidic tumor microenvironment. Mice bearing doxorubicin-resistant xenograft tumors were treated with doxorubicin, PBS, poly HPMA (pHPMA) precursor or pHPMA–doxorubicin conjugate at different equivalent doses of 5 mg/kg bodyweight doxorubicin up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of doxorubicin. Free doxorubicin induced significant toxicity but hardly any tumor-inhibiting effects. Administering at least a 3-fold dose of pHPMA–doxorubicin conjugate was necessary to induce a transient response, whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model, which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging–based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the current study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance. Mol Cancer Ther; 15(5); 998–1007. ©2016 AACR.

Supplemental material including synthesis of the polymer-drug conugates and Supplementary Figure Legends.

Development of mouse body weight under respective therapy over time.

Summary 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 ( 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; 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).

Background The XELAVIRI trial compared sequential (fluoropyrimidine and bevacizumab; irinotecan (Iri) at progression) versus initial combination therapy (fluoropyrimidine, bevacizumab, Iri) of treatment-naive metastatic colorectal cancer (mCRC). In the confirmatory analysis, the primary end-point (non-inferiority of sequential therapy regarding time to failure of strategy, TFS) was not met. Nevertheless, significant differences regarding treatment efficacy were observed according to RAS status. Here, we evaluate the consensus molecular subtypes (CMS) as additional biomarkers for sequential versus combination therapy. Material and methods Gene expression was measured using NanoString after mRNA extraction from formalin-fixed paraffin-embedded tumour specimens. CMS were predicted using multinomial regression and correlated with updated data for TFS, overall (OS) and progression-free survival. Results CMS were predicted in 337 of 421 (80.0%) patients (CMS1: 18.4%; CMS2: 51.6%; CMS3: 2.7%; CMS4: 27.3%). CMS2 together with RAS/BRAF wild-type status was identified as potential predictive marker of benefit from initial combination therapy for OS (HR 0.56, 95% CI 0.33–0.96, p = 0.036) and progression-free survival (HR 0.28, 95% CI 0.29–0.79, p = 0.004) and also trending in TFS (HR 0.63, 90% CI 0.41–0.95, p = 0.066). In patients with RAS-mutated mCRC, CMS1 was associated with longer OS after initial combination therapy (HR 0.43, 95% CI 0.20–0.95, p = 0.038). Interaction testing (two-sided) of CMS and RAS/BRAF status in favour of the combination treatment strategy was significant for OS (p = 0.012) Conclusions In patients with RAS/BRAF wild-type mCRC, CMS2 may serve as an additional biomarker of benefit from the initial combination therapy, including Iri. Trial registration Trial registration ID ( clinicaltrials.gov ) NCT01249638 .

Immunotherapy with checkpoint inhibitors - monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4) or the programmed death-1 receptor (PD-1) and its ligand PD-L1 - is now standard of care in the treatment of patients with various tumor types. Therefore, the management of immune-related adverse events (irAEs) has become part of clinical routine.Immune-related adverse events can involve any organ or tissue. They can occur very early within days or weeks after initiation of treatment but can also occur months into treatment and after termination of treatment. Newest data suggest that irAEs can occur until 2 years after stopping therapy.Immune-related adverse events are graded according to Common Terminology Criteria for Adverse Events (CTCAE). Treatment ranges from local or symptomatic treatment, systemic application of corticosteroids to other immunosuppressive agents according to severity.The following article seeks to give a general approach to the management of patients receiving immunotherapy and experiencing irAEs including prevention, diagnostics and treatment.

Secondary resection of metastases is recommended in metastatic colorectal cancer (mCRC). Data describing changes in mutational profiles of corresponding primary tumor and metastatic tissue after conversion treatment are limited. Next generation sequencing was performed in formalin-fixed mCRC samples from patients of the FIRE-3 trial (FOLFIRI plus cetuximab or bevacizumab) before treatment start (baseline) and after secondary resection of metastases (post baseline). Changes of mutational profiles and tumor mutational burden (TMB) were assessed within a post-hoc analysis. Median overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were compared between treatment arms. Paired tumor samples were obtained from 25 patients (19 RAS wild-type, 6 RAS mutant by pyrosequencing). ORR (92.0% vs 58.0%) and OS (60.8 vs 35.4 months, hazard ratio = 0.39 [95% CI 0.14-1.12], P = .08) were higher for patients receiving cetuximab. After conversion therapy, 56 alterations (42 in the cetuximab and 14 in the bevacizumab arm) were newly observed in 18 patients (9 each treated with cetuximab or bevacizumab). Gains (n = 21) and losses (n = 21) of alterations occurred during cetuximab-based treatment, while mainly gains of alterations occurred during bevacizumab (n = 10). Three of nine patients treated with cetuximab that presented a change of mutational profiles, developed resistance to cetuximab. Mutational profiles were largely comparable before and after treatment with anti-VEGF or anti-EGFR directed monoclonal antibodies after secondary resection. Mutations associated with resistance to anti-EGFR antibodies were observed in only one-third of patients.

Background Tumor assessments after first-line therapy of RAS wild-type mCRC with cetuximab (cet) versus bevacizumab (bev) in combination with FOLFIRI were evaluated for factors influencing resectability, conversion to resectability, and survival after best response. Methods Conversion to resectability was defined as conversion of initially unresectable to resectable disease at best response as determined by retrospective assessment. Univariate and multivariate logistic models were fitted with resectability at best response as response variable. A Cox model comparing the survival from best response was used to measure the influence of treatment, resectability at best response, and resection. Interaction of resection and treatment arm on survival was tested by likelihood ratio test. Results Overall, 270 patients were evaluable (127 cet-arm, 143 bev-arm). Lung metastases (odds ratio [OR] 0.35, 95% confidence response [CI] 0.19–0.63), BRAF mutation (OR 0.33, 95% CI 0.12–0.82), and elevated alkaline phosphatase (OR 0.42, 95% CI 0.18–0.9) before randomization were associated with less chance of successful conversion and were integrated into a nomogram. Early tumor shrinkage (OR 1.86, 95% CI 1.06–3.3; p 0.034) and depth of response (OR 1.02, 95% CI 1.01–1.03; p p = 0.039), predominantely in cet-treated patients (interaction test, p = 0.02). Conclusions Conversion to resectability is significantly associated with baseline characteristics that can be used in a nomogram to predict conversion. Moreover, early efficacy parameters (ETS and DpR) are associated with successful conversion therapy. In FIRE-3, resection of metastases was associated with improved post-best response survival, this effect originated predominantly from the cetuximab-based study arm.

100 Background: FIRE-4 (AIO KRK-0114) is performed in RAS wild-type (wt) mCRC patients. This randomized study tests the efficacy of early switch maintenance during 1st-line therapy (part 1) and re-challenge with cetuximab (part 2) in later-line treatment. In part 1, all patients received first-line induction treatment with FOLFIRI plus cetuximab (FOLFIRI/Cet). In arm A, patients were randomized to continue FOLFIRI/Cet until progression or intolerable toxicity. In arm B, patients received FOLFIRI/Cet for 8-12 cycles, after which maintenance therapy with 5-FU/FA plus bevacizumab (5-FU/Bev) was applied. The first randomization evaluates the question if an early switch from cetuximab to bevacizumab during maintenance therapy may prolong PFS. The study protocol explicitly allowed a first cycle of chemotherapy to be applied before randomization. Methods: Within this randomized, controlled, open-label phase-III study, patients received FOLFIRI (irinotecan plus 5-FU/FA) plus cetuximab every two weeks at the standard dosing schedule. In arm A, FOLFIRI plus cetuximab was continued until progression or intolerable toxicity. De- and re-escalation was allowed according to the local standard of care. In arm B, patients received 8 cycles of FOLFIRI plus cetuximab (in case of tumor response) or 12 cycles (in case of stable disease) followed by maintenance with 5-FU/FA plus bevacizumab (5mg/kg) until disease progression or intolerable toxicity. Overall survival after second randomization (part 2) is evaluated as a primary endpoint. Here, we report PFS in first-line (part 1) as a secondary study endpoint of the study. Other secondary endpoints included ORR, OS, safety, and tolerability. Results: From August 2015 to January 2021, 672 patients were randomized, and 656 patients were assigned to treatment in 120 German and 10 Austrian centers (327 arm A and 329 in arm B). Of those, 205 patients received one cycle of FOLFIRI alone before randomization. In both arms, ORR was comparable for patients receiving cetuximab from the first cycle when compared to those receiving one cycle of chemotherapy only (arm A: 58.7% vs 62.9% (p = 0.54), arm B 60.2% vs 55.6% (p = 0.48). PFS was also not influenced in both arms (arm A: 10.8mo vs. 10.6mo (p = 0.91); arm B 11.2mo vs. 11.4mo (p = 0.62)). Preliminary results suggest that also OS (event rate 38.3%) was not influenced by one cycle applied without cetuximab (arm A: 33.7 mo vs. 29.1 mo (p = 0.20); arm B: 35.6 mo vs. 28.9 mo (p = 0.13)). Conclusions: Application of one initial cycle with chemotherapy alone did not influence the efficacy of a first-line strategy of FOLFIRI plus cetuximab. If RAS mutational analysis is not timely available, a start with FOLFIRI alone adding cetuximab in cycle 2 seems to be safe with respect of overall efficacy. Clinical trial information: NCT02934529 .

Immunotherapy with checkpoint inhibitors - monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4) or the programmed death-1 receptor (PD-1) and its ligand PD-L1 - is now standard of care in the treatment of patients with various tumor types. Therefore, the management of immune-related adverse events (irAEs) has become part of clinical routine.Immune-related adverse events can involve any organ or tissue. They can occur very early within days or weeks after initiation of treatment but can also occur months into treatment and after termination of treatment. Newest data suggest that irAEs can occur until 2 years after stopping therapy.Immune-related adverse events are graded according to Common Terminology Criteria for Adverse Events (CTCAE). Treatment ranges from local or symptomatic treatment, systemic application of corticosteroids to other immunosuppressive agents according to severity.The following article seeks to give a general approach to the management of patients receiving immunotherapy and experiencing irAEs including prevention, diagnostics and treatment.

CAR-T-Zell-Therapien haben Eingang in die hamatoonkologische Standardbehandlung gefunden. CAR-T-Zellen, die gegen das CD19-Antigen gerichtet sind, wurden zur Therapie refraktarer akuter lymphatischer Leukamien und hochmaligner B-Zell-Lymphome auf Basis hoher Ansprechraten zugelassen. Diesen potenten Therapien stehen starke Nebenwirkungen gegenuber, die sich deutlich von denen konventioneller Verfahren unterscheiden. Ziel dieser Ubersichtsarbeit ist es, einen Uberblick uber diese Nebenwirkungen und deren Behandlung zu geben.

Das Prinzip der Prazisionsonkologie beruht heute im Wesentlichen auf einer sich standig verfeinernden molekularen Charakterisierung von Tumoren. Im Idealfall bedingt diese Charakterisierung eine personalisierte, zielgerichtete, molekular gesteuerte medikamentose Behandlung. In diesem Kontext verschiebt sich das diagnostische Spektrum zunehmend in Richtung einer breiten genomischen Charakterisierung mittels neuer massiv paralleler Sequenziertechnologien („next generation sequencing“). Diese Weiterentwicklung birgt jedoch nicht nur Chancen fur die onkologische Patientenversorgung, sondern bringt auch eine Reihe von inhaltlichen und strukturellen Herausforderungen mit sich, die nur durch eine enge interdisziplinare Zusammenarbeit gemeistert werden konnen. In diesem Ubersichtsartikel sollen verschiedene Aspekte der breiteren Genomanalyse maligner Tumoren zusammenfassend beleuchtet und diskutiert werden. Zudem wird – auf dieser Basis – ein Blick in die nahe Zukunft der Prazisionsonkologie geworfen.

The speed and spread of the COVID-19 pandemic has been affecting the entire world for the past several months. OncoAlert is a social media network made up of more than 140 oncology stakeholders: oncologists (medical, radiation, and surgical), oncology nurses, and patient advocates who share the mission of fighting cancer by means of education and dissemination of information. As a response to the COVID-19 pandemic, OncoAlert hosted The Round Table Discussions. We have documented this effort along with further discussion about the COVID-19 pandemic and the consequences on patients living with cancer to disseminate this information to our colleagues worldwide. ispartof: JCO GLOBAL ONCOLOGY vol:7 pages:455-463 ispartof: location:United States status: published

BackgroundPrimary tumor location (left vs. right) has prognostic and predictive impact on the therapeutic management of metastatic colorectal cancer (mCRC) in particular in the context of anti-epithelial growth factor receptor (anti-EGFR) antibodies. This analysis evaluates the relevance of exact segment-by-segment tumor location in patients with metastatic colorectal cancer on outcome and efficacy of anti-EGFR-antibodies.MethodsThis is a retrospective, pooled analysis of five randomized clinical trials (FIRE-1, CIOX, FIRE-3, XELAVIRI and VOLFI) treating metastatic colorectal cancer patients in a first-line setting, published between 2011-2019. Each trial was a multicentre, phase 2 or phase 3 trial in which patients with untreated metastatic colorectal cancer received chemotherapy regimens with or without monoclonal antibodies (anti-VEGF, anti-EGFR). Eligible were patients with histologically confirmed metastatic colorectal cancer in good performance status who were at least 18 years old. Individual data of 1809 patients with available exact primary tumor location were included into this analysis. Prognostic and predictive effects of primary tumor location were evaluated in uni- and multivariate analyses using the Kaplan Meier method, log rank tests, Cox regressions and logistic regressionsResults Exact primary tumor location is an important determinant of overall survival (OS) in mCRC patients (PConclusions Primary tumor location of metastatic colorectal cancer affects prognosis. Anti-EGFR efficacy increases continuously from proximal to distal segments of the colorectum in metastatic colorectal cancer patients with RAS/BRAF wild-type and BRAF mutant tumors. Therefore, patients with BRAF mutant tumors of the distal segments may benefit from first-line Anti-EGFR-based therapy.Trial registrationFIRE1 trial registration ID n/aCIOX trial registration ID NCT00254137FIRE3 trial registration ID NCT00433927XELAVIRI trial registration ID NCT01249638VOLFI trial registration ID NCT01328171

Secondary resection of metastases is recommended in metastatic colorectal cancer (mCRC). Data describing changes in mutational profiles of corresponding primary tumor and metastatic tissue after conversion treatment are limited. Next generation sequencing was performed in formalin-fixed mCRC samples from patients of the FIRE-3 trial (FOLFIRI plus cetuximab or bevacizumab) before treatment start (baseline) and after secondary resection of metastases (post baseline). Changes of mutational profiles and tumor mutational burden (TMB) were assessed within a post-hoc analysis. Median overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were compared between treatment arms. Paired tumor samples were obtained from 25 patients (19 RAS wild-type, 6 RAS mutant by pyrosequencing). ORR (92.0% vs 58.0%) and OS (60.8 vs 35.4 months, hazard ratio = 0.39 [95% CI 0.14-1.12], P = .08) were higher for patients receiving cetuximab. After conversion therapy, 56 alterations (42 in the cetuximab and 14 in the bevacizumab arm) were newly observed in 18 patients (9 each treated with cetuximab or bevacizumab). Gains (n = 21) and losses (n = 21) of alterations occurred during cetuximab-based treatment, while mainly gains of alterations occurred during bevacizumab (n = 10). Three of nine patients treated with cetuximab that presented a change of mutational profiles, developed resistance to cetuximab. Mutational profiles were largely comparable before and after treatment with anti-VEGF or anti-EGFR directed monoclonal antibodies after secondary resection. Mutations associated with resistance to anti-EGFR antibodies were observed in only one-third of patients.

3502 Background: FIRE-4.5 (AIO KRK-0116) compared FOLFOXIRI plus either cetuximab or bevacizumab in BRAF V600E-mutant metastatic colorectal cancer (mCRC) patients not treated for metastatic disease before. Methods: Within this 1:2 randomized, controlled, open-label phase-II study, patients received FOLFOXIRI every two weeks at the following schedule: irinotecan 150mg/m² (30-90min, day 1), folinic acid 400mg/m² (120min, day 1), oxaliplatin 85mg/m² (120 min, day 1), followed by 5-fluorouracil 3,000 mg/m², 48h. FOLFOXIRI was combined with either bevacizumab (arm A) at a dose of 5mg/kg body weight, every 2 weeks or cetuximab (arm B) at a loading dose of 400mg/m² and subsequent weekly doses of 250mg/m². FOLFOXIRI was applied for a maximum of 12 cycles before maintenance treatment was recommended. Primary endpoint was superiority of Arm B with respect to overall response rate (ORR) according to RECIST 1.1 criterions. Secondary endpoints included PFS, OS, and tolerability. Results: From November 2016 to December 2020 108 patients were randomized in 90 German and 10 French centers (35 arm A and 73 in arm B). No new or unexpected toxicities were observed. Primary endpoint was not met with an ORR of 66.7% and 52.0% (p =0.23) in the respective arms. Median PFS was significantly longer in arm A vs arm B (8.3 months vs 5.9 months; logrank p = 0.03; HR 1.8). While OS data is still immature, median OS time are comparable at the time of analysis. Patients with left-sided primary tumors had comparable results with either bevacizumab or cetuximab, whereas those with right-sided primary tumors showed a trend towards better efficacy of the bevacizumab combination. Updated results will be presented at the annual meeting. Conclusions: FIRE-4.5 is the first prospective and randomized study investigating efficacy of FOLFOXIRI combined with targeted therapy in the first-line treatment of BRAF V600E-mutant mCRC. FOLFOXIRI plus either bevacizumab or cetuximab have comparable efficacy with differential effects according to primary tumor sidedness supporting the heterogeneity of BRAF V600E-mutant subpopulation of mCRC. Clinical trial information: NCT04034459.

XELAVIRI compared sequential (Arm A) versus initial (Arm B) irinotecan in combination with fluoropyrimidine plus bevacizumab in patients with metastatic colorectal cancer, trial identification: NCT01249638. In the full analysis set of the study, non-inferiority of time to failure of strategy (TFS) was not shown. The present analysis was performed to evaluate the effect of gender on treatment outcome and tolerability.The study end-points overall response rate (ORR), progression-free survival (PFS), TFS and overall survival (OS) were evaluated in female versus male patients and in molecular subgroups (i.e. RAS mutational status). Interaction of treatment and gender was tested by likelihood ratio tests.In total, 281 male and 140 female patients (n = 421) were evaluated. Among the male patients, the ORR was 33.6% without and 58.3% with initial irinotecan (P 0.001). PFS (hazard ratio [HR] 0.54; 95% confidence interval [CI] 0.42-0.69; P 0.001) and OS (HR 0.63; 95% CI 0.47-0.85; P = 0.002) were also significantly better with initial irinotecan. Among the female patients, the ORR was 42.7% in Arm A and 43.1% in Arm B, PFS was similar (HR 1.09; 95% CI 0.76-1.55; P = 0.649) without and with initial irinotecan. A strong trend for inferior outcome with regard to OS with initial irinotecan was observed (HR 1.46; 95% CI 0.95-2.24; P = 0.081) and the trend reached significance in the multivariate analysis (HR 1.78; 95% CI 1.08-2.95; P = 0.02). Formal interaction of treatment and gender was observed for ORR (P = 0.018), PFS (P = 0.002) and OS (P = 0.001). Treatment-related adverse events were not significantly different between male and female patients.The present analysis suggests that gender interacts with efficacy of initial irinotecan when used in combination with fluoropyrimidines and bevacizumab. Although male patients derived a significant and clinically meaningful benefit from initial combination chemotherapy, this was not observed in female patients.

Magnesium wasting is a frequent side effect of epidermal growth factor receptor (EGFR)-antibody treatment as magnesium-absorption mechanisms are dependent on EGFR signaling. EGFR-inhibition results in decreased renal reabsorption. There is evidence that hypomagnesemia during cetuximab treatment correlates with response. The prognostic role of hypomagnesemia during bevacizumab treatment has not been studied yet. Here, we evaluate the prognostic value of hypomagnesemia in patients with metastatic colorectal cancer treated with FOLFIRI plus cetuximab or bevacizumab as first-line therapy. A total of 391 of 752 patients of the firstline irinotecan study population had magnesium levels measured at baseline and for the first three cycles (6 weeks) of treatment. Of those, 240 had Rat Sarkoma wildtype tumors. Overall hypomagnesemia was more common in the cetuximab compared to the bevacizumab arm (80 vs. 43%, P < 0.005). During therapy, magnesium showed a time-dependent decrease to 80% of baseline in the cetuximab and to 89% in the bevacizumab arm. Whereas magnesium continued to decrease over time in the cetuximab-treated patients, it remained stable in the bevacizumab-treated. Overall response rate (ORR) was associated with higher magnesium at week 6 (20.9 vs. 79.1%, P = 0.041). Bevacizumab-treated patients with magnesium levels below the median value at week 6 had a significantly longer progression-free survival (PFS; 11.7 vs. 9.9 months, P = 0.034; hazard ratio 0.73) and a trend towards longer overall survival (OS) (29.6 vs. 23.2 months, P = 0.089; hazard ratio 0.77). Hypomagnesemia at predefined time points and magnesium nadir had no significant effect on ORR, OS and PFS in the cetuximab arm. Our data show different magnesium kinetics in patients with metastatic colorectal cancer treated with cetuximab or bevacizumab. For patients treated with cetuximab, hypomagnesemia did not have an impact on response and survival. Hypomagnesemia might have a prognostic value in bevacizumab treatment.