Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Research Articles

The association between osimertinib and nutritional deficiency among patients with non-small cell lung cancer.

8031 Background: Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), is the standard-of-care in EGFR mutation-positive non-small-cell lung cancer (NSCLC) in various settings. Osimertinib commonly causes gastrointestinal adverse effects thereby potentially leading to nutritional deficiencies. Therefore, we aim to evaluate the association between the use of osimertinib and nutritional deficiencies among patients with NSCLC. Methods: We performed a retrospective, propensity score matched study using the TriNetX database, a network comprising deidentified data across more than 120 participating healthcare institutions. We included patients with NSCLC who received either osimertinib or other EGFR-TKIs (afatinib, dacomitinib, erlotinib, gefitinib). The outcomes of interest included vitamin B deficiency, vitamin D deficiency, iron deficiency as well as associated anemia including vitamin B12 deficiency anemia, folate deficiency anemia, and iron deficiency anemia within 5 years of EGFR-TKI initiation. Results: We matched 4264 patients who received osimertinib to patients who received other EGFR-TKIs. In Cox proportional hazard analysis, osimertinib was associated with a 50% higher risk of vitamin B deficiency (Hazard ratio, 1.52 [95% CI: 1.07-2.16]) compared to other EGFR-TKIs. Consistent with this observation, osimertinib was associated with an increased risk of vitamin B12 deficiency anemia and a tendency towards folate deficiency anemia. We also noted a 2-fold higher risk of vitamin D and 5-fold higher risk of iron deficiency in the osimertinib cohort. Consistent with this observation, osimertinib was associated with an increased risk of iron deficiency anemia compared to other EGFR-TKIs. Conclusions: The use of osimertinib is associated with a higher risk of nutritional deficiencies and associated anemias compared to other EGFR-TKIs. One potential explanation is the extended duration of osimertinib therapy, driven by its potent anti-cancer effects. Therefore, it is advisable to consider screening for specific nutritional deficiencies in individuals receiving osimertinib therapy. [Table: see text]

Dermatologic adverse events in EGFR-TKIs: A real-world analysis.

e20572 Background: Dermatologic adverse events (DAEs) affect a significant number of patients with non-small cell lung cancer (NSCLC) who are treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). While many DAEs have been identified during clinical trials and included in FDA drug labels, patients have raised concerns about experiencing unexpected DAEs. This study reviews the FDA Adverse Events Reporting System (FAERS) to identify DAEs in EGFR TKIs approved in NSCLC that are not included in drug labels. Methods: FAERS was queried for DAEs between 2003 – 2023 for osimertinib, afatinib, ertlotinib, gefitinib and mobocertinib. The reporting odds ratio (ROR) was calculated to compare DAEs between these EGFR-TKIs and all other drugs in the database. DAEs were considered statistically significant if the lower limit of the ROR 95% confidence interval (CI) was > 1 and if there were ≥ 3 reported adverse reactions. Results: 67,480 adverse events were reported for the 5 EGFR-TKIs studied. DAEs constituted 30.3% (20,426) of all adverse event reports. We identified skin (skin fissures, eczema, lip swelling, and skin infection), nail (onychalgia and onychomadesis), and hair (abnormal hair growth and hair disorder) DAEs not previously included in EGFR-TKI drug labels. RORs with 95% CIs are summarized in the table. Conclusions: Real-world FAERS data complements clinical trial data in identifying specific DAEs affecting NSCLC patients treated with EGFR TKIs. Our findings highlight DAEs that were previously not described, aiding clinicians in educating patients about side effects and giving patients a more nuanced understanding of what to expect before undergoing treatment. [Table: see text]

EGFR-TKI as neoadjuvant treatment in patients with NSCLC with EGFR sensitive mutation: A retrospective real-world analysis.

8081 Background: This study aimed to evaluate the efficacy and outcome of Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) as preoperative neoadjuvant treatment in patients with NSCLC and EGFR sensitive mutation. Methods: A retrospective analysis was conducted. Patients with resectable stage I-III NSCLCs and received neoadjuvant treatment with any generation of EGFR-TKI before surgical resection were enrolled. The primary endpoint were major pathological response (MPR) and objective response rate (ORR), the second endpoints included diseases down staging, surgical outcomes, disease-free survival (DFS) and overall survival (OS). Results: A total of 58 patients were enrolled. Female accounted for 62.1% and most of them (77.6%) were never-smoker. Forty-five (77.6%) patients received the first generation of EGFR-TKI and 11 received the third. The median duration of EGFR-TKI before surgery was 3.6 months (0.7-19.5m). Nine (15.5%) patients achieved MPR and one patient (1.71%) achieved pathological complete response (pCR). The ORR was 60.3% (35/58) according to RECIST v1.1. Eighteen patients achieved TNM downstaging with T downstaging occurred in 44.8% of patients and N downstaging was about 32.8%. Majority of patients (96.6%) underwent thoracoscopic surgery and the rate of R0 resection was 82.8% (48/58). The DFS and OS of the whole cohort was 25.7months and not reached respectively. Patients with MPR had statistically improved outcomes than those without. What noticeable was that patients with tumor regression grade 3 (13/58) (residual viable tumor cells counts for 10% to 50%) also demonstrated a significant benefit from EGFR-TKI preoperative treatment than those with TRG4 or 5 (residual viable tumor cells>50%) (p = 0.01). We define patients with TRG1 to TRG3 as deep pathological regression (DPR) and the rest as non-DPR, and the DPR cohort showed significantly prolonged DFS than those with non-DPR (median DFS, 60.9 vs 16.7 months; HR, 0.29 (95%CI: 0.11-0.74), p = 0.006), the data of OS was not mature. Subgroup analysis validated DPR was an independent predictive factor for DFS. Conclusions: EGFR-TKI as neoadjuvant therapy had good effect on tumor pathological regression and disease downstaging, DPR patients were more likely to achieve long-term disease-free survival. Patients with NDPR should be closely followed up and appropriate adjuvant therapy was necessary after surgery due to the high risk of reccurence.

IGF-1R, E-cadherin, N-cadherin, and occludin gene expression and resistance to EGFR tyrosine-kinase inhibitors in patients with lung adenocarcinoma in Serbia.

8524 Background: Mutations in epidermal growth factor-receptor ( EGFR) are found in approximately 10% of patients with lung adenocarcinoma in Serbia. EGFR tyrosine-kinase inhibitors ( EGFR-TKIs) is a safe and effective targeted therapy. However, most patients develop resistance. Acquired resistance to EGFR-TKI is defined as disease progression after achieving response or stable disease and there is a possible molecular association with epithelial-mesenchymal transition (EMT), particularly N-cadherin, E-cadherin, occludin and insulin-like growth factor-1 receptor (IGF-1R). We assessed the gene expression levels of IGF-1R, E-cadherin, N-cadherin, and occludin as predictive factors of resistance to EGFR-TKIs and survival outcomes in patients with advanced EGFR mutation-positive lung adenocarcinoma in Serbia. Methods: 101 patients with stage IIIB/IV EGFR mutation positive lung adenocarcinoma treated with EGFR-TKIs were included in the study. Quantitative RT-PCR was performed to determine mutations in EGFR, and expression of N-cadherin, E-cadherin, occludin and IGF-1R. Kaplan-Meier method was employed to estimate overall-survival (OS) and progression-free survival (PFS), with significance set at p<0.05. Results: Median age of patients was 61.7 (39 - 81) years, 65.3% were females and 91% were diagnosed with metastatic lung adenocarcinoma. EGFR mutations were more frequently detected in females (p <0.001). Median overall survival (OS) was 21 months (15.2–26.7 CI 95%) and progression-free survival (PFS) was 10 months (7.4-12.5 CI 95%). Patients whose tumors had lower levels of IGF-1R, and N-cadherin expression had statistically significantly longer PFS (p <0.001). Patients with lower levels of IGF-1R and higher levels of E-cadherin gene expression were more likely to have a complete or partial response to therapy (p = 0.04). There was a statistically significant association between elevated IGF-1R expression and the occurrence of EGFR-TKI resistance in patients (p <0.001). There was a statistically significant association between increased N-cadherin expression and reduced E-cadherin expression with EGFR-TKI resistance in patients. Conclusions: The hallmark of EMT is the upregulation of N-cadherin followed by the downregulation of E-cadherin. In this group of patients, higher levels of IGF-1R and N-cadherin gene expression were associated with shorter PFS and resistance to EGFR TKI, compared to higher levels of expression of E-cadherin, which may indicate potential value of expression of these genes in predicting acquired resistance to EGFR-TKI. Therefore, more research is needed to prove the potential predictive value of E-cadherin, N-cadherin and IFG-1R in acquired resistance to EGFR-TKI and developing novel therapeutic options with anti-EMT properties that can overcome this problem.

Genomic profiling of non-small cell lung cancer with rare aberrations in EGFR codon L858 and the survival outcome under real-world first-line EGFR tyrosine kinase inhibitor treatment compared to classic EGFRL858R.

8596 Background: Rare genomic aberrations in EGFR codon L858 causing L858R (rare EGFRL858R) or non-L858R mutations have been reported, besides the predominant c.2573T>G genomic mutation leading to classic EGFRL858R. However, molecular features, survival benefit under EGFR tyrosine kinase inhibitors (TKIs), and resistance mechanisms of these rare mutations lack comprehensive investigation in non-small cell lung cancer (NSCLC). Methods: We retrospectively included 489 NSCLCs with treatment-naive tumor tissues/plasma biopsies harboring rare EGFRL858R (N=124), EGFRL858Q/M (N=17), or classic EGFRL858R mutations (N=348). Mutational landscapes, tumor mutation burden (TMB), and chromosome instability (CIN) scores, were investigated using tissue samples subject to a targeted next-generation sequencing panel covering 437 cancer-related genes. Advanced NSCLCs receiving EGFR TKIs as first-line therapy were sub-grouped to study survival benefit and resistance mechanisms. Results: NSCLCs with rare EGFRL858R had less-frequently mutated TP53 (59% vs. 72%, P=0.04) and lower CIN scores (0.29 vs. 0.23, P=0.02) than those with classic EGFRL858R, while age, sex, stage at diagnosis, histology subtype, and TMB were comparable. We also detected the cooccurrence of EGFRL858Q/M with EGFRL861Q ( P<0.01), particularly in patients carrying EGFRL858M (100%). Compared to 233 advanced NSCLCs harboring classic EGFRL858R, 58 patients with rare EGFRL858R exhibited superior first-line progression-free survival (PFS) [median: 13.0 vs. 10.0 months, hazard ratio (HR): 0. 57, 95% confidence interval (CI): 0.41–0.80], with a similar association observed in approximately 80% of included patients who received first-generation EGFR TKIs (median: 12.0 vs. 10.0 months, HR: 0.64, 95% CI: 0.45–0.92). After controlling for age, sex, histological subtype, EGFR TKI category, and anti-vascular therapy, rare EGFRL858R remained associated with improved PFS (adjusted HR: 0.55, 95% CI: 0.39–0.77). Patients with EGFRL858Q/M also had better PFS than those with classic EGFRL858R (adjusted HR: 0.26, 95% CI: 0.10–0.67). Of note, NSCLCs with combined EGFRL858M and EGFRL861Q appeared to have lower progression risks when receiving afatinib than using gefitinib/icotinib as first-line therapy. Furthermore, matched samples at baseline and progression revealed similar resistance mechanisms between NSCLCs with rare and classic EGFRL858R. Conclusions: NSCLCs carrying rare genomic aberrations in EGFR codon L858 were likely to get more survival benefits from first-line EGFR TKI treatment than those with classic EGFRL858R, giving scientific evidence supporting the clinical application of EGFR TKIs in these patients.

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 .

A Visual Analysis of the Research Dynamics in Resistance to EGFR Inhibitors for NSCLC.

Activating mutations in epidermal growth factor receptor (EGFR) have been identified as key predictive biomarkers for the customized treatment with EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC), aiding in improving patient response rates and survival. However, resistance challenges the efficacy of these treatments, with limited understanding of post-resistance therapeutic strategies. A deep understanding of the biology and resistance mechanisms of EGFR-mutant NSCLC is crucial for developing new treatment approaches. This study, through bibliometric analysis, summarizes the trends in research on resistance to EGFR-TKIs. Research papers on NSCLC with EGFR inhibitor resistance were collected from the Web of Science Core Collection (WoSCC). The analysis utilized bibliometric tools like CiteSpace, VOSviewer, and other platforms for comprehensive analysis and visualization of the outcomes. The WoSCC database contains a total of 5866 documents on resistance to EGFR-TKIs treatment, including 4727 articles (93.48%) and 1139 reviews (6.52%), spanning 81 countries and regions, 4792 institutions, with the involvement of 23,594 authors. Since 2016, there has been a significant increase in publications in this field. China has the highest publication output, while the United States has the highest citation count for papers. Harvard University leads in terms of the number of publications. Among the top ten journals with the highest output, Clinical Cancer Research has the highest impact factor at 11.5, with 90% of the journals classified in Q1 or Q2. Rafael Rosell is one of the most influential authors in this field, ranking second in publication volume and fourth in citation count. Research on EGFR-TKIs resistance mainly focuses on genetic testing, resistance mechanisms, and post-resistance treatment strategies. This study provides researchers with a reliable basis and guidance for finding authoritative references, understanding research trends, and exploring potential directions.

Phase 1/2 clinical trial of JIN-A02, a 4th generation EGFR-TKI, in patients with 3rd generation EGFR-TKI resistance in EGFR mutated advanced/metastatic non-small cell lung cancer (NSCLC).

TPS8658 Background: Epidermal growth factor receptor (EGFR) mutations are the most common driver mutations in NSCLC. EGFR tyrosine kinase inhibitors (TKIs) are the recommended front-line option for EGFR-mutant advanced NSCLC patients, but patients invariably develop acquired resistance and face disease progression. JIN-A02, a 4th generation EGFR-TKI intended for oral administration, selectively and reversibly binds to EGFR mutations, including the C797S and/or T790M mutation that causes resistance to 3rd generation of EGFR-TKIs. Pre-clinical studies with EGFR C797S and/or T790M mutated cell lines showed that JIN-A02 can inhibit cell growth in a dose dependent manner and has a high degree of selectivity over wild-type EGFR. In vivo studies showed that administration of JIN-A02 dose-dependently inhibited tumor growth in the C797S+ xenograft mice model. Moreover, JIN-A02 shown to penetrate blood-brain barrier and exhibit anti-tumor activity in an intracranial tumor model. The strong potency and high selectivity of JIN-A02 for mutant EGFR may offer improved therapeutic window in the clinical setting vs available EGFR-TKIs. Methods: JIN-A02 is being evaluated in this Phase 1/2, multicenter, an open-label trial (NCT05394831) for subjects with advanced NSCLC harboring C797S and/or T790M mutation as a monotherapy. The primary object of this study is to assess safety, tolerability, pharmacokinetics, and anti-tumor effect for determining the recommended phase 2 dose (RP2D) of JIN-A02. The inclusion criteria are that the subject (≥ 18 years) must have an advanced or metastatic NSCLC showed progress disease (PD) after receiving approved standard EGFR-TKI therapies and/or platinum-based anticancer chemotherapy is allowed up to 1 time after using EGFR-TKI treatment with ECOG status 0 or 1. Before enrollment in the study, the EGFR mutation status is determined using either tumor tissue and/or plasma ctDNA. This study comprises three parts, dose escalation (Part A), dose exploration (Part B), and dose expansion (Part C). In Part A, dose escalation, comprised of 5 cohorts ranged from a starting dose of 12.5 mg P.O, QD to a top dose of 150 mg P.O, QD with every three subjects, is carried out where the maximum tolerated dose (MTD) is evaluated in subjects with 28-day cycles. Dose-limiting toxicities (DLT) are evaluated for 21 days. In Part B, dose exploration is carried out to evaluate the safety of JIN-A02 further and to determine the RP2D using 2 preliminary effective dose levels from Part A in subjects. In Part C dose-expansion study, subjects (n=36 for each cohort) are divided into 5 different cohorts based on the EGFR mutation (both or single positive of C797S and T790M), and the anti-tumor activity of JIN-A02 is evaluated according to RECIST v1.1 at RP2D. Clinical trial information: NCT05394831 .

REZILIENT2: Phase 2 study of zipalertinib in patients with advanced non-small cell lung cancer (NSCLC) with exon 20 insertions (ex20ins) and other uncommon epidermal growth factor receptor (EGFR) mutations.

TPS8670 Background: Patients with NSCLC harboring uncommon EGFR mutations, including ex20ins, have limited treatment options. Zipalertinib (CLN-081/TAS6417) is an oral tyrosine kinase inhibitor of EGFR with broad activity against EGFRmutations (including ex20ins) and increased selectivity for ex20ins versus wild-type EGFR. Zipalertinib has shown preclinical activity against a wide spectrum of EGFR ex20ins mutations and other uncommon EGFR mutations. In a phase 1/2a study (REZILIENT1), encouraging antitumor activity and an acceptable safety profile were observed in heavily pretreated patients with EGFRex20ins–mutant NSCLC, leading to ‘Breakthrough Therapy’ designation from the U.S. Food and Drug Administration. The aim of REZILIENT2 is to evaluate the efficacy and safety of zipalertinib in patients with NSCLC harboring EGFRex20ins and other uncommon single or compound EGFR mutations, including patients with brain metastases and leptomeningeal disease (LMD). Methods: In this global, phase 2b, open-label, multicohort study (NCT05967689), adult patients with locally advanced or metastatic NSCLC will be assigned to one of four cohorts depending on prior treatment and type of EGFR mutation: A) patients with EGFR ex20ins mutations who have progressed on or after first-line platinum-based chemotherapy and prior therapy targeting ex20ins (administered together or separately) for advanced disease; B) patients with EGFR ex20ins mutations who have not received prior treatment for advanced disease; C) patients with ex20ins or other uncommon single or compound EGFR mutations and active central nervous system metastases (including LMD) who may or may not have received prior treatment for advanced disease; and D) patients harboring other uncommon non-ex20ins single or compound EGFR mutations who have progressed on or after standard systemic therapy. Patients will receive zipalertinib at a starting dose of 100 mg orally twice daily, which will continue on a 21-day cycle until progression, unacceptable toxicity, or other discontinuation criteria are met. The primary endpoint is investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumours, version 1.1. Secondary endpoints include disease control rate, duration of response, progression-free survival, overall survival, intracranial efficacy per Response Assessment in Neuro-Oncology Brain Metastases (cohort C), safety and tolerability, and pharmacokinetics. Estimated enrollment is 40 patients per cohort (total 160), with potential expansion to ~100 patients per cohort if predefined threshold criteria of efficacy are met. Enrollment began in July 2023. Clinical trial information: NCT05967689 .

First-line treatment of EGFR mutation adenosquamous carcinoma of the lung with aumolertinib: A multicenter, single-arm, prospective study (ARISE Study).

e20541 Background: Adenosquamous carcinoma of the lung (ASC), which composed of squamous cell carcinoma and adenocarcinoma, is a rare lung cancer. In Asian population, the mutation rate of epidermal growth factor receptor (EGFR) in ASC is approximately 15.4% to 44%. There were no large prospective clinical studies using EGFR tyrosine kinase inhibitors (TKI) to treat ASC. Methods: We conducted a prospective, multicenter, single-arm clinical trial, designed to evaluate the efficacy and safety of Aumolertinib for ASC patients with EGFR mutations without prior systemic therapy (originally designed as a randomized controlled study versus chemotherapy; the protocol was revised to single-arm study due to insufficient enrollment; Clinical Trial Registry No. NCT04354961). Eligible participants of stage IIIB/IV ASC with EGFR mutations from six Chinese medical centers received Aumolertinib 110mg orally once daily. Follow-up were performed every 6 weeks conducted by independent central review (ICR), based on the RECIST 1.1 criteria. Primary endpoints was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. Results: Of the 18 patients recruited, 12 were evaluated for efficacy and safety. The median follow-up was 13.3 months, with 17 (range 4-26) doses of Aumolertinib treatment. The median PFS was 6.2 months (95% CI 5.0-8.2), while the median OS has not been reached. Of the 12 patients, 7 (58.3%) achieved PR, 3 (25.0%) achieved SD, and 2 (16.7%) were PD. The ICR-confirmed ORR and DCR were 58.3% (95% CI: 62.6%-74.6%) and 83.3% (95% CI: 89.6%-96.2%), respectively. A total of 9 patients (75%) experienced at least one treatment-related adverse events (TRAEs). the most common TRAEs were anemia (27.3%) and elevated aminotransferase (18.2%). three patients (25%) experienced grade 3-4 TRAEs in the form of paralysis, neutropenia and hypokalemia. No treatment-related deaths occurred. Conclusions: This is the first prospective clinical study showing that Aumolertinib is an effective and well-tolerated third-generation EGFR TKI for ASC with EGFR mutations, with favorable ORR and general PFS. In future, head-to-head comparisons of EGFR TKI with chemotherapy and combination therapy would be needed to be explored. Clinical trial information: NCT04354961 .

Identification of a patient tissue-based phosphorylation site as a biomarker for epidermal growth factor receptor (EGFR) activity in non-small cell lung cancer.

3143 Background: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths globally. EGFR tyrosine kinase inhibitors (TKIs) have shown promise in treating NSCLC, yet resistance to these agents is common and current biomarkers rely on genetic data alone. Therefore, identifying reliable biomarkers to more comprehensively monitor EGFR activity and predict therapeutic responses is paramount. Here, we report an uncharacterized threonine phosphorylation site within core regulator of the EGFR pathway SHP2, that is strongly predictive of EGFR activity as defined by genetic mutation status that shows potential as a clinically relevant biomarker. Methods: Using DIA mass spectrometry phosphoproteomics, we could quantify >20,000 phosphosites from patient normal adjacent tumor (NAT) and primary tumor tissue. We further characterized these tissues using whole genome sequencing allowing us to define the mutational status of the EGFR. Statistical analysis was undertaken across all phospho-sites that identified a single uncharacterized phospho-site as a strong predictor of EGFR kinase activity. Finally, we generated monoclonal antibodies against the phospho-peptide and tested these in patient FFPE primary tumor tissue using immunohistochemistry to correlate phosphorylation levels with EGFR activation status. Results: Our results highlight how an individual phosphosite on SHP2 closely correlates with EGFR activity as defined by genetic mutation status in patient tissue. Interestingly, we further identify a group of patients who carry wild type EGFR yet have a phospho-signal potentially indicative of high EGFR activation without genetic aberration. These results were corroborated by a phospho-site specific antibody in FFPE tissue IHC, with strong signals observed in patients with an activating EGFR mutation (n=5), and complete absence of signal in patients harboring a wild type EGFR and no detectable mass spec signal (n=5). Conclusions: Our findings suggest that this uncharacterised SHP2 phosphosite may serve as a potent biomarker for EGFR activity in NSCLC. Further validation of the monoclonal antibodies as tools for this clinically relevant biomarker is required in larger patient cohorts to elucidate the role of the phosphosite in therapy response. This novel biomarker has the potential to guide therapeutic decision-making and contribute to personalized medicine strategies for NSCLC patients.

Cancer mutational signatures identification in clinical assays using neural embedding-based representations

While mutational signatures provide a plethora of prognostic and therapeutic insights, their application in clinical-setting, targeted gene panels is extremely limited. We develop a mutational representation model (which learns and embeds specific mutation signature connections) that enables prediction of dominant signatures with only a few mutations. We predict the dominant signatures across more than 60,000 tumors with gene panels, delineating their landscape across different cancers. Dominant signature predictions in gene panels are of clinical importance. These included UV, tobacco, and apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) signatures that are associated with better survival, independently from mutational burden. Further analyses reveal gene and mutation associations with signatures, such as SBS5 with TP53 and APOBEC with FGFR3S249C. In a clinical use case, APOBEC signature is a robust and specific predictor for resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Our model provides an easy-to-use way to detect signatures in clinical setting assays with many possible clinical implications for an unprecedented number of cancer patients.

Influence of TP53 mutation on efficacy and survival in advanced EGFR-mutant non-small cell lung cancer patients treated with third-generation EGFR tyrosine kinase inhibitors.

TP53 comutation is related to poor prognosis of non-small cell lung cancer. However, there is limited study focusing on the structural influence of TP53 mutation on third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. We retrospectively analyzed the clinical and molecular data of patients treated with third-generation EGFR-TKIs in two independent cohorts. A total of 117 patients from the Sun Yat-sen University Cancer Center (SYSUCC) and 141 patients from the American Association for Cancer Research Project GENIE database were included. In the SYSUCC cohort, TP53 comutations were found in 59 patients (50.4%) and were associated with poor median progress-free survival (mPFS) and median overall survival (mOS). The additional subtype analysis found that TP53 mutation in the alpha-helix region had shorter mOS compared with those with TP53 mutations in other regions in the SYSUCC cohort (mOS, 12.2 vs. 21.7 months; p=0.027). Similar findings were confirmed in the GENIE cohort. Specifically, the presence of TP53 mutation in the alpha-helix region was an independent negative predictive factor for PFS [hazard ratio (HR) 2.05(1.01-4.18), p=0.048] and OS [HR 3.62(1.60-8.17), p=0.002] in the SYSUCC cohort. TP53 mutation in alpha-helix region was related to inferior clinical outcomes in patients treated with third-generation EGFR-TKIs.

The Design for a Phase II, Randomized, Multicenter Study of CtDNA-Guided Treatment With Furmonertinib Combined Therapy or Furmonertinib Alone for Untreated Advanced EGFR Mutant Non–small-cell Lung Cancer Patients: The FOCUS-C Study

BackgroundThird-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have significant antitumor activity to advanced non–small-cell lung cancer (NSCLC) patients with classic EGFR mutations. However, EGFR-TKI monotherapy shows poor efficacy in patients whose circulating tumor cell DNA (ctDNA) of EGFR mutations cannot be rapidly cleared. Materials and MethodsAs a third-generation TKI, furmonertinib has shown superior antitumor activity and minor toxicity. The FOCUS-C study is a prospective, multicenter, randomized controlled trial (NCT05334277) to explore the efficacy and safety of furmonertinib plus pemetrexed-platinum doublet chemotherapy with or without bevacizumab versus furmonertinib monotherapy in untreated advanced EGFR mutant NSCLC patients without EGFR clearance after the induction therapy of furmonertinib. Patients with EGFR clearance will still receive furmonertinib as Arm A. Patients without ctDNA clearance will be randomized in a 2:2:1 ratio as Arm B1 (furmonertinib), Arm B2 (furmonertinib combined with carboplatin and pemetrexed for 4 cycles, and then furmonertinib and pemetrexed as maintenance therapy) and Arm B3 (Arm B2 regimen plus bevacizumab). The primary endpoint is progression-free survival (PFS) in Arm B2/B1. Secondary endpoints include PFS in Arm B3/B1, PFS in Arm A/B1, PFS in Arm B3/B2, objective response and disease control rate, overall survival and safety in all Arms. Exploratory endpoints are focused on the efficacy based on plasma NGS at different timepoints. ConclusionThis study will evaluate the efficacy and tolerability of furmonertinib plus carboplatin and pemetrexed with or without bevacizumab verses furmonertinib alone in untreated patients with advanced EGFR mutant NSCLC without EGFR clearance.

Comparing the efficacy of two generations of EGFR-TKIs: An integrated drug-disease mechanistic model approach in EGFR-mutant lung adenocarcinoma.

e20578 Background: The epidermal growth factor receptor (EGFR) is frequently mutated in patients with lung adenocarcinoma (LUAD), leading to its constitutive activation and subsequent uncontrolled cell proliferation. To counteract this, tyrosine kinase inhibitors (TKIs) targeting EGFR have been developed. However, the emergence of metastases and resistance mutations often undermines the durability of the treatment response. Knowledge-based mechanistic models that replicate existing clinical trial outcomes, tailored to specific population characteristics, provide invaluable assistance in designing future clinical trials. Methods: We have developed physiologically based pharmacokinetic (PBPK) models for gefitinib and osimertinib, two EGFR TKIs, to accurately simulate the drugs' distribution within the primary tumor and metastatic sites following administration. These models were integrated with a mechanistic model of EGFR-mutant LUAD, enabling the representation of the mechanism of action of gefitinib and osimertinib. This model outputs the evolutions of the primary tumor and each metastasis, facilitating the evaluation of patient progression following RECIST criteria. Notably, the model encapsulates the heterogeneity within the tumor, representing various subclones defined by unique mutation profiles, thereby reflecting differential responses to treatment. Calibration of the model was achieved using publicly available data from the NEJ002, FLAURA and AURA3 clinical trials. Rigorous visual predictive checks and statistical tests were employed to ensure the proper behavior of the model. Results: The model adeptly replicated the time to progression in EGFR-mutant LUAD patients receiving gefitinib or osimertinib, whether as first-line or second-line therapy. Furthermore, it accurately mirrored the progression causes as per the RECIST criteria, including the emergence of new metastases in the lung, brain, liver, and bone. With a consistent virtual population as a reference, the combined model facilitated a comparative analysis of the efficacy of both treatments, thereby underscoring its utility in evaluating therapeutic strategies. Conclusions: The faithful replication of real-world data significantly enhances the credibility of our model, rendering it a promising tool for deriving pertinent insights and informing treatment strategies. Following its consecutive prospective validations in the FLAURA2 and MARIPOSA trials, the model is poised to facilitate the generation of synthetic control arms in future clinical trials. This advancement promises a more nuanced analysis of covariate relationships, especially when comparing investigational treatments to established standards of care. Additionally, it potentially reduces the requisite patient cohort size in such trials, optimizing resource utilization.

Amivantamab plus lazertinib in atypical EGFR-mutated advanced non-small cell lung cancer (NSCLC): Results from CHRYSALIS-2.

8516 Background: Afatinib is the only EGFR tyrosine kinase inhibitor (TKI) approved to treat patients (pts) with EGFR-mutated advanced NSCLC harboring atypical mutations (eg, S768I, L861Q, G719X), excluding exon 20 insertion mutations (Ex20ins). In a retrospective analysis of 38 TKI-naïve pts, 27 had a response to afatinib, with a median duration of response (mDoR) of 11.1 months (mo) and median progression-free survival (mPFS) of 10.7 mo (Yang Lancet Oncol 2015;16(7):830-8). Amivantamab (ami) is an EGFR- MET bispecific antibody with immune-cell directing activity. Lazertinib (laz) is a CNS-penetrant, 3rd-generation EGFR TKI. This combination was evaluated among pts with atypical EGFR-mutated advanced NSCLC. Methods: Cohort C of the CHRYSALIS-2 study (NCT04077463) enrolled pts with atypical EGFR mutations, excluding Ex20ins, who were treatment-naïve or had ≤2 prior lines, which may have included a 1st/2nd-generation EGFR TKI. Pts with Ex19del or L858R co-mutations were excluded. Ami was intravenously administered at 1050 mg (1400 mg, ≥80 kg) weekly for the first 4 weeks and then biweekly. Laz was given orally at 240 mg daily. Response was assessed by the investigator per RECIST v1.1. Results: As of 4 Dec 2023, 105 pts received ami+laz, with a median follow-up of 13.8 mo (range, 0.1–30.2). The median age was 64 years, 50% were female, 68% Asian, 30% White, and 35% had CNS lesions at baseline. The most common mutations were G719X (54%), L861Q (24%), and S768I (22%). The ORR was 51% (95% CI, 41–61). In the treatment-naïve subset (n = 49), ORR was 55% (95% CI, 40–69), with mDoR not estimable (NE; 95% CI, 9.9 mo–NE) and mPFS of 19.5 mo (95% CI, 11.0–NE). Among responders, 78% (21/27) had DoR ≥6 mo. The ORR for pts harboring solitary mutations at G719 (n = 13), L861 (n = 8), and S768 (n = 2) was 54%, 63%, and 100%, respectively. The ORR for pts with compound atypical mutations (n = 17) was 41%, with DoR ≥6 mo for all 7 responders. Among pts treated with prior afatinib (n = 40), ORR was 45% (95% CI, 29–62), with mDoR of 8.9 mo (95% CI, 2.8–NE) and mPFS of 5.7 mo (95% CI, 4.2–10.7). Among the 18 responders, 56% had DoR ≥6 mo. The most common AEs were primarily EGFR- and MET-related toxicities, primarily grade 1-2. Discontinuations of both ami and laz due to treatment-related AEs occurred in 9% of pts. The incidence of VTE was 30% (31/105), with the majority of events, 71% (22/31), occurring in the first 4 mo of treatment. The vast majority of pts, 97% (30/31), were not on anticoagulation at time of first VTE. The rate of pneumonitis/interstitial lung disease was 6%. Biomarker analyses are ongoing; updated results will be presented at time of meeting. Conclusions: In the largest, single-cohort, prospective study of atypical EGFR-mutated advanced NSCLC, ami+laz demonstrated clinically meaningful and durable antitumor activity in pts who were treatment-naïve or had disease progression on afatinib. Clinical trial information: NCT04077463 .

Associations of early adverse events with clinical outcomes in patients with NSCLC treated with EGFR tyrosine kinase inhibitors.

e20551 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) constitute the primary treatment modality for EGFR-mutant non-small cell lung cancer (NSCLC). While efficacious, EGFR TKIs are associated with adverse events (AEs) like dermatologic toxicities, diarrhea, and stomatitis. This study examined the prognostic implications of these on-target AEs in NSCLC patients receiving EGFR TKI therapy. Methods: A retrospective cohort study was conducted, encompassing advanced NSCLC patients treated with first-line EGFR TKIs within two distinct healthcare delivery systems in Taiwan between June 2011 and December 2019. Patients were stratified by TKI type, and those who had received AE reliever medications within 180 days prior to EGFR TKI initiation were excluded. We examined correlations between AEs and key endpoints: time to next treatment (TTNT) and overall survival (OS). To minimize immortal time bias, a landmark analysis at 60 days post-treatment initiation was utilized. On-target AEs were identified based on the issuance of at least two prescriptions for AE management on different dates within this period. Multivariable Cox proportional hazards models were utilized to evaluate the association between AEs and clinical endpoints, and a random-effects meta-analysis was performed to combine findings from both institutions. Results: Our analysis included 1,605 patients on gefitinib, 848 on erlotinib, and 1,236 on afatinib. Despite potential variations in AE reporting due to prescribing behaviors, the incidence of AE within the first 60 days of treatment was highest for afatinib, particularly with diarrhea (76.7%) and stomatitis (14.9%), followed by erlotinib with notable skin reactions (49.4%). Gefitinib showed the lowest incidence rates across all examined AEs. Of note, afatinib-treated patients who experienced diarrhea within the initial 60 days demonstrated a statistically significant extension in OS (HR 0.75, 95% CI 0.60-0.92). No significant prognostic link was found for other AEs in afatinib users or any AEs among users of gefitinib and erlotinib. Sensitivity analyses, incorporating modified AE definitions, corroborated these outcomes. Conclusions: Identifying AEs via prescription records for symptom relief poses methodological challenges and introduces uncertainty. Nevertheless, the occurrence of diarrhea within the first 60 days of therapy emerged as a significant predictor of enhanced OS in EGFR-mutant NSCLC patients receiving afatinib. This finding suggests a potential prognostic implication. The correlation was not evident in patients treated with first-line gefitinib or erlotinib.

Plasma ctDNA biomarker study in patients with non-small cell lung cancer with EGFR exon 20 insertion mutation treated with sunvozertinib.

8563 Background: There are limited reports on biomarker studies of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutation (exon20ins). Sunvozertinib (DZD9008), an oral, potent, irreversible and selective EGFR tyrosine kinase inhibitor (TKI), has been granted conditional approval in China for the treatment of NSCLC with EGFR exon20ins in the ≥ second-line setting. Here we report biomarker analysis of EGFR exon20ins in large sample size, by pooling data from WU-KONG series of studies. Methods: Serial plasma ctDNA samples were collected from baseline until progressive disease (PD). Next generation sequencing was used to assess EGFR exon20ins in baseline plasma ctDNA, and to analyze genetic alterations in baseline and PD plasma ctDNA to identify potential resistance mechanisms to sunvozertinib. Droplet digital PCR was used to dynamically monitor the quantity of EGFR exon20ins during treatment. In addition, association between baseline EGFR exon20ins and disease characteristics as well as antitumor activity of sunvozertinib was analyzed. Furthermore, in vitro and in vivo experiments were performed to explore potential approach which may overcome the resistance to sunvozertinib. Results: A total of 121 patients were included in this biomarker analysis, among them 81 out of 121 (66.9%) had detectable EGFR exon20ins in baseline plasma ctDNA. There was a positive correlation between detectable EGFR exon20ins and higher number of metastasis sites. In addition, higher EGFR exon20ins abundance was positively correlated with more metastasis sites and brain metastasis. Patients with EGFR exon20ins negative in plasma ctDNA achieved a higher objective response rate (ORR) (68.0% vs. 45.8%) and longer median progression free survival (PFS) (7.4 months vs. 5.5 months) with sunvozertinib treatment. In patients with baseline detectable EGFR exon20ins, the mutant allele decreased over time with treatment in majority of patients (12/14, 85.7%), and the earliest clearance of EGFR exon20ins occurred after one week of treatment. In patients who developed disease progression, 12 of 18 (66.7%) maintained EGFR exon20ins at PD, and among them, 3 concurrently acquired EGFR C797S, all in cis with exon20ins. In addition, EGFR G724S and other genetic aberrations in EGFR downstream signaling pathway, were also detected. Exploratory work on overcoming resistance to sunvozertinib suggests that combination of golidocitinib, a selective JAK1 inhibitor, with chemotherapy could be a potential approach. Conclusions: This study showed that positive EGFR exon20ins in plasma ctDNA is associated with advanced disease characteristics. Sunvozertinib can effectively clear EGFR exon20ins in plasma ctDNA, confirming its direct effect on EGFR pathway. The resistance to sunvozertinib can be through EGFR-dependent and EGFR-independent mechanisms.

OSIRAM-1/TORG1833: Overall survival results of a randomized phase II study of osimertinib plus ramucirumab versus osimertinib alone as initial chemotherapy for EGFR mutation-positive non-squamous non-small cell lung cancer.

8613 Background: Dual inhibition of the EGFR/VEGF pathways has demonstrated superior efficacy with 1st generation EGFR tyrosine kinase inhibitor (TKI) in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. This study aims to evaluate the efficacy and safety of combining osimertinib (Osi), a 3rd generation TKI considered the standard of care, with ramucirumab (Ram). We have previously shown the result of progression free survival (PFS) as a primary endpoint, the median PFS was 20.0 months for Osi+Ram and 24.0 months for Osi, hazard ratio of 1.054 (95% CI 0.674-1.648). In further analyses, we aimed to examine the effects of this combination therapy on overall survival (OS). Methods: Previously untreated EGFR mutation-positive advanced non-squamous NSCLC patients with a performance status of 0 or 1 were eligible. Asymptomatic and/or treated brain metastases were included. Eligible patients were randomized at a 1:1 ratio to receive Osi (80mg) every day either without or with Ram (10mg/kg) every 2 weeks until disease progression or unacceptable toxicity, stratified according to gender and the type of EGFR mutation (exon 19 deletion, L858R). The primary endpoint was PFS assessed by the independent blinded radiologic reviewer. Secondary endpoints included PFS assessed locally, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), OS and safety. Results: Between November 2018 and April 2020, 122 patients (Osi+Ram: 59, Osi: 63) were enrolled. The patients' characteristics were well balanced. 59% were females, and 61% had an exon 19 deletion. Median age was 70 years old (range, 29-86). With a median follow up of 36.0 months, the median OS was 43.4 months (95% CI 36.5-N.R.) for Osi+Ram and N.R. (95% CI 41.3-N.R.) for Osi, resulting in a hazard ratio of 1.159 (95% CI 0.645-2.083, p = 0.62). Median treatment duration for Ram was 140 (14-1239) days. Ram was discontinued in 45 patients (76%) by the treatment related adverse effects. Common reasons for Ram discontinuation were platelet count decreased (n=14), proteinuria (n=12), neutrophil count decreased (n=11), pneumonitis (n=3), bleeding (n=3) and infection (n=3). Pneumonitis was observed in 16% in Osi, 9% in Osi+Ram, with grade 3 observed in 2% of both arms. Conclusions: Both treatment arms demonstrated sustained OS over 43 months. However, this study did not show an advantage of biweekly Ram administration with Osi in terms of PFS and OS. Notably, there was surpassed increase of early discontinuation of Ram due to higher adverse events. Clinical trial information: 2080224085 .

Adjuvant icotinib of 12 months or 6 months versus observation following adjuvant chemotherapy for resected EGFR-mutated stage II–IIIA non-small-cell lung cancer (ICTAN, GASTO1002): A randomized phase 3 trial.

8004 Background: The efficacy, safety and ideal treatment duration of adjuvant icotinib (first-generation EGFR tyrosine kinase inhibitor) for patients with completely resected EGFR-mutated non-small-cell lung cancer (NSCLC) after adjuvant chemotherapy were not known in 2014, when this study was initiated. This phase 3 trial investigated whether icotinib following adjuvant chemotherapy improves clinical outcomes compared with observation in stage II-IIIA NSCLC harboring EGFR mutation. Methods: This is a multicenter, randomized, open-label, phase 3 trial. From July 2014 to December 2021, patients with completely resected, EGFR-mutated, stage II-IIIA NSCLC after platinum-based adjuvant chemotherapy were enrolled. Patients were assigned in a 1:1:1 ratio to receive icotinib (125mg, three times daily) for 12 months, icotinib for 6 months or to observation. The primary endpoint was disease-free survival (DFS) in the intention-to-treat population. Results: This trial was terminated early due to slow accrual.A total of 251 patients were randomized, with 84 patients in the 12-month icotinib group, 84 patients in the 6-month icotinib group, and 83 patients in the observation group. Baseline characteristics were balanced between the groups. After a median follow-up of 61.4 months, 6 months of icotinib significantly improved DFS (HR: 0.41, 95% CI, 0.27-0.62; P = 0.000025) and overall survival (OS, HR: 0.56, 95% CI, 0.32-0.98; P = 0.041) compared with observation. Adjuvant icotinib of 12 months also significantly improved DFS (HR: 0.40, 95% CI, 0.27-0.61; P = 0.000014) and OS (HR: 0.55, 95% CI, 0.32-0.96; P = 0.035) compared with observation. Adjuvant icotinib of 12 months did not improve DFS (HR: 0.97; P = 0.89) and OS (HR: 1.00; P = 0.99) compared with 6 months of this drug. Median DFS was 61.8 months (95% CI, 43.3 to 80.3) for the 12-month icotinib group, 63.2 months (95% CI, 44.8 to 81.6) for the 6-month icotinib group compared with 23.7 months (95% CI, 16.5 to 30.9) for the observation group. The 5-year DFS and OS for the 12-month icotinib, 6-month icotinib and observation groups were 51.3%, 50.1% and 24.8%; and 74.5%, 74.0% and 65.1%; respectively. No differences in efficacy pertaining to icotinib duration were found in any of the subgroups. Rates of adverse events of grade 3 or higher were 8.3%, 5.9% and 2.4% for the 12-month icotinib, 6-month icotinib and observation groups, respectively. The safety profile remained similar to the previous reports for icotinib. Conclusions: Adjuvant icotinib for 12 months and 6 months provide a significant DFS and OS benefit compared with observation in patients with completely resected EGFR-mutated stage II-IIIA NSCLC with a manageable safety profile. Nevertheless, 12 months of icotinib had no additional benefit compared with 6 months. Clinical trial information: NCT01996098 .