EGFR-mutant Lung Cancer Research Articles

Abstract C168: Prognostic value of tumor microenvironment (TME) features in advanced, EGFR-mutant non-small cell lung cancer (NSCLC)

Abstract Background: Prognostic role of tumor microenvironment (TME) features, although well-studied in the context of immunotherapy responses, remains unclear for oncogene-driven non-small cell lung cancer (NSCLC). Here, we interrogate the impact of TME features on survival outcomes of patients with advanced EGFR-mutant NSCLC. Methods: A single-center, retrospective study was carried out on patients with advanced EGFR-mutant (exon 19 deletion/L858R) NSCLC who underwent first-line targeted therapy or chemotherapy. Clinical, radiological, molecular, pathological data were collected. Hematoxylin-eosin diagnostic tissue slides, digitalized at 20x magnification, were analyzed by an expert pathologist and a medical oncologist, blinded to clinical data, to describe TME. Tumor-infiltrating lymphocytes (TILs), excluding polymorphonucleates, were assessed in the stromal compartment as positive (+) or negative (-), with positivity threshold of 10% of stromal tissue area. Fibrosis, necrosis, tertiary lymphoid structures (TLSs) and lymphangitis were assessed with a positivity threshold of 1%. Progression free survival (PFS) and overall survival (OS) were calculated from the start of first-line therapy and compared by log-rank test. Multivariable analysis by Cox regression model for OS included age, gender, PS-ECOG, number (n) of metastatic sites, presence of brain metastases and TME features. Results: A total of 118 patients were included: 52 treated with first-line osimertinib, 47 with gefitinib/erlotinib, 19 with platinum-based chemotherapy. The patient population included 84 (71%) females, 77 (65%) never smokers. Median age was 64 years (range 34-91), median n of metastatic sites was 2, PS ECOG was <2 in 91 (77%) and brain metastases were present in 48 (41%) cases. Most common biopsy site was lung (70%). Fibrosis, TILs, lymphangitis, necrosis, TLSs were found in 76/95 (80%), 34/93 (37%), 35/95 (37%), 28/94 (30%), and 12/92 (13%) of evaluable samples, respectively. After a median follow-up of 50.3 months (m), median OS was 35.2 (95%CI 27.8-41.6) m in the overall population; 23.1 (95%CI 18.2-39.3) vs 36.3 (95%CI 32.1-51.3) m (p=0.007) in necrosis+ vs -; 27.7 (95%CI 26.6- not reached, NR) vs 35.5 (95% CI 27.8-48.5) m (p=0.85) in TILs+ vs TILs-; 38.1 (95%CI 36.6-NR) vs 32.1 (95%CI 27-44.7) m (p=0.94) in TLS+ vs TLS-. Nine (26%) TILs+ tumors were also necrosis+. Necrosis (HR 2.05, p=0.026) and PS>1 (HR 2.52, p<0.01) were independently associated with worse OS in the multivariable analysis. In necrosis+ vs -, median PFS to first-line was 11.4 (95%CI 3,6-NR) vs 11.2 (95%CI 9.3-NR) m in osimertinib (p=0.67) and 7.8 (95%CI 5.4-NR) vs 13 (95%CI 8.7-20.1) in erlotinib/gefitinib group (p=0.84). Conclusions: Necrosis emerges as a negative prognostic factor for EGFR-mutant NSCLC. The role of osimertinib in counteracting the impact of necrosis should be elucidated on a larger scale to yield more substantial data. Further analyses will be performed on patients treated with anti-angiogenic agents. Citation Format: Lodovica Zullo, Maria Rosa Ghigna, Wael Salem Zrafi, Arianna Marinello, Damien Vasseur, Maxime Frelaut, Pamela Abdayem, Marco Tagliamento, Pernelle Lavaud, Anas Gazzah, Jean-Yves Scoazec, Jordi Remon, Fabrice Barlesi, Benjamin Besse, David Planchard, Mihaela Aldea. Prognostic value of tumor microenvironment (TME) features in advanced, EGFR-mutant non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C168.

A narrative review of antibody-drug conjugates in EGFR-mutated non-small cell lung cancer.

In the past 15 years, non-small cell lung cancer (NSCLC) treatment has changed with the discovery of mutations and the development of new targeted therapies and immune checkpoint inhibitors. Epidermal growth factor receptor (EGFR) was the first mutation in NSCLC to have a drug that was FDA-approved in 2013. Osimertinib, a third-generation tyrosine kinase inhibitor, is approved as first-line therapy for advanced NSCLC and in the adjuvant setting for Stage IB-IIIA resected NSCLC. However, resistance to osimertinib is inevitably an issue, and thus patterns of resistance to EGFR-mutated NSCLC have been studied, including MET amplification, EGFR C797X-acquired mutation, human epidermal growth factor 2 (HER2) amplification, and transformation to small cell and squamous cell lung cancer. Current management for EGFR-mutated NSCLC upon progression of EGFR TKI is limited at this time to chemotherapy and radiation therapy, sometimes in combination with the continuation of osimertinib. Antibody-drug conjugates (ADCs) are made up of a monoclonal antibody linked to a cytotoxic drug and are an increasingly popular class of drug being studied in NSCLC. Trastuzumab deruxtecan has received accelerated FDA approval in HER2-mutated NSCLC. ADCs offer a possible solution to finding a new treatment that could bypass the intracellular resistance mechanism. In this review article, we summarize the mechanism of ADCs and investigational ADCs for EGFR-mutated NSCLC, which include targets to MET amplification, HER3, Trop2, and EGFR, along with other ADC targets being investigated in NSCLC, and discuss future directions that may arise with ADCs in EGFR-mutated NSCLC.

Clinical advances in EGFR-TKI combination therapy for EGFR-mutated NSCLC: a narrative review.

Mutations located in epidermal growth factor receptor (EGFR) tyrosine kinase domains have been described as the 'Achilles heel' of non-small cell lung cancer (NSCLC) and can be targeted by epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). However, the clinical benefits of EGFR-TKIs are limited, and drug resistance inevitably occurs in NSCLC patients after long-term exposure to certain drugs. EGFR-TKI combination therapies, including combined targeted therapy, radiotherapy, chemotherapy, and immunotherapy, have shown promise in addressing this issue. This literature review analyzed the rationale and controversies of clinical research related to various EGFR-TKI combination therapies. The PubMed database was searched to retrieve articles published from January 1, 2001 to April 15, 2023 using the following Medical Subject Headings (MeSH) terms: "EGFR-mutated non-small cell lung cancer" and "clinical trial". Google Scholar was also reviewed to retrieve additional articles. The search was limited to articles published in English. In this review, we summarized EGFR-TKI combination therapies, including combined targeted therapy, radiotherapy, chemotherapy, and immunotherapy, most of which have shown efficacy and safety in patients with EGFR-mutated NSCLC. A number of clinical studies with large sample sizes have analyzed the activity and toxicity of combined therapies and explored potential and well-tolerated treatment options. EGFR mutations have been detected in many NSCLC patients and can be targeted by EGFR-TKIs. However, drug resistance after long-term exposure remains a significant challenge for this type of treatment. Most clinical trials have shown that the combination of EGFR-TKIs and targeted therapy, chemotherapy, radiotherapy or immunotherapy is efficacious and safe in the treatment of EGFR-mutated NSCLC. It should be noted that in some instances, serious adverse events have led to the termination of trials. However, EGFR-TKI combination therapy is indeed an effective approach for the treatment of patients with EGFR-mutated NSCLC and deserves further development.

PP402 Correlation of plasma cytokine levels and tumor response after EGFR tyrosine kinase inhibitor treatment in advanced EGFR-mutated non-small cell lung cancer

PP402 Correlation of plasma cytokine levels and tumor response after EGFR tyrosine kinase inhibitor treatment in advanced EGFR-mutated non-small cell lung cancer

ZYZ384 suppresses the growth of EGFR-mutant non-small cell lung cancer by activating JNK/MAPK signaling pathway.

The emergency of tyrosine kinase inhibitors has remarkably enhanced the clinical outcomes of cancer therapy, especially the use of EGFR inhibitors for non-small cell lung cancer (NSCLC). However, acquired resistance is inevitable after 8-12 months treatment. New agents or treatments are urgently required to resolve this problem. In this study, we identified that compound ZYZ384 can selectively inhibit the growth of gefitinib-resistant (G-R) lung cancer cells, without affecting that of normal lung epithelial cells. ZYZ384 induced G2 arrest in G-R NSCLC cells, decreasing the expression of Cyclin B1 and increasing the expression of P21. Meanwhile, ZYZ384 also induced apoptosis in NSCLC cells and correspondingly increased the expression of cleaved Caspase 3, 8, and 9 proteins. The expression of p-JNK, p-P38, and p-ERK were also increased in H1975 NSCLC cells treated with ZYZ384. Finally, we observed that the JNK inhibitor effectively reversed the pro-apoptotic effect of ZYZ384. In conclusion, ZYZ384 is a potential therapeutic agent to inhibit the growth of NSCLCs with EGFR mutations through activating JNK, which will help the development of related anticancer drugs.

Real-World Efficacy and Safety of Amivantamab for EGFR-Mutant NSCLC

IntroductionAmivantamab-vmjw (amivantamab) is a bispecific EGFR/MET antibody approved for patients with advanced NSCLC with EGFR exon 20 insertion mutations, after prior therapy. Nevertheless, the benefits and safety of amivantamab in other EGFR-mutant lung cancer, with or without osimertinib, and with concurrent radiation therapy, are less known. MethodsWe queried the MD Anderson Lung Cancer GEMINI, Fred Hutchinson Cancer Research Center, University of California Davis Comprehensive Cancer Center, and Stanford Cancer Center’s database for patients with EGFR-mutant NSCLC treated with amivantamab, not on a clinical trial. The data analyzed included initial response, duration of treatment, and concomitant radiation safety in overall population and prespecified subgroups. ResultsA total of 61 patients received amivantamab. Median age was 65 (31–81) years old; 72.1% were female; and 77% were patients with never smoking history. Median number of prior lines of therapies was four. On the basis of tumor’s EGFR mutation, 39 patients were in the classical mutation cohort, 15 patients in the exon 20 cohort, and seven patients in the atypical cohort. There were 37 patients (58.7%) who received amivantamab concomitantly with osimertinib and 25 patients (39.1%) who received concomitant radiation. Furthermore, 54 patients were assessable for response in the overall population; 19 patients (45.2%) had clinical response and disease control rate (DCR) was 64.3%. In the classical mutation cohort of the 33 assessable patients, 12 (36.4%) had clinical response and DCR was 48.5%. In the atypical mutation cohort, six of the seven patients (85.7%) had clinical response and DCR was 100%. Of the 13 assessable patients in the exon 20 cohort, five patients (35.7%) had clinical response and DCR was 64.3%. Adverse events reported with amivantamab use were similar as previously described in product labeling. No additional toxicities were noted when amivantamab was given with radiation with or without osimertinib. ConclusionsOur real-world multicenter analysis revealed that amivantamab is a potentially effective treatment option for patients with EGFR mutations outside of exon 20 insertion mutations. The combination of osimertinib with amivantamab is safe and feasible. Radiation therapy also seems safe when administered sequentially or concurrently with amivantamab.

Resistance to osimertinib in advanced EGFR-mutated NSCLC: a prospective study of molecular genotyping on tissue and liquid biopsies.

Resistance to osimertinib in advanced EGFR-mutated non-small cell lung cancer (NSCLC) constitutes a significant challenge for clinicians either in terms of molecular diagnosis and subsequent therapeutic implications. This is a prospective single-centre study with the primary objective of characterising resistance mechanisms to osimertinib in advanced EGFR-mutated NSCLC patients treated both in first- and in second-line. Next-Generation Sequencing analysis was conducted on paired tissue biopsies and plasma samples. A concordance analysis between tissue and plasma was performed. Sixty-five advanced EGFR-mutated NSCLC patients treated with osimertinib in first- (n = 56) or in second-line (n = 9) were included. We managed to perform tissue and liquid biopsies in 65.5% and 89.7% of patients who experienced osimertinib progression, respectively. Acquired resistance mechanisms were identified in 80% of 25 patients with post-progression samples, with MET amplification (n = 8), EGFR C797S (n = 3), and SCLC transformation (n = 2) the most frequently identified. The mean concordance rates between tissue and plasma for the EGFR activating mutation and for the molecular resistance mechanisms were 87.5% and 22.7%, respectively. Resistance to osimertinib demonstrated to be highly heterogeneous, with MET amplification the main mechanism. Plasma genotyping is a relevant complementary tool which might integrate tissue analysis for the study of resistance mechanisms.

Abstract 12757: Osimertinib-Associated Cardiotoxicity: Insights Into Echocardiographic Changes and Patients at Increased Risk

Introduction: Osimertinib is a third-generation epidermal growth factor (EGFR) tyrosine kinase inhibitor used in the treatment of EGFR-mutant non-small cell lung cancer (NSCLC). While osimertinib has known cardiotoxicity risks, there is a paucity of detailed transthoracic echocardiographic (TTE) changes and known predictors. Hypothesis: Osimertinib is associated with TTE changes other than reduced EF in patients with NSCLC; further, those with pre-existing cardiac risk factors may be at increased risk of cardiotoxicity. Methods: Single-center retrospective analysis of patients with NSCLC with available TTEs after starting osimertinib between 2007-2022. Cardiac event (any grade ≥2 cardiac common terminology criteria for adverse events [CTCAE]) cumulative incidence was estimated and Fine and Gray regressions performed (adjusting for non-cardiac death as a competing risk). Results: In total, 85 patients were included (mean age was 68 years, 67% female). Median interval between osimertinib initiation and first follow-up TTE was 17.6 months. After a median follow-up of 35 months, 17 patients developed grade ≥2 CTCAE (2-year cumulative incidence, 19.2%; 95% confidence interval [CI]: 11%-29%). These CTCAEs include QTc prolongation (n = 10), EF decline of ≤50% or ≥10% drop from baseline (n = 5), new valvular regurgitation/stenosis on imaging (n = 5), and supraventricular arrhythmia (n = 3). A pre-treatment TTE was available for 38 patients prior to osimertinib initiation. Comparing post- vs pre-osimertinib TTEs, there was significant LVEF decline (58 ± 11% vs 61 ± 8%), increased diastolic dysfunction (40% vs 32%, mitral regurgitation (49% vs 24%), and tricuspid regurgitation (45% vs 24%), all p <0.01. On multivariable analysis, preexisting arrhythmias (hazard ratio [HR] 3.90; 95% CI 1.11-1.13; p = 0.034) and BMI (HR 1.07, 95% CI 1.00-1.14; p = 0.04) were associated with an increased risk of cardiac events. Conclusions: Osimertinib was associated with a nearly 20% 2-year cumulative incidence of cardiac events and multiple echocardiographic changes. BMI is a potential modifiable risk factor to mitigate Osimertinib-associated cardiac events. These findings highlight the need for close surveillance in these higher cardiac-risk patients with NSCLC.

Brief Report: Droplet Digital Polymerase Chain Reaction Versus Plasma Next-Generation Sequencing in Detecting Clearance of Plasma EGFR Mutations and Carcinoembryonic Antigen Levels as a Surrogate Measure

IntroductionTo compare the performance of droplet digital polymerase chain reaction (ddPCR) and plasma next-generation sequencing (NGS) in detecting clearance of plasma EGFR (pEGFR) mutations. MethodsPatients with treatment-naive advanced EGFR-mutated lung cancer treated with first-line tyrosine kinase inhibitors (TKIs) were included. pEGFR were measured at baseline and first response assessment using ddPCR and NGS. Clearance of pEGFR was defined as undetectable levels after a positive baseline result. Results were correlated with time-to-treatment failure (TTF). In exploratory analysis, corresponding change in carcinoembryonic antigen (CEA) levels was evaluated. ResultsBetween January 1, 2020, and December 31, 2021, 27 patients were recruited. Ex19del comprised 74% (20 of 27) and L858R 26% (seven of 27). Osimertinib was used in 59% (16 of 27), dacomitinib 4% (one of 27), and gefitinib/erlotinib 37% (10 of 27). Sensitivity of ddPCR and NGS in detecting pEGFR mutation at baseline was 70% (19 of 27) and 78% (21 of 27), respectively (p = 0.16). All patients with detectable pEGFR by ddPCR were detected by NGS.At a median of 8 (range 3–24) weeks post-TKI initiation, clearance of pEGFR was achieved in 68% (13 of 19) and 71% (15 of 21) using ddPCR and NGS, respectively. Concordance between ddPCR and NGS was 79% (kappa = 0.513, p = 0.013). Clearance of pEGFR was associated with longer median TTF (not reached versus 6 months, p = 0.03) and median decrease in CEA levels by 70% from baseline.In another cohort of 124 patients, decrease in CEA levels by greater than 70% within 90 days of TKI initiation was associated with doubling of both TTF and overall survival. ConclusionsPlasma NGS trended toward higher sensitivity than ddPCR in detecting pEGFR, although both had similar concordance in detecting pEGFR clearance. Our results support using NGS at diagnosis and interchangeability of NGS and ddPCR for monitoring, whereas CEA could be explored as a surrogate for pEGFR clearance.

579P Real-world study of dacomitinib as first-line treatment for patients with EGFR-mutant non-small cell lung cancer

579P Real-world study of dacomitinib as first-line treatment for patients with EGFR-mutant non-small cell lung cancer

576P Clonality of both EGFR and co-occurring TP53 mutations affect the treatment efficacy of the third-generation EGFR-TKIs in advanced-stage EGFR-mutant non-small cell lung cancer

576P Clonality of both EGFR and co-occurring TP53 mutations affect the treatment efficacy of the third-generation EGFR-TKIs in advanced-stage EGFR-mutant non-small cell lung cancer

582P Furmonertinib treatment in patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastases: A real-world study

582P Furmonertinib treatment in patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastases: A real-world study

MO35-1 Prognostic evolution of EGFR-mutated non-small cell lung cancer over the past 20 years since the beginning with gefitinib

MO35-1 Prognostic evolution of EGFR-mutated non-small cell lung cancer over the past 20 years since the beginning with gefitinib

Osimertinib versus comparator first-generation epidermal growth factor receptor tyrosine kinase inhibitors as first-line treatment in patients with advanced EGFR-mutated non-small cell lung cancer: a Chinese, multicenter, real-world cohort study

Osimertinib versus comparator first-generation epidermal growth factor receptor tyrosine kinase inhibitors as first-line treatment in patients with advanced EGFR-mutated non-small cell lung cancer: a Chinese, multicenter, real-world cohort study

491P Furmonertinib as adjuvant therapy for elderly patients in resected EGFR-mutated non-small cell lung cancer: A double-center, real-world experience

491P Furmonertinib as adjuvant therapy for elderly patients in resected EGFR-mutated non-small cell lung cancer: A double-center, real-world experience

EGFR-Mutant NSCLC: Chemo-TKI Bests TKI Alone.

Findings from FLAURA2, a phase III trial, show that adding chemotherapy to osimertinib, the preferred standard of care for patients with EGFR-mutant non-small cell lung cancer, significantly boosts progression-free survival. Serious side effects are also more likely with the combination, though, so patients should weigh the risk-benefit ratio.

561P Mechanisms of osimertinib resistance using circulating tumor DNA analyses for EGFR-mutated non-small cell lung cancer, results from ELUCIDATOR: A prospective observational multicenter study

561P Mechanisms of osimertinib resistance using circulating tumor DNA analyses for EGFR-mutated non-small cell lung cancer, results from ELUCIDATOR: A prospective observational multicenter study

ME11 How to overcome and circumvent acquired resistance to osimertinib or lazertinib in advanced EGFR mutant lung cancer?

ME11 How to overcome and circumvent acquired resistance to osimertinib or lazertinib in advanced EGFR mutant lung cancer?

447P Quality of life in patients with EGFR-mutated lung cancer receiving gefitinib vs gefitinib plus pemetrexed and carboplatin chemotherapy

447P Quality of life in patients with EGFR-mutated lung cancer receiving gefitinib vs gefitinib plus pemetrexed and carboplatin chemotherapy

P2.05-07 Roles of p53 and AXL Expressions on the Efficacy of ICI-Based Therapy in Patients with EGFR Mutated Lung Cancer after Osimertinib

P2.05-07 Roles of p53 and AXL Expressions on the Efficacy of ICI-Based Therapy in Patients with EGFR Mutated Lung Cancer after Osimertinib