Low Baseline CXCL9 Predicts Early Progressive Disease in Unresectable HCC with Atezolizumab Plus Bevacizumab Treatment

Shunichi Hosoda; Goki Suda; Takuya Sho; Koji Ogawa; Megumi Kimura; Zijian Yang; Sonoe Yoshida; Akinori Kubo; Yoshimasa Tokuchi; Takashi Kitagataya; Osamu Maehara; Shunsuke Ohnishi; Akihisa Nakamura; Ren Yamada; Masatsugu Ohara; Naoki Kawagishi; Mitsuteru Natsuizaka; Masato Nakai; Kenichi Morikawa; Ken Furuya; Masaru Baba; Yoshiya Yamamoto; Kazuharu Suzuki; Takaaki Izumi; Takashi Meguro; Katsumi Terashita; Jun Ito; Takuto Miyagishima; Naoya Sakamoto

doi:10.1159/000527759

Low Baseline CXCL9 Predicts Early Progressive Disease in Unresectable HCC with Atezolizumab Plus Bevacizumab Treatment

Liver Cancer. 2022 Oct 31;12(2):156-170. doi: 10.1159/000527759. eCollection 2023 Jun.

Authors

Shunichi Hosoda¹, Goki Suda¹, Takuya Sho¹, Koji Ogawa¹, Megumi Kimura¹, Zijian Yang¹, Sonoe Yoshida¹, Akinori Kubo¹, Yoshimasa Tokuchi¹, Takashi Kitagataya¹, Osamu Maehara², Shunsuke Ohnishi², Akihisa Nakamura¹, Ren Yamada¹, Masatsugu Ohara¹, Naoki Kawagishi¹, Mitsuteru Natsuizaka¹, Masato Nakai¹, Kenichi Morikawa¹, Ken Furuya³, Masaru Baba³, Yoshiya Yamamoto⁴, Kazuharu Suzuki^{1

4}, Takaaki Izumi⁵, Takashi Meguro⁶, Katsumi Terashita⁷, Jun Ito⁸, Takuto Miyagishima⁹, Naoya Sakamoto¹

Affiliations

¹ Departments of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
² Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
³ Department of Gastroenterology and Hepatology, Japan Community Health Care Organization Hokkaido Hospital, Hokkaido, Japan.
⁴ Hakodate City Hospital, Hokkaido, Japan.
⁵ Sapporo City General Hospital, Hokkaido, Japan.
⁶ Hokkaido Gastroenterology Hospital, Hokkaido, Japan.
⁷ Japan Community Health Care Organization Sapporo Hokushin Hospital, Hokkaido, Japan.
⁸ The Hokkaido Medical Center, Hokkaido, Japan.
⁹ Kushiro Rosai Hospital, Hokkaido, Japan.

Abstract

Introduction: Atezolizumab plus bevacizumab treatment is highly effective in patients with unresectable hepatocellular carcinoma (HCC). However, progressive disease (PD) occurs in approximately 20% of HCC patients treated with atezolizumab plus bevacizumab, resulting in a poor prognosis. Thus, the prediction and early detection of HCC is crucial.

Methods: Patients with unresectable HCC treated with atezolizumab plus bevacizumab and had baseline preserved serum (n = 68) were screened and classified according to their PD, 6 weeks after treatment initiation (early PD; n = 13). Of these, 4 patients each with and without early PD were selected for cytokine array and genetic analyses. The identified factors were validated in the validated cohort (n = 60) and evaluated in patients treated with lenvatinib.

Results: No significant differences were observed in the genetic alterations in circulating tumor DNA. Cytokine array data revealed that baseline MIG (CXCL9), ENA-78, and RANTES differed substantially between patients with and without early PD. Subsequent analysis in the validation cohort revealed that baseline CXCL9 was significantly lower in patients with early PD than that in patients without early PD, and the best cut-off value of serum CXCL9 to predict early PD was 333 pg/mL (sensitivity: 0.600, specificity: 0.923, AUC = 0.75). In patients with lower serum CXCL9 (<333 pg/mL), 35.3% (12/34) experienced early PD with atezolizumab plus bevacizumab, while progression-free survival (PFS) was significantly shorter relative to that in patients without (median PFS, 126 days vs. 227 days; HR: 2.41, 95% CI: 1.22-4.80, p = 0.0084). While patients with objective response to lenvatinib had significantly lower CXCL9 levels compared with those of patients without.

Conclusion: Baseline low serum CXCL9 (<333 pg/mL) levels may predict early PD in patients with unresectable HCC treated with atezolizumab plus bevacizumab.

Keywords: Atezolizumab; Baseline; Bevacizumab; CXCL9; Early PD; Hepatocellular carcinoma; Prognosis.

Grants and funding

This study was supported in part by grants from the Japan Agency for Medical Research and Development (AMED; Grant No. JP21fk0210072, JP21fk0310101, JP21fk0210047, JP21fk0210064, JP21fk0210056, JP21fk0210048, JP21fk0210058, JP21fk0210066, and JP21fk0210067) and SPS KAKENHI (Grant No. 19K08458).