Efficacy and Treatment Strategies in Advanced Cancers with Liver Metastasis Receiving Atezolizumab Therapy

Abstract

Background: Atezolizumab has been used to treat patients with liver metastasis (LM). However, whether atezolizumab is superior to standard of care therapy in an all-comer or selective population with LM is still uncertain.

Methods: A pooled analysis based on 10 randomized controlled trials was conducted to evaluate the clinical benefit of atezolizumab versus standard therapy in patients stratified by liver metastatic status, followed by biomarker-based individual analyses of the non-small cell lung cancer (NSCLC) cohort (OAK and POPLAR studies) and urothelial cancer cohort (IMvigor210 study).

Results: The pooled analysis demonstrated an overall survival (OS) improvement using atezolizumab treatment versus standard therapy across cancer types and treatment lines regardless of liver metastatic status. However, the efficacy of atezolizumab in patients with LM from the second-line setting was limited, based on the individual analysis of NSCLC cohorts (P = 0.053). PD-L1 strong expression emerged as a predominant biomarker (P = 0.015) to screen atezolizumab-advantageous patients with LM. Notably, the combination of PD-L1 and LM improved the predictive power for atezolizumab therapy in both NSCLC and urothelial cancer cohorts. Exploratory translational analysis revealed that strong expression of PD-L1 might have reversed the non-inflamed immune phenotype of liver metastasis, thus sensitizing these patients to immunotherapy.

Conclusion: Our study demonstrated a preferable efficacy of atezolizumab in patients with LM as first-line therapy over standard of care therapy, while sensitive patients should be selected in second-line settings. PD-L1 was demonstrated as the most effective biomarker for screening atezolizumab-advantageous patients with LM.

Keywords: PD-L1; advantageous; atezolizumab; liver metastasis; pooled analysis.

Figure 1

The efficacy of atezolizumab versus standard therapy in terms of liver metastasis (LM). Forest plots of hazard ratios (HRs) with 95% confidence intervals (CIs) for (A) progression-free survival (PFS) and (B) overall survival (OS) in pan-cancer across treatment lines, comparing atezolizumab and standard therapy in patients with and without LM respectively. Kaplan-Meier estimates of OS with atezolizumab versus docetaxel in (C) LM population and (D) non-LM population in an individual non-small cell lung cancer cohort.

Figure 2

Impact of PD-L1 strong expression on efficacy of atezolizumab versus chemotherapy regarding liver metastasis (LM). Kaplan-Meier estimates of overall survival (OS) comparing atezolizumab and docetaxel in (A) all LM patients, (B) LM patients with a PD-L1 expression level of TC3 or IC3, (C) LM patients with a PD-L1 expression level of TC 0/1/2 or IC0/1/2, (D) all non-LM patients, (E) non-LM patients with TC3 or IC3, and (F) non-LM patients with TC0/1/2 or IC0/1/2.

Figure 3

Combination of PD-L1 expression and liver metastasis (LM) for risk stratification of patients received atezolizumab. Kaplan-Meier estimates of overall survival (OS) stratified by LM status in (A) the OAK cohort and (B) the IMvigor210 cohort. Kaplan-Meier estimates of OS stratified by LM status and PD-L1 expression level in (C) the OAK cohort and (D) the IMvigor210 cohort.

Figure 4

Association of PD-L1 strong expression and liver metastasis (LM) with immune profiles. Immune phenotype distributions by (A) liver metastatic status and (B) combination of liver metastatic status and PD-L1 strong expression status. (C) T-effector gene expression as a function of PD-L1 strong expression and liver metastatic status.