Although the median OS of patients with PDA, HNSCC, and GGA ranged from 3.1 to 10.6 months, the median PFS time was no more than 2 months. [53]. All rights reserved. Even nivolumab and durvalumab are working to block the PD-1/PD-L1 signaling pathway, the combining sites are different. Software: Bi-Cheng Wang, Peng-Cheng Li, Guo-He Lin. In this study, the combination therapeutic regimen showed no significant increase in treatment-related adverse events. Most patients had received 1 line of prior systemic therapy. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Findings from CASPIAN reported previously for the last of the 2 treatment arms showed that, after a median follow-up of 14.2 months, the addition of the durvalumab improved the median OS to 13.0 months versus 10.3 months with EP alone (HR 0.73; 95% CI 0.59-0.91; P=0.0047) [2]. Detailed reviews of full-text articles regarding basic characteristics, outcomes and toxicities were performed by B-CW and P-CL independently. Patients and Methods: Second-line patients were randomized 2:2:1 to receive durvalumab plus tremelimumab (arm A), or durvalumab (arm B) or tremelimumab … Okazaki T, Chikuma S, Iwai Y, et al. Francisco LM, Sage PT, Sharpe AH. Future explorations are needed to further confirm the application of durvalumab plus tremelimumab. Methods Eligible pts had ≥2 prior systemic treatments (1 platinum-based CT), WHO PS 0/1, no prior PDx and were EGFR/ALK WT. Medicine (Baltimore) 2019;98:e18054. In the current presentation, after a median follow-up of 25.1 months, the median OS was 12.9 months among patients who received durvalumab + EP compared with 10.5 months for those who received EP alone (HR 0.75; 95% CI 0.62-0.91; P=0.0032), fully supporting the initial report. Nizam A, Aragon-Ching JB. The forest plots of odds ratios for ORR and DCR are shown in Figures 2 and 3. One study was phase 1b clinical trial, 1 was phase 1b/2 clinical trial, and three were phase 2 clinical trials. Future explorations are needed to further confirm the application of durvalumab plus tremelimumab. Nat Med 2018;24:986–93. [48] A phase III clinical study, Checkmate-067, showed a median PFS of 11.5 months in patients treated with nivolumab and ipilimumab combination therapy, compared with 2.9 and 6.9 months in patients treated with ipilimumab or nivolumab monotherapy, respectively. Drake CG, Jaffee E, Pardoll DM. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. The median OS for this combination was 10.4 months versus 10.5 months for EP alone (HR 0.82; 95% CI 0.68-1.00; P=0.0451). Postow MA, Chesney J, Pavlick AC, et al. Lancet Oncol 2018;19:521–36. We report final results of the clinical efficacy, safety and correlatives. The addition of tremelimumab to durvalumab (Imfinzi) and the standard of care (SOC), platinum-based chemotherapy, did not demonstrate a statistically significant improvement in overall survival (OS) in patients with extensive-stage small cell lung cancer (ES-SCLC), missing the co-primary end point of the phase III CASPIAN trial (NCT03043872), according to high-level results from the final analysis … [13–19] Further, adding tremelimumab, a high affinity human IgG2 monoclonal antibody of CTLA-4,[20] to durvalumab therapy has also been under detection in different cancers. The action mechanism of CTLA-4 remains less clear. [28]. The rates of grade 3/4 and serious AEs were, respectively, 70.3% and 45.5% in the tremelimumab + durvalumab + EP arm, 62.3% and 32.1% in the durvalumab + EP arm, and 62.8% and 36.5% in the EP group. All registration fields are required. [34]. Paz-Ares LG, et al. However, future studies are also needed to identify the patients that most possibly benefit from dual immune checkpoint inhibitors. Mechanisms of immune evasion by tumors. Miska J, Abdulreda MH, Devarajan P, et al. Phase II study of dual immune checkpoint blockade (ICB) with durvalumab (Durva) plus, [24]. “Importantly, the separation among the curves seems to be observed over time and, indeed, survival at 2 years improves from 14% [of participants] in the control arm to 22% in the experimental arm. However, the study’s third arm testing dual checkpoint blockade with tremelimumab + durvalumab + EP did not meet the prespecified threshold for statistical significance (P≤0.0418). Register to view our latest news directly from the conference and receive news notifications in your field. Adv Immunol 2006;90:51–81. 800-638-3030 (within USA), 301-223-2300 (international). These cookies do not store any personal information. Keir ME, Butte MJ, Freeman GJ, et al. We also use third-party cookies that help us analyze and understand how you use this website. [13] Another open-label, phase III trial displayed that nivolumab plus ipilimumab prolong median OS compared to chemotherapy in advanced NSCLC patients regardless of the status of PD-L1 (17.1 versus 13.9 months), and suggested combining nivolumab and ipilimumab as a first-line treatment for advanced NSCLC.[6]. [5]. [50–52], The lack of efficacy of adding tremelimumab to durvalumab may be attributed to the mechanism of action, as tremelimumab is an IgG2 monoclonal antibody that does not cause lysis of regulatory T cells through the way of antibody-dependent cell-mediated cytotoxicity, which is observed with ipilimumab. Identification and characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. [12] Remarkable clinical activity and manageable safety of durvalumab were reported in various solid tumors, including melanoma, lung cancer, head and neck cancer, breast cancer, and urothelial carcinoma. In a randomized, double-blind, phase II study, the response rates of melanoma patients were significantly higher in nivolumab plus ipilimumab group (61%) than in ipilimumab group (11%) (P < .001). [40–42] In the peripheral tissues, PD-1 limits the activation of T-cell through suppressing the induction of cytokines and the expression of anti-apoptotic proteins. Tremelimumab will be provided for 4 cycles. These cookies will be stored in your browser only with your consent. Search for Similar Articles Lee JJ, Yothers G, George TJ, et al. Stewart R, Morrow M, Hammond SA, et al. However, there were no significant differences between dual immunotherapy and mono-immunotherapy in pancreatic ductal adenocarcinoma and gastric and gastroesophageal junction adenocarcinoma. A recent study indicated that T cells were stored in dense antigen-presenting-cell niches within the tumor microenvironment, but tumors that failed to form these immune niches were not extensively infiltrated by T cells. Terms and Conditions This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline. Treatment-related deaths were 12 in the tremelimumab + durvalumab + EP arm, 6 in the durvalumab + EP arm, and 2 in the EP arm. This website uses cookies to improve your experience while you navigate through the website. T-cell homing specificity and plasticity: new concepts and future challenges. [12]. In addition, open-label studies might increase publication bias even the trials were conducted in various centers. Wang BC, Zhang ZJ, Fu C, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. Both durvalumab and tremelimumab have been tested for mesothelioma alone, but not in combination. Cohen EEW, Soulieres D, Le Tourneau C, et al. Your account has been temporarily locked due to incorrect sign in attempts and will be automatically unlocked in A pilot study of durvalumab and tremelimumab and immunogenomic dynamics in metastatic breast cancer. Durvalumab with or without, [30]. Annu Rev Immunol 2008;26:677–704. Median progression-free survival and overall survival in the eligible studies. Eroglu Z, Zaretsky JM, Hu-Lieskovan S, et al. Four hundred eighty-seven potential records were included for the initial assessment. Similar clinical trials are underway in Italy and in 104 study locations worldwide. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. The randomized clinical studies had reported all their pre-defined results. Introduction. Romano E, Kusio-Kobialka M, Foukas PG, et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. The combination of durvalumab and tremelimumab results in clinical benefit, with a tolerable safety profile in patients with solid tumors. [27]. [5] The combination of nivolumab, a fully human anti–PD-1 inhibitor, and ipilimumab, a fully human anti–CTLA-4 inhibitor, has shown encouraging clinical benefit characterized by antitumor effects and tolerable safety profiles.[6–11]. Pooled results showed that combining durvalumab and tremelimumab did not significantly improve the ORR compared with durvalumab (OR 1.12, 95% CI 0.43–2.90, P = .81) or tremelimumab (OR 2.40, 95% CI 0.47–12.32, P = .29) (Fig. [28–32] All the selected studies were included in the systematic review, and 3 of 5 were included in the meta-analysis.[28–30]. Nevertheless, durvalumab plus tremelimumab displayed lower risks of grade ≥ 3 treatment-related adverse events against tremelimumab monotherapy (HNSCC: RR 0.93; GGA: RR 0.34). [33–35] Nowadays, immune checkpoint inhibitors have revolutionized the treatment of patients with solid tumors. We excluded 168 records because they were reviews/comments/letters/ news (n = 55), conference abstracts (n = 109), case reports (n = 3), or unregistered studies (n = 1). Senan S, Shire N, Mak G, et al. T cell motility is increased by CTLA-4 via limiting contact time between T cells and antigen-presenting cells (APCs). Durvalumab and tremelimumab combination therapy had a good safety profile and resulted in clinical benefit in head and neck squamous cell carcinoma. Writing – original draft: Bi-Cheng Wang, Ji-Quan Fan, Quentin Liu. 4). Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. 2). Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. In comparison with patients in monotherapy groups, patients in the durvalumab and tremelimumab combination therapy group showed no significant increases in grade ≥ 3 treatment-related adverse events (durvalumab and tremelimumab versus durvalumab: RR 1.64, 95% CI 0.86–3.13, P = .14; durvalumab and tremelimumab versus tremelimumab: RR 0.87, 95% CI 0.46–1.65, P = .67) (Fig. Safety of nivolumab plus low-dose ipilimumab in previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. We thank the members of the BCSNOWELL STUDIO for providing statistical supports and helping to improve the grammar and spelling. Design, setting, and participants: The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. During recent years, dual immune checkpoint inhibition has been a new treatment strategy for advanced patients. Lancet 2019;393:156–67. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Please enable scripts and reload this page. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Tumor cells elude recognition and destruction by the immune system via activating the immune checkpoint signaling pathway. But opting out of some of these cookies may have an effect on your browsing experience. Purpose: This randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric cancer or gastroesophageal junction (GEJ) cancer. J Exp Med 2014;211:441–56. CASPIAN randomised 805 patients to 3 treatment arms: durvalumab + tremelimumab + etoposide cisplatin/carboplatin (EP; n=268), EP alone (n=269), or durvalumab + EP (n=268). Sonpavde G, Peters S, Nordquist LT, et al. [21–26] Although combining durvalumab and tremelimumab results in clinical benefit, whether combination therapy is superior to durvalumab or tremelimumab monotherapy remains uncertain. The magnitude of the benefit is very similar and very consistent across all the prespecified subgroups of patients analysed, including those treated with cisplatin or those patients with liver or brain metastases,” said Prof. Paz-Ares. Durvalumab and tremelimumab combination therapy had a good safety profile and resulted in clinical benefit in head and neck squamous cell carcinoma. Highlight selected keywords in the article text. ADRIATIC: a phase III trial of durvalumab 6, [23]. You also have the option to opt-out of these cookies. Lancet Oncol 2016;17:883–95. Data for durvalumab alone showed activity consistent with that of other single-agent immune checkpoint inhibitors in this setting, including in the intention-to-treat population. 11 (28%) of 40 patients had an immune-related partial response, which was confirmed in ten (25%) patients; thus, the study reached its primary endpoint. 6). The first author, year of publication, register number, study design, county, cancer type, number of patients, mean age, lines of prior therapy, dosing schedule, objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and treatment-related adverse events data reporting in the articles and supplementary materials were collected from each eligible study. Please try after some time. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Overall, 5 studies were eligible for systematic review, 3 of which were further meta-analyzed. Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Consequently, in March 2020, the FDA approved durvalumab in combination with EP as first-line therapy for ES-SCLC. While compared with tremelimumab monotherapy, combination therapy showed a higher risk of any grade treatment-related adverse events in HNSCC (RR 1.05) but a lower risk in GGA (RR 0.68). First-line nivolumab plus ipilimumab in advanced non-small-cell lung cancer (CheckMate 568): outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers. durvalumab; immunotherapy; meta-analysis; solid tumor; tremelimumab. Jansen CS, Prokhnevska N, Master VA, et al. Cancer immunoediting: from immunosurveillance to tumor escape. Savas P, Virassamy B, Ye C, et al. Registered users can save articles, searches, and manage email alerts. Tumor-infiltrating lymphocytes are associated with the response to immunotherapy. [43–46] PD-L1 is mainly upregulated on the surface of cancer cells. N Engl J Med 2016;375:1856–67. [39]. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. In subgroup analysis, P value did not indicate statistical significance. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. [51]. Background: The combination of durvalumab (D), (anti- PD-L1) and tremelimumab (T), (anti-CTLA-4), was evaluated to determine activity in specific sarcoma subtypes (NCT02815995). Durvalumab/Tremelimumab in combination of cytotoxic chemotherapy has not been tested, especially in BTC. Efficacy and safety of combination immunotherapy for malignant solid tumors: a systematic review and meta-analysis. (A) Each risk of bias item presented as percentages across all included randomized clinical studies; (B) Each risk of bias item for each included randomized clinical study. Conceptualization: Bi-Cheng Wang, Peng-Cheng Li, Guo-He Lin. Mora JR, von Andrian UH. Accordingly, we conducted this systematic review and meta-analysis to assess the efficacy and safety of durvalumab plus tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy in solid tumors. Moher D, Liberati A, Tetzlaff J, et al. Nature 2018;553:347–50. Dunn GP, Bruce AT, Ikeda H, et al. Kelly RJ, Lee J, Bang YJ, et al. Durvalumab and tremelimumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Eur J Cancer 2019;116:137–47. We found that treatment with tremelimumab plus durvalumab in the first-line and second-line setting was clinically active and safe in patients with unresectable mesothelioma. However, compared with durvalumab, combination therapy exhibited higher risks of any grade treatment-related adverse events in PDA (RR 1.10) and GGA (RR 4.06). Mesothelioma patients treated with durvalumab plus tremelimumab had the longest median survival time (median PFS: 5.7 months, 95% confidence interval [CI] 1.7–9.7; median OS: 16.6 months, 95% CI 13.1–20.1). Durvalumab and tremelimumab combination therapy appeared active for the treatment of HNSCC. For immediate assistance, contact Customer Service: [email protected]. Fife BT, Pauken KE, Eagar TN, et al. Funding acquisition: Bi-Cheng Wang, Guo-He Lin. Safety and antitumour activity of durvalumab plus. Real-time immune cell interactions in target tissue during autoimmune-induced damage and graft tolerance. Owing to the synergistic roles of the PD-1 or PD-L1 and CTLA-4 in T-cell activation, the combination of inhibitors targeting PD-1/PD-L1 and CTLA-4 signaling pathways warrants investigation. Necessary cookies are absolutely essential for the website to function properly. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. The analysis of ORR and DCR comprised 3 types of cancers that might not fully represent the efficacy of combination therapy in solid tumors. Selumetinib may stop the growth of tumor … Your message has been successfully sent to your colleague. The addition of tremelimumab to frontline durvalumab and platinum-based chemotherapy did not demonstrate a statistically significant improvement in overall survival (OS) in patients with extensive-stage small cell lung cancer (ES-SCLC), missing the co-primary endpoint of the phase 3 CASPIAN study. Crit Rev Oncol Hematol 2019;138:178–89. [30] Nevertheless, durvalumab plus tremelimumab showed similar efficacy to durvalumab monotherapy in recurrent or metastatic head and neck squamous cell carcinoma and pancreatic ductal adenocarcinoma. Cancer Med 2019;8:5969–78. 3). APACHE: an open label, randomized, phase II study of Durvalumab (Durva), alone or in combination with. (2) patients did not previously receive immunotherapy. (A) Durvalumab plus, Forest plots of odds ratios for disease control in advanced solid tumors. In this condition, CTLA-4 ligation transmits “arrest” signals between T cells and APC. In BTC, the response rate of 1st-line gemcitabine/cisplatin chemotherapy is about 20% (20% in BT22 clinical trial, 25% in ABC-02 clinical trial). N Engl J Med 2019;381:2020–31. [21]. ASCO Virtual Meeting, 29-31 May 2020, Abstract 9002. Exp Hematol Oncol 2013;2:33. ‘green + ’: low risk, ‘red -’: high risk, ‘yellow?’: unclear risk of bias. PD-1 and its ligands in tolerance and immunity. By clicking “Accept”, you consent to the use of ALL the cookies. [4]. Medicine. [3]. Durvalumab plus tremelimumab was superior to tremelimumab monotherapy in improving disease control rate in head and neck squamous cell carcinoma. Nivolumab plus ipilimumab in non-small-cell lung cancer. The trial was suspended in late 2019 after criteria were not met, but researchers estimate completion in 2024. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. All studies were open-label clinical trials, with 2 non-randomized and 3 randomized trials. J Clin Oncol 2019;37:992–1000. Abbreviations: 95% CI = 95% confidence interval, APC = antigen-presenting cell, CTLA-4 = cytotoxic T-lymphocyte antigen 4, DCR = disease control rate, GGA = gastric and gastroesophageal junction adenocarcinoma, HNSCC = head and neck squamous cell carcinoma, NSCLC = non–small cell lung cancer, OR = odds ratio, ORR = objective response rate, PD-1 = programmed cell death-1, PDA = pancreatic ductal adenocarcinoma, PD-L1 = programmed cell death ligand-1, PFS = progression-free survival = OS = overall survival, RR = risk ratio. Das R, Verma R, Sznol M, et al. Tremelimumab and Durvalumab Discussion Board › Forums › Clinical Trials › Tremelimumab and Durvalumab This topic has 19 replies, 5 voices, and was last updated 3 years, 11 months ago by marions . The work cannot be used commercially without permission from the journal. Durvalumab plus tremelimumab is another combination regimen. The effects and safety of PD-1/PD-L1 inhibitors on head and neck cancer: a systematic review and meta-analysis. The blockage of CTLA-4 and PD-1 exerts critical anti-tumor effects. SBRT to 2-5 metastases will be administered between cycles 2 and 3 of immunotherapy. Schneider H, Downey J, Smith A, et al. One hundred sixty-four duplicates were excluded. The electronic databases PubMed, Web of Science, EMBASE and Cochrane Library were systemically searched for all relevant records until Nov 26, 2019. By continuing to use this website you are giving consent to cookies being used. Any cookies that may not be particularly necessary for the website to function and is used specifically to collect user personal data via analytics, ads, other embedded contents are termed as non-necessary cookies. The median PFS was 4.9 months for the tremelimumab + durvalumab + EP arm compared with 5.4 months for the EP arm (HR 0.84; 95% CI 0.70-1.01). Of note, the study design allowed the use of either backbone carboplatin or cisplatin; the OS data favoured durvalumab no matter whether carboplatin (HR 0.79; 95% CI 0.63-0.98) or cisplatin (HR 0.67; 95% CI 0.46-0.97) was used. [31]. Paz-Ares LG, et al. J Immunol 2015;194:950–9. Data curation: Bi-Cheng Wang, Peng-Cheng Li, Guo-He Lin. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. observed with durvalumab and durvalumab plus tremelimumab. The confirmed ORR and median duration of response were 58.4% and 5.2 months, respectively, in the tremelimumab + durvalumab + EP group compared with 58.0% and 5.1 months for the EP arm. Patients were randomized 2:1 to receive either 75 mg of tremelimumab every 28 days for the first 4 cycles plus 1500 mg of durvalumab every 28 days, or best supportive care alone.

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