EGFR T790M Resistance Mutation Research Articles

Molecular residual disease (MRD) analysis from the ADAURA trial of adjuvant (adj) osimertinib in patients (pts) with resected EGFR-mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC).

8005 Background: Osimertinib (osi) is a third-generation, central nervous system-active EGFR-TKI, that potently and selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations. Adj osi (3 years [yrs]) is recommended for resected EGFRm stage IB–IIIA NSCLC, based on significant improvements in disease-free survival (DFS) and overall survival (OS) in the Phase III ADAURA study (NCT02511106). A trend towards an increased DFS event rate beyond 3 yrs suggests some pts may benefit from longer adj osi treatment (tx). We explored if plasma ctDNA-based, tumor-informed MRD could predict disease recurrence. Methods: Eligible pts (≥18 yrs [≥20 in Japan/Taiwan], WHO PS 0/1 with completely resected EGFRm [Ex19del/L858R] stage IB, II or IIIA [AJCC 7th edition] NSCLC) were randomized 1:1 to osi 80 mg once daily or placebo (pbo) until disease recurrence, tx completion (up to 3 yrs), or a discontinuation criterion was met. Personalized MRD panels (RaDaR, NeoGenomics) were used, comprised of ≤50 tumor-specific variants, based on whole exome sequencing of resected tumor tissue (variants identified in germline DNA removed). Plasma sample collection: baseline (BL; at randomization surgery and adj Ctx, if received), on tx (every 12 weeks [wks]), tx discontinuation, and post-tx completion (wk 12, wk 24, then every 24 wks until 5 yrs). Plasma samples were analyzed for detection of ctDNA (MRD+). Molecular recurrence or DFS (MRD/DFS) was defined as time from randomization to post-BL MRD+, disease recurrence, or death and was compared across arms. DFS was investigator-assessed. Results: Of 682 pts randomized, 245 (36%) had samples required to produce MRD panels, which were evaluable for 220 (32%) pts across both arms. In the osi vs pbo arms, 5/112 (4%) vs 13/108 (12%) pts were MRD+ at BL; 4/5 pts became MRD– during osi tx vs 0/13 pts on pbo. On tx, MRD detection had clinical sensitivity of 65% (62 MRD+/96 DFS+), specificity of 95% (118 MRD–/124 DFS–) and preceded a DFS event by a median (95% CI) of 4.7 (2.2, 5.6) months (mos) across both arms. Median follow-up time from randomization was 44.2 (95% CI 42.4, 49.1) and 19.1 (95% CI 11.1, 28.3) mos for osi and pbo arms, respectively. Overall, 86% (95% CI 78, 92) vs 36% (95% CI 27, 45) pts in the osi vs pbo arms were MRD/DFS event free at 36 mos (HR: 0.23; 95% CI 0.15, 0.36). MRD/DFS events in the osi arm were detected at any time post-BL in 28 (25%) pts, of whom 19/28 (68%) had events post-adj osi. Most (11/19 [58%]) MRD/DFS events detected occurred within 12 mos of osi tx completion. Conclusions: MRD+ preceded DFS events in most pts with a median lead time of 4.7 mos across both arms. MRD– was maintained for most pts during adj osi tx with the majority of MRD/DFS events occurring after osi tx completion. MRD detection could potentially identify a subset of pts likely to benefit from longer adj osi. Clinical trial information: NCT02511106 .

Efficacy and safety of aumolertinib combined with or without chemotherapy as an adjuvant treatment for stage II-IIIA non-small cell lung cancer following complete tumour resection: The first third-generation EGFR-TKI versus chemotherapy phase III clinical study (APEX).

TPS8117 Background: Patients with stage II-III A non-small cell lung cancer (NSCLC) can benefit from adjuvant targeted therapy. ADAURA study shows a remarkable advantage of disease-free survival (DFS). However, there are still unresolved clinical issues. Firstly, the control group in the trial is received placebo, making it impossible to directly compare the efficacy of adjuvant targeted therapy with the traditionally recommended adjuvant chemotherapy in guidelines. Thus, it cannot address the direct comparison of third-generation TKIs with the current standard therapy (chemotherapy). Secondly, the necessity of combining chemotherapy with adjuvant targeted therapy need to explored. Aumolertinib is a third-generation epidermal growth factor receptor- tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits EGFR sensitizing and EGFR T790M resistance mutations. This study aims to evaluate the efficacy and safety of aumolertinib combined with or without chemotherapy as adjuvant treatment for EGFR-sensitive mutations stage II-III A non-squamous NSCLC patients. Methods: This is a multicenter, randomized, open label, phase III study. Patients with histologically confirmed stage II-III A non-squamous NSCLC harboring EGFR mutations without prior EGFR TKI treatment and R0 resection are eligible for this study. The performance status (Eastern Cooperative Oncology Group) is 0 or 1. This trial prepared to enroll approximately 606 patients, will be randomized (3:2:1) to receive either aumolertinib alone (110mg, po, once daily) or aumolertinib (110mg, po, once daily) plus pemetrexed (500mg/m2, iv) and cisplatin (500mg/m2, iv) or pemetrexed (500mg/m2, iv) plus cisplatin (500mg/m2, iv). The first patient was enrolled on August 2, 2021. The primary end point is DFS, The secondary endpoints include 2, 3, 4, 5-year DFS rates, 5-year overall survival (OS), OS, safety and quality of life. Adverse effects were graded per CTCAE v.4.0. This trial is registered as NCT04762459. Clinical trial information: NCT04762459 .

MiR-204 suppresses cancer stemness and enhances osimertinib sensitivity in non-small cell lung cancer by targeting CD44

Osimertinib is an effective treatment option for patients with advanced non-small cell lung cancer (NSCLC) with EGFR activation or T790M resistance mutations; however, acquired resistance to osimertinib can still develop. This study explored novel miRNA-mRNA regulatory mechanisms that contribute to osimertinib resistance in lung cancer. We found that miR-204 expression in osimertinib-resistant lung cancer cells was markedly reduced compared to that in osimertinib-sensitive parental cells. miR-204 expression levels in cancer cells isolated from treatment-naive pleural effusions were significantly higher than those in cells with acquired resistance to osimertinib. miR-204 enhanced the sensitivity of lung cancer cells to osimertinib and suppressed spheroid formation, migration, and invasion of lung cancer cells. Increased miR-204 expression in osimertinib-resistant cells reversed resistance to osimertinib and enhanced osimertinib-induced apoptosis by upregulating BIM expression levels and activating caspases. Restoration of CD44 (the direct downstream target gene of miR-204) expression reversed the effects of miR-204 on osimertinib sensitivity, recovered cancer stem cell and mesenchymal markers, and suppressed E-cadherin expression. The study demonstrates that miR-204 reduced cancer stemness and epithelial-to-mesenchymal transition, thus overcoming osimertinib resistance in lung cancer by inhibiting the CD44 signaling pathway.

Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC

BackgroundOsimertinib is a third-generation epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI–sensitizing and EGFR T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy.MethodsIn this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced non–small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed.ResultsA total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib–chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib–chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib–chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy — a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents.ConclusionsFirst-line treatment with osimertinib–chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with EGFR-mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.)

TARGET: A Phase II, Open-Label, Single-Arm Study of 5-Year Adjuvant Osimertinib in Completely Resected EGFR-Mutated Stage II to IIIB NSCLC Post Complete Surgical Resection

IntroductionOsimertinib is a central nervous system (CNS)-active, third generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations, with demonstrated efficacy in EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). We present the rationale and design for TARGET (NCT05526755), which will evaluate the efficacy and safety of 5 years of adjuvant osimertinib in patients with completely resected EGFRm stage II to IIIB NSCLC. Materials and MethodsTARGET is a phase II, multinational, open-label, single-arm study. Adults aged ≥18 years (Taiwan ≥20 years), with resected stage II to IIIB NSCLC are eligible; prior adjuvant chemotherapy is allowed. Eligible patients must have locally confirmed common (exon 19 deletion or L858R) or uncommon (G719X, L861Q, and/or S768I) EGFR-TKI sensitizing mutations, alone or in combination. Patients will receive osimertinib 80 mg once daily for 5 years or until disease recurrence, discontinuation or death. The primary endpoint is investigator-assessed disease-free survival (DFS) at 5 years (common EGFR mutations cohort). Secondary endpoints include: investigator-assessed DFS at 3 and 4 years; overall survival at 3, 4, and 5 years (common EGFR mutations cohort); DFS at 3, 4, and 5 years (uncommon EGFR mutations cohort); safety and tolerability, type of recurrence and CNS metastases (both cohorts). Exploratory endpoints include: tissue/plasma concordance; analysis of circulating molecules in plasma samples using different profiling approaches to detect minimal residual disease; incidence and change over time of incidental pulmonary nodules. ResultsTARGET is currently recruiting, and completion is expected in 2029.

Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR-mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC).

LBA3 Background: Osimertinib is a third-generation, central nervous system (CNS) active EGFR-TKI, that potently and selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations. In the primary analysis from the Phase III ADAURA study (NCT02511106), adjuvant osimertinib demonstrated a clinically meaningful, statistically significant, and practice-changing disease-free survival (DFS) benefit vs placebo in patients with completely resected EGFRm (ex19del/L858R) NSCLC ± adjuvant chemotherapy. In an updated DFS analysis, with 2 years additional follow-up, DFS and CNS DFS benefit with adjuvant osimertinib were sustained (stage II–IIIA DFS hazard ratio [HR] 0.23; 95% confidence interval [CI] 0.18, 0.30; stage IB–IIIA DFS HR 0.27; 95% CI 0.21, 0.34; stage II–IIIA CNS DFS HR 0.24; 95% CI 0.14, 0.42), with a tolerable safety profile observed over the extended treatment duration. Here, we report the planned final overall survival (OS) analysis from ADAURA. Methods: Eligible patients (aged ≥18 years [≥20 in Japan and Taiwan], WHO PS 0/1 with completely resected EGFRm (ex19del/L858R) stage IB, II or IIIA [AJCC/UICC 7th edition] NSCLC; adjuvant chemotherapy allowed) were randomized 1:1 to osimertinib 80 mg once daily or placebo until disease recurrence, treatment completion (3 years), or a discontinuation criterion was met. The primary endpoint was investigator-assessed DFS in stage II–IIIA. Key secondary endpoints: DFS in stage IB–IIIA, OS and safety. Data cut-off: January 27, 2023. Results: Globally, 682 patients were randomized; osimertinib n=339, placebo n=343. Adjuvant osimertinib significantly improved OS vs placebo. In patients with stage II–IIIA disease, OS HR was 0.49 (95% CI 0.33, 0.73; p=0.0004; 100/470 events, 21% maturity); 5-year OS rate was 85% with osimertinib vs 73% with placebo. Median follow-up for OS in stage II–IIIA was 59.9 months (osimertinib) and 56.2 months (placebo). In the overall population (stage IB–IIIA), OS HR was 0.49 (95% CI 0.34, 0.70; p&lt;0.0001; 124/682 events, 18% maturity); 5-year OS rate was 88% with osimertinib vs 78% with placebo, with a median follow-up for OS of 60.4 months (osimertinib) and 59.4 months (placebo). Median OS was not reached in either population or treatment group. Conclusions: Adjuvant osimertinib demonstrated an unprecedented, highly statistically significant and clinically meaningful OS benefit in patients with EGFRm stage IB–IIIA NSCLC after complete tumor resection, with or without adjuvant chemotherapy. ADAURA is the first global Phase III study to demonstrate a statistically significant DFS and OS benefit with targeted treatment for patients with EGFRm stage IB–IIIA NSCLC. Clinical trial information: NCT02511106 .

Clinical validity of oncogenic driver genes detected from circulating tumor DNA in the blood of lung cancer patients.

This study aimed to evaluate the concordance of oncogenic driver mutations between tumor tissues and circulating tumor DNA (ctDNA) in patients with lung cancer. In addition, this study attempted to reveal the clinical utility of ctDNA in lung cancer treatment. Recurrent or metastatic non-small cell lung cancer (NSCLC) patients were prospectively enrolled in this study. Tumor tissue and serial blood samples were obtained from newly diagnosed patients (Cohort A) or patients treated with targeted therapy (Cohort B) and targeted gene panel sequencing was conducted to identify tumor mutational profiles. At the time of diagnosis, patients in Cohort A with a high cell-free DNA (cfDNA) concentration had poorer overall survival than those with a low cfDNA concentration. The sensitivity and precision of ctDNA analysis in pre-treatment patients compared with those of tissue sequencing were 58.4% and 61.5%, respectively. Known lung cancer-associated variants of oncogenic driver genes, including EGFR and KRAS, and tumor suppressor genes, including TP53 and APC, were frequently detected in the ctDNA of the patients (76.9%). An association between smoking and TP53 mutation status was observed in both tissues and ctDNA (P=0.005 and 0.037, respectively). In addition, the EGFR T790M resistance mutation was detected solely from the ctDNA of two patients after treatment with an EGFR tyrosine kinase inhibitor. ctDNA may be a reliable prognostic biomarker with an additional role in treating patients with lung cancer. Further analyses are necessary to understand the properties of ctDNA and widen its clinical use.

CT Radiomics Predict EGFR-T790M Resistance Mutation in Advanced Non-Small Cell Lung Cancer Patients After Progression on First-line EGFR-TKI

We aim to explore the value of chest CT radiomics in predicting the epidermal growth factor receptor (EGFR)-T790M resistance mutation of advanced non-small cell lung cancer (NSCLC) patients after the failure of first-line EGFR-tyrosine kinase inhibitor (EGFR-TKI). A total of 211 and 135 advanced NSCLC patients with tumor tissue-based (Cohort-1) or circulating tumor DNA (ctDNA)-based (Cohort-2) EGFR-T790M testing were included, respectively. Cohort-1 was used for modeling and Cohort-2 was for models' validation. Radiomic features were extracted from tumor lesions on chest nonenhanced CT (NECT) and/or contrast-enhanced CT (CECT). We used eight feature selectors and eight classifier algorithms to establish radiomic models. Models were evaluated by area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA). CT morphological manifestations of peripheral location and pleural indentation sign were associated with EGFR-T790M. For NECT, CECT, and NECT+CECT radiomic features, the feature selector and classifier algorithms of LASSO and Stepwise logistic regression, Boruta and SVM, and LASSO and SVM were chosen to develop the optimal model, respectively (AUC: 0.844, 0.811, and 0.897). All models performed well in calibration curves and DCA. Independent validation of models in Cohort-2 revealed that both NECT and CECT models individually had limited power for predicting EGFR-T790M mutation detected by ctDNA (AUC: 0.649, 0.675), while the NECT+CECT radiomic model had a satisfactory AUC (0.760). This study proved the feasibility of using CT radiomic features to predict the EGFR-T790M resistance mutation, which could be helpful in guiding personalized therapeutic strategies.

Analysis of acquired resistance mechanisms to osimertinib in patients with EGFR-mutated advanced non-small cell lung cancer from the AURA3 trial

Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. This analysis evaluates acquired resistance mechanisms to second-line osimertinib (n = 78) in patients with EGFR T790M advanced non-small cell lung cancer (NSCLC) from AURA3 (NCT02151981), a randomized phase 3 study comparing osimertinib with chemotherapy. Plasma samples collected at baseline and disease progression/treatment discontinuation are analyzed using next-generation sequencing. Half (50%) of patients have undetectable plasma EGFR T790M at disease progression and/or treatment discontinuation. Fifteen patients (19%) have >1 resistance-related genomic alteration; MET amplification (14/78, 18%) and EGFR C797X mutation (14/78, 18%).

Candidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer

Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. In the Phase III FLAURA study (NCT02296125), first-line osimertinib improved outcomes vs comparator EGFR-TKIs in EGFRm advanced non-small cell lung cancer. This analysis identifies acquired resistance mechanisms to first-line osimertinib. Next-generation sequencing assesses circulating-tumor DNA from paired plasma samples (baseline and disease progression/treatment discontinuation) in patients with baseline EGFRm. No EGFR T790M-mediated acquired resistance are observed; most frequent resistance mechanisms are MET amplification (n = 17; 16%) and EGFR C797S mutations (n = 7; 6%). Future research investigating non-genetic acquired resistance mechanisms is warranted.

Predicting EGFR T790M Mutation in Brain Metastases Using Multisequence MRI-Based Radiomics Signature

Timely identifying T790M mutation for non-small cell lung cancer (NSCLC) patients with brain metastases (BM) is essential to adjust targeted treatment strategies. To develop and validate radiomics models based on multisequence MRI for differentiating patients with T790M resistance from no T790M mutation in BM and explore the optimal sequence for prediction. This retrospective study enrolled 233 patients with proven of BM in NSCLC which included 95 with T790M and 138 without T790M from two hospitals as the training cohort and testing cohort separately. Radiomics features extracted from T2WI, T2 fluid-attenuated inversion recovery (T2-FLAIR), diffusion weighted imaging (DWI) and contrast-enhanced T1-weighted imaging (T1-CE) sequence respectively. The most predictable features were selected based on the maximal information coefficient and Boruta method. Then four radiomics models were built to characterize T790M mutation by random forest classifier. ROC curves, F1 score and DCA curves were constructed to validate the capability and verify the performance of four models. The DWI model showed best performance with AUC and F1 score of 0.886 and 0.789 in the training cohort, 0.850 and 0.743 in the testing cohort. DCA curves also showed higher overall net benefit from the DWI model than from the remaining three models in the testing cohort. Other three models also had some classification power whether in the training or testing cohort, especially T2-FLAIR model. Multisequence MRI-based radiomics has potential to predict the emergence of EGFR T790M resistance mutations especially the radiomics signature based on DWI sequence.

The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells

Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or EGFR T790M resistance mutations. While patients treated with osimertinib show clinical benefit, disease progression and drug resistance are common. Emergence of de novo acquired resistance from a drug tolerant persister (DTP) cell population is one mechanism proposed to explain progression on osimertinib and other targeted cancer therapies. Here we profiled osimertinib DTPs using RNA-seq and ATAC-seq to characterize the features of these cells and performed drug screens to identify therapeutic vulnerabilities. We identified several vulnerabilities in osimertinib DTPs that were common across models, including sensitivity to MEK, AURKB, BRD4, and TEAD inhibition. We linked several of these vulnerabilities to gene regulatory changes, for example, TEAD vulnerability was consistent with evidence of Hippo pathway turning off in osimertinib DTPs. Last, we used genetic approaches using siRNA knockdown or CRISPR knockout to validate AURKB, BRD4, and TEAD as the direct targets responsible for the vulnerabilities observed in the drug screen.

296P Osimertinib as adjuvant therapy in patients (pts) with resected EGFR-mutated (EGFRm) stage IB-IIIA non-small cell lung cancer (NSCLC): Updated results from ADAURA

Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits EGFR-TKI sensitising and EGFR T790M resistance mutations. It has efficacy in EGFRm NSCLC, including in central nervous system (CNS) metastases. In the Phase III ADAURA (NCT02511106) primary analysis adjuvant osimertinib showed a significant and clinically meaningful disease-free survival (DFS) benefit vs placebo (PBO) in pts with completely resected EGFRm (ex19del/L858R) NSCLC, ± adjuvant chemotherapy (CT): stage IIꟷIIIA DFS HR, 0.17; 99.06% CI, 0.11, 0.26; p<0.0001; stage IBꟷIIIA DFS HR, 0.20; 99.12% CI 0.14, 0.30; p<0.0001.

Efficacy and safety of osimertinib for patients with EGFR-mutated NSCLC: a systematic review and meta-analysis of randomized controlled studies

Background Osimertinib is a recently approved third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR-T790M resistance mutations. The aim of the present meta-analysis was to investigate the efficacy and safety of osimertinib for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Materials and methods Databases were searched for randomized controlled studies that reported the efficacy and safety of osimertinib versus other treatments (chemotherapy, other EGFR-TKIs, etc.) in treating EGFR-mutated NSCLC. The measured effects included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), central nervous system progression-free survival (CNS-PFS), and overall survival (OS). Additional outcome was the incidence of adverse event. Relative risk (RR) for incidence and hazard ratio (HR) for survival outcomes were pooled. Results Seven studies containing 3335 participants were finally included. Osimertinib tended to improve ORR and DCR (RRs >1) as compared with other treatments. Osimertinib was also a significant protective factor for PFS, CNS-PFS, and OS (HRs <1 and p < .05). Osimertinib showed similar advantages in improving tumor response and patient survival when used as first-line, second-line, and third-line/adjuvant therapy, respectively, as compared with other treatments (RRs >1 for ORR and DCR; HRs <1 for PFS, CNS-PFS, and OS). Osimertinib also had better therapeutic effects as compared with chemotherapy, other EGFR TKIs, docetaxel + bevacizumab, and placebo, respectively. The five most common adverse events with pooled incidence > 20% were diarrhea, rash, nail effects, dry skin, and stomatitis, yet the pooled incidence of serious adverse events was less than 2%. Conclusions This meta-analysis suggests that osimertinib has a positive effect in disease control and survival for patients with EGFR-mutated NSCLC with acceptable toxicities.

1188TiP ORCHARD platform study: Osimertinib + datopotamab deruxtecan (Dato-DXd) cohort in patients (pts) with advanced NSCLC (aNSCLC) who have progressed on first-line (1L) osimertinib

Osimertinib, a third-generation, irreversible epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits both EGFR-TKI sensitising (EGFRm) and EGFR T790M resistance mutations, with demonstrated efficacy in EGFRm NSCLC, including CNS metastases. Osimertinib is the preferred 1L treatment in EGFRm a NSCLC, with significant improvements in progression-free survival/overall survival vs comparators; however, pts may eventually develop disease progression. ORCHARD (NCT03944772) aims to identify mechanisms of resistance to 1L osimertinib and explore novel therapeutic options by allocating pts to biomarker/non-biomarker directed cohorts based on tumour molecular profile. Trophoblast cell-surface antigen 2 (TROP2) is a transmembrane glycoprotein that is overexpressed in NSCLC. Dato-DXd is a TROP2-directed antibody conjugated to a topoisomerase I inhibitor via a tumour-selective cleavable linker that has encouraging antitumour activity in a NSCLC. A new ORCHARD cohort will evaluate osimertinib + Dato-DXd in pts without identifiable, actionable resistance mechanisms. In the open-label, multicentre, multidrug, biomarker-directed, Phase II platform ORCHARD study, pts with EGFRm aNSCLC with progression on 1L osimertinib are allocated to treatment. Pts without a biomarker match (ALK, RET, BRAF) may enrol to receive oral osimertinib 80 mg once daily + intravenous Dato-DXd 4 mg/kg every 3 weeks (Q3W). If no dose-limiting toxicities occur in the first 3–4 pts, pts may enrol to receive osimertinib + 6mg/kg Dato-DXd. Safety/tolerability data will inform expansion of the 4 or 6 mg/kg Dato-DXd + osimertinib cohort to ∼16 pts. Tumour assessments (RECIST 1.1) will be performed Q6W for the first 24 weeks, then Q9W until disease progression. Primary outcome: investigator-assessed confirmed objective response rate. Secondary outcomes include safety/tolerability, duration of response, and pharmacokinetics; exploratory outcomes include change in tumour burden using circulating tumour DNA in plasma, and tumour/plasma biomarker analyses and their correlation with treatment effect. NCT03944772, 10 May 2019. The authors would like to acknowledge Bernadette Tynan, MSc, of Ashfield MedComms, Macclesfield, UK, part of UDG Healthcare for medical writing support that was funded by AstraZeneca. AstraZeneca.

EP08.02-108 Osimertinib Long-Term Tolerability in Patients with EGFRm NSCLC Enrolled in the AURA Program or FLAURA Study

Osimertinib is a third-generation, irreversible, oral EGFR-TKI that potently and selectively inhibits EGFR TKI-sensitizing (EGFRm) and EGFR T790M resistance mutations, including CNS metastases. Osimertinib is the preferred first-line treatment in metastatic EGFRm NSCLC, approved as ≥second-line treatment in EGFRm NSCLC with T790M mutations, and approved as adjuvant treatment in resectable EGFRm NSCLC. This post-hoc analysis of AURA program and FLAURA trials reports for the first time, long-term safety data in EGFRm metastatic NSCLC treated with osimertinib 80 mg once-daily (QD) for ≥36 months.

LBA47 Osimertinib as adjuvant therapy in patients (pts) with resected EGFR-mutated (EGFRm) stage IB-IIIA non-small cell lung cancer (NSCLC): Updated results from ADAURA

Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits EGFR-TKI sensitising and EGFR T790M resistance mutations. It has efficacy in EGFRm NSCLC, including in central nervous system (CNS) metastases. In the Phase III ADAURA (NCT02511106) primary analysis adjuvant osimertinib showed a significant and clinically meaningful disease-free survival (DFS) benefit vs placebo (PBO) in pts with completely resected EGFRm (ex19del/L858R) NSCLC, ± adjuvant chemotherapy (CT): stage IIꟷIIIA DFS HR, 0.17; 99.06% CI, 0.11, 0.26; p<0.0001; stage IBꟷIIIA DFS HR, 0.20; 99.12% CI 0.14, 0.30; p<0.0001. We report updated exploratory analyses of DFS and recurrence patterns after 2 yrs added follow up. Eligible pts (aged ≥18 yrs [≥20 in Japan/Taiwan], WHO PS 0/1, completely resected EGFRm stage IBꟷIIIA [AJCC 7th edition] NSCLC; adjuvant CT allowed) were randomised 1:1 to osimertinib 80 mg once daily or PBO for up to 3 yrs. Primary endpoint: investigator-assessed DFS in stage IIꟷIIIA. Secondary endpoints: DFS in stage IBꟷIIIA, overall survival and safety. Patterns of recurrence and CNS DFS were pre-specified exploratory endpoints. Data cut-off: 11 April 2022. Globally, 682 pts were randomised; osimertinib n=339, PBO n=343. In this updated analysis, in pts with stage IIꟷIIIA disease DFS HR was 0.23 (95% CI 0.18, 0.30; 242/470 events; 51% maturity); 3-yr DFS rate was 84% with osimertinib vs 34% with PBO. In the overall population (stage IBꟷIIIA) DFS HR was 0.27 (95% CI 0.21, 0.34; 305/682 events); 3-yr DFS rate was 85% with osimertinib vs 44% with PBO. In the osimertinib arm, fewer pts experienced local/regional and distant recurrence vs PBO. CNS DFS HR was 0.24 (95% CI 0.14, 0.42; 63/470 events) in stage IIꟷIIIA. The long-term safety profile remains consistent with the known profile of osimertinib. With 2 yrs further follow-up, a continued DFS benefit was sustained with osimertinib vs PBO, consistent with the primary analysis. These mature data reinforce adjuvant osimertinib as standard of care for pts with EGFRm stage IB–‍IIIA NSCLC after complete tumour resection and adjuvant CT, when indicated.

Abstract P3110: Mechanism Of Cardiotoxicity Associated With Tyrosine Kinase Inhibitor Osimertinib

Background: Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for non-small cell lung cancer (NSCLC) treatment. Osimertinib potently and selectively inhibits EGFR-T790M resistance mutations in patients with NSCLC harboring these mutations. Emerging evidence from clinical trials has identified potential cardiotoxic effects of osimertinib including heart failure, atrial fibrillation (AF), and QT interval prolongation. The mechanisms underlying osimertinib-induced cardiotoxicity, however, are poorly understood. Methods: To investigate potential mechanisms of osimertinib-induced cardiotoxicity, we tested the drug in both in vitro cultured cardiomyocytes (CMs) and wild-type C57BL/6 mice in vivo , corresponding to doses used in preclinical development. Echocardiography was performed in mice to assess the effect on cardiac function. In vivo electrophysiology studies were also performed to assess effects on osimertinib-induced AF and QT prolongation susceptibility. Results: Osimertinib (500 nM, 72 hours) reduced CM viability in NRVMs (p=0.0001), and induced apoptosis as determined by TUNEL assay (p=0.004) and upregulated Bax/Bcl-2 ratio (mRNA: 1.45-fold, p=0.001). In wild-type C57BL/6 mice, osimertinib (5 mg/Kg/day, 4 weeks) decreased ejection fraction (37.15±3.99% vs control: 51.04±2.23%, p=0.0001) and fractional shortening (17.69±2.18% vs control: 25.56±1.51%, p=0.0001). This was associated with an increase in cardiac BNP expression (mRNA: 1.72-fold, p=0.005) and apoptotic Bax/Bcl-2 ratio (protein: 1.85-fold, p=0.02). Electrophysiology studies also demonstrated 2:1 atrioventricular block (p=0.03) in osimertinib treated mice and increased AF susceptibility. A combination of in vitro and in vivo mechanistic analyses demonstrated that osimertinib significantly inhibits pro-survival ERK signaling pathway. Conclusions: Our results demonstrate that the cardiotoxicity seen with osimertinib in clinical trials is largely recapitulated in preclinical models, and that osimertinib can directly induce CM death. These models may provide a foundation for further investigating mechanism of osimertinib-induced cardiotoxicity and interventions to mitigate it.

The Presence of EGFR T790M in TKI-Naïve Lung Cancer Samples of Patients Who Developed a T790M-Positive Relapse on First or Second Generation TKI Is Rare.

Simple SummaryTreatment outcomes for non-small cell lung cancer (NSCLC) patients have significantly improved since the introduction of targeted therapy using tyrosine kinase inhibitors (TKI). Despite the initial promising results, most patients develop resistance due to on- or off-target mechanisms. On-target mutations prevent the effective binding of TKIs. In this study, we determined whether the most common on-target resistance mutation for treatment with EGFR-TKI mutation, i.e., the EGFR T790M mutation, can be detected in pre-treatment tissue samples and can predict treatment outcome. We included 33 patients who progressed with a T790M positive relapse upon treatment with EGFR-TKI between 2013 to 2019. Progression-free survival (PFS) time of the single T790M positive patient was 9 months, while the T790M negative patients had a median PFS of 10 months (range 2–27). Our results show that the presence of EGFR T790M mutations in pre-TKI samples is rare, even in patients who subsequently progressed with an EGFR T790M mutation.EGFR-mutated non-small cell lung cancer (NSCLC) patients can be effectively treated with tyrosine kinase inhibitors (TKI) but frequently present with an EGFR T790M resistance mutation at relapse. We aimed to screen for T790M in pre-treatment formalin-fixed and paraffin-embedded (FFPE) tissue samples of patients with a confirmed T790M mutation at progression. We analyzed 33 pre-treatment DNA samples of NSCLC patients who progressed upon TKI between 2013 to 2019. To establish storage-time dependent formalin fixation-induced background levels for C>T mutations, we analyzed DNA isolated from archival (stored >1 year, n = 22) and recently generated (stored <1 month, n = 11) FFPE samples and included DNA isolated from white blood cells (WBC) (n = 24) as controls. DNA samples were analyzed by droplet digital (dd)PCR, and positivity was defined by outlier detection according to Grubb’s criterion. The T790M background allele frequency levels were 0.160% in DNA isolated from archival-FFPE, 0.100% in fresh FFPE, and 0.035% in WBC. Progression-free survival (PFS) time of the single T790M positive patient was 9 months, while T790M negative patients had a median PFS of 10 months (range 2–27). Proper storage time matched FFPE control samples are essential for reliable detection of T790M mutation at low VAF. The presence of EGFR T790M mutations in pre-TKI samples is rare, even in patients who progressed with EGFR T790M mutations.

Abstract CT184: Emerging evidence of activity of BLU-945 in patients with advanced EGFR-mutant NSCLC utilizing circulating tumor DNA (ctDNA) in the phase 1/2 SYMPHONY study

Abstract Background: Despite recent advances in the treatment of EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), most patients treated with third-generation (3G) EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, experience disease progression. The most common on-target EGFR resistance mutation is at the EGFR C797 residue (i.e., C797S), which prevents covalent binding to 3G EGFR TKIs. While 3G TKIs are effective in patients with EGFR activating and T790M mutations (commonly seen post-progression after first-/second-generation TKIs), there are no targeted therapies approved after their failure. BLU-945 is an investigational, reversible, and selective next-generation EGFR TKI intended for use as a single agent or in combination with other agents to suppress activating and on-target resistance EGFR mutants, including T790M and C797S, while sparing wildtype (wt) EGFR. BLU-945 has shown in vivo antitumor activity in 3G EGFR TKI-naïve as well as resistant NSCLC patient-derived xenograft models with EGFR T790M and C797S mutations. Based on this, we started SYMPHONY (NCT04862780), a phase 1/2 study in patients with metastatic EGFRm NSCLC, to determine the maximum tolerated dose and/or the recommended phase 2 dose (RP2D); and to assess the safety, pharmacokinetics (PK), and antitumor activity of BLU-945. Methods: In the ongoing phase 1 dose-escalation part of the study, patients aged ≥18 years with metastatic EGFRm NSCLC previously treated with ≥1 EGFR TKI (Eastern Cooperative Oncology Group performance status of 0-2) received BLU-945 once daily (QD) on a 28-day cycle following a Bayesian Optimal Interval escalation design. Adverse events (AEs), dose-limiting toxicities (DLTs), PK, ctDNA (in real-time using FoundationOne Liquid panel), and radiographic antitumor activity (by RECIST 1.1 criteria) were assessed in the first 4 treatment cohorts. Results: As of the January 7, 2022, data cut, 18 patients have been treated with BLU-945 at 25-200 mg QD. Of these, 14 (77.8%) patients had received ≥2 lines of prior systemic anticancer therapy in the metastatic setting. There were no DLTs, and most AEs were low grade. Treatment-related AEs (all Grade 1) occurred in 8 (44.4%) patients with the most common being nausea (n=3). EGFR mutation allele fraction assessment by ctDNA at C1D1 and C1D15 showed that tumors were heterogeneous at baseline. At doses of 50 mg QD and higher, reductions in EGFR resistance mutation allele fraction were seen in all patients (n=3) with EGFR C797S (n=2) and/or T790M (n=3) resistance mutations, with a median 48% reduction of these mutations. 50% of patients remain on treatment and dose escalation continues to determine the RP2D. Conclusion: As of the data cut, BLU-945 was generally well tolerated in heavily pre-treated patients with EGFRm NSCLC. There was also early evidence of a reduction in EGFR mutation allele fractions by ctDNA. Citation Format: Elaine Shum, Yasir Elamin, Karen L. Reckamp, Zofia Piotrowska, Julia Rotow, Daniel S. Tan, Koichi Goto, Jagan Parepally, Faris Albayya, Melinda Louie-Gao, Renata Sawtell, Alena Zalutskaya, David Spigel. Emerging evidence of activity of BLU-945 in patients with advanced EGFR-mutant NSCLC utilizing circulating tumor DNA (ctDNA) in the phase 1/2 SYMPHONY study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT184.