Mutant Lung Cancer Research Articles

Advancing neoadjuvant immunotherapy in non-small cell lung cancer (NSCLC): commentary on the Lung Cancer Mutation Consortium 3 trial (LCMC3)

Advancing neoadjuvant immunotherapy in non-small cell lung cancer (NSCLC): commentary on the Lung Cancer Mutation Consortium 3 trial (LCMC3)

Comparison of diagnostic performance between Oncomine Dx target test and AmoyDx panel for detecting actionable mutations in lung cancer

Companion diagnostic (CDx) tests play important roles in identifying oncogenic driver genes and tailoring effective molecularly targeted therapies for lung cancer patients. In Japan, the Oncomine Dx target test (ODxTT) and the AmoyDx pan lung cancer PCR panel (AmoyDx) are prominent CDx tests and only one of these tests is covered by the domestic insurance system. However, these CDx tests cover different target regions and apply different technologies (ODxTT is amplicon-based next-generation sequencing and AmoyDx is multiplex PCR-based assay), which may lead to missing of actionable mutations affecting patient prognosis. Here, we performed a direct comparison analysis of 1059 genetic alterations of eight driver genes from 131 samples and evaluated the concordance between two CDx tests for detecting actionable variants and fusions. When excluding the eight uncovered variants (ODxTT: two variants, AmoyDx: six variants), the overall percent agreement was 97.6% (1026/1051) with 89.0% of overall positive percent agreement (89/100) and 98.5% of overall negative percent agreement (937/951). Of the 25 discordant genetic alterations, two were undetected despite being covered in the AmoyDx (one EGFR variant and one ROS1 fusion). Furthermore, there were potential false positives in the ODxTT (nine MET exon 14 skippings) and in the AmoyDx (five variants, six ROS1 and three RET fusions). These potential false positives in the AmoyDx likely due to non-specific amplification, which was validated by the unique molecular barcoding sequencing. The ODxTT missed two uncovered EGFR rare variants, which was visually confirmed in the raw sequencing data. Our study provides insights into real-world performance of CDx tests for lung cancer and ensures reliability to advance precision medicine.

Retrospective Analysis to Optimize the Detection of MET Exon 14 Skipping Mutations in Non-Small Cell Lung Cancer.

Our study optimized METex14 skipping mutation detection by analyzing 223 Oncomine™ Focus Assay-positive cases using Pan Lung Cancer PCR Panel and reverse transcription (RT)-PCR. Among the 11 METex14 skipping mutation-positive cases (average read counts: 1390), 2 with Oncomine™ Focus Assay read counts of 2540 and 10,177 were positive on all platforms. Those with Oncomine™ Focus Assay read counts ranging from 179 to 612 tested negative elsewhere. Specimens with low ratios (average ratio: 0.12% for nine cases) may yield false-positive results. Our results suggested that monitoring read counts and ratios and validating the results with RT-PCR are crucial to prevent false positives.

CLINICAL FACTORS PREDECTING T790M MUTATION IN NON-SMALL CELL LUNG CANCER PROGRESSED AFTER FIRST- AND SECOND-GENERATION TKI TREATMENT

Objective: We aimed to identify the T790M mutation rate and clinical factors predicting the occurrence of acquired T790M mutations in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations after first- and second-generation tyrosine kinase inhibitor (TKI) treatment. Method: The EGFR-mutant NSCLC patients who experienced progression after first- and second-generation TKI treatment and underwent testing for EGFR using plasma samples between January 2021 and April 2023 were enrolled. The T90M mutation rate and related clinical factors were evaluated. We utilized the Chi-square test or Fisher’s exact test for univariate analysis and multivariable logistic binary regression for multivariate analysis. Results: A total of 247 patients were eligible for the study. Patients harbored the exon 19 deletion mutation (Del19), exon 21 L858R point mutation, and uncommon mutations in 63.2%, 34.4%, and 2.4% of cases, respectively. The overall T790M mutation rate was 33.6%. In multivariate analyses, the Del19 mutation versus L858R mutation, duration of first-line TKI exceeding 12 months versus below 12 months, and solitary lesion progression versus multiple lesion progression were identified as favorable prognostic factors for the occurrence of T790M mutation. Conclusion: Patients with EGFR exon 19 deletion, a prolonged treatment duration of first-line EGFR-TKI, and solitary lesion progression pattern are more likely to acquire the T790M mutation, as detected by the PCR method in plasma samples.

EGFR-mutant NSCLC may remodel TME from non-inflamed to inflamed through acquiring resistance to EGFR-TKI treatment

BackgroundEGFR-TKI represent the standard first-line therapy for advanced NSCLC harboring EGFR mutations. However, resistance to EGFR-TKI inevitably develops in nearly all patients. Previous clinical study have demonstrated that, some patients that failed EGFR-TKI therapy show a benefit outcome from immunotherapy. Our objective is to explore the immune microenviroment remodeling induced by EGFR-TKI treatment in EGFR mutant lung cancer patients and to investigate the immune cell types and potential molecular signatures involved. MethodsA cohort of 37 EGFR mutant advanced-stage NSCLC patients, who are resistant to at least one type of TKI treatment, was retrospectively established. Both pre-treatment and TKI resistance tumor FFPE samples of each pairs were collected. Transcriptional profiling and bioinformatics analysis were employed to evaluate the change of immune associated hallmarks before and after EGFR-TKI therapy. ResultsTumor samples after EGFR-TKI treatment displayed enrichment of proinflammatory signaling like interferon-γ, allograft rejection and inflammatory response. Of note, cytotoxic factor granzyme A as well as PD-L1 were found to be more expressed in EGFR-TKI resistance samples. Approximately 33.3 % (11/33) of EGFR-TKI treated samples were classified as “hot” tumor, especially for EGFR L858R mutated NSCLC patients (46.7 %,7/15). Effector cells were significantly overexpressed in ‘hot’ tumors feature following TKI resistance. In addition, we found that four effector genes (CD8A, CDB8, GZMB, GZMK) showed higher expression in ‘hot’ tumors post-TKI resistance, and its 4-gene effector cell signature was found to have a good correlation with survival benefit in external immunotherapy database. ConclusionsTKI treatment may initiate immune activation in EGFR mutant NSCLC, leading to changes in immune cell infiltration following TKI resistance. We mechanistically explored that this might be due to an increased immune response caused by the rise in effector cells post-TKI resistance.

Detection of EGFR exon 20 insertion mutations in non-small cell lung cancer: implications for consistent nomenclature in precision medicine

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (E20ins) are the third most frequent mutations observed in non-small cell lung cancer, accounting for approximately 1-10% of all EGFR mutations. In the era of precision medicine and targeted therapies, consistent naming of genetic alterations is crucial to avoid confusion and errors. However, the annotation of EGFR E20ins mutations has been inconsistent, leading to confusion in the scientific literature and product documentation. In this study, our primary objective was to investigate the usage of different annotation related to EGFR E20ins in independent studies. Additionally, we assessed the distribution of EGFR E20ins mutations and estimated the detection coverage expected from each available EGFR E20ins detection assay. A total of 1,418 EGFR E20ins mutations were collected from six studies (FoundationInsights, Geneseeq Technology Inc, mobocertinib phase I/II trial, poziotinib phase II trial, sunvozertinib phase I trial, and Samsung Medical Center) and reorganised according to Human Genome Variation Society (HGVS) nomenclature. Our analysis revealed that the majority of EGFR E20ins mutations requiring correction were 'insertion' or 'deletion-insertion', which should be appropriately designated as 'duplication'. Additionally, duplicated variants were reported using different annotations in each study, and furthermore, even identical variant sequences were annotated differently within the same study. In all six studies, p.A767_V769dup and p.S768_D770dup were the most frequently observed EGFR E20ins. The Oncomine Dx Target Test showed the highest patient coverage at 77.2%, followed by the Droplex EGFR Mutation Test v2 with a patient coverage of 70.5% for EGFR E20ins patients. To ensure comprehensive coverage in real-world settings, it is essential to standardise the annotations for each variant, for example using the HGVS nomenclature. The accurate classification and analysis of drug responsiveness in EGFR E20ins necessitate consideration of the nomenclature, particularly with respect to the locations where the actual mutations occur.

Novel therapeutic strategies for rare mutations in non-small cell lung cancer

Lung cancer is still the leading cause of cancer-related mortality. Over the past two decades, the management of non-small cell lung cancer (NSCLC) has undergone a significant revolution. Since the first identification of activating mutations in the epidermal growth factor receptor (EGFR) gene in 2004, several genetic aberrations, such as anaplastic lymphoma kinase rearrangements (ALK), neurotrophic tropomyosin receptor kinase (NTRK) and hepatocyte growth factor receptor (MET), have been found. With the development of gene sequencing technology, the development of targeted drugs for rare mutations, such as multikinase inhibitors, has provided new strategies for treating lung cancer patients with rare mutations. Patients who harbor this type of oncologic driver might acquire a greater survival benefit from the use of targeted therapy than from the use of chemotherapy and immunotherapy. To date, more new agents and regimens can achieve satisfactory results in patients with NSCLC. In this review, we focus on recent advances and highlight the new approval of molecular targeted therapy for NSCLC patients with rare oncologic drivers.

Predictive value of spectral computed tomography parameters for EGFR gene mutation in non-small–cell lung cancer

To explore the predictive value of morphological signs and quantitative parameters from spectral CT for EGFR gene mutations in intermediate and advanced non-small-cell lung cancer (NSCLC). This retrospective observational study included patients with intermediate or advanced NSCLC at Xinjiang Medical University Affiliated Tumor Hospital between January 2017 and December 2019. The patients were divided into the EGFR gene mutation-positive and -negative groups. Seventy-nine patients aged 60.75±9.66 years old were included: 32 were EGFR mutation-positive, and 47 were negative. There were significant differences in pathological stage (P<0.001), tumor diameter (P=0.019), lobulation sign, intrapulmonary metastasis, mediastinal lymph node metastasis, distant metastasis (P<0.001), bone metastasis (P<0.001), arterial phase normalized iodine concentration (NIC) (P=0.001), venous phase NIC (P=0.001), slope of the energy spectrum curve (λ) (P<0.001), and CT value at 70 keV in arterial phase (P=0.004) and venous phase (P=0.003) between the EGFR mutation-positive and -negative patients. The multivariable logistic regression analysis showed that intrapulmonary metastasis, distant metastasis, venous phase NIC, venous phase λ, and pathological stage were independent factors predicting EGFR gene mutations, with high diagnostic power (AUC=0.975, 91.5% sensitivity, and 90.6% specificity). The pathological stage and the spectral CT parameters of intrapulmonary metastasis, distant metastasis, venous phase NIC, and venous phase λ might pre-operatively predict EGFR gene mutations in intermediate and advanced NSCLC.

Evaluation of Prevalence and Patterns of Oncogenic Driver Mutations in Nonsmall Cell Lung Cancer in a Tertiary Care Center - A Cross-sectional Study

Abstract Background: Better understanding of the molecular pathways that drive malignancy led to the development of agents that target specific molecular pathways that target the malignant cells. Identification of specific driver mutation is the key to targeted therapy in advanced nonsmall-cell carcinomas. This study was done to assess the prevalence and patterns of driver oncogenic mutations in nonsmall cell lung cancer (NSCLC) among the patients subjected to molecular study in a tertiary care center. Materials and Methods: This is a cross-sectional study done in 1.5 years in a tertiary care center in 103 patients diagnosed with NSCLC. Patients with NSCLC were subjected to molecular study in the department of oncology as a part of management. The demographics, clinical details, laboratory parameters, and pathology were noted from the medical records. The molecular study was done from the biopsied specimen in an outside laboratory. The frequency of driver oncogenic mutation, along with other clinical parameters was studied. Results: Out of 103 patients subjected to the study, 46 (44.6%) subjects had driver oncogenic mutations. Among them, 38 (36.9%) subjects had epidermal growth factor receptor mutations, 7 (6.8%) had anaplastic lymphoma kinase mutations, and 1 (1%) had ROS mutation. Conclusion: The frequency of driver oncogenic mutations is higher in our population, compared to the Western population. From a clinical point of view, there is a dire need for advocacy and increased awareness for screening and early detection of thoracic malignancies, and advanced treatment options, including targeted therapy, so that disease-related morbidity and mortality can be reduced to an extent.

The association of EGFR amplification with aberrant exon 20 insertion report using the cobas EGFR Mutation Test v2.

Determining the exact type of epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutation in lung cancer has become important. We found that not all ex20ins mutations reported by cobas EGFR test v2 could be validated by Sanger sequencing even using surgical specimens with high tumor contents. This study aimed to validate the ex20ins results reported by the cobas test and to determine whether there were clinicopathological factors associated with aberrant cobas ex20ins report. In total, 123 cobas-reported cases with ex20ins were retrospectively collected and validated by Sanger sequencing and Idylla assay. Clinicopathological features between ex20ins cobas+/Sanger+ group (n = 71) and cobas+/Sanger- group (n = 52) were compared. The Idylla assay detected ex20ins in 82.6% of cobas+/Sanger+ cases but only in 4.9% of cobas+/Sanger- cases. The cobas+/Sanger- group was significantly associated with higher tumor contents, poorly differentiated patterns, tumor necrosis, and a lower internal control cycle threshold value reported by the Idylla which suggesting the presence of increased EGFR gene copy numbers. EGFR fluorescence in situ hybridization (FISH) revealed the majority of cobas+/Sanger- group had EGFR high copy number gain (16%) or amplification (76%) according to the Colorado criteria. Among cases reported to have concomitant classic EGFR and ex20ins mutations by the cobas, the classic EGFR mutations were all detected by Sanger sequencing and Idylla, while the ex20ins mutations were undetected by Sanger sequencing (0%) or rarely reported by Idylla assay (3%). FISH revealed high EGFR copy number gain (17.9%) and amplification (79.5%) in cases reported having concomitant classic EGFR and ex20ins mutations by the cobas. This study demonstrated an unusually high frequency of EGFR amplification in cases with aberrant cobas ex20ins report which could not be validated by Sanger sequencing or Idylla assay. Ex20ins reported by the cobas test should be validated using other methods especially those reported having concomitant ex20ins and classic EGFR mutations.

Predicting epidermal growth factor receptor mutations in non-small cell lung cancer through dual-layer spectral CT: a prospective study

ObjectiveTo determine whether quantitative parameters of detector-derived dual-layer spectral computed tomography (DLCT) can reliably identify epidermal growth factor receptor (EGFR) mutation status in patients with non-small cell lung cancer (NSCLC).MethodsPatients with NSCLC who underwent arterial phase (AP) and venous phase (VP) DLCT between December 2021 and November 2022 were subdivided into the mutated and wild-type EGFR groups following EGFR mutation testing. Their baseline clinical data, conventional CT images, and spectral images were obtained. Iodine concentration (IC), iodine no water (INW), effective atomic number (Zeff), virtual monoenergetic images, the slope of the spectral attenuation curve (λHU), enhancement degree (ED), arterial enhancement fraction (AEF), and normalized AEF (NAEF) were measured for each lesion.ResultsNinety-two patients (median age, 61 years, interquartile range [51, 67]; 33 men) were evaluated. The univariate analysis indicated that IC, normalized IC (NIC), INW and ED for the AP and VP, as well as Zeff and λHU for the VP were significantly associated with EGFR mutation status (all p < 0.05). INW(VP) showed the best diagnostic performance (AUC, 0.892 [95% confidence interval {CI}: 0.823, 0.960]). However, neither AEF (p = 0.156) nor NAEF (p = 0.567) showed significant differences between the two groups. The multivariate analysis showed that INW(AP) and NIC(VP) were significant predictors of EGFR mutation status, with the latter showing better performance (p = 0.029; AUC, 0.897 [95% CI: 0.816, 0.951] vs. 0.774 [95% CI: 0.675, 0.855]).ConclusionQuantitative parameters of DLCT can help predict EGFR mutation status in patients with NSCLC.Critical relevance statementQuantitative parameters of DLCT, especially NIC(VP), can help predict EGFR mutation status in patients with NSCLC, facilitating appropriate and individualized treatment for them.Key PointsDetermining EGFR mutation status in patients with NSCLC before starting therapy is essential.Quantitative parameters of DLCT can predict EGFR mutation status in NSCLC patients.NIC in venous phase is an important parameter to guide individualized treatment selection for NSCLC patients.Graphical

Genome-wide CRISPR screens identify the YAP/TEAD axis as a driver of persister cells in EGFR mutant lung cancer

Most lung cancer patients with metastatic cancer eventually relapse with drug-resistant disease following treatment and EGFR mutant lung cancer is no exception. Genome-wide CRISPR screens, to either knock out or overexpress all protein-coding genes in cancer cell lines, revealed the landscape of pathways that cause resistance to the EGFR inhibitors osimertinib or gefitinib in EGFR mutant lung cancer. Among the most recurrent resistance genes were those that regulate the Hippo pathway. Following osimertinib treatment a subpopulation of cancer cells are able to survive and over time develop stable resistance. These ‘persister’ cells can exploit non-genetic (transcriptional) programs that enable cancer cells to survive drug treatment. Using genetic and pharmacologic tools we identified Hippo signalling as an important non-genetic mechanism of cell survival following osimertinib treatment. Further, we show that combinatorial targeting of the Hippo pathway and EGFR is highly effective in EGFR mutant lung cancer cells and patient-derived organoids, suggesting a new therapeutic strategy for EGFR mutant lung cancer patients.

Prevalence and Associations of Co-occurrence of NFE2L2 Mutations and Chromosome 3q26 Amplification in Lung Cancer.

Background NFE2L2 (nuclear factor erythroid-2-related factor-2) encodes a basic leucine zipper (bZIP) transcription factor and exhibits variations in various tumor types, including lung cancer. In this study, we comprehensively investigated the impact of simultaneous mutations on the survival of NFE2L2 -mutant lung cancer patients within specific subgroups. Methods A cohort of 1,103 lung cancer patients was analyzed using hybridization capture-based next-generation sequencing. Results The NFE2L2 gene had alterations in 3.0% (33/1,103) of lung cancer samples, including 1.5% (15/992) in adenocarcinoma and 16.2% (18/111) in squamous cell carcinoma. Thirty-four variations were found, mainly in exons 2 (27/34). New variations in exon 2 (p.D21H, p.V36_E45del, p.F37_E45del, p.R42P, p.E67Q, and p.L76_E78delinsQ) were identified. Some patients had copy number amplifications. Co-occurrence with TP53 (84.8%), CDKN2A (33.3%), KMT2B (33.3%), LRP1B (33.3%), and PIK3CA (27.3%) mutations was common. Variations of NFE2L2 displayed the tightest co-occurrence with IRF2 , TERC , ATR , ZMAT3 , and SOX2 ( p < 0.001). In The Cancer Genome Atlas Pulmonary Squamous Carcinoma project, patients with NFE2L2 variations and 3q26 amplification had longer median survival (63.59 vs. 32.04 months, p = 0.0459) and better overall survival. Conclusions NFE2L2 mutations display notable heterogeneity in lung cancer. The coexistence of NFE2L2 mutations and 3q26 amplification warrants in-depth exploration of their potential clinical implications and treatment approaches for affected patients.

Abstract LB266: AMG510-mediated inactivation of BCL-xL protein promotes Gasdermin-E-dependent pyroptosis in KRAS-G12C mutant non-small cell lung cancer

Abstract Introduction: Studies have shown that molecular targeted therapy can mediate Gasdermin-E (GSDME) dependent pyroptosis. However, GSDME expression is suppressed in many mutated patients, including those with KRAS-G12C-mutated non-small-cell lung cancer (NSCLC). The efficacy of AMG510 against KRAS-G12C inhibition (KRAS-G12Ci) is constrained by tumor recurrence. Pyroptosis is widely involved in the occurrence and development of tumors. However, the role and molecular mechanism of AMG510 in pyroptosis have not been well identified. Here, we demonstrate that inactivation of anti-apoptotic Bcl-2 family members during KRAS-G12Ci treatment enhances pyroptosis, which then promotes the sensitivity of AMG510 in NSCLC. Methods: We assessed pyroptosis using live cells imaging, LDH release assays, ELISA, Western blotting, and flow cytometry. In vitro assays were used to investigate the function of GSDME. Co-culture between peripheral blood mononuclear cells (PBMCs) and KRAS-G12C mutant lung cancer cell lines explored the anti-tumor immunity of cytotoxic T lymphocytes affected by knockdown of GSDME. The molecular mechanism was determined using bulk RNA sequencing, molecular cloning technology, and Western blotting. Results: We demonstrated that KRAS G12Ci treatment promotes cleavage of GSDME, release of high mobility group protein B1 (HMGB1), and LDH, markers of pyroptotic cell death. Additionally, GSDME was significantly downregulated in KRAS-mutated NSCLC compared with patients of KRAS wild type in TCGA cohort, while significantly upregulated after AMG510 treatment and downregulated after AMG510 resistance in vitro assay. We identified that KRAS-G12Ci resulted in the inactivation of BCL-xL, leading to caspase-3-dependent cleavage of gasdermin E. Conversely, amplification of BCL-xL downregulated the expression of GSDME, therefore suppressing the process of pyroptosis. GSDME knockdown in KRAS-G12C mutant lung cancer cell lines showed defective HMGB1 release, reduced caspase-3 viability, and decreased granzyme B and IFN-γ secretion by CD8+ T cells in response to KRAS-G12Ci, and more frequent tumor cell growth. Conclusion: Our findings indicate that GSDME-dependent pyroptosis is a critical determinant of KRAS-G12C-targeted inhibitor AMG510, and through the modulation exerted by the Bcl-2 family protein BCL-xL upon GSDME. These findings suggest that activation of GSDME may provide an effective strategy to sensitize cancer cells to KRAS-G12Ci treatment. Citation Format: Linfeng Luo, Anlin Li, Wei Du, Maojian Chen, JIng Li, Yixin Zhou, Li Zhang, Shaodong Hong. AMG510-mediated inactivation of BCL-xL protein promotes Gasdermin-E-dependent pyroptosis in KRAS-G12C mutant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB266.

Abstract LB359: Lung epithelial specific IL-1R promotes K-ras mutant lung cancer by inducing angiogenesis that might be medicated via myeloid tumor microenvironment

Abstract As the leading cause of cancer-related deaths worldwide, the development of targeted therapeutics and immunotherapies as a means for treating lung cancer remains crucial. Non-small cell lung cancer (NSCLC), the most common histological subtype accounting for 85%, predominantly arises from lung adenocarcinoma with driver mutations in the K-ras oncogene (KM-LUAD). Studies have shown that KM-LUAD progression partly occurs through activation of the NF-κB pathway initiating an inflammatory response and creating a pro-tumor microenvironment. Notably, the pro-inflammatory cytokine IL-1β a potent activator and product of the NF-κB pathway is elevated in the lungs and sera of KM-LUAD patients. Our preliminary studies have shown that IL-1β blockade reprograms the lung immune microenvironment to that of an anti-tumor immune phenotype in a mouse model of KM-LUAD driven by lung epithelial cell-specific expression of KRASG12D (CCSPCre/LSL-KRASG12D, CC-LR mouse), suggesting that indeed this cytokine mediates tumor-promoting inflammation in KM-LUAD pathogenesis. Yet, cell-specific mechanisms that underlie tumor-promoting roles of IL-1β signaling are still poorly understood. Thus, we sought to elucidate the role of IL-1β signaling via its ability to bind to its receptor, IL-1R, in the context of KM-LUAD by conditionally knocking out the IL-1R in KRAS-mutant lung epithelial cells in CC-LR mice. Tumor development as well as immune microenvironment in 14 and 18-week-old CC-LR mice with epithelial specific conditional knockout of IL-1R (LR/IL-1RΔ/Δ) in comparison to age- and sex-matched control CC-LR littermates were studied. Notably reduced tumor burden in LR/IL-1RΔ/Δ mice with an interesting shift toward atypical adenomatous hyperplasia (AHH) lesion formation was evident when compared to their CC-LR counterpart. Having previously shown that targeting IL-1R leads to a reduction in the myeloid cell compartment also known for the regulation and production of angiogenic markers, an immunohistochemical evaluation of the angiogenic marker ERG was performed, showing a significantly diminished expression in tissue collected from LR/IL-1RΔ/Δ mice. Further studies assessing the role of angiogenic modulation by IL-1R in the context of KM-LUAD progression and its regulation by myeloid cells are currently under investigation. Overall, these findings provide insight into cell-specific mechanisms underlying the tumor-promoting effects of IL-1β signaling and support the role of tumor cell-intrinsic factors in tumor progression via shaping the tumor microenvironment. Citation Format: Avantika Krishna, Michael J. Clowers, Bo Yuan, Vivian Ha, Katherine Larsen, Nastaran Karimi, Arnav Gaitonde, Jocelynn Colunga, Maria T. Grimaldo, Maria Jose Arredondo Sancristobal, Valentina Villalba-Sabat, Angelica Baca De Anda, Yasmina Rezai, Jyotika Sharma, Humam Kadara, Seyed Javad Moghaddam. Lung epithelial specific IL-1R promotes K-ras mutant lung cancer by inducing angiogenesis that might be medicated via myeloid tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB359.

Mobocertinib in Patients with EGFR Exon 20 Insertion-Positive Non-Small Cell Lung Cancer (MOON): An International Real-World Safety and Efficacy Analysis.

EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24-45). The response rate in treatment-naïve patients was 27% (95% CI, 8-58). The median progression-free and overall survival was 5 months (95% CI, 3.5-6.5) and 12 months (95% CI, 6.8-17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.

Efficacy of targeted therapy in patients with non-small cell lung cancer harboring very rare mutations in EGFR exon 18.

Somatic mutations in epidermal growth factor receptor (EGFR) exon 18 are classified as uncommon or rare mutations in non-small cell lung cancer (NSCLC), in this context, other than G719X or E709X exon 18 mutations are even more rare and heterogeneous. In such scenario, first line treatment options are still debated. The aim of this study was to investigate the response of NSCLC patients harboring very rare exon 18 mutations to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This retrospective descriptive study included 105 patients with NSCLC harboring mutations in EGFR exon 18 diagnosed at West China Hospital. The clinical response to EGFR-TKIs was evaluated according to different classifications of mutations in 45 NSCLC patients: 39 harboring G719X or E709X mutations and 6 harboring very rare mutations in EGFR exon 18. Among 105 patients, 84% (88/105) harbored rare mutations in EGFR exon 18, including G719X and E709X mutations. The remaining 16% (17/105) had very rare mutations in EGFR exon 18, including E709_710delinsX and G724S. For the subsequent efficacy analysis of EGFR-TKI in 45 NSCLC patients, patients harboring very rare mutations achieved a favorable disease control rate (DCR) of 100% and had a median progression-free survival (PFS) of 17.2 months, which was not significantly different compared to patients harboring G719X or E709X (P=0.59). EGFR-TKIs showed great efficacy in terms of responses and survival in patients harboring exon 18 EGFR rare mutations. This may justify the use of targeted therapies as a potential treatment strategy for these patients.

84 National Real World Study of Adjuvant Osimertinib in Resected EGFR Mutated Lung Cancer

84 National Real World Study of Adjuvant Osimertinib in Resected EGFR Mutated Lung Cancer

Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.

Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with poor prognosis and resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We previously showed that KEAP1 mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. Here, using preclinical patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the glutamine antagonist prodrug DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumors by inhibiting glutamine-dependent nucleotide synthesis and promoting antitumor T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we demonstrate that DRP-104 reverses T cell exhaustion, decreases Tregs, and enhances the function of CD4 and CD8 T cells, culminating in an improved response to anti-PD1 therapy. Our preclinical findings provide compelling evidence that DRP-104, currently in clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer.

Development, testing and validation of a targeted NGS-panel for the detection of actionable mutations in lung cancer (NSCLC) using anchored multiplex PCR technology in a multicentric setting.

Lung cancer is a paradigm for a genetically driven tumor. A variety of drugs were developed targeting specific biomarkers requiring testing for tumor genetic alterations in relevant biomarkers. Different next-generation sequencing technologies are available for library generation: 1) anchored multiplex-, 2) amplicon based- and 3) hybrid capture-based-PCR. Anchored multiplex PCR-based sequencing was investigated for routine molecular testing within the national Network Genomic Medicine Lung Cancer (nNGM). Four centers applied the anchored multiplex ArcherDX-Variantplex nNGMv2 panel to re-analyze samples pre-tested during routine diagnostics. Data analyses were performed by each center and compiled centrally according to study design. Pre-defined standards were utilized, and panel sensitivity was determined by dilution experiments. nNGMv2 panel sequencing was successful in 98.9% of the samples (N = 90). With default filter settings, all but two potential MET exon 14 skipping variants were identified at similar allele frequencies. Both MET variants were found with an adapted calling filter. Three additional variants (KEAP1, STK11, TP53) were called that were not identified in pre-testing analyses. Only total DNA amount but not a qPCR-based DNA quality score correlated with average coverage. Analysis was successful with a DNA input as low as 6.25ng. Anchored multiplex PCR-based sequencing (nNGMv2) and a sophisticated user-friendly Archer-Analysis pipeline is a robust and specific technology to detect tumor genetic mutations for precision medicine of lung cancer patients.