Actionable Driver Mutations Research Articles

Concurrent EGFR mutation and SMARCA4 deficiency in non-small cell lung cancer: A case report and literature review.

SMARCA4-deficient non-small cell lung cancer (NSCLC) represents a highly aggressive subtype with poor prognosis. While clinical studies have identified common co-mutations in TP53, LRP1B, STK11, KEAP1, and KRAS, actionable driver mutations such as EGFR or ALK are rarely reported in conjunction with SMARCA4 deficiency. This case presents a rare instance of NSCLC featuring both an EGFR exon 21 L858R mutation and SMARCA4 deficiency, highlighting the challenges in treatment and the need for novel therapeutic strategies. A 79-year-old female patient presented with concerns of a lung mass, suspected to be peripheral lung cancer based on diagnostic imaging. Histopathological evaluation confirmed SMARCA4-deficient NSCLC. Molecular genetic analysis further revealed an EGFR exon 21 L858R mutation. The patient was initially treated with osimertinib, an EGFR tyrosine kinase inhibitor. Upon disease progression, treatment was adjusted to include anlotinib in combination with ongoing osimertinib. The initial treatment with osimertinib led to partial remission. However, disease progression necessitated a change in therapy. The combination treatment stabilized the disease temporarily, achieving a stable disease status. This case underscores the transient efficacy of targeted therapy in SMARCA4-deficient NSCLC with concurrent EGFR mutations. It highlights the need for continuous therapeutic adjustments and emphasizes the importance of further research into effective strategies for treating this complex and challenging subset of NSCLC, as current modalities have limitations in sustained efficacy.

Systemic Therapy for Metastatic Pancreatic Cancer-Current Landscape and Future Directions.

Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer-associated mortality, with a rising global incidence. A paucity of strong predictive risk factors mean screening programmes are difficult to implement. Historically, a lack of identifiable and actionable driver mutations, coupled with a relatively immunosuppressed tumour microenvironment, has led to a reliance on cytotoxic chemotherapy. The NAPOLI-3 trial has reported data supporting consideration of NALIRIFOX as a new first-line standard of care. Kirsten Rat Sarcoma Virus (KRAS) G12D mutations are present in >90% of all PDAC's; exciting breakthroughs in small molecule inhibitors targeting KRAS G12D may open new modalities of treatment, and therapies targeting multiple KRAS mutations are also in early clinical trials. Although immunotherapy strategies to date have been disappointing, combination with chemotherapy and/or small molecule inhibitors hold promise and warrant further exploration.

Co-Occurring Driver Genomic Alterations in Advanced Non-Small-Cell Lung Cancer (NSCLC): A Retrospective Analysis.

Background: Actionable driver mutations account for 40-50% of NSCLC cases, and their identification clearly affects treatment choices and outcomes. Conversely, non-actionable mutations are genetic alterations that do not currently have established treatment implications. Among co-occurring alterations, the identification of concurrent actionable genomic alterations is a rare event, potentially impacting prognosis and treatment outcomes. Methods: We retrospectively evaluated the prevalence and patterns of concurrent driver genomic alterations in a large series of NSCLCs to investigate their association with clinicopathological characteristics, to assess the prognosis of patients whose tumor harbors concurrent alterations in the genes of interest and to explore their potential therapeutic implications. Results: Co-occurring driver alterations were identified in 26 out of 1520 patients with at least one gene alteration (1.7%). Within these cases, the incidence of concurrent actionable gene alterations was 39% (0.7% of the overall cohort). Among compound actionable gene mutations, EGFR was the most frequently involved gene (70%). The most frequent association was EGFR mutations with ROS1 rearrangement. Front-line targeted treatments were the preferred approach in patients with compound actionable mutations, with dismal median PFS observed (6 months). Conclusions: Advances in genomic profiling technologies are facilitating the identification of concurrent mutations. In patients with concurrent actionable gene alterations, integrated molecular and clinical data should be used to guide treatment decisions, always considering rebiopsy at the moment of disease progression.

Histologic transformation of non-small-cell lung cancer in response to tyrosine kinase inhibitors: Current knowledge of genetic changes and molecular mechanisms.

Lung cancer is the leading cause of cancer death and includes two major types: non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), accounting for 85% and 15% of cases, respectively. Non-small-cell lung cancer harboring actionable driver mutations is generally treated with tyrosine kinase inhibitors (TKIs) molecularly targeting individual oncogenes. Although TKIs have greatly contributed to better clinical outcomes, acquired resistance to them inevitably occurs. Histologic or lineage transformation is a rare but well-documented off-target mechanism associated with acquired resistance, and has been identified in settings following treatment with multiple different TKIs and other drugs. It includes neuroendocrine transformation, squamous cell transformation, and epithelial-to-mesenchymal transition. Here, we review the clinicopathologic features of transformed tumors and current understanding of the key genetic alterations and biologic mechanism of lineage transformation in NSCLC, particularly TKI-triggered transformation.

ALK testing patterns in early-stage non-small cell lung cancer: A real-world evidence study.

8074 Background: Comprehensive biomarker testing in advanced non-small cell lung cancer (aNSCLC) is standard of care, but disparities exist. As new clinical data emerge in early disease (eNSCLC), the set of actionable lung driver mutations (LDMs) and therefore the testing landscape in that setting will change. In particular, following the results of the ALINA trial, therapies that target ALK fusions are anticipated to become part of routine treatment of eNSCLC in 2024.This study thus sought to identify the factors associated with receipt of timely ALK testing in eNSCLC, prior to this shift. Methods: We retrospectively analyzed patients with resected stage I-IIIa NSCLC diagnosed between 2018-2023 using the expanded nationwide (US-based) de-identified Flatiron Health EHR-derived database; data were consolidated from approximately 280 US cancer clinics (≅800 sites of care), using natural language processing with machine learning (ML) to extract patient characteristics. The primary endpoint was ALK testing results (by any modality) within 90 days of initial diagnosis. We used multivariable logistic regression to assess the association between clinico-demographic characteristics and likelihood of testing. Results: The sample contained 21,982 stage I-IIIa patients. Of these, 6,685 (30%) were tested within 90 days, and 15,297 (70%) were not. Patients were more likely to be tested within 90 days if they were diagnosed in more recent years (2023 vs. 2018 odds ratio (OR) 2.12); had no history of smoking (OR 1.21); had highest socioeconomic status (SES) quintile (OR vs. lowest SES 1.14); had more advanced disease (stage IIIa vs. stage I OR 2.43); or were treated in a community setting (OR vs. academic 1.13), all p < 0.05. Patients with Medicare insurance (OR vs. commercial insurance 0.89, p = 0.014) or squamous histology (OR vs. non-squamous 0.46, p < 0.01) were less likely to be tested. There were no significant differences between black and white patients (OR 0.91, p = 013). Conclusions: In this real-world analysis of patients diagnosed between 2018-2023 most patients did not have testing within 90 days of diagnosis. Our data show variation in the baseline probability of testing with respect to clinico-demographic factors. Given that barriers to testing persist in aNSCLC, this suggests that once ALK inhibitors become part of routine care in eNSCLC, some groups might be less likely to be tested and therefore to receive efficacious targeted treatment. Preemptive measures such as education of patients, providers, payers, and policy makers could help prevent disparities from emerging.

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 < 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.

Ethnic disparities in biomarker testing of patients with metastatic NSCLC in the United States: A real-world analysis.

e20617 Background: National Comprehensive Cancer Network guidelines recommend biomarker testing prior to intervention in metastatic non-small cell lung cancer (mNSCLC). However, biomarker testing remains low, particularly in minorities, especially when targeted therapy against actionable driver mutations improves outcomes and quality of life significantly. We sought to determine testing rates and assess disparities between Hispanic and non-Hispanic Whites. Methods: A retrospective cohort study was conducted in accordance with "strengthening the reporting of observational studies in epidemiology" (STROBE) guidelines. All Hispanic and non-Hispanic White patients across a US oncology-focused hospital consortium (Guardian Research Network) were identified from 01/2018 to 01/2023. Socio-demographic details, clinical profiles, and details related to biomarker testing, treatment, and clinical outcomes were extracted. We also ascertained the area deprivation index (ADI) based on zip code as a surrogate for socio-economic stratification. We grouped patients into validated quintiles of ADI. We extracted testing details of the most common driver mutations – EGFR, ALK, KRASG12C, and PDL1. Data were analyzed using descriptive and inferential statistics. Results: Out of 4898 eligible patients with mNSCLC, 9.89% (n = 484/4898) were Hispanic, and 90.11% (n = 4414/4898) were non-Hispanic Whites. Overall testing rates for EGFR, ALK, KRASG12C and PD-L1 were 36.07% (n = 1767/4898), 33.60% (n = 1646/4898), 3.76% n = 184/4898) and 48.42% (n = 2372/4898). EGFR and ALK testing revealed significant differences showing reduced testing in the non-Hispanic White population (Table 1.) Multivariate logistic regression revealed no significant association between ADI, ethnicity and biomarker testing. Four hundred and eighty-three individuals underwent biomarker testing but did not receive treatment. Forty-three percent (n = 205/483) were alive at the time of data extraction, with 5.18% (n = 25/483) identified as Hispanic. Conclusions: Our analysis reveals that biomarker testing remains low in patients with mNSCLC, showing decreased testing rates of EGFR and ALK in non-Hispanic Whites when compared to Hispanic Whites. Purposeful strategies such as education and testing awareness campaigns are warranted to overcome low testing rates in patients diagnosed with mNSCLC.[Table: see text]

Survey of actionable driver mutations KRAS and EGFR in non–small cell lung cancer to evaluate coexisting splicing gene and pathway mutations: A CBioportal database analysis.

8561 Background: Molecularly targeted therapies have advanced treatment for certain cancers, such as lung cancer with specific EGFR or KRAS mutations. However, oftentimes the tumor becomes eventually treatment resistant. This may be partly because cancers driven by EGFR/KRAS mutations may also harbor additional co-occurring genetic alterations. In non-small cell lung cancer (NSCLC), aberrations in RNA splicing pathways have shown substantial implications for tumor behavior and therapeutic responsiveness. Our study focuses on elucidating the interplay between RNA splicing defects and prominent NSCLC mutations. Methods: In this retrospective, cross-sectional study, we analyzed data from 20,719 NSCLC patients enrolled in participating institutions between 2017 and 2022. The data were sourced from the American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange (version 13.0). EGFR L858R, EGFR E746_750del, KRAS G12C, KRAS G12D and other KRAS G12 mutations cases were identified and individually analyzed to abstract co-occurring RNA splicing genomic alterations. Results: Among 20,719 patients with NSCLC, we identified 1309 patients with EGFR L 858R mutation, 1121 patients with EGFR E746_750del mutation, 2446 with KRAS 12C, 852 with KRAS G12D, 1107 with KRAS G12V, 452 with KRAS G12A, 173 with KRAS G12F, and 109 with KRAS G12S. RBM 10 was the most common co-occurring RNA splicing gene for EGFR L 858R (178, 13.6%), followed by CDK12 (31, 2.3%) and SPEN (27, 2 %). Similarly, the most prevalent co-occurring RNA splicing genes with EGFR E746_750del were RBM 10 (38, 3.4%) and SPEN (23, 2 %). RBM 10 was the most prevalent co-existing RNA splicing gene for KRAS G12C (211, 8.6 %), KRAS G12D (63, 7.4 %), KRAS G12V (80, 7.2%), KRAS G12A (59, 13.1%), KRAS G12F (12, 7.0%), KRAS G12S (11, 10.1%) and KRAS G12R (6, 8%). Conclusions: Our study uncovers a crucial link between EGFR and KRAS mutations in NSCLC and RNA splicing gene dysregulation, particularly involving RBM10. Further research in this field is warranted as targeting RNA splicing, alone or alongside existing targeted inhibitors, could substantially enhance treatment efficacy for EGFR+ or KRAS+ NSCLC patients. [Table: see text]

Abstract PO2-20-08: Metastatic Lung Cancer Masquerading as Metaplastic Breast Cancer

Abstract Background Metaplastic breast carcinoma (MBC) is an unusual malignancy that presents a diagnostic challenge due to the presence of varying cytomorphologies that can be seen in benign and malignant tumors. We posit that metastatic disease to the breast, itself an uncommon entity, should be considered in the differential diagnosis of MBC. We report a unique case of metastatic non-small cell lung cancer (NSCLC) with an actionable driver mutation that presented as a symptomatic breast mass and was initially considered to represent MBC. Report A 74-year-old woman with a 22-pack-year smoking history presented to the breast clinic complaining of a palpable left breast mass that had grown rapidly over the previous month. Ultrasound-guided biopsy of the breast mass revealed high-grade poorly differentiated carcinoma. On immunohistochemical (IHC) evaluation, tumor cells were strongly positive for epithelial markers CAM5.2 and keratin AE1/AE3, weakly positive for breast cancer (BC) marker TRPS1, and negative for BC marker GATA3, squamous cell carcinoma markers p63 and CK5, and melanoma marker SOX10. Metaplastic triple-negative BC was diagnosed. However, concern remained for metastasis from a non-breast primary tumor due to the patient’s constitutional symptoms such as fatigue, night sweats, and 60-pound unintentional weight loss over the previous year, as well as interval development of a suspicious nodular rash on her right upper extremity. An FDG-PET-CT was obtained and demonstrated a hypermetabolic left lung consolidation (maximum SUV 33.3) measuring 7.2 cm, pulmonary nodules, and extensive thoracic lymphadenopathy. Due to rising suspicion for a primary lung tumor, additional IHC staining on the original breast biopsy was requested. Tumor cells were positive for TTF-1, consistent with metastatic lung adenocarcinoma. Tissue next-generation sequencing (NGS) identified a MET exon 14 skipping mutation, making the patient eligible for treatment with capmatinib, a first-line kinase inhibitor targeted therapy for metastatic NSCLC. At the time of this report, the patient has completed a course of palliative stereotactic body radiation therapy to the left lung and started capmatinib 400 mg BID, which she is tolerating well. Her first restaging scans after treatment initiation will be obtained one week after the time of this report. Conclusion In the absence of heightened suspicion for a non-breast primary tumor, our patient had initially received a diagnosis of triple-negative MBC. This diagnosis would have exposed her to increased treatment-related toxicities from cytotoxic chemotherapy and poor prognosis from MBC without survival benefit from targeted therapy for NSCLC. We advocate for the use of supplemental body imaging, expert and comprehensive IHC evaluation, and multidisciplinary discussion in cases of MBC and undifferentiated breast malignancy to facilitate accurate diagnosis and treatment. Citation Format: Tanmayi Pai, Marte Wasserman, Jason Lewis, Miglena Komforti, James Jakub, Augustine Lee, Yanyan Lou, Pooja Advani, Rohit Rao. Metastatic Lung Cancer Masquerading as Metaplastic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-08.

LIBRETTO-431: Confirming the Superiority of Selpercatinib to Chemotherapy and the Lack of Efficacy of Immune Checkpoint Inhibitors in Advanced RET Fusion-Positive (RET+) NSCLC, Another Unique Never-Smoker Predominant Molecular Subtype of NSCLC.

Selpercatinib, a potent and highly selective RET kinase inhibitor with significant CNS activity, has recently gained US approval for the treatment of NSCLC harboring RET fusions (RET+) based on a large-scale single-arm study. The LIBRETTO-431 trial was the global pivotal registration phase 3 trial comparing selpercatinib to platinum-based chemotherapy with or without pembrolizumab as the first-line treatment of patients with advanced RET+ NSCLC. Never-smokers constituted 67.4% of the RET+ NSCLC patients enrolled. KIF5B-RET made up the vast majority (77%) of the RET+ fusion variant with known fusion partner. The results of this study demonstrated significant improvement in progression-free survival (PFS) benefit as well as impressive intracranial disease response in participants treated with selpercatinib as compared to those treated with chemotherapy, with a HR [hazard ratio] of 0.46 (95% CI 0.33-0.70; P < 0.001) for the intention-to-treat (ITT)-pembrolizumab group and HR of 0.46 (95% CI 0.31-0.70, P < 0.001) for the overall ITT-group of patients. The addition of pembrolizumab to platinum/pemetrexed chemotherapy resulted in numerically identical PFS (11.2 months). These results point to selpercatinib's superiority to traditional chemotherapy regimens in the treatment of NSCLC harboring RET fusions and add to literature on the salience of targeted precision oncology and lack of efficacy of immune checkpoint inhibitor in NSCLC patients with never-smoker predominant actionable driver mutations. RET+ NSCLC should be added to the list of molecular subtypes (EGFR+, ALK+, ROS1+) of NSCLC to be excluded in chemoimmunotherapy trial.

Distinct Driver Pathway Enrichments and a High Prevalence of TSC2 Mutations in Right Colon Cancer in Chile: A Preliminary Comparative Analysis.

Colorectal cancer (CRC) is the second leading cause of cancer deaths globally. While ethnic differences in driver gene mutations have been documented, the South American population remains understudied at the genomic level, despite facing a rising burden of CRC. We analyzed tumors of 40 Chilean CRC patients (Chp) using next-generation sequencing and compared them to data from mainly Caucasian cohorts (TCGA and MSK-IMPACT). We identified 388 mutations in 96 out of 135 genes, with TP53 (45%), KRAS (30%), PIK3CA (22.5%), ATM (20%), and POLE (20%) being the most frequently mutated. TSC2 mutations were associated with right colon cancer (44.44% in RCRC vs. 6.45% in LCRC, p-value = 0.016), and overall frequency was higher compared to TCGA (p-value = 1.847 × 10-5) and MSK-IMPACT cohorts (p-value = 3.062 × 10-2). Limited sample size restricts definitive conclusions, but our data suggest potential differences in driver mutations for Chilean patients, being that the RTK-RAS oncogenic pathway is less affected and the PI3K pathway is more altered in Chp compared to TCGA (45% vs. 25.56%, respectively). The prevalence of actionable pathways and driver mutations can guide therapeutic choices, but can also impact treatment effectiveness. Thus, these findings warrant further investigation in larger Chilean cohorts to confirm these initial observations. Understanding population-specific driver mutations can guide the development of precision medicine programs for CRC patients.

Abstract CT277: BGB-LC-201 (NCT05635708): A phase 2, open-label, multi-arm study of tislelizumab (TIS; anti-PD-1) in combination with investigational agents +/- chemotherapy as first-line treatment for patients with locally advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC)

Abstract Background: Prognosis for locally advanced, unresectable, or metastatic NSCLC remains poor despite advances in the use of immune checkpoint inhibitors (ICI) with or without histology-appropriate chemotherapy (chemo), partly due to innate or adaptive resistance to ICI. Combination therapies aim to overcome resistance to anti-programmed cell death protein-1 or programmed death-ligand-1 (PD-1/PD-L1) therapy and thus improve anticancer activity. This phase 2 study will determine whether adding investigational agents BGB-A445 (OX40 agonistic monoclonal antibody [mAb]), LBL-007 (anti-lymphocyte activation gene-3 mAb), or BGB-15025 (hematopoietic progenitor kinase 1 [HPK1] inhibitor) improves the therapeutic benefit of TIS (anti-PD-1 mAb) +/- chemo in patients with locally advanced, unresectable, or metastatic NSCLC. Methods: The umbrella design allows for the use of multiple investigational drugs, administered alone or in combination, in patients with untreated locally advanced, unresectable, or metastatic NSCLC without actionable driver mutations. Approximately 400 patients aged ≥18 years will be enrolled in 1 of 2 Substudies based on PD-L1 expression and randomized 2:1 to either the experimental or reference arm within each Substudy. Patients in Substudy 1 (PD-L1 ≥50%) will be randomized to receive either TIS (200 mg intravenously [IV] every 3 weeks [Q3W]) in combination with BGB-A445 (2400 mg IV Q3W), LBL-007 (600 mg IV Q3W), or BGB-15025 (experimental arms) or TIS monotherapy (reference arm). Those in Substudy 2 (PD-L1 &amp;lt;50%) will receive TIS + chemo in combination with BGB-A445 (2400 mg IV Q3W), LBL-007 (300 mg, 600 mg, or 1200 mg IV Q3W), or BGB-15025 (experimental arms) or TIS + chemo (reference arm). Patients will receive up to 36 cycles (each cycle lasting 3 weeks) or until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint is investigator-assessed confirmed overall response rate per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; secondary endpoints include investigator-assessed progression-free survival, duration of response, clinical benefit rate, disease control rate (per RECIST v1.1), pharmacokinetics, immunogenicity, and safety. Exploratory endpoints include overall survival, time to response, and relevant biomarker associations with response or resistance to study treatments. Enrollment is ongoing at 66 sites in China, Asia-Pacific, the United States, and the European Union. Citation Format: George Blumenschein, Benjamin Besse, Justin F. Gainor, DingZhi Huang, Steven Kao, Se-Hoon Lee, Luis Paz-Ares, Xin Chen, Wanyu He, Sridharan Gururangan, Kathy Zhang, Caicun Zhou. BGB-LC-201 (NCT05635708): A phase 2, open-label, multi-arm study of tislelizumab (TIS; anti-PD-1) in combination with investigational agents +/- chemotherapy as first-line treatment for patients with locally advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC) [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 CT277.

Abstract 4967: Predicting progression-free survival (PFS) in first-line (1L) immune checkpoint inhibitor (ICI)-treated patients (pts) with advanced non-small cell lung cancer (aNSCLC): Machine learning (ML) application in real-world data

Abstract Introduction: Anti-programmed cell death (ligand)-1 ICIs are the standard of care 1L treatment for pts with aNSCLC without actionable oncogenic driver mutations. Heterogeneity in ICI utilization and outcomes is observed in real-world pts. By leveraging ML in electronic health records (EHRs), we identified predictors influencing key clinical outcomes, and developed a nomogram to predict likelihood of median PFS in 1L ICI-treated aNSCLC pts for potential risk stratification for interventions. Methods: 1L ICI-treated aNSCLC pts without ALK/ROS1/KRAS/BRAF/EGFR alterations were identified in a US oncology EHR database (ConcertAI; Jan 2015-Feb 2023). Survival ML models were trained on 112 clinical and demographic features with 5-fold nested cross-validation. The top predictors, determined by the best-performing ML model through SHapley Additive exPlanations and clinical judgement, were used to create a Cox proportional hazard (CPH) nomogram of median PFS. All models were evaluated using the concordance index (c-index). Patients were categorized as having high and low risk of progression/death at median PFS according to median risk predicted by the nomogram. Results: The study cohort had 4668 pts (median PFS: 6.1 months; 3811 events). The CPH nomogram predicting 6-month PFS had a c-index of 0.60 with the top 10 predictors identified using the XGBoost model (c-index: 0.62). Nomogram predictors included increased number of metastases, ECOG PS, cough suppressant use, WBC counts, and NLR (Table). Median probability of 6-month PFS for low- and high-risk groups was 35.9% and 19.4%, respectively. Conclusions: Future research should validate these findings and evaluate the opportunity to guide clinical practice to optimize outcomes in aNSCLC pts treated with 1L ICIs. Summary of top 10 clinical predictors at baseline Mean HR (95% CI) Max nomogram points Total metastases, n 1.15 (1.11-1.19) 100 ECOG PS, ordinal 1.14 (1.10-1.19) 55 Basophils, % 0.81 (0.73-0.90) 52 Albumin, g/dL 0.81 (0.75-0.87) 46 Chloride, mmol/L 0.98 (0.97-0.99) 46 Cough suppressants/expectorants, n 1.08 (1.03-1.14) 42 NLR 1.03 (1.02-1.05) 33 WBC counts, 103 cells/mL 1.02 (1.01-1.03) 29 PD-L1 expression, % 1.00 (1.00-1.00) 28 Presence of liver metastases 1.26 (1.15-1.39) 24 ECOG PS, Eastern Cooperative Oncology Group performance status; NLR, neutrophils-to-lymphocytes ratio; PD-L1, programmed cell death-ligand 1; WBC, white blood cell. Citation Format: Deep K. Hathi, James Harnett, Ning Wu, Zhenxing Xu, Weishen Pan, T G. Hager, Ruben G. Quek, Shivani Aggarwal, Young Kim, Petra Rietschel, Frank Seebach, Fei Wang, Ying Li. Predicting progression-free survival (PFS) in first-line (1L) immune checkpoint inhibitor (ICI)-treated patients (pts) with advanced non-small cell lung cancer (aNSCLC): Machine learning (ML) application in real-world data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4967.

Long-Term Survival in Patients with Oligometastatic Non-Small Cell Lung Cancer by a Multimodality Treatment-Comparison with Stage III Disease.

Background: In patients with oligometastatic NSCLC, a cT3-cT4 primary tumor or an cN2/cN3 lymph node status was reported to be associated with unfavorable outcome. The aim of this study was to assess the importance of definitive or neoadjuvant thoracic radiochemotherapy for long-term outcome of these patients in order to find more appropriate treatment schedules. Methods: Analysis of the West Cancer Centre (WTZ) institutional database from 08/2016 to 08/2020 was performed. Patients with primary synchronous OMD, all without actionable driver mutations, who received definitive thoracic radiochemotherapy (RCT) or neoadjuvant RCT followed by surgery (trimodality treatment) were included. Survival outcome is compared with stage III NSCLC. Results: Altogether, 272 patients received concurrent radiochemotherapy. Of those, 220 presented with stage III (158 with definitive RCT, 62 with trimodality approach). A total of 52 patients had OMD patients with cT3/cT4 or cN2/cN3 tumors. Overall survival (OS) at five years for OMD patients was 28.3% (95%-CI: 16.4-41.5%), which was not significantly different from OS of patients with stage III NSCLC treated with definitive or neoadjuvant RCT (34.9% (95%-CI: 27.4-42.8%)). However, the PFS of OMD patients at five years or last follow-up was significantly worse than that of stage III patients (13.0% vs. 24.3%, p = 0.0048). The latter was due to a higher cumulative incidence of distant metastases in OMD patients (50.2% vs. 20.4% at 48 months, p < 0.0001) in comparison to stage III patients. A cross-validated classifier that included severe comorbidity, ECOG performance status, gender and pre-treatment serum CRP level as the most important factors in the univariable analysis, was able to divide the OMD patient group into two equally sized groups with a four-year survival rate of 49.4% in the good prognosis group and 9.9% in the poor prognosis group (p = 0.0021). Laboratory chemistry and clinical parameters, in addition to imaging and high-precision therapies, can help to predict and improve prognosis. Conclusions: A multimodality treatment approach and local metastases-directed therapy in addition to chemoimmunotherapy can lead to good long-term survival in patients with cT3/cT4 or cN2/cN3 OMD NSCLC without severe comorbidities and in good performance status and is therefore recommended.

Analysis of tumor mutational burden and mutational landscape comparing whole-exome sequencing and comprehensive genomic profiling in patients with resectable early-stage non-small-cell lung cancer

Background: Identifying actionable driver mutations via tissue-based comprehensive genomic profiling (CGP) is paramount in treatment decisions for metastatic non-squamous, non-small-cell lung cancer (NSCLC). However, the role of CGP remains elusive in resectable NSCLC. Here, we elucidate the feasibility of CGP in early-stage NSCLC Korean patients and compare the tumor mutational burden (TMB) and mutation landscape using three different platforms. Methods: All surgically resected NSCLC samples ( N = 96) were analyzed to assess the concordance in TMB calculation and targetable mutations using whole-exome sequencing (WES) and TruSight Oncology 500 (TSO500). In all, 26 samples were analyzed with Foundation One CDx Assay (F1CDx). Programmed death-ligand 1 (PD-L1) expression was evaluated using Vectra Polaris. Results: Stage distribution post-surgery was 80% I ( N = 77) and 20% II ( N = 19). Ninety-nine percent ( N = 95) were adenocarcinoma. The median TMB with WES and TSO500 was 1.6 and 4.7 mut/Mb, respectively ( p &lt; 0.05). Using all three platforms, the median TMB was 1.9, 5.5, and 4 mut/Mb for WES, TSO500, and F1CDx, respectively ( p = 0.0048). Linear regression analysis of TMB values calculated between WES and TSO500 resulted in a concordance correlation coefficient of 0.83. For the PD-L1 tumor proportion score of &lt;1% (negative, N = 18), 1–49% (low, N = 68), and ⩾50% (high, N = 10), the R2 values were 0.075, 0.79, and 0.95, respectively. The R2 values for TMB concordance were variable between the three platforms. Mutation landscape revealed EGFR mutation (51%, N = 49) as the most common actionable driver mutation, comprising L858R ( N = 22), E19del ( N = 20), and other non-common EGFR mutations ( N = 7). Conclusion: TSO500 and F1CDx showed robust analytical performance for TMB assessment with TSO500 showing stronger concordance of TMB with high PD-L1 expression. As the paradigm for the management of early-resected NSCLC continues to evolve, understanding TMB and the mutation landscape may help advance clinical outcomes for this subset of patients.

Standard-of-care systemic therapy with or without stereotactic body radiotherapy in patients with oligoprogressive breast cancer or non-small-cell lung cancer (Consolidative Use of Radiotherapy to Block [CURB] oligoprogression): an open-label, randomised, controlled, phase 2 study

Most patients with metastatic cancer eventually develop resistance to systemic therapy, with some having limited disease progression (ie, oligoprogression). We aimed to assess whether stereotactic body radiotherapy (SBRT) targeting oligoprogressive sites could improve patient outcomes. We did a phase 2, open-label, randomised controlled trial of SBRT in patients with oligoprogressive metastatic breast cancer or non-small-cell lung cancer (NSCLC) after having received at least first-line systemic therapy, with oligoprogression defined as five or less progressive lesions on PET-CT or CT. Patients aged 18 years or older were enrolled from a tertiary cancer centre in New York, NY, USA, and six affiliated regional centres in the states of New York and New Jersey, with a 1:1 randomisation between standard of care (standard-of-care group) and SBRT plus standard of care (SBRT group). Randomisation was done with a computer-based algorithm with stratification by number of progressive sites of metastasis, receptor or driver genetic alteration status, primary site, and type of systemic therapy previously received. Patients and investigators were not masked to treatment allocation. The primary endpoint was progression-free survival, measured up to 12 months. We did a prespecified subgroup analysis of the primary endpoint by disease site. All analyses were done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03808662, and is complete. From Jan 1, 2019, to July 31, 2021, 106 patients were randomly assigned to standard of care (n=51; 23 patients with breast cancer and 28 patients with NSCLC) or SBRT plus standard of care (n=55; 24 patients with breast cancer and 31 patients with NSCLC). 16 (34%) of 47 patients with breast cancer had triple-negative disease, and 51 (86%) of 59 patients with NSCLC had no actionable driver mutation. The study was closed to accrual before reaching the targeted sample size, after the primary efficacy endpoint was met during a preplanned interim analysis. The median follow-up was 11·6 months for patients in the standard-of-care group and 12·1 months for patients in the SBRT group. The median progression-free survival was 3·2 months (95% CI 2·0-4·5) for patients in the standard-of-care group versus 7·2 months (4·5-10·0) for patients in the SBRT group (hazard ratio [HR] 0·53, 95% CI 0·35-0·81; p=0·0035). The median progression-free survival was higher for patients with NSCLC in the SBRT group than for those with NSCLC in the standard-of-care group (10·0 months [7·2-not reached] vs 2·2 months [95% CI 2·0-4·5]; HR 0·41, 95% CI 0·22-0·75; p=0·0039), but no difference was found for patients with breast cancer (4·4 months [2·5-8·7] vs 4·2 months [1·8-5·5]; 0·78, 0·43-1·43; p=0·43). Grade 2 or worse adverse events occurred in 21 (41%) patients in the standard-of-care group and 34 (62%) patients in the SBRT group. Nine (16%) patients in the SBRT group had grade 2 or worse toxicities related to SBRT, including gastrointestinal reflux disease, pain exacerbation, radiation pneumonitis, brachial plexopathy, and low blood counts. The trial showed that progression-free survival was increased in the SBRT plus standard-of-care group compared with standard of care only. Oligoprogression in patients with metastatic NSCLC could be effectively treated with SBRT plus standard of care, leading to more than a four-times increase in progression-free survival compared with standard of care only. By contrast, no benefit was observed in patients with oligoprogressive breast cancer. Further studies to validate these findings and understand the differential benefits are warranted. National Cancer Institute.

Non-Canonical Transcription Activator Activity of RNA-Binding Protein MBNL1 Uniquely Controls FLT3 expression in MLL-Rearranged Leukemias

MLL-rearranged (MLL-r) leukemias count for more than 80% of infant leukemia, ~5-10% of B-cell acute lymphoblastic leukemia (B-ALL), and ~10% of acute myeloid leukemia (AML) cases, where they confer a particularly poor outcome. Despite treatment with intensive multi-agent chemotherapy, most MLL-r patients ultimately relapsed after an initial remission. So far, the molecular mechanism by which MLL-r leukemia maintains progression and prevents differentiation remains largely unclear. Observations in the clinic support aberrant expression and concomitant activating driver mutations in the gene encoding the tyrosine kinase FLT3 that occur in leukemia, including the MLL-r subtype. To interrogate the novel MLL-r vulnerable genes regulating FLT3, we developed an algorithm so-called “context-dependent association analysis” (CDAA) to explore potential MLL-r dependent FLT3 regulators using the DepMap dataset. The RNA-binding protein MBNL1 was identified as the top candidate. MBNL1 has been recognized as an RNA-binding protein (RBP) involved in splicing, RNA export, and stability. However, our study suggested its non-canonical transcriptional activator function by uniquely controlling FLT3 expression in MLL-r leukemias. CRISPR/Cas9 disruption of the coding region of MBNL1 or CRISPR-interference (CRISPRi) against the MBNL1-bound site in the FLT3 distal enhancer notably decreased FLT3 mRNA expression in MLL-r leukemia cell lines. However, the FLT3 gene splicing defect was not observed upon MBNL1 loss, suggesting MBNL1 could be affecting FLT3 expression through a transcriptional regulation mechanism. Genome-wide ChIP-seq assays performed in MLL-r SEM and MOLM13 cells identified only two reproducible MBNL1-bound peaks at a genome-wide scale, one of which was located in the distal enhancer of FLT3, ~170kb away from the FLT3 promoter. CRISPR-interference (CRISPRi) against the MBNL1-bound site in the FLT3 distal enhancer notably decreased FLT3 mRNA expression in MLL-r leukemia cell lines without affecting enhancer-promoter looping. Using in vivo assay, SEM cells targeted with sgRNA against the MBNL1-bound site in the distal enhancer of FLT3 transplanted into NSG mice exhibited significant growth retardation. Furthermore, the impaired cell fitness crisis phenotype could be entirely rescued by overexpression of FLT3 cDNA. To identify the protein domains of MBNL1 required for its oncogenic function in MLL-r leukemia cells, an MBNL1 domain CRISPR screen was performed on the SEM cell line, stably expressing Cas9 and a pooled sgRNA library targeting the coding region of MBNL1. Essential domains observed from the screen included MBNL1's zinc finger domains. A biochemistry electrophoretic mobility shift assay (EMSA) was conducted using purified recombinant MBNL1 protein and a 207 bp DNA oligo synthesized based on the MBNL1 ChIP-seq peak at the FLT3 enhancer. The result clearly demonstrated that MBNL1 could directly bind to the enhancer DNA of FLT3 through its zinc fingers 1 and 2 domains, supporting its role as a novel transcriptional regulator of FLT3. Using state-of-art research tools, including genome editing, ChIP-seq, and EMSA assays, we have systematically interrogated an undocumented transcriptional regulation axis of MBNL1/FLT3 in MLL-r leukemias. This work will significantly advance our understanding of how transcription programs and novel factors reconstruct the regulatory network specifying MLL-r dependency, promoting the future development of alternative therapeutic targets for MLL-r leukemia in patients.

Biomarker Testing for Actionable Alterations in NSCLC-Perspectives from US-Based Academic and Community Oncologists: A Podcast.

The identification of actionable oncogenic driver mutations in patients with non-small cell lung cancer impacts therapy selection, and appropriate therapy administration results in improvements in clinical outcomes. Although biomarker testing for actionable oncogenic driver mutations is recommended in national and international guidelines, there are still unmet needs in the real world. Through this podcast we provide, from a US perspective, an overview and discuss challenges in biomarker testing from both an academic and a community oncologist viewpoint. We describe the importance of comprehensive testing, actionable biomarkers as recommended by guidelines such as National Comprehensive Cancer Network® (NCCN®) and European Society for Medical Oncology, types of tests and assessment techniques for detection of actionable biomarkers, and challenges in testing. These challenges include the lack of awareness of the biomarker testing guidelines among physicians, inconsistent reimbursement, longer turnaround time resulting in delays in therapy initiation, and nihilism associated with particular patient characteristics. To tackle these challenges, we offer recommendations from the perspective of our own clinical settings.

Impact of SPARC expression on treatment response of pembrolizumab and brain metastasis in patients with metastatic non-small cell lung cancer

BackgroundNon-small cell lung cancer (NSCLC) often exhibits elevated Secreted Protein Acidic and Cysteine-Rich (SPARC) expression. In this study, we investigated the impact of SPARC expression on clinicopathologic features, pembrolizumab response, and prognosis in metastatic NSCLC patients. MethodsThirty-six patients diagnosed with metastatic NSCLC without actionable driver mutation and who received pembrolizumab with or without chemotherapy were included in this study. PD-L1 and SPARC expression were evaluated, with PD-L1 expression categorized based on tumor proportion score and SPARC staining intensity graded as 1+, 2+, and 3 +. Patients’ characteristics were compared across groups, and possible predictive markers were determined by binary logistic regression analysis. ResultsNo significant associations were found between SPARC expression and smoking status, histopathological tumor type, T and N status, and liver and bone metastasis. Higher SPARC expression was significantly linked to lower brain metastasis rates but higher CNS progression rates (p = 0.022 and p = 0.011, respectively. The objective response rate (ORR) showed a trend of being higher in the SPARC 1 + group (85.7% vs. 43.8% and 50.0% in 2 + and 3 + groups, respectively, p = 0.052. Univariate analysis did not find SPARC expression to be a significant prognostic factor for progression-free survival (PFS) (p = 0.7) and overall survival (OS) (p = 0.07).SPARC 1 + expression negatively affected the pembrolizumab response(p = 0.04,OR:0.11, 95%CI 0.01–0.92). ConclusionsOur study sheds light on a novel aspect of SPARC expression as a potential predictor of pembrolizumab response and a marker for CNS progression in metastatic NSCLC patients treated in the first-line setting.

Mutational landscape and predictors of survival in head and neck mucosal melanoma.

Head and neck mucosal melanomas have a diverse mutational landscape with low mutational burden. A molecular subset (∼13%) has ROS1 mutations, which is an actionable driver mutation. ROS1-mutated patients have improved overall survival likely due to high mutational burden.