Addition Of Cetuximab Research Articles

MITO (Multicentre Italian Trials in Ovarian cancer): CERV 2 trial—A randomized phase II study of carboplatin and paclitaxel +/- cetuximab, in advanced and/or recurrent cervical cancer.

5520 Background: Carboplatin (C) plus paclitaxel (P) is among standard options for treatment of advanced or recurrent cervical cancer (ARCC) patients (pts). Cervical cancer cells often express Epidermal Growth Factor receptor (EGFR). Cetuximab (CET), an anti-EGFR monoclonal antibody, can be safely combined with CP. MITO-CERV 2 is a comparative randomized phase 2 study, testing the addition of CET to CP. Methods: ARCC pts, < 2 previous chemotherapy, ECOG PS≤1, were randomized to CP (C AUC5 + P 175 mg/m², d1q21) for 6 cycles +/- CET (400 mg/m² one week before starting CP, then 250 mg/m² weekly) until disease progression or unacceptable toxicity. Primary endpoint was event-free survival (EFS), i.e. time from randomization to progression, death, definitive discontinuation of the whole treatment or loss to follow-up, whichever occurred first. With a 4.5 mos expected median EFS and a 6.4 mos auspicated EFS (HR 0.70), 0.20 one-tailed α and 80% power, 89 events were required for the final intent-to-treat analysis...

A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer

Previous clinical trials have not proved that adding epidermal growth factor receptor inhibitors to chemotherapy confers a survival benefit for patients with advanced biliary tract cancer (ABTC). Whether the KRAS mutation status of tumor cells confounded the results of past studies is unknown. ABTC patients stratified by KRAS status, Eastern Cooperative Oncology Group performance status, and primary tumor location were randomized 1 : 1 to receive GEMOX (800 mg/m(2) gemcitabine and 85 mg/m(2) oxaliplatin) or C-GEMOX (500 mg/m(2) cetuximab plus GEMOX) every 2 weeks. The primary end point was objective response rate (ORR). The study enrolled 122 patients between December 2010 and May 2012 (62 treated with C-GEMOX and 60 with GEMOX). Compared with GEMOX alone, C-GEMOX was associated with trend to better ORR (27% versus 15%; P = 0.12) and progression-free survival (PFS, 6.7 versus 4.1 months; P = 0.05), but not overall survival (OS, 10.6 versus 9.8 months; P = 0.91). KRAS mutations, which were detected in 36% of tumor samples, did not affect the trends of difference in ORR and PFS between C-GEMOX and GEMOX. The two treatment arms had similar adverse events, except that more patients had skin rashes, allergic reactions, and neutropenia in the C-GEMOX arm. Of patients with C-GEMOX, the presence of a grade 2 or 3 skin rash was associated with significantly better ORR, PFS, and OS. Addition of cetuximab did not significantly improve the ORR of GEMOX chemotherapy in ABTC, although a trend of PFS improvement was observed. The trend of improvement did not correlate with KRAS mutation status. This study is registered at ClinicalTrials.gov (NCT01267344). All patients gave written informed consent.

Biologic therapies in colorectal cancer: indications and contraindications.

The role of antiangiogenic and anti-epidermal growth factor receptor (EGFR) agents has been investigated extensively in colorectal cancer in the palliative, adjuvant, and neoadjuvant settings. Although the role of biologic agents has become well-defined in the first, second, and subsequent lines of treatment of metastatic colorectal cancer (mCRC), considerable debate continues around the optimal sequencing and around optimal patient selection. The benefits from integrating bevacizumab or cetuximab in the adjuvant setting have been investigated in several randomized phase III clinical trials in stage II/III disease, all with disappointing results. Neoadjuvant approaches incorporating biologic therapy in patients with liver metastatic disease have led to mixed results. Although the current evidence does suggest increased down-staging and increased resectability with the addition of cetuximab in patients with initially unresectable or borderline resectable liver metastases, a positive effect of anti-EGFR therapy on the overall survival (OS) in this setting is not conclusive. Patients with resectable liver metastases derive no benefit and may experience potential harm from the addition of cetuximab to neoadjuvant chemotherapy. Similarly, there is neither rationale nor adequate data to support the addition of bevacizumab to neoadjuvant chemotherapy in patients with resectable liver metastases. In this review, we examine the role of antiangiogenesis and anti-EGFR therapies across the spectrum of adjuvant, neoadjuvant, and metastatic disease.

Systemic Therapy for Metastatic or Recurrent Squamous Cell Carcinoma of the Head and Neck.

This article summarizes the systemic treatment options for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck, with an emphasis on recommendations based on phase II and III comparison trials of commercially available agents. Many single-agent and combination regimens have activity against these cancers, but improvement in overall survival remains a challenge, and median survivals in this population with best available therapy remain less than 1 year. The major recent advancement has been the introduction of epidermal growth factor receptor inhibitors, with mixed success. Although single-agent treatment with methotrexate, paclitaxel, docetaxel, or 5-fluorouracil remains one standard for many patients, the use of cisplatin- or carboplatin-based multidrug regimens that include cetuximab has become more popular, primarily based on one randomized study demonstrating a modest survival improvement of approximately 3 months associated with the addition of cetuximab. The burdensome adverse event profile of multidrug regimens makes appropriate patient selection for such aggressive treatment challenging, and consideration should include factors such as need for palliation, performance status of the patients, history of prior treatment, convenience, and cost. Genetically targeted and immunologically mediated treatments are promising but remain experimental. Given the worrisome prognosis for these patients, innovative clinical trials are a good option for many patients and deserve support.

FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer

BackgroundThe OPUS study demonstrated that addition of cetuximab to 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX4) significantly improved objective response and progression-free survival (PFS) in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer (mCRC). In patients with KRAS exon 2 mutations, a detrimental effect was seen upon addition of cetuximab to FOLFOX4. The current study reports outcomes in subgroups defined by extended RAS testing. Patients and methodsSamples from OPUS study KRAS exon 2 wild-type tumours were reanalysed for other RAS mutations in four additional KRAS codons (exons 3–4) and six NRAS codons (exons 2–4) using BEAMing. A cutoff of ⩾5% mutant/wild-type sequences was selected to define RAS status; we also report an analysis using a cutoff based on the technical lower limit for mutation identification (0.1%). ResultsOther RAS mutations were detected in 31/118 (26%) evaluable patients. In the extended analysis of RAS wild-type tumours (n=87), objective response was significantly improved by addition of cetuximab to FOLFOX4 (58% versus 29%; odds ratio 3.33 [95% confidence interval 1.36–8.17]; P=0.0084); although limited by population size, there also appeared to be trends favouring the cetuximab arm in terms of PFS and overall survival in the RAS wild-type group compared with the RAS evaluable group. There was no evidence that patients with other RAS mutations benefited from cetuximab, but small numbers precluded precise estimations of treatment effects. In the combined population of patients with any RAS mutation (KRAS exon 2 or other RAS), a clear detrimental effect was associated with addition of cetuximab to FOLFOX4. ConclusionPatients with RAS-mutant mCRC, as defined by mutations in KRAS and NRAS exons 2–4, derive no benefit and may be harmed by the addition of cetuximab to FOLFOX4. Restricting cetuximab administration to patients with RAS wild-type tumours will further tailor therapy to maximise benefit.

A randomized, phase II trial of cetuximab with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer

The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. A phase I trial demonstrated tolerability of this combination. This randomized phase II study evaluated PX-866 combined with cetuximab in patients with advanced, refractory HNSCC. Patients with recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1 : 1) to cetuximab with or without PX-866 (8 mg p.o. daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival (OS), toxicity, and correlation of key biomarkers with efficacy outcomes. Eighty-three patients were enrolled. There was a similar response rate between arms (10% versus 7%). Of patients for whom tissue was assessable, 57% were human papillomavirus (HPV) positive. Median PFS was 80 days in both arms and there was no difference in OS between the two arms (211 versus 256 days). Overall toxicity was higher in arm A compared with arm B, especially in terms of nausea (53% versus 23%), vomiting (45% versus 15%), fatigue (43% versus 23%), diarrhea (40% versus 21%), and hypokalemia (25% versus 10%). Grade 3 or higher adverse events were infrequent, but more common in the combination arm although without a specific pattern. PIK3CA mutations were observed in 17% of the cases assessed, and PTEN loss was infrequently observed. The addition of PX-866 to cetuximab did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC enrolled without molecular preselection. In this contemporary cohort, HPV-positive patients comprised the majority, and neither HPV-positive nor HPV-negative patients derived clinical benefit for the addition of cetuximab plus PX-866.

Optimizing the sequence of anti-EGFR-targeted therapy in EGFR-mutant lung cancer.

Metastatic EGFR-mutant lung cancers are sensitive to the first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib, and afatinib, but resistance develops. Acquired resistance to gefitinib or erlotinib occurs most commonly (>50%) via the emergence of a second-site EGFR mutation, T790M. Two strategies to overcome T790M-mediated resistance are dual inhibition of EGFR with afatinib plus the anti-EGFR antibody cetuximab (A+C), or mutant-specific EGFR inhibition with AZD9291. A+C and AZD9291 are now also being tested as first-line therapies, but whether these therapies will extend progression-free survival or induce more aggressive forms of resistance in this setting remains unknown. We modeled resistance to multiple generations of anti-EGFR therapies preclinically to understand the effects of sequential treatment with anti-EGFR agents on drug resistance and determine the optimal order of treatment. Using a panel of erlotinib/afatinib-resistant cells, including a novel patient-derived cell line (VP-2), we found that AZD9291 was more potent than A+C at inhibiting cell growth and EGFR signaling in this setting. Four of four xenograft-derived A+C-resistant cell lines displayed in vitro and in vivo sensitivity to AZD9291, but four of four AZD9291-resistant cell lines demonstrated cross-resistance to A+C. Addition of cetuximab to AZD9291 did not confer additive benefit in any preclinical disease setting. This work, emphasizing a mechanistic understanding of the effects of therapies on tumor evolution, provides a framework for future clinical trials testing different treatment sequences. This paradigm is applicable to other tumor types in which multiple generations of inhibitors are now available.

HER2 as a therapeutic target in head and neck squamous cell carcinoma.

The majority of patients with head and neck squamous cell carcinoma (HNSCC) present with advanced-stage disease. The current standard of care is surgery followed by adjuvant radiotherapy with or without chemotherapy or chemoradiation alone. The addition of cetuximab for the treatment of patients with locally advanced or recurrent/metastatic HNSCC has improved overall survival and locoregional control; however, responses are often modest, and treatment resistance is common. A variety of therapeutic strategies are being explored to overcome cetuximab resistance by blocking candidate proteins implicated in resistance mechanisms such as HER2. Several HER2 inhibitors are in clinical development for HNSCC, and HER2-targeted therapy has been approved for several cancers. This review focuses on the biology of HER2, its role in cancer development, and the rationale for clinical investigation of HER2 targeting in HNSCC.

Acquired mutations in MAPK signaling pathway following initial pharmacological response in BRAF-mutated metastatic colorectal cancer (mCRC).

629 Background: BRAF V600 mutations are associated with inferior survival and limited responses to standard therapies. Blockade of BRAF by vemurafenib generates reflexive activation of EGFR, whose activity can be overcome by concomitant addition of cetuximab. Early-phase clinical trials have demonstrated objective responses with the combination of vemurafenib and cetuximab in patients with BRAFmutmCRC. Mechanisms of resistance following initial anti-tumor response have not yet been described. Methods: Patient-derived xenograft (PDX) models of BRAFmut mCRC have been established at our institution by subcutaneous implantation of tumor into NSG female mice. Here, two different models of BRAFmut mCRC, one with innate sensitivity to vemurafenib and another with innate resistance, were selected for further study. Mice were given vemurafenib chow (417 mg/kg) and/or intraperitoneal cetuximab (1 mg/kg twice a week). Tumor dimensions were serially measured. Tumor resistance developed after a median of 35 days. Tumor DNA was extracted, and whole exome sequencing was performed and compared to untreated controls. Results: In one model of BRAFmut mCRC, 8 mice treated with vemurafenib demonstrated an initial complete response but later developed resistance despite continued treatment. Exome sequencing of the resistant tumors from 6 of 8 mice revealed novel mutations in EGFR, KRAS, NRAS, and MEK not detected in untreated controls (Table). All mutations are predicted to be damaging in COSMIC. Expansion of tumors with acquired NRAS G13D mutation into another generation of mice showed cross-resistance with the combination of BRAF and EGFR inhibition in vivo. In contrast, another PDX model with innate resistance to vemurafenib did not acquire additional mutations in MAPK oncogenes. Conclusions: Acquired activating mutations in oncogenes critical to MAPK signaling have not been described in BRAFmut mCRC after initial pharmacological response. Such mutations, if present as low-frequency clones prior to treatment, may generate resistance following treatment with BRAF and EGFR inhibitors. [Table: see text]

Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study

We aimed to compare overall survival after standard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer. In this open-label randomised, two-by-two factorial phase 3 study in 185 institutions in the USA and Canada, we enrolled patients (aged ≥ 18 years) with unresectable stage III non-small-cell lung cancer, a Zubrod performance status of 0-1, adequate pulmonary function, and no evidence of supraclavicular or contralateral hilar adenopathy. We randomly assigned (1:1:1:1) patients to receive either 60 Gy (standard dose), 74 Gy (high dose), 60 Gy plus cetuximab, or 74 Gy plus cetuximab. All patients also received concurrent chemotherapy with 45 mg/m(2) paclitaxel and carboplatin once a week (AUC 2); 2 weeks after chemoradiation, two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). Randomisation was done with permuted block randomisation methods, stratified by radiotherapy technique, Zubrod performance status, use of PET during staging, and histology; treatment group assignments were not masked. Radiation dose was prescribed to the planning target volume and was given in 2 Gy daily fractions with either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy. The use of four-dimensional CT and image-guided radiation therapy were encouraged but not necessary. For patients assigned to receive cetuximab, 400 mg/m(2) cetuximab was given on day 1 followed by weekly doses of 250 mg/m(2), and was continued through consolidation therapy. The primary endpoint was overall survival. All analyses were done by modified intention-to-treat. The study is registered with ClinicalTrials.gov, number NCT00533949. Between Nov 27, 2007, and Nov 22, 2011, 166 patients were randomly assigned to receive standard-dose chemoradiotherapy, 121 to high-dose chemoradiotherapy, 147 to standard-dose chemoradiotherapy and cetuximab, and 110 to high-dose chemoradiotherapy and cetuximab. Median follow-up for the radiotherapy comparison was 22.9 months (IQR 27.5-33.3). Median overall survival was 28.7 months (95% CI 24.1-36.9) for patients who received standard-dose radiotherapy and 20.3 months (17.7-25.0) for those who received high-dose radiotherapy (hazard ratio [HR] 1.38, 95% CI 1.09-1.76; p=0.004). Median follow-up for the cetuximab comparison was 21.3 months (IQR 23.5-29.8). Median overall survival in patients who received cetuximab was 25.0 months (95% CI 20.2-30.5) compared with 24.0 months (19.8-28.6) in those who did not (HR 1.07, 95% CI 0.84-1.35; p=0.29). Both the radiation-dose and cetuximab results crossed protocol-specified futility boundaries. We recorded no statistical differences in grade 3 or worse toxic effects between radiotherapy groups. By contrast, the use of cetuximab was associated with a higher rate of grade 3 or worse toxic effects (205 [86%] of 237 vs 160 [70%] of 228 patients; p<0.0001). There were more treatment-related deaths in the high-dose chemoradiotherapy and cetuximab groups (radiotherapy comparison: eight vs three patients; cetuximab comparison: ten vs five patients). There were no differences in severe pulmonary events between treatment groups. Severe oesophagitis was more common in patients who received high-dose chemoradiotherapy than in those who received standard-dose treatment (43 [21%] of 207 patients vs 16 [7%] of 217 patients; p<0.0001). 74 Gy radiation given in 2 Gy fractions with concurrent chemotherapy was not better than 60 Gy plus concurrent chemotherapy for patients with stage III non-small-cell lung cancer, and might be potentially harmful. Addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival for these patients. National Cancer Institute and Bristol-Myers Squibb.

Does the Addition of Cetuximab to Radiochemotherapy Improve Outcome of Patients with Locally Advanced Rectal Cancer? Long-Term Results from Phase II Trials.

Purpose. The addition of cetuximab to radiochemotherapy (RCT) failed to improve complete response rates in locally advanced rectal cancer (LARC). We report the long-term results in patients treated within two sequential clinical trials. Methods. Patients receiving neoadjuvant RCT using capecitabine and irinotecan (CapIri) within a phase I/II trial or CapIri + cetuximab within a phase II trial were evaluated for analysis of disease-free survival (DFS) and overall survival (OS). KRAS exon 2 mutational status had been analyzed in patients receiving cetuximab. Results. 37 patients from the CapIri trial and 49 patients from the CapIri-cetuximab treatment group were evaluable. Median follow-up time was 75.2 months. The 5-year DFS rate was 82% (CapIri) and 79% (CapIri-cetuximab) (P = 0.62). The median OS was 127.4 months. 5-year OS was 73% for both groups (CapIri and CapIri-cetuximab) (P = 0.61). No significant difference in DFS (P = 0.86) or OS (P = 0.39) was noticed between patients receiving CapIri and those receiving CapIri-cetuximab with KRAS wild-type tumors. Conclusions. As the addition of cetuximab did not improve neither DFS nor OS it should not play a role in the perioperative treatment of patients with LARC, not even of patients with (K)RAS WT tumors.

Cost-effectiveness Analysis of Cetuximab in Treatment of Metastatic Colorectal Cancer in Iranian Pharmaceutical Market.

Background:Cetuximab is a monoclonal antibody which acts against the epidermal growth-factor receptor. Randomized controlled trials show that the addition of cetuximab to folinic acid, 5-flourouracil, irinotecan (FOLFIRI), folinic acid, 5-flourouracil, oxaliplatin (FOLFOX) and capecitabin + oxaliplatin (CAPOX) regimens, as the first-line treatment for metastatic colorectal cancer (CRC), increases the overall survival (OS) and progression-free survival (PFS) compared to FOLFIRI, FOLFOX and CAPOX regimens alone. The aim of this study was to analyze the cost-effectiveness of different treatment programs for managing metastatic CRC with and without cetuximab in the first-line treatment of unresectable metastatic CRC in Iran.Methods:A systematic search of the literature was performed in PubMed, Centre for Reviews and Dissemination Databases and Cochrane Library to assess the effectiveness of the drug in the context of PFS, OS and the adverse events. The incremental cost-effectiveness ratio of each treatment program was calculated. An extensive sensitivity analysis was conducted on the results regarding the effectiveness.Results:The addition of cetuximab to FOLFIRI, FOLFOX and CAPOX programs increased PFS by 0.1, 0.042 and 0.042 years, respectively. Similarly, the addition of cetuximab to FOLFIRI, FOLFOX and CAPOX increased OS by 0.325, 0.442 and 0.442 years and also cost $212825, $202484 and $204198 individually. Whereas, based on the World Health Organisation (WHO) suggested threshold for cost-effectiveness analysis, even FOLFOX + cetuximab was very higher than the threshold in Iran (37.4 times higher).Conclusions:The FOLFOX regimen + cetuximab provides lower costs per additional life years gained (more cost-effective) compared with its alternatives in the treatment of patients with unresectable metastatic CRC. However, according to the WHO indicator, none of the cetuximab regimens could be considered as cost effective for the Iranian health care market.

Prognostic effect of a single nucleotide polymorphism (SNP) in MIR608 in patients with high-risk locally advanced rectal cancer (LARC): Results of the EXPERT-C trial.

581 Background: An association between rs4919510, a SNP of mir-608, and prognosis of patients with colorectal cancer has been reported. However, no studies have analysed the role of this SNP in LARC. We conducted a pharmacogenomic analysis of rs4919510 in EXPERT-C, a randomised phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX ± cetuximab in high-risk LARC. Methods: SNP analysis was performed on DNA extracted from tumour tissue. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms. Results: A total of 155/164 (94.5%) patients had tumours assessable for rs4919510 genotyping. 95 (61.3%) were homozygous for CC, 55 (35.5%) heterozygous (CG) and 5 (3.2%) homozygous for GG with no deviation from the Hardy-Weinberg equilibrium (p=0.379). Genotypes were evenly distributed in the two treatment groups and no association with baseline clinico-pathological characteristics or tumour molecular status (including RAS) was observed. Complete response did not differ according to the tumour genotype in the entire population (14.7% for CC, 13.3% for CG/GG) and was not influenced by treatment (12.0% for CC and 14.3% for CG/GG in CAPOX, 17.8% for CC and 12.5% for CG/GG in CAPOX-C) (all p values&gt;0.05). Median follow-up was 64.9 months. In the CAPOX arm the 5-yr PFS and OS rates were 54.6% and 60.7% for CC and 82.0% and 82.1% for CG/GG, respectively (HR PFS 0.13, 95% CI: 0.12-0.83, p=0.02, HR OS 0.38, 95% CI: 0.14-1.01, p=0.05). In the CAPOX-C arm the same survival figures were 73.2% and 82.2% for CC and 64.6% and 73.1% for CG/GG (HR PFS 1.38, 95% CI: 0.61-3.13, p=0.44, HR OS 1.34, 95% CI: 0.52-3.48, p=0.55). An interaction was found between study treatment and rs4919510 genotype for both PFS (p=0.02) and OS (p=0.07). Conclusions: This is the first study investigating rs4919510 in LARC. We found that the CC genotype was associated with worse prognosis compared to the CG/GG genotype in patients treated with chemotherapy alone but not in those treated with cetuximab. The addition of cetuximab to chemotherapy may mitigate the unfavourable prognostic associated with the CC genotype.

Electrolyte disorders assessment in solid tumor patients treated with anti-EGFR monoclonal antibodies: a pooled analysis of 25 randomized clinical trials.

The role of anti-epithelial growth factor receptor monoclonal antibodies (anti-EGFR MoAbs) in treatment-related electrolyte disorders is still controversial. Therefore, we conducted a meta-analysis of published randomized controlled trials (RCTs) to evaluate the incidences and overall risks of all-grade and grade 3/4 electrolyte disorder events. We searched relevant clinical trials from PubMed, EMBASE, and Web of Knowledge databases, meeting proceedings of American Society of Clinical Oncology and the European Society of Medical Oncology, as well as ClinicalTrials.gov. Eligible studies included phases II, III, and IV RCTs. Statistical analysis was performed to calculate the summary incidence, relative risk (RR), and 95 % confidence intervals (CIs) using fixed effects or random effects models based on the heterogeneity of included studies. A total of 16,411 patients from 25 RCTs were included in this meta-analysis. The all-grade incidence of hypomagnesemia related to anti-EGFR MoAbs was 34.0 % (95 % CI 28.0–40.5 %), and that for hypokalemia and hypocalcemia were 14.5 % (95 % CI 8.2–24.4 %) and 16.8 % (95 % CI 14.2–19.7 %), respectively. Compared with chemotherapy alone in colorectal cancer, addition of cetuximab increased the risk of grade 3/4 hypomagnesemia and grade 3/4 hypokalemia with RRs of 7.14 (95 % CI 3.13–16.27, p < 0.001) and 2.19 (95 % CI 1.14–4.23, p = 0.019). Additionally, colorectal cancer patients in panitumumab cases were more vulnerable to grade 3/4 hypomagnesemia and hypokalemia (RR 18.29, 95 % CI 7.29–48.41, p < 0.001, and RR 3.3, 95 % CI 1.32–8.25, p = 0.011). Treatment with anti-EGFR MoAbs is associated with significantly higher risks of electrolyte disorders such as hypomagnesemia, hypomagnesemia, and hypocalcemia, especially in colorectal cancer. Rigorous monitoring and early treatment of electrolyte disorders are proposed.Electronic supplementary materialThe online version of this article (doi:10.1007/s13277-014-2983-9) contains supplementary material, which is available to authorized users.

State of the art: colorectal liver metastases.

●● Adjuvant treatment post-R0 resection The efficacy of pure adjuvant chemotherapy in stage 4 disease is debatable. Certainly, the benefit of adjuvant chemotherapy in stage 4 disease appears to be less than that observed with adjuvant chemotherapy in stage 3 disease. Data from a meta-analysis showed that fluorouracil (FU) afforded a bor derline significant benefit in terms of recurrence-free survival compared with surgery alone [1], while folinic acid (leucovorin), 5-fluorouracil (5-FU), irinotecan (FOLFIRI) produced a numerically better recurrence-free survival than FU, but this difference was not statistically significant [2]. Importantly, folinic acid (leucovorin), 5-FU, oxaliplatin (FOLFOX) has not been studied in this setting, although it is the regimen that is most commonly employed in clinical practice around the world. ● ● Neoadjuvant chemotherapy of resectable metastases ‘Neoadjuvant chemotherapy’ of resectable metastases has only been investigated as a ‘perioperative strategy’ (i.e., as part of a strategy in which chemotherapy is continued after surgery). A systematic review of 23 neoadjuvant chemotherapy trials for resectable colorectal liver metastases reported a median response rate of 64% (leading to a 93% R0 resection rate) and a median disease-free survival of 21 months [3]. The European Organisation for Research and Treatment of Cancer (EORTC) conducted the only randomized controlled Phase III study comparing perioperative chemotherapy (six cycles of FOLFOX before and six cycles after surgery) versus surgery alone. This study found that the absolute increase in the rate of progression-free survival at 3 years was only 7.3% (from 28.1% [95.66% CI: 21.3–35.5] to 35.4% [95.66% CI: 28.1–42.7]; HR: 0.79 [95.66% CI: 0.62–1.02]; p = 0.058) [4], with a non-significant difference in overall survival at 5 years of follow-up (HR: 0.88; 95% CI: 0.68–1.14; p = 0.339) [5]. Last year, the New EPOC study investigated the addition of adjunct cetuximab to FOLFOX perioperative chemotherapy in K-RAS-wild-type patients [6]. This study unexpectedly found that the addition of the cetuximab had a detrimental effect on survival compared with FOLFOX alone in the neoadjuvant setting (14.8 vs 24.2 months; HR: 1.5; 95% CI: 1.0–2.2; p < 0.048).

Efficacy and toxicity of adding cetuximab to chemotherapy in the treatment of metastatic colorectal cancer: a meta-analysis from 12 randomized controlled trials.

Cetuxiamb, a monoclonal antibody against epidermal growth factor receptor (EGFR), has been used in combination with chemotherapy for patients with metastatic colorectal cancer (mCRC). However, the efficacy of combined therapies of cetuximab and different chemotherapy regimens remains controversial. Therefore, we conducted a meta-analysis to evaluate the efficacy and toxicity of adding cetuximab to oxaliplatin-based or irinotecan-based chemotherapeutic regimens for the treatment of patients with mCRC with wild-type/mutated KRAS tumors. Randomized controlled trials (RCTs), published in Pubmed and Embase were systematically reviewed to assess the survival benefits and toxicity profile mCRC patients treated with cetuximab plus chemotherapy. Outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and toxicities. Results were expressed as the hazard ratio (HR) with 95% confidence intervals (CI). Pooled estimates were generated by using a fixed-effects model or a randomized-effects model, depending on the heterogeneity among studies. A total of 12 trials involving 6,297 patients met the inclusion criteria and were included in this meta-analysis. All patients were administered oxaliplatin-based or irinotecan-based chemotherapy with or without cetuximab. Pooled results showed that the addition of cetuximab did not significantly improve the OS (HR = 0.99, 95% CI = 0.89-1.09; Z = 0.28, P = 0.78) or PFS (HR = 0.94, 95% CI = 0.81-1.10; Z = 0.76, P = 0.49), but did improve ORR (RR = 1.34, 95% CI = 1.08-1.65; Z = 2.72, P = 0.00), when compared with chemotherapy alone. Subgroup analysis showed the highest PFS benefit in patients with wild-type KRAS tumors (HR = 0.80, 95% CI = 0.65-0.99; Z = 2.1, P = 0.04) or wild-type KRAS/BRAF tumors (HR = 0.64, 95% CI = 0.52-0.79; Z = 4.15, P = 0.00). When combined with cetuximab, irinotecan-based chemotherapy was significantly associated with prolonged PFS (HR = 0.79, 95% CI = 0.66-0.96; Z = 2.36, P = 0.02) for all patients with differing gene-status. The incidence of grade 3/4 adverse events, including skin toxicity, diarrhea, hypertension, anorexia, and mucositis/stomatitis, was slightly higher in the combined therapy group than in the chemotherapy-only group. Based on the current evidence, the addition of cetuximab to chemotherapy significantly improves the PFS in patients with wild-type KRAS or wild-type KRAS/BRAF tumors as well as the ORR in all patients. In addition, irinotecan-based combination therapy showed a beneficial effect on the PFS in all patients. These findings confirm the use of cetuximab in combination with chemotherapy for the treatment of patients with mCRC with wild-type KRAS tumors. Further multi-center RCTs are needed to indentify these findings.

Should the results of the new EPOC trial change practice in the management of patients with resectable metastatic colorectal cancer confined to the liver?

Biologic agents, specifically epidermal growth factor receptor blockers and vascular endothelial growth factor inhibitors, combined with cytotoxic agents have become a standard of care for the treatment of metastatic colorectal cancer (CRC) but lack proven benefit as adjuvant treatment of primary colon cancer. Patients with resectable CRC metastases limited to the liver represent an intermediate group in terms of their burden of disease and prognosis. In those patients, the 5-year life expectancy after surgery is approximately 35% to 40% compared with 75% in patients with stage III disease and 10% in unselected patients with stage IV disease. In patients with resectable liver-limited CRC randomly assigned to treatment with surgery alone or perioperative chemotherapy with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX), the risk of cancer relapse after surgery in the cohort randomly assigned to perioperative FOLFOX was reduced by one quarter. A logical next step is to raise the question, Can outcomes be improved further by combining treatment with biologic and cytotoxic agents in the perioperative setting in this increasingly common patient population? The New EPOC (Eloxatin Peri-Operative Chemotherapy) trial was organized in the United Kingdom to address this question, and the results were published and recently updated. The trial compared two groups of patients who were determined to have resectable liver metastases, all of whom received perioperative chemotherapy with FOLFOX, oxaliplatin and capecitabine (XELOX), or fluorouracil, leucovorin, and irinotecan (FOLFIRI) with a random assignment to treatment with or without the addition of the epidermal growth factor receptor–blocking antibody cetuximab. The trial initially enrolled patients regardless of KRAS mutation status in the tumor but was later restricted to patients whose tumors were found to be KRAS (exon 2) wild type. On the basis of their study’s outcome, the investigators concluded that combinations of cetuximab with chemotherapy in the perioperative setting for treatment of patients with potentially resectable colorectal liver metastases conferred no survival benefit and were actually detrimental. Data from studies in patients with advanced disease show that the addition of cetuximab or panitumumab to combination chemotherapy in patients whose tumors harbor a KRAS (exon 2) or other RAS mutations can be detrimental, although overall, patients without RAS mutations benefit from the combination. If this biology applies in the setting of resected stage IV disease, the initial inclusion of patients who did not have RAS testing may have influenced the outcome. In the N0147 (Comparison of Combination Chemotherapy Regimens With or Without Cetuximab in Treating Patients Who Have Undergone Surgery for Stage III Colon Cancer) study, which assigned patients with resected stage III CRC to FOLFOX with or without cetuximab, there was a statistically nonsignificant trend toward a detrimental effect that was independent of RAS status in the cetuximab-treated cohort. The New EPOC investigators hypothesize that molecular interactions may be playing a role in the observed outcomes in both N0147 and New EPOC, suggesting that the interplay of chemotherapy with cetuximab is different in patients with microscopic residual disease than it is in those with gross residual disease. Organizing randomized clinical trials that involve surgery and chemotherapy is difficult, and few such combined modality studies have been completed. We congratulate the investigators for meeting their accrual goal, but we are concerned that the data they published may not support the conclusions that they drew from their study because of issues surrounding surgical quality control, inclusion of patients whose surgical outcomes did not meet the predetermined study goals, incomplete data, and diversity in both the population enrolled and the regimens they received. Surgery is both an art and a science, and its practice depends on the judgment and skills of the surgeons. Studies have shown that the experience of the surgeon and the surgical team can be an important variable in patient outcomes. The impact of quality assurance of the operative procedures performed in cancer surgery trials has been explicitly demonstrated in two large, randomized Dutch trials that addressed gastric and rectal cancer surgery, both of which were practice changing. In those trials, surgeons could only recruit to the JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 33 NUMBER 3 JANUARY 2

Continued Afatinib (A) With the Addition of Cetuximab (C) After Progression on Afatinib in Patients With Acquired Resistance (AR) to Gefitinib (G) or Erlotinib (E): Metastatic Non-Small Cell Lung Cancer

In a phase 1b trial we demonstrated that combination of A+C induces robust responses (objective response rate (ORR), 29%; progression-free survival (PFS), 4.7 months) in pts with EGFR mutation-positive non-small cell lung cancer (NSCLC) who develop resistance to E/G, regardless of secondary T790M mutation status. A separate cohort in this trial additionally explored sequential use of A then A+C in such pts; we report safety and efficacy in this cohort. Pts with EGFR mutation-positive NSCLC who progressed on E/G received A 40 mg daily oral until progression, followed by A 40 mg daily oral + C 500 mg/m2 IV every 2 weeks. Endpoints included efficacy, safety, and pharmacokinetics (PK) of A+C. Thirty-seven pts received A; baseline characteristics were: median age, 58 years; female, 62%; white, 84%; T790M +/-, 54%/46%. Upon progression 31 transitioned to A+C; 4 additional pts from other A trials meeting enrollment criteria received A+C. ORR, median duration of response (DR), disease control rate (DCR) and median PFS on A alone were 5.4% (2/37 pts), 3.9 months, 56.8% (21/37), and 2.7 months, respectively. Upon progression on A, 3/35 (8.6%) of pts achieved OR (median DR, 3.7 months) and 17/35 (48.6%) of pts achieved DC on subsequent A+C, with a median PFS of 2.7 months. The 3 pts responding to A+C were different from the 2 pts responding to A. Exploratory analyses showed that pts who received A for ≥12 weeks (18/35) tended to have higher ORR (11.1 vs 5.9%), DCR (55.6 vs 41.2%) and PFS (4.8 vs 1.8 months) with A+C than those who received A for <12 weeks (17/35). Median overall exposure to A (A + A+C) for the 31 pts who transitioned from A to A+C was 5.3 months. Most frequent drug-related adverse events (DRAEs) of any grade (G) with A/A+C were diarrhea (70.3%/31.4%), rash (48.6%/71.4%), fatigue (37.8%/22.9%), stomatitis (32.4%/34.3%), nail effect (24.3%/51.4%) and dry skin (13.5%/37.1%). G3 DRAEs with A/A+C occurred in 35.1%/45.7% of pts, the most frequently occurring of which were diarrhea (5.4%/0%), rash (2.7%/20.0%), fatigue (8.1%/0%), headache (5.4%/5.7%), acne/dermatitis acneiform (0%/5.7%) and hypophosphatemia (0%/ 5.7%). Two pts on A+C (5.7%) had G4 DRAEs (hypomagnesaemia, 1 pt; rash, 1 pt). There were no G5 DRAEs. PK parameters, which did not identify a clinically relevant effect of A on exposure to C, or vice versa, will be presented. Sequential EGFR blockade with A then A+C had an acceptable safety profile and was effective, achieving responses and DC in pts with EGFR mutation-positive NSCLC with acquired resistance to E/G. Despite a low ORR, sequential use of A+C was associated with a median PFS of 2.7 months after progression on A, and may offer an alternate, more tolerable approach for treating such pts.

Cetuximab reduces the accumulation of radiolabeled bevacizumab in cancer xenografts without decreasing VEGF expression.

Bevacizumab and cetuximab are approved for the treatment of cancer. However, in advanced colorectal cancer, addition of cetuximab to chemotherapy with bevacizumab did not improve survival. The reason for the lack of activity remains unclear. The aim of this study was to determine the effect of cetuximab on VEGF expression and targeting of bevacizumab to the tumor. Mice with subcutaneous SUM149 or WiDr xenografts were treated with cetuximab, bevacizumab, or a combination of the two. Before the start of cetuximab treatment and after 7 and 21 days of treatment, the uptake of radiolabeled bevacizumab in the tumor was measured by immunoSPECT/CT. Tumor growth of SUM149 xenografts was significantly inhibited by cetuximab, bevacizumab, or their combination, whereas growth of WiDr xenografts was not affected. Cetuximab caused a significant reduction of bevacizumab uptake in SUM149 xenografts, whereas tumor-to-blood ratios in mice with WiDr xenografts did not change. Biodistribution studies with an irrelevant antibody in the SUM149 model also showed significantly reduced tumor-to-blood ratios. Cetuximab treatment did not decrease VEGF expression. Without decreasing VEGF levels, cetuximab reduces tumor targeting of bevacizumab. This could, at least partly, explain why the combination of bevacizumab and cetuximab does not result in improved therapeutic efficacy.

Abstract 3840: Cetuximab-induced testicular toxicity

Abstract Background: Cetuximab, an anti-EGFR monoclonal antibody, is the only targeted therapy approved for the treatment of head and neck squamous cell carcinoma (HNSCC) in patients with locally advanced tumors, in association with radiotherapy, and in patients with recurrent or metastatic disease, in association with cisplatin-based chemotherapy. We aimed to study the effect of cetuximab on testicular function and reserve. Methods: Male mice were injected intraperitoneally with cetuximab (1mg), or cisplatin (8mg/kg) or the combination of both and sacrificed either 1 week or 6 weeks later. Saline-injected mice served as controls. Testes were excised, weighed and further processed. Glutathione and apoptosis assays were performed on 6 weeks samples for determination of oxidative stress. Immunohistochemistry and confocal microscopy were used to study the effect of cetuximab, cisplatin and their combination on the testis histology as well as on the spermatogonial reserve. Results: Cetuximab induced mild apoptosis in the testis. Cisplatin induced enhanced apoptosis and depleted spermatogonial reserve, reflected by reduced DAZL staining (early spermatocyte marker). The combined treatment resulted in further decline in testicular weight compared with cisplatin-only treated mice at 1-month post treatment (p&amp;lt;0.05). Cetuximab enhanced cisplatin-induced oxidative stress, and further depletion of spermatogonial reserve (p&amp;lt;0.05). Conclusions: Cetuximab has a mild effect on testicular reserve. Nevertheless, the addition of cetuximab to cisplatin exacerbates cisplatin-induced testicular toxicity. Citation Format: Mattan Levi, Aaron Popovtzer, Moran Tzabari, Salomon M. Stemmer, Ruth Shalgi, Irit Ben-Aharon. Cetuximab-induced testicular toxicity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3840. doi:10.1158/1538-7445.AM2014-3840