Inhibition of lysine acetyltransferase KAT6 in ER+HER2− metastatic breast cancer: a phase 1 trial
Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER + ) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics...
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| Veröffentlicht in: | Nature medicine 2024-08, Vol.30 (8), p.2242-2250 |
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| creator | Mukohara, Toru Park, Yeon Hee Sommerhalder, David Yonemori, Kan Hamilton, Erika Kim, Sung-Bae Kim, Jee Hyun Iwata, Hiroji Yamashita, Toshinari Layman, Rachel M. Mita, Monica Clay, Timothy Chae, Yee Soo Oakman, Catherine Yan, Fengting Kim, Gun Min Im, Seock-Ah Lindeman, Geoffrey J. Rugo, Hope S. Liyanage, Marlon Saul, Michelle Le Corre, Christophe Skoura, Athanasia Liu, Li Li, Meng LoRusso, Patricia M. |
| description | Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER
+
) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (
n
= 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER
+
human epidermal growth factor receptor-negative (HER2
−
) metastatic breast cancer (mBC). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as monotherapy and in combination with fulvestrant, were met. Secondary endpoints included characterization of PK and evaluation of antitumor activity, including objective response rate (ORR) and progression-free survival (PFS). Common treatment-related adverse events (any grade; grades 3–4) included dysgeusia (83.2%, 0%), neutropenia (59.8%, 35.5%) and anemia (48.6%, 13.1%). Exposure was approximately dose proportional. Antitumor activity was observed as monotherapy. For the PF-07248144–fulvestrant combination (
n
= 43), the ORR (95% confidence interval (CI)) was 30.2% (95% CI = 17.2–46.1%) and the median PFS was 10.7 (5.3–not evaluable) months. PF-07248144 demonstrated a tolerable safety profile and durable antitumor activity in heavily pretreated ER
+
HER2
−
mBC. These findings establish KAT6A and KAT6B as druggable cancer targets, provide clinical proof of concept and reveal a potential avenue to treat mBC. clinicaltrial.gov registration:
NCT04606446
.
In this phase 1 trial, treatment of patients with ER
+
HER2
−
metastatic breast cancer with a selective catalytic inhibitor of the lysine acetyltransferase KAT6 shows a manageable safety profile and encouraging preliminary clinical efficacy. |
| doi_str_mv | 10.1038/s41591-024-03060-0 |
| format | Article |
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+
) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (
n
= 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER
+
human epidermal growth factor receptor-negative (HER2
−
) metastatic breast cancer (mBC). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as monotherapy and in combination with fulvestrant, were met. Secondary endpoints included characterization of PK and evaluation of antitumor activity, including objective response rate (ORR) and progression-free survival (PFS). Common treatment-related adverse events (any grade; grades 3–4) included dysgeusia (83.2%, 0%), neutropenia (59.8%, 35.5%) and anemia (48.6%, 13.1%). Exposure was approximately dose proportional. Antitumor activity was observed as monotherapy. For the PF-07248144–fulvestrant combination (
n
= 43), the ORR (95% confidence interval (CI)) was 30.2% (95% CI = 17.2–46.1%) and the median PFS was 10.7 (5.3–not evaluable) months. PF-07248144 demonstrated a tolerable safety profile and durable antitumor activity in heavily pretreated ER
+
HER2
−
mBC. These findings establish KAT6A and KAT6B as druggable cancer targets, provide clinical proof of concept and reveal a potential avenue to treat mBC. clinicaltrial.gov registration:
NCT04606446
.
In this phase 1 trial, treatment of patients with ER
+
HER2
−
metastatic breast cancer with a selective catalytic inhibitor of the lysine acetyltransferase KAT6 shows a manageable safety profile and encouraging preliminary clinical efficacy.</description><identifier>ISSN: 1078-8956</identifier><identifier>ISSN: 1546-170X</identifier><identifier>EISSN: 1546-170X</identifier><identifier>DOI: 10.1038/s41591-024-03060-0</identifier><identifier>PMID: 38824244</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/154/556 ; 631/67/1059/153 ; Acetyltransferase ; Anemia ; Anticancer properties ; Antitumor activity ; Biomarkers ; Biomedical and Life Sciences ; Biomedicine ; Breast cancer ; Cancer Research ; Effectiveness ; ErbB-2 protein ; Estrogen receptors ; Estrogens ; Fulvestrant ; Growth factors ; Histones ; Infectious Diseases ; Inhibitors ; Lysine ; Metabolic Diseases ; Metastases ; Metastasis ; Molecular Medicine ; Neurosciences ; Neutropenia ; Pharmacodynamics ; Pharmacokinetics ; Receptors ; Safety ; Safety management</subject><ispartof>Nature medicine, 2024-08, Vol.30 (8), p.2242-2250</ispartof><rights>The Author(s) 2024. corrected publication 2024</rights><rights>2024. The Author(s).</rights><rights>The Author(s) 2024. corrected publication 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2024, corrected publication 2024 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c356t-50617f170a8e646fa14005c2b06a24faece23f18b8825407b768f327645716f03</cites><orcidid>0000-0003-4156-9212 ; 0000-0003-3801-6174 ; 0000-0002-7624-7611 ; 0000-0002-1911-0336 ; 0009-0002-5406-8345 ; 0000-0001-7144-036X ; 0000-0002-8663-0331 ; 0000-0002-6479-1660 ; 0000-0001-9386-2416 ; 0000-0002-7033-9064 ; 0000-0001-6710-4814</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41591-024-03060-0$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41591-024-03060-0$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38824244$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mukohara, Toru</creatorcontrib><creatorcontrib>Park, Yeon Hee</creatorcontrib><creatorcontrib>Sommerhalder, David</creatorcontrib><creatorcontrib>Yonemori, Kan</creatorcontrib><creatorcontrib>Hamilton, Erika</creatorcontrib><creatorcontrib>Kim, Sung-Bae</creatorcontrib><creatorcontrib>Kim, Jee Hyun</creatorcontrib><creatorcontrib>Iwata, Hiroji</creatorcontrib><creatorcontrib>Yamashita, Toshinari</creatorcontrib><creatorcontrib>Layman, Rachel M.</creatorcontrib><creatorcontrib>Mita, Monica</creatorcontrib><creatorcontrib>Clay, Timothy</creatorcontrib><creatorcontrib>Chae, Yee Soo</creatorcontrib><creatorcontrib>Oakman, Catherine</creatorcontrib><creatorcontrib>Yan, Fengting</creatorcontrib><creatorcontrib>Kim, Gun Min</creatorcontrib><creatorcontrib>Im, Seock-Ah</creatorcontrib><creatorcontrib>Lindeman, Geoffrey J.</creatorcontrib><creatorcontrib>Rugo, Hope S.</creatorcontrib><creatorcontrib>Liyanage, Marlon</creatorcontrib><creatorcontrib>Saul, Michelle</creatorcontrib><creatorcontrib>Le Corre, Christophe</creatorcontrib><creatorcontrib>Skoura, Athanasia</creatorcontrib><creatorcontrib>Liu, Li</creatorcontrib><creatorcontrib>Li, Meng</creatorcontrib><creatorcontrib>LoRusso, Patricia M.</creatorcontrib><title>Inhibition of lysine acetyltransferase KAT6 in ER+HER2− metastatic breast cancer: a phase 1 trial</title><title>Nature medicine</title><addtitle>Nat Med</addtitle><addtitle>Nat Med</addtitle><description>Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER
+
) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (
n
= 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER
+
human epidermal growth factor receptor-negative (HER2
−
) metastatic breast cancer (mBC). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as monotherapy and in combination with fulvestrant, were met. Secondary endpoints included characterization of PK and evaluation of antitumor activity, including objective response rate (ORR) and progression-free survival (PFS). Common treatment-related adverse events (any grade; grades 3–4) included dysgeusia (83.2%, 0%), neutropenia (59.8%, 35.5%) and anemia (48.6%, 13.1%). Exposure was approximately dose proportional. Antitumor activity was observed as monotherapy. For the PF-07248144–fulvestrant combination (
n
= 43), the ORR (95% confidence interval (CI)) was 30.2% (95% CI = 17.2–46.1%) and the median PFS was 10.7 (5.3–not evaluable) months. PF-07248144 demonstrated a tolerable safety profile and durable antitumor activity in heavily pretreated ER
+
HER2
−
mBC. These findings establish KAT6A and KAT6B as druggable cancer targets, provide clinical proof of concept and reveal a potential avenue to treat mBC. clinicaltrial.gov registration:
NCT04606446
.
In this phase 1 trial, treatment of patients with ER
+
HER2
−
metastatic breast cancer with a selective catalytic inhibitor of the lysine acetyltransferase KAT6 shows a manageable safety profile and encouraging preliminary clinical efficacy.</description><subject>631/154/556</subject><subject>631/67/1059/153</subject><subject>Acetyltransferase</subject><subject>Anemia</subject><subject>Anticancer properties</subject><subject>Antitumor activity</subject><subject>Biomarkers</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Breast cancer</subject><subject>Cancer Research</subject><subject>Effectiveness</subject><subject>ErbB-2 protein</subject><subject>Estrogen receptors</subject><subject>Estrogens</subject><subject>Fulvestrant</subject><subject>Growth factors</subject><subject>Histones</subject><subject>Infectious Diseases</subject><subject>Inhibitors</subject><subject>Lysine</subject><subject>Metabolic Diseases</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Molecular Medicine</subject><subject>Neurosciences</subject><subject>Neutropenia</subject><subject>Pharmacodynamics</subject><subject>Pharmacokinetics</subject><subject>Receptors</subject><subject>Safety</subject><subject>Safety 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Erika</creator><creator>Kim, Sung-Bae</creator><creator>Kim, Jee Hyun</creator><creator>Iwata, Hiroji</creator><creator>Yamashita, Toshinari</creator><creator>Layman, Rachel M.</creator><creator>Mita, Monica</creator><creator>Clay, Timothy</creator><creator>Chae, Yee Soo</creator><creator>Oakman, Catherine</creator><creator>Yan, Fengting</creator><creator>Kim, Gun Min</creator><creator>Im, Seock-Ah</creator><creator>Lindeman, Geoffrey J.</creator><creator>Rugo, Hope S.</creator><creator>Liyanage, Marlon</creator><creator>Saul, Michelle</creator><creator>Le Corre, Christophe</creator><creator>Skoura, Athanasia</creator><creator>Liu, Li</creator><creator>Li, Meng</creator><creator>LoRusso, Patricia M.</creator><general>Nature Publishing Group US</general><general>Nature Publishing 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of lysine acetyltransferase KAT6 in ER+HER2− metastatic breast cancer: a phase 1 trial</title><author>Mukohara, Toru ; Park, Yeon Hee ; Sommerhalder, David ; Yonemori, Kan ; Hamilton, Erika ; Kim, Sung-Bae ; Kim, Jee Hyun ; Iwata, Hiroji ; Yamashita, Toshinari ; Layman, Rachel M. ; Mita, Monica ; Clay, Timothy ; Chae, Yee Soo ; Oakman, Catherine ; Yan, Fengting ; Kim, Gun Min ; Im, Seock-Ah ; Lindeman, Geoffrey J. ; Rugo, Hope S. ; Liyanage, Marlon ; Saul, Michelle ; Le Corre, Christophe ; Skoura, Athanasia ; Liu, Li ; Li, Meng ; LoRusso, Patricia M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-50617f170a8e646fa14005c2b06a24faece23f18b8825407b768f327645716f03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>631/154/556</topic><topic>631/67/1059/153</topic><topic>Acetyltransferase</topic><topic>Anemia</topic><topic>Anticancer properties</topic><topic>Antitumor activity</topic><topic>Biomarkers</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Breast cancer</topic><topic>Cancer Research</topic><topic>Effectiveness</topic><topic>ErbB-2 protein</topic><topic>Estrogen receptors</topic><topic>Estrogens</topic><topic>Fulvestrant</topic><topic>Growth factors</topic><topic>Histones</topic><topic>Infectious Diseases</topic><topic>Inhibitors</topic><topic>Lysine</topic><topic>Metabolic Diseases</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Molecular Medicine</topic><topic>Neurosciences</topic><topic>Neutropenia</topic><topic>Pharmacodynamics</topic><topic>Pharmacokinetics</topic><topic>Receptors</topic><topic>Safety</topic><topic>Safety management</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mukohara, Toru</creatorcontrib><creatorcontrib>Park, Yeon Hee</creatorcontrib><creatorcontrib>Sommerhalder, David</creatorcontrib><creatorcontrib>Yonemori, 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Meng</creatorcontrib><creatorcontrib>LoRusso, Patricia M.</creatorcontrib><collection>Springer Nature OA/Free Journals</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical 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Christophe</au><au>Skoura, Athanasia</au><au>Liu, Li</au><au>Li, Meng</au><au>LoRusso, Patricia M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of lysine acetyltransferase KAT6 in ER+HER2− metastatic breast cancer: a phase 1 trial</atitle><jtitle>Nature medicine</jtitle><stitle>Nat Med</stitle><addtitle>Nat Med</addtitle><date>2024-08-01</date><risdate>2024</risdate><volume>30</volume><issue>8</issue><spage>2242</spage><epage>2250</epage><pages>2242-2250</pages><issn>1078-8956</issn><issn>1546-170X</issn><eissn>1546-170X</eissn><abstract>Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER
+
) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (
n
= 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER
+
human epidermal growth factor receptor-negative (HER2
−
) metastatic breast cancer (mBC). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as monotherapy and in combination with fulvestrant, were met. Secondary endpoints included characterization of PK and evaluation of antitumor activity, including objective response rate (ORR) and progression-free survival (PFS). Common treatment-related adverse events (any grade; grades 3–4) included dysgeusia (83.2%, 0%), neutropenia (59.8%, 35.5%) and anemia (48.6%, 13.1%). Exposure was approximately dose proportional. Antitumor activity was observed as monotherapy. For the PF-07248144–fulvestrant combination (
n
= 43), the ORR (95% confidence interval (CI)) was 30.2% (95% CI = 17.2–46.1%) and the median PFS was 10.7 (5.3–not evaluable) months. PF-07248144 demonstrated a tolerable safety profile and durable antitumor activity in heavily pretreated ER
+
HER2
−
mBC. These findings establish KAT6A and KAT6B as druggable cancer targets, provide clinical proof of concept and reveal a potential avenue to treat mBC. clinicaltrial.gov registration:
NCT04606446
.
In this phase 1 trial, treatment of patients with ER
+
HER2
−
metastatic breast cancer with a selective catalytic inhibitor of the lysine acetyltransferase KAT6 shows a manageable safety profile and encouraging preliminary clinical efficacy.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>38824244</pmid><doi>10.1038/s41591-024-03060-0</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0003-4156-9212</orcidid><orcidid>https://orcid.org/0000-0003-3801-6174</orcidid><orcidid>https://orcid.org/0000-0002-7624-7611</orcidid><orcidid>https://orcid.org/0000-0002-1911-0336</orcidid><orcidid>https://orcid.org/0009-0002-5406-8345</orcidid><orcidid>https://orcid.org/0000-0001-7144-036X</orcidid><orcidid>https://orcid.org/0000-0002-8663-0331</orcidid><orcidid>https://orcid.org/0000-0002-6479-1660</orcidid><orcidid>https://orcid.org/0000-0001-9386-2416</orcidid><orcidid>https://orcid.org/0000-0002-7033-9064</orcidid><orcidid>https://orcid.org/0000-0001-6710-4814</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1078-8956 |
| ispartof | Nature medicine, 2024-08, Vol.30 (8), p.2242-2250 |
| issn | 1078-8956 1546-170X 1546-170X |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11333285 |
| source | Nature Journals Online; SpringerLink Journals - AutoHoldings |
| subjects | 631/154/556 631/67/1059/153 Acetyltransferase Anemia Anticancer properties Antitumor activity Biomarkers Biomedical and Life Sciences Biomedicine Breast cancer Cancer Research Effectiveness ErbB-2 protein Estrogen receptors Estrogens Fulvestrant Growth factors Histones Infectious Diseases Inhibitors Lysine Metabolic Diseases Metastases Metastasis Molecular Medicine Neurosciences Neutropenia Pharmacodynamics Pharmacokinetics Receptors Safety Safety management |
| title | Inhibition of lysine acetyltransferase KAT6 in ER+HER2− metastatic breast cancer: a phase 1 trial |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-08T03%3A32%3A34IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Inhibition%20of%20lysine%20acetyltransferase%20KAT6%20in%20ER+HER2%E2%88%92%20metastatic%20breast%20cancer:%20a%20phase%201%20trial&rft.jtitle=Nature%20medicine&rft.au=Mukohara,%20Toru&rft.date=2024-08-01&rft.volume=30&rft.issue=8&rft.spage=2242&rft.epage=2250&rft.pages=2242-2250&rft.issn=1078-8956&rft.eissn=1546-170X&rft_id=info:doi/10.1038/s41591-024-03060-0&rft_dat=%3Cproquest_pubme%3E3063468658%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3094586320&rft_id=info:pmid/38824244&rfr_iscdi=true |