Efficacy Of Osimertinib Research Articles

EP.12A.15 ACTN4 as a Predictive Biomarker for Osimertinib Efficacy in EGFR Mutant Non-Small Cell Lung Cancer

EP.12A.15 ACTN4 as a Predictive Biomarker for Osimertinib Efficacy in EGFR Mutant Non-Small Cell Lung Cancer

Negative-predictive value of SUVmax for Ascertaining the efficacy of osimertinib in EGFR mutation-positive non-small cell lung cancer

BackgroundFluorine-18 2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) is routinely used to stage non-small cell lung cancer (NSCLC). However, whether 18F-FDG accumulation in primary tumors affects the efficacy of osimertinib in patients with epidermal growth factor receptor (EGFR) mutation-positive NSCLC remains unclear. MethodsWe retrospectively investigated 74 patients with advanced or postoperative recurrent EGFR mutation-positive NSCLC who underwent 18F-FDG PET/CT and were treated with osimertinib as first-line therapy between September 2018 and March 2023 at Kumamoto University Hospital. The maximum standardized uptake value (SUVmax) of each primary tumor was measured, and the patients were divided into two groups according to the median SUVmax. The effects of SUVmax on progression-free survival (PFS) and overall survival (OS) were assessed using a multivariate Cox proportional hazards model. ResultsThe median SUVmax was 8.2 (interquartile range: 5.5–11.4). The median PFS in the high SUVmax group (≥8.2) was significantly shorter than that in the low SUVmax group (<8.2). The respective median PFSs were 11.2 months (95% confidence interval [CI]: 3.1–19.3 months) vs. 22.9 months (95% CI: 12.4–33.4 months) (P = 0.015), although the OS values did not differ significantly. Multivariate analysis showed that a high SUVmax was an independent negative predictive factor for PFS in patients treated with osimertinib (hazard ratio, 2.25; 95% CI: 1.15–4.39, P = 0.017). ConclusionsHigh primary-lesion SUVmax in patients with EGFR mutation-positive NSCLC correlated with shorter PFS with first-line osimertinib therapy, suggesting that SUVmax is a useful predictive marker for the antitumor efficacy of osimertinib.

Inhibition of hTERT/telomerase/telomere mediates therapeutic efficacy of osimertinib in EGFR mutant lung cancer.

The inevitable acquired resistance to osimertinib (AZD9291), an FDA-approved third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) for the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR activating or T790M resistant mutations, limits its long-term clinical benefit. Telomere maintenance via telomerase reactivation is linked to uncontrolled cell growth and is a cancer hallmark and an attractive cancer therapeutic target. Our effort toward understanding the action mechanisms, including resistance mechanisms, of osimertinib has led to the identification of a novel and critical role in maintaining c-Myc-dependent downregulation of hTERT, a catalytic subunit of telomerase, and subsequent inhibition of telomerase/telomere and induction of telomere dysfunction in mediating therapeutic efficacy of osimertinib. Consequently, osimertinib combined with the telomere inhibitor, 6-Thio-dG, which is currently tested in a phase II trial, effectively inhibited the growth of osimertinib-resistant tumors, regressed EGFRm NSCLC patient-derived xenografts, and delayed the emergence of acquired resistance to osimertinib, warranting clinical validation of this strategy to manage osimertinib acquired resistance.

Meta-analysis of Targeted Therapies in EGFR-mutated Non-Small Cell Lung Cancer: Efficacy and Safety of Osimertinib, Erlotinib, and Gefitinib as First-line Treatment.

Some of the non-small cell lung cancer (NSCLC) cases enhance somatic mutations of the epidermal growth factor receptor (EGFR) gene within the tyrosine kinase inhibitor (TKI) domain. In such cases, first-line treatments are EGFR-TKIs, including osimertinib, erlotinib, or gefitinib. Therefore, this meta-analysis aims to assess the safety and efficacy of first-line targeted therapies for EGFR-mutated advanced NSCLC patients, focusing on osimertinib, erlotinib, and gefitinib. A systematic electronic search was conducted on 3 electronic databases-Scopus, PubMed, and Web of Science-from inception to May 2024 to locate relevant trials reporting the safety and efficacy of osimertinib, erlotinib, or gefitinib in treating EGFR-mutated advanced NSCLC. No language or data restriction was applied to the search strategy. The assessed effects were objective response rate (ORR) and disease control rate (DCR). RoB 2 tool was utilized to determine the risk of bias while R programming language performed all the statistical synthesis. Out of 15,275 search results, only 19 trials were eligible for this meta-analysis. All the 3 EGFR-TKIs depicted effectiveness and safety among NSCLC patients, but osimertinib improved the ORR by 72% (95% CI: 65%, 78%) as compared with erlotinib (69% [95% CI: 58%, 79%]) and gefitinib (64% [95% CI: 64%, 78%]). Overall, the 3 EGFR-TKIs were effective by improving ORR 68% (95% CI: 63%, 73%). Similarly, osimertinib demonstrated highly effective impacts in disease control among NSCLC patients by 94% (95% CI: 91%, 97%) compared with gefitinib (68% [95% CI: 41%, 89%]). Overall, the 2 EGFR-TKIs were effective in disease control among NSCLC patients (82% [95% CI: 67%, 93%]). The pooled analyses have shown that erlotinib, gefitinib, and osimertinib are safe and effective first-line treatment options for patients with EGFR-mutated advanced NSCLC. The meta-analysis outcomes have demonstrated that osimertinib, erlotinib, or gefitinib positively impact overall response rate and disease control.

NUAK1-Mediated Phosphorylation of NADK Mitigates ROS Accumulation to Promote Osimertinib Resistance in Non-Small Cell Lung Carcinoma.

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is approved as a first-line therapy in advanced non-small cell lung carcinoma (NSCLC) patients with EGFR-activating mutations or the T790M resistance mutation. However, the efficacy of osimertinib is limited due to acquired resistance, highlighting the need to elucidate resistance mechanisms to facilitate the development of improved treatment strategies. Here, we screened for significantly upregulated genes encoding protein kinases in osimertinib-resistant NSCLC cells and identified NUAK1 as a pivotal regulator of osimertinib resistance. NUAK1 was highly expressed in osimertinib-resistant NSCLC and promoted the emergence of osimertinib resistance. Genetic or pharmacological blockade of NUAK1 restored the sensitivity of resistant NSCLC cells to osimertinib in vitro and in vivo. Mechanistically, NUAK1 directly interacted with and phosphorylated NADK at serine 64 (S64), which mitigated osimertinib-induced accumulation of reactive oxygen species (ROS) and contributed to the acquisition of osimertinib resistance in NSCLC. Furthermore, virtual drug screening identified T21195 as an inhibitor of NADK-S64 phosphorylation, and T21195 synergized with osimertinib to reverse acquired resistance by inducing ROS accumulation. Collectively, these findings highlight the role of the NUAK1-NADK axis in governing osimertinib resistance in NSCLC and indicate the potential of targeting this axis as a strategy for circumventing resistance.

Early-Stage Non-Small Cell Lung Cancer: New Challenges with Immune Checkpoint Blockers and Targeted Therapies.

The recent advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint blockers (ICBs) in early-stage non-small cell lung cancer (NSCLC) has dramatically modified treatment strategies by improving the prognosis in this setting. Osimertinib and alectinib, both TKIs, have shown significant improvements in outcomes for patients with resected EGFR- and ALK-positive NSCLC, respectively, changing the standard of care in these subgroups. More recently, the LAURA trial showed the efficacy of osimertinib after chemoradiotherapy in patients with unresectable stage III NSCLC harboring EGFR mutations. Numerous trials are still ongoing to investigate neoadjuvant/perioperative TKIs in several oncogene-driven NSCLC. In addition, several ICBs have been tested and approved as adjuvant (atezolizumab and pembrolizumab), neoadjuvant (nivolumab), and perioperative treatments (pembrolizumab) for patients with resectable early-stage NSCLC. Despite these advances, many challenges remain regarding the use of TKIs and ICBs in this setting, including the optimal duration of adjuvant TKI or induction ICB therapy, the role of minimal residual disease to identify patients at high-risk of disease relapse and to guide adjuvant treatment decisions, and the role of adjuvant chemotherapy in resected oncogene-driven NSCLC. Furthermore, potential predictive biomarkers for efficacy are needed to eventually intensify the entire perioperative strategies. This review aims to summarize and discuss the available evidence, the ongoing trials, and the challenges associated with TKI- and ICB-based approaches in early-stage NSCLC.

Cancer-associated fibroblast-derived colony-stimulating factor 2 confers acquired osimertinib resistance in lung adenocarcinoma via promoting ribosome biosynthesis.

Acquired resistance is a major obstacle to the therapeutic efficacy of osimertinib in lung adenocarcinoma (LUAD), but the underlying mechanisms are still not fully understood. Cancer-associated fibroblasts (CAFs) are the most abundant stromal cell type in LUAD tumor-microenvironment (TME) and have emerged as a key player in chemoresistance. However, the function of CAFs in osimertinib resistance is still unclear. Here, we showed that CAFs derived from osimertinib-resistant LUAD tissues (CAFOR) produced much more colony-stimulating factor 2 (CSF2) than those isolated from osimertinib-sensitive tissues. CAFOR-derived CSF2 activated the Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) signaling pathway and upregulated lnc-CSRNP3 in LUAD cells. Lnc-CSRNP3 then promoted the expression of nearby gene CSRNP3 by recruiting chromodomain helicase DNA binding protein 9 (CHD9) and inhibited the phosphatase activity of the serine/threonine protein phosphatase 1 catalytic subunit α (PP1α), thereby induced osimertinib resistance by enhancing ribosome biogenesis. Collectively, our study reveals a critical role for CAFs in the development of osimertinib resistance and identifies the CSF2 pathway as an attractive target for monitoring osimertinib efficacy and overcoming osimertinib resistance in LUAD.

Targeting Transient Receptor Potential Melastatin-2 (TRPM2) Enhances Therapeutic Efficacy of Third Generation EGFR Inhibitors against EGFR Mutant Lung Cancer.

There is an urgent need to fully understand the biology of third generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs), particularly osimertinib, and to develop mechanism-driven strategies to manage their acquired resistance. Transient receptor potential melastatin-2 (TRPM2) functions as an important regulator of Ca2+ influx, but its role in mediating therapeutic efficacies of EGFR-TKIs and acquired resistance to EGFR-TKIs has been rarely studied. This study has demonstrated a previously undiscovered role of suppression of TRPM2 and subsequent inhibition of Ca2+ influx and induction of ROS and DNA damage in mediating apoptosis induction and the therapeutic efficacy of osimertinib against EGFR mutant NSCLC. The rebound elevation represents a key mechanism accounting for the emergence of acquired resistance to osimertinib and other third generation EGFR-TKIs. Accordingly, targeting TRPM2 is a potentially promising strategy for overcoming and preventing acquired resistance to osimertinib, warranting further study in this direction including the development of cancer therapy-optimized TRPM2 inhibitors.

Anti-HDGF antibody targets EGFR tyrosine kinase inhibitor-tolerant cells in NSCLC patient-derived xenografts.

Constitutively active mutant epidermal growth factor receptor (EGFR) is one of the major oncogenic drivers in NSCLC. Targeted therapy using EGFR tyrosine kinase inhibitor (TKI) is a firstline option in patients that have metastatic or recurring disease. However, despite the high response rate to TKI, most patients have a partial response, and the disease eventually progresses in 10 to 19 months. It is believed that drug-tolerant cells that survive TKI exposure during the progression-free period facilitate the emergence of acquired resistance. Thus, targeting the drug-tolerant cells could improve the treatment of NSCLC with EGFR mutations. We demonstrated here that EGFR mutant patient-derived xenograft (PDX) tumors responded partially to osimertinib despite near complete inhibition of EGFR activation. Signaling in AKT/mTOR and MAPK pathways could be reactivated shortly after initial inhibition. As a result, many tumor cells escaped drug killing and regained growth following about 35 days of continuous osimertinib dosing. However, when an antibody to hepatoma-derived growth factor (HDGF) was given concurrently with osimertinib, tumors showed complete or near-complete responses.There was significant prolongation of progression-free survival (PFS) of tumor-bearing mice as well. Immunohistochemistry and western blot analysis of tumors collected in the early stages of treatment suggest that increased suppression of the AKT/mTOR and MAPK pathways could be a mechanism that results in enhanced efficacy of osimertinib when it is combined with anti-HDGF antibody.

Supramolecular self-assembly strategy for the enhanced solubility/dissolution rate and anti-cancer efficacy of osimertinib: Insights from multi-component crystals to drug chemistry

Multi-component crystal based on supramolecular self-assembly is an effective strategy to modify the physicochemical properties of poorly water-soluble drugs. In this study, eight novel multi-component crystals of Osimertinib (AZD) were firstly synthesized under the guidance of theoretical analysis. Five single crystals were successfully obtained, and the AZD-FMS cocrystal shows a distinctive structure wherein free FMS filled in the skeleton, which may be crucial for maintaining morphology. Analysis of crystal structures and Hirshfeld surfaces indicated the involvement of N−H···O and N···H−O hydrogen bonds in the multi-component crystals. Owing to robust intermolecular interactions, multi-component crystals exhibited improved solubility/dissolution rate compared to pure AZD. Multivariate analysis revealed coformers and strong solute–solvent interactions determined the solubility/dissolution rate. Multi-component crystals showed superior stability in solution and low humidity. Moreover, AZD-FSM increased 5.2-fold anti-tumor activity over AZD, which is anticipated to enhance efficacy, reduce drug toxicity, combat drug resistance, and transform from laboratory to clinical application.

A phase II study of osimertinib in patients with NSCLC harboring EGFR exon 20 insertion: A multicenter trial of the Korean Cancer Study Group (LU17-19)

BackgroundEpidermal growth factor receptor (EGFR) exon 20 insertions account for up to 10% of all EGFR mutations. Clinical outcomes in patients receiving approved EGFR exon 20 insertion–specific inhibitors have been variable. Although osimertinib has demonstrated antitumor activity in clinical trials, its clinical efficacy and translational potential remain to be determined in non-small cell lung carcinoma (NSCLC) with EGFR exon 20 insertion. MethodsIn this multicenter phase II study, patients with advanced NSCLC harboring EGFR exon 20 insertions for whom the standard chemotherapy failed received 80 mg osimertinib once daily. The primary endpoint was the investigator-assessed objective response rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety profile. ResultsAmong 15 patients enrolled at stage 1, the best response was most commonly disease stabilization (73.3 %), which did not meet the stage 1 threshold (objective response ≥ 2/15). As of data cutoff, two patients remained on the treatment. The median PFS and OS were 3.8 (95 % confidence interval [CI] = 1.7–5.5) months and 6.5 (95 % CI = 3.9–not reached) months, respectively. Adverse events (≥grade 3) were anemia, hypercalcemia, and pneumonia (13.3 % each), and asthenia, femur fracture, increased alkaline phosphate, hyperkalemia, bone pain, and azotemia (6.7 % each). Pre-existing EGFR C797S mutation detected in plasma limited the efficacy of osimertinib. ConclusionOsimertinib at 80 mg once daily had limited efficacy and mostly showed disease stabilization with an acceptable safety profile in advanced NSCLC harboring EGFR exon 20 insertions.ClinicalTrials.govIdentifier: NCT03414814.

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 &lt; 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]

Safety and efficacy of osimertinib plus bevacizumab as first-line treatment in EGFR-mutant NSCLC with brain metastases: A dynamic ctDNA-guided study.

e20606 Background: Non-small cell lung cancer (NSCLC) patients with positive driver genes had a higher incidence of brain metastasis. This study evaluates the efficacy and safety of Osimertinib combined with Bevacizumab as first line treatment in EGFR-mutant NSCLC with brain metastases, utilizing liquid biopsy and dynamic molecular detection to guide treatment strategies. This approach is anticipated to bring progression-free survival (PFS) benefits and shows different resistant mechanisms. Methods: We enrolled EGFR-mutant NSCLC patients with brain metastases receiving Osimertinib and Bevacizumab as first-line therapy. Paired plasma and cerebrospinal fluid (CSF) samples were collected at baseline, during stable disease, and at disease progression for Next-Generation Sequencing (NGS) analysis. The study's primary endpoints were central nervous system (CNS) PFS and objective response rate (ORR). Secondary endpoints included overall PFS, ORR, disease control rate (DCR), and safety. We also investigated resistance mechanisms to the combination therapy. Results: A total of 28 patients from Beijing TianTan Hospital (May 2020 - July 2023) were retrospectively enrolled. The average Bevacizumab treatment duration was 8.21 months (range: 1-27 months). CNS PFS was 26.73 months (95% CI, not reached), and overall PFS was 21.93 months (95% CI, 18.84-25.02 months). The CNS PFS for patients with 19del and L858R mutations were not reached and 26.73 months (95% CI, 15.11-38.35 months), respectively (p = 0.25). Patients undergoing intracranial local treatment showed a CNS PFS not reached, compared to 23.33 months (95% CI, 16.21-30.45 months) for those who did not (p = 0.417). The CNS ORR was 88%, ORR was 76%, and DCR was 100%. At the time of data cutoff (Dec 15th, 2023), 1 patient progressed in both lung and CNS metastases, 8 patients only progressed in lung, 8 patients only progressed in CNS metastases .EGFR C797S mutation was detected in 2 plasma sample, Met amplification in 1 tumor tissue, EGFR C719S mutation in 1 paired plasma-tumor tissue and PIK3CA in 2 plasma sample. Increasing abundance in TP53 and CDKN2A were detected in 2 paired plasma-tumor tissue. Adverse events of grade 3 or higher included one case (3.6%) of severe ulcerative colitis leading to Osimertinib discontinuation and two cases (7.1%) of bevacizumab discontinuation due to bleeding events. Conclusions: Osimertinib combined with Bevacizumab as a first-line treatment significantly prolonged CNS PFS in EGFR-mutant NSCLC patients with brain metastases, offering superior control over intracranial lesions compared to Osimertinib monotherapy (15.2 months, FLAURA study). This study underscores the potential of dynamic ctDNA monitoring in guiding effective treatment strategies for this patient population. Further research is warranted to explore the broader clinical implications of these findings.

Safety and efficacy of osimertinib plus consolidative stereotactic ablative radiation (SABR) in advanced EGFR mutant non-small cell lung cancer (NSCLC): Results from a multi-center phase II trial.

8518 Background: Despite high response rates to EGFR inhibitors, patients with advanced EGFR mutant NSCLC generally experience disease progression within two years (osimertinib median PFS 18.9 months, median OS 38.6 months). We sought to determine whether administration of SABR to residual sites of disease at the time of expected best response to EGFR inhibition could prolong disease control. Methods: This was a multi-center single-arm phase 2 study. Eligible patients had advanced EGFR mutant (exon 19 or 21) NSCLC not restricted by number, site, or size of metastases; ECOG 0-2; no prior treatment with EGFR inhibitors or immune checkpoint inhibitors; and no history of interstitial lung disease. Patients with stable or responding disease after 8 weeks of osimertinib received SABR to persisting lesions, followed by continued osimertinib until progression or intolerance. At subsequent progression, patients could receive further SABR and continue osimertinib if deemed clinically feasible and appropriate. The primary endpoint was progression-free survival (PFS); secondary endpoints included duration on osimertinib, toxicity, and overall survival (OS). Results: A total of 43 patients (32 women, 11 men) were enrolled and initiated osimertinib, of whom 29 (67%) received SABR. Reasons SABR was not administered included inadequate response (9%), insufficient residual disease (19%), and other (5%). At a median follow-up of 35.7 months (95% CI, 28.8, 37.6), 42 evaluable patients had a median PFS of 32.6 months and a median OS of 45.7 months. The median duration of osimertinib was 31.5 months. Grade ≥3 toxicities included one incidence each (2%) of the following: pain at the site of radiation, paronychia, liver enzyme elevation, fatigue, hyponatremia, diarrhea, and pneumonitis. Conclusions: Osimertinib plus consolidative SABR appears to provide a PFS and OS benefit when considered against historical data with osimertinib alone. This treatment strategy may offer a well-tolerated and practical approach to improving outcomes for patients with advanced EGFR mutant NSCLC. Clinical trial information: NCT03667820 .

Real-world outcomes of osimertinib in Peruvian patients with advanced NSCLC with EGFR T790M-positive: A multi-institutional experience.

e20605 Background: Osimertinib is the standard of care for advanced NSCLC patients with EGFR T790M-positive whose disease has progressed to EGFR TKI therapy, however, the knowledge on the real benefit of these therapies in the Latin American setting remains unclear due the lack of access in the most countries. The aim of this study is to evaluate the outcomes of Osimertinib as sencond line treatment of advanced NSCLC patients with EGFR T790M-positive in a real-world Peruvian setting. Methods: This is a retrospective study of advanced NSCLC patients with EGFR T790M-positive treated with osimertinib at seven Peruvian institutions between July 2018 and May 2023. Outcomes were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and OS from the start of first-line treatment to death. Results: We analyzed 41 T790M-positive patients with a median age of 60 years (range 36-87y), most of them were females (65.9%), 17.1% had smoking history and 19.5% biomass exposition as a main risk factor. About diagnosis and clinical features, T790M mutation was detected by liquid biopsy in 29.3% of cases, 36 patients (87.8%) had status performance 0 - 1 (ECOG) and 10 (24.4%) presented brain metastases as progression to the previous line of treatment. About outcomes, the ORR was 70.8%; with a median follow-up of 36 months, the median PFS was 15.2 months (95% IC, 9.6 - 20.7) and median OS since the start osimertinib was 16.3 months (95% IC, 7.6 - 24.9), no differences were found regarding the presence of brain metastases (p = 0.06 and p = 0.32) or type of mutation (p = 0.27 and p = 0.46) in both PFS and OS. Median OS from the start of first-line treatment was 46.6 months (95% IC, 34.5 - 58.7). As supplementary analysis, in the same period of time, 11 T790M-positive patients who did not receive osimertinib as second line of treatment achieved a median OS from the start of first-line treatment of 23.5 months (95% IC, 16.5 - 30.5). This OS was significantly lower compared to those who did receive osimertinib (p = 0.001). Conclusions: This study confirms the efficacy of osimertinib in the real world when used as a second line of treatment in T790M-positive patients, in addition the feasibility of osimertinib in this setting may significantly impact the survival.

First-line Osimertinib for Lung Cancer With Uncommon EGFR Exon 19 Mutations and EGFR Compound Mutations

IntroductionUp to 20% of EGFR-mutated NSCLC cases harbor uncommon EGFR mutations, including atypical exon 19 and compound mutations. Relatively little is known about the efficacy of osimertinib in these cases. MethodsPatients treated with first-line osimertinib for NSCLC with rare EGFR exon 19 (non E746_A750del) or compound mutations were included. Response assessment and time to progression were determined using Response Evaluation Criteria in Solid Tumors version 1.1 criteria. Kaplan-Meier analyses were used to estimate progression-free survival (PFS), time to treatment discontinuation (TTD), and overall survival (OS). ResultsThirty-seven patients with NSCLC harboring an atypical EGFR exon 19 mutation or compound mutation were treated with first-line osimertinib at Johns Hopkins from 2016 to 2021. Overall response rate (ORR) was 76% and median PFS, TTD, and OS were 13 months (95% confidence interval [CI]: 10–15), 22 months (95% CI: 17–32) and 36 months (95% CI, 29–48), respectively. Among atypical exon 19 mutations (n = 25), ORR was 80%, median PFS was 12 months (95% CI: 10–15), median TTD was 19 months (95% CI: 17–38), and median OS was 48 months (95% CI: 25–not reached). Compound mutations (n = 12) had an ORR of 67%, median PFS of 14 months (95% CI: 5–22), median TTD of 26 months (95% CI: 5–36), and median OS of 36 months (95% CI: 20–46). Twelve patients (32%) continued first-line osimertinib after local therapy for oligoprogression. ConclusionsOsimertinib exhibited favorable outcomes for rare EGFR exon 19 and compound mutations. The heterogeneity in outcomes among these groups of tumors with similar mutations underscores the need for continued reporting and further study of outcomes among rare variants to optimize management for each patient.

Patients' Preferences for Adjuvant Osimertinib in Non–Small-Cell Lung Cancer After Complete Surgical Resection: What Makes It Worth It to Patients?

BackgroundThe ADAURA trial confirmed adjuvant Osimertinib's efficacy in EGFR-mutated Non–small-cell lung cancer (NSCLC), yet the limited mature overall survival (OS) data at approval poses a challenge. This study explores patient preferences in the absence of complete OS information, hypothesizing that disease-free survival (DFS) benefit alone may influence adjuvant Osimertinib pursuit. MethodsAt Roswell Park Comprehensive Cancer Center (Jan-Dec 2021), patients assessed for adjuvant therapy received a survey probing OS and DFS preferences. Scenarios were (a) minimum OS justifying Osimertinib, (b) minimum DFS improvement justifying 3-years of adjuvant Osimertinib, (c) minimum 5-year DFS percent change, and (d) minimum OS justifying copay changes. Results were analyzed. ResultsOf 524 NSCLC patients, 51 participated. Scenario 1 saw 56% requiring a 12-month OS benefit for Osimertinib justification. In scenario 2, 72% deemed a 12-month DFS benefit sufficient. Scenario 3 revealed 31% opting out despite a 10% OS increase. Scenario 4 showed varied willingness to pay, with 33% unwilling to any shoulder copayment even with a 10-year OS benefit. ConclusionThis study explores patient preferences without complete OS data, revealing diverse thresholds. Factors include employment, education, and willingness to pay. Findings underscore shared decision-making importance. Limitations include sample size, potential biases, and regional focus; larger cohorts are needed for validation.

Osimertinib in combination with anti-angiogenesis therapy presents a promising option for osimertinib-resistant non-small cell lung cancer

BackgroundOsimertinib has become standard care for epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) patients whereas drug resistance remains inevitable. Now we recognize that the interactions between the tumor and the tumor microenvironment (TME) also account for drug resistance. Therefore, we provide a new sight into post-osimertinib management, focusing on the alteration of TME.MethodsWe conducted a retrospective study on the prognosis of different treatments after osimertinib resistance. Next, we carried out in vivo experiment to validate our findings using a humanized mouse model. Furthermore, we performed single-cell transcriptome sequencing (scRNA-seq) of tumor tissue from the above treatment groups to explore the mechanisms of TME changes.ResultsTotally 111 advanced NSCLC patients have been enrolled in the retrospective study. The median PFS was 9.84 months (95% CI 7.0–12.6 months) in the osimertinib plus anti-angiogenesis group, significantly longer than chemotherapy (P = 0.012) and osimertinib (P = 0.003). The median OS was 16.79 months (95% CI 14.97–18.61 months) in the osimertinib plus anti-angiogenesis group, significantly better than chemotherapy (P = 0.026), the chemotherapy plus osimertinib (P = 0.021), and the chemotherapy plus immunotherapy (P = 0.006).The efficacy of osimertinib plus anlotinib in the osimertinib-resistant engraft tumors (R-O+A) group was significantly more potent than the osimertinib (R-O) group (P<0.05) in vitro. The combinational therapy could significantly increase the infiltration of CD4+ T cells (P<0.05), CD25+CD4+ T cells (P<0.001), and PD-1+CD8+ T cells (P<0.05) compared to osimertinib.ScRNA-seq demonstrated that the number of CD8+ T and proliferation T cells increased, and TAM.mo was downregulated in the R-O+A group compared to the R-O group. Subtype study of T cells explained that the changes caused by combination treatment were mainly related to cytotoxic T cells. Subtype study of macrophages showed that proportion and functional changes in IL-1β.mo and CCL18.mo might be responsible for rescue osimertinib resistance by combination therapy.ConclusionsIn conclusion, osimertinib plus anlotinib could improve the prognosis of patients with a progressed disease on second-line osimertinib treatment, which may ascribe to increased T cell infiltration and TAM remodeling via VEGF-VEGFR blockage.

The impact of EGFR T790M mutation status following the development of Osimertinib resistance on the efficacy of Osimertinib in non-small cell lung cancer: A meta-analysis.

Previous studies have suggested that loss of the EGFR T790M gene mutation may contribute to the development of resistance to Osimertinib in non-small cell lung cancer (NSCLC). This study aims to assess the relationship between the clinical effectiveness of Osimertinib in NSCLC patients and the T790M mutation status following resistance to Osimertinib and examine differences between plasma and tissue tests and between Asian and non-Asian groups. The PubMed, Web of Science, Cochrane, and EMBASE databases were comprehensively searched for studies on the association between T790M mutation status and the efficacy of Osimertinib between January 2014 and November 2023. Meta-analysis was carried out using Review Manager 5.4 software. After evaluating 2727 articles, a total of 14 studies were included in the final analysis. Positive correlations between EGFR T790M mutation status after Osimertinib resistance and longer PFS (HR: 0.44, 95% CI: 0.30-0.66), longer OS (HR: 0.3, 95% CI: 0.10-0.86), longer TTD (HR: 0.69, 95% CI: 0.45-1.07), and improved clinical outcomes including PFS and TTD subgroups (HR: 0.58, 95% CI: 0.47-0.73) were observed. Subgroup analysis revealed that, compared with the blood tests, the results of the T790M mutation tests by the tissue are more significant (HR: 0.24, 95% CI: 0.11-0.52 for tissue tests; HR: 0.47, 95% CI: 0.22-1.00 for plasma tests), and the PFS of Osimertinib were similar for Asian and non-Asian patients (HR: 0.46, 95% CI: 0.31-0.68 for Asians; HR: 0.12, 95% CI: 0.01-1.27 for non-Asians). Persistence of the T790M gene mutation after the development of Osimertinib resistance is associated with higher therapeutic benefits of Osimertinib in NSCLC patients. The results of tissue detection are more significant than those of plasma detection.

Abstract 3220: Osimertinib-induced epigenetic and transcriptional reprogramming drives a BRD4-POUF-PDGFRB-YAP-EMT axis of resistance in NSCLC

Abstract Acquired resistance to Osimertinib continues to pose a major limitation to achieving durable therapeutic responses in EGFR mutant non-small cell lung cancer (NSCLC). While multiple actionable genetic mutations have been identified as the underlying molecular basis of resistance, a genomic mechanism cannot be identified in &amp;gt;50% of Osimertinib resistant tumors and thus an effective combinatorial treatment strategy cannot be deployed for these patients. Recently, we identified YAP/TEAD activation and ERK1/2 reactivation as two major non-mutational counter-regulatory pathways that diminish the efficacy of Osimertinib, promoting establishment of the drug tolerant persister (DTP) and resistant states. Moreover, it is well known that cancer cells escape tyrosine kinase inhibitor (TKI) therapy by developing dependence on alternate, non-mutated receptor tyrosine kinases (RTKs) through a treatment-induced “RTK switch” phenomenon. The link however between alternate RTK signaling and YAP/TEAD/ERK1/2 has never been explored in the context of Osimertinib resistance. In this study, we systemically uncover transcriptional de-repression of, and critical dependence on PDGFRβ as part of a novel “RTK switch” mechanism deployed by cells to evade Osimertinib-induced death. Genetic or pharmacologic co-inhibition of PDGFRβ renders NSCLC cells more sensitive to Osimertinib during drug naïve, DTP and resistant phases of treatment through suppression of ERK1/2 reactivation, YAP activity/nuclear translocation and YAP-mediated induction of EMT factors, SLUG and Zeb2. Importantly, compared to Osimertinib alone, co-targeting EGFR and PDGFRβ robustly suppresses tumor regrowth following treatment cessation both in vitro and in vivo which is consistent with a reduction in the DTP cell population. These data auspiciously demonstrate a two-fold utility of concomitant PDGFRβ inhibition: to enhance the initial efficacy of Osimertinib and to eliminate the DTP and resistant cells following chronic Osimertinib treatment. Further mechanistic studies from integration of ATAC-seq, CUT&amp;RUN and RNA-seq reveal that Osimertinib induces the dynamic cooperativity of chromatin modulator BRD4 with pluripotent POU-domain transcription factors Oct-4, Pit-1 and Brn-3 at putative proximal enhancer elements, facilitating upregulation of PDGFRβ. Collectively, we demonstrate a novel treatment-induced BRD4/POUF epigenetic/transcriptional mediated “RTK switch” that involves co-opting PDGFRβ signaling to activate YAP/TEAD and ERK1/2 as a means of driving adaptive resistance to Osimertinib. These data provide compelling rationale for combined anti-EGFR and PDGFRβ targeted therapy to improve patient outcomes. Citation Format: Antja-Voy Hartley, Caitlyn Weston, Simon Baldacci, William Feng, Mustafa Al-Dulaimi, Claudia Gentile, Matthew Booker, Michael Tolstorokuv, Cigall Kadoch, Pasi Janne. Osimertinib-induced epigenetic and transcriptional reprogramming drives a BRD4-POUF-PDGFRB-YAP-EMT axis of resistance in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3220.