Mutant Lung Cancer Research Articles

PP01.115 Real-World Characteristics and Outcomes Among Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) and HER2 Mutations

PP01.115 Real-World Characteristics and Outcomes Among Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) and HER2 Mutations

High throughput virtual screening and validation of Plant-Based EGFR L858R kinase inhibitors against Non-Small cell lung Cancer: An integrated approach Utilizing GC–MS, network Pharmacology, Docking, and molecular dynamics

Lung cancer ranks as the 2nd most common cancer globally. It’s the most prevalent cancer in men and the 2nd most common in women. The prominent events in EGFR-mutated non-small-cell lung cancer (NSCLC) include the emergence of the L858R mutation within EGFR exon 21. Despite the promising efficacy of EGFR inhibitors in managing lung cancer, the development of acquired resistance poses a significant hurdle. In the current investigation, we focused on the screening of two phytochemicals, namely Dehydrocostus lactone and Mokkolactone, derived from the Saussurea lappa plant, as potential inhibitors targeting EGFR L858R mutant lung cancer. The chloroform and ethanol extract of the plant demonstrated anti-proliferative activity through the Resazurin chemosensitivity assay, exhibiting an IC50 value of 37.90 ± 0.29 µg/ml with selectivity index 2.4. Through a GC–MS study, we identified 11 phytochemicals for further insilico analysis. These compounds underwent ADMET assessment followed by drug likeliness analysis before being subjected to molecular docking against EGFR L858R, identified through protein–protein interaction network analysis. All phytochemicals exhibited binding energy scores ranging from −6.9 to −8.1 kcal/mol. Dehydrocostus lactone and Mokkolactone were specifically identified for their binding profile. Findings from 100 ns molecular dynamics simulations demonstrated their enhanced stability compared to the reference ligand DJK. This was evident in the root mean square deviation (RMSD) values, ranging from 0.23 ± 0.01 nm to 0.30 ± 0.05 nm, the radius of gyration values, from 1.71 ± 0.01 nm to 1.72 ± 0.01 nm, and the solvent accessible surface area values, from 155.39 ± 2.40 nm2 to 159.32 ± 2.14 nm2. Additionally, favourable characteristics were observed in terms of hydrogen bonding, principal component analysis, and free energy landscape analysis. Examination of their electronic structure via density functional theory revealed efficient properties, with the highest occupied molecular orbital-least unoccupied molecular orbital energy gap values ranging from −3.984 eV to −6.547 eV. Further, in vivo analysis is required to gain a more comprehensive understanding and efficacy of these identified phytochemicals against lung cancer.

Highly consistency of PIK3CA mutation spectrum between circulating tumor DNA and paired tissue in lung cancer patients

BackgroundPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations are associated with drug resistance and prognosis in lung cancer; however, the consistency and clinical value of PIK3CA mutations between tissue and liquid samples are unknown. MethodsCirculating tumor DNA (ctDNA) and matched tumor tissue samples from 405 advanced lung cancer patients were collected at Jilin Cancer Hospital between 2018 and 2022, and the PIK3CA mutation status was sequenced using next-generation sequencing based on a 520 gene panel. The viability of different mutant lung cancer cells was detected using MTT assay. ResultsPIK3CA mutations were detected in 46 (5.68 %) of 810 lung cancer samples, with 21 (5.19 %) of 405 plasma samples and 25 (6.17 %) of 405 matched tissues. p.Glu542Lys, p.Glu545Lys, and p.His1047Arg were the most common mutation types of PIK3CA in both the ctDNA and tissue samples. The concordance of PIK3CA mutations was 97.53 % between ctDNA and matched tissues (kappa: 0.770, P = 0.000), with sensitivity/true positive rate of 72.0 %, specificity/true negative rate of 99.2 %, and negative predictive value and positive predictive value of 0.982 and 0.857, respectively (AUC = 0.856, P = 0.000). Furthermore, the concordance of PIK3CA mutations was 98.26 % in lung adenocarcinoma and 96.43 % in lung squamous cell carcinoma. TP53 and EGFR were the most common concomitant mutations in ctDNA and tissues. Patients with PIK3CA mutations showed a high tumor mutational burden (TMB) (P < 0.001) and a significant correlation between bTMB and tTMB (r = 0.5986, P = 0.0041). For the tPIK3CAmut/ctDNA PIK3CAmut cohort, PI3K pathways alteration was associated with male sex (P = 0.022), old age (P = 0.007), and smoking (P = 0.001); tPIK3CAmut/ctDNA PIK3CAwt patients harbored clinicopathological factors of adenocarcinoma stage IV, with low PS score (≤1) and TMB. ConclusionThis study showed that ctDNA is highly concordant and sensitive for identifying PIK3CA mutations, suggesting that PIK3CA mutation detection in liquid samples may be an alternative clinical practice for tissues.

Therapeutic Resistance in G-CSF Producing Lung Cancer With EGFR Mutation.

Granulocyte colony-stimulating factor (G-CSF)-producing neoplasms are relatively rare; however, little is known on the clinical features of G-CSF-producing lung cancer harboring activating epidermal growth factor receptor (EGFR) mutations. A 66-year-old female was definitively diagnosed with G-CSF-producing lung cancer that was positive for EGFR mutations. She repeatedly received epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as osimertinib and afatinib. However, she developed resistance to these molecular-targeting drugs within 2 to 3 months after immediate shrinkage. Thus, the patient was treated with chemoimmunotherapy including bevacizumab, and demonstrated a slight survival benefit. Overall, G-CSF-producing lung cancers positive for EGFR mutations were resistant to different treatment modalities. Clinicians should be attentive to the potential resistance of G-CSF-producing EGFR mutant lung cancer to EGFR-TKI therapy.

PP01.93 RET fusion as a treatable resistance mechanism in EGFR mutation lung cancer - A case report

PP01.93 RET fusion as a treatable resistance mechanism in EGFR mutation lung cancer - A case report

Pitavastatin sensitizes the EGFR-TKI associated resistance in lung cancer by inhibiting YAP/AKT/BAD-BCL-2 pathway

BackgroundDespite effective strategies, resistance in EGFR mutated lung cancer remains a challenge. Metabolic reprogramming is one of the main mechanisms of tumor drug resistance. A class of drugs known as “statins” inhibit lipid cholesterol metabolism and are widely used in patients with cardiovascular diseases. Previous studies have also documented its ability to improve the therapeutic impact in lung cancer patients who receive EGFR-TKI therapy. Therefore, the effect of statins on targeted drug resistance to lung cancer remains to be investigated.MethodsProlonged exposure to gefitinib resulted in the emergence of a resistant lung cancer cell line (PC9GR) from the parental sensitive cell line (PC9), which exhibited a traditional EGFR mutation. The CCK-8 assay was employed to assess the impact of various concentrations of pitavastatin on cellular proliferation. RNA sequencing was conducted to detect differentially expressed genes and their correlated pathways. For the detection of protein expression, Western blot was performed. The antitumor activity of pitavastatin was evaluated in vivo via a xenograft mouse model.ResultsPC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC9 cells, and the YAP expression was inhibited by pitavastatin administration. With YAP RNA interference, pAKT, pBAD and BCL-2 expression was decreased, while BAX expression as increased. Accordingly, YAP down-regulated significantly increased apoptosis and decreased the survival rate of gefitinib-resistant lung cancer cells. After pAKT was increased by SC79, apoptosis of YAP down-regulated cells induced by gefitinib was decreased, and the cell survival rate was increased. Mechanistically, these effects of pitavastatin are associated with the YAP pathway, thereby inhibiting the downstream AKT/BAD-BCL-2 signaling pathway.ConclusionOur study provides a molecular basis for the clinical application of the lipid-lowering drug pitavastatin enhances the susceptibility of lung cancer to EGFR-TKI drugs and alleviates drug resistance.

Association between PD-L1 expression with EGFR, ALK, and ROS1 driver oncogene mutations in non-small cell lung cancer.

Driver mutations and immunological expressions have gained importance in recent years for targeted therapies and immunotherapies of nonsmall cell lung cancer (NSCLC). This study examined the association between PD-L1 expression and ALK, ROS1, and EGFR driver oncogene mutations in patients with NSCLC. A total of 501 NSCLC patients were included for analysis. Immunohistochemistry was performed with a PD-L1 clone 22c3. EGFR mutations were detected by PCR. ALK and ROS1 rearrangement analysis was performed with FISH. Results: There was a highly statistically significant difference between PD-L1 expression and EGFR mutation. PD-L1 expression was higher in the EGFR wild-type than in mutated EGFR (P = 0.0002). There was no relationship between PD-L1 expression and ALK and ROS1 mutations (P = 0.8899, P = 0.2512, respectively). PD-L1 expression was higher in nonadenocarcinomas (non-AC) than in adenocarcinomas (AC) (P = 0.0438). The ALK rearrangement and EGFR mutations were higher in ACs (P = 0.0073, P = 0.0012, respectively). ALK, ROS1 rearrangements, and EGFR mutations were higher in nonsmokers (P < 0.05). EGFR mutations were detected more frequently in females than males (P = 0.001). There was no relationship between gender and ALK, ROS1, and PD-L1 (P > 0.05). The prevalence of EGFR, ALK, and ROS1 driver mutations in the Turkish population was 9.3%, 5.3%, and 2.4%, respectively. In conclusion, PD-L1 expression and mutated EGFR status have a highly negative association. PD-L1 expression was higher in EGFR wild-type patients. Therefore, it shows that the opportunity to receive PD-L1-related treatment may be higher in these patients. We think that PD-L1 immunohistochemical evaluation will increase the clinical predictive importance in EGFR wild-type cases.

From Rarity to Reality: Osimertinib's Promising Horizon in Treating Uncommon EGFR Mutations in Non-Small Cell Lung Cancer.

In the realm of advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) therapy with tyrosine kinase inhibitors (TKI), addressing optimal treatment for uncommon EGFR mutations like G719X in exon 18, S768I in exon 20, and L861Q in exon 21 remains a pivotal yet challenging frontier. Contrary to the well-established efficacy of EGFR-TKIs in common EGFR mutations, these uncommon alterations pose unmet medical needs due to a lack of comprehensive evidence. While afatinib, a second-generation EGFR-TKI, has received FDA approval for patients with these uncommon EGFR mutations, the approval was based on a post-hoc analysis of randomized clinical trials. Recent developments include multiple clinical trials investigating the efficacy of both second- and third-generation EGFR-TKIs in patients with uncommon EGFR mutations. A noteworthy example is a prospective phase II trial of osimertinib including the landmark UNICORN study, which has shown promising results in treating uncommon EGFR mutations. Despite various reports on the efficacy of afatinib and osimertinib in treating uncommon EGFR mutations, the appropriate use of these TKIs remains unclear. This review aims to consolidate the findings from the latest clinical trials focused on uncommon EGFR mutations, outlining variations in the therapeutic efficacy of these TKIs based on the specific genetic mutation. By synthesizing these findings, we aim to guide oncologists toward more informed decisions in employing TKIs for NSCLC with uncommon EGFR mutations other than exon 20 insertion. Additionally, we explore potential treatment strategies tailored to these patient populations to address the challenges posed by these mutations.

The therapeutic features of EGFR L858R exon 21 mutation in non-small cell lung cancer

Introduction. Monotherapy with EGFR tyrosine kinase inhibitors (TKIs) results in a worse prognosis for patients with the exon 21 L858R mutation than for patients with exon 19 Del. Thus, the search for alternative drug strategies that improve treatment outcomes for patients with NSCLC with the L858R mutation is an urgent problem. This article presents preliminary results of a pilot study of the effectiveness of chemotherapy integrated into targeted anti-EGFR therapy for patients with non-small cell lung cancer (NSCLC) with a mutation in exon 21 of the EGFR gene.Aim. To improve progression-free survival results on first-line therapy in patients with NSCLC with the L858R mutation.Materials and methods. From 2015 to 2021 23 patients were included in the study with advanced L858R 21 exon mutation NSCLC for the first line of treatment. Patients received TKI therapy for the first 2 months, followed by discontinuation of targeted therapy and receiving 3 courses of paclitaxel and carboplatin. Target therapy was then resumed until disease progression. The follow up period was 36 months.Results. The objective response rate (ORR) was 59.1%. Median progression-free survival 23 months [95% CI: 16–36]. Four (18.1%) patients developed grade 3-4 toxicity during chemotherapy, and therefore the 3rd course of chemotherapy was canceled in one patient. Due to toxicity during targeted therapy, gefitinib dose was reduced in one patient and the drug was changed from gefitinib to afatinib in the other one patient.Conclusion. Preliminary results of our study showed that integrating chemotherapy into targeted treatment for this category of patients may become a new worthy option to increase median PFS.

The current landscape, advancements, and prospects in the treatment of patients with EGFR exon 20 insertion mutations warrant scientific elucidation.

Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations are the third most prevalent mutation in non-small cell lung cancer (NSCLC), following the 19del and L858R mutations. The unique nature of the EGFR ex20ins mutation poses challenges for the effectiveness of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). As a result, chemotherapy remains the primary and more effective treatment approach. However, with advancements in time and technology, numerous experimental studies have revealed the potential of novel drugs and therapies to have stronger inhibitory effects on EGFR ex20ins mutations. In this comprehensive review, we provide an overview of the current treatment landscape, recent advancements, and the prospects for patients with advanced NSCLC characterized by EGFR ex20ins mutations.

Concomitant genomic features stratify prognosis to patients with advanced EGFR mutant lung cancer.

This study aimed to explore the clinical significance of genomics features including tumor mutation burden (TMB) and copy number alteration (CNA) for advanced EGFR mutant lung cancer. We retrospectively identified 1378 patients with advanced EGFR mutant lung cancer and next-generation sequencing tests from three cohorts. Multiple co-occurring genomics alternations occurred in a large proportion (97%) of patients with advanced EGFR mutant lung cancers. Both TMB and CNA were predictive biomarkers for these patients. A joint analysis of TMB and CNA found that patients with high TMB and high CNA showed worse responses to EGFR-TKIs and predicted worse outcomes. TMBhighCNAhigh, as a high-risk genomic feature, showed predictive ability in most of the subgroups based on clinical characteristics. These patients had larger numbers of metastatic sites, and higher rates of EGFR copy number amplification, TP53 mutations, and cell-cycle gene alterations, which showed more potential survival gain from combination treatment. Furthermore, a nomogram based on genomic features and clinical features was developed to distinguish prognosis. Genomic features could stratify prognosis and guide clinical treatment for patients with advanced EGFR mutant lung cancer.

Characterization of DNA damage repair mutations in lung cancer in an underserved urban patient population.

e20058 Background: DNA-damage repair (DDR) mutations in lung cancer have shown potential for use as therapeutic targets and predictive biomarkers. However, the relationship between DDR mutations and socioeconomic factors remains largely unknown. In this study, we characterize the distribution of DDR gene mutations in lung cancer patients at a single academic medical center serving a unique population consisting of primarily underserved, underinsured patients. Methods: All lung cancer patients seen at the University of Illinois Chicago (UIC) between 11/2/2015 and 9/11/2023 with TEMPUS genetic data available were included in the study (N = 235). DDR mutations of interest were ARID1A, ATM, ATR, ATRX, BAP1, BRCA1, BRCA2, BRIP1, CHEK2, ERCC3, FANCA, FANCC, MLH3, MRE11, MSH6, MUTYH, NBN, PALB2, and RAD50. The population was subdivided into a DDR mutation positive group and a DDR mutation negative group. Each group was compared with respect to lung cancer type, tumor mutational burden (TMB), and socioeconomic factors including sex, race, insurance category, and zip code. Results: The overall frequency of DDR mutations in the population was 28.5% (n = 67). The most common DDR mutations were ARID1A (20.7%), CHEK2 (12.8%), ATM (9.9%), BRCA2 (9.9%), ATRX (7.9%), and MUTYH (7.9%). The histological distribution of the DDR mutation positive group was adenocarcinoma (76.1%), squamous cell carcinoma (4.4%), adenosquamous carcinoma (2.9%), neuroendocrine carcinoma (5.9%), and other (10.4%). The histological distribution of the DDR negative group was adenocarcinoma (60.1%), squamous cell carcinoma (22.0%), adenosquamous carcinoma (1.1%), neuroendocrine carcinoma (4.1%), and other (12.5%). There was a significant effect in TMB, t(55) = 2.97, p = 0.004, with a higher mean TMB in the DDR positive group (M = 14.4, SD = 11.1) compared to the DDR negative group (M = 9.4, SD = 5.1). The most common zip codes in the DDR positive groupwere 60608 (9.0%), 60629 (9.0%), and 60616 (7.5%) compared to 60616 (8.3%), 60609 (5.3%), and 60624 (4.7%) in the DDR negative group. Demographic factors of the two groups are compared below. Conclusions: The frequency and distribution of DDR mutations in lung cancer at UIC appears similar to what has been previously reported in the literature. There is a higher tumor mutational burden in lung cancers with DDR mutations, which may suggest greater susceptibility to immunotherapy. There may be a correlation between the presence of DDR mutations and lung cancer type, insurance category, and patient geographic distribution. Future work will include obtaining further geographic data for the study population such as average income, pollution exposure, and smoking rate by neighborhood. [Table: see text]

Potential role and prognostic value of Globo-H in lung cancer.

e20037 Background: Globo-H (GH), a globo-series carbohydrate antigen highly expressed on multiple epithelial cancers, is a promising target for cancer immunotherapy. Clinical trials have been conducted to evaluate the efficacy of anti-GH vaccine Adagloxad Simolenin/OBI-821 (in Ph 3) and OBI-833/OBI-821 (in Ph 2) in cancer patients. Epidermal growth factor receptor (EGFR) mutations are well known as a frequent class of driver mutations in lung cancer (LC), which are responsible for tyrosine kinase inhibitors. Besides high expression in cancer cells, GH has been implicated in regulation of EGFR signaling pathway. Knockdown of key enzyme involved in GH biosynthesis β1,3-galactosyltransferase V (β3GalT5) induces apoptosis through disruption of EGFR-related signaling protein complex. In addition, GH is reported to associate the EGFR mutant in LC patients. This study aims to further investigate the potential role of GH in LC. Methods: Clinical study: The level of GH expression was evaluated by immunohistochemistry (IHC) using H-score in clinical samples from 141 patients with lung adenocarcinoma. In vitro study: FACS and Western blotting methods were used to measure the levels of total EGFR, phospho-EGFRs or GH in LC cell lines. Microwestern protein array (MWA) analysis was performed in LC NCI-H1975 cells. Results: Clinical study: Positive GH expression (H score≥1; 18.4%) was significantly associated with poor differentiation grade (p = 0.044) in all samples and disease specific survival in patients with metastasis and stage 4 LC (p = 0.033). In vitro study: Inhibition of EGFR by an EGFR-specific shRNA resulted in a decrease of GH expression in LC cells while overexpression of EGFR resulted in an increase of GH levels. β3GalT5 knockout cells and anti-GH-antibody-treated cells showed a reduction of cell proliferation as well as the total level of EGFR and phosphor-EGFRs expression, which is consistent with the results from previous studies. MWA analysis on LC cells with β3GalT5 knockout, GH ceramide-treated β3GalT5 knockout cells and anti-GH Ab-treated LC cells indicated a positive correlation between the level of GH and EGFR-related signaling proteins including phosphor-JNK, phosphor-c-Jun, phosphor-PP2A, phosphor-PP2A, phosphor-AKT, and Cyclin D1 proteins. In addition, JNK signaling inhibitor partially reduced GH expression in NCI-H1975 cells. These results revealed the mechanistic link between GH regulation and tumor promoting signals in LC. Conclusions: GH expression was associated with the worse survival of LC patients in clinical setting. In addition, the level of GH is positively correlated with levels of EGFR and EGFR-related signaling proteins in vitro. Expression of GH can induce the expression of EGFR and vice versa in LC cells. Furthermore, EGFR downstream JNK signaling pathway might involve in GH regulation by EGFR. Taken together, GH-targeting therapy has a potential application for the treatment of LC patients.

Osimertinib, platinum, etoposide as initial treatment for patients with EGFR mutant lung cancers with TP53 and RB1 alterations.

8565 Background: EGFR-mutant lung adenocarcinomas (EGFR+LC) transform to small cell lung cancer (SCLC) in up to 14% of cases, which creates an aggressive disease phenotype that is treated like de novo small lung cancer with platinum/etoposide chemotherapy. Transformed EGFR+LC molecularly mimic de novo small cell lung cancers and harbor TP53and RB1 loss. We hypothesized that if small cell directed chemotherapy is utilized prior to histologic transformation in EGFR/TP53/RB1 mutant LC, we may eradicate any pre-existing small cell clones, prevent small cell histologic transformation, and improve patient outcomes. Methods: We administered osimertinib, platinum, and etoposide in patients with newly diagnosed EGFR+LC with TP53and RB1alterations. Patients received 3 months of osimertinib induction, then 4 cycles of osimertinib, platinum and etoposide followed by osimertinib until progression. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were assessed. Patients were required to have an on-treatment biopsy prior to initiation of chemotherapy upon which single cell RNA sequencing (scRNAseq) was performed. All patients had pre-treatment and post-progression biopsies that underwent next-generation sequencing. Patients were evaluated for acquired resistance (classified as on-target, off-target, transformation, and unknown). Among patients that transformed, markers of SCLC (ASCL1, NEUROD1, POU2F3, YAP1, synaptophysin, chromogranin, and Ki-67) were analyzed. Results: Eleven patients were enrolled [median age 58 years old range (49-81), 45% female, 73% EGFRexon 19 deletions and 27% EGFR L858R]. Three patients received cisplatin/etoposide, six patients carboplatin/etoposide, and two patients progressed two months on induction osimertinib before they could start chemotherapy. The ORR was 82%, median PFS 15.6 months and median OS was 37.9 months. All patients retained EGFR, TP53, and RB1mutations on post-treatment biopsy. Acquired on-target resistance mechanisms were identified in 9% of patients ( EGFR C797S), off-target in 9% of patients ( CDKN2A), and small cell transformation in 46% of patients. Among the transformed patients, all had high Ki-67 (70-95%) and 80% were positive for synaptophysin and chromogranin. 40% of cases were ASCL1-dominant, 40% were NEUROD1-dominant, and 20% were unknown. Additionally, we utilized copy number inference and CytoTrace to identify subclones within pre-transformed EGFR+LC that potentially harbor features of early plasticity. Further scRNAseq and whole exome sequencing data are forthcoming. Conclusions: In patients with EGFR+LCs with concurrent TP53and RB1alterations, osimertinib plus platinum and etoposide demonstrated activity and no new safety signals were seen. Early addition of small cell directed chemotherapy did not prevent histologic transformation. Clinical trial information: NCT03567642 .

A phase 2 study of amivantamab plus lazertinib in patients with EGFR-mutant lung cancer and active central nervous system disease.

8517 Background: Patients (pts) with EGFR-mutant lung cancer (EGFR+LC) with active brain metastases (BrM) or leptomeningeal disease (LM) are often excluded from clinical trials. Despite central nervous system (CNS) disease control with osimertinib, &gt; 50% of pts with EGFR-mutant lung cancer have involvement of the brain (BrM) or leptomeninges (LM). Amivantamab and lazertinib have demonstrated systemic activity in pts with EGFR-mutant lung cancer whose disease progressed after osimertinib and/or platinum-based chemotherapy. This trial evaluated amivantamab +lazertinib in the setting of progressive CNS metastases (NCT04965090). Methods: We evaluated amivantamab and lazertinib in 2 cohorts: pts with 1) progressive or new BrM or 2) LM. All pts with EGFR exon 19 del/L858R/atypical mutations had prior osimertinib. All pts with EGFRexon 20 insertions (ex20ins) had prior chemotherapy. Each cohort was to enroll 20 pts powered to differentiate overall response rate (ORR) of 0.05 vs 0.25. Positive CSF assessment (cytology or circulating tumor cells (CTC)) +/- BrM allocated a pt to the LM cohort. Pts received standard dosing of amivantamab and lazertinib 240 mg daily. Co-primary endpoints were systemic ORR by RECIST v1.1 and CNS ORR by RANO-BM or LM. Paired pre-treatment tumor, blood, and CSF samples had targeted DNA sequencing and cell-free RNA (cfRNA) sequencing. Results: Trial enrolled 20 pts in BrM cohort and 22 pts in LM cohort. Median age 55 (range 31-80), 69% women,. 40% had L858R (n = 17), 40% del19 (n = 17), 12% ex20 ins (n = 5), and 8% atypical EGFR mutations (n = 3). Median lines of prior therapy: 2 (1-7). Except patients with ex20ins, all patients had prior osimertinib, and 55% had chemo. Efficacy Data: . 14 LM pts (64%) had decrease in CSF CTCs and 7 (32%) had improvement in neurologic symptoms. Most frequent treatment-related adverse events (TRAEs) (≥30% in overall population) were rash (71%), infusion-related reaction (59%), paronychia (43%), fatigue (40%), edema (40%), mucositis (33%), and nausea (33%). Most frequent (≥5%) grade ≥3 TRAEs were infusion related reactions (7%), thromboembolic event (5%), elevated AST/ALT (5%), and rash (5%). Three pts (7%) discontinued treatment due to TRAEs. Genomic data comparing concurrent systemic tumor, plasma and CSF samples, and ctDNA and cfRNA dynamics will be presented. Conclusions: The combination of amivantamab+lazertinib is a promising treatment for pts with EGFR-mutant lung cancer and active CNS disease, with clinically meaningful time on treatment and radiographic response. This is the first clinical trial successfully completed in pts with EGFR-mutant lung cancer and progressive CNS metastases. Clinical trial information: NCT04965090 .[Table: see text]

Real-world outcomes in patients with biomarker-selected early-stage non-small cell lung cancer.

11156 Background: Extensive literature has assessed the prognostic value of Lung driver mutations (LDMs) in advanced non-small cell lung cancer (aNSCLC). However, their role in predicting outcomes in early-stage cases (eNSCLC) is less defined due to limited data on biomarker-selected eNSCLC. Study variations have led to diverse findings on the prognostic value of individual LDMs in eNSCLC. Methods: We retrospectively analyzed patients with resected stage I-IIIa NSCLC diagnosed between 2011-2023 using the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine lung clinico-genomic database, which consolidates data from approximately 280 US cancer clinics (~800 sites of care). We allocated patients to five cohorts classified by early-stage LDM status: ALK+, EGFR+, KRAS G12C+, KRAS non-G12C+ and wild-type (WT - negative for the listed biomarkers). The clinical attributes and treatment patterns for this cohort were described by our group in a previous abstract; here we analyze recurrence-free and overall survival (RFS and OS) by cohort, using the Kaplan-Meier method. We used Cox regression for multivariate analysis, controlling for demographic and clinical characteristics including age, race, insurance status, stage, histology, and smoking status. Results: The sample contained 1,595 stage I-IIIa patients with known LDM status. Of these, 2.8%, 20.4%, 10.7%, 19.3%, and 46.8% were ALK+, EGFR+, KRAS G12C+, KRAS non-G12C+, and WT. Median OS and RFS were shorter in the WT group compared to any LDM group; results can be found in the table. These differences in OS and RFS persisted in multivariate analysis; hazard ratios (HR) were all statistically significant (p&lt;0.05) and can be found in the table below. Conclusions: In this real-world analysis, patients with eNSCLC LDM-positive tumors had improved OS and RFS relative to WT patients. Differences in OS between WT and LDM+ patients are likely due to frequent receipt of targeted therapy (TT) following progression to advanced disease. However, the small fraction of patients that received adjuvant TT within 6 months of surgery (described in our previous abstract) is not likely to explain observed differences in RFS; thus the differences may be due to innate characteristics of these LDMs. [Table: see text]

EGFR mutation testing trends for patients with metastatic, non-squamous non-small cell lung cancer (non-SQ NSCLC) in Queensland, Australia from 2014-2021.

e13505 Background: Lung cancer is the leading cause of cancer-related mortality worldwide. Epidermal growth factor receptor (EGFR) is the most common actionable mutation in non-small cell lung cancer (NSCLC) with routine testing recommended globally. In late 2013, screening for EGFR mutations was publicly funded in Australia for metastatic non-SQ-NSCLC. However, timely EGFR results are not universally available, often limited by tissue quantity/quality or prolonged turnaround times. This in turn affects access to treatment and thus survival. Methods: We aimed to examine the rates of EGFR testing over time and explore factors impacting results. Cases were identified from the Queensland Oncology Repository, a clinical database consolidating diagnostic, treatment and outcome data for all Queenslanders with cancer through the Queensland Cancer Registry. Cases were included if they had metastatic non-SQ-NSCLC, EGFR testing available via Pathology Queensland, and no other metastatic solid organ cancer within 1 year. Primary outcomes were EGFR mutation testing rates and time from first biopsy to EGFR mutation result, stratified by year of diagnosis and rurality. Results: A total of 3369 cases were included, of which 2871 had EGFR testing. The EGFR mutant (mt) rate was 12.6%, while 16.1% of cases had no EGFR results. Of cases without a conclusive EGFR result, reasons included: 179 transitioned to best supportive care before testing, 208 with insufficient tissue for a conclusive result, and 155 without testing for unclear reasons. The average time from biopsy to EGFR result improved from 29.9 days in 2014 to 21.5 days in 2021, with no significant difference in time to result between major cities, regional or remote areas. Cases with no EGFR results were more prevalent in rural areas. The proportion of patients living in outer regional/remote areas with no EGFR result was 21.1% compared to 15.5% in those living in major cities/inner regional sites. This was a relative increase of 36.2% (95% CI: 10.1% - 68.6%), a significant result (χ2 = 7.7483, p=0.005). Cases with no EGFR results in outer regional and remote sites declined from 30.1% in 2014-2015 to 15.3% in 2020-2021. Conclusions: EGFR mutation testing and result time has improved since 2014. Though time to result was not affected by rurality, significantly more rural patients lacked conclusive EGFR data, highlighting a gap in access to care. The cumulative EGFR no result rate of 16% and result time of 24 days indicates health systems need to more rapidly adapt to new treatment paradigms, particularly in the era of targeted therapies. [Table: see text]

A comparison of real-world incidence of EGFR exon 20 insertion mutations among patients with NSCLC in five Asian markets, stratified by testing methodology.

e20622 Background: Despite the arrival of drugs targeting EGFR exon 20 insertions mutations (ex20ins) in non-small cell lung cancer (NSCLC), testing practices for this specific mutation vary widely between hospitals. In addition, there is a lack of real world data on incidence of ex20ins in different countries in Asia. This study tracks real-world ex20ins incidence by country/region as well as by methodology across 5 different Asian markets. Methods: Ipsos’ Exon 20 Insertion Tracker is an ongoing physician-reported syndicated study. Hospitals in Asia (n = 7 in South Korea; n = 5 in Taiwan; n = 4 in India; n = 5 in Thailand; n = 1 in Hong Kong) were asked to submit data on total number of NSCLC patients tested for EGFR mutations using single marker tests vs multi-gene panel tests, and subsequently asked how many tested positive for ex20ins. Data were collected online on a regular basis from September 2022 in South Korea and Taiwan, from January 2023 in India, and from September 2023 in Thailand and Hong Kong, until December 2023 in all markets. A total of n = 7,657 EGFR-tested patients in South Korea, n = 2,260 in Taiwan, n = 3,970 in India, n = 407 in Thailand and n = 114 in Hong Kong were reported on. Results: Incidence of ex20ins was markedly higher in Hong Kong (3.5%) and Taiwan (3.7%) than in South Korea (1.6%), India (1.4%) and Thailand (1.0%), pointing to a potentially higher incidence in Greater China compared to other parts of Asia. Among this cohort, the use of panel testing for EGFR mutations was highest in India (99%) and lowest in Taiwan (1%). Across the markets, incidence of ex20ins appears to be somewhat higher among those tested with single-marker EGFR tests (2.2%) than those tested with panel-based tests (1.4%), although the opposite was observed in Thailand and Hong Kong. Conclusions: In this large study based on testing results from over 14,400 EGFR-tested patients across 5 different markets in Asia, clear differences in observed incidence of ex20ins mutations were observed, with the incidence in Taiwan being nearly 4 times as high as that in Thailand. This highlights that different testing and biomarker sequencing strategies may be necessary in markets with the highest observed incidence. A secondary finding from this study is that test methodology does appear to have an impact on observed incidence, though this is in part due to very different testing approaches (single-marker vs panel-based) between markets, with the majority of hospitals included in the study in Taiwan preferring a single-marker approach. [Table: see text]

Precision oncology and AI: The ACMA system for personalized treatment matching using real-world data.

e23134 Background: Precision oncology promises tailored cancer treatments, yet current methods often overlook individual patient variability. The AI-powered Case Matching Assistant (ACMA) system addresses this by utilizing real-world data (RWD) from over 100,000 clinical cases to personalize treatment strategies, considering genetic profiles, cancer types, treatment stages, and drug interactions. Methods: ACMA enhances the Large Language Model (LLM) with oncology-specific pretraining that encompasses both molecular and clinical data, ensuring a holistic understanding of patient profiles. It employs cosine similarity for multi-faceted case comparisons, integrating genetic, biomarker, and vital clinical information. Context-aware learning prompts fine-tune the LLM, generating recommendations that reflect the full spectrum of patient-specific data, from genetic variations to clinical histories and treatment responses, facilitating truly personalized treatment pathways. Results: Preliminary results show ACMA's tailored recommendations improve patient outcomes, with increased median survival rates and cost-effective treatment options. The system's 90% relevance match for clinical trial enrollment also expands access to novel therapies. In the absence of a standard treatment protocol for BRCA germline mutations in advanced lung cancer, ACMA provides crucial insights. For instance, a 36-year-old female with BRCA1 c.527del mutation achieved complete remission with a PFS of 38 months after a combination therapy trial. A 56-year-old male with a BRCA2 S1722Yfs*mutation saw partial remission and over 6 months PFS with olaparib. Another male patient, a smoker with concurrent BRCA2 G1712X and TP53 mutations, experienced partial remission following apatinib therapy. ACMA analyzed treatment data from similar genetic profiles and identified a targeted therapy that had shown efficacy in comparable cases. The oncologist used this information as a reference to adjust the treatment plan, resulting in a positive clinical outcome for the patient. This example underscores the potential of ACMA to provide actionable insights for personalized cancer care. Conclusions: Surpassing traditional single-feature matching, ACMA rapidly aligns multi-dimensional characteristics such as cancer type, disease stage, molecular data, and treatment phases. It customizes the interplay of these features with medical logic, delivering tailored outputs through the LLM. This approach offers an economical, convenient, and timely solution, setting a new benchmark in personalized oncology and establishing ACMA as a leader in the field. This distinctive advantage not only enhances patient outcomes but also establishes a formidable barrier to entry for competitors, solidifying ACMA's position at the forefront of oncology practice.

Comparison and performance of three plasma next-generation sequencing assays versus tissue testing for the detection of actionable driver mutations in advanced non-squamous non-small cell lung carcinoma.

e20018 Background: Liquid biopsy (LB) is a useful tool for the detection of actionable mutations in advanced non-squamous non-small cell lung cancer (NS-NSCLC) at progression. However, the clinical benefits of integrating both LB and tissue biopsy (TB)-based genomic profiling at diagnosis of NS-NSCLC remain uncertain. Methods: We tested three commercially available next-generation sequencing (NGS) gene panel assays in circulating cell-free DNA (cfDNA) using replicate sets of 85 LB samples from advanced NS-NSCLC patients at baseline and compared the results with matched TB for the detection of tier IA/B (AMP/ASCO/CAP classification) alterations. We used methylation testing of cfDNA to assess the tumor fraction (TF). We correlated molecular data with clinico-pathological features and follow-up data. Results: All TB-based NGS results were interpretable. 5 LB-based NGS results for one assay were not performed due to the material exhaustion. Tier IA/B gene alteration was detected by LB-based NGS and TB-based NGS in 18 to 23 (21 to 27%) patients and in 35 (41%) patients, respectively. The positive percent agreement of each LB-based NGS assay method compared with TB-based NGS assay ranged from 51% to 68%. The incremental add provided by first LB-based NGS ranged from 0 to 23% versus 25 to 45% for first TB-based NGS, depending on the LB-based NGS assay. It includes one EGFR uncommon mutation, 9 MET amplifications and 2 HER2 amplifications detected by LB-based NGS assays that were not detected by TB-based NGS. Overall agreement between the three LB-based NGS assays was 44%. Hybrid-capture based assay detects 14 MET/HER2 CNVs, two METex14 skipping mutation and two ALK fusions that were not detected by amplicon-based assay. Amplicon-based assay detects one uncommon EGFR mutation, one KRAS non-G12C and one ALK fusion that were not detected by hybrid-capture based assay. 64 LB samples were tested for cfDNA methylation. Positive predictive value and negative predictive value of the detection of TF by cfDNA methylation profiling was 90% and 92%, respectively. The only false-negative result of TF evaluation by cfDNA methylation profiling was observed for a variant with a cfDNA VAF &lt; 1%. Correlation analyses with clinicopathological data are ongoing. Conclusions: While concordance with tissue is relatively high, the incremental add provided by LB-based NGS at diagnosis of advanced NS-NSCLC compared to TB-based NGS is limited and greatly varies according to the sequencing method used. Thus, LB-based NGS at diagnosis of NSCLC can be used as a complement of TB-based NGS or as an alternative when tissue is not available.