Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma
Bruno Sangro 1 , Ignacio Melero 2 , Samir Wadhawan 3 , Richard S Finn 4 , Ghassan K Abou-Alfa 5 , Ann-Lii Cheng 6 , Thomas Yau 7 , Junji Furuse 8 , Joong-Won Park 9 , Zachary Boyd 3 , Hao Tracy Tang 3 , Yun Shen 3 , Marina Tschaika 3 , Jaclyn Neely 3 , Anthony El-Khoueiry 10
(1) Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain.
(2) Universidad de Navarra, Pamplona, Spain.
(3) Bristol Myers Squibb, Princeton, NJ, USA.
(4) University of California, Los Angeles, CA, USA.
(5) Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Medical College at Cornell University, New York, NY, USA.
(6) National Taiwan University Hospital, Taipei, Taiwan.
(7) University of Hong Kong, Hong Kong, China.
(8) Kyorin University Faculty of Medicine, Tokyo, Japan.
(9) National Cancer Center, Goyang, South Korea.
(10) USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
Background & aims: Nivolumab, a programmed death (PD)-1 (PD-1) inhibitor, demonstrated durable responses, manageable safety, and increased survival in patients with advanced hepatocellular carcinoma (HCC). Our retrospective analysis studied the immunobiology and potential associations between biomarkers and nivolumab outcomes in HCC.
Methods: Fresh and archival tumour samples from dose-escalation and -expansion phases of CheckMate 040 were analysed by immunohistochemistry and RNA sequencing to assess several inflammatory gene expression signatures, including CD274 (PD-L1), CD8A, LAG3, and STAT1. Biomarkers were assessed for association with clinical outcomes (best overall response [BOR] by blinded independent central review [BICR] per RECIST v1.1 and overall survival [OS]).
Results: Complete or partial tumour responses were observed in PD ligand 1 (PD-L1)-positive and -negative patients treated with nivolumab monotherapy. Median OS was 28.1 (95% CI 18.2-n.a.) vs. 16.6 months (95% CI 14.2-20.2) for patients with tumour PD-L1 ≥1% vs. <1 % (p = 0.03). Increased CD3 and CD8 showed a non-significant trend towards improved OS (both p = 0.08), and macrophage markers were not associated with OS.
Tumour PD-1 and PD-L1 expression were associated with improved OS (p = 0.05 and p = 0.03, respectively). An inflammatory gene signature consisting of 4 genes was associated with improved ORR (p = 0.05) and OS (p = 0.01).
Conclusions: PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory gene signatures trended with improved survival and response. While further confirmation within a larger phase III trial is needed to evaluate predictive value, these analyses indicate a role for anti-tumour immune response and treatment benefit following nivolumab treatment in HCC.
CITA DEL ARTÍCULO J Hepatol . 2020 Jul 22;S0168-8278(20)30479-7.