Analysis of genomic alternations in epidermal growth factor receptor (EGFR)-T790M-mutated non-small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib therapy.

BACKGROUND AND OBJECTIVES: Genomic alterations after resistance to osimertinib therapy in advanced T790M-mutated non-small cell lung cancer (NSCLC) are complex and poorly understood. In this study, we aimed to detect these genomic alternations via comprehensive next-generation sequencing (NGS) of tissue and liquid biopsies. PATIENTS AND METHODS: From September 2020 to June 2021, 31 stage IIIB/IV T790M-mutated NSCLC patients who exhibited progressive disease after osimertinib therapy and provided written informed consent were recruited. Liquid and tissue biopsy samples for NGS testing were collected from 31 and 18 patients, respectively. Eighteen study patients had paired NGS data from tissue and liquid biopsies. RESULTS: With respect to the T790M mutation status, the preservation and loss rates were 33% and 67%, respectively, in both liquid and tissue biopsy samples. Five patients (16.1%) had the C797S mutation (4 liquid samples and 1 tissue sample). Two (6.5%) had MET mutations, 3 (9.7%) had BRAF-V600E mutations, and 1 (3.2%) had a KRAS-G12C mutation. Among the 18 patients who underwent tissue rebiopsies, those with preserved T790M mutation had significantly longer progression-free survival (PFS) with osimertinib therapy than those with T790M mutation loss (10.8 vs. 5.0 months, P = 0.045). Among all patients, those with T790M mutation loss in liquid biopsy samples had longer PFS after osimertinib therapy (10.8 vs. 7.5 months, P = 0.209) and postprogression survival (17.7 vs. 9.6 months, P = 0.132) than those with preserved T790M mutation based on liquid biopsies. CONCLUSIONS: NGS using either tissue or liquid biopsy samples from advanced T790M-mutated NSCLC patients with acquired resistance to osimertinib therapy can detect various genomic alternations. Future studies focusing on subsequent tailored therapies on the basis of NGS results are warranted.

The antitumor activity of osimertinib plus palbociclib in non-small cell lung cancer patient-derived xenograft (PDX)/2D/3D culture models harboring EGFR amplification and CDKN2A/2B homozygous deletions.

Non-small cell lung cancer (NSCLC) patients without targetable driver mutation have limited treatment options. In this study, we aimed to explore a new therapeutic strategy by using established nine patient-derived xenograft (PDX) and two-dimensional (2D) /3D culture models with specific genetic alternations. The gene mutations and copy number aberrations were detected by next-generation sequencing and confirmed using polymerase chain reaction (PCR) followed by DNA sequencing, and genomic DNA quantitative PCR. Protein expression was evaluated by immunohistochemistry. Drug sensitivities of PDX/2D/3D models were evaluated by in vivo and in vitro antitumor assays. RNA interference was performed to silence gene expression. Our study found that 44.4 % (4/9) of cases had CDKN2A homozygous deletion (homdel), while 33.3 % (3/9) had CDKN2B homdel. Additionally, 22.2 % (2/9) had amplification (amp) in wildtype CDK4, 44.4 % (4/9) in CDK6, and 44.4 % (4/9) in EGFR. Among the cases, 77.8 % (7/9) lacked CDKN2A, and 33.3 % (3/9) had high CDK4, CDK6, and EGFR had high protein expression. Moreover, 33.3 % (3/9) had KRAS mutations, and 66.7 % (6/9) had TP53 mutations. Antitumor activity of osimertinib plus palbociclib was assessed in four PDX/2D/3D models, two of which had simultaneous EGFR amp and CDKN2A/2B homdel. The data showed that NSCLC with EGFR amp and CDKN2A/2B homdel were sensitive to combined drugs. Additional oncogenic KRAS mutation reduced the drug's antitumor effect. EGFR amp is responsible for osimertinib sensitivity. Osimertinib plus palbociclib effectively treat NSCLC with wildtype EGFR and CDK6 amp and CDKN2A/2B homdel in the absence of oncogenic KRAS mutation.

Subcutaneous Versus Intravenous Amivantamab, Both in Combination With Lazertinib, in Refractory Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer: Primary Results From the Phase III PALOMA-3 Study.

PURPOSE: Phase III studies of intravenous amivantamab demonstrated efficacy across epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy. PATIENTS AND METHODS: Patients with EGFR-mutated advanced NSCLC who progressed after osimertinib and platinum-based chemotherapy were randomly assigned 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Coprimary pharmacokinetic noninferiority end points were trough concentrations (Ctrough; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUCD1-D15). Key secondary end points were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory end point. RESULTS: Overall, 418 patients underwent random assignment (subcutaneous group, n = 206; intravenous group, n = 212). Geometric mean ratios of Ctrough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04 to 1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27 to 1.61) at cycle-4-day-1; the cycle-2 AUCD1-D15 was 1.03 (90% CI, 0.98 to 1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42 to 0.92; nominal P = .02). Fewer patients in the subcutaneous group experienced infusion-related reactions (IRRs; 13% v 66%) and venous thromboembolism (9% v 14%) versus the intravenous group. Median administration time for the first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab and to 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; the end-of-treatment rates were 85% and 35%, respectively. CONCLUSION: Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced IRRs, increased convenience, and prolonged survival.

A Clinical Analysis of Anti-Programmed Death-Ligand 1 (PD-L1) Immune Checkpoint Inhibitor Treatments Combined with Chemotherapy in Untreated Extensive-Stage Small-Cell Lung Cancer.

Real-world clinical experience of using anti-programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) combined with chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer (SCLC) patients has rarely been reported. In this study, we aimed to perform a retrospective multicenter clinical analysis of extensive-stage SCLC patients receiving first-line therapy with anti-PD-L1 ICIs combined with chemotherapy. Between November 2018 and March 2022, 72 extensive-stage SCLC patients receiving first-line atezolizumab or durvalumab in combination with chemotherapy, according to the cancer center databases of Linkou, Chiayi, and Kaohsiung Chang Gung Memorial Hospitals, were retrospectively included in the analysis. Twenty-one patients (29.2%) received atezolizumab and fifty-one (70.8%) received durvalumab. Objective response (OR) and disease control (DC) rates of 59.7% and 73.6%, respectively, were observed with first-line ICI plus chemotherapy. The median progression-free survival (PFS) was 6.63 months (95% confidence interval (CI), 5.25-8.02), and the median overall survival (OS) was 16.07 months (95% CI, 15.12-17.0) in all study patients. A high neutrophil-to-lymphocyte ratio (NLR; >4) and a high serum lactate dehydrogenase (LDH) concentration (>260 UL) were identified as independent unfavorable factors associated with shorter OS in the multivariate analysis. Regarding safety, neutropenia was the most common grade 3 treatment-related adverse event (AE), but no treatment-related deaths occurred in the study patients. First-line anti-PD-L1 ICIs combined with chemotherapy are effective and safe for male extensive-stage SCLC patients. Further therapeutic strategies may need to be developed for patients with unfavorable outcomes (e.g., baseline high NLR and serum LDH level).

Urinary cadmium concentration is associated with the severity and clinical outcomes of COVID-19: a bicenter observational cohort study.

BACKGROUND: Cadmium and nickel exposure can cause oxidative stress, induce inflammation, inhibit immune function, and therefore has significant impacts on the pathogenesis and severity of many diseases. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also provoke oxidative stress and the dysregulation of inflammatory and immune responses. This study aimed to assess the potential associations of cadmium and nickel exposure with the severity and clinical outcomes of patients with coronavirus disease 2019 (COVID-19). METHODS: We performed a retrospective, observational, bicenter cohort analysis of patients with SARS-CoV-2 infection in Taiwan between June 2022 and July 2023. Cadmium and nickel concentrations in blood and urine were measured within 3 days of the diagnosis of acute SARS-CoV-2 infection, and the severity and clinical outcomes of patients with COVID-19 were analyzed. RESULTS: A total of 574 patients were analyzed and divided into a severe COVID-19 group (hospitalized patients) (n = 252; 43.9%), and non-severe COVID-19 group (n = 322; 56.1%). The overall in-hospital mortality rate was 11.8% (n = 68). The severe COVID-19 patients were older, had significantly more comorbidities, and significantly higher neutrophil/lymphocyte ratio, C-reactive protein, and interleukin-6 than the non-severe COVID-19 patients (all p < 0.05). Blood and urine cadmium and urine nickel concentrations were significantly higher in the severe COVID-19 patients than in the non-severe COVID-19 patients. Among the severe COVID-19 patients, those in higher urine cadmium/creatinine quartiles had a significantly higher risk of organ failure (i.e., higher APACHE II and SOFA scores), higher neutrophil/lymphocyte ratio, lower PaO2/FiO2 requiring higher invasive mechanical ventilation support, higher risk of acute respiratory distress syndrome, and higher 60-, 90-day, and all-cause hospital mortality (all p < 0.05). Multivariable logistic regression models revealed that urine cadmium/creatinine was independently associated with severe COVID-19 (adjusted OR 1.643 [95% CI 1.060-2.547], p = 0.026), and that a urine cadmium/creatinine value > 2.05 µg/g had the highest predictive value (adjusted OR 5.349, [95% CI 1.118-25.580], p = 0.036). CONCLUSIONS: Urine cadmium concentration in the early course of COVID-19 could predict the severity and clinical outcomes of patients and was independently associated with the risk of severe COVID-19.

Effectiveness and safety of afatinib, gefitinib, and erlotinib for treatment-naïve elderly patients with epidermal growth factor receptor-mutated advanced non-small-cell lung cancer: a multi-institute retrospective study.

BACKGROUND: In real-world practice, most patients with lung cancer are diagnosed when they are aged ≥65 years. However, clinical trials tend to lack data for the elderly population. Therefore, we aimed to describe the effectiveness and safety of afatinib, gefitinib, and erlotinib for elderly patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC). METHODS: Treatment-naïve patients with EGFR-mutated advanced NSCLC were enrolled at many hospitals in Taiwan. Patient characteristics and the effectiveness and safety of afatinib, gefitinib, and erlotinib were compared. RESULTS: This study enrolled 1,343 treatment-naïve patients with EGFR-mutated advanced NSCLC, of whom 554 were aged <65 years, 383 were aged 65-74 years, 323 were aged 75-84 years, and 83 were aged ≥85 years. For elderly patients, afatinib was more effective, with a median progression-free survival (PFS) of 14.7 months and overall survival (OS) of 22.2 months, than gefitinib (9.9 months and 17.7 months, respectively) and erlotinib (10.8 months and 18.5 months, respectively; PFS: p = 0.003; OS: p = 0.026). However, grade ≥3 adverse events, including skin toxicities, paronychia, mucositis, and diarrhea, were more frequently experienced by patients receiving afatinib than those receiving gefitinib or erlotinib. CONCLUSIONS: This large retrospective study provides real-world evidence of the effectiveness and safety of EGFR-TKIs for elderly patients with EGFR-mutated advanced NSCLC, a population that is often underrepresented in clinical trials and real-world evidence. Afatinib was more effective as a first-line treatment than gefitinib or erlotinib for elderly patients with EGFR-mutated advanced NSCLC.

Differential prognostic value of tumor and plasma T790M mutations in EGFR TKI-treated advanced NSCLC.

Background: Substitution of methionine for threonine at codon 790 (T790M) of epidermal growth factor receptor (EGFR) represents the major mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer. We determined the prognostic impact and association of secondary T790M mutations with the outcomes of osimertinib and chemotherapy. Methods: Patients (n = 460) progressing from first-line EGFR-TKI treatment were assessed. Tissue and/or liquid biopsies were used to determine T790M status; post-progression overall survival (OS) was analyzed. Results: Overall, 143 (31.1%) patients were T790M positive, 95 (20.7%) were T790M negative, and 222 (48.2%) had unknown T790M status. T790M status [T790M positive versus T790M negative: hazard ratio (HR) 0.48 (95% confidence interval (CI), 0.32-0.70); p < 0.001, T790M unknown versus T790M negative: HR 1.97 (95% CI, 1.47-2.64); p < 0.001] was significantly associated with post-progression OS. T790M positivity rates were similar for tissue (90/168, 53.6%) and liquid (53/90, 58.9%) biopsies (Fisher's exact test, p = 0.433). Tumor T790M-positive patients had significantly longer post-progression OS than tumor T790M-negative patients (34.1 versus 17.1 months; log-rank test, p = 8 × 10-5). Post-progression OS was similar between plasma T790M-positive and -negative patients (17.4 versus not reached; log-rank test, p = 0.600). In tumor T790M-positive patients, post-progression OS was similar after osimertinib and chemotherapy [34.1 versus 29.1 months; log-rank test, p = 0.900; HR 1.06 (95% CI, 0.44-2.57); p = 0.897]. Conclusion: T790M positivity predicts better post-progression OS than T790M negativity; tumor T790M positivity has a stronger prognostic impact than plasma T790M positivity. Osimertinib and chemotherapy provide similar OS benefits in patients with T790M-positive tumors.

Different prognostic meaning of tumor resistant gene detected from tumor or blood in patients with EGFR-mutant lung cancer The study demonstrates that patients with EGFR-mutant lung cancer who develop resistance due to a secondary T790M mutation, defined by tumor or blood T790M positivity, achieve better survival than patients without secondary T790M mutation; this association was mainly contributed by tumour T790M positivity. Oismertinib and chemotherapy led to similar survival in tumour T790M-positive patients. However, compared to osimertinib, chemotherapy was associated with longer survival in blood T790M-positive patients.

Factors associated with prolonged progression-free survival of patients treated with first-line afatinib for advanced epidermal growth factor receptor-mutated non-small cell lung cancer.

BACKGROUND: This study aimed to investigate the factors associated with prolonged progression-free survival (PFS) (>36 months) of advanced non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations treated with first-line afatinib. METHODS: We performed a retrospective analysis of data of patients with advanced EGFR-mutated NSCLC receiving first-line afatinib at two tertiary care referral centers, Linkou and Kaohsiung Chang Gung Memorial Hospital, in Taiwan between June 2014 and April 2022. RESULTS: The data of 546 treatment-naïve EGFR-mutated advanced NSCLC patients were analyzed. Median PFS and overall survival were 14.5 months and 27.2 months, respectively. The PFS of 462 patients (84.6%) was less than 36 months and of 84 patients (15.4%) was more than 36 months. The PFS > 36 months group had a significantly higher percentage of patients with uncommon mutations (p = 0.002). The PFS ≤36 months group had significantly higher incidences of bone, liver, and adrenal metastases (all p < 0.05) and a higher rate of multiple distant metastases. Multivariate logistic regression analysis showed that liver metastasis was negatively and independently associated with prolonged PFS (adjusted odds ratio = 0.246 [95% CI: 0.067-0.908], p = 0.035). The median overall survival of the PFS >36 months group was 46.0 months and that of the PFS ≤36 months group was 22.9 months (log-rank test, p < 0.001). CONCLUSIONS: We found that EGFR-mutated NSCLC patients receiving first-line afatinib were prone to shorter PFS if they had distant organ metastasis, especially liver metastasis.

Brain metastasis, EGFR mutation subtype and generation of EGFR-TKI jointly influence the treatment outcome of patient with EGFR-mutant NSCLC.

Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation is brain metastasis (BM)-prone. We determined the impact of this hallmark, along with EGFR subtype and generation of tyrosine kinase inhibitor (TKI) treatment, on patients' outcome. 553 metastatic EGFR-mutant NSCLC patients received front-line EGFR-TKI treatment. Progression-free survival (PFS), overall survival (OS) and secondary T790M rate were analysed. BM was observed in 211 (38.2%) patients. BM (HR 1.20 [95% CI 0.99-1.48]; p = 0.053), ECOG PS 0-1 (HR 0.71 [95% CI 0.54-0.93]; p = 0.014) and afatinib treatment (HR 0.81 [95% CI 0.66-0.99]; p = 0.045) were associated with PFS. Afatinib-treated patients without BM demonstrated a significantly longer PFS (16.3 months) compared to afatinib-treated patients with BM (13.7 months) and to gefitinib/erlotinib-treated patients with (11.1 months) or without BM (14.2 months; p < 0.001). CNS-only progression trended higher in afatinib-treated patients. ECOG PS 0-1 (HR 0.41 [95% CI 0.31-0.56]; p < 0.001) and EGFR L858R mutation (HR 1.46 [95% CI 1.13-1.88]; p = 0.003), but not BM, were the predictors for OS. BM (OR 2.02 [95% CI 1.02-4.08]; p = 0.040), afatinib treatment (OR 0.26 [95% CI 0.12-0.50]; p < 0.001) and EGFR L858R mutation (OR 0.55 [95% CI 0.28-1.05]; p = 0.070) were associated with secondary T790M rate. In BM patients, gefitinib/erlotinib-treated ones with 19 deletion mutation and afatinib-treated ones with L858R mutation had the highest and the lowest T790M rate (94.4% vs. 27.3%, p < 0.001), respectively. BM and generation of EGFR-TKI jointly impact PFS and secondary T790M rate in patients with EGFR-mutant NSCLC, whereas OS was mainly associated with EGFR subtype.

Generation and validation of a predictive model for estimating survival among patients with EGFR-mutant non-small cell lung cancer.

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become the standard therapy for patients with EGFR-mutant non-small cell lung cancer (NSCLC), treatment outcomes vary significantly. Previous studies have indicated that concurrent mutations may compromise the effectiveness of first-line EGFR-TKIs. However, given the high cost of next-generation sequencing, this information is often inaccessible in routine clinical practice. A prediction model based on pre-treatment clinical characteristics may thus offer a more practical solution. This study established a nomogram based on pretreatment clinical characteristics to stratify patients according to optimal treatment strategies. We retrospectively reviewed 761 patients with EGFR-mutant NSCLC who received first- or second-generation EGFR-TKIs at a tertiary referral center between 2010 and 2019. The pretreatment clinical characteristics and progression-free survival data were collected. Using COX proportional hazard regression analysis, we constructed a nomogram based on seven clinically significant prognostic factors: sex, Eastern Cooperative Oncology Group performance status, histology subtype, mutation subtype, stage, and metastasis to the liver and brain. Our nomogram could stratify patients into three groups with different risks for disease progression and was validated in a patient cohort from other hospitals. This risk stratification can provide additional information for determining the optimal first-line treatment strategy for patients with EGFR-mutant NSCLC.

Sequential treatment in advanced epidermal growth factor receptor-mutated lung adenocarcinoma patients receiving first-line bevacizumab combined with 1st/2nd-generation EGFR-tyrosine kinase inhibitors.

Introduction: The clinical outcomes of sequential treatment of advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients with first-line bevacizumab combined with 1st/2nd-generation EGFR-TKIs are unclear. Thus, we aimed to analyze the outcomes of these patients. Methods: Between January 2015 and December 2020, data for 102 advanced EGFR-mutated lung adenocarcinoma patients receiving first-line bevacizumab combined with erlotinib or afatinib followed by treatments at multiple institutions were retrospectively analyzed. All patients with progressive disease (PD) after first-line therapy underwent secondary T790M mutation detection. Results: The secondary T790M mutation positive rate of all study patients was 57.9%. First-line erlotinib use and progression-free survival (PFS) after first-line therapy > 12 months were positively associated with the T790M mutation (P <0.05). The response rates (RRs) to second-line treatments were 51.7% and 22.7% for the osimertinib and nonosimertinib groups, respectively (P = 0.001). The median PFS associated with second-line osimertinib and nonosimertinib therapy was 13.7 and 7.1 months, respectively (hazard ratio (HR) = 0.38; 95% confidence interval (CI), 0.23-0.63; P< 0.001). Patients with a secondary T790M mutation receiving second-line osimertinib treatment had a median overall survival (OS) of 54.3 months, and the median OS was 31.9 months for non-T790M-mutated patients receiving second-line nonosimertinib treatments (HR = 0.36; CI: 0.21-0.62, P < 0.001). Conclusion: The majority of acquired resistance to first-line bevacizumab combined with 1st/2nd-generation EGFR-TKIs is associated with the T790M mutation. Sequential osimertinib treatment in patients with positive secondary T790M mutation is associated with better outcomes among these patients.

Clinical outcome analysis of non-small cell lung cancer patients with brain metastasis receiving metastatic brain tumor resection surgery: a multicenter observational study.

Brain metastasis is most common in primary non-small cell lung cancer (NSCLC), and some patients require neurosurgical resection for intracranial disease control. Because advances in systemic therapies for metastatic NSCLC have been developed in the past decade, we aimed to analyze and determine clinical factors associated with the postresection survival of NSCLC patients with brain metastasis who underwent neurosurgery followed by systemic therapy. Between January 2017 and December 2021, data for 93 NSCLC patients with brain metastasis treated with neurosurgery followed by systemic therapy at Linkou, Kaohsiung and Chiayi Chang Gung Memorial Hospitals were retrospectively retrieved for analysis. For all study patients, median postresection survival was 34.36 months (95% confidence interval (CI), 28.97-39.76), median brain metastasis (BM)-free survival was 26.90 months (95% CI, 22.71-31.09), and overall survival (OS) was 41.13 months (95% CI, 34.47-47.52). In multivariate analysis, poor performance status (Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2) and concurrent liver metastasis were identified as independent unfavorable factors associated with significantly shortened postresection survival (P<0.001). The histological type adenocarcinoma was associated with significantly longer postresection survival (P = 0.001). The median postresection survival for adenocarcinoma and nonadenocarcinoma patients was 36.23 and 10.30 months, respectively (hazard ratio (HR) = 0.122; 95% CI, 0.035-0.418; P<0.001); that for patients with and without concurrent liver metastasis was 11.43 and 36.23 months, respectively (HR = 22.18; 95% CI, 5.827-84.459; P<0.001). Patients with preserved ECOG PS, adenocarcinoma histology type and no concurrent liver metastasis appeared to have better postresection survival than nonadenocarcinoma patients. Our results provide counseling and decision-making references for neurosurgery feasibility in NSCLC patients with brain metastasis.

Comprehensive assessment of pretreatment sarcopenia impacts on patients with EGFR-mutated NSCLC treated with afatinib.

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.

Afatinib in Untreated Stage IIIB/IV Lung Adenocarcinoma with Major Uncommon Epidermal Growth Factor Receptor (EGFR) Mutations (G719X/L861Q/S768I): A Multicenter Observational Study in Taiwan.

BACKGROUND: Real-world clinical experience with afatinib as a treatment for advanced lung adenocarcinoma harboring uncommon epidermal growth factor receptor (EGFR) mutations (G719X, L861Q and S768I) has rarely been reported. OBJECTIVE: We aimed to perform a retrospective multicenter study to analyze afatinib therapy in untreated advanced lung adenocarcinoma harboring uncommon EGFR mutations. PATIENTS AND METHODS: Between May 2014 and June 2021, the data of 90 stage IIIB/IV lung adenocarcinoma patients with uncommon EGFR mutations (G719X/L861Q/S768I) treated with first-line afatinib from the cancer center database of Linkou, Tucheng, and Kaohsiung Chang Gung Memorial Hospitals were retrospectively retrieved and analyzed. RESULTS: Afatinib had an objective response rate (ORR) of 63.3% and a disease control rate (DCR) of 86.7%. The median progression-free survival (PFS) with first-line afatinib therapy was 17.3 months (95% confidence interval (CI), 12.07-22.53), and the median overall survival (OS) was 28.5 months (95% CI, 20.22-36.77) in all study patients. In the multivariate analysis, poor performance (Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2) and brain and liver metastases were independent predictors of unfavorable PFS. The G719X mutation (alone+compound) was an independent predictor of favorable PFS (hazard ratio (HR) = 0.578; 95% CI, 0.355-0.941; P = 0.027). Most afatinib-related adverse events (AEs) were limited to grades 1 and 2 and were manageable. CONCLUSIONS: First-line afatinib therapy is effective and safe for advanced lung adenocarcinoma harboring uncommon EGFR mutations. The G719X mutation was an independent factor associated with a favorable outcome. Poor performance (ECOG PS ≥ 2), brain metastasis, and liver metastasis were predictive factors of shorter PFS with first-line afatinib therapy.

Bevacizumab-Induced Thrombotic Microangiopathy (TMA) in Metastatic Lung Adenocarcinoma Patients Receiving Nivolumab Combined with Bevacizumab, Carboplatin and Paclitaxel: Two Case Reports.

Anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs), combined with bevacizumab and platinum-based chemotherapy, have shown promising efficacy in treating metastatic non-squamous cell lung cancer in phase 3 clinical trials. However, drug-induced nephrotoxicity is an uncommon but threatening adverse effect when using this combination therapy, and should be evaluated and managed carefully. Here, we present two patients experiencing late-onset asymptomatic heavy proteinuria during the clinical trial. Kidney biopsies performed finally identified bevacizumab-induced thrombotic microangiopathy (TMA), and the proteinuria was decreased after discontinuing bevacizumab permanently. Our report suggests that a kidney biopsy is needed for those receiving ICIs in combination with bevacizumab and chemotherapy and experiencing nephrotoxicity such as heavy proteinuria.

Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer harboring uncommon EGFR mutations: Real-world data from Taiwan.

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.

The survival after discontinuation of EGFR-TKIs due to intolerable adverse events in patients with EGFR-mutated non-small cell lung cancer.

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.

Zinc deficiency associated with cutaneous toxicities induced by epidermal growth factor receptor tyrosine kinase inhibitor therapy in patients with lung adenocarcinoma.

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.

The cancer stemness inhibitor napabucasin suppresses small cell lung cancer growth through SOX2 expression.

Small cell lung cancer (SCLC) is a high-grade malignancy of neuroendocrine origin characterized by aggressive cell growth and a poor survival rate of patients. Currently, the treatment options for SCLC remain limited despite platinum-based chemotherapy. Systemic chemotherapy is effective for SCLC, but most patients eventually acquire drug resistance, which leads to treatment failure. Stemness-high cancer cells show characteristics of advanced tumorigenesis and metastasis and have high potential in promoting treatment resistance and disease relapse. Napabucasin (BBI608), a novel small-molecule drug targeting on signal transducer and activator of transcription 3 (STAT3), was shown to suppress the progression and metastasis of stemness-high cancer stem cells in various cancers. Here, we demonstrated that napabucasin significantly decreased viability and colony formation and induced the arrest of S-phase cell cycle and apoptosis in cisplatin-resistant SCLC cells. Findings from mechanistic studies further indicated that napabucasin directly downregulated the expression of SOX2 in cisplatin-resistant SCLC cells; however, dysfunctional SOX2 expression in SCLC cells was associated with interference in the napabucasin-mediated reduction of cell viability. In contrast, napabucasin-induced viability reduction was restored in these cells when SOX2 expression was upregulated. Furthermore, napabucasin significantly inhibited cisplatin-resistant SCLC cell xenograft growth in vivo by downregulating SOX2 and inducing apoptosis. These data demonstrate that napabucasin may be a novel drug for the clinical treatment of cisplatin-resistant SCLC.

Impact of T790M Mutation Status on Later-Line Osimertinib Treatment in Non-Small Cell Lung Cancer Patients.

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.