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Antoni Ribas - One of the best experts on this subject based on the ideXlab platform.
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phase iii randomized clinical trial comparing Tremelimumab with standard of care chemotherapy in patients with advanced melanoma
Journal of Clinical Oncology, 2013Co-Authors: Antoni Ribas, Maribel Marmol, Cornelis J. A. Punt, Jacob Schachter, Margaret A Marshall, John B A G Haanen, Helen Gogas, Claus Garbe, Richard F Kefford, Gerald P LinetteAbstract:Purpose In phase I/II trials, the cytotoxic T lymphocyte–associated antigen-4–blocking monoclonal antibody Tremelimumab induced durable responses in a subset of patients with advanced melanoma. This phase III study evaluated overall survival (OS) and other safety and efficacy end points in patients with advanced melanoma treated with Tremelimumab or standard-of-care chemotherapy. Patients and Methods Patients with treatment-naive, unresectable stage IIIc or IV melanoma were randomly assigned at a ratio of one to one to Tremelimumab (15 mg/kg once every 90 days) or physician's choice of standard-of-care chemotherapy (temozolomide or dacarbazine). Results In all, 655 patients were enrolled and randomly assigned. The test statistic crossed the prespecified futility boundary at second interim analysis after 340 deaths, but survival follow-up continued. At final analysis with 534 events, median OS by intent to treat was 12.6 months (95% CI, 10.8 to 14.3) for Tremelimumab and 10.7 months (95% CI, 9.36 to 11.96)...
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safety profile and pharmacokinetic analyses of the anti ctla4 antibody Tremelimumab administered as a one hour infusion
Journal of Translational Medicine, 2012Co-Authors: Antoni Ribas, Jason Chesney, Michael Gordon, Amy P Abernethy, Theodore F Logan, David H Lawson, Bartosz Chmielowksi, John A Glaspy, Karl D Lewis, Bo HuangAbstract:CTLA4 blocking monoclonal antibodies provide a low frequency but durable tumor responses in patients with metastatic melanoma, which led to the regulatory approval of ipilimumab based on two randomized clinical trials with overall survival advantage. The similarly fully human anti-CTLA4 antibody Tremelimumab had been developed in the clinic at a fixed rate infusion, resulting in very prolonged infusion times. A new formulation of Tremelimumab allowed testing a shorter infusion time. A phase 1 multi-center study to establish the safety and tolerability of administering Tremelimumab as a 1-hour infusion to patients with metastatic melanoma. Secondary endpoints included pharmacokinetic and clinical effects of Tremelimumab. No grade 3 or greater infusion-related adverse events or other adverse events preventing the administration of the full Tremelimumab dose were noted in 44 treated patients. The overall side effect profile was consistent with prior experiences with anti-CTLA4 antibodies. Objective tumor responses were noted in 11% of evaluable patients with metastatic melanoma, which is also consistent with the prior experience with CTLA4 antagonistic antibodies. This study did not identify any safety concerns when Tremelimumab was administered as a 1-hour infusion. These data support further clinical testing of the 1-hour infusion of Tremelimumab. (Clinical trial registration number NCT00585000).
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clinical development of the anti ctla 4 antibody Tremelimumab
Seminars in Oncology, 2010Co-Authors: Antoni RibasAbstract:Tremelimumab (formerly CP-675,206) is a fully human IgG2 monoclonal antibody tested in patients with cancer, of whom the majority have had metastatic melanoma. Clinical trials using Tremelimumab demonstrate that this antibody can induce durable tumor regressions (up to 8 years at this time) in 7% to 10% of patients with metastatic melanoma. These tumor responses are mediated by the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) as demonstrated in patient-derived tumor biopsies. Grade 3 or 4 toxicities in the range of 20% to 25% are mainly inflammatory or autoimmune in nature, which are on-target effects after inhibiting CTLA-4–mediated self-tolerance. The lack of survival advantage in the early analysis of a phase III clinical trial comparing Tremelimumab with standard chemotherapy for metastatic melanoma highlights the importance of gaining a better understanding of how this antibody modulates the human immune system and how to better select patients for this mode of therapy.
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evaluation of baseline serum c reactive protein crp and benefit from Tremelimumab compared to chemotherapy in first line melanoma
Journal of Clinical Oncology, 2010Co-Authors: Margaret A Marshall, Antoni Ribas, Bo HuangAbstract:2609 Background: A3671009, a randomized phase III study comparing Tremelimumab (anti-CTLA4 monoclonal antibody) to dacarbazine or temozolomide in pts with unresectable melanoma, crossed the futility boundary at the second interim analysis, but survival follow-up continued. An exploratory analysis was done to evaluate baseline serum CRP as a potential predictive factor for benefit from immunotherapy with Tremelimumab compared to chemotherapy. Methods: The ratio of the CRP value to the ULN for the local lab was determined at each time point. Baseline CRP was defined as the CRP/ULN ratio on the day or previous day of first dose, prior to dosing, whichever later. Log-rank test and Cox proportional hazard regression model were applied to determine the optimal baseline CRP cutoff value to maximize treatment effect. A permutation test was performed to adjust for multiplicity. Results: BaselineCRP was available for 525 pts. “Low baseline CRP” was identified as ≤1.5 × ULN for optimal hazard ratio (HR) and p value ...
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dendritic cell vaccination combined with ctla4 blockade in patients with metastatic melanoma
Clinical Cancer Research, 2009Co-Authors: Antoni Ribas, Jason Jalil, Bartosz Chmielowski, Elizabeth Seja, Arturo Villanueva, Begona Cominanduix, Pilar De La Rocha, Tara A Mccannel, Maria Teresa Ochoa, Denise OsegueraAbstract:Purpose: Tumor antigen–loaded dendritic cells (DC) are believed to activate antitumor immunity by stimulating T cells, and CTL-associated antigen 4 (CTLA4)–blocking antibodies should release a key negative regulatory pathway on T cells. The combination was tested in a phase I clinical trial in patients with advanced melanoma. Experimental Design: Autologous DC were pulsed with MART-1 26-35 peptide and administered with a dose escalation of the CTLA4-blocking antibody Tremelimumab. Sixteen patients were accrued to five dose levels. Primary end points were safety and immune effects; clinical efficacy was a secondary end point. Results: Dose-limiting toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of three patients receiving Tremelimumab at 10 mg/kg monthly. Four patients had an objective tumor response, two partial responses and two complete responses, all melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response. Exploratory gene expression analysis suggested that immune-related gene signatures, in particular for B-cell function, may be important in predicting response. Conclusion: The combination of MART-1 peptide–pulsed DC and Tremelimumab results in objective and durable tumor responses at the higher range of the expected response rate with either agent alone. (Clin Cancer Res 2009;15(19):6267–76)
Jesus Gomeznavarro - One of the best experts on this subject based on the ideXlab platform.
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phase i study of Tremelimumab cp 675 206 plus pf 3512676 cpg 7909 in patients with melanoma or advanced solid tumours
British Journal of Cancer, 2013Co-Authors: Michael Millward, Margaret A Marshall, Bo Huang, S Lobb, J Mcburnie, Jesus Gomeznavarro, Craig Underhill, S Meech, C B MatherAbstract:Phase I study of Tremelimumab (CP-675 206) plus PF-3512676 (CPG 7909) in patients with melanoma or advanced solid tumours
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phase ii study of the anti cytotoxic t lymphocyte associated antigen 4 monoclonal antibody Tremelimumab in patients with refractory metastatic colorectal cancer
Journal of Clinical Oncology, 2010Co-Authors: Ki Y Chung, Bo Huang, Diane Healey, Prudence Dorazio, Ira Gore, Lawrence Fong, Alan P Venook, Stephen B Beck, Peggy J Criscitiello, Jesus GomeznavarroAbstract:Purpose Safety and efficacy of Tremelimumab (CP-675,206), a fully human anti-cytotoxic T-lymphocyte–associated antigen 4 (CTLA4) monoclonal antibody, were assessed in patients with treatment-refractory colorectal cancer. Patients and Methods A single-arm, multicenter, phase II trial was conducted in patients with Eastern Cooperative Oncology Group performance status ≤ 1 and measurable colorectal carcinoma for whom standard treatments for metastatic disease had failed. Patients received 15 mg/kg Tremelimumab intravenously every 90 days until progression. Primary end point was objective response status (per Response Evaluation Criteria in Solid Tumors). Secondary end points included safety, duration of response, progression-free survival, and overall survival. Results Forty-seven patients who had received extensive prior therapies (all had received fluoropyrimidines, oxaliplatin, and irinotecan; most [91%] had also received cetuximab) were treated. Grade 3/4 treatment-related adverse events (AEs) were diarr...
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phase ii trial of Tremelimumab cp 675 206 in patients with advanced refractory or relapsed melanoma
Clinical Cancer Research, 2010Co-Authors: John M Kirkwood, Margaret A Marshall, Jesus Gomeznavarro, Paul Lorigan, Peter Hersey, Axel Hauschild, Caroline Robert, David F Mcdermott, Jane Q Liang, C BulanhaguiAbstract:Purpose: This phase II study assessed the antitumor activity of Tremelimumab, a fully human, anti–CTL-associated antigen 4 monoclonal antibody, in patients with melanoma. Experimental Design: Patients with refractory/relapsed melanoma received 15 mg/kg Tremelimumab every 90 days. After 4 doses, patients with tumor response or stable disease were eligible to receive ≤4 additional doses. Primary endpoint was best overall tumor response assessed by an independent endpoint review committee, and secondary endpoints included duration of response, overall survival, progression-free survival, and safety. Results: Of 251 patients enrolled, 246 (241 response-evaluable) received Tremelimumab. Objective response rate was 6.6% (16 partial responses); duration of response was 8.9 to 29.8 months. Eight (50%) objective responses occurred in patients with stage IV M 1c disease, and 11 (69%) were ongoing at last tumor assessment. Eight (3.3%) patients achieved responses in target lesions (Response Evaluation Criteria in Solid Tumors) despite progressive disease within the first cycle. All 8 survived for >20 months; 5 (63%) remained alive. Clinical benefit rate (overall response + stable disease) was 21% (16 partial responses and 35 stable disease), and median overall survival was 10.0 months. Progression-free survival at 6 months was 15%, and survival was 40.3% at 12 months and 22% at 24 months. Common treatment-related adverse events were generally mild to moderate, and grade 3/4 adverse events included diarrhea ( n = 28, 11%), fatigue ( n = 6, 2%), and colitis ( n = 9, 4%). There were 2 (0.8%) treatment-related deaths. Conclusions: Tremelimumab showed an objective response rate of 6.6%, with all responses being durable ≥170 days since enrollment, suggesting a potential role for Tremelimumab in melanoma. Clin Cancer Res; 16(3); 1042–8
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phase i ii trial of Tremelimumab in patients with metastatic melanoma
Journal of Clinical Oncology, 2009Co-Authors: Luis H. Camacho, C. A. Bulanhagui, S. Antonia, Jeffrey A. Sosman, J. M. Kirkwood, Bruce G. Redman, Thomas F. Gajewski, Dmitri Pavlov, Viviana Bozon, Jesus GomeznavarroAbstract:Purpose Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade with Tremelimumab (CP-675,206), a fully human anti-CTLA4 monoclonal antibody, was tolerated and demonstrated antitumor activity in a single dose, dose-escalation phase I trial in patients with solid tumors. This phase I/II trial was conducted to examine safety of multiple doses of Tremelimumab, to further assess efficacy, and to identify an appropriate dosing regimen for further development. Patients and Methods Twenty-eight patients with metastatic melanoma received monthly intravenous infusions of Tremelimumab at 3, 6, or 10 mg/kg for up to 1 year to determine recommended monthly phase II dose. During phase II, 89 patients received Tremelimumab 10 mg/kg once every month or 15 mg/kg every 3 months. Results No dose-limiting toxicity was observed in phase I once every month dosing. In phase II, 8 (10%) of 84 response-assessable patients attained objective antitumor responses; best overall objective response was one complete response and t...
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phase iii open label randomized comparative study of Tremelimumab cp 675 206 and chemotherapy temozolomide tmz or dacarbazine dtic in patients with advanced melanoma
Journal of Clinical Oncology, 2008Co-Authors: A Ribas, Maribel Marmol, Cornelis J. A. Punt, John B A G Haanen, Claus Garbe, Richard F Kefford, Dmitri Pavlov, Jesus Gomeznavarro, Axel Hauschild, Margaret A MarshallAbstract:LBA9011 Background: Tremelimumab, a fully human anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) monoclonal antibody was tested in a phase III study to compare the overall survival (OS) with standard, single-agent chemotherapy. Methods: Pts with unresectable stage IIIc-IV melanoma without brain metastasis, LDH below 2x ULN, and no prior systemic treatment for advanced melanoma were randomized 1:1 to either Tremelimumab 15 mg/kg IV q90d, or physician's choice of TMZ 200 mg/m2 p.o. d1–5 q28d or DTIC 1,000 mg/m2 IV q21d (chemotherapy arm). Primary endpoint was OS, secondary endpoints included response, durable tumor response, 6-mo PFS, and safety. 537 deaths would provide 90% power to detect a 33% improvement in true median OS with an unstratified log-rank test at overall 2-sided significance level of 0.045. Two equally spaced interim analyses were planned based on the group sequential design using the Lan-DeMets alpha and beta spending approach to an O'Brien-Fleming boundary. Results: 655 pts were e...
Niels Reinmuth - One of the best experts on this subject based on the ideXlab platform.
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patient reported outcomes with durvalumab with or without Tremelimumab versus standard chemotherapy as first line treatment of metastatic non small cell lung cancer mystic
Clinical Lung Cancer, 2021Co-Authors: Edward B Garon, Byoung Chul Cho, Niels Reinmuth, Ki Hyeong Lee, Alexander Luft, Myungju Ahn, G Robinet, Sylvestre Le Moulec, Ronald B Natale, Jeffrey Gary SchneiderAbstract:Abstract Background The phase 3 MYSTIC study of durvalumab ± Tremelimumab versus chemotherapy in metastatic NSCLC patients with tumor cell (TC) PD-L1 expression ≥25% did not meet its primary endpoints. We report patient-reported outcomes (PROs). Patients and Methods Treatment-naive patients were randomized (1:1:1) to durvalumab, durvalumab + Tremelimumab, or chemotherapy. PROs were assessed in patients with PD-L1 TC ≥25% using EORTC QLQ-C30/LC13. Changes-from-baseline (12 months) for pre-specified PRO endpoints of interest were analyzed by mixed-model-for-repeated-measures (MMRM) and time-to-deterioration (TTD) by stratified log-rank test. Results There were no between-arm differences in baseline PROs (N=488). Between-arm differences (99% CI) in MMRM-adjusted mean changes from baseline favored at least one of the durvalumab-containing arms versus chemotherapy (nominal P Conclusions Durvalumab ± Tremelimumab versus chemotherapy reduced symptom burden and improved TTD of PROs, suggesting it had no detrimental effects on quality-of-life in metastatic NSCLC patients. Micro Abstract We investigated the impact of durvalumab ± Tremelimumab, versus chemotherapy, on patient-reported symptoms, functioning, and global health status/QoL in the phase 3 MYSTIC trial of metastatic NSCLC in patients with tumor cell PD-L1 expression ≥25%. Durvalumab ± Tremelimumab reduced symptom burden and improved times to deterioration, suggesting there were no detrimental effects with treatment.
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durvalumab with or without Tremelimumab plus platinum etoposide versus platinum etoposide alone in first line treatment of extensive stage small cell lung cancer caspian updated results from a randomised controlled open label phase 3 trial
Lancet Oncology, 2021Co-Authors: Jonathan W Goldman, Niels Reinmuth, Mikhail Dvorkin, Y Chen, Katsuyuki Hotta, D Trukhin, Galina Statsenko, Maximilian J Hochmair, Mustafa Ozguroglu, Marina Chiara GarassinoAbstract:Summary Background First-line durvalumab plus etoposide with either cisplatin or carboplatin (platinum–etoposide) showed a significant improvement in overall survival versus platinum–etoposide alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated results, including the primary analysis for overall survival with durvalumab plus Tremelimumab plus platinum–etoposide versus platinum–etoposide alone. Methods CASPIAN is an ongoing, open-label, sponsor-blind, randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and had treatment-naive, histologically or cytologically documented ES-SCLC, with a WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in blocks of six, stratified by planned platinum, using an interactive voice-response or web-response system to receive intravenous durvalumab plus Tremelimumab plus platinum–etoposide, durvalumab plus platinum–etoposide, or platinum–etoposide alone. In all groups, patients received etoposide 80–100 mg/m2 on days 1–3 of each cycle with investigator's choice of either carboplatin area under the curve 5–6 mg/mL/min or cisplatin 75–80 mg/m2 on day 1 of each cycle. Patients in the platinum–etoposide group received up to six cycles of platinum–etoposide every 3 weeks and optional prophylactic cranial irradiation (investigator's discretion). Patients in the immunotherapy groups received four cycles of platinum–etoposide plus durvalumab 1500 mg with or without Tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks. The two primary endpoints were overall survival for durvalumab plus platinum–etoposide versus platinum–etoposide and for durvalumab plus Tremelimumab plus platinum–etoposide versus platinum–etoposide in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered at ClinicalTrials.gov , NCT03043872 . Findings Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus Tremelimumab plus platinum–etoposide, 268 to durvalumab plus platinum–etoposide, and 269 to platinum–etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3–27·9). Durvalumab plus Tremelimumab plus platinum–etoposide was not associated with a significant improvement in overall survival versus platinum–etoposide (hazard ratio [HR] 0·82 [95% CI 0·68–1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6–12·0) versus 10·5 months (9·3–11·2). Durvalumab plus platinum–etoposide showed sustained improvement in overall survival versus platinum–etoposide (HR 0·75 [95% CI 0·62–0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3–14·7) versus 10·5 months (9·3–11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus Tremelimumab plus platinum–etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum–etoposide group, and 88 [33%] of 266 patients in the platinum–etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus Tremelimumab plus platinum–etoposide group, 85 (32%) in the durvalumab plus platinum–etoposide group, and 97 (36%) in the platinum–etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus Tremelimumab plus platinum–etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum–etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum–etoposide group (pancytopenia and thrombocytopenia [n=1 each]). Interpretation First-line durvalumab plus platinum–etoposide showed sustained overall survival improvement versus platinum–etoposide but the addition of Tremelimumab to durvalumab plus platinum–etoposide did not significantly improve outcomes versus platinum–etoposide. These results support the use of durvalumab plus platinum–etoposide as a new standard of care for the first-line treatment of ES-SCLC. Funding AstraZeneca.
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durvalumab Tremelimumab platinum etoposide in first line extensive stage sclc es sclc updated results from the phase iii caspian study
Journal of Clinical Oncology, 2020Co-Authors: Luis Pazares, Niels Reinmuth, Mikhail Dvorkin, Y Chen, Katsuyuki Hotta, D Trukhin, Galina Statsenko, Maximilian J Hochmair, Mustafa Ozguroglu, Oleksandr VoitkoAbstract:9002Background: CASPIAN is an open-label, Phase 3 study of durvalumab (D) ± Tremelimumab (T) + etoposide and either cisplatin or carboplatin (EP) for pts with 1L ES-SCLC. At the planned interim ana...
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durvalumab with or without Tremelimumab vs standard chemotherapy in first line treatment of metastatic non small cell lung cancer the mystic phase 3 randomized clinical trial
JAMA Oncology, 2020Co-Authors: Naiyer A Rizvi, Byoung Chul Cho, Niels Reinmuth, Ki Hyeong Lee, Alexander Luft, Myungju Ahn, Michel M Van Den Heuvel, Manuel Cobo, D Vicente, Alexey SmolinAbstract:Importance Checkpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti–cytotoxic T-lymphocyte–associated antigen 4 have shown clinical activity in patients with metastatic non–small cell lung cancer. Objective To compare durvalumab, with or without Tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non–small cell lung cancer. Design, Setting, and Participants This open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic non–small cell lung cancer who had no sensitizingEGFRorALKgenetic alterations were randomized to receive treatment with durvalumab, durvalumab plus Tremelimumab, or chemotherapy. Data were collected from July 21, 2015, to October 30, 2018. Interventions Patients were randomized (1:1:1) to receive treatment with durvalumab (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus Tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy. Main Outcomes and Measures The primary end points, assessed in patients with ≥25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus Tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory. Results Between July 21, 2015, and June 8, 2016, 1118 patients were randomized. Baseline demographic and disease characteristics were balanced between treatment groups. Among 488 patients with ≥25% of tumor cells expressing PD-L1, median OS was 16.3 months (95% CI, 12.2-20.8) with durvalumab vs 12.9 months (95% CI, 10.5-15.0) with chemotherapy (hazard ratio [HR], 0.76; 97.54% CI, 0.56-1.02;P = .04 [nonsignificant]). Median OS was 11.9 months (95% CI, 9.0-17.7) with durvalumab plus Tremelimumab (HR vs chemotherapy, 0.85; 98.77% CI, 0.61-1.17;P = .20). Median PFS was 3.9 months (95% CI, 2.8-5.0) with durvalumab plus Tremelimumab vs 5.4 months (95% CI, 4.6-5.8) with chemotherapy (HR, 1.05; 99.5% CI, 0.72-1.53;P = .71). Among 809 patients with evaluable bTMB, those with a bTMB ≥20 mutations per megabase showed improved OS for durvalumab plus Tremelimumab vs chemotherapy (median OS, 21.9 months [95% CI, 11.4-32.8] vs 10.0 months [95% CI, 8.1-11.7]; HR, 0.49; 95% CI, 0.32-0.74). Treatment-related adverse events of grade 3 or higher occurred in 55 (14.9%) of 369 patients who received treatment with durvalumab, 85 (22.9%) of 371 patients who received treatment with durvalumab plus Tremelimumab, and 119 (33.8%) of 352 patients who received treatment with chemotherapy. These adverse events led to death in 2 (0.5%), 6 (1.6%), and 3 (0.9%) patients, respectively. Conclusions and Relevance The phase 3 MYSTIC study did not meet its primary end points of improved OS with durvalumab vs chemotherapy or improved OS or PFS with durvalumab plus Tremelimumab vs chemotherapy in patients with ≥25% of tumor cells expressing PD-L1. Exploratory analyses identified a bTMB threshold of ≥20 mutations per megabase for optimal OS benefit with durvalumab plus Tremelimumab. Trial Registration ClinicalT rials.gov Identifier:NCT02453282
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arctic durvalumab with or without Tremelimumab as third line or later treatment of metastatic non small cell lung cancer
Annals of Oncology, 2020Co-Authors: David Planchard, Niels Reinmuth, Sergey Orlov, J R Fischer, S Sugawara, S Mandziuk, D Marquezmedina, Silvia Novello, Y Takeda, R SooAbstract:Background Many patients with metastatic non-small-cell lung cancer (mNSCLC) experience disease progression after first- and second-line treatment; more treatment options are required for these patients. ARCTIC, a phase III, randomized, open-label study, assessed durvalumab ± Tremelimumab versus standard of care (SoC) as ≥ third-line treatment of mNSCLC. Patients and methods ARCTIC comprised two independent sub-studies. Study A: 126 patients with ≥25% of tumor cells (TCs) expressing programmed cell death ligand-1 (PD-L1) were randomized (1 : 1) to durvalumab [up to 12 months 10 mg/kg every 2 weeks (q2w)] or SoC. Study B: 469 patients with PD-L1 TC Results Study A: median OS 11.7 (durvalumab) versus 6.8 (SoC) months {hazard ratio (HR) 0.63 [95% confidence interval (CI), 0.42–0.93]}; median PFS 3.8 (durvalumab) versus 2.2 (SoC) months [HR 0.71 (95% CI, 0.49–1.04)]. Study B: median OS 11.5 (durvalumab + Tremelimumab) versus 8.7 (SoC) months [HR 0.80 (95% CI, 0.61–1.05); P = 0.109]. Median PFS of 3.5 months for both groups [HR 0.77 (95% CI, 0.59–1.01); P = 0.056]. Treatment-related grade 3/4 adverse events: 9.7% (durvalumab) and 44.4% (SoC; study A) and 22.0% (durvalumab + Tremelimumab) and 36.4% (SoC; study B). Conclusions In heavily pretreated patients with mNSCLC, durvalumab demonstrated clinically meaningful improvements in OS and PFS versus SoC (patients with PD-L1 TC ≥25%); numerical improvements in OS and PFS for durvalumab + Tremelimumab versus SoC were observed (patients with PD-L1 TC Trial registration Clinicaltrials.gov identifier: NCT02352948 .
Byoung Chul Cho - One of the best experts on this subject based on the ideXlab platform.
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patient reported outcomes with durvalumab with or without Tremelimumab versus standard chemotherapy as first line treatment of metastatic non small cell lung cancer mystic
Clinical Lung Cancer, 2021Co-Authors: Edward B Garon, Byoung Chul Cho, Niels Reinmuth, Ki Hyeong Lee, Alexander Luft, Myungju Ahn, G Robinet, Sylvestre Le Moulec, Ronald B Natale, Jeffrey Gary SchneiderAbstract:Abstract Background The phase 3 MYSTIC study of durvalumab ± Tremelimumab versus chemotherapy in metastatic NSCLC patients with tumor cell (TC) PD-L1 expression ≥25% did not meet its primary endpoints. We report patient-reported outcomes (PROs). Patients and Methods Treatment-naive patients were randomized (1:1:1) to durvalumab, durvalumab + Tremelimumab, or chemotherapy. PROs were assessed in patients with PD-L1 TC ≥25% using EORTC QLQ-C30/LC13. Changes-from-baseline (12 months) for pre-specified PRO endpoints of interest were analyzed by mixed-model-for-repeated-measures (MMRM) and time-to-deterioration (TTD) by stratified log-rank test. Results There were no between-arm differences in baseline PROs (N=488). Between-arm differences (99% CI) in MMRM-adjusted mean changes from baseline favored at least one of the durvalumab-containing arms versus chemotherapy (nominal P Conclusions Durvalumab ± Tremelimumab versus chemotherapy reduced symptom burden and improved TTD of PROs, suggesting it had no detrimental effects on quality-of-life in metastatic NSCLC patients. Micro Abstract We investigated the impact of durvalumab ± Tremelimumab, versus chemotherapy, on patient-reported symptoms, functioning, and global health status/QoL in the phase 3 MYSTIC trial of metastatic NSCLC in patients with tumor cell PD-L1 expression ≥25%. Durvalumab ± Tremelimumab reduced symptom burden and improved times to deterioration, suggesting there were no detrimental effects with treatment.
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durvalumab with or without Tremelimumab vs standard chemotherapy in first line treatment of metastatic non small cell lung cancer the mystic phase 3 randomized clinical trial
JAMA Oncology, 2020Co-Authors: Naiyer A Rizvi, Byoung Chul Cho, Niels Reinmuth, Ki Hyeong Lee, Alexander Luft, Myungju Ahn, Michel M Van Den Heuvel, Manuel Cobo, D Vicente, Alexey SmolinAbstract:Importance Checkpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti–cytotoxic T-lymphocyte–associated antigen 4 have shown clinical activity in patients with metastatic non–small cell lung cancer. Objective To compare durvalumab, with or without Tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non–small cell lung cancer. Design, Setting, and Participants This open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic non–small cell lung cancer who had no sensitizingEGFRorALKgenetic alterations were randomized to receive treatment with durvalumab, durvalumab plus Tremelimumab, or chemotherapy. Data were collected from July 21, 2015, to October 30, 2018. Interventions Patients were randomized (1:1:1) to receive treatment with durvalumab (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus Tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy. Main Outcomes and Measures The primary end points, assessed in patients with ≥25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus Tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory. Results Between July 21, 2015, and June 8, 2016, 1118 patients were randomized. Baseline demographic and disease characteristics were balanced between treatment groups. Among 488 patients with ≥25% of tumor cells expressing PD-L1, median OS was 16.3 months (95% CI, 12.2-20.8) with durvalumab vs 12.9 months (95% CI, 10.5-15.0) with chemotherapy (hazard ratio [HR], 0.76; 97.54% CI, 0.56-1.02;P = .04 [nonsignificant]). Median OS was 11.9 months (95% CI, 9.0-17.7) with durvalumab plus Tremelimumab (HR vs chemotherapy, 0.85; 98.77% CI, 0.61-1.17;P = .20). Median PFS was 3.9 months (95% CI, 2.8-5.0) with durvalumab plus Tremelimumab vs 5.4 months (95% CI, 4.6-5.8) with chemotherapy (HR, 1.05; 99.5% CI, 0.72-1.53;P = .71). Among 809 patients with evaluable bTMB, those with a bTMB ≥20 mutations per megabase showed improved OS for durvalumab plus Tremelimumab vs chemotherapy (median OS, 21.9 months [95% CI, 11.4-32.8] vs 10.0 months [95% CI, 8.1-11.7]; HR, 0.49; 95% CI, 0.32-0.74). Treatment-related adverse events of grade 3 or higher occurred in 55 (14.9%) of 369 patients who received treatment with durvalumab, 85 (22.9%) of 371 patients who received treatment with durvalumab plus Tremelimumab, and 119 (33.8%) of 352 patients who received treatment with chemotherapy. These adverse events led to death in 2 (0.5%), 6 (1.6%), and 3 (0.9%) patients, respectively. Conclusions and Relevance The phase 3 MYSTIC study did not meet its primary end points of improved OS with durvalumab vs chemotherapy or improved OS or PFS with durvalumab plus Tremelimumab vs chemotherapy in patients with ≥25% of tumor cells expressing PD-L1. Exploratory analyses identified a bTMB threshold of ≥20 mutations per megabase for optimal OS benefit with durvalumab plus Tremelimumab. Trial Registration ClinicalT rials.gov Identifier:NCT02453282
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design and rationale for a phase iii randomized placebo controlled trial of durvalumab with or without Tremelimumab after concurrent chemoradiotherapy for patients with limited stage small cell lung cancer the adriatic study
Clinical Lung Cancer, 2020Co-Authors: Suresh Senan, Isamu Okamoto, Gyeong Won Lee, Yuanbin Chen, Seiji Niho, Gabriel Mak, Wenliang Yao, Norah J Shire, Haiyi Jiang, Byoung Chul ChoAbstract:Abstract Limited-stage (LS) small-cell lung cancer (SCLC) remains an area of high unmet medical need. The standard-of-care therapy comprises curative-intent platinum-based chemotherapy with concurrent radiotherapy (cCRT), which can be followed by prophylactic brain irradiation and then observation. However, most patients will relapse. Durvalumab (antiprogrammed cell death ligand-1) has enhanced the efficacy outcomes after cCRT for patients with unresectable, stage III non-small-cell lung cancer. Recently, durvalumab combined with platinum-etoposide demonstrated a significant survival benefit compared with platinum-etoposide as first-line treatment of patients with extensive-stage SCLC and has also shown antitumor activity as monotherapy and combined with Tremelimumab (anticytotoxic T-lymphocyte–associated antigen-4) in pretreated patients with extensive-stage SCLC. ADRIATIC, a phase III, randomized, double-blind, placebo-controlled, multicenter, global study ( ClinicalTrials.gov identifier, NCT03703297), is designed to investigate the efficacy of durvalumab, with or without Tremelimumab, as consolidation therapy for patients with LS-SCLC without disease progression after cCRT. Approximately 600 patients with documented histologic or cytologic LS-SCLC, World Health Organization/Eastern Cooperative Oncology Group performance status 0 or 1, and no progression after 4 cycles of cCRT will be randomized (1:1:1) to treatment (durvalumab 1500 mg plus placebo every 4 weeks [q4w] for 4 cycles, followed by durvalumab 1500 mg q4w; durvalumab 1500 mg plus Tremelimumab 75 mg q4w for 4 cycles, followed by durvalumab 1500 mg q4w; or dual placebo q4w for 4 cycles, followed by single placebo q4w) within 1 to 42 days of completing cCRT, stratified by stage and receipt of prophylactic brain irradiation. The primary endpoints are progression-free survival and overall survival. The secondary endpoints are overall survival and progression-free survival rates, objective response rate, and safety and tolerability. Recruitment began in September 2018.
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mogamulizumab in combination with durvalumab or Tremelimumab in patients with advanced solid tumors a phase i study
Clinical Cancer Research, 2020Co-Authors: Dmitriy Zamarin, Margaret A Marshall, Omid Hamid, Asha Nayakkapoor, Solmaz Sahebjam, Mario Sznol, Agron Collaku, Floyd E Fox, David S HongAbstract:Purpose: The study goal was to determine safety, antitumor activity, and pharmacodynamic profile of mogamulizumab, an anti–C-C chemokine receptor 4 (anti-CCR4) mAb targeting effector regulatory T cells (eTreg), in combination with mAb checkpoint inhibitors durvalumab or Tremelimumab. Patients and Methods: This was a multicenter, phase I, dose escalation study, followed by disease-specific cohort expansion (NCT02301130). Mogamulizumab dose escalation proceeded with concurrent dose escalation of durvalumab or Tremelimumab in patients with advanced solid tumors. Cohort expansion occurred with mogamulizumab 1 mg/kg plus durvalumab 10 mg/kg or Tremelimumab 10 mg/kg in patients with advanced pancreatic cancer. Results: Forty patients were enrolled during dose escalation, followed by 24 patients during dose expansion. No dose-limiting toxicities occurred during dose escalation. No new or unexpected toxicities were seen. Tolerability, the primary endpoint, was acceptable utilizing mogamulizumab 1 mg/kg plus durvalumab or Tremelimumab 10 mg/kg in the combined dose escalation and dose expansion cohorts (each n = 19). At these doses, the objective response rate was 5.3% (95% confidence interval, 0.1%–26.0%; one partial response) with each combination treatment. At all doses, mogamulizumab treatment led to almost complete depletion of peripheral eTregs, as well as reduction of intratumoral Tregs in the majority of patients. There was no clear correlation of clinical response with peripheral or intratumoral reduction in CCR4+ eTregs or with baseline degree of CCR4+ expression. Conclusions: Mogamulizumab in combination with durvalumab or Tremelimumab did not result in potent antitumor efficacy in patients with advanced solid tumors. Tolerability of mogamulizumab 1 mg/kg combined with durvalumab or Tremelimumab 10 mg/kg was acceptable.
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phase i study of Tremelimumab cp 675 206 plus pf 3512676 cpg 7909 in patients with melanoma or advanced solid tumours
British Journal of Cancer, 2013Co-Authors: Michael Millward, Margaret A Marshall, Bo Huang, S Lobb, J Mcburnie, Jesus Gomeznavarro, Craig Underhill, S Meech, C B MatherAbstract:Phase I study of Tremelimumab (CP-675 206) plus PF-3512676 (CPG 7909) in patients with melanoma or advanced solid tumours
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phase iii randomized clinical trial comparing Tremelimumab with standard of care chemotherapy in patients with advanced melanoma
Journal of Clinical Oncology, 2013Co-Authors: Antoni Ribas, Maribel Marmol, Cornelis J. A. Punt, Jacob Schachter, Margaret A Marshall, John B A G Haanen, Helen Gogas, Claus Garbe, Richard F Kefford, Gerald P LinetteAbstract:Purpose In phase I/II trials, the cytotoxic T lymphocyte–associated antigen-4–blocking monoclonal antibody Tremelimumab induced durable responses in a subset of patients with advanced melanoma. This phase III study evaluated overall survival (OS) and other safety and efficacy end points in patients with advanced melanoma treated with Tremelimumab or standard-of-care chemotherapy. Patients and Methods Patients with treatment-naive, unresectable stage IIIc or IV melanoma were randomly assigned at a ratio of one to one to Tremelimumab (15 mg/kg once every 90 days) or physician's choice of standard-of-care chemotherapy (temozolomide or dacarbazine). Results In all, 655 patients were enrolled and randomly assigned. The test statistic crossed the prespecified futility boundary at second interim analysis after 340 deaths, but survival follow-up continued. At final analysis with 534 events, median OS by intent to treat was 12.6 months (95% CI, 10.8 to 14.3) for Tremelimumab and 10.7 months (95% CI, 9.36 to 11.96)...
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evaluation of baseline serum c reactive protein crp and benefit from Tremelimumab compared to chemotherapy in first line melanoma
Journal of Clinical Oncology, 2010Co-Authors: Margaret A Marshall, Antoni Ribas, Bo HuangAbstract:2609 Background: A3671009, a randomized phase III study comparing Tremelimumab (anti-CTLA4 monoclonal antibody) to dacarbazine or temozolomide in pts with unresectable melanoma, crossed the futility boundary at the second interim analysis, but survival follow-up continued. An exploratory analysis was done to evaluate baseline serum CRP as a potential predictive factor for benefit from immunotherapy with Tremelimumab compared to chemotherapy. Methods: The ratio of the CRP value to the ULN for the local lab was determined at each time point. Baseline CRP was defined as the CRP/ULN ratio on the day or previous day of first dose, prior to dosing, whichever later. Log-rank test and Cox proportional hazard regression model were applied to determine the optimal baseline CRP cutoff value to maximize treatment effect. A permutation test was performed to adjust for multiplicity. Results: BaselineCRP was available for 525 pts. “Low baseline CRP” was identified as ≤1.5 × ULN for optimal hazard ratio (HR) and p value ...
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phase ii trial of Tremelimumab cp 675 206 in patients with advanced refractory or relapsed melanoma
Clinical Cancer Research, 2010Co-Authors: John M Kirkwood, Margaret A Marshall, Jesus Gomeznavarro, Paul Lorigan, Peter Hersey, Axel Hauschild, Caroline Robert, David F Mcdermott, Jane Q Liang, C BulanhaguiAbstract:Purpose: This phase II study assessed the antitumor activity of Tremelimumab, a fully human, anti–CTL-associated antigen 4 monoclonal antibody, in patients with melanoma. Experimental Design: Patients with refractory/relapsed melanoma received 15 mg/kg Tremelimumab every 90 days. After 4 doses, patients with tumor response or stable disease were eligible to receive ≤4 additional doses. Primary endpoint was best overall tumor response assessed by an independent endpoint review committee, and secondary endpoints included duration of response, overall survival, progression-free survival, and safety. Results: Of 251 patients enrolled, 246 (241 response-evaluable) received Tremelimumab. Objective response rate was 6.6% (16 partial responses); duration of response was 8.9 to 29.8 months. Eight (50%) objective responses occurred in patients with stage IV M 1c disease, and 11 (69%) were ongoing at last tumor assessment. Eight (3.3%) patients achieved responses in target lesions (Response Evaluation Criteria in Solid Tumors) despite progressive disease within the first cycle. All 8 survived for >20 months; 5 (63%) remained alive. Clinical benefit rate (overall response + stable disease) was 21% (16 partial responses and 35 stable disease), and median overall survival was 10.0 months. Progression-free survival at 6 months was 15%, and survival was 40.3% at 12 months and 22% at 24 months. Common treatment-related adverse events were generally mild to moderate, and grade 3/4 adverse events included diarrhea ( n = 28, 11%), fatigue ( n = 6, 2%), and colitis ( n = 9, 4%). There were 2 (0.8%) treatment-related deaths. Conclusions: Tremelimumab showed an objective response rate of 6.6%, with all responses being durable ≥170 days since enrollment, suggesting a potential role for Tremelimumab in melanoma. Clin Cancer Res; 16(3); 1042–8
