The efficacy and safety of combination of PD-1 and CTLA-4 inhibitors: a meta-analysis

Cancer-immunity cycle model was established in 2013 to describe a series of stepwise events regulating anti-tumor immune response [1]. In this model, immune checkpoints act as inhibitory modulators and help cancer cell escape immune surveillance [2, 3]. As a vital immune checkpoint molecule, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is constitutively expressed by regulatory T cells (Tregs) but transiently expressed by conventional T cells post activation [4‐6]. Apart from T cell receptor (TCR) recognizing antigen peptide-major histocompatibility complex, CD28 binding to CD80 or CD86 is an essential co-stimulatory signal for T cells activation. CTLA-4 is a competitive antagonist for CD28-CD80/86 binding which further impedes priming and activation of T cells [7].

Similarly to CTLA-4/CD28 pathway, programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis is another important regulatory signal determining immune status [8]. PD-1 is mainly expressed on activated T cell which could transduct extracellular signal (PD-L1) [9]. Intracellular domains of PD-1 subsequently inhibit Ras-Raf-MEK-ERK and PI3K-AKT pathways by which extracellular PD-L1 undermines cytotoxicity activity of T cell [10, 11].

In theory, anti-PD-1 (α-PD-1) plus anti-CTLA-4 (α-CTLA-4) treatment simultaneously block two inhibitory signaling pathways of anti-tumor immune response [12]. However, in some clinical trials, no significant advantage was observed in therapeutic effect parameters such as objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for patients undergoing α-PD-1 plus α-CTLA-4 treatment, especially in comparison with α-PD-1 monotherapy treated patients [13]. Besides, combination therapy might increase the risk of treatment related adverse event, causing treatment discontinuation [14]. Therefore, the combination therapy might not absolutely bring benefit to patients.

To comprehensively compare the efficacy and safety of combination therapy of α-PD-1 and α-CTLA-4 with monotherapy, chemotherapy, and targeted therapy, we reviewed the relevant clinical trials and conducted this meta-analysis. Moreover, given the crucial role of PD-L1 expression in immune checkpoint inhibitor treatment, we performed a subgroup analysis to evaluate efficacy difference among different treatments in the context of high or low PD-L1 expression [2].

Immune checkpoint inhibitors relieve inhibitory tumor immune microenvironment and restore T cells activity from exhausted status. Reactivated T cells could effectively recognize tumor cell-derived neoantigen and subsequently kill tumor cell. However, in clinical practice, the application of immune checkpoint inhibitor is limited by unsatisfactory response rate. Patients undergoing α-CTLA-4 or α-PD-1 monotherapy are prone to primary or adaptive resistance to immune checkpoint inhibitor. However, based on our meta-analysis, primary resistance could be overcome by α-CTLA-4 plus α-PD-1 treatment. The primary reason is that simultaneously blocked two inhibitory signaling pathways have a synergistic effect for anti-tumor immunity [19]. CTLA-4 mainly targets interaction between antigen presentation cells (APCs) and naïve T cells which interferes the expansion of T cells epitopes. Therefore, α-CTLA-4 broadens repertoire of TCR and enhances recognition of tumor associated antigen and neoantigen. Nevertheless, due to inhibitory tumor immune microenvironment, emergence of tumor specific T cells is a necessary but not sufficient condition for tumor elimination. Accompanied with accumulated tumor infiltrating lymphocytes, upregulated PD-L1 expression by inflammatory signals such as interferon-γ means deficient immune surveillance even though formation of “hot tumor”. Based on that, we speculated that α-PD-1 could substantially reduce primary resistance. Moreover, we supposed that decreased probability of adaptive resistance contributed to the improved prognosis as well. Immunoediting during the cancer progression is an important reason for adaptive resistance [20]. Broaden epitopes resulting from combination therapy could reduce the failure of recognition subclonal tumor cell-derived antigen, which provides durable and potent tumor-killing activity.

Despite all of this, the main concern of oncologists about combination therapy is the magnified risk of adverse event [21]. Our meta-analysis showed that there was no significant difference between patients received combination therapy and monotherapy in total adverse event rate. Even though monotherapy had fewer high-grade adverse event rate than combination therapy, we believed that adverse event of combination therapy was acceptable especially compared with chemotherapy or targeted therapy.

Given that PD-L1 expression strongly relates with efficacy of α-PD-1 treatment. Therefore, we investigated efficacy of combination therapy in different PD-L1 expression statuses. Notably, in the context of high PD-L1 expression, the advantage of combination therapy in efficacy over α-PD-1 monotherapy is not significant. However, in the condition of low PD-L1 expression, outcome of combination therapy was obviously better than α-PD-1 monotherapy. Our analysis suggested that for patients with high PD-L1 expression, α-PD-1 monotherapy would be a better option for minimized adverse event and medical cost. On the other hand, for patients with low PD-L1 expression, α-CTLA-4 treatment could increase patients’ sensitivity to α-PD-1 treatment. It is obvious that the combination therapy had better treatment effect than ipilimumab, chemotherapy, and targeted therapy in any PD-L1 expression condition.

In fact, other than α-CTLA-4, many interventions such as radiotherapy, oncolytic virus, and cancer vaccine have been adopted to enhance efficacy of α-PD-1 therapy [22, 23]. Due to interdependence between different anti-tumor immune stepwise events, enhanced neoantigen release, recognition, and priming/activation tumor-associated antigen or neoantigen specific T cells all indirectly promote downstream tumor-killing activity [24]. The complexity of tumor immune microenvironment suggests it is hard to completely reverse inhibitory microenvironment by a single-target therapy [25]. Therefore, combination therapy would be a promising strategy and deserves further attention.

The application of immune checkpoint inhibitors is changing the landscape of cancer therapeutics [26, 27]. In the meanwhile, from an economic point of view, it was reported the total healthcare cost of patients receiving nivolumab plus ipilimumab treatment was lower than patients undergoing nivolumab monotherapy or ipilimumab monotherapy [28]. This cost advantage of combination therapy was attributed to the lower non-drug cost due to decreased hospitalization rates after initiation treatment [28].

Some limitations still existed in our meta-analysis. Firstly, we resolved most heterogeneity by subgroup. However, we classified chemotherapy and sunitinib as one class named chemotherapy or targeted therapy, for distinguishing them from immunotherapy. Actually, this classification resulted in some heterogeneity existed in some subgroup analyses. Secondly, limited by amount of available studies, we did not analyzed efficacy of combination treatment in each specific cancer type, so our results should be carefully interpreted. Finally, our meta-analysis just included English literatures which might cause potential selection bias.

Combination therapy of α-CTLA-4 and α-PD-1 had significant advantages in efficacy over monotherapy, chemotherapy and targeted therapy without significantly increased adverse event. For high PD-L1 expression patients, combination therapy did not show obviously enhanced efficacy than α-PD-1. However, for low PD-L1 expression patients, simultaneous administration of α-CTLA-4 and α-PD-1 would be an optimized strategy to acquire better clinical benefits by overcoming primary drug resistance.