Synergistic Effect of HAD-B1 and Afatinib Against Gefitinib Resistance of Non-Small Cell Lung Cancer.

In epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC), acquired resistance to EGFR tyrosine kinase inhibitors (TKI) leads to disease progression. Strategies to overcome the resistance are required in treatment for advanced lung cancer. In this study, we investigated the therapeutic effect of afatinib and HangAmDan-B1 (HAD-B1) co-administration in gefitinib-resistant NSCLC using HCC827-GR, NSCLC cell line with gefitinib resistance, and the HCC827-GR cell implanted mouse model. HAD-B1 consists of 4 herbs, Panax notoginseng Radix, Cordyceps militaris, Panax ginseng C. A. Mey, and Boswellia carteri Birdwood, and has been reported to be effective in patients with advanced lung cancer in clinical practice. Our findings demonstrated that HAD-B1 combined with afatinib markedly inhibited cell proliferation and induced apoptosis compared to afatinib monotherapy and HAD-B1 monotherapy. Inhibition of HCC827-GR cell proliferation by HAD-B1 occurred through MET amplification and reduced phosphorylation, and the synergistic effect of afatinib and HAD-B1 induced cell cycle arrest and apoptosis in HCC827-GR cells via the downregulation of ERK and mTOR signaling pathways. In hematology and biochemistry tests, HAD-B1 alleviated the toxicity of tumor. In conclusion, HAD-B1 combined with afatinib would be a promising therapeutic strategy for NSCLC with EGFR-TKI resistance.

Durable clinical benefit from afatinib in a lung adenocarcinoma patient with acquired EGFR L718V mutation-mediated resistance towards osimertinib: a case report and literature review.

Osimertinib, as a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), targeting EGFR exon 19 deletions, L858R, and T790M, has shown robust clinical efficacy and promising survival advantages in a subset of non-small cell lung cancer (NSCLC) patients. However, osimertinib-treated patients ultimately develop secondary resistance. Besides EGFR C797S mutation and EGFR amplification, a rare EGFR mutation, L718V, has been reported to confer osimertinib resistance in the literature, which is developed in about 8.0% of osimertinib-resistant NSCLC patients. Although the National Comprehensive Cancer Network or Chinese Society of Clinical Oncology NSCLC guidelines recommend radiotherapy, anti-angiogenesis therapy, chemotherapy and or immunotherapy for the treatment of NSCLC patients who acquire resistance to osimertinib, the feasible treatment options for patients harboring EGFR L718V remain elusive. There is an unmet need to develop effective strategies to treat EGFR L718X-positive NSCLC patients. Herein, we report that a lung adenocarcinoma patient with acquired EGFR L718V mutation-mediated resistance towards osimertinib derived durable response to the second-generation EGFR-TKI afatinib with a progression-free survival of 18 months and counting. Our work provides clinical evidence to administer afatinib in metastatic NSCLC patients who develop EGFR L718V at progression to osimertinib and paves the way for its potential clinical utilization.

Efficacy of Prophylactic Traditional Chinese Medicine on Skin Toxicity of Afatinib in EGFR Mutation-Positive Advanced Lung Adenocarcinoma: A Single-Center, Prospective, Double-Blinded, Randomized-Controlled Pilot Trial.

OBJECTIVES: To evaluate the efficacy of prophylactic traditional Chinese medicine (TCM) on skin toxicities in patients with advanced lung adenocarcinoma treated with first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in a randomized-controlled trial (RCT). MATERIALS AND METHODS: This pilot study was a prospective, single-center, double-blinded RCT. The study enrolled patients with a new diagnosis of locally advanced and metastatic lung adenocarcinoma harboring EGFR mutations who were treated with first-line afatinib from July 1, 2016 to December 31, 2017. Thirty patients who met the inclusion and exclusion criteria were assigned to the TCM and placebo groups with simple randomization. TCM and placebo were initiated at the same time as afatinib and were administered for 3 months. The survival of each subject was followed until 3 years. RESULTS: There were 36 patients with newly diagnosed lung adenocarcinoma during the study period. After the exclusion of 6 patients, the remaining 30 patients were assigned to the TCM (n = 14) and placebo (n = 16) groups comprising the intention-to-treat population. The time to first skin toxicity was 22.3 days in the TCM group and 17.6 days in the placebo group (P = .510) in the per-protocol population. The analysis of the present pilot study results determined that the difference in time to first skin toxicity between the 2 groups would reach statistical significance with a sample size of 237 based on a power of 0.8. There were significant differences in certain subscales of quality of life between the TCM and placebo groups; however, there was no significant difference in progression-free survival or overall survival between the 2 groups. CONCLUSIONS: Integrative TCM may prolong the time to first skin toxicity in patients with advanced lung adenocarcinoma treated with first-line afatinib. Prophylactic TCM could delay skin toxicity of any grade and reduce the incidence of grade 3 skin toxicity. Future large-scale RCTs are warranted to validate these findings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05204758. Registered on 24 Jan 2022.

Oral targeted therapy dose adaptation in older patients with cancer: A real-life French cohort.

INTRODUCTION: Oral targeted therapies (OTTs) are widely used for cancer management. However, there is no consensus on OTT dose adaptation in older patients with cancer. METHODS: This noninterventional, retrospective study was a real-life assessment of dose adaptation for six OTTs (afatinib, everolimus, palbociclib, pazopanib, sorafenib and sunitinib), at baseline and during treatment, and the reasons for the changes, in ≥70-year-old patients treated between February 2016 and August 2019. Data were compared with univariate models fitted with all variables. RESULTS: Among the 986 patients treated with OTT, the group of ≥70-year-old patients (n = 122) received afatinib (15.6%), everolimus (14.8%), palbociclib (50.8%), pazopanib (9.8%), sorafenib (5.8%) or sunitinib (3.2%). At baseline, the prescribed OTT dose was adapted (reduction) in 29% of ≥70-year-old patients (35/122). These 35 patients were significantly older (mean age 80 vs 74 years, P < .001), and more frequently had a performance status score ≥2 (P < .01) than the other patients (n = 87). In the standard dose group, higher toxicity grades (P = .18) and subsequent dose reduction (41% of patients, 36/87) tended to be more frequent compared with the baseline adapted dose group (26%, 9/35, P = .1). At the study end, 53% of patients in the whole cohort (65/122) were taking a lower dose than the recommended one. CONCLUSION: At OTT initiation, dose was adapted in 29% of older adults with cancer, rarely after a formal oncogeriatric evaluation (6.5% of all patients). In the absence of recommendations, clinical studies are needed to evaluate the efficacy and safety of baseline OTT dose reduction in older adults with cancer.

Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Exploratory Study to Evaluate the Efficacy and Safety of HAD-B1 for Dose-Finding in EGFR Mutation Positive and Locally Advanced or Metastatic NSCLC Subjects Who Need Afatinib Therapy.

Afatinib is a target anticancer drug of the second-generation EGFR TKI type, showing an advantage in treatment effect compared to conventional chemotherapy. However, patients on EGFR-TKI drugs also usually progress after 9 to 13 months according to secondary resistance. HAD-B1 is composed of drugs that are effective against lung cancer. This study is an exploratory study to evaluate the efficacy and safety between dosage groups by conducting a clinical trial in subjects requiring afatinib drug treatment in non-small cell lung cancer with EGFR mutation positive to determine the optimal dosage for HAD-B1 administration. At the final visit compared to before administration, each change in the disease control rate was measured according to the HAD-B1 doses of the test group 1 (972 mg), the test group 2 (1944 mg), and the control group. The efficacy and safety of HAD-B1 were compared and evaluated through sub-evaluation variables. As a result of the study, there was no statistically significant difference in the disease control rate at 12 weeks after dosing, but complete and partial remission were evaluated as 1 patient each in the test group 1, and none in the other groups. There was no statistically significant difference between groups in the sub-evaluation variable. In addition, there was no problem of safety from taking the test drug. However, the initially planned number of subjects was 66, but the number of enrolled subjects was only 14, which may limit the results of this study.

Calcium-activated chloride channel is involved in the onset of diarrhea triggered by EGFR tyrosine kinase inhibitor treatment in rats.

EGFR tyrosine kinase inhibitors (TKIs) are mainly used to treat non-small cell lung cancer; however, adverse effects such as severe diarrhea represent a major obstacle towards the continuation of EGFR-TKIs therapy. Chloride channels, which control the fluid flow in the intestinal lumen, are proposed as an important target to remediate EGFR-TKIs-induced diarrhea, but the mechanism remains unclear. The aim of this study was to clarify the mechanism underlying EGFR-TKIs-induced diarrhea with a particular focus on the role of intestinal chloride channels. Here, we show that osimertinib-treated rats exhibit diarrhea and an increase in fecal water content without showing any severe histopathological changes. This diarrhea was attenuated by intraperitoneal treatment with the calcium-activated chloride channel (CaCC) inhibitor CaCCinh-A01. These findings were confirmed in afatinib-treated rats with diarrhea. Moreover, treatment with the Japanese traditional herbal medicine, hangeshashinto (HST), decreased fecal water content and improved fecal appearance in rats treated with EGFR-TKIs. HST inhibited the ionomycin-induced CaCC activation in HEK293 cells in patch-clamp current experiments and its active ingredients were identified. In conclusion, secretory diarrhea induced by treatment with EGFR-TKIs might be partially mediated by the activation of CaCC. Therefore, blocking the CaCC could be a potential new treatment for EGFR-TKI-induced diarrhea.

A randomized, multi-center, open-label study to compare the safety and efficacy between afatinib monotherapy and combination therapy of afatinib and HAD-B1 for the locally advanced or metastatic NSCLC patients with EGFR mutations.

BACKGROUND: Afatinib is an epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI) with proven efficacy for treating patients with advanced or metastatic non-small cell lung cancer (NSCLC). Unfortunately, responses are limited by acquired resistance. Because traditional Korean medicine may have synergistic effects when combined with chemotherapy or radiotherapy, the aim of our study is to elucidate the efficacy and safety of afatinib plus HangAmDan-B1 (HAD-B1) combination therapy in the treatment of patients with NSCLC, as well as EGFR mutations, who need afatinib therapy. METHODS/DESIGN: This study is a randomized, multi-center, open clinical trial. A total of 178 eligible subjects, recruited at 8 centers, are randomly assigned to take Afatinib (20-40 mg) ±â€ŠHAD-B1 (0.972 g/day) for 48 weeks. In the test group, HAD-B1 and afatinib will be used in combination. The primary outcome is a comparison of progression-free survival (PFS) between afatinib monotherapy and afatinib plus HAD-B1 combination therapy in patients with local advanced or metastatic (Stage IIIA, B, C/IV) NSCLC. Secondary outcomes are the overall survival rates, clinical responses, tumor size reductions, health-related qualities of life, and safety. DISCUSSION: The result of this clinical trial will provide evidence for the efficacy and safety of using HAD-B1 in the treatment of EGFR-positive patients with locally advanced or metastatic NSCLC who require afatinib therapy. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), Republic of Korea (ID: KCT0005414), on September 23, 2020.

Multi-center, randomized, double-blind, placebo-controlled, exploratory study to evaluate the efficacy and safety of HAD-B1 for dose-finding in EGFR positive and locally advanced or metastatic NSCLC subjects who need Afatinib therapy: Study protocol clinical trial (SPIRIT Compliant).

BACKGROUND: In recent studies, afatinib, a second-generation inhibitor, showed superior outcomes, when compared to the first-generation of EGFR-tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib, in patients with advanced non-small cell lung cancer (NSCLC) harboring mutations of epidermal growth factor receptor (EGFR). Patients who receive TKIs with a significant initial efficacy, inevitably experience an acquired resistance (AR) within 9 to 13 months. Traditional Korean medicine may have synergistic effects when combined with chemotherapy or radiotherapy. The purpose of this trial is to assess whether afatinib plus HAD-B1 improves disease control rates (DCRs) compared with afatinib alone and to evaluate the efficacy and safety of HAD-B1 for finding the proper dose. METHODS: This is a randomized, double-blind, placebo-controlled, multi-center, therapeutic, exploratory clinical trial. This trial is designed to determine whether HAD-B1 combined with afatinib results in better DCRs with less toxicity than afatinib alone. A total of 66 NSCLC patients with EGFR mutations will be randomly assigned to treatment group 1 (afatinib 40 mg/day plus HAD-B1 972 mg), treatment group 2 (afatinib 40 mg/day plus HAD-B1 1944 mg) and a control group (afatinib 40 mg/day). Afatinib combined with HAD-B1 or with a placebo will be administered to the participants for 12 weeks. The primary endpoint is a comparison of the DCRs among groups. Secondary endpoints are comparisons of the complete response (CR) and the partial response (PR) to the treatment, the stability of the disease (SD), progression free survival (PFS), time to progression (TTP), and tumor marker (CEA, NSE) and WBC differential count (LMR, NLR) and natural killer cell activity and quality of life (QOL) among groups. DISCUSSION: The results from this clinical trial will provide evidence of efficacy and safety of HAD-B1 in EGFR positive and locally advanced or metastatic NSCLC patients who need afatinib therapy.

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.

Inhibitory Effects of HangAmDan-B1 (HAD-B1) Combined With Afatinib on H1975 Lung Cancer Cell-Bearing Mice.

Epidermal growth factor receptor mutation-positive non-small cell lung cancer is cared for mainly by target therapeutics in the clinical treatment at present. We investigated the antitumor effect of HangAmDan-B1 (HAD-B1) combined with afatinib on H1975 (L858R/T790M double mutation) lung cancer cells. The combined treatment of HAD-B1 with afatinib inhibited the proliferation of H1975 cells in a dose-dependent manner compared with the treatment of afatinib or HAD-B1 alone. The combined treatment group significantly induced early apoptosis and cell cycle arrest of the cells compared with afatinib- or HAD-B1-treated control group. Profile analysis of cell cycle proteins in H1975 cells treated with the combination of HAD-B1 and afatinib using InnoPharmaScreen antibody microarray showed downregulation of pERK1/2 and upregulation of p16 in the cells. In vivo tumor growth assay in xenograft animal model of human H1975 lung cancer cells revealed that the mean tumor volume in the group treated with the combination of HAD-B1 and afatinib showed a significant reduction compared with the control groups.

YM155 as an inhibitor of cancer stemness simultaneously inhibits autophosphorylation of epidermal growth factor receptor and G9a-mediated stemness in lung cancer cells.

Cancer stem cell survival is the leading factor for tumor recurrence after tumor-suppressive treatments. Therefore, specific and efficient inhibitors of cancer stemness must be discovered for reducing tumor recurrence. YM155 has been indicated to significantly reduce stemness-derived tumorsphere formation. However, the pharmaceutical mechanism of YM155 against cancer stemness is unclear. This study investigated the potential mechanism of YM155 against cancer stemness in lung cancer. Tumorspheres derived from epidermal growth factor receptor (EGFR)-mutant HCC827 and EGFR wild-type A549 cells expressing higher cancer stemness markers (CD133, Oct4, and Nanog) were used as cancer stemness models. We observed that EGFR autophosphorylation (Y1068) was higher in HCC827- and A549-derived tumorspheres than in parental cells; this autophosphorylation induced tumorsphere formation by activating G9a-mediated stemness. Notably, YM155 inhibited tumorsphere formation by blocking the autophosphorylation of EGFR and the EGFR-G9a-mediated stemness pathway. The chemical and genetic inhibition of EGFR and G9a revealed the significant role of the EGFR-G9a pathway in maintaining the cancer stemness property. In conclusion, this study not only revealed that EGFR could trigger tumorsphere formation by elevating G9a-mediated stemness but also demonstrated that YM155 could inhibit this formation by simultaneously blocking EGFR autophosphorylation and G9a activity, thus acting as a potent agent against lung cancer stemness.

Construction of a novel cell-based assay for the evaluation of anti-EGFR drug efficacy against EGFR mutation.

Epidermal growth factor receptor (EGFR) overexpression and EGFR-mediated signaling pathway dysregulation have been observed in tumors from patients with various cancers, especially non-small cell lung cancer. Thus, several anti-EGFR drugs have been developed for cancer therapy. For patients with known EGFR activating mutations (EGFR exon 19 in-frame deletions and exon 21 L858R substitution), treatment with an EGFR tyrosine kinase inhibitor (EGFR TKI; gefitinib, erlotinib or afatinib) represents standard first-line therapy. However, the clinical efficacy of these TKIs is ultimately limited by the development of acquired drug resistance such as by mutation of the gatekeeper T790 residue (T790M). To overcome this acquired drug resistance and develop novel anti-EGFR drugs, a cell-based assay system for EGFR TKI resistance mutant-selective inhibitors is required. We constructed a novel cell-based assay for the evaluation of EGFR TKI efficacy against EGFR mutation. To this end, we established non-tumorigenic immortalized breast epithelial cells that proliferate dependent on EGF (MCF 10A cells), which stably overexpress mutant EGFR. We found that the cells expressing EGFR containing the T790M mutation showed higher resistance against gefitinib, erlotinib and afatinib compared with cells expressing wild-type EGFR. In contrast, L858R mutant-expressing cells exhibited higher TKI sensitivity. The effect of T790M-selective inhibitors (osimertinib and rociletinib) on T790M mutant-expressing cells was significantly higher than gefitinib and erlotinib. Finally, when compared with commercially available isogenic MCF 10A cell lines carrying introduced mutations in EGFR, our EGFR mutant-overexpressing cells exhibited obviously higher responsiveness to EGFR TKIs depending on the underlying mutations because of the higher levels of EGFR phosphorylation in the EGFR mutant-overexpressing cells than in the isogenic cell lines. In conclusion, we successfully developed a novel cell-based assay for evaluating the efficacy of anti-EGFR drugs against EGFR mutation.

Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity.

PURPOSE: Approximately one-third of patients with non-small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions. EXPERIMENTAL DESIGN: We performed preclinical assessments of brain penetration and activity of osimertinib (AZD9291), an oral, potent, irreversible EGFR-TKI selective for EGFRm and T790M resistance mutations, and other EGFR-TKIs in various animal models of EGFR-mutant NSCLC brain metastases. We also present case reports of previously treated patients with EGFRm-advanced NSCLC and brain metastases who received osimertinib in the phase I/II AURA study (NCT01802632). RESULTS: Osimertinib demonstrated greater penetration of the mouse blood-brain barrier than gefitinib, rociletinib (CO-1686), or afatinib, and at clinically relevant doses induced sustained tumor regression in an EGFRm PC9 mouse brain metastases model; rociletinib did not achieve tumor regression. Under positron emission tomography micro-dosing conditions, [11C]osimertinib showed markedly greater exposure in the cynomolgus monkey brain than [11C]rociletinib and [11C]gefitinib. Early clinical evidence of osimertinib activity in previously treated patients with EGFRm-advanced NSCLC and brain metastases is also reported. CONCLUSIONS: Osimertinib may represent a clinically significant treatment option for patients with EGFRm NSCLC and brain metastases. Further investigation of osimertinib in this patient population is ongoing. Clin Cancer Res; 22(20); 5130-40. ©2016 AACR.

[Mechanism of action and preclinical development of afatinib]. / Mecanismo de acción y desarrollo preclínico de afatinib.

Afatinib, together with gefitinib and erlotinib, is approved for first-line treatment of advanced non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR). This is an irreversible inhibitor of the ErbB family, acting on EGFR (HER1, ErbB1), ErbB2 (HER2) and ErbB4 (HER4). Covalent attachment to cysteine residues in the catalytic domain of EGFR, HER2 and ErbB4 inhibits the tyrosine kinase activity (TKIs) of these receptors, decreasing auto- and transphosphorylation between ErbB dimers, and thus blocking the activity of downstream signalling pathways related to growth and apoptosis suppression. In preclinical models, this has resulted in a reduction in tumour size. Furthermore, due to its mechanism of action, afatinib may be more potent than the first-generation EGFR TKIs (gefitinib and erlotinib) and may even be able to overcome acquired resistance to such treatments. Finally, because of the demonstrated synergism with other chemotherapeutic and target agents, it could be interesting to enhance its clinical development in combination with other drugs.

Pilot Study of a Next-Generation Sequencing-Based Targeted Anticancer Therapy in Refractory Solid Tumors at a Korean Institution.

We evaluated the preliminary efficacy and feasibility of a next-generation sequencing (NGS)-based targeted anticancer therapy in refractory solid tumors at a Korean institution. Thirty-six patients with advanced cancer underwent molecular profiling with NGS with the intent of clinical application of available matched targeted agents. Formalin-fixed paraffin-embedded (FFPE) tumors were sequenced using the Comprehensive Cancer Panel (CCP) or FoundationOne in the Clinical Laboratory Improvement Amendments-certified laboratory in the USA. Response evaluations were performed according to RECIST v1.1. Four specimens did not pass the DNA quality test and 32 specimens were successfully sequenced with CCP (n = 31) and FoundationOne (n = 1). Of the 32 sequenced patients, 10 (31.3%) were ≤40 years. Twelve patients (37.5%) had received ≥3 types of prior systemic therapies. Of 24 patients with actionable mutations, five were given genotype-matched drugs corresponding to actionable mutations: everolimus to PIK3CA mutation in parotid carcinosarcoma (partial response) and tracheal squamous cell carcinoma (stable disease; 21% reduction), sorafenib to PDGFRA mutation in auditory canal adenocarcinoma (partial response), sorafenib to BRAF mutation in microcytic adnexal carcinoma (progressive disease), and afatinib to ERBB2 mutation in esophageal adenocarcinoma (progressive disease). Nineteen of 24 patients with actionable mutations could not undergo targeted therapy based on genomic testing because of declining performance status (10/24, 41.7%), stable disease with previous treatment (5/24, 20.8%), and lack of access to targeted medication (4/24, 16.7%). NGS-based targeted therapy may be a good option in selected patients with refractory solid tumors. To pursue this strategy in Korea, lack of access to clinical-grade NGS assays and a limited number of genotype-matched targeted medications needs to be addressed and resolved.

Afatinib plus Cetuximab Delays Resistance Compared to Single-Agent Erlotinib or Afatinib in Mouse Models of TKI-Naïve EGFR L858R-Induced Lung Adenocarcinoma.

PURPOSE: The EGFR tyrosine kinase inhibitors (TKIs), erlotinib and afatinib, have transformed the treatment of advanced EGFR-mutant lung adenocarcinoma. However, almost all patients who respond develop acquired resistance on average approximately 1 year after starting therapy. Resistance is commonly due to a secondary mutation in EGFR (EGFR(T790M)). We previously found that the combination of the EGFR TKI afatinib and the EGFR antibody cetuximab could overcome EGFR(T790M)-mediated resistance in preclinical models. This combination has shown a 29% response rate in a clinical trial in patients with acquired resistance to first-generation TKIs. An outstanding question is whether this regimen is beneficial when used as first-line therapy. EXPERIMENTAL DESIGN: Using mouse models of EGFR-mutant lung cancer, we tested whether the combination of afatinib plus cetuximab delivered upfront to mice with TKI-naïve EGFR(L858R)-induced lung adenocarcinomas delayed tumor relapse and drug-resistance compared with single-agent TKIs. RESULTS: Afatinib plus cetuximab markedly delayed the time to relapse and incidence of drug-resistant tumors, which occurred in only 63.6% of the mice, in contrast to erlotinib or afatinib treatment where 100% of mice developed resistance. Mechanisms of tumor escape observed in afatinib plus cetuximab resistant tumors include the EGFR(T790M) mutation and Kras mutations. Experiments in cell lines and xenografts confirmed that the afatinib plus cetuximab combination does not suppress the emergence of EGFR(T790M). CONCLUSIONS: These results highlight the potential of afatinib plus cetuximab as an effective treatment strategy for patients with TKI-naïve EGFR-mutant lung cancer and indicate that clinical trial development in this area is warranted.

Seguridad y eficacia de afatinib en comparación a quimioterapia o erlotinib como tratamiento de segunda línea en cáncer de pulmón de células no pequeñas metastásico con mutación en el gen del receptor del factor de crecimiento epidérmico (EGFR) / Safety and efficacy of afatinib compared to chemotherapy or erlotinib as second-line treatment in metastatic non-small cell lung cancer with mutation in the epidermal growth factor receptor (EGFR) gene

INTRODUCCIÓN: El presente informe expone la evaluación del medicamento afatinib respecto a su uso en pacientes con cáncer pulmonar de células no pequeñas (NSCLC, por sus siglas en inglés), con mutación en el dominio de tirosina quinasa del receptor del factor de crecimiento epidérmico (EGFR, por sus siglas en inglés) que haya progresado a primera línea de tratamiento con quimioterapia estándar basada en platinos. Las guías de práctica clínica, revisiones sistemáticas y evaluación de tecnologías recomiendan de manera consistente erlotinib, docetaxel o pemetrexed como alternativas de tratamiento de segunda línea en cáncer de pulmón de células no pequeñas, independientemente de la mutación del gen del receptor del factor de crecimiento epidérmico (EGFR), ya que presentan similar perfil de seguridad y eficacia valorada en diversos ensayos clínicos aleatorizados y comparativos, especialmente, respecto a sobrevida global y sobrevida libre de enfermedad. La evidencia científica que apoya el uso de inhibidores de la tirosina quinasa (TKI, por sus siglas en inglés, tyrosine kinase inhibitors) de entre los que erlotinib y gefitinib (el cual no se encuentra en el mercado peruano), como segunda línea de tratamiento en este tipo de cáncer con mutación EGFR es débil ya que ha sido generada a partir de análisis post hoc de ensayos clínicos donde la aleatorización no fue realizada en base al estado de la mutación EGFR. METODOLOGÍA: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de afatinib para el tratamiento de cáncer de pulmón de células no pequeñas (NSCLC) en pacientes con mutaciones en el dominio de tirosina quinasa del EGFR que hubiera recibo quimioterapia estándar de primera línea. Esta búsqueda se realizó en las bases de datos de MEDLINE y TRIPDATABASE. Adicionalmente, 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, The National Institute for Health and Care Excellence (NICE), The Scottish Intercollegiate Guidelines Network (SIGN), The American Society of Clinical Oncology (ASCO), The European Society for Medical Oncology (ESMO) y The National Comprehensive Cancer Network (NCCN). RESULTADOS: La búsqueda bibliográfica y de evidencia científica para el sustento del uso de afatinib comparado en su beneficio respecto a erlotinib o quimioterapia como tratamiento de segunda línea para cáncer de pulmón, NSCLC avanzando (IIIB) o metastásico (IV) en pacientes con mutaciones en el gen EGFR, identificó guías de práctica clínica, evaluación de tecnologías sanitarias, revisiones sistemáticas, meta-análisis y ensayos clínicos. CONCLUSIONES: Las guías de práctica clínica, revisiones sistemáticas y evaluación de tecnologías recomiendan de manera consistente erlotinib, docetaxel o pemetrexed como alternativas de tratamiento de segunda línea en cáncer de pulmón de células no pequeñas, independientemente de la mutación EGFR, ya que presentan similar perfil de seguridad y eficacia valorada en diversos ensayos clínicos aleatorizados y comparativos, especialmente, respecto a sobrevida global y sobrevida libre de enfermedad. La evidencia científica que apoya el uso de TKIs, de entre los que erlotinib y gefitinib (el cual no se encuentra en el mercado peruano), como segunda línea de tratamiento en este tipo de cáncer con mutación EGFR es débil ya que ha sido generada a partir de análisis post hoc de ensayos clínicos donde la aleatorización no fue realizada en base al estado de la mutación EGFR. La presente evaluación de tecnología ha encontrado que la evidencia científica que apoya el uso de afatinib como segunda línea de tratamiento en pacientes con cáncer de pulmón de células no pequeñas con mutación EGFR es muy escasa, limitándose a un único ensayo clínico de fase 2, LUX-Lung 2, el cual tuvo un diseño no controlado. Es de notar que afatinib no es consistentemente recomendado o evaluado como alternativa en este tipo de tratamiento en las guías de práctica clínica, revisiones sistemáticas, meta-análisis y evaluaciones de tecnologías. El Petitorio Farmacológico de Essalud vigente incluye docetaxel y pemetrexed, quienes tienen evidencia de eficacia como tratamiento de segunda línea de tratamiento en cáncer de células no pequeñas, independientemente de la mutación EGFR. Este hecho de estar incluido en el Petitorio Farmacológico de Essalud hace que sea el tratamiento de mejor evidencia de eficacia más accesible para los beneficiarios de Essalud, lo que se traduce en una óptima oportunidad de uso. Al momento, la evidencia clínica que apoya el uso de erlotinib como segunda línea de tratamiento de cáncer de pulmón de células no pequeñas con mutaciones en el gen EGFR con enfermedad avanzada o metastásica es limitada. La escasez de evidencia es una limitación aún mayor para el caso de afatinib. La consideración de estos medicamentos como de uso fuera del petitorio para casos de cáncer de pulmón de células no pequeñas con mutación EGFR se puede reconsiderar si aparece nueva información proveniente de estudios clínicos de calidad metodológica que evidencie diferencias clínicas entre TKIs disponibles en el mercado peruano y docetaxel o pemetrexed (los cuales están disponibles en el Petitorio Farmacológico de Essalud).

[Hange-Shashin-to for preventing diarrhea during afatinib therapy].

Afatinib is an epidermal growth factor receptor-tyrosine kinase inhibitor(EGFR-TKI). In a randomized phase III study(Lux- Lung 3 study)employing patients harboring EGFR mutations, patients administered afatinib show a significantly longer progression free survival time(PFS)than those administeredcombination chemotherapy comprising cisplatin andpemetrexed . However, most of the patients(95.2%)treatedwith afatinib experiencedd iarrhea. In the present report, 16 patients with EGFR mutations were treatedby afatinib at our institution from May 2014 to December 2014. Twelve patients were administered a diarrhea prevention herbal medicine, Hange-shashin-to. Seven of 12 patients(58%)had no diarrhea during the 28 days of therapy. All 4 of the patients who did not receive Hange-shashin-to experienced diarrhea above Grade 1 within 6 days of starting therapy. The rate of diarrhea differed significantly between the patients receiving and not receiving Hangeshashin- to. In conclusion, preventive administration of Hange-shashin-to may reduce the occurrence of diarrhea during afatinib treatment.