Generation Epidermal Growth Factor Receptor Research Articles

Case report: NSCLC with pulmonary embolism after treatment with almonertinib

Rationale: Almonertinib is the first independently developed third generation epidermal growth factor receptor tyrosine kinase inhibitors in China. It can be used not only for epidermal growth factor receptor (EGFR) sensitive mutation patients but also for T790M (+) resistant patients, and has better safety and survivability compared to the first and second generation EGFR-TKIs. The previous literature and case studies have reported significant treatment-related adverse reactions in non-small cell lung cancers patients treated with almonertinib, including elevated blood creatine phosphatase, prolonged cardiac QT interval, altered myocardial contractility, interstitial lung disease, eye disease, and hematological events. But there are few individual reports of pulmonary embolism events. Patient concerns: A 55-year-old female with no history of smoking visited a local hospital with mild cough and lower sacrococcygeal pain without obvious cause. Diagnosis: She was diagnosed with right lung adenocarcinoma with multiple bone metastases (T2bN1M1c, stage IVB) after image and histological examination, with EGFR 21 exon L858R sensitive mutation. Interventions: She initially underwent surgical treatment due to the discovery of a sacral tumor, and the pathology of the surgery indicated metastatic lung adenocarcinoma. Genetic testing results showed EGFR 21 exon L858R sensitive mutation. Combined with positron emission tomography/computed tomography imaging results and sacral tumor surgical pathology results, it was considered that the patient had lung adenocarcinoma with multiple bone metastases. Treatment plan: targeted treatment with almonertinib which is the third-generation EGFR-TKIs. After only 1 month of targeted treatment, chest enhanced computed tomography revealed pulmonary embolism imaging, combined with coagulation indicators, considering pulmonary embolism. As the thromboembolic site is located at the end of the pulmonary artery branch and imaging shows that tumor lesions are stable. Consider continuing targeted treatment with almonertinib and adjuvant oral anticoagulant therapy with rivaroxaban for treatment. Outcomes: Two months later, the patient’s condition was followed up and it was found that the imaging manifestations of pulmonary embolism disappeared, but the coagulation indicators remained in a hypercoagulable state. The patient’s treatment plan remained unchanged, and the patient was hospitalized for follow-up every 6 to 8 weeks to closely observe changes in the condition. Lessons: There are many reasons for the occurrence of hypercoagulable blood in tumor patients, and there are very few reports of treatment-related pulmonary embolism events in patients who are treated with almonertinib targeted therapy. It is particularly important to determine whether the hypercoagulable blood in such patients is related to targeted therapy drugs in clinical practice, as this will affect the clinical benefits of patients in epidermal growth factor receptor tyrosine kinase inhibitors treatment and the clinical indicators which need to pay more attention in follow-up observation, to avoid serious pulmonary embolism events and thus affect the patient’s survival status and quality of life.

Abstract 7195: Repurposing non-oncology drugs with MET inhibitory effect to overcome osimertinib resistance in lung cancer

Abstract Background and Aim: Osimertinib is the only 3rd generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for the 1st line therapy of advanced NSCLC patients with EGFR mutations. However, drug resistance is severely limiting its clinical efficacy. Aberrant MET activation is an important mechanism causing osimertinib resistance. There is no effective therapeutic option after osimertinib failure. This study investigated the repurposing of non-oncology MET inhibiting drug to overcome osimertinib resistance. Method: A few clinically-approved drugs with putative MET inhibitory effects were identified by a computational drug repurposing tool called “DRAR-CPI” via analysis of the chemical-protein interactome of known MET inhibitors (crizotinib, cabozantinib, foretinib, and tivantinib). Fexofenadine (FEX), originally indicated for allergic rhinitis and chronic urticaria, was chosen for detailed investigation in osimertinib-resistant NSCLC cell lines that exhibit aberrant MET activation with/without other EGFR-dependent osimertinib resistance mechanisms. The selectivity of kinase inhibition by FEX was evaluated by a KINOME profiling assay against a panel of human protein kinases. Western blot analysis was conducted to examine the activation status of Met and EGFR downstream signaling. RNA sequencing was performed to identify differentially expressed genes (DEGs) triggered by the most promising repurposed drug, presumably contributing to osimertinib resistance circumvention. Sulforhodamine B assay was used to evaluate cell proliferation. The circumvention of osimertinib resistance by FEX was further verified in a patient-derived tumor xenograft (PDX) from an advanced-stage osimertinib-refractory NSCLC patient. Result: FEX was found to inhibit recombinant MET kinase in cell-free assays in a dose- and time-dependent manner. It also inhibited MET phosphorylation and other downstream signaling molecules in osimertinib-resistant NSCLC cell lines harboring EGFR T790M+MET amplification or EGFR T790M loss+MET amplification. KINOME profiling revealed a similar kinase inhibition profile between FEX and cabozantinib using Spearman rank order correlation analysis. Among the tested osimertinib-resistant NSCLC cell lines, FEX showed the highest effectiveness in potentiating the anticancer effect of osimertinib in H820 cells (having MET amplification & EGFR T790M mutation). Transcriptome profiling analysis in H820 cells before and after FEX treatment revealed that the majority of DEGs were enriched in EMT-related biological processes and pathways. FEX was further shown to significantly potentiate the antitumor effect of osimertinib in a drug refractory PDX model, without inducing notable weight loss in the animals. Conclusion: These findings advocate the clinical evaluation of repurposing FEX to overcome osimertinib resistance. Citation Format: Kenneth K.W. To, Kwong Sak Leung, William C.S. Cho. Repurposing non-oncology drugs with MET inhibitory effect to overcome osimertinib resistance in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7195.

Abstract C025: Trial in progress: First-in-human study of BBT-207 in advanced non-small cell lung cancer harboring EGFR mutation after treatment with EGFR TKI

Abstract Background: There is a high unmet need for an effective therapy for the treatment of non-small cell lung cancer (NSCLC) following osimertinib or other 3rd generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) failure, especially when resistance is driven by the occurrence of the C797S mutation. BBT-207 is a fourth-generation EGFR inhibitor. Preclinically BBT-207 has shown activity against treatment-emergent complex EGFR mutations containing T790M and/or C797S as well as drug-naïve mutants providing a possibility to overcome resistance to prior TKIs. Activity to intracranial lesions is also anticipated from animal models. Methods: Study BBT207-ONC-001 is an open-label, phase 1/2 study evaluating safety, tolerability, pharmacokinetic profile, pharmacodynamic characterization, and preliminary antitumor activity of BBT-207 monotherapy in approximately 92 patients with EGFR-mutant NSCLC. It consists of 3 phases: Phase 1a (dose escalation), phase 1b (recommended phase 2 dose selection), and phase 2 (dose expansion). Key eligibility criteria include patients ≥18 years of age with advanced stage and refractory NSCLC with an activating EGFR mutation, documented partial response, complete response, or durable stable disease after treatment of an EGFR TKI, and previous treatment with all standard therapeutic options and at least one third-generation EGFR TKI. There is no limit on the number of previous treatments received. Phase 1a requires confirmation that the tumor harbors a classical EGFR mutation (19Del or L858R), and phase 1b and phase 2 require confirmation that the tumor or the blood harbors complex EGFR mutations containing C797S. Patients with asymptomatic brain metastases who are on stable dose of corticosteroid are eligible. Primary endpoints are to determine recommended dose range (RDR) which is defined between the minimal reproducibly active dose, and the maximum tolerated dose or maximum administered dose and to characterize the overall safety and tolerability of BBT-207 (phase 1a); to determine the recommended phase 2 dose (phase 1b); to evaluate preliminary antitumor activity with objective response rate (phase 2). Phase 1a dose escalation will be guided by Bayesian logistic regression model. The safety monitoring committee will determine RDR and two recommended dose levels (RDs) within the RDR to be explored in phase 1b. In phase 1b, up to 20 patients will be randomized to each of the two RDs. At the end of phase 1b, a futility test will be performed in the dose level to be treated with the RP2D using Bayesian analysis. Phase 2 will be a non-randomized, open-label phase with up to 20 patients. Patients may receive treatment until disease progression or unacceptable toxicity. Treatment continuation beyond progression will be allowed if potential benefits are justified. Investigational new drug application was cleared by the U.S. FDA. Patient enrollment will begin in approximately August 2023 in the U.S. and Republic of Korea. Clinical trial information: NCT05920135. Citation Format: NaEun Jeon, Alexander Spira, Douglas Orr, Lyudmila Bazhenova, Misako Nagasaka, Jin Seok Ahn, Dong-Wan Kim, Yu Jung Kim, Jimin Cho, Agnes Jung, Eunsoo Jung, Chul-Won Kim, Taiguang Jin, Yong-Hee Lee, Sang-Yoon Lee. Trial in progress: First-in-human study of BBT-207 in advanced non-small cell lung cancer harboring EGFR mutation after treatment with EGFR TKI [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C025.

Real-world clinical evidence of lazertinib use in acquired EGFR T790M mutated non-small cell lung cancer.

Lazertinib is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) designed to overcome EGFR T790M mutation. Currently, lazertinib is approved for usage in the acquired EGFR T790M mutation population based on promising clinical and safety profiles. In this study, we evaluated the clinical outcomes of lazertinib in acquired EGFR T790M mutated non-small cell lung cancer (NSCLC) patients in a real-world clinical setting. Clinical outcomes of 103 patients treated with lazertinib, from July 2021 to August 2022, for NSCLC with acquired EGFR T790M mutation were retrospectively analyzed. EGFR T790M mutation was confirmed using either a cell-free EGFR test (48.5%) or a tissue-based test (51.5%). The median follow-up duration was 11.4 months [95% confidence interval (CI): 10.4-13.1], and 58.3% of patients remained on treatment at the time point of data analysis. The objective response rate was 72.8%. The median progression-free survival (PFS) was not reached, and the PFS rates at 6 and 12 months were 81.7% and 65.1%, respectively. The median PFS in a subgroup treated with lazertinib based on T790M-positive tissue was significantly longer than that in a subgroup treated based on T790M-positive plasma (not reached vs. 14.5 months) (hazard ratio, 0.43; 95% CI: 0.21-0.87). Related to adverse events, there was no treatment-related mortality. However, the lazertinib dose was adjusted in 39 patients (37.9%), including 10 patients (9.7%) with permanent discontinuation. Peripheral sensory-motor related adverse events were observed in 65 patients (63.1%) (paresthesia: n=58; muscle cramping: n=24), leading to dose reduction and permanent discontinuation in 17 (16.5%) and 5 (4.9%) patients, respectively. There was no difference in PFS between the groups with and without dose-adjustment (P=0.40). Our result demonstrates the real-world clinical efficacy of lazertinib in acquired EGFR T790M mutation. Although dose reduction due to adverse events was not uncommon, it did not impair clinical efficacy of lazertinib.

Artificial neural network model analysis in T790M detection after failure of first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors.

e21041 Background: Despite osimertinib availability, first or second generation (1st/2nd gen.) epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are commonly used in many countries. Clinical factors identified before first line EGFR TKIs treatment that correlate with T790M occurrence are not well-known. In this single center retrospective study we define the artificial intelligence-based model that support T790M detection in daily practice. Methods: In 80 patients (pts) consecutively progressed on 1st/2nd generation EGFR TKIs T790M mutation was assessed. In multivariate logistic regression factors predictive to T790M mutation were identified. Based on clinical and molecular factors present before EGFR TKIs initiation multi-layer perceptron (MLP) neural network was used for building model classifying patients according to T790M status. The artificial neural network consisted of three layers: input, hidden and output layers of 36, 6 (optimally due to the result of the neural network) and 1 neurons, respectively. During the learning process the weight links between the neurons were modified using Broyden-Fletcher-Goldfarb-Shanno algorithm. To calculate the diagnostic quality of the artificial neural network, we divided at random of all patients for two groups: training and testing. The training group contained 65 and testing group 15 cases. Sensitivity and specificity for both models were assessed. TIBCO Software Inc., Statistica (data analysis software system), version 13 software was used for all calculations. Results: In 49/80 pts (61.3%) T790M was present. In logistic regression model: del19 EGFR mutation, chest or liver metastases and 1st gen. TKI treatment correlated with T790M presence. Parameters included in building neural network model were: del19/L858R/other EGFR mutation status, sex, age, 1st/2nd gen. TKI in first line, clinical stage, metastases location, ECOG PS, smoking history. Learning and testing phase models detected T790M with sensitivity-94.7%, specificity – 91.3% and sensitivity-77.8%, specifity-83.3%. In testing set (15 pts) proposed neural network model achieved 80% accuracy in predicting correctly T790M status. Clinical stage, TKI generation in first line, metastases location, EGFR mutation were the most valuable entrance parameters. After conducting a sensitivity analysis for all 8 the analysed variables the observed error quotients were above 1, therefore, they are all significance and should be entered as input to the developed network. Conclusions: The proposed artificial neural network model used parameters identified before start of TKI treatment and achieved high accuracy in T790M status prevalence. Although this model need to be validated in large cohort it can be an useful tool to support clinicians decision.

First-Third generation EGFR inhibitor combined with cytotoxic chemotherapy in elderly Patients with advanced lung adenocarcinom in routine clinical practice-results from A Subgroup Analysis

The third generation Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) osimertinib has been initially approved for T790M positive lung adenocarcinoma patients and more recently for first-line treatment of EGFR-mutant T790M negative lung adenocarcinoma, Similarly to previous generation TKIs, despite the high response rate, disease progression eventually occurs and current clinical research is focused on novel strategies to delay the emergence of osimertinib resistance.In this study,we investigated as the combination of osimertinib/ gefitinib/ erlotinib with cytotoxicchemotherapy for EGFR-mutated positivelung adenocarcinoma patientsin long-term survivaloutcomes.

Therapeutic potential of the novel Bcl-2/Bcl-XL dual inhibitor, APG1252, alone or in combination against non-small cell lung cancer.

Targeting the induction of apoptosis is a promising cancer therapeutic strategy with some clinical success. This study focused on evaluating the therapeutic efficacy of the novel Bcl-2/Bcl-XL dual inhibitor, APG1252-M1 (also named APG-1244; an in vivo active metabolite of APG1252 or pelcitoclax), as a single agent or in combination, against non-small cell lung cancer (NSCLC) cells. APG1252-M1 effectively decreased the survival of some NSCLC cell lines expressing low levels of Mcl-1 and induced apoptosis. Overexpression of ectopic Mcl-1 in the sensitive cells substantially compromised APG1252-M1's cell-killing effects, whereas inhibition of Mcl-1 greatly sensitized insensitive cell lines to APG1252-M1, indicating the critical role of Mcl-1 levels in impacting cell response to APG1252-M1. Moreover, APG1252-M1, when combined with the third generation epidermal growth factor receptor (EGFR) inhibitor, osimertinib, synergistically decreased the survival of EGFR-mutant NSCLC cell lines including those resistant to osimertinib with enhanced induction of apoptosis and abrogated emergence of acquired resistance to osimertinib. Importantly, the combination was effective in inhibiting the growth of osimertinib-resistant tumors in vivo. Collectively, these results demonstrate the efficacy of APG1252 alone or in combination against human NSCLC cells.

EP08.02-057 Mechanism of Resistance to Second-Line Aumolertinib and Therapeutic Regime after Resistance

Aumolertinib is a novel, irreversible, 3rd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) with structure-predicted pharmacologic properties that selectively inhibit both EGFR sensitizing and resistance mutations. In phase II single-arm APOLLO study (NCT02981108), the most common mechanisms of resistance to Aumolertinib were acquired EGFR C797S mutation (26%) and aberration in PIK3CA bypass track(21%), which were different from AURA3(NCT02151981), where most common mechanisms of resistance to Osimertinib were MET amplification (19%) and acquired EGFR C797S mutation (15%).

Pharmacokinetic boosting of osimertinib with cobicistat in patients with non-small cell lung cancer: The OSIBOOST trial

IntroductionExposure to osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for treatment of non-small cell lung cancer (NSCLC) and a sensitizing EGFR mutation, can be substantially below average. We evaluated whether plasma levels could be boosted by co-administration of cobicistat, a strong Cytochrome P450 3A-inhibitor. MethodsThis was a pharmacokinetic, proof-of-concept clinical trial (the OSIBOOST trial, NCT03858491). NSCLC-patients with osimertinib were eligible if their steady state osimertinib plasma trough concentration was low (≤195 ng/mL). On day 1, the area under the plasma curve (AUC0-24,ss) of osimertinib and its metabolite (AZ5104) was calculated using a limited sampling strategy (four samples). Cobicistat co-treatment (150 mg, once daily) was started on day 2. Between day 22–26, a second AUC was determined. Cobicistat dose could be escalated if the osimertinib trough concentration was still ≤ 195 ng/mL, in the absence of toxicity. Primary endpoint was the increase in osimertinib exposure, secondary endpoint was toxicity. Cobicistat could be continued during the expanded access phase, with follow-up (2–4 months) of the boosting effect. ResultsThe mean baseline osimertinib trough concentration for the eleven enrolled patients was 154 ng/mL. In all patients, cobicistat addition led to an increase in osimertinib exposure. Mean increase in total AUC0-24ss (AUC osimertinib + AUC AZ5104) was 60%, (range 19%–192%). The boosting effect was consistent over time. No grade ≥ 2 toxicity was observed. ConclusionPharmacokinetic boosting of osimertinib with cobicistat in patients with NSCLC is feasible without increasing toxicity, although the degree of boosting is variable.

An exploration of the clinical progression models of osimertinib in the treatment of advanced EGFR-mutant non-small cell lung cancer.

BackgroundClassifying the progression pattern had been proved to be momentous for predicting efficacy and guiding treatment in the 1st/2nd generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), while lack evidence in the 3rd generation EGFR-TKIs. This study aimed to classify tumor progression of osimertinib in EGFR+ advanced non-small cell lung cancer (NSCLC), exploring the characteristics and the clinical significance of each progression pattern.MethodsAfter screening 1,125 lung cancer patients, 168 EGFR T790M+ advanced patients using osimertinib were enrolled and divided into two groups and five clinical progression models according to the time course of the tumor progression. The prognosis and characteristics, such as gender, age, metastases, of each model were analyzed and compared by Kaplan-Meier method, t-test, and linear regression.ResultsComplete follow-up data were available for 117 of the 168 patients. Progressive disease (PD) occurred in 89 patients at an average onset of 6.59 months since using osimertinib, with 79.78% of patients experiencing enlargement of some preexisting lesions before PD. Among the five progression models, the ‘Rapid Enlargement’ (10.11%) model, the ‘Rapid New Lesion’ model (10.11%), the ‘Delayed Enlargement’ model (29.21%), the ‘Delayed New Lesion’ model (15.73%), and the ‘Non-targeted Enlargement’ model (34.83%), the ‘Non-targeted Enlargement’ model had the worst prognosis, with a median progression-free survival (mPFS) of 7.1 months (P=0.046). The mPFS of other models was similar, with the largest difference in the time interval between the beginning of osimertinib treatment to the first appearance of target lesion enlargement (Tm-e). Smoking history (P=0.046) and the location of the initial (P=0.048), enlarged (P=0.003), and progressive lesions (P=0.002) affected the progression models, while gender, age, and treatment lines had no effect. The Tm-e was related to the overall disease control time with a correlation coefficient of 0.667 (P=0.000). The appearance of a malignant pleural effusion had an impact on progression.ConclusionsWe tried to create a classification system for describing the failure of the third-generation EGFR-TKI osimertinib including two groups, subdivided into five progression models based on the time course of tumor lesion changes. The system might be conducive to predict the prognosis and be potential to assist in selecting subsequent treatment strategies.

Triple positive lung cancer: A case report

Background: Targeted therapies in nonsmall cell lung cancer has changed the landscape of management and carved the disease in to more different sub types. Despite of considerable initial response to 1st generation and 2nd generation tyrosine kinase inhibitors patients develop resistance in the due course. Secondary mutations are due to threonine and methionine substitution at 790 (T790M) of EGFR. T790M mutation are resistant to 1st and 2nd generation TKI.Osimertinib is a irreversible third generation epidermal growth factor receptor tyrosine kinase inhibitor effective against EGFR T790M mutation positive lung cancer. Patients are inescapable of developing resistance with Osimertinib in spite of initial response and leaving no further definite therapeutic options. In 20-30% patients with osimertinib resistance develop EGFR C797S mutation. Our objective is to show the patient journey with primary, secondary mutation withT790M and tertiary mutation in C797S. Key Messages: Prospective molecular tumor profiling is now the standard of care in the treatment of metastatic NSCLC. Re-biopsy or liquid biopsy on progression of first and second line TKI to look for T790M has already been in routine practice. Re-biopsy or liquid biopsy on progression of third line TKI and molecular profiling can guide us in further management.

Ibrutinib reverses IL-6-induced osimertinib resistance through inhibition of Laminin \u03b15/FAK signaling

Osimertinib, a 3rd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the first-line standard-of-care for EGFR-mutant non-small cell lung cancer (NSCLC) patients, while acquired drug resistance will inevitably occur. Interleukin-6 (IL-6) is a keystone cytokine in inflammation and cancer, while its role in osimertinib efficacy was unknown. Here we show that clinically, plasma IL-6 level predicts osimertinib efficacy in EGFR mutant NSCLC patients. Highly increased IL-6 levels are found in patients with acquired resistance to osimertinib. Addition of IL-6 or exogenous overexpression of IL-6 directly induces osimertinib resistance. Proteomics reveals LAMA5 (Laminin α5) and PTK2, protein tyrosine kinase 2, also called focal adhesion kinase (FAK), are activated in osimertinib-resistant cells, and siRNA knockdown of LAMA5 or PTK2 reverses IL-6-mediated osimertinib resistance. Next, using a large-scale compound screening, we identify ibrutinib as a potent inhibitor of IL-6 and Laminin α5/FAK signaling, which shows synergy with osimertinib in osimertinib-resistant cells with high IL-6 levels, but not in those with low IL-6 levels. In vivo, this combination inhibits tumor growth of xenografts bearing osimertinib-resistant tumors. Taken together, we conclude that Laminin α5/FAK signaling is responsible for IL-6-induced osimertinib resistance, which could be reversed by combination of ibrutinib and osimertinib.

Identification of Stage IIIC/IV EGFR-Mutated Non-Small Cell Lung Cancer Populations Sensitive to Targeted Therapy Based on a PET/CT Radiomics Risk Model

ObjectivesThis project aimed to construct an individualized PET/CT prognostic biomarker to accurately quantify the progression risk of patients with stage IIIC-IV epidermal growth factor receptor (EGFR)-mutated Non-small cell lung cancer (NSCLC) after first-line first and second generation EGFR- tyrosine kinase inhibitor (TKI) drug therapy and identify the first and second generation EGFR-TKI treatment-sensitive population.MethodsA total of 250 patients with stage IIIC-IV EGFR-mutated NSCLC underwent first-line first and second generation EGFR-TKI drug therapy were included from two institutions (140 patients in training cohort; 60 patients in internal validation cohort, and 50 patients in external validation cohort). 1037 3D radiomics features were extracted to quantify the phenotypic characteristics of the tumor region in PET and CT images, respectively. A four-step feature selection method was performed to enable derivation of stable and effective signature in the training cohort. According to the median value of radiomics signature score (Rad-score), patients were divided into low- and high-risk groups. The progression-free survival (PFS) behaviors of the two subgroups were compared by Kaplan–Meier survival analysis.ResultsOur results shown that higher Rad-scores were significantly associated with worse PFS in the training (p < 0.0001), internal validation (p = 0.0153), and external validation (p = 0.0006) cohorts. Rad-score can effectively identify patients with a high risk of rapid progression. The Kaplan–Meier survival curves of the three cohorts present significant differences in PFS between the stratified slow and rapid progression subgroups.ConclusionThe PET/CT-derived Rad-score can realize the precise quantitative stratification of progression risk after first-line first and second generation EGFR-TKI drug therapy for NSCLC and identify EGFR-mutated NSCLC populations sensitive to targeted therapy, which might help to provide precise treatment options for NSCLC.

Comparing survival and treatment response of patients with acquired T790M mutation second‐line osimertinib versus sequential treatment of chemotherapy followed by osimertinib: A real‐world study

PurposeTo investigate the survival benefit with first/second generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) and osimertinib in different treatment sequences.MethodsWe retrospectively screened 3807 patients diagnosed with cancer between 2013 and 2019 at Kaohsiung Chang Gung Memorial Hospital. In total, 76 patients with EGFR T790M mutation who received osimertinib after re‐biopsy or liquid biopsy were enrolled for the analysis.ResultsThe median progression‐free survival (PFS), median overall survival (OS), and median OS2 of the 76 patients were 11.93, 66.53, and 29.57 months, respectively. A significant difference was observed in the disease control rate between those who received osimertinib treatment after chemotherapy (group A) and those who received osimertinib immediately following EGFR‐TKI therapy (group B) (34 [94.4%] vs. 31 [77.5%], p = 0.036). In addition, chronic obstructive pulmonary disease tended to be a poor prognostic factor for PFS and OS.ConclusionThis real‐world analysis revealed that previous chemotherapy could affect the treatment outcomes of patients with non‐small cell lung cancer treated with osimertinib. Osimertinib treatment following first/second generation EGFR‐TKI treatment or chemotherapy resulted in improved survival benefit.

P26.02 A Phase II Trial of Neoadjuvant Osimertinib for Surgically Resectable EGFR-Mutant Non-Small Cell Lung Cancer: Updated Results

The third generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is well-tolerated and effective for first-line treatment of metastatic EGFR-mutant non-small cell lung cancer (NSCLC). Adjuvant osimertinib therapy also significantly decreases the risk of disease recurrence for patients with surgically resected (stage IB-IIIA) EGFR-mutant NSCLC. The benefit of neoadjuvant osimertinib for the treatment of surgically resectable EGFR-mutant NSCLC is unknown. The use of neoadjuvant targeted therapies in oncogene-driven NSCLC may offer the advantages of increased pathologic response rates as well as more favorable toxicity profiles compared to cytotoxic chemotherapy. These trials also offer the opportunity to identify mechanisms underlying cancer cell persistence despite optimal oncogene-targeted therapy. This abstract is an update of https://doi.org/10.1016/j.jtho.2019.08.1209. This is an ongoing multi-institution phase II trial of neoadjuvant osimertinib (NCT03433469), which aims to enroll 27 patients with surgically resectable stage I-IIIA (AJCC V7) EGFR-mutant (exon 19 del or L858R) NSCLC. Eligible patients are treated with one to two 28-day cycles of osimertinib 80 mg orally daily followed by surgical resection. The primary endpoint of the study is major pathological response (mPR) rate. Secondary endpoints include safety, unanticipated delays to surgery, surgical complication rate, pathological response rate (0-49% residual viable tumor), pathological complete response rate (pCR), unconfirmed objective response rate, rate of lymph node downstaging, disease-free survival (DFS), and overall survival (OS). As of April 2021, 13 patients with early-stage (6 stage IA/B, 2 Stage IIA/B, and 5 Stage IIIA) EGFR-mutant (7 exon 19 del, 6 L858R) NSCLC have been enrolled and treated with osimertinib for an average of 59 days prior to surgical resection. The mPR rate was 15% (2 of 13). The pathological response rate was 69% (9 of 13). No pCR’s were observed. Partial radiographic responses (PR) were observed in 46% (6 of 13) of patients and stable disease (SD) in 7 patients (100% DCR). Lymph node downstaging was achieved in 4 of 5 patients (80%) with positive lymph nodes detected prior to treatment. DFS and OS data are immature. Treatment was well-tolerated without SAEs and all patients proceeded to surgical resection without unscheduled delay or surgical complications. One patient developed grade 2 treatment-related pneumonitis that resolved without steroid treatment. Pre-treatment tumor biopsies were available for targeted exome sequencing analysis of ∼ 500 cancer-related genes from 7 patients. Loss of function mutations in RBM10 were identified in 3 of 4 (75%) tumors that showed no evidence of pathological response to osimertinib treatment. Interim analysis of this phase II study indicates that neoadjuvant osimertinib treatment in surgically resectable, EGFR-mutant NSCLC is well-tolerated without unforeseen delays in surgery and can induce pathological responses and lymph node-downstaging of disease. However, major pathological responses are rare and complete pathological responses to neoadjuvant osimertinib are not observed. RBM10 mutations were observed in the majority of tumors that did not exhibit a pathological response to osimertinib. Combination therapy approaches, as are being studied in the NeoADAURA trial (NCT04351555), are likely needed to achieve clinically meaningful major pathological response rates in EGFR-mutant lung cancers.

P46.07 Afatinib-Related Pneumonitis in Metastatic EGFR-Positive NSCLC

Lung cancer is the third commonest cancer in Indonesia, and the first case of death in all cancer in both gender. EGFR mutation frequency in cytological sample in Indonesia was 44.4%. Afatinib is second generation epidermal growth factor receptor tyrosine kinase inhibiot, which inhibits epidermal growth factor receptor (EGFR), human epidermal factor receptor-2 (HER2) and HER4. Afatinib first introduced in Indonesia in 2016, and get approval for national health insurance program in 2018. The side effect of afatinib are skin rash, diarrhea, paronichia and pneumonitis. Here were reported a 69 yo female with diagnosis of lung adenocarcinoma T3N3M1 brain, lung EGFR mutation exon 19 deletion. She was treated with afatinib 40mg. Her condition was improved, but after 2 months of treatment, she complained of cough and shortness of breath. On chest HRCT showed bilateral pneumonitis. After inclusion of infection and heart failure, she was treated with pulse-dose steroid, but her condition deterioriated, and she passed away with respiratory failure. This is a case report, written informed consent has been obtained from her family member. HRCT of lung showed bilateral pneumonitis. Pneumonitis is a very rare adverse event of EGFR TKI, however can be devastating. We reported acute pneumonitis related to afatinib in metastatic adenocarcinoma, although already been diagnosed and treated early, but difficult to manage.

1208P Final results of APOLLO study: Overall survival (OS) of aumolertinib in patients with pretreated EGFR T790M-positive locally advanced or metastatic non-small cell lung cancer (NSCLC)

Aumolertinib is a novel, irreversible third generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI). APOLLO, a pivotal phase II single-arm study (NCT02981108), has demonstrated progression-free survival (PFS) benefit with a favorable safety profile in pretreated EGFR T790M positive NSCLC patients.

1225P The progression-free survival of the first-line EGFR-TKI is a strong prognosticator of the second-line osimertinib in non-small cell lung cancer (NSCLC) patients with EGFR-T790M mutation: A real-world study

As a third generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), osimertinib is recommended as standardized treatment for advanced or metastatic non-small cell lung cancer (NSCLC) patients with EGFR-T790M mutation after progressed on first-line EGFR-TKI. Our study aims to investigate the prognostic value of first-line EGFR-TKI on the second-line osimertinib in the real-world practice.

H1975 세포에서 황금추출물에 의한 gefitinib 저항성 억제 효과

Gefitinib, a first generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), provides obvious clinical benefit in patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, patients ultimately develop gefitinib resistance which mainly caused by EGFR T790M secondary mutation. In the current study, we investigated whether the root extract of Scutellaria baicalensis (SB) overcomes gefitinib resistance. Gefitinib-resistant H1975 human NSCLC cells (EGFR L858R/ T790M double mutant) were treated with gefitinib and/or ethanol extract of SB (ESB) to evaluate the effect of ESB on the gefitinib sensitivity. The cell viability was measured by MTT assay and trypan blue exclusion assay. The colony-forming ability was evaluated by anchorage-dependent colony formation assay. Combined treatment with gefitinib and ESB markedly decreased the cell viability and colony formation than single treatment with gefitinib or ESB in H1975 cells. In addition, cells treated with both gefitinib and ESB exhibited a significant increase of sub-G1 DNA content which indicates apoptotic cells compared with those treated with gefitinib or ESB alone. As a molecular mechanism, combined treatment with gefitinib and ESB strongly downregulated the phosphorylation of ERK and JNK than single treatment with gefitinib or ESB. Taken together, our results demonstrate that ESB sensitizes H1975 cells to gefitinib treatment. We cautiously propose that ESB can be used in combination with gefitinib for the advanced NSCLC patients with acquired resistance to EGFR TKIs.

EphB4 as a Novel Target for the EGFR-Independent Suppressive Effects of Osimertinib on Cell Cycle Progression in Non-Small Cell Lung Cancer.

Osimertinib is the latest generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor used for patients with EGFR-mutated non-small cell lung cancer (NSCLC). We aimed to explore the novel mechanisms of osimertinib by particularly focusing on EGFR-independent effects, which have not been well characterized. We explored the EGFR-independent effects of osimertinib on cell proliferation using NSCLC cell lines, an antibody array analysis, and the association between the action of osimertinib and the ephrin receptor B4 (EphB4). We also studied the clinicopathological significance of EphB4 in 84 lung adenocarcinoma patients. Osimertinib exerted significant inhibitory effects on cell growth and cell cycle progression by promoting the phosphorylation of p53 and p21 and decreasing cyclin D1 expression independently of EGFR. EphB4 was significantly suppressed by osimertinib and promoted cell growth and sensitivity to osimertinib. The EphB4 status in carcinoma cells was positively correlated with tumor size, T factor, and Ki-67 labeling index in all patients and was associated with poor relapse-free survival in EGFR mutation-positive patients. EphB4 is associated with the EGFR-independent suppressive effects of osimertinib on cell cycle and with a poor clinical outcome. Osimertinib can exert significant growth inhibitory effects in EGFR-mutated NSCLC patients with a high EphB4 status.