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Immune-Related Adverse Events (irAEs): Implications for Immune Checkpoint Inhibitor Therapy

Nanruoyi Zhou, Maria A. Velez, Dwight Owen, and Aaron E. Lisberg

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CRE24-044: Response to Dabrafenib and Trametinib in a Patient With an Uncommon Activating BRAF Mutation: A First in Metastatic Non–Small Cell Lung Cancer

John Sharp, Daniel Jones, Julia Rotow, Panos Fidias, Erin Bertino, and Dwight Owen

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Response to Dabrafenib Plus Trametinib in a Patient With an Uncommon Activating BRAF Mutation: A First in Non–Small Cell Lung Cancer

John A. Sharp, Daniel Jones, Julia K. Rotow, Panos M. Fidias, Erin Bertino, and Dwight H. Owen

Mutations in BRAF are present in 4% of non–small cell lung cancer (NSCLC), of which half are well-characterized activating variants affecting codon 600 (classified as class I). These mutations, most commonly BRAF V600E, have been associated with response to BRAF/MEK-directed small molecule kinase inhibitors. NSCLC with kinase-activating BRAF mutations occurring at other codons (class II variants) represent a substantial portion of BRAF-mutated NSCLC, but use of targeted therapy in these tumors is still under investigation. Class II mutations have been described in other tumor types and have been associated with response to BRAF/MEK-targeted agents, although optimal treatment strategies for these patients are lacking. This report presents a case of a woman with metastatic NSCLC harboring a class II BRAF p.N486_P490del variant who had a sustained clinical response to combination therapy with dabrafenib and trametinib. This first report of the use of BRAF/MEK-targeted therapy for this variant in NSCLC supports consideration of such treatment for tumors with class II BRAF variants.

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HSR24-160: Immune Checkpoint Inhibitor-Induced Type 1 Diabetes Mellitus: Patient Characteristics, Clinical Outcomes, and Survival Implications of Autoantibodies

John Sharp, Cassandra Pasadyn, Songzhu Zhao, Lai Wei, Carolyn Presley, Dwight Owen, Kathleen Wyne, and Alexa Meara

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KRAS G12V Mutation in Acquired Resistance to Combined BRAF and MEK Inhibition in Papillary Thyroid Cancer

Dwight H. Owen, Bhavana Konda, Jennifer Sipos, Tom Liu, Amy Webb, Matthew D. Ringel, Cynthia D. Timmers, and Manisha H. Shah

BRAF V600E mutations occur in approximately 40% of all patients with papillary thyroid cancer (PTC) and are associated with a worse prognosis in population studies. Treatment with single-agent BRAF inhibitors can result in nondurable partial responses (PRs) in clinical trials, but resistance inevitably develops. The mechanisms of resistance are not completely understood, but in non-thyroid tumors harboring BRAF V600E mutations, resistance has been ascribed to concurrent or acquired mutations in MEK1/2, RAC1, KRAS, and NRAS. This case report describes a patient with radioactive iodine–refractory metastatic PTC treated in a clinical trial with combination BRAF and MEK inhibition who achieved a durable PR. At time of progression, biopsy revealed an acquired KRAS G12V–activating mutation. The patient subsequently went on to have a PR to cabozantinib therapy in the clinical trial. This is the first reported case of an acquired KRAS-activating mutation that developed during treatment with BRAF and MEK inhibition in a patient with BRAF-mutated PTC. The KRAS mutation was also detected in peripheral blood samples taken as part of the trial, indicating that resistant mutations may be identified through noninvasive means. The identification of resistant mutations in patients at time of progression is necessary to identify possible therapeutic options including potential clinical trials.

ClinicalTrials.gov identifier: NCT01723202

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Targeting BRAF Mutations in High-Grade Neuroendocrine Carcinoma of the Colon

Jarred Burkart, Dwight Owen, Manisha H. Shah, Sherif R. Z. Abdel-Misih, Sameek Roychowdhury, Robert Wesolowski, Sigurdis Haraldsdottir, Julie W. Reeser, Eric Samorodnitsky, Amy Smith, and Bhavana Konda

Mutations in the RAS/RAF/MEK/ERK pathway leading to constitutive activation and uncontrolled cellular growth have been identified in various human malignancies, making this pathway a target for potential therapeutics. The activating BRAF V600E mutation is one well-characterized oncogenic mutation that has been described and targeted with clinical success in various malignancies, including melanoma and hairy cell leukemia. Although BRAF-directed treatments have yielded clinical benefit in a subset of tumor types, such as melanoma, thyroid cancer, and lung cancer, BRAF inhibition fails to confer a clinical benefit in colon cancer. Identification of patients for whom BRAF inhibition may produce clinically meaningful outcomes is imperative. The incidence of BRAF mutations in neuroendocrine carcinoma (NEC) is estimated to be 5% to 10%. A recent case series demonstrated benefit in targeting the BRAF V600E mutation in metastatic high-grade rectal NECs. Combination BRAF and MEK inhibition is known to yield improved outcomes compared with BRAF inhibition alone in melanoma. This report presents 2 patients with high-grade colorectal NECs who had different responses to treatment with combined BRAF/MEK inhibition after experiencing disease progression through first-line platinum-based chemotherapy. One patient experienced an excellent initial response to therapy before ultimately experiencing progression, and in the other patient initially had stable disease before eventually experiencing progression. These cases highlight the complicated role BRAF mutations play in gastrointestinal NECs, and the need for further research to identify not only patients who may benefit from BRAF-directed therapies but also strategies to avoid development of resistance.

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CLO20-054: A Phase 2 Trial of Nivolumab and Temozolomide in Advanced Neuroendocrine Tumors (NETs): Interim Efficacy Analysis

Dwight H. Owen, Lai Wei, Ashima Goyal, Ye Zhou, Sheryl-Ann Suffren, Rajani Jacob, Carly Pilcher, Gregory A. Otterson, Claire F. Verschraegen, Manisha H. Shah, and Bhavana Konda

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HSR22-165: Pulmonary Function Tests (PFTs) and Immune Checkpoint Inhibitor Pneumonitis

Maria Kathleen Riley, Alex Wong, Songzhu Zhao, Jing Wang, Vince Esguerra, Mingjia Li, Kari Kendra, Gabrielle Lopez, Carolyn Presley, Lai Wei, Dwight Owen, and Kevin Ho

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Frequency, Morbidity, and Mortality of Bone Metastases in Advanced Hepatocellular Carcinoma

James J. Harding, Ghaith Abu-Zeinah, Joanne F. Chou, Dwight Hall Owen, Michele Ly, Maeve Aine Lowery, Marinela Capanu, Richard Do, Nancy E. Kemeny, Eileen M. O'Reilly, Leonard B. Saltz, and Ghassan K. Abou-Alfa

Background: Bone metastases are common in hepatocellular carcinoma (HCC), but their incidence, morbidity, and mortality are not well defined. Methods: The Memorial Sloan Kettering Cancer Center database was queried for all patients with HCC and metastases seen from 2002 to 2014. The prevalence of bone metastasis was determined and cumulative incidence function was used to estimate the probability of developing a bone metastasis. Regression models were created to identify risk factors for osseous metastasis. The frequency of skeletal-related events (SREs), defined as pathologic fracture, spinal cord compression, need for radiation therapy to bone, and/or surgical resection of bone, was determined and cumulative incidence function was used to estimate the probability of SRE development. Regression models were created to identify SRE risk factors. Correlation of clinicopathologic parameters, including bone metastases and SREs, with overall survival was analyzed using Kaplan-Meier methodology. Results: A total of 459 patients with HCC and extrahepatic metastases were identified; 151 patients (32.9%) had or developed bone metastases: 128 (27.9%) as a primary site and 23 (4.6%) as a secondary site of extrahepatic disease. Among the 331 patients without bone metastasis at presentation, the yearly incidence of bone metastasis was 6.4% (95% CI, 3.6%–9.2%). Hepatitis B virus (HBV) infection increased the chance of developing a bone metastasis (P=.02). The cumulative incidence of SREs was 50% at 6 months. Univariate analysis showed that patients with HBV-related HCC had a significantly higher incidence of SREs (P=.02). Sorafenib and bisphosphonates each protected against SREs. The presence of SREs was independently associated with a worse overall survival (hazard ratio, 2.13; 95% CI, 1.52–2.97; P<.01) in the multivariable model. Conclusions: Patients with AJCC stage IV HCC and bone metastases that are clinically evident on routine radiography or on clinical examination at presentation are apt to develop frequent, morbid, and mortal SREs, whereas those without evident bone metastasis at presentation are unlikely to develop these complications.

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Harmonized Outcome Measures for Use in Non–Small Cell Lung Cancer Patient Registries and Clinical Practice

Martin J. Edelman, Daniel P. Raymond, Dwight H. Owen, Michelle B. Leavy, Kari Chansky, Sriram Yennu, Felix G. Fernandez, Carolyn J. Presley, Tithi Biswas, Gwendolyn P. Quinn, Matthew B. Schabath, Seth Sheffler-Collins, Laura Chu, and Richard E. Gliklich

Background: Lung cancer is the leading cause of cancer-related death in the United States and globally, and many questions exist about treatment options. Harmonizing data across registries and other data collection efforts would yield a robust data infrastructure to help address many research questions. The purpose of this project was to develop a minimum set of patient and clinician relevant harmonized outcome measures that can be collected in non–small cell lung cancer (NSCLC) patient registries and clinical practice. Methods: Seventeen lung cancer registries and related efforts were identified and invited to submit outcome measures. Representatives from medical specialty societies, government agencies, health systems, health information technology groups, patient advocacy organizations, and industry formed a stakeholder panel to categorize the measures and harmonize definitions using the Agency for Healthcare Research and Quality’s supported Outcome Measures Framework (OMF). Results: The panel reviewed 66 outcome measures and identified a minimum set of 8 broadly relevant measures in the OMF categories of patient survival, clinical response, events of interest, and resource utilization. The panel harmonized definitions for the 8 measures through in-person and virtual meetings. The panel did not reach consensus on 1 specific validated instrument for capturing patient-reported outcomes. The minimum set of harmonized outcome measures is broadly relevant to clinicians and patients and feasible to capture across NSCLC disease stages and treatment pathways. A pilot test of these measures would be useful to document the burden and value of the measures for research and in clinical practice. Conclusions: By collecting the harmonized measures consistently, registries and other data collection systems could contribute to the development research infrastructure and learning health systems to support new research and improve patient outcomes.