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Background: This study aimed to comprehensively evaluate the efficacy and toxicity of afatinib in patients with sarcopenia, an important prognostic factor for treatment efficacy and toxicity in patients with cancer. Methods: The clinical features of patients with advanced NSCLC treated with frontline afatinib between 2014 and 2018 at a medical center in Taiwan were retrospectively reviewed. Sarcopenia was evaluated based on the total cross‐sectional area of skeletal muscles assessed by computed tomography (CT) imaging at the L3 level. Baseline characteristics, response rates, survival rates, and adverse events (AEs) were compared between sarcopenic and nonsarcopenic patients. Results: A total of 176 patients evaluated for sarcopenia by CT and treated with afatinib were enrolled in the current study. Sarcopenia was significantly associated with good performance status, low body mass index (BMI), low body surface area (BSA), and low total mass area (TMA). Sarcopenia did not influence the response rate (69.2% vs. 72.0%, p = 0.299), progression‐free survival (median 15.9 vs. 14.9 months, p = 0.791), or overall survival (median 26.5 vs. 27.2 months, p = 0.441). However, BSA ≤ 1.7 and the 40 mg afatinib dose were associated with dose reduction. TMA was the only independent factor for afatinib discontinuation due to AEs. Conclusion: Sarcopenia was not associated with treatment efficacy or toxicity among patients with NSCLC harboring common mutations treated with afatinib, indicating sarcopenic patients should not be excluded from afatinib treatment. Other factors, such as BSA and TMA, were associated with dose reduction and afatinib discontinuation, respectively, which may require additional evaluations in future studies. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) are standard treatments for advanced non–small cell lung cancer (NSCLC) patients harboring the EGFR mutation. Patients experiencing intolerable adverse events (AEs) would discontinue EGFR‐TKIs. This study aimed to evaluate the impact of intolerable AEs and subsequent treatment on the survival of patients who discontinued EGFR‐TKIs. Patients: The data of advanced NSCLC patients treated with EGFR‐TKIs as frontline treatment at Chang Gung Memorial Hospitals from June 2014 to March 2018 were retrospectively reviewed. Results: A total of 2190 patients were enrolled and treated with frontline EGFR‐TKIs. In August 2021, 114 (5.2%) patients experienced intolerable AEs requiring discontinuation of EGFR‐TKIs. The time median of EGFR‐TKIs discontinuation was 2.56 months. Age >65 years, females, body weight, and body surface area were associated with the occurrence of intolerable AEs for patients treated with afatinib. Patients experiencing skin/paronychia/mucositis and abnormal liver function test had favorable survivals results. Patients who received subsequent EGFR‐TKIs treatment, experienced better progression‐free survival (PFS), total PFS (from frontline line EGFR‐TKIs), and overall survival (OS) compared to patients receiving chemotherapy or no treatment. Patients undergoing subsequent EGFR‐TKIs had better total PFS (median, 14.9 vs. 11.3 months, p = 0.013) and OS (median, 31.3 vs. 20.1 months, p = 0.001) than patients who did not discontinue because of AEs. Favorable OS was validated by propensity score matching. Conclusion: Patients experiencing intolerable AEs during EGFR‐TKI treatment should consider switching to an alternative EGFR‐TKI, which increase the survival results as compared to those patients who did not experience intolerable AEs. [ABSTRACT FROM AUTHOR]

Purpose: Cutaneous toxicities are common adverse effects following epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) therapy. Zinc deficiency causes diverse diseases, including skin toxicities. Therefore, this study aimed to investigate the role of zinc deficiency in patients with EGFR‐TKI‐induced skin toxicities. Experimental Design: This retrospective study enrolled 269 patients with diverse skin disorders who visited our hospital between January 2016 and December 2017. The skin toxicity severities and plasma zinc levels of 101 EGFR‐TKI‐treated cancer patients were analysed and compared with those of 43 non‐EGFR‐TKI‐treated cancer patients and 125 patients without cancer but presenting cutaneous manifestations. Additionally, the role of zinc in erlotinib‐induced skin eruptions was established in a 14‐day‐murine model. Clinical features were further evaluated following systemic zinc supplementation in EGFR‐TKI‐treated cancer patients. Results: EGFR‐TKI‐treated patients demonstrated severe cutaneous manifestations and a significant decrease in plasma zinc levels than those of the control groups. The serum zinc level and Common Terminology Criteria for Adverse Events (CTCAE) 5.0 grading of EGFR‐TKI‐induced skin toxicities showed a significant negative correlation (r = −0.29; p < 0.0001). Moreover, erlotinib treatment decreased the plasma zinc levels and induced periorificial dermatitis in rats confirming zinc deficiency following EGFR‐TKI treatment. Zinc supplementation to the EGFR‐TKI‐treated cancer patients showed a significant decrease in the CTCEA grading (p < 0.0005 for mucositis and p < 0.0.0001 for all other cases) after 8 weeks. Conclusions: Skin impairment following EGFR‐TKI therapy could be ameliorated through zinc supplementation. Thus, zinc supplementation should be considered for cancer patients undergoing EGFR‐TKI therapy. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) are the standard treatment for patients with non‐small cell lung cancer (NSCLC) harboring EGFR mutations. This study aimed to evaluate the efficacy of EGFR‐TKIs and prognostic factors for patients with NSCLC harboring uncommon EGFR mutations, which account for 10% of EGFR mutations. Methods: A total of 230 treatment‐naive patients with NSCLC harboring uncommon EGFR mutations treated with first‐line EGFR‐TKIs between 2011 and 2018 at four hospitals (belonging to four institutions, Linkou, Kaohsiung, Keelung, and Chiayi, of the Chang Gung Memorial Hospital) in Taiwan were retrospectively reviewed. Their clinicopathological characteristics, adverse events (AEs), objective response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), and overall survival (OS) were collected. Univariate and multivariate analyses were performed to identify potential prognostic factors for PFS. Results: Overall, patients who received afatinib (n = 62) had better PFS (median: 6.4 vs. 5.9 months, p = 0.022) and OS (median: 13.4 vs. 13.0 months, p = 0.008) than those who received gefitinib/erlotinib (n = 124), although no significant differences were observed for ORR (46.8% vs. 35.5%, p = 0.137) or DCR (59.7% vs. 58.9%, p = 0.916). Patients who received afatinib showed significantly higher ORR (58.3% vs. 31.3%, p = 0.027) but not DCR compared with gefitinib/erlotinib for major uncommon mutations. Afatinib trended toward better PFS and OS for major uncommon mutations and compound mutations. No EGFR‐TKIs were effective for most NSCLC patients with exon 20 insertions. Performance status, metastasis of the liver and pleura, and dose reduction were independent prognostic factors for PFS. Conclusion: Afatinib demonstrated better survival outcomes than gefitinib/erlotinib for NSCLC patients harboring major EGFR uncommon mutations and compound mutations. Performance status and metastatic sites may be useful for predicting PFS for major uncommon mutations and compound mutations. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard treatments for advanced EGFR-mutated non–small cell lung cancer (NSCLC) patients. Osimertinib is an effective therapy for NSCLC patients with acquired resistance due to T790M mutation after first- and second-generation EGFR-TKI treatment. This study aimed to analyze the clinical outcomes of sequential therapy following first-line EGFR-TKIs and the predictive factors of an acquired T790M mutation. Methods: Between January 2014 and December 2018, data from 2190 advanced NSCLC patients with common EGFR mutations (exon 19 deletion and L858R) receiving first- and second-generation EGFR-TKIs in Linkou, Kaohsiung, Chiayi and Keelung Chang Gung Memorial Hospitals were retrospectively retrieved and analyzed. Results: Until August 2021, among 1943 patients who experienced progressive disease, 526 underwent T790M mutation tests, and their T790M-positive rate was 53.6%. Exon 19 deletion mutation and progression-free survival (PFS) of >12 months were positively associated with secondary T790M mutation. Different first-line first- and second-generation EGFR-TKI therapies did not affect the appearance of acquired T790M mutations. The median overall survival (OS) was 58.3 [95% confidence interval (CI): 49.0–67.5] months among the patients with T790M mutation who received second-line osimertinib therapy compared with 31.0 (95% CI: 27.5–34.5) months among the patients without T790M mutation who received chemotherapy alone. The multivariate analysis showed that a poor performance status (score: >2), nonadenocarcinoma histology, stage IV cancer, liver metastasis, brain metastasis, PFS while on first-line EGFR-TKIs, and subsequent chemotherapy without third-generation EGFR-TKIs were significant independent unfavorable prognostic factors for OS. Conclusion: This study demonstrated the efficacy of first-line EGFR-TKIs and sequential osimertinib therapy. The results of our study suggest that T790M mutation tests are important for the use of subsequent osimertinib, which yielded favorable survival outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) designed to overcome acquired T790M resistance mutations in non-small cell lung cancer (NSCLC). A total of 172 patients with advanced NSCLC treated with osimertinib following frontline EGFR-TKIs were retrospectively reviewed and divided into three groups based on the T790M status (positive, negative, or unknown T790M). The study confirmed the greater efficacy of later-line osimertinib for NSCLC with acquired T790M mutation than for NSCLC without acquired T790M mutation. Detection of the T790M mutation after frontline treatment (first- and second-generation EGFR-TKI) is crucial for prolonging the survival of NSCLC patients harboring EGFR mutation. Osimertinib may be considered an option for NSCLC with unknown T790M mutations, as a certain subpopulation may benefit from osimertinib. Background: Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) designed to overcome acquired T790M resistance mutations in non-small cell lung cancer (NSCLC). However, the efficacy of osimertinib in patients without acquired T790M mutations has not been well studied. This study aimed to evaluate the efficacy of osimertinib in patients treated with first- and second-generation EGFR-TKIs followed by later-line osimertinib treatment. Patients: The clinical data and survival outcomes of 172 patients with advanced NSCLC treated with osimertinib following frontline EGFR-TKIs at Chang Gung Memorial Hospital from 2014 to 2018 were retrospectively reviewed. T790M mutations were detected using tissue sequencing and/or liquid biopsy. Results: A total of 172 EGFR-mutated NSCLC patients treated with frontline EGFR-TKI therapy followed by later-line osimertinib were enrolled in the current study and divided into three groups based on the T790M status (positive, negative, or unknown T790M). Patients with NSCLC harboring acquired T790M mutation treated with osimertinib had the best objective response rate (ORR) (52.6%, 25.0%, and 32.0%, p = 0.044), disease control rate (DCR) (79.3%, 41.7%, and 68.0%, p = 0.011), and progression-free survival (PFS, median PFS, 12.6, 3.1, 10.4 months, p = 0.001) among the three groups (positive, negative, and unknown T790M, respectively). However, a marked difference was found between positive and negative T790M mutations but not between positive and unknown T790M mutations. Univariate analysis was performed to identify potential prognostic factors for PFS in 172 patients treated with osimertinib. Lung metastasis (p < 0.001), brain metastasis (p < 0.009), number of metastatic sites (p < 0.001), PFS with frontline EGFR-TKIs (p = 0.03), and T790M status (p = 0.006) were identified as prognostic factors for PFS with osimertinib. Multivariate analysis showed that lung metastasis (p < 0.001) and PFS with frontline EGFR-TKIs and T790M status were independent prognostic factors. Conclusion: This study confirmed the greater efficacy of later-line osimertinib for NSCLC with acquired T790M mutation than for NSCLC without acquired T790M mutation. Detection of the T790M mutation after frontline treatment (first- and second-generation EGFR-TKI) is crucial for prolonging the survival of NSCLC patients harboring EGFR mutation. Osimertinib may be considered an option for NSCLC with unknown T790M mutations, as a certain subpopulation may benefit from osimertinib. [ABSTRACT FROM AUTHOR]

Background: We developed a hybrid platform using a negative combined with a positive selection strategy to capture circulating tumor cells (CTCs) and detect epidermal growth factor receptor (EGFR) mutations in patients with metastatic lung adenocarcinoma. Methods: Blood samples were collected from patients with pathology-proven treatment-naïve stage IV lung adenocarcinoma. Genomic DNA was extracted from CTCs collected for EGFR mutational tests. The second set of CTC-EGFR mutational tests were performed after three months of anti-cancer therapy. Results: A total of 80 samples collected from 28 patients enrolled between July 2016 and August 2018. Seventeen patients had EGFR mutations, including Exon 19 deletion (n = 11), L858R (n = 5), and de-novo T790 and L858R (n = 1). Concordance between tissue and CTCs before treatment was 88.2% in EGFR- mutant patients and 90.9% in non-mutant patients. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of EGFR mutation tests for CTCs were 89.3%, 88.2%, 90.9%, 93.8%, and 83.3%, respectively. Conclusions: CTCs captured by a hybrid platform using a negative and positive selection strategy may serve as a suitable and reliable source of lung cancer tumor DNA for detecting EGFR mutations, including T790M. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate possible treatment strategies for patients with de novo T790M mutation‐positive (T790M+) non‐small‐cell lung cancer (NSCLC). Methods: Patients diagnosed with de novo T790M+ NSCLC and treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) between 2011 and 2018 at a regional hospital in Taiwan were retrospectively reviewed. Their clinicopathological characteristics and subsequent treatment information were collected, and potential prognostic factors were identified using univariate and multivariate analyses. Results: All tumors with T790M mutations coexisted with sensitizing mutations. Through the last follow‐up in May 2021, afatinib and osimertinib demonstrated better progression‐free survival (PFS, p < 0.01) and overall survival (OS, p < 0.01) than gefitinib and erlotinib. Additionally, patients with low T790M ratios had better PFS than those with high T790M ratios, implying that the proportion of T790M+ tumors determined the response to EGFR‐TKIs. Multivariate analysis confirmed that both EGFR‐TKI treatment (osimertinib hazard ratio [HR] 0.06, 95% confidence interval [CI] 0.01–0.30; afatinib HR 0.09, 95% CI 0.02–0.39) and a low T790M ratio (HR 0.29, 95% CI 0.12–0.69) were independently favorable prognostic factors for patients with de novo T790M+ NSCLC. Median PFS was 6.1 (95% CI 4.4–7.8) months. In addition, patients treated with first‐generation (1G)/second‐generation (2G) EGFR‐TKIs followed by osimertinib (n = 8) demonstrated the best OS compared with patients treated with frontline osimertinib (n = 5) or 1G/2G EGFR‐TKIs without osimertinib (n = 28, p < 0.01). Conclusion: Sequential TKIs may represent an alternative option for de novo T790M mutation, particularly frontline afatinib and tumors with low T790M ratios. [ABSTRACT FROM AUTHOR]

Objective: Platelet activation and adhesion to cancer cells increase the release of multiple factors that contribute to EMT and chemoresistance. Elevated levels of D-dimer have been associated with poor clinical outcomes in lung cancer. Platelets in high D-dimer plasma may be activated and implicated in acquired resistance to EGFR TKI in advanced lung adenocarcinoma with mutant EGFR. Materials and Methods: Clinical responsive rate (RR), progression-free survival (PFS), and overall survival (OS) were prospectively measured in treatment-naïve lung adenocarcinoma patients with activation mutation. Plasma or platelets from patients with high or low D-dimer level were obtained to investigate the cytotoxic effects of TKIs on mutant cancer cells, and the mechanistic pathways were also explored. Results: Patients with high D-dimer had worse RR, PFS, and OS. High D-dimer plasma induced resistance to gefitinib, erlotinib, afatinib, or osimertinib in EGFR mutant lung cancer cells. Depletion of platelets in high D-dimer plasma reversed the resistance to TKI. Platelets of high D-dimer plasma had higher adherence capacity to cancer cells, and induced EGFR and Akt activation as well as EMT through Src activation. Inhibition of platelet adherence or activation of Src or Akt conquered the resistance to TKI. The acquired resistance to TKI by high D-dimer plasma was less attributed to secondary gene mutation. Conclusion: Increased platelet activation in the high D-dimer plasma may contribute to first-line acquired EGFR TKI resistance. Thus, therapeutic strategy against platelet activation in patients with high D-dimer levels may improve the efficacy of first-line treatment with EGFR TKI. [ABSTRACT FROM AUTHOR]

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) afatinib improves survival in nonsmall cell lung cancer (NSCLC) patients with EGFR mutation. We analysed the outcome between EGFR mutation subtypes in a large afatinib‐treated cohort in which 516 EGFR‐mutated NSCLC patients receiving afatinib as front‐line treatment. EGFR uncommon mutations include exon 20 insertion, de novo T790M of high or low allele frequency (dT790MHAF/dT790MLAF), non‐T790M compound mutation and others, where EGFR exon 20 insertion and dT790MHAF were defined as type‐I and the rest as type‐II uncommon mutation. Four hundred and sixty‐one (89.3%) and 55 (10.7%) patients were common and uncommon mutation, respectively. Exon 20 insertion and dT790MHAF patients demonstrated a significantly shortened progression‐free survival (PFS) (2.6 and 4.1 months) compared to EGFR common mutation, dT790MLAF and other uncommon mutation patients (15.1, 27.0 and 18.4 months; P = 3 × 10−8). Type‐I uncommon mutation was an independent predictor of PFS (HR 4.46 [95% CI, 2.60‐7.64]; P <.001) and OS (HR 2.56 [95% CI, 1.37‐4.75]; P =.003). EGFR L858R patients demonstrated a significantly higher CNS progression (cause‐specific HR, 3.16; 95% CI 1.24‐8.08; P =.016), and type‐I uncommon mutation patients exhibited a significantly higher systemic progression (cause‐specific HR, 4.95; 95% CI 2.30‐10.60; P = 4.3 × 10−5). Tendencies of higher CNS and lower systemic progression were observed in type‐II uncommon mutation patients. A PFS ≥ 12 months (OR 2.38 [95% CI, 1.18‐4.89]; P =.016) and uncommon EGFR mutation (OR 0.08 [95% CI, 0.01‐0.48]; P =.021) were independent predictors of secondary T790M. Afatinib‐treated NSCLC patients presented an EGFR genotype‐specific pattern of disease progression and outcome. What's new? For patients with nonsmall cell lung cancer (NSCLC), epidermal growth factor tyrosine kinase inhibitors (EGFR‐TKIs) can significantly improve survival. EGFG‐TKI effectiveness, however, is compromised by acquired EGFR mutations, especially de novo T790M mutations. Here, the impact of EGFR genotypes on the efficacy of afatinib, a second‐generation EGFR‐TKI, was investigated in a cohort of EGFR‐mutated NSCLC patients. Afatinib efficacy was associated with T790M allele quantity in patients with de novo T790M mutation. In particular, front‐line afatinib therapy was associated with favourable survival in EGFR‐mutated patients, whereas resistance was marked by a genotype‐specific pattern of disease progression, with secondary T790M development. [ABSTRACT FROM AUTHOR]

Topical dicloxacillin solution wash could thus not only be a promising treatment for PPE and PDE but could also reduce the total amount of antibiotics used by patients receiving EGFRI treatment. Dear Editor, Epidermal growth factor inhibitor (EGFRI)-induced papulopustular eruption (PPE) and purpuric drug eruption (PDE) remain challenging problems for clinicians. Meanwhile, frequent oral antibiotics prophylaxis or treatment for PPE not only causes gastrointestinal discomfort but also significantly increases systemic antibiotic consumption by patients, contributing to the emergence of multi-resistant strains of bacteria like MRSA. [Extracted from the article]

Background: High rates of posttreatment discomfort, infection, recurrence, and increased time to return to work have been noted after nail plate avulsion resulting from epidermal growth factor receptor tyrosine kinase inhibitor(EGFR‐TKI)‐induced paronychia, which may even interrupt the course of treatment for EGFR‐TKI therapy. Thus, we conducted this study to determine how effectively a topical β‐blocker, betaxolol, prevents EGFR‐TKI‐induced paronychia. Methods: This case–control cohort study included a total of 131 non‐small‐cell lung cancer patients. The prevention group comprised 40 patients treated with topical betaxolol 0.25% solution to prevent paronychia while they received EGFR‐TKI therapy. The control group comprised 91 patients who did not preventively use topical betaxolol 0.25% solution while receiving EGFR‐TKI therapy. The patients' age, gender, antineoplastic regimen, duration of antineoplastic treatment before the appearance of lesions, number of involved digits (fingernails or toenails) with lesions, grading of paronychia, and pain score were recorded. Results: In terms of the cumulative incidence of paronychia, significant differences (P < 0.01) were noted at both the 2nd and 3rd months after starting EGFR‐TKIs. Furthermore, the average visual analogue scale scores were 3.125 and 6.29 in the prevention group and control group, respectively (P < 0.01). The average grades of paronychia were 1.5 and 2.12 in the prevention group and control group, respectively (P < 0.01). The average numbers of involved digits were 2.25 (range: 1–5 digits) in the prevention group and 3.03 (range: 1–7) in the control group (P = 0.07). Conclusions: Preventively using topical betaxolol can significantly decrease the incidence, VAS score, and grading of EGFR‐TKI‐induced paronychia. [ABSTRACT FROM AUTHOR]

Introduction: The prognostic value of epidermal growth factor receptor (EGFR) mutations and the correlation between EGFR mutations and the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) histological classification remain controversial. The current study aimed to investigate the pure prognostic role of EGFR mutations in treatment-naïve patients with resected stage I lung adenocarcinoma. Methods: We retrospectively reviewed 373 patients with stage I pulmonary non-small-cell lung cancer who underwent complete surgical resection between January 2010 and May 2014. The tumors were classified according to IASLC/ATS/ERS criteria. EGFR mutation status was determined by established methods. Results: A total of 120 patients were included for analysis; 87 had tumors with EGFR mutations and 33 had wild-type tumors. More low- and intermediate-grade tumors had EGFR mutations, and nearly half of the high-grade tumors were wild-type (75.7% versus 46.2%, p = 0.041). Patients with low-grade tumors had significantly greater median disease-free survival (DFS) (76.8 versus 13 months, p < 0.0001) and better overall survival (OS) (median OS not reached, p = 0.0003) than those with intermediate- and high-grade tumors. Tumor recurrence was 41.4% and 30.3% in mutant and wild-type patients. The 5-years survival rate was 54% and 71.2%. Multivariate analysis revealed that the new histological classification and the pathologic stage were independent predictors of both DFS and OS. EGFR mutation status had no prognostic implications. Conclusion: Low grade tumors according to IASLC/ATS/ERS histological classification and the pathologic stage IA tumors of resected stage I lung adenocarcinomas independently predict better DFS and OS. EGFR mutations were frequently seen in histologically low- and intermediate-grade tumors but not a prognostic factor. [ABSTRACT FROM AUTHOR]

Simple Summary: Previous studies of first-generation EGFR-TKI erlotinib and bevacizumab combination have demonstrated superior treatment efficacy compared to erlotinib monotherapy for advanced EGFR-mutant NSCLC patients. Whether this combination benefit can also be observed in second-generation EGFR-TKI afatinib-treated patients remains unclear. The study presented a real-world cohort of advanced NSCLC patients with EGFR mutation treated by afatinib plus bevacizumab or single-agent afatinib. After balancing the key characteristics between the two treatment groups, the result showcased a similar therapeutic efficacy of afatinib plus bevacizumab compared to afatinib monotherapy. The incidence of drug-resistant mutation was also similar between the two groups. This study provided a clinical practice-based evidence that the additional benefit of bevacizumab is likely moderate in afatinib-treated patients. Background: Treatment outcome between afatinib alone or with bevacizumab in non-small cell lung cancer (NSCLC) patient with epidermal growth factor receptor (EGFR) mutation remains insufficiently reported. Methods: A total of 405 advanced NSCLC patients with sensitizing-EGFR mutation receiving first-line single-agent afatinib or with bevacizumab were grouped and propensity score-matched. Progression-free survival (PFS), overall survival (OS) and secondary T790M mutation were analyzed. Results: In the original cohort, 367 (90.6%) patients received afatinib treatment alone and 38 (9.4%) patients received afatinib plus bevacizumab. Patients who received bevacizumab combination were significantly younger (54.6 ± 10.9 vs. 63.9 ± 11.5; p < 0.001) compared to the afatinib alone group. After propensity score matching, the afatinib alone and afatinib plus bevacizumab groups contained 118 and 34 patients, respectively. A non-significantly higher objective response was noted in the afatinib plus bevacizumab group (82.4% vs. 67.8%; p = 0.133). In the propensity score-matched cohort, a bevacizumab add-on offered no increased PFS (16.1 vs. 15.0 months; p = 0.500), risk reduction of progression (HR 0.85 [95% CI, 0.52–1.40]; p = 0.528), OS benefit (32.1 vs. 42.0 months; p = 0.700), nor risk reduction of death (HR 0.85 [95% CI, 0.42–1.74] p = 0.660) compared to the single-agent afatinib. The secondary T790M rate in afatinib plus bevacizumab and afatinib alone groups was similar (56.3% vs. 49.4%, p = 0.794). Multivariate analysis demonstrated that EGFR L858R (OR 0.51 [95% CI, 0.26–0.97]; p = 0.044), EGFR uncommon mutation (OR 0.14 [95% CI, 0.02–0.64]; p = 0.021), and PFS longer than 12 months (OR 2.71 [95% CI, 1.39–5.41]; p = 0.004) were independent predictors of secondary T790M positivity. Conclusion: Bevacizumab treatment showed moderate efficacy in real-world, afatinib-treated NSCLC patients with EGFR-sensitizing mutation. [ABSTRACT FROM AUTHOR]

Background: The experience of using consolidation durvalumab in post-concurrent chemoradiation (CCRT) unresectable stage III non-small cell lung cancer (NSCLC) is rare in real-world clinical practice, and the factors associated with its efficacy are also unclear. We sought to analyze the efficacy of consolidation durvalumab and the factors associated with its efficacy using a multicenter observational study. Methods: The data for 61 patients with post-CCR unresectable stage III NSCLC receiving consolidation durvalumab at the Chang Gung Memorial Hospitals in Linkou, Keelung, Chiayi, and Kaohsiung from November 2017 to March 2020 were analyzed. (3) Results: The median post-CCRT progression-free survival (PFS) and time to metastatic disease or death (TMDD) for consolidation durvalumab were 14.0 months and 16.7 months, respectively. In multiple variant factors analysis, we found that an epidermal growth factor receptor (EGFR) mutation was an independently unfavorable predictive factor for consolidation durvalumab therapy regarding PFS. The median post-CCRT PFS was 6.50 months for EGFR-mutated patients and 33.63 months for EGFR wild-type and unknown patients (HR = 10.47; 95% CI, 4.55–24.07; p < 0.001). Conclusions: Consolidation durvalumab is effective and safe for post-CCRT unresectable stage III NSCLC in clinical practice, but EGFR mutation is an unfavorable factor for consolidation durvalumab. Thus, searching for a better consolidation therapy for EGFR-mutated patients is warranted. [ABSTRACT FROM AUTHOR]

The efficacy of afatinib in combination with bevacizumab in untreated advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma is currently unclear. We sought to investigate the efficacy of this combination through a multicenter observational analysis. Data for 57 patients with advanced EGFR-mutated lung adenocarcinoma who received afatinib combined with bevacizumab as first-line therapy at the Chang Gung Memorial Hospitals in Linkou and Kaohsiung and Taipei Tzu Chi Hospital from May 2015 to July 2019 were analyzed. The objective response rate and disease control rate of afatinib combined with bevacizumab therapy were 87.7% and 100%, respectively. In all patients, the median progression-free survival (PFS) and overall survival (OS) were 23.9 (95% confidence interval (CI) (17.56–29.17)) and 45.9 (95% CI (39.50–53.60)) months, respectively. No statistical significance between exon 19 deletion and L858R mutations was noted in PFS or OS. The most frequent adverse events (AEs) were diarrhea (98.2%) and dermatitis (96.5%), and most AEs were grade 2 or lower and manageable. The combination of afatinib and bevacizumab is an effective therapy for untreated advanced EGFR-mutated lung adenocarcinoma with acceptable safety. Future prospective studies focusing on this combination for untreated advanced EGFR-mutated lung adenocarcinoma are warranted. [ABSTRACT FROM AUTHOR]

Summary: Epidermal growth factor receptor (EGFR) initiates a signaling cascade that leads to DNA synthesis and cell proliferation, but its role in regulating DNA replication licensing is unclear. Here, we show that activated EGFR phosphorylates the p56 isoform of Lyn, p56Lyn, at Y32, which then phosphorylates MCM7, a licensing factor critical for DNA replication, at Y600 to increase its association with other minichromosome maintenance complex proteins, thereby promoting DNA synthesis complex assembly and cell proliferation. Both p56Lyn Y32 and MCM7 Y600 phosphorylation are enhanced in proliferating cells and correlated with poor survival of breast cancer patients. These results establish a signaling cascade in which EGFR enhances MCM7 phosphorylation and DNA replication through Lyn phosphorylation in human cancer cells. [Copyright &y& Elsevier]