Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway
Background PI3K pathway activation is common in endometrial cancer. We evaluated the safety and efficacy of the dual PI3K/mTOR inhibitor, LY3023414, in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway. Methods We conducted a single‐arm phase 2 study of mon...
Gespeichert in:
| Veröffentlicht in: | Cancer 2020-03, Vol.126 (6), p.1274-1282 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1282 |
|---|---|
| container_issue | 6 |
| container_start_page | 1274 |
| container_title | Cancer |
| container_volume | 126 |
| creator | Rubinstein, Maria M. Hyman, David M. Caird, Imogen Won, Helen Soldan, Krysten Seier, Kenneth Iasonos, Alexia Tew, William P. O’Cearbhaill, Roisin E. Grisham, Rachel N. Hensley, Martee L. Troso‐Sandoval, Tiffany Sabbatini, Paul Guillen, Joyce Selcuklu, S. Duygu Zimel, Catherine Torrisi, Jean Aghajanian, Carol Makker, Vicky |
| description | Background
PI3K pathway activation is common in endometrial cancer. We evaluated the safety and efficacy of the dual PI3K/mTOR inhibitor, LY3023414, in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway.
Methods
We conducted a single‐arm phase 2 study of monotherapy LY3023414. Eligible patients had advanced endometrial cancer of any grade, prior management with 1‐4 cytotoxic lines, and PI3K pathway activation prospectively defined as a loss‐of‐function PTEN alteration or activating alteration in PIK3CA, AKT1, PIK3R1, PIK3R2, or MTOR. The primary objective was best overall response rate (ORR) per RECIST 1.1.
Results
Twenty‐eight patients were treated; histologies included endometroid (39%), carcinosarcoma (25%), serous (21%), and mixed (14%). Patients were heavily pretreated, with a median of 2 prior cytotoxic lines (range, 1‐3). The most common alterations involved PIK3CA (68%), PTEN (43%), and PIK3R1 (32%). In the 25 efficacy‐evaluable patients, the ORR was 16% (90% CI, 7%‐100%), and the clinical benefit rate was 28% (90% CI, 16%‐100%). Four patients had a confirmed partial response, and 2 responses lasted for >9 months. The median progression‐free survival and overall survival were 2.5 months (95% CI, 1.2‐3.0) and 9.2 months (95% CI, 5.0‐15.9), respectively. The most common all‐grade treatment‐related adverse events were anemia (71%), hyperglycemia (71%), hypoalbuminemia (68%), and hypophosphatemia (61%). No correlation between molecular alterations and response was observed.
Conclusion
In patients with heavily pretreated advanced endometrial cancer prospectively selected for tumors with activating PI3K pathway mutations, LY3023414 demonstrated modest single‐agent activity and a manageable safety profile.
The authors conducted a single‐arm phase 2 study of LY3023414, a dual PI3K/mTOR inhibitor, in patients with advanced endometrial cancer who were prospectively selected to have activating PI3K pathway mutations. LY3023414 was tolerable and had a modest clinical response (overall response rate, 16% [90% CI, 7%‐100%]). |
| doi_str_mv | 10.1002/cncr.32677 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2366629350</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2366629350</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3937-d116f03bce3b99f46539fa5bd6166e1501856d33918dc56ac5d16018995407c3</originalsourceid><addsrcrecordid>eNp9kMtKxDAUhoMoOl42PoAE3AnVJKdJm6UM3nDQQWahq5Imqa3MtGOSOoxPb-qoS1fnwne-Az9Cx5ScU0LYhW61OwcmsmwLjSiRWUJoyrbRiBCSJzyF5z207_1bHDPGYRftAc1zkjMxQp_TWnmLGfahN2vcVXjyAoRBSlPctHipQmPb4PGqCTVW5kO12hpsW9MtbHCNmmM9rByulSs717SvWOnQfMS72C76EJuu9YMr1BZP7-B-kNYrtT5EO5Wae3v0Uw_Q7PpqNr5NJo83d-PLSaJBQpYYSkVFoNQWSimrVHCQleKlEVQISzmhORcGQNLcaC6U5oaKuJSSpyTTcIBON9ql695760Px1vWujR8LBkIIJoGTSJ1tKO06752tiqVrFsqtC0qKIeViSLn4TjnCJz_KvlxY84f-xhoBugFWzdyu_1EV44fx00b6BRD5hhk</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2366629350</pqid></control><display><type>article</type><title>Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway</title><source>MEDLINE</source><source>Access via Wiley Online Library</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Wiley Online Library (Open Access Collection)</source><source>Alma/SFX Local Collection</source><creator>Rubinstein, Maria M. ; Hyman, David M. ; Caird, Imogen ; Won, Helen ; Soldan, Krysten ; Seier, Kenneth ; Iasonos, Alexia ; Tew, William P. ; O’Cearbhaill, Roisin E. ; Grisham, Rachel N. ; Hensley, Martee L. ; Troso‐Sandoval, Tiffany ; Sabbatini, Paul ; Guillen, Joyce ; Selcuklu, S. Duygu ; Zimel, Catherine ; Torrisi, Jean ; Aghajanian, Carol ; Makker, Vicky</creator><creatorcontrib>Rubinstein, Maria M. ; Hyman, David M. ; Caird, Imogen ; Won, Helen ; Soldan, Krysten ; Seier, Kenneth ; Iasonos, Alexia ; Tew, William P. ; O’Cearbhaill, Roisin E. ; Grisham, Rachel N. ; Hensley, Martee L. ; Troso‐Sandoval, Tiffany ; Sabbatini, Paul ; Guillen, Joyce ; Selcuklu, S. Duygu ; Zimel, Catherine ; Torrisi, Jean ; Aghajanian, Carol ; Makker, Vicky</creatorcontrib><description>Background
PI3K pathway activation is common in endometrial cancer. We evaluated the safety and efficacy of the dual PI3K/mTOR inhibitor, LY3023414, in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway.
Methods
We conducted a single‐arm phase 2 study of monotherapy LY3023414. Eligible patients had advanced endometrial cancer of any grade, prior management with 1‐4 cytotoxic lines, and PI3K pathway activation prospectively defined as a loss‐of‐function PTEN alteration or activating alteration in PIK3CA, AKT1, PIK3R1, PIK3R2, or MTOR. The primary objective was best overall response rate (ORR) per RECIST 1.1.
Results
Twenty‐eight patients were treated; histologies included endometroid (39%), carcinosarcoma (25%), serous (21%), and mixed (14%). Patients were heavily pretreated, with a median of 2 prior cytotoxic lines (range, 1‐3). The most common alterations involved PIK3CA (68%), PTEN (43%), and PIK3R1 (32%). In the 25 efficacy‐evaluable patients, the ORR was 16% (90% CI, 7%‐100%), and the clinical benefit rate was 28% (90% CI, 16%‐100%). Four patients had a confirmed partial response, and 2 responses lasted for >9 months. The median progression‐free survival and overall survival were 2.5 months (95% CI, 1.2‐3.0) and 9.2 months (95% CI, 5.0‐15.9), respectively. The most common all‐grade treatment‐related adverse events were anemia (71%), hyperglycemia (71%), hypoalbuminemia (68%), and hypophosphatemia (61%). No correlation between molecular alterations and response was observed.
Conclusion
In patients with heavily pretreated advanced endometrial cancer prospectively selected for tumors with activating PI3K pathway mutations, LY3023414 demonstrated modest single‐agent activity and a manageable safety profile.
The authors conducted a single‐arm phase 2 study of LY3023414, a dual PI3K/mTOR inhibitor, in patients with advanced endometrial cancer who were prospectively selected to have activating PI3K pathway mutations. LY3023414 was tolerable and had a modest clinical response (overall response rate, 16% [90% CI, 7%‐100%]).</description><identifier>ISSN: 0008-543X</identifier><identifier>EISSN: 1097-0142</identifier><identifier>DOI: 10.1002/cncr.32677</identifier><identifier>PMID: 31880826</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>1-Phosphatidylinositol 3-kinase ; Activation ; advanced ; Aged ; AKT1 protein ; Anemia ; Cancer ; Class I Phosphatidylinositol 3-Kinases ; Class Ia Phosphatidylinositol 3-Kinase - genetics ; Cytotoxicity ; dual PI3K/mTOR inhibitor ; Endometrial cancer ; Endometrial Neoplasms - drug therapy ; Endometrial Neoplasms - genetics ; Endometrial Neoplasms - pathology ; Endometrium ; Enzyme Activation ; Female ; Humans ; Hyperglycemia ; Hyperglycemia - chemically induced ; Hypoalbuminemia - chemically induced ; Hypophosphatemia ; Hypophosphatemia - chemically induced ; LY3023414 ; Middle Aged ; Mutation ; Oncology ; Patients ; Phosphatidylinositol 3-Kinases - genetics ; PI3K pathway ; Progression-Free Survival ; Proto-Oncogene Proteins c-akt - genetics ; PTEN Phosphohydrolase - genetics ; PTEN protein ; Pyridines - adverse effects ; Pyridines - therapeutic use ; Quinolones - adverse effects ; Quinolones - therapeutic use ; Safety management ; Signal Transduction ; Survival ; TOR protein ; TOR Serine-Threonine Kinases ; Treatment Outcome ; Tumors</subject><ispartof>Cancer, 2020-03, Vol.126 (6), p.1274-1282</ispartof><rights>2019 American Cancer Society</rights><rights>2019 American Cancer Society.</rights><rights>2020 American Cancer Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3937-d116f03bce3b99f46539fa5bd6166e1501856d33918dc56ac5d16018995407c3</citedby><cites>FETCH-LOGICAL-c3937-d116f03bce3b99f46539fa5bd6166e1501856d33918dc56ac5d16018995407c3</cites><orcidid>0000-0001-8150-9762 ; 0000-0002-7943-8245</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcncr.32677$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcncr.32677$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31880826$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rubinstein, Maria M.</creatorcontrib><creatorcontrib>Hyman, David M.</creatorcontrib><creatorcontrib>Caird, Imogen</creatorcontrib><creatorcontrib>Won, Helen</creatorcontrib><creatorcontrib>Soldan, Krysten</creatorcontrib><creatorcontrib>Seier, Kenneth</creatorcontrib><creatorcontrib>Iasonos, Alexia</creatorcontrib><creatorcontrib>Tew, William P.</creatorcontrib><creatorcontrib>O’Cearbhaill, Roisin E.</creatorcontrib><creatorcontrib>Grisham, Rachel N.</creatorcontrib><creatorcontrib>Hensley, Martee L.</creatorcontrib><creatorcontrib>Troso‐Sandoval, Tiffany</creatorcontrib><creatorcontrib>Sabbatini, Paul</creatorcontrib><creatorcontrib>Guillen, Joyce</creatorcontrib><creatorcontrib>Selcuklu, S. Duygu</creatorcontrib><creatorcontrib>Zimel, Catherine</creatorcontrib><creatorcontrib>Torrisi, Jean</creatorcontrib><creatorcontrib>Aghajanian, Carol</creatorcontrib><creatorcontrib>Makker, Vicky</creatorcontrib><title>Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway</title><title>Cancer</title><addtitle>Cancer</addtitle><description>Background
PI3K pathway activation is common in endometrial cancer. We evaluated the safety and efficacy of the dual PI3K/mTOR inhibitor, LY3023414, in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway.
Methods
We conducted a single‐arm phase 2 study of monotherapy LY3023414. Eligible patients had advanced endometrial cancer of any grade, prior management with 1‐4 cytotoxic lines, and PI3K pathway activation prospectively defined as a loss‐of‐function PTEN alteration or activating alteration in PIK3CA, AKT1, PIK3R1, PIK3R2, or MTOR. The primary objective was best overall response rate (ORR) per RECIST 1.1.
Results
Twenty‐eight patients were treated; histologies included endometroid (39%), carcinosarcoma (25%), serous (21%), and mixed (14%). Patients were heavily pretreated, with a median of 2 prior cytotoxic lines (range, 1‐3). The most common alterations involved PIK3CA (68%), PTEN (43%), and PIK3R1 (32%). In the 25 efficacy‐evaluable patients, the ORR was 16% (90% CI, 7%‐100%), and the clinical benefit rate was 28% (90% CI, 16%‐100%). Four patients had a confirmed partial response, and 2 responses lasted for >9 months. The median progression‐free survival and overall survival were 2.5 months (95% CI, 1.2‐3.0) and 9.2 months (95% CI, 5.0‐15.9), respectively. The most common all‐grade treatment‐related adverse events were anemia (71%), hyperglycemia (71%), hypoalbuminemia (68%), and hypophosphatemia (61%). No correlation between molecular alterations and response was observed.
Conclusion
In patients with heavily pretreated advanced endometrial cancer prospectively selected for tumors with activating PI3K pathway mutations, LY3023414 demonstrated modest single‐agent activity and a manageable safety profile.
The authors conducted a single‐arm phase 2 study of LY3023414, a dual PI3K/mTOR inhibitor, in patients with advanced endometrial cancer who were prospectively selected to have activating PI3K pathway mutations. LY3023414 was tolerable and had a modest clinical response (overall response rate, 16% [90% CI, 7%‐100%]).</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>Activation</subject><subject>advanced</subject><subject>Aged</subject><subject>AKT1 protein</subject><subject>Anemia</subject><subject>Cancer</subject><subject>Class I Phosphatidylinositol 3-Kinases</subject><subject>Class Ia Phosphatidylinositol 3-Kinase - genetics</subject><subject>Cytotoxicity</subject><subject>dual PI3K/mTOR inhibitor</subject><subject>Endometrial cancer</subject><subject>Endometrial Neoplasms - drug therapy</subject><subject>Endometrial Neoplasms - genetics</subject><subject>Endometrial Neoplasms - pathology</subject><subject>Endometrium</subject><subject>Enzyme Activation</subject><subject>Female</subject><subject>Humans</subject><subject>Hyperglycemia</subject><subject>Hyperglycemia - chemically induced</subject><subject>Hypoalbuminemia - chemically induced</subject><subject>Hypophosphatemia</subject><subject>Hypophosphatemia - chemically induced</subject><subject>LY3023414</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Oncology</subject><subject>Patients</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>PI3K pathway</subject><subject>Progression-Free Survival</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>PTEN Phosphohydrolase - genetics</subject><subject>PTEN protein</subject><subject>Pyridines - adverse effects</subject><subject>Pyridines - therapeutic use</subject><subject>Quinolones - adverse effects</subject><subject>Quinolones - therapeutic use</subject><subject>Safety management</subject><subject>Signal Transduction</subject><subject>Survival</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases</subject><subject>Treatment Outcome</subject><subject>Tumors</subject><issn>0008-543X</issn><issn>1097-0142</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtKxDAUhoMoOl42PoAE3AnVJKdJm6UM3nDQQWahq5Imqa3MtGOSOoxPb-qoS1fnwne-Az9Cx5ScU0LYhW61OwcmsmwLjSiRWUJoyrbRiBCSJzyF5z207_1bHDPGYRftAc1zkjMxQp_TWnmLGfahN2vcVXjyAoRBSlPctHipQmPb4PGqCTVW5kO12hpsW9MtbHCNmmM9rByulSs717SvWOnQfMS72C76EJuu9YMr1BZP7-B-kNYrtT5EO5Wae3v0Uw_Q7PpqNr5NJo83d-PLSaJBQpYYSkVFoNQWSimrVHCQleKlEVQISzmhORcGQNLcaC6U5oaKuJSSpyTTcIBON9ql695760Px1vWujR8LBkIIJoGTSJ1tKO06752tiqVrFsqtC0qKIeViSLn4TjnCJz_KvlxY84f-xhoBugFWzdyu_1EV44fx00b6BRD5hhk</recordid><startdate>20200315</startdate><enddate>20200315</enddate><creator>Rubinstein, Maria M.</creator><creator>Hyman, David M.</creator><creator>Caird, Imogen</creator><creator>Won, Helen</creator><creator>Soldan, Krysten</creator><creator>Seier, Kenneth</creator><creator>Iasonos, Alexia</creator><creator>Tew, William P.</creator><creator>O’Cearbhaill, Roisin E.</creator><creator>Grisham, Rachel N.</creator><creator>Hensley, Martee L.</creator><creator>Troso‐Sandoval, Tiffany</creator><creator>Sabbatini, Paul</creator><creator>Guillen, Joyce</creator><creator>Selcuklu, S. Duygu</creator><creator>Zimel, Catherine</creator><creator>Torrisi, Jean</creator><creator>Aghajanian, Carol</creator><creator>Makker, Vicky</creator><general>Wiley Subscription Services, Inc</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>7TO</scope><scope>7U7</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><orcidid>https://orcid.org/0000-0001-8150-9762</orcidid><orcidid>https://orcid.org/0000-0002-7943-8245</orcidid></search><sort><creationdate>20200315</creationdate><title>Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway</title><author>Rubinstein, Maria M. ; Hyman, David M. ; Caird, Imogen ; Won, Helen ; Soldan, Krysten ; Seier, Kenneth ; Iasonos, Alexia ; Tew, William P. ; O’Cearbhaill, Roisin E. ; Grisham, Rachel N. ; Hensley, Martee L. ; Troso‐Sandoval, Tiffany ; Sabbatini, Paul ; Guillen, Joyce ; Selcuklu, S. Duygu ; Zimel, Catherine ; Torrisi, Jean ; Aghajanian, Carol ; Makker, Vicky</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3937-d116f03bce3b99f46539fa5bd6166e1501856d33918dc56ac5d16018995407c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>Activation</topic><topic>advanced</topic><topic>Aged</topic><topic>AKT1 protein</topic><topic>Anemia</topic><topic>Cancer</topic><topic>Class I Phosphatidylinositol 3-Kinases</topic><topic>Class Ia Phosphatidylinositol 3-Kinase - genetics</topic><topic>Cytotoxicity</topic><topic>dual PI3K/mTOR inhibitor</topic><topic>Endometrial cancer</topic><topic>Endometrial Neoplasms - drug therapy</topic><topic>Endometrial Neoplasms - genetics</topic><topic>Endometrial Neoplasms - pathology</topic><topic>Endometrium</topic><topic>Enzyme Activation</topic><topic>Female</topic><topic>Humans</topic><topic>Hyperglycemia</topic><topic>Hyperglycemia - chemically induced</topic><topic>Hypoalbuminemia - chemically induced</topic><topic>Hypophosphatemia</topic><topic>Hypophosphatemia - chemically induced</topic><topic>LY3023414</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Oncology</topic><topic>Patients</topic><topic>Phosphatidylinositol 3-Kinases - genetics</topic><topic>PI3K pathway</topic><topic>Progression-Free Survival</topic><topic>Proto-Oncogene Proteins c-akt - genetics</topic><topic>PTEN Phosphohydrolase - genetics</topic><topic>PTEN protein</topic><topic>Pyridines - adverse effects</topic><topic>Pyridines - therapeutic use</topic><topic>Quinolones - adverse effects</topic><topic>Quinolones - therapeutic use</topic><topic>Safety management</topic><topic>Signal Transduction</topic><topic>Survival</topic><topic>TOR protein</topic><topic>TOR Serine-Threonine Kinases</topic><topic>Treatment Outcome</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rubinstein, Maria M.</creatorcontrib><creatorcontrib>Hyman, David M.</creatorcontrib><creatorcontrib>Caird, Imogen</creatorcontrib><creatorcontrib>Won, Helen</creatorcontrib><creatorcontrib>Soldan, Krysten</creatorcontrib><creatorcontrib>Seier, Kenneth</creatorcontrib><creatorcontrib>Iasonos, Alexia</creatorcontrib><creatorcontrib>Tew, William P.</creatorcontrib><creatorcontrib>O’Cearbhaill, Roisin E.</creatorcontrib><creatorcontrib>Grisham, Rachel N.</creatorcontrib><creatorcontrib>Hensley, Martee L.</creatorcontrib><creatorcontrib>Troso‐Sandoval, Tiffany</creatorcontrib><creatorcontrib>Sabbatini, Paul</creatorcontrib><creatorcontrib>Guillen, Joyce</creatorcontrib><creatorcontrib>Selcuklu, S. Duygu</creatorcontrib><creatorcontrib>Zimel, Catherine</creatorcontrib><creatorcontrib>Torrisi, Jean</creatorcontrib><creatorcontrib>Aghajanian, Carol</creatorcontrib><creatorcontrib>Makker, Vicky</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><jtitle>Cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rubinstein, Maria M.</au><au>Hyman, David M.</au><au>Caird, Imogen</au><au>Won, Helen</au><au>Soldan, Krysten</au><au>Seier, Kenneth</au><au>Iasonos, Alexia</au><au>Tew, William P.</au><au>O’Cearbhaill, Roisin E.</au><au>Grisham, Rachel N.</au><au>Hensley, Martee L.</au><au>Troso‐Sandoval, Tiffany</au><au>Sabbatini, Paul</au><au>Guillen, Joyce</au><au>Selcuklu, S. Duygu</au><au>Zimel, Catherine</au><au>Torrisi, Jean</au><au>Aghajanian, Carol</au><au>Makker, Vicky</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway</atitle><jtitle>Cancer</jtitle><addtitle>Cancer</addtitle><date>2020-03-15</date><risdate>2020</risdate><volume>126</volume><issue>6</issue><spage>1274</spage><epage>1282</epage><pages>1274-1282</pages><issn>0008-543X</issn><eissn>1097-0142</eissn><abstract>Background
PI3K pathway activation is common in endometrial cancer. We evaluated the safety and efficacy of the dual PI3K/mTOR inhibitor, LY3023414, in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway.
Methods
We conducted a single‐arm phase 2 study of monotherapy LY3023414. Eligible patients had advanced endometrial cancer of any grade, prior management with 1‐4 cytotoxic lines, and PI3K pathway activation prospectively defined as a loss‐of‐function PTEN alteration or activating alteration in PIK3CA, AKT1, PIK3R1, PIK3R2, or MTOR. The primary objective was best overall response rate (ORR) per RECIST 1.1.
Results
Twenty‐eight patients were treated; histologies included endometroid (39%), carcinosarcoma (25%), serous (21%), and mixed (14%). Patients were heavily pretreated, with a median of 2 prior cytotoxic lines (range, 1‐3). The most common alterations involved PIK3CA (68%), PTEN (43%), and PIK3R1 (32%). In the 25 efficacy‐evaluable patients, the ORR was 16% (90% CI, 7%‐100%), and the clinical benefit rate was 28% (90% CI, 16%‐100%). Four patients had a confirmed partial response, and 2 responses lasted for >9 months. The median progression‐free survival and overall survival were 2.5 months (95% CI, 1.2‐3.0) and 9.2 months (95% CI, 5.0‐15.9), respectively. The most common all‐grade treatment‐related adverse events were anemia (71%), hyperglycemia (71%), hypoalbuminemia (68%), and hypophosphatemia (61%). No correlation between molecular alterations and response was observed.
Conclusion
In patients with heavily pretreated advanced endometrial cancer prospectively selected for tumors with activating PI3K pathway mutations, LY3023414 demonstrated modest single‐agent activity and a manageable safety profile.
The authors conducted a single‐arm phase 2 study of LY3023414, a dual PI3K/mTOR inhibitor, in patients with advanced endometrial cancer who were prospectively selected to have activating PI3K pathway mutations. LY3023414 was tolerable and had a modest clinical response (overall response rate, 16% [90% CI, 7%‐100%]).</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>31880826</pmid><doi>10.1002/cncr.32677</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0001-8150-9762</orcidid><orcidid>https://orcid.org/0000-0002-7943-8245</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0008-543X |
| ispartof | Cancer, 2020-03, Vol.126 (6), p.1274-1282 |
| issn | 0008-543X 1097-0142 |
| language | eng |
| recordid | cdi_proquest_journals_2366629350 |
| source | MEDLINE; Access via Wiley Online Library; EZB-FREE-00999 freely available EZB journals; Wiley Online Library (Open Access Collection); Alma/SFX Local Collection |
| subjects | 1-Phosphatidylinositol 3-kinase Activation advanced Aged AKT1 protein Anemia Cancer Class I Phosphatidylinositol 3-Kinases Class Ia Phosphatidylinositol 3-Kinase - genetics Cytotoxicity dual PI3K/mTOR inhibitor Endometrial cancer Endometrial Neoplasms - drug therapy Endometrial Neoplasms - genetics Endometrial Neoplasms - pathology Endometrium Enzyme Activation Female Humans Hyperglycemia Hyperglycemia - chemically induced Hypoalbuminemia - chemically induced Hypophosphatemia Hypophosphatemia - chemically induced LY3023414 Middle Aged Mutation Oncology Patients Phosphatidylinositol 3-Kinases - genetics PI3K pathway Progression-Free Survival Proto-Oncogene Proteins c-akt - genetics PTEN Phosphohydrolase - genetics PTEN protein Pyridines - adverse effects Pyridines - therapeutic use Quinolones - adverse effects Quinolones - therapeutic use Safety management Signal Transduction Survival TOR protein TOR Serine-Threonine Kinases Treatment Outcome Tumors |
| title | Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-27T18%3A00%3A23IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Phase%202%20study%20of%20LY3023414%20in%20patients%20with%20advanced%20endometrial%20cancer%20harboring%20activating%20mutations%20in%20the%20PI3K%20pathway&rft.jtitle=Cancer&rft.au=Rubinstein,%20Maria%20M.&rft.date=2020-03-15&rft.volume=126&rft.issue=6&rft.spage=1274&rft.epage=1282&rft.pages=1274-1282&rft.issn=0008-543X&rft.eissn=1097-0142&rft_id=info:doi/10.1002/cncr.32677&rft_dat=%3Cproquest_cross%3E2366629350%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2366629350&rft_id=info:pmid/31880826&rfr_iscdi=true |