397 results on '"Nir Peled"'
Search Results
2. The interaction of mast cells with membranes from lung cancer cells induces the release of extracellular vesicles with a unique miRNA signature
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Rachel Shemesh, Smadar Laufer-Geva, Yaara Gorzalczany, Alaa Anoze, Ronit Sagi-Eisenberg, Nir Peled, and Laila C. Roisman
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Medicine ,Science - Abstract
Abstract Mast cells (MCs) are immune cells that play roles in both normal and abnormal processes. They have been linked to tumor progression in several types of cancer, including non-small cell lung cancer (NSCLC). However, the exact role of MCs in NSCLC is still unclear. Some studies have shown that the presence of a large number of MCs is associated with poor prognosis, while others have suggested that MCs have protective effects. To better understand the role of MCs in NSCLC, we aimed to identify the initial mechanisms underlying the communication between MCs and lung cancer cells. Here, we recapitulated cell-to-cell contact by exposing MCs to membranes derived from lung cancer cells and confirming their activation, as evidenced by increased phosphorylation of the ERK and AKT kinases. Profiling of the microRNAs that were selectively enriched in the extracellular vesicles (EVs) released by the lung cancer-activated MCs revealed that they contained significantly increased amounts of miR-100-5p and miR-125b, two protumorigenic miRNAs. We explored the pathways regulated by these miRNAs via enrichment analysis using the KEGG database, demonstrating that these two miRNAs regulate p53 signaling, cancer pathways, and pathways associated with apoptosis and the cell cycle.
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- 2023
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3. Radiological artificial intelligence - predicting personalized immunotherapy outcomes in lung cancer
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Laila C. Roisman, Waleed Kian, Alaa Anoze, Vered Fuchs, Maria Spector, Roee Steiner, Levi Kassel, Gilad Rechnitzer, Iris Fried, Nir Peled, and Naama R. Bogot
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Personalized medicine has revolutionized approaches to treatment in the field of lung cancer by enabling therapies to be specific to each patient. However, physicians encounter an immense number of challenges in providing the optimal treatment regimen for the individual given the sheer complexity of clinical aspects such as tumor molecular profile, tumor microenvironment, expected adverse events, acquired or inherent resistance mechanisms, the development of brain metastases, the limited availability of biomarkers and the choice of combination therapy. The integration of innovative next-generation technologies such as deep learning—a subset of machine learning—and radiomics has the potential to transform the field by supporting clinical decision making in cancer treatment and the delivery of precision therapies while integrating numerous clinical considerations. In this review, we present a brief explanation of the available technologies, the benefits of using these technologies in predicting immunotherapy response in lung cancer, and the expected future challenges in the context of precision medicine.
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- 2023
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4. Mobocertinib in Patients with EGFR Exon 20 Insertion-Positive Non-Small Cell Lung Cancer (MOON): An International Real-World Safety and Efficacy Analysis
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Oliver Illini, Felix Carl Saalfeld, Petros Christopoulos, Michaël Duruisseaux, Anders Vikström, Nir Peled, Ingel Demedts, Elizabeth Dudnik, Anna Eisert, Sayed M. S. Hashemi, Urska Janzic, Waleed Kian, Katja Mohorcic, Saara Mohammed, Maria Silvoniemi, Sacha I. Rothschild, Christian Schulz, Claas Wesseler, Alfredo Addeo, Karin Armster, Malinda Itchins, Marija Ivanović, Diego Kauffmann-Guerrero, Jussi Koivunen, Jonas Kuon, Nick Pavlakis, Berber Piet, Martin Sebastian, Janna-Lisa Velthaus-Rusik, Luciano Wannesson, Marcel Wiesweg, Robert Wurm, Corinna Albers-Leischner, Daniela E. Aust, Melanie Janning, Hannah Fabikan, Sylvia Herold, Anna Klimova, Sonja Loges, Yana Sharapova, Maret Schütz, Christoph Weinlinger, Arschang Valipour, Tobias Raphael Overbeck, Frank Griesinger, Marko Jakopovic, Maximilian J. Hochmair, and Martin Wermke
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non-small cell lung cancer ,EGFR exon 20 inhibitors ,mobocertinib ,real-world data ,exon 20 insertion ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
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.
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- 2024
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5. Correlations between pathogenic variants in DNA repair genes and anticancer treatment efficacy in stage IV non‐small cell lung cancer: A large real‐world cohort and review of the literature
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Itamar Averbuch, Roi Tschernichovsky, Oded Icht, Daniel A. Goldstein, Raz Mutai, Elizabeth Dudnik, Ofer Rotem, Nir Peled, Aaron M. Allen, Smadar Laufer‐Geva, Yael Goldberg, and Alona Zer
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DNA damage repair mutations ,immunotherapy ,non‐small cell lung cancer ,platinum‐based chemotherapy ,radiotherapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Mutations in genes involved in DNA damage repair (DDR), a hallmark of cancer, are associated with increased cancer cell sensitivity to certain therapies. This study sought to evaluate the association of DDR pathogenic variants with treatment efficacy in patients with advanced non‐small cell lung cancer (NSCLC). Methods A retrospective cohort of consecutive patients with advanced NSCLC attending a tertiary medical center who underwent next‐generation sequencing in 01/2015‐8/2020 were clustered according to DDR gene status and compared for overall response rate (ORR), progression‐free survival (PFS) (patients receiving systemic therapy), local PFS (patients receiving definitive radiotherapy), and overall survival (OS) using log‐rank and Cox regression analyses. Results Of 225 patients with a clear tumor status, 42 had a pathogenic/likely pathogenic DDR variant (pDDR), and 183 had no DDR variant (wtDDR). Overall survival was similar in the two groups (24.2 vs. 23.1 months, p = 0.63). The pDDR group had a higher median local PFS after radiotherapy (median 45 months vs. 9.9 months, respectively; p = 0.044), a higher ORR (88.9% vs. 36.2%, p = 0.04), and a longer median PFS (not reached vs. 6.0 months, p = 0.01) in patients treated with immune checkpoint blockade. There was no difference in ORR, median PFS, and median OS in patients treated with platinum‐based chemotherapy. Conclusion Our retrospective data suggest that in patients with stage 4 NSCLC, pathogenic variants in DDR pathway genes may be associated with higher efficacy of radiotherapy and immune checkpoint inhibitors (ICIs). This should be further explored prospectively.
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- 2023
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6. Overcoming CEP85L-ROS1, MKRN1-BRAF and MET amplification as rare, acquired resistance mutations to Osimertinib
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Waleed Kian, Bilal Krayim, Hadel Alsana, Betsy Giles, Ofer Purim, Wafeek Alguayn, Farouq Alguayn, Nir Peled, and Laila C. Roisman
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EGFR ,L833V ,V834L ,compound mutations ,lung cancer ,CEP85L-ROS1 fusion ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Lung cancer is the most common cancer-related cause of death worldwide, most of which are non-small cell lung cancers (NSCLC). Epidermal growth factor receptor (EGFR) mutations are common drivers of NSCLC. Treatment plans for NSCLC, specifically adenocarcinomas, rely heavily on the presence or absence of specific actionable driver mutations. Liquid biopsy can guide the treatment protocol to detect the presence of various mechanisms of resistance to treatment. We report three NSCLC EGFR mutated cases, each treated with Osimertinib in a combination therapy regimen to combat resistance mechanisms. The first patient presented with EGFR L858R/L833V compound mutation with MET amplification alongside CEP85L-ROS1 fusion gene, the second with EGFR exon 19del and MKRN1-BRAF fusion, and the last EGFR L858R/V834L compound mutation with MET amplification. Each regimen utilized a tyrosine kinase inhibitor or monoclonal antibody in addition to osimertinib and allowed for a prompt and relatively durable treatment response.
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- 2023
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7. Real-world efficacy and safety of mobocertinib in EGFR exon 20 insertion-mutated lung cancer
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Waleed Kian, Petros Christopoulos, Areen A. Remilah, Esther Levison, Elizabeth Dudnik, Walid Shalata, Bilal Krayim, Ranin Marei, Alexander Yakobson, Martin Faehling, Dolev Kahala, Inbal Sara Granot, Dina Levitas, Nir Peled, and Laila C. Roisman
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mobocertinib ,nsclc ,lung cancer ,EGFR exon 20 insertion mutation ,Real World Data ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
BackgroundNon-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertions (EGFRex20ins) is relatively resistant to the existing EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is a novel TKI that selectively targets EGFRex20ins and has demonstrated therapeutic efficacy in pretreated patients with tumors harboring these mutations.MethodsThis is a retrospective, non-interventional, multicenter real-world study aimed at assessing the efficacy and safety of mobocertinib in patients with EGFRexon20ins who received 160 mg QD monotherapy as part of expanded access. Data collection was based on patients’ records. PET-CT or CT scans were used to measure systemic response, while brain MRIs were used to examine intracranial response as part of the follow-up.Results16 patients were included in this report. Mobocertinib was administered to 31.3% (5) of patients as first-line, 50% (8) as second-line, and 18.7% (3) as a later-line therapy. The median age was 65 years (range, 38-83), 75% (12/16) were female, and 50% (8/16) had brain metastases at baseline before mobocertinib treatment. The objective response rate (ORR) to mobocertinib was 25% (4/16) (1/5 for first line and 3/11 for other lines), disease control rate (DCR) was 75% (12/16) with a follow-up period of 11 months. The median duration of treatment (mDoT) was 5.6 months across all patients, and 8.6 months in responders. Based on the presence or absence of brain metastasis, the mDoT was 14.8 and 5.4 months (p=0.01), respectively. Mobocertinib Grade ≥3 treatment-related adverse events (TRAEs) included diarrhea (19%), nausea (6%) and renal failure (6%). Dose reduction was reported in 25% of cases to 80 mg.ConclusionMobocertinib in compassionate use exhibited an ORR of 25%, which is very similar to that of the phase 2 EXCLAIM study and clearly better than historical data of monochemotherapy or conventional EGFR inhibitors. The greatest benefit was noted in patients without brain metastases, who showed durable effects with mDoT 14.8 months, while intracranial activity was limited. These findings may assist therapeutic considerations, inasmuch as results from the EXCLAIM cohort-3 dedicated to brain lesions are not available yet.
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- 2022
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8. Liquid First Is 'Solid' in Naïve Non-Small Cell Lung Cancer Patients: Faster Turnaround Time With High Concordance to Solid Next-Generation Sequencing
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Or Sehayek, Waleed Kian, Amir Onn, Ronen Stoff, Hadas Gantz Sorotsky, Melanie Zemel, Jair Bar, Yulia Dudnik, Hovav Nechushtan, Yakir Rottenberg, Lior Soussan-Gutman, Addie Dvir, Laila C. Roisman, and Nir Peled
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circulating tumor DNA (ctDNA) ,turnaround time (TAT) ,driver mutation ,liquid biopsy ,non-small cell lung carcinoma (NSCLC) ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
PurposeMolecular profiling is crucial in naïve non-small cell lung cancer (NSCLC). While tissue-based analysis is challenged by turnaround time and scarcity of tissue, there is increasing demand for liquid biopsy. We aimed to analyze the use of upfront liquid biopsy as a molecular profiling approach.MethodsThis retrospective multicenter, non-interventional study compared findings and turnaround times of liquid vs. standard-of-care (SOC) tissue-biopsy molecular profiling. The study included naïve advanced NSCLC patients with available liquid biopsy (Guardant360 CDx).ResultsA total of 42 consecutive patients (60% men; median age, 69.5 [39–87] years; 86% stage IV NSCLC) were identified between September 2017 and December 2020. Liquid-biopsy analysis provided results for all 42 patients, whereas the tissue-based analysis failed in 5 (12%) patients due to insufficient tumor samples. In 17 patients, 18 actionable driver mutations were identified. Eleven mutations were detected by both approaches (i.e., concordance of 61%), 4 only by liquid biopsy and 3 only by tissue biopsy. The median time from the molecular request to receiving the molecular solid report on the last biomarker was 21 (range: 5–66) days, whereas the median time from blood draw to the liquid-biopsy results was 10.5 (7–19) days. The median time between the availability of liquid-biopsy findings and that of the last biomarker was 5 days. Treatment changes following the liquid-biopsy results were observed in 3 (7%) patients.ConclusionPerforming liquid-biopsy upfront is feasible and accurate and allows a shorter time for treatment in NSCLC, especially when tumor tissue is scarce.
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- 2022
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9. Real-world experience with capmatinib in exon 14-mutated non-small cell lung cancer (RECAP): a retrospective analysis from an early access program
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Oliver Illini, Hannah Fabikan, Aurélie Swalduz, Anders Vikström, Dagmar Krenbek, Michael Schumacher, Elizabeth Dudnik, Michael Studnicka, Ronny Öhman, Robert Wurm, Luciano Wannesson, Nir Peled, Waleed Kian, Jair Bar, Sameh Daher, Alfredo Addeo, Ofer Rotem, Georg Pall, Alona Zer, Akram Saad, Tanja Cufer, Hadas Gantz Sorotsky, Sayed M. S. Hashemi, Katja Mohorcic, Ronen Stoff, Yulia Rovitsky, Shoshana Keren-Rosenberg, Thomas Winder, Christoph Weinlinger, Arschang Valipour, and Maximilian J. Hochmair
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Patients with non-small cell lung cancer (NSCLC) presenting with mesenchymal–epithelial transition ( MET ) exon 14 skipping mutation have an unfavorable prognosis with standard treatments. Capmatinib is a selective MET inhibitor, which showed promising efficacy in this patient population in early trials. Methods: We performed a retrospective, international, multicenter efficacy and safety analysis in patients with NSCLC treated with capmatinib in an early access program between March 2019 and December 2021. Results: Data from 81 patients with advanced MET exon 14 mutated NSCLC treated with capmatinib in first- or later-line therapy were analyzed. Median age was 77 years (range, 48–91), 56% were women, 86% had stage IV disease, and 27% had brain metastases. For all patients, the objective response rate (ORR) to capmatinib was 58% (95% CI, 47–69), whereas it was 68% (95% CI, 50–82) in treatment-naïve and 50% (95% CI, 35–65) in pretreated patients. The median progression-free survival was 9.5 months (95% CI, 4.7–14.3), whereas it was 10.6 months (95% CI, 5.5–15.7) in first-line and 9.1 months (95% CI, 3.1–15.1) in pretreated patients. After a median follow-up of 11.0 months, the median overall survival was 18.2 months (95% CI, 13.2–23.1). In patients with measurable brain metastases ( n = 11), the intracranial ORR was 46% (95% CI, 17–77). Capmatinib showed a manageable safety profile. Grade ⩾ 3 treatment-related adverse events included peripheral edema (13%), elevated creatinine (4%), and elevated liver enzymes (3%). Conclusion: In patients with MET exon 14 skipping mutation, capmatinib showed durable systemic and intracranial efficacy and a manageable safety profile. This analysis confirms previously reported phase II data in a real-world setting.
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- 2022
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10. The Impact of Comprehensive Genomic Profiling (CGP) on the Decision-Making Process in the Treatment of ALK-Rearranged Advanced Non-Small Cell Lung Cancer (aNSCLC) After Failure of 2nd/3rd-Generation ALK Tyrosine Kinase Inhibitors (TKIs)
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Ari Raphael, Amir Onn, Liran Holtzman, Julia Dudnik, Damien Urban, Waleed Kian, Aharon Y. Cohen, Mor Moskovitz, Alona Zer, Jair Bar, Natalie Maimon Rabinovich, Shirly Grynberg, Cecilie Oedegaard, Abed Agbarya, Nir Peled, Tzippy Shochat, and Elizabeth Dudnik
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comprehensive genomic profiling ,next-generation sequencing ,ALK ,failure of ALK TKI ,acquired resistance ,decision impact ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
BackgroundThe use of CGP in guiding treatment decisions in aNSCLC with acquired resistance to ALK TKIs is questionable.MethodsWe prospectively assessed the impact of CGP on the decision-making process in ALK-rearranged aNSCLC patients following progression on 2nd/3rd-generation ALK TKIs. Physician’s choice of the most recommended next-line systemic treatment (NLST) was captured before and after receival of CGP results; the percentage of cases in which the NLST recommendation has changed was assessed along with the CGP turnaround time (TAT). Patients were divided into groups: patients in whom the NLST was initiated after (group 1) and before (group 2) receival of the CGP results. Time-to-treatment discontinuation (TTD) and overall survival (OS) with NLST were compared between the groups.ResultsIn 20 eligible patients (median [m]age 63 years [range, 40-89], females 75%, adenocarcinoma 100%, failure of alectinib 90%, FoundationOne Liquid CDx 80%), CGP has altered NLST recommendation in 30% of cases. CGP findings were as follows: ALK mutations 30% (l1171X 10%, G1202R, L1196M, G1269A, G1202R+l1171N+E1210K 5% each), CDKN2A/B mutation/loss 10%, c-met amplification 5%. CGP mTAT was 2.9 weeks [IQR, 2.4-4.4]. mTTD was 11.3 months (95% CI, 2.1-not reached [NR]) and 5.4 months (95% CI, 2.0-NR) in groups 1 and 2, respectively (p-0.34). mOS was 13.2 months (95% CI, 2.9-NR) and 13.0 months (95% CI, 6.0-NR) in groups 1 and 2, respectively (p-0.86).ConclusionCGP has a significant impact on the decision-making process in ALK-rearranged aNSCLC following progression on 2nd/3rd-generation ALK TKIs.
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- 2022
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11. Epithelioid Hemangioendothelioma and Epithelioid Hemangioma: Pazopanib as a Potential Salvage Therapy
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Alexander Yakobson, Wafeek Alguayn, Walid Shalata, Daniel Levin, Tawfeek A. Kian, Amir Korngreen, Rachel Gibbs, Mahmuod A. Salah, Benzion Samueli, Konstantin Lavrenkov, Laila C. Roisman, Yulia Dudnik, Nir Peled, Yael Refaely, and Waleed Kian
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rib epithelioid hemangioma ,epithelioid hemangioendothelioma ,pazopanib ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Epithelioid hemangioma (EH) and epithelioid hemangioendothelioma (EHE) are both rare vascular tumors. EH tumors are often benign while EHE tumors have moderate malignant potential. Here, we present three unique cases at Soroka Medical Center, two featuring EH of the bone and one presenting EHE of the mediastinum. Each case demonstrates distinct treatment challenges due to the rarity of both diseases and lack of established guidelines. We propose three treatment approaches including pazopanib for salvage therapy of EH of the bone and minimally invasive surgical resection which in these cases lead to complete symptom relief and tumor stabilization upheld over time with close follow-up.
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- 2021
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12. Can Ipilimumab restore immune response in advanced NSCLC after progression on anti‐PD‐1/PD‐L1 agents?
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Michal Sternschuss, Nir Peled, Aaron M. Allen, Elizabeth Dudnik, Ofer Rotem, Noga Kurman, Omer Gal, Hiba Reches, and Alona Zer
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Immune‐related adverse events ,ipilimumab ,nivolumab ,NSCLC ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Anti‐PD‐1/PD‐L1 agents play a crucial part in the treatment of non‐small cell cancer (NSCLC) demonstrating improved overall response rate (ORR) and overall survival (OS). Recent studies evaluating combination treatment with anti‐PD‐1 and anti‐CTLA‐4 suggests improved outcome but also increased toxicity. Evidence is scarce regarding subsequent treatment with immune checkpoint inhibitors (ICPI) after progression on anti‐PD‐1/PD‐L1. A total of 15 patients were treated with a combination of anti‐PD1 agent and ipilimumab after confirmed progression of disease on anti‐PD1/PDL1 alone during 2017. Clinical data were retrieved retrospectively. Disease control rate (DCR) was defined as partial response (PR) or stable disease (SD). The overall DCR was 33.3% (n = 5); two patients with PR and three patients with SD, three of whom had prior documented disease control on anti‐PD1. The immune‐related adverse event (irAE) rate was 40% (n = 6); two patients had grade 3 AE and one patient died of pneumonitis. While the median time to progression was two months (range 0.5–16), four of the five patients with PR/SD experienced durable benefit for 8–16 months. This small retrospective cohort of heavily pretreated unselected patients suggests ipilimumab might reboost the immune response in patients with advanced NSCLC following progression of disease on anti‐PD1 therapy, while delaying exposure to the higher toxicity rates associated with upfront combination therapy. This strategy should be explored prospectively.
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- 2020
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13. Associated Myocarditis: A Predictive Factor for Response?
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Walid Shalata, Nir Peled, Itzhak Gabizon, Omar Abu Saleh, Waleed Kian, and Alexander Yakobson
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immune checkpoint inhibitors ,myocarditis ,melanoma ,pembrolizumab ,nivolumab ,ipilimumab ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
In the present case report, we aimed to describe 2 cases of myocarditis occurring as serious adverse effects of immune checkpoint inhibitors (ICIs) administered as treatment for metastatic melanoma. We describe 2 female patients: an 81-year-old treated with pembrolizumab and a 55-year-old treated with a combination of nivolumab and ipilimumab. Both patients underwent resection of metastases; while under treatment, both developed myocarditis, most probably as a toxicity from pembrolizumab and nivolumab plus Ipilimumab, respectively. While they achieved complete response, the occurrence of myocarditis as a toxicity of ICIs may have been a predictive sign that the immune system was sufficiently activated by the checkpoint inhibitor therapy to induce complete remission.
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- 2020
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14. Treatment patterns, testing practices, and outcomes in the pre-FLAURA era for patients with EGFR mutation-positive advanced NSCLC: a retrospective chart review (REFLECT)
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Alfredo Addeo, Maximilian Hochmair, Urska Janzic, Elizabeth Dudnik, Andriani Charpidou, Adam Płużański, Tudor Ciuleanu, Ivan Shterev Donev, Judith Elbaz, Jørgen Aarøe, René Ott, and Nir Peled
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Introduction: For epidermal growth factor receptor mutation-positive (EGFRm) non-small-cell lung cancer (NSCLC), EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are the preferred first-line (1 L) treatment in the advanced setting. Osimertinib, a third-generation EGFR-TKI, received full approval in 2017 for second-line (2 L) treatment of EGFR T790M-positive NSCLC. The REFLECT study characterizes real-world treatment/testing patterns, attrition rates, and outcomes in patients with EGFRm advanced NSCLC treated with 1 L first-/second-generation (1G/2G) EGFR-TKIs before 1 L osimertinib approval. Methods: Retrospective chart review (NCT04031898) of European/Israeli adults with EGFRm unresectable locally advanced/metastatic NSCLC, initiating 1 L 1G/2G EGFR-TKIs 01/01/15–30/06/18 (index date). Results: In 896 patients (median follow-up of 21.5 months), the most frequently initiated 1 L EGFR-TKI was afatinib (45%). Disease progression was reported in 81%, including 10% (86/896) who died at 1 L. By the end of study, most patients discontinued 1 L (85%), of whom 33% did not receive 2 L therapy. From index, median 1 L real-world progression-free survival was 13.0 (95% confidence interval (CI): 12.3–14.1) months; median overall survival (OS) was 26.2 (95% CI: 23.6–28.4) months. 71% of patients with 1 L progression were tested for T790M; 58% were positive. Of those with T790M, 95% received osimertinib in 2 L or later. Central nervous system (CNS) metastases were recorded in 22% at index, and 15% developed CNS metastases during treatment (median time from index 13.5 months). Median OS was 19.4 months (95% CI: 17.1–22.1) in patients with CNS metastases at index, 24.8 months (95% CIs not available) with CNS metastases diagnosed during treatment, and 30.3 months (95% CI: 27.1, 33.8) with no CNS metastases recorded. Conclusion: REFLECT is a large real-world study describing treatment patterns prior to 1 L osimertinib availability for EGFRm advanced NSCLC. Given the attrition rates highlighted in the study and the impact of CNS progression on outcomes, offering a 1 L EGFR-TKI with CNS penetration may improve patient outcomes in this treatment setting.
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- 2021
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15. Genomic profiling of solid tumors harboring BRD4-NUT and response to immune checkpoint inhibitors
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Jonathan W. Riess, Shaila Rahman, Waleed Kian, Claire Edgerly, Andreas M. Heilmann, Russell Madison, Shakti H. Ramkissoon, Shai Shlomi Klaitman, Jon H. Chung, Sally E. Trabucco, Dexter X. Jin, Brian M. Alexander, Samuel J. Klempner, Lee A. Albacker, Garrett M. Frampton, Laila C. Roisman, Vincent A. Miller, Jeffrey S. Ross, Alexa B. Schrock, Jeffrey P. Gregg, Nir Peled, Ethan S. Sokol, and Siraj M. Ali
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NUT midline carcinoma ,NUT carcinoma ,BRD4-NUT ,Checkpoint inhibitor ,PD-L1 ,BRD4 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: The translocation t(15:19) produces the oncogenic BRD4-NUT fusion which is pathognomonic for NUT carcinoma (NC), which is a rare, but extremely aggressive solid tumor. Comprehensive genomic profiling (CGP) by hybrid-capture based next generation sequencing of 186+ genes of a cohort of advanced cancer cases with a variety of initial diagnoses harboring BRD4-NUT may shed further insight into the biology of these tumors and possible options for targeted treatment. Case presentation: Thirty-one solid tumor cases harboring a BRD4-NUT translocation are described, with only 16% initially diagnosed as NC and the remainder carrying other diagnoses, most commonly NSCLCNOS (22%) and lung squamous cell carcinoma (NSCLC-SCC) (16%). The cohort was all microsatellite stable and harbored a low Tumor Mutational Burden (TMB, mean 1.7 mut/mb, range 0–4). In two index cases, patients treated with immune checkpoint inhibitors (ICPI) had unexpected partial or better responses of varying duration. Notably, four cases – including the two index cases - were negative for PD-L1 expression. Neo-antigen prediction for BRD4-NUT and then affinity modeling of the peptide-MHC (pMHC) complex for an assessable index case predicted very high affinity binding, both on a ranked (99.9%) and absolute (33 nM) basis. Conclusions: CGP identifies BRD4-NUT fusions in advanced solid tumors which carry a broad range of initial diagnoses and which should be re-diagnosed as NC per guidelines. A hypothesized mechanism underlying responses to ICPI in the low TMB, PD-L1 negative index cases is the predicted high affinity of the BRD4-NUT fusion peptide to MHC complexes. Further study of pMHC affinity and response to immune checkpoint inhibitors in patients with NC harboring BRD4-NUT is needed to validate this therapeutic hypothesis.
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- 2021
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16. NKp44-Derived Peptide Used in Combination Stimulates Antineoplastic Efficacy of Targeted Therapeutic Drugs
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Muhammed Iraqi, Priyanka Bolel, Rhitajit Sarkar, Baisali Bhattacharya, Muhammad Abu Ahmad, Avishay Edri, Laila C. Roisman, Moshe Elkabets, Walid Shalata, Nir Peled, and Angel Porgador
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lung cancer ,NKp44 ,PCNA-binding peptide ,personalized medicine ,synergistic effect ,tumor xenograft ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Lung cancer cells in the tumor microenvironment facilitate immune evasion that leads to failure of conventional chemotherapies, despite provisionally decided on the genetic diagnosis of patients in a clinical setup. The current study follows three lung cancer patients who underwent “personalized” chemotherapeutic intervention. Patient-derived xenografts (PDXs) were subjected to tumor microarray and treatment screening with chemotherapies, either individually or in combination with the peptide R11-NLS-pep8; this peptide targets both membrane-associated and nuclear PCNA. Ex vivo, employing PDX-derived explants, it was found that combination with R11-NLS-pep8 stimulated antineoplastic effect of chemotherapies that were, although predicted based on the patient’s genetic mutation, inactive on their own. Furthermore, treatment in vivo of PDX-bearing mice showed an exactly similar trend in the result, corroborating the finding to be translated into clinical setup.
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- 2022
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17. Outcomes With Pembrolizumab Monotherapy in Patients With Programmed Death-Ligand 1–Positive NSCLC With Brain Metastases: Pooled Analysis of KEYNOTE-001, 010, 024, and 042
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Aaron S. Mansfield, MD, Roy S. Herbst, MD, PhD, Gilberto de Castro, Jr., MD, PhD, Rina Hui, MB, BS, PhD, Nir Peled, MD, PhD, Dong-Wan Kim, MD, Silvia Novello, MD, PhD, Miyako Satouchi, MD, Yi-Long Wu, MD, Edward B. Garon, MD, Martin Reck, MD, PhD, Andrew G. Robinson, MD, Ayman Samkari, MD, Bilal Piperdi, MD, Victoria Ebiana, MD, Jianxin Lin, MS, and Tony S.K. Mok, MD
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Pembrolizumab ,Brain metastases ,Chemotherapy ,Non‒small-cell lung cancer ,PD-L1 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Introduction: We retrospectively evaluated outcomes in patients with programmed death-ligand 1 (PD-L1)–positive non–small-cell lung cancer (NSCLC) to determine whether baseline (i.e., at study enrollment) brain metastases were associated with the efficacy of pembrolizumab versus chemotherapy. Methods: We pooled data for patients with previously treated or untreated PD-L1‒positive (tumor proportion score [TPS], ≥1%) advanced or metastatic NSCLC in KEYNOTE-001 (NCT01295827), KEYNOTE-010 (NCT01905657), KEYNOTE-024 (NCT02142738), and KEYNOTE-042 (NCT02220894). Patients received pembrolizumab (2 mg/kg, 10 mg/kg, or 200 mg every 3 wk or 10 mg/kg every 2 wk); chemotherapy was a comparator in all studies except KEYNOTE-001. All studies included patients with previously treated, stable brain metastases. Results: A total of 3170 patients were included, 293 (9.2%) with and 2877 (90.8%) without baseline brain metastases; median (range) follow-up at data cutoff was 12.9 (0.1‒43.7) months. Pembrolizumab improved overall survival versus chemotherapy in patients with or without baseline brain metastases: benefit was seen in patients with PD-L1 TPS ≥50% (0.67 [95% confidence intervals (CI): 0.44‒1.02] and 0.66 [95% CI: 0.58‒0.76], respectively) and PD-L1 TPS ≥1% (0.83 [95% CI: 0.62‒1.10] and 0.78 [95% CI: 0.71‒0.85], respectively). Progression-free survival was improved, objective response rates were higher, and duration of response was longer with pembrolizumab versus chemotherapy regardless of brain metastasis status. The incidence of treatment-related adverse events with pembrolizumab versus chemotherapy was 66.3% versus 84.4% in patients with brain metastases and 67.2% versus 88.3% in those without. Conclusions: Pembrolizumab monotherapy improved outcomes and was associated with fewer adverse events than chemotherapy in patients with treatment-naive and previously treated PD-L1‒positive advanced/metastatic NSCLC regardless of the presence of baseline treated, stable brain metastases.
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- 2021
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18. Nivolumab in Non-Small Cell Lung Cancer: Real World Long-Term Survival Results and Blood-Based Efficacy Biomarkers
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Sameh Daher, Yaacov R. Lawrence, Elizabeth Dudnik, Ekaterina Hanovich, Damien Urban, Nir Peled, Rossie Navon, Raya Leibowitz, Ariel Hammerman, Erez Battat, Teodor Gottfried, Amir Onn, and Jair Bar
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nivolumab ,NSCLC ,long term survival ,real life data ,biomarker ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
ObjectivesWe aimed to examine clinical data and baseline blood test results as potential predictive biomarkers for benefit from nivolumab, in advanced non-small cell lung cancer patients (NSCLC).Materials and MethodsA chart review was performed of 108 advanced NSCLC patients who commenced treatment with nivolumab between 2015-6 at three Israeli cancer centers, and for whom laboratory tests results were available. Data collected included sex, age, ECOG-PS, histology and number of previous lines of treatment. Baseline blood test results collected: absolute lymphocyte and neutrophil count (ANC), white blood cells (WBC), hemoglobin, platelets, albumin and lactate dehydrogenase (LDH). Neutrophil to Lymphocyte Ratio and ‘derived NLR’ (dNLR = (ANC/[WBC-ANC])) were calculated. Disease control at six months (DC6) was defined as any tumor shrinkage or stable disease during the first six months of nivolumab treatment. The association between clinical/laboratory variables and survival was tested with a Cox proportional hazard model. Data cut-off occurred in November 2019.Results35 patients (32.4%) achieved DC6. Median overall survival (OS) of entire study population was 5.4 months. Four year survival rate was 16%. Achievement of DC6 strongly correlated with longer OS (HR 0.12, 95% C.I. 0.07-0.21, p
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- 2021
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19. Lung Cancer in Young Patients: Higher Rate of Driver Mutations and Brain Involvement, but Better Survival
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Anna May Suidan, Laila Roisman, Anna Belilovski Rozenblum, Maya Ilouze, Elizabeth Dudnik, Alona Zer, and Nir Peled
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2019
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20. Nivolumab Induced Lethal Aplastic Anemia in a Patient with Metastatic Melanoma
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Keren Rouvinov, Karen Nalbandyan, Victor Kozlov, Nir Peled, and Alexander Yakobson
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Nivolumab ,Immunotherapy ,Melanoma ,Aplastic anemia ,Programmed death 1 inhibitor ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Nivolumab is an active treatment in patients with metastatic melanoma. We report a case of a patient with metastatic malignant melanoma who was given nivolumab as an advanced-line treatment. She received nivolumab 3 mg/kg every 2 weeks for 4 cycles and developed aplastic anemia. To the best of our knowledge, there are only three published case reports that have shown aplastic anemia in patients who have been treated by immunotherapy. This is the first report of a lethal aplastic anemia during nivolumab monotherapy in a metastatic melanoma patient.
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- 2019
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21. Trimodally treatment for stage IIIa NSCLC patients increases survival while not effecting surgical mortality or complexity
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Dan Aravot, Yaron D. Barac, Efrat Krutzwald-Josefson, Aaron M. Allen, Dov Flex, Nir Peled, Mordechai R. Kramer, Yuri Peysakhovich, and Milton Saute
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Pneumonectomy ,Neo adjuvant therapy ,Chemo-radiation ,Surgery ,RD1-811 ,Anesthesiology ,RD78.3-87.3 - Abstract
Abstract Introduction Advanced non-small cell lung cancer (NSCLC) is still a therapeutic challenge as the 5-year survival is under 30%. The optimal treatment regimen is still under debate. Hypothesis Neo adjuvant (NA) treatment given pre-pneumonectomy does not increase surgical complexity or peri-OP mortality while it has a potential to increase long term survival. Methods We have conducted a retrospective study of 169 patients who underwent a pneumonectomy for NSCLC between January 2005 to December 2015 and focused on stage IIIa patients; a cohort of 51 patients, 30 which received neo adjuvant chemo-radiation (NA group) prior to pneumonectomy and 21 patients who had undergone pneumonectomy followed by adjuvant treatment (Adjuvant group). Surgical complexity and short- and long-term survival were evaluated. Surgical complexity was assessed by surrogates as surgery duration, hospitalization length and interdepartmental transfer. Results While no statistically significant differences were found in surgery duration, hospitalization length, morbidity in the 1st year post-OP and the peri-OP mortality; The long term beneficiary effect among the neo adjuvant patients was clear; while 30% of the NA patients were alive 8 years post-OP, there were no survivors in the adjuvant group 5.5 years post-OP. Conclusion We conclude that while NA treatment has no effect on operation complexity, peri-OP mortality or post-OP morbidity; its impact on long term survival is protuberant, therefore, we believe that NA treatment should be considered as the treatment of choice in advanced NSCLC in need for pneumonectomy.
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- 2019
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22. FGFR Fusions as an Acquired Resistance Mechanism Following Treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR TKIs) and a Suggested Novel Target in Advanced Non-Small Cell Lung Cancer (aNSCLC)
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Ari Raphael, Elizabeth Dudnik, Dov Hershkovitz, Suyog Jain, Steve Olsen, Lior Soussan-Gutman, Taly Ben-Shitrit, Addie Dvir, Hovav Nechushtan, Nir Peled, Amir Onn, Abed Agbarya, and on behalf of the Israel Lung Cancer Group
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FGFR ,FGFR fusion ,acquired resistance to EGFR TKIs ,lung cancer ,liquid biopsy ,ctDNA ,Medicine - Abstract
Background. FGFR1/2/3 fusions have been reported infrequently in aNSCLC, including as a rare, acquired resistance mechanism following treatment with EGFR TKIs. Data regarding their prevalence and therapeutic implications are limited. Methods. The Guardant Health (GH) electronic database (ED) was evaluated for cases of aNSCLC and FGFR2/3 fusions; FGFR2/3 fusion prevalence with and without a co-existing EGFR mutation was assessed. The ED of Tel-Aviv Sourasky Medical Center (TASMC, June 2020–June 2021) was evaluated for cases of aNSCLC and de novo FGFR1/2/3 fusions. Patients with EGFR mutant aNSCLC progressing on EGFR TKIs and developing an FGFR1/2/3 fusion were selected from the ED of Davidoff Cancer Center (DCC) and Oncology Department, Bnei-Zion hospital (BZ) (April 2014–April 2021). Clinicopathological characteristics, systemic therapies, and outcomes were assessed. Results. In the GH ED (n = 57,445), the prevalence of FGFR2 and FGFR3 fusions were 0.02% and 0.26%, respectively. FGFR3-TACC3 fusion predominated (91.5%). In 23.8% of cases, FGFR2/3 fusions co-existed with EGFR sensitizing mutations (exon 19 del, 64.1%; L858R, 33.3%, L861Q, 2.6%). Among samples with concurrent FGFR fusions and EGFR sensitizing mutations, 41.0% also included EGFR resistant mutations. In TASMC (n = 161), 1 case of de novo FGFR3-TACC3 fusion was detected (prevalence, 0.62%). Of three patients from DCC and BZ with FGFR3-TACC3 fusions following progression on EGFR TKIs, two received EGFR TKI plus erdafitinib, an FGFR TKI, with clinical benefit duration of 13.0 and 6.0 months, respectively. Conclusions. Over 23% of FGFR2/3 fusions in aNSCLC may be associated with acquired resistance following treatment with EGFR TKIs. In this clinical scenario, a combination of EGFR TKIs and FGFR TKIs represents a promising treatment strategy.
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- 2022
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23. BAP1-Altered Malignant Pleural Mesothelioma: Outcomes With Chemotherapy, Immune Check-Point Inhibitors and Poly(ADP-Ribose) Polymerase Inhibitors
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Elizabeth Dudnik, Jair Bar, Assaf Moore, Teodor Gottfried, Mor Moskovitz, Julia Dudnik, Tzippy Shochat, Aaron M. Allen, Alona Zer, Ofer Rotem, Nir Peled, and Damien Urban
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mesothelioma ,BAP1 ,immune check-point inhibitors ,PARP inhibitors ,chemotherapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
ObjectivesLittle is known regarding the outcomes of systemic treatments in BAP1-altered malignant pleural mesothelioma (MPM).Materials and MethodsForty five patients with MPM [group A: eight MPM patients with BAP1 inactivating mutation/copy number loss (FoundationOne® CDx/TEMPUSxT), selected from the electronic databases of four Israeli cancer centers (ICC); group B: 37 consecutive (years 2016–2018) MPM patients selected from the electronic databases of two ICC—of those six patients without a BAP1 alteration (group B1) and 31 patients not tested for BAP1 (group B2)] were analyzed for ORR, PFS (mRECIST), and OS with 1st-line platinum/pemetrexed+/−antiangiogenic drug (CT, n-28), immune check-point inhibitors (ICPi, n-16) and poly (ADP-ribose) polymerase inhibitors (PARPi, n-4). OS since diagnosis (OSDx) was assessed.ResultsThere were no differences in ORR or mPFS with CT between the groups: ORR-50% vs. 47% vs. 50% vs. 47% (p>0.9), mPFS-9.1mo (95% CI, 1.2–16.1) vs. 9.2mo (95% CI, 2.9–13.3) vs. 7.2mo (95% CI, 2.3-NR) vs. 10.9mo (95% CI, 2.9–20.3) (p>0.8) in groups A, B, B1, and B2, respectively. There were no differences in ORR or mPFS with ICPi between the groups: ORR-0% vs. 27% vs. 33% vs. 25% (p>0.2), mPFS-2.5mo (95% CI, 1.4–3.7) vs. 3.0mo (95% CI, 1.3–10.5) vs. 2.0mo (95% CI, 1.9-NR) vs. 4.5mo (95% CI, 0.3–10.5) (p>0.3) in groups A, B, B1, and B2, respectively. In group A, no responses were seen with PARPi; mPFS with PARPi was 1.8mo (95% CI, 1.8-NR). OSDx was 98.3mo (95% CI, 9.7–98.3) vs. 19.4mo (95% CI, 9.7–47.3) vs. 18.8mo (95% CI, 8.5-NR) vs. 19.5mo (95% CI, 8.3–82.2) in groups A, B, B1, and B2, respectively (p>0.3).ConclusionsBAP1-altered MPM, as compared to non-selected MPM, is characterized by similar efficacy of CT and ICPi. Numerically longer OS in BAP1-altered MPM may reflect favorable tumor biology. No responses were observed with PARPi.
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- 2021
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24. Hypercalcemia as a Rebound Phenomenon of LOXO-292 Efficacy in Medullary Thyroid Cancer
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Waleed Kian, MD, Dina Levitas, MD, Wafeek Alguayn, MD, Walid Shalata, MD, Adam A. Sharb, MD, Daniel Levin, MD, Laila C. Roisman, PhD, Margarita Tokar, MD, Nir Peled, MD, PhD, FCCP, and Alexander Yakobson, MD
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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25. Stereotactic body radiotherapy for central lung tumors, yes we can!
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Yasmin Korzets ceder, Eyal Fenig, Aron Popvtzer, Nir Peled, Mordechai R. Kramer, Milton Saute, Dima Bragilovsky, Tzippy Schochat, and Aaron M. Allen
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Medical physics. Medical radiology. Nuclear medicine ,R895-920 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background SBRT is standard therapy for early stage lung cancer. Toxicity in central tumors has been a concern. RTOG 0813 showed that central SBRT is safe and effective. We report our experience with central SBRT. Methods We reviewed the records of patients treated with SBRT for central lung tumors (
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- 2018
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26. Rapid Response to the Combination of Lenvatinib and Pembrolizumab in Patients with Advanced Carcinomas (Lung Adenocarcinoma and Malignant Pleural Mesothelioma)
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Walid Shalata, Muhammed Iraqi, Baisali Bhattacharya, Vered Fuchs, Laila C. Roisman, Ahron Yehonatan Cohen, Ismaell Massalha, Alexander Yakobson, Manu Prasad, Moshe Elkabets, Angel Porgador, and Nir Peled
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lung adenocarcinoma ,NSCLC ,malignant pleural mesothelioma ,multikinase inhibitor ,immune checkpoint inhibitor ,lenvatinib ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The new era of cancer treatments has made immune checkpoint inhibitors (ICIs) and emerging multikinase inhibitors (TKIs) the standards of care, thus drastically improving patient prognoses. Pembrolizumab is an anti-programmed cell death-1 antibody drug, and lenvatinib is a TKI with preferential antiangiogenic activity. We present, to our knowledge, the first reported series of cases consisting of patients with metastatic non–small cell lung cancer and malignant pleural mesothelioma who were treated with several types of chemotherapy combinations and ICIs followed by disease progression. They were subsequently treated with combined immunotherapy and TKI treatment, resulting in a near complete response within a very short time. Clinical responses were supported by in vitro testing of each patient’s lymphocytic response to pembrolizumab after pre-exposure of target cancer cells to lenvatinib.
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- 2021
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27. Recommendations for Implementing Lung Cancer Screening with Low-Dose Computed Tomography in Europe
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Giulia Veronesi, David R. Baldwin, Claudia I. Henschke, Simone Ghislandi, Sergio Iavicoli, Matthijs Oudkerk, Harry J. De Koning, Joseph Shemesh, John K. Field, Javier J. Zulueta, Denis Horgan, Lucia Fiestas Navarrete, Maurizio Valentino Infante, Pierluigi Novellis, Rachael L. Murray, Nir Peled, Cristiano Rampinelli, Gaetano Rocco, Witold Rzyman, Giorgio Vittorio Scagliotti, Martin C. Tammemagi, Luca Bertolaccini, Natthaya Triphuridet, Rowena Yip, Alexia Rossi, Suresh Senan, Giuseppe Ferrante, Kate Brain, Carlijn van der Aalst, Lorenzo Bonomo, Dario Consonni, Jan P. Van Meerbeeck, Patrick Maisonneuve, Silvia Novello, Anand Devaraj, Zaigham Saghir, and Giuseppe Pelosi
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consensus ,statement ,screening ,lung cancer ,mortality ,reduction ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Lung cancer screening (LCS) with low-dose computed tomography (LDCT) was demonstrated in the National Lung Screening Trial (NLST) to reduce mortality from the disease. European mortality data has recently become available from the Nelson randomised controlled trial, which confirmed lung cancer mortality reductions by 26% in men and 39–61% in women. Recent studies in Europe and the USA also showed positive results in screening workers exposed to asbestos. All European experts attending the “Initiative for European Lung Screening (IELS)”—a large international group of physicians and other experts concerned with lung cancer—agreed that LDCT-LCS should be implemented in Europe. However, the economic impact of LDCT-LCS and guidelines for its effective and safe implementation still need to be formulated. To this purpose, the IELS was asked to prepare recommendations to implement LCS and examine outstanding issues. A subgroup carried out a comprehensive literature review on LDCT-LCS and presented findings at a meeting held in Milan in November 2018. The present recommendations reflect that consensus was reached.
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- 2020
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28. Assembly 11: thoracic oncology
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Clementine Bostantzoglou and Nir Peled
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Diseases of the respiratory system ,RC705-779 - Published
- 2018
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29. Correction to: Trimodally treatment for stage IIIa NSCLC patients increases survival while not effecting surgical mortality or complexity
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Dan Aravot, Yaron D. Barac, Efrat Krutzwald-Josefson, Aaron M. Allen, Dov Flex, Nir Peled, Mordechai R. Kramer, Yuri Peysakhovich, and Milton Saute
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Surgery ,RD1-811 ,Anesthesiology ,RD78.3-87.3 - Abstract
The original article [1] contained an error whereby all authors’ names were mistakenly inverted. This error has now been corrected.
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- 2019
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30. Review: Predictive and prognostic markers for epidermal growth factor receptor inhibitor therapy in non-small cell lung cancer
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Nir Peled, Koichi Yoshida, Murry W. Wynes, and Fred R. Hirsch
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Epidermal growth factor receptor (EGFR) related therapies - mainly tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib, but also monoclonal antibodies targeting EGFR, for example, cetuximab - have been investigated in numerous settings in non-small cell lung cancer (NSCLC) and in different combinations. The overall clinical benefit of EGFR TKI therapy is roughly 10-30%, with higher benefit in nonsmoker Asiatic women with EGFR-mutated adenocarcinoma. Currently, there are several biomarkers that are able to direct and predict the yield of EGFR-related therapies in NSCLC. These include EGFR mutation status, EGFR protein expression, EGFR gene copy number and a serum proteomic marker (Veristrat ® , Biodesix; CO). The usage of such biomarkers is important from many aspects. First, it helps clinicians to make the right treatment decisions and second, it leads to a wiser usage of financial resources. This review will focus on EGFR-related biomarkers for their prognostic power and their ability to predict clinical benefit from EGFR-related therapy.
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- 2009
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31. BRCA mutations detected by tumour next-generation sequencing in non-small cell lung cancer: impact on response to therapy and disease course
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Roi Tschernichovsky, Itamar Averbuch, Daniel Alex Goldstein, Raz Mutai, Elizabeth Dudnik, Ofer Rotem, Smadar Laufer-Geva, Nir Peled, Yael Goldberg, and Alona Zer
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Oncology - Published
- 2023
32. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non–Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study
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Marina C. Garassino, Shirish Gadgeel, Giovanna Speranza, Enriqueta Felip, Emilio Esteban, Manuel Dómine, Maximilian J. Hochmair, Steven F. Powell, Helge G. Bischoff, Nir Peled, Francesco Grossi, Ross R. Jennens, Martin Reck, Rina Hui, Edward B. Garon, Takayasu Kurata, Jhanelle E. Gray, Paul Schwarzenberger, Erin Jensen, M. Catherine Pietanza, Delvys Rodríguez-Abreu, Institut Català de la Salut, [Garassino MC] Knapp Center for Biomedical Discovery, University of Chicago Medicine & Biological Sciences, Chicago, IL. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. [Gadgeel S] Henry Ford Cancer Institute/Henry Ford Health, Detroit, MI. [Speranza G] Centre Integré de Cancérologie de la Montérégie, Hôpital Charles-Le Moyne, Greenfield Park, QC, Canada. [Felip E] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Esteban E] Department of Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, Spain. [Dómine M] Department of Oncology, Hospital Universitario Fundación Jiménez Díaz, IIS-FJD, Madrid, Spain, and Vall d'Hebron Barcelona Hospital Campus
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Cancer Research ,Oncology ,Otros calificadores::/uso terapéutico [Otros calificadores] ,Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Medicaments antineoplàstics - Ús terapèutic ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,Other subheadings::/therapeutic use [Other subheadings] ,Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Carcinoma, Non-Small-Cell Lung [DISEASES] ,neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares::neoplasias de los bronquios::carcinoma broncogénico::carcinoma de pulmón de células no pequeñas [ENFERMEDADES] ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,Pulmons - Càncer - Tractament - Abstract
Pembrolizumab; Non-small-cell lung cancer Pembrolizumab; Cáncer de pulmón de células no pequeñas Pembrolizumab; Càncer de pulmó de cèl·lules no petites Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680). Eligible patients with previously untreated metastatic nonsquamous non-small-cell lung cancer without EGFR/ALK alterations were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and investigator's choice of carboplatin/cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or unacceptable toxicity. Primary end points were overall survival (OS) and progression-free survival (PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time from random assignment to data cutoff (March 8, 2022) was 64.6 (range, 60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%. Toxicity was manageable. Among 57 patients who completed 35 cycles of pembrolizumab, objective response rate was 86.0% and 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%. Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1 expression. These data continue to support pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations.
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- 2023
33. The EU-funded I3LUNG Project:Integrative Science, Intelligent Data Platform for Individualized LUNG Cancer Care With Immunotherapy
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Arsela Prelaj, Monica Ganzinelli, Francesco Trovo’, Laila C. Roisman, Alessandra Laura Giulia Pedrocchi, Sokol Kosta, Marcello Restelli, Emilia Ambrosini, Massimo Broggini, Gabriella Pravettoni, Dario Monzani, Alessandro Nuara, Ramon Amat, Nikos Spathas, Michael Willis, Alexander Pearson, James Dolezal, Laura Mazzeo, Sabina Sangaletti, Ana Maria Correa, Alfonso Aguaron, Iris Watermann, Crina Popa, Giulia Raimondi, Tiziana Triulzi, Stefan Steurer, Giuseppe Lo Russo, Helena Linardou, Nir Peled, Enriqueta Felip, Martin Reck, Marina Chiara Garassino, Prelaj A., Ganzinelli M., Trovo' F., Roisman L.C., Pedrocchi A.L.G., Kosta S., Restelli M., Ambrosini E., Broggini M., Pravettoni G., Monzani D., Nuara A., Amat R., Spathas N., Willis M., Pearson A., Dolezal J., Mazzeo L., Sangaletti S., Correa A.M., Aguaron A., Watermann I., Popa C., Raimondi G., Triulzi T., Steurer S., Lo Russo G., Linardou H., Peled N., Felip E., Reck M., and Garassino M.C.
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Pulmonary and Respiratory Medicine ,Cancer Research ,Artificial intelligence ,Oncology ,Non-small cell lung cancer ,Predictive biomarkers ,Machine learning ,Personalized medicine - Abstract
Although immunotherapy (IO) has changed the paradigm for the treatment of patients with advanced non-small cell lung cancers (aNSCLC), only around 30% to 50% of treated patients experience a long-term benefit from IO. Furthermore, the identification of the 30 to 50% of patients who respond remains a major challenge, as programmed Death-Ligand 1 (PD-L1) is currently the only biomarker used to predict the outcome of IO in NSCLC patients despite its limited efficacy. Considering the dynamic complexity of the immune system-tumor microenvironment (TME) and its interaction with the host's and patient's behavior, it is unlikely that a single biomarker will accurately predict a patient's outcomes. In this scenario, Artificial Intelligence (AI) and Machine Learning (ML) are becoming essential to the development of powerful decision-making tools that are able to deal with this high-complexity and provide individualized predictions to better match treatments to individual patients and thus improve patient outcomes and reduce the economic burden of aNSCLC on healthcare systems. I3LUNG is an international, multicenter, retrospective and prospective, observational study of patients with aNSCLC treated with IO, entirely funded by European Union (EU) under the Horizon 2020 (H2020) program. Using AI-based tools, the aim of this study is to promote individualized treatment in aNSCLC, with the goals of improving survival and quality of life, minimizing or preventing undue toxicity and promoting efficient resource allocation. The final objective of the project is the construction of a novel, integrated, AI-assisted data storage and elaboration platform to guide IO administration in aNSCLC, ensuring easy access and cost-effective use by healthcare providers and patients.
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- 2023
34. Correlations between pathogenic variants in <scp>DNA</scp> repair genes and anticancer treatment efficacy in stage <scp>IV</scp> non‐small cell lung cancer: A large real‐world cohort and review of the literature
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Itamar Averbuch, Roi Tschernichovsky, Oded Icht, Daniel A. Goldstein, Raz Mutai, Elizabeth Dudnik, Ofer Rotem, Nir Peled, Aaron M. Allen, Smadar Laufer‐Geva, Yael Goldberg, and Alona Zer
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Pulmonary and Respiratory Medicine ,Oncology ,General Medicine - Published
- 2023
35. Supplemental Figure S3 from Co-occurring Alterations in the RAS–MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer
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Collin M. Blakely, Trever G. Bivona, Tianhong Li, Lyudmila Bazhenova, Jose Pacheco, D. Ross Camidge, Caroline E. McCoach, Eric A. Collisson, James S. Fraser, Alexander M. Wolff, Victor R. Olivas, Kimberly Newsom, Petr Starostik, Boris C. Bastian, Iwei Yeh, Ryan B. Corcoran, Brandon Nadres, Ferran Fece de la Cruz, Nir Peled, Frederic J. Kaye, Richard B. Lanman, Victoria M. Raymond, Wei Wu, Philippe Gui, and Julia K. Rotow
- Abstract
MET tyrosine kinase domain modeling location of the F1200 residue
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- 2023
36. Supplementary Methods from MET Exon 14 Mutation Encodes an Actionable Therapeutic Target in Lung Adenocarcinoma
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Eric A. Collisson, Matthew Meyerson, Angela Brooks, Byron Hann, Youngho Seo, Kuang-Yu Jen, Sergio Wong, Alice H. Berger, Peter Choi, Wei Wu, John Greer, Nir Peled, and Xinyuan Lu
- Abstract
Supplementary Methods
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- 2023
37. Supplemental Table 1 from Co-occurring Alterations in the RAS–MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer
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Collin M. Blakely, Trever G. Bivona, Tianhong Li, Lyudmila Bazhenova, Jose Pacheco, D. Ross Camidge, Caroline E. McCoach, Eric A. Collisson, James S. Fraser, Alexander M. Wolff, Victor R. Olivas, Kimberly Newsom, Petr Starostik, Boris C. Bastian, Iwei Yeh, Ryan B. Corcoran, Brandon Nadres, Ferran Fece de la Cruz, Nir Peled, Frederic J. Kaye, Richard B. Lanman, Victoria M. Raymond, Wei Wu, Philippe Gui, and Julia K. Rotow
- Abstract
Demographics of the METex14-mutated and EGFR-mutated cohorts.
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- 2023
38. Data from Co-occurring Alterations in the RAS–MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer
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Collin M. Blakely, Trever G. Bivona, Tianhong Li, Lyudmila Bazhenova, Jose Pacheco, D. Ross Camidge, Caroline E. McCoach, Eric A. Collisson, James S. Fraser, Alexander M. Wolff, Victor R. Olivas, Kimberly Newsom, Petr Starostik, Boris C. Bastian, Iwei Yeh, Ryan B. Corcoran, Brandon Nadres, Ferran Fece de la Cruz, Nir Peled, Frederic J. Kaye, Richard B. Lanman, Victoria M. Raymond, Wei Wu, Philippe Gui, and Julia K. Rotow
- Abstract
Purpose:Although patients with advanced-stage non–small cell lung cancers (NSCLC) harboring MET exon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.Experimental Design:Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stage METex14-mutated NSCLC.Results:Prominent co-occurring RAS–MAPK pathway gene alterations (e.g., in KRAS, NF1) were detected in NSCLCs with METex14 skipping alterations as compared with EGFR-mutated NSCLCs. There was an association between decreased MET TKI treatment response and RAS–MAPK pathway co-occurring alterations. In a preclinical model expressing a canonical METex14 mutation, KRAS overexpression or NF1 downregulation hyperactivated MAPK signaling to promote MET TKI resistance. This resistance was overcome by cotreatment with crizotinib and the MEK inhibitor trametinib.Conclusions:Our study provides a genomic landscape of co-occurring alterations in advanced-stage METex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes.
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- 2023
39. Data from MET Exon 14 Mutation Encodes an Actionable Therapeutic Target in Lung Adenocarcinoma
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Eric A. Collisson, Matthew Meyerson, Angela Brooks, Byron Hann, Youngho Seo, Kuang-Yu Jen, Sergio Wong, Alice H. Berger, Peter Choi, Wei Wu, John Greer, Nir Peled, and Xinyuan Lu
- Abstract
Targeting somatically activated oncogenes has revolutionized the treatment of non–small cell lung cancer (NSCLC). Mutations in the gene mesenchymal–epithelial transition (MET) near the exon 14 splice sites are recurrent in lung adenocarcinoma and cause exon skipping (METΔ14). Here, we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. METΔ14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of METΔ14 transformed human epithelial lung cells in a hepatocyte growth factor–dependent manner. In addition, overexpression of the orthologous mouse allele induced lung adenocarcinoma in a novel, immunocompetent mouse model. Met inhibition showed clinical benefit in this model. In addition, we observed a clinical response to crizotinib in a patient with METΔ14-driven NSCLC, only to observe new missense mutations in the MET activation loop, critical for binding to crizotinib, upon clinical progression. These findings support genomically selected clinical trials directed toward METΔ14 in a fraction of NSCLC patients, confirm second-site mutations for further therapeutic targeting prior to and beyond acquired resistance, and provide an in vivo system for the study of METΔ14 in an immunocompetent host. Cancer Res; 77(16); 4498–505. ©2017 AACR.
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- 2023
40. Supplemental Table 3 from Co-occurring Alterations in the RAS–MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer
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Collin M. Blakely, Trever G. Bivona, Tianhong Li, Lyudmila Bazhenova, Jose Pacheco, D. Ross Camidge, Caroline E. McCoach, Eric A. Collisson, James S. Fraser, Alexander M. Wolff, Victor R. Olivas, Kimberly Newsom, Petr Starostik, Boris C. Bastian, Iwei Yeh, Ryan B. Corcoran, Brandon Nadres, Ferran Fece de la Cruz, Nir Peled, Frederic J. Kaye, Richard B. Lanman, Victoria M. Raymond, Wei Wu, Philippe Gui, and Julia K. Rotow
- Abstract
The MET F1200 residue is conserved across multiple tyrosine kinases
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- 2023
41. Supplementary Figure Legends from Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models
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James G. Christensen, Pasi A. Jänne, Mark M. Awad, Nir Peled, Geoffrey I. Shapiro, Mizuki Nishino, Carrie Graveel, Sandip Pravin Patel, Lyudmilla Bazhenova, Peter Olson, Richard B. Lanman, Darya I. Chudova, Richard Chao, Vanessa Tassell, Manuel Hidalgo, Camino Menendez, Natalia Baños, Pedro P. Lopez-Casas, Jill Hallin, David Briere, Harrah Chiang, Zachary Madaj, Curt J. Essenburg, Elizabeth A. Tovar, Matthew Lee, Ruth Aranda, and Lars D. Engstrom
- Abstract
Supplementary Figure Legends
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- 2023
42. Supplementary Figures from Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models
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James G. Christensen, Pasi A. Jänne, Mark M. Awad, Nir Peled, Geoffrey I. Shapiro, Mizuki Nishino, Carrie Graveel, Sandip Pravin Patel, Lyudmilla Bazhenova, Peter Olson, Richard B. Lanman, Darya I. Chudova, Richard Chao, Vanessa Tassell, Manuel Hidalgo, Camino Menendez, Natalia Baños, Pedro P. Lopez-Casas, Jill Hallin, David Briere, Harrah Chiang, Zachary Madaj, Curt J. Essenburg, Elizabeth A. Tovar, Matthew Lee, Ruth Aranda, and Lars D. Engstrom
- Abstract
Supplemental Figure 1. Glesatinib is a potent and selective MET inhibitor. Supplemental Figure 2. Waterfall plot of glesatinib activity across pre-clinical tumor models. Supplemental Figure 3. SNU-638 Criz-res line is homogeneous and harbors the F1200L and Y1230H resistance mutations on the same allele. Supplemental Figure 4. Long term treatment of a METex14 del mutant and amplified PDX model (PULM-039) leads to capmatinib and crizotinib-resistant tumors but not glesatinib-resistant tumors. Supplemental Figure 5. Molecular basis for resistance that arises from the G1163R mutation. Supplemental Figure 6. Glesatinib is active against type I MET inhibitor-resistance mutations in a spheroid growth assay.
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- 2023
43. Supplementary Tables 1 and 2 from MET Exon 14 Mutation Encodes an Actionable Therapeutic Target in Lung Adenocarcinoma
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Eric A. Collisson, Matthew Meyerson, Angela Brooks, Byron Hann, Youngho Seo, Kuang-Yu Jen, Sergio Wong, Alice H. Berger, Peter Choi, Wei Wu, John Greer, Nir Peled, and Xinyuan Lu
- Abstract
Supplementary Tables 1 and 2
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- 2023
44. supplementary figures 1-5 from MET Exon 14 Mutation Encodes an Actionable Therapeutic Target in Lung Adenocarcinoma
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Eric A. Collisson, Matthew Meyerson, Angela Brooks, Byron Hann, Youngho Seo, Kuang-Yu Jen, Sergio Wong, Alice H. Berger, Peter Choi, Wei Wu, John Greer, Nir Peled, and Xinyuan Lu
- Abstract
Supplementary Figure 1: A survey of MET mutations and expression across TCGA datasets from diverse cancer types. Supplementary figure 2, MET exon 14 status and trypsin assay Supplementary Figure 3 MET half-life assay results Supplementary Figure 4 tumor grade and size changes Supplementary Figure 5: Acquired resistance alleles are in trans
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- 2023
45. Data from Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models
- Author
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James G. Christensen, Pasi A. Jänne, Mark M. Awad, Nir Peled, Geoffrey I. Shapiro, Mizuki Nishino, Carrie Graveel, Sandip Pravin Patel, Lyudmilla Bazhenova, Peter Olson, Richard B. Lanman, Darya I. Chudova, Richard Chao, Vanessa Tassell, Manuel Hidalgo, Camino Menendez, Natalia Baños, Pedro P. Lopez-Casas, Jill Hallin, David Briere, Harrah Chiang, Zachary Madaj, Curt J. Essenburg, Elizabeth A. Tovar, Matthew Lee, Ruth Aranda, and Lars D. Engstrom
- Abstract
Purpose: MET exon 14 deletion (METex14 del) mutations represent a novel class of non–small cell lung cancer (NSCLC) driver mutations. We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in METex14 del–positive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET inhibitors.Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials.Results: Glesatinib inhibited MET signaling, demonstrated marked regression of METex14 del-driven patient-derived xenografts, and demonstrated a durable RECIST partial response in a METex14 del mutation-positive patient enrolled on a glesatinib clinical trial. Prolonged treatment of nonclinical models with selected MET inhibitors resulted in differences in resistance kinetics and mutations within the MET activation loop (i.e., D1228N, Y1230C/H) that conferred resistance to type I MET inhibitors, but remained sensitive to glesatinib. In vivo models exhibiting METex14 del/A-loop double mutations and resistance to type I inhibitors exhibited a marked response to glesatinib. Finally, a METex14 del mutation-positive NSCLC patient who responded to crizotinib but later relapsed, demonstrated a mixed response to glesatinib including reduction in size of a MET Y1230H mutation-positive liver metastasis and concurrent loss of detection of this mutation in plasma DNA.Conclusions: Together, these data demonstrate that glesatinib exhibits a distinct mechanism of target inhibition and can overcome resistance to type I MET inhibitors. Clin Cancer Res; 23(21); 6661–72. ©2017 AACR.
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- 2023
46. Supplemental Table 2 from Co-occurring Alterations in the RAS–MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer
- Author
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Collin M. Blakely, Trever G. Bivona, Tianhong Li, Lyudmila Bazhenova, Jose Pacheco, D. Ross Camidge, Caroline E. McCoach, Eric A. Collisson, James S. Fraser, Alexander M. Wolff, Victor R. Olivas, Kimberly Newsom, Petr Starostik, Boris C. Bastian, Iwei Yeh, Ryan B. Corcoran, Brandon Nadres, Ferran Fece de la Cruz, Nir Peled, Frederic J. Kaye, Richard B. Lanman, Victoria M. Raymond, Wei Wu, Philippe Gui, and Julia K. Rotow
- Abstract
Genes included in NGS Panels
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- 2023
47. Conflict of Interest Form from MET Exon 14 Mutation Encodes an Actionable Therapeutic Target in Lung Adenocarcinoma
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Eric A. Collisson, Matthew Meyerson, Angela Brooks, Byron Hann, Youngho Seo, Kuang-Yu Jen, Sergio Wong, Alice H. Berger, Peter Choi, Wei Wu, John Greer, Nir Peled, and Xinyuan Lu
- Abstract
Conflict of Interest Form
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- 2023
48. Supplementary Figure Legends from MET Exon 14 Mutation Encodes an Actionable Therapeutic Target in Lung Adenocarcinoma
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Eric A. Collisson, Matthew Meyerson, Angela Brooks, Byron Hann, Youngho Seo, Kuang-Yu Jen, Sergio Wong, Alice H. Berger, Peter Choi, Wei Wu, John Greer, Nir Peled, and Xinyuan Lu
- Abstract
Supplementary Figure Legends
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- 2023
49. Patient-derived xenograft models of human non-small cell lung cancer: pre-clinical and clinical factors for consideration
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Nir Peled, Vered Fuchs, Ariel Sobarzo, Maha Masamra, Yarden Kezerle, Liat Linde, Gur Sevillya, Yael Refaeli, Ahron Cohen, Israel Melamed, Amit Azriel, Rami Shoukrun, Yael Raviv, Angel Porgador, and Laila Roisman
- Abstract
Despite the widespread utilization of Patient-Derived Xenografts (PDXs) as preclinical platforms in lung cancer research, there are concerns regarding their capability to accurately represent the tumor's clinical and molecular features across sequential passages. In this study, we established a Non-Small Cell Lung Cancer (NSCLC) PDX model in NSG-SGM3 mice and assessed clinical and preclinical factors throughout subsequent passages. Our cohort consisted of 40 NSCLC patients, which were used to successfully create 20 patient-specific PDX models in NSG-SGM3 mice. We found that the main factors that contributed to the growth of the engrafted PDX in mice were a higher grade or stage of disease, in contrast to a long duration of chemotherapy treatment which was negatively correlated with PDX propagation. Successful PDX growth was also linked to poorer prognosis and overall survival, while growth pattern variability was affected by the tumor's aggressiveness, primarily affecting the first passage. Pathology analysis showed preservation of histological type and grade; however, Whole Exome Sequence (WES) analysis revealed genomic instability in advanced passages, leading to the inconsistency of clinically relevant alterations between PDXs and biopsies. Multiple clinical and preclinical factors affect the engraftment success, growth kinetics, and tumor stability of patient-specific NSCLC PDXs; thus, their use for prolonged treatment evaluation studies remains questionable.
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- 2023
50. Neoadjuvant Osimertinib Followed by Sequential Definitive Radiation Therapy and/or Surgery in Stage III Epidermal Growth Factor Receptor–Mutant Non-Small Cell Lung Cancer: An Open-Label, Single-Arm, Phase 2 Study
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Nir Peled, Laila C. Roisman, Esther Levison, Julia Dudnik, Elena Chernomordikov, Norman Heching, Elizabeth Dudnik, Shoshana Keren-Rosenberg, Hovav Nechushtan, Ayman Salhab, Dov Hershkovitz, Shlomo Tsuriel, Victoria Hannes, Ofer Rotem, Irina Lazarev, Rachel Lichtenberg, Inbal S. Granot, Bilal Krayim, Walid Shalata, Daniel Levin, Yanay Krutman, Aaron M. Allen, Philip Blumenfeld, Konstantin Lavrenkov, and Waleed Kian
- Subjects
Cancer Research ,Radiation ,Oncology ,Radiology, Nuclear Medicine and imaging - Published
- 2023
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