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Background/Objectives: Epidermal growth factor receptor (EGFR) plays a vital role in cell proliferation and survival, with its overexpression linked to various malignancies, including non-small cell lung cancer (NSCLC). Although EGFR tyrosine kinase inhibitors (TKIs) are a key therapeutic strategy, acquired resistance and relapse remain challenges. This study aimed to synthesize and evaluate novel rhenium-based complexes incorporating EGFR TKIs to enhance anticancer efficacy, particularly in radiosensitization. Methods: We synthesized a rhenium tricarbonyl complex (Complex 2) and its 99mTc analog (Complex 2') by incorporating triphenylphosphine instead of bromine as the monodentate ligand and P F 6 − as the counter-ion, resulting in a positively charged compound that forms cationic structures. Cytotoxicity and EGFR inhibition were evaluated in A431 cells overexpressing EGFR using MTT assays, Western blotting, and flow cytometry. Radiosensitization was tested through MTT and clonogenic assays. The 99mTc complex's radiochemical yield, stability, and lipophilicity were also assessed. Results: Complex 2 exhibited significant cytotoxicity with an IC50 of 2.6 μM and EGFR phosphorylation inhibition with an IC50 of 130.6 nM. Both complex 1 and 2 induced G0/G1 cell cycle arrest, with Complex 2 causing apoptosis. Radiosensitization was observed at doses above 2 Gy. Complex 2' demonstrated high stability and favorable lipophilicity (LogD7.4 3.2), showing 12% cellular uptake after 30 min. Conclusions: Complexes 2 and 2' show promise as dual-function anticancer agents, offering EGFR inhibition, apoptosis induction, and radiosensitization. Their potential as radiopharmaceuticals warrants further in-depth investigation in preclinical models. [ABSTRACT FROM AUTHOR]

The epidermal growth factor receptor (EGFR) tyrosine kinase plays an important role in tumor formation and growth by mediating cell growth and other physiological processes. Therefore, EGFR is a promising target for the treatment of cancer. In this work, we combined ligand‐based and structure‐based virtual screening methods to identify novel EGFR inhibitors from a library of more than 103 thousand compounds. We first obtained hundreds of compounds with similar physiochemical properties through 3D molecular shape and electrostatic similarity screening with potent inhibitors AEE788 and Afatinib as queries. Next, we identified compounds with strong binding affinities to the EGFR pocket through molecular docking, which makes good use of the structure information of the receptor. After molecular scaffold analysis, our bioassay confirmed 13 compounds with EGFR inhibitory activity and three compounds had IC50 values below 1000 nM. In addition, we collected 5371 EGFR inhibitors from online databases, and clustered them into 7 groups by K‐means method using their ECFP4 fingerprints as input. Each cluster had typical molecular fragments and corresponding activity characteristics, which could guide the design of EGFR inhibitors, and we concluded that the fragments from some of the hits are indicated in the highly active scaffolds. [ABSTRACT FROM AUTHOR]

Background: The combination of antiangiogenic agents with epidermal growth factor receptor inhibitors (EGFR‐TKIs) and chemotherapy with EGFR‐TKIs are the most common combination treatment options in epidermal growth factor receptor (EGFR) positive non‐small cell lung cancer (NSCLC). This network meta‐analysis was performed to evaluate the differences between them. Methods: We searched the PubMed, EMBASE and the Cochrane Controlled Trials Register up to August 2022. The primary outcomes were progression‐free survival (PFS) and objective response rate (ORR). The secondary endpoints were overall survival (OS), disease control rate (DCR) and adverse events (AEs). The data of hazard ratio (HR) or risk ratio (RR) with their corresponding 95% confidence intervals (CIs) were extracted in the studies. A network meta‐analysis (NMA) was used to indirectly compare the efficacy and safety of antiangiogenic agents plus EGFR‐TKIs and chemotherapy plus EGFR‐TKIs. Results: Pooled data of included studies were demonstrated that chemotherapy plus EGFR‐TKIs had a benefit in ORR compared to antiangiogenic agents plus EGFR‐TKIs in patients with EGFR mutated NSCLC (RR = 1.1, 95% CI: 1.0–1.2). However, there were no significant differences in PFS, OS and DCR between in the two group (PFS: HR = 1.0, 95% CI: 0.74–1.6; OS: HR = 0.78, 95% CI: 0.45–1.5; DCR: RR = 1.0, 95% CI: 0.94–1.1). The common treatment‐related AEs in the two groups were relatively manageable. Conclusion: Based on the efficacy and safety, the combination of chemotherapy with EGFR‐TKIs is considered the best combination treatment options in advanced NSCLC with EGFR mutation. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor inhibitors(EGFRIs) improve the survival rate of patients with EGFR-mutated non-small cell lung cancer significantly, but may simutaneously cause a series of adverse dermatological events. In traditional Chinese medicine(TCM) theory, EGFRIs could be classified as of dryness-heat nature that injures yin, therefore the adverse dermatological events are caused by heat-toxin of EGFRIs. Heat underpins the whole process of EGFR-mutated non-small cell lung cancer, and the disease location is the lung. The whole course of the disease can be divided into three stages, including wind-heat pattern combined with dampness-heat at the initial stage, yin deficiency and blood dryness pattern at the middle stage, and pattern of dual yin-yang deficiency at the advanced stage. Therefore, in the treatment of EGFRIs-related adverse dermatological events, on the basis of clearing heat, the therapeutic method differ in different stages, i. e. dispelling wind and eliminating dampness, nourishing yin and blood, as well as nourishing the spleen and kidney at the initial, middle, and advanced stages respectively. The formulae include Zhiyang Pingfu(Itch-relieving and Skin-soothing) Formula, Zizao Yangrong Tang(Dryness-relieving and Skin-Nourishing Decoction), Jingui Shenqi Wan(Golden Cabinet’s Kidney Qi Pill) and so on. [ABSTRACT FROM AUTHOR]

Introduction: The PRIDE (Papulopustules and/or paronychia, Regulatory abnormalities of hair growth, Itching, Dryness due to EGFR inhibition) syndrome is a cutaneous adverse effect of EGFR inhibitors. Case report: We describe an 80-year-old man, who presented with itchy papules over the suprapubic region and hair growth over the lower back for 1 month. He was diagnosed with squamous cell carcinoma of the lung, and was treated with oral gefitinib 250 mg daily for 4 months. Cutaneous examination revealed generalized xerosis, discrete papules and pustules with overlying yellow crusts over the suprapubic region, and paronychia with dystrophic changes over the right first and third toe nail. Localised hypertrichosis was seen over the back in midline lumbosacral region. Conclusions: Hair overgrowth such as trichomegaly and hypertrichosis have been described in the PRIDE syndrome. We describe an atypical presentation of the syndrome with lumbosacral hypertrichosis. [ABSTRACT FROM AUTHOR]

Pharmacists are an integral part of medication management, with the positive impact of their clinical services in patient outcomes previously studied and reported in literature. The roles and responsibilities of pharmacists continue to expand, including optimizing patient medication and health outcomes related to complex oral anticancer drugs.To evaluate the impact of a pharmacist-managed oral chemotherapy clinic in patients with non-small cell lung cancer (NSCLC) taking oral epidermal growth factor receptor inhibitor (EGFRi) regimens within an integrated healthcare delivery system.This was an observational cohort study using data from Kaiser Permanente Northern and Southern California regions on adult patients who received oncology pharmacist-managed care compared to patients with usual care. Patients were newly initiated with EGFRi therapy to treat NSCLC between 2017 and 2019. The follow-up period was defined as the time from index date (first sold date of EGFRi) to December 2020 or end of membership or death, whichever occurred first. Primary outcome measures included adherence to EGFRi, frequency of imaging during drug exposure, and presence of imaging prior to treatment change. Outcomes were analyzed with Chi-square test for categorical variables, and Student's t-test or Wilcoxon rank-sum test for continuous variables.There were 613 patients in the pharmacist-managed group and 714 patients in the usual care group. Overall, the mean age was 68.2 ± 11.3 years, and 65.1% were female. In the pharmacist-managed group, there was a significantly higher mean proportion of days covered (PDC) during the first three months of therapy (0.86 ± 0.24 vs 0.82 ± 0.36, p = 0.01) and a higher percentage of patients who were adherent to EGFRi therapy (with PDC ≥0.80) during the drug exposure period (95.8% vs 92.4%, p = 0.01). The rate of computed tomography (CT) and magnetic resonance imaging (MRI) during drug exposure was higher in the pharmacist-managed group compared to the usual care group (31.8% vs 20.7%, p < 0.01) with a higher number of mean scans completed per patient (1.15 ± 2.42 vs 0.62 ± 1.63, p < 0.01) and per patient-year (2.60 ± 7.27 vs 1.58 ± 5.95, p < 0.01). Overall, 66.2% of patients had a treatment change, with a higher percentage of patients in the pharmacist-managed group who completed a CT or MRI scan prior to treatment change (36.3% vs 26.3%, p < 0.01). Additionally, the median time between the scan and treatment change was shorter for patients with pharmacist-managed care (1.8 vs 4 months, p = 0.04).Clinical pharmacy services contributed to improved adherence, higher rates of imaging, and shorter time between imaging and treatment changes in NSCLC patients who were taking EGFRi regimens. [ABSTRACT FROM AUTHOR]

We evaluated the efficacy and safety of red light LED as an adjuvant treatment for epidermal growth factor receptor inhibitor-induced paronychia. Eight patients were recruited in this randomized, single-blinded controlled trial. They were randomized to receive red-light on one hand or foot 2–3 times/week for 6 weeks while the contralateral side served as controls. The standard treatments were continued. Erythema and lesion elevation observed by Anthera® 3D, severity and pain scores were obtained at weeks 0, 2, 4, 6, and 8. The red light group showed significantly lower erythema, severity, and pain scores at weeks 4, 6, and 8. The elevation was significantly lower in the red light group at every follow-up visit. No adverse events occurred. Red light therapy may be an option as adjunctive treatment for EGFRi-induced paronychia. [ABSTRACT FROM AUTHOR]

Introduction: Evolution of targeted molecular therapies has greatly improved patient survival in cancer. Gefitinib is an oral, reversible, epidermal growth factor receptor inhibitor used in advance non-small cell lung cancer. Skin rashes and diarrhea are common adverse effects associated with gefitinib. However, electrolytes disorders are rarely reported with gefitinib, particularly hyponatremia. Case report: We describe a 65-year-old male with metastatic non-small cell lung cancer treated with gefitinib for the last three weeks. He presented to our hospital with complaints of acute onset drowsiness. On evaluation of drowsiness, patient was diagnosed with severe hyponatremia. Management and outcome: After ruling out other common causes of hyponatremia, gefitinib was attributed as a cause of hyponatremia. Gefitinib was immediately stopped and IV hypertonic saline (3% sodium chloride) was started due to severe symptomatic hyponatremia. After seven days of cessation of gefitinib, he became asymptomatic with normalisation of serum sodium levels. Discussion: Hyponatremia in cancer patients is associated with poor prognosis and prolonged hospital stay. Possibility of gefitinib-induced hyponatremia should be considered in order to achieve early diagnosis and prevent significant mortality in cancer patients. [ABSTRACT FROM AUTHOR]

Background The optimal management of hypomagnesemia (hMg) induced by epidermal growth factor receptor inhibitors (egfris) for advanced colorectal cancer is unclear. We surveyed gastrointestinal medical oncologists in Canada to determine practice patterns for the management of egfri-induced hMg. Methods Based on distribution lists from the Eastern Canadian Colorectal Cancer Consensus Conference and the Western Canadian Gastrointestinal Cancer Consensus Conference, medical oncologists were invited to participate in an online questionnaire between November 2013 and February 2014. Results From the 104 eligible physicians, 40 responses were obtained (38.5%). Panitumumab was more commonly prescribed than cetuximab by 70% of respondents, with 25% prescribing cetuximab and panitumumab equally. Most respondents obtain a serum magnesium level before initiating a patient on an egfri (92.5%) and before every treatment (90%). Most use a reactive strategy for magnesium supplementation (90%) and, when using supplementation, favour intravenous (iv) alone (40%) or iv and oral (45%) dosing. Magnesium sulfate was used for iv replacement, and the most common oral strategies were magnesium oxide (36.4%) and magnesium rougier (18.2%). Under the reactive strategy, intervention occurred at hMg grade 1 (70.3%) or grade 2 (27%). Of the survey respondents, 45% felt that 1-5 of their patients have ever developed symptoms attributable to hMg, and 35% have had to interrupt egfri therapy because of this toxicity, most commonly at grade 3 (30%) or grade 4 (45%) hMg. The most important question about egfri-induced hMg was its relevance to clinical outcomes (45%) and its symptoms (37.5%). Conclusions In Canada, various strategies are used in the management of egfri-induced hMg, including prophylactic and reactive approaches that incorporate iv, oral, or a combination of iv and oral supplementation. Clinicians are concerned about the effect of hMg on clinical outcomes and about the symptoms that patients experience as a result of this toxicity. [ABSTRACT FROM AUTHOR]

Antineoplastic targeted therapies, such as EGFR inhibitors, tyrosine kinase inhibitors and BRAF inhibitors, frequently lead to systemic and cutaneous side effects, significantly affecting patient's quality of life. Patients with new targeted therapies have an increased risk of developing skin reactions. The new molecular target therapies developed in the last decades can induce severe skin reactions, which may require dose reduction or discontinuation of treatment and consequently, a decrease in patient's quality of life. The present paper describes toxic cutaneous reactions associated with the most frequently used molecular therapies (epidermal growth factor receptor inhibitors, tyrosine kinase inhibitors, BRAF-inhibitors), frequency of occurrence and methods of diagnosis and treatment, in order to offer a clinically efficient management for maintaining a good quality of life, with compliance to treatment and good therapeutic efficacy. Knowledge of cutaneous adverse reactions in new therapies is mandatory in order to have a proper management of oncologic patients. Recognizing target therapy toxicities by both oncologists and dermatologists, understanding therapeutic mechanisms and choosing optimum treatments for oncologic patients are critical. A correct evaluation of skin toxicity can allow for an adequate decision regarding treatment dose or discontinuation, impacting therapy response and patient survival. [ABSTRACT FROM AUTHOR]

Over the past decades, considerable progress has been made in the management of colorectal cancer (CRC), leading to a significant improvement in overall survival. Although part of this success has been rightly attributed to aggressive surgical management and advances in other adjunct treatments, our understanding of the pathogenesis of CRC and emergence of newer molecular targets for colon cancer has created a powerful impact. In this review article, we will discuss various targeted therapies in the management of metastatic CRC (mCRC). In particular, vascular endothelial growth factor (VEGF)- and epidermal growth factor receptor (EGFR)-targeting monoclonal antibodies have become integral components of the first-line treatment strategies for mCRC. Newer agents on the horizon soon to be incorporated in clinical practice will be briefly reviewed as well. Currently, the only predictive biomarker for treatment selection in patients with mCRC is tumor RAS mutational status. [ABSTRACT FROM AUTHOR]

Purpose: Epidermal growth factor receptor inhibitors such as panitumumab are associated with characteristic skin toxicities. We summarise data from three panitumumab clinical trials to investigate the potential impact of skin toxicity on quality of life (QoL) in patients with metastatic colorectal cancer (mCRC).Methods: The studies were randomised, open-label trials comparing standard treatment (first-line FOLFOX4 [n = 456], second-line FOLFIRI [n = 381], or best supportive care [n = 114]) with or without panitumumab in adults with KRAS/NRAS (RAS) wild-type mCRC. QoL was assessed using the EuroQoL 5-domain health state index (HSI) and overall health rating (OHR) measures. Impact of skin toxicity on changes in QoL scores was estimated using a linear mixed-effects model. Worst skin toxicity was defined in separate models as a subgroup variable or as a measure over time.Results: Regardless of analysis method, there were no statistically significant differences between the panitumumab and comparator arms in any of the studies in terms of change in HSI or OHR scores. There were no statistically significant differences in QoL outcomes between patients with worst skin toxicity grade <3 and those with grade ≥3. In addition, there were no statistically significant differences between the panitumumab and comparator arms in subgroups of patients with worst skin toxicity of grade <3 and ≥3.Conclusions: Addition of panitumumab to chemotherapy in RAS wild-type mCRC has no statistically significant negative effect on overall QoL, despite skin toxicity. Skin toxicity of worst grade ≥3 appeared to have similar impact on QoL as skin toxicity of grade <3. [ABSTRACT FROM AUTHOR]

Wprowadzenie: Inhibitory receptora naskórkowego czynnika wzrostu (ang. epidermal growth factor receptor inhibitors - EGFRI) są coraz częściej stosowane w leczeniu guzów litych. Skórne działania niepożądane, występujące u ponad 80% pacjentów, należą do najczęstszych powikłań terapii. W piśmiennictwie istnieją jedynie pojedyncze opisy łysienia bliznowaciejącego u pacjentów leczonych EGFRI. Cel pracy: Przedstawienie i omówienie skórnych działań niepożądanych EGFRI ze szczególnym zwróceniem uwagi na rzadko opisywane łysienie bliznowaciejące. Opis przypadku: Przedstawiamy 63-letnią kobietę z rakiem gruczołowym płuca lewego leczonym EGFRI (erlotynibem), u której wystąpiły rozsiane zmiany grudkowo-krostkowe, najbardziej nasilone na skórze głowy, z towarzyszącym łysieniem bliznowaciejącym. Ponadto obecne były: trichomegalia, zapalenie wałów paznokciowych ze zmianami przypominającymi ziarniniaki naczyniowe, suchość i świąd skóry. W wyniku zastosowanej ogólnie antybiotykoterapii i leczenia miejscowego ustąpiły wykwity krostkowe. Wnioski: Rozległe łysienie bliznowaciejące u przedstawionej pacjentki może być następstwem późnego rozpoczęcia leczenia dermatologicznego. Dermatolodzy powinni być świadomi zagrożeń związanych ze stosowaniem leków z grupy EGFRI. Introduction: Epidermal growth factor receptor inhibitors (EGFRI) are commonly used in the treatment of solid tumors. Cutaneous side effects occur in 80% of patients and are the most frequent adverse events. However, cicatricial alopecia is a rarely described side effect of EGFRI. Objective: To present cutaneous toxicities in a patient treated with erlotinib and underscore cicatricial alopecia, rarely described in the literature. Case report: We present a 63-year-old woman diagnosed with non-small cell lung cancer and treated with erlotinib, who developed extensive papulo-pustular eruption with severe involvement of the scalp and cicatricial alopecia. Other adverse events included trichomegaly, paronychia, granuloma pyogenicum-like lesions, dryness of the skin and pruritus. Conclusions: Cicatricial alopecia in the presented patient may be a result of delayed introduction of dermatological treatment. Therefore, all dermatologists should be aware of treatment modalities of EGFRI-induced toxicities. [ABSTRACT FROM AUTHOR]

Background Erythematous papulopustular eruption ( EPPE) is the most frequent skin adverse event to epidermal growth factor receptor ( EGFR) inhibitors but its histopathologic features have been poorly studied. As EPPE is a strong predictor of patient's treatment response, the EPPE histopathologic features and their correlations with skin eruption severity and involved drug were investigated. Method An involved skin biopsy was carried out in 39 informed patients treated with EGFR inhibitors (mainly cetuximab and erlotinib). The cutaneous changes in hematoxylin-eosin stained sections were evaluated. Results The EPPE to EGFR inhibitors is histopathologically characterized by neutrophilic subcorneal or intraepidermal pustules and polymorphous infiltrate of the superficial dermis during the earliest phases and by lymphocytic perifolliculitis and/or suppurative folliculitis at a later phase. The widespread dermis inflammation was more frequent in severe EPPEs and in patients treated with cetuximab, while the hair follicle inflammation was observed only in mild/moderate EPPEs. Conclusion Our study shows the histopathologic signs of EPPE and their correlation with clinical severity and the offending drug. [ABSTRACT FROM AUTHOR]

ABSTRACT [ABSTRACT FROM AUTHOR]

Background: Previous reports regarding the cutaneous adverse events of epidermal growth factor receptor inhibitors are mostly limited to small case reports and case series, mainly involving Caucasian patients. Aims: We describe the trends in the clinical presentation of Asian patients who had cutaneous adverse events induced by epidermal growth factor receptor inhibitors and to explore the relationship between skin adverse events and tumor response. Methods: From 2006 to 2010, medical records of Thai patients with non-small cell lung cancer receiving epidermal growth factor receptor inhibitors were retrieved and analyzed. Results: In all, 99 patients were reviewed and analyzed. Erlotinib and gefitinib were commenced in 75 (75.8%) and 24 (24.2%) patients, respectively. Cutaneous adverse events occurred in 43 (57.3%) patients receiving erlotinib and in 15 (62.5%) patients receiving gefitinib. The most common adverse event was xerosis (52.5%). Less common adverse events included papulo-pustular eruption (27.3%), erythematous maculopapular rash (11.1%), mucositis (6.7%), paronychia (5.1%), and trichomegaly (2%). Elderly patients had a higher occurrence of xerosis. The presence of cutaneous adverse events was significantly higher in subjects who had a tumor response. Limitations: The limitations of study include its retrospective nature, and the initial screening of cutaneous adverse events was done by non-dermatologists. Conclusions: Cutaneous adverse events due to epidermal growth factor receptor inhibitors are not uncommon in the Asian population. We found a positive correlation between the occurrences of cutaneou adverse events and tumor response supporting the view that they are surrogate markers for therapeutic response. [ABSTRACT FROM AUTHOR]

Background: Skin toxicity is frequent and debilitating in oncologic patients treated with epidermal growth factor receptor inhibitors (EGFRIs). Grading and management of skin adverse events (AEs) are poorly standardized. Materials and Methods: We developed a new score (EGFRISTI: Epidermal Growth Factor Receptor Inhibitor-Related Skin Toxicity Index) which is able to quantify and monitor all EGFRI-related dermatologic AEs over time. The utility of this tool was validated in 130 patients treated with 5 different EGFRIs including both monoclonal antibodies and tyrosine kinase inhibitors. Results: The mean baseline EGFRISTI score was 26.9 (range: 6.0-64.5). Mild toxicity was found in 55 patients (42.3%), moderate toxicity in 43 (33.1%), and severe toxicity in 32 patients (24.6%). After the first-line toxicity treatment, an EGFRISTI score reduction of >75% was obtained in 31 patients (34.1%) and one of 50% in 40 patients (43.9%), while an improvement of <50% was observed in the remaining 20 subjects (22.0%). Conclusions: The EGFRISTI is a simple and reliable tool to quantify and express the severity of all clinical signs and symptoms of EGFRI skin toxicity with a single numerical value, to choose the most suitable therapy, and to measure its efficacy. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Despite advances in treatment options for metastatic colorectal cancer over the past decade, the number of chemotherapy agents available remains limited. We report here a retrospective review of 11 patients who were treated with panitumumab following documented disease progression on cetuximab. Two patients demonstrated minor radiographic responses, albeit only for a short period of time. We conclude that the use of one epidermal growth factor receptor inhibitor following failure on the other may be of benefit to patients who would otherwise have no other treatment options. However, studies to help identify the subset of patients who might benefit from this strategy are needed. [ABSTRACT FROM PUBLISHER]

Acneiform rash associated with epidermal growth factor receptor inhibitors frequently presents facial manifestations. The treatment modality for such lesions still needs to be elucidated. The aim of this original report was to evaluate the effectiveness of high-level laser therapy in reducing the severity of facial acneiform rash induced by cetuximab, an epidermal growth factor receptor inhibitors. Four patients with metastatic colorectal cancer and two patients with head and neck cancer showing cetuximab-induced facial rash were treated by high-level laser therapy in two 8-min-long consecutive sessions/day over a 4-day treatment. Patients wore protective glasses to prevent eye damage related to laser light. Subsequently, patients were seen once a week for up to 21 days and after 180 days. During each day of treatment and each follow-up recall, patients were asked to complete a questionnaire about the onset and progression of their acneiform rash (for a total of eight sessions). Cetuximab-related toxicity and general discomfort visual analogue scales were also recorded in each of these eight sessions in the treated and control areas in each patient. After the fourth session of high-level laser therapy, the patients showed a noteworthy decrease in both cetuximab-related toxicity and visual analogue scales, up to a complete regression of the lesions at the end of the follow-up in all treated areas. The high-level laser therapy was effective in the healing of acneiform rash associated with epidermal growth factor receptor inhibitors with no side effects. [ABSTRACT FROM AUTHOR]

Overexpression and impaired signaling of the epidermal growth factor receptor (EGFR) are involved in the can-cerogenesis. The EGFR inhibitors such as cetuximab have shown efficacy in the targeted therapy of neoplasm. The acneiform rash has been revealed as the most common side effect of treatment, usually occurring within 2 weeks after therapy onset. We report perifollicular pustules and papules with impetiginization in a 63-year-old patient with metastatic colorectal cancer treated with cetuximab. The neoplasm was diagnosed in 2008 and treat-ed surgically (resection of the sigmoid). After 3 years, a combined therapy was administered due to the disease progression. It consisted of cetuximab and FOLFOX (Folinic acid, Fluorouracil, Oxaliplatin) chemotherapy regimen. The effective dermatologic management (with systemic doxycycline and topical tacrolimus and fusidic acid) of the skin toxicity allowed for maintenance of oncologic treatment. Despite the proper dermatological therapy, the described side effects may persist, and the exacerbation of skin lesions can cause discontinuation of treatment of cancer with those modern biological agents (EGFR inhibitors and other kinase inhibitors). When discontinuation is not neces-sary - cutaneous symptoms adversely affect the quality of life. However, there are reports that recognition of the skin lesions in the course of the above therapies is a good prognostic factor, confirming effectiveness of treatment. More-over, the association between genetic polymorphisms, the risk of treatment adverse effects and the response of the tumorto monoclonal antibody targeted therapy is well established. This leads to the increasing role of pharmacogenetics in the management of neoplasms. [ABSTRACT FROM AUTHOR]

Background Skin rash is an adverse event which might be associated with longer survival in patients treated with epidermal growth factor receptor tyrosine kinase inhibitors. The aim of this nonrandomised phase II clinical trial is to prospectively evaluate the relationship between skin rash and overall survival (OS) in advanced/metastatic pancreatic cancer treated with erlotinib plus gemcitabine. Patients and methods Patients were given gemcitabine (1000 mg/m2/week, 3 weeks every 4 weeks) plus erlotinib (100 mg/day orally continuously) until disease progression/unacceptable toxicity. The primary end point was OS. Results A total of 153 eligible patients were enrolled (grade ≥ 2 rash, 25%; grade < 2 rash, 75%). OS was longer in patients with grade ≥2 rash versus grade <2 (11 versus 5 months; P < 0.001). Progression-free survival was longer in patients with grade ≥2 rash versus grade <2 (6 versus 3 months; P < 0.001) and shorter in those without rash versus grade 1 (2 versus 4 months; P = 0.005) or grade ≥2 (2 versus 6 months; P < 0.001). Patients with grade ≥2 rash showed higher rates of overall response (21% versus 7%; P < 0.05) and disease control (84% versus 43%; P < 0.05) versus grade <2. Conclusions This study prospectively confirms the relationship between rash and longer OS in unresectable locally advanced/metastatic pancreatic cancer treated with erlotinib plus gemcitabine. [ABSTRACT FROM PUBLISHER]

Purpose: Cutaneous adverse events induced by epidermal growth factor receptor (EGFR) inhibitors can hamper the patients' quality of life. The aim of our work was to draft an algorithm for the optimised management of this skin toxicity. Methods: This algorithm was built in three steps under the responsibility of a steering committee. Step I: a systematic literature analysis (SLA) has been performed. Step II: the collection of information about practices was performed through a questionnaire.These questions were asked during regional meetings to which oncologists, gastro-enterologists, radiotherapists, and dermatologists were invited. Step III: a final meeting was organised involving the bibliography group and the steering committee and regional scientific committees for proposing a final algorithm. Results: Step I: 14 publications were selected to evaluate the use of cyclines as curative or prophylactic treatment of the folliculitis induced by EGFR inhibitors. Nineteen publications were retained for the topical treatment of the folliculitis. Forty-six articles were selected for the management of the cutaneous lesions in link with appendages and 12 for xerosis and pruritus. Step II: 96 delegates attended the seven regional meetings and 67 questionnaires were analysed. Step III: a final algorithm was proposed on the basis of the conclusions of the first two steps and expert opinions present at this final meeting. The different propositions were unanimously approved by the 14 experts who voted. Conclusions: This multidisciplinary study summarising published data and current practices produced a therapeutic algorithm, which should facilitate the standardised, optimised management of skin toxicity associated with EGFR inhibitors in France. [ABSTRACT FROM AUTHOR]

Background: The optimal treatment sequence of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) and pemetrexed in previously treated advanced lung adenocarcinoma patients is currently unknown. Methods: This retrospective study explored two sequential regimens incorporating EGFR TKIs and pemetrexed in advanced lung adenocarcinoma patients who had failed standard first-line chemotherapy. The medical records of 83 patients were carefully reviewed. 45 patients who received second-line EGFR TKIs followed by third-line pemetrexed were grouped as cohort A. 38 patients who received a strategy with the reverse sequence were grouped as cohort B. Progression-free survival, disease control duration and survival time were compared between the two cohorts. Results: Median survival time is significantly longer in cohort A compared with cohort B (23.615 months vs. 16.269 months, HR: 0.549, 95% CI: 0.308-0.979, P = 0.042). Median disease control duration is 17.463 months in cohort A versus 11.587 months in cohort B (HR: 0.700, 95% CI: 0.409-1.196, P = 0.191). Median progression-free survival with second-line EGFR TKIs is significantly longer than second-line pemetrexed (8.056 months vs. 4.200 months, HR: 0.462, 95% CI: 0.281-0.758, P = 0.001). Median progression-free survival with third-line EGFR TKIs is 6.885 months versus 7.624 months with third-line pemetrexed (HR: 0.462, 95% CI: 0.605-1.767, P = 0.902). The rate of response to EGFR TKIs is higher in second-line setting than in third-line (44% vs. 34%). Conclusions: We hypothesized that for EGFR-mutated patients, second-line EGFR TKIs followed by third-line pemetrexed is preferable to the reverse sequence. [ABSTRACT FROM AUTHOR]

Objective: Over 50% of cancer patients who are treated with epidermal growth factor receptor (EGFR) inhibitors develop a papulopustular rash that involves the face, neck, and upper torso. However, because relatively few previous reports have focused on the full ramifications of this drug-induced side effect, this qualitative study was undertaken. Methods: Fifteen patients who had either an active or previous rash from these agents participated in scripted interviews. All interviews were transcribed and examined by means of a qualitative methodologic approach. Results: Four major themes emerged: (1) actual physical discomfort was associated with the rash; (2) patients were concerned about their appearance; (3) despite initial denial, patients did suffer social isolation; and (4) high medical morbidity was associated with the rash. Patients voiced concerns such as: (1) 'Especially when I try to sleep, I can feel the itch and burn all over...'; (2) 'My face looks so bad that if I go to see my friends and they say, 'What happened to you.' I am self conscious about that'; (3) 'I just told them they would be better off just calling me, don't come visit...'; and (4) 'I went to the hospital for my face...they made a bandage to put all over [my] face.... [I] just had a little nose hole, a mouth hole and holes for...eyes.'. Conclusion: Rash from EGFR inhibitors can have a major negative impact upon cancer patients. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Erlotinib belongs to the targeted cancer treatments acting through epidermal growth factor receptor inhibition. Papulopustular eruption is the most common cutaneous toxicity. The pathogenesis of the rash is not clear. There is no consensus on treatment. In this report, we describe a 73-year-old female patient who was referred to our outpatient clinic for evaluation and treatment of a widespread acneiform eruption. She was put on erlotinib therapy for 3 months for the treatment of lung adenocarcinoma. The patient has developed nonpruritic papules and pustules widespread over the body except the face for the past 2 weeks. Bacterial culture obtained from a pustule on the back grew methicillin-sensitive Staphylococcus aureus (SA). Histopathological examination of a papule demonstrated vacuolar degeneration of basal layer, prominent walls of vessels, a mixed infiltration of eosinophils, and lymphocytes and erythrocyte extravasation. The eruption was successfully treated with two weekly pulses of azithromycin 500 mg for 3 consecutive days. This case demonstrated that erlotinib may cause purpuric papular eruption secondarily infected with SA. Routine bacterial culture should be performed from pustules before any treatment. [ABSTRACT FROM AUTHOR]

Background Acute and subacute cutaneous side-effects of epidermal growth factor receptor inhibitors (EGFRIs) are very frequent and well known. Much less is known about the chronic cutaneous effects of these drugs and about their potential psychosocial impact on patients. Objectives We performed a retrospective study of patients treated with EGFRIs for more than 6 months. Methods All patients had a detailed dermatological examination. The primary cancer, associated chemotherapies, skin treatment, evolution of skin symptoms and their impact on quality of life (QoL) as evaluated by the Dermatology Life Quality Index (DLQI) were noted. Results Seven men and nine women were identified. The mean length of EGFRI treatment was 10 months (range 6–27). At the time of examination, all patients (100%) had cutaneous side-effects. Grade I or II folliculitis was found in 37·5% of the patients. Additional skin manifestations were xerosis (100%), mucositis (69%), hair abnormalities (87·5%), eyelash trichomegaly (62·5%), facial hypertrichosis (56%), painful paronychia (56%) and onycholysis (44%). Dose reduction or EGFRI discontinuation for skin toxicity were needed in six patients (37·5%). DLQI evaluation showed a moderate to strong impact on QoL in four patients (25%). Conclusions Cutaneous side-effects are found in 100% of patients treated with EGFRIs for more than 6 months and have a significant effect on patients’ QoL. The clinical spectrum of skin manifestation varies over time. As the use of EGFRIs rapidly increases, it is critical for us to improve our knowledge in the understanding and managment of these skin manifestations. [ABSTRACT FROM AUTHOR]

Objective: Epidermal growth factor receptor inhibitors can result in a severe rash in 5–10% of patients and can detract from quality of life. The objective of this study was to identify clinical predictors of severe rash in the hope of utilizing such factors in the design of future rash palliative and prevention trials. Methods: 933 cetuximab-treated patients enrolled on N0147, an adjuvant chemotherapy trial for colon cancer, were evaluated for clinical risk factors of severe rash. Results: Within this cohort, 50 patients (5%) developed a severe rash (grade 3). More men compared to women developed such a rash: 34 (7%) versus 16 (3%) (multivariate odds ratio = 2.12; 95% confidence interval: 1.14–3.88; p = 0.017). A greater number of younger patients (<70 years of age) also developed a rash: 48 (6%) versus 2 (1%) (multivariate odds ratio = 0.21; 95% confidence interval: 0.05–0.88; p = 0.032). Race and performance score were not predictive. Conclusion: Men and younger patients are at greater risk for a severe cetuximab-induced rash although overall the risk is low. These observations are particularly important in designing future rash prevention and palliation trials. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Epidermal growth factor receptor (EGFR) is highly expressed in many human tumors including hepatocellular carcinoma (HCC). Therefore, inhibition of EGF receptors could be a potential target for anticancer therapy. In this study, we investigated the effects of two EGFR tyrosine kinase inhibitors, PD153035 and its analogue 4-[[3-chloro-4-fluorophenyl]amino]-6,7-dimethoxyquinazoline hydrochloride (ANAPD) on human HCC cell lines by cell proliferation assay, flow cytometry and Western blot. Our results demonstrated that both EGFR inhibitors inhibited tumor cell growth in a dose-dependent manner, but ANAPD was more potent than PD153035. These specific inhibitors not only blocked EGF-stimulated EGFR autophosphorylation but also targeted EGFR signaling including MAPK and Akt pathways. Furthermore, EGFR inhibitors induced a delay in cell cycle progression and a G1 arrest together with a partial G2/M block. EGFR inhibitors also induced tumor cells to undergo apoptosis. In conclusion, this study demonstrated that both PD153035 and ANAPD inhibit tumor cell growth in HCC through inhibition of EGFR signaling pathway, and ANAPD is a more potent inhibitor than PD153035. This suggested that blockage of EGF receptors may provide an effective therapeutic approach for human HCC and ANAPD could be a potential drug candidate for the treatment of HCC. [Copyright &y& Elsevier]

Biologic agents targeting the epidermal growth factor receptor (EGFR) have emerged as a robust treatment option for various solid tumors. Despite lower systemic side effects than conventional chemotherapy, the majority of patients treated with these agents experience cutaneous toxicities, including papulopustular rashes, hair and nail changes, xerosis and pruritus, which have a significant impact on health and quality of life. Currently no consensus or management guidelines exist for these untoward events. Therefore, a retrospective survey was carried out across 110 oncology practioners in the US that were administering EGFR inhibitors. Providers were queried on the impact and management of these untoward events in their practices. Responses suggest that combination therapies (topical and oral) were more effective than either therapy alone, and also lead to a more rapid resolution of the papulopustular rash. Providers also reported that patients frequently complained of physical symptoms associated with the rash (itching and pain), and that they had a positive perception when being treated for their cutaneous side effects. The survey results support that attentive cutaneous care is important in patients treated with EGFR inhibitors, and that proactive/combined interventions may enhance quality of life and optimize consistent drug administration. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The objective of the five clinical studies presented in this article was to investigate the single-dose pharmacokinetics of gefitinib (IRESSA®, ZD1839), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in healthy volunteers and patients with advanced cancer. Methods: Studies 1 and 3–5 recruited healthy male volunteers aged 18–65 years; study 2 recruited male or female patients aged ≥18 years with any solid malignant tumour expressing EGFR and refractory to standard therapy. Gefitinib administration was as follows: study 1 (bioavailability in healthy volunteers; n = 12) – intravenous infusion of 50 or 100mg followed by a single oral dose of 250mg; study 2 (bioavailability in cancer patients; n = 19) - intravenous infusion of 50mg followed by a single oral dose of 250mg; study 3 (intrasubject variability; n = 24) – two single oral doses of 250mg; study 4 (dose-proportionality; n = 15) – three single oral doses of 50–500mg; study 5 (effect of food; n = 26) – two single doses of 250mg under either fed or fasted conditions. In all studies, venous blood samples for determination of gefitinib plasma concentrations were collected at predetermined intervals. Plasma concentrations of gefitinib were measured using liquid-liquid extraction after basification followed by high-performance liquid chromatography with tandem mass spectrometric detection. Appropriate pharmacokinetic parameters were determined by noncompartmental methods. Results: Study 1: Oral bioavailability of a gefitinib 250mg dose was 57% in healthy volunteers. Absorption was moderately slow, with geometric mean (gmean) peak plasma concentration (Cmax) of 85 ng/mL (range 43.5–110 ng/mL) reached 5 hours following an oral dose of 250mg. Study 2: Oral bioavailability of a gefitinib 250mg dose was 59% in patients. Absorption was again moderately slow, with gmean Cmax of 159 ng/mL (range 48.7–324 ng/mL) typically reached 3 hours (range 1–8 hours) following an oral dose of 250mg. Study 3: Area under the plasma concentration-time curve from time zero to infinity (AUC∞) and Cmax were variable – up to 15-fold between subjects and 2-fold within an individual. Study 4: AUC∞ and Cmax increased with dose across the range of 50–500mg, and increased dose-proportionally up to 250mg. Study 5: Small, clinically insignificant increases in AUC∞ and Cmax were seen in the presence of food (32% and 37%, respectively). Conclusions: The gefitinib 250mg tablet is orally bioavailable in both healthy volunteers and cancer patients; bioavailability is independent of dose and unaffected by food to any clinically significant extent. Gefitinib undergoes rapid plasma clearance and has an extensive volume of distribution, resulting in a pharmacokinetic profile supportive of a once-daily dosage regimen. [ABSTRACT FROM AUTHOR]

Background and Objectives: Gefitinib (IRESSA, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, has been approved in several countries for the treatment of advanced non-small-cell lung cancer. Preclinical studies were conducted to determine the cytochrome P450 (CYP) isoenzymes involved in the metabolism of gefitinib and to evaluate the potential of gefitinib to cause drug interactions through inhibition of CYP isoenzymes. Based on these findings, three clinical studies were carried out to investigate pharmacokinetic drug interactions in vivo with gefitinib.Methods: In preclinical studies radiolabelled gefitinib was incubated with: (i) hepatic microsomal protein in the presence of selective CYP inhibitors; and (ii) expressed CYP enzymes. Human hepatic microsomal protein was incubated with selective CYP substrates in the presence of gefitinib. Clinical studies were all phase I, open-label, single-centre studies; two had a randomised, two-way crossover design and the third was nonrandomised. The first and second studies investigated the pharmacokinetics of gefitinib in the presence of a potent CYP3A4 inducer (rifampicin [rifampin]) or inhibitor (itraconazole) in healthy male volunteers. The third study investigated the effects that gefitinib had on the pharmacokinetics of metoprolol, a CYP2D6 substrate, in patients with solid tumours.Results: The results of preclinical studies demonstrated that CYP3A4 is involved in the metabolism of gefitinib and that gefitinib is a weak inhibitor of CYP2D6 activity. In clinical studies when gefitinib was administered in the presence of rifampicin, geometric mean (gmean) maximum concentration and area under the plasma concentration-time curve (AUC) were reduced by 65% and 83%, respectively; these changes were statistically significant. When gefitinib was administered in the presence of itraconazole, gmean AUC increased by 78% and 61% at gefitinib doses of 250 and 500 mg, respectively; these changes also being statistically significant. Coadministration of metoprolol with gefitinib resulted in a 35% increase in the metoprolol area under plasma concentration-time curve from time zero to the time of the last quantifiable concentration; this change was not statistically significant. There was no apparent change in the safety profile of gefitinib as a result of coadministration with other agents.Conclusions: Although CYP3A4 inducers may reduce exposure to gefitinib, further work is required to define any resultant effect on the efficacy of gefitinib. Exposure to gefitinib is increased by coadministration with CYP3A4 inhibitors, but since gefitinib is known to have a good tolerability profile, a dosage reduction is not recommended. Gefitinib is unlikely to exert a clinically relevant effect on the pharmacokinetics of drugs that are dependent on CYP2D6-mediated metabolism for their clearance, but the potential to increase plasma concentrations should be considered if gefitinib is coadministered with CYP2D6 substrates that have a narrow therapeutic index or are individually dose titrated. [ABSTRACT FROM AUTHOR]

Pancreatic adenocarcinoma (PAC) remains one of the most lethal cancers. The overall 5-year survival rate (all stages) remains <5%. Most people present with advanced disease and even the minority who present with resectable disease still, predominantly, die of recurrent metastatic cancer. Adjuvant treatment after surgical resection has been proposed as a method of increasing the cure rate of patients with PAC, but despite developments in new systemic and radiation treatment techniques, the optimal adjuvant therapy, according to the available evidence, is yet to be clearly defined. Adjuvant systemic chemotherapy, radiotherapy or chemoradiotherapy have all been investigated as strategies to improve locoregional and distant recurrence rates following resection of PAC. Whilst the early trials concentrated on combined modality adjuvant treatment, the large randomized controlled trials published to date have compared the various modalities and have concluded that chemoradiation therapy does not significantly improve survival, whereas adjuvant chemotherapy alone does. Despite the large numbers of patients involved in these trials, statistical and methodological flaws have lead to skepticism regarding these results. This review examines published trials of adjuvant therapy for resectable PAC, with particular emphasis on randomized studies. However, there is still ample room for further developments. Only a better understanding of the underlying biology contributing to the aggressive phenotype of PAC and the development of targeted molecular agents will finally allow significant progress to be made in the area of adjuvant therapy for resectable PAC. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article on basal cell carcinoma (BCC) prognosis published in the previous issue.

Focuses on epidermal growth factor receptor (EGFR) pharmacogenomics. Significance of the initially reported activity of EGFR tyrosine kinase inhibitors (TKI) on the oncology community; List of clinical parameters predictive of individuals who are most likely to benefit from EGFR TKI therapy; Information on clinical observation that has been suggested to predict improved response or survival with EGFR inhibitors.

Background MET amplification (METamp) is a resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) occurring via over activation of downstream signaling pathways such as PI3K and MAPK. METamp occurs in ≈10% of patients receiving erlotinib, gefitinib, afatinib, or icotinib, and is the most common resistance mechanism to osimertinib in phase III trials, occurring in ≈19% of patients. Tepotinib, an oral once daily potent and selective MET inhibitor, is associated with improved survival in combination with gefitinib in patients with EGFR-mutant MET-amplified NSCLC with EGFR TKI resistance compared with standard chemotherapy in the INSIGHT study (NCT01982955): investigator-reported progression free survival (PFS) was 21.2 vs 4.2 months (HR 0.13; 90% CI 0.04, 0.43) and overall survival, (OS) was 37.3 vs. 13.1 months (HR 0.08; 90% CI 0.01, 0.51). Trial design INSIGHT 2 (NCT03940703) is a global single-arm, open-label, phase II trial of tepotinib in patients with advanced (stage IIIB/IV) NSCLC with resistance to 1st–3rd generation EGFR TKIs driven by METamp. Eligibility criteria include patients aged ≥18 years with advanced EGFR-mutant NSCLC and known T790M status, having acquired resistance to EGFR TKIs, and are METamp positive by plasma 'liquid' biopsy, with an ECOG PS of 0 or 1 and normal organ function. Prior immunotherapy is permitted but prior MET pathway-targeted therapy is not. Tepotinib (500 mg orally once daily) in combination with osimertinib (80 mg once daily) will be administered until disease progression, unacceptable toxicity, or withdrawal of consent. An initial safety run-in will comprise 6 patients (endpoint; dose-limiting toxicities); anticipated full enrollment is 90 patients. The primary endpoint is objective response rate (ORR) by independent review committee (RECIST v1.1). Secondary objectives include investigator-assessed ORR, duration of response, disease control, PFS, OS, pharmacokinetics, health-related quality of life, tolerability, and safety (NCI-CTCAE v5.0). Recruitment is ongoing and approximately 80 study sites in 17 countries in Europe, Asia, and North America are expected to participate in this study. Clinical trial identification NCT03940703. Legal entity responsible for the study Merck Healthcare KGaA. Funding Merck Healthcare KGaA. Disclosure J.C-H. Yang: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Roche/Genentech/Chugai; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Merrimack; Honoraria (self), Advisory / Consultancy: Yuhan Pharmaceuticals; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo ; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Takeda Oncology; Honoraria (self), Advisory / Consultancy: Blueprint Medicines; Honoraria (self), Advisory / Consultancy: Hansoh Pharmaceuticals. B. Ellers-Lenz: Full / Part-time employment: Merck Healthcare KGaA. J. Straub: Full / Part-time employment: Merck Healthcare KGaA. A. Johne: Full / Part-time employment: Merck Healthcare KGaA. Y-L. Wu: Honoraria (self), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self): Sanofi. [ABSTRACT FROM AUTHOR]

Background The third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is a standard treatment in case of T790M mutation positive after failure to first or second generation EGFR TKI in patients with EGFR-mutant non-small cell lung cancer (NSCLC). We investigated a success rate of rebiopsy and sequential EGFR TKI treatment in real world setting in Korea. Methods We retrospectively reviewed medical records of patients with EGFR mutant advanced NSCLC who received first- or second- generation EGFR TKI between Jan 2012 and Jun 2018 at a single center in Korea. Results Among 221 patients with EGFR-mutant NSCLC, 68 patients who were lost to follow up (n = 19) or still on 1st- or 2nd- generation TKI (n = 49) at time of analysis were excluded. Forty-three out of remaining 153 patients (28%) did not have a chance of consideration for second line treatment because of deterioration of performance status (n = 21) or death (n = 22), especially in elderly over 70 years. Tests for acquired EGFR mutation were performed in 76% (84/110), among which 73 cases were tissue rebiopsy and 11 cases were plasma EGFR mutation analysis. Acquisition of tumor tissue in rebiopsy was successful in 93% (68/73). The most common reason of not doing rebiopsy was lack of sequential treatment options (n = 24). Ten patients with negative T790M or failure at initial rebiopsy underwent more than two times of repeated EGFR mutation analysis, among which four patients had eventually positive T790M at some point of disease course. Overall T790M positive rate was 54% (45/84). Among 7 patients with initially negative T790M mutation in plasma analysis, further rebiopsy from tumor tissue was performed only in one patients because of patient's refusal (n = 2), physician's decision to continue post-progression EGFR TKI (n = 2), poor performance status (n = 1), and unaccessibility to tumor tissue (n = 1). Conclusions About 30% of patients with EGFR mutant NSCLC did not have a chance of consideration for second line EGFR TKI treatment, especially in elderly over 70 years. Success rate of tumor tissue rebiopsy was over 90% in real world setting, and repeated rebiopsy may increase detection rate of acquired T790M mutation. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Epidermal growth factor receptor (EGFR) deletion of exon 19 and exon 21 mutations are the most common mutations in advanced non-small cell lung cancer (NSCLC) and predict higher sensitivity to EGFR tyrosine kinase inhibitors (TKI). The present study is a retrospective analysis of patients harboring EGFR exon 19 deletions and exon 21 mutations in advanced NSCLC. Methods Data of patients diagnosed with advanced NSCLC patients with EGFR mutations from January 2012 to March 2019 was analysed. EGFR mutation analysis was performed using DNA sequencing by real time polymerase chain reaction method. Exon 19 and exon 21 mutated patients were compared for clinicopathological features and outcomes. Results Data of 697 patients with lung cancer was retrieved of which 613 patients had advanced NSCLC. A total of 441 patients were evaluated for EGFR mutations and 135 (30.6%) patients were positive for EGFR mutations. The median age at presentation was 57.5 years(range, 30-88). Smoking history was seen in 38 (28.1%) patients and 97 (71.8%) were non smokers. Of these 135 patients with EGFR positivity, 129(95.6%) had adenocarcinoma histology and 6(4.4%) had adenosquamous histology. Exon 19 and exon 21 mutations accounted for 79(58.5%) and 45(33.33%) cases respectively. Mutations in exon 18, exon 20 and double mutations were seen in 2(1.4%), 3(2.2%) and 6(4.4%) patients respectively. Thirty nine (28.8%) patients received initial chemotherapy followed by switch maintenance. Geftinib (82.2%) was the most common TKI used followed by erlotinib (9.6%), Afatinib (4.5%), Osimeritinib (0.8%) and chemotherapy (2.9%). The clinical profile, treatment details and outcomes are tabulated below. The median PFS and OS were 8.9 months (range, 4-42 months) and 18 months (range,4-46 months) respectively. Table: 493P   Overall EGFR Positive(n = 135)  Exon 19 deletions(n = 79)  Exon 21 Mutated (n = 45)  P Value  Median Age (years)  57.5 (range, 30-88)  55 (range, 35-88)  61 (range, 30-80)    Sex: Male Female Ratio  75 60 1.25:1  44 35 1.25:1  25 20 1.25:1  0.98  Smoker: Yes No  38 97  26 53  11 34  0.32  Metastases: Bone B/L lung Pleural effusion Brain Liver  67 58 40 22 10  39 32 22 20 8  26 22 13 2 1  0.36 0.38 0.9 0.03 0.24  Rash Grade 1 Grade 2 Grade 3  37 20 10 7  23 8 10 5  13 11 0 2  0.8  Response evaluated Partial response Stable disease Progressive disease  111 48 (43.3%) 49 (44.1%) 14 (12.6%)  65 27 (41.6%) 31 (47.7%) 7 (10.7%)  38 18 (47.4%) 16 (42.1%) 4 (10.5%)  0.5 0.6 0.7  Median PFS (months)  8.9  9.2  8.3  0.8  Median OS (months)  18  18.9  17  0.5    Overall EGFR Positive(n = 135)  Exon 19 deletions(n = 79)  Exon 21 Mutated (n = 45)  P Value  Median Age (years)  57.5 (range, 30-88)  55 (range, 35-88)  61 (range, 30-80)    Sex: Male Female Ratio  75 60 1.25:1  44 35 1.25:1  25 20 1.25:1  0.98  Smoker: Yes No  38 97  26 53  11 34  0.32  Metastases: Bone B/L lung Pleural effusion Brain Liver  67 58 40 22 10  39 32 22 20 8  26 22 13 2 1  0.36 0.38 0.9 0.03 0.24  Rash Grade 1 Grade 2 Grade 3  37 20 10 7  23 8 10 5  13 11 0 2  0.8  Response evaluated Partial response Stable disease Progressive disease  111 48 (43.3%) 49 (44.1%) 14 (12.6%)  65 27 (41.6%) 31 (47.7%) 7 (10.7%)  38 18 (47.4%) 16 (42.1%) 4 (10.5%)  0.5 0.6 0.7  Median PFS (months)  8.9  9.2  8.3  0.8  Median OS (months)  18  18.9  17  0.5  Table: 493P   Overall EGFR Positive(n = 135)  Exon 19 deletions(n = 79)  Exon 21 Mutated (n = 45)  P Value  Median Age (years)  57.5 (range, 30-88)  55 (range, 35-88)  61 (range, 30-80)    Sex: Male Female Ratio  75 60 1.25:1  44 35 1.25:1  25 20 1.25:1  0.98  Smoker: Yes No  38 97  26 53  11 34  0.32  Metastases: Bone B/L lung Pleural effusion Brain Liver  67 58 40 22 10  39 32 22 20 8  26 22 13 2 1  0.36 0.38 0.9 0.03 0.24  Rash Grade 1 Grade 2 Grade 3  37 20 10 7  23 8 10 5  13 11 0 2  0.8  Response evaluated Partial response Stable disease Progressive disease  111 48 (43.3%) 49 (44.1%) 14 (12.6%)  65 27 (41.6%) 31 (47.7%) 7 (10.7%)  38 18 (47.4%) 16 (42.1%) 4 (10.5%)  0.5 0.6 0.7  Median PFS (months)  8.9  9.2  8.3  0.8  Median OS (months)  18  18.9  17  0.5    Overall EGFR Positive(n = 135)  Exon 19 deletions(n = 79)  Exon 21 Mutated (n = 45)  P Value  Median Age (years)  57.5 (range, 30-88)  55 (range, 35-88)  61 (range, 30-80)    Sex: Male Female Ratio  75 60 1.25:1  44 35 1.25:1  25 20 1.25:1  0.98  Smoker: Yes No  38 97  26 53  11 34  0.32  Metastases: Bone B/L lung Pleural effusion Brain Liver  67 58 40 22 10  39 32 22 20 8  26 22 13 2 1  0.36 0.38 0.9 0.03 0.24  Rash Grade 1 Grade 2 Grade 3  37 20 10 7  23 8 10 5  13 11 0 2  0.8  Response evaluated Partial response Stable disease Progressive disease  111 48 (43.3%) 49 (44.1%) 14 (12.6%)  65 27 (41.6%) 31 (47.7%) 7 (10.7%)  38 18 (47.4%) 16 (42.1%) 4 (10.5%)  0.5 0.6 0.7  Median PFS (months)  8.9  9.2  8.3  0.8  Median OS (months)  18  18.9  17  0.5  Conclusions In patients with EGFR-sensitizing mutations, tyrosine kinase inhibitors offer superior progression free survival and response rates and are well tolerated. Brain metastases at presentation were significantly higher in exon 19 compared to exon 21. No significant differences were observed in median PFS or median OS in EGFR exon 19 deleted or Exon 21 mutated subgroup. Legal entity responsible for the study Department of Medical Oncology, Nizam's Institute of Medical Sciences. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background In patients with EGFR-mutant NSCLC, MET amplification (METamp) is a resistance mechanism to EGFR tyrosine kinase inhibitors (TKI). In the randomized phase Ib/II INSIGHT study (NCT01982955) that halted full enrolment due to low recruitment, tepotinib (TEP), a potent, selective MET TKI, plus gefitinib (GEF) improved progression-free survival (PFS) and objective response rate (ORR) vs chemotherapy (CTx) in patients with EGFR-mutant NSCLC and resistance to 1st-line EGFR TKIs due to METamp (≥6-month follow-up). We now present long-term survival outcomes (≥18-month follow-up) for this predefined analysis. Methods Patients were randomized to TEP 500 mg + GEF 250 mg orally once daily (until progressive disease, intolerable toxicity or other withdrawal) or platinum + pemetrexed IV (≤6 x 21-day cycles). METamp was defined as GCN ≥5 and/or MET/CEP7 ratio ≥2. Primary endpoint was investigator-assessed (INV) PFS. Secondary endpoints included overall survival (OS), ORR, PFS by independent review (IRC), safety. Results From 04/24/15 to 06/12/17, 55 patients enrolled in the INSIGHT study and 19 were METamp (TEP+GEF 12; CTx 7); this predefined subgroup is analysed here. Median GCN was 8.8 (range 4.8–29.5); 18 patients had GCN ≥5, 13 had MET/CEP7 ratio ≥2. At data cutoff (12/12/18), median treatment duration (weeks [range]) for TEP+GEF was 49 (4.6–110.9; 3 patients still ongoing for ≥24 months), pemetrexed was 18.0 (5.9–60.4), cisplatin 12.0 (6.6–25.1) or carboplatin 12.8 (5.9–19.7), all CTx patients discontinued. TEP+GEF compared with CTx improved PFS (INV mPFS 21.2 vs 4.2 months, HR [90% CI] 0.13 [0.04, 0.43]; IRC mPFS 19.3 vs 5.5 months; 0.18 [0.06, 0.61]) and OS (mOS 37.3 vs 13.1 months, 0.08 [0.01, 0.51]), as well as ORR (INV 66.7 v 42.9%; OR 2.67 [0.37, 19.56]; IRC 75.0 vs 42.9%; OR 4.00 [0.51, 31.38]). Grade ≥3 treatment-related AEs in METamp patients (≥15% in either arm, TEP+GEF vs CTx) were amylase or lipase increased (both 33.3% vs 0%), anemia, neutrophil or WBC count decreased (all 0 vs 28.6%). Conclusions TEP+GEF improved survival of patients with EGFR TKI-resistant NSCLC due to METamp. TEP + osmertinib is currently being investigated in patients with METamp, EGFR-mutant NSCLC with acquired EGFR TKI resistance (NCT03940703). Clinical trial identification NCT01982955. Editorial acknowledgement Medical writing assistance was provided by Lisa Jolly, Bioscript, Macclesfield, UK, and funded by Merck KGaA, Darmstadt, Germany. Legal entity responsible for the study Merck KGaA, Darmstadt, Germany. Funding Merck KGaA, Darmstadt, Germany. Disclosure K. Park: Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Clovis; Elli Lilly; Hanmi; ONO; Roche; Novartis. R.A. Soo: Honoraria (self): BMS, Celgene, Ignyta, Lilly, Merck, Novartis, Pfizer, Roche, Taiho, Takeda, Yuhan; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim. R. Bruns: Full / Part-time employment: Merck KGaA. J. Straub: Full / Part-time employment: Merck KGaA. A. Johne: Full / Part-time employment: Merck KGaA. J. Scheele: Full / Part-time employment: Merck KGaA. J.C-H. Yang: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech/Chugai, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono pharmaceutical, Daiichi Sankyo and AstraZeneca, Takeda Oncology, Blueprint Medicines, Hansoh Pharmaceu. Y-L. Wu: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim ; Advisory / Consultancy: Merck; Honoraria (self): Eli Lilly, Pierre Fabre, Pfizer, Sanofi. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background The standard of care for LA-NSCLC is a definitive concurrent chemoradiotherapy (CRT). In addition, durvalumab shows significant survival benefit as a consolidation therapy. However, the role of EGFR tyrosine kinase inhibitors (TKIs) in this setting has not been established, despite their efficacy in metastatic disease. The aim of this prospective phase II trial was to evaluate the efficacy and safety of induction gefitinib followed by CRT in EGFR-mutant LA-NSCLC. Methods Patients with unresectable stage III NSCLC harboring activating EGFR mutations received induction gefitinib monotherapy (250 mg/body) for 8 weeks. Patients whose disease had not progressed during induction therapy received cisplatin (40 mg/m2) and docetaxel (40 mg/m2) on days 1, 8, 29, and 36, and concurrent radiotherapy with a total dose of 60 Gy. The primary endpoint was 2-year overall survival (OS) rate. We assumed an expected 2-year OS rate of 85%; a rate of 60% was the threshold of the lower limit. Results Between 2011 and 2017, 20 patients (median age, 65.5 years; male/ female, 9/11; histology, all adenocarcinoma; stage IIIA/IIIB, 9/11; exon 19 / 21 mutations, 10/10) were enrolled. The overall response rate was 75.0% in the induction phase and 85.0% in the entire phase. The 1 and 2-year progression-free survival rates were 58.1% and 36.9%, respectively. The 2-year OS rate was 90% (95% confidence interval, 65.6-97.4), indicating this trial met the primary objective. Grade (Gr) 3 or worse adverse events (>10%) in the induction phase included transient AST elevation (25%) and ALT elevation (45%), and those in the CRT phase included neutropenia (64.7%) and febrile neutropenia (10.8%). In the 6-month follow-up period after completion of CRT, Gr > 2 radiation pneumonitis occurred in 11.8% of patients. The completion rate of the protocol therapy was 80%. No treatment-related death was observed. Conclusions This is the first prospective study to show favorable efficacy and tolerable safety of induction EGFR-TKIs in addition to standard CRT in EGFR-mutant LA-NSCLC. Further confirmatory research is warranted. Clinical trial identification UMIN000005086: 15/Feb/2011 jRCTs071180036: March/2019. Legal entity responsible for the study The authors. Funding LOGIK (Lung Oncology Group In Kyushu, Japan). Disclosure S. Saeki: Research grant / Funding (institution): Pfizer; Honoraria (institution): ONO; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Takeda. K. Hotta: Honoraria (self), Research grant / Funding (self), Relevant financial activities OUTSIDE the submitted work.: AstraZeneca; Honoraria (self), Relevant financial activities OUTSIDE the submitted work.: Nippon Kayaku. M. Yamaguchi: Honoraria (self): AstraZeneca; Honoraria (self): Daiichi Sankyo; Honoraria (self): Eli Lilly; Honoraria (self): Taiho. D. Harada: Honoraria (self), Relevant financial activities OUTSIDE the submitted work.: Chugai; Honoraria (self), Relevant financial activities OUTSIDE the submitted work.: MSD; Honoraria (self), Relevant financial activities OUTSIDE the submitted work.: Kyowa Hakko; Honoraria (self), Relevant financial activities OUTSIDE the submitted work.: ONO; Honoraria (self), Relevant financial activities OUTSIDE the submitted work.: Bristol-Myers Squibb; Honoraria (self), Relevant financial activities OUTSIDE the submitted work.: Eli Lilly; Honoraria (self), Relevant financial activities OUTSIDE the submitted work.: TAIHO; Honoraria (self), Relevant financial activities OUTSIDE the submitted work.: Boehringer Ingelheim; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution), Relevant financial activities OUTSIDE the submitted work.: AstraZeneca; Research grant / Funding (self), Relevant financial activities OUTSIDE the submitted work.: Novartis; Research grant / Funding (self), Relevant financial activities OUTSIDE the submitted work.: Kissei ; Research grant / Funding (self), Relevant financial activities OUTSIDE the submitted work.: Takeda. A. Bessho: Honoraria (self), Research grant / Funding (institution): AstraZeneca. K. Tanaka: Honoraria (self), Honoraria (institution), Research grant / Funding (self), Research grant / Funding (institution): Chugai; Honoraria (self), Honoraria (institution): AstraZeneca; Honoraria (self), Honoraria (institution): Taiho; Honoraria (self), Honoraria (institution): Pfizer; Honoraria (self), Honoraria (institution): MSD; Honoraria (self), Honoraria (institution): Eli Lilly; Honoraria (self), Honoraria (institution): Bristol-Myers Squibb; Honoraria (self), Honoraria (institution): Novartis; Honoraria (self), Honoraria (institution): Kyowa-Kirin; Honoraria (self), Honoraria (institution): AbbVie; Honoraria (self), Honoraria (institution), Research grant / Funding (self), Research grant / Funding (institution): ONO; Honoraria (institution): Daichi-Sankyo; Honoraria (institution), Research grant / Funding (self), Research grant / Funding (institution): Boehringer Ingelheim. K. Inoue: Honoraria (self): AstraZeneca. E. Ichihara: Honoraria (self): AstraZeneca; Research grant / Funding (institution): Eli Lilly. T. Sasaki: Honoraria (self): AstraZeneca. Y. Shioyama: Full / Part-time employment: FUJIFILM Corporation/FUJIFILM Medical Co. Ltd. K. Katsui: Full / Part-time employment: Tsuyama Chuo Hospital. J. Sasaki: Honoraria (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Chugai; Honoraria (self): MSD; Honoraria (self): Daiichi Sankyo; Honoraria (self): Shionogi; Honoraria (self), Research grant / Funding (self): Taiho; Honoraria (self): Kyowa Kirin; Honoraria (self), Research grant / Funding (self): ONO; Honoraria (self): Bristol-Myers Squibb; Research grant / Funding (self): Yakult. K. Kiura: Honoraria (self): AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Novartis; Honoraria (self), Research grant / Funding (self): Taiho; Honoraria (self), Research grant / Funding (self): Chugai; Honoraria (self), Research grant / Funding (self): Pfizer; Honoraria (self), Research grant / Funding (self): ONO; Honoraria (self), Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self): MSD; Honoraria (self), Research grant / Funding (self): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): Kyorin; Research grant / Funding (self): Nippon Kayaku. K. Sugio: Research grant / Funding (institution): MSD. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Analysis of ctDNA in operable NSCLC for the identification of patients at high risk of relapse could allow tailoring of adjuvant therapy with EGFR tyrosine kinase inhibitors (TKIs). We assessed whether tracking of EGFR mutations in plasma circulating tumor DNA (ctDNA) predicts relapse in completely resected EGFR-mutant NSCLC. Methods A prospective cohort of 45 EGFR-mutant stage I-IIIB NSCLC patients, all of whom underwent complete resection of their tumors, had plasma samples for ctDNA analysis taken post-surgery and in follow-up. Cobas EGFR Mutation Test (cobas) was used for tissue genotyping of the baseline tumor biopsy or surgical specimens, and droplet digital PCR (ddPCR) was performed to track the identified EGFR mutations in ctDNA. Results We identified EGFR exon 19 deletions (n = 23), L858R (n = 18), and L861Q (n = 4) mutations by cobas in pre-surgical tissue biopsies and/or surgical specimens, and used ddPCR assays for each EGFR mutation to measure ctDNA after surgery. Detection of ctDNA after complete tumor resection in 11 of 45 (24%) patients significantly predicted clinical relapse (hazard ratio [HR] 7.0, 95% confidence interval [CI] 2.13 to 22.68; log-rank p = 0.001). Multivariable analysis demonstrated that detection of ctDNA remained a significant predictor of clinical relapse after adjusting for clinical factors (HR 6.16, 95% CI 1.80 to 21.06; p = 0.004). Notably, ctDNA-based molecular relapse demonstrated a lead time of up to 8.1 months over clinical relapse. Conclusions Tracking of EGFR mutations in cfDNA following surgical treatment can identify NSCLC patients at high risk of relapse. Whether ctDNA monitoring could allow tailoring of adjuvant therapy with EGFR tyrosine kinase inhibitors will have to be determined in future clinical trials. Legal entity responsible for the study The authors. Funding AstraZeneca. Disclosure M. Filipits: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. M.J. Hochmair: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. A. Buder: Honoraria (self): AstraZeneca. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Epidermal growth factor receptor (EGFR) inhibitors are a standard treatment for various malignant tumors, especially in colon cancer and lung cancer. The most common adverse reaction of EGFR inhibitors is skin toxicity, including acneiform rash, xerosis, paronychial inflammation, pruritus, photosensitivity, and hair/eyelash alterations. Even though EGFR inhibitor-related skin adverse events (ERSEs) are predictive marker of EGFR inhibitors treatment survivals, those are frequently also the reason for premature termination of anti-EGFR therapy. It is therefore important to understand the mechanisms underlying the skin toxicities caused by EGFR inhibition to improve anti-EGFR–based cancer therapies and minimize debilitating side effects for patients. Methods Twelve patients' ERSEs skin biopsies which were treated with EGFR inhibitors were compared to same numbers of controlled skin biopsies those who did not use EGFR inhibitors. We evaluated Ki-67, EGFR, Melan-A, interleukin-17 (IL-17), and tumor necrosis factor-α (TNF-α) expression based on immunohistochemical (IHC) stains between 2 groups. Among them, five patients were treated with EGF ointment for ERSE. We also observed skin changes before and after EGF ointment. Results Control and ERSE group's Ki-67 expression of epidermis were 40.8% vs 21.2% (P = 0.015). EGFR presentation range of epidermis was 98.3% vs 84.6% in control and ERSEs group, respectively (P = 0.001). We could observe 14.2% vs 8.1% (P = 0.069) of Melan-A IHC stain. In the IL-17, ERSE group's IL-17 expression intensity (16.1) was higher than control group (9.8) (P = 0.038). Much higher TNF-α expression intensity (13.3) was also observed in ERSE group compared control group (7.9) (P = 0.037). After treatment with EGF ointment of 5 patients, values of Ki-67, EGFR, Melan-A, IL-17, and TNF-α were changed to 28%, 94%, 8.2%, 12.5 and 10, respectively. Conclusions Treatment with EGFR inhibitors decreased expression of Ki-67 and EGFR in the patients' dermis. This seems to lead to secondary inflammation of the skin. The treatment of EGF ointment for ERSEs is thought to normalize EGFR level and the inflammatory response to some extent. Clinical trial identification NCT02284139. Legal entity responsible for the study The authors. Funding Daewoong Pharmaceutical Company. Disclosure J.M. Kim: Full / Part-time employment: Daewoong pharmacy. J.E. Choo: Full / Part-time employment: Daewoong pharmacy. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Around 30% of non-small cell lung cancer (NSCLC) patients harbor sensitizing mutations in the epidermal growth factor receptor (EGFR) gene. Most common EGFR mutations are exon 19 deletions and EGFR-L858R, that comprise 85% of EGFR-mutated cases, and whose drug sensitivity profile is already known. However, rare EGFR mutations represent 10-15% of EGFR-mutated NSCLCs with diverse sensitivity to different EGFR inhibitors. Methods Scientific literature and database search were conducted to identify pathogenicity and drug sensitivity of rare and common EGFR mutations. Structured data were uploaded in the database of the RealTime Oncology Treatment CalculatorTM (Calculator) to enable automated interpretation of variants. A structured database of clinical trials testing EGFR targeted therapies was also established for matching trial search. Molecular diagnostics of an NSCLC patient were performed (next-generation sequencing of 58 genes and FISH analyses) for therapeutic decision support. A rare EGFR mutation was identified (H773_V774insNPH) and automated classification was carried out using the Calculator. Results The Calculator is now able to automatically classify the most frequent 100+ EGFR mutations based on structured scientific evidence and by using a proprietary algorithm it prioritizes the associated EGFR inhibitors. The system can also handle complex molecular profiles so that resistance-associated alterations (e.g. KRAS mutation or ALK translocation) can be identified and optimal targeted therapies can be suggested. Matching clinical trials can be listed within seconds based on histology, biomarker criteria, compounds, previous therapies, etc. The NSCLC patient with the rare EGFR mutation (who had quickly progressed on gefitinib) had stable disease for 2 years on afatinib, which compound was suggested by the Calculator. Gefitinib was negatively associated with the molecular profile. Conclusions This case clearly demonstrates that knowledge on the drug sensitivity profile of the exact mutation is very important for the therapeutic decision. We demonstrate that RealTime Oncology Treatment CalculatorTM is an efficient tool for evidence-based prioritization of EGFR inhibitors even in the case of rare EGFR variants. Legal entity responsible for the study Oncompass Medicine Hungary Ltd. Funding National Research, Development and Innovation Office, National Oncogenomics and Precision Oncotherapy Program (NVKP_16-1-2016-0005), WESPED (KFI_16-1-2016-0048). Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Brain tumours are among "hard-to treat" world malignancy with the median survival time of 15 months for the most aggressive form - Glioblastoma multiforme (GBM). It is extremely complex and heterogeneous brain cancer, characterized by rapid progression, infiltration and therapeutic resistance. Currently, many trials for target therapy are focused on understanding the molecular heterogeneity of GBM and designing molecules that inhibit most common genetic alterations. Methods In the present study, somatic copy number variations (CNVs) in critical signalling genes suitable for future target therapy are examined among Bulgarian patients. Fresh brain biopsies were collected from patients with primary and secondary GBM. Genomic DNA was isolated and CNVs were analysed by Multiplex ligation – dependent probe amplification (MLPA). Results CDKN2A deletion is the most frequent genetic alteration (78%) among Bulgarian patients with GBM. The loss of this gene is a progression-associated genetic marker. Nearly 60% of GBM patients showed EGFR amplification. It is a prognostic and predictive marker and some patients with this aberration are suggested to respond better to EGFR inhibitors in combination therapy. PTEN deletion is another common event with the incidence rate of 33% and its loss corelates with the choice of mTOR and MEK inhibitors, as well as, the resistance to some EGFR inhibitors. TP53 deletion was found in only 11% of the analysed patients which is a positive marker and the presence of wild-type TP53 is targeted by a MDM2 inhibitors. In addition, MDM2 amplification was observed in one patient and this event also serve as a potential target by MDM2 inhibitors.Amplification in PDGFRA is observed in one patient. Depending on the status of other receptor tyrosine kinases, it could be targeted by PDGFR inhibitor and is also suggested to be a poor prognostic marker. Conclusions Personalized treatment, customized for an individual patient genetics, has the potential to improve the therapy response. CNVs data could be useful for designing more effective personalized therapy. This is a small study on CNVs with potentially targeted therapeutic application in GBM for Bulgaria and recruitment of more patients is in progress. Legal entity responsible for the study The authors. Funding Medical University Sofia, Grant number D-127/2019. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Extensive use of NGS profiling in precision oncology is uncovering a staggering amount of novel alterations in the sequenced genes. Strikingly, the number of variants of uncertain significance (VUS) increases linearly with the addition of sequenced samples. While some of the VUS are inconsequential mutations many other VUS lead to activation of the proteins and are therefore involved in oncogenicity and may cause drugs resistance. These new activating mutations can also serve as novel drug targets. Methods We report here a method for functional annotation of these VUS as well as their sensitivity to targeted therapy. The system is based on rapid synthesis of the mutations and expression of the mutated protein together with fluorescently labeled reporters in a cell-based assay. The assay allows the accurate measurement of signaling pathway activation using fluorescence imaging coupled with high content image analysis. This process can also be performed with targeted agents to determine the sensitivity of the mutation. The output of the system is the level of activity of the mutant relative to a mutation with known activity in the same gene. Results Our results show that this method is able to accurately identify known driver mutations in 10 different oncogenes spanning 4 major cancer associated signaling pathways as well as over 100 different VUS in these genes. We also extend this analysis and show that the method correctly recapitulates differential sensitivity of EGFR mutations to 2nd and 3rd generation EGFR inhibitors and that different classes of BRAF mutations differ in response to specific inhibitors. Finally, we establish the importance of concurrent mutations in the response to EGFR inhibitors. Conclusions Taken together, this system provides crucial information for the development of new targeted agents and establishes an experimental tool both for patient stratification into clinical trials and patient treatment. Legal entity responsible for the study The authors. Funding NovellusDx. Disclosure Z. Barbash: Full / Part-time employment: NovellusDx. G. Tarcic: Full / Part-time employment: NovellusDx. D. Haham: Full / Part-time employment: NovellusDx. L. Hafzadi: Full / Part-time employment: NovellusDx. R. Zipor: Full / Part-time employment: NovellusDx. S. Barth: Full / Part-time employment: NovellusDx. A. Aizenman: Full / Part-time employment: NovellusDx. [ABSTRACT FROM AUTHOR]

Background Despite a primary benefit, almost all patients (pts) develop acquired resistance to EGFR TKIs. Some mechanisms were related to the selective pressure of the different generations (G) EGFR TKIs, but the complete alteration profile at resistance remains to be elucidated. Methods Metastatic NSCLC pts who performed a tissue and plasma biopsy at EGFR TKI progression, and optionally before, were identified from the prospective MATCH-R trial (NCT02517892). Targeted next-generation sequencing (NGS, 74 to 82 genes), comparative genomic hybridization (CGH), whole-exome sequencing (WES), and RNA sequencing (RNA-Seq) were performed on the tissue. All molecular oncogenic alterations were classified as definitive/potential resistance mechanism or concomitant genetic alterations using OncoKB and Cancer Genome Interpreter. Results Among 62 pts included, tissue analysis at TKI progression was successful with NGS (94%), CGH (76%) and WES+RNA-Seq (53%). In the post 1st-2nd G EGFR TKI cohort (31 pts) the most frequent resistance alteration was p.T790M (n = 23, 74%). EGFR amplification (amp) was found in 7 (23%) pts and off-target mutations (mut) at resistance in 9 (29%, 2 KRAS, 2 JAK2, 1 PIK3CA, and 1 MET). Median PFS to EGFR TKI was 17 months (mo) for the pts with p.T790M as the only resistance mechanism vs 8 mo for the other resistance profiles (HR 2.42 [95% CI, 1.04-5.65]; p = 0.028). In the post 3rd G cohort (31 pts), acquired resistance alterations were mostly on-target (n = 12, 39%): 9 p.C797S, 2 p.L718Q and 1 EGFR amp. Off-target resistance alterations were found in 11 (35%) tumors: 5 fusions involving oncogenes (16%, RET, BRAF, ALK, and FGFR3), 2 BRAF p.V600E (6%), then MET amp, HER2 amp, KRAS mut, and PIK3CA mut in 1 pts (3%). p.T790M loss (54%) was associated with a shorter time to osimertinib discontinuation vs maintained (median 13 vs 22 mo; HR 2.16 (95% CI, 1.00-4.73); p = 0.046). More than one resistance mechanism was found in 12 (39%) and 14 (45%) pts in the post 1st-2nd and 3rd G cohort, respectively. Conclusions Genetic alteration landscape at EGFR TKIs progression is complex and heterogeneous since more than one resistance alteration was recognized in 42% of pts. Combination strategy might be needed. Legal entity responsible for the study Gustave Roussy, Cancer Campus. Funding Gustave Roussy, Cancer Campus. Disclosure Y. Loriot: Honoraria (self): Roche, MSD, Astellas, Janssen, AstraZeneca, BMS, Seattle Genetics, Sanofi, Clovis, Pfizer; Honoraria (institution): Roche, MSD, Astellas, Janssen, AstraZeneca, BMS, Seattle Genetics, Sanofi, Clovis, Incyte, Pfizer; Research grant / Funding (institution): Roche, MSD, Sanofi; Travel / Accommodation / Expenses: Roche, MSD, Janssen, AstraZeneca, Seattle Genetics; Licensing / Royalties: Pending patent (USA 62/455211, Europe 17209098.7). D. Planchard: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, MedImmune, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, AbbVie, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, MedImmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo; Travel / Accommodation / Expenses: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim , Roche, Merck, Novartis, prIME Oncology, Pfizer. S. Michiels: Advisory / Consultancy, Punctual statistical advice : IDDI Belgium, Janssen Cilag France; Advisory / Consultancy, Data and Safety Monitoring Member: Hexal, J&J, Ipsen, Neovacs, Genticel, Mabxience, Steba, IQVIA, Roche, Sensorion, Biophytis. C. Massard: Advisory / Consultancy: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, Novartis, Pfizer, Roche, Sanofi, Orion; Principal/sub-Investigator of Clinical Trials for AbbVie, Agios Pharmaceuticals, Amgen, Argen-X; Research grant / Funding (institution): AstraZeneca, BMS, Boehringer Ingelheim, Janssen-Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Non-remunerated activity/ies: AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Johnson & Johnson, Lilly, MedImmune, Merck, NH TherAGuiX, Pfizer, Roche. J-C. Soria: Advisory / Consultancy: AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche/Genentech, Sanofi, Servier, Symphogen, and Takeda; Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options: AstraZeneca and Gritstone. F. André: Research grant / Funding (institution): NVS, AZ, Roche, Daiichi, Lilly, Pfizer. G. Vassal: Advisory / Consultancy, Non-remunerated activity/ies: AstraZeneca, Bayer, BMS, Celgene, Incyte, Ipsen, Lilly, MSD, Merck, Pierre-Fabre, Novartis, Pfizer, Roche/Genentech, Servier, Takeda. B. Besse: Research grant / Funding (institution): AbbVie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, Ipsen, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, PharmaMar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Inframe insertions in exon 20 of the epidermal growth factor receptor (EGFR) gene are oncogenic drivers in non-small cell lung cancer (NSCLC). However, unlike more common EGFR mutations, low frequency EGFR exon 20 insertions are resistant to clinically approved EGFR inhibitors and are associated with poor patient prognosis. There is an unmet clinical need to identify novel therapies that will be effective for patients with EGFR exon 20 insertions. Methods Cell viability of three patient-derived NSCLC cell line models harbouring EGFR exon 20 insertions, CUTO14 (A767_V769dupASV), CUTO17 (N771_H773dupNPH) and CUTO18 (S768_D770dupSVD) was assessed after treatment with a chemical compound screen targeting cancer-associated pathways. Western blotting was used to probe cell signalling following dasatinib treatment. Mutant SRC expression constructs were introduced into cell lines via lentiviral transduction and depletion of endogenous SRC levels was achieved using RNAi. Models of acquired drug resistance were developed by long-term drug exposure. Results Out of 58 screened compounds, the tyrosine kinase inhibitor dasatinib was a shared hit across all EGFR exon 20 insertion models and was superior to the EGFR inhibitor gefitinib in cell viability and apoptosis assays. Dasatinib sensitivity was rescued by expression of a gatekeeper mutant SRC that does not bind dasatinib, whilst all models were sensitive to RNAi-mediated depletion of endogenous SRC expression. Importantly, models of acquired dasatinib resistance maintain sensitivity to poziotinib, an EGFR inhibitor that can target EGFR exon 20 insertions. Similarly, dasatinib effectively inhibits cell viability of a model of acquired resistance to poziotinib, indicating two independent, targetable signalling nodes. Combined treatment with dasatinib and poziotinib prevented the emergence of drug resistance. Conclusions EGFR exon 20 insertion lung cancer models are sensitive to inhibition of parallel SRC signalling via dasatinib treatment. In a patient population with limited therapeutic options, an upfront rational combination of dasatinib with EGFR inhibitors that target EGFR exon 20 insertions has the potential to achieve durable responses. Legal entity responsible for the study Paul Huang. Funding Institute of Cancer Research, Cancer Research UK. Disclosure R. Doebele: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Licensing / Royalties: Genentech/Roche; Advisory / Consultancy, Travel / Accommodation / Expenses, Licensing / Royalties: Ignyta; Licensing / Royalties: Foundation Medicine; Advisory / Consultancy, Licensing / Royalties: Loxo Oncology; Advisory / Consultancy: Bayer; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Licensing / Royalties: Rain Therapeutics; Honoraria (self), Advisory / Consultancy: Takeda/Millenium; Licensing / Royalties: Abbot Molecular. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background The treatment of HNSCC in Taiwan is still very challenging. Betel-nuts chewing contributes to (1)strong iinvasion & angiogenesis; (2)poor response to chemotherapy, radiation, and EGFR inhibitors. In our previous studies, betel-nuts related TW2.6 (p53 defective mutation, p16 loss, BCL2+) was resistant to all traditional therapies. PI3K alpha inhibitor, AKT inhibitor, FGFR inhibitor, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, maybe through the inhibition of mesenchymal transformation & PI3K/AKT /mTOR signaling and the modulation of stemness & PD1/PDL1 pathway. PLK1 overexpression is prominent in HNSCC and related to poor prognosis. In our previous animal study for esophageal cancer, PLK1 inhibitor could induce p-Histone3 and synergize with radiation to further apoptosis.(Chen in Strahlenther Onkol 2016) Purpose We try to find out PLK1 inhibitor use for betel-nus related HNSCC. Methods Polo-like kinase 1 inhibitor(volasertib) was tested on TW2.6 to evaluate (1)in vitro drug sensitivity; (2)synergistic effects with some therapies by MTT, colony formation, flow cytometry, and western blotting. Results Combination of volasertib and radiation significantly enhanced radiation-induced death. The flow-cytometry revealed volasertib and radiation resulted in significant G2/M arrest. Western blotting also showed volasertib and radiation combination increased p-Histone3, p-CDK1, & cyclin B levels and apoptosis. TW2.6 was resistant to olaparib(PARP inhibitor), volasertib, or radiation alone; however, TW2.6 was sensitive again to (1)volasertib with radiation and (2)olaparib & volasertib. Conclusions PLK1 inhibition might be combined with radiation and other DNA damage response interventions in betel-nuts related HNSCC in Taiwan. Further predictive and dynamic biomarkers should be explored; however, PLK1 inhibitor will induce reduced immune cell death(ICD). [ABSTRACT FROM AUTHOR]

Background Although osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) is approved for first-line (1L) treatment of EGFR -mutated metastatic non-small cell lung cancer (NSCLC) and second-line (2L) treatment of pts who acquired the EGFR T790M mutation during 1L therapy with other TKIs, treatment options after progression on TKIs are limited; platinum-doublet chemotherapy (PT-DC) remains the standard therapy, including for pts with no T790M mutation. Nivolumab (NIVO), a fully human IgG4 programmed death-1 immune checkpoint inhibitor antibody, is approved worldwide for the treatment of advanced NSCLC on or after prior chemotherapy. CheckMate 722 (NCT02864251) will compare the efficacy and safety of NIVO + PT-DC vs PT-DC alone in pts with EGFR -mutated metastatic or recurrent NSCLC progressed on 1L or 2L EGFR TKI therapy. Methods This open-label phase 3 trial is enrolling ∼500 adults with confirmed stage IV or recurrent EGFR -mutated NSCLC progressed on prior EGFR TKI therapy. Patients are eligible if they progressed on 1L first- or second-generation TKIs with no T790M mutation or 1L or 2L osimertinib regardless of T790M status. Pts with CNS metastases that are adequately controlled and/or treated during screening are eligible. Pts are randomized 1:1 to NIVO (360 mg Q3W) + PT-DC (pemetrexed 500 mg/m2 Q3W + cisplatin 75 mg/m2 or carboplatin AUC 5 or 6 Q3W), or PT-DC alone; pts without disease progression after 4 cycles will receive NIVO + pemetrexed or pemetrexed, respectively, until disease progression or unacceptable toxicity. Randomization is stratified by programmed death ligand-1 status (≥ 1% or < 1%/not evaluable), presence or absence of brain metastases, smoking history and prior osimertinib treatment. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, objective response rate, duration of response, and PFS rates at 9 and 12 months. Results The estimated primary completion date is September 2019. [ABSTRACT FROM AUTHOR]