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 KRASmut patients have a better response to PD-1 inhibitors, showing a longer progression-free survival (PFS) and overall survival (OS) than KRASwt 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.

KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic nonsquamous NSCLC / Cinausero, M.; Laprovitera, N.; Maglio, G. D.; Gerratana, L.; Riefolo, M.; Macerelli, M.; Fiorentino, M.; Porcellini, E.; Buoro, V.; Gelsomino, F.; Squadrilli, A.; Fasola, G.; Negrini, M.; Tiseo, M.; Ferracin, M.; Ardizzoni, A.. - In: THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY. - ISSN 1758-8340. - 11(2019), p. 175883591988554. [10.1177/1758835919885540]

KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic nonsquamous NSCLC

Tiseo M.;
2019

Abstract

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 KRASmut patients have a better response to PD-1 inhibitors, showing a longer progression-free survival (PFS) and overall survival (OS) than KRASwt 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.
KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic nonsquamous NSCLC / Cinausero, M.; Laprovitera, N.; Maglio, G. D.; Gerratana, L.; Riefolo, M.; Macerelli, M.; Fiorentino, M.; Porcellini, E.; Buoro, V.; Gelsomino, F.; Squadrilli, A.; Fasola, G.; Negrini, M.; Tiseo, M.; Ferracin, M.; Ardizzoni, A.. - In: THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY. - ISSN 1758-8340. - 11(2019), p. 175883591988554. [10.1177/1758835919885540]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2872435
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