Mutational profiles of metastatic colorectal cancer treated with FOLFIRI plus cetuximab or bevacizumab before and after secondary resection (AIO KRK 0306; FIRE-3).

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.

Factors That Influence Conversion to Resectability and Survival After Resection of Metastases in RAS WT Metastatic Colorectal Cancer (mCRC): Analysis of FIRE-3- AIOKRK0306.

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 < 0.001) were associated with successful conversion therapy. Resection of metastases improved post-best-response survival (hazard ratio 0.53, 95% CI 0.29-0.97; 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.

Predictive and prognostic value of magnesium serum level in FOLFIRI plus cetuximab or bevacizumab treated patients with stage IV colorectal cancer: results from the FIRE-3 (AIO KRK-0306) study.

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.

Treatment of advanced gastrointestinal cancer with genetically modified autologous mesenchymal stem cells: Results from the phase 1/2 TREAT-ME-1 trial.

TREAT-ME-1, a Phase 1/2 open-label multicenter, first-in-human, first-in-class trial, evaluated the safety, tolerability and efficacy of treatment with genetically modified autologous mesenchymal stromal cells (MSC), MSC_ apceth_101, in combination with ganciclovir in patients with advanced gastrointestinal adenocarcinoma. Immunological and inflammatory markers were also assessed. All patients (3 in Phase 1; 7 in Phase 2) received three treatment cycles of MSC_apceth_101 at one dose level on Day 0, 7, and 14 followed by ganciclovir administration according to the manufacturer's instructions for 48─72 h after MSC_apceth_101 injection. Ten patients were treated with a total dose of 3.0 x 106 cells/kg MSC_apceth_101. 36 adverse events and six serious adverse events were reported. Five patients achieved stable disease (change in target lesions of -2 to +28%). For all patients, the median time to progression was 1.8 months (95% CI: 0.5, 3.9 months). Median overall survival could not be estimated as 8/10 patients were still alive at the end of the study (1 year) and therefore censored. Post-study observation of patients showed a median overall survival of 15.6 months (ranging from 2.2─27.0 months). Treatment with MSC_apceth_101 and ganciclovir did not induce a consistent increase or decrease in levels of any of the tumor markers analyzed. No clear trends in the immunological markers assessed were observed. MSC_apceth_101 in combination with ganciclovir was safe and tolerable in patients with advanced gastrointestinal adenocarcinoma, with preliminary signs of efficacy in terms of clinical stabilization of disease.

Relevance of liver-limited disease in metastatic colorectal cancer: Subgroup findings of the FIRE-3/AIO KRK0306 trial.

In metastatic colorectal cancer (mCRC), liver-limited disease (LLD) is associated with a higher chance of metastectomy leading to long-term survival. However, limited data describes the prognostic and predictive relevance of initially unresectable LLD with regard to targeted first-line therapy. The present analysis investigated the relevance of initially unresectable LLD in mCRC patients treated with targeted therapy against either the epidermal growth factor receptor (EGFR) or vascular epithelial growth factor (VEGF). The analysis was performed based on FIRE-3, a randomized phase III trial comparing first-line chemotherapy with FOLFIRI plus either cetuximab (anti-EGFR) or bevacizumab (anti-VEGF) in RAS wild-type (WT) mCRC. Of 400 patients, 133 (33.3%) had LLD and 267 (66.8%) had non-LLD. Median overall survival (OS) was significantly longer in LLD compared to non-LLD patients (36.0 vs. 25.4 months; hazard ratio [HR] = 0.66; 95% confidence interval [CI]: 0.51-0.87; p = 0.002). In a multivariate analysis also including secondary hepatic resection as time-dependent variable, LLD status was independently prognostic for OS (HR = 0.67; 95% CI: 0.50-0.91; p = 0.01). As assessed by interaction tests, treatment benefit from FOLFIRI plus cetuximab compared to FOLFIRI plus bevacizumab was independent of LLD status with regard to objective response rate (ORR), early tumour shrinkage ≥20% (ETS), depth of response (DpR) and OS (all p > 0.05). In conclusion, LLD could be identified as a prognostic factor in RAS-WT mCRC, which was independent of hepatic resection in patients treated with targeted therapy. LLD had no predictive relevance since benefit from FOLFIRI plus cetuximab over bevacizumab was independent of LLD status.

Relation of early tumor shrinkage (ETS) observed in first-line treatment to efficacy parameters of subsequent treatment in FIRE-3 (AIOKRK0306).

We explored the association of early tumor shrinkage (ETS) and non-ETS with efficacy of first-line and consecutive second-line treatment in patients with KRAS wild-type metastatic colorectal cancer treated in FIRE-3. Assessment of tumor shrinkage was based on the sum of longest diameters of target lesions, evaluated after 6 weeks of treatment. Shrinkage was classified as ETS (shrinkage by ≥ 20%), mETS (shrinkage by 0 to <20%), mPD (minor progression >0 to <20%) and PD (progression ≥20%). Overall survival (OS) was 33.2 (95% CI 28.0-38.4) months in ETS patients, while non-ETS was associated with less favorable outcome (mETS 24.0 (95% CI 21.2-26.9) months, mPD 19.0 (95% CI 13.0-25.0) months, PD 12.8 (95% CI 11.1-14.5) months). Differences in PFS of first-line therapy were less pronounced. ETS subgroups defined in first-line therapy also correlated with efficacy of second-line therapy. Progression-free survival in second-line (PFS2nd) was 6.5 months (5.8-7.2) for ETS, and was 5.6 (95% CI 4.7-6.5) months for mETS, 4.9 (95% CI 3.7-6.1) months for mPD and 3.3 (95% CI 2.3-4.3) months for PD. PFS of first-line and PFS2nd showed a linear correlation (Bravais-Pearson coefficient: 0.16, p = 0.006). While ETS is associated with the most favorable outcome, non-ETS represents a heterogeneous subgroup with distinct characteristics of less favorable initial tumor response to treatment. This is the first analysis to demonstrate that early tumor response observed during first-line FOLFIRI-based therapy may also relate to efficacy of second-line treatment. Early response parameters may serve as stratification factors in trials recruiting pretreated patients.

Prevalence and influence on outcome of HER2/neu, HER3 and NRG1 expression in patients with metastatic colorectal cancer.

Our aim was to explore the impact of the HER2/neu, HER3 receptor as well as their ligands' neuregulin (NRG1) expression on the outcome of patients with metastatic colorectal cancer (mCRC). NRG1, HER2/neu and HER3 expression was evaluated in 208 patients with mCRC receiving 5-FU/LV plus irinotecan or irinotecan plus oxaliplatin as the first-line treatment. Biomarker expression was correlated with the outcome of patients. NRG1 (low: 192 vs. high: 16), HER2/neu (low: 201 vs. high: 7) and HER3 (low: 69 vs. high: 139) expressions were assessed in 208 patients. High versus low NRG1 expression significantly affected progression-free survival (PFS) [4.7 vs. 8.2 months, hazard ratio (HR): 2.45; 95% confidence interval (CI): 1.45-4.13; P=0.001], but not overall survival (OS) (15.5 vs. 20.7 months, HR: 1.33; 95% CI: 0.76-2.35; P=0.32). High versus low HER3 expression (PFS: 7.1 vs. 8.8 months, HR: 1.11; 95% CI: 0.82-1.50; P=0.50; OS: 19.8 vs. 21.1 months, HR: 0.95; 95% CI: 0.70-1.30; P=0.75) and high compared with low HER2/neu expression (PFS: 7.7 vs. 8.0 months, HR: 1.07; 95% CI: 0.71-1.60; P=0.75; OS: 16.6 vs. 21.1 months, HR: 1.13; 95% CI: 0.75-1.71; P=0.57) did not influence outcome. High NRG1 expression was associated with inferior PFS in the FIRE-1 trial. We did not detect a prognostic impact of HER2/neu and HER3 overexpression in mCRC. The frequency of overexpression was comparable with other studies.

Assessing novel prognostic serum biomarkers in advanced pancreatic cancer: the role of CYFRA 21-1, serum amyloid A, haptoglobin, and 25-OH vitamin D3.

The present prospective single-center study investigated the prognostic role of novel serum biomarkers in advanced pancreatic cancer (PC). Patients (pts) with locally advanced or metastatic PC treated with first-line palliative chemotherapy were included. Among others, the serum markers CYFRA 21-1, haptoglobin, serum-amyloid A (SAA), and 25-OH vitamin D3 were determined at baseline and categorized by pre-defined cut-offs [median values (MV), upper limits of normal (ULN), lower limits of normal (LLN), or the natural logarithm (ln)] and correlated with overall survival (OS). Among the 59 pts included, pre-treatment CYFRA 21-1 levels showed a strong correlation with OS independent of the applied cut-off (MV 4.9 ng/ml-14.2 vs. 4.2 months, HR 0.18, p = 0.001; ULN 3.3 ng/ml-14.2 vs. 4.4 months, HR 0.28, p = 0.003; [ln] CYFRA 21-1-HR 0.77, p = 0.013). Lower values of haptoglobin were additionally associated with an improvement in OS (categorized by LLN of 2.05 g/l-10.4 vs. 5.5 months, HR 0.46, p = 0.023; [ln] haptoglobin-HR 0.51, p = 0.036). Pts with baseline SAA values below the MV of 22 mg/l also had a prolonged OS (10.4 vs. 5.0 months, HR 0.47, p = 0.036). For 25-OH vitamin D3 levels, no significant correlation with OS was found. In multivariate analyses, pre-treatment CYFRA 21-1 levels (categorized by MV-HR 0.15, p = 0.032) as well as [ln] haptoglobin (HR 0.30, p = 0.006) retained their independent prognostic significance for OS. CYFRA 21-1, haptoglobin, and SAA might provide useful prognostic information in advanced PC. An external multicenter validation of these results is necessary.

Treatment of advanced gastrointestinal tumors with genetically modified autologous mesenchymal stromal cells (TREAT-ME1): study protocol of a phase I/II clinical trial.

BACKGROUND: Adenocarcinoma originating from the digestive system is a major contributor to cancer-related deaths worldwide. Tumor recurrence, advanced local growth and metastasis are key factors that frequently prevent these tumors from curative surgical treatment. Preclinical research has demonstrated that the dependency of these tumors on supporting mesenchymal stroma results in susceptibility to cell-based therapies targeting this stroma. METHODS/DESIGN: TREAT-ME1 is a prospective, uncontrolled, single-arm phase I/II study assessing the safety and efficacy of genetically modified autologous mesenchymal stromal cells (MSC) as delivery vehicles for a cell-based gene therapy for advanced, recurrent or metastatic gastrointestinal or hepatopancreatobiliary adenocarcinoma. Autologous bone marrow will be drawn from each eligible patient after consent for bone marrow donation has been obtained (under a separate EC-approved protocol). In the following ~10 weeks the investigational medicinal product (IMP) is developed for each patient. To this end, the patient's MSCs are stably transfected with a gamma-retroviral, replication-incompetent and self-inactivating (SIN) vector system containing a therapeutic promoter - gene construct that allows for tumor-specific expression of the therapeutic gene. After release of the IMP the patients are enrolled after given informed consent for participation in the TREAT-ME 1 trial. In the phase I part of the study, the safety of the IMP is tested in six patients by three treatment cycles consisting of re-transfusion of MSCs at different concentrations followed by administration of the prodrug Ganciclovir. In the phase II part of the study, sixteen patients will be enrolled receiving IMP treatment. A subgroup of patients that qualifies for surgery will be treated preoperatively with the IMP to verify homing of the MSCs to tumors as to be confirmed in the surgical specimen. DISCUSSION: The TREAT-ME1 clinical study involves a highly innovative therapeutic strategy combining cell and gene therapy and is conducted at a high level of pharmaceutical quality ensuring patient safety. This patient-tailored approach represents the first clinical study worldwide utilizing genetically engineered MSCs in humans. TRIAL REGISTRATION: EU Clinical Trials Register/European Union Drug Regulating Authorities Clinical Trials Database number: 2012-003741-15.

Outcome of patients with metastatic colorectal cancer depends on the primary tumor site (midgut vs. hindgut): analysis of the FIRE1-trial (FuFIRI or mIROX as first-line treatment).

The aim of this study was to investigate the impact of midgut versus hindgut as the primary tumor site in patients with metastatic colorectal cancer (mCRC) receiving chemotherapy with FuFIRI or mIROX. We analyzed 423 patients from a phase III trial that randomized patients in a 1 : 1 fashion to either FuFIRI or mIROX. The cohort was grouped into midgut (n=82) and hindgut (n=341) primary tumors. The primary tumor site (midgut vs. hindgut) was correlated with parameters of treatment efficacy and survival. Our cohort comprised 82 patients presenting with primary midgut tumors and 341 with primary hindgut tumors. Tumors of midgut origin compared with hindgut origin were associated with inferior outcome. Objective response rate was 37 versus 43% (P=0.34), median progression-free survival was 6.0 versus 8.2 months (P=0.024, hazard ratio: 0.75), and median overall survival was 13.6 versus 21.8 months (P=0.001, hazard ratio: 0.65). Patients with midgut mCRC showed a clear trend toward inferior outcome in both study arms. However, the effect appeared less pronounced in the mIROX arm. Further datasets from large trials with various regimens are required as confirmation.

Key Prognostic Factors Create a Composite Risk Score to Stratify Patients into High- and Low-Treatment Benefit Groups: A Multicenter, Retrospective Data Analysis of 84 Metastatic Colorectal Cancer Patients Treated with Regorafenib as Part of the CORRECT and CONSIGN Trials.

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 = <0.001), AP ≤200 U/L (p = 0.001), CRP ≤3.2 mg/dL (p = <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 (<1.4), patients had a median OS of 10.5 months after initiating regorafenib. Patients with a high-risk score (>1.4) survived only 3.3 months after starting therapy with regorafenib (n = 43, p < 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.

Perfusion MRI for monitoring the effect of sorafenib on experimental prostate carcinoma: a validation study.

OBJECTIVE: The purpose of this study was to investigate with immunohistochemical validation whether dynamic contrast-enhanced MRI with small-molecule contrast medium is useful for monitoring the effects of the multikinase inhibitor sorafenib on prostate carcinomas in rats. MATERIALS AND METHODS: Copenhagen rats (n = 20) into which prostate carcinoma (MAT-Ly-Lu-B2) had been implanted subcutaneously were imaged on the day of implantation and 7 days later with 3-T dynamic gadobutrol-enhanced MRI. The therapy group (n = 10) received daily administration of 10 mg/kg body weight sorafenib. Quantitative measurements of tumor perfusion, tumor vascularity, and permeability-surface area product were calculated with a two-compartment model. Dynamic contrast-enhanced MRI values were correlated with immunohistochemical results for validation. RESULTS: Tumor perfusion in sorafenib-treated prostate carcinoma declined significantly from day 0 to day 7 (47.9 ± 36.8 mL/100 mL/min to 24.4 ± 18.6 mL/100 mL/min; p < 0.05). No significant effect on permeability-surface area product was observed in either the therapy or the control group (p > 0.05). Tumor vascularity decreased significantly (p < 0.05) from day 0 to day 7 under sorafenib treatment (15.6% ± 11.4% to 5.4% ± 2.1%). Immunohistochemical analysis revealed significantly lower tumor vascularity in the therapy than in the control group (rat endothelial cell antigen 1, 74.4 ± 16.9 cells vs 197 ± 75.4 cells; p < 0.05). In sorafenib-treated tumors, significantly more apoptotic cells (terminal deoxynucleotidyl transferase-mediated nick end labeling, 6923 ± 3761 vs 3167 ± 1500; p < 0.05) and significantly fewer proliferating cells (Ki-67, 10,198 ± 3064 vs 15,003 ± 3674; p < 0.05) were observed than in the control group. Modest but significant correlations were observed between tumor perfusion and immunohistochemical tumor cell apoptosis (r = -0.56; p < 0.05) and between tumor perfusion and immunohistochemical tumor vascularity (r = 0.56; p < 0.05). CONCLUSION: Tumor perfusion quantified with gadobutrol-enhanced dynamic contrast-enhanced MRI can be used as a noninvasive surrogate parameter for monitoring the antiangiogenic, antiproliferative, and proapoptotic effects of sorafenib on prostate carcinoma allografts as validated with immunohistochemical analysis.

Toxic epidermal necrolysis after pemetrexed and cisplatin for non-small cell lung cancer in a patient with sharp syndrome.

BACKGROUND: Pemetrexed is an antifolate drug approved for maintenance and second-line therapy, and, in combination with cisplatin, for first-line treatment of advanced nonsquamous non-small cell lung cancer. The side-effect profile includes fatigue, hematological and gastrointestinal toxicity, an increase in hepatic enzymes, sensory neuropathy, and pulmonary and cutaneous toxicity in various degrees. CASE REPORT: We present the case of a 58-year-old woman with history of Sharp's syndrome and adenocarcinoma of the lung, who developed toxic epidermal necrolysis after the first cycle of pemetrexed, including erythema, bullae, extensive skin denudation, subsequent systemic inflammation and severe deterioration in general condition. The generalized skin lesions occurred primarily in the previous radiation field and responded to immunosuppressive treatment with prednisone. CONCLUSION: Although skin toxicity is a well-known side effect of pemetrexed, severe skin reactions after pemetrexed administration are rare. Caution should be applied in cases in which pemetrexed is given subsequent to radiation therapy, especially in patients with pre-existing skin diseases.

Exact Primary Tumor Location in mCRC: Prognostic Value and Predictive Impact on Anti-EGFR mAb Efficacy.

Primary tumor sidedness (left vs. right) has prognostic and predictive impact on anti-EGFR agent efficacy and thus management of metastatic colorectal cancer (mCRC). This analysis evaluates the relevance of primary tumor location (PTL) in RAS/BRAF wild-type mCRC patients, when dividing the colorectal frame into six segments. This pooled analysis, performed on a single-patient basis of five randomized first-line therapy trials, evaluates the impact of exact PTL classification on baseline characteristics, prognosis and prediction of anti-EGFR antibody efficacy by chi-square and log-rank tests, the Kaplan-Meier method, Cox and logistic regressions. The PTL was significantly associated with metastatic spread: liver (p = 0.001), lung (p = 0.047), peritoneal (p < 0.001) and lymph nodes (p = 0.048). A multivariate analysis indicated an impact on anti-EGFR agent efficacy in terms of overall survival depending on the exact primary tumor location: from detrimental in caecal (HR 2.63), rather neutral effects in the ascending colon (HR 1.24), right flexure/transverse colon (HR 0.99) and left flexure/descending colon (HR 0.91) to clear benefit in sigmoid (HR 0.71) and rectal (HR 0.58) primaries. Exact primary tumor location affects anti-EGFR antibody efficacy in a rather continuous than a dichotomous fashion in RAS/BRAF wild-type mCRC patients. This perspective might help to support clinical decisions when anti-EGFR antibodies are considered.

Response and Disease Dynamics in Untreated Metastatic Colorectal Cancer With Bevacizumab-Based Sequential vs. Combination Chemotherapy-Analysis of the Phase 3 XELAVIRI Trial.

INTRODUCTION: Early tumor shrinkage (ETS), depth of response (DpR), and time to DpR represent exploratory endpoints that may serve as early efficacy parameters and predictors of long-term outcome in metastatic colorectal cancer (mCRC). We analyzed these endpoints in mCRC patients treated with first-line bevacizumab-based sequential (initial fluoropyrimidines) versus combination (initial fluoropyrimidines plus irinotecan) chemotherapy within the phase 3 XELAVIRI trial. METHODS: DpR (change from baseline to smallest tumor diameter), ETS (≥20% reduction in tumor diameter at first reassessment), and time to DpR (study randomization to DpR image) were analyzed. We evaluated progression-free survival and overall survival with ETS as stratification parameter according to treatment arm, molecular subgroup, and sex. RESULTS: In 370 patients analyzed, a higher rate of ETS (60.9% vs. 43.5%; p = 0.001) and significantly greater DpR (-40.0% vs. -24.7%; p < 0.001) were observed in the initial combination therapy arm. The improvement was pronounced in RAS/BRAF wild-type tumors. ETS correlated with improved survival irrespective of treatment arm (PFS: p < 0.001; OS: p = 0.012) and molecular subgroup (PFS: p < 0.001; OS: p < 0.001). Male patients in contrast to female patients with ETS had survival benefit (PFS: p < 0.001, HR 0.532; OS: p < 0.001, HR 0.574 vs. PFS: p = 0.107; OS: p = 0.965). CONCLUSIONS: Initial irinotecan-based combination therapy with bevacizumab improved ETS and DpR in mCRC patients with a particularly high irinotecan sensitivity of RAS/BRAF wild-type tumors. ETS seems to be a suitable prognostic marker for fluoropyrimidine- and bevacizumab-based combinations in mCRC. This finding was rather driven by male patients, potentially indicating that ETS might be less predictive of long-term outcome in an elderly, female population.

NeoRAS wild-type in metastatic colorectal cancer: Myth or truth?-Case series and review of the literature.

Upfront KRAS and NRAS gene testing ('RAS') is the standard of care for metastatic colorectal cancer (mCRC), to guide first-line treatment. The presence of RAS mutation (MT) is a negative predictor for the efficacy of anti-EGFR antibodies and the use of cetuximab and panitumumab is restricted to RAS wild-type (WT) mCRC. Conversion from RAS WT to RAS MT mCRC after treatment with anti-EGFR antibodies is a known and well-described acquired resistance mechanism. The by far less frequent 'NeoRAS wild-type' phenomenon (reversion from RAS MT to RAS WT) has recently drawn attention. The proposed effect of chemotherapy on RAS status in mCRC patients is not fully understood. Because of the intriguing biological consequence of a RAS MT to RAS WT reversion, subsequent treatment of NeoRAS WT patients with anti-EGFR antibodies is increasingly being discussed. Here, we report three clinical cases of NeoRAS WT mCRC patients, which received standard-of-care regimens for RAS MT mCRC. Anti-EGFR antibodies were used in two out of three patients after progression of the disease. One of the patients had a long-term response. In line with our observations, NeoRAS WT phenomenon occurs in clinical practice. Retesting of RAS status during treatment should be discussed in patients with unusual long-term clinical courses of RAS MT mCRC to optimise treatment strategy and to evaluate the use of anti-EGFR antibodies.

Frameless Single Robotic Radiosurgery for Pulmonary Metastases in Colorectal Cancer Patients.

Background Surgical intervention and radiation therapy are common approaches for pulmonary metastasectomy. The role of minimally invasive techniques in pulmonary metastases remains unclear. Frameless single robotic radiosurgery [CyberKnife (CK); Accuray Incorporated, Sunnyvale, CA] of pulmonary metastases in colorectal cancer (CRC) patients offers high precision local radiation therapy. Methods We analyzed the efficacy and safety of CK treatment for lung metastases in CRC in 34 patients and a total of 45 lesions. The primary endpoint was local control (LC); secondary endpoints were progression-free survival (PFS), overall survival (OS), distant control (DC), and safety-relevant events. Results Of the treated lesions, 34/45 (77.8%) decreased in size or remained unchanged [complete response (CR), partial response (PR), stable disease (SD)]; 8/45 (17.8%) lesions increased in size [progressive disease (PD)] and 2/45 (4.4%) lesions were not evaluable. Local progression was shown in 2 lesions (4.4 %). The median PFS period was six months. In a median follow-up time of 19.4 months, medium OS was 19.9 months (range: 3-61 months). Distant recurrence was observed in 21/34 patients (61.8 %). Intrapulmonary progression occurred in six patients. In 4/45 cases, fiducial placement led to a pneumothorax; three out of four patients needed chest tube insertion. No radiation-associated side effects were reported in 57.8% of patients. In 10/45 cases (22.2%), patients suffered asymptomatic radiographic changes; 7/45 cases (15.6%) reported a late onset of radiation-associated side effects. Maximal radiation-associated side effects reached the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) Grade 1. Conclusion CK treatment of pulmonary metastases is safe and well-tolerated. For metastatic colorectal cancer (mCRC) patients with pulmonary metastases and not eligible for surgery, CK radiation offers a valuable treatment option.

Current treatment options in RAS mutant metastatic colorectal cancer patients: a meta-analysis of 14 randomized phase III trials.

PURPOSE: Although biomarkers for patients with metastatic colorectal cancer exist, the benefit patients with RAS mutated tumors derive from established regimens is unclear. METHODS: Efficacy of therapeutic strategies available for RAS mutated patients (addition of chemotherapeutic agents and/or anti angiogenic agents) were investigated in fourteen randomized controlled phase III trials at trial level by meta-analysing individual study hazard ratios and 95% confidence intervals (95% CI) for overall survival (OS) and progression free survival (PFS). RESULTS: 6810 of 10,748 patients (63.3%) were available (48.5% RAS wildtype, 51.5% RAS mutated). Across all treatment lines, additional treatment efficacy (chemotherapy and/or anti angiogenic agents) was significantly smaller in RAS mutated compared to wildtype tumors for OS and PFS. In detail, patients with RAS mutated metastatic colorectal cancer derived significant benefit in PFS but not in OS by the addition of either chemotherapy or anti angiogenic agents to the respective comparator. In patients with RAS wildtype metastatic colorectal cancer, PFS and OS were improved by the addition of chemotherapy or anti angiogenic agent. CONCLUSION: The therapeutic benefit of additional substances is less distinct in patients with RAS mutated as compared to RAS wildtype metastatic colorectal cancer, especially with regard to OS.

Single-nucleotide variants, tumour mutational burden and microsatellite instability in patients with metastatic colorectal cancer: Next-generation sequencing results of the FIRE-3 trial.

BACKGROUND: Molecular biomarkers and primary tumour sidedness guide treatment decisions in metastatic colorectal cancer. Comprehensive molecular profiling aims to identify targetable alterations and measure tumour mutational burden (TMB) to enable precision oncology. MATERIAL AND METHODS: FoundationOne® next-generation sequencing identified single-nucleotide variants (SNVs), copy number alterations, high TMB (TMB-H) and high-grade microsatellite instability (MSI-H) in patients treated in the FIRE-3 trial. Data were correlated with objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: Three hundred seventy-three (49.6%) of 752 patients provided material for this analysis. Frequent SNVs included TP53, APC, KRAS, PIK3CA, BRAF, SMAD4 and FBXW7. KRAS, BRAF V600E and SMAD4 mutations were confirmed as prognostic biomarkers by logistic penalised regression for ORR. OS was significantly longer in patients with SMAD4 wild-type (WT) tumours than in those with SMAD4-mutated tumours (hazard ratio = 0.59 [95% confidence interval {CI} = 0.34-1.01], p = 0.05), with a higher probability of ORR [odds ratio, SMAD4 SNV versus WT = 0.32 [95% CI = 0.10-0.98], p = 0.05] when treated with cetuximab. MSI-H (30.0%, p = 0.03) and TMB-H (17.3%, p = 0.003) tumours were enriched by FBXW7 mutations. Numerically lower ORR, OS and PFS were observed in MSI-H tumours. CONCLUSIONS: RAS, BRAF V600E and SMAD4 mutations were identified as poor prognostic biomarkers in patients of the FIRE-3 trial, whereas improved outcome was observed for BRAF non-V600E mutation. SMAD4 mutation might provide predictive relevance for cetuximab efficacy. MSI-H tumours showed numerically lower ORR, OS and PFS.

Impact of age on efficacy and early mortality of initial sequential treatment versus upfront combination chemotherapy in patients with metastatic colorectal cancer: a subgroup analysis of a phase III trial (AIO KRK0110, XELAVIRI study).

INTRODUCTION: The XELAVIRI study compared application of fluoropyrimidine (FP) and bevacizumab (Bev) followed by sequential escalation to irinotecan (Iri), FP and Bev (arm A) to upfront combination therapy with FP, Iri and Bev (arm B) in patients with metastatic colorectal cancer (mCRC). To elucidate the impact of age on survival, we evaluated efficacy and early mortality in the underlying trial. METHODS: Patients were stratified for age in three cohorts (<65 years, 65-74 years and ≥75 years). Survival end-points were expressed by the Kaplan-Meier method and compared by log-rank testing and Cox regression. Objective response and 60-day mortality were evaluated by chi-square testing. RESULTS: The efficacy analyses suggest more substantial benefit from upfront combination chemotherapy in younger patients with mCRC. Elderly patients (≥75 years) derived limited benefit from upfront combination chemotherapy, particularly in terms of overall survival. Of 421 randomised patients, 13 patients (3.1%) died within 60 days after treatment initiation with the highest prevalence in elderly patients (1.6% < 65 years, 2.8% 65-74 years and 5.2% ≥ 75 years, p = 0.26). The frequency of 60-day mortality was significantly associated with age (with a maximum of 8.7% in patients aged ≥75 years) in patients undergoing upfront combination therapy (p = 0.027) but not in patients receiving sequential treatment (p = 0.63). CONCLUSION: Combination therapy with FP, Iri and Bev does not substantially improve the outcome of patients aged ≥75 years as compared with sequential treatment algorithm. These patients appear to be at a relevant risk for 60-day mortality under Iri-based combination chemotherapy plus Bev.