EGFR-positive Non-small Cell Lung Cancer Research Articles

Prognosis prediction of icotinib as targeted therapy for advanced EGFR-positive non–small cell lung cancer patients

Clinical trials on icotinib, a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), have shown promising results as targeted therapy for non-small cell lung cancer (NSCLC). This study aimed to establish an effective scoring system to predict the one-year progression-free survival (PFS) of advanced NSCLC patients with EGFR mutations treated with icotinib as targeted therapy. A total of 208 consecutive patients with advanced EGFR-positive NSCLC treated with icotinib were enrolled in this study. Baseline characteristics were collected within 30 days before icotinib treatment. PFS was taken as the primary endpoint and the response rate as the secondary endpoint. Least absolute shrinkage and selection operator (LASSO) regression analysis and Cox proportional hazards regression analysis were used to select the optimal predictors. We evaluated the scoring system using a five-fold cross-validation. PFS events occurred in 175 patients, with a median PFS of 9.9 months (interquartile range, 6.8-14.5). The objective response rate (ORR) was 36.1%, and the disease control rate (DCR) was 67.3%. The final ABC-Score consisted of three predictors: age, bone metastases and carbohydrate antigen 19-9 (CA19-9). Upon comparison of all three factors, the combined ABC-score (area under the curve (AUC)= 0.660) showed a better predictive accuracy than age (AUC = 0.573), bone metastases (AUC = 0.615), and CA19-9 (AUC = 0.608) individually. A five-fold cross-validation showed good discrimination with AUC = 0.623. The ABC-score developed in this study was significantly effective as a prognostic tool for icotinib in advanced NSCLC patients with EGFR mutations.

Abstract 6348: ABN202 (αEGFR-interferon-β mutein), a potent antibody-cytokine fusion protein for the treatment of EGFR-positive non-small cell lung cancer

Abstract ABN202 is an antibody-cytokine fusion protein consisting of interferon-β mutein (ABN102) molecularly fused to a anti-EGFR monoclonal antibody that recognizes the EGFR expressed on various types of cancer cells. In previous studies, we developed ABN102, a bio-better version of recombinant human interferon-β with hyperglycosylation via site-directed mutagenesis to improve stability, productivity, and pharmacokinetics properties. An addition of glycosylation at the N25 residue of ABN102 is expected to reduce the peripheral toxicity of ABN202, as it can shield the IFNAR2 binding interface. In this study, the binding ability and biological activity of ABN202 was evaluated in vitro models. ABN202 downregulates the EGFR protein expression and reduces EGFR phosphorylation by degrading target proteins via internalization in the EGFR-positive NSCLC cell line. In addition, we also determined the direct and indirect anti-cancer activity of ABN202 in preclinical models. Taken together, we suggest that ABN202 has potent anti-cancer activities, via direct cytotoxicity in EGFR-positive tumors and indirectly activating immune cells through Type I IFN signaling. we conclude ABN202 is a promising drug candidate for patients with EGFR-positive NSCLC. Citation Format: Heegeon Park, Saehyung Lee, Hayeon Park, Sunghyun Hong, Jaemun Kim, Sungyoul Hong, Ji-hyun Park, Young Kee Shin, Jun Young Choi, Na Young Kim. ABN202 (αEGFR-interferon-β mutein), a potent antibody-cytokine fusion protein for the treatment of EGFR-positive non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6348.

Abstract 2009: Gemcitabine-loaded EGFR aptamer for targeted therapy of lung cancer

Abstract Lung cancer is the leading cause of cancer-related death in the world and non-small cell lung cancer (NSCLC) is the most common types of the lung cancer. Epidermal growth factor receptor (EGFR) is an attractive therapeutic target due to its high expression in NSCLC. Gemcitabine (Gem) has shown antitumor activity against many kinds of solid tumors, including NSCLC. Aptamers emerged as promising drug delivery vehicles because of their high binding affinity for the target molecules. The objective of this study was to develop the aptamer-drug conjugates using the EGFR-specific aptamer. EGFR aptamers selected by the SELEX process and gemcitabine was internally incorporated into the EGFR aptamer. In vitro binding affinity of EGFR and Gem-loaded EGFR aptamer was evaluated on EGFR-positive A549, H460, H1299 cell lines, as well as EGFR-negative H522 cells using confocal microscopy. To determine whether the Gem-loaded EGFR aptamer was effectively internalized, Z-stack images were acquired after 1 hr incubation of Cy5-conjugated EGFR aptamer at 37°C. The ex vivo biodistribution of Cy7-conjugated EGFR aptamer was investigated in NSCLC xenograft nude mice. To confirm the antiproliferative effects of Gem-loaded EGFR aptamer, the MTT cell proliferation assay was carried out in NSCLC cells. In the confocal image of EGFR-positive cells, Gem-loaded EGFR aptamers were selectively bound to the cell surface, while no aptamer binding was observed in H522 cells. Z-stack imaging showed that internalized Gem-loaded EGFR aptamer accumulated in EGFR-positive cells. The ex vivo biodistribution data showed that the Gem-loaded EGFR aptamer exhibited higher binding in EGFR-positive A549 tumors than scramble EGFR aptamer. A549 cells showed significant reduction in proliferation following treatment with Gem-loaded EGFR aptamer. Our results indicated that Gem-loaded EGFR aptamer has a potential therapeutic agent in EGFR-positive NSCLC therapy. Citation Format: Jun Young Park, Ye Lim Cho, Ju Ri Chae, Won Jun Kang. Gemcitabine-loaded EGFR aptamer for targeted therapy of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2009.

Construction of IMMS Containing Multi-site Liposomes for Dynamic Monitoring of Blood CTC in Patients with Osimertinib-resistant Non-small-cell Lung Cancer and its Mechanism.

This article aims to establish a liquid biopsy system for gene detection of circulating tumor cells (CTC) in lung cancer, systematically analyze the significance of osimertinib resistance, and formulate an individualized diagnosis and treatment plan. Liposome-contained magnetic microspheres coated with Fe3O4 nanoparticles were synthesized by microemulsion, and the surface was modified with EGFR antibody to form EGFR/EpCAM multi-site liposome-contained immunomagnetic microspheres (IMMSs). The CTCs were isolated and identified from peripheral blood samples and the cell lines of lung cancer patients collected by the multi-site liposome-contained IMMSs. To investigate the effects of the order of use of IMMSs sequence at different sites on the sorting and trapping efficiency of non-small-cell lung cancer (NSCLC) cells . The preliminary verification of drug-resistant gene function and dynamic monitoring of CTCs in 20 patients with EGFR-positive NSCLC were screened and statistically analyzed before and after osimertinib treatment. Sensitivity analysis and drug resistance evaluation of oxitidine were detected in vitro. Results showed the prepared multi-site liposome-contained IMMSs had high stability and specificity. The number of CTCs in blood samples of the patients with NSCLC was detected, revealing high sorting efficiency, and positive sorting rate reaching more than 90%. We investigated the effect of osimertinib on the HER-2 expression on the EGFR-mutated NSCLC cells and found that osimertinib increased the expression of HER-2 on the cell surface of NSCLC cell lines., And further explored the therapeutic potential of osimertinib combined with T-DM1 at different dosing times. Our results demonstrate that the prepared multi-site liposome-contained IMMSs can efficiently isolate CTCs from the peripheral blood in lung cancer. Combined with the experimental data about osimertinib can be effectively identified, the resistant genes of NSCLC including EGFR, which will provide a new scientific basis for guiding clinical medication and formulating individualized treatment plans.

A Real-world Study on the Expression Characteristics of PD-L1 in Patients with Advanced EGFR Positive NSCLC and Its Relationship with the Therapeutic Efficacy of EGFR-TKIs

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. 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. The PD-L1 expression of the included patients was classified according to the tumor promotion score (TPS): negative (TPS<1%) accounted for 47.2%, low expression (1%≤TPS<50%) accounted for 32.1%, and high expression (TPS≥50%) accounted for 20.7%. Among them, patients with solid predominant cancer cell pathomorphology classification are more likely to have high expression of PD-L1, accounting for 52.9% (P<0.0001). The median progression-free survival (mPFS) of patients with PD-L1 negative expression, low expression and high expression who received first generation EGFR-TKIs treatment were 12.4 months, 10.5 months and 3.7 months, respectively, with significant statistical difference (P<0.0001). During the EGFR-TKIs treatment, patients with a history of radiotherapy for lung lesions have a longer PFS benefit than those without a history of radiotherapy (mPFS: 17.0 months vs 9.3 months, P<0.0001). The expression level of PD-L1 in advanced EGFR positive NSCLC patients was significantly correlated with the pathomorphology classification of cancer cells. The efficacy of EGFR-TKIs in patients with PD-L1 overexpression NSCLC was significantly poor. PFS can be significantly prolonged during targeted therapy combined with radiotherapy of lung lesions.

Rare mutation-dominant compound EGFR-positive NSCLC is associated with enriched kinase domain-resided variants of uncertain significance and poor clinical outcomes

BackgroundCompound epidermal growth factor receptor (EGFR) mutations are less responsive to tyrosine kinase inhibitors (TKIs) than single EGFR mutations in non-small cell lung cancer (NSCLC). However, the detailed clinical characteristics and prognosis of various compound EGFR mutations remain to be elucidated.MethodsWe retrospectively studied the next-generation sequencing (NGS) data of treatment-naïve tumors from 1025 NSCLC patients with compound EGFR mutations, which were sub-categorized into different combinations of common mutations (19-Del and EGFR exon 21 p.L858R), rare mutations, and variants of uncertain significance (VUSs). Prognosis and drug resistance to first-line TKIs were analyzed in 174 and 95 patients, respectively.ResultsCompound EGFR mutations were enriched with EGFR exon 21 p.L858R and rare mutations, but not 19-Del (P < 0.001). The common + rare and rare + rare subtypes had fewer concurrent mutations in the PI3K pathway (P = 0.032), while the rare + rare and common + VUSs subtypes showed increased association with smoking- and temozolomide-related mutational signatures, respectively (P < 0.001). The rare mutation-dominant subtypes (rare + VUSs and rare + rare) had the worst clinical outcomes to first-line TKIs (P < 0.001), which was further confirmed using an external cohort (P = 0.0066). VUSs in the rare + VUSs subtype selectively reside in the EGFR kinase domain (P < 0.001), implying these tumors might select additional mutations to disrupt the regulation/function of the kinase domain.ConclusionsDifferent subtypes of compound EGFR mutations displayed distinct clinical features and genetic architectures, and rare mutation-dominant compound EGFR mutations were associated with enriched kinase domain-resided VUSs and poor clinical outcomes. Our findings help better understand the oncogenesis of compound EGFR mutations and forecast prognostic outcomes of personalized treatments.

Efficacy of Osimertinib for EGFR Exon 20 Insertion Mutation-positive Non-small Cell Lung Cancer with Brain Metastases in a Very Elderly Man

Background. Epidermal growth factor receptor (EGFR) exon 20 insertion mutations represent the third most common EGFR mutation in non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are highly effective for EGFR-positive NSCLC but not for EGFR exon 20 insertion mutations, which carry a poor prognosis. Case. A 90-year-old man was referred to our hospital because of an infiltrative shadow and a small nodule in the right lung on chest X-ray. Chest computed tomography revealed a mass in the right lung apex, a small nodule in the right upper lobe, a hypoattenuated area in the left lobe of the liver, bilateral pleural effusion, and enlarged mediastinal lymph nodes. Thoracentesis on the right and transbronchial lung biopsy of the mass were performed. Magnetic resonance imaging of the brain revealed contrast-enhanced nodules. We finally diagnosed the patient with lung adenocarcinoma, cT3N3M1c stage IVB. Genetic testing detected EGFR exon 20 insertion mutations. Considering the patient's age, renal function and performance status (PS), we administered osimertinib, which led to the resolution of the bilateral pleural effusion and a reduction in the size of the primary lesion, as well as the intrapulmonary and brain metastases. The progression-free survival was 5.9 months. Conclusion. In EGFR exon 20 insertion mutation-positive NSCLC, platinum-based chemotherapy has been shown to be more effective than EGFR-TKIs, including osimertinib, and has been the recommended by guidelines. EGFR exon 20 insertion mutations are generally unresponsive to EGFR-TKIs, but some case reports have demonstrated the efficacy of osimertinib. In our case, osimertinib was effective in a very old patient with EGFR exon 20 insertion mutation-positive NSCLC with brain metastases. Osimertinib may be a treatment option in the elderly for whom chemotherapy and late-line treatment options are limited.

Brain metastases in Japanese NSCLC patients: prognostic assessment and the use of osimertinib and immune checkpoint inhibitors—retrospective study

BackgroundThe Graded Prognostic Assessment for lung cancer using molecular markers (Lung-molGPA) has not been validated for use with Japanese non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) and the factors impacting survival need to be assessed.MethodsWe retrospectively analyzed 294 NSCLC patients who were newly diagnosed with BM between 2013 and 2020 and had received radiotherapy for BM initially at the Hokkaido Cancer Center. We evaluated the effect on the prognosis of Lung-molGPA items, the expression of PD-L1 (classified as high, low, and no expression), and the treatment history. The main outcome was the survival measured from the day of the diagnosis of BM, and log-rank tests were performed to evaluate the results.ResultsThe median overall survival (OS) times for adenocarcinoma by groups of GPA scores (0‒1.0, 1.5‒2.0, 2.5‒3.0, and 3.5‒4.0) were 5.5, 14.8, 28.3, and 39.0 months (p < 0.0001), respectively. The median survival times for non-adenocarcinoma by groups of GPA scores (0‒1.0, 1.5‒2.0, and 2.5‒3.0) were 3.2, 11.0, and 16.0 months (p = 0.0011), respectively. In adenocarcinoma patients with gene mutations, osimertinib significantly improved the outcome (median OS: 34.2 and 17.6 months with and without osimertinib, respectively (p = 0.0164)). There was no significant difference in the OS between patients who were initially treated with tyrosine-kinase inhibitor for BM and those who initially received radiotherapy (p = 0.5337). In patients tested for PD-L1 expression, the median survival times after the diagnosis of BM were 5.6, 22.5, and 9.3 months for the high-, low- and no-expression groups (p = 0.2198), respectively. Also, in patients with high PD-L1 expressions, those with ICI had survival (median OS, 8.6 months) than those without (median OS, 3.6 months).ConclusionsWe confirmed that Lung-molGPA successfully classified Japanese NSCLC patients with BM by the prognosis. Osimertinib prolonged survival of EGFR-positive NSCLC patients with BM, and ICI was effective in patients with high PD-L1 expressions.

Osimertinib Resistance: Molecular Mechanisms and Emerging Treatment Options.

The development of tyrosine kinase inhibitors (TKIs) targeting the mutant epidermal growth factor receptor (EGFR) protein initiated the success story of targeted therapies in non-small-cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR-TKI, is currently indicated as first-line therapy in patients with NSCLC with sensitizing EGFR mutations, as second-line therapy in patients who present the resistance-associated mutation T790M after treatment with previous EGFR-TKIs, and as adjuvant therapy for patients with early stage resected NSCLC, harboring EGFR mutations. Despite durable responses in patients with advanced NSCLC, resistance to osimertinib, similar to other targeted therapies, inevitably develops. Understanding the mechanisms of resistance, including both EGFR-dependent and -independent molecular pathways, as well as their therapeutic potential, represents an unmet need in thoracic oncology. Interestingly, differential resistance mechanisms develop when osimertinib is administered in a first-line versus second-line setting, indicating the importance of selection pressure and clonal evolution of tumor cells. Standard therapeutic approaches after progression to osimertinib include other targeted therapies, when a targetable genetic alteration is detected, and cytotoxic chemotherapy with or without antiangiogenic and immunotherapeutic agents. Deciphering the when and how to use immunotherapeutic agents in EGFR-positive NSCLC is a current challenge in clinical lung cancer research. Emerging treatment options after progression to osimertinib involve combinations of different therapeutic approaches and novel EGFR-TKI inhibitors. Research should also be focused on the standardization of liquid biopsies in order to facilitate the monitoring of molecular alterations after progression to osimertinib.

Afatinib plus osimertinib in the treatment of osimertinib-resistant non-small cell lung carcinoma: a phase I clinical trial

BackgroundConquering acquired resistance to osimertinib remains a major challenge in treating patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Thus, we aimed to determine the safety and efficacy of combination treatment with osimertinib and afatinib for patients with acquired resistance to osimertinib.MethodsThis open-label phase I study was a feasibility study of the combination of afatinib and osimertinib for patients with advanced EGFR-positive NSCLC who had progressive disease after receiving osimertinib. The primary endpoint was to determine the maximum tolerated dose (MTD). We enrolled patients who received afatinib at three different dose levels (level 1, 20 mg; level 2, 30 mg; level 3, 40 mg) combined with osimertinib at a standard dose of 80 mg once per day.ResultsThirteen patients were enrolled in this study. The MTD was defined as 30 mg afatinib when combined with daily oral administration of osimertinib (80 mg). The most frequent adverse events were diarrhea (76.9%), anemia (76.9%), and rash (69.2%). Considering the toxicity profiles during all treatment periods, the recommended oral dose of afatinib was determined as 20 mg daily, with an osimertinib dose of 80 mg. For all evaluable patients (n = 12), the response rate was 7.7% and the disease-control rate was 46.2%.ConclusionCombination therapy with osimertinib and afatinib was tolerable; however, the synergistic effect of afatinib with osimertinib may be limited in osimertinib-resistant patients.Trial registrationJapan Registry of Clinical Trials ID: jRCTs051180008, registered date: 08/11/2018.

The role of T790M mutation in first- and second-line therapy of patients with EGFR-positive non-small cell lung cancer

The role of T790M mutation in first- and second-line therapy of patients with EGFR-positive non-small cell lung cancer

Efficacy and safety of icotinib in the treatment of advanced EGFR mutation-positive nonsmall cell lung cancer: A meta-analysis of randomized controlled trials

Icotinib is the first generation of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) independently developed in China, which has been widely used in the treatment of advanced EGFR mutation-positive nonsmall cell lung cancer (NSCLC). The purpose of this study was to systematically evaluate the efficacy and safety of icotinib in the treatment of advanced EGFR mutation-positive NSCLC and to provide evidence-based evidence for clinical rational drug use. Up to September 30, 2022, the databases of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, and Wanfang were searched, and the randomized controlled trials (RCTs) of icotinib (experimental group) versus gefitinib or erlotinib (control group) in the treatment of EGFR-positive advanced NSCLC were included. Two researchers independently screened the literature, extracted data, and evaluated the quality of the included literature. Revman5.4 software was used for meta-analysis. A total of 957 patients were included in 12 studies. The results of meta-analysis showed that the objective response rate (ORR) and disease control rate (DCR) of the experimental group were better than those of the control group (relative risk (RR) = 1.29, 95% confidence interval (CI): 1.10-1.50, P = .001; RR = 1.10, 95%CI: 1.02-1.18, P = .01). There was no significant difference in progression-free survival (PFS) and overall survival between the 2 groups (P > .05). The results of stratified analysis showed that icotinib significantly improved the ORR of EGFR-positive advanced NSCLC patients compared with gefitinib (RR = 1.20, 95%CI: 1.01-1.43, P = .03), but had no significant improvement in DCR (RR = 1.08, 95%CI: 0.99-1.16, P = .07). Compared with erlotinib, icotinib significantly improved ORR and DCR (RR = 1.69, 95%CI: 1.17-2.45, P = .005; RR = 1.21, 95%CI: 1.01-1.44, P = .04). In terms of adverse events of drugs, the incidence of nausea and vomiting in the experimental group was significantly lower than that in the control group (P < .05). Icotinib is safer than gefitinib or erlotinib in the treatment of advanced EGFR-positive NSCLC and seems to bring more clinical benefits to patients. However, there is no obvious advantage in improving the survival rate of patients, and long-term follow-up clinical studies are needed to verify its efficacy.

Efficacy and safety of original EGFR-TKI combined with bevacizumab in advanced lung adenocarcinoma patients harboring EGFR-mutation experiencing gradual progression after EGFR-TKI treatment: a single-arm study.

Keeping on original epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment is the standard treatment for gradual progression EGFR-positive metastatic non-small cell lung cancer (NSCLC). Angiogenic pathway can lead to EGFR-TKI resistance, but the effectiveness of combination strategies in this group is still controversial. This study aimed to assess the efficacy and safety of the original EGFR-TKI combined with bevacizumab in advanced and metastatic lung adenocarcinoma patients harboring EGFR-mutation who experience gradual progression in a real-world setting. From June 2019 to December 2021, a total of 35 metastatic EGFR positive NSCLC patients experienced gradual progression after EGFR-TKI treatments and received original TKI combined with bevacizumab were identified at Chongqing University Cancer Hospital, China. All patients were confirmed EGFR positive by rebiopsy before treatment. Patients were treated with EGFR-TKI and bevacizumab (15 mg/kg Q3W) after gradual progression until rapid progression or intolerable toxicity. The overall survival (OS), progression-free survival 1 (PFS1, period from the beginning of EGFR-TKI treatment to the rapid progression of the disease), PFS2 (period from the beginning of EGFR-TKI combined with bevacizumab treatment to the rapid progression of the disease), disease control rate (DCR), and adverse events of the combined treatment were collected and analyzed. A total of 33 patients could participate the efficacy evaluation. Median PFS1 and PFS2 were 20.5 and 8 months, respectively; DCR was 93.94%; median OS was immature. Multivariate Cox proportional hazards model showed that smoking status [hazard ratio (HR) =3.692, 95% confidence interval (CI): 1.450-9.404, P=0.006], combined EGFR T790M mutation or rare mutation (HR =2.480, 95% CI: 1.073-5.729, P=0.034), and malignant pleural effusion (HR =3.707, 95% CI: 1.460-9.414, P=0.006) were independent risk factors for PFS2. The most common treatment-related adverse events greater than grade 3 included hypertension (23.7%), proteinuria (8.3%), and increased alanine aminotransferase (ALT; 4.1%) and aspartate aminotransferase (AST; 2.9%). Continuous original TKI combined with bevacizumab showed partly favorable efficacy and safety and may represent a therapeutic option for metastatic EGFR-mutation NSCLC patients experiencing gradual progression after EGFR-TKI treatment.

Volumetric Response of Brain Metastases in EGFR-Positive NSCLC Treated with CNS-Penetrant Tyrosine Kinase Inhibitors with or without Radiation Therapy

<h3>Purpose/Objective(s)</h3> In patients with brain metastases (BM) from EGFR-positive non-small cell lung cancer, recent data has indicated that treating with central nervous system (CNS)-penetrant tyrosine kinase inhibitors such as osimertinib (osi) may enable radiation therapy (RT) to be deferred in select patients. How to appropriately select such patients remains unclear. The purpose of this study was to describe the radiographic response of newly diagnosed BM to osi alone and osi with stereotactic radiosurgery (SRS) or whole brain radiotherapy, to identify volumetric parameters that may be used to guide early versus delayed salvage RT. <h3>Materials/Methods</h3> 35 patients with a total of 186 newly diagnosed symptomatic or asymptomatic BM from EGFR-positive NSCLC who were started on osi between 2014 and 2020 at a single institution were retrospectively reviewed. This cohort had at least one MRI brain after initiating therapy. BM with initial tumor volume ≥ 0.1 cm³ were included in the volumetric analyses (N = 106 BM). Variables were compared using the Wilcoxon rank-sum test for continuous variables and the Chi-squared test for categorical variables. Survival times were estimated with the Kaplan-Meier method and univariable analysis was performed using log-rank tests. The Cox proportional hazards regression model was performed for multivariable analyses for local control, distant brain failure, and overall survival (OS). <h3>Results</h3> Of the 35 patients, 8 (23%) received osi alone. Median clinical and radiologic follow-up from the date of treatment initiation were 29 months and 26 months, respectively. The 1- and 2-year local control rates were 94% and 86%, respectively. The 1- and 2-year OS rates were 89% and 66%. Median time to distant brain failure was 24 months. Patients treated with concurrent osi with RT were more likely to have a significant radiographic volumetric response at early follow-up (4-12 weeks after treatment initiation), compared to patients treated with osi alone (median volumetric response of –80% vs. –41%, <i>p</i> = 0.05). Of the patients who received osi alone, 5 eventually developed intracranial failure, of whom 4 patients (50%) received SRS. Median per lesion BM volume at baseline was 0.22 cm³ for the osi alone group vs. 0.41 cm³ for the osi with RT group (<i>p</i> = 0.004). On per lesion analysis, early radiographic volumetric response of ≥ 80% was significantly associated with improved durable local control (3-year local control 98% vs 72%, <i>p</i> = 0.04). <h3>Conclusion</h3> The combination of osi and CNS RT is associated with a more significant early volumetric response in patients with BM from EGFR-positive NSCLC compared to administration of osi alone. BM with a significant volumetric response at early follow-up remain well-controlled in the long term. Patients whose BM demonstrate limited initial volumetric response may benefit from targeted radiotherapy to provide long term control.

Brain Metastases in Japanese NSCLC Patients: Prognostic Assessment and the Use of Osimertinib and Immune Checkpoint Inhibitors

<h3>Purpose/Objective(s)</h3> To validate the Graded Prognostic Assessment for lung cancer using molecular markers (Lung-molGPA) for Japanese non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) and assess the factors impacting survival. <h3>Materials/Methods</h3> We retrospectively analyzed 294 NSCLC patients who were newly diagnosed with brain metastases (BM) between 2013 and 2020 and received radiotherapy for BM initially at the Hokkaido Cancer Center. Lung-molGPA items, sequence of therapy, use of osimertinib, expression of PD-L1 (classified as high, low, and no) and use of immune checkpoint inhibitors (ICI) were evaluated for influence. The main outcome measure was survival from the day of diagnosis of BM, and log-rank tests were performed to compare the results. <h3>Results</h3> The median survival times for adenocarcinoma by groupings of GPA score (0‒1.0, 1.5‒2.0, 2.5‒3.0, and 3.5‒4.0) were 5.5, 14.8, 28.3, and 39.0 months (p<0.0001), respectively. The median survival times for non-adenocarcinoma by groupings of GPA score (0‒1.0, 1.5‒2.0 and 2.5‒3.0) Group were 3.2, 11.0 and 16.0 months (p=0.0011), respectively. In adenocarcinoma patients with gene mutations, osimertinib significantly improved the outcome. The median survival times for the group with and without osimertinib treatment were 34.2 and 17.6 months, respectively (p=0.0164). In a comparison of treatment sequences, no significant differences were found between groups; however, patients who received both irradiation and tyrosine-kinase inhibitor for BM had better prognoses than patients with only irradiation for BM (35.8 months vs 14.8 months, p=0.0007). In patients tested for PD-L1 expression, the median survival times after diagnosis of brain metastasis were 5.6, 22.5 and 9.3 months for high-, low- and no-expression groups (p=0.2198), respectively. Also, in patients with high PD-L1 expression, those with ICI had better survival (median OS, 8.6 months) than those without (median OS, 3.6 months). <h3>Conclusion</h3> We conformed that Lung-molGPA successfully classified Japanese NSCLC patients with brain metastasis by prognosis. Osimertinib was shown to extend survival of EGFR-positive NSCLC patients with BM, and ICI proved effective in patients with high PD-L1 expression.

1000P Common and uncommon mutations in NSCLC: Differences in response to treatment with tyrosine kinase inhibitors: A single-center retrospective analysis

Uncommon EGFR mutations are a heterogeneous group, discovered in ∼10% of the population with EGFR-positive non-small cell lung cancer (NSCLC), whose sensitivity to tyrosine-kinase inhibitors is not yet widely demonstrated. We propose to retrospectively analyze how patients with various EGFR mutations respond differently to treatment with tyrosine-kinase inhibitors. 48 patients with EGFR-positive NSCLC were identified and divided into subgroups by mutation. Progression-free survival (PFS), overall survival (OS) and time to treatment failure (TTF) in those who were treated with Afatinib (Giotrif®) were evaluated. Subgroups were compared using the log-rank test and a multivariate analysis was performed. Patients with common mutations, deletion in exon 19 and L85R, had median OS of 31 months (95% CI: 22-51) and 23 months (95% CI: 6-33) and a median PFS of 16 months (95% CI: 9-33) and 10 months (95% CI: 6-22), respectively. OS and PFS, in patients with common mutations, were superior to those with an uncommon mutation with a p value of 0.003 and 0.0001. Patients with mutations in exon 18 and 21 and patients with mutations in exon 20 had the worst outcome with an OS of 6.5 months (95% CI: 4-30) a PFS of 2.5 months (95% CI: 1-4) and an OS of 3 months (95% CI: 2-4) and a PFS of 4.5 (95% CI: 4-5), respectively. Patients with these mutations also had significantly lower TTF. Multivariate analysis confirmed the results: patients with point mutations in exon 19-21 and mutations in exon 20 had the highest risk of death (HR 6.01 CI: 1.02-35.46, p value=0.001 and HR 12.81 CI: 2.46-62.19 p value=0.004).Table: 1000PMutationNo.FrequencyProgression Free Survival (months)Overall survival (months)Del191837.5%15.5 (9-33)31 (22-51)L858R1837.5%10 (6-22)23 (6-33)Complex mutations24.1%8.25 (0.5-16)8.25 (0.5-16)DelIns1948.3%11 (2-30)21.5 (2-43)Exon 18-2148.3%2.5 (1-4)6.5 (4-30)Exon 2024.1%4.5 (4-5)3 (2-4) Open table in a new tab Patients with uncommon mutations respond heterogeneously to tyrosine-kinase inhibitor treatments. Patients with deletion-insertion or complex mutations respond less than patients with common mutations but they are sensitive to treatment, whereas patients with insertion in exon 20 or mutations in exons 18 and 21 respond very poorly.

1103P Drug-related pneumonitis induced by osimertinib as first-line treatment for EGFR-positive non-small cell lung cancer: A real-world setting

Osimertinib has demonstrated impressive efficacy as a first-line treatment for patients with advanced epidermal growth factor receptor (EGFR) mutation-positive (m+) lung cancer. Drug-related pneumonitis (DRP) is a potentially lethal complication of osimertinib treatment, but reliable real-world data are currently lacking. We conducted a retrospective multicenter cohort study of patients who received osimertinib as a first-line treatment for advanced EGFR m+ non-small cell lung cancer (NSCLC) between August 2018 and December 2019. All chest computed tomography (CT) scans and clinical information during osimertinib exposure were collected until June 2020. The primary endpoint was DRP incidence identified through central review. A total of 452 patients from 18 institutions were evaluated. Eighty patients (18%) were diagnosed with DRP (all grades), and 21 patients (4.6%) had ≥grade 3 DRP. Among the patients with DRP, 46% were identified as having transient asymptomatic pulmonary opacity (TAPO). Regarding the CT patterns, organizing pneumonia, simple pulmonary eosinophilia, hypersensitivity pneumonia, diffuse alveolar damage, and non-specific interstitial pneumonia were found in 30, 21, 18, 9, and 2 patients (38%, 26%, 23%, 11%, and 3%), respectively. In multivariate analysis, smoking history was identified as an independent risk factor for DRP (hazard ratio: 1.72, 95% confidence interval: 1.01–2.89, P=0.046). In the 3-month landmark analysis, DRP was associated with poor treatment efficacy; however, the presence of TAPO did not negatively affect treatment efficacy. For osimertinib treatment in first-line settings, the frequency of DRP was considerably elevated to 18 %, and half of these patients exhibited TAPO features.

EP02.04-003 A Retrospective Comparison of Survival Outcomes in EGFR-mutated, NSCLC Patients on Osimertinib +/- Brain Metastases

Intracranial disease progression is a significant complication in patients with EGFR-positive non-small cell lung cancer (NSCLC) that can impact performance status, quality of life, and treatment options for patients. There is an increased need of oral tyrosine kinase inhibitors with central nervous system (CNS) activity in treating this population to prolong survival. Osimertinib is an oral tyrosine kinase inhibitor (TKI) which has demonstrated penetration of the blood brain barrier and effective treatment of intracranial metastases in some patients.

1005P Indirect treatment comparisons of relative efficacy for aumolertinib vs osimertinib in EGFR-positive non-small cell lung cancer (NSCLC)

Aumolertinib (aumo), a third-generation (3rd gen) EGFR inhibitor (EGFRi), is being developed as a first-line treatment (1L tx) for patients with advanced EGFR mutation-positive (EGFR+) NSCLC. Osimertinib (osi) is a widely used 3rd gen EGFRi for 1L tx of EGFR+ NSCLC. Although both aumo and osi have demonstrated superior safety and efficacy to earlier generation EGFRis in clinical trials, no direct comparison of efficacy and safety has been done. The objective of this analysis was to compare progression-free survival (PFS), overall survival (OS), and any-grade treatment-emergent adverse events (AG-TEAE) for aumo vs osi utilizing an anchored indirect treatment comparison (ITC).

MMAP-11 VOLUMETRIC STUDY OF BRAIN METASTASES IN EGFR-POSITIVE NSCLC TREATED WITH OSIMERTINIB WITH OR WITHOUT CNS-DIRECTED RADIATION THERAPY

BACKGROUNDIn patients with brain metastases (BM) from EGFR-positive non-small cell lung cancer (NSCLC), recent data indicated that treating with CNS-penetrant tyrosine kinase inhibitors such as osimertinib may enable deferring radiotherapy (RT) in select patients. The purpose of this study was to describe the radiographic response of newly diagnosed BM to osimertinib with or without stereotactic radiosurgery or whole brain radiotherapy, to identify parameters that may guide early versus delayed salvage RT. METHODSIn this single-institution retrospective study, 35 patients with 186 newly diagnosed BM started on osimertinib between 2014 and 2020 were reviewed. BM with tumor volume ≥ 0.1 cm3 were included in the volumetric analyses (N=106 BM). Survival was estimated with the Kaplan-Meier method, and univariable analysis was performed using log-rank tests. Cox proportional hazards was used for multivariable analyses for local control (LC), distant brain failure (DBF), and overall survival (OS). RESULTSOf the 35 patients, 8 (23%) received osimertinib alone. Median follow-up was 29 months. The 1- and 2-year LC rates were 94% and 86%. The 1- and 2-year OS rates were 89% and 66%. Median time to DBF was 24 months. Patients treated with osimertinib and RT were more likely to have a significant radiographic volumetric response at early follow-up (4-12 weeks after treatment initiation) compared to osimertinib alone (median volumetric response of –80% vs. –41%, p=0.05). On per lesion analysis, early volumetric response of ≥ 80% was associated with improved LC (3-year LC 98% vs 72%, p=0.04). CONCLUSIONSThe combination of osimertinib and CNS RT is associated with greater early volumetric response in patients with BM from EGFR-positive NSCLC compared to osimertinib alone. BM with significant initial radiographic response remain well-controlled in the long term. Patients whose BM demonstrate limited initial volumetric response may benefit from targeted RT to provide long term control.