Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer

Abstract

Background

We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).

Patients and Methods

ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing (NGS) and FISH analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were performed to exclude confounders.

Results

Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients median PFS and OS was significantly lower compared to TP53 wildtype patients (PFS 3.9 months [95% CI: 2.4-5.6] vs. 10.3 months [95% CI: 8.6-12.0], p<0.001; OS 15.0 months [95% CI: 5.0-24.9] vs. 50.0 months [95% CI: 22.9-77.1], p=0.002). This difference was confirmed in all treatment-related subgroups including chemotherapy only (PFS first line chemotherapy 2.6 months [95% CI: 1.3-4.1] vs. 6.2 months [95% CI: 1.8-10.5], p=0.021; OS 2.0 months [95% CI: 0.0-4.6] vs. 9.0 months [95% CI: 6.1-11.9], p=0.035), crizotinib plus chemotherapy (PFS crizotinib 5.0 months [95% CI: 2.9-7.2] vs. 14.0 months [95% CI: 8.0-20.1], p<0.001; OS 17.0 months [95% CI: 6.7-27.3] versus not reached, p=0.049) and crizotinib followed by next-generation ALK-inhibitor (PFS next-generation inhibitor 5.4 months [95% CI: 0.1-10.7] vs. 9.9 months [95% CI: 6.4-13.5], p=0.039; OS 7.0 months vs. 50.0 months [95% CI: not reached] (p=0.001).

Conclusions

In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.