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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 .

BACKGROUND: FIRE-3 compared first-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. The consensus molecular subgroups (CMS) are grouping CRC samples according to their gene-signature in four different subtypes. Relevance of CMS for the treatment of mCRC has yet to be defined. PATIENTS AND METHODS: In this exploratory analysis, patients were grouped according to the previously published tumor CRC-CMSs. Objective response rates (ORR) were compared using chi-square test. Overall survival (OS) and progression-free survival (PFS) times were compared using Kaplan-Meier estimation, log-rank tests. Hazard ratios (HR) were estimated according to the Cox proportional hazard method. RESULTS: CMS classification could be determined in 438 out of 514 specimens available from the intent-to-treat (ITT) population (n = 592). Frequencies for the remaining 438 samples were as follows: CMS1 (14%), CMS2 (37%), CMS3 (15%), CMS4 (34%). For the 315 RAS wild-type tumors, frequencies were as follows: CMS1 (12%), CMS2 (41%), CMS3 (11%), CMS4 (34%). CMS distribution in right- versus (vs) left-sided primary tumors was as follows: CMS1 (27% versus 11%), CMS2 (28% versus 45%), CMS3 (10% versus 12%), CMS4 (35% versus 32%). Independent of the treatment, CMS was a strong prognostic factor for ORR (P = 0.051), PFS (P

Doublet or triplet chemotherapy regimens in combination with anti–epidermal growth factor receptor (anti-EGFR) monoclonal antibodies (mAb), such as cetuximab or panitumumab, or the anti–vascular endothelial growth factor mAb bevacizumab, are the current recommended standard of care therapies for unresectable metastatic colorectal cancer (mCRC). While the recommended dosing schedule for the triplet chemotherapy regimen with 5-fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI) in combination with bevacizumab is well established, the optimal dosing of FOLFOXIRI in combination with anti-EGFR agents is unknown. Several randomized, phase 3 clinical trials of patients with mCRC have demonstrated improved survival and response rates with FOLFOXIRI, alone or when combined with bevacizumab, compared with doublet chemotherapy regimens. Trials of anti-EGFR agents in combination with FOLFOXIRI have also shown promising results. In this review, we summarize the emerging evidence regarding the safety and efficacy of anti-EGFR agents in combination with triplet chemotherapy regimens and discuss the potential for this combination as a future treatment option for patients with RAS-wild-type mCRC.

Retrospective subgroup analyses suggest that primary tumour location (PTL) has a prognostic importance and relates to response to targeted therapy.We conducted a meta-analysis of first-line clinical trials available up to October 2016, which assessed the relevance of PTL in patients with metastatic colorectal cancer (mCRC). Right- and left-sided colorectal cancers were differentiated (RC and LC).In 13 first-line randomised controlled trials and one prospective pharmacogenetic study, RC was associated with a significantly worse prognosis compared with LC (hazard ratio [HR] for overall survival: 1.56; 95% confidence interval [CI]: 1.43-1.70; P 0.0001). A meta-analysis of PRIME and CRYSTAL study suggests that PTL was predictive of survival benefit from addition of anti-EGFR antibody to standard chemotherapy in patients with RAS wild-type tumour (overall survival, HR for LC: 0.69; 95% CI: 0.58-0.83; P 0.0001 and HR for RC: 0.96; 95% CI: 0.68-1.35; P = 0.802). A meta-analysis of FIRE-3/AIO KRK0306, CALGB/SWOG 80405 and PEAK study indicates that patients with RAS wild-type LC had a significantly greater survival benefit from anti-EGFR treatment compared with anti-VEGF treatment when added to standard chemotherapy (HR 0.71; 95% CI: 0.58-0.85; P = 0.0003). By contrast, in patients with RC, benefit from standard therapy was poor and bevacizumab-based treatment was numerically associated with longer survival (HR 1.3; 95% CI: 0.97-1.74; P = 0.081).The present meta-analysis demonstrates that PTL is prognostic in mCRC. Further, it supports the conclusion that patients with left-sided RAS wild-type mCRC should be preferentially treated with an anti-EGFR antibody. In right-sided mCRC, chemotherapy plus bevacizumab is a treatment option, but optimal treatment has yet to be defined.

In this pooled analysis of metastatic colorectal cancer patients, mutations in KRAS, and BRAF were associated with inferior progression-free and overall survival compared with patients with non-mutated tumors. KRAS exon 2 mutation variants were associated with heterogeneous outcome compared with unmutated tumors with KRAS G12C and G13D being associated with rather poor survival., Background To explore the impact of KRAS, NRAS and BRAF mutations as well as KRAS mutation variants in patients with metastatic colorectal cancer (mCRC) receiving first-line therapy. Patients and methods A total of 1239 patients from five randomized trials (FIRE-1, FIRE-3, AIOKRK0207, AIOKRK0604, RO91) were included into the analysis. Outcome was evaluated by the Kaplan–Meier method, log-rank tests and Cox models. Results In 664 tumors, no mutation was detected, 462 tumors were diagnosed with KRAS-, 39 patients with NRAS- and 74 patients with BRAF-mutation. Mutations in KRAS were associated with inferior progression-free survival (PFS) and overall survival (OS) [multivariate hazard ratio (HR) for PFS: 1.20 (1.02–1.42), P = 0.03; multivariate HR for OS: 1.41 (1.17–1.70), P < 0.001]. BRAF mutation was also associated with inferior PFS [multivariate HR: 2.19 (1.59–3.02), P < 0.001] and OS [multivariate HR: 2.99 (2.10–4.25), P < 0.001]. Among specific KRAS mutation variants, the KRAS G12C-variant (n = 28) correlated with inferior OS compared with unmutated tumors [multivariate HR 2.26 (1.25–4.1), P = 0.001]. A similar trend for OS was seen in the KRAS G13D-variant [n = 71, multivariate HR 1.46 (0.96–2.22), P = 0.10]. More frequent KRAS exon 2 variants like G12D [n = 152, multivariate HR 1.17 (0.86–1.6), P = 0.81] and G12V [n = 92, multivariate HR 1.27 (0.87–1.86), P = 0.57] did not have significant impact on OS. Conclusion Mutations in KRAS and BRAF were associated with inferior PFS and OS of mCRC patients compared with patients with non-mutated tumors. KRAS exon 2 mutation variants were associated with heterogeneous outcome compared with unmutated tumors with KRAS G12C and G13D (trend) being associated with rather poor survival.

Summary Background Cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens; however, their comparative effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. We aimed to compare these agents in patients with KRAS (exon 2) codon 12/13 wild-type metastatic colorectal cancer. Methods In this open-label, randomised, phase 3 trial, we recruited patients aged 18–75 years with stage IV, histologically confirmed colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, an estimated life expectancy of greater than 3 months, and adequate organ function, from centres in Germany and Austria. Patients were centrally randomised by fax (1:1) to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab (using permuted blocks of randomly varying size), stratified according to ECOG performance status, number of metastatic sites, white blood cell count, and alkaline phosphatase concentration. The primary endpoint was objective response analysed by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00433927. Findings Between Jan 23, 2007, and Sept 19, 2012, 592 patients with KRAS exon 2 wild-type tumours were randomly assigned and received treatment (297 in the FOLFIRI plus cetuximab group and 295 in the FOLFIRI plus bevacizumab group). 184 (62·0%, 95% CI 56·2–67·5) patients in the cetuximab group achieved an objective response compared with 171 (58·0%, 52·1–63·7) in the bevacizumab group (odds ratio 1·18, 95% CI 0·85–1·64; p=0·18). Median progression-free survival was 10·0 months (95% CI 8·8–10·8) in the cetuximab group and 10·3 months (9·8–11·3) in the bevacizumab group (hazard ratio [HR] 1·06, 95% CI 0·88–1·26; p=0·55); however, median overall survival was 28·7 months (95% CI 24·0–36·6) in the cetuximab group compared with 25·0 months (22·7–27·6) in the bevacizumab group (HR 0·77, 95% CI 0·62–0·96; p=0·017). Safety profiles were consistent with the known side-effects of the study drugs. The most common grade 3 or worse adverse events in both treatment groups were haematotoxicity (73 [25%] of 297 patients in the cetuximab group vs 62 [21%] of 295 patients in the bevacizumab group), skin reactions (77 [26%] vs six [2%]), and diarrhoea (34 [11%] vs 40 [14%]). Interpretation Although the proportion of patients who achieved an objective response did not significantly differ between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab groups, the association with longer overall survival suggests that FOLFIRI plus cetuximab could be the preferred first-line regimen for patients with KRAS exon 2 wild-type metastatic colorectal cancer. Funding Merck KGaA.

Background This trial evaluated activity and safety of mFOLFOXIRI + panitumumab (P) vs FOLFOXIRI in ECOG 0-1, primarily non-resectable mCRC patients. Here, we report the quality of life data. Methods Prospective 2:1 randomized, phase II trial comparing mFOLFOXIRI (Ox 85 mg/m2, Iri 150 mg/m2, 5FU 3000mg/m2 cont. 48h, LV 200 mg/m2) + P 6 mg/KG (arm A) with FOLFOXIRI (Ox 85 mg/m2, Iri 165 mg/m2, 5FU 3200mg/m2 cont. 48h, LV 200 mg/m2; arm B), both arms q2w. Cohort 1: irresectable mCRC; cohort 2: chance of secondary resection of metastatic lesions. Primary endpoint was ORR, secondary endpoints were secondary resection rate (cohort 2), toxicity, quality of life (QoL, QLQ-C30). Between-treatment differences in QoL were assessed from baseline to disease progression, and to discontinuation of 1st-line treatment, using analysis of covariance (ANCOVA). Results A total of 96 patients were randomized (63 arm A, 33 arm B). There were significantly higher ORR (87.3% vs. 60.6%, p = 0.004), ETS (85.7% vs 60.0%, p = 0.01) and DpR (58.9% vs. 40.9%) in the P arm compared to FOLFOXIRI alone. QoL analyses was performed in 51 patients in arm A and 26 patients in arm B. There were no statistically significant differences between treatment arms from baseline to progression or to discontinuation. Although significantly more secondary resections of metastases were achieved in the P arm of cohort 2 (75.0% vs. 36.4%, p = 0.05), QoL was not different between cohorts 1 and 2 and the treatment arms, respectively. Toxicity or patient wish as the reason for end of therapy were not different between the treatment arms A and B (12.7% vs. 21.2% and 0% vs 6.1%, respectively). Grade III/IV toxicities were numerically higher in the P arm (81.3% vs. 66.7%). This increase was mainly due to toxicities such as diarrhea (25.0% vs 12.1%), mucositis (9.4 vs. 0%), rash (14.1% vs. 0%), and fatigue (7.8% vs. 0%). Conclusions mFOLFOXIRI plus P results in significantly higher response rates compared to FOLFOXIRI in RAS wild-type mCRC. Although toxicity was increased, QL reporting was similar in both arms. Therefore, intensive upfront therapy with modified FOLFIRINOX+P represents a valuable treatment option in patients with the need of a highly active 1st-line therapy. Clinical trial identification NCT01328171. Legal entity responsible for the study Arbeitsgemeinschaft Internistische Onkologie (AIO). Funding Amgen. Disclosure M. Geissler: Honoraria (institution), Advisory / Consultancy: Amgen. D. Modest: Honoraria (institution), Advisory / Consultancy: Amgen. V. Heinemann: Honoraria (institution), Advisory / Consultancy: Amgen. All other authors have declared no conflicts of interest.

The AIO KRK-0306 trial compares the efficacy of infusional 5-fluorouracil, folinic acid, irinotecan (FOLFIRI) plus cetuximab with FOLFIRI plus bevacizumab in first-line treatment of metastatic colorectal cancer (mCRC). In October 2008, an amendment terminated the inclusion of patients with KRAS-mutated tumours. This subgroup of patients is evaluated in the present analysis, while the study is ongoing for patients with KRAS wild-type tumours.Patients were randomly assigned to FOLFIRI (Tournigand regimen) every 2 weeks plus cetuximab (400 mg/m2 day 1, followed by 250 mg/m2 weekly=arm A) or bevacizumab (5 mg/kg every 2 weeks=arm B). Among 336 randomised patients, KRAS mutation was demonstrated in 100 assessable patients. The primary study end point was objective response rate (ORR).ORR was 44% [95% confidence interval (CI) 29% to 59%] in arm A versus 48% (95% CI, 33% to 62%) in arm B. Progression-free survival was 7.5 versus 8.9 months (hazard ratio: 1.0) and overall survival was 22.7 versus 18.7 months (hazard ratio: 0.86) in arms A versus B, respectively.This is the first head to head comparison of cetuximab versus bevacizumab in first-line treatment of mCRC. In the present evaluation of patients with KRAS-mutated tumours, neither strategy demonstrated a clearly superior outcome.

Background Mortality rates in published irinotecan-based trials range between 1.7% and 5.0%. This analysis aimed to evaluate clinical and histopathologic factors associated with 60-day mortality in first-line therapy for metastatic colorectal cancer (mCRC). Patients and Methods Sixty-day all-cause and disease-specific mortality rates from 479 patients who participated in a randomized phase III study comparing FUFIRI (5-fluorouracil [5-FU], leucovorin, irinotecan) (n = 238) vs. mIROX (modified irinotecan plus oxaliplatin (n = 241) were evaluated for association with prognostic factors such as platelet counts, alkaline phosphatase (AP) levels, white blood cell (WBC) counts, hemoglobin values, lactate dehydrogenase (LDH) levels, carcinoembryonic antigen (CEA) levels, and several other baseline parameters using univariate and multivariate logistic regression analyses applied to patients combined from both treatment groups. Results The all-cause 60-day mortality rate was 5.0% (24/479). Thirteen patients (5.5%) in the FUFIRI arm died within the first 60 days of treatment compared with 11 (4.6%) patients in the mIROX arm (P = .68). Among the 24 patients in both treatment arms, mortality was qualified as disease related in 15 (63%) patients and treatment related in 7 (29%) patients (P = .695). In multivariate analyses, high LDH levels (P = .010) and an elevated WBC count (P = .006) remained as significant independent prognostic factors. Low Karnofsky performance status (KPS) showed a strong trend but failed to reach statistical significance (P = .057) as did AP levels and the number of metastatic sites. Conclusion In this study 63% of the early deaths were disease related, whereas only 29% were possibly related to study medication. Independent prognostic factors for early mortality were LDH levels and WBC counts. KPS showed a strong trend in the multivariate analysis. Future investigation may consider LDH levels and WBC counts for exclusion criteria.

Aim: To investigated choice and duration of 2nd-line therapies according to 1st-line efficacy as well as overall survival (OS) according to 2nd-line therapy in FIRE-3: FOLFIRI plus either cetuximab (arm a) or bevacizumab (arm b) as 1st-line treatment of KRAS exon 2 wild-type mCRC. Methods: The study-protocol recommended 2nd-line therapy with FOLFOX plus bevacizumab in arm A and irinotecan plus cetuximab in arm B, but physician were free to choose any regimen. 2nd-line treatment was defined as any new anticancer drug for mCRC following 1st-line therapy. Duration of 2nd-line therapy was calculated as time from first to last application of 2nd-line treatment. Results: 260/297 patients in arm A and 250/295 patients in arm B were alive after 1st-line therapy. Of those, 78.5% of patients arm A and 76.4% in arm B received 2nd-line therapy so far. 1st-line PFS according to 2nd-line antibody use was 9.2 (anti-VEGF), comparing to 9.7 (anti-EGFR) and 11.3 months (no mAB); p = 0.001. Correspondingly, OS was 25.2 (anti-VEGF) vs. 23.7 (anti-EGFR) vs. 30.8 months (no mAB), p = 0.02. 1st-line PFS according to 2nd-line oxaliplatin (Ox) use was associated with 9.9 (Ox), comparing to 9.9 months (no Ox); p = 0.56. OS according to Ox-use was 27.1 (ox) vs. 29.1 months (no Ox); p = 0.10. 2nd-line therapy was administered for a median of 17.2 weeks in arm A and 14.0 weeks in arm b (p = 0.08). 2nd-line regimens with antibody-crossover were administered for a median of 23.9 weeks in arm A and 16.1 weeks arm B (p = 0.06). Updated results might be presented at the meeting. Conclusions: This post-hoc analysis indicates that 2nd-line application of mAbs was favoured in patients with shorter 1st-line PFS. Correspondingly, 2nd-line treatment without antibodies compared to antibody-based regimens was associated with longer OS. A trend towards longer 2nd-line therapy was observed in favour of patients receiving cetuximab as 1st-line therapy. Disclosure: S. Stintzing: Advisory boards: Roche/Genentech, BMS, Merck Honoraria: Roche/Genentech, Amgen, Merck, Sanofi Travel support: MerckSerono, Roche;L. Fischer von Weikersthal: Travel support: Roche;F. Kullmann: Honoraria: Roche;W. Scheithauer: Advisory boards and honoraria: MerckSerono, Roche; C. Giessen: Travel support: Roche;A. Jung: Advisory boards, and honoraria: MerckSerono;T. Kirchner: Advisory boards: Novartis, Amgen, Pfizer, Roche Honoraria: MerckSerono, Amgen, Roche, AstraZeneca research funding: MerckSerono, Amgen:V. Heinemann: Research grant: MerckSerono, Roche, Amgen Honoraria and advisory boards: MerckSerono, Roche, Amgen Travel support: MerckSerono. All other authors have declared no conflicts of interest.

Aim: FIRE-3 compared 1st-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type mCRC patients. An independent radiological review was carried out to evaluate tumor response according to RECIST 1.1 and to define early tumor shrinkage (ETS) and depth of response (DpR). Methods: Extended RAS analysis was carried out in KRAS and NRAS exon 2, 3 and 4 (codons 12, 13, 59, 61, 117 and 146) using pyro-sequencing technique. Radiological data were evaluated independently. ETS was defined as a reduction in tumor diameter of more than 20% at first-tumor assessment after baseline (week 6). DpR was defined as the maximal tumor shrinkage observed in a patient. Reviewers were blinded to patient data. Calculations were done for both, the ITT- and the extended RAS wild-type population. Results: Within the ITT population, 475 patients (80.2%) were successfully tested for all RAS locations. Primary outcome data for the RAS wt population (n = 400) (table). FOLFIRI + Cetuximab (n= 199) FOLFIRI + Bevacizumab (n = 201) p HR ORR (%) 65.8 58.2 0.92* PFS (months) (95% CI) 10.3 (9.5 - 11.8) 10.2 (9.3 - 11.7) 0.77 0.97 OS (months) (95% CI) 33.1 (24.5 - 39.4) 25.0 (23.0 - 28.1) 0.0059 0.697 p = log-rank test; * = one-sided Fisher's exact test; HR = Hazard ratio 459 patients (77.5%) were evaluable according to RECIST. ORR significantly favored the FOLFIRI plus cetuximab arm (71.4% vs. 56.4%; two sided Fisher's exact test p = 0.015). The proportion of patients reaching ETS was significantly greater in the FOLFIRI plus cetuximab treated population (67.5% vs. 47.9% p = 0.0013), and was significantly associated with PFS in the cetuximab arm (logrank test p = 0.023) and OS (logrank test p = 0.0005 and p = 0.0043) in the respective treatment arms. Depth of response was significantly greater in FOLFIRI plus cetuximab treated patients (48.2% vs. 33.0%, Wilcoxon test p = 0.0005) and associated with post progression survival (Bravais Pearson test p Conclusions: Based on an independent radiological review, FOLFIRI plus cetuximab induced a significantly higher ORR, a greater rate of ETS, and an increased DpR compared to FOLFIRI plus bevacizumab. These response-related outcomes may in part explain the significant OS advantage of FOLFIRI plus cetuximab observed in FIRE-3. Disclosure: S. Stintzing: Honoraria: Amgen, Merck, Roche, Sanofi Travel expenses: Amgen, Merck, Roche, Sanofi; D.P. Modest: Honoraria and travel grants: Merck, Roche, Amgen; C. Giessen: Travel support: Roche; M. Moehler: Merck: Research grants and advisory board member Roche: congress speaker and advisory board member; V. Heinemann: Honoraria and travel expenses: Roche, Merck, Amgen, Sanofi, Bayer Research Fund: Merck, Roche. All other authors have declared no conflicts of interest.