EGFR-mutant Lung Cancer Research Articles

Advancements in Cancer Therapeutics: Emerging Agents and Combination Strategies in Drug Discovery

In the last few years, there have been significant advances in cancer agent research, most of which entered clinical trials after succeeding in initial preclinical studies. Here, we discuss successful accomplishments in the promising approaches of targeted therapies, immunotherapies, and combination therapies. The development in these areas includes sotorasib - targeting the mutation of KRAS for lung and pancreatic cancer and pembrolizumab - an immune checkpoint inhibitor for melanoma therapy; the latter has been synergistic with chemotherapy. In addition, exciting results emerge from trials with the DNA damage repair inhibitor olaparib in BRCA-mutated cancers and the tyrosine kinase inhibitor osimertinib for EGFR-mutant lung cancer. Bevacizumab continues to establish itself as an evolving therapy in colorectal cancer, and niraparib enters Phase III in ovarian cancer. New combinations will include alpelisib and PD-1 inhibitors and nanoparticle-based Abraxane for triple-negative breast cancers leading toward precision medicine. These would improve the survival rates and quality of life in patients with advanced or refractory malignancies.

Rebiopsy Enhances Survival with Afatinib vs. Osimertinib in EGFR Exon 19 Deletion Non-Small Cell Lung Cancer: A Multicenter Study in Taiwan.

Afatinib and Osimertinib are first-line treatments for EGFR-mutated advanced non-small cell lung cancer (NSCLC), but their comparative efficacies and the patient groups that benefit the most remain unclear. This multicenter retrospective study evaluated the efficacy of first-line Afatinib and Osimertinib in NSCLC patients with EGFR 19del and no brain metastases at diagnosis. The primary endpoints were time on treatment (ToT) and overall survival (OS). Survival analyses were performed for three groups: Afatinib followed by Osimertinib, Afatinib followed by other therapies, and Osimertinib (alone or followed by other therapies). Rebiopsy practices, including T790M mutation detection, were also analyzed in patients with disease progression on Afatinib. Among 97 Afatinib-treated and 60 Osimertinib-treated patients, Osimertinib showed a significantly longer ToT (23.3 vs. 16.5 months; p = 0.007). Median OS was numerically higher for Afatinib with sequential Osimertinib (40.5 vs. 34.6 months for Osimertinib; p = 0.473). Osimertinib demonstrated advantages, with fewer brain metastases upon progression and fewer adverse effects. In the Afatinib group, 64% of patients with disease progression underwent rebiopsy, with 39% testing positive for T790M mutation and subsequently receiving Osimertinib. Rebiopsy was most frequently performed on the lung parenchyma using non-surgical methods. In this real-world study, Osimertinib achieved a significantly longer ToT compared to Afatinib in NSCLC patients with EGFR 19del and no brain metastases. The sequential use of Afatinib followed by Osimertinib showed a trend toward improved OS, highlighting the importance of rebiopsy for identifying T790M mutations to guide subsequent therapy.

Effects of EGFR-TKIs combined with intracranial radiotherapy in EGFR-mutant non-small cell lung cancer patients with brain metastases: a retrospective multi-institutional analysis

BackgroundPatients with non-small cell lung cancer (NSCLC) are prone to developing brain metastases (BMs), particularly those with epidermal growth factor receptor (EGFR) mutations. In clinical practice, treatment-naïve EGFR-mutant NSCLC patients with asymptomatic BMs tend to choose EGFR-tyrosine kinase inhibitors (TKIs) as first-line therapy and defer intracranial radiotherapy (RT). However, the effectiveness of upfront intracranial RT remains unclear.MethodsThis was a retrospective study including 217 patients from two institutions between January 2018 and December 2022. Clinical data of NSCLC patients with BMs who received EGFR-TKIs were collected. The patients were assigned to one of the three groups according to the therapeutic modality used: the upfront TKI + stereotactic radiosurgery (SRS) / fractionated stereotactic radiotherapy (fSRS) group (upfront TKI + SRS/fSRS ), the upfront TKI + whole-brain radiotherapy (WBRT) group (upfront TKI + WBRT) and the upfront TKI group.ResultsAs of March 8, 2023, the median follow-up duration was 37.3 months (95% CI, 32.5–42.1). The median overall survival (OS) for the upfront TKI + SRS/fSRS, upfront TKI + WBRT, and upfront TKI groups were 37.8, 20.7, and 24.1 months, respectively (p = 0.015). In subgroup analysis, the upfront TKI + SRS/fSRS group demonstrated longer OS compared to the upfront TKI + WBRT and upfront TKI groups in patients treated with first or second-generation EGFR-TKIs (p = 0.021) and patients with L858R mutation (p = 0.017), whereas no survival benefit was observed in three-generation EGFR-TKIs or 19del subgroup. In the multivariable analysis, metachronous BMs, EGFR L858R mutation and nonclassic EGFR mutation were identified as independent risk factors for OS, while a DS-GPA score of 2.0–4.0 was the only independent protective factor.ConclusionsThis study demonstrated that upfront addition of SRS/fSRS to EGFR-TKIs was associated with longer OS compared to upfront WBRT or upfront TKI alone in EGFR-mutant NSCLC patients with BMs. This improvement was more significant in patients with L858R mutation and those treated with first or second-generation EGFR-TKIs. Further research with a larger sample size is warranted.

Stage-specific efficacy of osimertinib in treatment-naïve EGFR-mutant non-small cell lung cancer according to baseline genetic alterations in circulating tumor DNA.

The impact of clinical stage on the effectiveness of osimertinib for epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) remains unexamined. We investigated osimertinib therapeutic efficacy variation between stage IVA or lower and stage IVB EGFR mutation-positive lung cancers, focusing on differences in pretreatment co-occurring genetic alterations in circulating tumor DNA. This was a secondary analysis of the ELUCIDATOR study, a multicenter prospective observational study in Japan that assessed the mechanisms underlying resistance to osimertinib as a first-line treatment for advanced NSCLC with EGFR mutations. We compared the progression-free survival (PFS), overall survival (OS), and pretreatment co-occurring genetic alterations detected in plasma between patients with stages IVA (n = 83) and IVB disease (n = 84). Multivariate analysis of PFS and OS revealed that stage IVB was associated with a poor prognosis (hazard ratio [HR]: 2.03, 95% confidence interval [CI]: 1.36-3.04, p < 0.001, HR: 2.35, 95% CI: 1.45-3.90, p < 0.001, respectively). Pre-osimertinib treatment, significantly more TP53- (52.4% vs. 27.7%, p = 0.002), EGFR amplification- (58.3% vs. 23.2%, p < 0.001), and MET amplification-positive cases (22.6% vs. 7.2%, p = 0.008) were found among stage IVB than among stage IVA or lower cases. Patients with EGFR-positive NSCLC in stage IVB exhibited significantly shorter PFS and OS than those in earlier stages when treated with first-line osimertinib. The prevalence of baseline TP53 mutations, EGFR amplification, and MET amplification in plasma were significantly higher in stage IVB cases, implicating them in the worse outcomes of this group.

Prognosis of TP53 and Its Concomitant EGFR Mutation in Lung Cancer Especially Non-Small Cell Lung Cancer.

Human Lung Carcinoma (LC) is among the most diagnosed cancers across the world among those non-small cell lung cancer (NSCLC) comprises about 85%. Next Generation Sequencing based detection of mutations are now well established in molecular oncology. With the advent of modern diagnostic methods, it is now well known that there are several mutations and gene rearrangements which are associated with the development of LC. Among those mutations, TP53 is the most prevalent with the concomitant EGFR mutation. In this retrospective study, a total number of 414 patients have been incorporated who have attended RGCIRC in the period between November 2015 to March 2024. Clinical stage has been determined as per NCCN Guideline version 2.2024. Nucleic Acid (DNA and RNA) from FFPE samples were extracted and detection of mutation was performed by Next generation sequencing (NGS) method. All 414 patients opted for the customised NGS panel for lung cancer among those 203 patients were TP53 mutation and 87 patients were EGFR mutation positive. 62 patients were TP53-EGFR double mutation positive. The results of this study have shown that TP53 mutated patients show poor prognosis with conventional therapy. However, TP53-EGFR co-mutated patient's recovery rates are comparatively promising due to the availability of the targeted therapy of EGFR. Studies have shown that TP53 mutation is unlikely to derive clinical benefit in LC patients and shows poorer prognosis when compared to TP53 wild type and EGFR mutated patients show improved recovery due to availability of the Kinase Inhibitor (KI) treatment. In this study we have observed and concluded that TP53-EGFR co-mutated group also shows promising prognosis for the application of KI treatment. A further large cohort study will establish this clinical observation and enlighten more therapeutically relevant information.

Pathological Features and Differential Efficacy of Cisplatin-Based Adjuvant Chemotherapy in Lung Cancer Harboring Epidermal Growth Factor Receptor Mutations.

We aimed to elucidate the efficacy of conventional cisplatin-based adjuvant chemotherapy for patients with lung cancers harboring epidermal growth factor receptor (EGFR) mutation. This retrospective cohort study included 110 patients (EGFR mutation group: n = 51; EGFR wild-type group: n = 59) receiving cisplatin-based adjuvant chemotherapy following complete resection of non-small-cell non-squamous-cell lung cancer (2010-2021). Clinicopathological characteristics, recurrence-free survival (RFS), and overall survival (OS) were investigated. The pStage distribution was not statistically different. The EGFR mutation group was characterized by more advanced pN, papillary predominance, and presence of micropapillary components, whereas the EGFR wild-type group exhibited more advanced pT and solid predominant patterns. The median RFS was significantly worse in the EGFR mutation group (23.0 vs. 76.1 months, p = 0.017). Nevertheless, the median OS was not significantly different (85.6 months vs. not reached, p = 0.151). Multivariable analysis demonstrated that EGFR mutation and lymphatic invasion were significant risk factors in RFS; however, no independent factors were identified in OS. Cisplatin-based adjuvant chemotherapy might be less effective in patients with EGFR-mutated lung cancer. The style of progression and histological pattern related with EGFR mutation may be associated with the efficacy of adjuvant chemotherapy and poor RFS.

Brief Report: Preventing Infusion-related Reactions With Intravenous Amivantamab: Results From SKIPPirr, a Phase 2 Study.

Amivantamab, an EGFR-MET bispecific antibody, is approved for multiple indications in EGFR-mutated advanced non-small cell lung cancer (NSCLC) as monotherapy or combined with other agents. Intravenous amivantamab is associated with a 67% infusion-related reactions (IRR) rate. The phase 2 SKIPPirr study (NCT05663866) enrolled patients with EGFR-mutated (Ex19del/L858R) advanced NSCLC after progression on osimertinib and platinum-based chemotherapy who received intravenous amivantamab plus oral lazertinib (amivantamab-lazertinib), a third-generation tyrosine kinase inhibitor. Aiming to mitigate IRRs, 4 independent prophylactic approaches were evaluated using Simon's 2-stage design with an expansion stage if a cohort passed both stages: oral dexamethasone 4-mg twice daily (BID) given on cycle (C) 1 day (D) -1; oral dexamethasone 8-mg BID given on C1D-2, C1D-1, and morning of C1D1 (5 doses); oral montelukast 10-mg once daily given on C1D-4, C1D-3, C1D-2, C1D-1, and C1D1 (5 doses); subcutaneous methotrexate 25-mg (1 dose) given anytime between C1D-7 and C1D-3. Primary endpoint was C1D1 IRR incidence. As of 24-June-2024, 68 patients were treated across all cohorts. The dexamethasone 8-mg cohort passed stages 1 and 2 proceeding to the expansion stage, with 24 additional patients treated. At C1D1, 9/40 patients (22.5%) experienced IRRs, resulting in an ∼3-fold decrease versus historical data (67.4%). By end of C3, 10/41 (24.4%) patients in the dexamethasone 8-mg cohort experienced IRRs (grades 1-2, except 1 grade 3 on C2D1). Amivantamab-lazertinib safety and efficacy were consistent with previous reports. Prophylaxis with 8-mg oral dexamethasone meaningfully reduced IRRs and can be readily implemented in clinical practice.

Atezolizumab, bevacizumab, pemetrexed and platinum for EGFR-mutant NSCLC patients after EGFR TKI failure: A phase II study with immune cell profile analysis.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) remains a significant hurdle forpatients with EGFR-mutated non-small cell lung cancer (NSCLC), particularly those lacking the EGFRT790M. IMpower 150 study demonstrated promising efficacy for a combination of immune-chemotherapy and bevacizumab in patients with EGFR-mutated NSCLC. This open-label, single-arm, phase II trial evaluated the efficacy and immune cell profile of the modified regimen combining atezolizumab, bevacizumab (7.5mg/kg) and chemotherapy in patients with EGFR-mutated NSCLC following TKI failure. The primary endpoint was objective response rate (ORR). The re-biopsy tissue specimens and serial peripheral blood samples were collected to analyse the immune cell profile and tumour microenvironments. 22 EGFR-mutant NSCLC patients participated in this study. The ORR was 42.9%, with a disease control rate (DCR) of 100%. Median progression-free survival (PFS) was 6.3 months. Patients with programmed death-ligand 1 (PD-L1) expression ≥1% exhibited significantly higher ORR (75 vs. 23.1%; p=.032) and longer PFS (14.0 vs. 6.1 months; p=.022) compared with those with PD-L1 expression<1%. Grade≥3 adverse events occurred in 40.9% of patients. Higher peritumour nature killer (NK) cell infiltration and lower peripheral helper T cell counts before treatment were associated with favourable ORR and longer PFS, respectively. After disease progression, the proportion of S100A9+ myelod-derived suppressor cells (MDSCs) increased, while regulatory T cells decreased. This modified combination regimen may be a promising therapeutic option for EGFR-mutant NSCLC patients with TKI resistance, especially those with PD-L1-positive tumours. Furthermore, immune cell profiling may aid in identifying patients who may benefit from this approach. The combination regimen yielded promising efficacy in NSCLC patients after EGFR-TKI resistance, particularly those with PD-L1-positive tumours. Higher peritumour NK cell and lower peripheral helper T cell were associated with favourable ORR and longer PFS, respectively. After disease progression, the proportion of S100A9+ MDSC increased, but Treg cells decreased.

Third generation vs first generation EGFR-TKIs in the first line treatment for EGFR-mutated locally advanced or metastatic non-small cell lung cancer: a meta-analysis based on randomized controlled trials.

Background: The prevailing belief is that third-generation tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) (TGET) outperform first-generation EGFR-TKIs (FGET) in managing advanced-stage EGFR-mutated non-small cell lung cancer (NSCLC). However, this standpoint lacks substantiation in evidence-based medicine. Therefore, this meta-analysis was conducted to compare the efficacy and adverse effects (AEs) of these two categories. Methods: We searched seven databases for relevant randomized controlled trials (RCTs), focusing on primary endpoints such as progression-free survival (PFS), overall survival (OS), and central nervous system PFS (CNS-PFS). Additional factors considered included treatment responses and AEs. Results: We analyzed 15 studies from 6 RCTs on six third-generation TKIs: Osimertinib, Lazertinib, Furmonertinib, Aumolertinib, Naquotinib, and Befotertinib. TGET showed better efficacy in PFS (hazard ratio [HR]: 0.55 [0.41, 0.75]), CNS-PFS (HR: 0.48 [0.35, 0.66]), CNS-objective response rate (CNS-ORR, risk ratio [RR]: 1.40 [1.19, 1.65]), and duration of response (DOR, HR: 0.52 [0.38, 0.72]). Most subgroups confirmed the PFS advantage. With longer survival time, the superiority in PFS, OS, and CNS-PFS of TGETs became more evident. Both groups had similar OS (HR: 0.86), ORR, CNS-DOR, total AEs, and grade 3-5 AEs. However, TGETs had more severe AEs (RR: 1.17 [1.02, 1.35]). Additionally, there were more grade 3-4 cases of diarrhea, decreased platelet count, pulmonary embolism, fatigue, decreased neutrophil count, and rash, and fewer grade 3-4 increases in alanine transaminase (ALT) and aspartate transaminase (AST) in the TGET group. The top 5 AEs in the TGET group were diarrhea (36.32%), rash (30.24%), decreased platelet count (29.15%), elevated serum creatinine (23.63%), and decreased white blood cell count (22.02%). Conclusions: Except for Naquotinib, TGETs demonstrate superiority over FGETs in treating EGFR-mutated locally advanced or metastatic NSCLC, showing improved survival and responses. However, the increased incidence of AEs necessitates careful consideration.

Recurrence as a small cell lung cancer transformation in a resected stage IIIA EGFR-mutated non-small cell lung cancer treated with adjuvant osimertinib: a case report

Recurrence as a small cell lung cancer transformation in a resected stage IIIA EGFR-mutated non-small cell lung cancer treated with adjuvant osimertinib: a case report

COMPOSIT study: evaluating osimertinib combination with targeted therapies in EGFR-mutated non-small cell lung cancer.

The emergence of diverse resistance mechanisms after osimertinib therapy, including on-target epidermal growth factor receptor (EGFR) mutations and off-target alterations, warrants investigation of novel therapeutics to overcome these challenges and improve patient outcomes. COMPOSIT was a French, retrospective, multicenter, cohort study of the effectiveness and tolerability of osimertinib in combination with other targeted therapies in patients with advanced EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC) who harbored other oncogenic drivers as primary or acquired resistance mechanisms. Real-world progression-free survival (rwPFS), overall survival (OS), and objective response rate (ORR) were the primary endpoints. The study included 61 patients (63.9% women; median age, 61 years). Chemotherapy was administered to 26 patients (42.6%) before the combinations. The most frequently targeted resistance mechanisms were MET amplification (n = 40) and BRAF alterations (n = 11). Sixteen combinations of osimertinib with other targeted therapies were reported. Overall (except for 10 patients in clinical trials), median rwPFS and OS were 3.9 (95% CI, 2.9-5.2) and 9.8 months (95% CI, 6.8-14.8). Best ORR (n = 54) was 50% (95% CI, 33.0-72.8). In patients with MET amplification (n = 29), median rwPFS and OS were 4.9 (95% CI, 2.9-7.2) and 8.6 months (95% CI, 5.3-21.6). Grade ≥3 adverse events occurred in 15 patients (24.6%). No deaths were related to treatment. Combinations of osimertinib with other targeted therapies appeared to be feasible and safe and may offer clinical benefit to overcome resistance to osimertinib in EGFRm NSCLC, especially in patients with MET amplification.

Itraconazole Reversing Acquired Resistance to Osimertinib in NSCLC by Inhibiting the SHH/DUSP13B/p-STAT3 Axis.

There is an urgent necessity to devise efficient tactics to tackle the inevitable development of resistance to osimertinib, which is a third-generation epidermal growth factor receptor (EGFR) inhibitor used in treating EGFR-mutant nonsmall cell lung cancer (NSCLC). This study demonstrates that combining itraconazole with osimertinib synergistically reduces the proliferation and migration, enhances the apoptosis of osimertinib-resistant cells, and effectively inhibits the growth of osimertinib-resistant tumors. Mechanistically, itraconazole combined with osimertinib promotes the proteasomal degradation of sonic hedgehog (SHH), resulting in inactivation of the SHH/Dual-specificity phosphatase 13B (DUSP13B)/p-STAT3 and Hedgehog pathways, suppressing Myc proto-oncogene protein (c-Myc). Additionally, DUSP13B interacts with signal transducer and activator of transcription 3 (STAT3) and modulates its phosphorylation. Interestingly, it is observed that SHH overexpression partially rescues the synergistic effects of this combination treatment strategy through the SHH/DUSP13B/p-STAT3 signaling axis. Moreover, it is found that SHH, (GLI1), p-STAT3, and DUSP13B play significant predictive roles in osimertinib resistance. In lung adenocarcinoma, p-STAT3 is positively correlated with SHH but negatively correlated with DUSP13B. Together, these results highlight the crucial role of itraconazole in reversing the acquired resistance to osimertinib and provide a scientific rationale for the therapeutic strategy of combining osimertinib with itraconazole.

Outcomes of patients receiving urgent palliative radiotherapy for advanced lung cancer: an observational study

BackgroundThere is considerable variability in the management of patients with advanced lung cancer referred for palliative radiotherapy owing to uncertainties in prognosis and the benefit of treatment. This study presents the outcomes of patients seen in the Fast Track Lung Clinic, an urgent access palliative radiotherapy clinic, and aims to identify factors associated with treatment response and survival.MethodsConsecutive patients with advanced lung cancer seen in the Fast Track Lung Clinic between January 2014 and July 2020 were included. Patients who underwent radiotherapy were contacted beginning 30 days after radiotherapy to evaluate treatment response. Cluster bootstraps were used to compute confidence intervals for treatment response rate. Prognostic factors for treatment response and overall survival were identified using multivariable generalized estimating equations and Cox regression models, respectively.ResultsA total of 558 patients were included, of whom 459 (82.3%) consented to palliative radiotherapy for 1053 indications. The overall treatment response rate was 70.0% (95% CI, 65.8-74.2) for indications with follow-up (70.8%). Higher response rates were observed in patients with better ECOG performance status (OR per point, 0.71; 95% CI, 0.55-0.93; P=0.01) and EGFR-mutant non-small cell lung cancer (OR vs wild-type, 2.46; 95% CI, 1.35-4.51; P=0.003), whereas patients treated for neurological symptoms had lower response rates (OR, 0.27; 95% CI, 0.16-0.45; P<0.001). There was no difference in response rate between patients who died within 30 days of starting radiotherapy and those who survived longer (OR, 0.83; 95% CI, 0.42-1.67; P=0.61). Age; ECOG performance status; smoking history; pathology; EGFR or ALK mutation status; and the presence of liver, adrenal, or brain metastases were associated with overall survival.ConclusionsPalliative radiotherapy was effective for patients with advanced lung cancer, although response rates varied by patient characteristics and treatment indication. This study identified prognostic factors for radiotherapy response and overall survival that can inform treatment decisions in this population.

Clinical outcomes of patients with EGFR-mutated NSCLC developing interstitial lung disease during first-line osimertinib therapy: a sub-analysis of the Reiwa study.

Osimertinib-induced interstitial lung disease in untreated EGFR-mutated, advanced non-small cell lung cancer is being reported at a higher rate in Japan than elsewhere. However, data on the interstitial lung disease incidence during first-line osimertinib therapy and the course of lung cancer treatments administered after interstitial lung disease onset in the real-world setting are scarce. The present study reviewed the data from the Reiwa study, a multicentric, observational study examining the efficacy and safety of first-line osimertinib therapy in the clinical setting. Patients with EGFR-mutated non-small cell lung cancer who began osimertinib therapy between September 2018 and August 2020 were enrolled and followed until August 2022. Among 583 patients receiving first-line osimertinib therapy, 75 (12.8%) had interstitial lung disease development, and 18 (3.0%) had at least grade 3 interstitial lung disease. Fifty-nine patients (78%) received some form of treatment following interstitial lung disease onset. An epidermal growth factor receptor-tyrosine kinase inhibitor rechallenge was performed in 31 patients (41%), with 18 (24%) receiving osimertinib again. Interstitial lung disease recurred in five (28%) of these 18 patients, none of 13 patients receiving another type of tyrosine kinase inhibitor, and seven (25%) of 28 patients receiving chemotherapy and/or immune checkpoint inhibitor therapy. The median overall survival after the initial osimertinib therapy was 38.4months and 12.2months for patients with interstitial lung disease grade 1-2 and grade 3-4, respectively (hazard ratio: 0.37; 95% confidence interval: 0.20-0.70; P=0.002). Patients with interstitial lung disease grade 3-4 had poorer survival during the first-line osimertinib therapy. A substantial risk of interstitial lung disease recurrence was associated with post-osimertinib therapy. Trial registration code: UMIN000038683.

Weight loss in patients on osimertinib for metastatic EGFR-mutant non-small cell lung cancer.

Cachexia is characterized by weight loss and decline in muscle mass and function and is a poor prognostic factor among patients with cancer. Patients with metastatic EGFR-mutant non-small cell lung cancer (NSCLC) derive remarkable survival benefits with osimertinib, a third-generation EGFR tyrosine kinase inhibitor. It is not known whether patients treated with osimertinib experience any weight loss or whether weight loss impacts patient outcomes. Therefore, we sought to describe the frequency and consequences of weight loss in this patient population. We conducted a single-center retrospective pilot study of 56 patients treated with first-line osimertinib for metastatic EGFR-mutant NSCLC. We defined on-treatment weight loss as a loss of ≥5% body weight at 6 or 12 months of treatment. We described the characteristics of patients with and without on-treatment weight loss and differences in progression-free survival (PFS), time on treatment with osimertinib, and overall survival (OS). Forty-six percent (n = 26) of patients met the criteria for on-treatment weight loss. There were no significant differences in patient or disease characteristics between patients with and without weight loss. Compared to patients without weight loss, patients with weight loss had similar PFS and time on treatment with osimertinib. Yet, patients with weight loss had significantly worse overall survival (HR 4.91, 95% CI, 1.56-15.5, P = .007). Weight loss was observed in nearly half of patients with metastatic EGFR-mutant NSCLC treated with osimertinib, and patients with weight loss had significantly worse overall survival.

The Impact of Bevacizumab and miR200c on EMT and EGFR-TKI Resistance in EGFR-Mutant Lung Cancer Organoids.

Objectives: This research aims to investigate the mechanisms of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC), particularly focusing on the role of the epithelial-mesenchymal transition (EMT) within the tumor microenvironment (TME). Materials and Methods: We employed an in vitro three-dimensional organoid model that mirrors the physiology of human lung cancer. These organoids consist of lung cancer cells harboring specific EGFR mutations, human mesenchymal stem cells, and human umbilical vein endothelial cells. We analyzed EMT and drug resistance markers, and evaluated the effects of the anti-angiogenic agent Bevacizumab and micro-RNA miR200c. Results: The study identified a significant link between EMT and EGFR-TKI resistance. Notable findings included a decrease in E-cadherin and an increase in Zinc Finger E-Box Binding Homeobox 1 (ZEB1), both of which influenced EMT and resistance to treatment. Bevacizumab showed promise in improving drug resistance and mitigating EMT, suggesting an involvement of the Vascular Endothelial Growth Factor (VEGF) cascade. Transfection with miR200c was associated with improved EMT and drug resistance, further highlighting the role of EMT in TKI resistance. Conclusions: Our research provides significant insights into the EMT-driven EGFR-TKI resistance in NSCLC and offers potential strategies to overcome resistance, including the use of Bevacizumab and miR200c. However, due to the limitations in organoid models in replicating precise human cancer TME and the potential influence of specific EGFR mutations, further in vivo studies and clinical trials are necessary for validation.

The Effectiveness of Afatinib as First-Line Treatment in Vietnamese Patients With EGFR-Mutant Non-Small Cell Lung Cancer and Brain Metastases.

The role of afatinib in the first-line treatment of EGFR-mutant advanced non-small cell lung cancer (NSCLC) patients has been proven through clinical trials and real-world studies. However, additional data on the effectiveness of afatinib in patients with brain metastases are lacking. EGFR-mutant NSCLC patients with brain metastases were retrospectively reviewed across nine cancer centers in Vietnam from April 1, 2018 to June 1, 2022. The primary endpoints included central nervous system progression-free survival (CNS-PFS) and overall survival (OS). The secondary endpoints were the objective response rate (ORR) and CNS-ORR. Among 87 enrolled patients, 21.8%, 17.2%, and 60.9% received whole-brain radiation, gamma knife, and no locoregional therapy, respectively. With a median follow-up of 32.2 months for CNS-PFS and 35.3 months for OS, the median CNS-PFS and OS were 17.9 and 29.9 months, respectively. In multivariate analysis, patients receiving whole-brain radiation had significantly shorter CNS-PFS than those untreated with local therapy (16.1 vs. 22.6 months, p = 0.019), but not translating to an inferior OS. Furthermore, both the CNS-PFS and OS of patients with uncommon mutations were significantly worse than those of patients with Del19 (11.3 vs. 24.2 months, p = 0.013 and 17.7 vs. 34.0 months, p = 0.003, respectively). Univariate and multivariate analyses showed that a lower afatinib starting dose did not significantly affect CNS-PFS or OS. The CNS-ORR and ORR were 77.4% and 71.3%, respectively. In our real-world study, afatinib showed encouraging effectiveness in Vietnamese patients with EGFR-mutant NSCLC and brain metastases at baseline.

Real-World Study of EGFR-TKI Rechallenge With Another TKI After First-Line Osimertinib Discontinuation in Patients With EGFR-Mutated Non-Small Cell Lung Cancer: A Subset Analysis of the Reiwa Study.

First-line osimertinib is widely used to treat patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancers (NSCLC). In clinical practice, rechallenge therapy with another EGFR-tyrosine kinase inhibitor (TKI) is often performed after first-line TKI discontinuation owing to resistance or toxicity; however, the efficacy and toxicity of EGFR-TKI rechallenge after first-line osimertinib have not been adequately investigated. This study aimed to examine the efficacy and safety of EGFR-TKI rechallenge with another TKI. This multicenter prospective observational study enrolled patients with EGFR-mutated NSCLC who received first-line osimertinib and another EGFR-TKI as second- or third-line treatment between September 2018 and August 2020. Fifty-three patients received rechallenge with another EGFR-TKI in the second-line (n = 38, 71.7%) or third-line (n = 15, 28.3%) setting. The primary reason for first-line osimertinib discontinuation was toxicity in 32 (60.4%, 17 patients with pneumonitis) and disease progression in 20 (37.7%) patients. The most common rechallenge EGFR-TKI was afatinib (n = 24, 45.3%), followed by gefitinib (n = 16, 30.2%) and erlotinib (n = 8, 15.1%). The real-world time to treatment failure (rwTTF) was 7.3 months. The rwTTF for the toxicity discontinuation and progressive disease discontinuation groups was 9.3 months and 5.1 months, respectively, (HR 1.61, p = 0.119). EGFR-TKI rechallenge was discontinued due to toxicity in nine patients (17.0%), but no patient developed pneumonitis. EGFR-TKI rechallenge with another TKI is well tolerated in patients with EGFR-mutated NSCLC. Thus, it may be a useful treatment option after first-line osimertinib failure, especially after osimertinib discontinuation due to toxicity.

CXCR1+ neutrophil infiltration orchestrates response to third-generation EGFR-TKI in EGFR mutant non-small-cell lung cancer

Although third-generation Epidermal growth factor receptor—tyrosine kinase inhibitors (EGFR-TKI) is standard of care for patients with EGFR-mutant Non-small cell lung cancer (NSCLC), little is known about the predictors of response or resistance. Here, we integrated single-cell RNA (scRNA) sequencing, bulk RNA sequencing, multiplexed immunofluorescence and flow cytometry data from pretreatment and post-resistant tumor samples of EGFR-mutant NSCLC patients received third-generation EGFR-TKIs. We show that resistant samples had a markedly enriched CXCR1+ neutrophils infiltration (P < 0.01) than pretreatment samples, which were distinguished from other subtypes of neutrophils and displayed immunosupressive characteristics. Spatial analysis showed that increased CXCR1+ neutrophils predominantly infiltrated into the tumor core in resistant samples and the average distance of neutrophils to tumor cells markedly reduced from 33 to 19 μm. Deep analysis of scRNA and bulk RNA sequencing data revealed the increased interactions between CXCR1+ neutrophils and tumor cells and activated TNF-α/NF-κB signaling pathway in tumor cells of resistant samples. In vitro and in vivo experiments validated that CXCR1+ neutrophils resulted in resistance to third-generation EGFR-TKI via activating TNF-α/NF-κB signaling pathway in tumor cells. Importantly, patients with low pretreatment CXCR1+ neutrophil infiltration abundance had a dramatically longer progression-free survival (11.8 vs. 7.5 months; P = 0.019) and overall survival (33.0 vs. 23.5 months; P = 0.029) than those with high infiltration abundance. Collectively, these findings suggest that CXCR1+ neutrophils infiltration was associated with the efficacy of third-generation EGFR-TKI in patients with EGFR-mutant NSCLC.

Cardiac Events and Survival in Patients With EGFR-Mutant Non–Small Cell Lung Cancer Treated With Osimertinib

Although it has been reported that osimertinib mesylate provides better survival benefits compared with first- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), it remains unclear whether osimertinib is associated with more cancer therapy-related cardiac events (CTRCEs) compared with other EGFR TKIs, as does the extent of the association these adverse effects may have with overall survival. This issue is particularly critical due to the high prevalence of EGFR variants within Asian populations, including that of Taiwan. To compare CTRCEs and their association with survival in patients treated with osimertinib vs other EGFR TKIs. This cohort study was conducted at the National Cheng Kung University Hospital, a college hospital and tertiary academic referral center in Taiwan. The median follow-up duration was 23.2 (IQR, 15.2-31.5) months. A total of 401 patients with EGFR-mutant non-small cell lung cancer (NSCLC) beginning treatment with EGFR TKIs from September 1, 2019, to July 31, 2022, were retrospectively analyzed. CTRCEs included newly emerging arrhythmias, valvular heart diseases (moderate and more), myocardial infarction, and heart failure and were analyzed after adjusting for age, sex, smoking, alcohol consumption, body mass index, cardiovascular comorbidities, thoracic radiotherapy, and cardiovascular medications. Follow-up was completed January 31, 2024. Osimertinib. The Cox proportional hazards model was used to estimate CTRCEs in patients treated with osimertinib or other EGFR TKIs. Considering that death can lower the incidence of CTRCEs, the competing risk method was used to calculate CTRCEs after adjusting for potential confounders. Multivariable Cox proportional hazard regression analysis for overall survival was used to explore whether CTRCEs were independently associated with overall survival. Among the 401 patients (253 [63.1%] female; mean [SD] age, 69.2 [11.3] years), 195 (48.6%) treated with osimertinib were matched with 206 (51.4%) treated with other EGFR TKIs. Occurrence of CTRCEs in patients receiving osimertinib was significantly higher compared with patients treated with other EGFR TKIs (29 [14.9%] vs 9 [4.4%]; hazard ratio [HR], 3.37; 95% CI, 1.56-7.26; P = .002). After adjustment for relevant cardiovascular risk factors, the HR of CTRCEs was significantly higher in the group treated with osimertinib (adjusted subdistribution HR, 4.00; 95% CI, 1.81-8.85; P < .001). In addition, CTRCEs were independently associated with overall survival (HR, 4.02; 95% CI, 2.44-6.63; P < .001). In this cohort study of patients with EGFR-mutant NSCLC, osimertinib was associated with a higher incidence of CTRCEs compared with other EGFR TKIs; CTRCEs were independently associated with overall survival. These findings highlight the need for ongoing cardiac monitoring in these patients, regardless of preexisting cardiac risk factors.