EGFR-mutated lung cancer as a secondary neoplasm in a patient with Li-Fraumeni syndrome: case report.

Background: Li-Fraumeni syndrome (LFS) is a rare hereditary disorder caused by mutations in the tumor protein p53 (TP53). It causes a predisposition for the development of multiple malignancies, primarily including breast cancers, sarcomas, and central nervous system tumors. There are a few cases reported in the literature of patients with LFS presenting with an epidermal growth factor receptor (EGFR) mutated lung cancer. Still, it has been suggested that there may be an association between the TP53 pathogenic variant and lung cancer with EGFR mutation in somatic cells. Case Description: A 47-year-old non-smoker woman with LFS with a history of multiple tumors, including bilateral breast cancer, pecoma, and sarcoma. In one of her computed tomography, a lesion in the lingula of the lung was detected. It was biopsied, which diagnosed lung adenocarcinoma, and genetic studies detected an EGFR exon 19 deletion. She was treated with a left inferior lobectomy, followed by pemetrexed and cisplatin. Conclusions: The association between TP53 and lung cancer with EGFR mutation has been suggested in case reports. Studies in lung cancer cell lines have shown a link between TP53 mutation and EGFR overexpression. Nonetheless, as more cases are reported, further research is needed to comprehend the interrelation between these two pathologies and the risk posed by LFS to the emergence of EGFR-mutated lung cancer.

High-cost treatments for advanced lung cancer in Japan (Lung Cancer Study Group of the Japan Clinical Oncology Group).

BACKGROUND: The treatment of lung cancer has made dramatic progress in the past decade, but due to the high cost of drugs, the total pharmaceutical cost has been rising explosively. There are currently no data available in Japan on which regimens are used, to what extent they are used, and what their total cost is. METHODS: Sixty Japanese centers belonging to the Lung Cancer Study Group of the Japan Clinical Oncology Group were surveyed for information about the first-line treatment for advanced lung cancer in practice from July 2021 to June 2022. Three types of cancer were included: driver gene mutation-negative NSCLC, EGFR mutation-positive NSCLC, and extensive-stage small cell lung cancer (ES-SCLC). RESULTS: Recent treatment costs for ICIs or ICI plus chemotherapy were about 20-55 times higher than those for conventional chemotherapy. Of the 3738 patients with driver gene aberration-negative NSCLC, 2573 (68.8%) received treatments with monthly cost of 500 000 Japanese yen (JPY) or more; 2555 (68.4%) received ICI therapy. Of the 1486 patients with EGFR mutation-positive NSCLC, 1290 (86.8%) received treatments with a monthly cost of 500 000 JPY or more; 1207 (81.2%) received osimertinib. ICI treatments with a monthly cost of 500 000 JPY or more were administered to 607 (56.3%) of 1079 patients with ES-SCLC. Elderly NSCLC patients received slightly more high-cost treatment than younger patients. CONCLUSION: Recent treatments cost many times more than conventional chemotherapy. This study revealed that high-cost treatments were widely used in advanced lung cancer and some of high-cost treatments were used despite the lack of clear evidence. Physicians should pay attention to the cost of treatments they use.

Real-World Treatment Patterns and Clinical Outcomes Among Patients with Metastatic or Unresectable EGFR-Mutated Non-Small Cell Lung Cancer Previously Treated with Osimertinib and Platinum-Based Chemotherapy.

INTRODUCTION: For patients with epidermal growth factor receptor-mutated (EGFRm) locally advanced/metastatic non-small cell lung cancer (mNSCLC) whose disease has progressed on or after osimertinib and platinum-based chemotherapy (PBC), no uniformly accepted standard of care exists. Moreover, limited efficacy of standard treatments indicates an unmet medical need, which is being addressed by ongoing clinical investigations, including the HERTHENA-Lung01 (NCT04619004) study of patritumab deruxtecan (HER3­DXd). However, because limited information is available on real-world clinical outcomes in such patients, early-phase trials of investigational therapies lack sufficient context for comparison. This study describes the real-world clinical characteristics, treatments, and outcomes for patients with EGFRm mNSCLC who initiated a new line of therapy following previous osimertinib and PBC, including a subset matched to the HERTHENA-Lung01 population. METHODS: This retrospective analysis used a US database derived from deidentified electronic health records. The reference cohort included patients with EGFRm mNSCLC who had initiated a new line of therapy between November 13, 2015 and June 30, 2021, following prior osimertinib and PBC. A subset of patients resembling the HERTHENA-Lung01 population was then extracted from the reference cohort; this matched subset was optimized using propensity score (PS) weighting. Endpoints were real-world overall survival (rwOS) and real-world progression-free survival (rwPFS). Confirmed real-world objective response rate (rwORR; partial/complete response confirmed ≥ 28 days later) was calculated for the response-evaluable subgroups of patients (with ≥ 2 response assessments spaced ≥ 28 days apart). RESULTS: In the reference cohort (N = 273), multiple treatment regimens were used, and none was predominant. Median rwPFS and rwOS were 3.3 and 8.6 months, respectively; confirmed rwORR (response evaluable, n = 123) was 13.0%. In the matched subset (n = 126), after PS weighting, median rwPFS and rwOS were 4.2 and 9.1 months, respectively; confirmed rwORR (response evaluable, n = 57) was 14.1%. CONCLUSION: The treatment landscape for this heavily pretreated population of patients with EGFRm mNSCLC is fragmented, with no uniformly accepted standard of care. A high unmet need exists for therapeutic options that provide meaningful improvements in clinical benefit.

Management of oligometastatic and oligoprogressive epidermal growth factor receptor mutated non-small cell lung cancer patients: state of the art of a combined approach.

Recently, the development of targeted therapy approaches such as those based on tyrosine kinase inhibitor (TKI) greatly improved the clinical outcomes of patients affected by oncogene addicted advanced non-small cell lung cancer (NSCLC). Similarly, the improvement of radiation therapy techniques has permitted to deliver high radiation doses to a limited number of metastatic target lesions (oligopersistent or oligoprogressive), with limited high-dose normal tissue exposure that leads to low severe toxicity rates. The aim of this narrative review was to provide an overview of the currently established definition of oligometastatic and oligoprogressive disease, to define first line and subsequent lines targeted therapies and the role of consolidative non-invasive local ablative treatments (LATs) in these settings. The potential benefit of local treatment (LT) such as radiotherapy (RT) or surgery might be represented by an overall reduction of switching to subsequent systemic treatments lowering the risk of further systemic dissemination. Further randomized clinical trials will clarify the role of LT and their correct timing in relation to systemic targeted therapies.

[Selection of postoperative adjuvant therapy for patients with stage IB lung adenocarcinoma: analysis of 653 cases].

OBJECTIVE: To explore the optimal postoperative adjuvant regimens for patients with stage IB lung adenocarcinoma. METHODS: We respectively analyzed the data of 653 patients undergoing surgery for stage IB lung adenocarcinoma in our hospital from January, 2013 to December, 2021. The 5-year disease-free survival (DFS) and overall survival (OS) rates were compared among the patients receiving postoperative adjuvant therapy with epidermal growth factor-tyrosine kinase inhibitors (EGFR-TKIs group, n=111), chemotherapy (CT group, n=108) and clinical observation (CO group, n=434). RESULTS: In TKIs, CT, and CO groups, the 5-year DFS rates were 92.8%, 80.7%, and 81.7%, respectively, significantly higher in TKIs group than in CO group (P < 0.01). The 3-year OS rates of the 3 groups were 96.8%, 97.1%, and 91.7%, respectively. Subgroup analysis showed that in TKIs, CT, and CO groups, the 5-year DFS rates of patients with with T3-4 cmN0M0 were 92.6%, 84.0%, and 81.4%, respectively, significantly higher in TKIs group than in CO group (P < 0.05); the 5-year DFS rates of T2ViscPlN0M0 patients were 95.1%, 71.4%, and 83.5%, respectively. Multivariate COX regression analysis showed that age (P < 0.05; HR=0.631, 95% CI: 0.401-0.993), solid nodules (P < 0.01; HR=7.620, 95% CI: 3.037-19.121), micropapillary or solid component (P < 0.05; HR= 1.776, 95% CI: 1.010-3.122), lymphovascular invasion (P < 0.05; HR=2.981, 95% CI: 1.198-7.419), and adjuvant therapy (P < 0.01) were independent predictors of DFS. The most common adverse effects included rashes, paronychia, and diarrhea for TKIs and hematological suppression and gastrointestinal reactions for chemotherapy, and TKIs were associated with a higher incidence of grade 3 or above adverse effects (44.4% vs 9.0%). CONCLUSION: Adjuvant therapy with TKIs helps improve DFS in patients with stage IB (T3-4cmN0M0) lung adenocarcinoma but not in patients with T2ViscPlN0M0. Adjuvant chemotherapy does not improve DFS or OS in patients with stage IB lung adenocarcinoma.

Salvage surgery following tyrosine kinase inhibitor treatment for advanced non-small cell lung cancer.

BACKGROUND: No standard therapy for non-small lung cancer patients that have acquired resistance to tyrosine kinase inhibitor (TKI) therapy has been established. Some can be effectively treated by salvage surgery, though indications for that procedure remain unclear. Reported here is the clinical course of a patient who experienced early post-operative distant metastases. CASE PRESENTATION: A 48-year-old woman without symptoms was referred to another hospital for abnormal chest radiography findings and diagnosed with adenocarcinoma of the left lower lobe (cT2aN3M1b, stage IVB; TNM staging 7th edition). Gene mutation analysis revealed positive for epidermal growth factor receptor exon 19 deletion. Afatinib treatment was started, resulting in partial response, though regrowth of the main tumor was noted 1.5 years later. Bronchoscopic re-biopsy findings revealed a T790M point mutation and afatinib was switched to osimertinib. At 1.5 years following the start of osimertinib administration, the primary tumor was found to have regrown again and stereotactic radiation therapy was administered. Findings at 3.5 years after osimertinib administration indicated that all lymph nodes and distant metastases, excluding the primary tumor, were well controlled, and the patient was referred to our hospital for salvage surgery. Osimertinib was discontinued, and a left lower lobectomy with a left lingular segmentectomy and pleural biopsy were performed. The patient was discharged following an uneventful postoperative course. Three days after discharge, glossodynia developed and examination findings revealed tongue metastasis. The symptoms improved following re-administration of osimertinib, though right adrenal gland metastasis appeared 8 months after surgery. Radiation therapy was performed for tongue and right adrenal gland metastases, and the patient was alive 1 year after salvage surgery without out-of-control lesion appearing after the radiation therapy under the administration of osimertinib. CONCLUSION: The present patient experienced multiple instances of systemic recurrence after undergoing salvage surgery. Experience with this case indicates that systemic therapy is essential for patients with distant metastatic lung cancer even following salvage surgery for the primary tumor.

Genomic evolutional analysis of surgical resected specimen to assess osimertinib as a first-line therapy in two patients with lung cancer harboring EGFR mutation: Case series.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is crucial for patients with lung cancer harboring EGFR mutations. However, almost all patients experience disease progression, regardless of their response to the targeted therapy, necessitating the development of additional treatment options. Two patients with lung cancer harboring EGFR-L858R mutations in exon 21 were treated by surgical resection during successful osimertinib treatment. Because the pathological diagnosis was suspected to be pleural metastasis, osimertinib treatment was continued until disease progression. We analyzed the evolution of genomic alterations and the levels of AXL using tumor specimens obtained by repeated biopsies during the course of treatment: initial diagnosis, operation, and disease progression. Genetic alterations detected at the three time points were dramatically changed and showed reductions in numbers, while EGFR-L858R mutations were detected in all samples tested in both patients. Immunohistochemical expression of AXL remained positive from the beginning of analysis to disease progression. Clonal evolution under oncogenesis is related to gradual accumulation of genomic alterations during tumor growth. However, our case series revealed that volume reduction procedures may cause this phenomenon. Therefore, identification of intrinsic drug-resistant cells in tumors may be as important as detection of acquired genetic alterations.

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.

Effect of Tegafur-Uracil in Resected Stage IB Lung Adenocarcinoma According to Presence or Absence of Epidermal Growth Factor Receptor Gene Mutation: A Retrospective Cohort Study.

PURPOSE: Tegafur-uracil (UFT) is the standard postoperative adjuvant therapy for stage IB lung adenocarcinoma (LUAD) in Japan. This study aimed to determine whether UFT is effective in stage IB LUAD with and without epidermal growth factor receptor (EGFR) mutations. METHODS: This retrospective study included 169 patients with stage IB LUAD who underwent complete resection at our department between 2010 and 2021. We investigated the clinicopathological and prognostic impact of EGFR mutations as well as the postoperative use of UFT. RESULTS: EGFR mutation-positive cases tended to show a higher cumulative recurrence rate than EGFR mutation-negative cases (p = 0.081), while overall survival was comparable between the groups (p = 0.238). In the entire cohort, UFT administration was not an independent prognostic factor in the multivariate regression analysis (p = 0.112). According to a stratification analysis, UFT administration was independently associated with favorable overall survival (p = 0.031) in EGFR mutation-negative cases, while it was not associated with recurrence-free survival (p = 0.991) or overall survival (p = 0.398) in EGFR mutation-positive cases. CONCLUSION: UFT administration can improve the prognosis of EGFR mutation-negative LUAD but not EGFR mutation-positive LUAD. Thus, clinical trials of adjuvant-targeted therapy for EGFR mutation-positive stage IB LUAD should also be conducted in Japan.

SMARCA4­deficient non­small cell lung cancer with an EGFR mutation: A case report.

SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4)-deficient non-small cell lung cancer (dNSCLC) is a rare malignant tumor that originates in the lungs. It occurs more frequently in male smokers, and the epidermal growth factor receptor (EGFR) gene is often mutation-free. In the present study, the case of a 60-year-old, non-smoking female patient diagnosed with SMARCA4-dNSCLC is reported. Biopsy of the tumor showed solid flaky, nest-like infiltrating growth. Immunohistochemistry revealed the following: SMARCA4/BRG1(-), SMARCB1/INI-1(+), cytokeratin7 (+), cytokeratin 5.2 (+), CK5/6(+) and calretinin(+). The Ki-67 positivity index was 75%, and the thyroid transcription factor-1, NapsinA, p40, nuclear protein in testis, CD34, Sal-like protein 4, SRY-box transcription factor 2 and synaptophysin were negative. Molecular analysis showed mutations in both EGFR and TP53. The pathological diagnosis was SMARCA4-dNSCLC with an EGFR gene mutation. The present case report could be used for broadening the pathological diagnosis of SMARCA4-dNSCLC and for selecting appropriate treatment approaches.

Long-term follow-up of a consecutive cohort validating an epidermal growth factor receptor mutation as an independent risk factor for postoperative recurrence in lung adenocarcinoma.

OBJECTIVES: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were recently reported to be effective as adjuvant therapy for resected lung adenocarcinoma (ADC) harbouring common EGFR mutations. However, whether the EGFR mutation is a direct risk factor for postoperative recurrence remains unknown. Therefore, we conducted a multi-institutional observational study to compare postoperative survival according to EGFR mutation status. METHODS: We collected the medical records of consecutive patients who underwent surgical resection for ADC between 2005 and 2012 at 4 participating institutions. Recurrence-free survival (RFS) and overall survival (OS) associated with EGFR mutation status were evaluated. We further analysed survival after pair-matching patients' clinicopathological characteristics. RESULTS: EGFR mutations were harboured by 401 of 840 (48%) enrolled patients. The number of patients with an EGFR mutation (M group) differed from that with the EGFR wild-type sequence (W group) in terms of sex, smoking history and pathological stage. The median follow-up period was 85 months. The five-year RFS/OS rates of the M and W groups were 70%/85% and 61%/75%, respectively (P < 0.001 for both groups). However, multivariable analysis revealed that EGFR mutation status was not independently related with both RFS and OS. In pair-matched analysis, the RFS and OS curves of the patients with an EGFR mutation and wild-type sequence were not statistically different, either. CONCLUSIONS: Long-term follow-up of consecutive patients did not show that a common EGFR mutation was an independent risk factor of recurrence or prognostic factor for completely resected lung ADC.

Successful Treatment with Osimertinib Based on Therapeutic Drug Monitoring in a Hemodialysis Patient with Non-Small Cell Lung Cancer: A Case Report.

Although osimertinib is a key drug in the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation, the safety in hemodialysis patients has not been established. A 76-year-old man was diagnosed with NSCLC with EGFR deletion mutation in exon 19. After treatment failure with first- and second-generation EGFR tyrosine kinase inhibitors, a T790M mutation was revealed by liquid biopsy. Hemodialysis was started three times a week because chronic renal failure worsened during treatment. Although the subsequent administration of osimertinib (80 mg daily) resulted in a tumor shrinkage and a gradual increase in the plasma concentration of osimertinib, which resulted in grade 3 general fatigue, reducing the dosage of osimertinib decreased its plasma concentration, leading to an improvement in his adverse event. Subsequently, with by adjusting the dosage while periodically measuring the plasma concentration of osimertinib, a stable therapeutic effect was sustained over the long term with no symptoms. Periodic plasma concentration measurements may be indispensable for successful treatment with osimertinib in hemodialysis patients.

Diagnostic Workup, Treatment Patterns, and Clinical Outcomes in Early-Stage IB-IIIA Non-Small-Cell Lung Cancer Patients in Denmark.

Despite recent improvements in early-stage non-small-cell lung cancer (NSCLC), disease relapse remains challenging. Moreover, real-world evidence on long-term follow-up of disease-free survival (DFS) and recurrence patterns in a large, unselected cohort of early-stage NSCLC patients is lacking. This cohort study aimed to assess clinical characteristics, diagnostic workup, treatment, survival, and risk of disease relapse among early-stage NSCLC patients. Adult patients with stage IB, II, or IIIA NSCLC diagnosed and/or treated at Aarhus University Hospital in Denmark from January 2010 to December 2020 were included and followed-up until May 2021. Comprehensive clinical data were collected from electronic medical records of eligible patients and linked to Danish register data. The study population comprised 1341 early-stage NSCLC patients: 22%, 40%, and 38% were diagnosed with stage IB, II, and IIIA disease, respectively. In total, 42% of patients were tested for epidermal growth factor receptor (EGFR), of whom 10% were EGFR-mutation-positive (EGFRm+). Half of all patients received surgery, and nine percent of patients received stereotactic body radiation therapy (SBRT). Disease-free survival 5 years post-diagnosis was 49%, 42%, and 22% for stage IB, II, and stage IIIA patients, respectively. DFS improved over time both for patients treated with surgery and SBRT. However, disease relapse remained a challenge, with approximately 40% of stage IIIA having relapsed 3 years post-diagnosis. This study contributes important knowledge that puts clinical trials on new perioperative treatment modalities for early-stage NSCLC patients into perspective. Our findings cover an essential evidence gap on real-world DFS and recurrence dynamics, confirming that despite an improvement in DFS over time and across different treatment modalities, disease relapse remains a monumental challenge. Therefore, better treatment strategies are needed.

Real-world treatment patterns and clinical outcomes in patients with stage III non-small cell lung cancer: results of KINDLE-Egypt cohort.

Background: Stage III non-small cell lung cancer (NSCLC) being highly heterogeneous requires multimodal therapeutic strategies for optimal management. We present findings on treatment patterns and their associated survival outcomes in patients with stage III NSCLC from the Egypt subset of the KINDLE global real-world study conducted across countries from Asia, Middle East, Africa, and Latin America. Method: Retrospective data from the Egypt subset (21 centers) of adult patients diagnosed with stage III NSCLC between January 2013 and December 2017 were analyzed. Descriptive and inferential statistics summarized treatment modalities, progression-free survival (PFS), and overall survival (OS). Results: Of 421 patients enrolled (median age: 59.0 years), 77.9% were males, 53.5% had stage IIIA disease, 60.8% had adenocarcinoma, 78.4% had an unresectable disease, and 81.5% had Eastern Cooperative Oncology Group performance status ⩽1. Overall, chemotherapy alone (40.4%) was predominantly used in the initial line, whereas definite radiotherapy was used in only 5.0% of patients. In resectable patients, chemotherapy plus surgery (33.8%), surgery alone (20.6%), or other surgery (20.6%) were the top three modalities used in initial line of treatment. Chemotherapy alone was most preferred (48.8%) in unresectable patients, followed by sequential chemoradiotherapy (CRT) (17.6%) and concurrent CRT (9.3%). The overall median PFS was 10.3 months [95% confidence interval (CI), 9.43-12.02], whereas the median OS was 18.5 months (95% CI, 16.46-21.88). Overall, female gender, adenocarcinoma histology, and radical therapy as surgery or CRT predicted significantly longer OS (all p < 0.05). Conclusion: KINDLE-Egypt cohort revealed wide heterogeneities in the treatment patterns of stage III NSCLC. Although deemed resectable, few patients did not undergo surgery, probably due to high smoking rates leading to poor lung function. Lower survival outcomes than other published real-world studies highlight the need for timely approval and availability of novel targeted and immunotherapies to enhance patient outcomes. Trial registration: NCT03725475.

Usefulness of bronchial washing fluid for detection of EGFR mutations in non-small cell lung cancer.

INTRODUCTION: The implementation of bronchial washing fluid (BWF) as a diagnostic specimen may complement the low diagnostic yields of plasma in detecting EGFR mutation (mEGFR) in non-small cell lung cancer. However, the diagnostic value of BWF in detecting mEGFR has yet to be clarified. MATERIALS AND METHODS: From March 2021 to August 2022, patients with histologically confirmed NSCLC with matched tumor tissue, BWF, and/or plasma samples were enrolled. Patients were classified into either initial diagnosis or rebiopsy groups. Diagnostic yields of mEGFR in BWF and plasma were evaluated using droplet digital polymerase chain reaction and compared to mEGFR in tumor tissue as standard. RESULTS: The study included 123 patients (74.1 %) in the initial diagnosis and 43 patients (25.9 %) in the rebiopsy group. BWF showed higher sensitivity, specificity, and concordance rates than plasma in both the initial diagnosis (57.4 %, 96.4 %, and 74.0 % vs. 16.4 %, 96.2 %, and 53.1 %) and the rebiopsy group (87.9 %, 60.0 %, and 81.4 % vs. 25.0 %, 75.0 %, and 41.7 %). In the initial diagnosis group, mEGFR was detected in the BWF of 13 out of 16 patients, even in the absence of tumor cells in the tissue biopsy. In these cases, EGFR test results obtained from BWF showed concordance with EGFR test results from the tumor tissue obtained through repeated biopsy or surgery later. In the rebiopsy group, T790M was detected in 16 patients (37.2 %) by tissue biopsy. The combined use of tissue biopsy and BWF increased detection, confirming T790M in 22 patients (51.2 %). DISCUSSION: The detection of mEGFR using BWF shows higher diagnostic yields than plasma for both initial diagnosis and rebiopsy. T790M was detected earlier in BWF than in tissue rebiopsy in some cases, providing patients with an early opportunity to access third-generation EGFR-TKIs. The complementary use of BWF with tumor tissue may improve precision in EGFR-mutated NSCLC treatment strategies.

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.

A protocol of a single arm, prospective, open-label, multicenter, phase II study of ramucirumab and erlotinib in treatment-naïve non-small cell lung cancer patients with EGFR mutation and brain metastases (SPIRAL-BRAIN study).

Background: The combination of erlotinib, a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), and ramucirumab, an anti-vascular endothelial growth factor receptor (VEGFR) antibody, is one of the most effective treatments for patients with non-small cell lung cancer (NSCLC) and EGFR mutation. However, little is known about the safety and efficacy of this combination treatment for patients with brain metastases. Methods: This single arm, prospective, open-label, multicenter, phase II study will recruit 32 NSCLC patients with EGFR mutation (except for T790M mutation) and brain metastases (asymptomatic or mild symptoms). Patients will be treated with erlotinib at a dose of 150 mg/body once daily and ramucirumab at a dose of 10 mg/kg once every 2 weeks. The primary endpoint is intracranial overall response rate (iORR) and the secondary endpoints are intracranial disease control rate, intracranial progression-free survival (iPFS), extracranial ORR, extracranial PFS, ORR, overall PFS, overall survival (OS), and safety. The planned number of enrollments was calculated based on a one-sample binomial test (normal approximation) with a two-sided α level of 5% and 80% power, assuming that the expected iORR is 65% and the iORR threshold is 40%. Discussion: A prospective study to confirm the safety and efficacy of the combined erlotinib plus ramucirumab treatment for NSCLC patients with EGFR mutation and brain metastases is ongoing. Trial Registration: Japan Registry of Clinical Trials, jRCTs051220059.

Almonertinib plus chemotherapy versus almonertinib alone in second-line treatment of advanced non-small cell lung cancer with mutated epidermal growth factor receptor: a retrospective study.

Objective: This study mainly observes the efficacy and safety of almonertinib plus chemotherapy compared with almonertinib alone in the second-line treatment of advanced non-small cell lung cancer (NSCLC) with mutated epidermal growth factor receptor (EGFR). Methods: In this study, clinical data of 68 patients with advanced NSCLC who were treated in Jiangsu Provincial People's Hospital and Nanjing Chest Hospital between April 2020 and December 2022 were collected. Among them, the study group (n=30) received second-line almonertinib combined with platinum-based chemotherapy, while the control group (n=38) received almonertinib alone. The near-term and long-term effects and adverse events of the two groups were compared respectively. Results: The median follow-up time until 31 December 2022 was 16.3 months (95% CI: 11.32-21.34). Results of chi-square analysis showed no statistically significant difference in objective response rate (ORR) and disease control rate (DCR) between the study group and the control group (56.73% vs. 55.3%, P>0.05; 100% vs. 86.8%, P>0.05). Log-rank test comparing the two groups revealed that the median progression-free survival (mPFS) of the study group was significantly longer than that of the control group by 3.1 months (12.7 vs. 9.6 months, P=0.01). Multivariate COX proportional risk model showed a statistically significant effect of treatment method and PS score on PFS (HR=0.43, P=0.023; HR=3.82, P=0.001). In terms of safety, most of the adverse events (AEs) were mild, with no grade 4-5 in the two groups, and the overall tolerance of patients was good. Conclusion: For advanced NSCLC patients with EGFR mutations, second-line treatment with almonertinib plus chemotherapy significantly improved PFS compared with almonertinib alone without a significant increase in adverse events, providing efficacy and safety.