EGFR-TKI-induced Factor V deficiency in a patient with advanced non-small cell lung cancer: The first case report.

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is routinely prescribed as first-line therapy for advanced non-small cell lung cancer, regardless of the presence of the T790M resistance mutation. This study reports a rare case of Factor V inhibitor detection during osimertinib therapy in a patient with lung adenocarcinoma. These findings underscore the importance of vigilant monitoring for coagulation abnormalities during EGFR-TKI therapy.

Case report: EGFR-TKI rechallenge after osimertinib-induced interstitial lung disease: a case report and literature review.

Background: Osimertinib, a third-generation tyrosine kinase inhibitor (TKI), has demonstrated significant efficacy in treating non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. However, EGFR-TKI-induced interstitial lung disease (ILD), a well-known adverse effect, can seriously affect the treatment outcome. There is currently no international consensus on the efficacy and safety of re-administration of EGFR-TKI after EGFR-TKI-induced ILD. Case summary: We report a case of a 62-year-old male with stage IV lung adenocarcinoma and EGFR L858R mutation who was treated with osimertinib at a dose of 80 mg/day as first-line therapy. On the sixth day of treatment, the patient developed grade 4 ILD, chest tightness, shortness of breath, and paroxysmal dry cough. Arterial blood gas analysis indicated the presence of type I respiratory failure, while the chest CT scan revealed newly developed ground-glass opacities in both lungs and a considerable amount of pleural effusion on the left side. Subsequently, the patient was administered methylprednisolone for anti-inflammatory therapy, in conjunction with oxygen therapy, anti-infection treatment, and closed thoracic drainage, which resulted in a favourable recovery and discharge after 18 days. During this period, the patient adhered to third-generation EGFR-TKI oral targeted therapy. Nevertheless, within a week of discharge, the patient was readmitted due to the recurrence of chest tightness and shortness of breath. A chest CT scan indicated a recurrent ILD. Despite the administration of high-dose methylprednisolone for 9 days, the patient's condition continued to deteriorate, ultimately resulting in death. Conclusion: It is of the utmost importance to conduct a meticulous evaluation of the severity of osimertinib-induced ILD in order to ascertain the potential risks and benefits of EGFR-TKI rechallenge. Particularly, for patients with grade 4 ILD, firm drug discontinuation should be considered.

Association between epidermal growth factor receptor-tyrosine kinase inhibitors and venous thromboembolism among older patients with advanced non-small cell lung cancer.

BACKGROUND: Venous thromboembolism (VTE) risk is higher among patients with non-small cell lung cancer (NSCLC) and specific subgroups, including the elderly, but little is known about the VTE risk of different generations of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and whether the risk differs by demographic characteristics. This study aims to compare the risk of VTE (deep venous thromboembolism [DVT]; pulmonary embolism [PE]) between a third-generation EGFR-TKI and first/second-generation EGFR-TKIs and stratify VTE risk by sex, age, and race/ethnicity in third-generation EGFR-TKI users. METHODS: Via the 2006-2019 Surveillance, Epidemiology, and End Results-Medicare database, this retrospective cohort study included older patients (aged ≥65 years) with advanced NSCLC who initiated on a third-generation EGFR-TKI (n = 493) and first/second-generation EGFR-TKIs (n = 1036). We estimated the hazard ratio (HR) and its 95% confidence interval (95% CI) with the Cox proportional hazards model. RESULTS: A third-generation EGFR-TKI had a significantly higher VTE risk than first/second-generation EGFR-TKIs (HR, 1.26 [95% CI, 1.01-1.57]; p = .037), with an elevated risk in males (HR, 2.16 [95% CI, 1.47-3.19]; p < .001), patients aged ≥75 years (HR, 1.38 [95% CI, 1.04-1.83]; p = .026), and non-Hispanic Whites (HR, 1.46 [95% CI, 1.10-1.95]; p = .010). Males consistently showed a significantly higher risk of DVT (HR, 2.49 [95% CI, 1.29-4.80]; p = .007) and PE (HR, 2.00 [95% CI, 1.29-3.11]; p = .002). A significantly higher risk of DVT (HR, 1.54 [95% CI, 1.00-2.37]; p = .050) and PE (HR, 1.47 [95% CI, 1.06-2.05]; p = .021) was shown in patients aged ≥75 years and non-Hispanic Whites, respectively. Among third-generation EGFR-TKI users, non-Hispanic Whites had a significantly higher risk of VTE (HR, 2.04 [95% CI, 1.03-4.02]; p = .041) and PE (HR, 2.88 [95% CI, 1.24-6.70]; p = .014) than non-Hispanic Asian/Pacific Islanders. CONCLUSIONS: Close monitoring of VTE events in high-risk patients is essential to promote early diagnosis and treatment.

Onset of takotsubo syndrome induced by osimertinib in a patient with lung adenocarcinoma.

The cardiotoxicity of osimertinib, an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, has been recently reported when treating EGFR mutation-positive non-small cell lung cancer. In this report, we describe a case of an 81-year-old female patient diagnosed with Takotsubo syndrome (TTS). TTS occurred despite the patient receiving osimertinib retreatment at reduced doses and having no history of cardiac or respiratory disease. The findings of this case suggest that clinicians should consider the possibility of TTS induced by osimertinib.

Osimertinib­induced erythromelalgia: A case report.

The present study reports a case of osimertinib-induced erythromelalgia in a patient with metastatic lung adenocarcinoma. Osimertinib is an antineoplastic drug that irreversibly inhibits the epidermal growth factor receptor (EGFR) pathway by binding to the intracellular receptor tyrosine kinase site, thus preventing EGFR signal transduction. A 77-year-old female with a lung adenocarcinoma recurrence with secondary metastases was prescribed osimertinib therapy. The patient presented with painful erythema and warmth in the distal phalanges of all fingers on both hands, which worsened with heat and relieved with cold. Based on clinical data, erythromelalgia was diagnosed. Considering the age of onset, a primary erythromelalgia was ruled out. Further investigations excluded other secondary causes of erythromelalgia, therefore osimertinib was suspected as the cause. Although no cases of EGFR inhibitor-induced erythromelalgia have been reported, cutaneous adverse events induced by EGFR inhibitors have been documented. The present case may be the first evidence of osimertinib-induced erythromelalgia and may help clinicians to properly support patients who develop this EGFR inhibitor adverse event.

Impact of sequential (first- to third-generation) EGFR-TKI treatment on corrected QT interval in NSCLC patients.

Objective: To evaluate the impact of sequential (first- to third-generation) epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment on top-corrected QT interval (top-QTc) in non-small cell lung cancer (NSCLC) patients. Methods: We retrospectively reviewed the medical records of NSCLC patients undergoing sequential EGFR-TKI treatment at Shanghai Chest Hospital between October 2016 and August 2021. The heart rate (HR), top-QT interval, and top-QTc of their ECGs were extracted from the institutional database and analyzed. Logistic regression was performed to identify predictors for top-QTc prolongation. Results: Overall, 228 patients were enrolled. Compared with baseline (median, 368 ms, same below), both first-generation (376 ms vs. 368 ms, p < 0.001) and sequential third-generation EGFR-TKIs (376 ms vs. 368 ms, p = 0.002) prolonged top-QT interval to a similar extent (p = 0.635). Top-QTc (438 ms vs. 423 ms, p < 0.001) and HR (81 bpm vs.79 bpm, p = 0.008) increased after first-generation EGFR-TKI treatment. Further top-QTc prolongation (453 ms vs. 438 ms, p < 0.001) and HR increase (88 bpm vs. 81 bpm, p < 0.001) occurred after treatment advanced. Notably, as HR elevated during treatment, top-QT interval paradoxically increased rather than decreased, and the top-QTc increased rather than slightly fluctuated. Moreover, such phenomena were more significant after treatment advanced. After adjusting for confounding factors, pericardial effusion and lower serum potassium levels were independent predictors of additional QTc prolongation during sequential third-generation EGFR-TKI treatment. Conclusion: First-generation EGFR-TKI could prolong top-QTc, and sequential third-generation EGFR-TKI induced further prolongation. Top-QT interval paradoxically increased and top-QTc significantly increased as HR elevated, which was more significant after sequential EGFR-TKI treatment. Pericardial effusion and lower serum potassium levels were independent predictors of additional QTc prolongation after sequential EGFR-TKI treatment.

Prognostic impact of concomitant pH-regulating drugs in patients with non-small cell lung cancer receiving epidermal growth factor receptor tyrosine kinase inhibitors: the Tokushukai REAl-world Data project 01-S1.

PURPOSE: This study aimed to examine the prognostic impact of concomitant pH-regulating drug use in patients with epidermal growth factor receptor (EGFR)-mutation-positive non-small-cell lung cancer (NSCLC) receiving EGFR-tyrosine kinase inhibitors (TKIs). METHODS: We conducted a nationwide retrospective cohort study and reviewed clinical data of consecutive patients with NSCLC treated with the first-line EGFR-TKIs in 46 hospitals between April 2010 and March 2020. Cox regression analyses were conducted to examine the differences in overall survival (OS) between patients treated with and without concomitant pH-regulating drugs, including potassium-competitive acid blockers (P-CABs), proton pump inhibitors (PPIs), and H2-receptor antagonists (H2RAs). RESULTS: A total of 758 patients were included in the final dataset, of which 307 (40%) were administered concomitant pH-regulating drugs while receiving frontline EGFR-TKIs. After adjusting for basic patient characteristics, patients administered gefitinib, erlotinib, afatinib, and osimertinib with concomitant pH-regulating drugs had lower OS than those without concomitant pH-regulating drugs, with hazard ratios of 1.74 (with a 95% confidence interval of 1.34-2.27), 1.33 (0.80-2.22), 1.73 (0.89-3.36), and 5.04 (1.38-18.44), respectively. The 2-year OS rates of patients receiving gefitinib with or without concomitant pH-regulating drugs were 65.4 and 77.5%, those for erlotinib were 55.8 and 66.6%, and those for afatinib were 63.2 and 76.9%, respectively. The 1-year OS rates of patients receiving osimertinib with or without concomitant pH-regulating drugs were 88.1% and 96.9%, respectively. CONCLUSION: In addition to the first-generation EGFR-TKIs, the second- and third-generation EGFR-TKIs also resulted in OS deterioration in patients with EGFR mutation-positive NSCLC when used concurrently with pH-regulating drugs.

Bilateral keratitis associated with afatinib therapy.

This case discussed a significant ocular side effect, bilateral keratitis, which could be induced by afatinib, an irreversible epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). We explored the disease progression of a 52-year-old, stage IV nasopharyngeal carcinoma male patient, who was under afatinib treatment and had experienced progressive bilateral eye dryness and tenderness on increasing afatinib from 40 mg every other day to 40 mg daily. Clinical examination noted bilateral visual acuity reduction, diffuse superficial punctate keratopathy in the right eye, and a central epithelial defect in the left eye. Seidel test results were negative for both eyes, with no corneal infiltration, lagophthalmos, anterior chamber cell precipitation, or retinal lesion. Symptoms subsequently resolved after reducing the frequency of afatinib used, along with intensive ocular hydration. In summary, this case highlighted afatinib's potential link to bilateral keratitis, and early afatinib dose adjustment with supportive medication could significantly reverse the condition.

Prognostic implications of combining EGFR-TKIs and radiotherapy in Stage IV lung adenocarcinoma with 19-Del or 21-L858R mutations: A real-world study.

OBJECTIVE: To elucidate the potential benefits of combining radiotherapy and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) for individuals with Stage IV lung adenocarcinoma (LUAD) harboring either exon 19 deletion (19-Del) or exon 21 L858R mutation (21-L858R). METHODS: In this real-world retrospective study, 177 individuals with Stage IV LUAD who underwent EGFR-TKIs and radiotherapy at Shandong Cancer Hospital from June 2012 to August 2017 were included. The main focus of this real-world study was overall survival (OS). RESULTS: The clinical characteristics of patients with Stage IV LUAD harboring 19-Del were similar to those harboring 21-L858R (p > 0.05). Overall, the patients had a median OS (mOS) of 32.0 months (95% confidence interval [CI]: 28.6-35.5). Subsequently, multivariate analysis indicated that both EGFR mutations and thoracic radiotherapy were independent predictors of OS (p = 0.001 and 0.013). Furthermore, subgroup analysis highlighted a longer OS for the 19-Del group compared to the 21-L858R group, especially when EGFR-TKIs were combined with bone metastasis or thoracic radiotherapy (mOS: 34.7 vs. 25.1 months and 51.0 vs. 29.6 months; p = 0.0056 and 0.0013, respectively). However, no significant differences were found in OS when considering patients who underwent brain metastasis radiotherapy (mOS: 34.7 vs. 25.1 months; p = 0.088). CONCLUSIONS: Patients with Stage IV LUAD harboring 19-Del experience a notably prolonged OS following combined therapy with EGFR-TKIs and radiotherapy, while this OS benefit is observed despite the absence of substantial differences in the clinical characteristics between the 19-Del and 21-L858R groups.

Negative impact of ratio of the microvascular area to tumor area on the response to EGFR-TKI in non-small cell lung cancer with an EGFR mutation.

Background: The clinical impact of tumor microvessels on the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutation-positive non-small cell lung cancer (NSCLC) is unclear. Thus, the aim of this study was to investigate whether a tumor microenvironment, abundant in microvessels, affects EGFR-TKI efficacy in patients with NSCLC and EGFR mutations. Methods: We retrospectively studied the data of 40 post-operative patients with recurrent NSCLC and EGFR mutations who received EGFR-TKIs as a first-line treatment at Kumamoto University Hospital from January 2010 to February 2021. Tumor sections were retrieved from the tissue registry and analyzed for CD34-positive microvessels using immunohistochemical techniques. The ratio of microvascular area to tumor area (RMV), which is the CD34-positive microvascular area compared to the total tumor area, was measured using StrataQuest. The predictive value of RMV on treatment outcome, assessed via progression-free survival (PFS), was evaluated using a multivariate Cox proportional hazard model. Results: The median PFS in the high RMV group (≥0.058) was significantly shorter than that in the low RMV group [<0.058; 296 days, 95% confidence interval (CI): 217-374 vs. 918 days, 95% CI: 279-1,556, P=0.002]. Multivariate analysis revealed that high RMV was an independent negative predictor of PFS (hazard ratio, 3.21; 95% CI: 1.18-8.76, P=0.022). Conclusions: High RMV may critically affect EGFR-TKI resistance in patients with NSCLC and EGFR mutations.

Feasibility and safety of EGFR-TKI neoadjuvant therapy for EGFR-mutated NSCLC: A meta-analysis.

BACKGROUND: The role of neoadjuvant epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) targeted therapy for EGFR-mutated non-small cell lung cancer (NSCLC) is unclear. Previous studies have shown that EGFR-TKIs have excellent anti-tumor activity. However, almost all studies on neoadjuvant EGFR-TKI treatment for EGFR-mutated NSCLC have been non-randomized controlled trials with small sample sizes and different methods of statistical analysis, which may lead to a lack of valid metrics to assess the feasibility and safety of neoadjuvant EGFR-TKI treatment. This meta-analysis aimed to assess the efficacy and safety of neoadjuvant EGFR-TKI treatment for NSCLC patients with EGFR mutations. METHODS: Relevant studies were systematically searched in PubMed, Embase, and Web of Science databases. Results including objective response rate (ORR), complete resection rate (R0), downstaging rate, pathological complete response (PCR), major pathological response (MPR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were used for further analysis. RESULTS: This meta-analysis ultimately included 11 studies involving 344 patients with EGFR-positive mutations in NSCLC. In terms of tumor response, the pooled ORR was 57% (95% CI: 42%-73%), and in the Osimertinib subgroup, the pooled ORR was 80% (95% CI: 63%-98%). Analysis of studies that reported a downstaging rate showed the pooled downstaging rate of 41% (95% CI: 9%-74%) and the pooled downstaging rate of 74% (95% CI: 22%-100%) in the Osimertinib subgroup. In terms of surgical outcomes, the pooled pCR rate was 3% (95% CI: 0%-7%), the pooled MPR rate was 11% (95% CI: 6%-17%), and the pooled R0 resection rate was 91% (95% CI: 85%-95%). The most common adverse events associated with neoadjuvant therapy were rash and diarrhea. The pooled incidence of any grade of rash was 47.1% (95% CI: 25.4%-69.3%), and the pooled incidence of grade ≥ 3 rash was 0.6% (95% CI: 0.0%-2.5%). The pooled incidence of diarrhea of any grade was 28.8% (95% CI: 14.4%-45.4%), with the pooled incidence of grade ≥ 3 diarrhea of 0.2% (95% CI: 0.0%-1.6%). The pooled incidence of ≥ grade 3 adverse events was significantly lower. CONCLUSIONS: Our meta-analysis confirmed the efficacy and safety of neoadjuvant EGFR-TKIs for the treatment of NSCLC patients with EGFR-positive mutations and that third-generation EGFR-TKIs were superior to first- and second-generation EGFR-TKIs in terms of shrinking tumor volume and lowering tumor stage; however, future large-scale and multicenter randomized controlled trials are needed to confirm this conclusion. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023466731.

EGFR-TKI rechallenge in patients with EGFR-mutated non-small-cell lung cancer who progressed after first-line osimertinib treatment: A multicenter retrospective observational study.

BACKGROUND: Rechallenge therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is known to confer some clinical benefit for patients with metastatic EGFR-mutated non-small cell lung cancer (NSCLC). However, little is known about the efficacy of EGFR-TKI rechallenge after resistance to first-line (1L) osimertinib. This study aimed to assess the efficacy and safety of EGFR-TKI rechallenge therapy after resistance to 1L osimertinib in a Japanese clinical setting. METHODS: Between April 2018 and August 2022, 26 patients who progressed after treatment with 1L osimertinib and received EGFR-TKI rechallenge were included in this multicenter retrospective analysis. Patients in whom 1L osimertinib was discontinued owing to toxicity and had subsequent disease progression were also included in the analysis. RESULTS: Overall, the objective response rate for rechallenge therapy was 23.1%. The disease control rate was 53.9%, and the median progression-free survival (PFS) was 3.4 months. Patients who discontinued 1L osimertinib for toxicity had a higher response rate (42.9% vs. 15.8%) and longer PFS than those who discontinued it due to disease progression (median: 11.4 vs. 2.7 months, P = 0.001). Three patients (11.5%) developed rechallenge therapy-associated pneumonitis, two of which were grade ≥3. CONCLUSIONS: Rechallenge with EGFR-TKI after 1L osimertinib resistance showed limited clinical efficacy. However, it could be considered as a subsequent salvage therapeutic option for patients in whom 1L osimertinib was discontinued owing to toxicity.

The impact of comorbidities, neutrophil-to-lymphocyte ratio, and drug toxicities on quality of life in lung cancer patients receiving EGFR-TKI therapy.

BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are used as the standard first-line treatment for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, the impact of comorbidities and treatment toxicities on quality of life (QoL) was seldom investigated. OBJECTIVE: We aimed to investigate the association of comorbidities, adverse events (AEs), and QoL in treatment-naïve advanced NSCLC patients receiving EGFR-TKI treatments. METHODS: This multi-center prospective observational study was conducted to evaluate QoL and AEs at baseline, the 2nd, 4th, 12th, and 24th week. Clinical characteristics, comorbidities, and pre-treatment laboratory data were recorded. QoL was assessed by using the summary score of the EORTC QLQ-C30 and the dermatology life quality index. The impact of comorbidities, neutrophil-to-lymphocyte ratio (NLR), and AEs on QoL was analyzed by generalized estimating equations. RESULTS: A total of 121 patients were enrolled. Diarrhea (p = 0.033), anorexia (p < 0.001), and NLR ≥4 (p = 0.017) were significantly associated with a QoL impairment. Among skin toxicities, acneiform rash (p = 0.002), pruritus (p = 0.002), visual analogue scale for pruritus (≥3 and < 7, p = 0.006; ≥7, p = 0.001) and pain (1-3, p = 0.041) were associated with a QoL impairment. No significant association was found between comorbidities and QoL changes. CONCLUSION: Diarrhea, anorexia, skin pain, and pruritus may cause a deterioration in QoL in patients receiving EGFR-TKI therapy. NLR may be a potential predictive factor for QoL impairment. Aggressive management and close monitoring for these clinical factors are crucial to improve QoL.

Stepwise prolongation of overall survival from first to third generation EGFR-TKIs for EGFR mutation-positive non-small-cell lung cancer: the Tokushukai REAl-world Data project (TREAD 01).

OBJECTIVE: The introduction of new-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has afforded promising overall survival outcomes in clinical trials for non-small-cell lung cancer. We aim to investigate the current adoption rate of these agents and the real-world impact on overall survival among institutions. METHODS: In a nationwide retrospective cohort study of 46 Tokushukai Medical Group hospitals in Japan, we analyzed clinical data of consecutive patients with non-small-cell lung cancer receiving EGFR-TKIs between April 2010 and March 2020. Univariate and multivariate Cox regression analyses examined the associations between overall survival and patient/tumor-related factors and first-line EGFR-TKIs. RESULTS: A total of 758 patients (58.5% females; median age, 73 years) were included. Of 40 patients diagnosed in 2010, 72.5% received gefitinib, whereas 81.3% of 107 patients diagnosed in 2019 received osimertinib as the first-line EGFR-TKI. With a median follow-up of 15.8 months, the median overall survival was 28.4 months (95% confidence interval, 15.3-31.0). In a multivariate Cox regression analysis, age, body mass index, disease status, EGFR mutational status and first-line epidermal growth factor receptor tyrosine kinase inhibitor were identified as significant prognostic factors after adjusting for background factors including study period, hospital volume and hospital type. The estimated 2-year overall survival rates for gefitinib, erlotinib, afatinib and osimertinib were 70.1% (95% confidence interval 59.7-82.4), 67.8% (95% confidence interval 55.3-83.2), 75.5% (95% confidence interval 64.7-88.0) and 90.8% (95% confidence interval 84.8-97.3), respectively. The median time to treatment failure of gefitinib, erlotinib, afatinib and osimertinib were 12.8, 8.8, 12.0 and 16.9 months or more, respectively. CONCLUSIONS: Our real-world data revealed that the swift and widespread utilization of newer-generation EGFR-TKIs in patients with EGFR mutation-positive non-small-cell lung cancer, and that these newer-generation EGFR-TKIs can prolong overall survival regardless of hospital volume or type. Therefore, osimertinib could be a reasonable first choice treatment for these patients across various clinical practice settings.

The advance of the third­generation EGFR­TKI in the treatment of non­small cell lung cancer (Review).

Lung cancer is currently the second most common type of cancer with the second incidence rate and the first mortality rate worldwide. Non­small cell lung cancer (NSCLC) accounts for ~85% of the total number of cases of lung cancers. Concerning the treatment of NSCLC, targeted therapy has become a research hotspot in recent years because of its favorable efficacy, high selectivity and minimal adverse reactions. Among the drugs used in targeted therapy, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the most common and are categorized into four generations. The use of first and second­generation drugs leads to drug resistance within 8­14 months. This resistance is primarily caused by the T790M mutation, which is the most observed mechanism. A third­generation drug has been developed to address this issue and a fourth­generation drug is expected to overcome multiple resistance mechanisms, including third­generation drug resistance. However, the fourth­generation drug has not been launched yet. At present, multiple third­generation targeted drugs have been launched globally, with three being launched in China and several being at research and clinical trial stages. The present article provides a review of the development process, mechanism of action and clinical trials of the third­generation EGFR­TKIs, aiming to provide some reference and suggestions for the clinical treatment of NSCLC and scientific research on third­generation targeted drugs.

Osimertinib versus comparator first-generation epidermal growth factor receptor tyrosine kinase inhibitors as first-line treatment in patients with advanced EGFR-mutated non-small cell lung cancer: a Chinese, multicenter, real-world cohort study.

Background: In the phase 3 FLAURA trial, osimertinib was compared with first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) as a first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). Osimertinib showed longer progression-free survival (PFS), overall survival (OS), and a similar safety profile. However, more studies demonstrating the effectiveness and safety of osimertinib as a first-line strategy are needed in real-world populations. Methods: We enrolled 1,556 patients with EGFR-mutated stage IIIc-IV NSCLC from the CAPTRA-Lung database. All patients received either osimertinib (n=202) or a first-generation EGFR-TKI (n=1,354) as their initial treatment. To adjust for differences in baseline characteristics between two groups, 1:2 propensity score matching (PSM) was performed. Propensity scores included gender, age, Eastern Cooperative Oncology Group performance status score, smoking history, family history of tumor, pathology, EGFR mutations, and central nervous system (CNS) metastases. The standardized mean differences (SMD) before and after PSM were calculated to examine the balance of covariate distributions between two groups. Results: After PSM, 202 patients receiving osimertinib and 404 patients receiving first-generation EGFR-TKIs were finally identified. SMD of each matched variable is less than 0.10. The median PFS was 19.4 months [95% confidence interval (CI): 14.3-24.4] in the osimertinib arm and 10.9 months (95% CI: 9.3-12.5) in the comparator arm [hazard ratio (HR) for progression, 0.47; 95% CI: 0.38-0.59; P<0.001). The median OS was 40.5 months (95% CI: 27.1-54.0) vs. 34.3 months (95% CI: 30.6-38.0) in two groups, respectively (HR for death, 0.76; 95% CI: 0.58-1.00; P=0.045). The incidence of grade 3 adverse events (AEs) between the two groups was 1% and 4.2%, respectively. No grade 4 AEs and treatment-related deaths were reported in both groups. Conclusions: In real-world settings, osimertinib demonstrates longer PFS and OS, with a similar safety profile to that of comparator EGFR-TKIs when used as a first-line strategy in NSCLC patients.

Efficacy and safety of anti-programmed cell death protein 1 antibody combination therapy in patients with advanced experienced epidermal growth factor receptor-tyrosine kinase inhibitor-resistant lung adenocarcinoma: a retrospective cohort study.

Background: The effectiveness of combining anti-programmed cell death protein 1 (PD-1) and chemotherapy has been evaluated as superior to that of chemotherapy alone in the patients with advanced epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-resistant non-small cell lung cancer (NSCLC). In this study the efficacy and safety of anti-PD-1 combination therapy were evaluated retrospectively in patients who experienced EGFR-TKI-resistant with advanced lung adenocarcinoma (LUAD), with the goal of providing helpful guidance for clinical application. Methods: The clinical results of patients with incurable LUAD who received anti-PD-1 antibody combined with or without anti-angiogenic or chemotherapy after EGFR-TKI therapy failure were collected. The efficacy was calculated based on the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The efficacy of the regimes was compared according to treatment groups and programmed cell death ligand 1 (PD-L1) expression. Results: The final analysis included a total of 43 patients with advanced EGFR-mutant LUAD. The overall cohort had an ORR of 23.3%, median PFS (mPFS) of 6.5 months, and median OS (mOS) of 10.6 months. No notable distinction was observed in mPFS and mOS among patients receiving three types of anti-PD-1 antibody combination therapies. Patients with positive PD-L1 expression showed a longer mPFS compared to patients with negative PD-L1 expression. No statistical difference was detected in terms of mPFS between the use of immune combination chemotherapy and immune combination anti-angiogenic therapy in the PD-L1 positive subgroup, and PFS was prolonged regardless of the PD-L1 expression status being positive or negative in the population receiving immune combination chemotherapy. Treatment-related adverse events (TRAEs) of grade 3 or higher were observed in 16.3% of patients, including chemotherapy-containing immunotherapy. No deaths resulting from immune-related adverse events (irAEs) were reported, and only 1 patient receiving immunotherapy plus chemotherapy had to discontinue treatment due to irAEs. Conclusions: Combination immunotherapy is feasible in post-TKI resistant individuals with LUAD harboring EGFR mutations. Immune combination chemotherapy and immune combination anti-angiogenic therapy have equivalent efficacy in the PD-L1 positive population. PD-L1 expression can be used as a reference for screening candidates for combination immunotherapy.

EGFR Tyrosine Kinase Inhibitor Lazertinib Activates a Subset of Mouse Sensory Neurons Via TRPA1.

Lazertinib (JNJ-73841937, YH25448) is a mutant-selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor targeting both the T790M and activating mutation while sparing wild-type epidermal growth factor receptor. Paresthesia is one of the most common adverse events seen with lazertinib treatment, suggesting that lazertinib could affect the sensory nervous system. However, the mechanism of action for this paresthesia remains unclear. In this study, we investigated whether and how lazertinib affects peripheral sensory neurons. Through Fura-2-based calcium imaging and whole-cell patch clamp recording in primary-cultured dorsal root ganglion (DRG) neurons from adult mice, we found that application of lazertinib elicits spontaneous calcium responses in a subset of small-to-medium-sized neurons. Moreover, lazertinib induced spontaneous firings and hyperexcitability in a subset of transient receptor potential vanilloid 1-lineage DRG neurons and sensitized transient receptor potential ankyrin 1 (TRPA1) response, while sparing transient receptor potential vanilloid 1 response. Lazertinib-responsive neurons were also responsive to capsaicin, further supporting that lazertinib selectively activates nociceptive neurons. Lazertinib-induced calcium responses were pharmacologically blocked with HC-030031 (TRPA1 antagonist) and MDL-12330A (adenylyl cyclase inhibitor), suggesting that lazertinib activates sensory neurons through indirect activation of TRPA1. However, unlike vincristine which produces peripheral neuropathy by axonal degeneration, lazertinib did not cause neurite fragmentation in cultured DRG neurons. Finally, intraplantar injection of lazertinib induced TRPA1-dependent pain-like behaviors in vivo. Collectively, our data suggest a direct effect of lazertinib on nociceptive sensory neurons via TRPA1 selective mechanisms, which could be a putative mechanism of lazertinib-induced sensory abnormalities in clinical patients. PERSPECTIVE: This article presents a TRPA1-dependent, lazertinib-induced activation of mouse sensory neurons in vitro and lazertinib-induced pain-like behaviors in vivo. The same mechanisms may underlie the clinical condition, suggesting that TRPA1 could be a potential therapeutic target to manage lazertinib-induced paresthesia.

A real-world study and network pharmacology analysis of EGFR-TKIs combined with ZLJT to delay drug resistance in advanced lung adenocarcinoma.

OBJECTIVE: This study aimed to explore the efficacy and safety of combining epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) with ZiLongJin Tablet (ZLJT) in delaying acquired resistance in advanced EGFR-mutant lung adenocarcinoma (LUAD) patients. Furthermore, we employed network pharmacology and molecular docking techniques to investigate the underlying mechanisms. METHODS: A retrospective comparative study was conducted on stage IIIc/IV LUAD patients treated with EGFR-TKIs alone or in combination with ZLJT at the Second Affiliated Hospital of the Air Force Medical University between January 1, 2017, and May 1, 2023. The study evaluated the onset of TKI resistance, adverse reaction rates, safety indicators (such as aspartate aminotransferase, alanine aminotransferase, and creatinine), and inflammatory markers (neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio) to investigate the impact of EGFR-TKI combined with ZLJT on acquired resistance and prognostic indicators. Additionally, we utilized the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine, PubChem, UniProt, and Swiss Target Prediction databases to identify the active ingredients and targets of ZLJT. We obtained differentially expressed genes related to EGFR-TKI sensitivity and resistance from the Gene Expression Omnibus database using the GSE34228 dataset, which included sensitive (n = 26) and resistant (n = 26) PC9 cell lines. The "limma" package in R software was employed to detect DEGs. Based on this, we constructed a protein‒protein interaction network, performed gene ontology and KEGG enrichment analyses, and conducted pathway network analysis to elucidate the correlation between the active ingredients in ZLJT and signaling pathways. Finally, molecular docking was performed using AutoDockVina, PYMOL 2.2.0, and Discovery Studio Client v19.1.0 software to simulate spatial and energy matching during the recognition process between predicted targets and their corresponding compounds. RESULTS: (1) A total of 89 patients were included, with 40 patients in the EGFR-TKI combined with ZLJT group (combination group) and 49 patients in the EGFR-TKI alone group (monotherapy group). The baseline characteristics of the two groups were comparable. There was a significant difference in the onset of resistance between the combination group and the monotherapy group (P < 0.01). Compared to the monotherapy group, the combination group showed a prolongation of 3.27 months in delayed acquired resistance. There was also a statistically significant difference in the onset of resistance to first-generation TKIs between the two groups (P < 0.05). (2) In terms of safety analysis, the incidence of adverse reactions related to EGFR-TKIs was 12.5% in the combination group and 14.3% in the monotherapy group, but this difference was not statistically significant (P > 0.05). There were no statistically significant differences in serum AST, ALT, CREA, TBIL, ALB and BUN levels between the two groups after medication (P > 0.05). (3) Regarding inflammatory markers, there were no statistically significant differences in the changes in neutrophil-to-lymphocyte Ratio(NLR) and Platelet-to-lymphocyte Ratio(PLR) values before and after treatment between the two groups (P > 0.05). (4) Network pharmacology analysis identified 112 active ingredients and 290 target genes for ZLJT. From the GEO database, 2035 differentially expressed genes related to resistant LUAD were selected, and 39 target genes were obtained by taking the intersection. A "ZLJT-compound-target-disease" network was successfully constructed using Cytoscape 3.7.0. GO enrichment analysis revealed that ZLJT mainly affected biological processes such as adenylate cyclase-modulating G protein-coupled receptor. In terms of cellular components, ZLJT was associated with the cell projection membrane. The molecular function primarily focused on protein heterodimerization activity. KEGG enrichment analysis indicated that ZLJT exerted its antitumor and anti-drug resistance effects through pathways such as the PI3K-Akt pathway. Molecular docking showed that luteolin had good binding activity with FOS (-9.8 kJ/mol), as did tanshinone IIA with FOS (-9.8 kJ/mol) and quercetin with FOS (-8.7 kJ/mol). CONCLUSION: ZLJT has potential antitumor progression effects. For patients with EGFR gene-mutated non-small cell LUAD, combining ZLJT with EGFR-TKI treatment can delay the occurrence of acquired resistance. The underlying mechanisms may involve altering signal transduction pathways, blocking the tumor cell cycle, inhibiting tumor activity, enhancing cellular vitality, and improving the bioavailability of combination therapy. The combination of EGFR-TKI and ZLJT represents an effective approach for the treatment of tumors using both Chinese and Western medicine.

Comparing Efficacy of Erlotinib and Bevacizumab Combination with Erlotinib Monotherapy in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC): A Systematic Review and Meta-Analysis.

The objective of this systematic review and meta-analysis was to assess and contrast the efficacy and safety of combining erlotinib and bevacizumab with erlotinib alone in the treatment of patients with advanced non-small cell lung cancer (NSCLC). The authors searched databases such as PubMed, Medline, Scopus, and Cochrane Central Register of Controlled Trials for randomized control trials (RCTs) comparing erlotinib plus bevacizumab with erlotinib in NSCLC patients. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) were the outcomes of interest. The pooled hazard ratio (HR) and relative risk (RR) were estimated utilizing both fixed- and random-effect models. Methodological quality of the included studies was assessed using the Cochrane Risk of Bias tool. Nine studies comprising 1698 patients with NSCLC were included in this meta-analysis, of whom 850 were treated with erlotinib plus bevacizumab, and 848 with erlotinib. The erlotinib plus bevacizumab combination significantly prolonged PFS (HR, 0.62, 95% CI: 0.56, 0.70, p < 0.00001) but did not show any significant improvement in OS (HR, 0.95; 95% CI: 0.83, 1.07, p = 0.39) and ORR (HR, 1.10; 95% CI: 0.98, 1.24, p = 0.09). Increased risks of hypertension (RR, 5.15; 95% CI: 3.59, 7.39; p < 0.00001), proteinuria (RR, 10.54; 95% CI: 3.80, 29.20; p < 0.00001) and grade 3 and higher AEs (RR, 2.09; 95% CI: 1.47, 2.97; p < 0.00001) were observed with the erlotinib-plus-bevacizumab combination compared to erlotinib monotherapy. On subgroup analyses, the erlotinib plus bevacizumab combination improved PFS only. Combining erlotinib and bevacizumab has been shown to improve PFS in advanced NSCLC patients but did not show any significant OS and ORR benefits. Furthermore, risks of hypertension, proteinuria, and grade 3 or higher AEs were greater with the erlotinib-and-bevacizumab combination.