Reference Detail

Ref Type

Journal Article

PMID

(31097096)

Authors

Assoun S, Theou-Anton N, Nguenang M, Cazes A, Danel C, Abbar B, Pluvy J, Gounant V, Khalil A, Namour C, Brosseau S, Zalcman G

Title

Association of TP53 mutations with response and longer survival under immune checkpoint inhibitors in advanced non-small-cell lung cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Lung cancer (Amsterdam, Netherlands)	132		2019 Jun	65-71	Lung Cancer

URL

Abstract Text

Tumor mutational burden (TMB) correlates with response to immune checkpoint inhibitors (ICI) in advanced non-small-cell lung cancer (aNSCLC). We hypothesized that TP53 mutations could reflect TMB and be associated with ICI benefit.TP53 mutations were assessed by next-generation sequencing in aNSCLC patients treated with programmed death-1 (PD-1) blockers. Clinical data, tumor programmed death ligand-1 (PD-L1) expression, and KRAS mutational status were collected. The primary endpoint was overall survival (OS).In total, 72 patients (median [interquartile range] age: 61 [33-83] years) were included; 52 (72%) were male; 39 (54%) had performance status 0-1; 53 (74%) had adenocarcinoma; 20 (28%) received first-line ICI, 52 (72%) second line or more. In 65 patients with available data, 36 (55%) expressed PD-L1 in ≥50% of tumor cells, 20 (31%) in 1-49% of cells, and nine (14%) were PD-L1-negative. Non-synonymous TP53 mutations were observed in 41 (57%) and 25 (35%) harbored KRAS-mutated tumors. After a median follow-up of 15.2 months (95% confidence interval [CI] 10.3-17.4 m), the median OS in the TP53-mutated group was 18.1 months (95% CI 6.6-not reached), vs. 8.1 months (95% CI 2.2-14.5, hazard ratio [HR] = 0.48; 95% CI 0.25-0.95, p = 0.04) in the TP53-wild-type group. Median progression-free survival was significantly longer in TP53-mutated patients (4.5 months, 95% CI 2.8-18.1 versus 1.4, 95% CI 1.1-3.5; p = 0.03), although TP53 mutation status failed to significantly influence PFS in the multivariate analysis (p = 0.32). Objective response rate (ORR) was higher in patients with TP53 mutation (51.2% vs. 20.7%; p = 0.01). In multivariate analysis, TP53 mutations independently associated with longer OS (HR = 0.35, 95% CI 0.16-0.77, p = 0.009).TP53-mutated status correlated with immunotherapy OS benefit in aNSCLC.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 mutant	lung non-small cell carcinoma	predicted - sensitive	Pembrolizumab	Clinical Study - Cohort	Actionable	In a clinical study, immune checkpoint inhibitor treatment including Keytruda (pembrolizumab) (n=1), Opdivo (nivolumab) with (n=8) or without (n=63) Yervoy (ipilimumab) resulted in improved median overall survival (18.1 vs 8.1 months, HR=0.48, p=0.04), median progression-free survival (4.5 vs 1.4 months, p=0.03), and objective response rate (51.2% vs 20.7%, p=0.01) in TP53 mutant (n=41) non-small cell lung cancer patients compared to TP53 wild-type (n=31) patients (PMID: 31097096).	31097096
TP53 mutant	lung non-small cell carcinoma	predicted - sensitive	Nivolumab	Clinical Study - Cohort	Actionable	In a clinical study, immune checkpoint inhibitor treatment including Keytruda (pembrolizumab) (n=1), Opdivo (nivolumab) with (n=8) or without (n=63) Yervoy (ipilimumab) resulted in improved median overall survival (18.1 vs 8.1 months, HR=0.48, p=0.04), median progression-free survival (4.5 vs 1.4 months, p=0.03), and objective response rate (51.2% vs 20.7%, p=0.01) in TP53 mutant (n=41) non-small cell lung cancer patients compared to TP53 wild-type (n=31) patients (PMID: 31097096).	31097096
TP53 mutant	lung non-small cell carcinoma	predicted - sensitive	Ipilimumab + Nivolumab	Clinical Study - Cohort	Actionable	In a clinical study, immune checkpoint inhibitor treatment including Keytruda (pembrolizumab) (n=1), Opdivo (nivolumab) with (n=8) or without (n=63) Yervoy (ipilimumab) resulted in improved median overall survival (18.1 vs 8.1 months, HR=0.48, p=0.04), median progression-free survival (4.5 vs 1.4 months, p=0.03), and objective response rate (51.2% vs 20.7%, p=0.01) in TP53 mutant (n=41) non-small cell lung cancer patients compared to TP53 wild-type (n=31) patients (PMID: 31097096).	31097096