Switching from FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab based on early tumor shrinkage in RAS wild-type metastatic colorectal cancer: A phase II trial (HYBRID).

BACKGROUND: Long-term anti-EGFR antibody treatment increases the risk of severe dermatologic toxicities. This single-arm, phase II trial aimed to investigate the strategy of switching from cetuximab to bevacizumab in combination with FOLFIRI based on early tumor shrinkage (ETS) in patients with RAS wild-type metastatic colorectal cancer (mCRC). METHODS: Radiologic assessment was performed to evaluate ETS, defined as ≥20% reduction in the sum of the largest diameters of target lesions 8 weeks after the introduction of FOLFIRI plus cetuximab. ETS-negative patients switched to FOLFIRI plus bevacizumab, whereas ETS-positive patients continued FOLFIRI plus cetuximab for eight more weeks, with a switch to FOLFIRI plus bevacizumab thereafter. The primary endpoint was progression-free survival. RESULTS: This trial was prematurely terminated due to poor accrual after a total enrollment of 30 patients. In 29 eligible patients, 7 were ETS-negative and 22 were ETS-positive. Two ETS-negative patients and 17 ETS-positive patients switched to FOLFIRI plus bevacizumab 8 weeks and 16 weeks after initial FOLFIRI plus cetuximab, respectively. Median progression-free and overall survival durations were 13.4 and 34.7 months, respectively. Six (20%) patients experienced grade ≥3 paronychia, which improved to grade ≤2 by 18 weeks. Grade ≥3 acneiform rash, dry skin, and pruritus were not observed in any patients. CONCLUSIONS: Our novel treatment strategy delivered acceptable survival outcomes and reduced severe dermatologic toxicities.

Risk Factors of Cetuximab-Induced Hypomagnesemia and the Effect of Magnesium Prophylaxis in Patients with Head and Neck Cancer: A Retrospective Study.

Hypomagnesemia is a characteristic adverse event of cetuximab in patients with head and neck cancer (HNC). However, there is limited information about its prevalence, risk factors, and preventive strategies. This study aimed to investigate the risk factors of hypomagnesemia and examine the preventive effects of prophylactic magnesium (Mg) administration. We initially investigated HNC patients treated with cetuximab between 2013 and 2019. Our institute started prophylactic Mg treatment (20-mEq Mg sulfate administration before cetuximab) in practice during this period. We retrospectively assess the preventive efficacy by comparing patients before and after its implementation. In total, 109 patients were included. In 60 patients without prophylaxis, all-grade and grade ≥2 hypomagnesemia at 3 months occurred in 61.7 and 15.0% of patients. The incidence of hypomagnesemia was not affected by regimens and concomitant medications. In 49 patients treated with prophylactic Mg treatment, there was no significant decrease in the cumulative incidence of hypomagnesemia. However, the preventive Mg treatment eliminated the need for additional Mg repletion to maintain Mg levels in patients treated with paclitaxel + cetuximab. A risk factor in patients without prophylaxis was a low Mg level at pre-treatment (≤2.0 mg/dL) (odds ratio: 6.03, 95% confidence interval: 1.78-20.4, p = 0.004), whereas that in patients with prophylaxis was the number of cetuximab doses (≥10) (odds ratio: 5.50, 95% confidence interval: 1.52-19.87, p = 0.009). In conclusion, a low pre-treatment Mg level was the only risk factor that could be avoided by prophylactic Mg administration. This preventive intervention is recommended for managing cetuximab-induced hypomagnesemia.

A meta-analysis of efficacy and safety data from head-to-head first-line trials of epidermal growth factor receptor inhibitors versus bevacizumab in adult patients with RAS wild-type metastatic colorectal cancer by sidedness.

The first-line treatment choice of EGFRIs plus doublet chemotherapy vs. bevacizumab plus doublet chemotherapy remains a topic of interest for patients with left-sided RAS WT mCRC. We conducted a systematic literature review and meta-analysis of clinical trial data published between 2015 and 2024. We evaluated the relative efficacy and safety of first-line EGFRIs plus doublet chemotherapy (FOLFIRI or FOLFOX) vs. bevacizumab plus doublet chemotherapy for patients with RAS WT left-sided mCRC, as well as in all- and right-sided tumors. We identified eight trials with 2624 patients. Five trials reported outcomes by tumor sidedness. In the left-sided population, overall survival (OS) (Hazard Ratio (HR) = 0.80, 95% Confidence Interval (CI): 0.71-0.90) and objective response rate (ORR) (Odds ratio [OR]=1.61, 95% CI: 1.30-1.99) favored EGFRI plus chemotherapy, while no statistically significant differences were observed for progression-free survival (PFS) (HR=0.93, 95% CI: 0.84-1.04) or resection rate (RR). Similar results were found in the all-sided population. In the right-sided population, PFS favored bevacizumab plus chemotherapy (HR=1.45, 95% CI: 1.19-1.78), while no statistically significant differences were observed for OS (HR=1.17, 95% CI: 0.95-1.44), ORR (OR=0.99, 95% CI: 0.69-1.41), and RR. Early tumor shrinkage in the all-sided population favored EGFRI plus chemotherapy (OR=1.72; 95% CI: 1.36-2.17); limited data precluded evaluation by sidedness. Safety was available in 6 trials for all-sided tumors and 1 trial for left-sided tumors, each demonstrating typical class-specific adverse events. This most comprehensive meta-analysis indicates a benefit for first-line EGFRI plus chemotherapy over bevacizumab plus chemotherapy in patients with left-sided RAS WT mCRC.

Cetuximab versus methotrexate in first-line treatment of older, frail patients with inoperable recurrent or metastatic head and neck cancer (ELAN UNFIT): a randomised, open-label, phase 3 trial.

BACKGROUND: At present, there is no established standard treatment for frail older patients with recurrent or metastatic head and neck squamous cell carcinoma. We aimed to compare the efficacy and safety of cetuximab to those of methotrexate (the reference regimen) in this population. METHODS: This randomised, open-label, phase 3 trial was done at 20 hospitals in France. Patients aged 70 years or older, assessed as frail by the ELAN Geriatric Evaluation, with recurrent or metastatic head and neck squamous cell carcinoma in the first-line setting and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were eligible for inclusion. Patients were randomly assigned (1:1) to receive cetuximab 500 mg/m2 intravenously every 2 weeks or methotrexate 40 mg/m2 intravenously every week, with minimisation by ECOG performance status, type of disease evolution, Charlson Comorbidity Index score, serum albumin concentration, and geriatrician consultation. To avoid deterministic minimisation and assure allocation concealment, patients were allocated with a probability of 0·80 to the treatment that most reduced the imbalance. Treatment was continued until disease progression or unacceptable toxicity, whichever occurred first. The primary endpoint was failure-free survival (defined as the time from randomisation to disease progression, death, discontinuation of treatment, or loss of 2 or more points on the Activities in Daily Living scale, whichever occurred first) and was analysed in the intention-to-treat population. 151 failures expected out of 164 patients were required to detect a hazard ratio (HR) of 0·625 with 0·05 alpha error, with 80% power. A futility interim analysis was planned when approximately 80 failures were observed, based on failure-free survival. Safety analyses included all patients who received at least one dose of the study drug. This study is registered on ClinicalTrials.gov (NCT01884623) and was stopped for futility after the interim analysis. FINDINGS: Between Nov 7, 2013, and April 23, 2018, 82 patients were enrolled (41 to the cetuximab group and 41 to the methotrexate group); 60 (73%) were male, 37 (45%) were aged 80 years or older, 35 (43%) had an ECOG performance status of 2, and 36 (44%) had metastatic disease. Enrolment was stopped for futility at the interim analysis. At the final analysis, median follow-up was 43·3 months (IQR 30·8-52·1). At data cutoff, all 82 patients had failure; failure-free survival did not differ significantly between the groups (median 1·4 months [95% CI 1·0-2·1] in the cetuximab group vs 1·9 months [1·1-2·6] in the methotrexate group; adjusted HR 1·03 [95% CI 0·66-1·61], p=0·89). The frequency of patients who had grade 3 or worse adverse events was 63% (26 of 41) in the cetuximab group and 73% (30 of 41) in the methotrexate group. The most common grade 3-4 adverse events in the cetuximab group were fatigue (four [10%] of 41 patients), lung infection (four [10%]), and rash acneiform (four [10%]), and those in the methotrexate group were fatigue (nine [22%] of 41), increased gamma-glutamyltransferase (seven [17%]), natraemia disorder (four [10%]), anaemia (four [10%]), leukopenia (four [10%]), and neutropenia (four [10%]). The frequency of patients who had serious adverse events was 44% (18 of 41) in the cetuximab group and 39% (16 of 41) in the methotrexate group. Four patients presented with a fatal adverse event in the cetuximab group (sepsis, decreased level of consciousness, pulmonary oedema, and death of unknown cause) as did two patients in the methotrexate group (dyspnoea and death of unknown cause). INTERPRETATION: The study showed no improvement in failure-free survival with cetuximab versus methotrexate. Patients with an ECOG performance status of 2 did not benefit from these systemic therapies. New treatment options including immunotherapy should be explored in frail older patients with recurrent or metastatic head and neck squamous cell carcinoma, after an initial geriatric evaluation, such as the ELAN Geriatric Evaluation. FUNDING: French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC and the Ligue Contre le Cancer), GEMLUC, GEFLUC, and Merck Santé. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Versus Cetuximab as Maintenance Therapy in First-Line Therapy for RAS and BRAF Wild-Type Metastatic Colorectal Cancer: Phase III ERMES Study.

PURPOSE: The intensity of anti-EGFR-based first-line therapy for RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC), once disease control is achieved, is controversial. A de-escalation strategy with anti-EGFR monotherapy represents a potential option to maintain efficacy while reducing cytotoxicity. METHODS: In this multicenter, open-label, phase III trial, patients with untreated RAS/BRAF wt mCRC were randomly assigned to receive either fluorouracil, leucovorin, and irinotecan/cetuximab (FOLFIRI/Cet) until disease progression (arm A) or FOLFIRI/Cet for eight cycles followed by Cet alone (arm B). The coprimary end points were a noninferior progression-free survival (PFS) in the modified per-protocol (mPP) population (>eight cycles) and a lower incidence of grade (G) 3-4 adverse events (AEs) for arm B compared with arm A. RESULTS: Overall, 606 patients were randomly assigned, with 300 assigned to arm A and 306 to arm B. The median follow-up was 22.3 months. In the mPP population, 291 events occurred with a PFS of 10 versus 12.2 months for arms B and A, respectively (P of noninferiority = .43). In the intention-to-treatment (ITT, ≥one cycle) population, 503 events occurred with a PFS of 9 versus 10.7 months (P = .39). The overall survival was 35.7 versus 30.7 months (P = .119) and 31.0 versus 25.2 months (P = .32) in the mPP and ITT population, respectively. Arm B had lower G3-4 AEs during the maintenance period than arm A (20.2% v 35.1%). CONCLUSION: The ERMES study did not demonstrate noninferiority of maintenance with Cet alone. Despite a more favorable safety profile, maintenance with single-agent Cet after induction with FOLFIRI/Cet cannot be recommended for all patients but could represent an option in selected cases.

A randomized study comparing the nutritional effects of radiotherapy with cetuximab versus cisplatin in patients with advanced head and neck cancer.

BACKGROUND: Head and neck cancer (HNC) patients have a high risk of developing malnutrition. This randomized study aimed to compare the effect of weekly cisplatin or cetuximab combined with radiotherapy on weight loss at 3 months after treatment was started. Secondary outcomes were the prevalence of malnutrition using the Global Leadership Initiative on Malnutrition (GLIM) criteria, feeding tube dependence and health related quality of life from a nutritional perspective. METHODS: Patients from the ARTSCAN III study with advanced HNC were assessed for weight, body composition, enteral tube dependence and selected quality-of-life scores (EORTC QLQ-C30 and QLQ-H&N35) at diagnosis and 6 weeks 3, 6 and 12 months after treatment initiation. RESULTS: Of the 80 patients, 38 and 42 were randomized to receive cetuximab and cisplatin treatment, respectively. There was no significant difference in weight loss at 3 months between the two study groups. However, the cetuximab group had significantly less weight loss, fewer enteral feeding tubes and better physical functioning at the end of treatment but more pain-related problems 3 months after treatment initiation. No differences between the groups were found at 6 and 12 months. The prevalence of malnutrition was not significantly different at any time point. CONCLUSION: The hypothesized benefit of concomitant treatment with cetuximab over cisplatin regarding the prevalence of malnutrition was not supported by this study.

Potential Efficacy of Shiunko for Anti-Epidermal Growth Factor Receptor (EGFR) Monoclonal Antibody-Induced Skin Fissure: A Single Institutional Case Series.

PURPOSE: Anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb) is the key drug for RAS/BRAF V600E wild-type metastatic colorectal cancer (mCRC). However, anti-EGFR mAb-induced skin fissures often affect a patient's quality of life. Shiunko, a traditional Japanese topical herbal medicine, is used for burns and dermatitis and may potentially have wound-healing effects. Herein, we report cases of patients with mCRC who were treated with Shiunko for anti-EGFR mAb-induced skin fissure. METHODS: We retrospectively reviewed consecutive patients with mCRC who received an anti-EGFR mAb-containing regimen and were treated with Shiunko twice a day for skin fissures at the National Cancer Center Hospital East between March 2022 and December 2022. Skin fissures were assessed at baseline and at every visit until 28 days after Shiunko initiation according to CTCAE v5.0. RESULTS: Among the 11 patients, 5 patients were female; the median age was 61 (range, 43-79) years. The median treatment duration with anti-EGFR mAb before Shiunko initiation was 13.1 (range, 6-52) weeks. Skin moisturizer and topical steroids were applied for skin fissures in 11 and 5 patients, respectively. All patients had grade 2 skin fissures at baseline of Shiunko initiation. Two weeks after Shiunko initiation, complete recovery was noted in 4 patients and improvement to grade 1 was noted in 6 patients. There were no Shiunko-related adverse events. Ten patients continued anti-EGFR mAb treatment until disease progression, while 1 patient discontinued anti-EGFR mAb treatment due to severe eruptions. CONCLUSION: Shiunko could be a treatment option for anti-EGFR mAb-induced skin fissure. Further studies are warranted to investigate the efficacy and safety of Shiunko for anti-EGFR mAb-induced skin fissure.

A phase 2 trial combining afatinib with cetuximab in patients with EGFR exon 20 insertion-positive non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations are the third most common EGFR mutations in patients with non-small cell lung cancer (NSCLC) and are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). There is evidence of activity of combining EGFR TKIs with monoclonal antibodies. This study reports on the efficacy and safety of afatinib in combination with cetuximab. METHODS: In this single-arm phase 2 trial, patients with advanced NSCLC harboring an EGFR ex20ins mutation were treated with afatinib 40 mg once daily in combination with cetuximab 500 mg/m2 every 2 weeks. The primary end point was disease control rate (DCR) at 18 weeks of treatment. RESULTS: Thirty-seven patients started treatment, with a median age of 65 years (range, 40-80 years), 78% female, and 95% White. The study achieved its primary end point with a DCR of 54% at 18 weeks, an overall response rate (ORR) of 43%, and a 32% confirmed ORR. Best responses were partial (n = 16), stable (n = 16), progressive disease (n = 2), or not evaluable (n = 3). Median progression-free survival was 5.5 months (95% CI, 3.7-8.3 months) and median overall survival was 16.8 months (95% CI, 10.7-25.8 months). The most common treatment-related adverse events (TRAEs) were diarrhea (70%), rash (65%), dry skin (59%), paronychia (54%), and erythema (43%). Grade 3 TRAEs were reported in 54% of all patients. CONCLUSIONS: Combination treatment with afatinib and cetuximab demonstrated antitumor activity with a DCR of 54% at 18 weeks and a 32% confirmed ORR. Toxicity was significant, although manageable, after dose reduction.

Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial.

KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS-MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRAS G12C-positive CRC (n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients (n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.ClinicalTrials.gov identifier: NCT04449874.

Risk factors for oral mucositis in patients with solid tumors under treatment with cetuximab: a retrospective cross-sectional study.

BACKGROUND: This study retrospectively analyzed the risk factors for oral mucositis (OM) during cetuximab treatment. MATERIAL AND METHODS: We screened patients using cetuximab and retrospectively evaluated the presence of OM based on medical records. We collected information from 2 years of evaluations. Patient medical records were reviewed to obtain data on chemotherapy cycle and dose, sex, age, primary tumor, TNM stage, and head and neck radiotherapy (HNR) history. The X2 test and multinomial logistic regression were used for statistical analysis (SPSS 20.0, p < 0.05). RESULTS: Among 1831 patients, OM was showed in 750 in any grade (41%), during cetuximab treatment. Most patients were female (n=944, 51.6%), <70years-old (n=1149, 62.8%), had larynx cancer (n=789, 43.1%) in T4 (n=579, 47.7%), N0 (n=509, 52.6%) stages. Primary tumor surgery was performed in 1476 (80.6%) patients, radiotherapy in 606 (33.1%) patients and cetuximab protocols most used involved up to four cycles (n=1072, 58.5%) of <400mg (n=996, 54.4%) cetuximab doses. Female (OR [odds ratio] = 2.17, CI95% = 1.26-3.75), >70 years-old patients (OR = 16.02, CI95% = 11.99-21.41), with HHNR (OR = 1.84, 1.41-2.40), treated with >4 cycles (OR = 1.52, CI95% = 1.16-2.01) and high doses of cetuximab (OR = 3.80, CI95% = 2.52-5.71) are the greatest risk factors for OM. CONCLUSIONS: Since the clinical benefit of cetuximab in the treatment of older patients is limited and there is a high OM, especially in women with head and neck treated with radiotherapy, high doses and a high number of cetuximab cycles must be administered with caution.

A Real-World Retrospective Study to Evaluate the Reliability of Cetuximab plus Capecitabine versus Capecitabine as Maintenance Therapy in Patients with RAS and BRAF Wild-Type Metastatic Colorectal Cancer.

BACKGROUND: The optimal maintenance therapy for rat sarcoma (RAS) and v-raf murine sarcoma viral oncogene homolog B (BRAF) metastatic colorectal cancers (mCRCs) remains unclear. It is critical to evaluate the reliability of cetuximab-capecitabine (the observation group) relative to capecitabine alone (control group). PATIENTS AND METHODS: In this retrospective analysis, patients with RAS and BRAF mCRC admitted to Huizhou Municipal Central Hospital, between January 2016 and October 2020 were enrolled and treated with cetuximab plus 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) as an initial therapy. Patients whose disease was controlled after at least six cycles of treatment were administered a maintenance therapy until disease progression. We also analyzed the prognosis of patients according to clinicopathological features. Altogether, 39 RAS and BRAF mCRC patients were recruited from January 2016 to October 2020, with 18 cases in the treatment group and 21 cases in the control group. The difference in baseline clinicopathological features between the two treatments is not obvious. RESULTS: The median progression-free survival after maintenance treatment in observation group (9.5 months [95% confidence interval (CI) = 6.4-12.6]), was significantly better than the control group (7.3 months [95% CI = 5.8-8.8]). During maintenance treatment, there were no deaths caused by treatment-related adverse events, and the overall incidence of rash acne was different between the observation and control groups (p < 0.05). Most adverse events were mild and easily controlled. Primary tumor site, baseline carcinoembryonic antigen levels, and microsatellite instability status were independent prognostic factors. CONCLUSION: Maintenance therapy using cetuximab plus capecitabine improved survival in patients with mCRC and was well tolerated by patients.

Leucovorin-induced Hypersensitivity Reaction in a Patient with Metastatic Colorectal Cancer Treated with Cetuximab Plus FOLFOX Chemotherapy: A Case Report.

The FOLFOX regimen (combination of leucovorin, 5-fluorouracil, and oxaliplatin) is the first-line treatment for high-risk stage 2 and 3 colorectal cancer patients. While hypersensitivity reactions (HSRs) caused by oxaliplatin are commonly reported, HSRs due to leucovorin have been infrequently reported. This report aims to investigate the clinical presentation, diagnosis, and management of leucovorin induced HSRs. A 60-year-old female developed generalized edema, dyspnea, and facial redness during cetuximab plus FOLFOX chemotherapy administered for management of metastatic colorectal cancer. Because HSRs induced by oxaliplatin are commonly reported, we initially presumed an oxaliplatin-induced HSR. However, despite undergoing oxaliplatin desensitization, HSRs persisted, and they were still observed when leucovorin was administered without oxaliplatin. The patient was diagnosed with leucovorin-induced HSR and underwent leucovorin desensitization. However, the reactions recurred within 30 minutes of the initiating the desensitization. Considering unsuccessful leucovorin desensitization, leucovorin was excluded. The patient received cetuximab and oxaliplatin chemotherapy without leucovorin to date without any adverse effects. While leucovorin-induced HSRs are infrequently reported, they should still be regarded as potential adverse effects.

Case report: Interstitial lung disease of XELOEX chemotherapy with cetuximab in advanced colon cancer induced.

INTRODUCTION: This paper presents a case of a Chinese patient with advanced colon cancer who developed drug-induced interstitial lung disease while undergoing treatment with cetuximab combined with XELOX. PATIENT CONCERNS: A 75-year-old man with a history of colon cancer, had metastases in the liver, peritoneum, and lungs, which were initially treated with XELOX and cetuximab (0.4 g) in 2019. However, the lung metastases progressed, and the cetuximab dosage was adjusted to 0.9 g and then readjusted to 0.4 g. DIAGNOSIS: In January 2021, computed tomography revealed developed interstitial lung disease, leading to the discontinuation of chemotherapy and cetuximab. INTERVENTIONS: Receiving methylprednisolone pulse therapy. OUTCOMES: The patient experienced respiratory failure and passed away. The Naranjo Algorithm Assessment score indicated a probable relationship between cetuximab and the adverse event. CONCLUSION: This case highlights the need for regular pulmonary imaging examinations during cetuximab therapy, as drug-induced interstitial lung disease may be associated with the dose and duration of treatment.

Polimorfismos genéticos asociados a la respuesta del carcinoma de cabeza y cuello al cetuximab / Genetic polymorphisms associated with the response of head and neck carcinoma to cetuximab

Objetivo: Exponer los principales polimorfismos genéticos que han sido asociados a la respuesta del carcinoma de cabeza y cuello al cetuximab. Método: Se realizó una revisión no exhaustiva de artículos publicados en el período de enero de 2000 a diciembre de 2022, para ello se emplearon las bases de datos Medline (vía Pubmed) y Science Direct. En la evaluación de la calidad metodológica de los artículos incluidos se utilizó la guía para los estudios de asociación genética (Q-Genie). Resultados: Se identificaron un total de 206 artículos, de los cuales 12 cumplieron con los criterios para el análisis final. Se reportaron varios polimorfismos, tales como: EGFR-R521K (AA/GA), FcγRIIIa (158VV) y FcγRIIa (131HH), KRASLCS6 (TG/GG), AKT2:rs8100018, PTEN: rs12569998 en sus variantes mutadas, HIF-1α (CT/TT) y XRCC5 (GG/AA) que se asociaron con las variables de supervivencia, riesgo de progresión, tiempos hasta la progresión de la enfermedad, así como toxicidad cutánea. Conclusiones: Varios polimorfismos pueden asociarse con la respuesta del carcinoma de cabeza y cuello al tratamiento con cetuximab, siendo EGFR-R521K y FcγR IIIa-V158F los más estudiados. La enorme incertidumbre de los resultados alcanzados no permite alcanzar conclusiones firmes sobre la influencia de los polimorfismos genéticos en la respuesta al cetuximab; sin embargo, pueden convertirse en biomarcadores farmacogenéticos en la práctica clínica como una valiosa herramienta en la medicina personalizada, para predecir la respuesta medicamentosa. Para ello se requiere la realización de ensayos controlados con estratos por genotipo, con asignación aleatoria del tratamiento y el análisis de otras variables con valor pronóstico conocido.(AU)

Objective: To present the main genetic polymorphisms that have been associated with the response of head and neck carcinoma to cetuximab. Method: A non-exhaustive review of articles published in the period from January 2000 to December 2022 was carried out, for this purpose the Medline (via Pubmed) and Science Direct databases were used. The guide for genetic association studies (Q-Genie) was used to evaluate the methodological quality of the included articles. Results: A total of 206 articles were identified, of which 12 met the criteria for the final analysis. Several polymorphisms were reported, such as: EGFR-R521K (AA/GA), FcγRIIIa (158VV) and FcγRIIa (131HH), KRAS-LCS6 (TG/GG), AKT2:rs8100018, PTEN: rs12569998 in its mutated variants, HIF- 1α (CT/TT) and XRCC5 (GG/AA) that were associated with survival variables, risk of progression, times to disease progression, as well as skin toxicity. Conclusions: Several polymorphisms can be associated with the response of head and neck carcinoma to treatment with cetuximab, being EGFR-R521K and FcγR IIIa-V158F the most studied. The enormous uncertainty of the results obtained does not allow firm conclusions to be reached about the influence of genetic polymorphisms on the response to cetuximab; however, they can become pharmacogenetic biomarkers in clinical practice as a valuable tool in personalized medicine, to predict drug response. This requires carrying out controlled trials with strata by genotype, with random assignment of treatment and the analysis of other variables with known prognostic value.(AU)

Increased risk of venous and arterial thromboembolism in patients with colorectal cancer receiving cetuximab-based combination chemotherapy: A population-based study in Korea.

INTRODUCTION: Limited data exist on the risk of venous and arterial thromboembolisms (VTE and ATE) in patients receiving cetuximab plus chemotherapy. We aimed to determine the thromboembolic risk of patients with recurrent/metastatic colorectal cancer (CRC) treated with cetuximab plus chemotherapy compared to chemotherapy alone. METHODS: This population-based study used nationwide claims data from the Health Insurance Review and Assessment Service of South Korea from 2013 to 2020. Patients with recurrent/metastatic CRC treated with first-line oxaliplatin- or irinotecan-based doublets with or without cetuximab and no secondary prevention for VTE and ATE were included. Primary outcomes were the occurrence of any thromboembolic events, VTE, and ATE, which were determined using the cumulative incidence method incorporating death as a competing event. RESULTS: We identified 19,723 patients (cetuximab plus chemotherapy, N = 7630; chemotherapy alone, N = 12,093). The cumulative incidence of any thromboembolic events in patients with cetuximab plus chemotherapy was significantly higher than in those receiving chemotherapy alone (6-month, 5.62 % vs. 3.58 %, P < 0.0001). The rates of VTE (6-month, 5.11 % vs. 3.28 %, P < 0.0001) and ATE (6-month, 0.53 % vs. 0.32 %, P = 0.0218) were also higher in patients receiving cetuximab plus chemotherapy. In multivariable analysis, cetuximab plus chemotherapy was independently associated with developing any thromboembolic events (hazard ratio [HR], 1.63; 95 % confidence interval [CI], 1.42-1.87), VTE (HR, 1.62; 95 % CI, 1.40-1.87), and ATE (HR, 1.77; 95 % CI, 1.16-2.71). CONCLUSIONS: Cetuximab with irinotecan- or oxaliplatin-based doublet chemotherapy was associated with an increased risk of any thromboembolic events, VTE, and ATE; further studies are warranted to examine the underlying mechanisms.

Portal vein thrombosis after cetuximab and 5-fluorouracil therapy in a patient with advanced colon cancer and decompensated cirrhosis: a case report and review of the literature.

BACKGROUND: Treatment options for advanced colon cancer are mainly combinations of chemotherapy and targeted drugs. However, poor physical health and medication intolerance limit the choice of anticancer drugs. Colon cancer with cirrhosis is a particular patient group that poses a challenge to clinical treatment. CASE PRESENTATION: This article presents a case of a patient in the decompensated stage of cirrhosis who was diagnosed with advanced colon cancer. The initial presentation was a nodule on his navel named the Sister Mary Joseph's nodule, which was later confirmed by biopsy and PET-CT as one of the metastases of colon cancer. The patient was treated with cetuximab and 5-fluorouracil at a below-guideline dose; however, portal vein thrombosis developed and led to death. This entire process, from diagnosis to death, occurred within a span of three months. CONCLUSION: Cancers with cirrhosis are a special group that deserves more attention. There is no unified treatment guideline for these patients, especially those with extrahepatic primary tumors. We should be more cautious when choosing treatment for such patients in the future. Both chemotherapy and targeted treatment may potentially induce portal vein thrombosis, which appears to have a higher incidence and worse prognosis than cancers without cirrhosis.

Cetuximab Plus Concurrent Radiotherapy in Patients With Nasopharyngeal Carcinoma.

BACKGROUND/AIM: Several reports have evaluated the efficacy and safety of concurrent radiotherapy with cetuximab (BRT) in patients with nasopharyngeal carcinoma (NPC). Combination therapy with cetuximab can be a treatment option for NPC. Although clinical data regarding the efficacy and safety of BRT without induction chemotherapy (ICT) or adjuvant chemotherapy is essential for the development of new therapeutic strategies, such data are rarely reported. PATIENTS AND METHODS: We retrospectively investigated a series of patients with NPC treated in our institution to evaluate the efficacy and safety of BRT. Eleven patients with newly diagnosed NPC were identified from an inpatient database from July 2015 to April 2018. Seven patients who received BRT were reviewed. RESULTS: All patients completed BRT without cessation of treatment. Six (85.7%) patients achieved a complete response and one (14.3%) achieved stable disease. The response rate was 85.7%. All patients with ≤T3 disease achieved a complete response. Both patients with T3 disease developed local recurrence, and one of the four patients with T1-2 disease developed distant metastases. The 1- and 3-year overall survival rates were 85.7% and 47.6%, respectively. The most common adverse events (AEs) were pharyngeal mucositis (100%), radiation dermatitis (100%), anorexia (28.6%), weight loss (28.6%), acneiform rash (28.6%), and dry mouth (28.6%). Grade 3 AEs were pharyngeal mucositis (42.9%), radiation dermatitis (28.6%), and anorexia (14.3%). No grade 4/5 AEs were observed. CONCLUSION: BRT for NPC was tolerable, but our findings suggest that BRT without induction chemotherapy or adjuvant chemotherapy is insufficient at least for ≥T3 disease.

NEXUS trial: a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant colorectal oligometastases.

BACKGROUND: The optimal treatment strategy for resectable BRAF V600E mutant colorectal oligometastases (CRM) has not been established due to the rarity and rapid progression of the disease. Since the unresectable recurrence rate is high, development of novel perioperative therapies are warranted. On December 2020, the BEACON CRC triplet regimen of encorafenib, binimetinib, and cetuximab was approved for unresectable metastatic colorectal cancer in Japan. METHODS: The NEXUS trial is a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant CRM. The key inclusion criteria are as follows: histologically diagnosed with colorectal adeno/adenosquamous carcinoma; RAS wild-type and BRAF V600E mutation by tissue or blood; and previously untreated resectable distant metastases. The triplet regimen (encorafenib: 300 mg daily; binimetinib: 45 mg twice daily; cetuximab: 400 mg/m2, then 250 mg/m2 weekly, 28 days/cycle) is administered for 3 cycles each before and after curative resection. The primary endpoint of the study is the 1-year progression-free survival (PFS) rate and the secondary end points are the PFS, disease-free survival, overall survival, and objective response rate. The sample size is 32 patients. Endpoints in the NEXUS trial as well as integrated analysis with the nationwide registry data will be considered for seeking regulatory approval for the perioperative use of the triplet regimen. DISCUSSION: The use of the triplet regimen in the perioperative period is expected to be safe and effective in patients with resectable BRAF V600E mutant CRM. TRIAL REGISTRATION: jRCT2031220025, April. 16, 2022.

Risk factor analysis for anti-epidermal growth factor receptor monoclonal antibody-induced skin toxicities in real-world metastatic colorectal cancer treatment.

PURPOSE: Anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies are effective in treating RAS wild-type metastatic colorectal cancer (mCRC). However, their administration induces skin toxicity, markedly reducing patients' quality of life. This study is aimed at identifying the risk factors associated with anti-EGFR monoclonal antibody-induced skin toxicities. METHODS: Patients with mCRC (n = 116) who received anti-EGFR monoclonal antibody treatment were retrospectively evaluated. Primary endpoint was evaluation of the risk factors for grade ≥ 2 overall skin toxicities during all the treatment periods. Furthermore, factors associated with each grade ≥ 2 skin symptoms were assessed. RESULTS: Incidence of total grade ≥ 2 skin toxicity symptoms was 61.2%, and those of grade ≥ 2 rash, dry skin, fissures, and paronychia were 34.5%, 25.9%, 20.7%, and 25.0%, respectively. Multivariate logistic regression analyses revealed that liver metastasis was an independent risk factor for overall grade ≥ 2 skin toxicities (adjusted odds ratio [OR], 2.88; 95% confidence interval [CI], 1.22-6.78; P = 0.02) and prophylactic administration of antibiotics as a preventive factor (OR 0.10; 95%CI 0.01-0.91; P = 0.04). For grade ≥ 2 rash, prophylactic use of systemic antibiotics and topical steroid ointment was a preventive factor (OR 0.37; 95%CI 0.16-0.89; P = 0.03). Moreover, liver metastasis (OR 8.37; 95%CI 1.98-35.47; P = 0.004) and prophylactic administration of antibiotics (OR 0.15; 95%CI 0.03-0.76; P = 0.02) were significantly associated with grade ≥ 2 paronychia. CONCLUSION: Liver metastasis was suggested to be a risk factor for the incidence of overall grade ≥ 2 skin toxicities; moreover, preemptive systemic antibiotic administration drastically decreased this risk during all periods of anti-EGFR treatment for mCRC.

Efficacy and Safety of a Parenteral Nutrition Program for Patients with RAS Wild-Type Metastatic Colorectal Cancer Administered First-Line Cetuximab Plus Chemotherapy: A Propensity Score Matching Study.

Malnutrition is a common problem in patients with metastatic colorectal cancer (mCRC) receiving targeted therapy plus chemotherapy, resulting in severe toxicity and decreased survival rates. This retrospective study employing propensity score matching (PSM) examined the efficacy and safety of a supplemental home parenteral nutrition (HPN) program for patients with RAS wild-type mCRC receiving cetuximab plus chemotherapy. This retrospective nationwide registry study included data from 14 medical centers/hospitals across Taiwan, and the data period ranged from November 2016 to December 2020. Patients with RAS wild-type mCRC receiving cetuximab plus chemotherapy as their first-line therapy were included and divided into HPN and non-HPN program groups. HPN was initiated based on patient-specific factors, such as baseline nutritional status, treatment-related toxicities, and comorbidities. Clinical outcomes were evaluated using response to therapy, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). This study recruited 758 patients, of whom 110 and 648 were included in the HPN and non-HPN program groups, respectively. After 1:3 PSM, the data of 109 and 327 patients from the HPN and non-HPN program groups were analyzed, respectively. The HPN program group had a higher metastasectomy rate (33.9% vs. 20.2%, p = 0.005), and longer duration of treatment and DoR than the non-HPN program group (13.6 vs. 10.3 and 13.6 vs. 9.9 months, p = 0.001 and < 0.001, respectively). The HPN program group tended to have a longer median PFS (18.2 vs. 13.9 months, p = 0.102). Moreover, we noted a significant improvement in the median OS in the same group (53.4 vs. 34.6 months, p = 0.002). Supplemental HPN programs may be recommended for select patients with mCRC receiving targeted therapy plus chemotherapy to improve oncological outcomes.