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Efficacy of immunotherapy in lung cancer with co-occurring mutations in NOTCH and homologous repair genes

BACKGROUND: Immune checkpoint inhibitors (ICIs) provide significant survival benefits in non-small cell lung cancer (NSCLC). Nevertheless, while some patients obtain a prolonged benefit, a non-negligible fraction of patients experiences an ultrarapid disease progression. Identifying specific molecul...

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Autores principales: Mazzotta, Marco, Filetti, Marco, Occhipinti, Mario, Marinelli, Daniele, Scalera, Stefano, Terrenato, Irene, Sperati, Francesca, Pallocca, Matteo, Rizzo, Francesco, Gelibter, Alain, Botticelli, Andrea, Scafetta, Giorgia, Di Napoli, Arianna, Krasniqi, Eriseld, Pizzuti, Laura, Barba, Maddalena, Carpano, Silvia, Vici, Patrizia, Fanciulli, Maurizio, De Nicola, Francesca, Ciuffreda, Ludovica, Goeman, Frauke, De Maria, Ruggero, Vecchione, Andrea, Giusti, Raffaele, Ciliberto, Gennaro, Marchetti, Paolo, Maugeri-Saccà, Marcello
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409965/
https://www.ncbi.nlm.nih.gov/pubmed/32759236
http://dx.doi.org/10.1136/jitc-2020-000946
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author Mazzotta, Marco
Filetti, Marco
Occhipinti, Mario
Marinelli, Daniele
Scalera, Stefano
Terrenato, Irene
Sperati, Francesca
Pallocca, Matteo
Rizzo, Francesco
Gelibter, Alain
Botticelli, Andrea
Scafetta, Giorgia
Di Napoli, Arianna
Krasniqi, Eriseld
Pizzuti, Laura
Barba, Maddalena
Carpano, Silvia
Vici, Patrizia
Fanciulli, Maurizio
De Nicola, Francesca
Ciuffreda, Ludovica
Goeman, Frauke
De Maria, Ruggero
Vecchione, Andrea
Giusti, Raffaele
Ciliberto, Gennaro
Marchetti, Paolo
Maugeri-Saccà, Marcello
author_facet Mazzotta, Marco
Filetti, Marco
Occhipinti, Mario
Marinelli, Daniele
Scalera, Stefano
Terrenato, Irene
Sperati, Francesca
Pallocca, Matteo
Rizzo, Francesco
Gelibter, Alain
Botticelli, Andrea
Scafetta, Giorgia
Di Napoli, Arianna
Krasniqi, Eriseld
Pizzuti, Laura
Barba, Maddalena
Carpano, Silvia
Vici, Patrizia
Fanciulli, Maurizio
De Nicola, Francesca
Ciuffreda, Ludovica
Goeman, Frauke
De Maria, Ruggero
Vecchione, Andrea
Giusti, Raffaele
Ciliberto, Gennaro
Marchetti, Paolo
Maugeri-Saccà, Marcello
author_sort Mazzotta, Marco
collection PubMed
description BACKGROUND: Immune checkpoint inhibitors (ICIs) provide significant survival benefits in non-small cell lung cancer (NSCLC). Nevertheless, while some patients obtain a prolonged benefit, a non-negligible fraction of patients experiences an ultrarapid disease progression. Identifying specific molecular backgrounds predicting opposite outcomes is instrumental to optimize the use of these agents in clinical practice. METHODS: We carried out an observational study with prospective design envisioning targeted next-generation sequencing (NGS) with an approved assay in 55 patients with metastatic NSCLC (Rome cohort), of whom 35 were treated with ICIs. Data from three clinically comparable datasets were collected and combined into a metadataset containing 779 patients. The datasets were related to the Memorial Sloan Kettering Cancer Center (MSKCC) cohort (tissue-based NGS) and the randomized phase II and III POPLAR and OAK trials (blood-based NGS). RESULTS: In patients treated with ICIs in the Rome cohort, co-occurring mutations in NOTCH1-3 and homologous repair (HR) genes were associated with durable clinical benefit. Using the MSKCC/POPLAR/OAK metadaset, we confirmed the relationship between the NOTCH(mut)/HR(mut) signature and longer progression-free survival (PFS) in ICI-treated patients (multivariate Cox: HR 0.51, 95% CI 0.34 to 0.76, p=0.001). The NOTCH(mut)/HR(mut) genomic predictor was also associated with longer survival (log-rank p=0.008), despite patients whose tumors carried the NOTCH(mut)/HR(mut) signature had higher metastatic burden as compared with their negative counterpart. Finally, we observed that this genomic predictor was also associated with longer survival in patients with other tumor types treated with ICIs (n=1311, log-rank p=0.002). CONCLUSIONS: Co-occurring mutations in the NOTCH and HR pathways are associated with increased efficacy of immunotherapy in advanced NSCLC. This genomic predictor deserves further investigation to fully assess its potential in informing therapeutic decisions.
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spelling pubmed-74099652020-08-17 Efficacy of immunotherapy in lung cancer with co-occurring mutations in NOTCH and homologous repair genes Mazzotta, Marco Filetti, Marco Occhipinti, Mario Marinelli, Daniele Scalera, Stefano Terrenato, Irene Sperati, Francesca Pallocca, Matteo Rizzo, Francesco Gelibter, Alain Botticelli, Andrea Scafetta, Giorgia Di Napoli, Arianna Krasniqi, Eriseld Pizzuti, Laura Barba, Maddalena Carpano, Silvia Vici, Patrizia Fanciulli, Maurizio De Nicola, Francesca Ciuffreda, Ludovica Goeman, Frauke De Maria, Ruggero Vecchione, Andrea Giusti, Raffaele Ciliberto, Gennaro Marchetti, Paolo Maugeri-Saccà, Marcello J Immunother Cancer Immunotherapy Biomarkers BACKGROUND: Immune checkpoint inhibitors (ICIs) provide significant survival benefits in non-small cell lung cancer (NSCLC). Nevertheless, while some patients obtain a prolonged benefit, a non-negligible fraction of patients experiences an ultrarapid disease progression. Identifying specific molecular backgrounds predicting opposite outcomes is instrumental to optimize the use of these agents in clinical practice. METHODS: We carried out an observational study with prospective design envisioning targeted next-generation sequencing (NGS) with an approved assay in 55 patients with metastatic NSCLC (Rome cohort), of whom 35 were treated with ICIs. Data from three clinically comparable datasets were collected and combined into a metadataset containing 779 patients. The datasets were related to the Memorial Sloan Kettering Cancer Center (MSKCC) cohort (tissue-based NGS) and the randomized phase II and III POPLAR and OAK trials (blood-based NGS). RESULTS: In patients treated with ICIs in the Rome cohort, co-occurring mutations in NOTCH1-3 and homologous repair (HR) genes were associated with durable clinical benefit. Using the MSKCC/POPLAR/OAK metadaset, we confirmed the relationship between the NOTCH(mut)/HR(mut) signature and longer progression-free survival (PFS) in ICI-treated patients (multivariate Cox: HR 0.51, 95% CI 0.34 to 0.76, p=0.001). The NOTCH(mut)/HR(mut) genomic predictor was also associated with longer survival (log-rank p=0.008), despite patients whose tumors carried the NOTCH(mut)/HR(mut) signature had higher metastatic burden as compared with their negative counterpart. Finally, we observed that this genomic predictor was also associated with longer survival in patients with other tumor types treated with ICIs (n=1311, log-rank p=0.002). CONCLUSIONS: Co-occurring mutations in the NOTCH and HR pathways are associated with increased efficacy of immunotherapy in advanced NSCLC. This genomic predictor deserves further investigation to fully assess its potential in informing therapeutic decisions. BMJ Publishing Group 2020-08-05 /pmc/articles/PMC7409965/ /pubmed/32759236 http://dx.doi.org/10.1136/jitc-2020-000946 Text en © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Immunotherapy Biomarkers
Mazzotta, Marco
Filetti, Marco
Occhipinti, Mario
Marinelli, Daniele
Scalera, Stefano
Terrenato, Irene
Sperati, Francesca
Pallocca, Matteo
Rizzo, Francesco
Gelibter, Alain
Botticelli, Andrea
Scafetta, Giorgia
Di Napoli, Arianna
Krasniqi, Eriseld
Pizzuti, Laura
Barba, Maddalena
Carpano, Silvia
Vici, Patrizia
Fanciulli, Maurizio
De Nicola, Francesca
Ciuffreda, Ludovica
Goeman, Frauke
De Maria, Ruggero
Vecchione, Andrea
Giusti, Raffaele
Ciliberto, Gennaro
Marchetti, Paolo
Maugeri-Saccà, Marcello
Efficacy of immunotherapy in lung cancer with co-occurring mutations in NOTCH and homologous repair genes
title Efficacy of immunotherapy in lung cancer with co-occurring mutations in NOTCH and homologous repair genes
title_full Efficacy of immunotherapy in lung cancer with co-occurring mutations in NOTCH and homologous repair genes
title_fullStr Efficacy of immunotherapy in lung cancer with co-occurring mutations in NOTCH and homologous repair genes
title_full_unstemmed Efficacy of immunotherapy in lung cancer with co-occurring mutations in NOTCH and homologous repair genes
title_short Efficacy of immunotherapy in lung cancer with co-occurring mutations in NOTCH and homologous repair genes
title_sort efficacy of immunotherapy in lung cancer with co-occurring mutations in notch and homologous repair genes
topic Immunotherapy Biomarkers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409965/
https://www.ncbi.nlm.nih.gov/pubmed/32759236
http://dx.doi.org/10.1136/jitc-2020-000946
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