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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 (HER3‑DXd). 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. [ABSTRACT FROM AUTHOR]

The discovery of targetable mutations in non-small-cell lung cancer (NSCLC) has opened up a plethora of therapeutic options. Epidermal growth factor receptor (EGFR) mutations are found in 10%–20% of NSCLC; however, it is extremely rare in small-cell lung cancer (SCLC), and the efficacy of EGFR tyrosine kinase inhibitors (TKIs) in SCLC is unclear. Here, we describe the case of a 57-year-old nonsmoker lady who was diagnosed with metastatic SCLC. She received multiple lines of palliative chemotherapy. She was deemed unfit for further chemotherapy and immunotherapy and was started on tablet erlotinib empirically. On follow-up imaging with positron emission tomography-computed tomography, she had a partial response and has currently on erlotinib for 2.5 years without disease progression. Although cases with transformation of EGFR-mutated NSCLC to SCLC have been observed, de novo EGFR mutation in SCLC is infrequent. It has been observed that de novo EGFR mutation in SCLC is associated with females, non-smokers, and patients in the eastern part of the world. The current guidelines do not recommend molecular testing for EGFR mutations in SCLC. We described a case of SCLC who had a response to TKI and such cases warrant an answer to whether EGFR mutation testing should be recommended in nonsmoker, females with SCLC, or for them who have failed the first line of chemotherapy.

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.

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. [ABSTRACT FROM AUTHOR]

Abstract 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.

Abstract 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 36 months group was 46.0 months and that of the PFS ≤36 months group was 22.9 months (log‐rank test, p

The treatment of non-small cell lung cancer (NSCLC) has increasingly been driven by the presence of targetable driver mutations, including epidermal growth factor receptor (EGFR) mutations. Tyrosine receptor inhibitors (TKIs) have subsequently emerged as the standard-of-care treatment for EGFR-mutant NSCLC. However, there are currently limited treatment options for TKI-refractory EGFR-mutant NSCLC. It is in this context that immunotherapy has arisen as a particularly promising player, especially in the context of favorable results from the ORIENT-31 and IMpower150 trials. Thus, the results of the CheckMate-722 trial were highly anticipated, as it was the first global trial to evaluate the efficacy of immunotherapy in addition to standard platinum-based chemotherapy, specifically in the treatment of EGFR-mutant NSCLC post-progression on TKIs.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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.

Abstract Background Long‐term survival can be achieved with radical local therapy in some cases of postoperative recurrence of non‐small cell lung cancer (NSCLC). Here, we evaluated post‐recurrence survival (PRS) after treatment of postoperative recurrent epidermal growth factor receptor (EGFR) mutated NSCLC and examined the effectiveness of radical local therapy. Methods This multicenter prospective cohort study was conducted in 14 hospitals. The inclusion criteria for this study were patients with recurrence after radical resection for NSCLC. Information about the patient characteristics at recurrence, tumor‐related variables, primary surgery, and treatment for recurrence was collected. After registration, follow‐up data (e.g., treatment and survival outcomes) were obtained and analyzed. Results From 2010 to 2015, 505 patients with recurrent NSCLC were enrolled into the study, and 154 EGFR mutation‐positive cases were included. As the initial treatment for recurrence, 111 patients (72%) received chemotherapy, 14 (9%) received chemoradiotherapy, 14 (9%) received definitive radiotherapy, and seven (5%) received surgical resection. The remaining eight patients (5%) received supportive care. The median PRS and 5‐year survival rates for all cases were 64 months and 53.2%, respectively. The 5‐year survival rate according to the initial treatment was as follows: supportive care, 0%; chemotherapy, 53.3% and radical local therapy, 60.1%. The six patients who received radical local treatment remained recurrence‐free for more than 3 years after recurrence with only initial treatment. Conclusions Although radical local therapy may be curative in some patients, chemotherapy including EGFR‐TKI treatment is expected to provide long‐term survival comparable to that of radical local therapy.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Alexandria TM Lee,1 Misako Nagasaka1,2 1University of California Irvine School of Medicine, Department of Medicine, Orange, CA, 92868, USA; 2St. Marianna University School of Medicine, Department of Medicine, Kawasaki, JapanCorrespondence: Misako Nagasaka, Department of Medicine, University of California Irvine School of Medicine, 200 South Manchester, Suite 400, Orange, CA, 92868, USA, Email nagasakm@hs.uci.eduAbstract: The treatment of non-small cell lung cancer (NSCLC) has increasingly been driven by the presence of targetable driver mutations, including epidermal growth factor receptor (EGFR) mutations. Tyrosine receptor inhibitors (TKIs) have subsequently emerged as the standard-of-care treatment for EGFR-mutant NSCLC. However, there are currently limited treatment options for TKI-refractory EGFR-mutant NSCLC. It is in this context that immunotherapy has arisen as a particularly promising player, especially in the context of favorable results from the ORIENT-31 and IMpower150 trials. Thus, the results of the CheckMate-722 trial were highly anticipated, as it was the first global trial to evaluate the efficacy of immunotherapy in addition to standard platinum-based chemotherapy, specifically in the treatment of EGFR-mutant NSCLC post-progression on TKIs.Keywords: immunotherapy, epidermal growth factor receptor mutation, osimertinib refractory

Background and objective Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is the first choice for first-line treatment of advanced patients with EGFR positive non-small cell lung cancer (NSCLC). For advanced NSCLC patients with negative drive gene and positive programmed cell death ligand 1 (PD-L1) or highly expressed NSCLC patients, the first-line treatment recommends immune checkpoint inhibitors (ICIs) monotherapy or ICIs combined chemotherapy. Therefore, the first-line treatment strategy for advanced NSCLC patients with EGFR positive at different PD-L1 expression levels is worth further exploring. Many previous studies have suggested that the expression of PD-L1 is obviously affected by EGFR mutation, and the expression of PD-L1 is likely to be related to the mechanism of EGFR-TKIs resistance. The purpose of this study was to analyze the expression characteristics of PD-L1 in patients with advanced EGFR positive NSCLC and its relationship with the efficacy of EGFR-TKIs. Methods 159 patients with newly diagnosed advanced NSCLC with EGFR positive (including 141 patients with EGFR sensitive mutations) were enrolled to analyze the relationship between clinicopathological characteristics and PD-L1 expression. The factors affecting the therapeutic effect of EGFR-TKIs in 141 patients with EGFR sensitive mutations were also explored. Results The PD-L1 expression of the included patients was classified according to the tumor promotion score (TPS): negative (TPS

IntroductionThe 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

Purpose: Whether prior radiotherapy (RT) affects the response of EGFR-mutated non-small cell lung cancer (NSCLC) to EGFR tyrosine kinase inhibitor (TKI) remains elusive. Methods: Patients with EGFR-mutated NSCLC treated with EGFR TKIs who recurred after curative treatment at Asan Medical Center, Seoul, Korea were included. The progression-free survival (PFS) and overall survival (OS) from the initiation of EGFR TKI in patients who recurred after definitive RT were analyzed and compared to the outcomes of RT-naïve patients with advanced NSCLC treated with EGFR TKIs from previously reported prospective clinical trial results. Results: A total of 60 patients who recurred after definitive RT were included. The median age was 70 years (range, 38–88), with 24 patients (40.0%) being males. Among the 60 patients, 52 patients (86.7%) had exon 19 deletion or L858R mutation, with 49 patients (81.7%) receiving gefitinib as the first-line EGFR TKI. The median PFS and OS from the initiation of EGFR TKI were 10.4 months (95% confidence interval [CI], 7.4–13.2) and 21.3 months (95% CI, 13.4–28.8), respectively. Conclusion: The EGFR TKI efficacy in EGFR-mutated patients with NSCLC who recurred after RT was comparable with that in historic controls of RT-naïve patients with advanced NSCLC treated with EGFR TKIs, indicating that RT may not affect EGFR TKI efficacy. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal epithelial transition (MET) overexpression has been reported in approximately 50–60% of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers. However, the prognostic significance of MET overexpression has not been established in advanced lung adenocarcinoma (ADC) patients with EGFR-sensitive mutations. Methods: A retrospective study was performed on a total of 406 treatment-naïve advanced ADC patients with EGFR mutation detection and MET expression information. EGFR mutations were detected by next‐generation sequencing or amplification refractory mutation system-polymerase chain reaction. Immuno-histochemistry staining of MET expression was evaluated by H-score and overexpression was defined as an H-score ≥ 200. Overall survival (OS) and progression-free survival (PFS) were analyzed according to MET expression. Results: Among the 406 patients, 208 patients had EGFR mutations, including 102 exon 19_del mutations, 94 L858R mutations and 12 other types of mutations. Of 110 patients with concomitant EGFR mutations and MET overexpression, 61 (59.8%) patients had 19_del mutations, 44 (46.8%) patients had L858R mutations and five (41.7%) patients had others. Patients with MET overexpression had a markedly shorter PFS and OS than patients with MET H-score < 200 in the EGFR L858R mutation subgroup (median PFS: 12 versus 26 months, p = 0.001; median OS: 24 versus 32 months, p = 0.038), whereas no significant difference was observed in 19_del mutation subgroup. Multivariate Cox analysis showed that MET overexpression was an independent poor prognostic factor for PFS and OS in patients with the L858R mutations (HR = 3.064, 95% CI 1.705–5.507, p < 0.001; HR = 2.043, 95% CI 1.000–4.172; p = 0.049), rather than 19_del. Conclusions: MET overexpression is a poor prognostic factor for advanced ADC patients with the EGFR L858R mutation. [ABSTRACT FROM AUTHOR]

Background: Long‐term survival can be achieved with radical local therapy in some cases of postoperative recurrence of non‐small cell lung cancer (NSCLC). Here, we evaluated post‐recurrence survival (PRS) after treatment of postoperative recurrent epidermal growth factor receptor (EGFR) mutated NSCLC and examined the effectiveness of radical local therapy. Methods: This multicenter prospective cohort study was conducted in 14 hospitals. The inclusion criteria for this study were patients with recurrence after radical resection for NSCLC. Information about the patient characteristics at recurrence, tumor‐related variables, primary surgery, and treatment for recurrence was collected. After registration, follow‐up data (e.g., treatment and survival outcomes) were obtained and analyzed. Results: From 2010 to 2015, 505 patients with recurrent NSCLC were enrolled into the study, and 154 EGFR mutation‐positive cases were included. As the initial treatment for recurrence, 111 patients (72%) received chemotherapy, 14 (9%) received chemoradiotherapy, 14 (9%) received definitive radiotherapy, and seven (5%) received surgical resection. The remaining eight patients (5%) received supportive care. The median PRS and 5‐year survival rates for all cases were 64 months and 53.2%, respectively. The 5‐year survival rate according to the initial treatment was as follows: supportive care, 0%; chemotherapy, 53.3% and radical local therapy, 60.1%. The six patients who received radical local treatment remained recurrence‐free for more than 3 years after recurrence with only initial treatment. Conclusions: Although radical local therapy may be curative in some patients, chemotherapy including EGFR‐TKI treatment is expected to provide long‐term survival comparable to that of radical local therapy. [ABSTRACT FROM AUTHOR]

Background: Concerning the different clinical behavior of epidermal growth factor receptor (EGFR) subtypes in advanced-stage lung cancer patients, the current study aimed to evaluate the clinical, pathological, and prognostic significance of EGFR mutation subtypes, and treatment response in patients with advanced-stage lung cancer. Methods and results: A retrospective study enrolled a total of 346 patients with advanced-stage lung cancer tested for EGFR mutation. EGFR mutation was analyzed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Statistical analysis was performed using SPSS version 20.0. EGFR mutation was evident in 38% of patients with the highest prevalence of exon 19 deletions. A higher incidence of 19-deletions and 20-insertions were observed in young patients, while a higher incidence of L858R was noted in old age patients. Patients with de-novo T790M failed to improve their OS by any of the treatment modalities. Patients with de-novo T790M mutation have a higher risk of developing lung, liver, and multiple site metastases while patients with L858R mutation have a higher risk of developing brain metastasis. Additionally, patients with 19 deletion mutation did not improve their OS after receiving conventional chemotherapy hence, they demonstrate better survival only after EGFR-TKIs. Multivariate survival analysis predicted chemotherapy as an independent predictor of OS. Conclusion: Besides clinicopathological and prognostic consequences of EGFR mutation and mutation subtypes, patients harboring TKI sensitive, or insensitive mutations reveal different secondary disease development and hence should be treated accordingly for better survival. Current findings may provide the basis for a better treatment strategy. [ABSTRACT FROM AUTHOR]

Abstract Non‐small cell lung cancer (NSCLC) accounts for the majority of all lung cancer diagnoses, and approximately 35% of patients with NSCLC are diagnosed at an early stage (I–IIIA). This study aimed to describe epidermal growth factor receptor (EGFR) testing, patient characteristics, and overall survival (OS) among patients with early‐stage NSCLC in Denmark. Patients with early‐stage NSCLC registered in the Danish Lung Cancer Registry in 2013–2018 were followed through 2019. We described EGFR testing, descriptively summarised patient characteristics, and calculated OS by EGFR testing and mutation status. The association between EGFR mutation (EGFRm) and all‐cause mortality was estimated using Cox proportional‐hazards regression, in subgroups defined by stage at diagnosis, age at diagnosis, comorbidity, and receipt of surgery. In 2013–2018, 21,282 patients with NSCLC were registered in the Danish Lung Cancer Registry, of whom 8758 were diagnosed at an early stage. Of those, 4071 (46%) were tested for EGFRm at diagnosis. Median OS was 5.7 years among patients with EGFRm‐positive status (n = 361) and 4.4 years among patients with EGFRm‐negative status (n = 3710). EGFRm‐positive status was associated with lower all‐cause mortality in all subgroups. This study contributes to population‐based evidence on the epidemiology of early‐stage NSCLC treated in routine clinical practice.

Dasatinib, a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI), inhibits multiple kinase pathways and is a promising anti-tumor agent for various solid tumors, including lung cancer. Herein, we report a patient with coexisting epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma and BCR-ABL1-positive chronic myeloid leukemia (CML). The patient received afatinib for a postoperative intrapulmonary recurrence of lung adenocarcinoma harboring EGFR exon 19 deletion. Tumor reduction was achieved with afatinib; however, dose reduction was required because of grade 2 diarrhea and skin toxicity. The reduced dose maintained a partial response. Thirty-one months after introduction of afatinib, he was diagnosed as having BCR-ABL1-positive CML and nilotinib was added to his treatment regimen. However, the combination of nilotinib and afatinib aggravated his diarrhea, prompting discontinuation of afatinib. Because nilotinib does not have sufficient anti-tumor efficacy for CML, dasatinib was substituted for nilotinib. Thirty-five months after introduction of dasatinib, bosutinib was substituted for dasatinib because of uncontrollable pleural effusions. Dasatinib achieved 31- and 35-month progression-free survivals for CML and EGFR-mutant lung adenocarcinoma, respectively. Dasatinib is thus a therapeutic option for coexisting EGFR-mutant lung adenocarcinoma and BCR-ABL1-positive CML when TKI combination therapy is contraindicated by severe adverse events. In our patient, adding nilotinib to afatinib led to severe diarrhea. When administering TKI combination therapy, drug-drug interactions should be considered.

Abstract Background The aim of this study was to investigate the effects of different thoracic radiotherapy doses on OS and incidence of radiation pneumonia which may provide some basis for optimizing the comprehensive treatment scheme of these patients with advanced EGFR mutant lung adenocarcinoma. Methods Data from 111 patients with EGFR-mutant lung adenocarcinoma who received thoracic radiotherapy were included in this retrospective study. Overall survival (OS) was the primary endpoints of the study. Kaplan–Meier method was used for the comparison of OS. The Cox proportional-hazard model was used for the multivariate and univariate analyses to determine the prognostic factors related to the disease. Results The mOS rates of the patients, who received radiotherapy dose scheme of less than 50 Gy, 50–60 Gy (including 50 Gy), and 60 Gy or more were 29.1 months, 34.4 months, and 51.0 months, respectively (log-rank P = 0.011). Although trend suggested a higher levels of pneumonia cases with increasing radiation doses, these lack statistical significance (χ2 = 1.331; P = 0.514). The multivariate analysis showed that the thoracic radiotherapy dose schemes were independently associated with the improved OS of patients (adjusted hazard ratio [HR], 0.606; 95% CI, 0.382 to 0.961; P = 0.033). Conclusions For the patients with advanced EGFR-mutant lung adenocarcinoma, the radical thoracic radiotherapy dose scheme (≥ 60 Gy) could significantly prolong the OS of patients during the whole course management.

Objectives: The study aims to evaluate the efficacy and safety of thoracic radiotherapy in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-treated patients with stage IV non-small-cell lung cancer (NSCLC). Methods: Patients with non-oligometastatic NSCLC harboring EGFR mutations were recruited. All patients received the first-generation TKI treatment with or without radiotherapy. The irradiated sites included primary and/or metastatic lesions. Of all the patients who underwent thoracic radiotherapy, some received radiotherapy before EGFR-TKI resistance, others received radiotherapy after progressive disease. Results: No statistically significant difference was observed in progression-free survival (PFS) (median 14.7 versus 11.2 months, p = 0.075) or overall survival (OS) (median 29.6 versus 40.6 months, p = 0.116) between patients treated with EGFR-TKIs alone and those with additional radiotherapy to any sites. However, EGFR inhibitors with thoracic radiation significantly improved OS (median 47.0 versus 31.0 months, p < 0.001) but not PFS (median 13.9 versus 11.9 months, p = 0.124). Moreover, longer PFS (median 18.3 versus 8.5 months, p < 0.001) was achieved in the preemptive thoracic radiation cohort than in the delayed thoracic radiation cohort. However, OS was similar between the two cohorts (median 40.6 versus 52.6 months, p = 0.124). The lower incidence rate of grade 1–2 pneumonitis occurred in preemptive radiation cohort (29.8% versus 75.8%, p < 0.001). Conclusion: Non-oligometastatic NSCLC patients with EGFR mutations benefited from thoracic radiotherapy while using EGFR inhibitors. Preemptive thoracic radiotherapy could be a competitive first-line therapeutic option due to superior PFS and favorable safety. [ABSTRACT FROM AUTHOR]

Summary: The survival benefit of icotinib (an oral epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor) in patients with advanced lung cancer has been confirmed in several studies. This study (ICAPE) evaluated the efficacy of icotinib as adjuvant therapy for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma. Patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma were enrolled in the multicenter, open-label, single-arm, phase II study. Eligible patients received oral icotinib 125 mg thrice daily for 1.5 years after complete surgical resection. The primary endpoint was disease-free survival (DFS). Between March 2014 and January 2018, 79 patients were enrolled. The median follow-up time was 39.7 months with a median DFS and overall survival (OS) of 41.4 months (95% CI: 33.6–51.8) and 67.0 months (95% CI: 21.2-not reached [NR]), respectively. The 1-year, 3-year, and 5-year OS rates were 100%, 83.3%, and 61.7%, respectively. No significant difference was found in the median DFS between patients with Bcl-2 interacting mediator of cell death (BIM) mutant-type and wild-type (NR vs. 41.7 months; p = 0.75). No significant difference was found in the median DFS according to EGFR mutation types. Icotinib as adjuvant therapy demonstrated a favorable survival benefit in patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma, indicating that icotinib might be a promising treatment option for this patient population. The optimal adjuvant duration of icotinib is still not clear and needs more incoming data to answer. [ABSTRACT FROM AUTHOR]

Objective: Osimertinib is a third-generation, irreversible, small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that can effectively penetrate the blood brain-barrier (BBB). This study mainly explored the factors affecting the prognosis of EGFR-mutant advanced non-small cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM), and whether osimertinib could improve the survival benefit in these patients compared with those not treated with osimertinib. Methods: We retrospectively analyzed patients who had been admitted with EGFR-mutant NSCLC and cytologically confirmed LM to the Peking Union Medical College Hospital between January 2013 and December 2019. Overall survival (OS) was defined as the primary outcome of interest. Results: A total of 71 patients with LM were included in this analysis, with a median OS (mOS) of 10.7 months (95% CI [7.6, 13.8]). Among them, 39 patients were treated with osimertinib after LM while 32 patients were untreated. Patients treated with osimertinib had a mOS of 11.3 months (95%CI [0, 23.9]) compared with the untreated patients who had a mOS of 8.1 months (95%CI [2.9, 13.3]), with a significant difference between the groups (hazard ratio [HR]): 0.43, 95%CI:0.22–0.66, p = 0.0009). Multivariate analysis revealed the use of osimertinib were correlated with superior OS with a HR of 0.43 (95%CI [0.25, 0.75]), with a statistically significant difference (p = 0.003). Conclusions: Osimertinib can prolong the overall survival of EGFR-mutant NSCLC patients with LM and improve patient outcomes.

Abstract Background Gefitinib (G) is a recommended molecular‐targeted agent for elderly patients with epidermal growth factor receptor (EGFR)‐mutant non‐small cell lung cancer (NSCLC). Docetaxel (Doc) and pemetrexed (Pem) have similar efficacies, and either is often used as the sole agent during treatment. The efficacy of continuing G after progressive disease (PD) develops has been reported. It remains unclear whether the continuation of G in combination with a single cytotoxic agent beyond PD is beneficial for elderly patients. Here, we conducted a randomized phase II study to assess the efficacy and safety of cytotoxic chemotherapy with G for elderly patients with progressive EGFR‐mutant NSCLC. Methods Elderly patients with EGFR‐mutant NSCLC with PD previously treated with G were enrolled. Patients received Pem 500 mg/m or Doc 60 mg/m every 21 days and were randomly assigned to receive chemotherapy with 250 mg G (G+ Doc/Pem arm) or without G (Doc/Pem arm) until further disease progression or unacceptable toxicity. Results This trial was terminated early owing to slow accrual. A group of 22 patients underwent analysis. The primary endpoint, progression‐free survival (PFS), was significantly longer in the G + Doc/Pem arm (median: 1.6 months vs. 5.6 months, hazard ratio = 0.40, 95% CI: 0.16–0.99, p = 0.0391). Adverse events ≥ grade 3 were more frequent in the G + Doc/Pem arm (45.5% vs. 90.9%, p = 0.032). Conclusions Patients on G and Pem or Doc beyond PD showed a longer PFS than those on single‐agent chemotherapy; however, it was associated with increased toxicity.

Abstract Background Dacomitinib is the second‐generation epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor (TKI) for mutant non–small cell lung cancer (NSCLC). EGFR‐TKIs are often re‐administered in Japan after the disease progression prior EGFR‐TKI. There is little evidence of dacomitinib in rechallenge setting. This study evaluated clinical outcomes of dacomitinib in rechallenge setting. Methods Patients who received dacomitinib for advanced EGFR‐mutant NSCLC who had progressed after EGFR‐TKI in nine institutions in Japan were included in the analyses. Results In total, 43 patients were analyzed. The median progression‐free survival (PFS) was 4.3 months (95% confidence interval [CI], 2.5–5.6). The overall survival (OS) was 10.5 months (95% CI, 7.4–not reached). The overall response rate was 25.5% (95% CI, 13.1–33.7). Subset analysis indicated that patients with EGFR exon 21 L858R showed longer PFS than those with EGFR exon 19 deletion (5.8 vs. 4.1 months) (p = 0.018). The most common adverse events leading to dose modification were diarrhea, paronychia, rash, and oral mucositis. Conclusion In the real practice in Japan, dacomitinib showed a worthwhile treatment option for NSCLC patients with EGFR mutation after failure of previous EGFR‐TKI. The benefit was especially pronounced in patients with the exon 21 mutation.

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. [ABSTRACT FROM AUTHOR]

Non‐small cell lung cancer (NSCLC) accounts for the majority of all lung cancer diagnoses, and approximately 35% of patients with NSCLC are diagnosed at an early stage (I–IIIA). This study aimed to describe epidermal growth factor receptor (EGFR) testing, patient characteristics, and overall survival (OS) among patients with early‐stage NSCLC in Denmark. Patients with early‐stage NSCLC registered in the Danish Lung Cancer Registry in 2013–2018 were followed through 2019. We described EGFR testing, descriptively summarised patient characteristics, and calculated OS by EGFR testing and mutation status. The association between EGFR mutation (EGFRm) and all‐cause mortality was estimated using Cox proportional‐hazards regression, in subgroups defined by stage at diagnosis, age at diagnosis, comorbidity, and receipt of surgery. In 2013–2018, 21,282 patients with NSCLC were registered in the Danish Lung Cancer Registry, of whom 8758 were diagnosed at an early stage. Of those, 4071 (46%) were tested for EGFRm at diagnosis. Median OS was 5.7 years among patients with EGFRm‐positive status (n = 361) and 4.4 years among patients with EGFRm‐negative status (n = 3710). EGFRm‐positive status was associated with lower all‐cause mortality in all subgroups. This study contributes to population‐based evidence on the epidemiology of early‐stage NSCLC treated in routine clinical practice. [ABSTRACT FROM AUTHOR]

Early stereotactic body radiation therapy (SBRT) to the primary tumor combined with epidermal growth factor receptor tyrosine kinase inhibitor (EFGR-TKI) treatment may increase progression-free survival (PFS) by delaying resistance in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). In this prospective, single arm, phase II study, patients with advanced NSCLC were treated with EGFR-TKI (icotinib 125 mg tid or gefitinib 250 mg qd) for one month followed by SBRT (40–60 Gy/5–8 F/5–10 d) to the primary tumor with concurrent EGFR-TKI until disease progression. The primary endpoint was PFS and the patterns of failure. Overall survival (OS) and adverse effects (AEs) were secondary endpoints. Overall, 41 advanced NSCLC patients with EGFR mutations received treatment with 24.42 months of median follow-up time. On average, SBRT was initiated 1.49 months after EGFR-TKI administration. Tumors were found to have an average shrinkage rate of 42.50%. Median PFS was 15.23 months (95% CI 13.10–17.36), while median OS was 27.57 months (95% CI 23.05–32.09). Thirty-three patients were found to have disease progression, of which new site failure (NF) (22 patients, 66.66%) was the most common pattern, followed by original site failure (OF) (7 patients, 21.21%) and simultaneous OF/NF (ONF) (4 patients, 12.12%). There were no Aes equal to or greater than grade 3, with the most frequent AE being radiation pneumonitis. Therefore, administering therapy targeted at the primary tumor using early SBRT after EGFR-TKI initiation is a new potentially safe and effective approach to treat EGFR-mutant advanced NSCLC. [ABSTRACT FROM AUTHOR]

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

Background: The aim of this study was to investigate the effects of different thoracic radiotherapy doses on OS and incidence of radiation pneumonia which may provide some basis for optimizing the comprehensive treatment scheme of these patients with advanced EGFR mutant lung adenocarcinoma.Methods: Data from 111 patients with EGFR-mutant lung adenocarcinoma who received thoracic radiotherapy were included in this retrospective study. Overall survival (OS) was the primary endpoints of the study. Kaplan-Meier method was used for the comparison of OS. The Cox proportional-hazard model was used for the multivariate and univariate analyses to determine the prognostic factors related to the disease.Results: The mOS rates of the patients, who received radiotherapy dose scheme of less than 50 Gy, 50-60 Gy (including 50 Gy), and 60 Gy or more were 29.1 months, 34.4 months, and 51.0 months, respectively (log-rank P = 0.011). Although trend suggested a higher levels of pneumonia cases with increasing radiation doses, these lack statistical significance (χ2 = 1.331; P = 0.514). The multivariate analysis showed that the thoracic radiotherapy dose schemes were independently associated with the improved OS of patients (adjusted hazard ratio [HR], 0.606; 95% CI, 0.382 to 0.961; P = 0.033).Conclusions: For the patients with advanced EGFR-mutant lung adenocarcinoma, the radical thoracic radiotherapy dose scheme (≥ 60 Gy) could significantly prolong the OS of patients during the whole course management. [ABSTRACT FROM AUTHOR]

Dasatinib, a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI), inhibits multiple kinase pathways and is a promising anti-tumor agent for various solid tumors, including lung cancer. Herein, we report a patient with coexisting epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma and BCR-ABL1-positive chronic myeloid leukemia (CML). The patient received afatinib for a postoperative intrapulmonary recurrence of lung adenocarcinoma harboring EGFR exon 19 deletion. Tumor reduction was achieved with afatinib; however, dose reduction was required because of grade 2 diarrhea and skin toxicity. The reduced dose maintained a partial response. Thirty-one months after introduction of afatinib, he was diagnosed as having BCR-ABL1-positive CML and nilotinib was added to his treatment regimen. However, the combination of nilotinib and afatinib aggravated his diarrhea, prompting discontinuation of afatinib. Because nilotinib does not have sufficient anti-tumor efficacy for CML, dasatinib was substituted for nilotinib. Thirty-five months after introduction of dasatinib, bosutinib was substituted for dasatinib because of uncontrollable pleural effusions. Dasatinib achieved 31- and 35-month progression-free survivals for CML and EGFR-mutant lung adenocarcinoma, respectively. Dasatinib is thus a therapeutic option for coexisting EGFR-mutant lung adenocarcinoma and BCR-ABL1-positive CML when TKI combination therapy is contraindicated by severe adverse events. In our patient, adding nilotinib to afatinib led to severe diarrhea. When administering TKI combination therapy, drug-drug interactions should be considered. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the relationship between treatment efficacy and exposure of total and unbound erlotinib in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations.Patients and Methods: EGFR-tyrosine kinase inhibitor naïve NSCLC patients were enrolled, and erlotinib was started at 150 mg/day. Total and unbound exposure of erlotinib were prospectively evaluated.Results: Of the 70 enrolled patients, 61 had EGFR-activating mutations (30 patients with exon 19 deletions, 31 patients with L858R). The median area under the concentration-time curve from 0 to 24 h (AUC0-24) of total and unbound erlotinib on day 1 was 37,004 ng·h/mL (range, 9683-63,257 ng·h/mL) and 2338 ng·h/mL (581-5904 ng·h/mL), respectively. The median progression-free survival (PFS) was 10.9 months, and PFS did not differ between each tertile of total and unbound AUC0-24 on day 1 in 59 patients with EGFR-activating mutations. The worst grade of skin toxicities was significantly correlated with total trough concentration at steady state (Ctrough,ss) at each visit for 3 months after the initiation of erlotinib treatment (P < 0.0001). Total and unbound Ctrough,ss on day 7-15 in 20 patients whose dose was reduced due to intolerable toxicities was significantly higher than those in 48 patients whose dose was unchanged for 3 months (P = 0.0046, 0.0008).Conclusion: The lack of relationship between efficacy and exposure of total and unbound erlotinib demonstrates that the standard dose of 150 mg/day is sufficient for the treatment of NSCLC harboring EGFR-activating mutations, despite wide inter-individual variability in exposure and dose reduction.Clinical Trials Registration Number: UMIN000012862. [ABSTRACT FROM AUTHOR]

EGFR exon 20 insertion mutation-positive non-small cell lung cancer (NSCLC) is rare, has a poor prognosis, and outcomes are not fully established. We describe and evaluate outcomes from real-world and clinical evidence in these patients. A systematic literature review (SLR) identified interventional and real-world evidence (RWE) studies reporting clinical outcomes for EGFR exon 20 insertion mutation-positive NSCLC. Meta-analyses were conducted by line of therapy to synthesize pooled survival and response outcomes across RWE. Published evidence from interventional studies was summarized individually. The SLR identified 23 RWE and 19 original interventional studies. In the meta-analysis of RWE, pooled response and survival outcomes were low for first-line EGFR-tyrosine kinase inhibitors (TKIs) and immuno-oncology (IO) agents. First-line chemotherapy resulted in a pooled ORR 25.7%, pooled PFS 5.6 months, and pooled OS 18.3 months. Pooled outcomes were further reduced in second or later lines (≥2 L): pooled ORR was 5.0%, 3.3%, and 13.9%; pooled PFS was 2.1 months, 2.3 months, and 4.4 months; and pooled OS was 14.1 months, 8.8 months, and 17.1 months (not a pooled result) for EGFR-TKIs, IO agents, and chemotherapy, respectively. Interventional studies reported outcomes for TKIs (mobocertinib, poziotinib, osimertinib, afatinib, CLN-081, DZD9008), a monoclonal antibody (amivantamab), and a heat shock protein 90 inhibitor (luminespib). While there is limited RWE for the recently approved agents mobocertinib and amivantamab, which specifically target exon 20 insertion mutations, interventional evidence supports their potential as effective treatment options. Conventional treatments used in patients with EGFR exon 20 insertion mutation-positive NSCLC have limited efficacy, though chemotherapy appeared to be associated with better response and survival outcomes than non-exon 20 targeting EGFR-TKIs and IO agents. This supports the need to identify EGFR exon 20 insertion mutations as the availability of new targeted treatments may offer additional therapeutic options to these patients. [ABSTRACT FROM AUTHOR]

Background: Distant metastases in non-small-cell lung cancer (NSCLC) are a poor prognostic factor that negatively impact quality of life. The central nervous system (CNS) is a common site of distant progression in epidermal growth factor receptor-mutated (EGFRm) NSCLC. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor recommended for advanced EGFRm NSCLC and as adjuvant treatment for resected EGFRm NSCLC. In LAURA (NCT03521154), osimertinib demonstrated statistically significant improvement in progression-free survival (PFS) versus placebo in unresectable stage III EGFRm NSCLC without progression during/following chemoradiotherapy (CRT). CNS efficacy and time to death or distant metastases (TTDM) analyses are reported here., Patients and Methods: Patients without progression during/following definitive platinum-based CRT were randomised 2 : 1 to receive osimertinib (80 mg daily) or placebo until progression [by blinded independent central review (BICR)] or discontinuation. The primary endpoint was PFS by BICR. CNS PFS by neuroradiologist BICR and TTDM by BICR were secondary endpoints., Results: Overall, 216 patients were randomised (143 osimertinib, 73 placebo). Median CNS PFS by neuroradiologist BICR was not reached [95% confidence interval (CI) not calculable (NC)-NC] with osimertinib versus 14.9 months (95% CI 7.4 months-NC) with placebo; hazard ratio (HR) for CNS PFS: 0.17 (95% CI 0.09-0.32). CNS PFS analysis by investigator assessment was consistent with BICR assessment. The cumulative incidence of CNS progression at 12 months was 9% (95% CI 5% to 14%) with osimertinib and 36% (95% CI 24% to 47%) with placebo. There was clinically meaningful improvement in TTDM with osimertinib versus placebo; HR for TTDM: 0.21 (95% CI 0.11-0.38). The cumulative incidence of distant metastases at 12 months was 11% (95% CI 6% to 17%) with osimertinib and 37% (95% CI 26% to 48%) with placebo., Conclusions: Osimertinib demonstrated clinically meaningful improvements in CNS PFS and TTDM versus placebo, supporting osimertinib post-CRT as the standard of care in unresectable stage III EGFRm NSCLC., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Abstract Background Transformation to small cell lung cancer (SCLC) is a resistance mechanism of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (LADC) patients treated with EGFR tyrosine kinase inhibitors (TKIs). Here, we describe the clinical characteristics and prognosis of these patients and explore the treatment modes after transformation. Methods EGFR‐mutant LADC patients with SCLC transformation were retrospectively included in the study. Demographic and clinical data were collected. Survival outcomes and corresponding influential factors were analyzed. Results Twenty‐nine patients were included in the study. The median progression‐free survival (PFS) of patients who received first‐line EGFR‐TKIs was 13.1 months. The median time to SCLC transformation was 27.5 months. After transformation, the objective response rates of patients who received first‐line chemotherapy with or without EGFR‐TKIs were 43.8% and 37.5%, respectively. The median PFS of patients reveiving chemotherapy with EGFR‐TKIs was significantly longer than that of patients receiving chemotherapy without EGFR‐TKIs (5.2 vs. 3.0 months; HR, 0.19; 95% CI: 0.05–0.72; p = 0.014). However, there was no significant difference in median overall survival (OS) between patients who received chemotherapy with or without EGFR‐TKIs (14.8 vs. 13.0 months; p = 0.474). In the multivariate Cox proportional hazards regression analysis, both anti‐angiogenic treatment (HR, 0.04; 95% CI: 0.01–0.29; p = 0.001) and local radiotherapy (HR, 0.28; 95% CI: 0.08–0.97; p = 0.044) were significantly associated with better patient OS after transformation. Conclusions Compared with chemotherapy alone, the combination of chemotherapy and EGFR‐TKIs as first‐line treatment after SCLC transformation can benefit patients in PFS but not in OS. However, anti‐angiogenic therapies and local radiotherapy can significantly prolong OS after transformation.

A 77-year-old woman with postoperative recurrent non-small cell lung adenocarcinoma, which exhibited an epidermal growth factor receptor (EGFR) L858R mutation, was treated with gefitinib and erlotinib. Seven years after the start of treatment, the patient experienced a recurrence of malignant pleural effusion. However, 3 different genetic tests revealed that the lung adenocarcinoma cells in the pleural effusion had lost EGFR L858R mutation, suggesting that long-term treatment with EGFR-tyrosine kinase inhibitors (TKIs) converted EGFR mutation from positive to negative. The negative conversion of EGFR mutation as a mechanism of acquired resistance to EGFR-TKIs is considered rare and needs to be further investigated.

Background: Although bevacizumab in combination with afatinib or erlotinib is an effective and safe first-line therapy for advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), there are very few clinical data comparing afatinib and erlotinib combined with bevacizumab. We performed a retrospective multicenter analysis for the comparison of two combination therapies. Methods: Between May 2015 and October 2020, data of 135 stage IIIB/IV EGFR-mutated NSCLC patients receiving first-line afatinib or erlotinib combined with bevacizumab combination therapy in Linkou, Keelung, Chiayi, and Kaohsiung Chang Gung Memorial Hospitals were retrieved and retrospectively analyzed. Results: In all, 67 patients received afatinib plus bevacizumab, and 68 patients received erlotinib plus bevacizumab. Afatinib combined with bevacizumab had an objective response rate (ORR) of 82.1% and a disease control rate (DCR) of 97.0%, and the ORR and DCR were 83.8 and 95.6%, respectively, in the erlotinib combined with bevacizumab group (p = 0.798 and p = 1.000). The median progression-free survival was 20.7 and 20.3 months for the afatinib plus bevacizumab group and the erlotinib plus bevacizumab group, respectively [hazard ratio (HR) = 1.02; 95% confidence interval (CI), 0.891–1.953; p = 0.167). The overall survival was 41.9 and 51.0 months for the afatinib plus bevacizumab group and erlotinib plus bevacizumab group, respectively (HR = 1.42; 95% CI, 0.829–2.436; p = 0.201). The secondary EGFR-T790M mutation rates after disease progression were 44% in the afatinib plus bevacizumab group and 58.8% in the erlotinib plus bevacizumab group (p = 0.165). Skin toxicity was the most frequent treatment-related adverse event (AE) in both treatment groups. Diarrhea, an AE, occurred significantly more frequently in the afatinib plus bevacizumab group than in the erlotinib plus bevacizumab group (p < 0.05). Conclusion: Afatinib combined with bevacizumab was equally as effective as erlotinib combined with bevacizumab for untreated advanced EGFR-mutated NSCLC. Prospective clinical studies that explore bevacizumab combined with afatinib or erlotinib for advanced EGFR-mutated NSCLC are warranted. Graphic abstract [ABSTRACT FROM AUTHOR]

Background: Gefitinib (G) is a recommended molecular‐targeted agent for elderly patients with epidermal growth factor receptor (EGFR)‐mutant non‐small cell lung cancer (NSCLC). Docetaxel (Doc) and pemetrexed (Pem) have similar efficacies, and either is often used as the sole agent during treatment. The efficacy of continuing G after progressive disease (PD) develops has been reported. It remains unclear whether the continuation of G in combination with a single cytotoxic agent beyond PD is beneficial for elderly patients. Here, we conducted a randomized phase II study to assess the efficacy and safety of cytotoxic chemotherapy with G for elderly patients with progressive EGFR‐mutant NSCLC. Methods: Elderly patients with EGFR‐mutant NSCLC with PD previously treated with G were enrolled. Patients received Pem 500 mg/m or Doc 60 mg/m every 21 days and were randomly assigned to receive chemotherapy with 250 mg G (G+ Doc/Pem arm) or without G (Doc/Pem arm) until further disease progression or unacceptable toxicity. Results: This trial was terminated early owing to slow accrual. A group of 22 patients underwent analysis. The primary endpoint, progression‐free survival (PFS), was significantly longer in the G + Doc/Pem arm (median: 1.6 months vs. 5.6 months, hazard ratio = 0.40, 95% CI: 0.16–0.99, p = 0.0391). Adverse events ≥ grade 3 were more frequent in the G + Doc/Pem arm (45.5% vs. 90.9%, p = 0.032). Conclusions: Patients on G and Pem or Doc beyond PD showed a longer PFS than those on single‐agent chemotherapy; however, it was associated with increased toxicity. [ABSTRACT FROM AUTHOR]

Background: Dacomitinib is the second‐generation epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor (TKI) for mutant non–small cell lung cancer (NSCLC). EGFR‐TKIs are often re‐administered in Japan after the disease progression prior EGFR‐TKI. There is little evidence of dacomitinib in rechallenge setting. This study evaluated clinical outcomes of dacomitinib in rechallenge setting. Methods: Patients who received dacomitinib for advanced EGFR‐mutant NSCLC who had progressed after EGFR‐TKI in nine institutions in Japan were included in the analyses. Results: In total, 43 patients were analyzed. The median progression‐free survival (PFS) was 4.3 months (95% confidence interval [CI], 2.5–5.6). The overall survival (OS) was 10.5 months (95% CI, 7.4–not reached). The overall response rate was 25.5% (95% CI, 13.1–33.7). Subset analysis indicated that patients with EGFR exon 21 L858R showed longer PFS than those with EGFR exon 19 deletion (5.8 vs. 4.1 months) (p = 0.018). The most common adverse events leading to dose modification were diarrhea, paronychia, rash, and oral mucositis. Conclusion: In the real practice in Japan, dacomitinib showed a worthwhile treatment option for NSCLC patients with EGFR mutation after failure of previous EGFR‐TKI. The benefit was especially pronounced in patients with the exon 21 mutation. [ABSTRACT FROM AUTHOR]

As more molecular-targeted drugs for advanced non-small cell lung cancer are brought to market, batch tests for the identification of gene mutations are needed at initial diagnosis. However, since current gene panel tests require a sufficient amount of tissue sample, there are many instances where panel tests cannot be performed. Therefore, we have developed a highly sensitive next generation sequencing (NGS) panel test to facilitate cytological specimens. Herein, we describe three cases positive for epidermal growth factor receptor (EGFR) exon 19 deletion, MET exon 14 skipping, and KRAS G12A using NGS analysis from sputum. In each case, genetic information was consistent with companion diagnostic analysis obtained from tissue samples collected under bronchoscopy. In cases of EGFR and MET mutations, the corresponding tyrosine kinase inhibitors were highly effective. This is the first report to demonstrate that a novel panel test could detect gene mutations in sputum samples in clinical practice and compare the gene allele ratio with the sample directly collected from the lesion. [ABSTRACT FROM AUTHOR]

Background and objective Epidermal growth factor receptor (EGFR) is the gene with the highest mutation rate in non-small cell lung cancer (NSCLC) patients, and the accurate evaluation of its mutational status can facilitate patients receiving targeted drug therapy and thereby prolong patients’ survival. The gene testing platform has adequacy requirements for the specimen quality in order to obtain accurate examination results. It has been reported that the number and proportion of tumor cells in samples will affect the detection rate of EGFR gene mutation. The present study aims to analyze the relationship between the quality of small biopsy specimens of NSCLC and the mutation rate of EGFR gene with amplification refractory mutation system (ARSM) test. Methods After collecting the clinical characteristics of 299 cases small biopsy of lung adenocarcinoma, DNA concentration of the specimens and the mutational status of EGFR gene, the number and proportion of tumor cells in HE stained sections evaluated using light microscopy, the relationship between specimen quality and the mutation rate of EGFR gene were analyzed. Results The mutation rates of EGFR for the groups with tumor cell number ≤500 and >500 were 40.7% (11/27) and 43.8% (119/272) respectively, without significant difference (P=0.764). The mutation rates for the groups with DNA concentration ≤20.4 ng/μL and >20.4 ng/μL were 42.7% (64/150) and 44.3% (66/149) respectively, without significant difference (P=0.776). The mutation rates for the groups with tumor cells proportion ≤30% and >30% were 29.4% (20/68) and 47.6% (110/231) respectively, demonstrating significant difference (P=0.008). Multivariate Logistic analysis showed that male, thyroid transcription factor-1 (TTF-1) negative, smoking history and tumor cell proportion less than 30% were main factors that contributes to the low detection rate of EGFR gene mutation. Conclusion After meeting the minimum requirements for detection, the EGFR mutation rate is affected by the proportion of tumor cells in the sample. Therefore, it is necessary to re-evaluate the tumor cell proportion in the last section after the genetic test section. For samples with lower tumor cell proportion, enriching tumor cells through microdissection and other methods is recommended for a more accurate detection result. For specimens that cannot be enriched with tumor cells, circulating tumor DNA (ctDNA) test can be performed as a supplement. If the result is still negative, another biopsy should be considered to obtain enough tumor specimens for molecular testing.

Objectives: To identify clinical and staging chest CT characteristics predictive of brain metastasis in patients with newly diagnosed NSCLC dichotomized according to resectability. Methods: Patients newly diagnosed with NSCLC of clinical stages II–IV between November 2017 and October 2018 were enrolled and classified into resectable (stage II+IIIA) and unresectable stages (stage IIIB/C+IV) according to chest CT. Associations of clinicopathological characteristics and CT findings with brain metastasis were analyzed using logistic regression. Predictive models were evaluated using receiver operating characteristics curve analysis. A subgroup analysis for unresectable-stage patients with known epidermal growth factor receptor gene (EGFR) mutation status was performed. Results: This study included 911 NSCLC patients (mean age, 65 ± 11 years; 620 men), 194 of whom were diagnosed with brain metastasis. For resectable stages, independent predictors for brain metastasis were N2-stage (13 of 25 patients), absence of air-bronchogram/bubble lucency (23 of 25 patients), and presence of spiculation (15 of 25 patients), with a model combining the two imaging features showing an AUC of 0.723. In unresectable stages, independent predictors of brain metastasis were younger age, female sex, extrathoracic metastasis, and adenocarcinoma, with models combining these showing AUCs of 0.675–0.766. In the subgroup with known EGFR-mutation status, extrathoracic metastasis and positive EGFR mutation were independent predictors of brain metastasis, with the model showing AUCs of 0.641–0.732. Conclusion: CT-derived imaging features, clinical stages, lung cancer subtype, and EGFR mutation were associated with brain metastasis in patients with newly diagnosed NSCLC. The predictors were completely different between resectable and unresectable stages. Key Points: • In resectable stages of NSCLC, two imaging features (absence of air-bronchogram/bubble lucency and presence of spiculation) and N2 stage were independent predictors of brain metastasis. • In unresectable stages of NSCLC, younger age, female sex, extrathoracic metastasis, and adenocarcinoma were associated with brain metastasis. • In the subgroup of NSCLC with known EGFR-mutation status, extrathoracic metastasis and positive EGFR mutation were independent predictors of brain metastasis. [ABSTRACT FROM AUTHOR]

Background and objective The lack of pathological quality control standard in detecting epidermal growth factor receptor (EGFR) gene mutation in malignant pleural effusion leads to confusion in the interpretation of detection results and the clinical use of EGFR-tyrosine kinase inhibitor (TKI). Therefore, it is very important to propose quality control standards and guide the detection of EGFR mutation in pleural effusion. The aim of this study is to retrospectively analyze the results of EGFR gene mutation in pleural effusion sediment section according to strict pathological quality control standards, and the therapeutic effect of EGFR-TKIs guided by this detection results. Methods From January 2012 to June 2018, the clinical data of patients with pleural effusion collected from Department of Pathology of Peking Union Medical College Hospital were analyzed retrospectively. Among them, 132 patients with relatively complete clinical data and with EGFR gene mutation detection of paraffin-embedded pleural effusion sediment section according to the established quality control standard were included. According to the results of EGFR gene mutation, it was divided into positive group and negative group, and the efficacy of EGFR-TKIs in different groups was compared. Results After the centrifugation of pleural effusion, the sediment was embedded in paraffin, sectioned, and observed under the microscope after HE staining. If the number of tumor cells ≥100, it met the pathological quality control standard, and it could be used for subsequent EGFR gene mutation detection. EGFR gene mutations were detected in 72 (54.5%) of 132 patients. EGFR-TKIs were used in 69 of 72 mutation positive patients. Of 60 EGFR mutation negative patients, only 15 used EGFR-TKIs. In EGFR mutation positive group, the disease control rate (DCR) was 95.8%, and the median progression-free survival (PFS) was 11 months. In EGFR mutation negative group, the DCR was 0%, and the median PFS was 1 month. The DCR and PFS were significantly different between the two groups (P

Large cell neuroendocrine carcinoma (LCNEC) of the lung with epidermal growth factor receptor (EGFR) mutation is rare, and few cases have been treated with EGFR tyrosine kinase inhibitors (TKIs). We report the treatment of combined LCNEC with adenocarcinoma harboring an EGFR mutation with EGFR-TKIs and bevacizumab. Our patient was a 70-year-old asymptomatic woman who underwent surgical resection of the lung for combined LCNEC with adenocarcinoma harboring an activating EGFR mutation 11 months previously. Magnetic resonance imaging (MRI) and positron emission tomography revealed metastatic lesions in the brain and lung. The patient was diagnosed with recurrence of combined LCNEC with adenocarcinoma. The brain lesion was irradiated, followed by administration of afatinib. Eight months after irradiation, brain MRI revealed ringed enhancement and perilesional edema after radiotherapy without new metastatic lesions. We switched treatment to erlotinib and bevacizumab, resulting in maintenance of stable disease for 10 months. Overall, the disease was controlled for 18 months with EGFR-TKIs and bevacizumab. Combination treatment with EGFR-TKIs and bevacizumab could be a treatment option for LCNEC of the lung harboring EGFR mutations, especially with brain metastasis.