First-line immunotherapy for lung cancer with MET exon 14 skipping and the relevance of TP53 mutations
The efficacy of checkpoint inhibitors for non-small cell lung cancer (NSCLC) with MET exon 14 skipping (METΔ14ex) remains controversial. 110 consecutive METΔ14ex NSCLC patients receiving first-line chemotherapy (CHT) and/or immunotherapy (IO) in 10 German centers between 2016–2022 were analyzed. Com...
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| Veröffentlicht in: | European journal of cancer (1990) 2024-03, Vol.199, p.113556-113556, Article 113556 |
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| creator | Blasi, Miriam Kuon, Jonas Lüders, Heike Misch, Daniel Kauffmann-Guerrero, Diego Hilbrandt, Moritz Kazdal, Daniel Falkenstern-Ge, Roger-Fei Hackanson, Björn Dintner, Sebastian Faehling, Martin Kirchner, Martina Volckmar, Anna-Lena Kopp, Hans-Georg Allgäuer, Michael Grohé, Christian Tufman, Amanda Reck, Martin Frost, Nikolaj Stenzinger, Albrecht Thomas, Michael Christopoulos, Petros |
| description | The efficacy of checkpoint inhibitors for non-small cell lung cancer (NSCLC) with MET exon 14 skipping (METΔ14ex) remains controversial.
110 consecutive METΔ14ex NSCLC patients receiving first-line chemotherapy (CHT) and/or immunotherapy (IO) in 10 German centers between 2016–2022 were analyzed.
Combined CHT-IO was given to 35/110 (32%) patients, IO alone to 43/110 (39%), and CHT to 32/110 (29%) upfront. Compared to CHT, CHT-IO showed longer progression-free survival (median PFS 6 vs. 2.5 months, p = 0.004), more objective responses (ORR 49% vs. 28%, p = 0.086) and numerically longer overall survival (OS 16 vs. 10 months, p = 0.240). For IO monotherapy, OS (14 vs. 16 months) and duration of response (26 vs. 22 months) were comparable to those of CHT-IO. Primary progressive disease (PD) was more frequent with IO compared to CHT-IO (13/43 vs. 3/35, p = 0.018), particularly for never-smokers (p = 0.041). Higher PD-L1 TPS were not associated with better IO outcomes, but TP53 mutated tumors showed numerically improved ORR (56% vs. 32%, p = 0.088) and PFS (6 vs. 3 months, p = 0.160), as well as longer OS in multivariable analysis (HR=0.54, p = 0.034) compared to their wild-type counterparts. Any second-line treatment was administered to 35/75 (47%) patients, with longer survival for capmatinib or tepotinib compared to crizotinib (PFS 10 vs. 3 months, p = 0.013; OS 16 vs. 13 months, p = 0.270).
CHT-IO is superior to CHT, and IO alone also effective for METΔ14ex NSCLC, especially in the presence of TP53 mutations and independent of PD-L1 expression, but never-smokers are at higher risk of primary PD.
•Chemoimmunotherapy prolongs PFS compared to chemotherapy in METΔ14ex NSCLC.•IO monotherapy confer long responses and OS similar to that of CHT-IO.•PD-L1 expression does not correlate with immunotherapeutic efficacy.•TP53 mutations are linked to better IO outcomes and may assist therapeutic decisions.•The rate of second-line treatment in the real-world setting is approximately 50%. |
| doi_str_mv | 10.1016/j.ejca.2024.113556 |
| format | Article |
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110 consecutive METΔ14ex NSCLC patients receiving first-line chemotherapy (CHT) and/or immunotherapy (IO) in 10 German centers between 2016–2022 were analyzed.
Combined CHT-IO was given to 35/110 (32%) patients, IO alone to 43/110 (39%), and CHT to 32/110 (29%) upfront. Compared to CHT, CHT-IO showed longer progression-free survival (median PFS 6 vs. 2.5 months, p = 0.004), more objective responses (ORR 49% vs. 28%, p = 0.086) and numerically longer overall survival (OS 16 vs. 10 months, p = 0.240). For IO monotherapy, OS (14 vs. 16 months) and duration of response (26 vs. 22 months) were comparable to those of CHT-IO. Primary progressive disease (PD) was more frequent with IO compared to CHT-IO (13/43 vs. 3/35, p = 0.018), particularly for never-smokers (p = 0.041). Higher PD-L1 TPS were not associated with better IO outcomes, but TP53 mutated tumors showed numerically improved ORR (56% vs. 32%, p = 0.088) and PFS (6 vs. 3 months, p = 0.160), as well as longer OS in multivariable analysis (HR=0.54, p = 0.034) compared to their wild-type counterparts. Any second-line treatment was administered to 35/75 (47%) patients, with longer survival for capmatinib or tepotinib compared to crizotinib (PFS 10 vs. 3 months, p = 0.013; OS 16 vs. 13 months, p = 0.270).
CHT-IO is superior to CHT, and IO alone also effective for METΔ14ex NSCLC, especially in the presence of TP53 mutations and independent of PD-L1 expression, but never-smokers are at higher risk of primary PD.
•Chemoimmunotherapy prolongs PFS compared to chemotherapy in METΔ14ex NSCLC.•IO monotherapy confer long responses and OS similar to that of CHT-IO.•PD-L1 expression does not correlate with immunotherapeutic efficacy.•TP53 mutations are linked to better IO outcomes and may assist therapeutic decisions.•The rate of second-line treatment in the real-world setting is approximately 50%.</description><identifier>ISSN: 0959-8049</identifier><identifier>EISSN: 1879-0852</identifier><identifier>DOI: 10.1016/j.ejca.2024.113556</identifier><identifier>PMID: 38271745</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>B7-H1 Antigen ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Carcinoma, Non-Small-Cell Lung - genetics ; Exons ; Humans ; Immunotherapy ; Lung cancer ; Lung Neoplasms - drug therapy ; Lung Neoplasms - genetics ; Met exon 14 skipping ; Mutation ; TP53 ; Tumor Suppressor Protein p53 - genetics ; Tyrosine kinase inhibitors</subject><ispartof>European journal of cancer (1990), 2024-03, Vol.199, p.113556-113556, Article 113556</ispartof><rights>2024 The Authors</rights><rights>Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c351t-33208a2cfc4d14247dfb625d972957a1670ff05d0a379127d564947714f465733</cites><orcidid>0000-0003-4518-7887 ; 0000-0003-4426-2400 ; 0000-0001-7242-7503 ; 0000-0002-2439-7538 ; 0000-0002-1036-5391 ; 0000-0002-5348-4462 ; 0000-0001-7452-7129 ; 0000-0002-0825-8888 ; 0000-0001-8187-3281</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0959804924000327$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38271745$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Blasi, Miriam</creatorcontrib><creatorcontrib>Kuon, Jonas</creatorcontrib><creatorcontrib>Lüders, Heike</creatorcontrib><creatorcontrib>Misch, Daniel</creatorcontrib><creatorcontrib>Kauffmann-Guerrero, Diego</creatorcontrib><creatorcontrib>Hilbrandt, Moritz</creatorcontrib><creatorcontrib>Kazdal, Daniel</creatorcontrib><creatorcontrib>Falkenstern-Ge, Roger-Fei</creatorcontrib><creatorcontrib>Hackanson, Björn</creatorcontrib><creatorcontrib>Dintner, Sebastian</creatorcontrib><creatorcontrib>Faehling, Martin</creatorcontrib><creatorcontrib>Kirchner, Martina</creatorcontrib><creatorcontrib>Volckmar, Anna-Lena</creatorcontrib><creatorcontrib>Kopp, Hans-Georg</creatorcontrib><creatorcontrib>Allgäuer, Michael</creatorcontrib><creatorcontrib>Grohé, Christian</creatorcontrib><creatorcontrib>Tufman, Amanda</creatorcontrib><creatorcontrib>Reck, Martin</creatorcontrib><creatorcontrib>Frost, Nikolaj</creatorcontrib><creatorcontrib>Stenzinger, Albrecht</creatorcontrib><creatorcontrib>Thomas, Michael</creatorcontrib><creatorcontrib>Christopoulos, Petros</creatorcontrib><title>First-line immunotherapy for lung cancer with MET exon 14 skipping and the relevance of TP53 mutations</title><title>European journal of cancer (1990)</title><addtitle>Eur J Cancer</addtitle><description>The efficacy of checkpoint inhibitors for non-small cell lung cancer (NSCLC) with MET exon 14 skipping (METΔ14ex) remains controversial.
110 consecutive METΔ14ex NSCLC patients receiving first-line chemotherapy (CHT) and/or immunotherapy (IO) in 10 German centers between 2016–2022 were analyzed.
Combined CHT-IO was given to 35/110 (32%) patients, IO alone to 43/110 (39%), and CHT to 32/110 (29%) upfront. Compared to CHT, CHT-IO showed longer progression-free survival (median PFS 6 vs. 2.5 months, p = 0.004), more objective responses (ORR 49% vs. 28%, p = 0.086) and numerically longer overall survival (OS 16 vs. 10 months, p = 0.240). For IO monotherapy, OS (14 vs. 16 months) and duration of response (26 vs. 22 months) were comparable to those of CHT-IO. Primary progressive disease (PD) was more frequent with IO compared to CHT-IO (13/43 vs. 3/35, p = 0.018), particularly for never-smokers (p = 0.041). Higher PD-L1 TPS were not associated with better IO outcomes, but TP53 mutated tumors showed numerically improved ORR (56% vs. 32%, p = 0.088) and PFS (6 vs. 3 months, p = 0.160), as well as longer OS in multivariable analysis (HR=0.54, p = 0.034) compared to their wild-type counterparts. Any second-line treatment was administered to 35/75 (47%) patients, with longer survival for capmatinib or tepotinib compared to crizotinib (PFS 10 vs. 3 months, p = 0.013; OS 16 vs. 13 months, p = 0.270).
CHT-IO is superior to CHT, and IO alone also effective for METΔ14ex NSCLC, especially in the presence of TP53 mutations and independent of PD-L1 expression, but never-smokers are at higher risk of primary PD.
•Chemoimmunotherapy prolongs PFS compared to chemotherapy in METΔ14ex NSCLC.•IO monotherapy confer long responses and OS similar to that of CHT-IO.•PD-L1 expression does not correlate with immunotherapeutic efficacy.•TP53 mutations are linked to better IO outcomes and may assist therapeutic decisions.•The rate of second-line treatment in the real-world setting is approximately 50%.</description><subject>B7-H1 Antigen</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Carcinoma, Non-Small-Cell Lung - genetics</subject><subject>Exons</subject><subject>Humans</subject><subject>Immunotherapy</subject><subject>Lung cancer</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - genetics</subject><subject>Met exon 14 skipping</subject><subject>Mutation</subject><subject>TP53</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tyrosine kinase inhibitors</subject><issn>0959-8049</issn><issn>1879-0852</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM1O3DAURq0KVKbTvkAXyEs2Gfwbx1I31WhokajKYlhbxr4uHpI4tZOhvD0ZDWXJ6m7Od6R7EPpKyYoSWl_uVrBzdsUIEytKuZT1B7SgjdIVaSQ7QQuipa4aIvQZ-lTKjhCiGkE-ojPeMEWVkAsUrmIuY9XGHnDsuqlP4wNkOzzjkDJup_4PdrZ3kPFTHB_wr80Ww7_UYypweYzDEGfA9h7PK5yhhf0Bxing7a3kuJtGO8bUl8_oNNi2wJfXu0R3V5vt-md18_vH9fr7TeW4pGPFOSONZS444algQvlwXzPptWJaKktrRUIg0hPLlaZMeVkLLZSiIohaKs6X6OLoHXL6O0EZTReLg7a1PaSpGKaZFI2seTOj7Ii6nErJEMyQY2fzs6HEHPqanTn0NYe-5th3Hp2_-qf7Dvzb5H_QGfh2BGD-ch8hm-IizE18zOBG41N8z_8CW0GJvw</recordid><startdate>202403</startdate><enddate>202403</enddate><creator>Blasi, Miriam</creator><creator>Kuon, Jonas</creator><creator>Lüders, Heike</creator><creator>Misch, Daniel</creator><creator>Kauffmann-Guerrero, Diego</creator><creator>Hilbrandt, Moritz</creator><creator>Kazdal, Daniel</creator><creator>Falkenstern-Ge, Roger-Fei</creator><creator>Hackanson, Björn</creator><creator>Dintner, Sebastian</creator><creator>Faehling, Martin</creator><creator>Kirchner, Martina</creator><creator>Volckmar, Anna-Lena</creator><creator>Kopp, Hans-Georg</creator><creator>Allgäuer, Michael</creator><creator>Grohé, Christian</creator><creator>Tufman, Amanda</creator><creator>Reck, Martin</creator><creator>Frost, Nikolaj</creator><creator>Stenzinger, Albrecht</creator><creator>Thomas, Michael</creator><creator>Christopoulos, Petros</creator><general>Elsevier Ltd</general><scope>6I.</scope><scope>AAFTH</scope><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>7X8</scope><orcidid>https://orcid.org/0000-0003-4518-7887</orcidid><orcidid>https://orcid.org/0000-0003-4426-2400</orcidid><orcidid>https://orcid.org/0000-0001-7242-7503</orcidid><orcidid>https://orcid.org/0000-0002-2439-7538</orcidid><orcidid>https://orcid.org/0000-0002-1036-5391</orcidid><orcidid>https://orcid.org/0000-0002-5348-4462</orcidid><orcidid>https://orcid.org/0000-0001-7452-7129</orcidid><orcidid>https://orcid.org/0000-0002-0825-8888</orcidid><orcidid>https://orcid.org/0000-0001-8187-3281</orcidid></search><sort><creationdate>202403</creationdate><title>First-line immunotherapy for lung cancer with MET exon 14 skipping and the relevance of TP53 mutations</title><author>Blasi, Miriam ; Kuon, Jonas ; Lüders, Heike ; Misch, Daniel ; Kauffmann-Guerrero, Diego ; Hilbrandt, Moritz ; Kazdal, Daniel ; Falkenstern-Ge, Roger-Fei ; Hackanson, Björn ; Dintner, Sebastian ; Faehling, Martin ; Kirchner, Martina ; Volckmar, Anna-Lena ; Kopp, Hans-Georg ; Allgäuer, Michael ; Grohé, Christian ; Tufman, Amanda ; Reck, Martin ; Frost, Nikolaj ; Stenzinger, Albrecht ; Thomas, Michael ; Christopoulos, Petros</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c351t-33208a2cfc4d14247dfb625d972957a1670ff05d0a379127d564947714f465733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>B7-H1 Antigen</topic><topic>Carcinoma, Non-Small-Cell Lung - drug therapy</topic><topic>Carcinoma, Non-Small-Cell Lung - genetics</topic><topic>Exons</topic><topic>Humans</topic><topic>Immunotherapy</topic><topic>Lung cancer</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - genetics</topic><topic>Met exon 14 skipping</topic><topic>Mutation</topic><topic>TP53</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tyrosine kinase inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Blasi, Miriam</creatorcontrib><creatorcontrib>Kuon, Jonas</creatorcontrib><creatorcontrib>Lüders, Heike</creatorcontrib><creatorcontrib>Misch, Daniel</creatorcontrib><creatorcontrib>Kauffmann-Guerrero, Diego</creatorcontrib><creatorcontrib>Hilbrandt, Moritz</creatorcontrib><creatorcontrib>Kazdal, Daniel</creatorcontrib><creatorcontrib>Falkenstern-Ge, Roger-Fei</creatorcontrib><creatorcontrib>Hackanson, Björn</creatorcontrib><creatorcontrib>Dintner, Sebastian</creatorcontrib><creatorcontrib>Faehling, Martin</creatorcontrib><creatorcontrib>Kirchner, Martina</creatorcontrib><creatorcontrib>Volckmar, Anna-Lena</creatorcontrib><creatorcontrib>Kopp, Hans-Georg</creatorcontrib><creatorcontrib>Allgäuer, Michael</creatorcontrib><creatorcontrib>Grohé, Christian</creatorcontrib><creatorcontrib>Tufman, Amanda</creatorcontrib><creatorcontrib>Reck, Martin</creatorcontrib><creatorcontrib>Frost, Nikolaj</creatorcontrib><creatorcontrib>Stenzinger, Albrecht</creatorcontrib><creatorcontrib>Thomas, Michael</creatorcontrib><creatorcontrib>Christopoulos, Petros</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of cancer (1990)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Blasi, Miriam</au><au>Kuon, Jonas</au><au>Lüders, Heike</au><au>Misch, Daniel</au><au>Kauffmann-Guerrero, Diego</au><au>Hilbrandt, Moritz</au><au>Kazdal, Daniel</au><au>Falkenstern-Ge, Roger-Fei</au><au>Hackanson, Björn</au><au>Dintner, Sebastian</au><au>Faehling, Martin</au><au>Kirchner, Martina</au><au>Volckmar, Anna-Lena</au><au>Kopp, Hans-Georg</au><au>Allgäuer, Michael</au><au>Grohé, Christian</au><au>Tufman, Amanda</au><au>Reck, Martin</au><au>Frost, Nikolaj</au><au>Stenzinger, Albrecht</au><au>Thomas, Michael</au><au>Christopoulos, Petros</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>First-line immunotherapy for lung cancer with MET exon 14 skipping and the relevance of TP53 mutations</atitle><jtitle>European journal of cancer (1990)</jtitle><addtitle>Eur J Cancer</addtitle><date>2024-03</date><risdate>2024</risdate><volume>199</volume><spage>113556</spage><epage>113556</epage><pages>113556-113556</pages><artnum>113556</artnum><issn>0959-8049</issn><eissn>1879-0852</eissn><abstract>The efficacy of checkpoint inhibitors for non-small cell lung cancer (NSCLC) with MET exon 14 skipping (METΔ14ex) remains controversial.
110 consecutive METΔ14ex NSCLC patients receiving first-line chemotherapy (CHT) and/or immunotherapy (IO) in 10 German centers between 2016–2022 were analyzed.
Combined CHT-IO was given to 35/110 (32%) patients, IO alone to 43/110 (39%), and CHT to 32/110 (29%) upfront. Compared to CHT, CHT-IO showed longer progression-free survival (median PFS 6 vs. 2.5 months, p = 0.004), more objective responses (ORR 49% vs. 28%, p = 0.086) and numerically longer overall survival (OS 16 vs. 10 months, p = 0.240). For IO monotherapy, OS (14 vs. 16 months) and duration of response (26 vs. 22 months) were comparable to those of CHT-IO. Primary progressive disease (PD) was more frequent with IO compared to CHT-IO (13/43 vs. 3/35, p = 0.018), particularly for never-smokers (p = 0.041). Higher PD-L1 TPS were not associated with better IO outcomes, but TP53 mutated tumors showed numerically improved ORR (56% vs. 32%, p = 0.088) and PFS (6 vs. 3 months, p = 0.160), as well as longer OS in multivariable analysis (HR=0.54, p = 0.034) compared to their wild-type counterparts. Any second-line treatment was administered to 35/75 (47%) patients, with longer survival for capmatinib or tepotinib compared to crizotinib (PFS 10 vs. 3 months, p = 0.013; OS 16 vs. 13 months, p = 0.270).
CHT-IO is superior to CHT, and IO alone also effective for METΔ14ex NSCLC, especially in the presence of TP53 mutations and independent of PD-L1 expression, but never-smokers are at higher risk of primary PD.
•Chemoimmunotherapy prolongs PFS compared to chemotherapy in METΔ14ex NSCLC.•IO monotherapy confer long responses and OS similar to that of CHT-IO.•PD-L1 expression does not correlate with immunotherapeutic efficacy.•TP53 mutations are linked to better IO outcomes and may assist therapeutic decisions.•The rate of second-line treatment in the real-world setting is approximately 50%.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>38271745</pmid><doi>10.1016/j.ejca.2024.113556</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0003-4518-7887</orcidid><orcidid>https://orcid.org/0000-0003-4426-2400</orcidid><orcidid>https://orcid.org/0000-0001-7242-7503</orcidid><orcidid>https://orcid.org/0000-0002-2439-7538</orcidid><orcidid>https://orcid.org/0000-0002-1036-5391</orcidid><orcidid>https://orcid.org/0000-0002-5348-4462</orcidid><orcidid>https://orcid.org/0000-0001-7452-7129</orcidid><orcidid>https://orcid.org/0000-0002-0825-8888</orcidid><orcidid>https://orcid.org/0000-0001-8187-3281</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | European journal of cancer (1990), 2024-03, Vol.199, p.113556-113556, Article 113556 |
| issn | 0959-8049 1879-0852 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | B7-H1 Antigen Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Exons Humans Immunotherapy Lung cancer Lung Neoplasms - drug therapy Lung Neoplasms - genetics Met exon 14 skipping Mutation TP53 Tumor Suppressor Protein p53 - genetics Tyrosine kinase inhibitors |
| title | First-line immunotherapy for lung cancer with MET exon 14 skipping and the relevance of TP53 mutations |
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