KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic nonsquamous NSCLC
Background: Programmed cell death 1 (PD-1) and PD-ligand 1 (PD-L1) inhibitors represent novel therapeutic options for advanced non-small cell lung cancer (NSCLC). However, approximately 50% of patients do not benefit from therapy and experience rapid disease progression. PD-L1 expression is the only...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
SAGE Publishing
2019-11-01
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| Series: | Therapeutic Advances in Medical Oncology |
| Online Access: | https://doi.org/10.1177/1758835919885540 |
| _version_ | 1819290565163876352 |
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| author | Marika Cinausero Noemi Laprovitera Giovanna De Maglio Lorenzo Gerratana Mattia Riefolo Marianna Macerelli Michelangelo Fiorentino Elisa Porcellini Vanessa Buoro Francesco Gelsomino Anna Squadrilli Gianpiero Fasola Massimo Negrini Marcello Tiseo Manuela Ferracin Andrea Ardizzoni |
| author_facet | Marika Cinausero Noemi Laprovitera Giovanna De Maglio Lorenzo Gerratana Mattia Riefolo Marianna Macerelli Michelangelo Fiorentino Elisa Porcellini Vanessa Buoro Francesco Gelsomino Anna Squadrilli Gianpiero Fasola Massimo Negrini Marcello Tiseo Manuela Ferracin Andrea Ardizzoni |
| author_sort | Marika Cinausero |
| collection | DOAJ |
| description | Background: Programmed cell death 1 (PD-1) and PD-ligand 1 (PD-L1) inhibitors represent novel therapeutic options for advanced non-small cell lung cancer (NSCLC). However, approximately 50% of patients do not benefit from therapy and experience rapid disease progression. PD-L1 expression is the only approved biomarker of benefit to anti-PD-1/PD-L1 therapy. However, its weakness has been evidenced in many studies. More recently, tumor mutational burden (TMB) has proved to be a suitable biomarker, but its calculation is difficult to obtain for all patients. Methods: We tested specific NSCLC genetic alterations as potential immunotherapy biomarkers. Tumor DNA was obtained from advanced NSCLC patients treated with anti-PD-1 monoclonal antibody nivolumab ( n = 44) or pembrolizumab ( n = 3). The mutational status of 22 genes was assessed by targeted next-generation sequencing and the association with survival was tested in uni- and multivariate models. The association between gene mutations and clinical benefit was also investigated. Results: The most frequently mutated genes were TP53 (49%), KRAS (43%), ERBB2 (13%), SMAD4 (13%), DDR2 (13%), STK11 (9%), ERBB4 (6%), EGFR (6%), BRAF (6%), and MET (6%). We confirmed that KRAS mut patients have a better response to PD-1 inhibitors, showing a longer progression-free survival (PFS) and overall survival (OS) than KRAS wt patients. In addition, we observed that patients with ERBB -family mutations, including EGFR, ERBB2 , and ERBB4 all failed to respond to PD-1 antibodies, independently of KRAS status. Conclusions: This study suggests that the analysis of KRAS and ERBB -family gene mutational status is valuable when assessing the clinical practice for the selection of NSCLC patients to treat with PD-1 inhibitors. |
| first_indexed | 2024-12-24T03:24:46Z |
| format | Article |
| id | doaj.art-bbe74f39c6134ab4a55c01b9a32b30e3 |
| institution | Directory Open Access Journal |
| issn | 1758-8359 |
| language | English |
| last_indexed | 2024-12-24T03:24:46Z |
| publishDate | 2019-11-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Therapeutic Advances in Medical Oncology |
| spelling | doaj.art-bbe74f39c6134ab4a55c01b9a32b30e32022-12-21T17:17:23ZengSAGE PublishingTherapeutic Advances in Medical Oncology1758-83592019-11-011110.1177/1758835919885540KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic nonsquamous NSCLCMarika CinauseroNoemi LaproviteraGiovanna De MaglioLorenzo GerratanaMattia RiefoloMarianna MacerelliMichelangelo FiorentinoElisa PorcelliniVanessa BuoroFrancesco GelsominoAnna SquadrilliGianpiero FasolaMassimo NegriniMarcello TiseoManuela FerracinAndrea ArdizzoniBackground: Programmed cell death 1 (PD-1) and PD-ligand 1 (PD-L1) inhibitors represent novel therapeutic options for advanced non-small cell lung cancer (NSCLC). However, approximately 50% of patients do not benefit from therapy and experience rapid disease progression. PD-L1 expression is the only approved biomarker of benefit to anti-PD-1/PD-L1 therapy. However, its weakness has been evidenced in many studies. More recently, tumor mutational burden (TMB) has proved to be a suitable biomarker, but its calculation is difficult to obtain for all patients. Methods: We tested specific NSCLC genetic alterations as potential immunotherapy biomarkers. Tumor DNA was obtained from advanced NSCLC patients treated with anti-PD-1 monoclonal antibody nivolumab ( n = 44) or pembrolizumab ( n = 3). The mutational status of 22 genes was assessed by targeted next-generation sequencing and the association with survival was tested in uni- and multivariate models. The association between gene mutations and clinical benefit was also investigated. Results: The most frequently mutated genes were TP53 (49%), KRAS (43%), ERBB2 (13%), SMAD4 (13%), DDR2 (13%), STK11 (9%), ERBB4 (6%), EGFR (6%), BRAF (6%), and MET (6%). We confirmed that KRAS mut patients have a better response to PD-1 inhibitors, showing a longer progression-free survival (PFS) and overall survival (OS) than KRAS wt patients. In addition, we observed that patients with ERBB -family mutations, including EGFR, ERBB2 , and ERBB4 all failed to respond to PD-1 antibodies, independently of KRAS status. Conclusions: This study suggests that the analysis of KRAS and ERBB -family gene mutational status is valuable when assessing the clinical practice for the selection of NSCLC patients to treat with PD-1 inhibitors.https://doi.org/10.1177/1758835919885540 |
| spellingShingle | Marika Cinausero Noemi Laprovitera Giovanna De Maglio Lorenzo Gerratana Mattia Riefolo Marianna Macerelli Michelangelo Fiorentino Elisa Porcellini Vanessa Buoro Francesco Gelsomino Anna Squadrilli Gianpiero Fasola Massimo Negrini Marcello Tiseo Manuela Ferracin Andrea Ardizzoni KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic nonsquamous NSCLC Therapeutic Advances in Medical Oncology |
| title | KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic nonsquamous NSCLC |
| title_full | KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic nonsquamous NSCLC |
| title_fullStr | KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic nonsquamous NSCLC |
| title_full_unstemmed | KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic nonsquamous NSCLC |
| title_short | KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic nonsquamous NSCLC |
| title_sort | kras and erbb family genetic alterations affect response to pd 1 inhibitors in metastatic nonsquamous nsclc |
| url | https://doi.org/10.1177/1758835919885540 |
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