Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade
This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patien...
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| Veröffentlicht in: | Journal for immunotherapy of cancer 2022-05, Vol.10 (5), p.e004076 |
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| creator | Gomez-Roca, Carlos Cassier, Philippe Zamarin, Dmitriy Machiels, Jean-Pascal Perez Gracia, Jose Luis Stephen Hodi, F Taus, Alvaro Martinez Garcia, Maria Boni, Valentina Eder, Joseph P Hafez, Navid Sullivan, Ryan Mcdermott, David Champiat, Stephane Aspeslagh, Sandrine Terret, Catherine Jegg, Anna-Maria Jacob, Wolfgang Cannarile, Michael A Ries, Carola Korski, Konstanty Michielin, Francesca Christen, Randolph Babitzki, Galina Watson, Carl Meneses-Lorente, Georgina Weisser, Martin Rüttinger, Dominik Delord, Jean-Pierre Marabelle, Aurelien |
| description | This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs).
Emactuzumab (500-1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients.
Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients.
Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation. |
| doi_str_mv | 10.1136/jitc-2021-004076 |
| format | Article |
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Emactuzumab (500-1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients.
Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients.
Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.</description><identifier>ISSN: 2051-1426</identifier><identifier>EISSN: 2051-1426</identifier><identifier>DOI: 10.1136/jitc-2021-004076</identifier><identifier>PMID: 35577503</identifier><language>eng</language><publisher>England: BMJ Publishing Group</publisher><subject>Antibodies, Monoclonal - adverse effects ; Antibodies, Monoclonal, Humanized ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Carcinoma, Non-Small-Cell Lung - pathology ; Clinical/Translational Cancer Immunotherapy ; Fatigue - chemically induced ; Humans ; Immune Checkpoint Inhibitors ; Ligands ; Lung Neoplasms - drug therapy ; Melanoma - drug therapy ; Receptor Protein-Tyrosine Kinases ; Urinary Bladder Neoplasms - drug therapy</subject><ispartof>Journal for immunotherapy of cancer, 2022-05, Vol.10 (5), p.e004076</ispartof><rights>Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.</rights><rights>Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3116-6cc58c0f4c6d1e2b3aa5af02cc36a90e46b800d01e816073ae4406a47baa32103</citedby><cites>FETCH-LOGICAL-c3116-6cc58c0f4c6d1e2b3aa5af02cc36a90e46b800d01e816073ae4406a47baa32103</cites><orcidid>0000-0001-6369-9742 ; 0000-0002-0094-0161 ; 0000-0002-8171-7542 ; 0000-0001-5344-6645 ; 0000-0002-5816-3019</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9114963/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9114963/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35577503$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gomez-Roca, Carlos</creatorcontrib><creatorcontrib>Cassier, Philippe</creatorcontrib><creatorcontrib>Zamarin, Dmitriy</creatorcontrib><creatorcontrib>Machiels, Jean-Pascal</creatorcontrib><creatorcontrib>Perez Gracia, Jose Luis</creatorcontrib><creatorcontrib>Stephen Hodi, F</creatorcontrib><creatorcontrib>Taus, Alvaro</creatorcontrib><creatorcontrib>Martinez Garcia, Maria</creatorcontrib><creatorcontrib>Boni, Valentina</creatorcontrib><creatorcontrib>Eder, Joseph P</creatorcontrib><creatorcontrib>Hafez, Navid</creatorcontrib><creatorcontrib>Sullivan, Ryan</creatorcontrib><creatorcontrib>Mcdermott, David</creatorcontrib><creatorcontrib>Champiat, Stephane</creatorcontrib><creatorcontrib>Aspeslagh, Sandrine</creatorcontrib><creatorcontrib>Terret, Catherine</creatorcontrib><creatorcontrib>Jegg, Anna-Maria</creatorcontrib><creatorcontrib>Jacob, Wolfgang</creatorcontrib><creatorcontrib>Cannarile, Michael A</creatorcontrib><creatorcontrib>Ries, Carola</creatorcontrib><creatorcontrib>Korski, Konstanty</creatorcontrib><creatorcontrib>Michielin, Francesca</creatorcontrib><creatorcontrib>Christen, Randolph</creatorcontrib><creatorcontrib>Babitzki, Galina</creatorcontrib><creatorcontrib>Watson, Carl</creatorcontrib><creatorcontrib>Meneses-Lorente, Georgina</creatorcontrib><creatorcontrib>Weisser, Martin</creatorcontrib><creatorcontrib>Rüttinger, Dominik</creatorcontrib><creatorcontrib>Delord, Jean-Pierre</creatorcontrib><creatorcontrib>Marabelle, Aurelien</creatorcontrib><title>Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade</title><title>Journal for immunotherapy of cancer</title><addtitle>J Immunother Cancer</addtitle><description>This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs).
Emactuzumab (500-1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients.
Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients.
Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.</description><subject>Antibodies, Monoclonal - adverse effects</subject><subject>Antibodies, Monoclonal, Humanized</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Clinical/Translational Cancer Immunotherapy</subject><subject>Fatigue - chemically induced</subject><subject>Humans</subject><subject>Immune Checkpoint Inhibitors</subject><subject>Ligands</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Melanoma - drug therapy</subject><subject>Receptor Protein-Tyrosine Kinases</subject><subject>Urinary Bladder Neoplasms - drug therapy</subject><issn>2051-1426</issn><issn>2051-1426</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkcFO3DAURa2qqCBgz6ryD5i-FydOZlMJTaFFGqlVgbX14jiMYWJHiTNt-ZN-RT-CH6ujoSO6sn19732WD2NnCOeIUn14cNGIDDIUADmU6g07yqBAgXmm3r7aH7LTcXwAAAQpq6p6xw5lUZRlAfKI_b7w0YnlzZXA79x2ZOL0NHVUc-e5CV3tPEUXPP_h4prT7P32SayQU7RPYeP2Xmq25I1t-JjUhsepCwPvU9b6OHJPz3-2lifJ_uztkMTZ2qaz67rJW27W1jz2wfnI600wj9TYE3bQ0ma0py_rMbu7urxdfhGrr5-vlxcrYSSiEsqYojLQ5kY1aLNaEhXUQmaMVLQAm6u6AmgAbYUKSkk2z0FRXtZEMktfcsw-7nr7qe5sY9KDB9rofnAdDb90IKf_v_Fure_DVi8Q84WSqQB2BWYI4zjYdp9F0DMpPZPSMym9I5Ui71_P3Af-cZF_AYr2k-g</recordid><startdate>20220501</startdate><enddate>20220501</enddate><creator>Gomez-Roca, Carlos</creator><creator>Cassier, Philippe</creator><creator>Zamarin, Dmitriy</creator><creator>Machiels, Jean-Pascal</creator><creator>Perez Gracia, Jose Luis</creator><creator>Stephen Hodi, F</creator><creator>Taus, Alvaro</creator><creator>Martinez Garcia, Maria</creator><creator>Boni, Valentina</creator><creator>Eder, Joseph P</creator><creator>Hafez, Navid</creator><creator>Sullivan, Ryan</creator><creator>Mcdermott, David</creator><creator>Champiat, Stephane</creator><creator>Aspeslagh, Sandrine</creator><creator>Terret, Catherine</creator><creator>Jegg, Anna-Maria</creator><creator>Jacob, Wolfgang</creator><creator>Cannarile, Michael A</creator><creator>Ries, Carola</creator><creator>Korski, Konstanty</creator><creator>Michielin, Francesca</creator><creator>Christen, Randolph</creator><creator>Babitzki, Galina</creator><creator>Watson, Carl</creator><creator>Meneses-Lorente, Georgina</creator><creator>Weisser, Martin</creator><creator>Rüttinger, Dominik</creator><creator>Delord, Jean-Pierre</creator><creator>Marabelle, Aurelien</creator><general>BMJ Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6369-9742</orcidid><orcidid>https://orcid.org/0000-0002-0094-0161</orcidid><orcidid>https://orcid.org/0000-0002-8171-7542</orcidid><orcidid>https://orcid.org/0000-0001-5344-6645</orcidid><orcidid>https://orcid.org/0000-0002-5816-3019</orcidid></search><sort><creationdate>20220501</creationdate><title>Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade</title><author>Gomez-Roca, Carlos ; Cassier, Philippe ; Zamarin, Dmitriy ; Machiels, Jean-Pascal ; Perez Gracia, Jose Luis ; Stephen Hodi, F ; Taus, Alvaro ; Martinez Garcia, Maria ; Boni, Valentina ; Eder, Joseph P ; Hafez, Navid ; Sullivan, Ryan ; Mcdermott, David ; Champiat, Stephane ; Aspeslagh, Sandrine ; Terret, Catherine ; Jegg, Anna-Maria ; Jacob, Wolfgang ; Cannarile, Michael A ; Ries, Carola ; Korski, Konstanty ; Michielin, Francesca ; Christen, Randolph ; Babitzki, Galina ; Watson, Carl ; Meneses-Lorente, Georgina ; Weisser, Martin ; Rüttinger, Dominik ; Delord, Jean-Pierre ; Marabelle, Aurelien</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3116-6cc58c0f4c6d1e2b3aa5af02cc36a90e46b800d01e816073ae4406a47baa32103</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Antibodies, Monoclonal - 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Emactuzumab (500-1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients.
Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients.
Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.</abstract><cop>England</cop><pub>BMJ Publishing Group</pub><pmid>35577503</pmid><doi>10.1136/jitc-2021-004076</doi><orcidid>https://orcid.org/0000-0001-6369-9742</orcidid><orcidid>https://orcid.org/0000-0002-0094-0161</orcidid><orcidid>https://orcid.org/0000-0002-8171-7542</orcidid><orcidid>https://orcid.org/0000-0001-5344-6645</orcidid><orcidid>https://orcid.org/0000-0002-5816-3019</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2051-1426 |
| ispartof | Journal for immunotherapy of cancer, 2022-05, Vol.10 (5), p.e004076 |
| issn | 2051-1426 2051-1426 |
| language | eng |
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| source | MEDLINE; PubMed Central (PMC); BMJ Journals (Open Access); DOAJ Directory of Open Access Journals; EZB Electronic Journals Library |
| subjects | Antibodies, Monoclonal - adverse effects Antibodies, Monoclonal, Humanized Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - pathology Clinical/Translational Cancer Immunotherapy Fatigue - chemically induced Humans Immune Checkpoint Inhibitors Ligands Lung Neoplasms - drug therapy Melanoma - drug therapy Receptor Protein-Tyrosine Kinases Urinary Bladder Neoplasms - drug therapy |
| title | Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T16%3A41%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Anti-CSF-1R%20emactuzumab%20in%20combination%20with%20anti-PD-L1%20atezolizumab%20in%20advanced%20solid%20tumor%20patients%20na%C3%AFve%20or%20experienced%20for%20immune%20checkpoint%20blockade&rft.jtitle=Journal%20for%20immunotherapy%20of%20cancer&rft.au=Gomez-Roca,%20Carlos&rft.date=2022-05-01&rft.volume=10&rft.issue=5&rft.spage=e004076&rft.pages=e004076-&rft.issn=2051-1426&rft.eissn=2051-1426&rft_id=info:doi/10.1136/jitc-2021-004076&rft_dat=%3Cpubmed_cross%3E35577503%3C/pubmed_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/35577503&rfr_iscdi=true |