1139 - Multicentric prospective study of validation of angiogenesis-related gene polymorphisms in HCC patients treated with sorafenib: Final results of INNOVATE study

Background

In two retrospective studies we analyzed endothelial-derived nitric oxide synthase (eNOS) and angiopoietin-2 (ANGPT2) polymorphisms, and patients with eNOS-786CC+TC genotype and ANGPT2rs55633437 GG genotypes had significantly higher median PFS and OS compared to those with other genotypes. On the basis of these preliminary results, our aim was to validate in a prospective study these data in patients with HCC treated with sorafenib (S).

Methods

The primary outcomes were PFS. 160 total sample size was planned with the aim to confirm a HR of 0.58. Event-time distributions were estimated using the Kaplan-Meier method and survival curves were compared using the log-rank test

Results

165 patients were prospectively enrolled in the study between 03/2015 and 06/2018. Median OS was 13.1 months and median PFS was 4.2 months. We confirmed that eNOS-786 CC+CT genotype was significantly associated with a higher median PFS (2.4 vs 5.9 months, HR 0.43, 95% CI 0.26-0.70 p = 0.0007) and OS (15.7 vs 8.6 months, HR 0.38, 95% CI 0.24-0.60 p < 0.0001) than the other genotypes. We did not confirm that ANGPT2rs55633437 GG genotypes were significantly associated with a lower median OS (p = 0.55) and PFS (p = 0.13). No differences were found between eNOS-786 TTand eNOS-786 CT/CCgenotypes in terms of disease control rate and best response. No correlations were found between eNOS polymorphisms and toxicity. Following adjustment for clinical covariates positive in univariate analzsis, multivariate analysis confirmed eNOS as the only independent prognostic factor predicting OS (p = 0.0072). After progression to S in all population we highlight that patients with the eNOS-786 CC+CT genotype was significantly associated with a lower median OS (HR 0.56, p = 0.03) and a trend was found for patients treated with regorafenib (HR 0.13 p = 0.057).

Conclusions

Our Italian multicenter, prospective study met its primary and secondary end points, and we confirmed that eNOS-786 CC+CT genotype may be capable of identifying a subset of HCC patients who have a higher median OS and PFS. For the first time in ten years of sorafenib research our study confirms the prognostic role of a biological marker in a prospective study.

Clinical trial identification

NCT02786342.

Editorial acknowledgement

Legal entity responsible for the study

University of Modena.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.