EGFR-mutated Advanced NSCLC Research Articles

MA12.04 FLAURA2: Impact of Tumor Burden on Outcomes of 1L Osimertinib ± Chemotherapy in Patients with EGFR-mutated Advanced NSCLC

MA12.04 FLAURA2: Impact of Tumor Burden on Outcomes of 1L Osimertinib ± Chemotherapy in Patients with EGFR-mutated Advanced NSCLC

P1.12A.12 Liquid Biopsy Based Risk Stratification and Intensification of Treatment in EGFR Mutant Advanced NSCLC (L-BRITE) Preliminary Analysis

P1.12A.12 Liquid Biopsy Based Risk Stratification and Intensification of Treatment in EGFR Mutant Advanced NSCLC (L-BRITE) Preliminary Analysis

EP.12A.05 Evaluation of the Role of VAF/cellularity as Proxy of Gene Aberration in EGFR Mutated Advanced NSCLC During Osimertinib

EP.12A.05 Evaluation of the Role of VAF/cellularity as Proxy of Gene Aberration in EGFR Mutated Advanced NSCLC During Osimertinib

EP.12A.22 Aumolertinib with Chemotherapy as First-Line Treatment in Patients with EGFR-Mutated Advanced NSCLC: A Real-World Study

EP.12A.22 Aumolertinib with Chemotherapy as First-Line Treatment in Patients with EGFR-Mutated Advanced NSCLC: A Real-World Study

P2.10A.07 Trofuse-009: Phase 3 Study of Sac-TNT vs Platinum-Doublet Chemotherapy for Previously Treated EGFR-Mutated Advanced NSCLC

P2.10A.07 Trofuse-009: Phase 3 Study of Sac-TNT vs Platinum-Doublet Chemotherapy for Previously Treated EGFR-Mutated Advanced NSCLC

EP.12A.03 Overall Survival after Treatment with First-Line Osimertinib for EGFR-Mutant Advanced NSCLC in the US

EP.12A.03 Overall Survival after Treatment with First-Line Osimertinib for EGFR-Mutant Advanced NSCLC in the US

EP.08F.03 Efficacy and Safety of Aumolertinib with Radiotherapy in the Treatment of Unresectable Locally Advanced EGFR-Mutant NSCLC: A Phase II Study

EP.08F.03 Efficacy and Safety of Aumolertinib with Radiotherapy in the Treatment of Unresectable Locally Advanced EGFR-Mutant NSCLC: A Phase II Study

HERTHENA-Lung02: Phase III clinical trial of patritumab deruxtecan in advanced EGFR-mutated NSCLC following EGFR TKI therapy

This video article presents the phase III HERTHENA-Lung02 study protocol, investigating the use of patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC.

164P A spatially informed transcriptomic model to forecast early resistance to front-line osimertinib in advanced EGFR-mutant NSCLC

164P A spatially informed transcriptomic model to forecast early resistance to front-line osimertinib in advanced EGFR-mutant NSCLC

Liquid Biopsy and 18F-FDG PET/CT Derived Parameters as Predictive Factors of Osimertinib Treatment in Advanced EGFR-Mutated NSCLC

ObjectivesDespite the outstanding results achieved by osimertinib for the treatment of advanced EGFR-mutated NSCLC, the development of resistance is almost inevitable. While molecular mechanism responsible for osimertinib resistance are being mostly revealed, the definition of predictive biomarkers is crucial in order to identify patients at higher risk of progression and optimize treatment strategy. Materials and MethodsThis is a prospective single-center study aimed to assess the potential role of liquid biopsy and 18F-FDG PET/CT derived metabolic parameters as noninvasive predictive biomarkers of osimertinib outcomes in advanced EGFR-mutated NSCLC patients. Patients underwent blood samples for ctDNA analysis at baseline, after 15 days and 1 month (t1) of osimertinib. 18F-FDG PET/CT was performed at baseline and after 1 month of osimertinib. ResultsSeventy-two advanced EGFR-mutated NSCLC patients treated with osimertinib in first (n = 63) and in second-line (n = 9) were prospectively enrolled. Baseline positive shedding status was significantly associated with a shorter progression-free survival (PFS) (9.5 vs. 29.2 months, P = .031). The achievement of an early metabolic response (MR) after 1 month of treatment led to a significantly improved PFS (16.8 vs. 5.5 months, P = .038) and OS (35.2 vs. 15.3 months, P = .047). Early MR was significantly correlated with subsequent radiologic response (P = .010). All 18F-FDG PET/CT baseline parameters were significantly related to baseline EGFR activating mutation allele frequency. Both clearance and no detection of EGFR at t1 were significantly associated with MR (P = .001 and P = .004, respectively). ConclusionMolecular and 18F-FDG PET/CT derived metabolic parameters might represent a useful tool to predict osimertinib outcome in advanced EGFR-mutated NSCLC patients.

Immune Cell Dynamics in EGFR-Mutated NSCLC Treated With Afatinib and Pembrolizumab: Results From a Phase IB Study

IntroductionEGFR-mutated NSCLC is minimally responsive to programmed cell death protein 1 or programmed death-ligand 1 blockade. We evaluated the safety, tolerability, and immunomodulatory effects of the EGFR tyrosine kinase inhibitor (TKI) afatinib in combination with the programmed cell death protein 1 antibody pembrolizumab in patients with EGFR-mutant NSCLC. MethodsPatients with advanced EGFR-mutant NSCLC with progression (PD) on previous EGFR TKI(s), aged above or equal to 18 years, Eastern Cooperative Oncology Group performance status less than or equal to 1, acceptable organ function, no significant autoimmune disease, measurable disease, and controlled brain metastases were eligible. Primary end point was determination of the maximum tolerated dose and recommended phase 2 dose. Serial specimens were collected to assess for alterations in cytokines and immune cell subsets by quantitative immunofluorescence in tissue and Luminex and flow cytometry in the blood. ResultsA total of 11 patients were enrolled, six in dose finding and five in dose expansion. No dose-limiting toxicities were observed. The maximum tolerated dose was determined to be afatinib 40 mg orally daily and pembrolizumab 200 mg intravenously every 21 days. Four (36%) patients had immune-related adverse events (irAEs). Ten patients were assessable for response: two partial response, seven stable disease, and one PD. Peripheral natural killer and natural killer T-cells (p = 0.027, p = 0.01) increased and exhausted CD8+ T-cells decreased on treatment (p = 0.0035). Peripheral CD4/CD8 T-cells (area under the curve = 0.96, p = 0.042) and central memory T-cells (CD4/CD8) (area under the curve = 1.0, p = 0.0006) increased in patients who had disease control more than 6 months or partial response to afatinib/pembrolizumab as did CD3+ T-cells in a patient with progression-free survival more than 6 months after afatinib/pembrolizumab treatment. ConclusionsAfatinib and pembrolizumab were found to have modest activity associated with irAEs after PD on previous EGFR TKI setting. Proinflammatory changes in immune cell subsets in tissue and blood were detected and associated with antitumor activity and irAEs.

PP01.10 Real-World Outcomes of Patients with Advanced EGFR-Mutated NSCLC in Canada Using AI-Extracted Data

PP01.10 Real-World Outcomes of Patients with Advanced EGFR-Mutated NSCLC in Canada Using AI-Extracted Data

Effect of longitudinal ctDNA monitoring with resistance genomic signatures on prognostication in patients with EGFR-mutated advanced NSCLC.

e20507 Background: Targeted therapies against activating receptor tyrosine kinases (TKi) (EGFR, ALK, ROS) mutations have significantly improved the SOC in NSCLC. Although mutant EGFR (mEGFR) targeting TKi show survival benefits, their efficacy is contingent upon the presence of de novo or emergent TKi mutations. A comprehensive gene panel (CGP) designed to detect a multitude of actionable and resistance signatures may enhance informed treatment decisions and outcome. Additionally, longitudinal monitoring of a patient may help to monitor the dynamics (disappearance/emergence) of actionable or resistance-conferring gene alterations for timely decisions on therapy alterations. Methods: In prospective clinical trial, ctDNA was evaluated at multipoint and longitudinally in 75 advanced NSCLC patients. On average 06 samples were collected from each patient at treatment initiation (baseline) and subsequently during maturation until one year. Libraries were prepared using a hybridization-capture method based on custom-designed OncoIndx 1080 CGP and sequenced (depth 5500 X) on Illumina Nextseq 2000 in a pair-end mode (150 x2). Variant calling was performed using a proprietary bioinformatics pipeline iCare. Results: Patients with mEGFR (exon 19 deletion and L858R variants) at the baseline, 60 % were accompanied by resistance signature of one or multiple pathogenic mutations in downstream components (PIK3CA, mTOR, PTEN, BRAF) of EGFR pathway, or other receptor TKs (ROS1, ERBB3, MET and RET), while 36 % showed presence of concurrent pathogenic TP53, RB1 or NF2 variants. Nearly 58 % of patients were clinically Non-respondent (NR) while the rest were Responders (R). Patients carrying resistance signatures at the treatment initiation and subsequently during treatment maturation showed dismal PFS (median 10.4 months, P < 0.0001, HR:9.4, CI:3.2-27) and OS (median 10.4 months, P = 0.0004, HR:14.8, CI:4.7-46) compared to population without resistant signatures. Prevalence of resistant signatures at the baseline was highly enriched in the NR population (90 %), compared to the R population (20 %). Multivariate analysis indicated the presence of resistant signatures as an independent bad prognosticator (HR:8.4, CI: 2.8-12.4, P < 0.0001). Tumor fraction value (TF) correlated well with clinical endpoints (AUC = 0.97, < 0.0001), high TF value (cutoff 0.3) showed shorter OS compared to pts with low TF (HR:10, CI: 3.8-29.4, P < 0.0001, median = 21.3 months). Conclusions: Inclusion of CGP as a standard of care may help to stratify patients who are EGFR positive yet may not respond to TKi due to the presence of resistance signatures, and provide the benefit of Tx modification. Longitudinal monitoring of ctDNA in advanced NSCLC patients showed distinct mutational signatures in the R and NR populations.

Safety and efficacy of osimertinib in patients with NSCLC and uncommon tumoral EGFR mutations: A systematic review and meta-analysis.

8642 Background: Osimertinib is broadly used for advanced EGFR-mutant NSCLC patients. However, the activity of osimertinib is not fully characterized in tumors harboring uncommon EGFR mutations, which represents about 10% of EGFR-mutated NSCLC cases. Hence, we conducted a systematic review and meta-analysis to assess the efficacy and safety of osimertinib in patients with NSCLC and uncommon tumoral EGFR mutations. Methods: PubMed, Embase, and the Cochrane Library were searched for eligible studies. Uncommon EGFR mutations were defined as any mutation other than the exon 19 deletion, L858R and T790M mutations, and exon 20 insertion, except when in compound. Efficacy was assessed by objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Heterogeneity was examined with I2 statistics and random-effect model was used for a meta-analysis. Results: Nine studies comprising 331 patients were included. Median follow-up ranged from 12.6 to 22.0 months (mos). Median age in each study ranged from 51 to 72 years old (table). Overall, 62% (205/331) of patients were female and 77% (256/331) of patients had an ECOG PS ≤1. About 78% (258/331) of patients received Osimertinib in a 1st line setting. Uncommon tumoral EGFR mutations included G719X in 40% (131/331) of patients, L861X in 27% (91/331), and S768I in 15% (49/331). Pooled analysis showed an overall ORR of 49.5% (95% CI, 42.2 – 56.9), a DCR of 90.2% (95% CI, 86.2 – 94.3), a median OS of 24.5 mos (95% CI, 11.9 – 24.5), a median PFS of 9.5 mos (95% CI, 8.2 – 11.0), and a median DOR of 17.4 mos (95% CI, 7.9 – 22.7). Intracranial (i) efficacy had an iORR of 50.3% (95% CI, 30.3 – 70.3), an iDCR of 92.8% (95% CI, 76.2 – 100), and a median iPFS of 6.1 mos (95% CI, 4.5 – 6.6). In a subgroup analysis according to EGFR mutation, overall ORR was significantly different in patients with tumoral G719X, S768I and L861 mutations (ORRs of 28.8%, 33.3%, and 67.7%, respectively, p for subgroup differences < 0.01). Overall, osimertinib was well tolerated with a frequency of all-grade AEs of 86.2% (95% CI, 61.2 – 100) and ≥ G3 of 18.0% (95% CI, 1.2 – 34.7). Conclusions: This systematic review and meta-analysis suggests that patients with NSCLC with uncommon tumoral EGFR mutations may benefit from osimertinib treatment. Patients harboring tumoral L861 mutation achieved a significantly higher ORR compared to the modest ORR in G719X, S768I cases. [Table: see text]

The later-line efficacy and safety of immune checkpoint inhibitors plus anlotinib in EGFR-mutant patients with EGFR-TKI-resistant NSCLC: a single-center retrospective study

BackgroundEffective treatment after EGFR-TKI resistance is of great clinical concern. We aimed to investigate the efficacy and safety of anlotinib in combination with an anti-PD-1/PD-L1 antibody in later-line therapy for EGFR-mutant NSCLC patients after TKI treatment failure and to explore the independent predictive factors of therapeutic efficacy.MethodsA total of 71 patients with confirmed advanced EGFR-mutated NSCLC who progressed after previous standard EGFR-TKI therapy but still failed after multiline treatments were included retrospectively in this study. Most of the patients had previously received at least three lines of treatment. All were treated with anlotinib combined with anti-PD-1 or anti-PD-L1 therapy. The safety of this combined treatment was assessed by the incidence of adverse events. The efficacy of the regimens was evaluated by survival analysis (OS, PFS, ORR, DCR).ResultsThe median follow-up period was 28.6 months (range: 2.3–54.0 months), and the median number of treatment lines was 4. The overall response rate (ORR) and disease control rate (DCR) were 19.7% and 77.5%, respectively. The median PFS was 5.8 months (95% CI 4.2–7.4 months), and the median OS was 17.1 months (95% CI 12.0–22.3 months). Patients who received immune checkpoint inhibitors plus anlotinib had an encouraging intracranial ORR of 38.5% and a DCR of 80.8%. ECOG performance status < 2 at baseline was independent protective factors of PFS. Metastatic organs and ECOG performance status were independent parameters in predicting OS. Treatment-related adverse events occurred in 66 (93.0%) patients; most of the adverse events were Grade 1–2, and no increase in adverse events was observed compared to monotherapy.ConclusionAnlotinib combined with an anti-PD-1/PD-L1-based regimen exhibited promising efficacy and tolerance in NSCLC patients with EGFR mutations after previous TKI failure. The efficacy of this combined regimen in patients with EGFR mutations should be further evaluated.

Tanshinone IIA acts as a regulator of lipogenesis to overcome osimertinib acquired resistance in lung cancer

Osimertinib is a novel epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), acting as the first-line medicine for advanced EGFR-mutated NSCLC. Recently, the acquired resistance to osimertinib brings great challenges to the advanced treatment. Therefore, it is in urgent need to find effective strategy to overcome osimertinib acquired resistance. Here, we demonstrated that SREBP pathway-driven lipogenesis was a key mediator to promote osimertinib acquired resistance, and firstly found Tanshinone IIA (Tan IIA), a natural pharmacologically active constituent isolated from Salvia miltiorrhiza, could overcome osimertinib-acquired resistance in vitro and in vivo via inhibiting SREBP pathway-mediated lipid lipogenesis by using LC-MS based cellular lipidomics analysis, quantitative real-time PCR (qRT-PCR) analysis, western blotting analysis, flow cytometry, small interfering RNAs transfection, and membrane fluidity assay et al. The results showed that SREBP1/2-driven lipogenesis was highly activated in osimertinib acquired resistant NSCLC cells, while knockdown or inhibition of SREBP1/2 could restore the sensitivity of NSCLC to osimertinib via altered the proportion of saturated phospholipids and unsaturated phospholipids in osimertinib acquired-resistant cells. Furthermore, Tanshinone IIA (Tan IIA) could reverse the acquired resistance to osimertinib in lung cancer. Mechanically, Tan IIA inhibited SREBP signaling mediated lipogenesis, changed the profiles of saturated phospholipids and unsaturated phospholipids, and thus promoted osimertinib acquired resistant cancer cells to be attacked by oxidative stress-induced damage and reduce the cell membrane fluidity. The reversal effect of Tan IIA on osimertinib acquired resistant NSCLC cells was also confirmed in vivo, which is helpful for the development of strategies to reverse osimertinib acquired resistance.

Real-world outcomes on platinum-containing chemotherapy for EGFR-mutated advanced nonsquamous NSCLC with prior exposure to EGFR tyrosine kinase inhibitors.

Front-line therapy with an EGFR tyrosine kinase inhibitor (TKI) is the standard of care for treating patients with advanced nonsquamous NSCLC with the common sensitizing EGFR exon 19 deletion and exon 21 L858R point mutations. However, EGFR TKI resistance inevitably develops. The optimal subsequent therapy remains to be identified, although platinum-containing chemotherapy regimens are often administered. Our objectives were to describe baseline characteristics, survival, and subsequent treatment patterns for patients with advanced nonsquamous NSCLC with EGFR exon 19 deletion or L858R mutation who received a platinum-based combination regimen after front-line EGFR TKI therapy. This retrospective study used a nationwide electronic health record-derived deidentified database to select adult patients with advanced nonsquamous NSCLC, evidence of EGFR exon 19 deletion or L858R mutation, and ECOG performance status of 0-2 who initiated platinum-containing chemotherapy, with or without concomitant immunotherapy, from 1-January-2011 to 30-June-2020 following receipt of any EGFR TKI as first-line therapy or, alternatively, a first- or second-generation EGFR TKI (erlotinib, afatinib, gefitinib, dacomitinib) as first-line therapy followed by the third-generation EGFR TKI osimertinib as second-line therapy. Data cut-off was 30-June-2022. The Kaplan-Meier method was used to estimate overall survival (OS) after initiation of pemetrexed-platinum (n=119) or any platinum-based combination regimen (platinum cohort; n=311). The two cohorts included two-thirds women (65%-66%) and 57%-58% nonsmokers; median ages were 66 and 65 years in pemetrexed-platinum and platinum cohorts, respectively. Median OS was 10.3 months (95% CI, 8.1-13.9) from pemetrexed-platinum initiation and 12.4 months (95% CI, 10.2-15.2) from platinum initiation; 12-month survival rates were 48% and 51%, respectively; 260 patients (84%) had died by the end of the study. The suboptimal survival outcomes recorded in this study demonstrate the unmet need to identify more effective subsequent treatment regimens for patients with EGFR-mutated advanced nonsquamous NSCLC after EGFR TKI resistance develops.

3MO Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutant advanced NSCLC after progression on osimertinib: A post-progression analysis of MARIPOSA-2

3MO Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutant advanced NSCLC after progression on osimertinib: A post-progression analysis of MARIPOSA-2

5MO Effect of amivantamab dose interruptions on efficacy and safety of first-line amivantamab plus lazertinib in EGFR-mutant advanced NSCLC: Exploratory analyses from the MARIPOSA study

5MO Effect of amivantamab dose interruptions on efficacy and safety of first-line amivantamab plus lazertinib in EGFR-mutant advanced NSCLC: Exploratory analyses from the MARIPOSA study

8P Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutant advanced NSCLC after progression on osimertinib: Secondary analyses of patient-relevant endpoints from MARIPOSA-2

8P Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutant advanced NSCLC after progression on osimertinib: Secondary analyses of patient-relevant endpoints from MARIPOSA-2