Clinically approved combination immunotherapy: Current status, limitations, and future perspective

Abstract

Immune-checkpoint inhibitor-based combination immunotherapy has become a first-line treatment for several major types of cancer including hepatocellular carcinoma (HCC), renal cell carcinoma, lung cancer, cervical cancer, and gastric cancer. Combination immunotherapy counters several immunosuppressive elements in the tumor microenvironment and activates multiple steps of the cancer-immunity cycle. The anti-PD-L1 antibody, atezolizumab, plus the anti-vascular endothelial growth factor antibody, bevacizumab, represents a promising class of combination immunotherapy. This combination has produced unprecedented clinical efficacy in unresectable HCC and become a landmark in HCC therapy. Advanced HCC patients treated with atezolizumab plus bevacizumab demonstrated impressive improvements in multiple clinical endpoints including overall survival, progress-free survival, objective response rate, and patient-reported quality of life when compared to current first-line treatment with sorafenib. However, atezolizumab plus bevacizumab first-line therapy has limitations. First, cancer patients falling into the criteria for the combination therapy may need to be further selected to reap benefits while avoiding some potential pitfalls. Second, the treatment regimen of atezolizumab plus bevacizumab at a fixed dose may require adjustment for optimal normalization of the tumor microenvironment to obtain maximum efficacy and reduce adverse events. Third, utilization of predictive biomarkers is urgently needed to guide the entire treatment process. Here we review the current status of clinically approved combination immunotherapies and the underlying immune mechanisms. We further provide a perspective analysis of the limitations for combination immunotherapies and potential approaches to overcome the limitations.

Keywords: Atezolizumab; Bevacizumab; Biomarker; Combination immunotherapy; Dose; First-line therapy; Gene signature; HCC; Patient selection.

Graphical abstract

Fig. 1

Mechanism of current and future first-line therapy for HCC. Sorafenib and lenvatinib are multikinase inhibitors primarily targeting tumor cells and endothelial cells. Atezolizumab blocks PD-1 engagement of PD-L1 while bevacizumab blocks VEGF interaction with its receptor in immune cells as well as endothelial cells. Clinical trials with different combinations of ICIs (anti-PD-1/L1 and anti-CTLA-4) plus bevacizumab or bevacizumab biosimilar (IBI305) and ICIs plus TKIs (lenvatinib, cabozantinib, apatinib) are under active investigation.

Fig. 2

Limitations and potential approaches of first-line atezolizumab plus bevacizumab combination therapy for HCC. Subgroups of advanced HCC patients falling into the treatment criteria of first-line atezolizumab plus bevacizumab therapy may be further selected based on superior or nonsuperior OS when compared to first-line sorafenib therapy. The dose of atezolizumab and bevacizumab may be adjusted according to clinical studies in the indicated ranges. A composite biomarker consisting of three types is likely needed to guide patient selection and therapeutic course.