PURPOSEBRAFV600E 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 BRAFV600E-mutant mCRC. PATIENTS AND METHODSIn 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. RESULTSEighteen 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). CONCLUSIONTo our knowledge, FIRE-4.5 is the first prospective and randomized study investigating first-line treatment of BRAFV600E-mutant mCRC. FOLFOXIRI plus cetuximab does not induce a higher ORR when compared with FOLFOXIRI plus bevacizumab in first-line treatment of BRAFV600E-mutant mCRC. Bevacizumab-based chemotherapy remains the preferable first-line treatment of patients with BRAFV600E-mutant mCRC.
Body weight loss is frequently regarded as negatively related to outcomes in patients with malignancies. This retrospective analysis of the FIRE‐3 study evaluated the evolution of body weight in ...patients with metastatic colorectal cancer (mCRC). FIRE‐3 evaluated first‐line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab or bevacizumab in mCRC patients with RAS‐WT tumors (ie, wild‐type in KRAS and NRAS exons 2‐4). The prognostic and predictive relevance of early weight loss (EWL) regarding patient outcomes and treatment side effects were evaluated. Retrospective data on body weight during first 6 months of treatment were evaluated (N = 326). To correlate with efficacy endpoints and treatment side effects, patients were grouped according to clinically significant EWL ≥5% and <5% at Month 3. Age constituted the only significant predictor of EWL following a linear relationship with the corresponding log odds ratio (P = .016). EWL was significantly associated with the incident frequencies of diarrhea, edema, fatigue, nausea and vomiting. Further, a multivariate analysis revealed EWL to be an independent negative prognostic factor for overall survival (32.4 vs 21.1 months; hazard ratio HR: 1.64; 95% confidence interval CI = 1.13‐2.38; P = .0098) and progression‐free survival (11.8 vs 9.0 months; HR: 1.72; 95% CI = 1.18‐2.5; P = .0048). In conclusion, EWL during systemic treatment against mCRC is significantly associated with patient age. Patients exhibiting EWL had worse survival and higher frequencies of adverse events. Early preventative measures targeted at weight maintenance should be evaluated, especially in elderly patients being at highest risk of EWL.
What's new?
When patients with metastatic colorectal cancer (mCRC) rapidly lose weight early in the course of treatment, that often forebodes a negative outcome. Here, the authors examined changes in body weight in the first 3 months of treatment. Older patients had the highest risk of extreme early weight loss (greater than 5%). This weight loss was correlated with adverse events such as nausea, vomiting, and diarrhoea, and also with an 11‐month reduction in overall survival. These results should increase oncologists' awareness of patients' body weight change early in treatment and encourage intervention from dietitians to help prevent weight loss.
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.
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).
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).
Extended molecular profiling beyond RAS may have the potential to improve the patient selection for anti-EGFR containing maintenance regimens.
Amphiregulin (
) and epiregulin (
) are ligands of
. Predictive information for anti-
treatment in metastatic colorectal cancer (mCRC) was observed, but data for other agents is limited.
Ligand mRNA ...expression;
mutations; and
expression were assessed by qRT-PCR, pyrosequencing, and IHC, respectively, in mCRC tumor tissue of patients participating in the randomized controlled trials FIRE-1, CIOX, and FIRE-3. Normalized mRNA expression was dichotomized using median and third quartile. Overall (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method including univariate and multivariate Cox regression analyses. Penalized spline regression analysis tested interaction of mRNA expression and outcome.
Of 688 patients with available material, high
expression was detected in 343 (>median) and 172 (>3rd quartile) patients. High
expression was associated with significantly higher OS 26.2 vs. 21.5 months, HR = 0.80; 95% confidence interval (CI), 0.68-0.94;
= 0.007, PFS (10.0 vs. 8.1 months, HR = 0.74; 95% CI, 0.63-0.86;
= 0.001), and objective response rate (63.1% vs. 51.6%,
= 0.004) compared to low expression at both threshold values. This effect remained significant in multivariate Cox regression analysis (OS:
= 0.01, PFS:
= 0.002). High
mRNA expression interacted significantly with the efficacy of cetuximab compared with bevacizumab (OS:
= 0.02, PFS:
= 0.04) in
WT mCRC.
High
mRNA expression is a favorable prognostic biomarker for mCRC which interacted significantly with efficacy of anti-
treatment.
Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma. This study reports on the safety and efficacy of the docetaxel-based triplet FLOT ...(fluorouracil plus leucovorin, oxaliplatin and docetaxel) as a perioperative therapy for patients with locally advanced, resectable tumours.
In this controlled, open-label, phase 2/3 trial, we randomly assigned 716 patients with histologically-confirmed advanced clinical stage cT2 or higher or nodal positive stage (cN+), or both, resectable tumours, with no evidence of distant metastases, via central interactive web-based-response system, to receive either three pre-operative and three postoperative 3-week cycles of 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 plus either 200 mg/m2 fluorouracil as continuous intravenous infusion or 1250 mg/m2 capecitabine orally on days 1 to 21 (ECF/ECX; control group) or four preoperative and four postoperative 2-week cycles of 50 mg/m2 docetaxel, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin and 2600 mg/m2 fluorouracil as 24-h infusion on day 1 (FLOT; experimental group). The primary outcome of the trial was overall survival (superiority) analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01216644.
Between Aug 8, 2010, and Feb 10, 2015, 716 patients were randomly assigned to treatment in 38 German hospitals or with practice-based oncologists. 360 patients were assigned to ECF/ECX and 356 patients to FLOT. Overall survival was increased in the FLOT group compared with the ECF/ECX group (hazard ratio HR 0·77; 95% confidence interval CI; 0.63 to 0·94; median overall survival, 50 months 38·33 to not reached vs 35 months 27·35 to 46·26). The number of patients with related serious adverse events (including those occurring during hospital stay for surgery) was similar in the two groups (96 27% in the ECF/ECX group vs 97 27% in the FLOT group), as was the number of toxic deaths (two <1% in both groups). Hospitalisation for toxicity occurred in 94 patients (26%) in the ECF/ECX group and 89 patients (25%) in the FLOT group.
In locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma, perioperative FLOT improved overall survival compared with perioperative ECF/ECX.
The German Cancer Aid (Deutsche Krebshilfe), Sanofi-Aventis, Chugai, and Stiftung Leben mit Krebs Foundation.
The AIO KRK-0104 randomized phase II trial investigated the efficacy and safety of cetuximab combined with capecitabine and irinotecan (CAPIRI) or capecitabine and oxaliplatin (CAPOX) in the ...first-line treatment of metastatic colorectal cancer (mCRC).
A total of 185 patients with mCRC were randomly assigned to cetuximab (400 mg/m(2) day 1, followed by 250 mg/m(2) weekly) plus CAPIRI (irinotecan 200 mg/m(2), day 1; capecitabine 800 mg/m(2) twice daily days 1 through 14, every 3 weeks; or cetuximab plus CAPOX (oxaliplatin 130 mg/m(2) day 1; capecitabine 1,000 mg/m(2) twice daily day 1 through 14, every 3 weeks). The primary study end point was objective response rate (ORR).
In the intention-to-treat patient population (n = 177), ORR was 46% (95% CI, 35 to 57) for CAPIRI plus cetuximab versus 48% (95% CI, 37 to 59) for CAPOX plus cetuximab. Analysis of the KRAS gene mutation status was performed in 81.4% of the intention to treat population. Patients with KRAS wild-type in the CAPIRI plus cetuximab arm showed an ORR of 50.0%, a PFS of 6.2 months and an OS of 21.1 months. In the CAPOX plus cetuximab arm, an ORR of 44.9%, a PFS of 7.1 months and an OS of 23.5 months were observed. While ORR and PFS were comparable in KRAS wild-type and mutant subgroups, a trend toward longer survival was associated with KRAS wild-type. Both regimens had manageable toxicity profiles and were safe.
This randomized trial demonstrates that the addition of cetuximab to CAPIRI or CAPOX is effective and safe in first-line treatment of mCRC. In the analyzed regimens, ORR and PFS did not differ according to KRAS gene mutation status.
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.
•We evaluate the efficacy of initial irinotecan according to gender in mCRC.•Male patients seem to benefit from initial irinotecan, whereas women do not.•Baseline characteristics and toxicities were similar in male versus female patients.
The randomised open-label phase III XELAVIRI trial failed to demonstrate non-inferiority of the sequential application of fluoropyrimidine plus bevacizumab followed by additional irinotecan at first ...progression (Arm A) versus initial combination of all agents (Arm B) for untreated metastatic colorectal cancer in the initial analysis of time-to-failure-of-strategy (TFS, 90% confidence boundary of 0.8). Here, we evaluate efficacy in the full analysis set (FAS), the per-protocol set, in addition to age-related and molecular subgroups.
Median TFS, overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan–Meier method and log-rank test. Cox regression models assessed hazard ratios (HRs) and confidence intervals (CIs) (TFS: 90%; OS, PFS: 95%).
Of 421 patients, 390 (92.6%), 391 (92.9%) and 357 (84.8%) events for TFS, OS and PFS were observed in the FAS with a median follow-up of 54.2 months (Arm A) versus 52.9 months (Arm B). Non-inferiority of sequential treatment for TFS was missed in the FAS (HR 0.93; 90% CI, 0.79–1.10; P = 0.482) and not shown in the per-protocol set (HR 0.93; 90% CI, 0.75–1.13, P = 0.433). Formal non-inferiority for TFS was observed for patients older than 70 years (HR 1.06; 90% CI, 0.80–1.41; P = 0.670) and patients with RAS mutant tumours (HR 1.12; 90% CI, 0.87–1.43; P = 0.465). In RAS/BRAF wild-type tumours, combination treatment was significantly superior to sequential therapy in all end-points.
In the overall population, XELAVIRI just missed to demonstrate the non-inferiority of sequential compared to combination therapy for TFS. However, the non-inferiority of sequential treatment was observed in elderly patients and RAS mutant tumours.
Trial registration ID (clinicaltrials.gov) NCT01249638.
•Sequential vs. combination of fluoropyrimidine (FP), bevacizumab (Bev), irinotecan.•Sequential arm: start with FP + Bev, escalation with irinotecan at progression.•Sequential arm was inferior for primary end-point time-to-failure-of-strategy.•Patients >70 years and with RAS mutant mCRC benefit from sequential therapy.•Combination chemotherapy is advised in younger patients with RAS wild-type mCRC.
The XELAVIRI trial compared sequential (fluoropyrimidine and bevacizumab; irinotecan (Iri) at progression) versus initial combination therapy (fluoropyrimidine, bevacizumab, Iri) of treatment-naïve ...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.
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.
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)
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 ID (clinicaltrials.gov) NCT01249638.
•Consensus molecular subtypes (CMS) are novel biomarkers in colorectal cancer (CRC).•CMS were predicted in the randomised phase III XELAVIRI trial using gene expression.•No prognostic benefit of CMS in a collective with elderly patients with colorectal cancer.•CMS and RAS status might act as biomarkers of treatment intensification in XELAVIRI.•RAS WT CMS2 tumours most likely to benefit from initial combination treatment.
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