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  • American Association for Cancer Research (AACR)  (8)
  • Medicine  (8)
  • 1
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    Online Resource
    A Dose-Escalation and Signal-Generating Study of the Immunocytokine L19-IL2 in Combination with Dacarbazine for the Therapy of Patients with Metastatic Melanoma
    American Association for Cancer Research (AACR) ; 2011
    In:  Clinical Cancer Research Vol. 17, No. 24 ( 2011-12-15), p. 7732-7742
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 17, No. 24 ( 2011-12-15), p. 7732-7742
    Abstract: Purpose: L19-IL2 is an immunocytokine composed of an antibody fragment specific to the EDB domain of fibronectin, a tumor angiogenesis marker, and of human interleukin-2 (IL2). L19-IL2 delivers IL2 to the tumor site exploiting the selective expression of EDB on newly formed blood vessels. Previously, the recommended dose of L19-IL2 monotherapy was defined as 22.5 million international units (Mio IU) IL2 equivalents. In this study, safety and clinical activity of L19-IL2 in combination with dacarbazine were assessed in patients with metastatic melanoma. Experimental Design: The first 10 studied patients received escalating doses of L19-IL2 on days 1, 3, and 5 in combination with 1 g/m2 of dacarbazine on day 1 of a 3-weekly therapy cycle. Subsequently, 22 patients received L19-IL2 at recommended dose plus dacarbazine. Up to six treatment cycles were given, followed by a maintenance regimen with biweekly L19-IL2. Results: The recommended dose of L19-IL2 in combination with dacarbazine was defined as 22.5 Mio IU. Toxicity was manageable and reversible, with no treatment-related deaths. Twenty-nine patients were evaluable for efficacy according to Response Evaluation Criteria in Solid Tumors (RECIST). In a centralized radiology analysis, eight of 29 (28%) patients achieved a RECIST-confirmed objective response, including a complete response still ongoing 21 months after treatment beginning. The 12-month survival rate and median overall survival of the recommended dose–treated patients (n = 26) were 61.5% and 14.1 months, respectively. Conclusions: The repeated administration of L19-IL2 in combination with dacarbazine is safe and shows encouraging signs of clinical activity in patients with metastatic melanoma. This combination therapy is currently evaluated in a randomized phase II trial with patients with metastatic melanoma. Clin Cancer Res; 17(24); 7732–42. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-11-1203
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 2
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    Abstract 3034: 18F-FDG-positron emission tomography (PET)/CT enables the identification of checkpoint inhibitor immunotherapy (CIT) responders by determination of CIT-induced metabolic changes in secondary lymphatic organs
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3034-3034
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3034-3034
    Abstract: Although the majority of patients with metastatic melanoma achieve a prolongation of overall survival by using checkpoint inhibitor based immunotherapy (CIT), there is still a larger number of patients who do not benefit from this therapy. As a CIT-induced systemic immune response is required to promote the anti-tumor effect we analyzed the glucose metabolism in secondary lymphoid organs such as the spleen by 18F-FDG-Positron Emission Tomography (PET). In preclinical studies, we were able to distinguish responders from non responders by focusing on the spleen 18F-FDG-uptake of mice with CIT in experimental tumor models. Thus, we aimed to gain deeper insights into impact of CIT on the metabolism in secondary lymphatic organs to identify responders and to stratify patients for differential treatment strategies. We retrospectively analyzed 18F-FDG-PET/CT scans (baseline and post-therapy) of 38 patients with metastatic melanoma with CTLA-4 or PD-1 Ab treatment as third line therapy (21 responder: 5x nivolumab; 7x pembrolizumab; 9x ipilimumab; 17 non-responder: 2x nivolumab; 11x pembrolizumab; 4x ipilimumab). Spleen regions of interest (ROI) were defined in the CT data, copied to the coregistered PET and analyzed semiquantitatively. Total lesion glycolysis (TLG) was calculated by multiplication of the spleen volume and the SUVmean. We determined in the baseline 18F-FDG-PET/CT-scans (prior to CIT), no significant differences in spleen volume (221±18 cm3 vs. 209 ±22 cm3) and in the spleen 18F-FDG-uptake (SUVmean: 1,74±0,06vs.1,72±0,05; TLG: 384±37 vs. 359±36) between responders and non-responders. In the follow up 18F-FDG-PET/CT-scans 110±68 days after onset of CIT we measured a similar increase in spleen volume in responders (+8±6%) and non-responders (+7±5%). 15 out of 21 responders revealed an enhanced spleen 18F-FDG uptake when compared to the baseline 18F-FDG-PET/CT-scans. The mean standard uptake values in the spleen of responders increased by +10±9% SUVmean. In sharp contrast, we determined hardly any change in the spleen 18F-FDG uptake of non-responders (SUVmean -1,3±2,6%). Additionally, the total lesion glycolysis (TLG) in the CIT-responders increased stronger (+25±22%) than in non-responders (+6±6%). Our results suggest that CIT-induced metabolic changes in secondary lymphatic organs are associated with therapy responds. Thus, non invasive 18F-FDG-PET/CT investigations might represent a powerful tool to monitor CIT-induced systemic immune responses in patients. Consequently, preclinical research is prerequisite to uncover the exact mode of action of CIT-induced systemic immune response in secondary lymphatic organs. Moreover, prospective clinical studies are essential to evaluate the prognostic value of our method. Citation Format: Johannes Schwenck, Barbara Schörg, Francesco Fiz, Kilian Wistuba-Hamprecht, Andrea Forschner, Thomas Eigentler, Benjamin Weide, Claus Garbe, Martin Röcken, Christina Pfannenberg, Bernd J. Pichler, Christian la Fougere, Manfred Kneilling. 18F-FDG-positron emission tomography (PET)/CT enables the identification of checkpoint inhibitor immunotherapy (CIT) responders by determination of CIT-induced metabolic changes in secondary lymphatic organs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3034.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-3034
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 3
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    Abstract LB-021: Intratumoral RNA-based TLR-7/-8 and RIG-I agonist CV8102 alone and in combination with anti-PD-1 in a Phase I dose-escalation and expansion trial in patients with advanced solid tumors
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. LB-021-LB-021
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. LB-021-LB-021
    Abstract: CV8102 comprises a single-stranded non-coding RNA complexed with a cationic peptide. It acts as an agonist to TLR-7/-8 and RIG-I (Ziegler 2018) to stimulate the innate and adaptive immune system. CV8102 was shown to induce an upregulation of inflammatory cytokines, chemokines and IFN-γ related genes at the injection site along with an activation of T, NK, NKT and migratory dendritic cells in the draining lymph nodes (Heidenreich 2015). Intratumoral (IT) CV8102 demonstrated dose-dependent anti-tumor activity and synergized with systemic PD-1 inhibition in preclinical models. Methods This Phase I study investigates IT CV8102 as single agent and in combination with systemic anti-PD-1 antibodies (as per product label). Patients (pts) with advanced inoperable melanoma (MEL), cutaneous/head and neck squamous cell or adenoid cystic carcinoma (cSCC, SCCHN, ACC) are eligible for single agent CV8102, pts with MEL and SCCHN who did not respond or slowly progressed on anti-PD-1 therapy are eligible for the combination. CV8102 is administered for up to 8 IT injections into a single accessible tumor lesion over a 12-week period. A Bayesian logistic regression model with overdose control is used for the dose escalation parts. Response is assessed by RECIST 1.1/irRECIST (injected and non-injected target lesions). Pre- and on-treatment samples are collected for biomarker analyses. Results A total of 20 pts have been treated with either CV8102 alone (N=15: 6 MEL, 2 SCCHN, 5 ACC, 2 cSCC) or CV8102 in combination with anti-PD-1 (N=5: 4 MEL, 1 SCCHN). Dose cohorts with doses up to 150 µg (CV8102 alone) and 100µg (CV8102+anti-PD-1) have been completed. Most common AEs were mild to moderate flu-like symptoms and injection site reactions. No dose limiting toxicities (DLT) were observed during the DLT period of the first two weeks of treatment. 12 pts treated with CV8102 alone were evaluable for response assessment. 1 MEL pt treated at 150µg experienced a complete regression of injected and non-injected lesions. This patient also experienced a marked increase of IL-6 and CRP at 6 and 24 hours after the first injection, respectively. 7 pts achieved stable disease, with two pts treated at 100 µg (SCCHN pt) and 200µg (MEL pt who had developed acquired resistance to previous anti-PD-1 therapy) showing regression of non-injected lymph node lesions. Dose escalation parts are continuing, updated safety and efficacy results will be presented. Conclusion Intratumoral single agent CV8102 appears well tolerated and showed preliminary evidence of clinical efficacy with shrinkage of injected and non-injected lesions. Citation Format: Thomas Eigentler, Juergen Krauss, Jutta Schreiber, Carsten Weishaupt, Patrick Terheyden, Lucie Heinzerling, Peter Mohr, Benjamin Weide, Ralf Gutzmer, Juergen C. Becker, Felix Kiecker, Angelika Daehling, Fatma Funkner, Regina Heidenreich, Sarah-Katharina Kays, Ute Klinkhardt, Birgit Scheel, Oliver Schoenborn-Kellenberger, Tobias Seibel, Claudia Stosnach, Tanja Strack, Ulrike Gnad-Vogt. Intratumoral RNA-based TLR-7/-8 and RIG-I agonist CV8102 alone and in combination with anti-PD-1 in a Phase I dose-escalation and expansion trial in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-021.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-LB-021
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 4
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    Abstract CT004: Adjuvant therapy with nivolumab (NIVO) combined with ipilimumab (IPI) vs NIVO alone in patients (pts) with resected stage IIIB-D/IV melanoma (CheckMate 915)
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. CT004-CT004
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. CT004-CT004
    Abstract: Background: NIVO has demonstrated significant benefit over IPI as adjuvant treatment in pts with resected stage IIIB–C or stage IV melanoma (AJCC v7). Combination NIVO + IPI has shown numerically longer survival than NIVO alone in pts with metastatic melanoma. CheckMate 915 evaluated adjuvant NIVO + IPI 1 mg/kg Q6W vs NIVO. Methods: Pts aged ≥ 12 y with completely resected stage IIIB–D or stage IV melanoma (AJCC v8) were stratified by tumor PD-L1 expression and stage and treated with NIVO 240 mg Q2W + IPI 1 mg/kg Q6W (NIVO + IPI1) or placebo-controlled NIVO 480 mg Q4W alone for ≤ 1 y (NIVO + IPI were to be discontinued together). Dual endpoints were recurrence-free survival (RFS) in the PD-L1 & lt; 1% and intent-to-treat populations. Distant metastasis-free survival (DMFS) in pts with stage III disease was an exploratory endpoint. Results: Of 920 pts randomized to NIVO + IPI1 and 924 to NIVO alone, most had stage IIIB (31% vs 31%) or IIIC (53% vs 52%) disease and had undergone complete lymph node dissection (64% vs 64%). Pts treated with NIVO + IPI1 vs NIVO alone had a shorter median duration of therapy (7.6 vs 11.1 mo) and therefore, a lower median cumulative NIVO dose (3840 vs 6240 mg). At a minimum follow-up of 24 mo, RFS and DMFS did not differ between treatment groups (table). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 33% of pts treated with NIVO+IPI1 and 13% with NIVO alone; any-grade TRAEs led to discontinuation of therapy in 32% vs 10% of pts, respectively. There were 4 treatment-related deaths (all with NIVO + IPI1). Conclusions: The NIVO + IPI1 regimen did not result in RFS or DMFS improvement vs NIVO in stage IIIB–D/IV resectable melanoma; safety profiles were consistent with previous studies. NIVO 480 mg Q4W outcomes in CheckMate 915 were similar to previous NIVO results and reinforce NIVO as an adjuvant standard of care in a study population that included pts with and without complete lymphadenectomy. NIVO 240 mg Q2W + IPI 1 mg/kg Q6W (ITT)NIVO 480 mg Q4W (ITT)NIVO 240 mg Q2W + IPI 1 mg/kg Q6W (tumor PD-L1 & lt; 1%)NIVO 480 mg Q4W (tumor PD-L1 & lt; 1%)RFS24-mo rate64.6% (95% CI, 61.3-67.7)63.2% (95% CI, 59.9-66.4)53.6% (95% CI, 48.0-58.8)52.4% (95% CI, 46.8-57.7)Median, mo (events/pts)Not reached (327/920)Not reached (347/924)33.2 (159/349)25.3 (166/351)HR, NIVO + IPI1 vs NIVO0.92 (97.295% CI, 0.77-1.09); P = 0.2690.91 (95% CI, 0.73-1.14)DMFS in pts with stage III disease24-mo rate75.4% (95% CI, 72.1-78.4)77.4% (95% CI, 74.1-80.3)67.9% (95% CI, 61.9-73.1)68.4% (95% CI, 62.5-73.7)Median, mo (events/pts)Not reached (195/797)Not reached (194/798)Not reached (92/305)Not reached (96/307)HR, NIVO + IPI1 vs NIVO1.01 (95% CI, 0.83-1.23)0.94 (95% CI, 0.70-1.25) Citation Format: Georgina V. Long, Dirk Schadendorf, Michele Del Vecchio, James Larkin, Victoria Atkinson, Michael Schenker, Jacopo Pigozzo, Helen J. Gogas, Stéphane Dalle, Nicolas Meyer, Paolo A. Ascierto, Shahneen Sandhu, Thomas Eigentler, Ralf Gutzmer, Jessica C. Hassel, Caroline Robert, Matteo Carlino, Anna Maria Di Giacomo, Marcus O. Butler, Eva Muñoz-Couselo, Michael P. Brown, Piotr Rutkowski, Andrew Haydon, Jean-Jacques Grob, Jacob Schachter, Paola Queirolo, Alexander Menzies, Sandra Re, Tuba O. Bas, Veerle de Pril, Daniel Tenney, Hao Tang, Jeffrey S. Weber. Adjuvant therapy with nivolumab (NIVO) combined with ipilimumab (IPI) vs NIVO alone in patients (pts) with resected stage IIIB-D/IV melanoma (CheckMate 915) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT004.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-CT004
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 5
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    Baseline Peripheral Blood Biomarkers Associated with Clinical Outcome of Advanced Melanoma Patients Treated with Ipilimumab
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 12 ( 2016-06-15), p. 2908-2918
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 12 ( 2016-06-15), p. 2908-2918
    Abstract: Purpose: To identify baseline peripheral blood biomarkers associated with clinical outcome following ipilimumab treatment in advanced melanoma patients. Experimental Design: Frequencies of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), serum lactate dehydrogenase (LDH), routine blood counts, and clinical characteristics were assessed in 209 patients. Endpoints were overall survival (OS) and best overall response. Statistical calculations were done by Kaplan–Meier and Cox regression analysis, including calibration and discrimination by C-statistics. Results: Low baseline LDH, absolute monocyte counts (AMC), Lin−CD14+HLA-DR−/low-MDSC frequencies, and high absolute eosinophil counts (AEC), relative lymphocyte counts (RLC), and CD4+CD25+FoxP3+-Treg frequencies were significantly associated with better survival, and were considered in a combination model. Patients (43.5%) presenting with the best biomarker signature had a 30% response rate and median survival of 16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3% response rate and median survival of 4 months. The occurrence of adverse events correlated with neither baseline biomarker signatures nor the clinical benefit of ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC, and RLC, the number of favorable factors (4 vs. 3 vs. 2–0) was also associated with OS (P & lt; 0.001 for all pairwise comparisons) in the main study and additionally in an independent validation cohort. Conclusions: A baseline signature of low LDH, AMC, and MDSCs as well as high AEC, Tregs, and RLC is associated with favorable outcome following ipilimumab. Prospective investigation of the predictive impact of these markers following ipilimumab and other treatments, e.g., PD-1 antibodies, is warranted. Clin Cancer Res; 22(12); 2908–18. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-15-2412
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 6
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    PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain Metastases In Vitro and In Vivo
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 23 ( 2016-12-01), p. 5818-5828
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 23 ( 2016-12-01), p. 5818-5828
    Abstract: Purpose: Great advances have recently been made in treating patients with metastatic melanoma. However, existing therapies are less effective on cerebral than extracerebral metastases. This highlights the potential role of the brain environment on tumor progression and drug resistance and underlines the need for “brain-specific” therapies. We previously showed that the PI3K-AKT survival pathway is hyperactivated in brain but not extracerebral melanoma metastases and that astrocyte-conditioned medium activates AKT in melanoma cells in vitro. We therefore tested the PI3K inhibitor buparlisib as an antitumor agent for melanoma brain metastases. Experimental Design and Results: Buparlisib inhibited AKT activity, decreased proliferation, and induced apoptosis in metastatic melanoma cell lines and short-term brain melanoma cells, irrespective of their BRAF and NRAS mutation status. In addition, buparlisib inhibited hyperactivated AKT and induced apoptosis in melanoma cells that were stimulated with astrocyte-conditioned medium. The growth of tumors induced by injecting human BRAF- and NRAS-mutant metastatic melanoma cells into the brain of mice was significantly inhibited by buparlisib. Conclusions: These results emphasize the value of targeting the PI3K pathway as a strategy to develop drugs for melanoma brain metastases. Clin Cancer Res; 22(23); 5818–28. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-16-0064
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 7
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    Circulating CD4+ T Cells That Produce IL4 or IL17 When Stimulated by Melan-A but Not by NY-ESO-1 Have Negative Impacts on Survival of Patients with Stage IV Melanoma
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 16 ( 2014-08-15), p. 4390-4399
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 16 ( 2014-08-15), p. 4390-4399
    Abstract: Purpose: We initially observed that the presence of circulating NY-ESO-1– and/or Melan-A–specific T cells in patients with stage IV melanoma was significantly associated with prolonged survival. Here, we report the ways in which the phenotypes and functions of these T cells differentially affect survival in patients preselected for NY-ESO-1 and/or Melan-A reactivity. Experimental Design: We assayed functional antigen-reactive T cells recognizing NY-ESO-1 and/or Melan-A after in vitro stimulation using overlapping peptide pools. After restimulation, we assayed six cytokines simultaneously by intracellular cytokine staining. This allowed us to analyze the functional antigen response of both CD4+ and CD8+ T cells at the single-cell level. Results: We observed that NY-ESO-1 stimulated mainly CD4+ T cells, whereas Melan-A more often stimulated CD8+ T cells. NY-ESO-1 reactivity was not associated with an additional impact on survival, whether CD4+ T cells, CD8+ T cells, or both types of T cells were responding. In contrast, recognition of Melan-A by CD4+ T cells was associated with reduced survival in our cohort of patients preselected for NY-ESO-1 and/or Melan-A reactivity (that is, in patients with exceptionally long survival). We further observed a negative effect on survival in patients with CD4+ T cells producing IL4 and IL17 upon Melan-A stimulation. Their prognosis was comparable to patients without any Melan-A reactivity. Conclusions: The nature and prognostic impact of specific T-cell responses is different according to targeted antigen. Independent from phenotype and functional aspects, NY-ESO-1 reactivity is associated with good prognosis. In terms of Melan-A, antigen-specific CD8+ but not CD4+ responses are associated with prolonged survival. Clin Cancer Res; 20(16); 4390–9. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-14-1015
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 8
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    Abstract CT012: Evaluation of atezolizumab (A), cobimetinib (C), and vemurafenib (V) in previously untreated patients with BRAF V600 mutation-positive advanced melanoma: Primary results from the phase 3 IMspire150 trial
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. CT012-CT012
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. CT012-CT012
    Abstract: Background: Approved systemic treatments for advanced melanoma include immune checkpoint inhibitor therapy (CIT) and targeted therapy with BRAF plus MEK inhibitors for BRAFV600E/K mutant melanoma. Response rates with CITs are typically lower than those observed with targeted therapy, but CIT responses are more durable. Preclinical and clinical data suggest a potential for synergy between CIT and BRAF plus MEK inhibitors. We therefore evaluated whether combining CIT with targeted therapy could improve efficacy vs targeted therapy alone. Methods: Treatment-naive patients with unresectable stage IIIc/IV melanoma (AJCC 7th ed), measurable disease by RECIST 1.1, and BRAFV600 mutations in their tumors were randomized to the anti-programmed death-ligand 1 antibody A + C + V or placebo (Pbo) + C + V. A or Pbo were given on days 1 and 15 of each 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity. The primary outcome was investigator-assessed progression-free survival (PFS). Results: 514 patients were enrolled (A + C + V = 256; Pbo + C + V = 258) and followed for a median of 18.9 months. Investigator-assessed PFS was significantly prolonged with A + C + V vs Pbo + C + V (15.1 vs 10.6 months, respectively; hazard ratio: 0.78; 95% confidence interval: 0.63-0.97; P=0.025), an effect seen in all prognostic subgroups. While objective response rates were similar in the A + C + V and Pbo + C + V groups, median duration of response was prolonged with A + C + V (21.0 months) vs Pbo + C + V (12.6 months). Overall survival data were not mature at the time of analysis. Common treatment-related adverse events (AEs; & gt;30%) in the A + C + V and Pbo + C + V groups were blood creatinine phosphokinase (CPK) increase (51.3% vs 44.8%), diarrhea (42.2% vs 46.6%), rash (40.9% in both arms), arthralgia (39.1% vs 28.1%), pyrexia (38.7% vs 26.0%), alanine aminotransferase (ALT) increase (33.9% vs 22.8%), and lipase increase (32.2% vs 27.4%). Common treatment-related grade 3/4 AEs ( & gt;10%) that occurred in the A + C + V and Pbo + C + V groups were lipase increase (20.4% vs 20.6%), blood CPK increase (20.0% vs 14.9%), ALT increase (13.0% vs 8.9%), and maculopapular rash (12.6% vs 9.6%). The incidence of treatment-related serious AEs was similar between the A + C + V (33.5%) and Pbo + C + V (28.8%) groups. 12.6% of patients in the A + C + V group and 15.7% in the Pbo + C + V group stopped all treatment because of AEs. The safety profile of the A + C + V regimen was generally consistent with the known profiles of the individual components. Conclusion: Combination therapy with A + C + V was tolerable and manageable, produced durable responses, and significantly increased PFS vs Pbo + C + V. Thus, A + C + V represents a viable treatment option for BRAFV600 mutation-positive advanced melanoma. ClinicalTrials.gov ID: NCT02908672 Citation Format: Grant A. McArthur, Daniil Stroyakovskiy, Helen Gogas, Caroline Robert, Karl Lewis, Svetlana Protsenko, Rodrigo Pereira, Thomas Eigentler, Piotr Rutkowski, Lev Demidov, Georgy Moiseevich Manikhas, Yibing Yan, K. C. Huang, Anne Uyei, Virgina McNally, Ralf Gutzmer, Paolo Ascierto. Evaluation of atezolizumab (A), cobimetinib (C), and vemurafenib (V) in previously untreated patients with BRAFV600 mutation-positive advanced melanoma: Primary results from the phase 3 IMspire150 trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT012.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-CT012
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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