ALK Mutations Research Articles

Genomic profiling of NSCLC tumors with the TruSight oncology 500 assay provides broad coverage of clinically actionable genomic alterations and detection of known and novel associations between genomic alterations, TMB, and PD-L1

IntroductionMatching patients to an effective targeted therapy or immunotherapy is a challenge for advanced and metastatic non-small cell lung cancer (NSCLC), especially when relying on assays that test one marker at a time. Unlike traditional single marker tests, comprehensive genomic profiling (CGP) can simultaneously assess NSCLC tumors for hundreds of genomic biomarkers and markers for immunotherapy response, leading to quicker and more precise matches to therapeutics.MethodsIn this study, we performed CGP on 7,606 patients with advanced or metastatic NSCLC using the Illumina TruSight Oncology 500 (TSO 500) CGP assay to show its coverage and utility in detecting known and novel features of NSCLC.ResultsTesting revealed distinct genomic profiles of lung adenocarcinoma and squamous cell carcinomas and detected variants with a current targeted therapy or clinical trial in >72% of patient tumors. Known associations between genomic alterations and immunotherapy markers were observed including significantly lower TMB levels in tumors with therapy-associated alterations and significantly higher PD-L1 levels in tumors with ALK, MET, BRAF, or ROS1 driver mutations. Co-occurrence analysis followed by network analysis with gene module detection revealed known and novel co-occurrences between genomic alterations. Further, certain modules of genes with co-occurring genomic alterations had dose-dependent relationships with histology and increasing or decreasing levels of PD-L1 and TMB, suggesting a complex relationship between PD-L1, TMB, and genomic alterations in these gene modules.DiscussionThis study is the largest clinical study to date utilizing the TSO 500. It provides an opportunity to further characterize the landscape of NSCLC using this newer technology and show its clinical utility in detecting known and novel facets of NSCLC to inform treatment decision-making.

Overview of Systematic Reviews of ICIs in NSCLC With EGFR, ALK, ROS1, and RET Actionable Driver Mutations

The effectiveness and safety of immune checkpoint inhibitor (ICI) monotherapy in patients with previously treated advanced or metastatic non–small cell lung cancer with EGFR, ALK, ROS1, or RET actionable driver mutations or chromosomal rearrangements is currently uncertain. We assessed the efficacy and safety of ICIs in patients with this condition whose disease did not respond well to previous chemotherapy. We reviewed 13 systematic reviews of randomized controlled trials (RCTs). The quality assessment of these reviews revealed critical methodological flaws. All 13 systematic reviews focused on survival and progression-free survival (PFS) for patients with non–small cell lung cancer and EGFR gene mutations. The systematic reviews generally considered the same set of 4 clinical trials and did not report on other outcomes or patient groups, except for 1 review that looked at patients with different levels of anti-PD-L1 expression. We found no evidence on the efficacy and safety of ICIs in patients with ALK, ROS1, or RET mutations. Overall, the systematic reviews concluded that using ICIs alone, as a second-line therapy or beyond, does not significantly improve overall survival (OS) and PFS compared to chemotherapy in patients with non–small cell lung cancer with EGFR gene mutations. No conclusions can be made regarding the benefits of ICIs in patients with EGFR mutations based on histology or high antiprogrammed death-ligand 1 antibody expression levels. The safety of ICIs in patients with EGFR, ALK, ROS1, or RET actionable driver mutations could not be assessed because of the lack of evidence provided in the included systematic reviews.

The genomic landscape of papillary thyroid carcinoma on next-generation sequencing in patients undergoing total thyroidectomy.

Thyroidectomy is increasingly performed for suspected malignancy. This cohort study aimed to identify genetic markers associated with malignancy and determine the molecular landscape of papillary thyroid carcinoma (PTC) through next-generation sequencing (NGS) in patients undergoing total thyroidectomy. Among 116 surgical candidates, 103 patients (age=42.9±13.7years; Male: Female=14:89) with benign or malignant thyroid nodules were eligible. Live thyroid tissue samples harvested intraoperatively with adequate DNA and RNA yield were subjected to NGS on the Illumina NovaSeq 6000 platform for genomic and transcriptomic analysis, respectively. Histopathology comprised 20 malignant (19.4%) and 83 benign (80.6%) cases, including 16 PTC (15.5%) cases. On NGS, single nucleotidepolymorphisms (SNPs) in NTRK1 at NC_000001.11:156879016 on chromosome 1 and ALK at NC_000002.12:29717663 on chromosome 2 were frequent in malignant lesions (p<0.05). A SNP in ALK at NC_000002.12:29193706 was consistently a homozygous alternate alleleacross the cohort. DNA-sequencing of PTC lesions identified recurrentsomatic mutations in BRAF (100%), ALK (56.3%), RET (18.8%), PIK3CA (12.5%), NTRK1 (12.5%), NTRK2 (87.5%), NTRK3(12.5%), NRAS(6.3%), and PTCH1 (31.3%) genes. RNA sequencing revealednovelfusiongenes, including MKRN1-BRAF, RN7SL1-CDH1, IRF2BPL-MED12, MED12-IRF2BPL, CPM-MDM2, and AC005895.3-PDGFRB. Inreceiveroperative characteristics analysis, the AUCs ofALKmutationpredictingrecurrence and metastases were 0.818 and 0.783. This Indian study identified novel somatic mutations and fusion genes in PTC, revealing a distinct genomic landscape with implications in precision diagnostics and personalized therapies. NGS with intraoperative live sampling shows promise in prognostication and therapeutic optimization of advanced/metastatic PTC cases. CTRI/2020/09/027607dt 04/09/2020; REF/2020/08/036119.

CIGB-300 internalizes and impairs viability of NSCLC cells lacking actionable targets by inhibiting casein kinase-2 signaling

Overall response rates in advanced Non-Small Cell Lung Cancer (NSCLC) remains low. Thus, novel molecular targets, tailored drugs and/or drug combinations are needed. Casein Kinase-2 (CK2) is a constitutively active and frequently over-expressed enzyme which fosters tumor survival, proliferation and metastasis. By using a clinical-grade and Cell Penetrating Peptide-based inhibitor coined as CIGB-300, we explore the anti-neoplastic effects caused by interruption of CK2 signaling in lung cancer cells lacking EGFR, ALK and ROS mutations. CIGB-300 penetrated and impaired viability and proliferation of Lung Adenocarcinoma (LUAD) (A549, NCI-H522) and Lung Squamous Carcinoma (LUSC) (NCI-H226 and SK-MES-1) cells in a dose-response manner. The differential activity could not be explained by overall peptide uptake or its subcellular distribution, as evidenced by flow cytometry and confocal microscopy. Upon internalization, CIGB-300 interacted with CK2 catalytic subunits (ɑ1/ɑ2) and CK2 substrates, thus impairing phosphorylation of enzyme substrates (CDC37s13, NPM1s125) and downstream proteins (RPS6s325/326). CK2 inhibition induced an early Reactive Oxygen Species (ROS) and mitochondrial membrane depolarization, which predates lung cancer cell death. Finally, intravenous injection of CIGB-300 in a cell line-based xenograft corroborated CIGB-300’s anti-tumor effects and suggested concurrent in situ reductions of CSNK2ɑ subunit and downstream RPS6s235/236 phosphorylation. Overall, CIGB-300 therapeutic hypothesis and antineoplastic effects demonstrated herein, further support the evaluation of this clinical-grade CK2 inhibitor in advanced NSCLC with limited therapeutic options.

The Detailed Analysis of Polish Patients with Non-Small Cell Lung Cancer Through Insights from Molecular Testing (POL-MOL Study).

Molecular testing is recommended in patients with metastatic non-small cell lung cancer (NSCLC), but the extent of its use in Poland is unknown. The aim of the POL-MOL study was to investigate the frequency of using molecular testing in Polish patients with NSCLC. The invited Polish oncologists completed two questionnaires, and data for 1001 patients undergoing systemic treatment for NSCLC were collected. The use of molecular tests for the following genetic mutations was recorded: EGFR (del19, sub21), EGFR (other than del19/sub21), EGFR T790M, ALK (expression and rearrangement), RET, NTRK, ROS1, BRAF, HER2, and MET, as well as for immunochemical assessment of programmed cell death ligand 1 (PD-L1). Thanks to the weighting procedure, the results are representative of the population of Polish patients treated for NSCLC. Molecular tests were applied in 78% of patients with NSCL, 70% of patients with NSCLC not otherwise specified, and in 12% of patients with squamous cell carcinoma of the lung. The frequency of application increased with disease stage in all groups. In patients with squamous cell carcinoma, approximately 30% of tests for EGFR, ALK, and RET mutations were positive, which confirms the importance of testing at least a preselected subgroup of patients.

Clinical Outcomes of Maintenance Durvalumab After Definitive Concurrent Chemoradiotherapy in Unresectable Locally Advanced Stage III NSCLC According to EGFR and ALK Status: Korean Cancer Study Group LU-22-18

IntroductionThe role of maintenance durvalumab after definitive concurrent chemoradiotherapy (CCRT) in unresectable locally advanced NSCLC with EGFR mutation or ALK translocation remains unclear. We compared the effectiveness of durvalumab maintenance therapy in groups with EGFR/ALK wild-type versus those with EGFR or ALK mutations. MethodsIn this retrospective multicenter observational study, patients with locally advanced NSCLC without progression after CCRT followed by maintenance durvalumab and available molecular test results (EGFR and ALK) were eligible. The primary objective was to compare progression-free survival (PFS) between EGFR/ALK wild-type and EGFR or ALK mutant NSCLC. Secondary objectives include overall survival according to EGFR or ALK mutation and programmed death-ligand 1 (PD-L1) expression. ResultsAmong 339 patients, 279 had wild-type EGFR/ALK, 41 had EGFR mutations and 19 had ALK translocations. The median age was 68 years with 276 male individuals (81.4%) and 63 female individuals (18.6%), 165 (49.3%) had adenocarcinoma, 149 (44.5%) had squamous cell carcinoma, and 21 (6.3%) had other histologic types, 120 (35.4%) had stage IIIA, 168 (49.6%) stage IIIB, and 51 (15.0%) had stage IIIC. Most of the patients (n = 288, 85%) achieved partial response to CCRT, two (0.6%) had a complete response, and 49 patients (14.4%) had stable disease. Excluding four patients with unknown PD-L1 tumor proportion score (TPS), 16 (4.8%) had a PD-L1 TPS of 0, 168 (50.1%) had 1 to 49, and 151 (45.1%) had 50 or higher. The median PFS was 21.4 months (95% confidence interval [CI]: 17.3–25.3) for the EGFR/ALK wild-type group and 21.0 months (95% CI: 15.7–not available [NA]) for the EGFR or ALK mutant group with no significant difference (p = 0.74). Significant differences occurred in PFS on the basis of PD-L1 expression with values of 13.6 (95% CI: 10.5–NA), 18.7 (95% CI: 15.1–26.9), and 24.7 (95% CI: 20.7–NA) months for TPS of 0, 1–49, and 50 or higher, respectively (p = 0.02). ConclusionsDurvalumab maintenance therapy after definitive CCRT in unresectable locally advanced NSCLC patients with EGFR or ALK mutation demonstrates comparable clinical outcomes to those with wild-type EGFR/ALK when PD-L1 expression is present.

Expression of p63 and TTF1 in Non-small Cell Lung Carcinoma with Special Reference to Mutation of EGFR and ALK in Adenocarcinoma of the Lung: An Institutional Experience

Expression of p63 and TTF1 in Non-small Cell Lung Carcinoma with Special Reference to Mutation of EGFR and ALK in Adenocarcinoma of the Lung: An Institutional Experience

Pulmonary sarcomatoid carcinoma:report of three cases

Pulmonary sarcomatoid carcinoma (PSC) is a rare disease with strong aggressiveness, low response rates to treatment, short survival span and poor prognosis, belonging to a group of non-small cell lung carcinomas (NSCLC) that remains incompletely understood. Here, we presented three PSC cases with epidermal growth factor receptor (EGFR) L858R, BRAF V600E and ALK mutations respectively, described their clinical characteristics and conducted a review of literature, in order to improve its therapeutic level, which also provided evidence-based medical evidence for driver gene screening and molecular targeted drug application in PSC patients.

EP.12E.05 Exploring Clinical Characteristics and Treatment Outcomes of Squamous Cell Lung Cancers Harboring EGFR and ALK Mutations: A Case Series

EP.12E.05 Exploring Clinical Characteristics and Treatment Outcomes of Squamous Cell Lung Cancers Harboring EGFR and ALK Mutations: A Case Series

Response to platinum-based therapies in second-line after immunotherapy in advanced or metastatic non-small-cell lung cancer PD-L1 ≥50.

Platinum-based therapies for patients with advanced non-small-cell lung cancer (NSCLC) have classically provided overall survival (OS) rates of six to nine months and objective response rates (ORRs) of 20-30%. Whether prior immunotherapy determines a different response to platinum is currently unknown. This study aimed to analyse the current response characteristics to platinum as a second-line treatment for advanced NSCLC (PD-L1 ≥50%) after first-line immunotherapy. This retrospective study was conducted at the University Hospital of Salamanca (CAUSA) between 2016 and 2023 with patients who had advanced NSCLC (PD-L1 ≥50%) treated with second-line platinum-based therapies after immunotherapy (without mutations in EGFR, ALK or ROS1 and with Eastern Cooperative Oncology Group (ECOG) ≤1 during the first- and second-line treatments). Survival and response correlation analyses (Kaplan-Meier and log rank tests in SPSS v. 25) were performed. Subsequently, the results were compared with historical cohorts (PubMed, COCHRANE, ScienceDirect, Embase, and the clinical trial registry) who had received platinum-based therapies for advanced NSCLC. Seventeen patients were analysed (11 male and 6 female). Their median age was 67 years (interquartile range, 50-77 years). Fifteen patients (88.2%) were smokers or former smokers. The patients' main histology was adenocarcinoma (9 patients, 52.9%). All first-line treatments applied pembrolizumab (median dose: 12 cycles). Second-line platinum-based therapy achieved OS of 25 months (95% CI: 7-45 months) and progression-free survival (PFS) of 6 months (95% CI: 2.5-95 months). The ORR was 47.1% [seven patients with a partial response (PR) and one patient with a complete response (CR)]. Of the patients with PRs or CRs, 75% were treated with platinum plus pemetrexed. The one-year survival rate was 58.8%. The historical OS for first-line platinum-based doublets is 7 to 12 months, with PFS of three to five months and an ORR of 17-30%. The current response to second-line platinum-based therapies for patients with advanced NSCLC after immunotherapy appears to achieve favourable response rates and be an optimal treatment after progression to immunotherapy. Prior immunotherapy appears to enhance these patients' platinum response, though future confirmatory studies are necessary.

Inadequate staging and excessive surveillance imaging: Evaluating the magnitude of benefit of targeted therapies in lung cancer

Several phase III trials have altered the management of oncogenic driven non-small cell lung cancer (NSCLC) including those harboring EGFR and ALK mutations. However, several of these pivotal trials deviated from standard-of-care practices for either baseline imaging or surveillance imaging. This occurred despite sponsor acknowledgement in a clinical trial protocol that historical trials utilized imaging modalities that potentially under-staged patients. Inadequate baseline imaging for adjuvant trials instead of PET/CT may not identify individuals with metastatic disease, and thereby subject such individuals with metastatic disease to inferior treatment if randomized to the control arm. Similarly, more frequent surveillance imaging than what is considered standard-of-care may identify disease progression earlier than what is expected in real-world clinical practice and therefore embellish the magnitude of benefit between a targeted therapy and the control arm. While targeted therapies have provided clinical benefit for individuals with oncogenic driven NSCLC, physicians and patients must be cognizant that clinical trial deviations from standard-of-care imaging practices may have embellished the magnitude of benefit for several of these therapies.

Abstract A105: Clinical characteristics of Hispanic patients ages 50 and younger with lung adenocarcinoma: A multi-center experience

Abstract Introduction: While uncommon, there has been an increase in non-small cell lung cancer (NSCLC) cases in patients under the age of 50 with little data on young Hispanic patients with NSCLC. This multicenter study describes the clinical characteristics of young Hispanic lung adenocarcinoma patients between two cities with a large Hispanic population. Methods: This retrospective study examined 90 Hispanic patients (18-50 years old) with metastatic lung adenocarcinoma treated at University of Miami (Miami) Sylvester Comprehensive Care Center (n=50), University of Southern California (USC) Norris Comprehensive Care Center/Los Angeles General Medical Center (n=26), and the Memorial Cancer Institute at West (Memorial) (n=14) from 2009-2023. We looked at age at diagnosis, sex, smoking history, stage at diagnosis, brain metastasis at diagnosis, mutations, tyrosine kinase inhibitor (TKI) exposure, and survival status at 24 months, 36 months, and 60 months. Fisher’s exact test was used to compare differences between USC (n=26) in Los Angeles, California, USA and Miami/Memorial (n=64) in Miami, Florida, USA. Results: 63.33% (n=57) of the patients were female. The median age at diagnosis was 41.5 years, including 8.89% (n=8) diagnosed from age 18-30, 33.33% (n=30) diagnosed from age 31-40, and 57.78% (n=52) diagnosed from age 41-50. 63.33% (n=57) identified as never smokers, 30.00% (n=27) identified as former smokers, and 6.67% (n=6) identified as current smokers. 85.56% (n=77) were found to have metastatic disease at diagnosis, including 34.44% (n=31) with brain metastasis at diagnosis. 28.89% (n=26) had an EGFR mutation, 28.89% (n=26) were ALK positive, and 8.89% (n=8) had a KRAS mutation. 55 (61.11%) had been exposed to a TKI. Between treatment sites, there was a greater prevalence of brain metastasis at USC versus Miami/Memorial (15/26, 57.69% vs. 16/64, 25.00%, p&amp;lt;0.01) and a trend towards greater prevalence of EGFR and KRAS mutations (EGFR: 11/26 (42.31%) vs. 15/64 (23.44%), p = 0.12; KRAS: 4/26 (15.38%) vs. 4/64 (6.25%), p = 0.22) and TKI exposure (19/26, 73.08% vs. 36/64, 56.25%, p=0.15) at USC versus Miami/Memorial. Regarding survival for stage IV patients, 37/61 (60.65%) of patients were alive at 24 months, 22/51 (43.1%) at 36 months, and 14/46 (30.4%) at 60 months with a trend towards more USC patients being alive at 36 months (10/18, 55.56% vs. 12/33, 36.36%) and 60 months (6/15, 40% vs. 8/31 25.8%). Conclusion: Young Hispanic lung adenocarcinoma patients are predominantly female, never smokers, diagnosed with metastatic disease, and enriched in EGFR and ALK mutations. There are differences in prevalence of brain metastasis, EGFR and KRAS mutations, TKI exposure, and survival between the USC and Miami/Memorial young lung adenocarcinoma patients. These notable frequencies may be attributed to the different Hispanic subgroups in the west coast versus southeastern USA. This study highlights the need for more attention towards Hispanic ethnicity in the young lung cancer population. Citation Format: Kyle Edwards, Darin Poei, Suset Almuinas de Armas, Coral Olazagasti, Zhonglin Hao, Jorge J. Nieva, Luis E Raez, Gilberto Lopes, Estelamari Rodriguez, Robert Hsu. Clinical characteristics of Hispanic patients ages 50 and younger with lung adenocarcinoma: A multi-center experience [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A105.

Tumor markers in non-small cell lung cancer spine metastasis: an assessment of prognosis and overall survival

PurposeThe identification of gene mutations in the modern medical workup of metastatic spine tumors has become more common but has not been highly utilized in surgical planning. Potential utility of these genetic markers as surrogates for cancer behavior in current prognosis scoring systems and overall survival (OS) remains underexplored in existing literature. This study seeks to investigate the association of frequently identified tumor markers, EGFR, ALK, and PD-L1, in metastatic non-small cell lung cancer (NSCLC) to the spine with Tokuhashi prognosis scoring and OS.MethodsPatients with NSCLC metastasis to spine were identified through chart review. EGFR, ALK, and PD-L1 wild type vs. mutant type were identified from targeted chemotherapy genetic testing. Multiple linear regression was performed to assess gene profile contributions to Tokuhashi score. Cox Proportional Hazards models were generated for each tumor marker to assess the relationship between each marker and OS.ResultsA total of 119 patients with NSCLC spine metastasis were identified. We employed a multiple linear regression analysis to investigate the influence of EGFR, ALK, and PD-L1 genotypes on the Tokuhashi score, revealing statistically significant relationships overall (p = 0.002). Individual genotype contributions include EGFR as a non-significant contributor (p = 0.269) and ALK and PD-L1 as significant contributors (p = 0.037 and p = 0.001 respectively). Overall survival was not significantly associated with tumor marker profiles through Kaplan-Meier analysis (p = 0.46) or by multivariable analysis (p = 0.108).ConclusionALK and PD-L1 were significantly associated with Tokuhashi score while EGFR was not. Tumor markers alone were not predictive of OS. These findings indicate that genetic markers found in NSCLC metastases to the spine may demonstrate prognostic value. Therefore, employing standard tumor markers could enhance the identification of appropriate surgical candidates, although they demonstrate limited effectiveness in predicting overall survival.

Outcomes of EGFR, ALK, ROS1, BRAF, MET, and RET mutated non-small cell lung cancer with brain metastases (NSCLC BM).

201 Background: Non-small cell lung cancer (NSCLC) is a leading cause of brain metastases. Advances in gene-directed therapies have shifted the focus away from traditional platinum-based chemotherapies. Key targeted mutations in NSCLC include EGFR, ALK, BRAF, MET exon skipping, RET fusions, and ROS1 rearrangements. This retrospective study aims to explore overall survival (OS) and progression-free survival (PFS) in NSCLC BM patients with these gene mutations. Methods: In this retrospective study, conducted by the Department of Medical Oncology at Beijing Tiantan Hospital and the First Medical Center, PLA General Hospital, we reviewed 1526 patients with NSCLC brain metastasis from 2010 to 2022. Data collected included molecular marker status, systemic therapies, and dates of progression. The analysis focused on determining OS and PFS from the time of brain metastasis diagnosis to the last follow-up or death. Statistical analysis used the Cox proportional hazards model. Results: The study reviewed 1526 patients, identifying the following mutation distribution: EGFR mutations in 628 patients, ALK rearrangements in 207 patients, ROS1 rearrangements in 64 patients, BRAF mutations in 31 patients, MET exon skipping in 55 patients, and RET fusions in 42 patients. Significant variations in median OS (mOS) and median PFS (mPFS) were observed across these mutation groups. Patients with EGFR and ALK mutations demonstrated longer mOS and mPFS. Patients with RET and ROS1 mutations also showed better outcomes compared to those with BRAF and MET mutations. Conclusions: This study highlights the importance of molecular mutations in NSCLC BM as prognostic indicators and therapeutic targets. EGFR and ALK mutations were associated with more favorable outcomes, emphasizing the need for personalized medicine in managing NSCLC BM. The study suggests further research focused on specific mutation types is crucial to refine treatment strategies and improve patient care.

A phase 2, open-label, single-arm study evaluating the combination of pembrolizumab (pembro), lenvatinib, and chemotherapy in patients (pts) with metastatic non-small cell lung cancer (NSCLC) harbouring a targetable mutation who experienced disease progression on standard tyrosine kinase inhibitors (TKIs).

198 Background: Pts with metastatic NSCLC harbouring a targetable mutation who progressed on standard TKIs often receive chemotherapy as the next line of treatment. We report efficacy and safety of a novel combination of pembro, lenvatinib and chemotherapy for these pts. Methods: This was a phase 2, open-label, single-centre, single-arm study enrolling pts with metastatic NSCLC with sensitizing EGFR, ALK or ROS1 mutation who progressed on standard TKIs. Eligible pts had measurable disease, no untreated brain metastasis and ECOG PS ≤1. Pts received pembro 200 mg, pemetrexed 500 mg/m2 and carboplatin AUC 5 every 3 weeks for 4 cycles plus lenvatinib 8 mg QD. The maintenance regimen without carboplatin was continued as tolerated for up to 2 years. The primary endpoint was objective response rate (ORR) by independent radiology review (IRR) as per RECIST 1.1. The secondary endpoints were PFS, overall survival (OS) and safety. Results: At the data cutoff date (2nd February 2024), 24 pts were screened and 19 were enrolled: median age 64 years (range 29–77); 10 (53%) female. Four pts were excluded at screening due to untreated brain metastasis. All enrolled pts were evaluated for safety while 15 pts were evaluable for response. All pts had adenocarcinoma with targetable mutation: EGFR mutation in 18 (95%) pts and ALK fusion in 1 (5%) pt. The median follow-up time was 11.3 months. Treatment was ongoing in 8 pts on the date of analysis, while 6 pts permanently discontinued due to disease progression and 1 pt permanently discontinued due to a treatment-related adverse event (TRAE). The ORR was 40% (6/15, 95% CI 19.8%–64.3%). All responses were partial responses. The median PFS was 11.9 months (range 3.5–20.3). The OS was not reached. TRAEs of any grade (Gr) occurred in 74% (14/19) of the pts. Most of the TRAEs were Gr 1–2, which occurred in 63% (12/19) of the pts. The most common TRAEs were hypothyroidism (31.6%), nausea (26.3%), neutropenia (26.3%), thrombocytopenia (26.3%), anorexia (21.1%), hypertension (15.8%), anaemia (10.5%), pruritus (10.5%) and rash (10.5%). G1 diarrhoea was reported in 1 pt (5.3%) and G1 adrenal insufficiency in 1 pt (5.3%). Gr 3 TRAEs were neutropenia in 2 pts, anaemia in 1 pt and thrombocytopenia in 1 pt. The only Gr 4 TRAE was thrombocytopenia. No treatment related death was observed. Conclusions: The combination of pembro, lenvatinib and chemotherapy demonstrated a favourable ORR and safety in treating metastatic NSCLC pts with a targetable mutation who progressed on standard TKIs. Clinical trial information: NCT04989322 .

MRNA Expression Level of ALK in Neuroblastoma Is Associated with Histological Subtype, ALK Mutations and ALK Immunohistochemical Protein Expression

mRNA Expression Level of ALK in Neuroblastoma Is Associated with Histological Subtype, ALK Mutations and ALK Immunohistochemical Protein Expression

Current and Emerging Biomarkers: Impact on Risk Stratification for Neuroblastoma.

Neuroblastoma has heterogenous clinical presentations that are reflected by several well-defined clinical factors and biomarkers. Combinations of these clinical and biologic prognostic factors have been used for decades to generate classifiers to stratify patients into risk groups (low, intermediate, and high), which in turn are used to inform and tailor treatment as reported in the new NCCN Clinical Practice Guidelines in Oncology for Neuroblastoma. Risk classification uses clinical features, such as age and tumor stage, along with the most significant prognostic tumor biomarkers, including histologic features (differentiation and mitosis-karyorrhexis index), MYCN amplification status, chromosomal copy number alterations (segmental or numerical), and ploidy (DNA content). Recent next-generation sequencing approaches have identified additional tumor-specific genetic factors that have potential roles as prognostic and predictive biomarkers. These emerging biomarkers include telomerase maintenance mechanisms, such as telomerase reverse transcription (TERT) expression and alternative lengthening of telomeres (ALT) status. Somatic alterations of genes, including mutations in the anaplastic lymphoma kinase gene ALK, detected in >10% of patients with newly diagnosed disease, have both prognostic and predictive roles in determining eligibility for targeted therapies (eg, ALK tyrosine kinase inhibitors). In addition to diagnostic tumor-derived biomarkers, significant effort is being directed toward identification of markers to predict response to chemotherapy and immunotherapies. With the increasing use of GD2-containing immunotherapy regimens, efforts are aimed at identifying host or tumor microenvironment immune correlatives that can serve as predictive biomarkers. Understanding the potential role of liquid biopsies as biomarkers during and following treatment, including sequential circulating tumor DNA or tumor-specific mRNA transcripts, is expected to enhance the ability to predict recurrences and also inform understanding of tumor evolution and therapy resistance. These and other emerging biomarkers will lead to refinement and optimization of future neuroblastoma risk classification systems.

Survival among patients with lung cancer managed at a tertiary care center in North India.

Though there has been advancement in the management of lung cancer, it is not well utilized due to its limited availability and high cost. This is a prospective observational study done at a tertiary care center from January 2014 to December 2022, involving patients with primary lung cancer. After tumor-node-metastasis staging and molecular testing, the patients received chemotherapy, radiotherapy, surgery, targeted therapy, and immunotherapy in various combinations as per the prevailing National Comprehensive Cancer Network Guidelines. 92 patients were enrolled in the study, with the mean age being 58.94±10.33 and 72 (78.26%) being males. 69 (75%) patients were either current or former smokers. 78 (84.78%) patients had an Eastern Cooperative Oncology Group (ECOG) score of 0-2 while the remaining had an ECOG of 3-4. 80 (86.95%) patients had non-small cell lung cancer (NSCLC) [44 (47.83%) adenocarcinoma, 25 (27.17%) squamous cell carcinoma, and 11 (11.95%) NSCLC: not otherwise specified], while 12 (13.04%) patients had small cell lung cancer. One (1.08%) patient each presented in stage I and stage II, 31 (33.69%) patients presented in stage III, and 59 (64.13%) patients presented in stage IV. 44 patients with adenocarcinoma were subjected to mutational analysis, and an epidermal growth factor receptor mutation was found in 13 (29.5%) patients. None of the patients had ALK mutation, ROS-1 rearrangement, or BRAF mutation. PD-L1 expression was evaluated in 9 patients with NSCLC, and it was found in 6 (66.66%) patients. The overall mean survival was 12.7 months. The mean survival for patients with stages I, II, III, and IV was 70, 96, 8.1, and 12.7 months, respectively. Survival in stage IV was better than in stage III, as the eligible patients received targeted therapy and immunotherapy. Targeted therapy and immunotherapy have improved survival. Molecular analysis should be done whenever indicated, and eligible patients must be administered targeted therapy and immunotherapy.

Integrating the Idylla™ System Alongside a Real-Time Polymerase Chain Reaction and Next-Generation Sequencing for Investigating Gene Fusions in Pleural Effusions from Non-Small-Cell Lung Cancer Patients: A Pilot Study.

Malignant pleural effusion (MPE) from patients with advanced non-small-cell lung cancer (NSCLC) has been proven valuable for molecular analysis; however, simultaneous detection of driver fusions in MPE is still challenging. In this study, we investigated the Idylla™ GeneFusion Panel, a stand-alone test in tissue samples, in the evaluation of ALK, ROS1, RET and MET ex14 skipping mutations in MPE and compared its performance with routine reference methods (Real-time-based and Next-generation Sequencing-NGS). The inclusion criteria for sample selection were as follows: advanced NSCLC harboring ALK, ROS1, RET fusions or MET exon-skipping alterations and the availability of MPE collected at diagnosis or disease progression. Molecular alterations have been investigated on tissue by fluorescence in situ hybridization (FISH) or Real-time PCR or NGS. For molecular profiling with the Idylla™ GeneFusion, 200 µL of MPE supernatants combined with 50 µL of RNA Later solution were loaded into the Idylla™ cartridge without cfRNA extraction. The Idylla™ GeneFusion Assay performed on MPEs was able to confirm molecular profile, previously diagnosed with conventional methods, in all cases. Our data confirm that MPE are suitable material for investigating fusion alterations. The Idylla™ GeneFusion, although indicated for investigation of tissue samples, offers the possibility of performing a molecular characterization of supernatants without undertaking the entire cfRNA extraction procedure providing a rapid and reliable strategy for the detection of actionable genetic alterations.

Comparison of treatment outcome between first-line combination immunotherapy (anti-PD-L1 or anti-PD1) with or without chemotherapy and chemotherapy alone in advanced non-small cell lung cancer patients in tertiary care hospital.

Despite promising outcomes of first-line immunotherapy with or without chemotherapy in advanced non-small cell lung cancer (NSCLC), limited accessibility due to reimbursement was remain the problem in low to middle income countries. This study aimed to evaluate real-world effectiveness of immunotherapy in patients with advanced NSCLC in Northern Thailand. A retrospective, single-centered cohort, was conducted. Patients with advanced NSCLC who underwent PD-L1 testing (excluding EGFR and ALK mutations) and were treated with immunotherapy or without chemotherapy or chemotherapy alone were included. The primary end point was progression-free survival (PFS). The secondary endpoints were overall survival (OS), objective response rate (ORR), and adverse events. A total of 123 patients, of which 21 patients received immunotherapy-based regimen and 102 patients received chemotherapy alone. The median PFS was 11.9 months in immunotherapy-based group compared to 5.93 months in the chemotherapy group, with a. hazard ratio (HR) of 0.4 (95% confidence interval [CI], 0.23 to 0.68; p = 0.001). Similarly, the median OS was 26.68 months in the immunotherapy-based group and 11.21 months in the chemotherapy group, with HR of 0.42 (95% CI 0.22-0.8; p = 0.009). ORRs were significantly higher in the immunotherapy-based group, with 65% of patients showing a response compared to 32% in the chemotherapy group (p = 0.006). The result of this real-world study in patients with advanced stage NSCLC indicate that first-line immunotherapy-based regimen was associated with significantly greater PFS, OS, and ORR with a safety profile consistent with pivotal studies.