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Purpose: This study has a purpose to investigate the side effects of three EGFR-TKIs targeted therapeutic agents (gefitinib, erlotinib, and afatinib) and all-cause mortality in patients with metastatic lung cancer., Methods: We performed a prospective cohort study. We selected all patients with newly diagnosed metastatic lung cancer between January and November 2019. Main exposure was daytime versus nighttime use of targeted EGFR TKIs. The study outcome was a symptom change using the mobile application, and all-cause mortality between January 2019 and March 2023., Results: Among the 87 study participants, 35 (40%) took their medication at night. Among the 87 study participants, 35 (40%) took their medication at night. At 6 weeks of treatment, acne (1.36; 95% confidence interval [CI] 1.09, 1.64; p for interaction = 0.04) and dry skin (1.35; 95% CI 1.09, 1.61, p for interaction = 0.01) in the day group showed a much increase from baseline compared to the night group. In contrast, the night group reported greater reductions in lung cancer-related symptoms from baseline compared to the day. During follow-up (median 43 months), the night group had a lower risk of all-cause death than the day group, especially in younger patients (adjusted hazard ratio = 0.34; 95% CI 0.13, 0.87)., Conclusions: The group taking EGFR-TKIs at night experienced fewer side effects and had longer overall survival compared to the day group. Clinicians should consider recommending that lung cancer patients take their once-daily oral anticancer drugs in the evening rather than the morning to improve treatment outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The new second-generation tyrosine kinase inhibitors (TKIs) have superior survival outcome and worse toxicity profile when compared with first-generation TKIs according to the results of clinical trials. However, there are limited studies that investigate the efficacy and safety of the new generation TKIs in real-world patients. Thus, we aimed to compare the efficacy and safety of the afatinib, an irreversible inhibitor of ErbB family receptor, and first-generation TKIs in real-world patients., Materials and Methods: We included advanced nonsmall cell lung cancer (NSCLC) patients who had EGFR exon 19del mutation and treated with afatinib or first-generation TKIs as upfront treatment between 2016 and 2020. All patient's information was collected retrospectively. The study cohort was divided as afatinib arm and erlotinib/gefitinib arm., Results: A total of 283 patients at the 24 oncology centers were included. The 89 and 193 of whom were treated with afatinib and erlotinib/gefitinib, respectively. After 12.9 months (mo) of follow-up, the median PFS was statistically longer in the afatinib arm than erlotinib/gefitinib arm (19.3 mo vs. 11.9 mo, p: 0.046) and the survival advantage was more profound in younger patients (< 65 years). The 24-mo overall survival rate was 76.1% and 49.5% in the afatinib arm and erlotinib/gefitinib arm, respectively. Although all-grade adverse event (AE) rates were similar between the two arms, grade 3-4 AE rates were higher in the afatinib arm (30.7% vs. 15.2%; p: 0.004)., Discussion: In our real-world study, afatinib has superior survival outcomes despite worse toxicity profile as inconsistent with clinical study results and it is the good upfront treatment option for younger patients and elderly patients who have good performance status.

Background: Lung cancer is most common among older individuals. However, polypharmacy and comorbidities, which are also more common in older individuals, can limit treatment options. Previous studies suggest that afatinib can be used safely and effectively in elderly patients. This study investigated the anti-tumour activity and safety profile of first-line afatinib in previously-untreated elderly Japanese patients with EGFR mutation-positive non-small cell lung cancer (NSCLC)., Methods: This was a single-arm, open-label, phase II study, performed in multiple centres in Japan. Previously untreated patients, aged ≥75 years, with EGFR mutation-positive (Del19 or L858R) advanced NSCLC were treated with afatinib 40 mg until disease progression or unacceptable toxicity. Adverse events (AEs) were managed with protocol-defined dose adjustments. The primary endpoint was objective response rate (ORR) by central review., Results: In total, 38 patients received at least one dose of afatinib, and 37 were evaluable for response. Median age was 77.5 years (range 75-91), all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 60.5% had Del19-positive disease. Median follow-up was 838 days. ORR was 75.7% (2 complete responses and 26 partial responses). Median progression-free survival was 14.2 months (95% confidence interval [CI], 9.5-19.0). Median overall survival (OS) was 35.2 months (95% CI, 35.2-not reached); the 2-year OS rate was 78.3%. The most common grade 3/4 treatment-related AEs (TRAEs) were diarrhoea (28.9%), paronychia (23.7%), and rash/acne (15.8%). Dose reductions due to TRAEs were reported in 78.9% of patients, and eight (21.1%) patients discontinued afatinib due to TRAEs. No treatment-related deaths were reported., Conclusion: Although dose adjustments were relatively common in this small group of Japanese patients aged ≥75 years with EGFR mutation-positive NSCLC, discontinuation occurred much less frequently, and most patients were able to stay on treatment for well over a year. Further, afatinib was associated with high response rates and prolonged PFS and OS., Trial Registration: The trial is registered with Japan Registry of Clinical Trials (JRCT) as trial number 031180136 (date of initial registration: 19 February 2019), and the University Hospital Network (UMIN) as trial number 000017877 (date of initial registration: 11 June 2015).

Introduction Afatinib is used to treat patients with advanced non-small cell lung cancer (NSCLC) harboring common EGFR mutations; however, the clinicopathological factors that predict this drug's effectiveness in real-world settings remain unclear. We therefore evaluated the effectiveness of afatinib in such patients and assessed potential prognostic factors. Methods We retrospectively investigated patients with NSCLC who received first-line afatinib between July 2014 and August 2018. Variables (including sex, age, performance status, neutrophil-to-lymphocyte ratio, EGFR genotype, smoking status, clinical stage prior to treatment [stage IV vs.. postoperative recurrence], presence or absence of brain metastases, body surface area, any afatinib dose reductions, and afatinib starting dose [40 vs.. 20 or 30 mg]) were subjected to a Cox proportional hazards regression model to estimate progression-free survival (PFS). Results Forty-eight patients with a median age of 67 years were included; the objective response rate was 62.5% (30 patients). The median PFS was 14.1 months; the PFS periods were 11.8 and 15.9 months for patients receiving 40 mg versus 20-30 mg of afatinib (P = 0.41), respectively, and were 14.5 and 13.8 months for patients who required afatinib dose reduction and those who did not, respectively (P = 0.80). The PFS tended to be longer in patients without brain metastases (albeit not significantly). Ultimately, no significant predictive values for PFS were identified. Conclusions Afatinib is effective for patients with NSCLC harboring common EGFR mutations irrespective of their clinicopathological backgrounds. A direct comparison of afatinib and osimertinib in treatment-naïve patients is warranted to determine the optimal standard of care.

Background Osimertinib is one of the first-line treatments for advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. However, the occurrence rate of osimertinib-induced interstitial lung disease (ILD) is particularly high in Japanese patients and little information on subsequent cancer treatment options after recovery from osimertinib-induced ILD is currently available. Thus, this study aims to determine the safety and efficacy of afatinib for the treatment of NSCLC following osimertinib-induced ILD. Methods We retrospectively investigated the clinical courses of all NSCLC patients with EGFR mutations at our facility between August 2018 and September 2019, who received osimertinib as first-line treatment and were subsequently treated with afatinib after developing osimertinib-induced ILD. Results Forty-two patients received osimertinib treatment at our facility during the study period, and four patients received afatinib after developing osimertinib-induced ILD. All events of ILD improved either spontaneously or with steroid therapy before the initiation of afatinib. For the four patients who were retrospectively reviewed, the overall response rate to afatinib therapy was 75%, and the disease control rate was 100%. During the study period, no ILD recurrence was observed in any of the four patients. Conclusions According to our study findings, afatinib treatment after osimertinib-induced ILD is considered safe and effective and it can be used as one of the treatment options for NSCLC following osimertinib-induced ILD.

Background: Only a few randomized trials directly compared the relative efficacy of tyrosine kinase inhibitors (TKIs) in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), and most trials comprised selected series from Asian populations. Therefore, the aim of this study was to assess the overall survival (OS) of advanced EGFR-mutated NSCLC in a large white population and to evaluate variation between different TKIs and identify predictors of survival., Patients and Methods: Information about clinical characteristics, treatment, and survival for 873 patients with stage IV EGFR + NSCLC, diagnosed from 2015 through 2017, was derived from the Netherlands Cancer Registry. OS was evaluated by actuarial analysis and multivariable Cox regression. Prognostic factors are reported as hazard ratios and 95% confidence intervals., Results: A total of 596 (68%) patients received first-line treatment with regular TKIs, providing a median survival of 20.2 months. Forty-five percent of patients were 70 years and older, and 54% of patients had distant metastasis in multiple organs. In the multivariate analysis, survival was significantly worse for men, and patients with higher age, poorer performance, and ≥ 3 organs with metastasis. Compared with erlotinib, OS was worse for gefitinib users (adjusted hazard ratio, 1.30; 95% confidence interval, 1.02-1.64), predominantly in patients with brain metastasis., Conclusion: Dutch patients with EGFR-mutated NSCLC who received first-line treatment with regular TKIs have a median OS of 20.2 months in a nationwide real-world cohort. In patients with brain metastasis, erlotinib showed superior results compared with gefitinib and was similar to afatinib., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We constructed a data set of EGFR-mutant non-small-cell lung carcinoma (NSCLC) patients, and compared the overall survival of first-generation (1G), and second-generation (2G) EGFR-tyrosine kinase inhibitors (TKIs) in clinical practice using a propensity score. We reviewed the clinical data of consecutive EGFR-mutated NSCLC patients who received EGFR-TKI therapy between January 2008 and August 2017 at 11 institutions in Japan. The primary endpoint was overall survival (OS). When comparing OS between 1G and 2G EGFR-TKIs, propensity score analyses were performed using 2 methods: matching and inverse probability of treatment weighting (IPTW). (Clinical Trial information: UMIN000030121) In total, 1400 patients from 11 institutions were enrolled in this study, and the data from the 1366 patients who received only EGFR-TKI therapy were analyzed (gefitinib [GEF], N = 732; erlotinib [ERL], N = 416; afatinib, N = 218). Median OS times (months [95%CI]) were 29.7 [27.5-33.5] in the 1G group (gefitinib, 32.0 [28.1-35.8]; erlotinib, 27.5 [23.9-31.7]), and 38.6 [32.2-NR] in the 2G group (afatinib), respectively. The trend of longer OS for afatinib against 1G EGFR-TKIs remained, even after adjusted by propensity score. (unadjusted, hazard ratio [HR] 0.676, P = .0023; adjusted by IPTW, HR 0.685 P < .0001; adjusted by matching, HR 0.725, P = .0418). Exploratory analysis showed that OS using the 2G EGFR-TKI was superior to that of the 1G EGFR-TKIs, suggesting the potential of sequential therapy of 2G EGFR-TKI followed by osimertinib. (HR 0.419, P = .0519) Real-world data analysis using 1354 data records, using propensity scoring, indicated that 2G EGFR-TKI had a trend of longer OS compared with 1G EGFR-TKIs., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Tyrosine-kinase inhibitors (TKIs) have become the cornerstone treatment of patients with non-small cell lung cancer that harbor oncogenic EGFR mutations. The counterpart of these drugs is the financial burden that they impose, which often creates a barrier for accessing treatment in developing countries. The aim if the present study was to compare the cost-effectiveness of three different first and second generation TKIs., Methods: We designed a retrospective cost-effectiveness analysis of three different TKIs (afatinib, erlotinib, and gefitinib) administered as first-line therapy for patients with NSCLC that harbor EGFR mutations., Results: We included 99 patients with the following TKI treatment; 40 treated with afatinib, 33 with gefitinib, and 26 with erlotinib. Median PFS was not significantly different between treatment groups; 15.4 months (95% CI 9.3-19.5) for afatinib; 9.0 months (95% CI 6.3- NA) for erlotinib; and 10.0 months (95% CI 7.46-14.6) for gefitinib. Overall survival was also similar between groups: 29.1 months (95% CI 25.4-NA) for afatinib; 27.1 months (95% CI 17.1- NA) for erlotinib; and 23.7 months (95% CI 18.6-NA) for gefitinib. There was a statistically significant difference between the mean TKIs costs; being afatinib the most expensive treatment. This difference was observed in the daily cost of treatment (p < 0.01), as well as the total cost of treatment (p = 0.00095). Cost-effectiveness analysis determined that afatinib was a better cost-effective option when compared with first-generation TKIs (erlotinib and gefitinib)., Conclusion: In our population, erlotinib, afatinib, and gefitinib were statistically equally effective in terms of OS and PFS for the treatment of patients with advanced EGFR-mutated NSCLC population. Owing to its marginally increased PFS and OS, the cost-effectiveness analysis determined that afatinib was a slightly better cost-effective option when compared with first-generation TKIs (erlotinib and gefitinib).

Background: Epidermal growth factor receptor (EGFR)-sensitizing mutation, exon 19 deletion consists of several molecular variants. Influences of these variants on clinical response to EGFR tyrosine kinase inhibitors remain elusive., Methods: West Japan Oncology Group 8114LTR is a prospective, multi-institutional biomarker study. Treatment naïve, advanced non-small-cell lung cancer patients with EGFR-sensitizing mutation received afatinib monotherapy. We conducted a preplanned subset analysis of patients harboring exon 19 deletion. Tumor tissue exon 19 deletion molecular variants were identified by blocking-oligo-dependent polymerase chain reaction (PCR) and by Luminex Technology. Plasma cfDNA was also obtained before and after the treatment and EGFR mutations were detected with multiplexed, pico-droplet digital PCR assay., Results: Among 57 registered patients, twenty-nine patients were exon 19 deletion. Tissue DNA and cfDNA were available in 26 patients. Among the detected seven molecular variants, the most frequent was p.E746&#95;A750delELREA (65.4%). According to the various classifications of molecular variants, twenty one (80.8%) were classified into 15-nucleotide deletion, one (3.8%) into 18-nucleotide deletion, and four patients (15.4%) into other insertion/substitution variant subgroups. The patient subgroup with 15-nucleotide deletion showed significantly longer progression-free survival than patients in other mixed insertion/substitution variant subgroup (p = 0.0244)., Conclusions: The clinical significance of molecular variants of exon 19 deletion on the first line afatinib monotherapy is reported here for the first time. Further investigation is needed for development of better therapeutic strategies., Trial Registration: This trial was registered at UMIN Clinical Trials Registry at 2014/12/4 (UMIN000015847).

Aim: Acquired resistance to EGFR tyrosine kinase inhibitors is inevitable in non-small-cell lung cancer. To inform subsequent treatment decisions, we retrospectively assessed therapies following afatinib in Japanese patients from LUX-Lung 3. Patients & methods: LUX-Lung 3 was a randomized, open-label, Phase III study of afatinib versus cisplatin/pemetrexed in treatment-naive patients with EGFR mutation-positive ( EGFR m + ) advanced lung adenocarcinoma. Results: Among 47 Japanese patients who discontinued first-line afatinib, 91/81/62% received ≥one/two/three subsequent therapies. The most common second-line therapies were platinum-based chemotherapy (38%) and a first-generation EGFR tyrosine kinase inhibitor (17%). Median overall survival (afatinib vs cisplatin/pemetrexed) was 47.8 versus 35.0 months (not significant). Conclusion: First-line afatinib does not appear to diminish suitability for subsequent therapies in EGFR m + non-small-cell lung cancer.

Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were developed to target the EGFR T790M resistance mutation in non-small cell lung cancer (NSCLC) patients resistant to first- or second-generation EGFR-TKIs. To investigate the efficacy of afatinib treatment for EGFR T790M-positive NSCLC patients showing resistance to osimertinib and alterations in somatic mutations and tumor mutation burden (TMB) in plasma circulating tumor DNA (ctDNA) during afatinib treatment, we conducted a prospective study using Cancer Personalized Profiling by deep Sequencing (CAPP-Seq). Nine NSCLC patients with EGFR T790M mutation who showed resistance to third-generation EGFR-TKIs were enrolled in this study and treated with afatinib. Plasma samples were collected before treatment, 4 weeks after treatment, and at disease progression. The mutation profile and TMB in plasma ctDNA were analyzed by CAPP-Seq. The objective response rate and median progression-free survival associated with afatinib were 0% and 2.0 months, respectively. The C797S mutation-mediated resistance to osimertinib was observed in one patient and following afatinib treatment in two patients; the C797S mutations occurred in the same allele as the T790M mutation. After afatinib treatment, afatinib-sensitive mutant alleles, such as ERBB2, and TMB decreased. We have demonstrated that detection of mutant allele frequency and TMB of ctDNA by CAPP-Seq could help determine the effectiveness of and resistance to afatinib. Although afatinib monotherapy for T790M-positive NSCLC resistant to osimertinib was less effective, the action for multiclonal mutant alleles and TMB might contribute to further treatment strategy.

Objectives: Clinical trials with first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) reported severe adverse events (SAEs) in 6%-49% of patients with EGFR-mutated non-small cell lung cancer. This study describes incremental healthcare resource utilization (HRU) and costs associated with real-world management of AEs in this population, with a focus on SAEs., Materials and Methods: Patients receiving erlotinib, gefitinib, or afatinib as first-line (1L) monotherapy were identified from IQVIA™ Real-World Data Adjudicated Claims-US database (04/01/2012-03/31/2017). Relevant AEs were selected from corresponding prescribing information; SAEs were identified from hospitalization claims. HRU and cost per-patient-per-month (PPPM) were assessed during 1L treatment and compared for patients with and without each AE using multivariate Poisson and linear regression, respectively, adjusting for baseline characteristics., Results: Of 1646 patients, 86.9% were treated with erlotinib, 12.1% with afatinib, and 1.0% with gefitinib. In 1L, 12.2% of patients had ≥1 acute SAE (220.1/1000 patient-years). Patients with any SAE had higher PPPM costs than patients without SAEs (cost difference = $4700, p < 0.001). Incremental costs ranged from $2604 PPPM for diarrhea to $10,143 PPPM for microangiopathic hemolytic anemia (MAHA), and were statistically significant for all SAEs (all p < 0.001) except MAHA (p < 0.0528). Patients with any SAEs had higher rates of HRU relative to patients without SAEs (hospitalization rate ratio = 6.15; outpatient visits rate ratio = 1.21; all p < 0.001)., Conclusion: More than one-tenth of patients experienced SAEs, resulting in sizeable economic burden with respect to HRU and costs. EGFR-TKIs with more favorable safety profiles may reduce the burden of managing this population., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer has been successfully treated with tyrosine kinase inhibitors (TKIs). Acquired resistance becomes a tough issue when patients fail to respond to the third-generation TKI osimertinib. This study aimed to report a case baring acquired EGFR L858R/L718Q mutation in the central nervous system induced by osimertinib, which was successfully overcome using afatinib., Case Presentation: A 65-year-old female patient was diagnosed with stage IV non-small-cell lung adenocarcinoma with synchronic brain metastasis in February 2015. Before and during treatment, 416 tumor-related genes were monitored dynamically by liquid biopsies using next-generation sequencing, and the treatment strategy was decided according to the gene status. At baseline, an EGFR L858R mutation in exon 21 was detected, so treatment with icotinib was started. After 8 months, she experienced disease progression with leptomeningeal metastasis and switched to osimertinib based on an acquired EGFR T790 M mutation. After 9 months, her disease progressed and an EGFR L718Q mutation was found in the cerebrospinal fluid. The patient was then challenged with afatinib, and her disease was under control for 4 months. In January 2017, the patient passed away, with an overall survival time of 23 months, 15 months after leptomeningeal metastasis., Conclusion: The acquired EGFR L718Q mutation in the cerebrospinal fluid resulted in subsequent resistance to osimertinib and could be partly overcome using afatinib, indicating a promising treatment option in the clinic.

Background: Afatinib is an irreversible ErbB family blocker that improves progression-free survival (PFS) of advanced EGFR-mutant lung adenocarcinoma compared to chemotherapy. However, afatinib leads to more adverse events than first-generation EGFR inhibitors. Hence, exploration of the optimal afatinib initial dose and its efficacy and safety in Asian patients has drawn extensive attention., Methods: We retrospectively evaluated demographic and clinical information, survival data, and adverse events in advanced non-small cell lung cancer patients treated with afatinib from 27 February 2017 to 30 October 2018., Results: A total of 60 patients were included in the study. Thirty-nine (65%) patients received afatinib as first-line treatment. The median PFS was 12.3 months (95% confidence internal 7.6-17.0). Multivariate Cox regression analysis revealed that age, gender, smoking history, baseline brain metastasis status, afatinib starting dose, and mutation type did not significantly influence PFS. No significant difference in median PFS between patients treated with an initial dose of afatinib of 40 mg or 30 mg, either in the first-line (14.5 vs. 5.2 months; P = 0.101) or in a second or later-line setting (3.0 vs. 5.0 months; P = 0.375) was observed. The incidence of all grades of rash/acne (92.5% vs. 61.1%; P = 0.011) and paronychia (82.5% vs. 50.0%; P = 0.010) in the 40 mg group was significantly higher than in the 30 mg group., Conclusion: First-line afatinib treatment is beneficial for advanced lung adenocarcinoma patients with sensitive EGFR mutations. Initial dose and baseline brain metastasis status do not significantly impact PFS., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Despite trastuzumab and pertuzumab improving outcome for patients with HER2-positive metastatic breast cancer, the disease remains fatal for the majority of patients. This study evaluated the anti-proliferative effects of adding anti-HER2 tyrosine kinase inhibitors (TKIs) to trastuzumab and pertuzumab in HER2-positive breast cancer cells. Afatinib was tested alone and in combination with trastuzumab in HER2-positive breast cancer cell lines. TKIs (lapatinib, neratinib, afatinib) combined with trastuzumab and/or pertuzumab were tested in 3 cell lines, with/without amphiregulin and heregulin-1β. Seven of 11 HER2-positive cell lines tested were sensitive to afatinib (IC 50  < 80 nM). Afatinib plus trastuzumab produced synergistic growth inhibition in eight cell lines. In trastuzumab-sensitive SKBR3 cells, the TKIs enhanced response to trastuzumab. Pertuzumab alone did not inhibit growth and did not enhance trastuzumab-induced growth inhibition or antibody-dependent cellular cytotoxicity. Pertuzumab enhanced response to trastuzumab when combined with lapatinib but not neratinib or afatinib. In two trastuzumab-resistant cell lines, the TKIs inhibited growth but adding trastuzumab and/or pertuzumab did not improve response compared to TKIs alone. Amphiregulin plus heregulin-1β stimulated proliferation of SKBR3 and MDA-MB-453 cells. In the presence of the growth factors, neither antibody inhibited growth and the TKIs showed significantly reduced activity. The triple combination of trastuzumab, pertuzumab and a TKI showed the strongest anti-proliferative activity in all three cell lines, in the presence of exogenous growth factors. In summary, addition of anti-HER2 TKIs to combined anti-HER2 monoclonal antibody therapy results in enhanced anticancer activity. These data contribute to the rationale for studying maximum HER2 blockade in the clinic.

Gold nanoparticles (AuNPs) have emerged as promising drug delivery candidates that can be leveraged for cancer therapy. Lung cancer (LC) is a heterogeneous disease that imposes a significant burden on society, with an unmet need for new therapies. Chemotherapeutic drugs such as afatinib (Afb), which is clinically approved for the treatment of epidermal growth factor receptor positive LC, is hydrophobic and has low bioavailability leading to spread around the body, causing severe side effects. Herein, we present a novel afatinib-AuNP formulation termed Afb-AuNPs, with the aim of improving drug efficacy and biocompatibility. This was achieved by synthesis of an alkyne-bearing Afb derivative and reaction with azide-functionalized lipoic acid using copper-catalyzed click chemistry, then conjugation to AuNPs via alkylthiol-gold bond formation. The Afb-AuNPs were found to possess up to 3.7-fold increased potency when administered to LC cells in vitro and were capable of significantly inhibiting cancer cell proliferation, as assessed by MTT assay and electric cell-substrate impedance sensing, respectively. Furthermore, when exposed to Afb-AuNPs, human alveolar epithelial type I-like cells, a model of the healthy lung epithelium, maintained viability and were found to release less proinflammatory cytokines when compared to free drug, demonstrating the biocompatibility of our formulation. This study provides a new platform for the development of nontraditional AuNP conjugates which can be applied to other molecules of therapeutic or diagnostic utility, with potential to be combined with photothermal therapy in other cancers.

Background: Re-challenge of erlotinib after gefitinib failure is reported to yield some benefit in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation. However, little is known about the re-challenge of afatinib after 1st generate on EGFR tyrosine kinase inhibitor (TKI) failure., Methods: From May 2015 to August 2018, 62 patients with advanced NSCLC harboring sensitive EGFR mutation received afatinib after gefitinib and/or erlotinib failure at our institution was included in our retrospective study., Results: The overall response rate (ORR) and disease control rate (DCR) of afatinib as re-challenge were 17.0% and 79.2%, respectively. The median time on treatment of 1st generation EGFR-TKI (1st TKI) was 14 months. By multivariate analysis, smoking, performance status (PS), and time on treatment of 1st TKI with more than 10 months were confirmed to be independent prognostic factors predicting a worse progression-free survival (PFS), and significant prognostic markers for overall survival (OS) were PS and time on treatment of 1st TKI with more than 10 months, especially in patients with exon 19 deletion., Conclusions: Re-challenge of afatinib was identified as one of the therapeutic options after 1st TKI failure in the patients with advanced NSCLC harboring EGFR mutation when the time of treatment by prior 1st TKI is more than 10 months.

Background: In the LUX-Lung 3 and LUX-Lung 6 trials, afatinib improved overall survival in previously untreated patients with EGFR 19del mutated non-small cell lung cancer (NSCLC) compared to chemotherapy. The appropriate management of adverse events and dose reduction of afatinib are important for EGFR-positive NSCLC patients. We conducted a retrospective and observational study of patients treated with first-line afatinib for EGFR-positive NSCLC in Nagano prefecture, Japan, focusing on efficacy and toxicities., Methods: We retrospectively collected the medical records of NSCLC patients initially treated with afatinib between May 2014 and March 2018., Results: A total of 62 patients with a median age of 67 years and a median body surface area (BSA) of 1.57 m 2 were included. The overall response rate was 87.7% and median progression-free survival (PFS) was 15.7 months. The median PFS was similar between standard initial dose (40 mg) and reduced initial doses (30 and 20 mg) (15.7 vs. 14.2 months; P = 0.978). The frequency of dose reduction and the discontinuation rate in the 40 mg daily dose group was higher in patients with BSA < 1.58 m 2 (100%) compared to BSA ≥ 1.58 m 2 (68.2%) (P = 0.014). The frequency of diarrhea was higher in patients with BSA < 1.58 m 2 (93.5%) compared to BSA ≥ 1.58 m 2 (71.0%) (P = 0.02)., Conclusion: In real-world clinical practice, first-line afatinib was well managed and was equally as effective as in previous clinical trials of EGFR-positive NSCLC. BSA is considered a predictive marker for appropriate afatinib dose reduction., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: The aim of our study was to retrospectively assess the incidence of interstitial lung disease (ILD) related to EGFR-tyrosine kinase inhibitor (TKI) treatment immediately before and/or after the administration of a PD-1 antibody., Methods: We analyzed the data of 26 patients who underwent treatment with EGFR-TKIs immediately before and/or after the administration of an anti-PD-1 antibody., Results: Four out of the 26 patients developed ILD during EGFR-TKI treatment: three patients during the administration of osimertinib immediately after, and one during afatinib immediately before treatment with an anti-PD-1 antibody. Three of 12 patients who underwent EGFR-TKI therapy immediately after anti-PD-1 antibody treatment experienced osimertinib-induced ILD. ILD was not observed in the five patients administered an anti-PD-1 antibody followed by first or second-generation EGFR-TKIs., Conclusion: ILD was observed in the treatment sequence of an anti-PD-1 antibody followed by osimertinib, but not with first or second-generation EGFR-TKIs., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Effective targeted therapy for non-small-cell lung cancer (NSCLC) patients with human epidermal growth factor receptor 2 (HER2) mutations remains an unmet need. This study investigated the antitumor effect of an irreversible pan-HER receptor tyrosine kinase inhibitor, pyrotinib., Patients and Methods: Using patient-derived organoids and xenografts established from an HER2-A775&#95;G776YVMA-inserted advanced lung adenocarcinoma patient sample, we investigated the antitumor activity of pyrotinib. Preliminary safety and efficacy of pyrotinib in 15 HER2-mutant NSCLC patients in a phase II clinical trial are also presented., Results: Pyrotinib showed significant growth inhibition of organoids relative to afatinib in vitro (P = 0.0038). In the PDX model, pyrotinib showed a superior antitumor effect than afatinib (P = 0.0471) and T-DM1 (P = 0.0138). Mice treated with pyrotinib displayed significant tumor burden reduction (mean tumor volume, -52.2%). In contrast, afatinib (25.4%) and T-DM1 (10.9%) showed no obvious reduction. Moreover, pyrotinib showed a robust ability to inhibit pHER2, pERK and pAkt. In the phase II cohort of 15 patients with HER2-mutant NSCLC, pyrotinib 400 mg resulted in a objective response rate of 53.3% and a median progression-free survival of 6.4 months., Conclusion: Pyrotinib showed activity against NSCLC with HER2 exon 20 mutations in both patient-derived organoids and a PDX model. In the clinical trial, pyrotinib showed promising efficacy., Clinical Trial Registration: NCT02535507., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Diarrhea is a major side effect of ErbB receptor tyrosine kinase inhibitors (TKIs) in cancer chemotherapy. Here, we show that the primary mechanism of ErbB TKI diarrhea is activation of basolateral membrane potassium (K+) channels and apical membrane chloride (Cl-) channels in intestinal epithelia and demonstrate the efficacy of channel blockers in a rat model of TKI diarrhea. Short-circuit current in colonic epithelial cells showed that the TKIs gefitinib, lapatinib, and afatinib do not affect basal secretion but amplify carbachol-stimulated secretion by 2- to 3-fold. Mechanistic studies with the second-generation TKI afatinib showed that the amplifying effect on Cl- secretion was Ca2+ and cAMP independent, was blocked by CF transmembrane conductance regulator (CFTR) and K+ channel inhibitors, and involved EGFR binding and ERK signaling. Afatinib-amplified activation of basolateral K+ and apical Cl- channels was demonstrated by selective membrane permeabilization, ion substitution, and channel inhibitors. Rats that were administered afatinib orally at 60 mg/kg/day developed diarrhea with increased stool water from approximately 60% to greater than 80%, which was reduced by up to 75% by the K+ channel inhibitors clotrimazole or senicapoc or the CFTR inhibitor (R)-BPO-27. These results indicate a mechanism for TKI diarrhea involving K+ and Cl- channel activation and support the therapeutic efficacy of channel inhibitors.

A sensitive quantitative liquid chromatography-tandem mass spectrometry assay for afatinib in rat plasma was developed and validated using afatinib dimaleate as a standard. The analyte was determined to be ionized using the positive ion multiple reaction monitoring mode through electrospraying on an AB Sciex Triple Quad™ 4500 system. Protein precipitation was used for sample preparation, and an Agilent Eclipse XDB-CN column (100 × 2.1 mm, 3.5 μm) was applied for chromatographic separation. The mobile phase was water and methanol (15:85, v/v) containing 0.1% formic acid with a flow rate of 0.5 mL/min. The linear range was 0.5-200 ng/mL, with r 2  = 0.9994 ± 0.0004 calculated from linear regression, with 1/x 2 as the weighting factor for the calibration. The average recovery of the plasma samples was stable and reproducible. The analyte is sufficiently stable for handling and analysis. The pharmacokinetic study and comparison were performed by analyzing plasma concentrations in rats administered afatinib solution or prepared afatinib liposomes using the developed determination method. The C max of the afatinib liposomes was nearly 400-fold higher than that of the afatinib solution. These results indicate that liposome-encapsulation protected afatinib from endogenous protein binding, thereby reducing the risk of idiosyncratic drug reactions by protein adducts. Thus, Afatinib liposomes seem to be a promising strategy for the treatment of non-small cell lung cancer., (Copyright © 2018 Elsevier B.V. All rights reserved.)

HER2 mutations are a rare group of driving genes that respond to HER2 targeted therapy, particularly afatinib. No more than 20 such cases have been reported, but afatinib was used after first-line chemotherapy. We present the case of a never-smoking female patient diagnosed with stage IV lung adenocarcinoma harboring a Her2 exon 20 inserted mutation who achieved a durable response (12 months) to first-line afatinib treatment. We review the literature concerning afatinib therapy in this rare cohort of mutated lung cancer patients., (© 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

We developed a screening assay in which luciferized ID8 expressing OVA was cocultured with transgenic CD8 + T cells specifically recognizing the model antigen in an H-2b-restricted manner. The assay was screened with a small-molecule library to identify compounds that inhibit or enhance T cell-mediated killing of tumor cells. Erlotinib, an EGFR inhibitor, was the top compound that enhanced T-cell killing of tumor cells. Subsequent experiments with erlotinib and additional EGFR inhibitors validated the screen results. EGFR inhibitors increased both basal and IFNγ-induced MHC class-I presentation, which enhanced recognition and lysis of tumor cell targets by CD8 + cytotoxic T lymphocytes. The ID8 cell line was also transduced to constitutively express Cas9, and a pooled CRISPR screen, utilizing the same target tumor cell/T-cell assay, identified single-guide (sg)RNAs targeting EGFR that sensitized tumor cells to T cell-mediated killing. Combination of PD-1 blockade with EGFR inhibition showed significant synergistic efficacy in a syngeneic model, further validating EGFR inhibitors as immunomodulatory agents that enhance checkpoint blockade. This assay can be screened in high-throughput with small-molecule libraries and genome-wide CRISPR/Cas9 libraries to identify both compounds and target genes, respectively, that enhance or inhibit T-cell recognition and killing of tumor cells. Retrospective analyses of squamous-cell head and neck cancer (SCCHN) patients treated with the combination of afatinib and pembrolizumab demonstrated a rate of clinical activity exceeding that of each single agent. Prospective clinical trials evaluating the combination of an EGFR inhibitor and PD-1 blockade should be conducted., (©2018 American Association for Cancer Research.)

Background: Preclinical studies suggested that the addition of bevacizumab could overcome acquired resistance (AR) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The aim of this study was to evaluate the clinical efficacy and safety of a combination of afatinib and bevacizumab after AR., Methods: Patients with EGFR-mutant non-small cell lung cancer after AR were enrolled during any line of therapy. Afatinib was prescribed at 30 mg, and 15 mg/kg bevacizumab was administered every 3 weeks until progression., Results: Between October 2014 and May 2017, 32 eligible patients were evaluated. The mutation subtypes were Del-19 (20 [63%]), L858R (11 [34%]), and L861Q (1 [3%]). T790M was detected in 14 patients (44%). The median number of prior regimens was 4 (range, 1-10). Six patients obtained a partial response, and 23 had stable disease; this resulted in an objective response rate (ORR) of 18.8% (95% confidence interval [CI], 7.2%-36.4%) and a disease control rate of 90.7% (95% CI, 75.0%-98.0%). The median progression-free survival (PFS) was 6.3 months (95% CI, 3.9-8.7 months). The ORRs and median PFS times of T790M+ and T790M- patients were 14.3% and 22.2%, respectively, and 6.3 and 7.1 months, respectively; those of Del-19 and L858R patients were 20.0% and 11.1%, respectively, and 6.3 and 5.1 months, respectively. Grade 3 or higher adverse events (incidence ≥ 10%) included paronychia (25%), hypertension (41%), and proteinuria (19%). There were no treatment-related deaths, interstitial lung disease, or bevacizumab-associated severe bleeding., Conclusions: Afatinib plus bevacizumab demonstrated clinical efficacy and safety after AR to EGFR TKIs and could be a therapeutic salvage option for T790M- populations., (© 2018 American Cancer Society.)

Overexpression of HER2 has been reported in around 25% of human breast cancers. Despite recent advances in HER2 targeted therapy, many patients still experience primary and secondary resistance to such treatments, the mechanisms for which are poorly understood. Here, we investigated the sensitivity of a panel of breast cancer cell lines to treatment with various types of HER-family inhibitors alone or in combination with other tyrosine kinase inhibitors or chemotherapeutic agents. We found that treatment with the second-generation irreversible HER-family inhibitors, particularly afatinib and neratinib, were more effective than treatment with the first-generation reversible inhibitors in inhibiting growth, migration and downstream cell signalling in breast cancer cells. Of the three HER2 overexpressing cell lines in this panel, SKBr3 and BT474 were highly sensitive to treatment with HER-family inhibitors, while MDA-MB-453 was comparatively resistant. Combinations of HER-family inhibitors with NVP-AEW541, dasatinib or crizotinib (inhibitors of IGF-1R, Src and c-Met/ALK, respectively) led to synergistic effects in some of the cell lines examined. In particular, treatment with a combination of Src and HER-family member inhibitors resulted in synergistic growth inhibition of MDA-MB453 cells, implicating Src as a mediator of resistance to HER2-targeting agents. Our results suggest that combining HER-family inhibitors with other TKIs such as dasatinib may have therapeutic advantages in certain breast cancer subtypes and warrants further investigation.