Augmenting external control arms using Bayesian borrowing: a case study in first-line non-small cell lung cancer.

Aim: This study aimed to improve comparative effectiveness estimates and discuss challenges encountered through the application of Bayesian borrowing (BB) methods to augment an external control arm (ECA) constructed from real-world data (RWD) using historical clinical trial data in first-line non-small-cell lung cancer (NSCLC). Materials & methods: An ECA for a randomized controlled trial (RCT) in first-line NSCLC was constructed using ConcertAI Patient360™ to assess chemotherapy with or without cetuximab, in the bevacizumab-inappropriate subpopulation. Cardinality matching was used to match patient characteristics between the treatment arm (cetuximab + chemotherapy) and ECA. Overall survival (OS) was assessed as the primary outcome using Cox proportional hazards (PH). BB was conducted using a static power prior under a Weibull PH parameterization with borrowing weights from 0.0 to 1.0 and augmentation of the ECA from a historical control trial. Results: The constructed ECA yielded a higher overall survival (OS) hazard ratio (HR) (HR = 1.53; 95% CI: 1.21-1.93) than observed in the matched population of the RCT (HR = 0.91; 95% CI: 0.73-1.13). The OS HR decreased through the incorporation of BB (HR = 1.30; 95% CI: 1.08-1.54, borrowing weight = 1.0). BB was applied to augment the RCT control arm via a historical control which improved the precision of the observed HR estimate (1.03; 95% CI: 0.86-1.22, borrowing weight = 1.0), in comparison to the matched population of the RCT alone. Conclusion: In this study, the RWD ECA was unable to successfully replicate the OS estimates from the matched population of the selected RCT. The inability to replicate could be due to unmeasured confounding and variations in time-periods, follow-up and subsequent therapy. Despite these findings, we demonstrate how BB can improve precision of comparative effectiveness estimates, potentially aid as a bias assessment tool and mitigate challenges of traditional methods when appropriate external data sources are available.

The impact of socioeconomic status on stage at presentation, receipt of diagnostic imaging, receipt of treatment and overall survival in colorectal cancer patients.

Socioeconomic factors influence patterns of care in colorectal cancer. Our study investigates the impact of socioeconomic status (SES) on stage at presentation, receipt of diagnostic imaging, receipt of treatment and overall survival (OS) in a universal healthcare system. The Ontario Cancer Registry (OCR) was accessed to identify a cohort of patients diagnosed with colorectal adenocarcinoma from 2007 to 2016 in Ontario, Canada. SES was measured using median neighborhood income divided into quintiles (Q1-Q5; Q1 = lowest income). Logistic regression analyses were used to evaluate stage, imaging and treatment. Cox proportional hazards models were used to evaluate OS. All endpoints were adjusted for demographics and comorbidities with OS models also adjusting for stage, imaging and treatment. In total, 39 802 colon and 13 164 rectal patients were identified. Lower SES was associated with advanced stage at presentation in both cohorts (Q1 vs Q5: Colon odds ratio [OR] = 1.08, P = .046, rectal OR = 1.25, P < .0001). Lower SES colon patients were less likely to receive adjuvant oxaliplatin (Q1 vs Q5: OR = 0.78, P < .001) and all palliative chemotherapies studied including oxaliplatin (Q1 vs Q5: OR = 0.60, P < 0.0001), irinotecan (Q1 vs Q5: OR = 0.65, P < .0001), bevacizumab (Q1 vs Q5: OR = 0.70, P < .001), cetuximab (Q1 vs Q5: OR = 0.40, P = .0053) and panitumumab (Q1 vs Q5: OR = 0.54, P = .0036). In rectal patients, lower SES was associated with decreased receipt of rectal cancer resection for stages I-III (Q1 vs Q5: OR = 0.78, P < .001), adjuvant oxaliplatin (Q1 vs Q5: OR = 0.72, P = .0020) and palliative chemotherapies including oxaliplatin (Q1 vs Q5: OR = 0.59, P < .001), irinotecan (Q1 vs Q5: OR = 0.53, P < .001) and bevacizumab (Q1 vs Q5: OR = 0.71, P = .046). All survival models identified poorer OS for lower SES patients (total colorectal; Q1 vs Q5: Hazard ratio [HR] = 1.25, P < .0001). These findings suggest disparities persist even within universal healthcare.

Cost-utility analysis of stereotactic body radiotherapy plus cetuximab in previously irradiated recurrent squamous cell carcinoma of the head and neck.

BACKGROUND: This study aimed to estimate the cost-utility of stereotactic body radiotherapy (SBRT) plus cetuximab for patients with previously irradiated recurrent squamous cell carcinoma of the head and neck. METHODS: We constructed a Markov health-state transition model to simulate costs and clinical outcomes of recurrent squamous cell carcinoma of the head and neck. Model parameters were derived from the published literature and the National Health Insurance Administration reimbursement price list. Incremental cost-effectiveness ratio and the net monetary benefit were calculated from a health payer perspective. The impact of uncertainty was modeled with one-way and probabilistic sensitivity analyses. RESULTS: In the base-case, SBRT plus cetuximab compared to SBRT alone resulted in an ICER of NT$ 840,455 per QALY gained. In the one-way sensitivity analysis, the utility of progression-free state for patients treated with SBRT plus cetuximab or SBRT alone and the cost of progression-free survival for SBRT+Cet were the most sensitive parameters in the model. Probabilistic sensitivity analysis showed that the probability of cost-effectiveness at a willingness-to-pay threshold of NT$ 2,252,340 per QALY was 100% for SBRT plus cetuximab but 0% for SBRT alone. CONCLUSIONS: This study showed that SBRT+Cet was cost-effective and benefited patients with previously irradiated rSCCHN.

Evaluation of the Cost-effectiveness of Doublet Therapy in Metastatic BRAF Variant Colorectal Cancer.

Importance: The BEACON trial showed that combination therapy with encorafenib (BRAF inhibitor) and cetuximab (EGFR inhibitor) was associated with prolonged overall survival compared with standard chemotherapy in patients with metastatic BRAF variant colorectal cancer. However, the cost-effectiveness of using these agents in this clinical setting is unknown. Objective: To create a cost-effectiveness model to compare doublet therapy (encorafenib plus cetuximab) with standard chemotherapy (cetuximab plus irinotecan or cetuximab plus folinic acid, fluorouracil, and irinotecan) in treating patients with metastatic BRAF variant colorectal cancer. Design, Setting, and Participants: This economic evaluation constructed a Markov model to compare the lifetime cost and utility of doublet therapy and standard chemotherapy. Parametric survival modeling was used to extrapolate the effectiveness of each line of therapy from large clinical trials. One-way and probabilistic sensitivity analyses assessed the uncertainty in the model. Patients mirrored the cohorts in the BEACON trial: they had metastatic BRAF variant colorectal cancer and were followed up as they progressed through multiple lines of therapy, best supportive care, and death. Data collection and data analysis were performed from November 15, 2019, to July 14, 2020. Main Outcomes and Measures: The main outcome was the incremental cost-effectiveness ratio, which was calculated using the cumulative cost and effectiveness in quality-adjusted life years (QALYs), of doublet therapy compared with standard chemotherapy. Results: The model patient cohort had a mean age of 61 years, and 53% of the patients were women, 66% had 1 previous line of therapy, and 8% had high microsatellite instability. Doublet therapy was associated with an improvement of 0.15 QALYs compared with standard chemotherapy. However, the incremental cost of doublet therapy was $78 233, leading to an incremental cost-effectiveness ratio of $523 374 per QALY gained. Concomitant decreases in the price of encorafenib and cetuximab are needed to achieve cost-effectiveness at a willingness-to-pay threshold of $150 000 per QALY gained. Conclusions and Relevance: This study found that doublet therapy for metastatic BRAF variant colorectal cancer was unlikely to be cost-effective under current pricing. Cost-effectiveness needs to be considered in clinical trial design, particularly when combining new therapies with non-cost-effective treatments that are coadministered without a fixed duration.

Budget impact of bimonthly use of cetuximab in patients diagnosed with metastatic colorectal cancer.

Aim: Cetuximab is used for the treatment of RAS wild-type metastatic colorectal cancer patients. Standard administration schedule is once a week; however, the bioequivalence of an every-other-week (EOW) schedule was demonstrated. Methods: We compared a base case scenario of 100% weekly administration to an EOW at 50 or 100%. Medical examinations, patient management and loss of productivity were considered. Results: Base case was estimated at €100.6 million versus €92.8 million and €84.9 million of EOW 50 and 100%, which showed a cost reduction of 8 and 16%, respectively. Indirect costs accounted for 65% in both scenarios. Conclusion: The adoption of an EOW administration schedule of cetuximab reduced direct and indirect costs substantially.

An evaluation of cetuximab dosing strategies using pharmacokinetics and cost analysis.

OBJECTIVES: Cetuximab dosing is based on body surface area (BSA), an approach that is associated with significant wastage due to available vial sizes. NHS England recently introduced an alternative strategy for cetuximab dosing based on dose banding. The aim of this work was to investigate approaches to cetuximab dosing to improve its cost-effectiveness. METHODS: A simulation study using a population pharmacokinetic model was used to assess the performance of dosing strategies using exposure, probability of target attainment and cost. Two dosage regimens (500 and 400/250 mg/m2 ) were investigated; 5% and 10% dose banding, fixed and optimised dosing strategies were evaluated and compared to BSA strategy. KEY FINDINGS: The percentage of the total cost associated with wastage for the 400/250 mg/m2 regimen were 8.75%, 5.13%, 3.61%, 9.2% and 0% for BSA; 5 and 10% bands; fixed and optimal strategies, respectively. Similar results were obtained for 500 mg/m2 regimen. In comparison with BSA strategy, other strategies have comparable or improved performance. Optimised strategy showed consistent performance and ensures equal exposure and probability of target attainment. CONCLUSIONS: Cost-effectiveness of cetuximab treatment can be improved with alternative strategies by reducing wastage without compromising exposure.

Rationale and budget impact of bimonthly use of Cetuximab in patients with recurrent and/or metastatic head and neck cancer.

BACKGROUND: In recurrent and/or metastatic head and neck squamous cell cancer, Cetuximab is administered once a week, followed by weekly doses. We present the clinical rationale of a different schedule of maintenance Cetuximab and we estimate the potential economic benefits on the health care budget from a societal perspective in Italy. METHODS: A budget impact (BI) excel-based model was developed comparing a base case scenario of 100% weekly administration with a dose of 250 mg/m2 to an every-other-week (EOW) administration at 50% or 100% with a dose of 500 mg/m2 . RESULTS: In the EOW, 50% scenario it was calculated a cost reduction of €347 000 of which 70% attributable to indirect costs, increasing to €694 000 after 4 months. CONCLUSIONS: In our analysis, we showed that this simplified schedule could also reduce the costs of treatments both for the health system (direct costs) and for the society (indirect costs).

Total cell-free DNA, carcinoembryonic antigen, and C-reactive protein for assessment of prognosis in patients with metastatic colorectal cancer.

In late-stage metastatic colorectal cancer, difficult treatment decisions should incorporate a thorough evaluation of the patient's general condition and subject for shared decision making. Assessment of the individual patients' prognosis is valuable in this setting. The aim was to analyze the prognostic value of plasma levels of total cell-free DNA, carcinoembryonic antigen and C-reactive protein in 97 heavily pretreated patients with metastatic colorectal cancer. Patients received irinotecan, cetuximab, and everolimus in a phase-2 clinical trial ( clinicaltrials.gov NCT01387880). Plasma samples were used for DNA purification and quantification of total cell-free DNA by droplet digital polymerase chain reaction. Serum carcinoembryonic antigen and C-reactive protein were analyzed by routine methods. Clinical endpoints were overall survival and progression-free survival. A total of 82 patients had blood samples available for quantification of total cell-free DNA. Patients with pre-treatment cell-free DNA levels higher than the median total cell-free DNA (9800 alleles per milliliter plasma) had a significantly shorter overall survival of 4.3 months (95% confidence interval: 3.6-5.8) compared to patients with cell-free DNA levels below the median with an overall survival of 11.3 months (95% confidence interval: 8.0-14.8, p < 0.0001). When using the upper normal limit from a previously analyzed normal control group, the median overall survival was 11.3 (95% confidence interval: 7.3-14.8) and 4.3 (95% confidence interval: 3.7-6.1) months, respectively (p < 0.0001). Serum carcinoembryonic antigen and C-reactive protein had similar prognostic value with short overall survival and progression-free survival in patients with elevated levels compared to those within normal range. A high-risk profile of elevated cell-free DNA, carcinoembryonic antigen, and C-reactive protein was described, but in combined Cox regression multivariate analysis, only total cell-free DNA preserved a strong prognostic value. In conclusion, total cell-free DNA in plasma, carcinoembryonic antigen, and C-reactive protein could all contribute to assessment of patients' prognosis and potentially aid in clinical decision making in patients with metastatic colorectal cancer.

Consequences of Biomarker Analysis on the Cost-Effectiveness of Cetuximab in Combination with FOLFIRI as a First-Line Treatment of Metastatic Colorectal Cancer: Personalised Medicine at Work.

BACKGROUND: Therapies may be more efficacious when targeting a patient subpopulation with specific attributes, thereby enhancing the cost-effectiveness of treatment. In the CRYSTAL study, patients with metastatic colorectal cancer (mCRC) were treated with cetuximab plus FOLFIRI or FOLFIRI alone until disease progression, unacceptable toxic effects or withdrawal of consent. OBJECTIVE: To determine if stratified use of cetuximab based on genetic biomarker detection improves cost-effectiveness. METHODS: We used individual patient data from CRYSTAL to compare the cost-effectiveness, cost per life-year (LY) and cost per quality-adjusted LY (QALY) gained of cetuximab plus FOLFIRI versus FOLFIRI alone in three cohorts of patients with mCRC: all randomised patients (intent-to-treat; ITT), tumours with no detectable mutations in codons 12 and 13 of exon 2 of the KRAS protein ('KRAS wt') and no detectable mutations in exons 2, 3 and 4 of KRAS and exons 2, 3 and 4 of NRAS ('RAS wt'). Survival analysis was conducted using RStudio, and a cost-utility model was modified to allow comparison of the three cohorts. RESULTS: The deterministic base-case ICER (cost per QALY gained) was £130,929 in the ITT, £72,053 in the KRAS wt and £44,185 in the RAS wt cohorts for cetuximab plus FOLFIRI compared with FOLFIRI alone. At a £50,000 willingness-to-pay threshold, cetuximab plus FOLFIRI has a 2.8, 20 and 63% probability of being cost-effective for the ITT, KRAS wt and RAS wt cohorts, respectively, versus FOLFIRI alone. CONCLUSION: Screening for mutations in both KRAS and NRAS may provide the most cost-effective approach to patient selection.

[Economic Evaluation of mFOLFOX6-based First-line Regimens for Unresectable Advanced or Recurrent Colorectal Cancer Using Clinical Decision Analysis].

We evaluated four representative chemotherapy regimens for unresectable advanced or recurrent KRAS-wild type colorectal cancer: mFOLFOX6, mFOLFOX6+bevacizumab (Bmab), cetuximab (Cmab), or panitumumab (Pmab). We employed a decision analysis method in combination with clinical and economic evidence. The health outcomes of the regimens were analyzed on the basis of overall and progression-free survival. The data were drawn from the literature on randomized controlled clinical trials of the above-mentioned drugs. The total costs of the regimens were calculated on the basis of direct costs obtained from the medical records of patients diagnosed with unresectable advanced or recurrent colorectal cancer at Yamagata University Hospital and Yamagata Prefecture Central Hospital. Cost effectiveness was analyzed using a Markov chain Monte Carlo (MCMC) method. The study was designed from the viewpoint of public medical care. The MCMC analysis revealed that expected life months and expected cost were 20 months/3,527,119 yen for mFOLFOX6, 27 months/8,270,625 yen for mFOLFOX6+Bmab, 29 months/13,174,6297 yen for mFOLFOX6+Cmab, and 6 months/12,613,445 yen for mFOLFOX6+Pmab. Incremental costs per effectiveness ratios per life month against mFOLFOX6 were 637,592 yen for mFOLFOX6+Bmab, 1,075,162 yen for mFOLFOX6+Cmab, and 587,455 yen for mFOLFOX6+Pmab. Compared to the conventional mFOLFOX6 regimen, molecular-targeted drug regimens provide better health outcomes, but the cost increases accordingly. mFOLFOX 6+Pmab is the most cost-effective regimen among those surveyed in this study.

Cost-Effectiveness of Cetuximab as First-line Treatment for Metastatic Colorectal Cancer in the United States.

PURPOSE: We conducted a cost-effectiveness analysis incorporating recent phase III clinical trial (FIRE-3) data to evaluate clinical and economic tradeoffs associated with first-line treatments of KRAS wild-type (WT) metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: A cost-effectiveness model was developed using FIRE-3 data to project survival and lifetime costs of FOLFIRI plus either cetuximab or bevacizumab. Hypothetical KRAS-WT mCRC patients initiated first-line treatment and could experience adverse events, disease progression warranting second-line treatment, or clinical response and hepatic metastasectomy. Model inputs were derived from FIRE-3 and published literature. Incremental cost-effectiveness ratios (ICERs) were reported as US$ per life year (LY) and quality-adjusted life year (QALY). Scenario analyses considered patients with extended RAS mutations and CALGB/SWOG 80405 data; 1-way and probabilistic sensitivity analyses were conducted. RESULTS: Compared with bevacizumab, KRAS-WT patients receiving first-line cetuximab gained 5.7 months of life at a cost of $46,266, for an ICER of $97,223/LY ($122,610/QALY). For extended RAS-WT patients, the ICER was $77,339/LY ($99,584/QALY). Cetuximab treatment was cost-effective 80.3% of the time, given a willingness-to-pay threshold of $150,000/LY. Results were sensitive to changes in survival, treatment duration, and product costs. CONCLUSIONS: Our analysis of FIRE-3 data suggests that first-line treatment with cetuximab and FOLFIRI in KRAS (and extended RAS) WT mCRC patients may improve health outcomes and use financial resources more efficiently than bevacizumab and FOLFIRI. This information, in combination with other studies investigating comparative effectiveness of first-line options, can be useful to clinicians, payers, and policymakers in making treatment and resource allocation decisions for mCRC patients.

The clinical effectiveness and cost-effectiveness of cetuximab (review of technology appraisal no. 176) and panitumumab (partial review of technology appraisal no. 240) for previously untreated metastatic colorectal cancer: a systematic review and economic evaluation.

BACKGROUND: Colorectal cancer is the fourth most commonly diagnosed cancer in the UK after breast, lung and prostate cancer. People with metastatic disease who are sufficiently fit are usually treated with active chemotherapy as first- or second-line therapy. Targeted agents are available, including the antiepidermal growth factor receptor (EGFR) agents cetuximab (Erbitux®, Merck Serono UK Ltd, Feltham, UK) and panitumumab (Vecitibix®, Amgen UK Ltd, Cambridge, UK). OBJECTIVE: To investigate the clinical effectiveness and cost-effectiveness of panitumumab in combination with chemotherapy and cetuximab in combination with chemotherapy for rat sarcoma (RAS) wild-type (WT) patients for the first-line treatment of metastatic colorectal cancer. DATA SOURCES: The assessment included a systematic review of clinical effectiveness and cost-effectiveness studies, a review and critique of manufacturer submissions, and a de novo cohort-based economic analysis. For the assessment of effectiveness, a literature search was conducted up to 27 April 2015 in a range of electronic databases, including MEDLINE, EMBASE and The Cochrane Library. REVIEW METHODS: Studies were included if they were randomised controlled trials (RCTs) or systematic reviews of RCTs of cetuximab or panitumumab in participants with previously untreated metastatic colorectal cancer with RAS WT status. All steps in the review were performed by one reviewer and checked independently by a second. Narrative synthesis and network meta-analyses (NMAs) were conducted for outcomes of interest. An economic model was developed focusing on first-line treatment and using a 30-year time horizon to capture costs and benefits. Costs and benefits were discounted at 3.5% per annum. Scenario analyses and probabilistic and univariate deterministic sensitivity analyses were performed. RESULTS: The searches identified 2811 titles and abstracts, of which five clinical trials were included. Additional data from these trials were provided by the manufacturers. No data were available for panitumumab plus irinotecan-based chemotherapy (folinic acid + 5-fluorouracil + irinotecan) (FOLFIRI) in previously untreated patients. Studies reported results for RAS WT subgroups. First-line treatment with anti-EGFR therapies in combination with chemotherapy appeared to have statistically significant benefits for patients who are RAS WT. For the independent economic evaluation, the base-case incremental cost-effectiveness ratio (ICER) for RAS WT patients for cetuximab plus oxaliplatin-based chemotherapy (folinic acid + 5-fluorouracil + oxaliplatin) (FOLFOX) compared with FOLFOX was £104,205 per quality-adjusted life-year (QALY) gained; for panitumumab plus FOLFOX compared with FOLFOX was £204,103 per QALY gained; and for cetuximab plus FOLFIRI compared with FOLFIRI was £122,554 per QALY gained. The ICERs were sensitive to treatment duration, progression-free survival, overall survival (resected patients only) and resection rates. LIMITATIONS: The trials included RAS WT populations only as subgroups. No evidence was available for panitumumab plus FOLFIRI. Two networks were used for the NMA and model, based on the different chemotherapies (FOLFOX and FOLFIRI), as insufficient evidence was available to the assessment group to connect these networks. CONCLUSIONS: Although cetuximab and panitumumab in combination with chemotherapy appear to be clinically beneficial for RAS WT patients compared with chemotherapy alone, they are likely to represent poor value for money when judged by cost-effectiveness criteria currently used in the UK. It would be useful to conduct a RCT in patients with RAS WT. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015016111. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Real-world Direct Health Care Costs for Metastatic Colorectal Cancer Patients Treated With Cetuximab or Bevacizumab-containing Regimens in First-line or First-line Through Second-line Therapy.

BACKGROUND: The present study examined real-world direct health care costs for metastatic colorectal cancer (mCRC) patients initiating first-line (1L) bevacizumab (BEV)- or cetuximab (CET)-containing regimen in 1L or 1L-through-second-line (1L-2L) therapy. PATIENTS AND METHODS: Using a large US insurance claims database, patients with mCRC initiating 1L BEV- or 1L CET-containing regimen from January 1, 2008 to September 30, 2014 were identified. The per-patient per-month (PPPM) all-cause health care costs (2014 US dollars) were measured during 1L therapy and, for patients continuing to a 2L biologic-containing regimen, 1L-2L therapy. Multivariable regression analyses were used to compare PPPM total health care costs between patients initiating a 1L BEV- versus 1L CET-containing regimen. RESULTS: A total of 6095 patients initiating a 1L BEV- and 453 initiating a 1L CET-containing regimen were evaluated for 1L costs; 2218 patients initiating a 1L BEV- and 134 initiating a 1L CET-containing regimen were evaluated for 1L-2L costs. In 1L therapy, 1L CET had adjusted PPPM costs that were $3135 (95% confidence interval [CI], $1174-$5040; P < .001) greater on average than 1L BEV. In 1L-2L therapy, 1L BEV-2L CET had adjusted PPPM costs that were $1402 (95% CI, $1365-$1442; P = .010) greater than those for 1L BEV-2L BEV, and 1L CET-2L BEV had adjusted PPPM costs that were $4279 (95% CI, $4167-$4400; P = .001) greater on average than those for 1L BEV-2L BEV. The adjusted PPPM cost differences for 1L BEV-2L other biologic or 1L CET-2L other biologic agent were numerically greater but statistically insignificant. CONCLUSION: PPPM total health care costs for 1L and 2L therapy tended to be greater for patients treated with 1L CET-containing regimens than for 1L BEV-containing regimens. Also, continuing treatment with BEV-containing regimens 1L-2L was less costly than switching between BEV and CET. The cost differences between BEV and CET hold important implications for treatment decisions of mCRC patients in real-world clinical practice.

Assessment of cetuximab-induced infusion reactions and administration rechallenge at an academic medical center.

Cetuximab is approved for treatment of squamous cell carcinoma of the head and neck (SCCHN). Cetuximab is generally well tolerated, but does carry a black box warning for infusion reactions (IRs). Incidence of IR in clinical trials was 15-20% for all grades and 3-5% for grades III-IV. Retrospective studies reported a higher incidence of all grade IRs and grades III-IV IR in areas of the Southeastern United States. Information regarding rechallenge doses after an IR has not been well described. At our institution, we frequently rechallenge on the same day after an initial IR. The primary objective was to determine the incidence, timing, IR grade, and completion of a rechallenge dose in patients who experienced an initial IR. Secondary objectives included: (1) determining the incidence and grade of IR in patients who received a first dose of cetuximab and (2) identifying specific risk factors for cetuximab IR with the first dose. A single-center retrospective chart review was conducted in SCCHN patients treated with cetuximab between June 2008 and September 2015 at the University of Kansas Hospital Cancer Center and inpatient setting. The majority of patients (87.9%) were able to be quickly and successfully rechallenged after an initial IR. Minimal patients (27.6%) experienced a rechallenge IR, resulting in only 1 patient discontinuation. Rechallenge doses were most frequently (37.9%) administered between 30 and 59 min after initial dose discontinuation. This was a single-center retrospective study based on data collected from electronic medical records. Other limitations include interpretation of infusion reactions on a subjective basis by providers. These findings demonstrate the practice of same-day rechallenges in initial IR patients is feasible and safe.

Quantitative assessment of Zirconium-89 labeled cetuximab using PET/CT imaging in patients with advanced head and neck cancer: a theragnostic approach.

Biomarkers predicting treatment response to the monoclonal antibody cetuximab in locally advanced head and neck squamous cell carcinomas (LAHNSCC) are lacking. We hypothesize that tumor accessibility is an important factor in treatment success of the EGFR targeting drug. We quantified uptake of cetuximab labeled with Zirconium-89 (89Zr) using PET/CT imaging.Seventeen patients with stage III-IV LAHNSCC received a loading dose unlabeled cetuximab, followed by 10 mg 54.5±9.6 MBq 89Zr-cetuximab. PET/CT images were acquired either 3 and 6 or 4 and 7 days post-injection. 89Zr-cetuximab uptake was quantified using standardized uptake value (SUV) and tumor-to-background ratio (TBR), and correlated to EGFR immunohistochemistry. TBR was compared between scan days to determine optimal timing.Uptake of 89Zr-cetuximab varied between patients (day 6-7: SUVpeak range 2.5-6.2). TBR increased significantly (49±28%, p < 0.01) between first (1.1±0.3) and second scan (1.7±0.6). Between groups with a low and high EGFR expression a significant difference in SUVmean (2.1 versus 3.0) and SUVpeak (3.2 versus 4.7) was found, however, not in TBR. Data is available at www.cancerdata.org (DOI: 10.17195/candat.2016.11.1).In conclusion, 89Zr-cetuximab PET imaging shows large inter-patient variety in LAHNSCC and provides additional information over FDG-PET and EGFR expression. Validation of the predictive value is recommended with scans acquired 6-7 days post-injection.

Eficacia y seguridad de la adición de cetuximab a folfiri como tratamiento de primera linea en pacientes con carcinoma colorrectal metastásico con gen kras no mutado (wild type) e irresecable / Efficacy and safety of the addition of cetuximab to folfiri as a first-line treatment in patients with metastatic colorectal carcinoma with non-mutated (wild type) kras gene and unresectable

INTRODUCCIÓN: Antecedentes: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad de la adición de cetuximab a FOLFIRI en el tratamiento de pacientes con diagnóstico de cáncer colorrectal metastásico e irresecable (CCRm) con estudio de KRAS WT (tipo salvaje), sin tratamiento sistémico previo en enfermedad metastásica. Aspectos Generales: El cáncer colorrectal (CCR) se origina en la parte baja del sistema digestivo, incluyendo el colon y el recto. El cáncer puede extenderse produciendo metástasis a lugares adyacentes a la lesión original, a los ganglios y también a otras partes distantes del cuerpo. Globalmente, el cáncer colorrectal (CCR) es el tercer cáncer más frecuentemente diagnosticado en hombres y el segundo en mujeres en el mundo (Torres). En el Perú, en el 2012 se estimó que la incidencia de este tipo de cáncer en hombres era de 9% a 16.1% con mortalidad alrededor del 5.8% a 9%; mientras que en mujeres la incidencia estimada fue de alrededor de 7.6% y 13.2%, con una mortalidad entre 5.3% y 6.9%(1,2). Tecnologia Sanitaria de Interés: El cetuximab (Erbitux, Merck Serono) es un anticuerpo monoclonal recombinante que bloquea el receptor del factor de crecimiento de la epidermis (EGFR), inhibiendo la proliferación de células que dependen de la activación de EGFR para crecer. Cetuximab está indicado en combinación con quimioterapia en el tratamiento de pacientes con CCRm que expresan EGFR y el tipo salvaje de KRAS (Kirsten rat sarcoma). METODOLOGIA: Estrategia de Búsqueda: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de la adición de cetuximab a FOLFIRI en el tratamiento de pacientes con diagnóstico de cáncer colorrectal metastásico e irresecable (CCRm) con estudio de KRAS WT no mutado (tipo salvaje), sin tratamiento sistémico previo para enfermedad metastásica. Esta búsqueda se realizó utilizando los meta-buscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline) y Health Systems Evidence. RESULTADOS: Sinopsis de la Evidencia: Se realizó la búsqueda bibliográfica y de evidencia científica para el sustento de la adición de cetuximab a FOLFIRI como tratamiento de primera línea en pacientes con \r\ncarcinoma colorrectal metastásico irresecable y con estudio negativo de la mutación KRAS. Se presenta la evidencia disponible según el tipo de publicación priorizada en los criterios de inclusión. CONCLUSIONES: La mayoría de los pacientes con cáncer colorrectal metastásico (CCRm) no pueden ser curados, siendo candidatos a tratamiento paliativo con quimioterapia sistémica, como FOLFIRI, XELOX o FOLFOX, los cuales se encuentran disponibles en el Petitorio Farmacológico de EsSalud. No se han encontrado reportes sobre el impacto de adicionar cetuximab a la quimioterapia en pacientes con cáncer colorrectal metastásico. Sin embargo, del estudio CRYSTAL se evidencia que la incidencia general de eventos adversos grado 3 o 4 fue mayor en el grupo cetuximab­FOLFIRI que en el grupo FOLFIRI. el Instituto de Evaluación en Tecnologías en Salud e Investigación-IETSI, no aprueba el uso de cetuximab en combinación con FOLFIRI para el tratamiento de cáncer colorrectal metastásico KRAS WT.

Assessment of Pharmacokinetic Interaction Between Capecitabine and Cetuximab in Metastatic Colorectal Cancer Patients.

AIM: This study focuses on the plasma disposition and metabolic activation of capecitabine (CCB) when administered alone or when combined with cetuximab (CTX). PATIENTS AND METHODS: Twenty-four chemo-naïve patients with KRAS wild-type colorectal cancer were randomized into two arms and received either CCB alone (1,000 mg/m(2) bid p.o.), followed by CCB plus CTX (loading dose (LD)=400 mg/m(2) followed by 250 mg/m(2) weekly i.v. maintenance dose) (Arm A; n=12 patients (patients)) or CCB plus CTX followed by CCB alone (Arm B; n=12 patients). Plasma samples were collected from the cubital vein and CCB, 5'-desoxy-5-fluorocytidine (5'-DFCR) and 5'-desoxy-5 fluorouridine (5'-DFUR) were quantified by a sensitive, selective reversed phase high-performance liquid chromatography (HPLC) assay. Non-compartment pharmacokinetic parameters have been calculated by Phoenix WinNonlin. RESULTS: No clinically relevant impact of CTX on CCB pharmacokinetic parameters and metabolic conversion could be detected in both arms after statistical evaluation (ANOVA). CONCLUSION: From the pharmacokinetic point of view, co-administration of CTX to CCB seems to be safe.

The prognostic value of WHO performance status in relation to quality of life in advanced colorectal cancer patients.

INTRODUCTION: Performance status (PS) is an established prognostic factor in patients with advanced cancer and is usually scored by the treating physician. The EORTC QLQ-C30 questionnaire as reported by cancer patients is a validated tool to assess quality of life (QoL). Subjectivity plays a role in both assessments, and data on a direct comparison are scarce. METHODS: We compared the prognostic value for overall survival (OS) of the WHO PS to the baseline physical function scale of the EORTC QLQ-C30 (QLQ-C30 PF) in a prospective randomised phase 3 trial in advanced colorectal cancer (ACC), the CAIRO study. Patients were divided into two groups based on the baseline QLQ-C30 PF. QLQ-C30 PF was considered 'good' if the score was more than 66.7% and 'poor' if 66.7% or less. Results were validated in a subsequent phase 3 study in ACC, the CAIRO2 study. RESULTS: The median OS for patients with a 'good' QLQ-C30 PF and a 'poor' PF in patients with WHO PS 0 was 20.3 months (n = 300) and 10.4 months (n = 44), in patients with WHO PS 1 16.8 months (n = 125) and 10.1 months (n = 63), and in patients with WHO PS 2 16.2 months (n = 11) and 9.9 months (n = 12), respectively. In a Cox regression model which included other prognostic factors, 'good' versus 'poor' QLQ-C30 PF was significantly prognostic for OS (0.57 95% confidence interval: 0.46-0.72), but not WHO PS. These results were confirmed in the CAIRO2 study. CONCLUSIONS: We demonstrate in ACC patients that PF, as assessed by patients using the EORTC QLQ-C30, is superior in terms of prognostic value to WHO PS as scored by physicians. Our data support to include the results of baseline EORTC QLQ-C30 PF instead of WHO PS as a stratification parameter in oncology trials.

Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer.

Several studies have reported that epidermal growth factor receptor (EGFR)-related molecules may serve as predictors of cetuximab treatment for metastatic colorectal cancer (mCRC), such as EGFR gene copy number (GCN), expression of 2 ligands of EGFR, amphiregulin (AREG) and epiregulin (EREG), and EGFR CA simple sequence repeat 1 (CA-SSR1) polymorphism; however, these biomarkers still remain not useful in clinical practice since they have been evaluated using cohorts with patients treated in various settings of chemotherapy. We therefore analyzed associations of mRNA expression of AREG and EREG, EGFR GCN, and CA-SSR1 polymorphism [short (S;≤ 19) / long (L; ≥ 20)] with clinical outcomes in 77 Japanese patients with KRAS exon 2 wild-type mCRC enrolled in phase II trials of FOLFOX (n = 28/57, UMIN000004197) or SOX (n = 49/67, UMIN000007022) plus cetuximab as first-line therapy. High AREG expression correlated with significantly better progression-free survival (median 11.6 vs. 66 months, HR 0.52, P = 0.037); moreover, it remained statistically significant in multivariate analysis (HR: 0.48, P = 0.027). S/S genotype of CA-SSR1 predicted severe skin toxicity (P = 0.040). Patients with both AREG-low and EGFR low-GCN had significantly shorter overall survival than the others (median 22.2 vs. 42.8 months, HR 2.34, P = 0.042). The multivariate analysis showed that molecular status with both AREG-low and EGFR low-GCN was a predictor of worse survival (P = 0.006). In conclusion, AREG mRNA expression and EGFR CA-SSR1 polymorphism predict survival and skin toxicity, respectively, of initial chemotherapy with cetuximab. Our results also suggest potential prognostic value of the combined assessment of AREG and EGFR GCN for first-line cetuximab treatment.

Seguridad y eficacia de cetuximab más irinotecán en comparación a irinotecán como monoterapia para el tratamiento de segunda línea en cáncer colorrectal metastásico con gen kras no mutado (Wild Type) / Safety and efficacy of cetuximab plus irinotecan compared to irinotecan as monotherapy for second line treatment in metastatic colorectal cancer with non-mutated kras gene (Wild Type)

INTRODUCCIÓN: Antecedentes: El presente dictamen expone la evaluación del medicamento cetuximab en combinación con irinotecán respecto a su uso en pacientes con cáncer colorrectal metastásico y gen KRAS' no mutado (WT) con progresión a primera línea de quimioterapia basada oxaliplatino. Aspectos Generales: A nivel mundial, en cáncer colorrectal es el tercer tipo de cáncer más frecuente, representando el 9.4% de todas las incidencias de cáncer en hombres y el 10.1% en mujeres. Aproximadamente el 25% de los pacientes diagnosticados con cáncer colorrectal presentan enfermedad metastásica al momento del diagnóstico y del resto de pacientes, el 25% a 35% desarrollará metástasis en el transcurso de la enfermedad. Tecnología Sanitaria de Interés: Cetuximab: Cetuximab con nombre comercial Erbitux, es un anticuerpo monoclonal recombinante que inhibe la proliferación de células bloqueando los EGFR(15). El EGFR es uno de los cuatro receptores pertenecientes a la familia de proteínas c-erbB de receptores de tirosina quinasa (i.e., c-erb-1, c-erb-2, c-erb-3, c-erb-4). METODOLOGÍA: Estrategia de Búsqueda: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de cetuximab para el tratamiento de cáncer colorrectal metastásico en pacientes sin mutación el en gen KRAS (KRAS WT) en las bases de datos de MEDLINE y TRIPDATABASE. Se hizo una búsqueda adicional en www.clinicaltrials.gov, para poder identificar ensayos aún en elaboración o que no hayan sido publicados. Asimismo, se hizo una búsqueda dentro de la información generada por grupos que realizan revisiones sistemáticas, evaluación de tecnologías sanitarias y guías de práctica clínica, tales como The Cochrane Library y The National Institute for Health and Care Excellence (NICE). RESULTADOS: Sinopsis de la Evidencia: Se realizó la búsqueda bibliográfica y de evidencia científica para el sustento del uso de cetuximab como tratamiento para cáncer colorrectal metastásico con KRAS no mutado (WT), en pacientes con progresión a primera línea de quimioterapia basada en fluoropirimidina y oxaliplatino. Se presenta la evidencia disponible en Guías de Práctica Clínica, Evaluación de tecnologías sanitarias, Meta-análisis/Network Meta-análisis y Ensayos clínicos. CONCLUSIONES: -\tEn la actualidad el fármaco irinotecán se encuentra incluido en el petitorio farmacológico de ESSALUD para su uso en el tratamiento de cáncer colorrectal metastásico, lo que incluye su uso como alternativa en pacientes que no hayan recibido previamente regímenes con este fármaco. Así, ESSALUD cuenta con una alternativa para pacientes con cáncer colorrectal metastásico que hayan utilizado previamente regímenes con fluoropirimidina y oxaliplatino. Es por ello que se requiere que la adición de cetuximab a irinotecán suponga un beneficio adicional para dichos pacientes. Sin embargo, hasta la fecha (i.e., Marzo 2016) no se ha encontrado evidencia sólida con relación a la hipótesis que añadir cetuximab a irinotecán, en el contexto de progresión a regímenes con fluoropirimidina y oxaliplatino, ofrezca un beneficio mayor al obtenido con regímenes a base de irinotecán como monodroga. Así, la evidencia disponible al momento no justifica el uso de cetuximab en combinación con irinotecán para el tratamiento de cáncer colorrectal metastásico en pacientes que han progresado a regímenes de quimioterapia a base de fluoropirimidina y / u oxaliplatino; ya que en el petitorio de la Institución ya se cuenta con un tratamiento utilizado para dichos pacientes. -\tPor lo expuesto, el Instituto de evaluación en Tecnologías en Salud e Investigación-IETSI, no aprueba el uso de cetuximab en combinación con irinotecán para el tratamiento de cáncer colorrectal metastásico KRAS WT, en pacientes refractarios a quimioterapia pasada en fluoropirimidina y oxaliplatino.