195 results on '"Ammar Sukari"'
Search Results
2. Biomarkers predictive of response to pembrolizumab in head and neck cancer
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David G. Pfister, Robert I. Haddad, Francis P. Worden, Jared Weiss, Ranee Mehra, Laura Q. M. Chow, Stephen V. Liu, Hyunseok Kang, Nabil F. Saba, Lori J. Wirth, Ammar Sukari, Erminia Massarelli, Mark Ayers, Andrew Albright, Andrea L. Webber, Robin Mogg, Jared Lunceford, Lingkang Huang, Razvan Cristescu, Jonathan Cheng, Tanguy Y. Seiwert, and Joshua M. Bauml
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biomarker ,head and neck squamous cell carcinoma ,immunotherapy ,pembrolizumab ,tumor microenvironment ,tumor mutational burden ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background We performed an integrated biomarker evaluation in pembrolizumab‐treated patients with R/M HNSCC enrolled in KEYNOTE‐012 or KEYNOTE‐055. The relationship between biomarkers and HPV status was explored. Methods We evaluated PD‐L1 (combined positive score [CPS]), TMB, T‐cell‐inflamed gene expression profile (TcellinfGEP), and HPV status. Associations between biomarkers were evaluated by logistic regression (ORR) and Cox regression (PFS, OS). Results Two hundred and fifty‐seven patients (KEYNOTE‐012, n = 106; KEYNOTE‐055, n = 151) had TMB data available; of these, 254 had PD‐L1 and 236 had TcellinfGEP. TMB, PD‐L1, and TcellinfGEP were each significantly associated with ORR (p
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- 2023
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3. NTRK3 mutation in secretory carcinoma of the parotid gland: A Case report
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Fahad AlKaabba, Abdurahman Alloghbi, Yazeed Deajim, Mohamad W. Sukkari, Mir Yousufuddin Ali Khan, and Ammar Sukari
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case report ,mammary analog secretory carcinoma ,salivary gland carcinoma ,Medicine ,Medicine (General) ,R5-920 - Abstract
Abstract Mammary analog secretory carcinoma (MASC) is a newly described carcinoma with a molecular hallmark of ETV6‐NTRK3 fusion that promotes oncogenesis. While MASC histopathology was well‐studied in the literature, clinical behavior remains unstudied. We present a 22‐year‐old man with painless parotid mass, which was diagnosed as salivary gland cancer, MASC subtype.
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- 2022
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4. Femoral metastasis in previously treated bladder cancer patient: A case report
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Tala Jouma Alhejazi, Hassan Bdeiwi, Mohamad W. Sukkari, Mohamad Ibrahim, Ammar Sukari, and Hani Alloush
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bladder ,bone metastasis ,case report ,femur metastasis ,TCC ,transitional carcinoma ,Medicine ,Medicine (General) ,R5-920 - Abstract
Abstract Although treated appropriately, bladder cancer can recur and metastasize. We are reporting the case of a patient with a well‐cured bladder cancer who presented after 14 months with femoral pain which turned out to be a bony metastasis. The patient underwent surgical excision followed by chemotherapy.
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- 2022
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5. Liquid biopsy for therapy monitoring in early-stage non-small cell lung cancer
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Misako Nagasaka, Mohammed Hafiz Uddin, Mohammed Najeeb Al-Hallak, Sarah Rahman, Suresh Balasubramanian, Ammar Sukari, and Asfar S. Azmi
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Liquid biopsy ,Circulating nucleic acid ,ctDNA ,ctRNA ,miRNA ,lncRNA ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Liquid biopsy is now considered a valuable diagnostic tool for advanced metastatic non-small cell lung cancer (NSCLC). In NSCLC, circulating tumor DNA (ctDNA) analysis has been shown to increase the chances of identifying the presence of targetable mutations and has been adopted by many clinicians owing to its low risk. Serial monitoring of ctDNA may also help assess the treatment response or for monitoring relapse. As the presence of detectable plasma ctDNA post-surgery likely indicates residual tumor burden, studies have been performed to quantify plasma ctDNA to assess minimal residual disease (MRD) in early-stage resected NSCLC. Most data on utilizing liquid biopsy for monitoring MRD in early-stage NSCLC are from small-scale studies using ctDNA. Here, we review the recent research on liquid biopsy in NSCLC, not limited to ctDNA, and focus on novel methods such as micro RNAs (miRNA) and long non-coding (lncRNA).
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- 2021
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6. Anti‐PD‐1 therapy using cemiplimab for advanced cutaneous squamous cell carcinoma in HIV patient: A case report
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Abdurahman Alloghbi, James Ninia, Bayan Alshare, Jeffrey Hotaling, Syed Raza, and Ammar Sukari
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advanced cutaneous squamous cell carcinoma ,cemiplimab ,immunotherapy ,skin cancer ,squamous cell carcinoma ,Medicine ,Medicine (General) ,R5-920 - Abstract
Abstract This is a case of a 60‐year‐old man living with HIV who presented with advanced cutaneous squamous cell carcinoma. After workup, medical and surgical treatment, and disease recurrence, he achieved a complete response with no unexpected toxicities after immunotherapy with cemiplimab.
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- 2021
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7. 957 NKTR-255+cetuximab in patients with solid tumors: interim safety and efficacy results from the phase 1b dose-escalation study
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Manish Patel, Amita Patnaik, Ammar Sukari, Minal Barve, Mary Tagliaferri, Neha Dixit, Mehmet Altan, Christie Fanton, Xiaoli Wang, Sunil Sharma, Mario Marcondes, Sue Currie, Zachary Lee, Wildaliz Nieves, Haijun Ma, Lara Dunn, Patrick Cobb, Ari Rosenberg, Johnathan Zalevsky, and Assuntina Sacco
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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8. 438 A phase 1 trial of CUE-101, a novel HPV16 E7-pHLA-IL2-Fc fusion protein, alone and in combination with pembrolizumab in patients with recurrent/metastatic HPV16+ head and neck cancer
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Michael Gibson, Ammar Sukari, Julie Bauman, Tanguy Seiwert, Barbara Burtness, Sara Pai, Cristina Rodriguez, Bonnie Glisson, Kenneth Pienta, Francis Worden, Lara Dunn, Douglas Adkins, Christine Chung, A Dimitrios Colevas, Lori Wirth, Nabil Saba, Laura Agensky, Matteo Levisetti, Reena Lynam, Steven Margossian, Raymond Moniz, and Steve Quayle
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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9. 485 Long term results from a phase 1 trial of GEN-009, a personalized neoantigen vaccine, combined with PD-1 inhibition in advanced solid tumors
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Thomas Davis, Jessica Price, Mark Awad, Ammar Sukari, Roger Cohen, Mark Stein, Przemyslaw Twardowski, Jessica Flechtner, Melissa Johnson, Maura Gillison, Rudy Lackner, Arthur DeCillis, Richard Hernandez, Kevin Mancini, Mara Shainheit, Gabriella Santone, Syukri Shukor, Ece Bicak, Vijetha Vemulapalli, and Emily Tjon
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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10. JNJ-64041757 (JNJ-757), a Live, Attenuated, Double-Deleted Listeria monocytogenes–Based Immunotherapy in Patients With NSCLC: Results From Two Phase 1 Studies
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Julie R. Brahmer, MD, Melissa L. Johnson, MD, Manuel Cobo, MD, PhD, Santiago Viteri, MD, Juan Coves Sarto, MD, Ammar Sukari, MD, Mark M. Awad, MD, PhD, Ravi Salgia, MD, PhD, Vali A. Papadimitrakopoulou, MD, Arun Rajan, MD, Nibedita Bandyopadhyay, PhD, Alicia J. Allred, PhD, Mark Wade, MA, Gary E. Mason, MD, Enrique Zudaire, PhD, Roland E. Knoblauch, MD, PhD, Nicole Stone, PhD, Matthew V. Lorenzi, PhD, and Raffit Hassan, MD
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Non–small cell lung cancer ,Mesothelin ,LADD Lm ,JNJ-757 ,Vaccine ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Introduction: JNJ-64041757 (JNJ-757) is a live, attenuated, double-deleted Listeria monocytogenes–based immunotherapy expressing human mesothelin. JNJ-757 was evaluated in patients with advanced NSCLC as monotherapy (phase 1) and in combination with nivolumab (phase 1b/2). Methods: Patients with stage IIIB/IV NSCLC who had received previous therapy were treated with JNJ-757 (1 × 108 or 1 × 109 colony-forming units [CFUs]) alone (NCT02592967) or JNJ-757 (1 × 109 CFU) plus intravenous nivolumab 240 mg (NCT03371381). Study objectives included the assessment of immunogenicity, safety, and efficacy. Results: In the monotherapy study, 18 patients (median age 63.5 y; women 61%) were treated with JNJ-757 (1 × 108 or 1 × 109 CFU) with a median duration of 1.4 months (range: 0–29). The most common adverse events (AEs) were pyrexia (72%) and chills (61%), which were usually mild and resolved within 48 hours. Peripheral proinflammatory cytokines and lymphocyte activation were induced posttreatment with transient mesothelin-specific T-cell responses in 10 of 13 biomarker-evaluable patients. With monotherapy, four of 18 response-evaluable patients had stable disease of 16 or more weeks, including one patient with a reduction in target lesions. In the combination study, 12 patients were enrolled (median age 63.5 y; women 33%). The most common AEs with combination therapy were pyrexia (67%) and chills (58%); six patients had grade 3 AEs or greater, including two cases of treatment-related fatal pneumonitis. The best overall response for the combination was stable disease in four of nine response-evaluable patients. Conclusions: As monotherapy, JNJ-757 was immunogenic and tolerable, with mild infusion-related fever and chills. The limited efficacy of JNJ-757, alone or with nivolumab, did not warrant further investigation of the combination.
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- 2021
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11. STRN-ALK, A Novel In-Frame Fusion With Response to Alectinib
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Misako Nagasaka, MD, Nagaratna Sarvadevabatla, MD, Shawn Iwata, BSN, Yubin Ge, PhD, Ammar Sukari, MD, Christian Klosowski, MS, and Ronald Yanagihara, MD
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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12. 390 Emerging safety and activity data from GEN-009–101: A phase 1/2a trial of GEN-009, a neoantigen vaccine in combination with PD-1 check-point inhibitors (CPI) in advanced solid tumors
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Thomas Davis, Jessica Price, Ammar Sukari, Roger Cohen, Przemyslaw Twardowski, Jessica Flechtner, Melissa Johnson, Maura Gillison, Rudy Lackner, Arthur DeCillis, Richard Hernandez, Kevin Mancini, and Mara Shainheit
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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13. Genomic and Molecular Profiling of Human Papillomavirus Associated Head and Neck Squamous Cell Carcinoma Treated with Immune Checkpoint Blockade Compared to Survival Outcomes
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Hira Shaikh, Julie E. McGrath, Brittany Hughes, Joanne Xiu, Pavel Brodskiy, Ammar Sukari, Sourat Darabi, Chukwuemeka Ikpeazu, Chadi Nabhan, Wolfgang Michael Korn, and Trisha M. Wise-Draper
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head and neck squamous cell carcinoma ,oropharyngeal cancer ,p16 ,human papillomavirus (HPV) ,personalized medicine ,immune checkpoint blockade ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients overall have a poor prognosis. However, human papillomavirus (HPV)-associated R/M oropharyngeal squamous cell carcinoma (OPSCC) is associated with a better prognosis compared to HPV−negative disease. Immune checkpoint blockade (ICB) is the standard of care for R/M HNSCC. However, whether HPV and its surrogate marker, p16, portend an improved response to ICB remains controversial. We queried the Caris Life Sciences CODEai database for p16+ and p16− HNSCC patients using p16 as a surrogate for HPV. A total of 2905 HNSCC (OPSCC, n = 948) cases were identified. Of those tested for both HPV directly and p16, 32% (251/791) were p16+ and 28% (91/326) were HPV+. The most common mutation in the OPSCC cohort was TP53 (33%), followed by PIK3CA (17%) and KMT2D (10.6%). TP53 mutations were more common in p16− (49%) versus the p16+ group (10%, p < 0.0005). Real-world overall survival (rwOS) was longer in p16+ compared to p16− OPSCC patients, 33.3 vs. 19.1 months (HR = 0.597, p = 0.001), as well as non-oropharyngeal (non-OP) HNSCC patients (34 vs. 17 months, HR 0.551, p = 0.0001). There was no difference in the time on treatment (TOT) (4.2 vs. 2.8 months, HR 0.796, p = 0.221) in ICB-treated p16+ vs. p16− OPSCC groups. However, p16+ non-OP HNSCC patients treated with ICB had higher TOT compared to the p16− group (4.3 vs. 3.3 months, HR 0.632, p = 0.016), suggesting that p16 may be used as a prognostic biomarker in non-OP HNSCC, and further investigation through prospective clinical trials is warranted.
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- 2021
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14. Cancer Care at Times of Crisis and War: The Syrian Example
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Eman Sahloul, Riad Salem, Wessam Alrez, Tayseer Alkarim, Ammar Sukari, Wasim Maziak, and M. Bassel Atassi
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Purpose: As Syria enters its fifth year of conflict, the number of civilians killed and injured continues to rise sharply. Along with this conflict comes the rapid decline of medical care, specifically cancer care. To determine physician and equipment availability, cancer screening and management, and possible solutions relative to various major cities, a survey was distributed to physicians inside Syria through the help of the humanitarian organization Syrian American Medical Society. Methods: Online surveys were distributed to both certified oncologists who work in cancer clinics and general physicians who work in rural and mobile clinics inside Syria. Variables assessed were physician specialty, location, population, cost, regional situation (besieged versus government controlled), and resource availability and access. Results were stratified by location and physician specialty. Results: Survey results revealed a large shortage of specialized physicians and inhibited accessibility to screening and management options in besieged areas compared with government-controlled regions. Physicians within both government-controlled and besieged cities reported limited or no targeted agents, radiation therapy, clinical trials, bone marrow transplantation, positron emission tomography scans, magnetic resonance imaging, and genetic testing. Conclusion: The Syrian civil war has resulted in suboptimal oncology care in the majority of the region. In consideration of specific deficiencies in cancer care, we recommend several solutions that may better the level of care in Syria: patient education on medical documentation and self-examination; online consultation; and cheap, effective screening methods. The implementation of these recommendations may change the course of cancer care in a country that has deteriorated into the worst humanitarian crisis of the century.
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- 2017
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15. Targeting XPO1 and PAK4 in 8505C Anaplastic Thyroid Cancer Cells: Putative Implications for Overcoming Lenvatinib Therapy Resistance
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Husain Yar Khan, James Ge, Misako Nagasaka, Amro Aboukameel, Gabriel Mpilla, Irfana Muqbil, Mark Szlaczky, Mahmoud Chaker, Erkan Baloglu, Yosef Landesman, Ramzi M. Mohammad, Asfar S. Azmi, and Ammar Sukari
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thyroid cancer ,lenvatinib ,therapy resistance ,selinexor ,pak4 inhibitor ,selective inhibitors of nuclear export ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) that shows improved median progression-free survival (PFS) in patients with thyroid carcinomas. However, virtually all patients ultimately progress, indicating the need for a better understanding of the mechanisms of resistance. Here, we examined the molecular profile of anaplastic thyroid cancer cells (8505C) exposed to lenvatinib and found that long-term exposure to lenvatinib caused phenotypic changes. Consistent with change toward mesenchymal morphology, activation of pro-survival signaling, nuclear exporter protein exportin 1 (XPO1) and Rho GTPase effector p21 activated kinases (PAK) was also observed. RNA-seq analysis showed that prolonged lenvatinib treatment caused alterations in numerous cellular pathways and several oncogenes such as CEACAM (carcinoembryonic antigen-related cell adhesion molecule) and NUPR1 (Nuclear protein 1) were also upregulated. Further, we evaluated the impact of XPO1 and PAK4 inhibition in the presence or absence of lenvatinib. Targeted inhibition of XPO1 and PAK4 could sensitize the 8505C cells to lenvatinib. Both XPO1 and PAK4 inhibitors, when combined with lenvatinib, showed superior anti-tumor activity in 8505C sub-cutaneous xenograft. These studies bring forward novel drug combinations to complement lenvatinib for treating anaplastic thyroid cancer. Such combinations may possibly reduce the chances of lenvatinib resistance in thyroid cancer patients.
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- 2019
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16. Biweekly gemcitabine and paclitaxel in patients with relapsed or metastatic squamous cell carcinoma of the head and neck
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Ammar Sukari, Marwan Al-Hajeili, Mohamed Salem, Lance Heilbrun, Daryn Smith, George Yoo, John R Jacobs, Ho-Sheng Lin, and Omer Kucuk
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gemcitabine ,head and neck cancer ,paclitaxel ,Medicine - Abstract
Purpose: We conducted a Phase II, clinical trial to evaluate the efficacy and safety of a biweekly gemcitabine and paclitaxel (GEMTAX) regimen as second-line treatment in patients with recurrent or metastatic unresectable, squamous cell carcinoma of the head and neck (SCCHN). The primary endpoint was response rate. Patients and Methods: Patients with recurrent unresectable or metastatic platinum refractory SCCHN, who had performance status ≤2 and adequate organ function, were eligible. Gemcitabine (3000 mg/m 2 intravenous) and paclitaxel (150 mg/m 2 intravenous) was given on days 1 and 15of 4 weeks cycle, until patients had disease progression or unacceptable toxicity. Results: Disease control (partial response [PR] + complete response [CR] + stable disease [SD]) was noted in 19 patients (54%) and overall response (CR + PR) was noted in 8 patients (23%). However, the most frequent response outcomes were progressive disease in 16 patients (46%) and SD in 11 patients (31%). The most frequent Grade 3-4 adverse events were lymphopenia in 38 patients (75%), anemia in 20 patients (39%), and infection in 16 patients (31%). Median progression-free survival was 3.6 months; median overall survival was 6.3 months. Conclusion: The biweekly GEMTAX regimen has statistically significant grade 3 and 4 adverse events and has meaningful clinical activity as a second-line treatment in patients with recurrent or metastatic SCCHN who have received prior chemotherapy. This regimen may particularly be a useful treatment option in patients who progressed in
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- 2015
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17. PD1/PD-L1 inhibition as a potential radiosensitizer in head and neck squamous cell carcinoma: a case report
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Harold Kim, Misako Nagasaka, Mark Zaki, S. Naweed Raza, George Yoo, Ho-sheng Lin, and Ammar Sukari
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Immunotherapy targeting the checkpoint PD1 (programmed cell death protein 1) or PDL1 (programmed death ligand 1) has led to advances in the treatment of melanoma and non-small cell lung cancer (NSCLC). The use of such therapies has also been introduced into the treatment of other malignancies, including head and neck cancer. The combined effects of checkpoint inhibitors and anti-PD1(L1) antibodies and radiation therapy have not yet been sufficiently investigated.Case presentation We report a case of locally relapsed non-resectable oral cavity squamous cell carcinoma, with excellent local control after pembrolizumab (MK3475) followed by radiotherapy.Conclusion T cell activation induced by checkpoint inhibition may dramatically improve tumor response to radiation. More data are needed to identify the toxicity and efficacy of sequential or concurrent checkpoint inhibitors and radiotherapy.
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- 2016
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18. Understanding the Risk Factors and Long-Term Consequences of Cisplatin-Associated Acute Kidney Injury: An Observational Cohort Study.
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Zeenat Yousuf Bhat, Pravit Cadnapaphornchai, Kevin Ginsburg, Milani Sivagnanam, Shamit Chopra, Corey K Treadway, Ho-Sheng Lin, George Yoo, Ammar Sukari, and Mona D Doshi
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Medicine ,Science - Abstract
Acute kidney injury (AKI) is a well-known complication of cisplatin-based chemotherapy; however, its impact on long-term patient survival is unclear. We sought to determine the incidence and risk factors for development of cisplatin-associated AKI and its impact on long-term renal function and patient survival. We identified 233 patients who received 629 cycles of high-dose cisplatin (99±9mg/m2) for treatment of head and neck cancer between 2005 and 2011. These subjects were reviewed for development of AKI. Cisplatin nephrotoxicity (CN) was defined as persistent rise in serum creatinine, with a concomitant decline in serum magnesium and potassium, in absence of use of nephrotoxic agents and not reversed with hydration. All patients were hydrated per protocol and none had baseline glomerular filtration rate (GFR) via CKD-EPI
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- 2015
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19. Trastuzumab for Her2/neu-positive metastatic salivary gland carcinoma: Case report and review of the literature
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Belal Firwana, Bassel Atassi, Rim Hasan, Nour Hasan, and Ammar Sukari
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metastasis ,salivary gland tumor ,salivary glands ,trastuzumab ,Medicine - Abstract
Salivary gland carcinomas metastasize to distant organs in 20% of salivary gland malignancies. Applying immunohistochemistry (IHC) measures, salivary gland tumors showed a wide range of oncogene markers expression, including the human epidermoid receptor 2 (Her2/neu), which could be targeted with monoclonal antibody. Treating salivary gland tumors, which have Her2/neu over-expression, with trastuzumab was reported in a few case reports. We report a 61-year-old Caucasian male, with a history of salivary gland tumor, who presented after 20 years of complete surgical resection with kidney mass. He was treated as primary renal cell carcinoma, unclassified, with nephrectomy and adjuvant clinical trail where he received placebo. Subsequently, he developed multiple hepatic lesions and retroperitoneal mesenteric lymphadenopathy; CT-guided biopsy revealed adenocarcinoma with Her2/neu, 3+ by IHC. The patient was treated successfully with trastuzumab with near-complete response.
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- 2012
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20. Supplementary Tables S1-S3 from Safety and Efficacy of MEDI0457 plus Durvalumab in Patients with Human Papillomavirus–Associated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma
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Rakesh Kumar, Amaya Gascó Hernández, Natalia Ceaicovscaia, Maozhen Gong, Delphine Lissa, Karl Fraser, Nicholas M. Durham, Emily C. Jennings, Sonia Agrawal, Lily I. Cheng, Mark T. Esser, Jean Boyer, Marcelo Bonomi, Mercedes Porosnicu, Missak Haigentz, Tanguy Y. Seiwert, Ammar Sukari, Alain Algazi, Nabil F. Saba, and Charu Aggarwal
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Supplementary Table S1. Representativeness of Study Participants Supplementary Table S2. Disease response as assessed by RECIST v1.1 by PD-L1 tumor cell expression (response-evaluable population). Supplementary Table S3. Disease response as assessed by RECIST v1.1 in prior line of therapy subgroups (response-evaluable population) and survival (as-treated population).
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- 2023
21. Supplementary Figures S1-S9 from Safety and Efficacy of MEDI0457 plus Durvalumab in Patients with Human Papillomavirus–Associated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma
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Rakesh Kumar, Amaya Gascó Hernández, Natalia Ceaicovscaia, Maozhen Gong, Delphine Lissa, Karl Fraser, Nicholas M. Durham, Emily C. Jennings, Sonia Agrawal, Lily I. Cheng, Mark T. Esser, Jean Boyer, Marcelo Bonomi, Mercedes Porosnicu, Missak Haigentz, Tanguy Y. Seiwert, Ammar Sukari, Alain Algazi, Nabil F. Saba, and Charu Aggarwal
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Supplementary Figure S1. Patient disposition. Supplementary Figure S2. Association of PD-L1 expression and HPV status with best antitumor response. Supplementary Figure S3. Kaplan-Meier distribution curves for (A) PFS and (B) OS in the as-treated population according to line of treatment and platinum-refractory status, including estimates of medians. Supplementary Figure S4. Peripheral HPV-18-specific T-cells on IFNγ ELISpot assay of PMBCs. Supplementary Figure S5. Peripheral HPV-16 (A, C) E6-specific and (B, D) E7-specific T-cell responses on IFNγ ELISpot assay of PMBCs. Supplementary Figure S6. Peripheral HPV-18 (A, C) E6-specific and (B, D) E7-specific T-cell responses on IFNγ ELISpot assay of PMBCs. Supplementary Figure S7. Baseline peripheral (A) HPV-16-specific and HPV-16 (B) E6-specific and (C) E7-specific T-cell counts on IFNγ ELISpot assay of PMBCs according to best response to treatment. Supplementary Figure S8. Baseline peripheral (A) HPV-18-specific and HPV-18 (B) E6-specific and (C) E7-specific T-cell counts on IFNγ ELISpot assay of PMBCs according to best response to treatment. Supplementary Figure S9. (A) HPV-16-specific and (B) HPV-18-specific T-cell count measured by IFNγ ELISpot assay of PMBCs over time per individual patient (n = 34), color-coded by best response, plotted on a log10 y-axis.
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- 2023
22. Data from Safety and Efficacy of MEDI0457 plus Durvalumab in Patients with Human Papillomavirus–Associated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma
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Rakesh Kumar, Amaya Gascó Hernández, Natalia Ceaicovscaia, Maozhen Gong, Delphine Lissa, Karl Fraser, Nicholas M. Durham, Emily C. Jennings, Sonia Agrawal, Lily I. Cheng, Mark T. Esser, Jean Boyer, Marcelo Bonomi, Mercedes Porosnicu, Missak Haigentz, Tanguy Y. Seiwert, Ammar Sukari, Alain Algazi, Nabil F. Saba, and Charu Aggarwal
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Purpose:Tumoral programmed cell death ligand-1 (PD-L1) expression is common in human papillomavirus (HPV)–associated head and neck squamous cell carcinoma (HNSCC). We assessed whether a DNA vaccine targeting HPV-16/18 E6/E7 with IL12 adjuvant (MEDI0457) combined with the PD-L1 inhibitor durvalumab could enhance HPV-specific T-cell response and improve outcomes in recurrent/metastatic HPV-16/18–associated HNSCC.Patients and Methods:In this phase Ib/IIa study, immunotherapy-naïve patients with ≥1 previous platinum-containing regimen (neoadjuvant/adjuvant therapy or for recurrent/metastatic disease) received MEDI0457 7 mg intramuscularly with electroporation on weeks 1, 3, 7, and 12, then every 8 weeks, plus durvalumab 1,500 mg intravenously on weeks 4, 8, and 12, then every 4 weeks, until confirmed progression and/or unacceptable toxicity. Coprimary objectives were safety and objective response rate (ORR; H0: ORR ≤ 15%); secondary objectives included 16-week disease control rate (DCR-16), overall survival (OS), and progression-free survival (PFS).Results:Of 35 treated patients, 29 were response evaluable (confirmed HPV-associated disease; received both agents). ORR was 27.6% [95% confidence interval (CI), 12.7–47.2; four complete responses, four partial responses]; responses were independent of PD-L1 tumor-cell expression (≥25% vs. 2-fold increase in tumor-infiltrating CD8+ T cells.Conclusions:MEDI0457 plus durvalumab was well tolerated. While the primary efficacy endpoint was not reached, clinical benefit was encouraging.
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- 2023
23. Phase II Trial of Adjuvant Nivolumab Following Salvage Resection in Patients with Recurrent Squamous Cell Carcinoma of the Head and Neck
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Jennifer L. Leddon, Shuchi Gulati, Sulsal Haque, Casey Allen, Sarah Palackdharry, Maria Mathews, Nicky Kurtzweil, Muhammed Kashif Riaz, Vinita Takiar, Misako Nagasaka, Yash Patil, Chad Zender, Alice Tang, Brian Cervenka, Julie McGrath, W. Michael Korn, Benjamin H. Hinrichs, Roman Jandarov, Nusrat Harun, Ammar Sukari, and Trisha M. Wise-Draper
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Cancer Research ,Squamous Cell Carcinoma of Head and Neck ,Carcinoma ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Evaluation of treatments and therapeutic interventions ,B7-H1 Antigen ,Neoplasm Recurrence ,Nivolumab ,Rare Diseases ,Good Health and Well Being ,Squamous Cell ,Local ,Oncology ,Head and Neck Neoplasms ,Clinical Research ,6.1 Pharmaceuticals ,Humans ,Patient Safety ,Oncology & Carcinogenesis ,Dental/Oral and Craniofacial Disease ,6.4 Surgery ,Cancer - Abstract
Purpose: Locoregional relapse in patients with head and neck squamous cell carcinoma (HNSCC) is common, approaching 50% for some subsites despite multimodality therapy. Salvage surgery is the standard of care, but able to achieve durable control in only a minority of patients. While adjuvant radiotherapy or chemo-radiotherapy is offered to select patients, this approach can be prohibitively toxic. Given the activity and tolerability of programmed death-1 inhibitors in metastatic HNSCC, we investigated the safety and efficacy of adjuvant nivolumab after salvage surgical resection. Patients and Methods: This was an open-label, multi-institutional phase II clinical trial (NCT03355560). Patients with recurrent, resectable HNSCC were enrolled within 6 weeks of salvage surgery. Six 28-day cycles of adjuvant nivolumab were planned. The primary endpoint was 2-year disease-free survival (DFS) more than 58%, based on an institutional historical control group of 71 patients with recurrent HNSCC who underwent salvage surgery. Results: Between February 2018 and February 2020, 39 patients were enrolled. At a median follow-up of 22.1 months, 2-year DFS was 71.4% [95% confidence interval (CI), 57.8–88.1] and the 2-year overall survival (OS) was 73% (95% CI, 58–91.8). Three of 39 (8%) patients experienced grade 3 treatment-related adverse events and 3 of 39 (8%) discontinued treatment due to side effects. Ten of 39 had locoregional recurrence, while 2 of 10 also had synchronous metastatic disease. There was no difference in DFS between PD ligand-1 (PD-L1)–positive and PD-L1–negative patients. There was a nonsignificant trend toward improved DFS in patients with high tumor mutational burden (P = 0.083). Conclusions: Adjuvant nivolumab after salvage surgery in locally recurrent HNSCC is well tolerated and showed improved DFS compared with historical controls.
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- 2022
24. Supplementary Table from ARRY-382 in Combination with Pembrolizumab in Patients with Advanced Solid Tumors: Results from a Phase 1b/2 Study
- Author
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Jonathan W. Goldman, Yuanyuan Zhang, S. Michael Rothenberg, Allison Harney, Adele Golden, Patrice Lee, John Sarantopoulos, Justin F. Gainor, Karl Lewis, Paul R. Kunk, Justin Call, Ammar Sukari, Arkadiusz Z. Dudek, and Melissa Johnson
- Abstract
Supplementary Table from ARRY-382 in Combination with Pembrolizumab in Patients with Advanced Solid Tumors: Results from a Phase 1b/2 Study
- Published
- 2023
25. Supplementary Table 7 from Phase II, Randomized Study of Spartalizumab (PDR001), an Anti–PD-1 Antibody, versus Chemotherapy in Patients with Recurrent/Metastatic Nasopharyngeal Cancer
- Author
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Darren W-T. Lim, Luigi Manenti, Romain Séchaud, Jennifer Mataraza, Hongzi Liang, Yao Yao, Sebastian Szpakowski, Juan Gonzalez-Maffe, Steven McCune, Joël Guigay, Ammar Sukari, Alexander I. Spira, Zujun Li, Pei-Jen Lou, Victor H.F. Lee, Suebpong Tanasanvimon, Brigette B.Y. Ma, Somvilai Chakrabandhu, Po Chung Chan, Chia-Jui Yen, Li Zhang, Arunee Dechaphunkul, Roger K-C Ngan, Shau-Hsuan Li, Hung-Ming Wang, and Caroline Even
- Abstract
Supplemental Table S7. Primary PK parameters for spartalizumab
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- 2023
26. Supplementary Figure 2 from Phase II, Randomized Study of Spartalizumab (PDR001), an Anti–PD-1 Antibody, versus Chemotherapy in Patients with Recurrent/Metastatic Nasopharyngeal Cancer
- Author
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Darren W-T. Lim, Luigi Manenti, Romain Séchaud, Jennifer Mataraza, Hongzi Liang, Yao Yao, Sebastian Szpakowski, Juan Gonzalez-Maffe, Steven McCune, Joël Guigay, Ammar Sukari, Alexander I. Spira, Zujun Li, Pei-Jen Lou, Victor H.F. Lee, Suebpong Tanasanvimon, Brigette B.Y. Ma, Somvilai Chakrabandhu, Po Chung Chan, Chia-Jui Yen, Li Zhang, Arunee Dechaphunkul, Roger K-C Ngan, Shau-Hsuan Li, Hung-Ming Wang, and Caroline Even
- Abstract
Supplemental Figure S2. Adverse events in crossover group
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- 2023
27. Supplementary Table 2 from Phase II, Randomized Study of Spartalizumab (PDR001), an Anti–PD-1 Antibody, versus Chemotherapy in Patients with Recurrent/Metastatic Nasopharyngeal Cancer
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Darren W-T. Lim, Luigi Manenti, Romain Séchaud, Jennifer Mataraza, Hongzi Liang, Yao Yao, Sebastian Szpakowski, Juan Gonzalez-Maffe, Steven McCune, Joël Guigay, Ammar Sukari, Alexander I. Spira, Zujun Li, Pei-Jen Lou, Victor H.F. Lee, Suebpong Tanasanvimon, Brigette B.Y. Ma, Somvilai Chakrabandhu, Po Chung Chan, Chia-Jui Yen, Li Zhang, Arunee Dechaphunkul, Roger K-C Ngan, Shau-Hsuan Li, Hung-Ming Wang, and Caroline Even
- Abstract
Supplemental Table S2. Chemotherapy regimens given to patients in the chemotherapy arm
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- 2023
28. Supplementary Table 5 from Phase II, Randomized Study of Spartalizumab (PDR001), an Anti–PD-1 Antibody, versus Chemotherapy in Patients with Recurrent/Metastatic Nasopharyngeal Cancer
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Darren W-T. Lim, Luigi Manenti, Romain Séchaud, Jennifer Mataraza, Hongzi Liang, Yao Yao, Sebastian Szpakowski, Juan Gonzalez-Maffe, Steven McCune, Joël Guigay, Ammar Sukari, Alexander I. Spira, Zujun Li, Pei-Jen Lou, Victor H.F. Lee, Suebpong Tanasanvimon, Brigette B.Y. Ma, Somvilai Chakrabandhu, Po Chung Chan, Chia-Jui Yen, Li Zhang, Arunee Dechaphunkul, Roger K-C Ngan, Shau-Hsuan Li, Hung-Ming Wang, and Caroline Even
- Abstract
Supplemental Table S5. Adverse events ({greater than or equal to} 15% incidence of all grades events in any of the patient treatment arms)
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- 2023
29. Supplementary Figure from ARRY-382 in Combination with Pembrolizumab in Patients with Advanced Solid Tumors: Results from a Phase 1b/2 Study
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Jonathan W. Goldman, Yuanyuan Zhang, S. Michael Rothenberg, Allison Harney, Adele Golden, Patrice Lee, John Sarantopoulos, Justin F. Gainor, Karl Lewis, Paul R. Kunk, Justin Call, Ammar Sukari, Arkadiusz Z. Dudek, and Melissa Johnson
- Abstract
Supplementary Figure from ARRY-382 in Combination with Pembrolizumab in Patients with Advanced Solid Tumors: Results from a Phase 1b/2 Study
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- 2023
30. Supplementary Data from Association of TP53 and CDKN2A Mutation Profile with Tumor Mutation Burden in Head and Neck Cancer
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Erica A. Golemis, Barbara Burtness, Ammar Sukari, Trisha Wise-Draper, Michael J. Demeure, W. Michael Korn, Joanne Xiu, Theodore T. Nguyen, Mitchell I. Parker, Emmanuelle Nicolas, Ilya G. Serebriiskii, Yasmine Baca, and Alexander Y. Deneka
- Abstract
Supplementary Data from Association of TP53 and CDKN2A Mutation Profile with Tumor Mutation Burden in Head and Neck Cancer
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- 2023
31. Supplementary Table 6 from Phase II, Randomized Study of Spartalizumab (PDR001), an Anti–PD-1 Antibody, versus Chemotherapy in Patients with Recurrent/Metastatic Nasopharyngeal Cancer
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Darren W-T. Lim, Luigi Manenti, Romain Séchaud, Jennifer Mataraza, Hongzi Liang, Yao Yao, Sebastian Szpakowski, Juan Gonzalez-Maffe, Steven McCune, Joël Guigay, Ammar Sukari, Alexander I. Spira, Zujun Li, Pei-Jen Lou, Victor H.F. Lee, Suebpong Tanasanvimon, Brigette B.Y. Ma, Somvilai Chakrabandhu, Po Chung Chan, Chia-Jui Yen, Li Zhang, Arunee Dechaphunkul, Roger K-C Ngan, Shau-Hsuan Li, Hung-Ming Wang, and Caroline Even
- Abstract
Supplemental Table S6. Adverse events of special interest (patients treated with spartalizumab)
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- 2023
32. Supplementary Figure from Phase II Trial of Adjuvant Nivolumab Following Salvage Resection in Patients with Recurrent Squamous Cell Carcinoma of the Head and Neck
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Trisha M. Wise-Draper, Ammar Sukari, Nusrat Harun, Roman Jandarov, Benjamin H. Hinrichs, W. Michael Korn, Julie McGrath, Brian Cervenka, Alice Tang, Chad Zender, Yash Patil, Misako Nagasaka, Vinita Takiar, Muhammed Kashif Riaz, Nicky Kurtzweil, Maria Mathews, Sarah Palackdharry, Casey Allen, Sulsal Haque, Shuchi Gulati, and Jennifer L. Leddon
- Abstract
Supplementary Figure from Phase II Trial of Adjuvant Nivolumab Following Salvage Resection in Patients with Recurrent Squamous Cell Carcinoma of the Head and Neck
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- 2023
33. Data from Phase II, Randomized Study of Spartalizumab (PDR001), an Anti–PD-1 Antibody, versus Chemotherapy in Patients with Recurrent/Metastatic Nasopharyngeal Cancer
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Darren W-T. Lim, Luigi Manenti, Romain Séchaud, Jennifer Mataraza, Hongzi Liang, Yao Yao, Sebastian Szpakowski, Juan Gonzalez-Maffe, Steven McCune, Joël Guigay, Ammar Sukari, Alexander I. Spira, Zujun Li, Pei-Jen Lou, Victor H.F. Lee, Suebpong Tanasanvimon, Brigette B.Y. Ma, Somvilai Chakrabandhu, Po Chung Chan, Chia-Jui Yen, Li Zhang, Arunee Dechaphunkul, Roger K-C Ngan, Shau-Hsuan Li, Hung-Ming Wang, and Caroline Even
- Abstract
Purpose:No standard treatment exists for platinum-refractory, recurrent/metastatic nasopharyngeal cancer (NPC). This phase II study (NCT02605967) evaluated progression-free survival (PFS) of spartalizumab, an antiprogrammed cell death protein-1 (PD-1) monoclonal antibody, versus chemotherapy, in NPC.Patients and Methods:Patients with nonkeratinizing recurrent/metastatic NPC who progressed on/after platinum-based chemotherapy were enrolled. Spartalizumab was dosed 400 mg once every 4 weeks, and chemotherapy was received per investigator's choice.Results:Patients were randomized to receive either spartalizumab (82 patients) or chemotherapy (40 patients). The most common spartalizumab treatment-related adverse events were fatigue (10.3%) and pruritus (9.3%). Median PFS in the spartalizumab arm was 1.9 months versus 6.6 months in the chemotherapy arm (P = 0.915). The overall response rate in the spartalizumab arm was 17.1% versus 35.0% in the chemotherapy arm. Median duration of response was 10.2 versus 5.7 months in the spartalizumab versus chemotherapy arms, respectively. Median overall survival was 25.2 and 15.5 months in the spartalizumab and chemotherapy arms, respectively. Tumor RNA sequencing showed a correlation between response to spartalizumab and IFNγ, LAG-3, and TIM-3 gene expression.Conclusions:Spartalizumab demonstrated a safety profile consistent with other anti–PD-1 antibodies. The primary endpoint of median PFS was not met; however, median overall survival and median duration of response were longer with spartalizumab compared with chemotherapy.
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- 2023
34. Supplementary Figure 3 from Phase II, Randomized Study of Spartalizumab (PDR001), an Anti–PD-1 Antibody, versus Chemotherapy in Patients with Recurrent/Metastatic Nasopharyngeal Cancer
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Darren W-T. Lim, Luigi Manenti, Romain Séchaud, Jennifer Mataraza, Hongzi Liang, Yao Yao, Sebastian Szpakowski, Juan Gonzalez-Maffe, Steven McCune, Joël Guigay, Ammar Sukari, Alexander I. Spira, Zujun Li, Pei-Jen Lou, Victor H.F. Lee, Suebpong Tanasanvimon, Brigette B.Y. Ma, Somvilai Chakrabandhu, Po Chung Chan, Chia-Jui Yen, Li Zhang, Arunee Dechaphunkul, Roger K-C Ngan, Shau-Hsuan Li, Hung-Ming Wang, and Caroline Even
- Abstract
Supplemental Figure S3. Best percentage change from baseline in sum of diameters of target lesions for patients treated with spartalizumab (A) and chemotherapy (B)
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- 2023
35. Data from Phase II Trial of Adjuvant Nivolumab Following Salvage Resection in Patients with Recurrent Squamous Cell Carcinoma of the Head and Neck
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Trisha M. Wise-Draper, Ammar Sukari, Nusrat Harun, Roman Jandarov, Benjamin H. Hinrichs, W. Michael Korn, Julie McGrath, Brian Cervenka, Alice Tang, Chad Zender, Yash Patil, Misako Nagasaka, Vinita Takiar, Muhammed Kashif Riaz, Nicky Kurtzweil, Maria Mathews, Sarah Palackdharry, Casey Allen, Sulsal Haque, Shuchi Gulati, and Jennifer L. Leddon
- Abstract
Purpose:Locoregional relapse in patients with head and neck squamous cell carcinoma (HNSCC) is common, approaching 50% for some subsites despite multimodality therapy. Salvage surgery is the standard of care, but able to achieve durable control in only a minority of patients. While adjuvant radiotherapy or chemo-radiotherapy is offered to select patients, this approach can be prohibitively toxic. Given the activity and tolerability of programmed death-1 inhibitors in metastatic HNSCC, we investigated the safety and efficacy of adjuvant nivolumab after salvage surgical resection.Patients and Methods:This was an open-label, multi-institutional phase II clinical trial (NCT03355560). Patients with recurrent, resectable HNSCC were enrolled within 6 weeks of salvage surgery. Six 28-day cycles of adjuvant nivolumab were planned. The primary endpoint was 2-year disease-free survival (DFS) more than 58%, based on an institutional historical control group of 71 patients with recurrent HNSCC who underwent salvage surgery.Results:Between February 2018 and February 2020, 39 patients were enrolled. At a median follow-up of 22.1 months, 2-year DFS was 71.4% [95% confidence interval (CI), 57.8–88.1] and the 2-year overall survival (OS) was 73% (95% CI, 58–91.8). Three of 39 (8%) patients experienced grade 3 treatment-related adverse events and 3 of 39 (8%) discontinued treatment due to side effects. Ten of 39 had locoregional recurrence, while 2 of 10 also had synchronous metastatic disease. There was no difference in DFS between PD ligand-1 (PD-L1)–positive and PD-L1–negative patients. There was a nonsignificant trend toward improved DFS in patients with high tumor mutational burden (P = 0.083).Conclusions:Adjuvant nivolumab after salvage surgery in locally recurrent HNSCC is well tolerated and showed improved DFS compared with historical controls.
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- 2023
36. Supplementary Table 1 from Phase II, Randomized Study of Spartalizumab (PDR001), an Anti–PD-1 Antibody, versus Chemotherapy in Patients with Recurrent/Metastatic Nasopharyngeal Cancer
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Darren W-T. Lim, Luigi Manenti, Romain Séchaud, Jennifer Mataraza, Hongzi Liang, Yao Yao, Sebastian Szpakowski, Juan Gonzalez-Maffe, Steven McCune, Joël Guigay, Ammar Sukari, Alexander I. Spira, Zujun Li, Pei-Jen Lou, Victor H.F. Lee, Suebpong Tanasanvimon, Brigette B.Y. Ma, Somvilai Chakrabandhu, Po Chung Chan, Chia-Jui Yen, Li Zhang, Arunee Dechaphunkul, Roger K-C Ngan, Shau-Hsuan Li, Hung-Ming Wang, and Caroline Even
- Abstract
Supplemental Table S1. Patient disposition
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- 2023
37. Supplementary Figure 1 from Phase II, Randomized Study of Spartalizumab (PDR001), an Anti–PD-1 Antibody, versus Chemotherapy in Patients with Recurrent/Metastatic Nasopharyngeal Cancer
- Author
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Darren W-T. Lim, Luigi Manenti, Romain Séchaud, Jennifer Mataraza, Hongzi Liang, Yao Yao, Sebastian Szpakowski, Juan Gonzalez-Maffe, Steven McCune, Joël Guigay, Ammar Sukari, Alexander I. Spira, Zujun Li, Pei-Jen Lou, Victor H.F. Lee, Suebpong Tanasanvimon, Brigette B.Y. Ma, Somvilai Chakrabandhu, Po Chung Chan, Chia-Jui Yen, Li Zhang, Arunee Dechaphunkul, Roger K-C Ngan, Shau-Hsuan Li, Hung-Ming Wang, and Caroline Even
- Abstract
Supplemental Figure S1. CONSORT diagram
- Published
- 2023
38. Safety and Efficacy of MEDI0457 plus Durvalumab in Patients with Human Papillomavirus-Associated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma
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Charu Aggarwal, Nabil F. Saba, Alain Algazi, Ammar Sukari, Tanguy Y. Seiwert, Missak Haigentz, Mercedes Porosnicu, Marcelo Bonomi, Jean Boyer, Mark T. Esser, Lily I. Cheng, Sonia Agrawal, Emily C. Jennings, Nicholas M. Durham, Karl Fraser, Delphine Lissa, Maozhen Gong, Natalia Ceaicovscaia, Amaya Gascó Hernández, and Rakesh Kumar
- Subjects
Cancer Research ,Human papillomavirus 16 ,Human papillomavirus 18 ,Squamous Cell Carcinoma of Head and Neck ,Papillomavirus Infections ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Evaluation of treatments and therapeutic interventions ,Human Papillomavirus Viruses ,B7-H1 Antigen ,Vaccine Related ,Infectious Diseases ,Oncology ,Head and Neck Neoplasms ,Clinical Research ,6.1 Pharmaceuticals ,Humans ,Sexually Transmitted Infections ,Immunization ,Oncology & Carcinogenesis ,Dental/Oral and Craniofacial Disease ,6.2 Cellular and gene therapies ,Cancer - Abstract
Purpose: Tumoral programmed cell death ligand-1 (PD-L1) expression is common in human papillomavirus (HPV)–associated head and neck squamous cell carcinoma (HNSCC). We assessed whether a DNA vaccine targeting HPV-16/18 E6/E7 with IL12 adjuvant (MEDI0457) combined with the PD-L1 inhibitor durvalumab could enhance HPV-specific T-cell response and improve outcomes in recurrent/metastatic HPV-16/18–associated HNSCC. Patients and Methods: In this phase Ib/IIa study, immunotherapy-naïve patients with ≥1 previous platinum-containing regimen (neoadjuvant/adjuvant therapy or for recurrent/metastatic disease) received MEDI0457 7 mg intramuscularly with electroporation on weeks 1, 3, 7, and 12, then every 8 weeks, plus durvalumab 1,500 mg intravenously on weeks 4, 8, and 12, then every 4 weeks, until confirmed progression and/or unacceptable toxicity. Coprimary objectives were safety and objective response rate (ORR; H0: ORR ≤ 15%); secondary objectives included 16-week disease control rate (DCR-16), overall survival (OS), and progression-free survival (PFS). Results: Of 35 treated patients, 29 were response evaluable (confirmed HPV-associated disease; received both agents). ORR was 27.6% [95% confidence interval (CI), 12.7–47.2; four complete responses, four partial responses]; responses were independent of PD-L1 tumor-cell expression (≥25% vs. 2-fold increase in tumor-infiltrating CD8+ T cells. Conclusions: MEDI0457 plus durvalumab was well tolerated. While the primary efficacy endpoint was not reached, clinical benefit was encouraging.
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- 2023
39. ARRY-382 in Combination with Pembrolizumab in Patients with Advanced Solid Tumors: Results from a Phase 1b/2 Study
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Melissa Johnson, Arkadiusz Z. Dudek, Ammar Sukari, Justin Call, Paul R. Kunk, Karl Lewis, Justin F. Gainor, John Sarantopoulos, Patrice Lee, Adele Golden, Allison Harney, S. Michael Rothenberg, Yuanyuan Zhang, and Jonathan W. Goldman
- Subjects
Ovarian Neoplasms ,Cancer Research ,Oncology ,Antineoplastic Combined Chemotherapy Protocols ,Programmed Cell Death 1 Receptor ,Humans ,Female ,Antibodies, Monoclonal, Humanized ,Protein Kinase Inhibitors ,B7-H1 Antigen - Abstract
Purpose: ARRY-382 (PF-07265804) is a selective inhibitor of colony-stimulating factor-1 receptor. We evaluated the safety and preliminary efficacy of ARRY-382 plus pembrolizumab in patients with advanced solid tumors. Patients and Methods: This was an open-label, multicenter, Phase 1b/2 study (NCT02880371) performed over September 1, 2016 to October 24, 2019. In the Phase 1b dose-escalation, patients with selected advanced solid tumors received ARRY-382 [starting dose 200 mg once daily (QD) orally] plus pembrolizumab [2 mg/kg intravenously (IV) every 3 weeks (Q3W)]. Phase 2 patients had: Pancreatic ductal adenocarcinoma (PDA); programmed cell death protein-1 (PD-1)/PD-ligand 1 (PD-L1) inhibitor-refractory (PD-1/PD-L1 IR) advanced solid tumors; or platinum-resistant ovarian cancer (prOVCA). Patients received ARRY-382 at the maximum tolerated dose (MTD) of 300 mg QD plus pembrolizumab 200 mg IV Q3W. Results: Primary endpoints of dose-limiting toxicities (DLT; Phase 1b) and objective response rate (Phase 2) were met. In Phase 1b, 19 patients received ARRY-382 200–400 mg. Three patients reported DLTs. The MTD of ARRY-382 (plus pembrolizumab) was 300 mg QD. In Phase 1b, 2 patients (10.5%) had confirmed partial response (PR): 1 with PDA and 1 with ovarian cancer, lasting 29.2 and 3.1 months, respectively. In Phase 2, there were 27, 19, and 11 patients in the PDA, PD-1/PD-L1 IR, and prOVCA cohorts, respectively. One patient (3.7%) with PDA had a PR lasting 2.4 months. The most frequent ARRY-382–related adverse events were increased transaminases (10.5%–83.3%) and increased creatine phosphokinase (18.2%–50.0%). Conclusions: Although limited clinical benefit was observed, ARRY-382 plus pembrolizumab was well tolerated.
- Published
- 2022
40. The Effects of HER2 Alterations in EGFR Mutant Non-small Cell Lung Cancer
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Edward S. Kim, Stephen V. Liu, Rebecca Feldman, Matthew J. Oberley, W. Michael Korn, Sachin Gopalkrishna Pai, Hirva Mamdani, Yasmine Baca, Dipesh Uprety, Chukwuemeka Ikpeazu, Vijendra Singh, Ammar Sukari, Chul Kim, Luis E. Raez, Gerold Bepler, Misako Nagasaka, Joanne Xiu, Alexander I. Spira, Hossein Borghaei, and Antoinette J. Wozniak
- Subjects
Male ,Pulmonary and Respiratory Medicine ,Cancer Research ,Lung Neoplasms ,Receptor, ErbB-2 ,Mutant ,medicine.disease_cause ,Exon ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,HER2 Amplification ,In patient ,skin and connective tissue diseases ,Lung cancer ,neoplasms ,Aged ,Retrospective Studies ,Mutation ,business.industry ,Middle Aged ,medicine.disease ,ErbB Receptors ,Pyrimidines ,Oncology ,Cancer research ,Pyrazoles ,Adenocarcinoma ,Female ,Non small cell ,business - Abstract
Background HER2 alteration (mutation and/or amplification) is associated with poor survival in NSCLC and can mediate resistance to EGFR tyrosine kinase inhibitors. Methods We retrospectively analyzed de-identified molecular information from 12,946 NSCLC samples that underwent next-generation sequencing (NGS) with Caris Life Sciences. The objectives were to determine the prevalence and type of HER2 alterations with and without EGFR as a co-mutation. Insurance claims were utilized to obtain outcomes data. Results Three hundred and twenty-one patients (2.5%) had HER2 alteration: mutation in 197 patients and amplification in 134. Median age was 65 years and 62% were female. A total of 84% were adenocarcinoma. HER2 exon 20 insertion was most common (69%). A total of 1551 (12%) patients had EGFR mutations. Among samples with EGFR mutations, 24 (1.5%) had concurrent HER2 alteration (8 with HER2 mutation and 16 with amplification). Among 8 patients who had both EGFR and HER2 mutations, 3 had EGFR exon 19 deletions and exon 8 HER2 mutation (S310F). One-third of the patients (7/21) with HER2 extracellular domain (ECD) mutation had co-occurring EGFR mutations. All 7 were S310. Patients with concurrent EGFR mutation and HER2 amplification had longer median time on treatment with EGFR TKI(s) than those with EGFR mutation without HER2 amplification (HR 2.284, P =.004). Conclusion A minority of NSCLC samples with EGFR mutations had HER2 alterations. In patients with both mutations, exon 21 mutations for EGFR and exon 8 mutations for HER2 were common. It will be critical to continue to accumulate valuable clinical data for further real-world outcomes analysis.
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- 2022
41. Impact of XPO1 mutations on survival outcomes in metastatic non-small cell lung cancer (NSCLC)
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Misako Nagasaka, Joanne Xiu, W. Michael Korn, Asfar S. Azmi, Yasmine Baca, Gerold Bepler, Hafiz Uddin, Mohammad Fahad Bin Asad, Michael J. Demeure, Ammar Sukari, Stephen V. Liu, Jorge Nieva, Luis E. Raez, Gilberto Lopes, Mohammed Najeeb Al Hallak, Bing Xia, Patrick C. Ma, Dipesh Uprety, Hirva Mamdani, Chul Kim, Sonam Puri, Hossein Borghaei, and Dan Magee
- Subjects
Pulmonary and Respiratory Medicine ,Cancer Research ,Mutation ,Lung Neoplasms ,business.industry ,Hazard ratio ,Receptors, Cytoplasmic and Nuclear ,Cancer ,non-small cell lung cancer (NSCLC) ,Karyopherins ,medicine.disease ,medicine.disease_cause ,Article ,XPO1 ,Oncology ,Carcinoma, Non-Small-Cell Lung ,Cancer research ,medicine ,Humans ,Immunohistochemistry ,KRAS ,Nuclear protein ,business - Abstract
Background Nuclear protein transport is essential in guiding the traffic of important proteins and RNAs between the nucleus and cytoplasm. Export of proteins from the nucleus is mostly regulated by Exportin 1 (XPO1). In cancer, XPO1 is almost universally hyperactive and can promote the export of important tumor suppressors to the cytoplasm. Currently, there are no studies evaluating XPO1 amplifications and mutations in NSCLC and the impact on outcomes. Methods Tumor samples were analyzed using next-generation sequencing (NGS) (NextSeq, 592 Genes), immunohistochemistry (IHC), and whole transcriptome sequencing (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Survival was extracted from insurance claims data and calculated from time of tissue collection to last contact using Kaplan-Meier estimate. Results Among 18,218 NSCLC tumors sequenced, 26 harbored XPO1 mutations and 24 had amplifications. XPO1 mutant tumors were more likely to have high TMB (79% vs. 52%, p = 0.007) and less likely to have high PD-L1 (32% vs. 68%, p = 0.03). KRAS co-mutations were seen in 19% (n = 5) and EGFR co-mutations were rare (n = 2). Among the 17,449 NSCLC tumors with clinical data, there were 24 XPO1 mutant. Comparison of survival between XPO1 mutant and WT showed a negative association with a hazard ratio (HR) of 1.932 (95% CI: 1.144–3.264 p = 0.012). XPO1 amplification was not associated with survival. Conclusions XPO1 pathogenic mutations were associated with a poor survival in NSCLC. Although XPO1 mutations are rare in NSCLC, further studies to assess its associations with treatment responses are warranted.
- Published
- 2021
42. Spotlight on Trastuzumab Deruxtecan (DS-8201,T-DXd) for HER2 Mutation Positive Non-Small Cell Lung Cancer
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Misako Nagasaka, Mohammed Najeeb Al Hallak, Samer Alkassis, Jami Fukui, Fares Alsawah, Ibrahim Azar, Kalub Fedak, and Ammar Sukari
- Subjects
Antibody-drug conjugate ,business.industry ,Cancer ,medicine.disease ,chemistry.chemical_compound ,Breast cancer ,Oncology ,chemistry ,Trastuzumab ,Trastuzumab emtansine ,Cancer research ,Medicine ,Pertuzumab ,skin and connective tissue diseases ,business ,Lung cancer ,neoplasms ,Tyrosine kinase ,medicine.drug - Abstract
Human epidermal growth factor receptor 2 (HER2) is a proto-oncogene that, when mutated or overexpressed, plays an important role in oncogenesis. The landscape of HER2-positive breast cancer has changed dramatically over the past 2 decades with the FDA approval of a growing number of agents (antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates) targeting the HER2 receptor. HER2 inhibition has also been approved for HER2-positive gastric cancer. HER2 is amplified in 9% and mutated in 3% of lung cancer. Historically, HER2-targeted therapy for lung cancer with trastuzumab, pertuzumab, and trastuzumab emtansine has failed to demonstrate a survival benefit. Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate with a tetrapeptide linker, which delivers a topoisomerase I inhibitor with a drug-to-antibody ratio of 7~8. The potency of the active payload, as well as its significant bystander effect, resulted in significant anti-tumor activity. The DESTINY-Lung01 trial evaluated T-DXd in HER2-positive non-squamous non-small cell lung cancer (NSCLC) and reported a progression-free survival of 14 months in HER2-mutated NSCLC, earning its breakthrough designation by the FDA. In this review, we will discuss the structural characteristics, pharmacodynamics, and pharmacokinetics of T-DXd. We will also shed light on the preclinical and ongoing clinical trials of T-DXd along with future directions in the management of HER2 positive lung cancer.
- Published
- 2021
43. 681 A phase 1 study of CUE-101, a novel HPV16 E7-pHLA-IL2-Fc fusion protein, as monotherapy and in combination with pembrolizumab in patients with recurrent/metastatic HPV16+ head and neck cancer
- Author
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Christine Chung, Dimitrios Colevas, Douglas Adkins, Jong Chul Park, Cristina Rodriguez, Michael Gibson, Ammar Sukari, Barbara Burtness, Faye Johnson, Ricklie Julian, Nabil Saba, Lara Dunn, Tanguy Seiwert, Francis Worden, Rami Haddad, Nashat Gabrail, Julie Bauman, Laura Agensky, Apollina Goel, Reena Lynam, Steven Margossian, Raymond Moniz, Steve Quayle, Cynthia Rajan, Kenneth Pienta, Matteo Levisetti, and Sara Pai
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- 2022
44. Biomarkers predictive of response to pembrolizumab in head and neck cancer
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David G. Pfister, Robert I. Haddad, Francis P. Worden, Jared Weiss, Ranee Mehra, Laura Q. M. Chow, Stephen V. Liu, Hyunseok Kang, Nabil F. Saba, Lori J. Wirth, Ammar Sukari, Erminia Massarelli, Mark Ayers, Andrew Albright, Andrea L. Webber, Robin Mogg, Jared Lunceford, Lingkang Huang, Razvan Cristescu, Jonathan Cheng, Tanguy Y. Seiwert, and Joshua M. Bauml
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Cancer Research ,Oncology ,Radiology, Nuclear Medicine and imaging - Abstract
We performed an integrated biomarker evaluation in pembrolizumab-treated patients with R/M HNSCC enrolled in KEYNOTE-012 or KEYNOTE-055. The relationship between biomarkers and HPV status was explored.We evaluated PD-L1 (combined positive score [CPS]), TMB, T-cell-inflamed gene expression profile (TcellTwo hundred and fifty-seven patients (KEYNOTE-012, n = 106; KEYNOTE-055, n = 151) had TMB data available; of these, 254 had PD-L1 and 236 had TcellTMB and the inflammatory biomarkers PD-L1 and Tcell
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- 2022
45. <scp>NTRK3</scp> mutation in secretory carcinoma of the parotid gland: A Case report
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Fahad AlKaabba, Abdurahman Alloghbi, Yazeed Deajim, Mohamad W. Sukkari, Mir Yousufuddin Ali Khan, and Ammar Sukari
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General Medicine - Published
- 2022
46. Risk Factors Associated with a Second Primary Lung Cancer in Patients with an Initial Primary Lung Cancer
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Seongho Kim, Misako Nagasaka, Amanda Fisher, Kimberly Belzer, Frank A. Baciewicz, Ann G. Schwartz, Ammar Sukari, Hirva Mamdani, Antoinette J. Wozniak, Dina Farhat, Courtney French, and MaryAnn Milczuk
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Surgical resection ,Male ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Survival ,Article ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Survivorship curve ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Stage (cooking) ,Mortality ,Lung cancer ,Aged ,Aged, 80 and over ,Surveillance ,business.industry ,Proportional hazards model ,Cancer ,Neoplasms, Second Primary ,Second primary cancer ,Targeted monitoring ,Middle Aged ,medicine.disease ,Confidence interval ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Case-Control Studies ,Female ,business - Abstract
Targeted surveillance strategies following initial primary lung cancer (IPLC) treatment are currently limited. One hundred twenty patients diagnosed with IPLC who did not develop second primary lung cancer (SPLC) were matched to 121 patients who developed SPLC. Our analysis found IPLC surgical resection increases SPLC emergence risk regardless of procedure type. Increased survival after IPLC resection warrants close SPLC monitoring. Background: Increased patient survivorship following initial primary lung cancer (IPLC) diagnosis and treatment has uncovered new clinical challenges as individuals post-IPLC are at growing subsequent risk of developing second primary lung cancer (SPLC). Proper SPLC surveillance guidelines aimed at monitoring IPLC survivors are crucial to enhancing health outcomes. This study aims to categorize risk factors associated with SPLC emergence in IPLC survivors for clinical use following IPLC treatment. Materials and Methods: Using the Karmanos Cancer Institute Tumor Registry, patients diagnosed with IPLC from 2000 to 2017 were identified. Patients diagnosed with SPLC were matched to individuals who did not develop SPLC. Logistic and Cox regression analyses were performed to identify risk factors for SPLC emergence and overall survival (OS). Results: One hundred twenty-one patients diagnosed with IPLC who later developed SPLC were identified and compared with 120 patients with IPLC who did not develop SPLC. Several factors such as stage at first diagnosis, histology, age, and smoking history were not associated with SPLC risk. The median time to SPLC was 1.79 years. Patients who were treated with surgical resection had a significantly higher probability of developing SPLC. After correcting for potential immortal time bias, the median OS was 3.63 years (95% confidence interval [CI], 3.05–5.00) and 7.31 years (95% CI, 4.62–10.90) for SPLC and no SPLC groups, respectively. Conclusion: This study uncovered notable associations and lack thereof between several competing SPLC risk factors, as well as mortality. Further characterization of SPLC risk factors is essential for enhancing surveillance recommendations.
- Published
- 2021
47. Association of TP53 and CDKN2A mutation profile with tumor mutation burden (TMB) in head and neck cancer
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Alexander Y. Deneka, Yasmine Baca, Ilya G. Serebriiskii, Emmanuelle Nicolas, Mitchell I. Parker, Theodore T. Nguyen, Joanne Xiu, W. Michael Korn, Michael J. Demeure, Trisha Wise-Draper, Ammar Sukari, Barbara Burtness, and Erica A. Golemis
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Cancer Research ,Oncology ,Head and Neck Neoplasms ,Squamous Cell Carcinoma of Head and Neck ,Mutation ,Papillomavirus Infections ,Biomarkers, Tumor ,Carcinoma, Squamous Cell ,Humans ,Tumor Suppressor Protein p53 ,Article ,Cyclin-Dependent Kinase Inhibitor p16 - Abstract
Purpose:Head and neck squamous cell carcinoma (HNSCC) is a frequently devastating cancer that affects more than a half million people annually worldwide. Although some cases arise from infection with human papillomavirus (HPV), HPV-negative HNSCC is more common, and associated with worse outcome. Advanced HPV-negative HNSCC may be treated with surgery, chemoradiation, targeted therapy, or immune checkpoint inhibition (ICI). There is considerable need for predictive biomarkers for these treatments. Defects in DNA repair capacity and loss of cell-cycle checkpoints sensitize tumors to cytotoxic therapies, and can contribute to phenotypes such as elevated tumor mutation burden (TMB), associated with response to ICI. Mutation of the tumor suppressors and checkpoint mediators TP53 and CDKN2A is common in HPV-negative HNSCC.Experimental Design:To gain insight into the relation of the interaction of TP53 and CDKN2A mutations with TMB in HNSCC, we have analyzed genomic data from 1,669 HPV-negative HNSCC tumors with multiple criteria proposed for assessing the damaging effect of TP53 mutations.Results:Data analysis established the TP53 and CDKN2A mutation profiles in specific anatomic subsites and suggested that specific categories of TP53 mutations are more likely to associate with CDKN2A mutation or high TMB based on tumor subsite. Intriguingly, the pattern of hotspot mutations in TP53 differed depending on the presence or absence of a cooccurring CDKN2A mutation.Conclusions:These data emphasize the role of tumor subsite in evaluation of mutational profiles in HNSCC, and link defects in TP53 and CDKN2A to elevated TMB levels in some tumor subgroups.
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- 2022
48. African American race as a risk factor associated with a second primary lung cancer after initial primary head and neck cancer
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Yusra F. Shao, Seongho Kim, John D. Cramer, Dina Farhat, Jeffrey Hotaling, Syed Naweed Raza, George Yoo, Ho‐sheng Lin, Harold Kim, Ammar Sukari, and Misako Nagasaka
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Black or African American ,Lung Neoplasms ,Otorhinolaryngology ,Head and Neck Neoplasms ,Risk Factors ,Humans ,Neoplasms, Second Primary ,Retrospective Studies - Abstract
Initial primary head and neck cancer (IPHNC) is associated with second primary lung cancer (SPLC). We studied this association in a population with a high proportion of African American (AA) patients.Patients with IPHNC and SPLC treated between 2000 and 2017 were reviewed for demographic, disease, and treatment-related characteristics and compared to age-and-stage-matched controls without SPLC. Logistic and Cox regression models were used to analyze the relationship of these characteristics with the development of SPLC and overall survival (OS).Eighty-seven patients and controls were compared respectively. AA race was associated with a significantly higher risk of developing SPLC (OR 2.92, 95% CI 1.35-6.66). After correcting for immortal time bias, patients with SPLC had a significantly lower OS when compared with controls (HR 0.248, 95% CI 0.170-0.362).We show that AA race is associated with an increased risk of SPLC after IPHNC; reasons of this increased risk warrant further investigation.
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- 2022
49. The Gut Microbiome and Cancer: A Comprehensive Review of Melanoma, Lung, Head and Neck and Gastrointestinal Tumors
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Yusra F. Shao, Asfar S. Azmi, Rachel E. Sexton, Misako Nagasaka, Ammar Sukari, Mohammed Najeeb Al Hallak, and Bayan Al-Share
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Pathology ,medicine.medical_specialty ,Lung ,medicine.anatomical_structure ,Gastrointestinal tumors ,business.industry ,Melanoma ,medicine ,Cancer ,medicine.disease ,Head and neck ,business ,Gut microbiome - Published
- 2022
50. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048)
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Barbara Burtness, Kevin J Harrington, Richard Greil, Denis Soulières, Makoto Tahara, Gilberto de Castro, Amanda Psyrri, Neus Basté, Prakash Neupane, Åse Bratland, Thorsten Fuereder, Brett G M Hughes, Ricard Mesía, Nuttapong Ngamphaiboon, Tamara Rordorf, Wan Zamaniah Wan Ishak, Ruey-Long Hong, René González Mendoza, Ananya Roy, Yayan Zhang, Burak Gumuscu, Jonathan D Cheng, Fan Jin, Danny Rischin, Guillermo Lerzo, Marcelo Tatangelo, Mirta Varela, Juan Jose Zarba, Michael Boyer, Hui Gan, Bo Gao, Brett Hughes, Girish Mallesara, Anne Taylor, Martin Burian, Carlos Henrique Barrios, Dalvaro Oliveira de Castro Junior, Gilberto Castro, Fabio Andre Franke, Gustavo Girotto, Iane Pinto Figueiredo Lima, Ulisses Ribaldo Nicolau, Gustavo Dix Junqueira Pinto, Lucas Santos, Ana-Paula Victorino, Neil Chua, Felix Couture, Richard Gregg, Aaron Hansen, John Hilton, Joy McCarthy, Denis Soulieres, Rodrigo Ascui, Pablo Gonzalez, Luis Villanueva, Marco Torregroza, Angela Zambrano, Petra Holeckova, Zdenek Kral, Bohuslav Melichar, Jana Prausova, Milan Vosmik, Maria Andersen, Niels Gyldenkerne, Hannes Jurgens, Kadri Putnik, Petri Reinikainen, Viktor Gruenwald, Simon Laban, Gerasimos Aravantinos, Ioannis Boukovinas, Vassilis Georgoulias, Dora Kwong, Yousuf Al-Farhat, Tibor Csoszi, Jozsef Erfan, Geza Horvai, Laszlo Landherr, Eva Remenar, Agnes Ruzsa, Judit Szota, Salem Billan, Iris Gluck, Orit Gutfeld, Aron Popovtzer, Marco Benasso, Simona Bui, Vittorio Ferrari, Lisa Licitra, Franco Nole, Takashi Fujii, Yasushi Fujimoto, Nobuhiro Hanai, Hiroki Hara, Koji Matsumoto, Kenji Mitsugi, Nobuya Monden, Masahiro Nakayama, Kenji Okami, Nobuhiko Oridate, Kiyoto Shiga, Yasushi Shimizu, Masashi Sugasawa, Masanobu Takahashi, Shunji Takahashi, Kaoru Tanaka, Tsutomu Ueda, Hironori Yamaguchi, Tomoko Yamazaki, Ryuji Yasumatsu, Tomoya Yokota, Tomokazu Yoshizaki, Iveta Kudaba, Zinaida Stara, Soon Keat Cheah, Jose Aguilar Ponce, Rene Gonzalez Mendoza, Carlos Hernandez Hernandez, Francisco Medina Soto, Jan Buter, Ann Hoeben, S. Oosting, Karijn Suijkerbuijk, Aase Bratland, Marianne Brydoey, Renzo Alvarez, Luis Mas, Priscilla Caguioa, John Querol, Eugenio Emmanuel Regala, Maria Belen Tamayo, Ellie May Villegas, Andrzej Kawecki, Andrey Karpenko, Arkadiy Klochikhin, Alexey Smolin, Oleg Zarubenkov, Boon Cher Goh, Graham Cohen, Johanna du Toit, Christa Jordaan, Gregory Landers, Paul Ruff, Waldemar Szpak, Neonyana Tabane, Irene Brana, Lara Iglesias Docampo, Javier Lavernia, Ricard Mesia, Edvard Abel, Valentina Muratidu, Niels Nielsen, Valerie Cristina, Sacha Rothschild, Hung-Ming Wang, Muh-Hwa Yang, Su-Peng Yeh, Chia-Jui Yen, Nopadol Soparattanapaisarn, Virote Sriuranpong, Sercan Aksoy, Irfan Cicin, Meltem Ekenel, Hakan Harputluoglu, Ozgur Ozyilkan, Kevin Harrington, Sanjiv Agarwala, Haythem Ali, Robert Alter, Daniel Anderson, Justine Bruce, Nicholas Campbell, Miguel Conde, John Deeken, William Edenfield, Lawrence Feldman, Elizabeth Gaughan, Basem Goueli, Balazs Halmos, Upendra Hegde, Brian Hunis, Robert Jotte, Anand Karnad, Saad Khan, Noel Laudi, Douglas Laux, Danko Martincic, Steven McCune, Dean McGaughey, Krzysztof Misiukiewicz, Deborah Mulford, Eric Nadler, Johannes Nunnink, James Ohr, Meaghan O'Malley, Brian Patson, Doru Paul, Elizabeta Popa, Steven Powell, Rebecca Redman, Vincent Rella, Chaio Rocha Lima, Abirami Sivapiragasam, Yungpo Su, Ammar Sukari, Stuart Wong, Emrullah Yilmaz, Jeffrey Yorio, and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
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Oncology ,Male ,Humanized/therapeutic use ,Antimetabolites ,Cetuximab ,Phases of clinical research ,Pembrolizumab ,030204 cardiovascular system & hematology ,Antineoplastic/therapeutic use ,Cetuximab/therapeutic use ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Monoclonal ,Squamous Cell Carcinoma of Head and Neck/drug therapy ,030212 general & internal medicine ,Antineoplastic Agents, Immunological/therapeutic use ,education.field_of_study ,General Medicine ,Middle Aged ,Antimetabolites, Antineoplastic/therapeutic use ,Progression-Free Survival ,Antibodies, Monoclonal, Humanized/therapeutic use ,Head and Neck Neoplasms ,Female ,Fluorouracil ,medicine.drug ,Antimetabolites, Antineoplastic ,medicine.medical_specialty ,Population ,Antineoplastic Agents ,Antibodies, Monoclonal, Humanized ,Fluorouracil/therapeutic use ,Antibodies ,03 medical and health sciences ,Immunological/therapeutic use ,Internal medicine ,medicine ,Humans ,Progression-free survival ,education ,Aged ,Performance status ,Squamous Cell Carcinoma of Head and Neck ,business.industry ,Head and Neck Neoplasms/drug therapy ,medicine.disease ,Interim analysis ,Head and neck squamous-cell carcinoma ,Antineoplastic Combined Chemotherapy Protocols/therapeutic use ,business - Abstract
BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], pINTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.FUNDING: Merck Sharp & Dohme.
- Published
- 2019
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