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Aim: The open-label, nonrandomized, phase II APEC study enrolled 167 patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC) to investigate the safety and efficacy of first-line, every-2-weeks cetuximab plus investigator's choice of FOLFIRI or FOLFOX in this patient population., Methods: A subgroup analysis of the APEC study population by primary tumor location was performed., Results: A total of 130 patients (81.8%) had left-sided and 29 (18.2%) had right-sided mCRC. Median progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) were 14.0 months, 30.6 months and 68.5% for patients with left-sided tumors and 8.9 months, 24.6 months and 51.7% for patients with right-sided mCRC, concurring with pivotal phase III trial results. In patients with right-sided tumors, median PFS was 15.4 months vs 8.3 months with cetuximab plus FOLFIRI vs cetuximab plus FOLFOX, respectively; median OS was 32.1 months vs 21.8 months with cetuximab plus FOLFIRI vs cetuximab plus FOLFOX, respectively., Conclusion: The APEC tumor-location subgroup analysis results were largely consistent with available literature regarding the equivalent efficacy of cetuximab plus FOLFIRI/FOLFOX in patients with left-sided RAS wt mCRC. A trend toward improved efficacy with cetuximab plus FOLFIRI compared with cetuximab plus FOLFOX was observed in patients with right-sided tumors; however, a direct comparison between groups cannot be made due to the nonrandomized study design. Nevertheless, the similar ORR observed with either chemotherapy backbone in patients with right-sided RAS wt mCRC suggests a potential role for both regimens in this patient population when cytoreduction is a treatment goal., (© 2019 The Authors. Asia-Pacific Journal of Clinical Oncology Published by John Wiley & Sons Australia, Ltd.)

The First-Line Erbitux in Lung Cancer (FLEX) trial showed that the addition of cetuximab to chemotherapy followed by weekly cetuximab maintenance significantly improved survival in the first-line treatment of advanced non-small cell lung cancer (NSCLC). The phase IIIb NSCLC Erbitux Trial (NEXT) trial (NCT00820755) investigated the efficacy and safety of weekly and every 2 weeks cetuximab maintenance therapy in this setting. Patients were treated with platinum-based chemotherapy plus cetuximab, and those progression-free after four to six cycles were randomized to every 2 weeks (500 mg/m(2)) or weekly (250 mg/m(2)) cetuximab maintenance. Randomization was stratified for tumor histology and response status. The primary endpoint for a regimen would be reached if the lower boundary of the 95 % confidence interval (CI) for the 1-year survival rate exceeded 55 %. A planned 480 patients were to be randomized. However, enrollment was curtailed following a negative opinion from the European Medicines Agency with regard to the use of cetuximab in this setting. After combination therapy, 311/583 (53.3 %) patients without progression were randomized to maintenance therapy: 157 to every 2 weeks cetuximab and 154 to weekly cetuximab. Baseline characteristics were balanced between these groups and exposure to cetuximab was similar. The 1-year survival rate was 62.8 % (95 % CI, 54.7-70.0) for every 2 weeks cetuximab and 64.4 % (95 % CI, 56.2-71.4) for weekly cetuximab. Safety profiles were similar, manageable, and in line with expectations. Therefore, in patients with advanced NSCLC who were progression-free after four to six cycles of first-line chemotherapy plus cetuximab, weekly and every 2 weeks cetuximab maintenance therapy were associated with similar survival outcomes.

Cetuximab every 2 weeks (Q2W) dosing schedule is approved by the US FDA and by the Japanese Pharmaceuticals and Medical Devices Agency in patients with metastatic colorectal cancer and squamous cell carcinoma of the head and neck. Phase II trials have found comparable efficacy and safety for the weekly (Q1W) and Q2W schedules, and real-world studies have shown noninferiority of the Q2W compared with the Q1W schedule. Several guidelines recommend cetuximab Q2W administration as an alternative to the Q1W dosing schedule. Cetuximab Q2W can be administered with a Q2W dose of chemotherapy, making it a more convenient option to the Q1W schedule, potentially resulting in reduced costs for administration, increased flexibility for clinical staff and improved patient adherence. Cetuximab is a drug for patients with colorectal cancer or cancer of the head and neck. It is usually administered once a week. However, studies have shown that cetuximab given once every 2 weeks instead has similar clinical benefits and side effects. Based on this evidence, the every 2 weeks dosing schedule has been approved for use in USA and Japan. The every 2 weeks dosing schedule is a convenient alternative to the weekly schedule. It may result in fewer hospital visits, improved patient quality of life, reduced healthcare costs and more flexibility for medical staff. This review summarizes the current evidence and benefits for the every 2 weeks dosing schedule. A review highlights comparable pharmacokinetics, efficacy and safety data reported for #cetuximab #every2weeks and weekly dosing schedules. [ABSTRACT FROM AUTHOR]

Aim: To examine the impact of tumor sidedness on clinical outcomes in Chinese patients with metastatic colorectal cancer treated with folinic acid/fluorouracil/oxaliplatin (FOLFOX-4) ± cetuximab in the TAILOR trial. Patients & methods: Clinical data from 391 patients were evaluated for tumor sidedness. Results: Patients with left-sided tumors who received cetuximab plus FOLFOX-4 had a significantly longer overall survival (medians: 22.0 vs 18.3 months; p = 0.007) and progression-free survival (medians: 9.3 vs 7.9 months; p = 0.006) compared with FOLFOX-4 alone. Overall survival (medians: 11.5 vs 9.4 months; p = 0.664) and progression-free survival (medians: 7.4 vs 4.5 months; p = 0.068) also improved in patients with right-sided tumors. Conclusion: Adding cetuximab to first-line FOLFOX-4 in patients with metastatic colorectal cancer improved clinical outcomes irrespective of primary tumor side. Cetuximab is a drug used to treat people with advanced metastatic colorectal cancer (mCRC) with a gene called RAS wild-type (wt) and is given along with standard chemotherapy. The TAILOR study showed that in people with RAS wt mCRC cetuximab together with chemotherapy worked better than chemotherapy alone and had similar side effects. This analysis of the TAILOR study looked at whether Chinese people with RAS wt mCRC responded differently to treatment with cetuximab plus chemotherapy depending on the primary tumor location (whether left or right side of the colon). This analysis found that people with left- or right-sided primary tumors who received cetuximab plus chemotherapy lived longer and their cancer progressed more slowly compared with those who received chemotherapy alone. In the #TAILORstudy subanalysis #cetuximab plus chemotherapy in first-line treatment of RAS wild-type #metastaticcolorectalcancer improved #clinicaloutcomes irrespective of #primarytumorside. [ABSTRACT FROM AUTHOR]

Background: The multicenter, open‐label, randomized, phase III EPIC study (EMR 062202‐025) investigated cetuximab plus irinotecan versus irinotecan in patients with epidermal growth factor receptor–detectable metastatic colorectal cancer (mCRC) that progressed on first‐line fluoropyrimidine‐ and oxaliplatin‐based chemotherapy; we report the outcomes of patients with RAS‐wild‐type (wt) disease. Materials and Methods: Available DNA samples from RAS‐unselected patients (n = 1,164 of 1,298 [89.7%]) were reanalyzed for RAS mutations using beads, emulsion, amplification, and magnetics. Baseline characteristics, efficacy, safety, and poststudy therapy were assessed. RAS‐wt status was defined as a mutated RAS allele frequency of ≤5%, with all relevant alleles being analyzable. Results: Baseline characteristics were comparable between the groups (n = 452 patients with RAS‐wt mCRC; cetuximab plus irinotecan n = 231, irinotecan n = 221) and between the RAS‐wt and RAS‐unselected populations. In the cetuximab plus irinotecan versus irinotecan arms, median overall survival was 12.3 versus 12.0 months, median progression‐free survival (PFS) was 5.4 versus 2.6 months, and objective response rate (ORR) was 29.4% versus 5.0%, respectively. Quality of life (QoL) was improved in the cetuximab plus irinotecan arm. Serious adverse events occurred in 45.4% (cetuximab plus irinotecan) and 42.4% (irinotecan) of patients. In total, 47.1% of patients in the irinotecan arm received subsequent cetuximab therapy. Conclusion: PFS, ORR, and QoL were improved with cetuximab plus irinotecan as a second‐line treatment in patients with RAS‐wt mCRC, confirming that cetuximab‐based therapy is suitable in this population. Almost half of patients in the irinotecan arm received poststudy cetuximab, masking a potential overall survival benefit of cetuximab addition. Implications for Practice: Cetuximab is approved for the treatment of RAS–wild‐type metastatic colorectal cancer (mCRC). In this retrospective analysis of the phase III EPIC study (cetuximab plus irinotecan vs. irinotecan alone as second‐line treatment in patients with RAS‐unselected mCRC), the subgroup of patients with RAS–wild‐type mCRC who received cetuximab plus irinotecan had improved progression‐free survival, objective response rate, and quality of life compared with the RAS‐unselected population. These findings suggest that cetuximab‐based therapy is a suitable second‐line treatment for patients with RAS–wild‐type mCRC. This article analyzes outcomes of patients with RAS‐wild‐type metastatic colorectal cancer who received cetuximab plus irinotecan versus irinotecan alone in the EPIC trial. [ABSTRACT FROM AUTHOR]

Aim: The open‐label, nonrandomized, phase II APEC study enrolled 167 patients with RAS wild‐type (wt) metastatic colorectal cancer (mCRC) to investigate the safety and efficacy of first‐line, every‐2‐weeks cetuximab plus investigator's choice of FOLFIRI or FOLFOX in this patient population. Methods: A subgroup analysis of the APEC study population by primary tumor location was performed. Results: A total of 130 patients (81.8%) had left‐sided and 29 (18.2%) had right‐sided mCRC. Median progression‐free survival (PFS), overall survival (OS) and overall response rate (ORR) were 14.0 months, 30.6 months and 68.5% for patients with left‐sided tumors and 8.9 months, 24.6 months and 51.7% for patients with right‐sided mCRC, concurring with pivotal phase III trial results. In patients with right‐sided tumors, median PFS was 15.4 months vs 8.3 months with cetuximab plus FOLFIRI vs cetuximab plus FOLFOX, respectively; median OS was 32.1 months vs 21.8 months with cetuximab plus FOLFIRI vs cetuximab plus FOLFOX, respectively. Conclusion: The APEC tumor‐location subgroup analysis results were largely consistent with available literature regarding the equivalent efficacy of cetuximab plus FOLFIRI/FOLFOX in patients with left‐sided RAS wt mCRC. A trend toward improved efficacy with cetuximab plus FOLFIRI compared with cetuximab plus FOLFOX was observed in patients with right‐sided tumors; however, a direct comparison between groups cannot be made due to the nonrandomized study design. Nevertheless, the similar ORR observed with either chemotherapy backbone in patients with right‐sided RAS wt mCRC suggests a potential role for both regimens in this patient population when cytoreduction is a treatment goal. [ABSTRACT FROM AUTHOR]

The article presents a study which investigates the incidence of infusion-related reactions (IRR) of patients with metastatic colorectal cancer (mCRC) treated with Irinotecan, Cetuximab and premedications of corticosteroids and antihistamines. Methodology involves a post-hoc analysis of the monoclonal antibody erbitux in a European pre-license (MABEL) study in regards to IRR and premedications. It reveals that mCRC premedicated patients have reduced incidence of Cetuximab-associated IRRs.

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. [ABSTRACT FROM AUTHOR]

Treatment outcomes have improved with the advent of immune checkpoint inhibitors and small molecule inhibitors. However, many patients do not respond with single agents. Consequently, ongoing research is focused on the use of combination therapies to increase clinical efficacy by potential synergistic effects. Here, we outline ongoing trials and review the rationale and evidence for the combination of avelumab, an anti-programmed death ligand 1 (PD-L1) immunoglobulin G1 (IgG1) monoclonal antibody (mAb), with cetuximab, an anti-epidermal growth factor receptor (EGFR) IgG1 mAb. Avelumab is approved as a monotherapy for the treatment of Merkel cell carcinoma and urothelial carcinoma, and in combination with axitinib for renal cell carcinoma; cetuximab is approved in combination with chemotherapy for the treatment of squamous cell carcinoma of the head and neck (SCCHN) and RAS wild-type metastatic colorectal cancer, and in combination with radiation therapy for SCCHN. Avelumab binds to PD-L1 expressed on tumor cells and immune regulatory cells, thus blocking its interaction with programmed death 1 and reventing T-cell suppression; cetuximab inhibits the EGFR signaling pathway, inhibiting proliferation and inducing apoptosis. Both therapies have complementary mechanisms of action and may also activate the immune system to induce innate effector function through the binding of their Fc regions to natural killer (NK) cells. Furthermore, cetuximab combined with chemotherapy has been shown to induce immunogenic cell death and leads to an increase in tumor-infiltrating CD8+ T and NK cells, which should synergize with the immunostimulatory effects of avelumab. Prospective studies will investigate this combination and inform future treatment strategies. [ABSTRACT FROM AUTHOR]

This study assessed whether cetuximab 500 mg/m2 administered every 2 weeks (Q2W), when combined with chemotherapy as a first-line (1L) treatment, was noninferior to the approved dose (400 mg/m2 followed by 250 mg/m2 once weekly [Q1W]) for overall survival (OS) in adults with RAS wild-type metastatic colorectal cancer (mCRC). This pooled analysis included patients receiving 1L treatment with cetuximab Q1W or Q2W in combination with chemotherapy from post-authorisation studies with patient-level data available to the sponsor. Baseline characteristics were adjusted with a propensity score using inverse probability of treatment weighting (IPTW). Noninferiority in terms of OS was tested with a noninferiority margin for the hazard ratio (HR) of 1.25 using a Cox proportional hazards regression model. Secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and rates of lung/liver metastases resection and serious adverse events. OS time was noninferior in the Q2W cohort (n = 554) compared to the Q1W cohort (n = 763), with a HR after IPTW (95% confidence interval) of 0.827 (0.715–0.956) and median OS times of 24.7 (Q1W) and 27.9 (Q2W) months. There were no major differences in PFS (HR: 0.915 [0.804–1.042]). The odds ratios (ORs) after IPTW for ORR (1.292 [1.031–1.617]) and the rates of lung/liver metastases resection (1.419 [1.043–1.932]) favoured the Q2W regimen. No differences were noted in the occurrence rate of any SAE between groups; the OR after IPTW was 1.089 (0.858–1.382). The cetuximab Q2W regimen was noninferior to the Q1W regimen for OS in the 1L treatment of mCRC. • A pooled analysis of patients given 1L cetuximab Q1W or Q2W was performed. • Results showed noninferiority of Q2W dosing for OS. • PFS and safety were unaffected by dosing. • Resection rates of lung/liver metastases favoured Q2W schedule. [ABSTRACT FROM AUTHOR]

Abstract: Background: The phase III EXTREME and CRYSTAL studies demonstrated that the addition of cetuximab to chemotherapy significantly improved survival in the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) and KRAS wild-type metastatic colorectal cancer (mCRC). In advanced non-small-cell lung cancer (NSCLC), high EGFR expression was identified as a tumour biomarker that can predict survival benefit associated with the addition of cetuximab to first-line chemotherapy. We investigated whether tumour EGFR expression level was predictive of cetuximab benefit in EXTREME and CRYSTAL study patients. Methods: Prospectively collected tumour immunohistochemistry data were used to generate an EGFR immunohistochemistry score (scale 1–300) for patients in the EXTREME and CRYSTAL studies. For each study, the association between tumour immunohistochemistry score and cetuximab benefit was investigated. The EXTREME and CRYSTAL studies are registered with Clinical Trials.gov, numbers NCT00122460 and NCT00154102, respectively. Findings: Tumour EGFR immunohistochemistry data were available for 411 of 442 (93%) patients from the EXTREME study intention-to-treat (ITT) population and 664 of 666 (100%) patients from the ITT population of the CRYSTAL study with EGFR-expressing, KRAS wild-type disease. The distribution of immunohistochemistry scores was similar between the treatment arms of each study, but differed between studies. A clinically relevant benefit for progression-free and overall survival associated with the addition of cetuximab to chemotherapy was seen across the full score range in EXTREME study patients. Similarly, CRYSTAL study patients derived a clinical benefit across the full score range, with no meaningful association between EGFR expression level and benefit. Interpretation: The addition of cetuximab to chemotherapy improved survival in the first-line treatment of recurrent/metastatic SCCHN and KRAS wild-type mCRC regardless of tumour EGFR expression level, indicating that in contrast to findings in NSCLC, EGFR expression level is not a clinically useful predictive biomarker in these settings. [Copyright &y& Elsevier]