Zebrafish drug screening identifies Erlotinib as an inhibitor of Wnt/ß-catenin signaling and self-renewal in T-cell acute lymphoblastic leukemia.

The Wnt/ß-catenin pathway's significance in cancer initiation, progression, and stem cell biology underscores its therapeutic potential. However, the clinical application of Wnt inhibitors remains limited due to challenges posed by off-target effects and complex cross-talk of Wnt signaling with other pathways. In this study, we leveraged a zebrafish model to perform a robust and rapid drug screening of 773 FDA-approved compounds to identify Wnt/ß-catenin inhibitors with minimal toxicity. Utilizing zebrafish expressing a Wnt reporter, we identified several drugs that suppressed Wnt signaling without compromising zebrafish development. The efficacy of the top hit, Erlotinib, extended to human cells, where it blocked Wnt/ß-catenin signaling downstream of the destruction complex. Notably, Erlotinib treatment reduced self-renewal in human T-cell Acute Lymphoblastic Leukemia cells, which rely on active ß-catenin signaling for maintenance of leukemia-initiating cells. Erlotinib also reduced leukemia-initiating cell frequency and delayed disease formation in zebrafish models. This study underscores zebrafish's translational potential in drug discovery and repurposing and highlights a new use for Erlotinib as a Wnt inhibitor for cancers driven by aberrant Wnt/ß-catenin signaling.

Antitumor effects of erlotinib in combination with berberine in A431 cells.

BACKGROUND: First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib, have been shown to target tumors with L858R (exon 21) and exon 19 deletions, resulting in significant clinical benefits. However, acquired resistance often occurs due to EGFR mutations. Therefore, novel therapeutic strategies for treatment of patients with EGFR-positive tumors are needed. Berberine (BBR) is an active alkaloid extracted from pharmaceutical plants such as Coptis chinensis. Berberine has been shown to significantly inhibit EGFR activity and mediate anticancer effects in multiple preclinical studies. We investigated whether combining BBR with erlotinib could augment erlotinib-induced cell growth inhibition of EGFR-positive cells in a mouse xenograft model. METHODS: We examined the antitumor activities and potential mechanisms of erlotinib in combination with berberine in vitro and in vivo using the MTT assay, immunoblotting, flow cytometry, and tumor xenograft models. RESULTS: In vitro studies with A431 cells showed that synergistic cell growth inhibition by the combination of BBR and erlotinib was associated with significantly greater inhibition of pEGFR and pAKT, and inhibition of cyclin D and Bcl-2 expression compared to that observed in response to BBR or erlotinib alone. The efficacy of the combination treatment was also investigated in nude mice. Consistent with the in vitro results, BBR plus erlotinib significantly reduced tumor growth. CONCLUSION: Our data supported use of BBR in combination with erlotinib as a novel strategy for treatment of patients with EGFR positive tumors.

First-line systemic treatment strategies for unresectable hepatocellular carcinoma: A cost-effectiveness analysis.

BACKGROUND: Oral multikinase inhibitors and immune checkpoint inhibitors (ICIs) are effective for treating advanced hepatocellular carcinoma (aHCC) but may increase cost. This study compared the cost-effectiveness of oral multikinase inhibitors and ICIs in the first-line treatment of patients with aHCC. METHODS: A three-state Markov model was established to study the cost-effectiveness of drug treatment from the perspective of Chinese payers. The key outcomes in this study were total cost, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER). RESULTS: The total costs and QALYs of sorafenib, sunitinib, donafenib, lenvatinib, sorafenib plus erlotinib, linifanib, brivanib, sintilimab plus IBI305, and atezolizumab plus bevacizumab were $9070 and 0.25, $9362 and 0.78, $33,814 and 0.45, $49,120 and 0.83, $63,064 and 0.81, $74,814 and 0.82, $81,995 and 0.82, $74083 and 0.85, and $104,188 and 0.84, respectively. The drug regimen with the lowest ICER was sunitinib ($551 per QALY), followed by lenvatinib ($68,869 per QALY). For oral multikinase inhibitors, the ICER of lenvatinib, sorafenib plus erlotinib, linifanib and brivanib compared with sunitinib was $779576, $1534,347, $1768,971, and $1963,064, respectively. For ICIs, sintilimab plus IBI305 is more cost effective than atezolizumab plus bevacizumab. The model was most sensitive to the price of sorafenib, the utility of PD, and the price of second-line drugs. CONCLUSION: For oral multikinase inhibitors, the order of possible treatment options is sunitinib > lenvatinib > sorafenib plus erlotinib > linifanib > brivanib > donafenib. For ICIs, the order of possible treatment options is sintilimab plus IBI305 > atezolizumab plus bevacizumab.

Targeting EGFR in Combination with Nutritional Supplements on Antitumor Efficacy in a Lung Cancer Mouse Model.

Selenium (Se) and fish oil (FO) exert anti-epidermal growth factor receptor (EGFR) action on tumors. This study aimed to compare the anti-cancer efficacy of EGFR inhibitors (gefitinib and erlotinib) alone and in combination with nutritional supplements of Se/FO in treating lung cancer. Lewis LLC1 tumor-bearing mice were treated with a vehicle or Se/FO, gefitinib or gefitinib plus Se/FO, and erlotinib or erlotinib plus Se/FO. The tumors were assessed for mRNA and protein expressions of relevant signaling molecules. Untreated tumor-bearing mice had the lowest body weight and highest tumor weight and volume of all the mice. Mice receiving the combination treatment with Se/FO and gefitinib or erlotinib had a lower tumor volume and weight and fewer metastases than did those treated with gefitinib or erlotinib alone. The combination treatment exhibited greater alterations in receptor signaling molecules (lower EGFR/TGF-ß/TßR/AXL/Wnt3a/Wnt5a/FZD7/ß-catenin; higher GSK-3ß) and immune checkpoint molecules (lower PD-1/PD-L1/CD80/CTLA-4/IL-6; higher NKp46/CD16/CD28/IL-2). These mouse tumors also had lower angiogenesis, cancer stemness, epithelial to mesenchymal transitions, metastases, and proliferation of Ki-67, as well as higher cell cycle arrest and apoptosis. These preliminary results showed the Se/FO treatment enhanced the therapeutic efficacies of gefitinib and erlotinib via modulating multiple signaling pathways in an LLC1-bearing mouse model.

The "SEED" Study: The Feasibility of Selecting Patient-Specific Biologically Targeted Therapy with Sorafenib, Everolimus, Erlotinib or Dasatinib for Pediatric and Young Adult Patients with Recurrent or Refractory Brain Tumors.

BACKGROUND: Pediatric brain tumors are the leading cause of cancer death in children and represent a variety of diseases and molecular subtypes. This study sought to evaluate a rapid immunohistochemistry testing panel to aid in therapy selection at the time of malignant tumor recurrence. METHODS: With IRB approval and appropriate informed consent, we conducted a single-institution prospective clinical trial of selected kinase inhibitor therapy. A laboratory-developed immunohistochemical testing panel was performed on tumor tissue, and therapy with one of four small molecule inhibitors was recommended in combination with oral chemotherapy consisting of temozolomide and etoposide. RESULTS: All 20 enrolled subjects were assigned to Everolimus (n = 4), Erlotinib (n = 6) or Dasatinib (n = 10); 90% (18/20) within the pre-specified 14-day feasibility time period. Only two subjects elected treatment on study, 8 received targeted treatment based on testing results either alone (n = 5) or in combination with chemotherapy (n = 3). Other subjects received chemotherapy alone (n = 7), surgery alone (n = 2) or no further therapy (n = 3). Immunohistochemical targets were associated with correlative genetic changes in 28% (5/18) of those evaluated. CONCLUSIONS: It was feasible to rapidly select targeted therapy in recurrent pediatric brain tumors, but not feasible to treat with a uniform combination treatment regimen.

An EGFR signature predicts cell line and patient sensitivity to multiple tyrosine kinase inhibitors.

EGFR is an oncogene with a high frequency of activating mutations in nonsmall cell lung cancer (NSCLC). EGFR inhibitors have been FDA-approved for NSCLC and have shown efficacy in patients with certain EGFR mutations. However, only 9% to 26% of these patients achieve objective responses. In our study, we developed an EGFR gene signature based on The Cancer Genome Atlas (TCGA) RNA-seq data of lung adenocarcinoma (LUAD) to direct the preselection of patients for more effective EGFR-targeted therapy. This signature infers baseline EGFR signaling pathway activity (denoted as EGFR score) in tumor samples, which is associated with tumor sensitivity to EGFR inhibitors and other tyrosine kinase inhibitors (TKIs). EGFR score predicted sensitivity of lung cancer cell lines to Erlotinib, Gefitinib and Sorafenib. Importantly, EGFR score calculated from pretreated samples was associated with patient response to Gefitinib and Sorafenib in lung cancer. Additionally, integration of the EGFR signature with TCGA LUAD data showed that it accurately predicted functional effects of different somatic EGFR mutations, and identified other mutations affecting EGFR pathway activity. Finally, using cancer cell line and clinical trial data, the EGFR score was associated with patient response to TKIs in liver cancer and other cancer types. The EGFR signature provides a useful biomarker that can expand the application of EGFR inhibitors or other TKIs and improve their treatment efficacy through patient stratification.

Estimates of Overall Survival in Patients With Cancer Receiving Different Treatment Regimens: Emulating Hypothetical Target Trials in the Surveillance, Epidemiology, and End Results (SEER)-Medicare Linked Database.

Importance: The Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database may provide insights into the comparative effectiveness of oncological treatments for elderly individuals who are underrepresented in clinical trials. Objective: To evaluate the suitability of SEER-Medicare data for assessing the effectiveness of adding a drug to an existing treatment regimen on the overall survival of elderly patients with cancer. Design, Setting, and Participants: This comparative effectiveness study analyzed SEER-Medicare data from 9549 individuals who received a new diagnosis of stage II colorectal cancer (2008-2012) and 940 patients who received a new diagnosis of advanced pancreatic adenocarcinoma (2007-2012), with follow-up to December 31, 2013 (SEER-Medicare data released in 2015). Two (hypothetical) target trials were designed and emulated based on 2 existing randomized clinical trials: (1) adjuvant fluorouracil after curative surgery for individuals with stage II colorectal cancer and (2) erlotinib added to gemcitabine for individuals with advanced pancreatic adenocarcinoma. Data were analyzed January 2018 to March 2019. Exposures: The following treatment strategies were compared: (1) fluorouracil initiation vs no initiation within 3 months of tumor resection and (2) erlotinib initiation vs no initiation within 12 weeks of gemcitabine initiation. Main Outcomes and Measures: All-cause mortality within 60 months of baseline for the fluorouracil trial and within 72 weeks for the erlotinib trial. Results: Compared with 3293 individuals in the existing fluorouracil trial, 9549 eligible individuals included in the present analyses were more likely to have colon cancer (8565 [90%] vs 2291 [71%]) and were older (median [interquartile range], 79 [73-84] vs 63 [56-68] years). The 5-year risk difference for initiation vs noninitiation of fluorouracil after surgery was -3.8% (95% CI, -14.8% to 12.6%), and the mortality hazard ratio (HR) was 0.95 (95% CI, 0.85-1.04). Compared with 569 individuals in the existing erlotinib trial, 940 eligible patients included in the present analysis were older (median [range], 74 [66-93] vs 64 [36-92] years) and more likely to be male (547 [58%] vs 298 [52%]). The 1-year risk difference for initiation vs noninitiation of erlotinib was 4.7% (95% CI, -9.4% to 18.0%), and the corresponding mortality HR was 1.04 (95% CI, 0.86-1.42). In naive analyses, the mortality HR estimate was 1.14 (95% CI, 0.95-1.36) for the fluorouracil emulation and 0.68 (95% CI, 0.54-0.87) for the erlotinib emulation. Conclusions and Relevance: The present estimates were similar to those from randomized clinical trials that studied adding the same cancer drugs to existing regimens. The published HR was 1.02 (95% CI, 0.70-1.48) in the fluorouracil trial for individuals aged 70 or older and 0.96 (95% CI, 0.74-1.24) in the erlotinib trial for individuals aged 65 years or older. The SEER-Medicare database may be adequate for studying the real-world effectiveness of adding a drug to treatment regimens used for elderly individuals with cancer.

Upregulation of SNX5 predicts poor prognosis and promotes hepatocellular carcinoma progression by modulating the EGFR-ERK1/2 signaling pathway.

Endocytosis is an essential component of cell motility, which facilitates the malignant behavior of cancer. Sorting nexin (SNX) family members are associated with tumor progression. However, the role and mechanism of SNX5 in hepatocellular carcinoma (HCC) progression remain largely unknown. In this study, we investigated the clinical significance and possible involvement of SNX5 in the progression of HCC. Here, we showed that SNX5 was upregulated in tumors compared with adjacent nontumorous tissues in HCC patients. The upregulation of SNX5 in HCC was associated with vascular invasion, intrahepatic metastasis, and poor prognosis. The overexpression of SNX5 promoted HCC cell proliferation, migration, invasion, and metastasis, whereas silencing SNX5 expression resulted in decreased cell proliferation, migration, and invasion. Knockdown of SNX5 significantly inhibited HCC cell proliferation by inducing G1/S transition arrest. Mechanistically, we demonstrated that SNX5 promoted cell proliferation, migration, and invasion via the activation of the EGFR-ERK1/2 pathway by blocking EGF-mediated EGFR internalization. We found that SNX5 interacted with EGFR in HCC cells. Moreover, SNX5-induced cell proliferation, migration, and invasion were partially reversed by the knockdown of EGFR or by ERK1/2 inhibitors. In addition, we demonstrated that SNX5 knockdown sensitized HCC cells to tyrosine kinase inhibitors, including erlotinib and sorafenib. Taken together, our results indicate that SNX5 promotes HCC cell proliferation and metastasis via inhibiting the endocytosis and degradation of EGFR, thereby activating the ERK1/2 signaling pathway. Our work also suggests that SNX5 is a potential therapeutic target for HCC.

The repression and reciprocal interaction of DNA methyltransferase 1 and specificity protein 1 contributes to the inhibition of MET expression by the combination of Chinese herbal medicine FZKA decoction and erlotinib.

ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal medicine Fuzheng Kang-Ai (FZKA) decoction obtained from Guangdong Kangmei Pharmaceutical Company, which contains 12 components with different types of constituents, has been used as part of the adjuvant treatment of lung cancer for decades. We previously showed that FZKA decoction enhances the growth inhibition of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-resistant non-small cell lung cancer (NSCLC) cells by suppressing glycoprotein mucin 1 (MUC1) expression. However, the molecular mechanism underlying the therapeutic potential, particularly in sensitizing or/and enhancing the anti-lung cancer effect of EGFR-TKIs, remains unclear. MATERIALS AND METHODS: Cell viability was measured using 3-(4, 5-diMEThylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and 5-ethynyl -2'-deoxyuridine (EdU) assays. Western blot analysis was performed to examine the protein expressions of DNA methyltransferase 1 (DNMT1), specificity protein 1 (SP1), and MET, an oncogene encoding for a trans-membrane tyrosine kinase receptor activated by the hepatocyte growth factor (HGF). The expression of MET mRNA was measured by quantitative real-time PCR (qRT-PCR). Exogenous expression of DNMT1 and SP1, and MET were carried out by transient transfection assays. The promoter activity of MET was tested using Dual-luciferase reporter assays. A nude mouse xenografted tumor model further evaluated the effect of the combination of FZKA decoction and erlotinib in vivo. RESULTS: The combination of FZKA and erlotinib produced an even greater inhibition of NSCLC cell growth. FZKA decreased the expressions of DNMT1, SP1, and MET (c-MET) proteins, and the combination of FZKA and erlotinib demonstrated enhanced responses. Interestingly, there was a mutual regulation of DNMT1 and SP1. In addition, exogenously expressed DNMT1 and SP1 blocked the FZKA-inhibited c-MET expression. Moreover, excessive expressed MET neutralized FZKA-inhibited growth of NSCLC cells. FZKA decreased the mRNA and promoter activity of c-MET, which was not observed in cells with ectopic expressed DNMT1 gene. Similar findings were observed in vivo. CONCLUSION: FZKA decreases MET gene expression through the repression and mutual regulation of DNMT1 and SP1 in vitro and in vivo. This leads to inhibit the growth of human lung cancer cells. The combination of FZKA and EGFR-TKI erlotinib exhibits synergy in this process. The regulatory loops among the DNMT1, SP1 and MET converge in the overall effects of FZKA and EGFR-TKI erlotinib. This in vitro and in vivo study clarifies an additional novel molecular mechanism underlying the anti-lung cancer effects in response to the combination of FZKA and erlotinib in gefitinib-resistant NSCLC cells.

Effects of removing reimbursement restrictions on targeted therapy accessibility for non-small cell lung cancer treatment in Taiwan: an interrupted time series study.

INTERVENTIONS: Targeted therapies have been proven to provide clinical benefits to patients with metastatic non-small cell lung cancer (NSCLC). Gefitinib was initially approved and reimbursed as a third-line therapy for patients with advanced NSCLC by the Taiwan National Health Insurance (NHI) in 2004; subsequently it became a second-line therapy (in 2007) and further a first-line therapy (in 2011) for patients with epidermal growth factor receptor mutation-positive advanced NSCLC. Another targeted therapy, erlotinib, was initially approved as a third-line therapy in 2007, and it became a second-line therapy in 2008. OBJECTIVES: This study is aimed towards an exploration of the impacts of the Taiwan NHI reimbursement policies (removing reimbursement restrictions) related to accessibility of targeted therapies. SETTING: We retrieved 2004-2013 claims data for all patients with lung cancer diagnoses from the NHI Research Database. DESIGN AND OUTCOME MEASURES: Using an interrupted time series design and segmented regression, we estimated changes in the monthly prescribing rate by patient number and market shares by cost following each modification of the reimbursement policy for gefitinib and erlotinib for NSCLC treatment. RESULTS: Totally 92 220 patients with NSCLC were identified. The prescribing rate of the targeted therapies increased by 15.58%, decreased by 10.98% and increased by 6.31% following the introduction of gefitinib as a second-line treatment in 2007, erlotinib as a second-line treatment in 2008 and gefitinib as as first line treatment in 2011, respectively. The average time to prescription reduced by 65.84% and 41.59% following coverage of erlotinib by insurance and gefitinib/erlotinib as second-line treatments in 2007-2008 and following gefitinib as the first-line treatment in 2011. CONCLUSIONS: The changes in reimbursement policies had a significant impact on the accessibility of targeted therapies for NSCLC treatment. Removing reimbursement restrictions can significantly increase the level and the speed of drug accessibility.

Adjunctive Traditional Chinese Medicine Improves Survival in Patients With Advanced Lung Adenocarcinoma Treated With First-Line Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs): A Nationwide, Population-Based Cohort Study.

OBJECTIVES: The clinical effect of traditional Chinese medicine (TCM) on survival in patients with advanced lung adenocarcinoma treated with first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a major concern and requires more evidence from large-scale clinical studies. MATERIALS AND METHODS: This population-based cohort study used the Taiwan National Health Insurance Research Database to enroll patients between 2006 and 2012 who had newly diagnosed locally advanced and metastatic lung adenocarcinoma treated with first-line gefitinib or erlotinib. Survival was tracked until 2013. The patients were separated into TCM users and nonusers, and Cox regression models were applied to determine the association between the use of TCM and the survival of patients. RESULTS: A total of 1988 patients receiving first-line gefitinib or erlotinib for the treatment of EGFR-mutated advanced lung adenocarcinoma, with the exclusion of TCM users after tumor progression, were included in this cohort study. Compared with TCM nonuse, TCM use for ≥180 days was associated with a significantly decreased risk of mortality by 68% (adjusted hazard ratio [HR], 0.32 [95% CI, 0.21-0.50], P < .0001). Compared with TCM nonuse, TCM use for ≥180 days was associated with a significantly decreased risk of disease progression by 59% (adjusted HR, 0.41 [95% CI, 0.29-0.58], P < .0001). CONCLUSION: This cohort study suggests that adjunctive TCM therapy could improve overall survival and progression-free survival in patients with advanced lung adenocarcinoma treated with first-line TKIs. Future randomized, controlled trials are required to validate these findings.

From Diagnostic-Therapeutic Pathways to Real-World Data: A Multicenter Prospective Study on Upfront Treatment for EGFR-Positive Non-Small Cell Lung Cancer (MOST Study).

INTRODUCTION: Gefitinib, erlotinib, and afatinib represent the approved first-line options for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Because pivotal trials frequently lack external validity, real-world data may help to depict the diagnostic-therapeutic pathway and treatment outcome in clinical practice. METHODS: MOST is a multicenter observational study promoted by the Veneto Oncology Network, aiming at monitoring the diagnostic-therapeutic pathway of patients with nonsquamous EGFR-mutant NSCLC. We reported treatment outcome in terms of median time to treatment failure (mTTF) and assessed the impact of each agent on the expense of the regional health system, comparing it with a prediction based on the pivotal trials. RESULTS: An EGFR mutation test was performed in 447 enrolled patients, of whom 124 had EGFR mutation and who received gefitinib (n = 69, 55%), erlotinib (n = 33, 27%), or afatinib (n = 22, 18%) as first-line treatment. Because erlotinib was administered within a clinical trial to 15 patients, final analysis was limited to 109 patients. mTTF was 15.3 months, regardless of the type of tyrosine kinase inhibitor (TKI) used. In the MOST study, the budget impact analysis showed a total expense of €3,238,602.17, whereas the cost estimation according to median progression-free survival from pivotal phase III trials was €1,813,557.88. CONCLUSION: Good regional adherence and compliance to the diagnostic-therapeutic pathway defined for patients with nonsquamous NSCLC was shown. mTTF did not significantly differ among the three targeted TKIs. Our budget impact analysis suggests the potential application of real-world data in the process of drug price negotiation. IMPLICATIONS FOR PRACTICE: The MOST study is a real-world data collection reporting a multicenter adherence and compliance to diagnostic-therapeutic pathways defined for patients with epidermal growth factor receptor-mutant non-small cell lung cancer. This represents an essential element of evidence-based medicine, providing information on patients and situations that may be challenging to assess using only data from randomized controlled trials, e.g., turn-around time of diagnostic tests, treatment compliance and persistence, guideline adherence, challenging-to-treat populations, drug safety, comparative effectiveness, and cost effectiveness. This study may be of interest to various stakeholders (patients, clinicians, and payers), providing a meaningful picture of the value of a given therapy in routine clinical practice.

Eficacia y seguridad de erlotinib en pacientes adultos con cáncer de pulmón de células no pequeñas, metastásico o irresecable, con mutación del gen receptor del factor de crecimiento epidérmico, tras fallo a al menos una línea de quimioterapia / Efficacy and safety of erlotinib in adult patients with non-small cell lung cancer, metastatic or unresectable, with a mutation of the epidermal growth factor receptor gene, after failure of at least one line of chemotherapy

INTRODUCCIÓN: El cáncer de pulmón continúa siendo la primera causa de muerte por neoplasia maligna en el mundo. En el Perú, el cáncer de pulmón es la décima causa de muerte entre todas las enfermedades y la segunda causa de muerte entre todos los cánceres. En el contexto del Seguro Social de la Salud del Perú (EsSalud), en 2015 se diagnosticaron 1,828 casos nuevos de cáncer de pulmón, lo que representa el 73% de todos los casos nuevos de cáncer de pulmón diagnosticados en todo el país en ese año. El cáncer de pulmón de células no pequeñas (CPCNP) es el tipo más común de cáncer de pulmón (alrededor del 72%). Este generalmente se diagnostica en las últimas etapas de la enfermedad: 21% de los pacientes presentan enfermedad localmente avanzada (estadio IIIB) y 48% enfermedad metastásica (estadio IV) al momento del diagnóstico. El pronóstico para los estadios avanzados es desfavorable, estimándose una tasa de supervivencia general a 5 años de 7 a 9% y de 2 a 13% para los estadios IIIB y IV, respectivamente. Debido a ello, el principal objetivo del tratamiento del CPCNP avanzado o metastásico es prolongar la sobrevida y mantener la calidad de vida durante el mayor tiempo posible, minimizando al mismo tiempo los eventos adversos debido al tratamiento. La identificación de mutaciones en genes codificadores de señales que intervienen en la proliferación celular y rigen la formación del tumor, como el gen de la tirosina quinasa (TK) del receptor del factor de crecimiento epidérmico (EGFR, por sus siglas en inglés), ha llevado al desarrollo de agentes que se dirigen a vías moleculares específicas en las células neoplásicas. De ahí que, hoy en día, los inhibidores de la TK del EGFR (de aquí en adelante llamados TKI), como erlotinib, constituyan el tratamiento estándar de primera línea para el CPCNP avanzado o metastásico con mutación positiva para la TK del EGFR (de aquí en adelante llamado EGFR). En EsSalud, los pacientes con CPCNP metastásico o irresecable disponen de erlotinib como tratamiento de primera línea para los casos con mutación positiva para EGFR; sin embargo, existe un grupo de pacientes quienes reciben tratamiento con quimioterapia antes de ser diagnosticados con mutación positiva para EGFR. En este grupo de pacientes, los médicos especialistas de la institución sostienen que erlotinib, como tratamiento de segunda o mayor línea, sigue siendo una opción de tratamiento beneficiosa. OBJETIVO: evaluar la mejor evidencia disponible sobre la eficacia y seguridad de erlotinib, en comparación con la quimioterapia, en pacientes adultos con CPCNP, metastásico o irresecable, con mutación sensibilizadora del EGFR, tras fallo a al menos una línea de quimioterapia. Tecnología Sanitaria de Interés: Erlotinib: Erlotinib es un inhibidor de la tirosina quinasa del receptor del factor de crecimiento epidérmico humano tipo 1. La potente efectividad de erlotinib para bloquear la señal mediada por el EGFR en los tumores con mutación positiva del EGFR, se atribuye a la estrecha unión de erlotinib al lugar de unión del ATP en el dominio quinasa mutado del EGFR. Debido al bloqueo de la cascada de señales por debajo del receptor, se detiene la proliferación celular y se induce la muerte celular a través de la ruta intrínseca de apoptosis (European Medicines Agency 2019). METODOLOGÍA: Se realizó una búsqueda sistemática de literatura con el objetivo de identificar evidencia sobre la eficacia y seguridad de erlotinib, en comparación con la quimioterapia, en pacientes adultos con CPCNP, metastásico o irresecable, con mutación sensibilizadora del gen EGFR, tras fallo a al menos una línea de quimioterapia. Se utilizó la base de datos The Cochrane Library, PubMed, LILACS y el metabuscador TRIP Database, priorizándose evidencia proveniente de revisiones sistemáticas o meta-análisis de ensayos clínicos controlados y aleatorizados. RESULTADOS: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de erlotinib, en comparación con la quimioterapia, en pacientes adultos con CPCNP, metastásico o irresecable, con mutación sensibilizadora del gen EGFR, tras fallo a al menos una línea de quimioterapia. CONCLUSIONES: El presente dictamen tuvo como objetivo evaluar la mejor evidencia disponible hasta julio de 2019, con relación a la eficacia y seguridad de erlotinib, en comparación con la quimioterapia, en pacientes adultos con CPCNP, metastásico o irresecable, con mutación sensibilizadora del gen del EGFR, tras fallo a al menos una línea de quimioterapia. Nuestra revisión encontró limitada evidencia de alta calidad que evalúa la eficacia y seguridad de erlotinib en comparación con la quimioterapia en pacientes adultos con CPCNP, metastásico o irresecable, con mutación positiva para EGFR, tras fallo a al menos una línea de quimioterapia. Sin embargo, la evidencia indirecta procedente de dos ECA de fase III con erlotinib como tratamiento de primera línea (estudios pivotales EURTAC y OPTIMAL), sugiere que los pacientes con mutaciones sensibilizadoras del EGFR obtienen mayores beneficios con erlotinib, en comparación con la quimioterapia, en términos de un mejor perfil de seguridad y calidad de vida. Además, la evidencia de estudios observacionales con erlotinib como tratamiento de segunda o tercera línea, sugiere que los efectos de erlotinib no se ven influenciados con el estado funcional de pacientes y las líneas de quimioterapia previas. Brevemente, los resultados del estudio OPTIMAL mostraron que la quimioterapia se asoció con una mayor tasa de EA severos (65% frente a 17%; p<0.0001), EA serios relacionados al tratamiento (14% frente a 2%; p<0.005), reducción de dosis debido a EA (53% frente a 6%; p<0.0001) y discontinuación debido a EA (6% frente a 1%; valor de p no significativo). Además, la evaluación de la calidad de vida y los síntomas del cáncer de pulmón, medidos con los cuestionarios FACT-L y LCS, respectivamente, mostraron que los pacientes que recibieron erlotinib tuvieron una mejora significativa en su FACT-L total (p<0.0001) y puntuaciones de LCS (p<0.0001), en comparación con los que recibieron quimioterapia. Por su parte, los resultados del estudio EURTAC fueron consistentes con el estudio OPTIMAL en cuanto al mejor perfil de seguridad con erlotinib. Este estudio no reportó resultados sobre la calidad de vida. En ese sentido, a pesar de que erlotinib no ha demostrado prolongar la sobrevida global de los pacientes, los resultados de ambos estudios muestran que erlotinib, en comparación con la quimioterapia, ofrece la ventaja de una mejor calidad de vida y un menor riesgo de eventos adversos significativos. Estos hallazgos son consistentes con las recomendaciones de la guía de la ESMO, en donde se recomienda fuertemente el uso de erlotinib en todos los pacientes con CPCNP metastásico, con mutación EGFR, independientemente de la línea de tratamiento, siempre que el paciente no haya recibido previamente un TKI. Con ello, y considerando la plausibilidad biológica de la efectividad de erlotinib, la amplia experiencia de uso de erlotinib a nivel institucional y la opinión favorable por parte de los médicos especialistas de la institución, el equipo evaluador del IETSI encuentra suficientes argumentos técnicos para apoyar el uso de erlotinib en pacientes con CPCNP metastásico o irresecable, con mutación CPCNP, tras fallo a al menos una línea de quimioterapia. Este grupo de pacientes, quienes reciben regímenes de quimioterapia debido al diagnóstico tardío del estado de mutación del EGFR, son candidatos a recibir erlotinib dada la alta probabilidad de respuesta al tratamiento y los beneficios clínicos que ofrece en pacientes con mutaciones sensibilizadoras del EGFR. Por lo expuesto, el IETSI aprueba el uso de erlotinib para el tratamiento de pacientes adultos con CPCNP, metastásico o irresecable, con mutación sensibilizadora del gen EGFR, tras fallo a al menos una línea de quimioterapia, según lo establecido en el Anexo 1. La vigencia del presente dictamen preliminar es de un año a partir de la fecha de publicación. La continuación de dicha aprobación está sujeta a la evaluación de los resultados obtenidos y de nueva evidencia que pueda surgir en el tiempo. La presente evaluación reemplaza la decisión expuesta en el Dictamen Preliminar de Evaluación de Tecnología Sanitaria Nº 003-SDEPFyOTS-DETS IETSI-2015.

Efficacy of nano-particulated, water-soluble erlotinib against intracranial metastases of EGFR-mutant lung cancer.

Central nervous system (CNS) metastasis is one of the serious complications of epidermal growth factor receptor (EGFR)-mutant lung cancer, which arises due to poor penetration of the brain-blood barrier by EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Although osimertinib, a third-generation EGFR-TKI, has efficacy against CNS metastases, further treatment modalities are still needed as some of these lesions do not respond to osimertinib, or undergo progression after an initial response to this drug if radiotherapy has already been conducted. Here, we investigated the efficacy of water-soluble erlotinib (NUFS-sErt) against these metastases. This agent was synthesized using a nano-particulation platform technology utilizing fat and supercritical fluid (NUFS™) to resolve the low solubility problem that typically prevents the creation of injectable forms of EGFR-TKIs. The average NUFS-sErt particle size was 236.4 nm, and it showed time-dependent dissolution in culture media. The effects of NUFS-sErt were similar to those of conventional erlotinib in terms of inhibiting the proliferation of EGFR-mutant lung cancer cells and suppressing EGFR signaling. In an intraperitoneal xenograft model of HCC827 cells, intraperitoneal administration of NUFS-sErt produced a dose-dependent inhibition of tumor growth and enhanced survival rate. Notably, the injection of NUFS-sErt into the brain ventricle caused significant tumor growth inhibition in an intracranial xenograft model. Hence, our current findings indicate that NUFS-sErt is a novel, water-soluble form of erlotinib that can be administered using intraventricular or intrathecal injections. The target cases would be patients with a progressive CNS metastasis and no other therapeutic options. This drug could also be given intravenously to patients with swallowing difficulties or an inability to ingest due to a medical condition.

Selection of Protein Kinase Inhibitors Based on Tumor Tissue Kinase Activity Profiles in Patients with Refractory Solid Malignancies: An Interventional Molecular Profiling Study.

LESSONS LEARNED: Clinically applicable tools are needed for treatment selection and repurposing of available protein kinase inhibitors (PKIs) in patients with advanced solid tumors refractory to standard treatment.Using a tyrosine kinase peptide substrate microarray, observed inhibitory activity in vitro could not sufficiently predict clinical benefit of treatment with the selected PKI. BACKGROUND: This exploratory molecular profiling study determined the feasibility and benefit of the selection of protein kinase inhibitors (PKIs) based on kinase activity profiling in patients with refractory solid malignancies. METHODS: Adult patients with biopsy-accessible refractory solid tumors were eligible. Per patient, the inhibitory potency of sunitinib, dasatinib, erlotinib, sorafenib, everolimus, and lapatinib was determined in tumor lysates from fresh biopsies using a tyrosine kinase peptide substrate microarray. The most active PKI in this in vitro assay was selected for treatment. RESULTS: Thirteen patients were enrolled in the feasibility part and underwent tumor biopsy. Of 12 patients in whom kinase activity profiling was performed, 11 started treatment with a selected PKI: dasatinib in 8, sunitinib in 2, and erlotinib in 1 patient(s). Eight patients were evaluable for response. One patient had stable disease (SD) >4 months on sunitinib; one patient had SD at 6 weeks but progressive disease (PD) at 12 weeks. The remaining patients had PD after 6 weeks of treatment. CONCLUSION: Kinase inhibition profiles of multiple PKIs can be reliably determined using fresh tumor biopsies from patients with refractory solid tumors. However, the current in vitro microarray selection approach insufficiently predicted clinical benefit of PKI treatment in these patients.

A Randomized Phase II Open-Label Multi-Institution Study of the Combination of Bevacizumab and Erlotinib Compared to Sorafenib in the First-Line Treatment of Patients with Advanced Hepatocellular Carcinoma.

OBJECTIVES: To investigate the clinical efficacy and tolerability of the combination of bevacizumab (B) and erlotinib (E) compared to sorafenib (S) as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). METHODS: A total of 90 patients with advanced HCC, Child-Pugh class A-B7 cirrhosis, and no prior systemic therapy were randomly assigned (1: 1) to receive either 10 mg/kg B intravenously every 14 days and 150 mg E orally daily (n = 47) (B+E) or 400 mg S orally twice daily (n = 43). The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), objective response rate based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1), time to progression, and safety and tolerability. RESULTS: The median OS was 8.55 months (95% CI: 7.00-13.9) for patients treated with B+E and 8.55 months (95% CI: 5.69-12.2) for patients receiving S. The hazard ratio (HR) for OS was 0.92 (95% CI: 0.57-1.47). The median EFS was 4.37 months (95% CI: 2.99-7.36) for patients receiving B+E and 2.76 months (95% CI: 1.84-4.80) for patients receiving S. The HR for EFS was 0.67 (95% CI: 0.42-1.07; p = 0.09), favoring B+E over S. When OS was assessed among patients who were Child-Pugh class A, the median OS was 11.4 months (95% CI: 7.5-15.7) for patients treated with B+E (n = 39) and 10.26 months (95% CI: 5.9-13.0) for patients treated with S (n = 38) (HR = 0.88; 95% CI: 0.53-1.46). CONCLUSIONS: There was no difference in efficacy between the B+E and S arms, although the safety and tolerability profile tended to favor B+E over S based on competing risk analysis.

Curcumin mediated down-regulation of αV ß3 integrin and up-regulation of pyruvate dehydrogenase kinase 4 (PDK4) in Erlotinib resistant SW480 colon cancer cells.

Erlotinib is a potent, selective, and orally active inhibitor of the epidermal growth factor receptor, but the development of erlotinib resistance during chemotherapy can lead to treatment failure. To shed light on the erlotinib-resistant pathway, this study investigated the effect of combination therapy using curcumin- and erlotinib-loaded nanoparticles on the expression of αv ß3 integrin and pyruvate dehydrogenase kinase 4 (PDK4) in an erlotinib-resistant SW480 colon cancer cell line. An erlotinib-resistant SW480 colon cancer cell line was produced by long-term exposure to erlotinib. Curcumin-loaded Methoxy poly ethylene glycol Poly caprolactone (cur/mPEG-PCL) and erlotinib-loaded mPEG-PCL (erl/mPEG-PCL) micelles were provided using a single step nanoprecipitation method and used as combination therapy of resistant SW480 cancer cells. After that, gene expression levels of PDK4, αv, and ß3 mRNA were determined by the semiquantitative reverse transcription-polymerase chain reaction. Protein levels of whole αv ß3 integrin were evaluated using the enzyme-linked immunosorbent assay method. In SW480 cell line, the IC50 of nonresistant and resistant cells was 87.6 ± 1.2 nM and 19.1 ± 0.14 µM, for erlotinib and it was about 21.8 and 30 µM for curcumin, respectively. Although PDK4 expression was not significantly different in resistant and nonresistant cells, its expression was up regulated (1.4 fold) in resistant cells by a combination therapy of cur/mPEG-PCL at a dose of 3 µM and erl/mPEG-PCL at a dose of 5 µM. ß3 mRNA and the protein level of whole αv ß3 integrin was significantly higher in resistant SW480 cells as compared with those in nonresistant cells. In terms of treatment, a combination of 6-µM cur/mPEG-PCL and 5-µM erl/mPEG-PCL down regulated ß3 gene expression 6.6-fold in resistant cells as compared with nonresistant cells. At the protein level, a combination of 3-µM-cur/mPEG-PCL and 10-µM erl/mPEG-PCL reduced αv ß3 protein in resistant cells. The results indicated that combination therapy using cur/mPEG-PCL and erl/mPEG-PCL could decrease αv ß3 integrin expression and increase PDK4 gene expression in resistant colon cancer cells, which may have effects on drug resistance signaling pathways.

Chemoprevention of oral cancer in leukoplakia patients: A systematic review and meta-analysis.

The systematic review and meta-analysis of published randomised controlled trials (RCTs) was conducted to review the effectiveness of current chemopreventive agents in the treatment of oral leukoplakia lesions (OPLs) and prevention of their progression to oral cancer. Material was identified through a retrospective literature search of the electronic PubMed database, Embase and Cochrane Library between 2008 and 2016.Eight RCTs were included for systematic review. The pooled estimate showed a 14% greater chance of responding for those randomised to interventions compared with placebo (Risk Ratio [RR] 1.14, 95% confidence interval [CI] 0.72 to 1.81). The CI from individual studies overlapped. The results suggested that there were no significant differences in comparing clinical responses between chemopreventive agents with placebo in treatment of OPLs. It is time to investigate new agents for oral cancer chemoprevention.

A data mining approach for identifying pathway-gene biomarkers for predicting clinical outcome: A case study of erlotinib and sorafenib.

A novel data mining procedure is proposed for identifying potential pathway-gene biomarkers from preclinical drug sensitivity data for predicting clinical responses to erlotinib or sorafenib. The analysis applies linear ridge regression modeling to generate a small (N~1000) set of baseline gene expressions that jointly yield quality predictions of preclinical drug sensitivity data and clinical responses. Standard clustering of the pathway-gene combinations from gene set enrichment analysis of this initial gene set, according to their shared appearance in molecular function pathways, yields a reduced (N~300) set of potential pathway-gene biomarkers. A modified method for quantifying pathway fitness is used to determine smaller numbers of over and under expressed genes that correspond with favorable and unfavorable clinical responses. Detailed literature-based evidence is provided in support of the roles of these under and over expressed genes in compound efficacy. RandomForest analysis of potential pathway-gene biomarkers finds average treatment prediction errors of 10% and 22%, respectively, for patients receiving erlotinib or sorafenib that had a favorable clinical response. Higher errors were found for both compounds when predicting an unfavorable clinical response. Collectively these results suggest complementary roles for biomarker genes and biomarker pathways when predicting clinical responses from preclinical data.

Plasma rich in growth factors for the treatment of rapidly progressing refractory corneal melting due to erlotinib in nonsmall cell lung cancer.

RATIONALE: Erlotinib, an antineoplastic agent, is indicated for the treatment of patients with advanced nonsmall cell lung cancer. Most common adverse events are manageable, although more severe ones require dose reduction or discontinuation of erlotinib treatment. PATIENT CONCERNS: We present a case of severe corneal ulcer treated with autologous plasma rich in growth factors. DIAGNOSES: A 76-year-old woman with stage IVB (cT2a N0 M1c) lung cancer under erlotinib treatment presented with rapidly progressing corneal ulcer. Evolution was torpid and refractory to conventional treatment. INTERVENTIONS: Surgical options were dismissed because of the poor performance status of the patient. Despite temporary discontinuation of erlotinib treatment, the corneal ulcer continued to worsen with peripheral corneal neovascularization, stromal thinning, corneal edema, and profuse inflammation of the ocular surface. OUTCOMES: Treatment with autologous plasma rich in growth factors prevented an imminent corneal perforation and improved the corneal ulcer for over a year of follow-up. LESSONS: Considering the poor results of conventional treatment, both medical and surgical, management of the inflammation of the ocular surface together with the stimulation of the healing processes through regenerative therapy such as PRGF, can be an option worth considering in these cases.