47 results on '"Stephen, Bettzy"'
Search Results
2. Selinexor in combination with carboplatin and paclitaxel in patients with advanced solid tumors: Results of a single-center, multi-arm phase Ib study
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Thein, Kyaw Z., Karp, Daniel D., Tsimberidou, Apostolia, Gong, Jing, Sulovic, Selma, Shah, Jatin, Milton, Denái R., Hong, David S., Janku, Filip, McQuinn, Lacey, Stephen, Bettzy A., Colen, Rivka, Carter, Brett W., Yap, Timothy A., Piha-Paul, Sarina A., Fu, Siqing, Meric-Bernstam, Funda, and Naing, Aung
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- 2022
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3. Patient-reported symptom burden in patients with rare cancers receiving pembrolizumab in a phase II Clinical Trial
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Mendoza, Tito R., Hong, David S., Peterson, Christine B., Stephen, Bettzy, Dumbrava, Ecaterina, Pant, Shubbam, Tsimberidou, Apostolia Maria, Yap, Timothy Anthony, Sheshadri, Ajay, Altan, Mehmet, George, Goldy, Castillo, Lilibeth, Rodriguez, Enedelia, Gong, Jing, Subbiah, Vivek, Janku, Filip, Fu, Siqing, Piha-Paul, Sarina A., Ahnert, Jordi Rodon, Karp, Daniel D., Cleeland, Charles, Meric-Bernstam, Funda, and Naing, Aung
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- 2022
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4. Pembrolizumab for advanced penile cancer: a case series from a phase II basket trial
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Hahn, Andrew W., Chahoud, Jad, Campbell, Matthew T., Karp, Daniel D., Wang, Jennifer, Stephen, Bettzy, Tu, Shi-Ming, Pettaway, Curtis A., and Naing, Aung
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- 2021
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5. Effects of glutamine for prevention of radiation-induced esophagitis: a double-blind placebo-controlled trial
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Alshawa, Anas, Cadena, Alexandra Perez, Stephen, Bettzy, Reddy, Akhila, Mendoza, Tito R., McQuinn, Lacey, Lawhorn, Kristie, Zarifa, Abdulrazzak, Bernhardt, Alexander Maximilian, Fessaheye, Senait, Warneke, Carla L., Chang, Joe Y., and Naing, Aung
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- 2021
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6. Pembrolizumab in Patients with Refractory Cutaneous Squamous Cell Carcinoma: A Phase II Trial
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Ferrarotto, Renata, Sousa, Luana G., Qing, Yun, Kaya, Diana, Stephen, Bettzy, Jain, Dipti, Bell, Diana, Pant, Shubham, Tsimberidou, Apostolia M., Janku, Filip, Blumenschein, George, Glisson, Bonnie S., Ahnert, Jordi Rodon, Piha-Paul, Sarina A., Lee, J. Jack, Wong, Michael K., Lu, Charles, Meric-Bernstam, Funda, and Naing, Aung
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- 2021
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7. The clinical efficacy and safety of single-agent pembrolizumab in patients with recurrent granulosa cell tumors of the ovary: a case series from a phase II basket trial
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How, Jeffrey A., Jazaeri, Amir, Westin, Shannon N., Sood, Anil K., Ramondetta, Lois M., Xu, Mingxuan, Abonofal, Abdulrahman, Karp, Daniel D., Subbiah, Vivek, Stephen, Bettzy, Rodon, Jordi A., Yang, Fei, and Naing, Aung
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- 2021
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8. Phase Ib/II Study of Lacnotuzumab in Combination with Spartalizumab in Patients with Advanced Malignancies.
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Ahmed, Jibran, Stephen, Bettzy, Yali Yang, Kwiatkowski, Evan, Ejezie, Chinenye Lynette, and Pant, Shubham
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MACROPHAGE colony-stimulating factor , *ANTINEOPLASTIC agents , *TREATMENT of endometrial cancer , *CELL death , *CANCER cells - Abstract
Introduction: Blocking the colony-stimulating factor 1 (CSF-1) signal on tumor-associated macrophages can lead to an upregulation of checkpoint molecules, such as programmed cell death ligand 1 (PD-L1), thus causing resistance to this blockade. Combining spartalizumab (PDR001), a high-affinity, ligand-blocking, humanized anti– PD-1 immunoglobulin G4 antibody, with lacnotuzumab (MCS110), a high-affinity, humanized monoclonal antibody directed against human CSF-1 can potentially overcome this resistance. Methods: This was a multicenter, phase Ib/II trial using a combination of spartalizumab with lacnotuzumab in patients with advanced cancers, including anti–PD-1/PD-L1 treatment-resistant melanoma, and anti–PD-1/PD-L1 treatment-naı¨ve triplenegative breast cancer, pancreatic cancer, and endometrial cancer (ClinicalTrials.gov identifier: NCT02807844). The primary objective of dose escalation phase Ib was to assess safety, tolerability, and recommended phase II dose. The primary objective of the phase II expansion study was to assess the combination’s antitumor activity, including objective response rate and clinical benefit rate. Results: A total of eight patients (five in phase Ib and three in phase II) were evaluable for adverse events (AEs) at our study site. All eight patients experienced at least grade 1 AE. The most common treatment-related AEs were increased serum aspartate aminotransferase (38%), fatigue (38%), anemia (25%), increased alkaline phosphatase (25%), hyperbilirubinemia (25%), hypocalcemia (25%), and hypoalbuminemia (25%). Most of these AEs were grade 1 or 2. None of the patients experienced grade 4 AEs and no drug-related fatal AEs were reported among the eight patients treated in the study. One (13%) patient had stable disease (SD) (captured as unknown by the study sponsor because the evaluation criteria set per protocol was not met) and three (38%) patients had progressive disease. Four (50%) patients developed clinical disease progression based on investigator evaluation. One patient with pancreatic cancer achieved immune-related SD for 26 months while on the study treatments. Conclusion: The study completed phase Ib dose escalation and phase II. However, gating criteria for efficacy were not met for expansion beyond 80 patients in phase II and the sponsor did not continue development of the combination of spartalizumab and lacnotuzumab for oncology indications. The potential signal of activity in pancreatic cancer should be further explored. [ABSTRACT FROM AUTHOR]
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- 2024
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9. Pembrolizumab in vaginal and vulvar squamous cell carcinoma: a case series from a phase II basket trial
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How, Jeffrey A., Jazaeri, Amir A., Soliman, Pamela T., Fleming, Nicole D., Gong, Jing, Piha-Paul, Sarina A., Janku, Filip, Stephen, Bettzy, and Naing, Aung
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- 2021
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10. Therapeutic Role of Synthetic Lethality in ARID1A-Deficient Malignancies.
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Hein, Kyaw Z., Stephen, Bettzy, and Siqing Fu
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CANCER treatment , *IMMUNOSUPPRESSIVE agents , *TUMOR growth , *DNA methyltransferases , *IMMUNE checkpoint inhibitors - Abstract
AT-rich interaction domain 1A (ARID1A), a mammalian switch/sucrose nonfermenting complex subunit, modulates several cellular processes by regulating chromatin accessibility. It is encoded by ARID1A, an immunosuppressive gene frequently disrupted in a many tumors, affecting the proliferation, migration, and invasion of cancer cells. Targeting molecular pathways and epigenetic regulation associated with ARID1A loss, such as inhibiting the PI3K/AKT pathway or modulating Wnt/b-catenin signaling, may help suppress tumor growth and progression. Developing epigenetic drugs like histone deacetylase or DNA methyltransferase inhibitors could restore normal chromatin structure and function in cells with ARID1A loss. As ARID1A deficiency correlates with enhanced tumor mutability, microsatellite instability, high tumor mutation burden, increased programmed death-ligand 1 expression, and Tlymphocyte infiltration, ARID1A-deficient cells can be a potential therapeutic target for immune checkpoint inhibitors that warrants further exploration. In this review, we discuss the role of ARID1A in carcinogenesis, its crosstalk with other signaling pathways, and strategies to make ARID1A-deficient cells a potential therapeutic target for patients with cancer. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Phase I study of sapanisertib (CB‐228/TAK‐228/MLN0128) in combination with ziv‐aflibercept in patients with advanced solid tumors.
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Coleman, Niamh, Stephen, Bettzy, Fu, Siqing, Karp, Daniel, Subbiah, Vivek, Ahnert, Jordi Rodon, Piha‐Paul, Sarina A., Wright, John, Fessahaye, Senait N., Ouyang, Fengying, Yilmaz, Bulent, Meric‐Bernstam, Funda, and Naing, Aung
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VASCULAR endothelial growth factor receptors , *NEOVASCULARIZATION inhibitors , *CANCER fatigue , *RECOMBINANT proteins , *CHIMERIC proteins , *TUMORS - Abstract
Background: Sapanisertib is a potent ATP‐competitive, dual inhibitor of mTORC1/2. Ziv‐aflibercept is a recombinant fusion protein comprising human VEGF receptor extracellular domains fused to human immunoglobulin G1. HIF‐1α inhibition in combination with anti‐angiogenic therapy is a promising anti‐tumor strategy. This Phase 1 dose‐escalation/expansion study assessed safety/ tolerability of sapanisertib in combination with ziv‐aflibercept in advanced solid tumors. Methods: Fifty‐five patients with heavily pre‐treated advanced metastatic solid tumors resistant or refractory to standard treatment received treatment on a range of dose levels. Results: Fifty‐five patients were enrolled and treated across a range of dose levels. Forty were female (73%), median age was 62 (range: 21–79), and ECOG PS was 0 (9, 16%) or 1 (46, 84%). Most common tumor types included ovarian (8), colorectal (8), sarcoma (8), breast (3), cervical (4), and endometrial (4). Median number of prior lines of therapy was 4 (range 2–11). Sapanisertib 4 mg orally 3 days on and 4 days off plus 3 mg/kg ziv‐aflibercept IV every 2 weeks on a 28‐day cycle was defined as the maximum tolerated dose. Most frequent treatment‐related grade ≥2 adverse events included hypertension, fatigue, anorexia, hypertriglyceridemia, diarrhea, nausea, mucositis, and serum lipase increase. There were no grade 5 events. In patients with evaluable disease (n = 50), 37 patients (74%) achieved stable disease (SD) as best response, two patients (4%) achieved a confirmed partial response (PR); disease control rate (DCR) (CR + SD + PR) was 78%. Conclusion: The combination of sapanisertib and ziv‐aflibercept was generally tolerable and demonstrated anti‐tumor activity in heavily pre‐treated patients with advanced malignancies. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Phase 1/2 trial of avelumab combined with utomilumab (4‐1BB agonist), PF‐04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies.
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Knisely, Anne, Ahmed, Jibran, Stephen, Bettzy, Piha‐Paul, Sarina A., Karp, Daniel, Zarifa, Abdulrazzak, Fu, Siqing, Hong, David Sanghyun, Rodon Ahnert, Jordi, Yap, Timothy A., Tsimberidou, Apostolia M., Alshawa, Anas, Dumbrava, Ecaterina E., Yang, Yali, Song, Juhee, Meric‐Bernstam, Funda, Jazaeri, Amir A., and Naing, Aung
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Background: Immune checkpoint blockade has shown mixed results in advanced/recurrent gynecologic malignancies. Efficacy may be improved through costimulation with OX40 and 4‐1BB agonists. The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4‐1BB agonist), PF‐04518600 (an OX40 agonist), and radiotherapy in patients with recurrent gynecologic malignancies. Methods: The primary end point in this six‐arm, phase 1/2 trial was safety of the combination regimens. Secondary end points included the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors and immune‐related Response Evaluation Criteria in Solid Tumors, the disease control rate (DCR), the duration of response, progression‐free survival, and overall survival. Results: Forty patients were included (35% with cervical cancer, 30% with endometrial cancer, and 35% with ovarian cancer). Most patients (n = 33; 83%) were enrolled in arms A–C (no radiation). Among 35 patients who were evaluable for efficacy, the ORR was 2.9%, and the DCR was 37.1%, with a median duration of stable disease of 5.4 months (interquartile range, 4.1–7.3 months). Patients with cervical cancer in arm A (avelumab and utomilumab; n = 9 evaluable patients) achieved an ORR of 11% and a DCR of 78%. The median progression‐free survival was 2.1 months (95% CI, 1.8–3.5 months), and overall survival was 9.4 months (95% CI, 5.6–11.9 months). No dose‐limiting toxicities or grade 3–5 immune‐related adverse events were observed. Conclusions: The findings from this trial highlight that, in heavily pretreated patients with gynecologic cancer, even multidrug regimens targeting multiple immunologic pathways, although safe, did not produce significant responses. A DCR of 78% in patients with cervical cancer who received avelumab and utomilumab indicates that further research on this combination in select patients may be warranted. In a phase 1/2 trial of heavily pretreated patients who had recurrent gynecologic cancers, avelumab in combination with a 4‐1BB agonist, an OX40 agonist, and/or radiation was safe and had a similar rate of immune‐related adverse events compared with single‐agent immune checkpoint blockade. The combination of multiple immune‐modulating agents, however, did not result in increased efficacy. [ABSTRACT FROM AUTHOR]
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- 2024
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13. Correction to: Selinexor in combination with carboplatin and paclitaxel in patients with advanced solid tumors: results of a single‑center, multi‑arm phase Ib study
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Thein, Kyaw Z., Karp, Daniel D., Tsimberidou, Apostolia, Gong, Jing, Sulovic, Selma, Shah, Jatin, Milton, Denái R., Hong, David S., Janku, Filip, McQuinn, Lacey, Stephen, Bettzy A., Colen, Rivka, Carter, Brett W., Yap, Timothy A., Piha‑Paul, Sarina A., Fu, Siqing, Meric‑Bernstam, Funda, and Naing, Aung
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- 2022
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14. Immunotherapy in the First‐Line Treatment of Advanced Nasopharyngeal Carcinoma: A Systematic Review and Meta‐Analysis.
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Guven, Deniz Can, Stephen, Bettzy, Sahin, Taha Koray, Cakir, Ibrahim Yahya, and Aksoy, Sercan
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Objectives: Data regarding the clinical benefits of immune checkpoint inhibitors (ICIs) are limited in nasopharyngeal carcinoma (NPC). Therefore, we conducted a meta‐analysis of phase‐III clinical trials to evaluate the benefit of adding ICIs to chemotherapy in the first‐line treatment of advanced NPC. Methods: We conducted a systematic review using Web of Science, PubMed, and Embase for studies published until September 21, 2022. The meta‐analyses were performed with the generic inverse‐variance method with a random‐effects model. Hazard ratios (HRs) with 95% confidence interval (CI) for progression‐free survival (PFS) and overall survival (OS) were the principal summary measures. This protocol was registered in the PROSPERO database (registration number: CRD 42022361866). Results: Three eligible studies with a total of 815 patients were included. The addition of ICIs to standard chemotherapy significantly improved PFS (HR: 0.52, 95% CI: 0.43–0.63, p < 0.0001). Although the OS results were immature, ICIs significantly reduced the risk of death (HR: 0.63, 95% CI: 0.47–0.84, p = 0.0020). The benefit of ICIs was consistent regardless of initial disease presentation (recurrent or de novo), baseline EBV levels, PD‐L1 expression, and ECOG performance status. No significant difference in the rates of serious adverse events (HR = 0.98, 95% CI 0.74–1.30) was found between the two groups. Conclusion: The available evidence demonstrates that adding ICIs to chemotherapy in the first‐line treatment of advanced NPC provided better PFS with acceptable safety. However, a longer follow‐up is required to evaluate the true OS benefit of these combinations. Level of Evidence: NA Laryngoscope, 134:7–17, 2024 [ABSTRACT FROM AUTHOR]
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- 2024
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15. Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carcinoma
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Habra, Mouhammed Amir, Stephen, Bettzy, Campbell, Matthew, Hess, Kenneth, Tapia, Coya, Xu, Mingxuan, Rodon Ahnert, Jordi, Jimenez, Camilo, Lee, Jeffrey E., Perrier, Nancy D., Boraddus, Russell R., Pant, Shubham, Subbiah, Vivek, Hong, David S., Zarifa, Abdulrazzak, Fu, Siqing, Karp, Daniel D., Meric-Bernstam, Funda, and Naing, Aung
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- 2019
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16. Safety, tolerability, and clinical activity of selinexor in combination with pembrolizumab in treatment of metastatic non–small cell lung cancer.
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Altan, Mehmet, Tu, Janet, Milton, Denái R., Yilmaz, Bulent, Tian, Yanyan, Fossella, Frank V., Mott, Frank E., Blumenschein, George R., Stephen, Bettzy, Karp, Daniel D., Meric‐Bernstam, Funda, Heymach, John V., and Naing, Aung
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NON-small-cell lung carcinoma ,TUMOR suppressor proteins ,IMMUNE checkpoint inhibitors ,POISONS ,PEMBROLIZUMAB - Abstract
Background: In lung cancer, overexpression of nuclear export proteins can result in inactivation of critical tumor suppressor proteins and cell‐cycle regulators. Selective suppression of nuclear export proteins has immunomodulatory activities. Here, clinical safety and early efficacy data are presented on the combination of pembrolizumab and an oral selective nuclear export inhibitor, selinexor, for the treatment of metastatic non–small cell lung cancer (mNSCLC). Methods: The primary objective of this prospective investigator‐initiated study was to determine the safety and tolerability of selinexor in combination with pembrolizumab in patients with mNSCLC. Secondary objectives included determination of objective tumor response rate, disease control rate, and progression‐free survival duration. Results: A total of 17 patients were included in the final analysis. Fifteen (88%) received more than two lines of prior systemic therapy and 10 (59%) had prior exposure to anti–PD‐1/programmed death‐ligand 1 (PD‐L1) therapy. The median age was 67.5 years. Ten patients had grade ≥3 adverse events related to selinexor treatment. Responses to treatment occurred in patients who did and did not undergo previous anti–PD‐1/PD‐L1 therapy and in patients with activating driver mutations. The median overall survival and progression‐free survival were 11.4 months (95% CI, 3.4–19.8 months) and 3.0 months (95% CI, 1.7–5.7 months), respectively. The overall response rate was 18% and the 6‐month disease control rate was 24%. Conclusions: Selinexor in combination with pembrolizumab demonstrated promising antitumor activity in patients with mNSCLC, including those who had previously received anti–PD‐1/PD‐L1 therapy. The therapy‐related toxic effects were consistent with the prior safety data for both drugs, and no overlapping toxic effects were observed. Trial registration: ClinicalTrials.gov identifier: NCT02419495. Plain language summary: New strategies to prevent or reverse resistance to immune checkpoint inhibitors are under investigation. Selective inhibitors of nuclear export proteins, such as selinexor, can induce restoration of tumor‐suppressing pathways and induce potent immunomodulatory activities.This article contains the clinical safety and early efficacy data on the combination of pembrolizumab and selinexor in treatment of metastatic non–small cell lung cancer. New strategies to prevent or reverse resistance to immune checkpoint inhibitors are under investigation. This article contains the clinical safety and early efficacy data on the combination of pembrolizumab and the first‐in‐class oral selective nuclear export inhibitor selinexor in the treatment of metastatic non–small cell lung cancer. [ABSTRACT FROM AUTHOR]
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- 2023
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17. A Phase II Clinical Trial of Pembrolizumab Efficacy and Safety in Advanced Renal Medullary Carcinoma.
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Nze, Chijioke, Msaouel, Pavlos, Derbala, Mohamed H., Stephen, Bettzy, Abonofal, Abdulrahman, Meric-Bernstam, Funda, Tannir, Nizar M., and Naing, Aung
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THERAPEUTIC use of monoclonal antibodies ,THERAPEUTIC use of antineoplastic agents ,DRUG efficacy ,RENAL cell carcinoma ,DISEASE progression ,CANCER cells ,IMMUNE checkpoint inhibitors ,CLINICAL trials ,INFLAMMATION ,CANCER invasiveness ,ANTINEOPLASTIC agents ,LYMPHOCYTES ,RESEARCH funding ,PATIENT safety ,PHENOTYPES - Abstract
Simple Summary: Renal medullary carcinoma (RMC) is an aggressive type of kidney cancer. Traditional treatments have limited effectiveness, so new strategies are needed. Studies of RMC tissues found signs of inflammation, suggesting that immune checkpoint therapies could be a potential treatment option. In this study, we tested the effectiveness of pembrolizumab, an immune checkpoint inhibitor in a group of patients with RMC. Unfortunately, the results showed that pembrolizumab did not stop tumor growth. All the patients experienced rapid disease progression. One patient had such rapid progression that they had to stop the treatment less than a week after receiving pembrolizumab. In conclusion, this study demonstrated that pembrolizumab did not show any clinical benefits in patients with RMC. Background. Renal medullary carcinoma (RMC) is one of most aggressive renal cell carcinomas and novel therapeutic strategies are therefore needed. Recent comprehensive molecular and immune profiling of RMC tissues revealed a highly inflamed phenotype, suggesting the potential therapeutic role for immune checkpoint therapies. We present the first prospective evaluation of an immune checkpoint inhibitor in a cohort of patients with RMC. Methods. A cohort of patients with locally advanced or metastatic RMC was treated with pembrolizumab 200 mg intravenously every 21 days in a phase II basket trial (ClinicalTrials.gov: NCT02721732). Responses were assessed by irRECIST. Tumor tissues were evaluated for PD-L1 expression and for tumor-infiltrating lymphocyte (TIL) levels. Somatic mutations were assessed by targeted next-generation sequencing. Results. A total of five patients were treated. All patients had advanced disease, with the majority of patients (60%) having metastatic disease at diagnosis. All patients had rapid disease progression despite pembrolizumab treatment, with a median time to progression of 8.7 weeks. One patient (patient 5) experienced sudden clinical progression immediately after treatment initiation and was thus taken off trial less than one week after receiving pembrolizumab. Conclusions. This prospective evaluation showed no evidence of clinical activity for pembrolizumab in patients with RMC, irrespective of PD-L1 or TIL levels. [ABSTRACT FROM AUTHOR]
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- 2023
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18. Safety and Efficacy of Immune Checkpoint Inhibitors in Patients with Cancer and Viral Hepatitis: The MD Anderson Cancer Center Experience.
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Nardo, Mirella, Yilmaz, Bulent, Nelson, Blessie Elizabeth, Torres, Harrys A, Wang, Lan Sun, Granwehr, Bruno Palma, Song, Juhee, Pria, Hanna R F Dalla, Trinh, Van A, Oliva, Isabella C Glitza, Patel, Sapna P, Tannir, Nizar M, Kaseb, Ahmed Omar, Altan, Mehmet, Lee, Sunyoung S, Miller, Ethan, Zhang, Hao, Stephen, Bettzy A, and Naing, Aung
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DRUG efficacy ,HEPATITIS B ,PATIENT aftercare ,IMMUNE checkpoint inhibitors ,SPECIALTY hospitals ,CONFIDENCE intervals ,VIRAL hepatitis ,RETROSPECTIVE studies ,DISEASE incidence ,HEPATITIS C ,ANTIVIRAL agents ,TREATMENT duration ,CANCER treatment ,CANCER patients ,DESCRIPTIVE statistics ,RESEARCH funding ,TUMORS ,DRUG side effects ,PATIENT safety ,EVALUATION - Abstract
Background Despite the clinical benefit of immune checkpoint inhibitors (ICIs), patients with a viral hepatitis have been excluded from clinical trials because of safety concerns. The purpose of this study was to determine the incidence rate of adverse events (AEs) in patients with viral hepatitis who received ICIs for cancer treatment. Materials and Methods We conducted a retrospective study in patients with cancer and concurrent hepatitis B or C, who had undergone treatment with ICI at MD Anderson Cancer Center from January 1, 2010 to December 31, 2019. Results Of the 1076 patients screened, we identified 33 with concurrent hepatitis. All 10 patients with HBV underwent concomitant antiviral therapy during ICI treatment. Sixteen of the 23 patients with HCV received it before the initiation of ICI. The median follow-up time was 33 months (95% CI, 23-45) and the median duration of ICI therapy was 3 months (IQR, 1.9-6.6). Of the 33 patients, 12 (39%) experienced irAEs (immune-related adverse events) of any grade, with 2 (6%) having grade 3 or higher. None of the patients developed hepatitis toxicities. Conclusion ICIs may be a therapeutic option with an acceptable safety profile in patients with cancer and advanced liver disease. [ABSTRACT FROM AUTHOR]
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- 2023
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19. Incidence of infusion reactions to anti-neoplastic agents in early phase clinical trials: The MD Anderson Cancer Center experience
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Bupathi, Manojkumar, Hajjar, Joud, Bean, Stacie, Fu, Siqing, Hong, David, Karp, Daniel, Stephen, Bettzy, Hess, Kenneth, Meric-Bernstam, Funda, and Naing, Aung
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- 2017
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20. Phase I combination of pazopanib and everolimus in PIK3CA mutation positive/PTEN loss patients with advanced solid tumors refractory to standard therapy
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Rodrigues, Heloisa Veasey, Ke, Danxia, Lim, JoAnn, Stephen, Bettzy, Bellido, Jorge, Janku, Filip, Zinner, Ralph, Tsimberidou, Apostolia, Hong, David, Piha-Paul, Sarina, Fu, Siqing, Naing, Aung, Subbiah, Vivek, Karp, Daniel, Falchook, Gerald, Kurzrock, Razelle, and Wheler, Jennifer
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- 2015
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21. Clinical activity of checkpoint inhibitors in angiosarcoma: A retrospective cohort study.
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Ravi, Vinod, Subramaniam, Aparna, Zheng, Jing, Amini, Behrang, Trinh, Van A., Joseph, Jocelyn, Mennel, Robert G., Bishop, Andrew J., Sturgis, Erich M., Goepfert, Ryan P., Yalamanchili, Sudha, Botello, Gilberto, Stephen, Bettzy, Piha‐Paul, Sarina A., Patel, Anisha B., Lazar, Alexander J., Conley, Anthony P., Benjamin, Robert S., Patel, Shreyaskumar R., and Futreal, Phillip A.
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Background: Systemic treatments for angiosarcoma remains an area of unmet clinical need. The authors conducted this retrospective study to assess the clinical activity of checkpoint inhibitors in patients with angiosarcoma. The primary objective was to assess the objective response rate, and the secondary objective was to assess the progression-free and overall survival durations and disease control rate.Methods: Patient data were obtained using The University of Texas MD Anderson Cancer Center Tumor Registry database. The final study population was refined to only include patients who had undergone pembrolizumab monotherapy. The objective response rate was evaluated using RECIST/irRECIST version 1.1. Progression-free survival and overall survival were defined as the time from the initiation of immunotherapy to disease progression or recurrence, death, or last follow-up and to death or last follow-up, respectively.Results: The final cohort comprised 25 patients. Most patients had metastatic disease (72%) and had undergone at least two lines of systemic therapy (80%) before starting pembrolizumab. The objective response rate was 18%, whereas the disease control rate was 59%. The median progression-free survival duration was 6.2 months and was not significantly different between the cutaneous (4.7 months) and visceral angiosarcoma (6.2 months) groups (p = .42). The median overall survival duration was 72.6 months. Toxicities were recorded for eight patients, with fatigue, anemia, constipation, and rash being the most common.Conclusions: Pembrolizumab shows durable clinical activity in angiosarcoma. These findings suggest that checkpoint inhibition as monotherapy or combination therapy is likely to have a high probability of success.© 2022 American Cancer Society.Lay Summary: This is the largest retrospective study to assess the clinical activity of checkpoint inhibitor monotherapy in angiosarcomas. The study includes an adequate number of patients with visceral angiosarcoma that enabled to obtain meaningful clinical insights that were previously unavailable. Our findings indicate an improvement in progression-free survival with pembrolizumab that is comparable to other active agents in angiosarcoma. Pembrolizumab monotherapy in angiosarcomas also has a favorable tolerability profile. Our findings emphasize the need for prospective studies to evaluate the activity of pembrolizumab monotherapy and combination therapy. [ABSTRACT FROM AUTHOR]- Published
- 2022
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22. Clinical Outcomes of Patients with Recurrent Microsatellite-Stable Endometrial Cancer in Early-Phase Immunotherapy Clinical Trials.
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How, Jeffrey A., Jazaeri, Amir A., Fu, Siqing, Rodon Ahnert, Jordi, Gong, Jing, Stephen, Bettzy, Ferreira Dalla Pria, Hanna, Bhosale, Priya, Johnson, Amber, Yuan, Ying, Meric-Bernstam, Funda, and Naing, Aung
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THERAPEUTIC use of antineoplastic agents ,DRUG efficacy ,IMMUNE checkpoint inhibitors ,CLINICAL trials ,SPECIALTY hospitals ,CONFIDENCE intervals ,CANCER relapse ,RETROSPECTIVE studies ,ACQUISITION of data ,ANTINEOPLASTIC agents ,CANCER patients ,CANCER treatment ,COMPARATIVE studies ,ENDOMETRIAL tumors ,DESCRIPTIVE statistics ,MEDICAL records ,PROGRESSION-free survival ,IMMUNOTHERAPY ,LONGITUDINAL method ,EVALUATION - Abstract
Simple Summary: There is a crucial need to improve treatment regimens in patients with recurrent endometrial cancer. Although immunotherapy treatments have shown impressive benefit in microsatellite instability-high endometrial cancer, they have been less predictable in the majority of endometrial cancers, which are microsatellite stable. Our aim was to characterize clinical outcomes in patients with recurrent microsatellite stable endometrial cancer treated in early-phase immunotherapy clinical trials in order unravel treatment regimens that would improve response and survival. Our findings suggest that utilizing immunotherapy in combination with other non-immunotherapy agents resulted in greater duration of disease control and improved survival outcomes compared to immunotherapy only (monotherapy) or in combination with other immunotherapy agents. Future studies are needed to validate these findings. Recurrent microsatellite stable (MSS) endometrial cancer has poor response to conventional therapy and limited efficacy with immune checkpoint monotherapy. We conducted a retrospective study of recurrent MSS endometrial cancer patients enrolled in immunotherapy-based clinical trials at MD Anderson Cancer Center between 1 January 2010 and 31 December 2019. Patients were evaluated for radiologic response using RECIST 1.1 criteria, progression-free survival (PFS), and overall survival (OS). Thirty-five patients were treated with immune checkpoint inhibitors: 8 with monotherapy, 17 with immunotherapy (IO) in combination with another IO-only, and 10 with IO in combination with non-IO therapy. Among those treated with combination IO plus non-IO therapy, one had a partial response but 50% had clinical benefit. Patients who received combination IO plus non-IO therapy had improved PFS compared to those who received monotherapy (HR 0.56, 95% CI 0.33–0.97; p = 0.037) or combination IO-only therapy (HR 0.36, 95% CI 0.15–0.90; p = 0.028) and had improved OS when compared to monotherapy after adjusting for prior lines of therapy (HR 0.50, 95% CI 0.27–0.95; p = 0.036). The potential beneficial clinical outcomes of combination IO plus non-IO therapy in MSS endometrial cancer should be validated in a larger study. [ABSTRACT FROM AUTHOR]
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- 2022
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23. Exposure to anti‐PD‐1 causes functional differences in tumor‐infiltrating lymphocytes in rare solid tumors.
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Creasy, Caitlin A., Forget, Marie‐Andrée, Singh, Gopal, Tapia, Coya, Xu, Mingxuan, Stephen, Bettzy, Sabir, Sharjeel, Meric‐Bernstam, Funda, Haymaker, Cara, Bernatchez, Chantale, and Naing, Aung
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CORE needle biopsy ,LYMPHOCYTES ,TUMORS - Abstract
The pervasive use of therapeutic antibodies targeting programmed cell death protein 1 (PD‐1) to boost anti‐tumor immunity has positioned this approach to become the standard‐of‐care for some solid tumor malignancies. However, little is known as to how blockade of PD‐1 may alter the function or phenotype of tumor‐infiltrating lymphocytes (TIL). We used our ongoing Phase II clinical trial of pembrolizumab for patients with rare solid tumors from various types (NCT02721732) with matched core biopsies taken at baseline and after initial dose of anti‐PD‐1 (15–21 days post‐dose) to elucidate this question. One fresh core needle biopsy was used to propagate TIL ex vivo to analyze phenotype and function using flow cytometry in both CD8+ and CD4+ TIL populations. An enriched CTLA‐4 expression in the CD4+ TIL population was observed in TIL expanded from the on‐treatment samples compared to TIL expanded from the matched baseline (n = 22, p = 0.0007) but was not observed in patients who experienced tumor regression. Impact on functionality was evaluated by measuring secretion of 65 soluble factors by expanded TIL from 26 patients at baseline and on‐treatment. The CD8+ TIL population demonstrated a diminished cytokine secretion profile post‐pembrolizumab. Overall, our study assesses the ramifications of one dose of anti‐PD‐1 on TIL in rare solid tumor types. [ABSTRACT FROM AUTHOR]
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- 2019
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24. Radiomics to predict immunotherapy-induced pneumonitis: proof of concept.
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Colen, Rivka R., Fujii, Takeo, Bilen, Mehmet Asim, Kotrotsou, Aikaterini, Abrol, Srishti, Hess, Kenneth R., Hajjar, Joud, Suarez-Almazor, Maria E., Alshawa, Anas, Hong, David S., Giniebra-Camejo, Dunia, Stephen, Bettzy, Subbiah, Vivek, Sheshadri, Ajay, Mendoza, Tito, Fu, Siqing, Sharma, Padmanee, Meric-Bernstam, Funda, and Naing, Aung
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ALGORITHMS ,BIOMARKERS ,COMPUTED tomography ,IMMUNOTHERAPY ,PNEUMONIA ,PILOT projects ,TREATMENT effectiveness - Abstract
We present the first reported work that explores the potential of radiomics to predict patients who are at risk for developing immunotherapy-induced pneumonitis. Despite promising results with immunotherapies, immune-related adverse events (irAEs) are challenging. Although less common, pneumonitis is a potentially fatal irAE. Thus, early detection is critical for improving treatment outcomes; an urgent need to identify biomarkers that predict patients at risk for pneumonitis exists. Radiomics, an emerging field, is the automated extraction of high fidelity, high-dimensional imaging features from standard medical images and allows for comprehensive visualization and characterization of the tissue of interest and corresponding microenvironment. In this pilot study, we sought to determine whether radiomics has the potential to predict development of pneumonitis. We performed radiomic analyses using baseline chest computed tomography images of patients who did (N = 2) and did not (N = 30) develop immunotherapy-induced pneumonitis. We extracted 1860 radiomic features in each patient. Maximum relevance and minimum redundancy feature selection method, anomaly detection algorithm, and leave-one-out cross-validation identified radiomic features that were significantly different and predicted subsequent immunotherapy-induced pneumonitis (accuracy, 100% [p = 0.0033]). This study suggests that radiomic features can classify and predict those patients at baseline who will subsequently develop immunotherapy-induced pneumonitis, further enabling risk-stratification that will ultimately lead to better treatment outcomes. [ABSTRACT FROM AUTHOR]
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- 2018
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25. Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience.
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Fujii, Takeo, Colen, Rivka R., Bilen, Mehmet Asim, Hess, Kenneth R., Hajjar, Joud, Suarez-Almazor, Maria E., Alshawa, Anas, Hong, David S., Tsimberidou, Apostolia, Janku, Filip, Gong, Jing, Stephen, Bettzy, Subbiah, Vivek, Piha-Paul, Sarina A., Fu, Siqing, Sharma, Padmanee, Mendoza, Tito, Patel, Anisha, Thirumurthi, Selvi, and Sheshadri, Ajay
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TUMOR diagnosis ,TUMOR treatment ,TUMOR risk factors ,ADRENOCORTICAL hormones ,CANCER treatment ,CLINICAL trials ,IMMUNOTHERAPY ,SKIN inflammation ,TUMOR classification ,SPECIALTY hospitals ,TREATMENT effectiveness ,DISEASE incidence ,ENTEROCOLITIS ,THERAPEUTICS - Abstract
Background Immunotherapy is emerging as the cornerstone for treatment of patients with advanced cancer, but significant toxicity (immune-related adverse events [irAEs]) associated with unbridled T cell activity remains a concern. Patients and methods A retrospective review of the electronic medical records of 290 patients with advanced cancer treated on an immunotherapy-based clinical trial in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center between February 2010 and September 2015 was performed. Clinical and laboratory parameters were collected to determine the incidence of irAEs, risk factors, and their association with treatment outcomes. Results Ninety eight of 290 patients (34%) experienced any grade irAEs. Among the 15 (5.2%) patients with grade ≥ 3 irAEs, the most common irAEs were dermatitis and enterocolitis. Although 80% of the patients with grade ≥ 3 irAEs required systemic corticosteroids, all the 15 patients recovered from the irAEs. On re-challenge, 4 of the 5 patients who had received systemic corticosteroids for irAE continued to respond. There were no irAE-related deaths. Importantly, patients with grade ≥ 3 irAEs had improved overall response rate (25 vs. 6%; p = 0.039) and longer median time to progression (30 weeks vs. 10 weeks; p = 0.0040) when compared to those without grade ≥ 3 irAEs. Conclusion Incidence of irAEs with immunotherapeutic agents indicates an active immune status, suggestive of potential clinical benefit to the patient. Further validation of this association in a large prospective study is warranted. [ABSTRACT FROM AUTHOR]
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- 2018
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26. Phase II Clinical Trial of Pembrolizumab in Patients with Progressive Metastatic Pheochromocytomas and Paragangliomas.
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Jimenez, Camilo, Subbiah, Vivek, Stephen, Bettzy, Ma, Junsheng, Milton, Denai, Xu, Mingxuan, Zarifa, Abdualrazzak, Akhmedzhanov, Fechukwu Omolara, Tsimberidou, Apostolia, Habra, Mouhammed Amir, Rodon Anhert, Jordi, Fu, Siqing, and Naing, Aung
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THERAPEUTIC use of monoclonal antibodies ,CATECHOLAMINES ,CLINICAL trials ,CONFIDENCE intervals ,GERM cells ,METASTASIS ,GENETIC mutation ,PHEOCHROMOCYTOMA ,PARAGANGLIOMA ,MONONUCLEAR leukocytes ,ODDS ratio - Abstract
Metastatic pheochromocytomas and paragangliomas (MPPGs) are rare endocrine malignancies that are associated with high rates of morbidity and mortality because of their large tumor burden and location, progression, and release of catecholamines. Systemic therapies for MPPGs are limited. MPPGs are characterized by pseudohypoxia that may prevent immune system recognition. We conducted a phase II clinical trial of pembrolizumab in patients with progressive MPPGs. The primary endpoint was the non-progression rate at 27 weeks. The secondary endpoints included the objective response and clinical benefit rates, progression free and overall survival duration, and safety. We also determined whether PDL-1 expression and the presence of infiltrating mononuclear inflammatory cells in the primary tumor were associated with clinical response and hereditary background. Eleven patients were included in this trial, four (36%) with germline mutations and seven (64%) with hormonally active tumors. Four patients (40%, 95% confidence interval (CI) 12–74%) achieved the primary endpoint. The objective response rate was 9% (95% CI: 0–41%). The clinical benefit rate was 73% (95% CI: 39–94%). Four patients had grade 3 adverse events related to pembrolizumab. No patients experienced grade 4 or 5 adverse events or a catecholamine crisis. Progression free survival time was 5.7 months (95% CI: 4.37—not reached). The median survival duration was 19 months (95% CI: 9.9—not reached). PDL-1 expression and the presence of infiltrating mononuclear inflammatory cells in the primary tumor did not seem to be associated with disease response. Single-agent pembrolizumab has modest treatment efficacy in patients with progressive MPPGs. Positive responses seemed to be independent of patients' hereditary backgrounds, tumor hormonal status, and the presence of infiltrating mononuclear inflammatory cells or PDL-1 expression in the primary tumor. [ABSTRACT FROM AUTHOR]
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- 2020
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27. T-cell receptor beta variable gene polymorphism predicts immune-related adverse events during checkpoint blockade immunotherapy.
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Stephen B, Hajjar J, Sarda S, Duose DY, Conroy JM, Morrison C, Alshawa A, Xu M, Zarifa A, Patel SP, Yuan Y, Kwiatkowski E, Wang L, Rodon Ahnert J, Fu S, Meric-Bernstam F, Lowman GM, Looney T, and Naing A
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- Humans, Immune Checkpoint Inhibitors, Immunotherapy adverse effects, Receptors, Antigen, T-Cell, Autoimmune Diseases, Drug-Related Side Effects and Adverse Reactions
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Background: Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the past., Patients and Methods: We used a novel method for long-amplicon next generation sequencing of rearranged TCRB chains from peripheral blood total RNA to evaluate the link between TRBV polymorphisms and irAEs in patients treated with immunotherapy for cancer. We employed multiplex PCR to create amplicons spanning the three beta chain complementarity-determining regions (CDR) regions to enable detection of polymorphism within the germline-encoded framework and CDR1 and CDR2 regions in addition to CDR3 profiling. Resultant amplicons were sequenced via the Ion Torrent and TRBV allele profiles constructed for each individual was correlated with irAE annotations to identify haplotypes associated with severe irAEs (≥ grade 3)., Results: Our study included 81 patients who had irAEs when treated with immunotherapy for cancer. By using principal component analysis of the 81 TRBV allele profiles followed by k-means clustering, we identified six major TRBV haplotypes. Strikingly, we found that one-third of this cohort possessed a TRBV allele haplotype that appeared to be protective against severe irAEs., Conclusion: The data suggest that long-amplicon TCRB repertoire sequencing can potentially identify TRBV haplotype groups that correlate with the risk of severe irAEs. Germline-encoded TRBV polymorphisms may serve as a predictive biomarker of severe irAEs., Competing Interests: Competing interests: TL was employed as a research scientist by Thermo Fisher Scientific during the time of study. JH declares research funding from The Texas Medical Center Digestive Diseases Center, Jeffery Modell Foundation, Immune Deficiency Foundation, Baxalta US Inc, Chao Physician-Scientist Foundation, is Consultant/Advisory board: Takeda, Pharming Healthcare Inc, and Horizon Therapeutics USA, Inc. and Ad hoc consultancy speaker: Alfaisal University. SS is a full-time employee of Thermo Fisher Scientific, Inc. DYD received honorarium from Chrysalis Biomedical. JMC is an employee of OmniSeq and shareholder of Labcorp. SPP declares institutional funding for clinical trial from NCI, Bristol Myers Squibb, Novartis, Consulting fees: Immunocore; Payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events: Delcath (non-promotional), Merck & Co (non-promotional), Support for attending meetings and/or travel: Merck & Co, Cardinal Health, TriSalus LifeSciences, Participation on a Data Safety Monitoring Board or Advisory Board: Reata, Immunocore, Immatics, Bristol Myers Squibb, Cardinal Health, Castle Biosciences, Delcath, Novartis, Stock or stock options: Pfizer, Amgen. YY reports personal fees from AbbVie, personal fees from Amgen, personal fees from Bexion Pharmaceuticals, personal fees from BeyondSpring Pharmaceuticals, personal fees from Boehringer Ingelheim Pharmaceuticals, personal fees from Bristol Myers Squibb, personal fees from Century Therapeutics, personal fees from Enliven Therapeutics, personal fees from Repare Therapeutics, personal fees from Servier Pharmaceuticals, personal fees from Starpax Pharmaceuticals, personal fees from Vertex Pharmaceuticals, during the conduct of the study. JRA is on the advisory board of Peptomyc, Kelun Pharmaceuticals/Klus Pharma, Ellipses Pharma, Molecular Partners, IONCTURA, declares research funding (to institution): Blueprint Medicines, Black Diamond Therapeutics, Merck Sharp & Dohme, Hummingbird, Yingli, Vall d'Hebron Institute of Oncology/Cancer Core Europe, clinical research (to institution): Novartis, Spectrum Pharmaceuticals, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GalxoSmithKline, Taiho, Roche Pharmaceuticals, Hummingbird, Yingli, Bycicle Therapeutics, Merus, Curis, Bayer, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Hutchinson MediPharma, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati Linnaeus Therapeutics, travel reimbursement: European Society for Medical Oncology and Other: Vall d'Hebron Institute of Oncology/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC. SF receives Clinical Trial Research Support/Grant Funding through the institution from the following sources: NIH/NCI P30CA016672 – Core Grant (CCSG Shared Resources); Abbisko; BeiGene; BioAtla, LLC.; Boehringer Ingelheim; CUE Biopharma, Inc.; Eli Lilly & Co.; Exelisis; Greenfire Bio, Inc.; Hookipa Biotech; IMV, Inc.; Innovent Biologics, Co., Ltd.; K-Group Beta; Lyvgen Biopharm, Co., Ltd.; MacroGenics; MediLink Therapeutics, Co. Ltd.; Millennium Pharmaceuticals, Inc.; Nerviano Medical Sciences; NeuPharma, Inc.; NextCure, Inc.; Ningbo NewBay Technology Development Co., Ltd.; Novartis; NovoCure; Nykode Therapeutics AS.; Parexel International, LLC; Pionyr Immunotherapeutics, Inc.; PureTech Health, LLC; Sellas Life Sciences Group; Soricimed Biopharma, Inc.; SQZ Biotechnologies; Sumitomo Dainippon; Taiho Oncology and NCCN; Treadwell Therapeutics; Turnstone Biologics; Tyligand Bioscience, Ltd.; Virogin Biotech, Ltd. FM-B (36 months) declares: consulting <5,000/year: AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, Daiichi Sankyo Co. Ltd., DebioPharm, Ecor1 Capital, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., GT Apeiron, Genentech Inc., Harbinger Health, IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, Menarini Group, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Protai Bio Ltd, Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks, advisory committee <5,000/year: Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Sanofi, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis, sponsored research (to the institution): Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co., honoraria <5,000/year: Chugai Biopharmaceuticals, and other (travel related): none. GML is an employee/shareholder of Thermo Fisher Scientific. AN declares research funding from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor/Millendo, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol-Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, Immune-Onc Therapeutics, Surface Oncology, Monopteros Therapeutics, BioNTech SE, Seven & Eight Biopharma, and SOTIO Biotech AG, on advisory board/Consulting fees from Deka Biosciences, NGM Bio, PsiOxus Therapeutics, Immune-Onc Therapeutics, STCube Pharmaceuticals, OncoSec KEYNOTE-695, Genome & Company, CytomX Therapeutics, Nouscom, Merck Sharp & Dohme Corp, OncoNano, Servier, Lynx Health, AbbVie, PsiOxus, received travel and accommodation expense from ARMO BioSciences, NeoImmuneTech and honoraria for speaking engagements from AKH Inc, The Lynx Group, Society for Immunotherapy of Cancer (SITC), Korean Society of Medical Oncology (KSMO), Scripps Cancer Care Symposium, ASCO Direct Oncology Highlights, European Society for Medical Oncology (ESMO), CME Outfitters. All remaining authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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28. Targeting Cancer Metabolism to Improve Outcomes with Immune Checkpoint Inhibitors.
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Fatima Z, Abonofal A, and Stephen B
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Immune checkpoint inhibitors have revolutionized the treatment paradigm of several cancers. However, not all patients respond to treatment. Tumor cells reprogram metabolic pathways to facilitate growth and proliferation. This shift in metabolic pathways creates fierce competition with immune cells for nutrients in the tumor microenvironment and generates by-products harmful for immune cell differentiation and growth. In this review, we discuss these metabolic alterations and the current therapeutic strategies to mitigate these alterations to metabolic pathways that can be used in combination with checkpoint blockade to offer a new path forward in cancer management., Competing Interests: Conflict of Interest: None., (© 2023.)
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- 2023
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29. Spectrum of Immune Checkpoint Inhibitor Anemias: Results From a Single Center, Early-Phase Clinical Trials Case Series Experience.
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Nelson BE, Ejezie CL, Stephen BA, Nardo M, Campbell E, Gong J, Hong DS, Fu S, Yap TA, Murphy MB, Piha-Paul S, Daver NG, Rojas-Hernandez CM, and Naing A
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Immune checkpoint inhibitor anemias (ICI-A) are a rare entity which can be potentially life-threatening without prompt identification. The goal of the study is to characterize the presentation, evaluation, and outcomes of ICI therapy in early phase clinical trial setting to guide future research and to develop standardized care guidelines. Retrospective chart review of 333 patients who participated in early phase clinical trials at the University of Texas MD Anderson Cancer Center revealed four cases with ICI-A between 2016 and 2020. We identified a spectrum of four cases which included ICI-related autoimmune hemolytic anemias, hemophagocytic lymphohistiocytosis and thrombotic microangiopathy as a result of combinatory investigational therapies involving ICI. Patient presentation, evaluation, bone marrow pathology, interventions, and clinical course were reviewed. The median time to onset of hematological immune-related adverse events (heme-irAEs) in this retrospective series was 3.5 weeks (2 - 6 weeks). One patient had pre-existing untreated chronic lymphocytic leukemia. Glucocorticoids are an effective first-line treatment in most patients although most patients were not rechallenged but successfully had complete recovery and pursued further non-immunotherapy-based therapies. Cognizance of ICI-A in clinical trial setting is paramount to early recognition of heme-irAEs. Further research is needed to identify and stratify risk factors during clinical trial enrollment and optimal management strategies for immune-mediated hematologic toxicities., Competing Interests: BEN, CLE, MN and MBM have no interests declared. TAY received research funding (paid to his institution) from Artios, AstraZeneca, Bayer, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, ImmuneSensor, Ipsen, Jounce, Karyopharm, Kyowa, Merck, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, and Vertex Pharmaceuticals. In addition, he has received fees for consulting with Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, F-Star, Guidepoint, Ignyta, I-Mab, Jansen, Merck, Pfizer, Repare, Roche, Rubius, Schrodinger, Seattle Genetics, Varian, and Zai Labs. CMRH received research funding from Daichii Sankyo pharmaceuticals and Aspen pharmaceuticals. AN reports research funding from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Kymab, PsiOxus, Immune Deficiency Foundation (Spouse), Advisory board: CytomX Therapeutics, Novartis, Kymab, Genome. Travel and accommodation expenses: ARMO BioSciences. SPP reports research funding through the institution: AbbVie, Inc., ABM therapeutics, Inc., Acepodia, Inc., Alkermes, Inc., Aminex Therapeutics, Amphivena Therapeutics, Inc., BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol Myers Squib, Chugai Pharmaceutical Co., Ltd., Daichi Sankyo, Inc., Eli Lilly, Five Prime Therapeutics, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., Medimmune, LLC., Medivation, Inc., Merck Sharp and Dohme Corp., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Principia Biopharma, Inc., Puma Biotechnology, Inc., Rapt Therapeutics, Inc., Seattle Genetics, Taiho Oncology, Tesaro, Inc., TransThera Bio. DSH reports research funding from AbbVie, Adaptimmune, Aldi-Norte, Amgen, Astra-Zeneca, Bayer, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, GSK, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, miRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, Takeda, Turning Point Therapeutics. Travel, Accommodations, Expenses: Bayer, LOXO, miRNA, Genmab, AACR, ASCO, SITC. Consulting or Advisory Role: Alpha Insights, Amgen, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Prime Oncology, Seattle Genetics, Takeda, Trieza Therapeutics, WebMD. Other ownership interests: Molecular Match (Advisor), OncoResponse (Founder), Presagia Inc (Advisor). SF reports research funding from AstraZeneca, Abbisko, Anaeropharma Science, Arrien Pharmaceuticals, BeiGene, BioAtla, LLC, Boehringer Ingelheim, Eli Lilly & Co., Hookipa Biotech, Huya Bioscience International, IMV, Inc., Innovent Biologics, Co., Ltd., Lyvgen Biopharm, Co., Ltd., MacroGenics, Medivir AB, Millennium Pharmaceuticals, Inc., Nerviano Medical Sciences, NeuPharma, inc., Novartis, OncoMed Pharmaceuticals, Parexel International, LLC, Sellas Life Sciences Group, Soricimed Biopharma, Inc., Tolero Pharmaceuticals, NovoCure, Turnstone Biologics, Taiho Oncology, Abbisko (other). NGD receives honoraria from BMS, Jazz Pharmaceuticals, Novartis, Incyte, Otsuka, Immunogen, Pfizer, Astellas Pharma, AbbVie. His consulting or advisory role includes Celgene, Agios, Jazz Pharmaceuticals, Pfizer, AbbVie, Astellas Pharma, Daiichi Sankyo, Novartis, Bristol Myers Squibb, Otsuka, Incyte, Karyopharm Therapeutics, Sunesis Pharmaceuticals, Amgen, Immunogen, Genentech, Servier, Syndax, Trillium Therapeutics. His research funding includes Bristol Myers Squibb, Pfizer, Immunogen, Genentech, Nohla Therapeutics, AbbVie, Astellas Pharma, Servier, Daiichi Sankyo, Novartis, Karyopharm Therapeutics, Incyte, Sunesis Pharmaceuticals, Sobi., (Copyright 2022, Nelson et al.)
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- 2022
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30. Efficacy of pembrolizumab in patients with advanced cancer of unknown primary (CUP): a phase 2 non-randomized clinical trial.
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Raghav KP, Stephen B, Karp DD, Piha-Paul SA, Hong DS, Jain D, Chudy Onwugaje DO, Abonofal A, Willett AF, Overman M, Smaglo B, Huey RW, Meric-Bernstam F, Varadhachary GR, and Naing A
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- Adult, Antibodies, Monoclonal, Humanized pharmacology, Antibodies, Monoclonal, Humanized therapeutic use, Humans, Progression-Free Survival, B7-H1 Antigen, Neoplasms, Unknown Primary drug therapy
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Background: Cancer of unknown primary (CUP) is an aggressive rare malignancy with limited treatment options. Data regarding clinical activity of immune checkpoint inhibitors in CUP is lacking. Therefore, we evaluated the efficacy of pembrolizumab, a programmed cell death-1 inhibitor, in patients with CUP., Methods: The study was designed as a phase 2 basket trial for independent rare tumor cohorts including CUP. Adult patients with CUP who had progressed on previous systemic therapy, performance status 0/1 and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST V.1.1) were eligible. Patients received pembrolizumab (200 mg) intravenously every 21 days. Twenty-nine patients were enrolled and treated between August 2016 and June 2020. The primary endpoint was non-progression rate (NPR) at 27 weeks (NPR-27) per immune-related RECIST. Key prespecified secondary endpoints were confirmed objective response rate (ORR), safety, duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Pretreatment biopsies were examined for biomarkers of response (programmed cell death ligand-1 (PD-L1) expression and tumor infiltrating lymphocytes (TILs))., Results: Among 25 (of 29 enrolled) eligible and evaluable patients, 14 (56%) had poorly differentiated carcinoma. Patients received a median of two lines of therapy prior to enrollment. Median follow-up was 27.3 months. NPR-27 was observed in seven patients (28.0% (95% CI: 12.1 to 49.4)). ORR was 20.0% (95% CI: 6.8 to 40.7) with five patients achieving immune-related partial response with median DoR of 14.7 months (95% CI: 9.8 to 19.6). Median PFS and OS were 4.1 (95% CI: 3.1 to 5.1) and 11.3 (95% CI: 5.5 to 17.1) months, respectively. Treatment-related adverse events of any and grade ≥3 were seen in 19 (76%) and 4 (16%) patients, respectively. One (4%) patient had grade 3 immune-related acute kidney injury requiring treatment discontinuation. Neither PD-L1 nor TILs were associated with NPR-27. Both positive PD-L1 staining (44.4% vs 6.3%; p=0.040) and intense TIL infiltration (44.4% vs 6.3%; p=0.040) were associated with response., Conclusion: Pembrolizumab showed encouraging efficacy in patients with CUP with acceptable safety profile., Trial Registration Number: NCT02721732., Competing Interests: Competing interests: KPR reports research support from Bayer, AstraZeneca, and Daiichi outside the submitted work; SAP-P reports research support from AbbVie, ABM Therapeutics, Acepodia, Alkermes, Aminex Therapeutics, Amphivena Therapeutics, BioMarin Pharmaceutical, Boehringer Ingelheim, Bristol Myers Squibb, Cerulean Pharma, Chugai Pharmaceutical Co., Curis, Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, Gene Quantum, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp., Incyte Corp., Jacobio Pharmaceuticals Co., Medimmune, LLC., Medivation, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Pfizer; Principia Biopharma, Puma Biotechnology, Rapt Therapeutics, Seattle Genetics, Silverback Therapeutics, Taiho Oncology, Tesaro, TransThera Bio, NCI/NIH, P30CA016672 – Core Grant (CCSG Shared Resources) outside the submitted work; DSH reports research support from AbbVie, Adaptimmune, Adlai Nortye, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daichi-Sankyo, Eisai, Eli Lilly, EMD Sereno, Erasca, Fate Therapeutics, Genentech, Genmab, GlaxoSmithKline, Ignyta, Infinity, Kite, Kyowa, LOXO, Merck, MedImmune, Millenium, Mirati, miRNA, Molecular TeMpLaTeS, Mologen, NaVier, nci-cep, Novartis, Numab, Pfizer, Seattle Genetics, Takeda, Turning Point, Vernstam, VM Oncology, and other support from Adaptimmune, Amgen, AstraZeneca, Bayer, Genentech, GlaxoSmithKline, Infinity, Numab, Pfizer, Seattle Genetics, Alpha Insights, Acuta, Axiom, Baxter, Boxer Capital, COG, Ecor1, GLG, Group H, Guidepoint, HCW Precision, Janssen, Merrimack, Medscape, Prime Oncology, STCube, Tavistock, Trieza Therapeutics, Molecular Match, Oncoresponse, Presagia, AACR, ASCO, Celgene, Eli Lilly, SITC, and Phillips, outside of the submitted work; MO reports research support from Merck Sharp & Dohme Corp, AbbVie, Agilvax, Takeda Pharmaceuticals (Japan), Acrotech Biopharma, Janssen Research & Development LLC, Pfizer outside the submitted work; FM-B reports research support from Aileron Therapeutics, AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Curis, CytomX Therapeutics, Daiichi Sankyo Co., Debiopharm International, eFFECTOR Therapeutics, Genentech, Guardant Health, Klus Pharma, Millennium Pharmaceuticals, Novartis, Puma Biotechnology, Taiho Pharmaceutical Co.; consulting fees from Aduro BioTech, Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche, Genentech, IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer, Samsung Bioepis, Seattle Genetics, Tyra Biosciences, Xencor, Zymeworks; has served on advisory committees for Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology, Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis; receives honoraria from Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey; and support for travel and accommodation from Beth Israel Deaconess Medical Center outside the submitted work; AN reports research support from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor/Millendo, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera BioSciences, TopAlliance BioSciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, and Surface Oncology, non-financial support for travel and accommodation from ARMO BioSciences, has served as an advisory board member for Novartis, CytomX Therapeutics, Genome and Company, STCube Pharmaceuticals, OncoSec KEYNOTE-695, and Kymab, reports research funding for his spouse from Immune Deficiency Foundation, Jeffery Modell Foundation and chao physician-scientist, and Baxalta, and his spouse has served as an advisory board member for Takeda, CSL, Behring, Horizon, and Pharming outside the submitted work. BSt, DDK, DJ, DOCO, AA, AFW, BSm, RWH, GRV declare no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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31. Selinexor in Combination with Carboplatin and Pemetrexed in Patients with Advanced or Metastatic Solid Tumors: Results of an Open-Label, Single-Center, Multi-Arm Phase 1b Study.
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Thein KZ, Fu S, Janku F, Tsimberidou AM, Piha-Paul SA, Karp DD, Shah J, Milton DR, Gong J, Sulovic S, McQuinn L, Stephen BA, Colen RR, Carter BW, Meric-Bernstam F, and Naing A
- Abstract
Competing Interests: Conflict of Interest: Aung Naing reports the following: research funding from NCI, EMD Serono, MedImmune, Healios Inc. Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, BMS, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Kymab, PsiOxus, Arcus Biosciences, NeoimmuneTech, ImmuneOncia, Surface Oncology; on advisory boards of CytomX Therapeutics, Novartis, Genome & Company, OncoSec KEYNOTE-695, and STCube; travel and accommodation expense from ARMO BioSciences. Jatin Shah is an employee of and stockholder of Karyopharm Therapuetics. The remaining authors have declared that they have no conflicts of interest.
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- 2022
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32. Author response to Cunha et al .
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Colen RR, Rolfo C, Ak M, Ayoub M, Ahmed S, Elshafeey N, Mamindla P, Zinn PO, Ng C, Vikram R, Bakas S, Peterson CB, Rodon Ahnert J, Subbiah V, Karp DD, Stephen B, Hajjar J, and Naing A
- Subjects
- Humans, Retrospective Studies
- Abstract
The need to identify biomarkers to predict immunotherapy response for rare cancers has been long overdue. We aimed to study this in our paper, 'Radiomics analysis for predicting pembrolizumab response in patients with advanced rare cancers'. In this response to the Letter to the Editor by Cunha et al , we explain and discuss the reasons behind choosing LASSO (Least Absolute Shrinkage and Selection Operator) and XGBoost (eXtreme Gradient Boosting) with LOOCV (Leave-One-Out Cross-Validation) as the feature selection and classifier method, respectively for our radiomics models. Also, we highlight what care was taken to avoid any overfitting on the models. Further, we checked for the multicollinearity of the features. Additionally, we performed 10-fold cross-validation instead of LOOCV to see the predictive performance of our radiomics models., Competing Interests: Competing interests: CN reports grant support and personal fees from General Electric Healthcare, outside the submitted work; SB reports grant support from National Institutes of Health, outside the submitted work; JRA reports personal fees from Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharma, Peptomyc, and Merck Sharpe, on the advisory board for Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharma, Peptomyc, Merck Sharpe and Dome, Kelun Pharma/Klus Pharma, Pfizer, Roche Pharma, and Elipses Pharma, research funding from Bayer, Novartis, Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, KELUN-BIOTECH, Takeda-Millenium, GLAXOSMITHKLINE, and Ipsen, from null, outside the submitted work; VS reports clinical trial research funding from Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, Loxo oncology, Takeda and Roche/ Genentech, National Comprehensive Cancer Network, NCI-CTEP, and UT MD Anderson Cancer Center, outside the submitted work; JH reports grants from Immune Deficiency Foundation, Jeffrey Modell Foundation and Chao Physician-Scientist, and Baxalta, and has served as an advisory board member for Takeda, CSL Behring, and Horizon Pharma outside the submitted work; AN reports research support and non-financial support from Merck Sharp and Dohme, grants from NCI/NIH, research support from the University of Texas MD Anderson Cancer Center, during the conduct of the study; grants from NCI, research support from EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera BioSciences, TopAlliance BioSciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, and Surface Oncology, non-financial support for travel and accommodation from ARMO BioSciences, and has served as an advisory board member for Novartis, CytomX Therapeutics, Genome and Company, STCube Pharmaceuticals, OncoSec KEYNOTE-695, and Kymab, outside the submitted work. RRC, CR, MAk, MAyoub, SA, NE, PM, POZ, RV, CP, BS, and DDK declare no competing interests., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2021
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33. Implementation of a Novel Web-Based Lesion Selection Tool to Improve Acquisition of Tumor Biopsy Specimens.
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Xu M, Tapia C, Hajjar J, Sabir S, Colen R, Nagarajan P, Aung PP, Gong J, Rodon J, Fu S, Stephen B, Roy-Chowdhuri S, Le H, Yang V, Zarifa A, Abdelsalam ME, Jhingran A, Javle M, Pant S, Carter B, Milton DR, Sun R, Karp DD, Koay EJ, Yang Y, Wistuba II, Hwu P, Meric-Bernstam F, and Naing A
- Abstract
Introduction: For maximum utility of molecular characterization by next-generation sequencing (NGS) and better understanding of tumor microenvironment with immune correlates analysis, biopsy specimens must yield adequate tumor tissue, and sequential biopsy specimens should sample a consistent site. We developed a web-based lesion selection tool (LST) that enables management and tracking of the biopsy specimen collections., Methods: Of 145 patients, the LST was used for 88 patients; the other 57 served as controls. We evaluated consistency of the lesion biopsied in longitudinal collections, number of cores obtained, and cores with adequate tumor cellularity for NGS. The Fisher exact test and Wilcoxon rank sum test were used to identify differences between the groups., Results: The analysis included 30 of 88 (34%) patients in the LST group and 52 of 57 (91%) in the control group. The LST workflow ensured 100% consistency in the lesions biopsied compared with 75% in the control group in longitudinal collections and increased the proportion of patients in whom at least five cores were collected per biopsy., Conclusions: The novel LST platform facilitates coordination, performance, and management of longitudinal biopsy specimens. Use of the LST enables sampling of the designated lesion consistently, which is likely to accurately inform us the effect of the treatment on tumor microenvironment and evolution of resistant pathways. Such studies are important translational component of any clinical trials and research as they guide the development of next line of therapy, which has significant effect on clinical utility. However, validation of this approach in a larger study is warranted., Competing Interests: Conflict of Interest: None., (© Innovative Healthcare Institute 2021.)
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- 2021
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34. Radiomics analysis for predicting pembrolizumab response in patients with advanced rare cancers.
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Colen RR, Rolfo C, Ak M, Ayoub M, Ahmed S, Elshafeey N, Mamindla P, Zinn PO, Ng C, Vikram R, Bakas S, Peterson CB, Rodon Ahnert J, Subbiah V, Karp DD, Stephen B, Hajjar J, and Naing A
- Subjects
- Adult, Aged, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Agents, Immunological adverse effects, Clinical Decision-Making, Clinical Trials, Phase II as Topic, Disease Progression, Female, Humans, Immune Checkpoint Inhibitors adverse effects, Male, Middle Aged, Patient Selection, Predictive Value of Tests, Response Evaluation Criteria in Solid Tumors, Retrospective Studies, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, Young Adult, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents, Immunological therapeutic use, Immune Checkpoint Inhibitors therapeutic use, Neoplasms diagnostic imaging, Neoplasms drug therapy, Radiographic Image Interpretation, Computer-Assisted, Rare Diseases diagnostic imaging, Rare Diseases drug therapy, Tomography, X-Ray Computed
- Abstract
Background: We present a radiomics-based model for predicting response to pembrolizumab in patients with advanced rare cancers., Methods: The study included 57 patients with advanced rare cancers who were enrolled in our phase II clinical trial of pembrolizumab. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related RECIST (irRECIST). Patients were categorized as 20 "controlled disease" (stable disease, partial response, or complete response) or 37 progressive disease). We used 3D-slicer to segment target lesions on standard-of-care, pretreatment contrast enhanced CT scans. We extracted 610 features (10 histogram-based features and 600 second-order texture features) from each volume of interest. Least absolute shrinkage and selection operator logistic regression was used to detect the most discriminatory features. Selected features were used to create a classification model, using XGBoost, for the prediction of tumor response to pembrolizumab. Leave-one-out cross-validation was performed to assess model performance., Findings: The 10 most relevant radiomics features were selected; XGBoost-based classification successfully differentiated between controlled disease (complete response, partial response, stable disease) and progressive disease with high accuracy, sensitivity, and specificity in patients assessed by RECIST (94.7%, 97.3%, and 90%, respectively; p<0.001) and in patients assessed by irRECIST (94.7%, 93.9%, and 95.8%, respectively; p<0.001). Additionally, the common features of the RECIST and irRECIST groups also highly predicted pembrolizumab response with accuracy, sensitivity, specificity, and p value of 94.7%, 97%, 90%, p<0.001% and 96%, 96%, 95%, p<0.001, respectively., Conclusion: Our radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer., Interpretation: Our radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer., Competing Interests: Competing interests: CN reports grant support and personal fees from General Electric Healthcare, outside the submitted work. SB reports grant support from National Institutes of Health, outside the submitted work. JRA reports personal fees from Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharma, Peptomyc, and Merck Sharpe, on the advisory board for Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharma, Peptomyc, Merck Sharpe & Dome, Kelun Pharma/Klus Pharma, Pfizer, Roche Pharma, and Elipses Pharma, research funding from Bayer, Novartis, Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, KELUN-BIOTECH, Takeda-Millenium, GLAXOSMITHKLINE, Ipsen, from null, outside the submitted work. VS reports clinical trial research funding from Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, Loxo oncology, Takeda and Roche/ Genentech, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, outside the submitted work. JH reports grants from Immune Deficiency Foundation, Jeffery Modell Foundatoin and Chao Physician-Scientist, and Baxalta, and has served as an advisory board member for Takeda, CSL Behring, and Horizn Pharma outside the submitted work. AN reports research support and non-financial support from Merck Sharp & Dohme Corp., grants from NCI/NIH, research support from The University of Texas MD Anderson Cancer Center, during the conduct of the study; grants from NCI, research support from EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera BioSciences, TopAlliance BioSciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, and Surface Oncology, non-financial support for travel and accommodation from ARMO BioSciences, and has served as an advisory board member for Novartis, CytomX Therapeutics, Genome and Company, STCube Pharmaceuticals, OncoSec KEYNOTE-695, and Kymab outside the submitted work. RRC, CR, MAk, MAyoub, SA, NE, PM, POZ, RV, CP, BS, DDK declare no competing interests., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2021
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35. Immune System in Action.
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Stephen B and Hajjar J
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- Humans, Immunologic Surveillance, Killer Cells, Natural, Neutrophils, Neoplasms therapy, Tumor Microenvironment
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Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells is found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and the crosstalk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter, we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)
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- 2021
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36. Evaluating the psychometric properties of the Immunotherapy module of the MD Anderson Symptom Inventory.
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Mendoza T, Sheshadri A, Altan M, Hess K, George G, Stephen B, Castillo L, Rodriguez E, Gong J, Peterson C, Rodon Ahnert J, Fu S, Piha-Paul SA, Pant S, Dumbrava E, Yap TA, Janku F, Tsimberidou AM, Subbiah V, Karp DD, Zarifa A, McQuinn LM, Cleeland C, Hong DS, and Naing A
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- Female, Humans, Male, Prospective Studies, Texas, United States, Immunotherapy methods, Psychometrics methods, Severity of Illness Index
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Introduction: Immunotherapies have revolutionized the treatment of various cancers, but little is known about their symptomatic toxicity. Assessing these symptoms is best accomplished by asking the patients themselves. However, such reports are subjective and may face challenges as bonafide scientific data. Demonstrating the validity of symptom assessment tools, mainly through the reduction of measurement errors, has the potential to improve patient care if these tools are widely adopted. To that end, we present herein the psychometric properties of the Immunotherapy for Early-Phase Trials module of the MD Anderson Symptom Inventory (MDASI-Immunotherapy EPT) in patients receiving various immunotherapies in early phase trials at a major cancer center., Methods: One hundred forty-five patients completed the inventory at baseline, with 85 of them also doing so after 9 weeks of treatment. The mean (±SD) age of the patients was 57.0±12.9 years. Also, 56% of the patients were women, 79% identified as white, and 49% had at least some college education., Results: The internal consistency reliability of the MDASI-Immunotherapy EPT was excellent, as the Cronbach's alphas for all of its subscales were at least 0.88 (range 0.88-0.95). Known-group validity based on Eastern Cooperative Oncology Group performance status groupings was excellent at 9 weeks after the start of an immunotherapy trial for the MDASI-Immunotherapy EPT severity (effect size, 0.96) and interference (effect size, 0.82) subscales. We found substantial changes in the symptom items difficulty remembering (effect size, -0.85), fever and/or chills (effect size, -0.63), disturbed sleep (effect size, -0.52), diarrhea (effect size, -0.42), and swelling of hands, legs, or feet (effect size, -0.39)., Conclusions: In conclusion, the MDASI-Immunotherapy EPT is a valid, reliable, and sensitive tool for measuring symptomatic toxicity., Competing Interests: Competing interests: The MD Anderson Symptom Inventory and its derivative versions are copyrighted and licensed by The University of Texas MD Anderson Cancer Center and CC. CC has a financial interest in the MDASI and its derivative versions., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2020
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37. Decrease in tumor content assessed in biopsies is associated with improved treatment outcome response to pembrolizumab in patients with rare tumors.
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Tapia C, Aung PP, Roy-Chowdhuri S, Xu M, Ouyang F, Alshawa A, Hajjar J, Singh G, Yang V, Castillo L, Le H, Murthy R, Stephen B, Hess KR, Wistuba I, and Naing A
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- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Agents, Immunological adverse effects, Biopsy, Disease Progression, Female, Humans, Male, Middle Aged, Neoplasms drug therapy, Neoplasms immunology, Neoplasms pathology, Prognosis, Rare Diseases drug therapy, Rare Diseases immunology, Rare Diseases pathology, Treatment Outcome, Young Adult, Antibodies, Monoclonal, Humanized administration & dosage, Antineoplastic Agents, Immunological administration & dosage, Biomarkers, Tumor analysis, Neoplasms diagnosis, Rare Diseases diagnosis
- Abstract
Background: Decreased tumor content (TC) in resection specimens after neoadjuvant therapy is used to predict prognosis. We investigated whether TC assessed in biopsy specimens or the shift in TC from baseline to on-treatment can be used accordingly to predict response in patients with rare tumors who were treated with pembrolizumab., Methods: A total of 57 tumors (represented by 173 baseline and 179 on-treatment biopsies) from 57 patients with rare tumors participating in an ongoing phase II clinical trial of pembrolizumab were evaluated. TC was estimated on H&E-stained slides and tumors were dichotomized into low and high TC according to a cut-off of 10%. Necrosis, proliferative fibrosis (PF) and normal tissue were assessed in on-treatment biopsies. TC at baseline and on-treatment, as well as the shift in TC from baseline to on-treatment, was correlated with clinical response defined according to Response Evaluation Criteria in Solid Tumors., Results: A decrease in TC was seen in 14% (n=8); no change in TC was seen in 75% (n=43); and an increase in TC from baseline to on-treatment was seen in 11% (n=6). Objective response was significantly associated with decrease in TC from baseline to on-treatment (38%, 3/8) compared with no change/increase in TC (6%, 3/49) (p=0.031). Patients with a decrease in TC had a significantly increased time to progression (TTP) (75% probability) compared with patients with an increase (20% probability) or no change in TC (19% probability) (p=0.0042). Low TC was seen in 23% (13/57) of the tumors at baseline and in 26% (15/57) on-treatment. High TC was seen in 77% (44/57) of tumors at baseline and in 74% (42/57) on-treatment. No significant associations with response were seen for necrosis, PF or normal tissue in on-treatment biopsies., Conclusion: Patients with a decrease in TC from baseline to on-treatment had a significant improvement in objective response and a longer TTP. Our data suggest that the shift in TC might be used to predict response to pembrolizumab in rare tumors. However, further investigations in larger cohorts are needed to determine the clinical value of TC, the shift in TC and the cut-off of 10% assessed in biopsies., Trial Registration Number: NCT02721732., Competing Interests: Competing interests: Merck was the sponsor of the drug pembrolizumab. CT had salary support on this study., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2020
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38. Phase 2 study of pembrolizumab in patients with advanced rare cancers.
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Naing A, Meric-Bernstam F, Stephen B, Karp DD, Hajjar J, Rodon Ahnert J, Piha-Paul SA, Colen RR, Jimenez C, Raghav KP, Ferrarotto R, Tu SM, Campbell M, Wang L, Sabir SH, Tapia C, Bernatchez C, Frumovitz M, Tannir N, Ravi V, Khan S, Painter JM, Abonofal A, Gong J, Alshawa A, McQuinn LM, Xu M, Ahmed S, Subbiah V, Hong DS, Pant S, Yap TA, Tsimberidou AM, Dumbrava EEI, Janku F, Fu S, Simon RM, Hess KR, Varadhachary GR, and Habra MA
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- Adult, Aged, Aged, 80 and over, Carcinoma, Squamous Cell pathology, Cohort Studies, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasms pathology, Prognosis, Rare Diseases pathology, Survival Rate, Young Adult, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents, Immunological therapeutic use, Carcinoma, Squamous Cell drug therapy, Neoplasms drug therapy, Rare Diseases drug therapy
- Abstract
Background: Patients with advanced rare cancers have poor prognosis and few treatment options. As immunotherapy is effective across multiple cancer types, we aimed to assess pembrolizumab (programmed cell death 1 (PD-1) inhibitor) in patients with advanced rare cancers., Methods: In this open-label, phase 2 trial, patients with advanced rare cancers whose tumors had progressed on standard therapies, if available, within the previous 6 months were enrolled in nine tumor-specific cohorts and a 10th cohort for other rare histologies. Pembrolizumab 200 mg was administered intravenously every 21 days. The primary endpoint was non-progression rate (NPR) at 27 weeks; secondary endpoints were safety and tolerability, objective response rate (ORR), and clinical benefit rate (CBR)., Results: A total of 127 patients treated between August 15, 2016 and July 27, 2018 were included in this analysis. At the time of data cut-off, the NPR at 27 weeks was 28% (95% CI, 19% to 37%). A confirmed objective response (OR) was seen in 15 of 110 (14%) evaluable patients (complete response in one and partial response in 14). CBR, defined as the percentage of patients with an OR or stable disease ≥4 months, was 38% (n=42). Treatment was ongoing in 11 of 15 patients with OR at last follow-up. In the cohort with squamous cell carcinoma (SCC) of the skin, the NPR at 27 weeks was 36%, ORR 31%, and CBR 38%. In patients with adrenocortical carcinoma (ACC), NPR at 27 weeks was 31%, ORR 15%, and CBR 54%. In the patients with carcinoma of unknown primary (CUP), NPR at 27 weeks was 33%, ORR 23%, and CBR 54%. In the paraganglioma-pheochromocytoma cohort, NPR at 27 weeks was 43%, ORR 0%, and CBR 75%. Treatment-related adverse events (TRAEs) occurred in 66 of 127 (52%) patients, and 12 (9%) had grade ≥3 TRAEs. The most common TRAEs were fatigue (n=25) and rash (n=17). There were six deaths, all of which were unrelated to the study drug., Conclusions: The favorable toxicity profile and antitumor activity seen in patients with SCC of skin, ACC, CUP, and paraganglioma-pheochromocytoma supports further evaluation of pembrolizumab in this patient population., Trial Registration Number: NCT02721732., Competing Interests: Competing interests: AN reports research support and non-financial support from Merck Sharpe grants from NCI, research support from EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, Armo BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera BioSciences, TopAlliance BioSciences, Eli Lilly, Kymab, and PsiOxus, non-financial support for travel and accommodation from Armo BioSciences, and has served as an advisory board member for Novartis and CytomX Therapeutics outside the submitted work; FM-B reports grants from Novartis/Aduro, Calithera, Bayer, Jounce, CytoMx, eFFECTOR, PUMA Biotechnology, Curis, Millennium, GlaxoSmithkline, Daiichi Sankyo, Abbvie, Guardant Health, Takeda, and Aileron, personal fees for advisory from Inflection Biosciences, Darwin Health and Spectrum, personal fees for consulting from GRAIL, Clearlight Diagnostics, Dialectica, Samsung Bioepis, Aduro, Xencor, Jackson Laboratory, personal fees from OrigiMed, Kolon Life Science and Parexel International, personal fees for consulting/travel related from Pieris, Sumitomo Dainippon, and OrigMed, personal fees for advisory/travel related from Mersana, grants and personal fees for travel related from Taiho, grants and personal fees for Consulting/travel related from Genentech, Debio, and Pfizer, grants and personal fees for consulting from Zymeworks, grants and personal fees for advisory from Seattle Genetics, grants from AstraZeneca outside the submitted work; JH reports grant from Immune Deficiency Foundation, outside the submitted work; JRA reports personal fees from Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharma, Peptomyc, and Merck Sharpe, on the advisory board for Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharma, Peptomyc, Merck Sharpe & Dome, Kelun Pharma/Klus Pharma, Pfizer, Roche Pharma, and Elipses Pharma, research funding from Bayer, Novartis, Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, KELUN-BIOTECH, Takeda-Millenium, GlaxoSmithkline, Ipsen, from null, outside the submitted work. SAP-P reports grants from AbbVie, Inc., Aminex Therapeutics, BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol Myers Squibb, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd, Curis, Inc., Five Prime Therapeutics, Flex Bio, Inc., Genmab A/S, GlaxoSmithkline, Helix BioPharma Corp., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd, Medimmune, LLC, Medivation, Inc., Merck Sharpe & Dome Corp., NewLink Genetics Corporation/Blue Link Pharmaceuticals, Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Principia Biopharma, Inc., Puma Biotechnology, Inc., Seattle Genetics, Taiho Oncology, Tesaro, Inc., Transthera Bio, and XuanZhu Biopharma, outside the submitted work; RF reports personal fees for serving on advisory board from Ayala and Regeron-Sanofi, personal fees for consultation from Cellestia, and other from Merck, outside the submitted work; MC reports personal fees for consulting from Pfizer Inc., Genentech, Inc., and Apricity Health LLC, personal fees for serving as scientific/advisory committee member from EMD Serono, Inc., and Genentech, Inc., outside the submitted work; SHS reports personal fees from Angiodynamics, non-financial support from Neuwave Medical, Medtronic, and Merit Medical, outside the submitted work; CT reports salary support from Merck, during the conduct of the study; salary support from Merck, and for contract work to perform correlatives from Armo Bioscience, outside the submitted work; MF reports personal fees and non-financial support for speaking engagements and research funding from Stryker, personal fees for serving on advisory board from Biom’Up, Genetech, and Ipsen, outside the submitted work; VS reports clinical trial research funding from Novartis, Bayer, GlaxoSmithkline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, Loxo oncology, Takeda and Roche/ Genentech, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, outside the submitted work; DSH reports research/grant funding from Abbvie, Adaptimmune, Amgen, Astra-Zeneca, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genmab, Ignyta, Kite, Kyowa, Lilly, Medimmune, Merck, Merrimack, Mirati, MIRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer; personal fees from Axiom, Baxter, GLG, Group H, Guidepoint Global, Jannsen, Medscape, Numab, Trieza Therapeutics; research/grant funding and personal fees from Bayer, Genentech, Infinity, LOXO, Seattle Genetics, Takeda; and other from Molecular Match, OncoResponse, Presagia Inc, during the conduct of the study; SP reports personal fees and other for financial relationship/speakers bureau consultant from Tyme, Inc., and 4-D Pharma, outside the submitted work; TAY reports personal fees and other for research support, consulting, speakers bureau from AstraZeneca and Pfizer, personal fees and other for research support, consulting from Bayer, Seattle Genetics, and Vertex Pharmaceuticals, personal fees and other for research support, speakers bureau from Tesaro, personal fees for consultant, speakers bureau from Merck, research support from Jounce, Eli Lilly and Kyowa, personal fees for consultant services from Aduro, Almac, Atrin, Bristol-Meyers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, Ignyta, Jansen, and Roche, outside the submitted work; AMT reports grants from NIH/NCI, during the conduct of the study; grants from EMD Serono, Boston Biomedical, Inc., Verastem Oncology, Karus Therapeutics, Ltd., Immatics Biotechnologies, CPRIT, Tvardi Therapeutics, OBI Pharma, Parker Institute, Tempus, Foundation Medicine, and Placon Therapeutics, for consulting/advisory role from Genentech, Roche Europe, and Covance, outside the submitted work; FJ reports grants from Novartis, Genentech, BioMed Valley Discoveries, Plexxikon, Piqur, Symphogen, Bayer, and Fujifilm Corporation and Upsher-Smith Laboratories, research funding & SAB from Deciphera, SAB from IFM Therapeutics, Synlogic, Gaurdant Health, services as paid consultant & ownership interests in Trovagene, and paid consultant in Immunomet, outside the submitted work; SF reports clinical trial research support from Polaris Pharmaceuticals, Inc., Takeda., Lilly, Astra Zeneca, Endocyte, Novartis NIH/NCI, Aprea Therapeutics, Aneropharma Science, OncoMed Pharmaceuticals, Huya Bioscience International, Parexel International, LLC, Medivir AB, New Pharma, Inc, BioAtla LLC, MacroGenics, BeiGene, IMV, Inc, and Tolero Pharmaceuticals, outside the submitted work; RMS reports fees for consulting services from Amgen, Bristol-Myers Squibb, Jansen, Abbvie, Pfizer, Innocrin Therapeutics, Tessa Therapeutics during the conduct of the study; MAH reports grants from Exelixis Inc, grants and personal fees from Eisai Inc, and HRA Pharma, outside the submitted work. BS, DDK, RRC, CJ, KPR, S-MT, LW, CB, NT, VR, SK, JMP, AA (Abonofal), JG, AA (Alshawa), LMM, MX, SA, EEID, KRH, and GRV declare no competing interests., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2020
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39. Overview of Basic Immunology and Clinical Application.
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Stephen B and Hajjar J
- Subjects
- Humans, Immunologic Surveillance, Tumor Microenvironment immunology, Immunotherapy, Neoplasms immunology, Neoplasms therapy
- Abstract
Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells are found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and cross-talk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter, we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers.
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- 2020
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40. Overview of Basic Immunology and Translational Relevance for Clinical Investigators.
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Stephen B and Hajjar J
- Subjects
- Humans, Prognosis, Immunologic Surveillance, Leukocytes immunology, Neoplasms immunology, Tumor Microenvironment immunology
- Abstract
Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells are found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and the crosstalk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers.
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- 2018
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41. Overview of Basic Immunology for Clinical Investigators.
- Author
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Stephen B and Hajjar J
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Humans, Immune System drug effects, Immune System metabolism, Immune System pathology, Immunologic Factors therapeutic use, Immunotherapy methods, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Lymphocytes, Tumor-Infiltrating pathology, Neoplasms metabolism, Neoplasms pathology, Neoplasms therapy, Signal Transduction, Translational Research, Biomedical, Tumor Escape, Adaptive Immunity drug effects, Immune System immunology, Immunity, Innate drug effects, Neoplasms immunology, Tumor Microenvironment
- Abstract
Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells are found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and the cross talk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter, we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers.
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- 2017
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42. TP53 Alterations Correlate with Response to VEGF/VEGFR Inhibitors: Implications for Targeted Therapeutics.
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Wheler JJ, Janku F, Naing A, Li Y, Stephen B, Zinner R, Subbiah V, Fu S, Karp D, Falchook GS, Tsimberidou AM, Piha-Paul S, Anderson R, Ke D, Miller V, Yelensky R, Lee JJ, Hong D, and Kurzrock R
- Subjects
- Adult, Aged, Angiogenesis Inhibitors pharmacology, Antineoplastic Agents pharmacology, Biomarkers, Cell Line, Tumor, Combined Modality Therapy, Drug Resistance, Neoplasm genetics, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Molecular Targeted Therapy, Neoplasms diagnosis, Neoplasms mortality, Proportional Hazards Models, Protein Kinase Inhibitors pharmacology, Receptors, Vascular Endothelial Growth Factor genetics, Treatment Outcome, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, Angiogenesis Inhibitors therapeutic use, Antineoplastic Agents therapeutic use, Mutation, Neoplasms drug therapy, Neoplasms genetics, Protein Kinase Inhibitors therapeutic use, Receptors, Vascular Endothelial Growth Factor antagonists & inhibitors, Tumor Suppressor Protein p53 genetics, Vascular Endothelial Growth Factor A antagonists & inhibitors
- Abstract
TP53 tumor-suppressor gene mutations are among the most frequent abnormalities in cancer, affecting approximately 40% of patients. Yet, there is no accepted way to target these alterations in the clinic. At the same time, antagonists of VEGFR or its ligand are best-selling oncology drugs, with multiple, expensive compounds approved. Although only a subset of patients benefit from these antiangiogenesis agents, no relevant biomarker has been identified. Interestingly, TP53 mutations upregulate VEGF-A and VEGFR2. We prospectively enrolled 500 patients, to be interrogated by comprehensive genomic profiling (CGP) (next-generation sequencing, 236 genes), and to be matched, whenever possible, with targeted agents. Herein, we analyze outcomes based on VEGF/VEGFR inhibitor treatment and presence of TP53 mutations. Of the 500 patients, 188 (37.6%; with ≥1 alteration) were treated; 106 (56% of 188) had tumors that harbored TP53 mutations. VEGF/VEGFR inhibitor therapy was independently associated with improvement in all outcome parameters [rate of stable disease (SD) ≥6 months/partial and complete remission (PR/CR); (31% versus 7%; TP53-mutant patients (who received no other molecular-matched agents) treated with versus without VEGF/VEGFR inhibitors), time-to-treatment failure, and overall survival (multivariate analysis: all P ≤ 0.01)] for the patients harboring TP53-mutant cancers, but improvement was not seen in any of these parameters for patients with TP53 wild-type neoplasms. We conclude that TP53 mutations predict sensitivity to VEGF/VEGFR inhibitors in the clinic. TP53 alterations may therefore be a ready biomarker for treatment with antiangiogenesis agents, a finding of seminal importance across the cancer field. Mol Cancer Ther; 15(10); 2475-85. ©2016 AACR., (©2016 American Association for Cancer Research.)
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- 2016
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43. Cancer Therapy Directed by Comprehensive Genomic Profiling: A Single Center Study.
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Wheler JJ, Janku F, Naing A, Li Y, Stephen B, Zinner R, Subbiah V, Fu S, Karp D, Falchook GS, Tsimberidou AM, Piha-Paul S, Anderson R, Ke D, Miller V, Yelensky R, Lee JJ, Hong DS, and Kurzrock R
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Staging, Neoplasms drug therapy, Neoplasms pathology, Precision Medicine, Prognosis, Prospective Studies, Signal Transduction, Survival Rate, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor genetics, Gene Expression Profiling, High-Throughput Nucleotide Sequencing methods, Molecular Targeted Therapy, Neoplasms genetics
- Abstract
Innovative molecular diagnostics deployed in the clinic enable new ways to stratify patients into appropriate treatment regimens. These approaches may resolve a major challenge for early-phase clinical trials, which is to recruit patients who, while having failed previous treatments, may nevertheless respond to molecularly targeted drugs. We report the findings of a prospective, single-center study conducted in patients with diverse refractory cancers who underwent comprehensive genomic profiling (CGP; next-generation sequencing, 236 genes). Of the 500 patients enrolled, 188 (37.6%) received either matched (N = 122/188, 65%) or unmatched therapy (N = 66/188, 35%). The most common reasons that patients were not evaluable for treatment included insufficient tissue, death, or hospice transfer. The median number of molecular alterations per patient was five (range, 1-14); median number of prior therapies, four. The most common diagnoses were ovarian cancer (18%), breast cancer (16%), sarcoma (13%), and renal cancer (7%). Of the 339 successfully profiled patients, 317 (93.5%) had at least one potentially actionable alteration. By calculating matching scores, based on the number of drug matches and genomic aberrations per patient, we found that high scores were independently associated with a greater frequency of stable disease ≥6 months/partial/complete remission [22% (high scores) vs. 9% (low scores), P = 0.024], longer time-to-treatment failure [hazard ratio (HR) = 0.52; 95% confidence interval (CI) = 0.36-0.74; P = 0.0003], and survival (HR = 0.65; 95% CI = 0.43-1.0; P = 0.05). Collectively, this study offers a clinical proof of concept for the utility of CGP in assigning therapy to patients with refractory malignancies, especially in those patients with multiple genomic aberrations for whom combination therapies could be implemented. Cancer Res; 76(13); 3690-701. ©2016 AACR., (©2016 American Association for Cancer Research.)
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- 2016
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44. Triple-negative breast cancer patients treated at MD Anderson Cancer Center in phase I trials: improved outcomes with combination chemotherapy and targeted agents.
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Ganesan P, Moulder S, Lee JJ, Janku F, Valero V, Zinner RG, Naing A, Fu S, Tsimberidou AM, Hong D, Stephen B, Stephens P, Yelensky R, Meric-Bernstam F, Kurzrock R, and Wheler JJ
- Subjects
- Adult, Aged, Aged, 80 and over, Clinical Trials, Phase I as Topic, Disease Progression, Female, Humans, Male, Middle Aged, Molecular Targeted Therapy, Neoplasm Metastasis, Phosphatidylinositol 3-Kinases metabolism, Prognosis, Proto-Oncogene Proteins c-akt metabolism, Retrospective Studies, Signal Transduction, TOR Serine-Threonine Kinases metabolism, Texas, Treatment Outcome, Triple Negative Breast Neoplasms diagnosis, Triple Negative Breast Neoplasms metabolism, Triple Negative Breast Neoplasms mortality, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Triple Negative Breast Neoplasms drug therapy
- Abstract
Patients with metastatic triple-negative breast cancer (TNBC) have poor treatment outcomes. We reviewed the electronic records of consecutive patients with metastatic TNBC treated in phase I clinic at MD Anderson Cancer Center (Houston, TX) between Augu st 2005 and May 2012. One hundred and six patients received at least 1 phase I trial. Twelve of 98 evaluable patients (12%) had either complete response (CR; n = 1), partial response (PR; n = 7), or stable disease ≥ 6 months (SD; n = 4). Patients treated on matched therapy (n = 16) compared with those on nonmatched therapy (n = 90) had improved SD ≥ 6 months/PR/CR (33% vs. 8%; P = 0.018) and longer progression-free survival (PFS; median, 6.4 vs. 1.9 months; P = 0.001). Eleven of 57 evaluable patients (19%) treated with combination chemotherapy and targeted therapy had SD ≥ 6 months/PR/CR versus 1 of 41 evaluable patients (2%) treated on other phase I trials (P = 0.013), and longer PFS (3.0 vs. 1.6 months; P < 0.0001). Patients with molecular alterations in the PI3K/AKT/mTOR pathway treated on matched therapy (n = 16) had improved PFS compared with those with and without molecular alterations treated on nonmatched therapy (n = 27; 6.4 vs. 3.2 months; P = 0.036). On multivariate analysis, improved PFS was associated with treatment with combined chemotherapy and targeted agents (P = 0.0002), ≤ 2 metastatic sites (P = 0.003), therapy with PI3K/AKT/mTOR inhibitors for those with cognate pathway abnormalities (P = 0.018), and treatment with antiangiogenic agents (P = 0.023). In summary, combinations of chemotherapy and angiogenesis and/or PI3K/AKT/mTOR inhibitors demonstrated improved outcomes in patients with metastatic TNBC., (©2014 American Association for Cancer Research.)
- Published
- 2014
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45. Thymoma patients treated in a phase I clinic at MD Anderson Cancer Center: responses to mTOR inhibitors and molecular analyses.
- Author
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Wheler J, Hong D, Swisher SG, Falchook G, Tsimberidou AM, Helgason T, Naing A, Stephen B, Janku F, Stephens PJ, Yelensky R, and Kurzrock R
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Retrospective Studies, Survival Analysis, Thymoma enzymology, Thymoma genetics, United States, Protein Kinase Inhibitors therapeutic use, TOR Serine-Threonine Kinases antagonists & inhibitors, Thymoma drug therapy
- Abstract
Background: Thymomas and thymic carcinoma are rare tumors with no approved therapies. Our purpose was to analyze the molecular features and outcomes of patients referred to the Clinical Center for Targeted Therapy (Phase I Clinic)., Methods: We retrospectively reviewed the medical records of consecutive referred patients with advanced/metastatic thymoma or thymic carcinoma, Results: Twenty-one patients were identified (median age 52 years; 10 women; median number of prior systemic therapies = 2). Six of 10 patients (60%) treated with mTOR inhibitor combination regimens achieved stable disease (SD) ≥12 months or a partial response (PR). For patients treated on mTOR inhibitor regimens (N = 10), median time to treatment failure (TTF) was 11.6 months versus 2.3 months on last conventional regimen prior to referral (p=0.024). Molecular analyses (performed by next generation sequencing in seven patients and single polymerase chain reaction (PCR)-based assays in an additional six patients) showed diverse actionable mutations: PIK3CA (1 of 12 tested; 8%); EGFR (1 of 13; 8%); RET (1 of 7; 14%); and AKT1 (1 of 7; 14%). Of two patients with PIK3CA or AKT1 mutations, one was treated with an mTOR inhibitor-based regimen and achieved 26% regression with a TTF of 17 months., Conclusion: Patients with advanced/metastatic thymoma or thymic carcinoma demonstrated prolonged TTF on mTOR inhibitor-based therapy as compared to prior conventional treatment. Heterogeneity in actionable molecular aberrations was observed, suggesting that multi-assay molecular profiling and individualizing treatment merits investigation.
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- 2013
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46. Revisiting clinical trials using EGFR inhibitor-based regimens in patients with advanced non-small cell lung cancer: a retrospective analysis of an MD Anderson Cancer Center phase I population.
- Author
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Wheler J, Falchook G, Tsimberidou AM, Hong D, Naing A, Piha-Paul S, Chen SS, Heymach J, Fu S, Stephen B, Fok JY, Janku F, and Kurzrock R
- Subjects
- Adult, Aged, Aged, 80 and over, Angiogenesis Inhibitors therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents therapeutic use, Bevacizumab, Boronic Acids therapeutic use, Bortezomib, Carcinoma, Non-Small-Cell Lung mortality, Cetuximab, Dasatinib, ErbB Receptors genetics, Erlotinib Hydrochloride, Female, Humans, Lung Neoplasms mortality, Male, Middle Aged, Protein Kinase Inhibitors therapeutic use, Pyrazines therapeutic use, Pyrimidines therapeutic use, Quinazolines therapeutic use, Retrospective Studies, Sirolimus therapeutic use, Survival, Thiazoles therapeutic use, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, ErbB Receptors antagonists & inhibitors, Lung Neoplasms drug therapy
- Abstract
Purpose: Single-agent EGFR inhibitor therapy is effective mainly in patients with lung cancer and EGFR mutations. Treating patients who develop resistance, or who are insensitive from the outset, often because of resistant mutations, other aberrations or the lack of an EGFR mutation, probably requires rational combinations. We therefore investigated the outcome of EGFR inhibitor-based combination regimens in patients with heavily-pretreated non-small cell lung cancer (NSCLC) referred to a Phase I Clinic., Methods: We reviewed the electronic records of patients with NSCLC treated with an EGFR inhibitor-based combination regimen: erlotinib and cetuximab; erlotinib, cetuximab and bevacizumab; erlotinib and dasatinib; erlotinib and bortezomib; or cetuximab and sirolimus., Results: EGFR mutations were detected in 16% of patients (21/131). EGFR inhibitor-based combination regimens were administered to 15 patients with EGFR-mutant NSCLC and 24 with EGFR wild-type disease. Stable disease (SD) ≥6 months/partial remission (PR) was attained in 20% of EGFR-mutant patients (3/15; two with sensitive mutations and secondary resistance to prior erlotinib, and one with a resistant mutation), as well as 26% of evaluable patients (5/19) with wild-type disease. One of three evaluable patients with squamous cell histology achieved SD for 26.5 months (EGFR wild-type, TP53-mutant, regimen=erlotinib, cetuximab and bevacizumab)., Conclusions: Eight of 34 evaluable patients (24%) with advanced, refractory NSCLC evaluable for response achieved SD ≥6 months/PR (PR=3; SD ≥6 months=5) on EGFR inhibitor-based combination regimens (erlotinib, cetuximab; erlotinib, cetuximab and bevacizumab; and, erlotinib, bortezomib), including patients with secondary resistance to single-agent EGFR inhibitors, resistant mutations, wild-type disease, and, squamous histology.
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- 2013
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47. Survival of 1,181 patients in a phase I clinic: the MD Anderson Clinical Center for targeted therapy experience.
- Author
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Wheler J, Tsimberidou AM, Hong D, Naing A, Falchook G, Piha-Paul S, Fu S, Moulder S, Stephen B, Wen S, and Kurzrock R
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Gastrointestinal Neoplasms drug therapy, Humans, Liver Neoplasms drug therapy, Liver Neoplasms secondary, Male, Middle Aged, Neoplasm Grading, Neoplasm Metastasis, Prognosis, Risk Factors, Survival Rate, Treatment Outcome, Young Adult, Clinical Trials, Phase I as Topic methods, Neoplasms drug therapy
- Abstract
Purpose: To determine whether the Royal Marsden Hospital (RMH; London, UK) prognostic score for phase I patients can be validated in a large group of individuals seen in a different center and whether other prognostic variables are also relevant, we present an analysis of 1,181 patients treated in the MD Anderson Cancer Center (MDACC; Houston, TX) phase I clinic., Experimental Design: Medical records of 1,181 consecutive patients who were treated on at least one trial in the phase I clinic were reviewed., Results: The median age was 58 years and 50% were women. The median number of prior therapies was four and median survival 10 months [95% confidence interval (CI), 9.1-10.9 months]. Independent factors that predicted shorter survival in a multivariate Cox model and could be internally validated included RMH score of >1 (P < 0.0001; albumin <3.5 g/dL; lactate dehydrogenase >upper limit of normal, and >two sites of metastases), gastrointestinal tumor type (P < 0.0001), and Eastern Cooperative Oncology Group performance status ≥ 1 (P = 0.0004). The median survival was 24.0, 15.2, 8.4, 6.2, and 4.1 months for patients with 0, 1, 2, 3, and 4 or 5 of the above risk factors, respectively., Conclusion: The RMH score was validated in a large group of patients at MDACC. Internal validation of the independent prognostic factors for survival led to the development of the MDACC prognostic score, a modification of the RMH score that strengthens it., (©2012 AACR.)
- Published
- 2012
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